Organophosphorus Chemistry (SPR Organophosphorus Chemistry (RSC)) (v. 35)

Organophosphorus Chemistry Volume 35 A Specialist Periodical Report Organophosphorus Chemistry Volume 35 A Review of ...

Author: D. W. Allen | J. C. Tebby

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Organophosphorus Chemistry Volume 35

A Specialist Periodical Report

Organophosphorus Chemistry Volume 35 A Review of the Literature Published between July 2002 and June 2004 Editors D.W. Allen, Sheffield Hallam University, Sheffield, UK J.C. Tebby, Staffordshire University, Stoke-on-Trent, UK

Authors R. Bodalski, Technical University, Lodz, Poland C.D. Hall, University of Florida, Florida, USA D. Loakes, Laboratory for Molecular Biology, Cambridge M. Migaud, The Queen’s University of Belfast, Belfast, UK A. Skowron´ska, Polish Academy of Sciences, Lodz, Poland J.C. van de Grampel, University of Groningen, The Netherlands

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ISBN-10: 0-85404-344-6 ISBN-13: 978-0-85404-344-6 ISSN 0306-0713 A catalogue record for this book is available from the British Library r The Royal Society of Chemistry 2006 All rights reserved Apart from any fair dealing for the purpose of research or private study for non-commercial purposes, or criticism or review as permitted under the terms of the UK Copyright, Designs and Patents Act, 1988 and the Copyright and Related Rights Regulations 2003, this publication may not be reproduced, stored or transmitted, in any form or by any means, without the prior permission in writing of The Royal Society of Chemistry, or in the case of reprographic reproduction only in accordance with the terms of the licences issued by the Copyright Licensing Agency in the UK, or in accordance with the terms of the licences issued by the appropriate Reproduction Rights Organization outside the UK. Enquiries concerning reproduction outside the terms stated here should be sent to The Royal Society of Chemistry at the address printed on this page. Published by The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 0WF, UK Registered Charity Number 207890 For further information see our web site at www.rsc.org Typeset by Macmillan India Ltd, Bangalore, India Printed and bound by Henry Ling Ltd, Dorchester, Dorset, UK

Preface Organophosphorus chemistry continues to generate a very large volume of literature, with no sign of any decline in activity. In this volume, we have increased our period of coverage of the literature, bringing it up to June 2004, in order to try to remedy the increasingly evident problem that our team of writers has in putting together these volumes in a timely manner. Our coverage of the above period is complete apart from the absence of the usual chapter on ylide chemistry. This deﬁciency, and the fact that this volume will not appear until early 2006, reﬂect the conﬂicting pressures which our authors are facing in collecting the information and in ﬁnding the substantial time needed to write these usually comprehensive reports. In consequence, it is probable that this volume will be last in the current style. Future volumes are likely to offer a more selective and critical coverage of the area, since the increasing availability of computer-aided literature search facilities makes attempts to provide comprehensive coverage unnecessary. The period under review has seen the publication of several important books and general reviews. Franc¸ois Mathey has contributed a new book on heterocyclic organophosphorus compounds (Phosphorus-Carbon Heterocyclic Chemistry: The Rise of a New Domain; Elsevier, 2001) and Louis Quin and Anthony Williams have compiled a valuable new data resource on 31P NMR spectroscopy (Practical Interpretation of P-31 NMR Spectra and Computer-Assisted Structure Veriﬁcation; Advanced Chemistry Development, Toronto, 2004). A review of odd-electron bonds and biradicals in main group element chemistry (H. Grutzmacher and F. Breher, Angew Chem. Int. Ed., 2002, 41, 4006) contains much that is relevant to organophosphorus chemistry. A special edition of the journal Phosphorus, Sulfur, Silicon and the Related Elements (2004, 179, issue 4–5, 649) was devoted to the proceedings of the Tenth International Symposium on Inorganic Ring Systems held in August 2003 in Vermont, USA and this again contains much relevant material. Once again, the drive for improved performance in transition metal ioncatalysed processes has continued to stimulate the synthesis of new types of organophosphine and tervalent phosphorus-ester and -amide ligands. Activity in the chemistry of heteroaromatic phosphorus ring systems and low-coordination number pp-bonded systems has also remained at a high level. New mechanistic insights into the Mitsunobu reaction have been reported, and interest in synthetic applications of Staudinger/Mitsunobu procedures has continued to develop. The chemistry of phosphonium salts and phosphine chalcogenides has also continued to develop, although no major advances have appeared, doubtless reﬂecting the maturity of the area. In the area of mononucleotide chemistry, extensive work has been reported on the chemistry of polyphosphates, in particular that of dinucleoside and v

vi

Organophosphorus Chem., 2006, 35, v–viii

sugar nucleoside pyrophosphates. This reﬂects the reliability and ﬂexibility of phosphoramidate methods which have been developed over the past few years. Similarly, a wide range of oligonucleotide building blocks, incorporating extensive structural modiﬁcations when compared to the natural nucleoside structures, have been described. The review of polynucleotide chemistry focuses on oligonucleotide modiﬁcations, the largest group of which involves novel nucleobases that are used not only for duplex stabilisation and tertiary structures, but ﬁnd application in understanding the mode of action of other biological molecules, conjugation with small molecules as well as macromolecules, and in nanotechnology devices. Advances also relate to sugar and backbone modiﬁcations. Noteworthy emerging areas include templated organic synthesis, and single molecule detection. The three years since SPR 33 have seen considerable activity in the ﬁeld of hypervalent phosphorus chemistry especially in the area of hexacoordinate and pseudo-hexacoordinate phosphorus compounds. In this respect, the Holmes’ group has made further, substantial contributions to the subject of N, O and S donor interactions at hypervalent phosphorus and the relevance of such interactions to the mechanism of phosphoryl transfer enzymes. The utility of proazaphosphatranes as catalysts (or co-catalysts) has been established by Verkade et al. in an impressive range of synthetic procedures and both Kawashima and Akiba have reported outstanding work on bicyclic phosphorane systems, carbaphosphatranes and the relevance of anti-apicophilic phosphorane systems to the mechanism of the Wittig reaction. The Lacour group has detailed the use of C2-symmetric hexacoordinated phosphate anions for enantiodifferentiation of organic and organometallic cations and last, but not least, Gillespie et al. have produced a thought-provoking review on bonding in pentaand hexacoordinated molecules. After 25 years Dennis Hall is retiring as an author to this publication. We thank him for his invaluable contributions. Over the two year period covered, there have been impressive advances in several areas of P(V) chemistry. For example, biological aspects of quinquevalent phosphorus acids chemistry continue to increase in importance. A wide variety of natural and unnatural phosphates including inositols, lipids, some carbohydrates and their phosphonates, phosphinates and ﬂuorinated analogues have been synthesized. Highlights include the asymmetric synthesis of phosphates, access to enantiomerically pure a-ﬂuorinated phosphonate mimetics and a ﬂuorescent porphyrin conjugate. Special attention has been paid to the synthesis of phosphorus analogues of all types of amino acids and some peptides. Numerous investigations of phosphate ester hydrolysis and related reactions continue to be reported. They include ﬂuorescent monitoring probes and control of stereoselectivity of enzymatic hydrolysis of phosphonates. There have been interesting studies of phosphate complexation with lanthanide, zinc and copper complexes, the latter involving host-guest concepts. Interest in approaches to easier detoxiﬁcation of insecticides continues. A number of new and improved stereoselective synthetic procedures have been elaborated.

Organophosphorus Chem., 2006, 35, v–viii

vii

Notable were highly enantioselective additions of N-phosphonyl imines with dialkyl zinc or hydroxyketones and a one-pot reaction of alkynylzirconocenes with alkynyl phosphazenes and zinc carbenoids to give single isomer cyclopropylphosphonamides. The importance of enantioselective and dynamic kinetic asymmetric transformations is illustrated in many publications. Other interesting reports cover the use of phosphoramidates for the synthesis of allylic amines as well as the ﬁrst example of C–P cleavage of a-aminophosphono acids using periodate. Two books have appeared on phosphazene chemistry reﬂecting its continuing wide development. There has been keen interest in acyclic phosphazenes and the ever-useful Staudinger reaction has been employed to produce novel tricyclic oxazoles, linear oligophosphazenes, as well as a series of aryloxypolyphosphazenes with potential for producing dendrimeric structures. Phosphoranimines have been prepared in high yields and their use in aza-Wittig reactions has paved the way for the preparation of a wide variety of natural products. A novel N-trimethylsilylphosphoranimine cationic salt has been prepared in which the NP bond approaches that of a triple bond. The basicity of a number of phosphazene bases (P1-P4) in the gas phase has been calculated and it was found that But-P4 was by far the strongest phosphazene base (even stronger than Verkade’s superbase). It was used in UV-vis spectrophotometric titrations of acids and in various synthetic procedures. Thus Et-P2 was utilised in the asymmetric synthesis of disubstituted N-tosyl aziridines whereas But-P2 reacted with O-acyl hydroxamic acid derivatives to yield 2,3-dihydro-4-isoxazole carboxylic esters. But-P1, Et-P2 or BEMP has been used to solubilise a- amino acids to facilitate the synthesis of peptides. Other applications include dehydrochlorination, polymer modiﬁers, host-guest reactions and the tribology of phosphorylated carbon-coated surfaces, enhanced conductivity and fuel cell membranes. Various networks have been prepared by radical polymerization using phosphazenes as crosslinking reagents and a polyphosphazene has been utilised in bucky ball chemistry. Biomedical applications include membrane separations, biodegradable polymers and controlled drug release experiments. In conclusion, we would thank our team of contributors for their efforts in writing for these volumes in recent years. As noted above, this volume may represent the end of an era which has extended over more than 35 years, the ﬁrst volume having appeared in 1970 under the editorship of Professor Stuart Trippett. It would be a serious omission in writing this preface if we failed to note the passing of Professor Leopold Horner (1911–2005) who contributed so much to the development of organophosphorus chemistry, particularly to the development of routes to chiral phosphines and, of course, to the Horner modiﬁcation of the Wittig reaction. D.W. Allen and J.C. Tebby

Contents Cover A selection of organophosphorus molecules, image reproduced by permission of Dr David Loakes

Phosphines and Related Tervalent Phosphorus Systems D.W. Allen 1 2

Introduction Phosphines 2.1 Preparation 2.2 Reactions of Phosphines 3 pp-Bonded Phosphorus Compounds 4 Phosphirenes, Phospholes and Phosphinines References

Phosphonium Salts and Phosphine Chalcogenides D.W. Allen 1

2

Phosphonium Salts 1.1 Preparation 1.2 Reactions of Phosphonium Salts Phosphine Chalcogenides 2.1 Preparation

Organophosphorus Chemistry, Volume 35 r The Royal Society of Chemistry, 2006 ix

1

1 1 1 30 45 54 61

92

92 92 96 99 99

x

Organophosphorus Chem., 2006, 35, ix–xii

2.2 Reactions 2.3 Structural and Physical Aspects 2.4 Phosphine Chalcogenides as Ligands References

Tervalent Phosphorus Acid Derivatives D.W. Allen 1 2 3

Introduction Halogenophosphines Tervalent Phosphorus Esters 3.1 Phosphinites 3.2 Phosphonites 3.3 Phosphites 4 Tervalent Phosphorus Amides 4.1 Aminophosphines 4.2 Phosphoramidites and Related Compounds References Quinquevalent Phosphorus Acids A. Skowron´ska and R. Bodalski 1 2

Introduction Phosphoric Acids and Their Derivatives 2.1 Synthesis of Phosphoric Acids and Their Derivatives 2.2 Reactions of Phosphoric Acids and Their Derivatives 2.3 Selected Biological Aspects 3 Phosphonic and Phosphinic Acids 3.1 Synthesis of Phosphonic and Phosphinic Acids and Their Derivatives 3.2 Reactions of Phosphonic and Phosphinic Acids and Their Derivatives 3.3 Selected Biological Aspects 4 Structure References Pentacoordinated and Hexacoordinated Compounds C.D. Hall Summary 1 Introduction 2 Acyclic Phosphoranes 3 Monocyclic Phosphoranes

110 112 114 118

127

127 128 134 134 138 140 146 146 152 157 169 169 169 169 182 197 200 200 235 250 254 257 265 265 266 267 268

Organophosphorus Chem., 2006, 35, ix–xii

4 Bicyclic Phosphoranes 5 Hexacoordinate Phosphorus Compounds References Nucleic Acids and Nucleotides: Mononucleotides M. Migaud 1 2

Introduction Mononucleotides 2.1 Nucleoside Acyclic Phosphates 3 Nucleoside Polyphosphates 3.1 Polyphosphorylated Nucleosides 3.2 Nucleoside Pyrophosphates References Nucleotides and Nucleic Acids; Oligo- and Poly-nucleotides D. Loakes 1

Introduction 1.1 Oligonucleotide Synthesis 1.2 RNA Synthesis 1.3 The Synthesis of Modiﬁed Oligodeoxyribonucleotides and Modiﬁed Oligoribonucleotides 2 Aptamers 3 Oligonucleotide Conjugates 3.1 Oligonucleotide-Peptide Conjugates 3.2 DNA-Templated Organic Synthesis 3.3 Oligonucleotide-Metal Conjugates 3.4 Charge Transport 3.5 Fluorescence 3.6 Miscellaneous Conjugates 4 Nucleic Acid Structures References Phosphazenes J.C. van de Grampel 1 2 3 4 5

Introduction Linear Phosphazenes Cyclophosphazenes Polyphosphazenes Crystal Structures of Phosphazenes and Related Compounds References

xi

274 294 300 304 304 304 304 334 334 336 349 355

355 355 359 360 406 411 411 412 413 416 418 423 425 436 479

479 479 501 525 536 549

Abbreviations BAD cDPG CE CK CPE Cpmp CV DETPA DMAD DMF DMPC DRAMA DSC DTA ERMS ESI-MS EXAFS FAB Fpmp HPLC LA-FTICR MALDI MCE MIKE PAH QDA PMEA SATE SIMS SSAT SSIMS TAD tBDMS TFA TGA TLC TOF XANES

Benzamide adenine dinucleotide Cyclodiphospho D-glycerate Capillary electrophoresis Creatine kinase Controlled potential electrolysis 1-(2-chlorophenyl)-4-methoxylpiperidin-2-yl Cyclic voltammetry Di(2-ethylhexyl)thiophosphoric acid Dimethylacetylene dicarboxylate Dimethylformamide Dimyristoylphosphatidylcholine Dipolar restoration at the magic angle Diﬀerential scanning calorimetry Diﬀerential thermal analysis Energy resolved mass spectrometry Electrospray ionization mass spectrometry Extended X-ray absorption ﬁne structure Fast atom bombardment 1-(2-ﬂuorophenyl)-4-methoxylpiperidin-2-yl High-performance liquid chromatography Laser ablation Fourier Transform ion cyclotron resonance Matrix assisted laser desorption ionization Micellar electrokinetic chromatography Mass-analysed ion kinetic energy Polycyclic aromatic hydrocarbons Hydroquinone-O,O 0 -diacetic acid 9-[2-(phosphonomethoxy)ethyl] adenine S-acyl-2-thioethyl Secondary ion mass spectrometry Spermidine/spermine-N1-acetyltransferase Static secondary ion mass spectrometry Thiazole-4-carboxamide adenine dinucleotide tert-Butyldimethylsilyl Triﬂuoroacetic acid Thermogravimetric analysis Thin-layer chromatography Time of ﬂight X-Ray absorption near edge spectroscopy

Organophosphorus Chemistry, Volume 35 r The Royal Society of Chemistry, 2006 xiii

Phosphines and Related Tervalent Phosphorus Systems BY D.W. ALLEN Biomedical Research Centre, Shefﬁeld Hallam University, City Campus, Shefﬁeld, S1 1WB, UK

1

Introduction

As this chapter covers two years of the literature relating to the above area, it has been necessary to be somewhat selective in the choice of publications cited. Nevertheless, it is hoped that most significant developments have been noted. The period under review has seen the publication of a considerable number of review articles, and most of these are cited in the relevant sections. In addition, several reviews having a broad relevance to the chemistry of phosphines have appeared, relating to the chemistry of silicon-based phosphines,1 and the speciﬁc contribution of phosphorus in dendrimer chemistry2 and that of related nanomaterials.3

2

Phosphines

2.1 Preparation. – 2.1.1 From Halogenophosphines and Organometallic Reagents. This approach has been applied widely in the synthesis of a range of sterically-crowded monophosphines, some of which have attracted considerable interest in the development of new homogeneous transition metal catalyst systems, the bulky phosphine facilitating the formation of catalytically-active low-coordinate species. Typical of these are tris(2,4,6-triisopropylphenyl)phosphine (prepared by a modiﬁed Grignard procedure, together with the corresponding arsine, stibine and bismuthine),4 tris(a-methylbenzyl)phosphine, also obtained by a Grignard procedure and isolated in both racemic and enantiomerically pure forms,5 and an extensive range of o-alkylsubstituted arylphosphines.6,7 Two groups have reported the synthesis of the bowl-shaped tris(alkyl-substituted terphenyl)phosphines (1) using organolithium reagents.8,9 Organolithium routes have also been used to prepare phosphines bearing ﬂuorenyl10 and indenyl11,12 substituents. The bulky, arylfunctionalised trialkylphosphine (2) has been prepared in a stepwise manner Organophosphorus Chemistry, Volume 35 r The Royal Society of Chemistry, 2006 1

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Organophosphorus Chem., 2006, 35, 1–91

from the Grignard reagent 2,6-Me2C6H3CH2CH2MgCl, t-butylphosphonous dichloride, and t-butyllithium.13 Bulky ortho-methyl-substituted arylphosphines bearing additional alkyl or alkoxy groups in the para-position have been obtained by Grignard routes and subsequently made water-soluble by sulfonation.14 R CH2CH2PBut2

R P R

3

R

(2)

(1) R = H, Me or Pri

A wide range of phosphines bearing other functional groups has been prepared via the reactions of organometallic reagents with halogenophosphines. Phosphines bearing perﬂuoroalkyl-15 and perﬂuoroalkylsilylaryl-16 substituents have been prepared, the latter by a combinatorial approach which resulted in 108 different molecules. The tris(4-styrylphenyl)phosphine (3) has been prepared and converted into a range of simple derivatives, the luminescence properties of which have been of interest.17 A convenient route to the styrylphosphine (4) is afforded by the simple Grignard reaction of 4bromostyrene with magnesium, followed by addition of chlorodiphenylphosphine, giving the phosphine in 52% yield on a 30g scale. Direct radical polymerisation of the latter has given a range of phosphinated polystyrenes.18

P

Ph2P But 3 (3)

(4)

Selective lithiation of alkyl- or aryl-pyridines is the key to the synthesis of a range of new phosphinopyridine ligands, e.g., (5),19,20 (6),21 and a fused phosphinomethylpyridinoferrocene.22 A similar approach has been used in the synthesis of chelating phosphino-oxazoline ligands, e.g., (7),23,24 (8),25 (9),26 and (10),27 and also of related phosphino-imidazolines,28 phosphinoalkylimines, e.g., (11),29–31 and a phosphinodiimine system.32 Among a range of P,O-donor ligands prepared via organolithium reagents

Organophosphorus Chem., 2006, 35, 1–91

3

are the phenacyldiarylphosphines (12),33 further 2-phosphinophenols,34,35 and a bulky ortho-amidoarylphosphine.36 Metallation of diethyl benzylphosphonate, followed by treatment with chlorodiphenylphosphine, has given the b-phosphonato-phosphine (13).37 Three distinct groups of functionalised phosphines, (14), (15), and the heteroarylphosphine (16), have been developed as ligands for palladium-catalysed aryl aminations, each system having been obtained by the reaction of aryllithium reagents with halogenophosphines.38 Among other heteroarylphosphines prepared in this way are a series of 2-phosphino-N-aryl-pyrroles39 and -indoles,40 the diphosphinopyrazole (17),41 and further examples of bis(phosphino)oligothiophenes.42 A new approach to the 1-phosphabicyclo[3,3,0]octane system (18) starts from the Grignard reaction of 4-chloro-hepta-1,6-diene with magnesium in THF, which proceeds without rearrangement. Conversion to 1-allyl-3-butenylphosphonous dichloride, followed by reduction with lithium aluminium hydride affords 1-allyl-3-butenylphosphine which undergoes radical-promoted cyclisation to form the bicyclic system.43 Several reports of the synthesis of alkynylphosphines have appeared. Metallation at the terminal alkyne carbon of an imine derived from 4-ethynylbenzaldehyde, using lithium diisopropylamide, followed by treatment with chlorodimethylphosphine, affords the long chain phosphine (19), of interest as a source of metallomesogens.44 The reaction of a diethynylsilane with ethylmagnesium bromide, followed by an organodichlorophosphine has given the cyclic ethynylphosphine system (20).45 A 1, 4-dilithiobutadiyne reagent has been used in the synthesis of 1,4-bis(diphenylphosphino)butadiyne.46 Sequential treatment of o-dibromobenzene with butyllithium and chlorodiphenylphosphine, followed by a second lithiation step and addition of dichloro(bis-isopropyl)silane, provides a practical route to the o-chlorosilyl-functionalised phosphine (21).47 Lithiation of 4bromobenzonitrile, addition of chlorodiphenylphosphine, and subsequent reduction of the nitrile group with lithium aluminium hydride, yields the phosphinobenzylamine (22). A related procedure from 2-bromo-4 0 -cyanobiphenyl gives (23). The reactivity of the aminobenzylic groups of (22) and (23) was subsequently utilised to give a range of hydrophilic phosphines bearing carbohydrate side chains.48 A triarylphosphine having dimethylaminomethyl groups in every available meta-position has also been reported.49 Interest in the chemistry of phosphines bearing 1,2-dicarboranyl substituents has continued. A Grignard procedure has been used to prepare the tris(dicarboranylmethyl) analogue (24) of tribenzylphosphine from 1-bromomethyl-o-dicarba-closo-dodecaborane in 82% yield. The phosphine has a 31P n.m.r. chemical shift of 13.6 ppm, and forms the related phosphine oxide on prolongued treatment with hydrogen peroxide. Although it forms a complex with gold(I), the bulkiness of the molecule prevents alkylation at phosphorus, even with methyl triflate.50 Further studies of the chemistry of 1,2-bis(phosphino)-1,2-dicarba-closocarboranes have been reported,51 as have full details of the synthesis of (phosphino-o-carboranyl)silanes.52

4

Organophosphorus Chem., 2006, 35, 1–91

R O

R

PAr2

R (5)

X

N

N

R

PPh2

R = H, Me or Pri

O

S

S

S

S

S

Ph2P

(7) R = Me, Pri or But; X = H, F, Cl, NMe2 or OMe

(6)

Ar = Ph, o-tol or Mes

S

N

H

R

PPh2

N PPh2

Ph2P

O

N

O

N

But (8)

(9)

(10) R = H or Me

Ph

Pri

Ph N

PR2

Ar2P

OEt Ph2P

O

P O

OEt

Pri (12) Ar = Ph or bulky aryl

(11)

O

(13)

Cy2P

O

CPh3 N

S R1

PR2

R1

N

PR22 (15)

R1 =

(14) H or Me R2 = Cy, Pri or But

(16) R = Cy or Pri

N N Ph2P N

PPh2

P

N (17)

(18)

5

Organophosphorus Chem., 2006, 35, 1–91

R12Si

PR2

O

Me2P N

O

C

OC8H17

(19)

R2P

(20)

SiR12

R1 = R2 = Ph; R1 = Ph, R2 = But; R1 = Pri, R2 = Ph

PCy2 PPh2 PPh2 SiPri2

H2N

NH2

Cl (21)

(22)

(23)

The ferrocene system remains a favourite building block for the synthesis of new phosphines. Among new ferrocenylmonophosphines prepared via reactions of lithioferrocenes with halogenophosphines are the chiral systems (25) and (26),53 a series of chiral aryl(phosphino)ferrocenes (27),54,55 the chiral bis(ferrocenyl)monophosphines (28),56 and the bulky phosphines (29)57 and (30).58 Also reported is a wide range of monophosphinoferrocenes bearing a donor group either ortho to phosphorus (31)59,60 or in the remote ring (32), involving alkoxy,61 thioether,62,63 or sulﬁnyl64 groups. Progress has also been made on the synthesis of ferrocenylphosphines bearing two or more phosphine groups. Among new systems reported are the diphosphinoferrocenophane (33),65 the diphosphines (34)66 and (35),67 and the tetraphosphine ‘manphos’ (36).68 New ferrocenyldiphosphines incorporating additional donor groups have been described, including the chiral C2-symmetrical system (37)69 and a ferrocenyldiphosphine involving a chiral oxazoline group.70 New phosphines based on other metallocene scaffolds have also been reported, including osmocene,71 benzenechromium tricarbonyl,72,73 and the related cyclopentadienylrhenium(I) tricarbonyl system.74,75

CH2

P

B10C2

Me Fe

PR2

Fe

3

(24)

t (25) R = Ph, Cy or Bu

(26)

P 3 Me

6

Organophosphorus Chem., 2006, 35, 1–91

Fe

PBut2

PAr

Ar PR2

Fe

2

Fe

Ph

OMe

Ph Ph

Ph Ph (27) R = Ph or Cy Ar = o-MeOC6H4, p-MeOC6H4, 3,5-(CF3)2 C6H3 or Ph

(28)

Ar = p -CF3C6H4, p -MeOC6H4, 3,5- (CF3)2C6H3 or Ph

Cy2P

(29)

R PR2 Fe

Fe

PPh2 Fe

X

X R (31)

(30)

H

X = SR, SAr, S(O)But, or CONR2

(32) R = H or alkyl; X = OMe, SMe or S(O)Ar

Me

R PPh2

Fe

Ph2P

Ph2P H

Fe

Fe

PPh2

PPh2 PPh2

(33)

(34)

(35)

P Fe

3

Fe

N Me PPh2

R = Me or Et

Fe

Ph2P (36)

(37)

Organolithium reagents have been widely employed in the synthesis of new diphosphines, including chiral 2,2 0 -bis(phosphino)biphenyls,76,77 a series of new diphosphine ligands based on bisphenol A backbones, e.g., (38),78,79 various 2,2 0 -bis(phosphino)diphenylamines,80,81 and the C2-symmetric trans-coordinating ligand ‘SPANphos’ (39).82 The norbornene-based diphosphine (40) has been obtained and shown to undergo a ruthenium-catalysed metathesis polymerisation of the norbornene moiety to give the polymeric diphosphine (41).83 Dendrimer systems incorporating diphosphinoethane moieties have also been prepared.84 The synthesis of phosphines based on the [2,2]paracyclophane skeleton has continued to develop and several new systems have been described. Studies of the electrophilic substitution of 4,12-dibromo[2,2]paracyclophane have enabled the introduction of a range of functional groups into the basic

7

Organophosphorus Chem., 2006, 35, 1–91

structure, these intermediates being easily converted into the desired functionalised phosphines (42) by lithiation and treatment with a halogenophosphine.85 Phosphinoparacyclophanes involving oxazoline86 and imidazolium moieties87 have also been described. Further development of the ‘xantphos’ system (43) has been reported, new diphosphines including those in which perﬂuoroalkylor perﬂuoroalkylaryl- substituents are present at phosphorus,88,89 and a range of related molecules in which the diarylphosphino unit is the heterocyclic phenoxaphosphine system, e.g., (44).90,91 A related dicationic phenoxaphosphine-based diphosphine ligand has also been prepared via the introduction of imidazolium units into the xanthene skeleton.92 Among other heterocyclic phosphines prepared via the reactions of organometallic reagents with halogenophosphines are the chiral pentacyclic dodecahydrophenoxaphosphine (45),93,94 the 1,2-diphosphaacenaphthene (46), the naphtho[1,8-b,c]phosphete (47),95 and the benzophosphepine (48).96 Routes to halogenophosphines of type (49) have been developed, these being key intermediates for the synthesis of a range of monodentate and bidentate ligands involving the binaphthylphosphepin system.97,98 A simple route to the phospholanes (50) is afforded by the reactions of dihalophosphines with an aluminacyclopentane intermediate derived from an alkene and a simple organoaluminium reagent in the presence of a zirconium catalyst.99

X

PPh2 O

MeO

O

OMe Ph2P

PPh2

Ph2P

(38) X = CMe2, 1,2-C6H10, o-C6H4, C(Me)Ph or SiMe2

(39)

PPh2

PPh2

O

n O

O

Ph2P O

PPh2 PPh2

PPh2 (40)

R

(41)

(42) R = OMe, CH2OH, CH2OTIPS or CH2OCPh3

8

Organophosphorus Chem., 2006, 35, 1–91

But

But

Ph P

O O

P

R2P

P

PR2

O O

O

(43) (45)

(44)

R = CF3 or p-C6H4C6F13

NPri2 PhP

PPh

P PPh

(46)

(47)

(48)

R R P

R

Cl P Ph

R

(49) R = H or Ph

(50) R = Bu or hexyl

2.1.2 Preparation of Phosphines from Metallated Phosphines. Lithio-organophosphide reagents continue to dominate this approach to phosphine synthesis, although related sodium-, potassium-, and even caesium- organophosphide reagents also ﬁnd use. Further work has been reported on the stabilisation of the (CF3)2P anion with weak Lewis acids, enabling the structural characterisation of a salt with the (18-crown-6)potassium complex cation. The X-ray study reveals almost discrete phosphide anions, with an unusually short P–C distance of 184 pm, indicating a negative hyperconjugation effect. The (CF3)2P anion, and also the related (C6F5)2P anion, have also been stabilised by coordination to pentacarbonyltungsten, which has little effect on the electronic and geometric properties of the organophosphide ions.100 The proton afﬁnities of the anions PhPH and 2,6-(CF3)2C6H3PH have been compared by a theoretical treatment, shedding light on the substituent effect of the 2, 6-bis(triﬂuoromethyl)phenyl group.101 The reactions of secondary phosphines with alkyl halides in DMF in the presence of caesium hydroxide and molecular sieves afford a convenient and highly efﬁcient general synthesis of tertiary

Organophosphorus Chem., 2006, 35, 1–91

9

phosphines and diphosphines.102,103 These conditions have also been shown to promote ring-opening of epoxides in the presence of primary- or secondaryphosphines, with the formation of 2-hydroxyalkylphosphines.104 Epoxide ringopening has also been achieved using potassium diphenylphosphide, providing a route to the enantiopure phosphine (51, X¼OH).105 Related reactions of thiiranes with lithium-and potassium-diphenylphosphides have given chiral 2-mercaptoalkylphosphines, e.g., (51, X¼SH)106 and 1-(diphenylphosphino) butane-2-thiol.107 The reactions of lithiophosphide reagents with alkyl-halides or -tosylates have been used to prepare chelating ligand systems, e.g., the phosphinoalkylpyrazole (52)108 and the rigid phosphino-amide donor (53).109 Related reactions of sodio-organophosphide reagents have also given phosphino-amides, e.g., (54),110 heteroalkynes, e.g., (55),111 the chiral naphthyl(ethyl)phosphine (56),112 and (3-dimethylphosphino)propanethiol.113 The secondary phosphine (57), obtained by treatment of a carbonyl-protected bromoalkyl derivative of camphor with lithium phenylphosphide, undergoes a proton-catalysed hydrolysis, followed by a stereoselective, base-catalysed addition of P–H to the carbonyl group to give the phospholane (58). This is stable under polar protic conditions, but reverts to the phosphinoketone (59) in a non-polar solvent.114 Direct displacement of halogen from aromatic systems by organophosphide reagents has also continued to ﬁnd use in phosphine synthesis. Displacement of ﬂuorine by potassium diarylphosphide reagents is the key step in the synthesis of N-aryl substituted ortho-diphenylphosphinoanilines, of interest for the formation of anionic phosphino-amido metal complexes,115 and the ortho-diphenylphosphinohydrazones (60).116 A range of metallophosphide reagents and ortho-haloaryl imidazolines has been utilised in the synthesis of the phosphinoarylimidazolines (61), capable of being electronically tuned in three different regions of the molecule.117 Displacement of chlorine from an 8-chloroquinoline by lithium diphenylphosphide has enabled the preparation of the related 8-(diphenylphosphino)quinoline.118 Other routes to phosphines involving attack of metallophosphide reagents at carbon have also been reported. Treatment of spiro[2,4]hepta-4,6-dienes with either lithiumor potassium-diorganophosphide reagents proceeds with opening of the spirocyclopropane ring to give phosphinoalkylcyclopentadienyl ligands, e.g., (62), from which a range of ruthenium119,120 and rhodium121 metallocene complexes has been prepared. Metallophosphides have also been shown to displace a variety of groups bound to the arene rings of arene-chromium and -manganese complexes to form the related phosphinoarene systems.122 Acylphosphines are among the products of the reactions of lithium dialkylphosphides with benzocyclobutenone chromium complexes.123 Lithium mono(organo)phosphide reagents have been shown to add to fulvenes to give the phosphinoalkylsubstituted cyclopentadienides (63), subsequently used in the synthesis of catalytically-active constrained geometry titanium-and zirconium- metallocene complexes.124 Treatment of dialkylcarbodiimides with lithium diphenylphosphide, followed by protonation of the intermediate anion, yields the phosphinoguanidines (64).125 Phosphino[2,2]paracyclophanes (65) have been obtained by treatment of cyclopalladated oxazolinyl[2,2]paracyclophanes with

10

Organophosphorus Chem., 2006, 35, 1–91

potassium diphenylphosphide.126 An efﬁcient strategy for the synthesis of diphenylphosphino(trialkyl)stannanes in almost quantitative yield is afforded by the reaction of sodium diphenylphosphide (from the cleavage of triphenylphosphine in liquid ammonia) with chlorotrialkylstannanes.127 Whereas displacement of chlorine from chlorosilanes by lithium mono(organo)phosphide reagents proceeds normally to give a series of silyl-substituted secondary phosphines,128,129 the reaction of lithium bis(trimethylsilyl)phosphide with sterically crowded aryltriﬂuorosilanes results in the elimination of ﬂuorotrimethylsilane and formation of the lithiophosphides (66).130 The cyclic phosphine (67) has been obtained by treatment of a tris(2-iodoethyl)silane with dilithium phenylphosphide, and subsequently transformed in a series of steps to give the bicyclic system (68), having Me3P-like steric and electronic properties.131 Good yields of perﬂuoroalkyldiphenylphosphines have been obtained via an SRN1 mechanism in the reactions of sodium diphenylphosphide with iodoperﬂuoroalkanes under irradiation in HMPA and DMPU as solvents. Related reactions in liquid ammonia or tetraglyme are dominated by halogenmetal exchange, and only poor yields of phosphines are achieved.132 Applications of borane-protected metallophosphide reagents continue to appear. The alkylation of secondary phosphine-borane adducts with a variety of electrophiles has been achieved with good to excellent yields in a two-phase system, using aqueous potassium hydroxide as the base, and tetrabutylammonium bromide as a phase-transfer catalyst.133 Alkylation of the P-lithiated borane adduct of diphenylphosphine with ethyl chloroacetate affords an easy route to the related borane-protected phosphinoacetate ester, which is easily transformed into a series of chiral amides, subsequently involved in a study of diastereoselective alkylation at the carbon adjacent to phosphorus.134 In related work, diastereoselective Michael-addition of borane-protected lithium diphenylphosphide to chiral amides derived from crotonic acid has also been studied, enabling a synthesis of the chiral phosphinocarboxylic acids (69), useful synthetic intermediates.135 Borane-protected lithium diphenylphosphide has also found application in the synthesis of phosphino derivatives of C60.136 Linear hybrid aminoborane/phosphinoborane chains have been prepared from the reactions of P- or C-lithiated phosphinoborane adducts with dimethylaminechloroborane.137 The reaction of a borane-protected P-lithiated phospholane reagent with 1,2-ethylene ditosylate is the key to a simple route to the new bis(phospholanyl)ethane ligand (70).138 Phosphido-borane reagents have also been used in the synthesis of a wide range of chiral P,N-chelating ligands with pseudo-C2 and pseudo-Cs symmetry based on chiral pyrrolidine and phospholane rings, or on dinaphthodihydroazepine and dinaphthodihydrophosphepine moieties.139 The reactions of chiral cyclic sulfate esters with dilithio(organo)phosphide reagents continue to be widely exploited for the synthesis of new phospholanes. An improved route to the simple secondary phospholane (71) has been developed, enabling the introduction of the chiral phospholane ring as a substituent in ferrocene and arenechromium complexes, e.g., (72).140 The cyclic sulfate route has been applied in the synthesis of other ferrocenylphospholanes, e.g., (73)141 and (74),142 an

11

Organophosphorus Chem., 2006, 35, 1–91

ortho-phenylenebis(phospholane),143 the bis(phospholanyl)maleic anhydride (75),144 and a series of P-arylphospholanes bearing either chiral amine145 or chiral dioxolanyl substituents in the ortho-position to phosphorus.146 This route has also been used in the synthesis of sterically crowded phospholanes, e.g., (76).147,148 O

N Pr

PPh2

N

PPh2 i

N

(51)

(53) R = Me or But

(52)

Ar

Ar

R PPh2

X

PPh2 NMe2

N But

O

PPh2

PPh2

(54) Ar = 2,4,6-Me3C6H2 or 2,4,6-Pri3C6H2

(56)

(55)

PHPh PPh

1. H3O+ O

PHPh

non-polar solvent

2. OH

O

OH (57)

polar, protic solvent

O

(58)

(59)

R2

R3 N N R

N

PPh2

N OMe

PR12

(60)

R1

R2

(61)

R1 NR

Li+

PR22

(62) R1 = H, Me, Ph, Cy, CH2 OTBS; R2 = Ph or Mes

Li+

Ph2P NHR

PHR (63)

(64)

R = Cy or Pri

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Organophosphorus Chem., 2006, 35, 1–91

R

PPh2 N

F R

Li

Si P

R

SiMe3

F

O

R (66) R = aryl or But

(65) Ph P

P

Ph

R

Si

O

Ph2P

Si

OH

Ph I (67)

(69) R = Et, Pri or Ph

(68) Ph

Ph

Me

P

P

P P Ph

Ph

Fe

PPh2

H (71)

(70)

(72)

O PPh2

P

Fe

O

Fe

O P

P

O

(73)

(74)

O

O

O

R H

P

P

H

P R

(75)

(76) R = H, Me or But

13

Organophosphorus Chem., 2006, 35, 1–91

Metallophosphide reagents have been applied widely in the synthesis of new chelating ligands involving two or more phosphorus atoms, and sometimes other additional donor centres. A convenient general procedure has been developed for the synthesis of a range of long chain a,o-bis(diphenylphosphino)alkanes involving 18-32 methylene bridges.149 Also reported are the linear tetraphosphine (77),150 a series of new linear arene-bridged bis(1,4-diphenylphosphinoethoxy) systems, e.g., (78),151 unsymmetrical bis (diarylphosphino)propanes having partly ﬂuorinated aryl substituents,152 and various unsymmetrical arsino(phosphino)ethanes having bulky groups at phosphorus and arsenic, together with new chiral diphosphino-ethane153 and – propane154,155 systems, e.g., (79). Further reports have appeared of the synthesis of carbohydrate-based diphosphines, e.g., the rigid isomannide-based system (80),156 the water-soluble a,a-trehalose-based phosphinophosphinite (81)157 and both a diphosphino- and a tetraphosphino-a-cyclodextrin system.158,159 A new 1,3-alternate- bis(diphosphinoethyl)calix[4]arene system has also been prepared.160 A new water-soluble arene-sulfonated 2,2 0 -bis (diphenylphosphino)biphenyl and other diphosphines involving a sulfonated dibenzophosphole system have also been described.161 Metallophosphide routes have been applied to the preparation of a wide range of di-, tri- and tetra-phosphines bearing additional donor or other reactive functional groups. Findeis and Gade have described the synthesis of a series of di-and triphosphines bearing alkenyl, alkynyl162,163 and hydroxyalkyl groups,164 e.g., (82), these acting as linkers for the synthesis of phosphino-functional dendrimers and related catalyst systems. Various chiral oxo- and oxy-functional diphosphines, e.g., (83), have been prepared from the camphor system.165,166 Chiral C2-symmetric 1,4-dioxanyldiphosphines, e.g., (84), have been prepared from tartrate esters.167 Routes to a number of P,P,N-donor systems have been developed, including a trans-chelating 1,5-bis(di-t-butylphosphino)-2-(S)-dimethylaminopentane,168 2,2 0 -bis(diphenylphosphino)diphenylamine,169 and a series of tripod ligands (85) involving phosphine and dialkylamine or N-pyrazolyl donors.170,171 A phosphide route has also been used to prepare 2-(diphenylphosphinoethyl)-3,5-dimethylpyrazole.172 The diphosphinodiazadienes (86) have been prepared by treatment of a bis(imidoyl chloride) with sodium diphenylphosphide.173,174 Diphosphines,175,176 e.g., (87) and a tetraphosphine,177 which also incorporate pyridine moieties, have been described. New ferrocenylphosphines involving Si–P linkages (88) have been prepared from the reactions of a bis(chlorosilyl)ferrocene with lithium diorganophosphide reagents.178

R Ph2P

P

P

Ph

Ph

(77)

PPh2

Ph2P

O

O

(78)

PPh2

R

Ar2P

PAr2

(79)

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Organophosphorus Chem., 2006, 35, 1–91

HO

HO PPh2

O H

H

HO

OH O

O

O

Ph2P

OH

O

PPh2

O

PPh2

OH

PPh2

(80)

R

PPh2 PPh2

(81)

(82)

R = HC

H2C

CH or CH2OMe

C,

OR

Ph2P

Ar2P OH

O

Ar2P

O

NR2 OR

PPh2

(83)

(85) R = Me, Ph or CH2OMe Ar = Mes or Ph N R2N = Et2N or N

(84)

Ph2P Ph2P

P

F F

PPh2 (86)

Si PR2

Ph F

NAr

ArN

R

PAr2 PAr2

N

Fe Si PR2

F (87)

(88) R = Me or Ph

The structural characterisation of metallophosphide species (and their complexes with other ligands) continues to attract interest. New polyphosphide anions, (together with a variety of other products, including halogenophosphines, diphosphenes and diphosphines), are formed in the reactions of phosphorus trichloride with alkyl-sodium,-potassium and -zinc reagents.179 A range of sodium oligophosphane-a,o-diide systems has been characterised from the reactions of phenyldichlorophosphine with sodium.180 The reaction of lithium phenylphosphide with MeAlCl2 results in the selective formation of the anion [PhP(H)–PPh], isolated as a tetrameric lithium salt.181 The reactions of lithium- or sodium-cyclohexylphosphide with tris(dimethylamino)arsine in the presence of various ligands lead to the formation of the ﬁve-membered, heterocyclic phosphinoarsenide [(CyP)4AsLi], isolated as a series of complexes.182 The ability of mono(borane-protected)diorganophosphide ions to form complexes with lithium and aluminium acceptors has been investigated and a range of complexes structurally characterised.183 Various alkali metal silylphosphides have also been prepared and characterised.184,185 Lithium-, potassium- and tin-salts of monoanionic P,N-centred (iminophosphorano)

15

Organophosphorus Chem., 2006, 35, 1–91

1-phosphaallyl ligands, e.g., (89), have been obtained from the initial reaction of an N-(trimethylsilyl)phosphoranimine of an alkynyldiphenylphosphine with potassium phenylphosphide.186 Magnesium organophosphides have been obtained from the reactions of dibutylmagnesium with primary or secondary phosphines, and structurally characterised. Related calcium, strontium and barium organophosphides have also been prepared.187,188 A zinc organophosphide has been obtained and structurally characterised.189 Phosphido derivatives of the main group 13 elements continue to generate much interest. New systems include a tetraanionic alumino(mesityl)phosphide cage complex,190 and new gallium191,192 and indium193 organophosphides. The reactivity of aluminophosphides towards group 13 trialkyls has also been investigated.194,195 Novel routes to quantum dots of InP and GaP have been developed via the thermolysis of the corresponding metal diorganophosphides in 4-ethylpyridine.196 New main group element organophosphide cluster species involving tin and germanium have also been prepared and structurally characterised.197,198 A range of cyclic, oligomeric gold organophosphides has been prepared by treatment of gold(I) complexes of secondary phosphines with aqueous ammonia.199,200 The previously established alkali metal cleavage of the P–P bond of tetraphenyl-1,2-dihydrodiphosphetenes to give the diphosphide anion (90) has been used to prepare anionic cyclic organophosphidoplatinum complexes.201 OSiR3 Ph

Ph

Ph2P Me3Si

N

PPh

(89)

Ph

P

P

(90)

Ph

Ph2P

N

(91)

Interest has also continued in the use of phosphines metallated at atoms other than phosphorus as reagents in synthesis. Reagents of the type R2PCH2 Li, easily accessible by metallation of methylphosphines with alkyllithium reagents, have found use in the synthesis of a range of sterically crowded diphosphinomethane ligands,202,203 the unsymmetrical di(N-pyrrolyl)phosphino-functionalised diphosphinomethane Ph2PCH2P(NC4H4)2,204 and various chiral b-aminoethyldiphenylphosphines.205,206 Related lithiomethylphosphines, protected at phosphorus with borane, have also found wide application in the synthesis of new diphosphines, e.g., a series of P-chirogenic bis(phosphino)ethanes,207,208 a P-chirogenic 1,2-bis(phospholanyl)ethane,209 and a P-chirogenic 1,2-bis(ferrocenyl)diphosphinoethane.210 Derivatives of the alkaloid (-)-cytisine have advantages over the commonly used (-)-sparteine when used in combination with sec-butyllithium to desymmetrise prochiral organodimethylphosphine-borane complexes, giving access to the less accessible enantiomer of the chiral lithiomethylphosphine-borane reagent, and hence to a wide range of new chiral systems.211 Among other applications of Clithiated alkylphosphine reagents are routes to a series of C-functionalised

16

Organophosphorus Chem., 2006, 35, 1–91

o-diphenylphosphinoalkylpyridines, e.g., (91),212 various anionic phosphinoborate ligands, e.g., [PhB(CH2PiPr2)3],213,214 and the neutral diphosphine Ph2Si(CH2PPh2)2.215 Borane-protected Ph2PCH(Li)CH3 has been shown to react with electron-withdrawing aromatic systems via an SNAr mechanism to give functionalised aralkylphosphines, e.g., (92).216,217 Lithiation of bromoarylphosphines, followed by reactions with conventional electrophilic reagents, provides a route to functionalised arylphosphines, e.g., the phosphinotetraarylborates (93),218 the phosphinobenzhydrol (94), (an intermediate for the synthesis of helically chiral polymers),219 a series of ortho-silylated benzylphosphines,220 and the phosphinoarylcycloheptatriene (95).221 Phenacylphosphines of type (12) have been shown to undergo metallation with potassium hydride to form the related enolate ions, which have been trapped to give the phosphino-phosphates (96).222 The diphosphinocyclopentadienide reagent (97) has been used to prepare a tetraphosphinoferrocene.223 Phosphinoferrocenes have also been prepared from the phosphinoindenyl reagent (98).224 Metallation of diphosphinomethanes at the bridging carbon is a key step in a new route to vinylidene phosphines, e.g., (99).225 Compounds of this type undergo a Schlenk dimerisation on treatment with either lithium or sodium in THF to give the diphosphinomethanide complexes (100).226 Similar behaviour occurs with borane-protected 1-phosphino(1-silyl)-alkenes.227 CN Ph

R2P

Z

Li

BPh3 PPh2 (92) Z = H or electronwithdrawing group

Ph2P

OH Ph

(93)

(94)

Ph2P

Ph Ph2P

O

PPri2 (95)

P

OR OR O

Ph2P

(96)

(97)

PPh2

PR2 Pr2P Li+

CH2 Pr2P

(98)

R2P

PR2

R2P

(99)

2M+ (100)

Organophosphorus Chem., 2006, 35, 1–91

17

2.1.3 Preparation of Phosphines by Addition of P–H to Unsaturated Compounds. This method continues to ﬁnd use in phosphine synthesis, although the number of applications noted in the period under review is relatively small. Conventional thermal- or free radical-initiated conditions have been used for the addition reactions of the (R)-(þ)-limonene-based secondary phosphine (101, R¼H) to alkenes to give a series of new bicyclic tertiary phosphines (101, R¼alkyl),228 the addition of (þ)-8-phenyldeltacyclene to 1,2bis(phosphino)benzene to give the crowded chiral diphosphine (102) as a mixture of two diastereoisomers,229 addition of secondary phosphines to Nvinylpyrroles to give a series of 2-(1-pyrrolyl)ethylphosphines,230 addition of phenylphosphine to iminium salts to give the linear NPN-ligands (103),231 and for the addition of diphenylphosphine (in excess) with vinyl-functionalised polyhedral oligomeric silsesquioxane dendrimers.232 Base-catalysed conditions have been employed in the addition of secondary phosphines to functionalised alkenes, leading to polyfunctional tertiary phosphines in high yield,233 and also for the regio-and stereo-speciﬁc addition of primary and secondary phosphines to aryl(cyano)alkynes, giving functionalised secondary and tertiary phosphines of Z-conﬁguration.234 Borane complexes of secondary phosphines also undergo addition reactions with alkenes and alkynes. A simple route to alkylarylphosphines on a gram scale is offered by the addition of secondary phosphine-boranes to unactivated alkenes under mild thermal activation, the reaction proceeding in an anti-Markownikov mode. The new chiral phosphines (104) have been obtained by such additions to ()-b-pinene.235 Related additions to alkynes have been achieved under thermal and metal-catalysed conditions. Under thermal conditions, additions to terminal alkynes proceed in an anti-Markownikov mode to form largely Z-alkenylphosphine-boranes, whereas reactions promoted by a palladium(0) catalyst give the Markownikov products.236 Markownikov products have also been isolated from the addition of diphenylphosphine to alkenylalkyl ethers, catalysed by palladium or nickel complexes.237 Organoytterbium complexes have also been shown to catalyse the addition of secondary phosphines to alkynes, and other carbon-carbon multiple bonds. The regio-and stereo-selectivity of these reactions clearly differ from those of the corresponding radical-promoted additions, the reactions proceeding via insertion of alkynes into a Yb-PPh2 species, followed by protonation.238 Further studies have been reported of the intramolecular hydrophosphination/cyclisation of primary phosphino-alkynes and -alkenes to form cyclic phosphines in the presence of organolanthanide complexes.239 Diphenylphosphine has been shown to add diastereoselectively to benzaldimines coordinated to a chromium tricarbonyl acceptor, to form complexed chiral aminoalkylphosphines.240 The synthesis of P-chiral functionalised secondary phosphines by addition of iron-complexed primary phosphines to alkenes and alkynes has been reviewed.241 The tricyclic trislactonephosphine (105) has been obtained from the reaction of PH3 with pyruvic acid.242 Addition of diphenylphosphine to the isocyanate group of dimethylthiocarbamoyl isothiocyanate leads to the new ambidentate ligand (106).243

18

Organophosphorus Chem., 2006, 35, 1–91

P R

NR2.HBr

PR2 R= PHR

(101)

H

Ph P NR2.HBr

H (102)

(103) R = Me or Et

R = e.g., (CH2)nCH3, (n = 3-17),(CH2)3CN or (CH2)3OCH2Ph Ph P

R

BH3

Me O O

O Me P

PPh2

O S

O Me (104) R = Ph or But

H N

Me2N

(105)

S

O (106)

2.1.4 Preparation of Phosphines by Reduction. Although trichlorosilane remains the reagent of choice for many reduction procedures in phosphorus chemistry, other reagents also continue to ﬁnd use. Trimethyltin hydride and tributyltin hydride, respectively, have been used to reduce diorganophosphinous chlorides in a large scale, high yield route to the secondary phosphines (CF3)2PH and (C6H5)2PH.244 Lithium aluminium hydride has also been used for the reduction of halogenophosphines, in the synthesis of crowded diphosphines, e.g., (107),245 and (108).246 Various reducing agents have been compared for their effectiveness in the reduction of chlorophosphine-boranes to the related secondary phosphine-boranes, the main point to emerge being that there needs to be a judicious match between the steric and electronic requirements of both reagent and substrate.247 The desulfurisation of arylphosphine sulfides with tributylphosphine has been applied in a new route to a series of C-substituted phosphatriptycenes (109), (and, in turn, the related P¼Se derivatives).248 Raney nickel has also been used for the desulfurisation of phosphine sulfides in the synthesis of the phospholane-oxazoline ligands (110).249 However, a very common strategy in phosphine synthesis continues to be a ﬁnal stage reduction of phosphine oxides with silane reagents, of which trichlorosilane is the most popular. Among a considerable range of new monophosphines obtained by trichlorosilane reduction, usually in the ﬁnal step of the synthesis, are the phosphorus core conjugated triaryl-dendrimer unit (111),250 a range of triarylphosphines bearing branched ﬂuoroalkyl moieties (‘split pony tails’), e.g., (112),251 and a variety of chiral monophosphines,

19

Organophosphorus Chem., 2006, 35, 1–91

including the phosphinocarboxylic acid (113),252 phosphinoaryloxathianes, e.g., (114),253 a series of axially chiral ortho-aminoarylphosphines, e.g., (115)254,255 and (116),256 the axially chiral binaphthylphosphine (117),257 and the chiral arylferrocenylphosphines (118).258 Trichlorosilane reduction has also been used in the synthesis of phosphino-[6]- and -[7]-helicenes, e.g., (119), which are also chiral systems,259,260 and a variety of other chiral diphosphines, including the spiro system (120),261 the C2-symmetric cyclobutane system (121),262 and the tetraphenylene (122).263 In addition, many new chiral 2,2 0 -diphosphinobiphenyls have been described, including ‘SYNPHOS’ (123, X¼CH2CH2)264,265 and ‘DIFLUORPHOS’ (123, X¼CF2),266,267 the related system (124),268 and others involving simple alkoxy substituents in the biphenyl system269 and bulky aryl groups at phosphorus.270 Interest has also continued in the synthesis of ‘BINAP’ systems (125), with particular reference to the introduction of substituents in the naphthalene system which modify the effectiveness of the molecule as a ligand in catalyst systems271 or render it water soluble272 or soluble in supercritical carbon dioxide.273 BINAP-based phosphines and diphosphines bearing ﬂuorous substituents in the diarylphosphino groups have also been isolated following trichlorosilane reduction.274 Trichlorosilane reduction is a key step in a route to the new atropisomeric diphosphine ligand ‘BINAPFu’ (126), resolved into its enantiomeric forms, and shown to be more effective than BINAP in one Heck arylation system.275 Trichlorosilane has also been employed in the synthesis of ﬂuorous-tagged bis(diarylphosphino)propanes,276 a range of new bis(diarylphosphinoethyl)amines,277 and a series of 1,1 0 bis(diphenylphosphinoaryl)ferrocenes.278 Several other reagent systems have been used for the reduction of phosphine oxides, including polymethylhydrosilane/titanium isopropoxide (for the new diphosphinoferrocenes (127)),279 LiAlH4 (for reduction of chiral 2,5-diphenylphospholane oxides via the related triflate salts),280 and various transition metal tri(t-butyl)siloxides.281 Hexachlorodisilane has been used for the reduction of phosphine sulfides in the synthesis of the chiral bis(phosphepine) (128).282 The combination Me3SiCl– LiAlH4 has been used for the reduction of 2-(ferrocenyl)alkylphosphonic acid derivatives to give the related primary phosphines, surprisingly airstable compounds.283 Reduction of alkylphosphonates has also been achieved with LiAlH4 in the synthesis of the primary phosphine PhSeCH2CH2PH2.284

OMe

Me2N

P

NMe2

P

(Me3Si)2CH

CH(SiMe3)2 (107)

SMe P H

CH(SiMe3)2

(108)

OH

MeO P (109)

OMe

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Organophosphorus Chem., 2006, 35, 1–91

But P H O But

P N But

RF8

P

R

Pri,

(110) R = Ph or PhCH2

RF8

But,

(112)

(111)

n

MeO CO2H

PPh2 (113)

N

O S

MeO

R1 R2

(114) Ar = Ph or 3,5-xylyl

N

(115) R1,R2 = (CH)4; n = 1; R1,R2 = H or MeO, n = 1 or 2

X PR2

R

Fe

PAr2

(116) Ar = Ph or p-tol; R = Me or Et

PPh2

PAr2

Ph Ph

3

3

PPh2

OMe

(117) R = cyclopentyl

(118) R = OH, NH2, NHCOR

EtO2C

Ph2P

CO2Et

PAr2 PAr2 PAr2 Ar2P (119)

(120)

(121)

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Organophosphorus Chem., 2006, 35, 1–91

O

O X PPh2 PPh2

O

PPh2

O

O

PPh2

O

PPh2 PPh2

X O O (123)

(122)

R1

(124)

R2

O PPh2 Ph2P PPh2

PPh2 O

R1

R2

(125) R1 = H; R2 = e.g., Me3Si, CPh2OH or CH2NH2; R1 = CH2NH2 or RF; R2 = H

(126)

But P H R 22P

H But P

Fe R12P (127)

R1 = Ar; R2 = Cy, But or Ar

(128)

2.1.5 Miscellaneous Methods of Preparing Phosphines. Useful general reviews of phosphine chemistry which have appeared in the past two years include coverage of the synthesis and applications of primary phosphines,285 recent developments in the synthesis of chiral phosphetanes,286 the synthesis of P-modular homochiral bis(phosphines) having a 1,2-disubstituted cyclopentane backbone287 and new chiral phosphorus ligands for enantioselective hydrogenation.288 Reviews of the design of chiral ligands for asymmetric catalysis, covering C2-symmetric P,P-ligands to sterically and electronically non-symmetrical P,N-ligands,289 chiral P,N-ligands involving pyridine and phosphorus

22

Organophosphorus Chem., 2006, 35, 1–91

donor centres,290 mixed donor phosphine-phosphine oxide ligands,291 and combinatorial libraries of chiral ligands292 have also appeared. The reaction of vinylmagnesium bromide with triphenylphosphite provides an improved route to trivinylphosphine, which can be stored for several months at 321C without polymerisation. Its reactivity towards a range of reagents, e.g., alkyl halides, chalcogens, borane and boron trihalides, has also been explored.293 Copper-catalysed cross-coupling of terminal alkynes with chlorophosphines provides a convenient route to phosphinoalkynes.294 Related nickel- and palladium-catalysed procedures have also been described.295 Benzynezirconocene has been shown to promote the intramolecular coupling of bis(alkynyl)phosphines with silanes, providing a route to new monoand tri-cyclic heterocyclic systems, e.g., (129),296 and a zirconocene-mediated cross-coupling of alkynylphosphines provides a route to 1,3-butadienylphosphines.297 Oleﬁn metathesis catalysts have been used to achieve the cyclisation of diallyl(phenyl)phosphines to 1-phenyl-3-phospholenes298 and further studies have been reported on the macrocyclisation of phosphines bearing o-alkenyl(polymethylene) substituents, coordinated to platinum.299,300 The synthesis of phosphorus (and sulfur) heterocycles via ring-closing oleﬁn metathesis has also been reviewed.301 An improved synthesis of di(1-adamantyl)alkylphosphines by alkylation of di(1-adamantyl)phosphine, followed by deprotonation of the intermediate phosphonium salt with triethylamine, has been described.302 This approach has also been used independently in related reactions of di(1-adamantyl)phosphine with para-di(bromomethyl)benzene, to yield the cationic, phase-tagged phosphine (130), and related compounds derived from the intermediate salt by treatment with triphenylphosphine.303 A simple route to the fused phosphirane, dibenzophosphasemibullvalene, (131), has been developed.304 Further work has been reported on the reactions of the bicyclic system (132) with diGrignard reagents derived from a,odibromoalkanes. It has now been shown that treatment of the initial Grignard reagent adduct of (132) with water yields the secondary cyclic phosphines (133) in 70-80% yield. The biproduct (134) can also be isolated cleanly from the aqueous phase in 90% yield, and recycled back to (132) by treatment with phosphorus trichloride.305 The established ring-opening of aziridines on treatment with diphenylphosphine has been used to prepare further examples of chiral b-aminophosphines.306 The regiospeciﬁcity of the reaction of diphenylchlorophosphine with enamines derived from b-aminocrotonic acid has been studied, providing routes to enamino-vinyl- and -allyl-phosphines.307 A similar study of the reactions of propyneiminium salts with diorgano(trimethylsilyl)phosphines has provided access to enamino-allenyl-, -alkynyl- and -butadienyl-phosphines.308 A convenient route to acylphosphines (‘phosphomides’) is afforded by the reaction of secondary phosphines with acyl- and aroylchlorides, in the presence of a base.309 The o-phosphinoaryl-ylide (135), bearing a chiral sulﬁnyl moiety, has been prepared by the reaction of the related phosphinoaryl-methylide with (S)-menthyl p-tolylsulﬁnate.310 Further

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Organophosphorus Chem., 2006, 35, 1–91

examples have been reported of the synthesis of chiral C-functionalised phosphanorbornenes by the cycloaddition of functionalised alkenes to 1-phenyl-3,4- dimethylphosphole, coordinated to a chiral palladium complex as the chiral auxilliary.311,312 A related achiral cycloaddition of phenylethynyltriethoxysilane has given the triethoxysilyl-functionalised phosphanorbornadiene (136), capable of being anchored, as a rhodium complex, to mesoporous silica.313 New thiophene-, benzothiophene- and benzofuranoxazoline ligands, e.g., (137), bearing a diphenylphosphino group at different positions of the heterocyclic skeleton, have been prepared and studied as ligands in homogeneous metal-catalysed processes.314,315 Applications in homogeneous catalysis have also driven the synthesis of a series of N-(orthodiphenylphosphinoaryl)-pyrroles and -pyrazoles.316 Various established protocols have been explored for the synthesis of diphosphine ligands bearing highly symmetric, bulky substituents at a stereogenic phosphorus atom317 Full details of routes to the di- and tri-(phosphinomethyl)methanols (138) have been disclosed, these compounds giving rise to multidentate phosphinoalkoxides, of interest as ligands to main group as well as transition metals.318 Cycloaddition of the azide ion to the bis(phosphino)alkynyl diselenide, Ph2P(Se)CRCP(Se)Ph2, followed by removal of selenium with triethylphosphite, results in the bis(phosphino)-1,2,3 triazole (139), capable of deprotonation at nitrogen to give an anionic diphosphine ligand.319 Alternative approaches to biaryldiphosphines of type (123, X¼CF2) have also been described.320 The synthesis of resorcinarene derivatives having four or eight alkynyldiphenylphosphino (or diphenylphosphinito) functional groups has been reported.321 Routes to ﬂuoro(phosphino)- and diphosphino-stannanes, R2Sn(X)PH2 (X¼F or PH2),322 and triphosphinoﬂuorosilanes, RSi(PH2)3,323 of interest as reagents for PH2 transfer under mild conditions, have been developed. Ph

P(1-Ad)2 SiMe2 Et3N

P

Ph

P Br

Ph (129)

(130)

(131)

Me

Me

Me P S

P

S

(132)

P H

H P

n

(133) n = 1 or 2

SH HS (134)

Me

24

Organophosphorus Chem., 2006, 35, 1–91 Me Me Ph

Me

Ph P

S

Ph

O

Ph

P

Si(OEt)3

PPh2 (135)

(136)

O R

N

N

(Me2PCH2)nCH3-nOH

(137) X = O or S; R = Pri, Bus or Ph

N N H

PPh2

X

PPh2

Ph2P

(138) (n = 2 or 3)

(139)

A wide range of new phosphines based on the ferrocene system has been prepared, using a variety of synthetic methods. Their use in homogeneous catalyst systems has also been reviewed.324,325 The ephedrine-based oxazaphospholidine-borane route has been applied to the synthesis of eight P-chiral monodentate ferrocenylphosphines of the general structure FcP(Ph)R, (R¼aryl or alkyl).326 The reactivity of ferrocenylmethyl alcohols, esters, ethers and amines towards nucleophiles (often secondary phosphines) has been utilised in the synthesis of new phosphines, including a tridentate system, (140), combining planar-, P- and C-chirality,327,328 bulky phosphines, e.g., (141) and (142),329 a ferrocenylmethylphosphine-containing polymer,330 rac-[2-(diphenylphosphino) ferrocenyl]acetic acid and related compounds,331 and ferrocenylphosphines bearing imidazolium groups, precursors of phosphino-carbene ligands.332,333 The same approach has been used in the synthesis of new P,N-ferrocenyl ligands, e.g., (143)334 and (144).335 The established ring-opening of 1-phenyl-1-phospha[1]ferrocenophane with phenyllithium has been applied in the synthesis of the new enantiopure phosphino-phosphinito ligand (145).336 PR22

Me Ph P Fe

PPh2

R1 Ar

PPh2

Fe

Fe

Fe

Ph

P Ph

(140)

(141) R1 = H or Ar; R2 = Ph or But; Ar = Ph, o-anisyl or 1-naphthyl

(142)

Ph

25

Organophosphorus Chem., 2006, 35, 1–91 Me

Ph2P Ar1 Fe

Ar2

R1

PPh2

N Fe

PPh2

PR22

Fe P(OMenthyl)2

(143) Ar1 = o-tolyl or 3,5-xylyl; Ar2 = 2-pyrimidyl, 2-pyridyl or 2-quinolyl

1

(144) R = H or alkyl; 2 R = Ph or Cy

(145)

Methods for the synthesis of C-functionalised arylphosphines based on the direct introduction of phosphino groups into aryl halides or tosylates, catalysed by a variety of metals, have continued to develop. The reactions of secondary phosphines (and secondary phosphine oxides) with bromo- or iodo-arenes, catalysed by palladium acetate or other palladium complexes, have been used to prepare a range of ortho-substituted arylphosphines,337,338 including enantioselective syntheses of chiral systems, e.g., (146),339,340 and a series of diphosphine ligands having a barbiturate-binding receptor, e.g., (147).341 Related palladium- and nickel-catalysed reactions of primary phosphines with paradihalobenzenes have given a series of poly(arylene)phosphines.342 A palladium[0]-catalyst was used in the synthesis of para-diphenylphosphinophenol, subsequently attached to a polyethylene glycol ether support.343 Related palladium-catalysed reactions of aryl triflates with secondary arylphosphine oxides yield the corresponding tertiary phosphine oxides, subsequently reduced to the phosphines. This approach has been applied in the synthesis of new chirogenic binaphthylmonophosphines,344 the monoxide of 2,2 0 -bis(diphenylphosphino)-1,1 0 -binaphthalene345 and the chiral P,N-system (148).346 Palladium-catalysed phosphination of bromoarenes and aryl triflates bearing a wide variety of functional groups has also been achieved by the use of triarylphosphines as the phosphinating reagent.347,348 A microwave-assisted procedure for the palladium-or nickel-catalysed phosphination of aryl halides and triflates by diphenylphosphine has also been reported.349 Nickel-catalysed direct phosphination reactions of aryl triflates with secondary phosphines have also been achieved in the synthesis of hexamethyl-2,2 0 -bis (diarylphosphino)biphenyls,350 1-(2-diphenylphosphino-1 0 -naphthyl)isoquinoline,351and the new atropisomeric system (149).352 Functionalised triarylphosphines have also been prepared by a nickel-catalysed reaction of aryl bromides with chlorodiphenylphosphine, in the presence of zinc dust.353 This approach has also been used to prepare the unusual 2,8 0 -disubstituted-1,1 0 - binaphthyl (150).354 Copper(I) iodide, in the presence of a base, is an effective and inexpensive reagent for the phosphination of aryl- and vinyl-halides by secondary phosphines, the conditions tolerating the presence of a wide variety of functional groups.355,356

26

Organophosphorus Chem., 2006, 35, 1–91

PPh2 O

Ph P

Ph2P

NH

HN

N

Me

N NH

O

(147)

Me

Ph2P

Me

Me

(148)

OMe PPh2

PPh2 MeO

Ph

O

HN

O

(146)

Me N

PBut2

PPh2 O (149)

(150)

PPri2

(151)

The reactions of other functional groups present in organophosphines have been widely applied in the synthesis of new phosphines, usually of interest as ligands for use in homogeneous catalyst systems. A series of unsymmetrical PCP 0 pincer ligands, e.g., (151), has been obtained via reactions of metaphosphinomethyl-phenols and -benzyl alcohols with di(isopropyl)chlorophosphine in the presence of base.357 Unsymmetrical diphosphines of the type Ph2P(CH2)nNHPPri2 (n¼2 or 3) have been obtained by related reactions of o-aminoalkylphosphines.358 The reaction of 2-aminoethyldiphenylphosphine with a ﬂuoronitrobenzoxadiazole yields phosphine (152), of interest as a new reagent for the detection of hydroperoxides, the resulting phosphine oxide ﬂuorescing strongly.359 N-acylation of phosphinoalkylamines, derived from valinol and proline, with picolinic and quinaldic acids has given a new series of N,P-ligands.360 N-acylation and -alkylation of 2-(diphenylphosphino)methylpyrroline has been used to provide a series of unsymmetrical terdentate PNN ligands, e.g., (153).361 Twenty new chiral aminoalkylphosphines of type (154) have been prepared by transformations of related chiral phosphinoalkanoic acids.362 An eight stage route to the diphosphine (155) has been developed, starting from 5-amino-isophthalic acid dimethyl ester, involving Arbuzov and trichlorosilane reduction stages, and subsequent elaboration of the arylamino group. Covalent binding to silica is then possible via the succinimide ester group.363 The succinimidyl ester of diphenylphosphinopropionic acid has been used as an intermediate in the synthesis of the phosphino-amino acid system (156).364

27

Organophosphorus Chem., 2006, 35, 1–91

PPh2

HN

PPh2 O

R

N

R2

R1

N

N

Ph2P

N H

R3

NMe2 (152)

(153)

(154)

O O N

O O

O

NH

HN O

O

PPh2

O PPh2 (155)

HN

OMe

PPh2 HS (156)

Phosphino-amino acid components have also been used in a parallel approach in conjunction with natural amino acids to develop b-turn phosphinopeptide ligands.365 A series of polyphosphorus ligands, of interest for the construction of metallodendrimer systems, has been prepared from the reactions of 3-hydroxypropyldiphenylphosphine with P(O)Cl3 and phenyldichlorophosphine.366 Dendritic phosphines have also been obtained by N-acylation reactions of 3,4-bis(diphenylphosphino)pyrroline367,368 and 5,5 0 diamino-BINAP,369 and the synthesis of phosphorus-containing dendrimers has been reviewed.370 The reactions of thiolate anions with o-chloroalkylphosphines have given a range of new P,S-donor ligands, including the bis(phosphinoalkyl-thioether)arene (157),371 the aminoarylthioalkylphosphine 4-H2NC6H4SCH2CH2PPh2, from which the phenolic imine (158) was subsequently obtained,372 and a 3-(diphenylphosphino)propylthio-substituted tetrathiafulvalene.373 Addition of a trifunctional arenethiol to diphenylvinylphosphine has given the threefold symmetric phosphino-alkylthioether ligand (159), capable of forming macrocyclic metallo complexes.374 Phosphadithiamacrocycles have also been assembled by the reactions of the isomeric bis(chloromethyl)benzenes with the thiolate anions derived from bis(2-mercaptoethyl)phenylphosphine.375 Very many new phosphines have been prepared utilising the reactivity of functional groups in the ortho- or para-positions to phosphorus in an arylphosphine. Thus, e.g., the spiro-phosphino-oxazine (160) has been obtained by the reaction of ortho-diphenylphosphinobenzonitrile with a spiro-aminoalcohol,376 new chiral arylphosphino-phosphito ligands have been prepared from the reactions of chiral ortho-phosphinophenols with chlorophosphites,377 and treatment of o-(diphenylphosphino)benzyl chloride with various 1-substituted imidazoles has given a series of phosphino-imidazolium salts (161), potential precursors of nucleophilic carbene ligands.378 However, most reports of this nature centre on the reactions of phosphinoarylaldehydes, -carboxylic acids, and -amines. Imine formation from

28

Organophosphorus Chem., 2006, 35, 1–91

the commercially available o-(diphenylphosphino)benzaldehyde continues to be exploited. Among new phosphinoarylimines reported are those from 2-aminomethylpyridine,379 1-phenylazo-2-naphthylamine,380 chiral sulﬁnamides,381,382 chiral monosulfonamido derivatives of trans-1,2-diaminocyclohexane,383 and the primary amines H2N(CH2)nSePh (n¼3,4).384 Imine formation with o-diphenylphosphinobenzaldehyde has also been used for the surface functionalisation of dendritic primary alkylamines, giving dendrimeric P,N ligands.385 Aminal- and thioacetal-like cyclocondensations of o-diphenylphosphinobenzaldehyde with chiral amino-amides, disecondary amines, and 3-hydroxypropanethiols has afforded new chiral phosphines, e.g., (162),386,387 and (163).388,389 Imine formation from enantiopure 2-formyl-1phosphanorbornadiene has been utilised to give the new chiral phosphinoimines (164).390 Phosphino-aldehydes based on ferrocene and cymantrene have also been used in imine formation for the design of new planar chiral ligands.391 New ferrocenyl phosphino-imine ligands have also been prepared via the condensation reactions of primary aminoalkylferrocenylphosphines with aldehydes.392,393 Related condensation reactions of aminoalkylferrocenes with N,N-dimethylformamide dimethylacetal have given phosphinoferrocenyl-amidine ligands.394 New phosphino-imines have also been obtained from o-aminophenyldiphenylphosphine395,396 and also from o-aminomethylphenyldiphenylphosphine.397 New water-soluble phosphine systems have been obtained from the N-poly-ethoxylation of o-aminophenyldiphenylphosphine.398 New chiral 2,2 0 -biphenylyl-P,N-ligands have been prepared by N-acylation of 2-amino-2 0 -diphenylphosphino-biphenyls.399 Amide and ester formation from o- and p-diphenylphosphinobenzoic acids has also been exploited in synthesis. Among new phosphines prepared in this way are a series of simple amido derivatives of non-chiral400 and chiral401 primary amines, a series of glucosamine-based monophosphines,402,403 various tripeptide-linked phosphines,404 and various polystyrene-linked phosphines.405 Further examples of diphosphines linked via amide formation to vicinal-diamines have appeared,406,407 including a polymer-bound system.408 A diamidodiphosphine has also been prepared from 1,8-diaminonaphthalene, and the same report describes the synthesis of the thiol-ester linked system (165).409 Crown ether-tagged phosphines have been prepared by amide formation with 2-aminomethyl-18-crown6, and also by ether-formation involving para-diphenylphosphinophenol and mesylated hydroxymethyl-15-crown-5.410

F Ph2P

F

S

S

PPh2

N

S

OH F (157)

F (158)

PPh2

29

Organophosphorus Chem., 2006, 35, 1–91

Ph2P S

Ph2P N

PPh2

Ph2P

Ph2P (162)

N Ph2P

(159)

N

O

S

S

O

Cl Ar N

(160)

(161)

H N

Ph2P

O

S O

Me P

O RN

(163)

Me

Ph

O

Ph

(164 )R = CH2Ph, CH(Me) Ph(R &S ), Ph or But

The chemistry of hydroxymethylphosphines continues to develop and this has also led to the synthesis of new phosphines. Full details of the synthesis of ferrocenylhydroxymethylphosphines from the reactions of ferrocenyl primary phosphines with aqueous formaldehyde have appeared.411 Mannich reactions between hydroxymethylphosphines and amines have been applied in the synthesis of a variety of new aminomethylphosphines. Included among these are aminomethylphosphine derivatives of adenine,412 the new unsymmetrical phosphine Ph2PCH2NHC6H4PPh2,413 a polymer-bound (N-phosphinoethyl)aminomethylphosphine,414 and water-soluble aminomethyl(ferrocenylmethyl)phosphines.415 Bis(phosphinomethyl)amino systems have also been described, e.g., (166),416 the amphiphilic and water-soluble systems (167),417 and a bis(aminomethylphosphine) derived from 3,4-diaminotoluene.418 The related reactions of bis(hydroxymethyl)organophosphines with primary amines have led to the isolation of new cyclic- and macrocyclic-aminomethylphosphines, e.g., (168).419,420 A new macrocyclic tetraphosphine has also been isolated from the reaction of a disecondary bis(phosphino)propane with formaldehyde and benzylamine.421 The new cage-molecule (169) has been obtained from the reaction of tris(hydroxymethyl)phosphine with hexamethylenetetraamine in the presence of sulfamide and formaldehyde.422 The established reaction of PH3 with pentane-2,4-dione, giving the phospha-adamantane (170), has been re-examined, and procedures developed for alkylation and arylation at phosphorus.423 The one-pot reaction of the azine of 2-carboxybenzaldehyde, phenylphosphine and phthaloyl chloride provides a large-scale route to the chiral diazaphospholane system (171), capable of further elaboration via the carboxylic acid group to give a series of amidophenyldiazaphospholanes.424

30

Organophosphorus Chem., 2006, 35, 1–91

O Ph2P

S

S

PPh2

Ph2P

CH2PPh2 (CH2)n

O

N Ph2P

CH2PPh2

O

H N n

PO3Na2

X (165)

(166) X = e.g., H, CO2H, COMe or hal n = 0 or 1

(167) n = 1-3

Ph

Me

P

H Ph

N

N

O

N

H

Me

Ph Me

P N

PH

O

S O

Me

Me

N O Me

P

O

Ph (168)

(169)

(170)

O N N

COOH P

Ph COOH

O

(171)

2.2 Reactions of Phosphines. – 2.2.1 Nucleophilic Attack at Carbon. The formation of dipolar adducts from the reactions of tertiary phosphines with alkenes and alkynes bearing electron-withdrawing groups attached to the multiple bond, and their subsequent use in synthesis and catalysis, has again proved to be a very active area. A new crystalline adduct, (172), has been isolated from the reaction of tributylphosphine and dimethyl acetylenedicarboxylate, the mechanism involving an unusual rearrangement.425 A common theme in many of the subsequent reactions of the dipolar adducts is protonation by a third reagent, typically an amine or phenol, to generate a vinylphosphonium salt, which then suffers nucleophilic addition to generate a new ylide (173). In some cases, subsequent intramolecular Wittig reactions then ensue, or an elimination reaction occurs in which the original phosphine is regenerated, to give the ﬁnal products. Thus, e.g., new phosphorus ylides have been obtained in excellent yield from the reactions of triphenylphosphine, dimethyl acetylenedicarboxylate and strong NH acids, including pyrroles and

Organophosphorus Chem., 2006, 35, 1–91

31

indoles,426 hydantoins,427 benzimidazoles,428 saccharin,429 triﬂuoroacetamide,430 phthalimide and succinimide.431,432 New ylides have also been isolated from the related reactions of triphenylphosphine, dimethyl acetylenedicarboxylate and primary aromatic amines,433 including various aminophenols,434 2-aminothiophenol,435 and o-phenylenediamine.436 Other NH compounds used to trap the initial dipolar adduct in the triphenylphosphinedimethyl acetylenedicarboxylate system include perimidines,437 and various amides derived from aromatic amines, the latter reactions providing routes to 5-oxo-4,5-dihydro-1H-pyrroles.438,439 Further examples of the trapping of the initial adduct with phenols have also been reported,440 together with the use of this approach for the synthesis of coumarins,441,442 including examples of procedures involving catalysis by silica gel,443 and the use of microwave heating.444 Vinylphosphonium salts have been obtained from the reactions of the initial adducts of tertiary phosphines and acetylene dicarboxylate esters with hydroxycyclopentenones445 and hydroxy-4H-pyranones.446 Related work with b-diketones has given a range of new ylides,447,448 and provided a route to highly functionalised triﬂuoromethylated cyclobutenes.449 Reactions with other carbonyl compounds have also been reported, including those with arylaldehydes,450 and isatin derivatives, which lead to new g-spirolactones.451 In addition to the reactions of tertiary phosphines with acetylene dicarboxylate esters, the related reactions of a variety of other alkynes have also continued to attract attention. These include the reactions of terminal alkynes, usually alkyl propiolates452,453 and ethynyl ketones,454,455 dibenzoylacetylene456,457 (which, in the presence of arylisocyanates yield b-lactam derivatives),458 and a miscellany of other disubstituted alkynes, in which the tertiary phosphine catalyses reactions of the alkyne with other substrates. Thus, e.g., tertiary phosphines catalyse the zipper cyclisation of aliphatic diyne-dione and yne-dione systems,459 the formation of furans from g-acyloxy butynoates,460 [3þ2]-cycloadditions of alkynes with 5-methylenehydantoins461 and methylenecyclohexanones,462 the formation of a-vinylfurans from enynes and aldehydes,463 and the conjugate addition of alcohols to methyl propiolate.464 Metal-promoted reactions of tertiary phosphine-alkyne systems include a highly selective cross [2þ2þ2] cycloaddition of two different monoynes.465 Two consecutive [3þ2]-cycloadditions of the diphosphinoketenimine (174) with acetylenic esters give rise to the bicyclic 1l5,3l5-diphospholes (175).466 The reactivity of tertiary phosphines towards alkenes bearing electron-withdrawing groups has also continued to attract attention. Triphenylphosphine in refluxing methanol reduces maleimides to succinimides in good yield.467 Further studies have been made of charge-transfer complexes between tervalent phosphorus donors and tetracyanoethylene,468 and of the reactions with aryl isocyanates of the 1,3-zwitterion derived from triisopropylphosphine and ethyl 2-cyanoacrylate.469 However, most new work relates to systems in which initial nucleophilic attack by phosphorus at electron-deﬁcient carbon is involved in the catalysis by tertiary phosphines of new bond-forming processes. Included among these are the cyclisation of enones to cyclopentenes and cyclohexenes by tributylphosphine,470 and a related procedure involving co-catalysis by a palladium

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Organophosphorus Chem., 2006, 35, 1–91

complex,471 a phosphine-catalysed a-arylation of enones and enals using hypervalent bismuth reagents,472 a phosphine-mediated [4þ2]-annulation of bis(enones) to form decalins,473 the formation of tetrahydropyridines from a phosphine-catalysed [4þ2]-annulation of ethyl 2-methyl-2,3-butadienoate and N-tosylaldimines,474 the phosphine-catalysed hydration and hydroalkoxylation of activated alkenes,475 and a phosphine-catalysed Knoevenagel condensation of aldehydes with active methylene compounds to form a-cyanoacrylates and a-cyanoacrylonitriles.476 Phosphine-catalysed procedures have also been described for the regiospecific allylic amination and dynamic kinetic resolution of Morita-Baylis-Hillman acetates,477 the conversion of maleic anhydride into acrylate esters,478 the Michael addition of oximes to activated alkenes,479 and aza-Michael reactions of ab-unsaturated compounds with carbamates in the presence of trimethylsilyl chloride.480 Tributylphosphine has been shown to be an effective catalyst for the ring-opening of aziridines and epoxides,481,482 (even under aqueous conditions),483 enabling the development of procedures for the conversion of these substrates to conjugated dienes.484 Further synthetic applications of the tributylphosphine-carbon disulﬁde adduct have appeared, providing routes to 4-phosphonyl-1,3-dithioles, 1,3-dithiolanes,485 and 1,3, 4-thiazolidine-2-thiones.486 The reactions of tributylphosphine with triﬂuorovinyl(perﬂuoroalkyl) ethers lead to displacement of ﬂuorine from the triﬂuorovinyl group with the formation of phosphonium salts, the subsequent reactions of which were studied.487 A detailed study of the quaternisation of phosphines and amines with iodoethane in aliphatic alcohols has also been described.488 O MeO

CO2Me

Z H

Bu3P

R2O2C

CO2Me

MeO2C

PR13 CO2R2

(173) R1 = alkyl or aryl; R2 = alkyl; Z = e.g., OAr or NR2

(172)

Ph

Ph2P C

C

Ph

NPh R1

Ph2P (174)

NPh

P

R2

P Ph

R1 Ph R2

(175) R1 = H, R2 = CO2Me; R1 = CO2Me, R2 = H; R1, R2 = CO2Me

2.2.2 Nucleophilic Attack at Halogen. This ﬁeld of activity continues to be dominated by applications of well-known phosphine-positive halogen combinations. Alcohols can be oxidised to the related aldehydes and ketones under mild conditions by the DMSO-Ph3PX2 system, which provides an alternative to the Swern oxidation.489 The triphenylphosphine-iodine system has been

Organophosphorus Chem., 2006, 35, 1–91

33

shown to be an efﬁcient reagent for the regioselective dehydration of tertiary alcohols.490 The Ph3P-CCl4-Et3N system has been used for the SN2-cyclisation of N-Boc-b-aminoalcohols to anti-2-oxazolidinones491 and in a new approach for the synthesis of ureas from primary amines.492 Triphenylphosphine-CX4 reagents, (X¼Cl or Br), have been shown to promote the cyclisation of N-acylated a-aminonitriles to 2,4-disubstituted 5-halo-1H-imidazoles in good yield.493 Combination of a perﬂuoroalkoxy-substituted triarylphosphine with CBr4 provides a reagent system which converts alcohols to the related bromoalkanes in good yield, the ﬂuorous phosphine oxide being readily separated by liquid-liquid extraction, and subsequently reduced and recycled.494 The reaction of the Ph3P-CBr4 system with 2-O-benzyl-1-hydroxy sugars generates a glycosyl bromide in situ, which couples with an acceptor alcohol in the presence of N,N-tetramethylurea or DMF to give an a-glycosyl product in excellent yield. It is suggested that the reagent system plays a multiple role in the reaction sequence, facilitating generation of the glycosyl donor, activation of glycosylation and removal of water.495,496 Addition of diethylzinc to the triphenylphosphine-tribromoﬂuoromethane system leads to improvements in the generation of the ylide Ph3P¼CBrF, and its subsequent Wittig reactions with carbonyl compounds in the synthesis of bromoﬂuoroalkenes.497 The triphenylphosphine-trichloroacetonitrile system has been used as a reagent for the N-acylation of polymer-supported benzylamines498 and in a general procedure for the preparation of esters from carboxylic acids.499 The reaction of triphenylphosphine with bis(trichloromethyl) carbonate provides a reagent system that converts thiols into the related disulfides.500 Triphenylphosphine-N-halosuccinimide systems have found use in the synthesis of a-diazoketones from acyloxyphosphonium salts and diazomethane501 and for highly regioselective deoxyhalogenations at the C-6 positions of N-phthaloylchitosan.502 Tertiary phosphine-DDQ systems, (DDQ¼2,3-dichloro-5,6-dicyano-1,4-benzoquinone), have also generated some interest. A series of ferrocenylphosphines has been shown to form 1:1 adducts with DDQ which appear to be radical cation-radical anion salts in which oxidation has occurred at phosphorus, the electron being transferred to DDQ to form the radical anion DDQd.503 The triphenylphosphineDDQ combination, in the presence of halide, cyanide or azide ions, has been shown to be a new, selective and neutral system for the facile conversion of alcohols, thiols, selenols and trimethylsilyl ethers to alkyl-halides, -cyanides,504,505 and -azides.506 This system, in the presence of appropriate tetraalkylammonium salts, has also been used for the conversion of diethyl a-hydroxyphosphonates to the related a-halo-, a-azido- and a-thiocyanatophosphonates.507,508

2.2.3 Nucleophilic Attack at Other Atoms. A highly efﬁcient general synthesis of secondary- and tertiary- phosphine-borane adducts is afforded by treatment of the phosphine with sodium borohydride in the presence of acetic acid in THF. Any carbonyl groups present in the phosphine undergo concomitant

34

Organophosphorus Chem., 2006, 35, 1–91

reduction.509 Treatment of the trimethylamine-carbomethoxyborane adduct with triphenylphosphine in monoglyme gave the corresponding phosphine-carbomethoxyborane adduct in good yield, a structural study showing unambiguously that the phosphorus atom coordinates to boron, the ester group being unaffected.510 Various tertiary phosphine-cyanoborane adducts have been prepared by ligand exchange from trimethylamine-cyanoborane, and also by treatment of the phosphine hydrochloride with sodium cyanoborohydride.511 A trimethylphosphine adduct of a ﬂuorous organoborane has been characterised, and shown to suffer displacement of the phosphine on treatment with dimethylaminopyridine or piperidine at room temperature. The adduct is stable to trimethylamine.512 Trimethylphosphine has also been shown to form P–B adducts with methyl(methylidene)boranes, MeB¼CR2.513 Phosphine-borane adducts have been used as P-protecting systems in the synthesis of the chiral diphosphetanyl (176).514 The use of borane-protection in the synthesis of P-chiral phosphines has been reviewed,515 and two groups have reported the enzymatic resolution of hydroxyalkylphosphine-borane adducts.516,517 The efﬁciency of a range of amines, and other reagents, for the deprotection of phosphine-borane adducts has been compared, with speciﬁc reference to the use of monoethanolamine, diethanolamine and tetrabutylammonium cyanide.518 The intramolecular hydroboration of borane adducts of unsaturated phosphines has been studied.519 Heterodehydrocoupling of borane adducts of primary and secondary phosphines leads to the formation of new P–B bonds and offers a route to phosphinoborane rings, chains, and high molecular weight polymers. Further studies of the catalysis of these reactions by rhodium complexes have now been reported520 and tris(pentaﬂuorophenyl)borane has been shown to catalyse the dehydrocoupling of the PhPH2-BH3 adduct to form a P–B polymeric system.521 The reactivity of closo- and nido-carboranylmonophosphines towards BH3 THF (and also to oxygen and sulfur) has been compared, the nido-carboranyl substituent conferring a greater electron donor character on the phosphino group.522 The chemistry of the phosphacarboranes, in which one (or more) phosphorus atoms are members of the cage structure, together with boron and carbon, has also continued to attract attention. Further studies of the reactivity of the cage-phosphorus atoms in such systems have been reported, including reactions with BH3 THF, O2, and S8, and also with transition metal acceptors.523,524 The crystal structure of the low temperature polymorph of the tetramethyldiphosphine-bis(monoborane) adduct has been determined, providing an insight into the stabilisation of different rotational isomers in the solid state.525 The structure of the trimethylphosphine-gallane adduct has been determined by a gas-phase electron-diffraction study526 and the structures of a series of tertiary -phosphine, -arsine and -stibine adducts of trialkylgallium acceptors have been compared.527 The reactivity of secondary phosphines towards gallium(I) iodide has also been studied.528

Organophosphorus Chem., 2006, 35, 1–91

35

A relatively stable phosphadioxirane (177), having d31P¼48.3 ppm, has been obtained from the reaction of the sterically hindered tris (o-methoxyphenyl)phosphine with singlet oxygen at 801C. Oleﬁn-trapping experiments show that the phosphadioxirane can undergo non-radical oxygen atom-transfer reactions to form epoxides and the phosphine oxide. With protic solvents, the phosphine oxide is again formed, via a hydroxyphosphorane intermediate. At room temperature, the phosphadioxirane rearranges to form the phosphinate ester (178).529 Triphenylphosphine inserts into the peroxide bond of 1,2-dioxines, leading to ring-contraction products, with loss of triphenylphosphine oxide.530 Hydroperoxysultams have been shown to act as chemoselective electrophilic oxidants for phosphines and other oxidisable heteroatom compounds.531 In contrast to the reduction of hydroperoxides by a phosphine, in which initial nucleophilic attack occurs at the hydroxylic oxygen, the related reactions of sterically hindered arene-sulfenic and -selenic acids, ArSOH and ArSeOH, respectively, involve initial attack at sulfur or selenium to give an organothio- or organoseleno-phosphonium hydroxide, which subsequently decomposes to form the phosphine oxide, together with the thiol or selenol.532 Cyclic selenoxides having an optically active binaphthyl skeleton act as reagents for the enantioselective oxidation of phosphines to the corresponding phosphine oxides.533 The kinetics and mechanism of oxygen transfer from methylphenylsulfoxide to triarylphosphines in the presence of an oxorhenium(V) complex have been studied.534 Tertiary phosphines are cleanly and quantitatively converted into the corresponding phosphine oxides on exposure to dry air or dioxygen in dichloromethane solution in the presence of catalytic amounts of tin(IV) iodide.535 Further examples of transition metal-promoted oxidation of arylphosphines have also been reported.536 Treatment of the iminodiphosphine (o-CN)C6H4N¼P(Ph2)–PPh2 with dioxygen, hydrogen peroxide or sulfur, results in cleavage of the P–P bond.537 The dithianylphosphines (179), in which the diphenylphosphino group is equatorial, undergo air oxidation with cleavage of the dithiane ring to form the open chain thioesters (180). The related axial phosphino systems do not behave in this way, possibly due to steric hindrance of axial attack by molecular oxygen.538 Tris(2-carboxyethyl)phosphine has been used to cleave disulﬁde bridges in spider venom proteins, prior to protein sequencing by mass spectrometry.539 The tributylphosphine-diphenyldisulﬁde combination has been found to promote a one-step, enantiospecific transformation of cyclic ﬁve-membered 1,2-diols into their respective 1,2-bis(phenylsulfanyl) derivatives.540 A tributylphosphine-2-pyridylthioester combination has found use for acylative end-capping of pseudorotaxane systems.541 Treatment of 4, 5-dihydroxy-1,2-dithianes with tertiary phosphines results in a stereospecific rearrangement to form 4-hydroxy-3-mercaptotetrahydrothiophenes, via an initial disulﬁde-cleavage reaction.542 A tributylphosphine-promoted seleniumselenium cleavage step is involved in the rearrangement of the heterocyclic P,Se system (181) to give (182).543

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Organophosphorus Chem., 2006, 35, 1–91

MeO

P

O

O

P

P

Ar3P

ArO O MeO

(176)

(177) Ar = o-MeOC6H4

(178) Ar = o-MeOC6H4

O

R S

S

PPh2

R S

S

PPh2 O

(180) R = Me or Ph

(179) R = Me or Ph

Se Se P Ph

Se P

EtO2C

Ph Se

Se

P P

Ph

Se P

Ph

Ph (181)

N Se

(182)

N

Ph2P

OEt

t

Bu Me2SiO (183)

Reactions involving nucleophilic attack at nitrogen have also continued to attract attention, particularly so in the case of the Mitsunobu and Staudinger procedures. For both of these reactions, many routine synthetic applications have appeared over the past two years which are not noted here unless some novel aspect of the system is also apparent. In conventional Mitsunobu procedures involving the reaction of an alcohol with a carboxylic acid in the presence of the triphenylphosphine-diethyl azodicarboxylate combination, it has been assumed for a long time that the reaction proceeds directly to an alkoxyphosphonium salt which then reacts with the carboxylate anion to form triphenylphosphine oxide and the ester, with inversion of conﬁguration in the original alcohol. However, various experimental observations in recent years have indicated that acylphosphonium intermediates may also be involved under some conditions and lead to products in which the conﬁguration of the original alcohol is retained, via direct nucleophilic attack of the alcohol at the carbonyl carbon of the acyloxyphosphonium salt. It has now been shown that when benzoyloxyphosphonium cations are generated directly from the reaction of a tertiary phosphine with benzoyl peroxide (from which an alkoxyphosphonium cation cannot arise directly), subsequent reactions with an alcohol in the absence of a basic species result in formation

Organophosphorus Chem., 2006, 35, 1–91

37

of the ester with retention of conﬁguration. In the presence of a base, e.g., the hydrazide anion in a conventional Mitsunobu reaction, the inverted conﬁguration product is formed predominantly via an alkoxyphosphonium cation. The latter route arises as a result of a base-induced cross-over in which the acyloxy salt is converted into the alkoxy salt. These results show that the nature of any basic species present or generated in the reaction can have a profound effect on the stereochemistry of esteriﬁcation using Mitsunobu or related procedures.544 In N-alkylation reactions promoted by tertiary phosphine-azoester reagents, it has been shown that use of a phosphine more bulky than trimethylphosphine gives a high intramolecular selectivity between primary and secondary alcohol groups. Thus, trimethylphosphine is the only phosphine that enables alkylation of 2-nitrobenzenesulfonamides with a wide range of secondary alcohols, whereas tributylphosphine is selective for primary alcohol groups.545 Selective monoalkylation of dihydroxycoumarins via Mitsunobu dehydroalkylation has been achieved under high intensity ultrasound conditions.546 In the absence of a proton source, silylphosphines react with diethyl azodicarboxylate to form the adduct (183). However, when the above reagents are combined in the presence of an alcohol and a proton source such as pyridinium p-toluenesulfonate, the above adduct is not formed, the reagent system providing a source of a silyl cation which readily converts the alcohol into a silyl ether in good yield.547 Treatment of pentaﬂuorophenyldiphenylphosphine with azodicarboxylic acid dimorpholide results in the formation of the phosphine oxide (184), via initial nucleophilic attack at azo nitrogen, followed by intramolecular displacement of ﬂuorine by the hydrazide anion and hydrolysis of an intermediate ﬂuorophosphorane.548 Practical improvents to Mitsunobu procedures continue to appear. A chromatography-free procedure is afforded by the use of a combination of an anthracenetagged phosphine (185) and a polymer-supported azodicarboxylate. The anthracene-tagged phosphine allows for removal of the phosphinephosphine oxide by sequestration through a chemoselective Diels–Alder reaction with a maleimide resin. The polymer-bound azoester facilitates the removal of excess alcohol, reagent, and byproducts by ﬁltration. The pure products are obtained after the ﬁltration by a concentration step.549 A stereoselective carbon-carbon bond-forming procedure is afforded by Mitsunobu-promoted displacement of chiral secondary benzylic alcohols with triethyl methanetricarboxylate, the reactions proceeding in good yield and with a high degree of inversion. Subsequent saponiﬁcation and decarboxylation of the products provides chiral 3-aryl-3-substituted propanoic acids without racemisation.550 The betaine (186) has been used in a modiﬁed Mitsunobu procedure with 1,2,4-dithiazolidine-3,5dione as the source of the nucleophile in reactions with alcohols to give the related N-alkyldithiazolidinones, which are easily transformed into amine derivatives under very mild conditions.551 N-protected amines have also been obtained via conventional Mitsunobu routes involving bis(btrimethylsilylethanesulfonyl)imide as the nucleophile source.552

38

Organophosphorus Chem., 2006, 35, 1–91 F

F

F

HN O

N

N

O

O N O

(184)

Ph3P

X

N

N

P O

O S

Ph Ph

O

O

F

Ph2P

(185) X = O or NH

(186)

The Staudinger reaction of phosphines with azides to form aza-ylides, R3P¼NR, has found widespread use in synthetic organic chemistry. However, in recent years, the potential of the reaction as a highly chemoselective ligation method in chemical biology for the synthesis of bioconjugates has started to be recognised, the reaction being applicable even in living cells. Developments in this area have now been reviewed.553 The coumarinylphosphine (187) has been developed as a detectable marker system for use in Staudinger ligation reactions. When treated with an azide-functionalised biomolecule, it is converted to the amidoarylphosphine oxide (188), which, unlike the starting phosphine, is intensely ﬂuorescent, enabling the ligation product (188) to be readily distinguished from excess primary detection reagent.554 Among other C-functionalised arylphosphines used in Staudinger ligation chemistry are (189, X¼CONHR) (which, on treatment with arylazides form phosphine oxides bearing an ortho-O-alkyl imidate group rather than the anticipated orthoamido group),555,556 and (189, X¼COOH). The latter can be bound to an amino-functional sensor chip surface via the carboxylic acid group, and then used in a Staudinger procedure to immobilize an azidoglycoside on the chip.557 Various O-acyl derivatives of ortho-diphenylphosphinophenol,558,559 and mercaptomethyldiphenylphosphine560 have also been used in Staudinger ligation reactions, the latter reagent also being applied in a new synthesis of mediumsized lactams.561 These have also been prepared via a similar approach involving the reaction of tributylphosphine with pentaﬂuorophenyl esters of o-azidoalkanoic acids.562 The reaction of trimethylphosphine with azidopeptides is the basis of an alternative strategy for the synthesis of peptide nucleic acids.563 Staudinger ligation chemistry has also been used for probing glycosyltransferase activities.564 The mechanism of the Staudinger reaction continues to attract attention. Details of the initial approach of the phosphine to the azido group have been probed using density functional theory.565 Isocyanates and thiocyanates have been shown to trap E-phosphazide intermediates (190) in the Staudinger reaction of triphenylphosphine with azides, to form hydantoins and thiohydantoins, respectively, and this approach has found use in the synthesis of analogues of a pyrrole-imidazole marine alkaloid.566 In addition to the chemical biology applications noted above, the Staudinger reaction continues to be applied widely in general synthetic chemistry.

39

Organophosphorus Chem., 2006, 35, 1–91

Tris(2-carboxyethyl)phosphine has found use for the reduction of azides to amines (and also for deoxygenation of sulfoxides, sulfones, and sulfonyl chlorides).567 Azides can also be reduced to amines with good regioselectivity by a modiﬁcation of the Staudinger reaction using trimethylphosphine at low temperatures.568 The reaction of triarylphosphines with alkylazides and thiocarboxylic acids provides a new approach to the synthesis of amides.569 Polymer-bound triarylphosphines have been used in Staudinger-based routes to aziridines570,571 and in reactions with azidocyclodextrins.572 The Staudinger reaction has found further application in the synthesis of phosphorus-functional dendrimers573,574 and work in this area has also been reviewed.575 An interesting new approach to unsymmetrical binol-derived bidentate P,N-ligands is afforded by the reaction of the phosphino-nonaflate (191) with an azide, which proceeds with intramolecular nucleophilic displacement of the nonaflate group by the nitrogen of the intermediate aza-ylide to give, after hydrolysis, the aminoarylphosphine oxide (192), subsequently reduced to the related phosphine with phenylsilane.576 Further examples of linked Staudingeraza-Wittig synthetic schemes have also appeared,577,578 including the ﬁrst example of such reactions involving a non-cumulated sulfoxy group.579 The Staudinger reaction has also been used in the synthesis of new mixed donor ligands for use in catalysis, including (193),580 a series of pyridine- and imidazole-phospha-aza-ylides, e.g., (194)581 and the crowded system (195).582 The reaction of metal-coordinated 2-(azidomethyl)phenyl isocyanide with triphenylphosphine has given cationic carbene complexes, via intramolecular attack of the intermediate aza-ylide nitrogen at the carbon of the isocyanide group.583 Nucleophilic attack of phosphorus at nitrogen is also involved in the reactions of a-phosphino-zirconocene complexes with diazoalkenes, giving dipolar adducts, e.g., (196).584

Ph

P

P

N

O

N

O

O

O

(188)

(187)

MeO N

X N

O Ph2P (189)

Ph CONHAr

O

CO2Me

N

Ph3P (190)

R

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Organophosphorus Chem., 2006, 35, 1–91

PPh2

O PPh2

ONf

NHR

Ph2P

PPh2 N

P O

(191)

(192)

OR OR

(193) R = Et or Ph Pri

Ph R3

Ph

NH

P N R

Pri

N

N P

1

PPh2 Zr Cp N Cp N

Mes Ph

Ph R2

R

(194)

(196)

(195)

Reports of nucleophilic attack at atoms other than those above have also appeared. A kinetic study has compared the effectiveness of tertiary phosphines and phosphite esters in the catalysis of the cleavage of the silicon-silicon bond of methylchlorodisilanes, providing evidence for the involvement of a stabilised silylene intermediate.585 The anion of the g-phosphino-b-diketimine (197) has been shown to react with arsenic trichloride to give the phosphinoarsino-b-diketimine (198), in which there is a coordinative link from phosphorus to arsenic.586

Pri

Pri

NH

N

Pri

Pri PPh2 (197)

Pri

Pri

NH

N

i

Pri

Pr

Cl2As

PPh2 (198)

2.2.4 Miscellaneous Reactions of Phosphines. The effects of substituents at phosphorus on the basicity and donor properties of phosphines have continued to attract the attention of the theoretical chemists. Among recent papers are a quantum chemical study of the protonation of phenylphosphine and its

Organophosphorus Chem., 2006, 35, 1–91

41

halogenated derivatives,587 a discussion as to whether allylphosphine is a carbon or a phosphorus base in the gas phase,588 the relative merits of QSAR and QALE correlations in assessing donor properties of tervalent P systems589 and a new assessment of the stereoelectronic proﬁle of phosphine and phosphite ligands.590 Trimethylphosphine has been used to probe the acid sites in a dealuminated nanosized zeolite using 31P CP/MAS NMR and other NMR techniques.591 Gas-phase electron diffraction and quantum chemical calculations have been used to probe the molecular structure of phenylphosphine and its analogues,592 and also that of bis(trichlorosilyl) t-butylphosphine593 A review has appeared of the experimental and theoretical thermochemistry of primary and secondary phosphines, and other P–H compounds594 and the limitations of theoretical methods for estimating enthalpies of vaporisation of tervalent phosphorus compounds have been considered.595 Theoretical methods have also been used to probe P–P bond energies and homolytic dissociation enthalpies of tetraalkyldiphosphines.596 Magnetic ﬁeld effects on the photodissociation reactions of triarylphosphines in solution, giving diarylphosphanyl radicals, have been studied.597 The reactivity of radical cations derived from the anodic oxidation of trimesitylphosphine has also been investigated.598 The reactivity of phosphinometallocene systems has continued to attract interest. Heats of protonation of 1,1 0 -bis(diphenylphosphino)ferrocene and -ruthenocene have been determined by titration calorimetry using triﬂic acid in 1,2-dichloroethane. The basicity of these phosphines is lower than that of other bidentate phosphines as a result of the p-acceptor character of the metallocene cyclopentadienyl rings.599 The electrochemistry of a series of ferrocenylmethylphosphines, FcCH2PR2 (R¼Ph, CH2OH and CH2CH2CN), (and their simple oxidised derivatives), has been investigated.600 The mechanism of the facile meso to rac isomerization of the bis-planar chiral bis(phosphinoindenyl)iron (199) has been shown to proceed via a ring-ﬂipping process.601 Lithiation of 1-bromo-1 0 diphenylphosphinoferrocene, followed by addition of bis(trimethylsilyl) peroxide and subsequent in situ hydrolysis of the silylether, has given the ﬁrst structurally characterised hydroxyferrocenylphosphine (200).602 The reactions of the phosphinomethylferrocenyl aldehydes (201, X¼O) with primary amines have given a series of new chiral iminoferrocenylmethylphosphines (201, X¼NR).603 Ultraviolet photolysis of the metallosilylphosphines (202) results in the formation of the phosphasilaferracyclopropanes (203) that undergo a variety of reactions, including the insertion of small molecules into the three-membered ring to give new heterocyclic systems.604 Treatment of the phospholanozirconaindane (204) with the aza-ylide Cl3P¼NBut results in the formation of the heterocyclic system (205), the reactivity of which has been explored.605 The reactivity of the phosphinoazazirconaindenes (206) towards heterocumulenes, involving additions to the zirconium-nitrogen bond, has also been studied.606

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Organophosphorus Chem., 2006, 35, 1–91

Ph2P PPh2 Fe

Fe

PAr2

Fe

PPh2

X

OH

(200)

(199)

R

(201) Ar = Ph or 3,5-(CF3)2C6H3 R

R

Fe

Fe OC

CO

R

R

R

R

R

OC

SiMe2PPh2

PPh2 Si Me2

(203) R= H or Me

(202) R = H or Me

PR2 PPh

PPh Zr Ph2 (204)

P t

Bu N (205)

ZrPh2Cl

N Zr Ph2 (206)

The use of tertiary phosphines as ligands in a variety of metal ion-catalysed organic reactions has been reviewed.607 A review of the ligand properties of 2pyridylphosphines has also appeared.608 Combinations of triphenylphosphine with aluminium tribromide609 and titanium tetrachloride610 have found use as reagents for the reduction of 1,2-dicarbonyl compounds and reductive Claisentype condensations, respectively. The application of phosphine ligands in homogeneous and related supported catalyst systems continues to generate much interest. Homogeneous catalyst systems based on water-soluble phosphines have been reviewed.611 A procedure for the selective preparation of tri-, di-, and mono-sulfonated triarylphosphines has been developed, based on a low temperature sulfonation of arylphosphines bearing a range of simple electrondonating substituents, e.g., Me or OMe.612 Salts of phosphinoarylsulfonates with guanidinium613 and chiral quaternary ammonium cations have been characterised.614 The cage-opening reaction of the triazaphosphaadamantane (207) with acetic anhydride to give the water-soluble phosphine (208) has been revisited, the latter (and its oxide) having now been fully characterised both in

43

Organophosphorus Chem., 2006, 35, 1–91

solution and in the solid state. The phosphine has a molar solubility in water of 7.4 M, some four times the solubility of the triply sulfonated triphenylphosphine.615 A series of o-phosphinoalkylsulphonic acid salts, e.g., Ph2P(CH2)2S(CH2)nSO3Na (n¼2 or 3) also have high aqueous solubilities and are effective ligands in rhodium-catalysed hydroformylation reactions.616 The drive for improved phosphine ligand-based catalyst systems has prompted work on the development of dendrimeric phosphines,617,618 ionic liquid-soluble chiral diphosphines bearing imidazolium groups,619 and BINAP-based chiral porous solids.620 The reactions of tris(3-hydroxypropyl)phosphine with diisocyanatohexane have given a series of oligomeric phosphines for luminescent and stable nanocrystal quantum dots.621 The reactions of p-hydroxyphenylphosphine and various substituted arylbis(hydroxymethyl)phosphines with heterocumulenes have also been explored.622 Borane reduction of the carbonyl group of o-diphenylphosphino(N-2-hydroxyethyl)benzamide has given the related N-functionalised o-diphenylphosphinobenzylamine, from which new rhenium complexes have been prepared.623 A new route to optically active phosphapalladocycles is afforded by the asymmetric exchange of enantiopure cyclopalladated chiral amines with prochiral phosphines.624 The in-out isomerism of phosphorus bridgehead cage compounds has been reviewed.625 New phosphorus cage compounds have been isolated from the reactions of tetra-t-butyltetraphosphacubane with water in the presence of gallium(I) iodide.626 The transformation of the stannylphosphine P(SnMe3)3 into the P-Sn cage system P4(SnMe2)6 has also been studied.627 The reactions of the phosphines Me3MPMe2 (M¼Si or Sn) with ﬂuoroarenes, which proceed with displacement of ﬂuorine and introduction of the Me2P moiety, have now been applied to p-complexed ﬂuoroarenes628 and various ﬂuoroquinolines.629 A new nickel-catalysed coupling reaction between phosphines of the type Ph2PCF2Br with the silylphosphines R2PSiMe3 provides a route to the unsymmetrical diﬂuoromethylene-bridged diphosphines Ph2PCF2PR2.630 Ph P

P P N

N

MeCO N

N N

N (207)

(208)

COMe (209)

The conversion of free and Cr(CO)5-complexed 2-vinylphosphiranes into 3-phospholenes has now been studied using density functional theory. It is concluded that this rearrangement has much in common with the vinylcyclopropane-cyclopentene rearrangement, a pericyclic [1,3]-sigmatropic shift

44

Organophosphorus Chem., 2006, 35, 1–91

mechanism being implicated.631 Theoretical and spectroscopic techniques have also been applied to the ability of the phosphirane ring in the fused system (209) to ‘walk’ around the cyclooctatrienyl ring system.632 The nucleophilicity of tertiary phosphines has been compared to that of diaminocarbenes and related compounds in a series of Cr(CO)5 complexes, using theoretical methods.633 The reactivity of phosphinocarbenes has continued to attract attention. Bertrand’s group has explored the effects of alkyl and aryl substituents at the carbene carbon on the stability of the (phosphino)(aryl)carbenes (210),634,635 including studies of ground and excited state reactions.636 Reactions of (phosphino)(amino)carbenes (211, X¼NPri2),637 and (phosphino) (silyl)carbenes (211, X¼Me3Si) have also been studied by this group. The work on (phosphino)(silyl)carbenes includes a comparison of their reactions with aliphatic and aromatic aldehydes, giving phosphanyloxiranes and other products,638,639 and a reaction with dimethyl cyanamide to give the azaphosphete (212), via the transient formation of nitrile, keteneimine and 1-aza4l3-phosphabutadiene intermediates.640 Further work has also appeared on the reactions of diphosphanylcarbenes (211, X¼R2P).641,642 New supramolecular strategies have appeared for the assembly of bidentate phosphine ligands. Thus, 6-phosphino-substituted 2-pyridones self-assemble in the presence of a metal ion to give the hydrogen-bonded diphosphine (213),643 and zinc-complexed tetraarylporphyrins bearing a single diorganophosphito substituent in one of the aryl groups assemble with a series of pyridylphosphines via coordination of the pyridine nitrogen to the zinc atom, giving new, unsymmetrical bidentate P-P 0 ligand systems.644 The tetraphosphine ligand (214) has been separated into its meso and racemic forms, each of which has been converted into the related tetrasulﬁde.645 Reviews have appeared of the use of achiral and meso ligands to convey asymmetry in enantioselective catalysis646 and of the asymmetric synthesis of functionalised phosphines containing stereogenic phosphorus centres, largely via cycloaddition reactions of functionalised vinyl compounds with simple phospholes coordinated to chiral palladium complexes.647 Further evidence as to the non-existence of N-P donor-acceptor interactions in peri-(8-dialkylamino)(1-diphenylphosphino)naphthalenes has been presented.648,649 Tetraphenyldiphosphine is formed in the reaction of diphenylphosphine with indium(III) tris(cyclopentadienide).650 The reactions of tri(2-thienyl)phosphine with hexachloroethane, 2-bromothiophene (in the presence of nickel(II) bromide), and ‘chloramine T’ have given, respectively, chlorotri(2-thienyl)phosphonium chloride, tetra(2-thienyl)phosphonium bromide, and the tosyliminophosphorane (215, X¼S). Attempts to generate the homoleptic penta(2-thienyl)phosphorane by the reactions of these intermediates with 2-thienyllithium were unsuccessful. A similar lack of success attended the reaction of the related 2-furyl system (215, X¼O) with 2-furyllithium. The corresponding penta(2-furyl- and 2-thienyl)-arsoranes were, however, obtained from the related tosyliminoarsoranes.651

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Organophosphorus Chem., 2006, 35, 1–91

R

SiMe3 P

(Pri2N)2P

C

R2P

R

C

X Me2N

(210) R = Me, But, Mes or 2,6-(CF3)2C6H3

Ph2P

N

O

H H Ph2P

N

(213)

3

(211) R =

Ph P

But or

R

(212) R = Cy2N

R2N

O

Ph P

Ph2P

N

PPh2

P X

3

N

S O

O

(214)

(215)

pp-Bonded Phosphorus Compounds

Two major reviews of this area have appeared, one covering the chemistry of stable radicals derived from pp-bonded phosphorus compounds652 and a more general overview of the area and its possible future direction.653 The chemistry of ﬂuorine-containg phospha- and arsa-alkenes has also been reviewed.654 Among new contributions from the theoretical chemistry community are a quantum chemical study and vibrational analysis of compounds containing carbon-phosphorus multiple bonds,655 an investigation of one-bond phosphorus-phosphorus indirect nuclear spin–spin coupling tensors using density functional theory,656 and estimates of the E¼C s- and p- bond energies for E¼C, Si, Ge and P.657 Density functional theory has been applied to gain an understanding of the gas-phase formation of the pp-bonded, neutral hexaphosphorus species P6, from Cp*2P6.658 The use of bulky groups for the kinetic stabilisation of diphosphenes and phosphaalkenes has seen further development, examples of new stable systems including the metacyclophanes (216),659 the diphosphenes (217),660 (218),661 (219),662(220)663 and (221), together with related phosphaalkenes.664,665 A diphosphene having two silyl substituents has been isolated from the reaction of a silyldichlorophosphine with sodium.666 Studies of the reactivity of diphosphenes towards transition metal ions have continued. The reactions of bis(supermesityl)diphosphene and the bis(perﬂuoroalkylaryl)diphosphene (222) with a ruthenium carbonyl complex have been studied.667,668 Diphenyldiphosphene, coordinated to a tungsten carbonyl acceptor, has been shown to undergo addition of N,N-dimethylcyanamide to the P¼P bond.669

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Organophosphorus Chem., 2006, 35, 1–91

Treatment of the diphosphenium salt (223) with lithium diisopropylamide results in a high yield conversion into the diphosphirane (224), alkylation of which gives a diphosphiranium salt.670 EPR techniques have been used to study the products of sodium reduction of the bis(diphosphene) (225) and related phosphaalkenes.671

Mes X P Me Me

P

Me Me

(216) X = PMes* or C

P

R

Mes (217) R = Mes* or Ph

PMes*

Ar2N

Tip P

Tip

R1

R1

Tip

P

P

R2

P R1

R2 Tip

R1

NAr2

Pri Pri

(218) Tip =

Ar = p-Me2NC6H4

(219) R1 = CH(SiMe3)2; R2 = CH(SiMe3)2 or C(SiMe3)3

Pri

Ar

CF3

OMe Ar P

P P

P

CF3

CF3

P P

CF3

CF3

Ar Ar

(220) Ar = o-MeOC6H4

MeO

CF3

(221)

(222)

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Organophosphorus Chem., 2006, 35, 1–91

CF3SO3

Mes* P

P

Me

Mes*

P

(223)

Mes

Ar

Ar

P P Mes

Mes P

Ar

Ar

P Mes

(225) Ar = p-ButC6H4

P

Mes*

Mes*

(224)

Mes Me

Ar

Ar

P P Mes

Mes P

Ar

Ar

P

Me

Mes

(226)

The synthesis of conjugated polymers of the poly(p-phenylenevinylene) type involving diphosphene and phosphaalkene units in the polymer backbone has started to attract interest. Routes to oligomeric systems, e.g., (226),672 and related polymeric systems,673,674 including a ﬂuorescent poly(p-phenylenephosphaalkene) system675 have been developed. A convenient route to the new isolable phosphaalkenes (227) is afforded by the base-induced rearrangement of secondary vinylphosphines.676 Subtle differences have been noted in the ability of the 2,4,6-tri-t-butylphenyl and 2,4-di-t-butyl-6-methylphenyl groups to stabilise the P¼C bond of various diphosphaalkenes of the type (228).677 Routes to a series of diphosphathienoquinones (229)678 and the Pmetallophosphaalkene (230) (together with the corresponding arsa-and stibaalkenes)679 have also been developed. New P¼C bonded cage isomers derived from hexaphospha-pentaprismane, P6C4tBu4 have been obtained by uv-irradiation or protonation of the parent system680 and the stability of a C2vsymmetric P¼C bonded tetraphosphabarbaralane system has been assessed by theoretical methods.681 Studies of the reactivity of phosphaalkene systems have also continued to attract attention. An ab-initio study of the Diels-Alder addition of phosphaethene with 1,3-dienes reveals asynchronous transition structures, with activation energies that are lower than that of the parent ethene-butadiene reaction, even though these reactions have similar exothermicities.682 The substituent effect of the phosphaalkenyl group has been assessed in the series (231) by analysis of linear free energy relationships which indicate that the (E)-Mes*P¼CH group is a weak electron donor with a predominantly inductive effect on the linked benzene ring. In this respect, the P¼C bond is remarkably similar to the C¼C bond.683 Experimental and theoretical studies on the conjugation of the P¼C bond with a cyclopropyl group also indicate great similarity between P¼C and C¼C bonds.684 Further studies of

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Organophosphorus Chem., 2006, 35, 1–91

the reactivity of the phosphaalkenes RP¼C(NMe2)2, having inverted polarisation of the P¼C bond, have also appeared.685,686 The ﬁrst polymerisation of a phosphaalkene under either free radical or anionic initiation to give a poly(methylenephosphine) has been reported.687 Phosphaalkenes have been shown to trap dichlorosilylene (liberated from trichlorosilyltrimethylgermane) by double addition to the P¼C bond to form 2-phospha1,3-diseletanes (232),688 and reactions of this type have also been reviewed.689 Considerable interest has been shown in the chemistry of 2-phosphaalkenyllithium and -Grignard reagents. A theoretical study of these compounds has addressed factors affecting their E-Z ratio.690 Phosphaalkenyllithium reagents have been used in the synthesis of the 1,4-diphosphafulvene (233) via the dimerisation of an intermediate 1-phosphaallene691 The methanesulfanylfunctionalised reagent (234) undergoes oxidative coupling with copper(II) chloride and oxygen to form the 1,4-diphosphabutadiene (235).692 Lithiation of the 2-bromo-1-phosphaalkene (236) results in an isomerisation to give the phospha-2-propenyllithium reagent (237), subsequently transformed into the bis(phosphaalkene) (238) by copper(II)-mediated coupling.693 A similar pattern of reactivity is shown by the corresponding phosphaalkenyl Grignard reagents. With aldehydes, b-phosphaallylic alcohols, e.g., (239), are formed, and their reactivity has also been explored.694 New phosphaalkenes and new heterocyclic and cage compounds have been isolated from the reactions of phosphaalkenyl Grignard reagents with halides of main groups 13,14 and 15695,696 and also with an iridium(I) halide.697 Phosphaalkenyllithium and -Grignard reagents have also found use in the synthesis of new 1,3-diphosphapropenes, e.g., (240),698,699 and the 1,3-diphosphaallyllithium complex (241) in which the lithium ion is located asymmetrically.700 Further work on related 1-aza-3-phosphaallyllithium complexes has also been reported.701 Treatment of the phosphaalkene (242) with potassium t-butoxide has given the cyclopropylidenephosphaallene (243).702 Kinetically stabilised 1-phosphaalkenes have been shown to undergo a topochemical [2þ2] dimerisation on heating in the solid state to form either diphosphanylidenecyclobutanes or 2,4-dimethylene-1,3-diphosphacyclobutanes.703 The electronic properties of the phosphaarsaallene Mes*P¼C¼AsMes* (and the related diarsaallene) have been studied using UV photoelectron spectroscopy and theoretical methods.704 Theoretical studies have also been reported for the 1,4-diphosphabuta-1,3-diene705 and 2,3-diphosphabuta1,3-diene706,707 systems. The diphosphabutadiene (244) has been shown to undergo an unusual [2þ4] cyclodimerisation to form (245).708 The diphosphinidenecyclobutenes (246) continue to attract interest as diphosphabutadiene ligands for transition metal ions and related catalyst systems.709,710 Metal complexes of 1,4-diphosphabutadienes,711 2,3diphosphabutadienes,712 and 1-phospha-buta-1,3-dienes713 have also been investigated.

49

Organophosphorus Chem., 2006, 35, 1–91

R1 P N R2 CF3

R

2

R1

R2 R1

P

C

P Me

CF3 (228) R1 = H or But; R2 = Me or But

(227) R1 = H or CF3; R2 = Me or Ph

R

R

P

Mes*

P Mes*

S

(229)

P

R = H or Br

(230)

Cl Mes*

Ph

Cl Si

Me3Si

P

Mes*

PR Me3Si

(231) X = Br, CHO, COOH, CN, SiMe3 or SnMe3

SMe

(232)

MeS

P

(233)

Mes*

SMe

Br P

Mes*

P

(234)

P

Mes*

Me

[(OC)5W]

(235)

(236)

Ph Mes*

Cy

Mes* P

[W(CO)5]

P CH2Li

[(OC)5W]

Mes*

Ph

Cl

P Li

P

Si Cl

X

Mes*

Fe(CO)2Cp*

P

[(OC)5W]

(237) (238)

H OH

P

Mes*

(239)

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Organophosphorus Chem., 2006, 35, 1–91

Mes*

R1

Mes*P

P

Mes* But

PR22 S

Br P

Mes*P

(CH2)3Br Li(thf)3

(240) R1 = Cl or Me; R2 = Ph or NPri2

(241)

P

(242)

Ar

Mes*

ArP

P

C

(243)

Ar

P

But

Ar =

PAr

ArP

Me

ArP

(244) But

(245)

Interest in the chemistry of phosphaalkynes has continued, although perhaps at a slightly lower level than in recent years. Theoretical studies include consideration of the gas-phase acidities of HCRP, CH3CRP (and the related arsaalkynes),714 isomerism in the FCH2CRP system,715 and calculation of the indirect nuclear spin–spin coupling constants 1J(31P,13C).716 A review has appeared of efforts to prepare isophosphaalkynes, RPRC, still an elusive class of compounds.717 The ﬁrst diphosphaalkyne (247) has been prepared and structurally characterised, together with studies of its interactions with transition metals.718 Diphosphacyclobutenes (248) have been obtained by treatment of the phosphaalkyne Mes*CRP with a 0.5 mol equivalent of an alkyllithium reagent.719 The 2H-phosphasilirene (249) has been obtained from the reaction of the phosphaalkyne ButCRP with a sterically crowded silylene,720 and the cyclic zircona-thia-phosphacyclobutene (250) is formed from the reaction of a phosphaalkyne-zirconocene complex with triphenylphosphine sulﬁde.721 Radical additions to the triple bond of the phosphaalkyne Mes*CRP have been studied by ESR techniques.722 The gas-phase reaction of ButCRP with B4H10 has given a new nido- ﬁve vertex phosphacarborane cluster compound having an unusual 31P NMR chemical shift of -500.5 ppm.723 Interest has also continued in the cyclooligomerisation of phosphaalkynes in the presence of transition metals, with particular reference to the formation and reactions of coordinated diphosphacyclobutadienyl systems. Such ligands display electrophilic character in addition to their usual nucleophilicity.724 New complexes of this type, (251), involving germanium(II), tin(II) and lead(II),725,726 have been described, and other novel modes of coordination of phosphaalkynes have been reported.727,728 The reactions of the phosphaalkyne Mes*CRP with organolithium reagents, followed by alkylation with iodomethane, have given a series of stable 1,3-diphosphacyclobutane-2,4-diyl systems, e.g., (252),729,730 and the reactivity of such diradicaloid rings towards the addition of electrons has also been investigated.731

51

Organophosphorus Chem., 2006, 35, 1–91

Mes* Ar

P

P C

P

Mes*

Mes* Ar

H

P Mes* (246)

(Me3Si)2CH

P R

C P

(248) R = Bun, Bus, But or Me

(247) S

P Si

Cp*2 Zr

Mes Bu

P

t

But

P

t

Bu

Mes*

But

P

Me

P

P

But

M Mes*

(249)

(250)

(251)

(252)

The chemistry of compounds involving pp-bonds between phosphorus and elements other than carbon has also undergone further development, although only a small number of papers have appeared. New examples of iminophosphenes, RN¼PAr, have been prepared (253), involving an electron-acceptor substituent at phosphorus and a donor group at nitrogen, and fully characterised by structural and photoelectron spectroscopic studies, the latter complementing the results of density functional calculations. The data suggest that in these molecules, the aryl group at phosphorus is almost orthogonal to the p(P¼N) system, and hence its substituent effect is mainly steric.732 Conjugation effects in less sterically crowded systems have also been considered by theoretical methods.733 Evidence has been provided of a reversible iminophosphene-diazadiphosphetidine, monomer-dimer equilibrium involving the iminophosphene (254).734 Treatment of (254) with chalcogenoimidazolines or 1,3-dimethyldiphenylurea gives Lewis acid-base complexes. Structural studies show that the chalcogen donor atom is associated with the phosphorus atom and also that coordination causes a significant displacement of the OTf anion, the resulting cations being best described as neutral ligand complexes of the phosphadiazonium cation (255).735 The pp-bonded species CH3OP¼O 1 has been studied in the gas phase by mass spectrometry.736 Further work has also been reported on the chemistry of the ‘phospha-Wittig’ reagents, ArP¼PMe3. On treatment with ortho-quinones, the arylphosphinidene unit is converted into a 1,3,2-dioxaphospholane.737 The arylphosphinidene unit also exchanges reversibly with an aryldichlorophosphine to form a new phospha-Wittig system, the position of equilibrium enabling an assessment of the steric pressures of bulky aryl substituents on the stability of such pp-bonded molecules.738 The nature and reactivity of ‘free’phosphinidenes, RP:, and their more commonly encountered metal complexes, RP¼[M], has continued to attract interest. An overview of phosphinidene chemistry has appeared.739 Differences between singlet phenylphosphinidene and phenylnitrene in terms of

52

Organophosphorus Chem., 2006, 35, 1–91

their reactivity towards ring expansion have been the subject of theoretical treatment.740 The nature of the multiple bond between phosphorus and the metal in phosphinidene-titanium complexes has also received theoretical consideration.741 The most common way of generating phosphinidene complexes continues to be the thermal decomposition of 7-phosphanorbornadiene tungsten carbonyl adducts, obtained from a Diels-Alder addition of an alkyne to a complexed phosphole. The ability of copper(I) chloride to initiate elimination of the phosphinidene complex has been investigated by theoretical methods, which indicate the involvement of a solvent-assisted mechanism.742 The thermal elimination route has been used to generate the complexed bis(phosphinidene) (256), subsequently trapped with diphenylacetylene to form the bis(phosphirene) (257). The electronic structure of (256) has been investigated by ab initio methods.743 Phosphinidene-nickel744 and –cobalt745 complexes have also been trapped with alkynes to form phosphirenes. Other examples of trapping reactions of phosphinidene-metal complexes reported include reactions with alkenes to form phosphiranes,746 including 1,4-diphosphaspiropentanes747 and the phospha[7]triangulanes (258),748 and also with the malonate ion749 and azulenes.750 Weak Lewis base adducts of alkyl- and aryl-halides with terminal phosphinidene complexes (formed by thermolysis of azaphosphirene complexes) are involved as intermediates in reactions with benzyl bromide, 2-bromopyridine and bromobenzene, the overall course of the reaction depending on the nature of the organic halide. With benzyl bromide, insertion of phosphorus into the carbonbromine bond occurs to give a metal-complexed phosphinous bromide whereas with 2bromopyridine, a halophosphine complex arising from insertion into HBr was isolated. With bromobenzene, the 2,3-dihydro-1,2,3-azadiphosphete complex (259) is formed.751 Among new terminal phosphinidene metal complexes described are those involving titanium,752 vanadium,753 chromium,754 cobalt, rhodium and iridium,755,756 and iron, ruthenium and osmium.757,758 Also reported are niobium complexes of diorganophosphinophosphinidenes, R2P–P: ,759 and a molybdenum complex in which an arylphosphinidene acts as a ten-electron donor.760 The stabilisation of phosphenium cations, R2P:1, and other low coordination number phosphorus(III) species, by coordination to phosphorus has continued to be an active topic. Two reviews have been published761,762 and new complexes involving nitrogen-763 and phosphorus-764,765 donor ligands have been prepared and characterised. A simple route to stable complexes (260) of the simple cations P1 (and As1) with the chelating diphosphine diphos has been described766 and a series of air-and waterstable tertiary phosphine complexes of arsenium cations, R2As:1, has been prepared.767 The reactivity of coordination-stabilised cyclic triphosphenium cations similar to (260), involving ﬁve-, six- and seven-membered rings, towards methylation at the cationic phosphorus has been investigated.768 Gas-phase reactions of phosphenium ions with cis- and trans-1,2-diaminocyclohexanes have been studied using mass spectrometric techniques769 and the reactions of the diphenylphosphenium cation with glycals have given a series of phosphonylated sugars.770 Previously unknown silylenephosphenium cations, e.g., (261), are likely intermediates in the reactions of

53

Organophosphorus Chem., 2006, 35, 1–91

diaminophosphenium ions with singlet silylenes, which result in the formation of chlorosilyldiaminophosphines.771 Transition metal complexes of phosphenium ligands have been the subject of a review.772 But

CF3 N

R

P But

P

OSO2CF3

N Mes*

N

P

But

CF3 (253) R = But or NMe2

(255)

(254)

W(CO)5 Ph P

P

P

P Ph

Ph

W(CO)5

(256)

(257)

(Me3Si)2CH P N

Ph2P

NCy2

N

P W(CO)5

(258)

But

CH(SiMe3)2 P

Ph P

Ph

Si P

PPh2 N

Ph

NCy2

AlCl4

But (259)

(260)

(261)

Although strictly outside the remit of this chapter, it is appropriate to note continued activity in the chemistry of s3l5-pp -bonded phosphorus compounds that do not possess a lone pair of electrons at phosphorus. A monomeric metaphosphonate species (262, X¼O) has been stabilised by coordination (via the P¼O bond),773 and Harger’s group has provided evidence of the intermediacy of metathiophosphonates (262, X¼S) in the reactions of phosphonamidothioic acids with alcohols.774 The cation (263) has been stabilised by coordination at phosphorus with 4-dimethylaminopyridine775 and the reactivity of bis(methylene)phosphoranes (264) and related phosphoranylidene carbenoids has been investigated.776 O R

CR2

Cl

P

P X

(262) R = alkyl or aryl

N

SiMe3

Cl

Mes*

P C(tms)2

(263)

(264)

54

4

Organophosphorus Chem., 2006, 35, 1–91

Phosphirenes, Phospholes and Phosphinines

Phosphirene chemistry has continued to generate interest over the past two years. The exo-endo preferences of double bonds in the tautomeric threemembered ring systems (265), (266) and (267) have received theoretical consideration, and a comparison with related carbon and nitrogen ring systems has been made. The preference may be viewed as a composite of substituent and ring strain effects. The low strain 2H-phosphirenes (267) favour endocyclic unsaturation.777 Treatment of the 1H-phosphirene complex (268) with a stable silylene results in the initial formation of the 2-phospha-4-silabicyclo[1,1,0]butane (269) as a reactive intermediate, which subsequently rearranges in the presence of further silylene to give the ﬁrst isolable 2,3-dihydro-1,3-phosphasilete system (270), and other phosphasiletes.778 Gas-phase electron ionisation of the chloro-1H-phosphirene (271) yields the phosphirenylium cation (272). Mass spectrometric techniques have been used to probe the reactions of (272) with nucleophiles and dienes.779 Phosphenium cations, R2P:1, are believed to be formed as intermediates in the exchange reactions of the phosphirenium salt (273) with alkynes, to give new phosphirenium salts, e.g., (274).780 The 2-(phosphirenyl)ethylphosphinidene (275) (generated by thermolysis of a related 2-(phosphirenyl)ethylphosphole in the presence of dimethyl acetylenedicarboxylate) undergoes a selfcondensation to give the 2,4-diphosphabicyclobutane (276).781 The reactivity of the iridaphosphirene system (277) towards electrophiles has been studied, resulting in quaternization at phosphorus to give related iridaphosphirenium salts.782 The reactions of the 2H-azaphosphirene complexes (278) have also attracted further attention. When the complex (278, R¼CH(SiMe3)2) is heated in carbon tetrachloride, the chlorophosphine complex (279) is formed.783 Thermolysis of (278, R¼CH(SiMe3)2) in o-xylene results in the formation of the 2,3-dihydro-1,2,3-azadiphosphete complex (259) and other products, via the intermediate formation of a phosphinidene.784 The generation of phosphinidene intermediates by thermolysis of 2H-azaphosphirene complexes (or 7-phosphanorbornadiene complexes) and subsequent reactions with alkynes and other reagents has provided routes to a variety of heterocyclic compounds, including 2H-1,2-azaphospholes,785,786 2H-1,3,2diazaphospholes,787 D3-1,3,5-oxazaphospholenes and 2H-1,4,2-diazaphospholes.788

PH (265)

P

P

(266)

(267)

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Organophosphorus Chem., 2006, 35, 1–91

(OC)5W

(OC)5W

Ph

W(CO)5

Ph

Ph

P

P

P Ph

Me

Me

R2Si SiR2Ph

Si Me2 (268)

(269)

Ph

Ph

Ph P

(270)

Cl

Me

Ph

C

C

Et

Ph

Me

P

P

P Ph

But

But (271)

Ph

Ph

Ph

Et

TfO

(272)

(273)

(274)

Ph

Ph

P

P

Cy P

Ph W(CO)5

(OC)5W

P P

(OC)5W

TfO

(275)

W(CO)5

(Ph3P)2Ir OC

But

(277)

(276)

O (OC)5W

R P

(OC)5W

CH(SiMe3)2 EtO

P N

Cl

Cl

P Ph

Ph (278)

(279)

(280)

The chemistry of phospholes and related phospholide anion complexes remains a very active area, which also continues to attract the attentions of the theoretical community. Among recent theoretical contributions are a consideration of the stability, structure and bonding in lithium- and beryllium-pentaphospholide systems,789 the aromaticity of the pentaphospholide anion (and its arsenic analogue) as probed by ring currents,790 the remarkable inﬂuence of ﬂuorine-substitution (either at phosphorus or at a ring carbon) on the electronic and thermochemical properties of phospholes,791 and the effects of methyl and vinyl substitution at various positions on the geometries, relative stabilities and Diels-Alder reactivities of phospholes.792 An ab initio approach has been used to reinterprete some spectral and thermochemical properties of 1H-phospholes.793 The synthesis and reactivity of phospholes of reduced

56

Organophosphorus Chem., 2006, 35, 1–91

pyramidality as a result of bulky trialkylphenyl substitution at phosphorus has been reviewed.794 Mathey’s group has shown that the electrochemical reduction of phosphole-pentacarbonyltungsten complexes affords the free phospholes in good yield, and this approach has been used in the synthesis of the 4,5dihydrophosphole (280).795 The P-pyridinomethylphosphole (281) has been obtained from the reaction of the 2,5-diphenylphospholide anion with 2-chloromethylpyridine.796 This approach has also been used to prepare a range of phospholes bearing chiral substituents at phosphorus, subsequently used to generate chiral phosphinidine- and phosphaferrocene-complexes by established general procedures.797 Asymmetric alkylation of the 3,4-dimethyl5-phenyl-2,2 0 -biphospholyl dianion with a chiral pentane ditosylate has given the chirally ﬂexible 2,2 0 -biphosphole (282) as a mixture of three diastereoisomers. By complexation with Pd(II), a chirality control occurs to give an enantiopure complex.798 The electronic properties of homo- and hetero-oligomers and -polymers involving phosphole rings has continued to attract interest, and a review of their chemistry has appeared.799 New alternating a,a-thiophene-phosphole oligomers up to seven rings in length have been prepared, the HOMO-LUMO gap decreasing as the length of the conjugated system increases. Conversion of the phosphole unit into the related phosphole sulﬁde has a major effect on the electronic properties of the system,800 and this work has led to the ﬁrst example of the use of organophosphorus-based materials in light-emitting diodes.801 A route to the dibenzophosphole oxide-arylene polymer system (283) has been developed, these materials behaving as extended pconjugated polymers in UV-visible absorption spectroscopy, and exhibiting green-blue ﬂuorescence with high quantum yields.802 A one-pot route to 1,1 0 biphospholes bearing phenyl or thienyl substituents at the 2,2 0 and 5,5 0 positions, e.g., (284), has been described, enabling a study of the ability of the s-P– P skeleton to connect the p-chromophores. It was established that such through-bond interactions result in a lowering of the optical HOMO-LUMO gap of the molecule, and that oxidation at phosphorus leads to low optical band gap electroactive materials.803 The reactions of pentaﬂuorophenylphosphonite and -phosphinite esters with activated alkynes, followed by hydrolysis, yield benzophosphole oxides, e.g., (285).804 Interest has continued in studies of the thermal isomerisation of 1H-phospholes to the 2H-isomers, and the Diels-Alder and related cycloaddition reactions of the latter. Keglevich’s group has studied the rearrangement of slightly aromatic 1H-phospholes bearing a 2,4,6-trialkylphenyl substituent at phosphorus and subsequent [4þ2]-cycloaddition reactions with alkynes and maleic anhydride, giving new 1-phosphanorbornadienes, e.g., (286), and other products.805,806 Related reactions of a 1,1 0 -bis(phospholyl)ferrocene have given the chiral chelating diphosphine (287) as a mixture of diastereoisomers, subsequently separated and resolved.807 Mathey’s group has described hetero-Diels-Alder reactions of transient 2H-phospholes with aldehydes, which lead to the adducts (288) as a mixture of isomers.808 Dimerisation of 1H-, 2H- and 3H-phospholes through [4þ2] cycloaddition reactions have been studied by density functional theory, and compared to the related dimerisation of cyclopentadiene.809 Treatment of

Organophosphorus Chem., 2006, 35, 1–91

57

the [4þ2]-dimer (289) of 2,5-diphenyl-5H-phosphole with iodomethane gives a monophosphonium salt, which, with thallous ethoxide, is converted into the new chelating bis(phospholene), (290) via cleavage of the P–P bond.810 New tricyclic phosphines, e.g., (291), have been obtained via intramolecular Diels-Alder reactions of phospholes bearing an allyloxy, allylamino or 3-buten-1-yl substituent at phosphorus.811 The coordination chemistry of phospholes bearing 2-pyridyl groups in positions 2 and 5 of the phosphole ring has attracted some attention, the formation and reactivity of various palladium812,813 and ruthenium814 complexes having been studied. The dialkylaminomethyl(phospholyl)ferrocene (292) has been prepared, this representing a new class of chelating 1,2-disubstituted ferrocene ligand.815 Metal complexes of phospholide anions have continued to attract interest. Among new chiral phosphaferrocenes described are the phosphaferrocene-oxazoline (293),816 a phosphaferrocenyl analogue of tamoxifen,817 and the 1,1 0 -diphospha[4]ferrocenophane (294).818 Stereochemical aspects of phosphaferrocenes have seen further study, a 1,1 0 -diphosphaferrocene2-carboxaldehyde having been resolved and its absolute conﬁguration determined.819 The atropisomeric chirality of phosphametallocenes bearing two menthyl substituents in each ring has been investigated by variable temperature NMR techniques.820 Among investigations of the general reactivity of phosphametallocenes are studies of the titanium-mediated reductive coupling of chiral formylphosphaferrocenes to give bis(phosphaferrocenyl)-substituted ethenes and pinacols,821 the acylation of 1,1 0 -diphosphaferrocene with acyl triﬂuoroacetates,822and the oxidation of phosphaferrocenes to form the related phosphaferricinium cations.823,824 Palladium825 and gallium826 complexes of diphosphaferrocenes, involving s-donation from phosphorus, have also been prepared. Phosphametallocenes in which the phospholide anion is p-bonded to a transition metal other than iron have also generated much interest, reports having appeared concerning the chemistry of phosphatitanocenes,827,828 phosphazirconocenes,829 phospharuthenocenes,830,831 and a phosphacymantrene.832 Main group phospholide systems have also been reported, involving sodium, potassium, rubidium and caesium,833 and also phospholides involving the f-block elements samarium and thulium.834,835 Various sbonded bromoborane complexes of a phosphaferrocene have been characterised.836 The coordination chemistry of the phosphoniobenzophospholides (295) has received further study, the benzophospholide phosphorus being able to form both s- and p-coordinate links to transition metal ions such as copper,837 manganese and rhenium,838 and chromium.839 Further work on the chemistry of the 3,5-di-t-butyl-1,2,4-triphospholide anion (296) has been reported. Scandium salts of this phospholide have been characterised,840 and various transition metal complexes have been described.841,842 An improved route to (296) has also led to the isolation of the cationic species nido-[3,5-But2-1,2,4-C2P3]1, isoelectronic with [C5R5]1, but having a non-planar, square-based pyramidal structure.843 Complexes of the pentaphospholide anion have received further study844 and comment.845

58

Organophosphorus Chem., 2006, 35, 1–91

Ph

X

P Ph N

Ph P

Ph

P

P R

(281)

n

X

O

(283) R = Prn, C6H13n or C9H19n

(282)

X = OC6H13n or H

F R3 F S

P

R2

S

P

S

Me

S

Ph

P

F

P

O

1 F R

Ar

(285) R1 = EtO or C6F5; R2 = MeO2C or Ph; R3 = MeO2C or CN

(284)

Ph

(286) Ar = 2,4,6-Pri3C6H2 or 2-Me-4, 6-Pri2C6H2

Ph

P

Ph

P

Ph

H

Fe

R

P

O

Ph

Ph (287)

(288)

Ph

Ph

X

Ph

Ph

H 2C

P

R1 R2

P Ph

P

P

Ph

EtO

P

Ph

(289)

R1

Me

R2

Ph

(290)

(291) R1 = H or Ph; R2 = H or Me; X = O. NR or CH2

59

Organophosphorus Chem., 2006, 35, 1–91

O

CH2NR2 Fe

Ph

P

P

N

Fe

P

R

Fe P

(293) R = Ph or Pri

(292)

(294)

PPh3

PPh3 P

t

Bu

P

P

t

Bu

N

P

P

N

X (295) X = H or PPh2

(296)

(297)

Phospholes bearing additional heteroatoms other than phosphorus have also been the subject of further study. Cycloaddition reactions of heterophospholes have received a theoretical treatment846 and these reactions have also been reviewed.847 Improvements in the synthesis of fused 1,3-azaphospholes via the reactions of N-alkyl-isoquinolinium salts with phosphorus trichloride have been described and their reactivity towards cycloaddition studied.848 New fused 1,3-azaphospholes derived from N-alkylquinolinium salts,849 and new 2H1,2,3-diazaphospholes,850 have also been reported. The phosphonio-1,2,4-diazaphospholide (297) has been characterised851 and further studies of the coordination chemistry of 1H-1,3-benzazaphospholes, leading to complexes of the related benzazaphospholide anion, have been described.852 Routes to 1,3,4-thia- and -selena-diphospholes853 and 1,3,4-thiazaphospholes854 have been developed. Two groups have reported studies of cycloaddition reactions of 1,2-thiaphospholes.855,856 In the free state, the 1,2-thiaphospholo[a]phosphirane (298) undergoes a cycloreversion reaction and a fragmentation to form a butadienyl hydrosulﬁde on heating to 1201C. However, thermolysis of metal complexes of (298) results in a ring-expansion reaction to form the dihydrophosphaisoindole (299).857 The chemistry and complexing ability of 1,2,4-thiadiphospholes and their selenium and tellurium analogues (300) have received further study.858,859 Ph Ph

Ph

But

Ph Ph

P S (298)

Ph

P

S (OC)5W

(299)

P P X

But

Ph (300) X = S, Se or Te

60

Organophosphorus Chem., 2006, 35, 1–91

The chemistry of the potentially aromatic l3-phosphinine system (also known as phosphabenzene) has continued to be a very active area. Not surprisingly, several theoretical contributions have appeared, relating to the extent of aromaticity,860 the relative stabilities of various valence bond isomers,861,862 the possible existence of Mo¨bius phosphabenzene,863 and a study of the Diels-Alder reactions of azaphosphabenzenes.864 Theoretical and experimental techniques have also been applied to a consideration of the electronic properties of a 2,2 0 -biphosphinine ligand,865 and the s-donating and p-accepting properties of phosphinines bearing ortho-trimethylsilyl substituents.866 Reactions involving phosphabenzyne-zirconocene complexes have been the subject of a review.867 A seven step route has been developed to the fused phosphinine (301),868 and the 1,4-phosphaboratabenzene system (302) has been characterised as a p-bonded ruthenium complex.869 2,4,6-Triphenylphosphinine has been shown to undergo a cofacial oxidative coupling in the presence of a copper(I) perchlorate complex to form a new C2-symmetric cage compound.870 Cycloaddition of benzyne to various 2,4,6-trisubstituted phosphinines has given a series of phosphabarrelenes (303), the rhodium complexes of which are highly active catalysts for the isomerisation-free hydroformylation of internal alkenes.871 Further work has been reported on the reactions of phosphinines with nucleophiles, e.g., alkyllithium reagents, which lead initially to 1-R phosphahexadienyl anions, e.g., (304). The crystal structure of a lithium salt of (304, R¼Me) has been determined, and theoretical studies suggest that the negative charge is largely localised on the a-carbons.872 Treatment of related anions with hexachloroethane, followed by gallium trichloride, has given the 1-methylphosphinium salts (305), which readily add nucleophiles to form l5-phosphinines.873 The coordination chemistry of phosphahexadienyl anions has also attracted interest.874,875 The reactions of 1,3,5-triphosphabenzenes have also attracted further study. Reduction of 1,3,5-tris-(t-butyl)-phosphabenzene with LiMH4 (M¼Al or Ga) results in the formation of the triphosphabicyclo[3,1,0]hexane (306). Other bicyclic systems have been isolated from reactions of related complex hydrides.876 Grignard877 and organolithium reagents878,879 undergo 1,4-additions to 1,3,5-tris-(t-butyl)phosphabenzene, giving the anions (307). These give rise to 1,3-diphospholide anions on thermolysis, and can also be alkylated to give 1l5,3,5-triphosphabenzenes. 1,3,5-Triphosphabenzenes undergo 1,3-dipolar cycloaddition reactions with nitrile oxides to form new condensed heterocyclic systems880 and also add to terminal alkynes, giving phosphorus-carbon cage compounds.881 Cycloaddition reactions of alkynes to 1,3,2-diazaphosphinines, followed by elimination of a nitrile, have been used in the synthesis of new ring-substituted phosphinines, including an extended silacalix-[3]-phosphinine macrocycle.882,883 Related reactions with propargylphosphines have given new 1,2azaphosphinines, e.g., (308).884

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Organophosphorus Chem., 2006, 35, 1–91

NPri2 B

Me P

Ph

P

Me

P

Ph

R

R

(301)

(302)

(303) R = Ph, Pri or 2,4-xylyl

Ph R

R

GaCl4 Ph

P R

Me3Si

Ph

(304)

P Me

But

But H

H

(306)

Ph

But

P N

But

P But

(305) R = Ph or Me

P

P But

SiMe3

H P

H

P P R (307)

But

P Ph

P

(308)

Ph

(309)

Finally, it is of considerable interest to note the results of a theoretical treatment of the extent to which nine-membered monocycles can be aromatic, and which concludes that the phosphonide anion (309), as yet unknown, favours planar C2v symmetry.885 References 1. M.S. Balakrishna, P. Chandrasekaran and P.P. George, Coord. Chem. Rev., 2003, 241, 87. 2. J.-P. Majoral, A.-M. Caminade and V. Maraval, Chem. Commun., 2002, 2929. 3. A.-M. Caminade and J.-P. Majoral, Acc. Chem. Res., 2004, 37, 341. 4. S. Sasaki, K. Sutoh, F. Murakami and M. Yoshifuji, J. Am. Chem. Soc., 2002, 124, 14830. 5. P. Wyatt, H. Ely, J. Charmant, B.J. Daniel and A. Kantacha, Eur. J. Org. Chem., 2003, 4216. 6. H. Riihima¨ki, P. Suomalainen, H.K. Reinius, J. Suutari, S. Ja¨a¨skela¨inen, A.O.I. Krause, T.A. Pakkanen and J.T. Pursiainen, J. Mol. Catal. A: Chem., 2003, 200, 69.

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788. C. Neumann, A.P. Junquera, C. Wismach, P.G. Jones and R. Streubel, Tetrahedron, 2003, 59, 6213. 789. E.J.P. Malar, Inorg. Chem., 2003, 42, 3873. 790. F. De Proft, P.W. Fowler, R.W.A. Havenith, P. von R. Schleyer, G. Van Lier and P. Geerlings, Chem. Eur. J., 2004, 10, 940. 791. D. Delaere, N.-N. Pham-Tran and M.T. Nguyen, Chem. Phys. Lett., 2004, 383, 138. 792. K. Geetha, T.C. Dinadayalane and G.N. Sastry, J. Phys. Org. Chem., 2003, 16, 298. 793. D. Delaere, N.-N. Pham-Tran and M.T. Nguyen, J. Phys. Chem. A., 2003, 107, 7514. 794. G. Keglevich, Targets in Heterocyclic Systems, 2002, 6, 245. 795. D.G. Yakhvarov, Y.H. Budnikova, N.H.T. Huy, L. Ricard and F. Mathey, Organometallics, 2004, 23, 1961. 796. C. Thoumazet, M. Melaimi, L. Ricard, F. Mathey and P. Le Floch, Organometallics, 2003, 22, 1580. 797. X. Sava, A. Marinetti, L. Ricard and F. Mathey, Eur. J. Inorg. Chem., 2002, 1657. 798. C. Ortega, M. Gouygou and J.-C. Daran, Chem. Commun., 2003, 1154. 799. M. Hissler, P.W. Dyer and R. Re´au, Coord. Chem. Revs., 2003, 244, 1. 800. C. Hay, C. Fave, M. Hissler, J. Rault-Berthelot and R. Re´au, Org. Lett., 2003, 5, 3467. 801. C. Fave, T.-Y. Cho, M. Hissler, C.-W. Chen, T.-Y. Luh, C.-C. Wu and R. Re´au, J. Am. Chem. Soc., 2003, 125, 9254. 802. Y. Makioka, T. Hayashi and M. Tanaka, Chem. Lett., 2004, 33, 44. 803. C. Fave, M. Hissler, T. Ka´rpa´ti, J. Rault-Berthelot, V. Deborde, L. Toupet, L. Nyula´szi and R. Re´au, J. Am. Chem. Soc., 2004, 126, 6058. 804. Yu.G. Trishin, V.I. Namestnikov and V.K. Bel’skii, Russ. J. Gen. Chem., 2004, 74, 189. 805. G. Keglevich, R. Farkas, T. Imre, K. Luda´nyi, A. Szo¨llo¨sy and L. To¨ke, Heteroatom Chem., 2003, 14, 316. 806. G. Keglevich, L. Nyula´szi, T. Chuluunbaatar, B.-A. Namkhainyambuu, K. Luda´nyi, T. Imre and L. To¨ke, Tetrahedron, 2002, 58, 9801. 807. G. Frison, F. Brebion, R. Dupont, F. Mercier, L. Ricard and F. Mathey, C. R. Chimie, 2002, 5, 245. 808. P. Toullec, L. Ricard and F. Mathey, J. Org. Chem., 2003, 68, 2803. 809. T. Dinadayalane and G.N. Sastry, Organometallics, 2003, 22, 5526. 810. B. Deschamps, L. Ricard and F. Mathey, Organometallics, 2003, 22, 1356. 811. E. Mattman, F. Mercier, L. Ricard and F. Mathey, J. Org. Chem., 2002 67, 5422. 812. F. Leca, M. Sauthier, B. le Guennic, C. Lescop, L. Toupet, J.-F. Halet and R. Re´au, Chem. Commun., 2003, 1774. 813. F. Leca, M. Sauthier, V. Deborde and L. Toupet, and R. Re´au, Chem. Eur. J., 2003, 9, 3785. 814. A. Caballero, F.A. Jalo´n, B.R. Manzano, M. Sauthier, L. Toupet and R. Re´au, J. Organomet. Chem., 2002, 663, 118. 815. S. Mourgues, D. Serra, F. Lamy, S. Vincendeau, J.-C. Daran, E. Manoury and M. Gouygou, Eur. J. Inorg. Chem., 2003, 2820. 816. R. Shintani and G.C. Fu, Org. Lett., 2002, 4, 3699. 817. K. Kowalski, A. Vessie`res, S. Top, G. Jaouen and J. Zakrzewski, Tetrahedron Lett., 2003, 44, 2749.

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818. M. Ogasawara, T. Nagano and T. Hayashi, Organometallics, 2003, 22, 1174. 819. A. Kzys, J. Zakrzewski and L. Jerzykiewicz, Tetrahedron Asymmetry, 2003, 14, 3343. 820. M. Ogasawara, K. Yoshida and T. Hayashi, Organometallics, 2003, 22, 1783. 821. S.O. Agustsson, C. Hu, U. Englert, T. Marx, L. Wesemann and C. Ganter, Organometallics, 2002, 21, 2993. 822. D. Pla(uk and J. Zakrzewski, Synth. Commun., 2004, 34, 99. 823. X. Sava, L. Ricard, F. Mathey and P. Le Floch, J. Organomet. Chem., 2003, 671, 120. 824. X. Sava, L. Ricard, F. Mathey and P. Le Floch, Inorg. Chim. Acta, 2003, 350, 182. 825. M. Melaimi, L. Ricard, F. Mathey and P. Le Floch, J. Organomet. Chem., 2003, 684, 189. 826. X. Sava, M. Melaimi, N. Me´zailles, L. Ricard, F. Mathey and P. Le Floch, New J. Chem., 2002, 26, 1378. 827. T.K. Hollis, Y.J. Ahn and F.S. Tham, Chem. Commun., 2002, 2996. 828. T.K. Hollis, Y.J. Ahn and F.S. Tham, Organometallics, 2003, 22, 1432. 829. L.-S. Wang and T.K. Hollis, Org. Lett., 2003, 5, 2543. 830. M. Ogasawara, T. Nagano, K. Yoshida and T. Hayashi, Organometallics, 2002, 21, 3062. 831. (a) D. Carmichael, F. Mathey, L. Ricard and N. Seeboth, Chem. Commun., 2002, 2976; (b) D. Carmichael, J. Klankermayer, L. Ricard and N. Seeboth, Chem. Commun., 2004, 1144. 832. P. Toullec, L. Ricard and F. Mathey, Organometallics, 2003, 22, 1340. 833. M. Westerhausen, M.W. Ossberger, A. Keilbach, C. Gu¨ckel, H. Piotrowski, M. Suter and H. No¨th, Z. Anorg. Allg. Chem., 2003, 629, 2398. 834. F. Nief, D. Turcitu and L. Ricard, Chem. Commun., 2002, 1646. 835. D. Turcitu, F. Nief and L. Ricard, Chem. Eur. J., 2003, 9, 4916. 836. M. Scheibitz, J.W. Bats, M. Bolte and M. Wagner, Eur. J. Inorg. Chem., 2003, 2049. 837. D. Gudat, M. Nieger, K. Schmitz and L. Szarvas, Chem. Commun., 2002, 1820. 838. D. Gudat, B. Lewall, M. Nieger, I. Detmer, L. Szarvas, P. Saarenketo and G. Marconi, Chem. Eur. J., 2003, 9, 661. 839. Z. Bajko, J. Daniels, D. Gudat, S. Ha¨p and M. Nieger, Organometallics, 2002, 21, 5182. 840. G.K.B. Clentsmith, F.G.N. Cloke, J.C. Green, J. Hanks, P.B. Hitchcock and J.F. Nixon, Angew. Chem. Int. Ed., 2003, 42, 1038. 841. M.M. Al-Ktaifani, P.B. Hitchcock and J.F. Nixon, J. Organomet. Chem., 2003, 665, 101. 842. F.W. Heinemann, M. Zeller and U. Zenneck, Organometallics, 2004, 23, 1689. 843. J.M. Lynam, M.C. Copsey, M. Green, J.C. Jeﬀrey, J.E. McGrady, C.A. Russell, J.M. Slattery and A.C. Swain, Angew. Chem. Int. Ed., 2003, 42, 2778. 844. V.A. Miluykov, O.G. Sinyashin, P. Loennecke and E. Hey-Hawkins, Mendeleev Commun., 2003, 13, 212. 845. H. Sitzmann, Angew. Chem. Int. Ed., 2002, 41, 2723. 846. T. Jikyo, J. Schatz and G. Maas, J. Phys. Org. Chem., 2003, 16, 504. 847. R.K. Bansal, Ne. Gupta and Ni. Gupta, Heteroatom Chem., 2004, 15, 271. 848. R.K. Bansal, A. Dandia, N. Gupta and D. Jain, Heteroatom Chem., 2003, 14, 560. 849. P. Sharma, A. Kumar and P. Pandey, Phosphorus, Sulfur, Silicon, 2003, 178, 583. 850. V. Padmavathi, T.V.R. Reddy, K.A. Reddy and D.B. Reddy, J. Heterocyclic Chem., 2003, 40, 149.

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851. L. Szarvas, Z. Bajko, S. Fusz, S. Burck, J. Daniels, M. Nieger and D. Gudat, Z. Anorg. Allg. Chem., 2002, 628, 2303. 852. J. Heinicke, N. Gupta, S. Singh, A. Surana, O. Ku¨hl, R.K. Bansal, K. Karaghiosoﬀ and M. Voight, Z. Anorg. Allg. Chem., 2002, 628, 2869. 853. C. Peters, U. Fischbeck, F. Tabellion and M. Regitz, and F. Preuss, Z. Naturforsch., B: Chem. Sci., 2003, 58, 44. 854. (a) S. Sharma, Int. J. Chem. Sci., 2003, 1, 245; (b) S. Sharma, Chem. Abstr., 141, 38670. 855. J. Dietz, J. Renner, U. Bergstra¨sser, P. Binger and M. Regitz, Eur. J. Org. Chem., 2003, 512. 856. J. Kerth, T. Jikyo and G. Maas, Eur. J. Org. Chem., 2003, 1894. 857. T. Jikyo and G. Maas, Chem. Commun., 2003, 2794. 858. S.E. d’Arbeloﬀ-Wilson, P.B. Hitchcock, J.F. Nixon and L. Nyula´szi, J. Organomet. Chem., 2002, 655, 7. 859. M.L. Helm, P.B. Hitchcock, J.F. Nixon, L. Nyula´szi and D. Szieberth, J. Organomet. Chem., 2002, 659, 84. 860. C. Lepetit, V. Peyrou and R. Chauvin, Phys. Chem. Chem. Phys., 2004, 6, 303. 861. I. Yavari, M. Nikpoor-Nezhati and S. Dehghan, Phosphorus, Sulfur, Silicon, 2003, 178, 485. 862. I. Yavari, S. Dehghan and M. Nikpoor-Nezhati, Phosphorus, Sulfur, Silicon, 2003, 178, 869. 863. J. Jeevanandam, E.J.P. Malar and R. Gopalan, Organometallics, 2003, 22, 5454. 864. (a) L. Pacureanu and M. Mracec, Revista de Chimie, 2003, 54, 399; (b) L. Pacureanu and M. Mracec, Chem. Abstr., 140, 253634. 865. F. Hartl, T. Mahabiersing, P. Le Floch, F. Mathey, L. Ricard and P. Rosa, Inorg. Chem., 2003, 42, 4442. 866. V.R. Ferro, S. Omar, R.H. Gonza´lez-Jonte and J.M. Garcı´ a de la Vega, Heteroatom Chem., 2003, 14, 160. 867. J.-P. Majoral, A. Igau, V. Cadierno and M. Zablocka, Topics in Current Chem., 2002, 220, 53. 868. P. de Koe and F. Bickelhaupt, Z. Naturforsch., B: Chem. Sci., 2003, 58, 782. 869. A.J. Ashe III, Z. Bajko, M.D. Carr and J.W. Kampf, Organometallics, 2003, 22, 910. 870. T. Kojima, Y. Ishioka and Y. Matsuda, Chem. Commun., 2004, 366. 871. B. Breit and E. Fuchs, Chem. Commun., 2004, 694. 872. A. Moores, L. Ricard, P. Le Floch and N. Me´zailles, Organometallics, 2003, 22, 1960. 873. A. Moores, L. Ricard and P. Le Floch, Angew. Chem. Int. Ed., 2003, 42, 4940. 874. A. Moores, N. Me´zailles, L. Ricard, Y. Jean and P. Le Floch, Organometallics, 2004, 23, 2870. 875. (a) M. Doux, N. Me´zailles, M. Melaimi, L. Ricard and P. Le Floch, Chem. Commun., 2002, 1566; (b) M. Doux, N. Me´zailles, L. Ricard and P. Le Floch, Eur. J. Inorg. Chem., 2003, 3878. 876. C. Jones and M. Waugh, Dalton Trans., 2004, 1971. 877. J. Renner, U. Bergstra¨sser, P. Binger and M. Regitz, Angew. Chem. Int. Ed., 2003, 42, 1863. 878. J. Steinbach, J. Renner, P. Binger and M. Regitz, Synthesis, 2003, 1526; (see also Erratum, Synthesis, 2003, 2274). 879. J. Steinbach, P. Binger and M. Regitz, Synthesis, 2003, 2720.

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880. S. Weidner, J. Renner, U. Bergstra¨sser, M. Regitz and H. Heydt, Synthesis, 2004, 241. 881. H. Disteldorf, J. Renner, H. Heydt, P. Binger and M. Regitz, Eur. J. Org. Chem., 2003, 4292. 882. A. Moores, N. Me´zailles, N. Maigrot, L. Ricard, F. Mathey and P. Le Floch, Eur. J. Inorg. Chem., 2002, 2034. 883. M. Doux, L. Ricard, F. Mathey, P. Le Floch and N. Me´zailles, Eur. J. Inorg. Chem., 2003, 687. 884. N. Maigrot, M. Melaimi, L. Ricard and P. Le Floch, Heteroatom Chem., 2003, 14, 326. 885. P. von R. Schleyer, L. Nyula´szi and T. Ka´rpa´ti, Eur. J. Org. Chem., 2003, 1923.

2 Quinquevalent PhosphorusAcids BY A. SKOWRONSKA AND R. BODALSKI

1

Introduction

In this chapter we have adopted an approach similar to that used last year. The level of interest in chemistry of quinquevalent phosphorus remains quite high as a result of the diversity of its biological aspects and application in synthesis. A large number of natural and unnatural phosphates, including carbohydrates and their phosphonates and phosphinates analogues, as well as inositols have been synthesized usually with some biological related purpose. The synthesis of phosphorus analogues of all types of aminoacids and some peptides has been also developed. Mechanistic studies of reactions concerning phosphate esters hydrolysis continue to be reported. The importance of enantiomeric and asymmetric synthesis using chiral phosphorus (V) reagents is presented in a few papers. Throughout this year's report, although not pretending to offer comprehensive coverage of these aspects, there is an attempt to reflect this.

2

Phosphoric Acids and Their Derivatives

2.1 Synthesis of Phosphoric Acids and Their Derivatives.- The individual Rpand Sp-isomers of the organophosphate triesters (1-6) were synthesized and isolated on a preparative scale through the kinetic resolution of racemic mixtures via the hydrolysis of a single enantiomer by the bacterial phosphotriesteraze (PTE).' 0

2 11 R O-p-oR

Q

1

1

2

1 R =Me,R =Et 2 R

=Me,R2 =P+,

I

2 ' 3 R" = Et, R = Pr' 4 R1 =Ph,R2 =Me

5 R1 = Ph, R2 = Et NO2

6 R'=Ph,R*=P:

Enantiomeric alkyl phosphothioates (12-14)(16-18) and related alkyl phosphonothioates (11,15) have been prepared by stereoselective enzymatic hydrolysis of prochiral bis-p-nitrophenylphosphothioates (8-10) and Organophosphorus Chemistry, Volume 34 0 The Royal Society of Chemistry, 2005

77

78

Organophosphorus Chemistry

bis-p-nitrophenylphosphonothioate(7) respectively using engineered mutants of phosphotriesteraze (PTE). The prochiral stereoselectivity inherent to the wildtype of PTE was manipulated by specific modifications of the active site of this protein. (Scheme 1).2 0

R - ! - e N O z

R-P-SH I1

I

3 I

-

I

0

0 PTE

pros hydrolysis OpNP

0

HS-P-R It

0

P TE proR hydrolysis OpNP

Q

NO2

NO2

NO2

15 (S)R=Me 16 (R)R=MeO

17 (R)R=EtO

7 R=Me 8 R=MeO 9 R=EtO

11 (R)R=Me 12 (S) R = Me0 13 (S) R = EtO

18 (R)R=Pr‘O

10 R = Pr‘O

14 (S)R=Pr‘O

Scheme 1

Correlation of the 31PNMR chemical shift with the position of bond critical points (BCP) in 0,O-dialkyl o-aryl phosphorothionates has been r e p ~ r t e dThe .~ first isolable dialkyl iodophosphates were obtained by iodination of bis-(hexafluoroisopropy1)phosphites with NIS? Reactions of vinyl phosphites (19) with iodine produce dealkylated intermediates, the highly reactive phosphoroiodidates (20) which are efficient phosphorylation reagents to prepare biologically relevant vinylphosphates (21) (Scheme 2).5

20

19 1

R = vinyl or alkyl; R

21

* = alkyl Scheme 2

Reactions of phosphazenes (22) and (23) with aldehydes, ketones and nitriles provide a convenient route to new heterocycles containing 1,3-oxaza-4(25) rings phospha-2-phosphorine (24) and 1,3-diaza-4-phospha-2-phosphorine respectively (Scheme 3)697 The cyclocondensation of various dichlorophosphoryl carbamates with ring substituted 1,2-phenylenediamine and 2-aminobenzylamine are reported as an efficient approach to a number of cyclic amides of phosphoric acid (26)’ and (27).9

2: Quinquevalent Phosphorus Acids

79

q4

22

-

OPh

24

25

23

R I = HI alkyl, R 2 = H, alkyl, R 3 = alkyl, aryl, R 4 = H, alkyl Scheme 3

I

H

NHCOR'

27

R1= Me,Et, Bz,CH2CH=CHpl CH2C==CH1CHzCH2CI

Interest in phosphorus containing dendrimers and calixarenes continues. Examples of new dendrimer structures possessing P = 0,P = S , P = Se branching units within the same framework have been described." Four series of new ferrocenyl dendrimers (up to the 11th generation) with thiophosphoramidate linkages have been reported.'' Different processes have been devised for the synthesis of phosphorus - containing dendron depending on the type of function located at the core. In all cases, the divergent strategy allows the introduction of very reactive functionalities such as P-Cl, amine, phosphine or aldehyde groups on the surface of the dendron.'' The first example of the one-pot synthesis of a fourth generation dendrimer with thiophosphoamide linkages using two AB2

80

Organophosphorus Chemistry

unprotected monomers, one with aldehyde and azide functions AB21,the other one with hydrazine and phosphine functions, AB22,has been also r e p ~ r t e d . ' ~

The structures of calixC41arenesdescribed include those with phosphoric acids substituents (28)14,chlorophosphate, chlorothiophosphate bridges (29)15and the first calix[S]arene derivatives with three bridging phosphate units (30) and (31).l6 0

X

X

II X

II X

It

28

II

x=o,s 29

A novel sterically congested cliv-like receptor for dicationic quests, incorporating a hindered cyclophane possessing chiral spirobiindanol phosphonate and phosphate units (32) has been synthesised .17 P-Nitrosophosphates (33) have been obtained and used as new N - 0 heterodienophiles in the Diels-Alder type reaction with a few selected 1,3-dienes to give highly functionalized cycloadducts (34).The latter can be directly transformed by

2: Quinquevalent Phosphorus Acids

81

-But

Bu-'

31

OP(O)(OEt)z

32

reduction into allylic phosphoamidates (35). The compounds (33), subjected to reaction with nucleophiles,liberate nitroxyl(36), the biologically important one electron-reducedform of nitric oxide (Scheme 4).'*

33

35

34

H

33

YO

34 HNO

36 Scheme 4

82

Organophosphorus Chemistry

5-Methylene-1,3,2-dioxaphosphorinane(37) has been prepared by the phosphorylation of 2-methylene-1,3-propandiol (38). Ozonolysis of this compound afforded 5-oxo-1,3,2-dioxaphosphorinane (39).Both these compounds are promising synthons for the construction of keto-sugars (Scheme 5).19

38

I i

pa5

37

t

39

CH2CI2

Scheme 5

The four step synthesis of 2-C-methyl-D-erythrytol 2,4-~yclopyrophosphate (41) which is a biological intermediate in the deoxyxylulose pathway of isoprenoid biosynthesis has been described. Bisphosphorylation of 2-C-methylD-erythrytol-1,3-acetate (40), followed by carbodiimide cyclization and deprotection, led to the target product in 42% overall yield (Scheme 6).20 OR

OAc

-

I

C

a, b

--.---b

41

Reagents: (a) 3 equiv. of (BnO),PN’Pr,, tetrazol; (b) MCPBA; (c) H, 10% Pd/C, MeOH 1% NH,HCO,

4:l;(d) excess EDC, H,O; (e) 1.36 M NH,OH.

Scheme 6

(E)-l-Hydroxy-2-methyl-but-2-aryl-4-diphosphate (44) has been prepared in six steps from tetrahydropyranyl ether (42), derived from hydroxyacetone and phosphonium ylide (43), in 35% yield. The compound (44) was shown to be identical with the product of I spG protein, which serves as an intermediate in the non mevalonate terpene biosynthetic pathway (Scheme 7).2’

83

2: Quinquevalent Phosphorus Acids

43

0 . . L

0 42

0

OH

I

0’

I

0’

44

EtZ=6:1

Scheme 7

The diphosphate (44) is also available in 25% yield by regioselective hydroxylation and diphosphorylation of dimethylallyl alcohol (Scheme 8).22

OTHP

Reagents: (a) Ac,O-pyridine; (b) SeO,, Bu‘OOH,CH,CI,; (c) dihydropyran, CH,CI,, cat PPTS;(d) K,CO,, MeOH-H, 35; (e) N-chlorosuccinimide, Me,S, CH,CI,, 0°C; (f) tris(tetrabuty1ammonium)hydrogen diphosphate, (NH4),C0,, MeCN; (9) (NH,),CO,.

Scheme 8

A series of thiolo isomers of isoprenoid thiodiphosphate esters (45) was synthesized by treating homoallylic tosylates (46) and allylic bromides (47), with tris (tetra-n-butylamonium) thiopyrophosphates (51) (Scheme 9). The synthesis of thiopyrophosphate (51) involves selective monodemethylation of trimethyl phosphite (48) followed by condensation of the resulting phosphate (49) with thiophosphorochloridate and dealkylation of the obtained tetramethyl thiopyrophosphate (50)(Scheme Stable isotope-labelled intermediates playing an important role in the study of the mevalonate as well as the deoxyxylulose phosphate pathway of isoprenoid biosynthesis have been prepared. 13C-and I4C-labelled4-diphosphacytidyl-2C(53) have methyl-D-erythrytol (52) and 2C-methyl-D-erythrytol-4-phosphate been obtained in milimol quantity and in high yield by sequences of one-pot reactions using l3C-labe1led pyruvate, or dihydroxyacetone phosphate 13C-

Organophosphorus Chemistry

84

0..

0-

46

45

47

45

DMASPP (89%) GSPP (80%) FSPP (84%) GGSPP (65%) Reagents: (a) tris(tetra-n-butylammonium)thiopyrophosphate,CH,CN; (b) dowex AG 50W-X8 (NH,' form).

Scheme 9

OMe

OMe

48

49

OMe OMe

50

Ic 6-

051

OTMSOTMS

SPP,

Reagents: (a) nBu,NOH; (b) (MeO),P(S)CI; (c) TMS; (d) nBu,NOHm,O.

Scheme 10

labelled glucose and recombinant enzymes as ~atalysts.2~ Numerous isotopomers of 2C-methyl-D-erythritol-4-phosphate (53) carrying 3H, 13C,or 14Cemploying isotope - labeled glucose and purivate as starting materials have been also 0btained.2~One-pot strategies for the enzyme - assisted preparation of 2Cmethyl-D-erythrytol 2,4-cyclodiphosphate (54)from isotope-labelled pyruvate and glucose that are optimised for the introduction of 13Cand/or 14Chave been described.26 The compound (54)has been enzymatically converted into a phosphorylated derivative of (E)-2-methylbut-2-ene-l,4-diol, which most probably represents a novel intermediate in the methylerythritol phosphate pathway of isoprenoid bio~ynthesis.2~ The use of a photolabile acetal protecting group enables the synthesis of glycoaldehyde di-, and triphosphates (55)and (56) respectively.

2: Quinquevalent Phosphorus Acids

85

l i

OH OH

52

53

54

57

sa

Following dehydration these compounds undergo enolisation at significantly lower pH values than glucoaldehyde phosphate?* Amidotriphosphate (57) and diamidophosphate (58) are convenient reagents for the regioselective a-phosphorylation of aldoses in aqueous solution. 29 2,5-Anhydroglucitol (59), 2,5-anhydromannitol (60) and their 6-phosphate and 1,6-phosphate derivatives (61-64) are cyclic analogues of D-fructofuranose6-phosphate and D-fructofuranose-1,6-diphosphate.They were synthesized from protected D-mannose or D-glucose. The synthetic method has been developed with emphasis on selective 3Hlabelling of these corn pound^.^^ Simple one-pot synthesis of different 1-0-glycosylboranophosphate diesters (65), the stable analogues of 1-0-glycosylphosphates based on the anomeric H-phosphonate of a-L-rhamnopyranose as common precursor, has been reported.31Various phosphodisaccharides, structural analogues of phosphate (66) including deoxy, fluoro and aminodeoxy disaccharide phosphates e.g. (67) have been s y n t h e ~ i z e d .These ~ ~ . ~ ~phosphodisaccharides were tested as acceptor substrate/putative inhibitors for the Leishmania-a-D-mannosylphosphatetransferase. Inositol and structurally related phosphates continue to be popular targets for

Organophosphorus Chemistry

86

OH

OH

60

59

2,5-anhydromannitol “p-fnrctofuranose”

2,5anhydroglucitol “a-fructofuranose”

OH

OH

61 “a-fructofuranose-8phosphate”

OH 63 “a-fructofu ranose- 1,6-diphosphate”

62 “p-f ructofuranose-6-phosphate”

OH 64

‘‘P4ructofuranose-1,8diphosphate”

R = alkyl or sugar

0

HO OH

OW R = (CH*)&H=Cb 66

OH R = (CH&C H=CHz 67

synthesis. Enantio- and regio-selective phosphorylation of an appropriate myoinositol derivative (68) through selection of the ‘Kinase mimic’ small peptidebased catalyst (69) has been reported. The phosphorylation of (68) using diphenylchlorophosphate in the presence of triethylamine gives, following de-

2: Quinquevalent Phosphorus Acids

87

protection, D-myo-inositol-1-phosphate D-I-1P (70) as a single enantiomer in 65% isolated yield (Scheme 1l).34 0 II

CIP(O)(OPh)Z 2 mol % Peptide 69 EtnN

'""OBn

BnO"''

OR

PhCH3, O°C 65% isolated yield

OH

OH

70

68 Ph

R = Ph, Y = Bn (-) 70>98% ee after deprotonation: R = Y = H 70 Synthetic D-I-?P

Ph

(Natural, [orb +3.5)

Structure of Peptide 69

But'

RAQ

OMe

Scheme 11

Synthesis of inositol phosphoglycans (IPGs)(71), analogues to second messengers of insulin, has been described. These derivatives contain the glucosamine (a 1-6)myo-inositol 1,2 cyclic phosphate motif and the thiol-terminated spacers for efficient coupling to maleimide functionalized solid phases or protein^.^'

The total synthesis of the core heptasaccharyl myo-inositol 1-phosphate and the corresponding hexasaccharyl myo-inositol 1-phosphate, found in the lipophosphoglycan of Leishmania parasites, using a block strategy, has been successfully elaborated. The target molecule contains synthetic challenges such as an unusual internal galactofuranosyl residue and an anomeric phosphodiester. Both the assembly order, choice of deprotection methods and sequence of deprotection were crucial to the successful synthesis of these complex mole c u l e ~Phosphatidylinositol .~~ structures and their phosphates are involved in a variety of important biological processes. Few reports in this area have been presented but the difficulties of synthesising increasingly complex molecules are

88

Organophosphorus Chemistry

being overcome. A convenient alternative synthesis of a palmitoyl analogue of natural phosphatidylinsitol 5-phosphate P15-P (72) has been elaborated. An analogue bearing a fluorescent group NBP on a fatty acid chain (73)and a P15-P attached resin (74) for use in affinity chromatography have been also prepared. This will be of wide biological interest.37

72

74

L-a-Phosphatidyl-D-myo-inositol 3,5-bisphosphate PI 3,5 P2 (75, R2 = butyryl), a novel lipid analogue of (75, R = arachidonyol), has been synthesized from D-glucose by utilizing ring-closing metathesis and catalytic Os04 dihydroxylation. The key intermediate of this route is 1,7 diene (76). Efficient construction of the intermediate (76) has been elaborated which is adaptable for the synthesis of a series of inositol analogues, as well as various six-membered cyclitols. The purpose of the preparation of PI 3,5-P2 was the clarification of its biochemical function as a second messenger.38 The synthesis and biological activity of two new 3-hydroxy (phosphono)methyl-bearing phosphatidylinositol ether lipid analogues (77) has been reported. These compounds are structurally related to PI-3-phosphate and act as reasonable good inhibitors of Akt and P13-K. They were also shown to inhibit the growth of HT-29 human colon cancer cells and MCF-7 human breast cancer cells.39 An improved access to the ilmofosine fluorinated analogue (78) and to octadecyl homologue (79) based on compounds (80) and (81) has been realized in order to find phospholipids exhibiting higher antitumor reactivity in comparison to ilmofosine and other ether lipide~.~'

2: Quinquevalent Phosphorus Acids

89

key intermediate I,7diene

PI 3,5-P2 76

75 R'= stearoyl, F?= butyryl 75 R'= stearoyl, $= arachidonoyl

77X=H,Y=OH95% 77 X = OH, Y = H 96%

8

Mesh-

F CH20Me 0 - P - O A O R 0I -

HO 80 94% 81 89%

The acid-catalysed intramolecular 1,5-nucleophilic0-heterocyclization of (p4dieny1)tricarbonylirondiols (82) occurs with 1,2-migration of the side chain. This cyclization has been shown to be a key stereoselective step towards racemic and optically active conformationally locked phosphocholins (83) and (84) as potential anticancer agents (Scheme 12).41 The first synthetic route which may serve as a potential source of phosphatidylcholine-bearing docosahexaenoic acid (85) and tetracosahexanoenoic acid for physiological studies has been described. This method may also be applicable to the synthesis of phosphatidylocholine homologues having longer chains, such as those identified in bovine retina.42 A total synthesis of the ester of 2-lysophosphatydylcholine HOT-PC (86) has been devised to facilitate identification of this oxidized ph0spholipid.4~ A novel regioselective, convenient and efficient synthesis of model D-erythrosphingosine 1-phosphate (87) and D-erythro-ceramide 1-phosphate (88)has been presented" D-erythro-sphingosine and ceramide sphingosine (89) and ceramide (90) and their phosphates (87) and (88) constitute a highly conserved, plasma-membrane derived set of molecular tools which enkaryotic cells use to trigger a variety of

c x -

90

(several r p s )

Ho

6H33

I:

O-P-O-+

R'

Fe

Organophosphorus Chemistry

(COh

NMe3

I

0-

83

82

85 Phosphatidylcholine bearing DHA and a polyunsaturated acid [24:6 (n-3)]

86

responses in order to regulate their growth, differentiation, apoptosis and migration. OH H

8

O

OH

-

~

-

O

OH ~

C3H27I

NHR

87 D-erythro-sphingosine1-phosphate, R = H 88 Ceramide, 1-phosphateR = C O ( C H Z ) ~ C H ~

H

O

~

C3H27 I

NHR 89 D-erythro-sphingosine, R = H 90 Ceramide, R = CO(CH-&CHs

Methods have been developed for the phosphorylation of peptides. This is connected with the fact that the phosphorylation of proteins is probably the most important reversible element of the cell regulation. The H-phosphonate efficient approach has been applied to the solid-phase synthesis of phosphopeptides. Ammonium tert-butyl H-phosphonate (91) has been used as phosphorylation reagent for Tyr- and Ser-containing peptides synthesised by an Fmoc strategy. (Scheme 13).45This reaction, leading to a monoprotected peptide phosphate (92), is generally applicable. Moreover this method avoids undesired side reaction during chain elongation. Two novel classes of phosphopeptide mimetics, 0-boranophosphopeptides (93) and 0-dithiophosphopeptides (94), derivatized on tyrosine, serine and

2: Quinquevalent Phosphorus Acids

91

-

OH

I FITWC-X-Y

a, b

X=SerorTyr Y = protected peptide

8

(B~)O--P-OI

9 I

Ft~t0c-X -Y

92

0 91, pimloyl chloride, DMF, pyridine; (b)1% l2 inpyridine-water 982.

Reagents: (a) BU'b-O'NH,' I H

Scheme 13

threoine, have been synthesized on a solid-phase. The use of H-phosphonate and H-phosphonothioate monoesters containing the base labile 9-fluorenemethyl protecting group was key to the synthesis of phosphopeptide mimetics. (Schemes 14 and 15).46 It has been shown that the dithiophosphoryl and boranophosphoryl peptides are superior to the monothiophosphonyl derivative as an inhibitor of Yersinia PTP. The dithiophosphoryl peptides are additionally stable toward phosphatase activity. 0

It H-P-OFmpl Piv-CI I I 0 f I

0

II H-P-OFrnpl I OH

R

'RZH

AcN

AcN

I

0

V

II

H3BLP-OFmpl

II

H ~ B ~I P - O H NHdOH

Q

ri

AcN

Scheme 14

-

93

S I1 S-P-OFmpl

I

NH40H

0

k

A~N,---L+-NH~

I

?R

-

*td-+NH2

S II 'S-P-OH I 0

1. BSTFA 2. BbTHF

k

AcN

94

S II 'S-P-OH

AI

DBU

___)

R

AcN

(63-70%) Scheme 15

A general route to peptides containing 1-(2-nitrophenyl)ethyl-cagedphosphoserine (99, -threonine (96), and -tyrosine (97) has been developed. The

92

Organophosphorus Chemistry

synthesis is based on an interassembly approach integrated into Fmoc solid phase peptide synthesis.47Photochemical uncaging of these peptides releases the 2-nitrophenyl protecting group to afford the corresponding phosphopeptides. The biologically active phosphopeptides obtained may be used in real-time studies of kinases in vivo.

cpErk

Ac-Pro-LeltN I H

Pro-Ala-Lys-Leu-Ala-Phe-Gln-Phe-Pro-CONH2 O 95

cpChk2

Ac-Met-Ala -Arg-His- Phe-Asp-N I H

Tyr-Leu-lle-Arg-Arg-CONH2

O 96

cpPax

Ac-GIeGlu-GleHis-Val-N I H

Ser-Phe-Pro-Asn-Lys-Gln-Lys-CONH2 O 97

2.2 Reactions of Phosphoric Acids and Their Derivatives. - A wide range of investigations of phosphate ester hydrolysis continue to appear. The hydrolysis of phosphotriesters with high pK value leaving groups involves parallel reactions. The large primary and secondary ''0 isotope effect suggests an associative type transition state in which the nucleophile approaches very closely to the P center to eject the leaving group. The large values are also indicative of a large compression, or general movement, along the reaction ~ o o r d i n a t eAb . ~ ~initio calculations of the reaction coordinate revealed that the base-catalysed hydrolysis of toxic phosphorotriesters that have small pK values for the leaving group

93

2: Quinquevalent Phosphorus Acids

such as Sarin, Somon, diisopropyl phosphorofluoridate and dimethyl phosphorofluoridate occurs by the attack of hydroxide ion at the P center to form a pentacoordinate intermediate, whereas the hydrolysis of Paraxon proceeds through a one-step proce~s.''~Ab initio calculation has been also used to investigate the effect of the solvent on the associative/dissociative and the in line/sideways character of the hydrolysis of ethylene sulfate and ethylene phosphate and their acyclic counterparts. The change in the reaction induced by solvent has been interpreted by use of the Hammond and anti-Hammond postulate^.^^ The mechanism of hydroxide catalysis for phosphodiester hydrolysis by examining D20/k ionic strength effects, and 18k,,, to probe the hydroxidecatalysed hydrolysis of thimidine-5'-nitrophenyl phosphate was investigated. The results are most consistent with a direct nucleophilic attack by hydroxide, making phosphodiester hydrolysis distinct from both ester and amide hydrolyS~S.~' It was found that the rate of attack of hydroxide on the phosphorus of dialkyl phosphate esters is far slower than previously estimated. Consequently, nucleases are considerably more proficient than previously suggested.52 A novel Zn" complex bearing a mercaptoethyl group (98), the structure of which was determinated by X-ray crystallography, promoted the hydrolysis of sodium bis(p-nitrophenyl) hydrogenphosphate BNP-.The rate of Zn" -promoted hydrolysis increases with the increase in pH, indicating that zinc-bound hydroxide is an active species for the hydrolysis of BNP-.The major role of the thiolate coordination is structural stabilization rather then enzymatic activity.53

R

R R=NO;!

99

The introduction of cofactors in catalytic metal complexes can, by analogy to metal enzymes, lead to significantly improved performance. The presented results show that large rate enhancements of the hydrolysis of phosphate esters (99) can materialize by the use of stacking effects.54Both the experimental and computational results indicate that the rate acceleration imparted by the aprotic solvent is limited to phosphate monoesters having leaving groups less basic than phenol.55Quantum mechanical calculations support the existence of 'anionic zwitterion' MeO(H)P032-as a key intermediate in the dissociative hydrolysis of the methyl phosphate anion. 56 There are promising indications of the potential use of lanthanides in enhancing the reactivity of acyl compounds in general

94

Organophosphorus Chemistry

toward oxygen-centered nuclephiles. The effects of lanthanide ions upon the hydrolysis of the acyl phosphate monoester benzoyl methyl phosphate (BMP) and the reaction of BMP with methanol have been investigated. The results obtained indicate that lanthanide salts dramatically increase the reactivity of acyl- phosphates towards oxygen- centered nu~leophiles.~~ Nucleophilic substitution reactions of aryl bis(4-methoxy-phenyl) phosphates (100) with pyridines were studied (Scheme 16). It was found that in the case of quite strongly basic phenolate leaving groups, a concerted process is characteristic for the weakly basic pyridines, whereas more basic pyridines promote stepwise substitution involving a pentacoordinate phosphorus intermediate. In the case of less basic phenolate leaving groups, direct back side attack (TBP-5 CTS) takes place.58

4 00

4

2 = 4-CI,3-CN X = 4-NH2,3-CH3 Scheme 16

Two artificial neutral phosphate receptors with multi amide scaffolds have well-defined structures, on the basis of fluorescence titration, X-ray analysis and NMR studies, which promote efficient and selective complexation with phosphate in 1:l binding stoichiometry e.g. ( 101).59

represents I-pyrene

0 101

In recent years, methods for the catalytic cleavage of the P - 0 bond in phosphate esters have been developed. It is now reported that a cyclic p-sheet peptide -based binuclear zinc (11) complex markedly accelerated the cleavage of the phosphodiester linkage of the RNA model substrate 2-hydroxypropyl p-nitrophenyl phosphate (102)(Scheme 17).60

2: Quinquevalent Phosphorus Acids

95

Other authors found that a highly flexible crown ether - scaffold (103)constitutes a simplified activity - controllable catalytic system for phosphodiester bond cleavage of the same RNA model substrate ( 102).61

Lcu*4+ 104

Catalytic dealkylation of a broad range of phosphate esters through cleavage of an 0 - C bond with new binuclear boron compounds has been described. The chelated boron bromides appear to be promising candidates for the decontamination of chemical warfare agents such as VX and Sarin gas under organic conditions62.Photochemical P - 0 bond homolysis of aryl diethyl phosphates was activated via a resonant two-photon reaction giving 1,4-dihydroquinone and phenol derivative^.^^ Demethylation reaction of methyl diarylphosphates catalysed by complex of polyether ligands with alkali metal iodides MI M = Li,Na,K, has been reported. The data obtained reveal metal ion participation (‘electrophilic catalysis’)in this demethylation reaction.64The complex LCu2 (104) is the first monenzymatic catalyst for the transestrification of simple alkyl phosphodiesters under mild conditions. It may operate by a mechanism proposed for hydrolytic or alcoholytic phosphoryl transfer in various enzyme^.^' Investigations of phosphodiester alkylation with 2.6-dimethyl-p-quinone methide in various buffered phosphodiesters/acetonitrile solutions revealed that alkylation occurs with a faster rate constant relative to competitive hydrolysis at pH 4.0.66 The number of reports of work on applications of glucosyl phosphates continues to grow and the following is a selection. A linear solution - phase synthesis of a fully protected H-type I1 pentasaccharide utilizing glucosyl phosphate and glycosyl trichloroacetamidate building blocks has been e l a b ~ r a t e dSynthesis .~~ of various C-aryl and C-alkyl glucosides using glucosyl phosphate has been prepared? Glucosyl phosphates are also useful donors in the synthesis of challenging P-mannosidic and P-2-amino glucosidic li11kages.6~ An efficient one-pot synthesis of a-and P-glucosyl-phosphate and -dithiophosphate triesters has been described. The resulting glucosyl phosphates and dithiophosphates are versatile glucosylating agents for the synthesis of oligosa~charides.~~ The first automated solid-phase synthesis of a branched Leishmania Cap tetrasaccharide was readily achieved using glycosyl phosphate and glycosyl trichloroacetamidate building The preparation of resin-bound glucosyl phosphates and their successful use as glucosilating agents for coupling with the series of nucleophiles has been

96

Organophosphorus Chemistry

described. The stereochemical outcome of disaccharide formation is dependent on the nature of the link connecting the saccharide to the polymer.72Glycosyl donors having a diphenyl phosphinate or propane-1,3-diyl phosphate (105) leaving groups were selectively glycosylated with a number of primary and secondary oxygen nucleophiles in the presence of trimethylsilyl triflate.73Similarly the compounds (105) were employed in the stereoselective synthesis of Cgluc~sides.~~

RR@ RO

0,I?

R = Bn, Ac 105

The preparation of thiophosphoramidate (106) has enabled the specific thiophosphorylation of histidine (107) at its 3-position (Scheme 18). Alkylation of 3-thiophosphohistidine (108) by phenacyl bromide serves as a model for the introduction of labelling or probe reagents into hisitidne phosphorothioatecontaining protein~.~’

d 08

107 Scheme 18

Electrochemical oxidation of anticancer drugs ifosfamide and cyclophosphamide produced in high yield methoxylated analogues of the key hydroxymetabolites of these oxazaphosphorine prodrugs (Scheme 19).76

’

R’

R’ E CA hO TO Hs

cI

H 3 c Q ’ t + ~ - ~

carbone, 2 Flmole

R’ R2

b I? ,

0

CI

,”

3

c

~

R2

,

,

,

l

~

R’= (CH2)$I, R L H R’= H, R1=(CH&CI Scheme 19

The activity of diethyl phosphate was enhanced by attaching a trifluoromethyl sulfonamide group as an efficient leaving group thus making reagent (109) a useful amide and peptide coupling reagent (Scheme 20).77

c

l

2: Quinquevalent Phosphorus Acids

Ph(CH&NH2

+

97

PhN base \ PO(OEt)2 109

AcOH

Ph(CH2)2NHAc

+

____+

solent, r.t

Ph(CH&NHPO(OEt)2

Scheme 20

It has been shown that metallation of diisopropyl phosphates derived from primary aliphatic alcohols, except methanol, takes place at the alkyl as well as the isopropyl group in a ratio which is strongly influenced by steric effects. It was proposed that short-lived alkyllithium compounds were configurationally stable up to -50°C and rearrange, with retention of configuration, into the corresponding a-hydroxyphosphonates (phosphate-phosphonate rearrangement) (Scheme 2 l).78

Rq = H, Me, Pew, Pri, But; R2 = H R'l = Me; R2 = Me, Pew, Pd, But Scheme 21

Thiophosphates (110)derived from benzyl and vinylogous alcohols in CH3CN were conveniently isomerised into the corresponding thiolophosphates (111) under photochemical conditions through a non-chain radical pathway (Scheme 22).79 ROP(S)(OEt)2 110

hv,

[ROP(S)(OEt)$'

1 [R' +'SP(O)(OEt)2]

---w

RSP(S)(OEt),

111

Thionophosphate- thiolophosphatephotoisomerisation Scheme 22

New synthetic pathways for the preparation of chiral cyclic oxaza- and diazaphosphoramidates suitable for use in asymmetric chemistry were studied with respect to the imide-amide rearrangement of cyclic phosphorimidates (Scheme 23).80New types of oligomeric organophosphorus compounds (112),formed by a novel ring opening polymerisation, have been identified. These compounds are stable intermediates in the imide-amide rearrangement.

Organophosphorus Chemistry

98

112

Scheme 23

The data reported show that ‘PhS+’is a very good coupling agent for forming the P-0-P bond, probably via the intermediate sulfenic-phosphoric anhydride.81 Enhanced chromatographic resolution of alcohol enantiomers as phosphate or phosphonate derivatives has been demonstrated.82 Acyclic allylic phosphates (113)derived from the corresponding allylic alcohols can undergo SN2‘reactions with organocopper reagents with >98% regioselectivity and >98% anti-selectivity (Scheme 24).s3

113

Scheme 24

Allylic phosphates and allylic phosphinates (114) have been used as electrophiles in efficient silyl cupration reactions of a variety of acetylenes. This method provides an easy access to substituted 1,4-diene systems (115) (Scheme 25).84 R’l R l I R*

=

R2

+

PhMezSiCuCNLi

- ”HR2

THF -40%. I h

cu

= H, alkyl, aryt, TMS

Si Me2Ph

I I

R3, R4, R5 = H, Me, PP

R4 R 3 ~ 0 p ( 0 ’ ( 0 p h h

+

k3 SN2‘ Y

115

81\12a

Scheme 25

A new method for the synthesis of a-phosphono-a#-unsaturated ketones (116) involves iron coordination to a 1,3-diene bearing a phosphate group,

2: Quinquevalent Phosphorus Acids

99

proton abstraction at C-3, subsequent 1,3-migration of a phosphorus group in the 1,3-diene and removal of the iron moiety (Scheme 26).85

I . -'--Iv

THF, -78%

\2 -" '

It6 Scheme 26

31P NMR experiments on the reactions of halophosphates esters with pyridine showed that equilibria involving the formation of pyridinium salts in these reactions are almost entirely shifted to the left for chloro- and bromo-phosphates and to the right for the corresponding iodophosphates. This explains dramatic differences in chemical reactivity between these Substituted medium-sized and large N-heterocycles (117) have been prepared via an extension of the Suzuki reaction involving the palladium-catalysed coupling of vinylphosphates (118) with aryl or heteroaryl boronic acids (Scheme 27).87

Hydrolysis of the corresponding bicyclic phosphoric amides (119) has been used for the preparation of a series of bis(2-arylaminoethy1)amines(120)(Scheme 28).88 Ar

0 aqueous-dioxane solution of HCI

119 Scheme 28

c": H

NH

9

(-.:*'

3HCl

120

H

A facile one-pot synthesis of thiophosphoryl xanthates was carried out by using a mild base DBU-catalysed sequential reaction of excess alcohols with carbon disulfide and diethoxy thiophosphoryl ~hloride.~' A convenient method for the synthesis of selenocarboxamides (121) from aromatic and aliphatic nitriles using monoselenophosphate (122)has been elaborated. This method complements the previously reported methods since aqueous acidic conditions are used as opposed to basic conditions or BF3.OEtz in

100

Organophosphorus Chemistry

organic solvents (Scheme 29).90 Many further examples of the applications of thiophosphates in organic R-CZN

f

H2P03Se‘

ROH/H@

122

Se

)-( R NH2 121

Scheme 29

synthesis have been reported. A novel approach to highly substituted enynes (123) via a new single and double carbon-carbon bond forming reaction involving interaction between readily available thiophosphates (124) and lithium acetylides has been described.” Similar reactions of thiophosphates containing the a$-unsaturated carbonyl moiety (125) with sodium acetylides constitute a general and convenient route to a wide range of conjugated dieneynes (126) (Scheme 30).92

124

R’

R’ 123

125

R’

126

Scheme 30

A variety of lactones and cycloalkanones have been converted into their 2methylene derivatives using a one-pot procedure in which the key steps involve the formation of the corresponding thiophosphates (127) and their reactions with sodium borohydride under very mild conditions. This approach gives also ready access to racemic frullanolide in high yield and should be applicable to the synthesis of other endesmanolides. (An example of the synthesis of a-methylene lactones (128) is given in Scheme 31).93 It has been demonstrated that cycloadducts (129), which are enolphosphates obtained by regio- and stereospecific [4 + 21 cycloaddition reactions of dienes (130) to a variety of dienophiles, are functionalized versatile synthons having fixed stereochemistry. Their [2,3] sigmatropic rearrangement via allylic sulfoxides and selenoxides (131) provides a direct sterospecific entry to new functionalized bi- and tricyclic allylic alcohol systems (133). The latter has been transformed into the corresponding a-hydroxy ketones (1 32), key structural subunits of natural products and valuable synthetic intermediates (examples are given in Scheme 32).94

2: Quinquevalent Phosphorus Acids 0

101 0

1

(Et0)2P(O)SCI -78%

0

0

127

128

n = 1, 2; R = H, Me, Ph, Hep Scheme 31

It has been found that allenyltitaniums (134),prepared in situ by the reaction of optically active secondary propargyl phosphates (135) with a divalent titanium reagent, react readily with alkenylidenemalonates with excellent regio- and dia-stereoselectivity to afford the Michael addition products (136) with high optical purity (Scheme 33).95 In recent years the synthetic potential and mechanistic aspects of asymmetric catalysis with chiral Lewis base have been investigated. Aldol addition reactions between trichlorosilyl enolates with aldehydes have been also intensively studied. Now, full investigations of the trichlorosilyl enolates derived from achiral and chiral methyl ketones, in both uncatalysed and catalysed reactions with chiral and achiral aldehyde acceptors have been reported. The aldol addition is dramatically accelerated by the addition of chiral phosphoramides, particularly (137) and proceed with good to high enantioselectivity with achiral enolates and aldehydes (Scheme 34).96 The first catalytic, diastereoselectiveand enantioselective cross-aldol reactions of aldehydes have also been documented. Geometrically defined trichlorosilyl enolate derivatives of aldehydes undergo diastereoselective addition to a wide range of aldehyde acceptors with good enantioselectivity. The use of chiral Lewis base (138) was critical for achieving useful enantio~electivity?~ The synthesis of various new chiral (0-hydroxyary1)oxazaphospholidine oxides (139), derived from (S)-proline derivatives, from precursors (140) have been elaborated. This two-step reaction involves an unstable metallated intermediate that undergoes a fast 1,3-rearrangement with the formation of phosphoruscarbon bond. These catalysts have been successfully applied to the catalytic asymmetric borane reduction of numerous prochiral ketones with enantiomeric excess up to 84% ee (Scheme 35).98 The dirhodium tetrakisbinaphthol phosphate (141) and (142) catalysts provided some of the best levels of asymmetric induction in oxonium ylide formation -[3.2] sigmatropic rearrangement reported to date (Scheme 36).99

102

Organophosphorus Chemistry

I3O

n=1.2 X=S,Se

R1

I c,

129

132

Scheme 32

The preparation of four different types of oxaza spirobicyclic systems (143) by 1,6- and 1,7-hydrogen atom transfer promoted by phosphoramidyl radicals in carbohydrate models has been described. The N-radicals are generated by reaction of dibenzyl phosphoramidate derivatives of C-glycosides with (diacetoxyiodo)benzene and iodine through a homolytic fragmentation of iodoamide intermediates (Scheme 37).'O0 The aza-Claisen condensation of ethyl-[N-(diethoxyphosphory1)l-formimidate with enolizable ketones can be recommended as a simple and efficient route

2: Quinquevalent Phosphorus Acids

103

135

134

136

~ 9 7 %anti >92% enantiospecificity Scheme 33

'h,..

1. (S,S)- 137

Me

2.NaHC03 (as.)

Me

Ph

Y"

O, ,pN ,

PhA N '

\Me SIR = 9.9: 1

(S,S)-137

Scheme 34

to not readily accessible diethyl 1-a1keny1-3-oxo-phosphoamidates." A new strategy of thioacylation starting from carboxylic acids has been developed. Acyl chlorides react with the excess of dithiophosphoric acid (144) giving thioacyl dithiophosphates (145) which are excellent thioacylating reagents. Thus reagents (145) readily undergo reactions with nitrogen and sulfur nucleophiles affording the corresponding thioacyl derivatives (146) (Scheme 38).lo2

104

Organophosphorus Chemistry 0 I. LDA, -X0C

2.HzO

R

_____)

R

R

I 40

catalyst 139 (2 rnol%)

+

R

8H3-SMez

solvent

139 HO R1

Scheme 35 Scheme 35

Rb (R-BNP)d

R b (R-DDBNP)4

141

142

up to 62% ee Scheme 36

143 Scheme 37

2.3 Selected Biological Aspects. - It has been shown that in the co-translational transfer of a tetradecasaccharide (Glc3Man9GlcNAc2-)( 147), which is the asparagine residue of a nascent polypeptide chain inside the lumen of endoplasmic reticulum, N-glucosylation is catalysed by the enzyme oligosaccharyl trans-

105

2: Quinquevalent Phosphorus Acids

'R 145

146

Scheme 38

ferase (OT) and affords the P-linked glucopeptide (148).The substrate specificity of the glycosyl donor is discussed on the basis of the synthesis and biological evaluation of three unnatural dolichol-linked disa~charides."~ Oligosaccharyl fransferase

Glycopeptide

Bz-NLTK(Ac)-NH2

148

6

147 Y = NHCOMe,X = NHCOMe,NHCOCF Y = OH, X = NHCOMe

A-

or F

OH

'\

P/0&oc18H37

HO

o+

y e

149 X = H (DDPIEC) 150 X = OH (DPIEL)

'OH

The first synthesis of a novel PI analogue, namely lD-3,4-dideoxyphosphatydylinositol ether lipid (DDPIEL) (149) has been elaborated. DDPIEL is 18-fold more potent than its monodeoxy counterpart DPIEL (150) in the inhibition of P13K.lw Fostriecin (151)is a structurally novel phosphate ester produced by Streptomyces pulveraceus that is active in vitro against Leukemia, lung cancer and ovarian cancer, and which exhibits effications in vivo antitumor activity. The first total synthesis of fostriecin (CI-920) has been disclosed. This fostriecin is a unique phosphate monoester which exhibits weak topoisomerase I1 inhibition and more potent and selective protein phosphatase 2A and 4 (PP2A and PP4) inhibition.lo5 The naturally occurring PP2A inhibitor cytostatin (152), which was isolated from a Streptomyces inhibits the adhesion of B16 melanoma cells to laminin and collagen, displays anti metastatic and cytotoxic activity and induces apoptosis of B16 melanoma cells. The synthesis of the 4S,5S,6S,lOS,llS,12S isomer of cyto-

Organophosphorus Chemistry

106

Fostrecin 151

statin has been elaborated. This successful synthesis now opens up new opportunities for the development of new tools for biological studies and new cancer drugs.lM

(4S, 5S, 6S, IOS, 11S, 12s)

152

153

A GDP-azasugar conjugate (153) has been synthesized from an enzymatically obtained phosphorylated azasugar. It inhibits human fucosyltransferase V at micromolar concentrations, which is discussed in terms of transition state analo g ~ . ’ ’A~ series of 2- (154) and 3-substituted (155) indolequinone phosphoramidate prodrugs targeted to DT-diaphorase (DTD) have been obtained and evaluated. Compounds substituted at the 2- position are excellent substrates for human DTD, whereas those substituted at the 3-position are potent inhibitors of the target enzyme. A significant correlation between DTD activity and cytotoxicity was observed for the 2-series of compounds, suggesting that drug delivery from the 2-position is an attractive prodrug strategy for targeting DTD”* Octyl-0-P-D-mannopyranoside (156), a very simple caloporoside analogue, has been prepared from (157), (Scheme 39) and its functional effects on inhibitory ion channels characterised. At 100 pM this product significantly and reversibly increased the magnitude of GABAAcurrents evoked in cultured rat pyramidal neurones whilst concomitantly reducing the incidence of spontaneous synaptic activity. These results contradict earlier proposals that such molecules bind to the TBPS (tert-butylbicyclophosphorothionate)site to block the chloride channel.’”

2: Quinquevalent Phosphorus Acids

107

0

155

R1, R2 = M e ,

R3, R4 = CH2CHzBr R I , R*= (CH2CH2)zO; R3, R4 = H R1, R2 = CH2CH2Br; R3, R4 = H

b ----f

I 0

0 II

F ' '0 157

156

' 0

U

Reagents: (a) HO(CH 2)7Cti3, TMSOTf (cat.) -78%: (b) Pd(0H) 2, MeOH, cyclohexene.

Scheme 39

Pyridoxal phosphate derivatives (158 a-c) have been synthesized and identified, as highly potent and selective antagonists of P2X1receptors and antagonists of combined P2X1,3receptor selectivity. A selective P2X1 receptor antagonist may have potencies utility in controlling receptor -mediated contraction of visceral and vascular smooth muscle."o

3

Phosphonic and Phosphinic Acids

The synthesis and reactions of phosphonates containing alkynyl groups has been the subject of a review."' 3.1 Synthesis of Phosphonic and Phosphinic Acids and Their Derivatives. - New methods for the synthesis of phosphonic and phosphinic acids and their esters continue to attract attention because they display biologically important properties as natural products and as analogues of phosphates (including RNA/DNA), phosphono and phosphinopeptides, amino acid analogues and pro-drugs. 3.1.1 Alkyl, Cycloalkyl, Arylalkyl and Related Acids. An improved synthesis of alkyl methylphosphonic acids (1 59) has been reported. It involves partial transesterification of trimethyl phosphite, followed by an Arbuzov reaction of the

Organophosphorus Chemistry

108

ONa n.

,H

I

S03Na

S03Na

1

S 03Na 158a

158b

158c

resulting alkyl dimethyl phosphites with methyl iodide, giving alkyl methyl methylphosphonates (160), then rapid reaction with bromotrimethylsilane and methanolysis, providing (159) (Scheme 40).Il2

-

MeO,

ROH

P-OMe

cat. Na

MeO'

)-me

Melheat -w .

RO

Me,

/p

P RO' 'OMe

159

160 R = Pfi, Bu*, Bui, BUS, pinacolyl, cyclopentyl, cyclohexyl

Scheme 40

A novel route has been elaborated for the synthesis of 33P-labelledphosphonic acids and their derivatives. It involves the conversion of [33P]H3P04( 161) into [33P]PC13(162) through the unprecedented reaction of POcl3 with PPh3 followed by the facile formation of the key intermediate P(OTMS)3 (163) which undergoes the Arbuzov reaction with the formation of a P-C bond. Compound (164)is easily transformed to [33P]-ethephon (165) (Scheme 41).'13

If

9 0

II ( H O ) ~P"C H ~C H ~C I 165

Reagents: (a) PCI5, (b) PPh-j, toulene, (c) H20,(d) BSTFA, BrCH2CH2CI,(e) BrCH2CH2CI 2h,

(f) H201MeOH.

Scheme 41

2: Quinquevalent Phosphorus Acids

109

It has been demonstrated that it is possible to use a solid phase method for the synthesis of novel unsymmetrical phosphinic acids (168)by phosphinylation of a resin-bound aldehyde (169) and subsequent selective 'P' alkylation something that is generally very difficult to perform in solution (Scheme 42).'14 P-H

R-X

0

II R-P-H

------+

I

0

,R1--X,

11 R-~-RI

OH

OH

169

168 Scheme 42

Absolute configurations, predominant conformations and tautomeric structures of enantiomeric tert-butylphenylphosphinothioic acid were determined.'I5 A facile, high yielding synthesis of symmetric esters of methylenebisphosphonic acids by the 1H-tetrazole-catalysed coupling of methylenebis(phosphonic dichloride) with a variety of alcohols has been A systematic study on the preparation of different types of partial esters of (1-hydroxyethy1idene)-1,lbisphosphonates (HEBPA)(-)PEs has been performed.' l7 A selective and general method for the synthesis of new mixed alkanoic, phosphonic and sulfonic (dichloromethy1ene)bisphosphonic anhydride esters has been described."' A straightforward preparation of a representative number of a novel family of bisphosphorylated compounds, (H-phosphonylphosphonate esters) has been developed. Their reaction with aldehydes provides access to the hitherto almost unprecedented class of a-hydroxyphosphinyl phosphonates of potential value, in particular, in medicinal ~hemistry."~ The a-substituted phosphonates (170), which are useful precursors for Horner-Wadsworth-Emmons reactions, have been readily prepared by treating (171)with an aromatic aldehyde (examples are given in (Scheme 43).120

x

171 170

X = CI, OMe, NMe2,OSiMe3 Scheme 43

The reaction conditions necessary in ordei to obtain, in high yields and pure form, either 1-cyanomethylphosphonates or 1-cyanomethylenediphosphonates, has been reported.'*l Catalytic systems derived from Ru(C0) porphyrins are extremely efficient at converting styrene and diisopropyl diazomethylphosphonate to cyclopropyl phosphonate esters (172) in high yields and with high stereoselectivity.A monocarbene complex RU(TPP)(CH{P(O)(O~P~)}~) has been isolated as a possible catalytically active species.'22

110

Organophosphorus Chemistry 0

0

172

A new one-pot Pummerer phosphorylation reaction allowed an efficient synthesis of 2-phosphonathiolanes (173) starting from thiolane S-oxide (174) and trialkyl phosphites. The S-oxidation of the cyclic compounds (173) occurred with a total trans-stereoselectively (Scheme 44).'23

174

173

R l = R2 = Me, Et, Pri, L-menthyl R1= CH2CMezCI-42, R* = Me Scheme 44

The first asymmetric P-C bond formation under heterogeneous conditions has been achieved via a Fe203-mediated conjugate addition of a chiral phosphite (175) to alkylidene malonates. The easy cleavage of the chiral auxiliary from the addition products (176) leads to optically active P-substituted P-phosphono malonates (177) in good yields and high enantiomeric excesses (Scheme 45).'24

(R, R, S) 176 &=86-94%

(S)177 88 = 84 - 94% Reagents: (a) Fe &/KOH, CHzCI2; (b) TMSCI, Nal,, CH 3CN; (c) CH &i2/H$3;

Scheme 45

(d) CH2N2, MeOHRI2

2: Quinquevalent Phosphorus Acids

111

A scale-up synthesis of isosteric phosphonate analogue (178) of mannose-6phosphate (M6P) has been performed via regioselective nucleophilic displacement of the protected 4,6-cyclic sulfate precursor (179) by lithiated dialkyl methylphosphonates in the key

178

179

3.1.2 AlkenyZ, AZkynyZ, Aryl and Related Acids. Vinylphosphonates are an important group of compounds that have found use in organic transformations. They are also useful reagents for the synthesis of biologically active systems. The synthesis of vinylphosphonates is varied. However additional convenient routes to them are always welcome. Four recent reports demonstrated that zirconacycles (180), readily available from diethyl 1-alkynylphosphonates, are very useful precursors of different vinylphosphonates. They react with alkynes,'26 aldehydes,'27 ketones12*,acyl chlorides and nit rile^'^^ to produce, in a highly stereo- and regio-selective manner, substituted vinylphosphonates (18l), (182), (183) (184)and (185) respectively (Scheme 46).

0

Organophosphorus Chemistry

112

R1 = alkyl, aryl R* = H

186

A facile approach to alkyl- and aryl-substituted 3-furylphosphonates (186) based on cesium ammonium nitrate-promoted radical reactions has been elaborated.I3' Reactions of allylphosphonate (187) with N-tosylsulfonyl imines (188) using different conditions provided a route to 1-[3-methoxycarbonyl)-allylvinylphosphonates (189) or 3-methoxycarbonyl-l,3-dienylphosphonates (190) (Scheme 47).'31 a

0 II (Et0)2PdC02Me

R I87 188

C02Me

190 Reagents: (a) DMF, cat. Bu'OK (20 mot%), 130"C, 5 min.; (b) DMF, cat. Bu'OK (20 mol%), O"C, 5 min.

Scheme 47

Under suitable reaction conditions, monoalkylation of phosphonocrotonate (191) could be accomplished efficiently, leading to the preparation of a-substituted phosphonocrotonate derivatives ( 192).'32 The palladium-catalysed regio- and stereoselective hydrophosphorylation of allenes and 1,3-dienes using phosphite (193) offers a convenient and clean route to a variety of allylphosphonates (194 a-b) (examples are given in Scheme 48).131134

Substituted vinylphosphonates (195) and allylphosphonates (196) with Eolefin stereochemistry have been prepared for the first time via intermolecular olefin cross-metathesis (CM) using ruthenium alkylidene complex (197) in good yield. A variety of terminal olefins, styrenes and geminally substituted olefins has been successfully employed in these reactions (Scheme 49).'35 The oxidative addition of H-phosphonates (198)to platinum(0) complexes and the palladium-catalysed hydrophosphinylation of alkynes proceed stereo-specifically with retention of configuration at phosphorus. The latter provides a convenient and general synthetic route to enantiomerically pure P-chiral alkenylphosphinates (199) (an example is given in Scheme 50).136

113

2: Quinquevalent Phosphorus Acids

191

Pd catalyst

R/==

R

192

+ +>P(OlH

0 R

V

P

'

:

%

193

194a

194b Scheme 48

196

Scheme 49

A new approach to cyclic a-thiophosphonates (200) involves both a [2,3]sigmatropic rearrangement of an intermediate sulfur-ylide (catalysed by Rh2(0Ac)4)generated from a-diazaphosphonates (201) and subsequent metathesis of the resulting allylic sulfides using the Grubbs ruthenium benzylidene catalyst (202), producing (200) (Scheme 5 l).13' The first asymmetric synthesis of an a-mercapto y-unsaturated phosphonate (203) using the readily available chiral dimenthylphosphonyl ester group and a carbanionic [2,3] sigmatropic rearrangement was achieved. Absolute configuration of the newly formed chiral centre of nonracemic thiol(203) was determined.

Organophosphorus Chemistry

114 0

& '

+

198,198'

toluene, 70OC,4h

199

199'

95% yield (~96%regioselectivity)

0

0 II

198(Rp)

198' (SP)

11 ,P...,," Ro bh

0

5 mol% MezPd(PPhMez)2 10% Ph,P(O)OH

R = (-)menthy1

Scheme 50

The corresponding cyclic derivatives of (203), phosphonothiolane (204) and thiolane S-oxide (205) were also stereoselectivelyprepared (Scheme 52).13* A method for the palladium - catalysed synthesis of alkynylphosphonates (206) from 1,l-dibromo-1-alkenes (207) has been developed. The best catalyst system for this transformation was Pd(OAc)z,dppf, H-phosphonate (208). The reaction appears tolerant of a range of functional groups in both (207) and (208) (Scheme 53).139

//

201

200

Scheme 51

,,,$a 0

9-

0

I1

fC-

( M * o h P o 204

205

Reagents: (a) 5 equiv. (sec-BuLi/HMPA)THF; (b) UV, AIBN, THF; (c) m-CPBA, TH Scheme 52

2: Quinquevalent Phosphorus Acids

115

0

208

R20-, '.H R3O

/

, Pd(OAch, dppf

-

,DMF, 80OC

206

Scheme 53

The catalyst (PPh3)3RuC1in the presence of DPPB is an efficient reagent for the hydrophosphorylation of olefins. The reaction is highly sensitive to olefin substitution and monosubstituted olefins can be reliably converted to their aliphatic phosphonates in the presence of other olefins. Additionally, a trimethylsilyl group is an effective acetylene protecting functionality that reverses the normal preference for alkyne hydrophosphorylation over a terminal olefin (Scheme 54).I4O Two types of phosphonic acids with a n-conjugated ferrocenyl unit (209) and (210) have been synthesized (Scheme 55) and their electronic properties have been characterized in The (60) fullerenephosphonic acid (211) and methano-(60) fullerene diphos-

Y

pi-0

0

cat. (FPh3)31WCI

Scheme 54

+

a

4

0 Ti02

209

Reagents: (a) &O/MeOH.

Scheme 55

116

Organophosphorus Chemistry

phonic acid (212) have been synthesized through the terminal addition of dimethyl diazomethylphosphonate to c60 and the Bingel-type reaction of tetramethyl bromoethylenediphosphonate with c60 in the presence of DBU, re~pectively.'~~ Hydrolysis of the phosphonic esters obtained afforded the corresponding acids. 0

0

211

212

Reports on arylphosphonates include: the synthesis and resolution of new racemic phosphonic acid methyl (213) and dimethyl esters (214) via cinchonium salts (Scheme 56).143The absolute configuration of the phosphonic ester products was also established. Synthesis of monosubstituted phosphinic acids (215) based on the novel palladium-catalysed cross-coupling reactions of anilinium hypophosphite (216) with aromatic halides has been described (Scheme 57).14

213

214

Reagents: (a) Me 3SiSr, CH2C12, (b)MeOH, CH 2C12,r.t., (c) MeANOH, H20, (d) Mel, MeCN, ( 4 NalO 4, Me H20. (f) NaOH, H 2 0 , dioxan, H 2 0 ,

Scheme 56 0

0

fi

PhNH30PH2

leq.Phl, 2% Pd(0) conditions, 3eq. base)

216

215 Scheme 57

3-Alkenyl-3-phosphoryl chromanones and their thio- derivatives (2 17) have been synthesized from lithiated ally1 phosphonates (218) and ~alicylate.'~~ It is

2: Quinquevalent Phosphorus Acids

117

suggested that these reactions proceed by a tandem allyl-vinyl migration and cyclization of intermediate a-(0-hydroxybenzoy1)-ally1phosphonate, readily formed from (218). 60

0 II

(Eta* R’

base

X 218

F+

HX

217

x=o,s

3.1.3 Halogenoalkyl and Related Acids. Fluorinated phosphonates are often

designed as a new class of biological phosphate mimics. They are used as enzyme inhibitors and metabolite probes. Therefore, these compounds have attracted much attention. During the period of this review a number of new methods of synthesis, including the preparation of novel fluorinated phosphonates, have been reported. A complementary triflate displacement approach to (a-monofluoroalkyl) phosphonates (219)has been elaborated. Treatment of alkyl triflates or iodides with the potassium salt of (a-fluoro-a-phenylsulfonylmethyl) phosphonate (220) yields (a-fluoro-a-phenylsulfonylalkyl) phosphonates (221),which can be cleanly desulfonated affording (219) (Scheme 58).’46

221

219

Scheme 58

(a-Fluoroalky1)phosphonates (222) have been obtained via the synthesis of apyrimidine- and pyridin-2-yl sulfone derivatives of phosphonate esters (223), followed by a-fluorination of the latter with selectfluor, and then desulfonylation. providing (222) (an example is given in Scheme 59).147 Diethyl-3-triisopropylsilyl-1-propargylphosphonate(224) was fluorinated using DAST to give the corresponding monofluoroderivative (225), whereas the synthesis of difluoroderivative (226) was efficiently achieved following Burton’s methodology using CuCl/Cd to promote the coupling reaction of (227) with the corresponding alkynyl iodide (228) (Scheme 60).148 Stereoselective syntheses of polyhydroxycyclohexyl (a,a-difluoromethy1)phosphonic acid (DFMPA)- esters - (229 a-b), which are stable analogues of inositol phosphates, involved Diels-Alder and ,conjugated addition reactions to prepare precursor^.'^^

Organophosphorus Chemistry

118

223

Reagents: (a) 2-pyrimidinethiol, NaH, DMF; (b) 2-pyrimidinethiol, DEAD, Ph 3P, benzene; (c) m-CPBA, CH2CI,; (d) KH, Selecffluor, THF, DMF; (e) Bu3SnH(D),AIBN, benzene (or toluene); (9 Bu 3SnCI, PMH KF, H20, toluene; (9) Me3SiBr,CH2C12.

Scheme 59

224 (Et0)2P(O)CF*Br 227

225

+ Tips

=

-

F

CuCI/Cd

I

DMF. r.t.

228

Scheme 60

Phosphonic derivatives bearing chlorofluorinated chains e.g. diethyl-1,1,2trifluoro-2-chloroethylphosphonatehave been prepared by radical telomerization of chlorotrifluoroethylene with dialkyl hydrogenphosphonates in the presence of peroxide inhibit~rs.''~The 0,O-diethylaryldifluoromethylphosphono t hioates (230) undergo the sodium iodide-assisted thiono-t hiolo rearrangement and subsequent Pd-catalysed dealkylation of (231)provides several 1,l-difluoromethylenephosphonothioicacids (232) (Scheme 61).'" These compounds can act as small molecule inhibitors for the protein tyrosine phosphatase enzymes. A facile preparation of novel allenic (a,a-difluoromethy1ene)phosphonates (233) has been achieved by CuBr-promoted reaction of zinc reagent (234) with readily available propargylic ~ubstrates.'~~

119

2: Quinquevalent Phosphorus Acids

-

Ar-CFzP-OEt A--Et

230

X=H,K

0

II

Ar-CF2P-SbEt

231

Et

232

Scheme 61

ox BrZnCF2P03Et2234 DMF

*

RkR3 C F2PO3Et2

R*

233

X = Te or Ac

The same zinc reagent (234) reacts with 1-haloalkynes under CuBr catalytic condition leading to a,a-difluoropropargylphosphonates (235).'53 (Et0)z P(0)CF2ZnBr 234

1. CuBr

2. RC=CX

X = I, Br

OEt)2 RC=CC FzP(0)( 235

Stereoselctive synthesis of fluorinated (E)- and (Z)-allylphosphonates involves treatment of phosphonium ylides (236) with methyllithium derivative (237) giving, after protonation and elimination of Ph3P0, (Z)-allylphosphonates (238), whereas with alkyl lithium derivative (239), (E)-allylphosphonates (240) result (Scheme 62).154 The base-promoted reaction of fluoroalcohols RQH (Rf= CF3CH2 H(CF2)CH2,C2F5CH2,C3F7CH2,(CF3)2CHwith alkyl phosphonic dichlorides is an excellent method for the synthesis of bis(fluoroalky1) alkylphosphonates (RP)2 P(0)R. 3.1.4 Hydroxyalkyl Acids. The first reliable synthesis of l-hydroxyalkylphos-

phonates (241) in high enantiomeric excess has been achieved via titanium alkoxide-catalysed asymmetric phosphonylation of aldehydes then acetylation and enzyme-catalysed kinetic resolution of the acetates (Scheme 63).156 C. rugosa lipase-catalysed enantioselective hydrolysis of 2-butyryloxy-2arylethanephosphonates provides a convenient route to optically pure 2-

120

Organophosphorus Chemistry

R

1.i301, l-(OPr)d, Et20

0

2-15%. .Polyvinylpyridine (MeO),P(O)H b

(Meo)2+

, , ,Py

+

0

AcCI. CH3CN

mpr

minor

QAC

OAC

Bu'OMe, pH 7.0 buffer lipase

f

0

0

I1

I1

(MeohPvR + tMe*)zpG 68-79% yield, 79-99% e.e &I

241a

b

C

241b

Scheme 63

hydroxy-2-arylethane phosphonates (242). The reaction is simple yet highly enantio~elective.'~'

>95% e.e.

Lipase-mediated acylation of racemic P-chiral hydroxymethanephosphinates (243) was performed in ionic liquids under kinetic resolution conditions. Lipase AK (Amano)and lipase from Pseudomonas fluorescens were up to six time more enantioselective in BMIM PF6solutions than in common organic solvents.'58

243

Ammonolysis of trans 1,2-epoxy-2-arylethylphosphonic esters appears to be a

121

2: Quinquevalent Phosphorus Acids

valuable synthetic method for the preparation of p-amino-a-hydroxy arylalkylphosphonic derivative^.'^^ Significant improvements in the preparation of the racemic analogue of docetaxel side chain (244)and its resolution have been have been described.16' Protected 2-amino-1,3-dihydroxypropylphosphonates synthesized from Garner aldehyde and dialkyl phosphite in good 9:l diastereoselectivity, when triethylamine or fluorides were used as catalyst.161Diastereoselective synthesis of P-amino-a-hydroxy-H-phosphinates (245)through hydrophosphinylation of N,N-dibenzyl-a-amino aldehydes (246)catalysed by ALB has been developed. Both syn and anti compounds (245)could be prepared selectively by tuning the chirality of ALB (Scheme 64).162J63 The two starting 1-hydroxy-2-azidoethylphosphonatesof (S) and (R) configuration (247)have been obtained by a simple lipase-catalysed resolution and transformed by multistep synthesis into L-(R)-(-) phosphaserine and L-(R)-(-)-phosphaisoserine.The ee excess (97%) and absolute configuration of both aminoacids were determined by HPLC.lW

I

OH

244

245

Scheme 64

(R)-(+)-247

(I?)-(-) phosphaisoserine

3.1.5 Oxoalkyl Acids. Various types of readily available a-hydroxyphosphonates have been converted to a-ketophosphonates in high yield by potassium

122

Organophosphorus Chemistry

permanganate in dry benzene or by neutral alumina supported potassium permanganate (NASPP) oxidation uder solvent-free condition~.'~~ Preparatively useful access to 2-phosphonocyclopenten-2-ones (248)which would be new valuable cyclopentanone building blocks has been described.'66 The rhodium (11) catalysed thermolysis of E-trimethylsilyloxy-a-diazo+ketophosphonates (249)is reported to give rise to a-phosphono-f3-lactones (250) in moderate to good ~ i e 1 d s .Diels-Alder l~~ reactions of enone phosphonates (251) with different 1,3-dienes give adducts, which are complex phosphonate-containing polycycles with keto function (252)(e.g., Scheme 65).These fl-keto phosphonate systems found interesting synthetic applications.'68 0

R1' 248

252

251

Scheme 65

3.1.6 Aminoalkyl and Related Acids. - Further development of the classical three component approach to aminoalkylphosphonates (the Kabachnik-Fields reaction) has been reported. The reaction of aldehydes, hydroxylamines and dimethyltrimethylsilyl phosphite using lithium perchlorate/diethyl ether as a catalyst gives N-trimethylsilyloxy-a-aminophosphonatederivative^.'^^ The catalytic activities of various lanthanide triflates as well as indium trichloride have been examined for the Kabachnik-Fields type reactions of aldehydes, amines and the phosphorus nucleophiles HP(0)(OEt)2and P(OEt)3in ionic TaC15SiOz has been utilized as an efficient Lewis acid catalyst for the coupling of carbonyl compounds, aromatic amines and diethyl phosphite to produce a-

2: Quinquevalent Phosphorus Acids

123

aminopho~phonates.'~' MontmoriClay-catalyst under microwave irradiation in solvent-free conditions enhanced yields and reduced reaction times of the three component condensation (aldehydes, amine and diethyl phosphite) compared with conventional method~."~Alumina-supported ammonium formate was found to be an efficient reagent for the synthesis of a-aminophosphonates from aldehydes and diethyl ph0~phite.l~~ A number of examples of the addition of dialkyl phosphites to imines has been used to prepare aminoalkylphosphonates. The synthesis of diethyl N-Boc- 1-aminophosphonates involved Michael type of BrTMS addition of sodium diethyl phosphite to N-Boc i m i n e ~ .A' ~mixture ~ and trialkyl phosphate is a very efficient reagent for the phosphorylation of various aldimines giving the corresponding aminophosphonic acids or aminophosphonic acid esters.'75Diethyl phosphite undergoes nucleophilic addition to aldimines catalysed by ZrC4 to afford a-aminophosphonates in high yields with high ~e1ectivity.l~~ The addition of lithium diethyl phosphonate to enantiopure ketosulfimines is highly diastereoselective affording the first examples of quaternary a-alkyl a-amino (arylmethy1)phosphonates (Scheme 66).177

Scheme 66

>97% de

A method for the stereoselective synthesis of a-aminophosphonates and their N-hydroxy derivatives by aminophosphonylation of carbohydrate and amino acid derivatives using nitrone- based chemistry has been reported (an example of reactions of N-monoprotected a-amino nitrones, whose progenitors were alanine, phenylalanine and leucine respectively, affording the corresponding N-hydroxy a-aminophosphonates, is given in Scheme 67).'78

R = Me, PhCH2, MQCHCH~

Scheme 67

Catalytic hydrogenation (Pd-on-carbon) of N-Boc aziridine 2-phosphonates (253) derived from 3-amino-2-hydroxyphosphonates affords N-Boc aaminophosphonic esters (254) in high enantiomeric purity (Scheme 68).lB Unsymmetrical N-benzyloxycarbonyl-protected 1-amino-1-arylalkylphosphonate mixed esters have been synthesized using a one-pot reaction of benzyl carbamate aromatic aldehydes and alkoxydichlorophosphine followed by

124

Organophosphorus Chemistry

v

254

253

Scheme 68

treatment with alcohol in the presence of amine.18*An asymmetric synthesis of l-amino-2,2,2-trifluoroethanephosphonic acid was achieved starting from trifchloride, by a base-catalysed luoromethylated N-(-)-a-methylbenzylacetimidoyl [1,3]-proton shift in the intermediate dialkyl1-imino-2,2,2-trifluoroethanophosphonate.lgl The Cp2TiMe2-catalysedhydroamination of alkynes combined with a nucleophilic addition of dialkyl phosphite to imines (255) allows the synthesis of a,a-disubstituted a-aminophosphonates (256) (examples are given in Scheme 69).lg2 R1

= +

R2

a

R1-j-(R2

b

___)

R’.”x” R3HN

P(0)(OR4)2

R3-NH2 255

256 H

255

256

R1, R*, R3 = Aryl, Alkyl; R 4 = Me, Et; R5 = H, Aryl; n = 1 , 2

Reagents: (a) CpzTiMe2; (b) HP(0)(OR1)2, 5.0 mol% Me 2AICI.

Scheme 69

The P(II1) approach to phosphonopeptides described in Scheme 70 provides a route to dipeptides that was previously unattainable by P(V) methods. Phosphonoamide and thiophosphonoamide dipeptides (257) have been prepared using phosphitylating agent (258) derived from phosphonochloridite. Then the D-tryptophanamide or D-tryptophanmethyl ester was coupled to (258) to form the phosphonoamidite (259) followed by sulfurization with elemental sulfur or oxidation by ~ - B u O O H . ” ~ An optimised solid-phase method for the generation of diverse a-amino-alkyl or -aryl phosphonates derived from pep tide^'^^ and polymer-assisted solutionphase parallel synthesis of dipeptide p-nitroanilides and dipeptide diphenyl p h o ~ p h o n a t e shave ’ ~ ~ been reported. A modular method for the construction of polypeptides containing the Phe-Arg phosphinic acid isostere has been described.’86A novel methodology for the solid-phase synthesis of phosphinic peptides has been developed in which the phosphorus-carbon bond was formed

2: Quinquevalent Phosphorus Acids

125

APp

c-C6H1 1

DIEA

,

CbzHN

BnO

___)

OpNb C-CBHI1 258 H-D-Trip-Y HCI

Y = NH2, OCH,

CbzHN pNbO

y

-

CbMN pNbO

indole

indole

257 X = O , Y = N H 2,OCH3 X=S,Y=NH*,OCHs

259

Scheme 70

on a polymer support during peptide synthesis.187Using the phosphinic analogues of Cbz-Ph-Gly-OEt as a template, several phosphinic peptides were prepared and the reactivity of these derivatives under conventional deprotection conditions was studied.ls8The first synthesis of a pair of (R) and (S)-piperidazine3-phosphonic acid (260) has been performed uia a one-pot process of hetero Diels-Alder reaction and Lewis acid-catalysed phosphonylation (Scheme 7 1). The absolute configuration of the target compounds was established by a novel transformation into known (R) and (S)-pyrrolidine-2-phosphonic acids.189

&TMs

P(OM&

,N_N ROOC \COOR

+

N-N

TMSOTf in CHf12

ROOC’

‘COOR

R = (-)-menthyl

(-)- 260

H2iPd-C separatio

1.CP

P(OMe)z

/

ROOC

\

1.6N HCI-ACOH .c

2. propylene oxide^

COOR

(Zion,, N-N H H (+)- 260

Scheme 71

A new nitrone, 5-methyl-5-phosphono-1-pyrroline N-oxide (DHPMPO), has

126

Organophosphorus Chemistry

been prepared and explored for its biologically important spin-trap properties.1g0 Two simple diastereoselective syntheses of substituted @-amidophosphonates (261) have been described. The first one involved a Michael addition of diethyl phosphite to @-unsaturated amides (262) derived from chiral aminoalcohols, giving (261)with high diastereoselectivity(up to 95 YOee) through 1,5-asymmetric induction. The second one involved 1$inductive alkylation of chiral pamidophosphonates but proceeded with lower diastereoselectivity. Removal of the chiral auxiliary afforded the phosphonocarboxylic The conjugated addition of the lithiated bis-lactim ether derived from cyclo[Gly-D-Val] (263) to a-substituted vinylphosphonates (264) or electrophilic substitution on the lithiated bis-lactim ether derived from cyclo-[L-AP4-D-Val] (265) take place regio- and stereoselectively. These reactions allow direct access

HP(O)(OEt)2 2 ~ . base

0

(EtO)*P+

R1

0

Ph

0 262

261

to a series of 4-substituted 2-amino-4-phosphonobutanoicacids (266) in enantiomerically pure form (Scheme 72).Ig3 OEt

conjugate

f

addition

'

OEt

264

263 electrophilic

substitution

\

266

Scheme 72

A new synthesis of enantiomerically pure 2-amino-3-phenyl-l-cyclopropanephosphonic acid, a constrained analogue of phaclofen (267), has been described. The sulfoxide (268) of (S) configuration was found to undergo cyclopropanation

2: Quinquevalent Phosphorus Acids

127

with sulfur ylides in a highly diastereoselective manner. The latter compound has been converted (via multistep synthesis) into the target compound (267) (Scheme 73).'94 The first synthesis of phosphorylated analogues of pyrazinamides such as substituted pyrazines containing two phosphonate groups (2,Sposition) (269) and pyrazines containing one phosphonate group (2-position) (270) has been elaborated. The synthesis is based on thermal ring opening of 2H-azirines (271) followed by dimerization of unstable nitrile ylide intermediates (272) (Scheme 74).'95 Two 2-aminophosphonate heptens (273) and (274) derived from methyl a-Dglucopyranoside were synthesized to mimic the transition-state in the transesterification reaction between a-D-glucopyranoside and the 4-nitrophenyl M e 2(0) & yield 70%

0

0

II

0

0

0

H

R2

W

+-

II

m 2 m2 e

DME,-70 oc yield 95% E-(S)-268

[a10= +3.2

\

+-

Ms2scHco$3

P

/

NH2

(+)- 267

CH2a2, reflux, 2h yield 91%

Scheme 73

Scheme 74

ester of tert-BOC-a-alanine. Two sets of monoclonal antibodies were generated against these h e p t e n ~ . ' ~ ~

128

Organophosphorus Chemistry

Starting from achiral materials, two stereoisomeric phosphonylated dihydroxy pyrrolidines (275) and (276),containing four stereogenic centers, have been synthesized enantioselectively, employing a combination of enzymatic and transition-metal-mediated methods. Both compounds contain features of the transition state of the enzyme-catalysed fucosyl transfer reaction and represent building blocks of potential inhibitors against this class of enzymes.197 The synthesis of new sugar-derived phosphonic acids e.g. (277) from protected

I H

0

RO RO

R = Bz 273 R = H 274

275

276

nectrisine (278) has been described. The key step is a highly stereoselective addition of a phosphonate anion to a sugar-derived dihydropyrrole to provide a versatile synthetic intermediate (279) which can be functionalized in multiple ways. (Scheme 75).19*The first asymmetric synthesis of azetidinic 2-phosphonic acids e.g. (280) and derivatives starting from readily available P-aminoalcohols has been deve10ped.l~~

278

279

277

Reagents: (a) LiCH2P(OMe)2 (2 eq.). BF3 OEh, THF; (b) TMSBr, CH2C12; (c) BCb, CH;Cl2.

Scheme 75

Diels-Alder reactions of enantiomerically enriched 2H-azirine 3-phosphonates (28 l), a new class of chiral iminodienophiles, and dienes stereoselectively furnish optically pure, bicyclic aziridine adducts (282). Hydrogenation of (282) results in a ring opening that affords the first examples of optically pure quaternary piperidine phosphonates.200Two step synthesis of an enantiomeric pure cyclic phosphite (283) and its application as a chiral phosphorus nucleophile in the asymmetric Michael addition to nitroalkenes (284) provides an efficient

2: Quinquevalent Phosphorus Acids

129

280

A

281

282

route to optically active P-nitrophosphonic acids (285) in good yields and enantiomeric excess by a C-P bond forming reaction. The products are valuable synthetic bifunctional building blocks and constitute potential precursors of P-aminophosphonic acids (Scheme 76).201 Ph

-

0

II

____)

'\NO2

R

284

(R) 285 ee = 81-95%

86-91 %

Ph

Ph

(R, R, R) de = 84-96%

Reagents: (a) (R, R)- 283, TMEDA, Et2Zn, THF; (b) TMSCI, Nal, CH 3CN; ( c ) C H ~ C I ~ / H ~ , Scheme 76

A simple and mild method to prepare compounds (286), (287) and (288) which display an isothiazole dioxide moiety substituted with one or two phosphono

130

Organophosphorus Chemistry

groups has been reported. Starting from 3-amino-5-unsubstituted isothiazole dioxide or 3-amino-5-bromo-isothiazole dioxide, either 3-amino-4,5-dihydro-5isothiazolyl-phosphonates (286), or 3-amino-5-isothiazolylphosphonates(287) (288) have and 5-diethoxyphosphoryl-4,5-dihydro-4-isothiazolylphosphonates been prepared respectively (Scheme 77).202

286

4-Mex~H4 NEt2

toluene reflux 90% yield

NEt2

288 Scheme 77

3.1.6 Phosphorus-Containing Ring Systems. - The chiral a-diazophosphonic acid derivatives (289), (290) and (291)have been prepared from (-) ephedrine and (S,S)-N,N’-dimethyl-172-diaminocyclohexane. Preliminary experiments suggest that the new chiral auxiliaries investigated exert little influence over the subsequent reactions of the derived rhodium (11) acetate-catalysed O-H and N-H insertion reaction^."^ Me

289

290

291

Various N,N-disubstituted chiral dibromofluoromethylphosphonodiamides (292) have been easily prepared and reacted with tert-butyl acrylate in an asymmetric electrosynthesis of a-fluorinated cyclopropylphosphonoamides

131

2: Quinquevalent Phosphorus Acids

(293). The diastereoisomeric excesses obtained for the asymmetric electrolysis were generally low (Scheme 78).204

R1 trans 293

292

Scheme 78

cis293

A series of 2-alkyl-, 2-alkanoyl- and 2-aroyl-2-0x0-1,3,2-oxazaphosphorinanes bearing N-benzyl, N-benzhydryl and N-trityl substituents (294)have been obtained and their conformational preferences in solid state analysed. All 2-alkanoyl- and 2-aroyl-2-0x0-1,3,2-oxazaphosphorinaneshad a gauche or anti relationship between the P = 0 and C = 0 bonds. This is presumably to minimise dipolar interactions between the two bonds as observed in a - d i k e t o n e ~ ? ~ ~

294 R = Et, But, Ph, 2-IC 6H4; Z = CPh 3, CHPh2, CH2Ph, CHMePh

The nine-step synthesis and stereochemical elucidation of a 14-membered cyclic phosphonate (295) has been reported. The key step in the synthesis of the macrolide phosphonate was the cyclization of the acyclic precursor (296) using the Mitsunobu reaction, a mild reaction for the preparation of mixed phosphonates (Scheme 79).206

benzene, r.t.. 2h 82%

296

Scheme 79

295

132

Organophosphorus Chemistry

Synthesis of cyclic phosphonate (phostone) analogues of carbohydrates containing a phosphorus atom at the anomeric position (297) has been described. The ring-closing metathesis reaction of mixed allylic phenyl esters of alkylphosphonic acid (298) generates the six-membered allylphosphonates (299) in excellent yields. Introduction of polyhydroxy functionality in these cyclic phosphonate provides facile entry into an array of phostone sugar analogues.2o7

3.2 Reactions of Phosphonic and Phosphinic Acids and their Derivatives. - Investigations of nucleophilic substitution at phosphoryl (P = 0) and thiophosphoryl (P = S) centres in organophosphorus compounds have been continued. It has now been found that simple benzylphosphonamide chloride (300)reacts with Me2NH and Et2NH by the normal [SN2(P)] mechanism. For the diphenylmethylphosphonoamide chloride (301) the reaction with Me2NH is in part elimination - addition and in part sN2(P). However, the EA mechanism is dominant with Et2NH (steric hindrance; SN2(P)suppressed) (Scheme 80).208 0

II ArCH2-P-NMe2 I

0 R2NH

*

ti

ArCH2-P-NMe2

I

CI

NR2

300 Ar Ph

301

\

-

NMe2

Ph

NR2

302 Scheme 80

The P = S analogues of (301) resemble their P = 0 counterparts in as much as they react with amines by an EA mechanism rather than sN2(P).The elimination stage is most likely ElcB for both types but differences emerge because the three-coordinate P(V) intermediate (302) is less stable than the thiophosphene one?O9 A kinetic study on the behaviour of phenyl hydrogen a-hydroxyiminobenzylphosphonate (303) in aqueous hydrochloric acid solution has been reported. Compound (303) was found to undergo two competing acidcatalysed reactions, fragmentation to phenyl phosphate (304) and benzonitrile, similar to other hydroxyiminophosphonates and hydrolytic cleavage of the oxime group giving N H 2 0 H and P-ketophosphonate (305) (Scheme 81).210

2: Quinquevalent Phosphorus Acids

133

304

303

30 5

Scheme 81

The diastereoselective nucleophilic addition to vinylphosphonates containing an asymmetric phosphorus atom (306) has been reported. Fractional crystallisation of the diastereoisomeric mixture of products affords a diastereomerically pure sample of (307). The relative configuration of major diastereoisomers were confirmed by X-ray crystallography (Scheme 82).*11

307

306

R = Bun (65%,d.r > 6:l); CHz=CH (47%, d.r > 5:l); Pri (64%, d.r > 4:l); Ph (22%,d.r > 8:l); But (13% d.r r 7:l). Reagents: (a) RMgBr or RLi, THF, Cul, TMSCI, TMEDA, -78

OC to 40°C, Ar.

Scheme 82

This methodology has been extended to the addition of carbon nucleophiles to enantiomerically pure asymmetric vinylphosphonates (308).

308

309 R = BLP (78%. d.r > 1.3:l); CI-bCH (82%,d.r > 2.51); Pk(95%, d.r > 2:l); Ph (99%, d.r > 2.5:l); Ek(694 d.r > 83). Reagents: (a) RMgBr or RLi, THF, Cul, TMSCI, TMEDA, - 7 K to -10%; (b) TBAF, THF, r.t., quantitative.

Scheme 83

Modest diastereoselectivitywas observed with a bulky trityl nitrogen substituent, as well as with bulky carbon nucleophiles. In spite of the low stereoselec-

134

Organophosphorus Chemistry

tivity, it is the first example to show that nucleophilic addition to vinylphosphonates results in a consistent and predictable induction of chirality at the fJ-position relative to the asymmetric phosphorus atom (309) (Scheme 83).'12 Chiral salcyan complexes of aluminium and their application in asymmetric catalysis, specifically in the phospho-aldol reaction, have been de~cribed.2~~ Metallomicelles can serve as models for metalloenzymes. The simple Cu(I1) complex of N-n-hexadecyl-N,N',N'-trimethylethylenediamine (310, Cu(I1)-HT MED.) in cetyltrimethylammonium (CTA) ion micelles is highly reactive and catalyses the hydrolysis of a variety of phosphate and phosphonate substrates. Metallomicellar hydrolysis of 0-methyl 0-4-nitrophenyl phenylphosphonothioate (31 1) to 0-methyl phenylphosphonothioic acid (312) was found to takes place with complete inversion of configuration at phosphorus (Scheme 84). In this case, micellar Cu(I1)-HTMED most likely operates only via the CuOH nucleophilic mode.'14 Boron tribromide and methanol cleanly and quantitatively converted phosphonates (313) into the corresponding phosphonic acids (314).215 The metal mediated hydrolysis of phosphonoformates as well as rate accelerations in the acidic hydrolysis of dimethyl phosphonoformate (DMPF)(315), using Zr(IV), Hf(IV), Th(V1) and Ce(1V) cations, have been described. Unprecedented chemoselectivity of these reactions was observed. Zr(1V) and Hf(1V) are chemoselective for the P-OMe cleavage of DMPF, while Ce(1V) and Th(1V) are chemoselective for C-OMe cleavage.216 2+

S "CU(11)-OH Ph ~ ~ s , , , ~

ArOP'

'OMe

[INV]

S

I,, ,,,OMe

HO'

310

\Ph

/

H20

312

311

j

OH2

(CU(1I)-HTMED)

Ar = 4-N02Ph

Scheme 84

1. BBr3, toluene/hexane, -30OC to 7OoC

R--P(O)(OR')2 313

2 . MeOH, 2OoC 77 - 95%

*

R--P(O)(OH)2 314

R1= Me, Et, P$, But

Some 1- and 2-hydroxyalkanephosphonateshave been successfully resolved by a CALB (Candida antarctica lipase B)-catalysed acylation process to give both (R)-and (S)-isomers with high enantiomeric excess (in most cases with 95 % ee).'17 (S)-Naproxen* and (S)-Ibuprofen*chloride are convenient chemical derivatizing agents for the determination of the enantiomeric excess of hydroxy and aminophosphonates by 31PMR.218. New phosphorylating agents, 3-phosphoro-2(-N-cyanoimino)-thiazolidinederivatives (3-phosphoro-NCTS) (316), can be used as a stable alternative to phosphorochloridates. Phosphoryla

2: Quinquevalent Phosphorus Acids

135 NCN

0

315

R = Et, Ph

316

317

0

318

R = Me, Ph; R1= Me, Et

tion of primary and secondary alcohols proceeds in good yield. Compound (316, R = Ph) selectively phosphorylates different kinds of alcohols in good yields.219A variety of P-ketophosphonates (317)have been converted to y-ketophosphonates (318) through reaction with ethyl (iodomethy1)zinc. The ease with which pketophosphonates can be prepared, coupled with the simplicity of the one-step chain extension reaction, serves to make this zinc-mediated method very attractive for the preparation of y-ketophosphonates?20 A very efficient addition of alkyl and crotyl moieties to the carbonyl group of structurally varied Pketojhosphonates (319) through the corresponding ally1 indium reagents has been described. This reaction is regiospecific, providing only one isomer (320) corresponding to y-addition in high yield.221

Synthesis of fosfomycin (321) has been achieved through the asymmetric dihydroxylation AD reaction of dibenzyl (E)-1-propenylphosphonate (322) with modified AD-mix-a-(x3) and the highly regioselective sulfonylation of the resulting diol(323) at the a-hydroxyl group. High efficiency in the AD reaction was realised not only by the lipophilic nature of a benzyl group in the substrate but also by the modification of the AD reagent. a-Sulfonyloxoalkylphosphonates (324), available by the method described, have been converted into the fosfomycin and they would be also useful for synthesis of a-amino-f&hydroxy- or p-amino-a-hydroxyalkyl phosphonic acids (Scheme 85).222 Mechanistic studies have been reported on the addition of alkylphosphonic acid reagents (325) to trialkyl-substituted epoxides (326). The addition occurs according to a three-step mechanism starting with rapid nucleophilic attack of the phosphorylated anion on the most alkyl-substituted carbon of oxirane, followed by formation of a dioxaphospholane structure (327) with release of

136

Organophosphorus Chemistry

0

II

m P ( 0 R ) z

AD-mix-a

0

OH

II

r

m P ( O R ) 2

OH

322

323

I OH ?

ArS02CI

0

0

It

/.44P(ORh

base

vlPR)2

1 1 1 )

0

OS02Ar 324

321

Scheme 85

water. Finally hydrolytic cleavage of the dioxaphospholane cycle generates the regioisomer where the phosphonyl group is on the less alkyl-substituted carbon of the initial oxirane (Scheme 86).223

326

1

327

Scheme 86

A double diastereotopic differentiation strategy on a phosphonoacetate template has been described. The approach utilizes Rh2(OAc)4-catalysedintramolecular cyclopropanation (ICP) employing the (R)-pantolactone auxiliary in the ester functionality of the phosphonoacetate (328).Theolefinic diastereofacial selectivity is governed by inherent electronic and steric interactions in the reacting carbene intermediate, while the group selectivity is dictated by the chiral auxiliary. This approach is an effective method to access bicyclic P-chiral phosphonates (329)(Scheme S7).224 The first highly diastereoselective hydrophosphonylation of heterocyclic imines, 3-thiazolines (330) by a chiral phosphorus reagent BINOL, has been performed. The relative configuration of BINOL and the newly formed stereogenic centre in the a-amino phosphonic acid derivatives (331) have been elucidated by X-ray analysis.225

2: Quinquevalent Phosphorus Acids

i! I: / 0‘p’

137

OJ

-

0

Rhz(OAcb

CH2C12, r.t. 69-92%

CiS’PR

329

328 Scheme 87

An efficient synthesis of new chiral phosphonylated thiazolines (332), readily accessible from phosphonodithioacetate and commercial chiral aminoalcohols via intermediate (333), has been described. (Scheme 88). These thiazolinephosphonates (332) were then involved in H-W-E reactions to give asymmetric vinylic thiazolines.226

BINOL __I)

CHpC12

330 331

1.5 eq. NEt3

333

332 Scheme 88

Organophosphorus Chemistry

138

A two-step, high-yielding synthesis of A2-thiazolines containing a difluoromethyl-phosphonate diester moiety (3 34) has been devised using a building block approach. Racemic or chiral fbaminoalcohol and diols were coupled with methyl difluoro (diethoxyphosphono)dithioacetate(335) to give predominantly the corresponding p-hydroxythioamides, which were then cyclized to provide a series of novel substituted A2-thiazolines(Scheme 89). This method provides the possibility of linking nucleic base derivatives to the thiazoline backbone?*’

335

334

B = Gchloropurine, T

R = H, alkyl, aryl, CH20Ts, C02Me

Scheme 09

The phosphonodithioformate (336) has been used as an interesting heterodienophile in the Diels-Alder reactions with different dienes. A selective radical desulfanylation of the cycloadducts (337) using Bu3SnH leads to new (3,6dihydro-2H- thiop yran-2-yl) phosphonates (33 8)(Scheme 90).228

+

L or xylem

336 R‘ = H,Me;R*= H, Me

J Bu$lHmy 0

R i

338

Scheme 90

It has been shown that the phosphonodifluorodithioacetate (339) acts as a powerful heterodienophile and can be used to prepare a new class of phosphonodifluoromethyl thiopyrans (340). These adducts can be submitted to a selective dihydroxylation to produce diastereoisomers (341) (an example is given in Scheme 91).229 Two routes have been shown to produce sulfanyl- and selanyldifluoromethylphosphonates (342). Generation of phosphonodifluoromethyl radicals (343) from such precursors and their addition reactions with alkenes represents a

2: Quinquevalent Phosphorus Acids

139

viable approach for the introduction of such functionational groups into potentially bioactive molecules (344) (Scheme 92).230 (EtOhP(0)CF2C(S)SCHa

339 340

K:3F@cw6 K

~

3

OsCl3 cat. quinudidinecat. H ~ O / B U ~70% H.

H

BIJ"JS~H, ABN

toluene, reflux

R2XCF2P(O)(OR'b

342 R 1 = El,Pd

R3

[*CF2P(0)(OR1)2] 343

HC@R5HCR3CF,P(O)(OR1),

344

R2 = MeS, PhSe

Scheme 92

The course of the alkaline hydrolysis of (diphenoxyphosphonyl) p-tolyl sulfoxide (345) has been elucidated utilising l 8 0 isotopic labelling and mass spectrometric analysis of the hydrolysis products. The results obtained do not support a two-step mechanism for the hydrolysis of a-phosphoryl sulfoxides; instead there is participation of the neighbouring sulfinyl group and formation of a cyclic oxathiaphosphetane intermediate?31

345

It has been found that the reaction of dimethyloxosulfonium methylide and diazomethane with (E)-3-aryl-2-phosphonoacrylates(346) using the (-)-Sphenyl-menthyl group as a chiral auxiliary gives the trans cyclopropane derivatives with high diastereoselectivity. This can be attributed to the high n-face differentiation of the acrylate moiety by the face-to-face interaction with the phenyl ring of the chiral auxiliary in the s-cis conformer. On the other hand, (2)-isomers of (346)gave a mixture of cis and trans cyclopropane derivatives with low diastereoselectivity (Scheme 93).232 Phosphaalkynes, including those substituted by primary or secondary alkyl groups, can be synthesized under classical conditions in a sequence involving the

140

Organophosphorus Chemistry

chemoselective reduction of an ethereal solution of a-dichlorophosphonates with AlHC12 followed by the bis-dehydrohalogenation of the resulting a-dichlorophosphines by a strong Lewis base?33Phosphonate esters react with yalumina under microwave irradiation. This reaction is a simple preparative method to graft organic pendants onto the surface of alumina.234The behaviour of four stable P-phosphorylated aminoxyl radicals of the pyrrolidinoxyl series

346 trans

Cis

R* = (-)-8-phenylmenthyl, (-)-menthy1 Ar = Ph, pMeOPh, p-CIPh: p-NOZPh

Scheme 93

(347-350)has been studied by EPR spectroscopy in the presence of dimyristoylphosphatidylcholine (DMPC) unilamelar liposomes. The affinity of these compounds for the liposome structure was found to be more or less high depending on their h y d r ~ p h o b i c i t y . ~ ~ ~

A single bonded Ca dimer having a diethoxyphosphorylmethyl group on each cage (351) has been obtained by the reaction of c62-dianion with diethyl iodomethylphosphonate followed by treatment with iodine. The precise structure of the dimer was determined by X-ray crystallography, and its homolytic dissociation as well as spectroscopic and electrochemical properties were clarified (Scheme 94).236

c 6 0

Scheme 94

351

2: Quinquevalent Phosphorus Acids

141

Addition of secondary amines to alkynylphosphonates catalysed by Cu(1)salts proceeds regio- and stereo-specifically to form (E)-2-(dialkylamino)alkenylphosph0nates.2~~ Electron rich hydroxyarenes undergo self-catalytic Michael reactions with dicyclohexylammonium acrylate (352). The regiochemistry of this reaction is strongly dependent on structural features of the starting hydroxyarenes. In a nonpolar solvent, phenol and most of its mono-substituted derivatives, are converted into the corresponding 0-adducts, whereas conjugate addition of disubstituted phenols and naphthols leads to the C-adducts exclusi~ely.~~~

352

Starting from the achiral phosphinamides (353), high yields of previously unknown phosphorus-containing tricyclic compounds (354) and (355) (in the ratio 98:2), containing four stereogenic centres, have been obtained in a process involving the dearomatization of a naphthalene ring (Scheme 95).239 (S)-( )-1-Phenyl-2-carboxyethylphosphonic acid (S)-(356)has been prepared via diastereoselective alkylation of (3aR,7aR)-octahydro-1,2,3-tribenzyl-l,2,3benzodiaza-phosphole-2-oxide (357) using tert-butyl bromoacetate. The X-ray crystal structure of intermediate alkylation product (358) is described (Scheme 96).240 a-Chlorination of phosphonates, thio- and seleno-phosphonates (359)involving the direct reaction of their lithiated anion with phosphorus oxychloride

+

353

355

354

Reagents: (a) Bu SLi (2.5 equiv.), THF, -90 OC;(b)MeOH, -90OC.

Scheme 95

giving a-chlorinated products (360) has been described. This reaction gives good results where previously known methods are very A new synthetic route to bis-methylene analogues of triphosphate esters has been reported. Lithiated methaneselenophosphonate and methanethiophosphonate anions can condense several times with polyfunctional PI'' substrates such as chlorophosphites and phosphoramidous chlorides prior to esterification/trans-esterification and selenation or oxidation.242A water-soluble phosphonate-functionalized phosphine ligand (361) has been prepared in eight steps

Organophosphorus Chemistry

142

(S)-3%

Scheme 96

CI 359

360

361

from cyclod~decanone.~~~ (E)-bromovinylphosphonates have been readily prepared from 1,l-dibromoalkenes using a diethyl phosphonate/EtONa/EtOH system, in which the use of microwave irradiation enabled (E)-vinyl bromides to be obtained in high yields and high stereoslectivity within 1 rnin.244 The synthesis of primary fluoroalkyl enamino phosphonates (362) from fluoronitriles and alkyl phosphonates has been described. These primary enamines are versatile intermediates for the preparation of fluorinated a,p-unsaturated imines (363) and ketones (364) as well as of fluorinated allylamines (365) and vinylogous p-aminonitriles (366) (Scheme 97).245 a-Diazophosphonates (367) are disclosed as 1,l-ambiphilic one-carbon building blocks for one-pot construction of various heterocyclic compounds. Using this synthon, a mild and efficient synthetic method of 2,3-disubstituted indoles (368) and 3,4-disubstituted isocoumarins (369) have been developed (Scheme 98).246 A novel enantioselective synthesis of (2S,2’R,3’R)-2-(2’,3’-dicarboxycyclopropy1)glycine (370) (DCG-IV), a potent group I1 mGluRs agonist has been reported (Scheme 99).247

143

2: Quinquevalent Phosphorus Acids

363 X = N H 364 X = O

365 R = H 366 RzCHzCN

362

.

Scheme 97

367

+

_.

368

R3 367

+

R4

R5

369

Scheme 98

Stereoselective synthesis of monofluoroolefins (371) from diisopropyl(carboethoxyfluoro-methy1)phosphonates (372) by treatment with CH3MgI or CH3CuMgBr has been described. The intermediate compounds (372) have been prepared by the action of phosphonate anion (373) on oxalyl chloride or methyl oxalyl chloride (Scheme 100).248 Enantioselective ring opening of meso-epoxides catalysed by an 0methoxyaryldiaza-phosphonamideLewis base (374) has been achieved using various chloride ion silicon sources. The use of TMSCI leads to enantioselectivities varying from 6 to 98% ee depending on the nature of the ep0xide.2~~ Layered zirconium sulfonyl phosphonate was found to be an efficient hetero-

Organophosphorus Chemistry

144 Me

I

+

/+../4+02BU‘

Me

CI

I

Me

I

-

I

HOZC

___)

I

C02H

Me

C02Bi.1‘

370

DCG4

Scheme 99

372

(E,Z) 371

R = Me, Et

Scheme 100

A

R

R

OMe 0

1) “Chloride ion Source” 10 rno10/o374 Solvent, -780C

2) KFIKhf04

*

R 374

dioxane, 56C.

375

ZPSO 3H

HX

XH

reflux

xXx R R1

376

X = 0, n = 1, 1,3-dioxolane n = 2, I,3-dioxane n = 3, 1,3-dioxepane

X = S, n = 1, 1,3-dithiolane n = 2, 1,Sdithiane

2: Quinquevalent Phosphorus Acids

145

geneous catalyst for the preparation and deprotection of 1,l-diacetate (375). Aromatic, aliphatic as well as a$-unsaturated aldehydes are converted to (375) in solvent free conditions using acetic ahydride as acylating agent in the presence of zirconium phosphonate ~atalyst.2~' The same catalyst has been used in a convenient method for the preparation of cyclic ketals and thioketals (376).251 Examination of the catalytic activity of mixed phosphite-phosphonate ligands (377) on the rhodium-catalysed hydroformylation of styrene has shown promising results, particularly at low temperature. Increasing the bulkiness of both phosphite and phosphonate moieties leads to improved catalytic activities and selectivit

Eto, P-OAP;(OEt), Eto'

0

0 R = Et, Pri, Cy 377

It has been found that S-tert-butyl-P-phenyl-1-piperidinylphosphonamidothioate (378) served as a novel thermally latent anionic initiator in the polymerization of glycidyl phenyl ether.253Novel porphyrin phosphonates (379), (380) and (381) exhibit binding of alkyl pyranosides in organic media (receptor 379), monosaccharides, selected disaccharides in water (receptors 380 and 381), and effective binding for D-(-) fructose, D-(+) maltose and a-Dlact0se.2~~ Reaction of aldose derivatives with dimethyl(diazomethy1)phosphonate (382) generated in situ by methanolysis of dimethyl(1-diazo-2-oxopropyl)phosphonate leading to gluco-1-ynitol derivatives (383) has been described. This one-pot synthesis tolerates free hydroxyl groups.255 Hydrogenphosphinic acids (384) have been esterified with orthosilicate in excellent yields. Phosphinylidene acids react selectively under the same conditions (Scheme 101). One-pot procedures have been also described for the preparation of phosphinate esters from alcohols.256 General catalytic hydrophosphinylation reaction of alkenes and alkynes with hypophosphorous compounds (385) to give H-phosphinic acid derivatives (386) has been described. Compounds (386) are important biologically active compounds as well as being synthetic intermediates which can be converted into a variety of other organophosphorus compounds using well-established procedure~.~~' The [1,3]- and [1,2]-rearrangements of P-chiral phosphinates, phosphino t hiolates, phosp hinoamidates and their t hionophosphorous analogues bearing achiral substituents are completely stereoselective and proceed with retention of configuration at phosphorus. These rearrangements have synthetic importance in providing access to multifunctional chelating P-chiral phosphine oxides and phosphine sulfides (an example is given in Scheme 102).258

Organophosphorus Chemistry

146

S Pk-bl-SBd

Q 378

R = Et 379 R = H 380

~d‘OR R=H381

0 II R-P-OH I H

0

0.5-1.0eq. (RlO)&i toluene, 0.33 M, reflux, 24h 80-100%

II R-P-OR1 I H

384

Scheme 101

The Boyd-Regan methodology has been used for the preparation of various cyclic or benzylic mono- and bis-phosphinic acids. The reduction of phosphinic acids to secondary phosphines using silanes has been achieved. On the other hand, reduction of the bis-phosphinic acids with LiAlH4led to bis-ph~sphines.~’~ Arylethylene-derived, enantiomerically pure amino alcohols have been evalu-

2: Quinquevalent Phosphorus Acids

147

0

ROP(OH)2

+

solvent

ex/\/ P.

385

2 equiv.

H OR

\

2 mol% Pd

386 1 equiv.

Scheme 102

ated as ligands for the dual-catalysed (amino alcohol halosilane) enantioselective reaction of diethylzinc with diphenylphosphinoyl imines (387) to give phosphinamides (389). Among them, the conformationally restricted 9-fluorenonederived ligand (388) provides the highest enantioselectivities so far reported over a range of substrate imines (Scheme 103).2"

3.3 Selected Biological Aspects. - The design and preparation of haptens (390) and (391)for catalytic antibody-promoted dynamic kinetic resolution of racemic 4-substituted 4H-oxazolin-5-ones have been reported. Transition state mimicry and a 'bait and switch' strategies were adopted to propose the structure of the haptens. A key step in their synthesis is based on a ring-closing metathesis reaction.261

t l o A

OH

1) Et;rZn/toluene/@C 2) TIPSCi/-20°C

Et

0

'N H

387

389

388

4 examples 92-95% ee

Scheme 103

o-Phosphonatomethylcholine (392), an isopolar analogue of phosphocholine with catabolically stable P-C linkage replacing phosphate ester bond, has been synthesized. The synthesis consists of a stepwise replacement of chlorine in the

148

Organophosphorus Chemistry

starting diisopropyl 2-chloroethoxymethylphosphonate(393) to insert the trimethylammonium group, followed by hydrolysis of the isopropyl ester (394) (Scheme 104).

2 diastereomers ?:I

391

390

1

393

394

392

Scheme 104

It opened an efficient approach to a series of mono n-alkyl esters of o-phosphonomethylcholine (395) as potential membrane modifying cytostatics.262 The synthesis and evaluation of binding ability of new model host compounds, bis-phosphonates (396) triphosphonates (397) and (398), with guanidine have been reported. The introduction of electron donating or withdrawing substitutents in the 5-position of the parent bisphosphonate (396, X,Y = H) revealed the presence of z-cation interactions which contribute at least 0.5 kcal/mol for a single benzene guanidinium interaction. Even more effective was the introduction of a third phosphonate functionality at the correct distance, as shown in +

0

I1

Me3N-CH2CH20CH2-P-OCH2(CH2)&H3

b-

n = 8,10,12,13,14

395

(398) so that five hydrogen bonds can be formed to all five guanidinium NH protons surrounded by three phosphonate arms in (399), as was supported by X-ray analysis.263 Phosphonamidothioates show strong promise as potent tetrahedral-intermediate analogue inhibitors of metallopeptidases, with the unique value of probing enzyme active site architecture with complementary chiral phosphorus

2: Quinquevalent Phosphorus Acids

bc

149

2 Cat.* = B ~ N +Li',

(?I

POMe

0 ' 396 X = H, NO2, OMe; Y = H

397

XY = COzCH=CH XY = CHzCHzCH 0

-

II

MeOPH0-

0

II

O-POMe

3~ i +

V

399

398

centers. Individual diastereoisomers of glutamate-containing phosphonamidothioic acids (400) have been prepared by two methods. The crucial step of the first method relied on fractional crystallization of the easy accessible o-(9-fluorenomethyl)phosphonamidates (401). In the second method, flash chromatography produced fb(acy1mercapto)ethylphosphonoamidothionates (402).After stereospecificintroduction of a sulfur atom on phosphoryl groups of invidual crystallization products using Lawesson reagent, the diastereoisomerically pure phosphonoamidothioates (402)and (403)were deprotected in an usual way to produce stereochemically pure target acids (400) in high or satisfactory yield.64 A series of novel 2-amino-6-aryl-9-[2(phosphonomethoxy)ethyl]purine bis (2,2,2-trifluoroethyl)esters (404) has been synthesized by satisfactory regioselective alkylation of 2-amino-6-chloropurine (405) with the bis(tri-fluoroethyl)(2iodoethoxy)methylphosphonate (406),followed by exchanging the chlorine atom in the resultant intermediate (407) for various substituted and unsubstituted benzenethiols and naphthalenethiols. 6-Phenylt hio- and 6-(methoxypheny1)thioderivatives showed potent Hepatits B-specific antiviral activity in vitro, and 9[2-(phosphonomethoxy)ethyl] adenine and 9[2-(phosphonomethoxy)ethyl] 2,6-diaminopurine have a broad spectrum of activity against viruses (Scheme 105).265

150

Organophosphorus Chemistry

\C02H

R = Bun, Ph

X = O , 401 X = S , 403

402

405

I

407

R

I

404

R = arylthio

Scheme 105

New types of acyclic nucleoside phosphonates (408-412) have been obtained using a multistep synthetic approach based on N-1, 0-and S-alkylations of 4and 2,4-substituted 6-hydroxy and 6-mercaptopyrimidines with diisopropyl 2(ch1oroethoxy)methylphosphonate and (R) or (S) - [2-(diisopropylphosphony1)methoxyl propyl tosylate. Inhibitory activity against viruses of both the nucleoside phosphonates and the related phosphonic acids was investigated. It was found that the 6[2-(phosphonomethoxy)ethoxy]pyrimidines must bear an (unsubstituted) amino group concomitantly on both C-2 and C-4, or an amino on C-2 and an OH group on C-4, to display antiviral activity. Alkyl ethers are preferred over alkyl thioethers. The compounds of the 6-[2-(phosphonomethoxy)ethoxyJ and 6-[2-(phosphonomethoxy) propoxylpyrimidine

2: Quinquevalent Phosphorus Acids

151

series have in vitro antiviral activity that is comparable with the well known compounds 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) and 9-(R)-[2(phosphonomethoxy) propyl] adenine (PMPA)?66 R3

R3

Rl = H R1=pr'J 409

R2

=priJ 410

R1 = H

152

Organophosphorus Chemistry

The first study of enzyme binding affinity/turnover, as a function of both degree of fluorination and C-F stereochemistry, across a complete set of fluorinated mimics of G6P has been reported. The syntheses of all four phosphonates (413-416)diverge from glucopyranose 6-triflate (417) and highlight the utility of the triflate displacement approach for sugar homologenation and functionalization. In the course of the synthesis of (418) and (419), it was established that DAST-mediated conversion of a nonbenzylic, secondary (a-hydroxy)phosphonate to the (a-monofluoro)phosphonate proceeds with inversion of configuration (Scheme 106 and 107). Steady-state enzyme kinetic analysis with L-mescenteroides G6PDH yielded the corresponding k a t / K mvalues for (416 bridging (R)CHF; 414 bridging -CF2;419-bridging -CH2 and 415-bridging (S)-CHF) relative to G6P itself, largely reflecting differences to K,. The results suggest that the vectorial disposition of a C-F bond in an enzymatic phosphate binding pocket can contribute up to an order of magnitude in binding affinity in (a-monofluoro)pho~phonates?~~ TfO

\

0

\\ ,,,OEt

BnO Bfl&OBn BnO

414

413

Reagents: (a) MeP(O)(OEt),, BuLi (74%); (b) HF,CP(O)(OEt),, LDA (83%); (c) TMSBr, CH,CI,; (d) H, Pd(0H)JC (69Y0for 413,91% for 414,2 steps).

Scheme 106

Bisphosphonates pamidronate and alendronate (the most active bisphosphonates approved for clinical use) were converted into the peptidyl prodrugs prolyl-phenylalanylpamidronate [Pro-Phe-pamidonate (420)] and prolylphenylalanyl-alendronate [Pro-Phe-alendronate (421)l. It was shown that the bioavailability of bisphosphonates can be enhanced by using the peptide prodrug approach. The increased oral absorption of the prodrugs was reduced by an active carrier-mediated transport.268

2: Quinquevalent Phosphorus Acids

4

153

Structure

It has been shown that the X-ray diffraction analysis of the crystalline state combined with the solution NMR study of N-substituted aminomethane-1,ldiphosphonic acids (422), (423) and (424), can be very useful for revealing the inherent molecular properties of the molecules and their aggregation relations. The perfect molecular organization in hydrogen-bonded networks in the crystal provides valuable information to understand the molecular behaviour in sol~tion.~~~

'aBne c 0

B&

Bn BnO 417

B & :~~~

BnO

OBn

BnO

BnO

O $ *H

HO

HO 415

416

Reagents: (a) dithiane, BuLi (94%); (b) Hg(CIQ)2, CaC03, THF, l+O (88%); (c) HP(O)(OEtk, LiHMD. THF(93%); (d) DAST, CH2C12 (32-50%); (e) LDA, HOAc, quench (98%); (9 TMSBr, C&I2; (9) l-b, PcI(OH)~/C (60% for 415; 70% for 416; 2 steps).

Scheme 107

420 n = 2, Pm-Phe-pamidronate 421 n = 3, Pro-Phe-alendronate

154

Organophosphorus Chemistry

N*P H

(O)(OH)z

422

R1 = H, Me, COOH R* = H, CI, Me R3 = H, Me

424

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Phosphonium Salts and Phosphine Chalcogenides BY D.W. ALLEN Biomedical Research Centre, Shefﬁeld Hallam University, City Campus, Shefﬁeld, S1 1WB, UK 1

Phosphonium Salts

1.1 Preparation. – Not surprisingly, conventional quaternization reactions of tertiary phosphines have continued to be widely used in the synthesis of phosphonium salts, usually required as intermediates for Wittig procedures. Among new salts prepared in this way are the diphosphonium salt (1),1 various p-dialkylaminobenzylphosphonium (2)2 and 4-imidazolylmethylphosphonium (3)3 salts, the 2,2,2-triﬂuoroethylphosphonium triflate (4)4 and (5), the latter being obtained in high yield from an iodoalkyl precursor using an ultra high pressure quaternization procedure. Quaternization under conventional conditions is compromised by undesired intramolecular cyclisation reactions.5 The reaction of triphenylphosphine with b-haloaminoesters derived from the ring-opening of oxazolines has given the b-phosphonio-L-alanine salts (6).6 Whereas the reaction of H2C¼(CH2Cl)2 with dimethylphenylphosphine in refluxing N,N-dimethylacetamide gives the expected allylic diphosphonium salt (7), related reactions with triarylphosphines result in the formation of the allyl-vinyl diphosphonium salts (8). Allyl-vinyl diphosphonium salts (9) and (10) have also been obtained from the reactions of 2,3-dibromopropene and 1,3-dibromopropene, respectively, with triphenylphosphine under the same conditions, no catalyst being needed for the displacement of the vinylic bromine. These salts have been shown to undergo ortho-metallation reactions on treatment with a platinum(II) complex in refluxing 2-methoxyethanol.7 Two routes to the bis(phosphonioalkyl)calix[4]arene (11) have been developed, this system having been shown to have anion-receptor properties.8 Treatment of 2-hydroxymethylporphyrins with thionyl chloride in dry pyridine yields the corresponding 2-chloromethylporphyrins, which undergo quaternization in boiling chloroform to give the related triphenyl[(porphyrin-2yl)methyl]phosphonium salts. These have been used for the synthesis of porphyrin dimers and higher oligomers.9 The tetraphosphonioarylporphyrin system (12) has been obtained by treatment of the corresponding tetrakis(pentaﬂuorophenyl)porphyrin with triethylphosphine in the presence of trimethylsilyl triflate in an application of the SASAPOS method (self-activated silyl-assisted polyonio substitution).10 This approach was initially developed by Weiss and Pu¨hlhofer in the Organophosphorus Chemistry, Volume 35 r The Royal Society of Chemistry, 2006 92

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synthesis of the salt (13) from the reaction of pentaﬂuorobenzoyl chloride with triphenylphosphine, trimethylsilyl triflate and aqueous triﬂic acid.11 P-chirogenic trialkylphosphonium salts, e.g., (14) and (15), have been prepared by treatment of the related chiral tertiary phosphine-borane adducts with either HBF4 or triﬂic acid. The salts are resistant to racemisation in methanol or water, even at elevated temperatures, and may be used instead of the free phosphines in the rhodiumcatalysed asymmetric hydrogenation of enamides.12 A series of 2-ureidocytosines bearing a phosphonioalkyl functionality, e.g., (16), has been prepared by a simple quaternization approach. In solution, these self-assemble in an anti-parallel manner to form a hydrogen-bonded dimer which is found to catalyse the ring-opening of epoxides in the presence of thiols.13 PPh3 R1 O

Cl

PPh3

PPh3 I

N

2Cl

N

R

N

R2 PPh3 (1)

(2)

(3)

Ph3P PMBO

CF3CH2PPh3 TfO

OTBS

OPG

NHBz I

PPh3 (4)

X

CO2R

(5)

(6)

PPh3 Me2PhP

PAr3 2Cl

Ar3P

PPhMe2 2Cl (7)

2Br

Ph3P (9)

(8) Ar = Ph or p-C6H4

PPh3 Br

F

F

Et3P

O

PEt3 F

N H

F

F 4 TfO

N

N

2

F

H N

F

(11)

F TfO

PEt3

F

F

F

PPh3

F

F

F F

F

F Et3P

(10)

F

F F

OH

PPh3 2Br

Ph3P

(12)

(13) Bu

H But P Me

Ph BF4

(14)

H H But P (CH ) P Me 2 n Me But

NH

2X

(15) X = BF4 or TfO n = 1 or 2

O

N

N H

O N H (16)

PBu3 Br

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A high yield route to the tetravinylphosphonium salt (17) has been developed, starting from PH3. Radical-promoted addition to vinyl acetate yields tris(2-acetoxyethyl)phosphine. Quaternization with 2-iodoethanol, followed by acetylation of the hydroxyalkylphosphonium salt gives tetrakis(2-acetoxyethyl)phosphonium iodide, which undergoes a base-promoted elimination to form (17). A similar approach has given the cyclohexyltrivinylphosphonium salt (18).14 The 2-(2-azulenyl)ethynylphosphonium salt (19) has been obtained from the reaction of 2-bromoethynylazulene with triphenylphosphine. Subsequent treatment of this salt with o-substituted anilines provides a route to 2-(2azulenyl)benzoazoles.15 Full details have now appeared of the synthesis of b-(Nacylamino)vinylphosphonium salts (20) from the reactions of carbonyl-stabilised ylides with imidoyl chlorides.16 Further work has also been reported on the properties of the zwitterions (21) obtained from the reactions of the tris(isopropyl)phosphine-ethyl 2-cyanoacrylate adduct with arylisocyanates.17 Zwitterionic phosphonio-carborane systems have also been prepared and structurally characterised.18 A convenient one-pot synthesis of 1,2-azaphospholanium salts (22) is provided by the intramolecular alkylation of 3-halopropylaminophosphines.19 A series of water-soluble and thermosensitive copolymers bearing phosphonium groups has been prepared by the copolymerisation of acryloyloxyethyltrialkylphosphonium salts (23) with n-butyl methacrylate and N-isopropylacrylamide.20 R3 P

I

P

C C PPh3 Br

I

(19)

Ar

R2P

PR3

(21)

Cl

O

Cl O

CO2Et

O

O

R4

(20)

H N

CN

Pr i3P

X

N R1 R2

(18)

(17)

Ph3P

(22) R = Ph or Bun

(23) R = Et, Bun or Oct

Interest has continued in the synthesis of arylphosphonium salts by metal ion-catalysed routes from aryl halides. Nickel(II)-catalysed replacement of bromine in 1-amino-2-methyl-4-bromoanthraquinone by triphenylphosphine occurs readily under mild conditions (boiling ethanol) to give the phosphonioanthraquinone salt (24), the carbonyl group acting as a coordination template for the metal ion, facilitating replacement of the halogen. The extent to which the phosphonium group may be involved in hypercoordination from the adjacent carbonyl oxygen atom has been investigated by X-ray crystallography which shows considerable distortion of bond angles about phosphorus in the direction of trigonal bipyramidal geometry, the phosphorus-oxygen distance (2.661A˚) being well within the sum of the van der Waals radii. The related stibonium salt has also been prepared, this showing a stronger interaction between the Group 15 atom and the carbonyl oxygen, the antimony-oxygen distance being 2.497A˚. In both structures, the Group 15 element and the adjacent carbonyl oxygen atom are bent out of the plane of the anthraquinone system. However, the extent of out of plane deformation is smaller in the case

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of the larger antimony atom, suggesting that there is a genuine hypercoordinative interaction which increases as the Group is descended.21 In related work, the salt (25) has been obtained from the nickel(II)-catalysed displacement of bromine from 2-(2-bromophenyl)benzimidazole by tri(2-furyl)phosphine. XRay structural studies of the phosphoniobenzimidazole salt reveal the existence of a significant hypervalent coordinative interaction between heterocyclic nitrogen and the phosphonium centre, which also appears to be retained in solution, the 31P nmr spectrum showing a highly shielded phosphorus atom, d31P ¼ ca – 40 ppm in CDCl3. The nitrogen-phosphorus distance is 2.67A˚, this being the shortest observed in structures of this type, a consequence of the electron-withdrawing properties of the 2-furyl substituents at phosphorus. In contrast, the N-P interaction in the quinolylmethylphosphonium salt (26) is much less developed, with an N-P distance of 3.511A˚.22 A hypervalent intramolecular coordinative interaction between nitrogen and the phosphonium centre also appears to be present in the ortho-oximinoarylphosphonium salt (27), obtained from the nickel(II)-catalysed reaction of triphenylphosphine with the oxime of ortho-bromoacetophenone, the nitrogen-phosphorus distance being 2.78A˚.23 However, on the basis of NMR coupling constant data, Schiemenz et al. have continued to argue that, in spite of the short nitrogenphosphorus distances observed in the peri-naphthalene system (28), there is no evidence of such dative coordinative interactions, the short N-P distances being an artefact of the peri-substitution pattern in the naphthalene system.24 A crystallographic study of the BOC-salt (29) reveals no unusual features, conﬁrming the expected structure.25 H N O

Br

PPh3

N

N P Me O

O

NH2

(24)

P

ClO4 O

O

O (25)

R3 P N

NMe2

Br O

O (26)

X

N

OH

N N

PPh3 (27)

Br

O (28)

P(NMe2)3 PF6

(29)

As is usual, phosphonium cations have been used to stabilise unusual anions. The salt (Ph4P)2HP7, involving the hydrogenheptaphosphide anion, has been prepared as an ammonia solvate from the reaction of K3P7 with tetraphenylphosphonium bromide in liquid ammonia, and characterised by lowtemperature X-ray structural analysis.26 The reaction between the cyclic

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diiodoorganotellurane, C4H8TeI2, and triphenylphosphine has given, serendipitously, the ﬁrst triphenylmethylphosphonium salts containing the [C4H8TeI4]2 and [TeI6]2 anions.27 Phosphonium salts involving a mixed valence bromotellurate(IV)-selenate(II) anion28 and the hexaazidotellurate(IV) anion29 have also been prepared and characterised. A study of the reactions of germanium tetrachloride with primary and secondary phosphines has led to the isolation of the salts [CyPH3]1[GeCl3] and [Ph2PH2]1[GeCl3].30 Electrospray Fourier transform mass spectrometry of combinations of the cations MePh3P1 or Ph4P1 with cyanoferrate anions in the gas phase has identiﬁed the existence of nanocluster cation-anion aggregates, the study leading to a consideration of the principles of association of such ions in crystals. Multiple phenyl embraces, often observed in crystals involving such cations, are not inﬂuential in these systems.31 However, phenyl embraces and p-stacking are inﬂuential in controlling the supramolecular structure of tetraphenylphosphonium p-sulfonatocalix[4]arene.32 Among a wide range of other unusual anions stabilised by phosphonium cations reported in the period under review are diiodobromide,33 4-azidobenzenesulfonate,34 [Mg(BH4)2]2,35 various complex haloberyllates36 and other halometallates,37 haloorgano-stannates38 and -plumbates,39 [NiPS4] chains,40 a series of polyazidotitanates41 and a one-dimensional cyclic tetrameric metavanadate, [V4O11]2.42 Treatment of diphenyltrichlorophosphorane with chlorine has led to the isolation of the salt [Ph2PCl2]1Cl3 as a chlorine solvate. A related reaction with indium trichloride gave the salt [Ph2PCl21]2 [InCl5]2.43 A reinvestigation of tetramethylﬂuorophosphorane, originally prepared by Schmidbaur’s group in 1972, has revealed that it has an ionic structure, Me4P1F, in the solid state, which is stable below 1201C. Above this temperature, it sublimes, having a phosphorane structure in the gas phase.44 The crystallisation and crystal structures of three new crystalline forms of the salt MePh3P1I3 have been described, this compound now having been shown to exist in four polymorphic forms.45 1.2 Reactions of Phosphonium Salts. – The thermal stability of alkyl- and arylphosphonium salts incorporated into montmorillonite layered silicates as components of nanocomposite systems has been studied using thermogravimetry and pyrolysis GC-MS techniques. The alkylphosphonium silicates undergo initial degradation via two pathways, b-elimination and a nucleophilic displacement at phosphorus, reﬂecting the varying environments in the silicate. On the other hand, arylphosphonium silicates decompose via either a reductive elimination involving a ﬁve coordinate intermediate or radical generation through cleavage of a P-phenyl bond.46 A theoretical study has shown that whereas a-phosphonium groups destabilise a methyl radical, the effect on an adjacent benzyl radical depends on the extent of alkylation at phosphorus.47 Structure, bonding and reactivity in the 1,3-diphospha-2,4-diboretane system (30–32) has received considerable attention, with particular reference to the extent of their diradicaloid character. Substituent effects on electronic structures have received both theoretical consideration48,49 and solid state structural investigations.50 The radicaltype reactivity of these systems has also been the subject of an experimental study.51 NMR enantiodifferentiation of alkyltriphenylphosphonium salts

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bearing a stereogenic centre on the alkyl group has been shown to be facilitated by the chiral shift reagent BINPHAT (33).52 Relatively few new aspects of the reactivity of phosphonium salts have been reported in the period under review. Treatment of aminophenylpropenyltriphenylphosphonium salts (34) with an acid anhydride in the presence of a tertiary amine results in the formation of 1,3-diacylindoles.53 Amino(phosphonio)carbenes, e.g., (35), have been shown to undergo nucleophilic intermolecular as well as intramolecular substitution reactions at the carbene centre, enabling the synthesis of a variety of carbenes from a single carbene precursor. Thus, e.g., treatment of (35) with 2,6-Me2C6H3SLi results in displacement of dit-butyl(methyl)phosphine to form the carbene 2,6-Me2C6H3SC( : )NPri2 in quantitative yield.54 Phosphonium salt intermediates are involved in the reaction of Bayliss-Hillman acetates with phosphonium ylides, which provide a one-pot route to 5-arylpent-4-enoate derivatives.55 A study of the reactivity of electrophilic species also containing a phosphonium group has shown that the latter may dramatically enhance the reactivity of the electrophilic centre. Thus, e.g., treatment of the phosphonioaldehyde (36) with benzene and triﬂic acid results in quantitative formation of the salt (37). Allyl- and propargyl-phosphonium salts also undergo similar C-arylation reactions via dicationic electrophilic phosphonium intermediates.56 Phosphonium salt intermediates are also involved in the reactions of epoxides with carbon dioxide, which, in the presence of catalytic amounts of phenol, sodium iodide and a tertiary phosphine, result in the formation of ﬁve-membered cyclic carbonates.57 The reactivity of oxo- and amino-phosphonium salts has also received some attention.The glycosyl-methyldiphenylphosphonium iodide (38) has been shown to act as an efﬁcient glycosyl donor, enabling the synthesis of a-disaccharides in high yields at room temperature without the assistance of acid-promoters.58 A quantum chemical approach has been applied to an assessment of the stability of the diphosphonium salts (39), with particular reference to the P–P bond energy.59 A study of the sequential deprotonation of the tetraanilinophosphonium cation (40) has been reported, various intermediate species leading to the ﬁnal trianion (41) having been characterised.60 New routes to azides and diazonium compounds are afforded by the reactions of lithio-amides and -hydrazonides, respectively, with azidotris(diethylamino)phosphonium bromide (42), via initial nucleophilic attack of the anion on the azide group.61,62 A range of new tris(dialkylamino)oxophosphonium salts similar to BOP has been prepared and shown to have useful properties as peptide coupling reagents.63 R2

R2

B

B PR1 2

R12 P

R2 B PR12

R12P

PR12

R12P

B

B

B

R2

R2

R2

(30)

(31)

(32)

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Organophosphorus Chem., 2006, 35, 92–126 Cl

Cl

Cl O

R

O Bu4N

P

PPh3 Br

Cl

O

NH2

O

O O

Cl Cl

Cl

(34)

Cl (33)

NPr i2

But2MeP

TfO

O

Ph3P

C

Br

Ph

Ph3P

X

Ph

(35)

(36)

(37)

BnO Rn(R2N)3-nP

BnO BnO OBn

OPMePh2

P(NR2)3-nRn

2X

I

(38)

(39)

3 NHPh PhNH

P

NHPh NHPh

(40)

NPh

PhN P PhN

N3 NPh

(41)

P

NEt2 NEt2 NEt2

Br

(42)

Considerable interest also attaches to the use of phosphonium salts as reagents and ionic liquid solvents in synthetic work in areas other than the Wittig reaction. A study of the phase properties of a series of methyltri(n-decyl)phosphonium salts has shown that they act as ordered, room-temperature ionic liquids.64 The ability of a series of ionic liquid trihexyl(tetradecyl)phosphonium salts to solvate a coumarin dye has been investigated.65 Ionic liquid phosphonium salts have found use as solvents in the Suzuki coupling of aryl halides66 and in the electrodeposition of very electropositive metals.67 Trihexyl(tetradecyl)phosphonium decanoate is an effective promoter of the Henry nitroaldol reaction of nitromethane and aromatic aldehydes.68Acetonyltriphenylphosphonium bromide and its polymer-supported analogues act as catalysts for the protection of carbonyl compounds as acetals or thioacetals.69 Tetrabutylphosphonium chloride acts as a catalyst for the dehydrochlorination of hydrochlorosilanes in their coupling reactions with alkyl halides70 and conjugated dienes or alkynes.71 Methyltriphenylphosphonium iodide catalyses the addition of trimethylsilyl cyanide to aldehydes to give cyanohydrin trimethylsilyl ethers.72 The reaction of alcohols with an excess of (cyanomethyl)trimethylphosphonium iodide in the presence of a base, followed

Organophosphorus Chem., 2006, 35, 92–126

99

by aqueous hydrolysis, results in the clean formation of nitriles having two more carbon atoms than were present in the original alcohol. The reaction is applicable to benzylic, allylic and aliphatic alcohols without b-branching.73 Triphenylphosphonium perchlorate has been found to catalyse the diastereoselective synthesis of cis-fused pyrano- and furano-benzopyrans,74 mono- and bis-intramolecular imino Diels-Alder reactions in the synthesis of tetrahydrochromanoquinolines75 and indolylquinolines,76 and also the synthesis of a variety of 3,4-dihydropyrimidin-2(1H)-ones.77 Tetraalkylphosphonium salts catalyse a selective, solvent-free N,N-dibenzylation of primary aliphatic amines with dibenzyl carbonate.78 A fast and mild method for the nitration of activated aromatic rings is provided by the use of benzyltriphenylphosphonium nitrate in the presence of methanesulfonic anhydride, under solvent-free conditions.79 A considerable number of reports of the application of phosphonium salts bearing oxidising anions have appeared, these compounds having the advantage of being soluble in non-aqueous aprotic solvents such as acetonitrile, which facilitates product isolation. Butyltriphenylphosphonium dichromate has found use for the conversion of thiocarbonyls to the corresponding carbonyl compounds.80 A kinetic study has shown that the oxidation of benzylic alcohols by butyltriphenylphosphonium dichromate involves hydride transfer via a dichromate ester intermediate.81 Butyltriphenylphosphonium periodate has been used for the conversion of a-sulﬁnyl oximes and a-sulﬁnyl hydrazones to the corresponding b-ketosulfoxides in high yields and high enantiomeric purity.82 Tetraphenylphosphonium monoperoxosulfate is the reagent of choice for asymmetric epoxidation reactions mediated by iminium salts under non-aqueous conditions.83 Benzyltriphenylphosphonium monoperoxosulfate has been used in a highly selective iodination of phenols using potassium iodide,84 for the dethioacetalisation of 1,3-dithiolanes,85 and for the selective oxidation of sulfides and thiols in both solution and solid-state conditions.86,87 Both benzyl- and butyl-triphenylphosphonium peroxodisulfate salts have found use for the transformation of thiocarbonyls to the related carbonyl compounds.88 Benzyltriphenylphosphonium peroxodisulfate is a useful reagent for the oxidation of thiols to the corresponding symmetric disulfides89 and for the oxidative cleavage of phenylhydrazones and semicarbazones to their parent carbonyl compounds.90 Allyltriphenylphosphonium peroxodisulfate has been shown to be an efﬁcient reagent for the oxidation of primary and secondary alcohols and silyl- and THP-ethers under non-aqueous conditions.91

2

Phosphine Chalcogenides

2.1 Preparation. – The direct oxidation of tertiary phosphines with oxygen, hydrogen peroxide, sulfur, selenium or tellurium has continued to be widely applied in the synthesis of new phosphine chalcogenides. Included among these are the ﬂuorescent systems (43)92 and (44),93 the chelating pincer-ligand disulﬁde (45),94 the ferrocenyl systems (46)95 and (47),96 and a series of indenylphosphine chalcogenides (48).97 Direct oxidation reactions (and other

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Organophosphorus Chem., 2006, 35, 92–126

routes) have been used in the synthesis of a series of chalcogenides, e.g., (49), derived from 2,6-bis(diphenylphosphinomethyl)pyridine.98,99 The diselenide (50) has been prepared by direct reaction of the parent diphosphine with selenium. A comparison of the 1J(31P-77Se) coupling constant of (50) with those of a range of other phosphine selenides indicates that the parent diphosphine is a poorer s-donor than BINAP as a result of the electron-withdrawing properties of the furan ring.100 Direct oxidation with elemental tellurium of Nmetallated aminodiphosphines has afforded new anionic phosphine telluride ligands, e.g., (51).101 The synthesis of monochalcogenide derivatives of diphosphines has also proved to be of interest. Hydrogen peroxide oxidation of a mono(borane-protected)-bis(phospholane), followed by deprotection with DABCO, has given the chiral bis(phosphine) monoxide (52, X ¼ O), used as a chiral ligand in an asymmetric catalytic synthesis of a-chiral amines.102 The direct oxidation of BINAP and other chiral diphosphines with one equivalent of sulfur in benzene or THF has enabled the isolation (after chromatography) of a series of chiral monosulfides, e.g., (52, X ¼ S), (53), and (54).103,104 Treatment of the tetraphosphine (55) with an excess of hydrogen peroxide, sulfur or selenium gave the expected tetraphosphine tetra-oxide, -sulﬁde or selenide (56, X ¼ O, S, or Se), respectively. However, treatment of the tetraphosphine (55) with two equivalents of selenium, initially in hexane, followed by dichloromethane and ﬁnally toluene, enabled the isolation of the diselenide (57) in 44% yield.105,106 X P

Ph Ph

O Ph P n

C

C

C

C

OMe 3-n P Ph Ph

(43) n = 0 or 2

X

(44) X = O, S or Se X

CH2OH

P Ph P Ph

P

Fe

Ph

S

S

Ph

P X

Ph

Fe

Ph

CH2OH CH2OH

Y

(47) X = O, S or Se; Y = P(X)(CH2OH)2 or H

(46) X = O or S

(45) X Ph nP

N 3-n

(48) n = 0,1 or 2; X = O, S or Se

Ph O P P Ph X X

Ph Ph

(49) X = O or S

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Organophosphorus Chem., 2006, 35, 92–126

O

X

Ph P

Ph

Ph

Ph P Ph Se

Ph

Se O

N

P Te

P Te

Ph

P

(51)

(50)

(52)

S P

H

Ar

O

H

(53) Ar = Ph or p-tol X PPh2

Ph2P

PPh2

(54) X

Se

Ph2 P

PPh2

Ph2 P

PPh2

Ph2 P

PPh2

Ph2 P

PPh2

X (55)

Ar

Ar PAr2

Ar

PAr2

S P

O

Ph2P

P

Ph

X (56) X = O, S or Se

Se (57)

Apart from direct oxidation, other methods for the introduction of the phosphine oxide group have also been used. The reaction of diarylphosphinyl chlorides with an organolithium reagent has given the chiral hydroxyarylphosphine oxide (58), subsequently resolved via a camphorsulfonyl derivative.107 The nickel-catalysed Tavs reaction of 4-bromophthalonitrile with ethyl diphenylphosphinite has given the phosphine oxide (59), subsequently converted to the phthalocyanine tetra(phosphine oxide) (60) and related metal complexes.108 The reactions of ethyl bis(pentaﬂuorophenyl)phosphonite with activated alkynes proceed via two-stage cycloaddition processes, leading, after hydrolysis of intermediate ﬂuorophosphoranes, to the benzophosphole oxides (61).109 Russian workers have continued to explore the synthesis of phosphine oxides from the reactions of alkyl halides and elemental phosphorus in the presence of a superbase, e.g., KOH-dioxan. The main product of the reaction of allyl bromide with white phosphorus is the triallylphosphine oxide (62), together with smaller amounts of its prototropic isomers bearing prop-1-enyl substituents.110 A related reaction of red phosphorus with 1-chloromethylnaphthalene gave the tris(1-naphthylmethyl)phosphine oxide (63) in 70% yield, of interest as a complexing luminophore.111 Improved yields of phosphine oxides from the superbase-promoted reactions of red phosphorus with arylalkenes have been obtained by the use of red phosphorus formed by radiation-induced polymerisation of white phosphorus, rather than by the use of the usual thermally transformed allotrope, attributable to defect structures in the irradiated material.112 A combinatorial library of ﬂuorescent polymer-bound phosphine sulfides

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Organophosphorus Chem., 2006, 35, 92–126

(64) has been prepared by introduction of a dialkylphosphoryl group into various polymer-bound chloromethylanthracene units using a reagent generated in situ from diethyl phosphonate and an alkylmagnesium halide, followed by conversion of the resulting anthracylmethylphosphine oxides to the related sulfides by treatment with P4S10. These have been shown to act as sensor materials for the detection of metal ions.113 O O

Ph 2P O P

PPh2 Ar

O

Ar

Ph2 P

N CN

N

HN N

N

OH CN

N

NH N Ph2P

PPh2

O (58)

(59)

F

R

F

P O

P R F F

O

P C6F5 O

3

(61)

(62)

S O

O

(60)

P R R

(63)

Ph MeO

MeO O O P

MeO C OH P X 3

MeO (64) R = Bun, Bui or 1,1-dimethylpropyl

(65)

(66)

Most newly-reported phosphine oxides, however, have been prepared by transformation of the carbon skeletons of other phosphine oxides. A novel route to the 9-phosphatriptycene system involves ortho-metallation of tris(oanisyl)phosphine oxide and treatment with phenyl chloroformate to generate (65), which, with LDA (2-equivalents), is converted into the 9-phosphatriptycene oxide (66, X ¼ O). Treatment of the latter with P4S10 provides the related sulﬁde (66, X ¼ S). The phosphatriptycene selenide (66, X ¼ Se) has also been obtained (by direct reaction of the parent phosphatriptycene with selenium), the 1J(31P-77Se) coupling constant (827 Hz), indicating that the phosphorus orbital bonded to selenium has a significantly greater degree of s-character than that in, e.g., tris(o-anisyl)phosphine selenide (732 Hz).114 The behaviour of 2,2 0 bis(diphenylphosphinoyl)-1,1 0 -binaphthyl (BINAP(O)2) towards various lithium and magnesium amides has been studied, leading to the isolation of new phosphine oxides, e.g., (67) and (68).115 Various regioisomeric pairs of

Organophosphorus Chem., 2006, 35, 92–126

103

carboxylate-functionalised triarylphosphine oxides bearing the 9,10-dihydro-9, 10-ethanoanthracene moiety, e.g., (69), have been obtained by the cycloaddition of unsaturated esters to 2-anthryldiphenylphosphine oxide.116 A route to the phenyltelluroalkylphosphine oxide (70), is afforded by the metallation of diphenyl(methyl)phosphine oxide, followed by treatment with phenyltellurium bromide. This compound is a useful reagent for the synthesis of vinylic tellurides via Horner-Wittig procedures.117 b-Phenyltellurovinylphosphine oxides (71), (accessible from the hydrotelluration of alkynylphosphine oxides), have been shown to undergo a palladium-catalysed cross-coupling reaction with alkenes to form the 1,3-dienylphosphine oxides (72).118 Two groups have reported the application of ruthenium-catalysed oleﬁn cross-metathesis reactions for the synthesis of vinyl- and allyl-phosphine oxides, and related diphosphine oxides.119,120 Highly regio-controlled palladium-catalysed crosscoupling reactions of terminal alkynes with allenylphosphine oxides provide routes to the isomeric enynylphosphine oxides (73) and (74).121 Palladiumcatalysed Suzuki coupling reactions of triarylphosphine oxides having a reactive substituent at the 4-position (usually bromo or triflate) with a series of arylboronic acids have given a range of phosphine oxides bearing a biaryl group, e.g., (75), this being a precursor for the synthesis of poly(arylene) ether phosphine oxide polymers arising from nucleophilic displacement reactions of the ﬂuoroaryl groups.122 In related work, palladium-catalysed Heck coupling reactions of bromoarylphosphine oxides with alkenes have given linear alkenylsubstituted arylphosphine oxides. Amination and methoxycarbonylation reactions have also been shown to be feasible.123 Triarylphosphine oxides of type (76) undergo polymerisation to form (polyarylene)phosphine oxides (77), the basis of some new high-performance materials.124 The reactions of 1thioxophosphorinanones with terminal alkynes in the presence of base have given a series of aryloxypropynyl alcohol derivatives, e.g., (78).125,126 UVirradiation of the phosphaferrocenophane (79) in the presence of trimethylphosphite results in a ring-opening rearrangement to form the new phosphine sulﬁde (80). In the presence of trimethylphosphine, the rearrangement follows a different course, resulting in the zwitterion (81).127 Ethoxylation of tris (p-hydroxyphenyl)phosphine oxide has given a range of polyethoxylated derivatives (82), which have found use as a phase-separable homogeneous catalyst component in a rhodium-catalysed hydroformylation of higher alkenes.128 The reactions of the chlorosulfonylarylphosphine oxide (83) with an aminoalkyl-bcyclodextrin have given various phosphoryl tethered b-cyclodextrins, e.g., (84), which act as chiral molecular recognition systems for alicyclic alcohols and acids, and alanine derivatives.129 In a similar approach, treatment of the functionalised phosphine oxide (85), (obtained from the reaction of tris(chloromethyl)phosphine oxide with dimethyl 5-mercaptoisophthalate), with (1R,2R)diaminocyclohexane has given the phosphine oxide (86), isolated as two conformational isomers. The major isomer (10:1) has a bowl-shaped C3-symmetric structure, with the phosphoryl group directed to the interior of the bowl, and shows a remarkable selectivity for binding asparagine derivatives. In the minor isomer, the phosphoryl group is directed to the outside of the bowl.130 The anion of (chloromethyl)diphenylphosphinoyl chloride has been shown to

104

Organophosphorus Chem., 2006, 35, 92–126

react with various 4-substituted nitrobenzenes in the ortho position to the nitro group, with displacement of a proton to give the benzylphosphine oxides (87) by a vicarious nucleophilic substitution mechanism.131 A series of new chiral aminoalkylphosphine oxides, e.g., (88) and (89), has been prepared by the addition of chiral primary amines to vinyldiphenylphosphine oxide in methanol.132 Carbamoyl- and thiocarbamoyl-derivatives (90) of 3-aminopropyldimethylphosphine oxide have been prepared by the reaction of the aminopropylphosphine oxide with isocyanates and isothiocyanates.133 A similar addition of ﬂuorinated hydrazines to the allenylphosphine oxides (91) has afforded the hydrazone derivatives (92). Related compounds have also been prepared by the reactions of phenacylphosphine oxides with the hydrazines.134 Routes to various linear enediyne phosphine oxides and sulfides, e.g., (93), have been developed. Their cobalt(I)-mediated cyclisations, giving complexed tricyclic compounds bearing phosphine oxide substituents, e.g., (94) have also been explored.135 The cleavage of phosphine sulﬁde-functionalised peptides bound to the Kaiser oxime resin by aminooxazoline reagents has given a series of oxazolinyl-peptide phosphine sulfides (95).136 Palacios’ group has described routes to a series of heteroarylphosphine oxides. The aryliminophosphine oxides (96), easily accessible from the reactions of aromatic amines with phenacylphosphine oxides, have been shown to react with DMF-dimethylacetal to form the quinolylphosphine oxides (97).137 The phosphazenylalkyldiphenylphosphine oxide (98), obtained from the reaction of triphenylphosphine with azidomethyldiphenylphosphine oxide, has been converted via the amidine (99) into the oxazinylphosphine oxide (100).138 Routes to 2H-aziridinylphosphine oxides (101) have undergone further development, and these compounds have been shown to react with carboxylic acids to form the ketamidophosphine oxides (102), which cyclise to the oxazolylphosphine oxides (103) in the presence of the triphenylphosphine-hexachloroethane reagent.139,140 Conversion of 2H-aziridinylphosphine oxides to pyrazinylphosphine oxides (104) has also been described.141 A multistep route from D-glucose (as a chiral template) to the 19-norvitamin D A-ring phosphine oxide (105) has been developed.142 A regioselective synthesis of phosphonylated sugars, e.g., (106), is afforded by the reactions of glycals with the diphenylphosphenium cation.143 The synthesis of sugar analogues based on phospholene- and phospholane-oxide systems has also attracted much interest. Chromium trioxide oxidation of 2-phospholene oxide sugar analogues provides a convenient chemo- and regio-selective route to the 4-oxo-2-phospholene-1-oxides (107).144 Sodium peroxide has been used as a reagent for the stereospecific synthesis of the 2,3-epoxides (108) from 2phospholene-1-oxides.145 Oxidation of 3-phospholene oxides using m-chloroperbenzoic acid has given a series of 3,4-epoxyphospholane oxides (109), which have been shown to rearrange in the presence of a chiral base to form P,C-chirogenic 4-hydroxy-2-phospholene derivatives, e.g., (110), with up to 52% ee.146 In related work, it has also been shown that the 3,4-epoxides are converted into the enantioenriched, P-stereogenic trans-3-hydroxy-4-azido- and trans-3-hydroxy-4-cyano-functionalised phospholane oxides (111) on treatment with trimethylsilyl-azide and -cyanide, respectively, in the presence of the

105

Organophosphorus Chem., 2006, 35, 92–126

salen-Al complex.147 Bromohydrin derivatives of 2-phospholene oxides, e.g., (112), have found further use in synthesis. Treatment with potassium carbonate in methanol provides a route to the erythro-2,3-epoxides, which, with dimethylsulfonium methylide, are converted into the allylic alcohols (113).148 Routes from (112, R ¼ Ph) (and related O-methyl ethers) to new deoxyphosphasugar-pyrimidine nucleosides, e.g., (114),149 and deoxyphosphasugar-sugar disaccharides150 have been developed. An expedient cyclopentannulation route to the 2-phosphabicyclo[3,3,0]octene system (115) is provided by the treatment of 1-phenyl-3-phospholene-oxides and -sulfides with two equivalents of LDA, followed by quenching the metallated intermediates with 1,3-dihaloalkanes.151 Keglevich’s group has continued to develop its study of cycloaddition reactions of unsaturated cyclic phosphine chalcogenides, e.g., phospholene-, phospholeand 1,2-dihydrophosphinine-oxides, and the ability of such adducts to undergo thermally-induced elimination to form low-coordinate s3l5-species, mainly methylenephosphine oxides and sulfides, capable of acting as phosphorylating agents. Much of their earlier work on reactions of 1,2-dihydrophosphinine oxides has now been reviewed.152 Among new work in this area is a study of the formation and subsequent fragmentation of 2-phosphabicyclo[2,2,2]oct-5-ene-2oxides (116), and related bicyclo[2,2,2]octa-5,7-diene-2-oxides (117), obtained via Diels-Alder additions of 1,2-dihydrophosphinine-oxides with maleimides and related compounds153 and acetylenic esters,154 respectively. With tetracyanoethylene, 1,2-dihydrophosphinine oxides undergo a complex mode of cycloaddition to form the 2,8-diphosphatricyclododeca-3,5,9-triene 2,8-dioxides (118).155,156 Diels-Alder dimerisation of 1,2-dihydrophosphinine oxides has also been reported, giving new 2-phosphabicyclo[2,2,2]oct-5-ene-2-oxides, e.g., (119).157,158 The Baeyer-Villeger oxidation of the 7-phosphanorbornene 7-oxides (120) using m-chloroperbenzoic acid results in the formation of the P-aryl2,3-oxaphosphabicyclo[2,2,2]octene oxides (121) as a mixture of isomers.159 Anions derived from dialkyl phosphites or diphenylphosphine oxide have been shown to undergo Michael-type additions to 1,2-dihydrophosphinine oxides to form the 1,2,3,6-tetrahydrophosphinine-1-oxides (122) as a single diastereoisomer.160 The bicyclic phosphino-phosphine sulﬁde (123) has been obtained from a chiral palladium complex-promoted Diels-Alder addition between 3,4-dimethyl-1-phenylphosphole 1-sulﬁde and diphenylvinylphosphine, the (RP)-exo adduct being obtained with high stereoselectivity in the initial complex.161

R O

MeO2C

CO2Me

P P O Ph

(67)

Ph Ph P PPh2

O R (68) R = Li, MgBr or TMS

O (69)

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Organophosphorus Chem., 2006, 35, 92–126

R1 R1 O Ph2PCH2TeC6H5

PhTe

PPh2

R2

PPh2

O

O (70)

C R1

C

(71)

O

O

PR32

PR32

C R2

R1

C

(73) R1 = e.g., Bu or Ph; R2 = H or Me; R3 = Ph or NPri2

O P Ar Ar

CH3CO

R2

(75) Ar = p-FC6H4

(74) R1 = e.g., Bu or Ph; R2 = H or Me; R3 = Ph or NPr i2

X

O F

(72) R1 = Ph or Bu; R2 = Ph or COCH3

S

O

P

P

Ph

P OH C C CH2OR

n X F (76) X = Cl or mes

Fe

P

(78) R = Ph or PhCH2

(77)

Ph

xs P(OMe)3

S

THF, hν

S P Ph

S P Ph Fe

H

(MeO)3P (MeO)3P

(79)

Fe Me3P Me3P PMe3

(80)

(OCH2CH2)xOH

(81)

O P SO2Cl SO2NH N H

N HN H

O P (OCH2CH2)yOH

O P

SO2Cl ClO2S 3 (OCH2CH2)zOH

(82)

(83)

(84)

107

Organophosphorus Chem., 2006, 35, 92–126

O

O

HN

NH O

OC6F5

S NH

HN

O P

O

O

O P

O

S

S

NH

HN

S OC6F5

3 O

O

(85)

(86)

O NO2

O HN

PPh2

PPh2

NH HN PPh2

X

Ph2P

O (87) X = Cl or Br

X RN H

N H

NHRF N

O

(90) X = O or S

R

(92) R = Me or Pri; RF = CH2CF3 or C6F5

(91) R = H or Me

CpCo

n-2

n

(93) n = 3 or 4; X = O or S

O Ph2P

Ph2P

O

X

(89)

H C C CR2

PMe2

PPh2

O

(88)

H N

R

Ph2P

H O

(94)

R

N

S

O

Ph2P

O

O N H

O N R

R

(95) R = CO2Me, Pri or But

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Organophosphorus Chem., 2006, 35, 92–126

O

O R2

PPh2

R3

R

R1

N

O

O

2

PPh2

R3

N

(96) R1 = H, Me or Et; R2 = H, Me, Cl or OMe; R3 = H, Me, CF3 or OMe

Ph2P

Ph2P

N

N

PPh3

R1

(97)

(98)

(99)

R2 O Ph2P

O N

N Ph

R

O

N PPh2

R1

O

(101) R = Me or Et

(100)

O

R2

Ph2P

PPh2

R

O

H N

R1

O

O

(102) R1 = Me or Et; R2 = e.g., Me, Ph or vinyl

(103)

O PPh2

O R

AcO

N

PPh2

N

R

H

O TBSO

PPh2

AcO

OTBS

O

OTMS

(104) R = Me, Et or Ph (106)

(105)

O P

R

2

O

R1

O

R1

O R3

O

(107)

R2

(108)

O

Ph P

R

P

R

R

O

Ph P

R

Me OH

(110)

(109) R = H or Me

O O

Ph P

HO

X

O R P Br H H OH

R

O

R1

NR2

P H OH

Ph P N OH H OH

(111) X = N3 or CN

(112)

(113)

(114)

O

Ph

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Organophosphorus Chem., 2006, 35, 92–126

O Y

R2

P

O E

P

X

Ph

R1

P

Cl

E

R1

Ar

O

NR

CO2Me CO2Me

R2

O (115) X = O or S

(117) Ar = o-tol or p-tol; R1,R2 = H or Me

(116) Y = Me, Ph, or 2,4,6-Pri3C6H2; R1, R2 = H or Me; E = CH or N

Y

O

P Cl

O P

Me

NC

X

Cl

NC CN

Y

H

O

P

O P

Y

Me

H

Me Me

Ar

O

H H

P Y

X

O NPh

Me O

(118) Y = Ph, o-tol, p-tol or Et

O

O

O Ar

(119) Y = Me or Ph ; X = H or Cl

P H

Me H

O NPh

Cl

S

P

Z

(120) Ar = p-tol, Mes, 2,4,6-Pri3C6H2 or Ph

Me

Ph P

Z

Me O

P

Y

Ph2P Me

O (121)

(122) Y = Ph or EtO; Z = Ph or RO

(123)

Phosphine oxides have also been prepared using secondary phosphine oxides as building blocks. These compounds have been shown to undergo double basepromoted P-H additions to methylacetylene to form ditertiary phosphine oxides having a chiral carbon atom, e.g., (124).162 Triethylboron-catalysed anti-Markownikov radical addition of diphenylphosphine oxide to alkenes, unsaturated acids, allylic alcohols and other unsaturated species has given a wide range of new functionalised phosphine oxides under mild conditions.163 Further examples of additions to carbonyl groups have also appeared, providing routes to the furan derivatives (125),164 the trialkylsilyl- and trialkylgermyl-alkynyl hydroxyalkylphosphine oxides (126),165 the hydroxyethenylphosphine oxides (127),166 and the arylhydroxymethylphosphine oxides (128).167 The reaction of an ao-disecondary amine with formaldehyde and di(p-tolyl)phosphine oxide has given the bis(aminomethylphosphine oxide) (129).168 The 3,4-dihydro-2Hpyrroline N-oxide derivative (130) has been prepared via the alkylation of a secondary phosphine oxide using 5-chloropentan-2-one, followed by cyclisation with ammonia. This compound, and a related molecule derived from ethyl phenylphosphinate, act as spin trapping agents for oxygen-centred radicals.169

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Organophosphorus Chem., 2006, 35, 92–126

PhCH2CH2 PhCH2CH2

O P

O

O CH2CH2Ph P CH2CH2Ph

(124)

O

R12P

R2

P

R13E

OH

O

PhCH2CH2 P

R2

(127) R1 = Bun, C6H13n, or PhCH2CH2; R2 = H, Me or OPh

(126) R1 = Me or Et; R2 = Ph or 2-Py; E = Si or Ge

O

O

Ar2PCH2 R3

N Bu

PhCH2CH2 OH

CH2CH2R2

CH2CH2R2 OH

(125) R = Bun, C6H13n, PhCH2CH2 or 4-PyCH2CH2

R1 O

O

PR2

CH2CH2O 2

CH2PAr2 CH2CH2 N Bu

OH (128) R1 = H or OMe; R2,R3 = H, OH or OMe;

(129) Ar = p -Tolyl

2.2 Reactions. – Keglevich’s group has continued to study the reactions of sterically-bulky cyclic tertiary phosphine oxides with electron-withdrawing alkynes, which lead to stabilised ylides (131) in an inverse Wittig protocol. Further examples of this have now been described170 and a theoretical study has shown that pentacovalent spiro-oxaphosphoranes involving a four membered oxaphosphete ring system (132), in which the oxygen atom is equatorial, are likely intermediates in these reactions.171 Treatment of the tris(phosphine oxide) (133) with butyllithium results in a double-deprotonation to give what may be the ﬁrst formal phosphorus-stabilised 1,2-dianion (134), isolated as a THF-solvated lithium cluster complex.172 Tertiary phosphine selenides have been shown to react with chlorine at 901C to give the phosphonium salts [R3PSeCl]1Cl which then undergo deselenisation to form the chlorophosphonium salts [R3PCl]1Cl.173 Secondary phosphine oxides react with diacetoxyiodobenzene in the presence of sodium alkoxides to yield alkyl diorganophosphinate esters, involvement of the intermediates (135) being suggested on the basis of 31P NMR studies.174 The reactions of tris(2-pyridyl)phosphine oxides with arenesulfenyland -selenyl chlorides proceed with P-C cleavage, resulting in the formation of areneseleno- and arenethio-bipyridyls. Similar reactions occur with arenesulﬁnyl chlorides to give arenesulfonylbipyridyls.175 Thiols have been shown to undergo oxidation to disulfides on treatment with triphenylphosphine oxide and bis(trichloromethyl) carbonate, the phosphine oxide being reduced to triphenylphosphine. This may therefore provide a convenient new general method for reducing triarylphosphine oxides to the related phosphines.176 Further applications of the Hendrickson reagent, [Ph3POPPh3]1 OTf, arising from the dissolution of triphenylphosphine oxide in triﬂic anhydride, have appeared. It has been applied in the synthesis of thiazolines,177 oxazole- and thiazole- units in a macrocyclic antibiotic,178 and in a direct synthesis of sulfonamides and activated sulfonate esters from sulfonic acids.179 A polymer-supported version of the Hendrickson reagent has also been developed and found to have

111

Organophosphorus Chem., 2006, 35, 92–126

advantages in product isolation over the non-supported system for a range of dehydration reactions leading to ester and amide formation.180 The Hendrickson reagent can be used in place of Mitsunobu reagents (triphenylphosphine and a dialkyl azodicarboxylate ester) for the esteriﬁcation of primary alcohols. However, secondary alcohols such as menthol undergo elimination of water, attributed to the presence in the reaction mixture of trialkylammonium triflate salts. In the presence of azide ion, the Hendrickson reagent can also be used to convert a primary alcohol into an alkyl azide in high yield.181 Secondary phosphine oxides have continued to ﬁnd applications as reagents in synthesis, diethylphosphine oxide promoting a radical-cyclisation reaction in the synthesis of indolones from an acyclic amide precursor, in water.182 The reactions of dibenzylphosphine oxide with a,b-unsaturated O-methyloximes have been investigated, leading to the isolation of a wide range of tertiary phosphine oxide products. Thus, e.g., with the O-methyl ether of benzylideneacetone oxime, the methoxyiminophosphine oxide (136) is formed by attack at the b-carbon. Aldoxime-O-methyl ethers, on the other hand, can give rise to phospholene oxides, e.g., (137), obtained from 2-methylpent-2-enal O-methyloxime.183 The photolysis of acylphosphine oxides, generating both acyl- and diorganophosphinoyl-radicals, has continued to attract attention for the initiation of polymerization reactions of alkenes.184,185 Various tertiary phosphine oxides have been shown to act as catalysts in the stereoselective allylation of Nacylhydrazones.186

O P

Ar

R

P

CO2Me

O

CO2Me

(130) R = Me or OEt

PPh2

Ph2P

OMe

PPh2

PPh2

O

O

NH2

N P

O

I OAc

(135)

R

Me

Me

PR2 Ph

(134)

Ph Me

O

PPh2

Ph2P

(133)

N

(132)

O O

CO2Me

MeO2C

(131)

O O

PR2

O

N O

O

P Ar

O P 2

Ph (136) R = PhCH2

(137)

(138) R = H, CH2OH, CH2OMe, CH2OBn or CH2N(C4H4)

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Organophosphorus Chem., 2006, 35, 92–126

2.3 Structural and Physical Aspects. – Tertiary phosphine oxides have been shown to form 1:1 molecular donor-acceptor complexes with [60]- and [70]fullerenes, formation constants for complex formation having been determined by an NMR spectroscopic method from the systematic variation of chemical shifts of speciﬁc protons of the donor phosphine oxide in the presence of the fullerene.187 Detailed NMR studies have also been reported of the conformations in solution of the phosphine oxides (138)188 and a series of chiral phospholene- and phospholane-chalcogenides, e.g., (139).189 The enantiomeric purity of P-chirogenic phospholene oxides has been determined by 1H- and 31PNMR techniques using the classical Kagan chiral amides as NMR chiral shift reagents.190 The efﬁcient enantiodiscrimination of the chiral phospholane oxides (140) has been shown to be possible by the use of phosphorus-coupled 13 C-NMR spectroscopy in the presence of a chiral weakly-ordering polypeptide liquid crystalline phase. This approach allows determination of the enantiomeric composition and is a new efﬁcient alternative to classical methods of chiral analysis.191 The chiral racemic diphosphine dioxide (141, X ¼ O) has been resolved into its enantiomers by a classical approach involving fractional crystallisation of its diastereoisomeric adducts with (þ)-(2S,3S)-di-O-benzoyltartaric acid, followed by neutralisation. One racemic form of the disulﬁde (141, X ¼ S) and two racemic forms of the monosulﬁde (142), have been obtained by reactions of the parent diphosphine with sulfur, and subsequently characterised by NMR spectroscopy and X-ray crystallography.192 The enantiomers of tbutyl-1-(2-methylnaphthyl)phosphine oxide (143) have been separated using a chiral HPLC column. Vibrational absorption and circular dichroism spectra have been measured for both enantiomers, enabling a determination of their absolute conﬁgurations.193 The ﬁrst enzymatic desymmetrizations of prochiral phosphine oxides have been reported. Bis(methoxycarbonylmethyl)phenylphosphine oxide was subjected to hydrolysis in the presence of a pig liveresterase to give the chiral monoacetate (144) in 92% yield and 72% ee. Similarly, prochiral bis(hydroxymethyl)phenylphosphine oxide was desymmetrized using either a lipase-catalysed acetylation or hydrolysis of the corresponding diacetyl derivative to give the chiral monoacetate (145) in 76% yield and with e.e’s up to 79%. The absolute conﬁgurations of these monoesters were determined by means of chemical correlation.194 Interest in the structural characterisation of hydrogen-bonded adducts of phosphine-oxides and -sulﬁdes has continued. Infrared spectroscopy and theoretical techniques have been used to study the energetics of intramolecular hydrogen bonds and conformations of the o-diphenylphosphoryl- and o-diphenylthiophosphoryl-substituted aliphatic alcohols (146)195 and also molecular interactions in the carboxy(diphenylphosphinoyl)cyclopentanone (147).196 Intramolecular hydrogen bonding in the salts (148) has been studied in the solid state by X-ray structural work and in solution by multinuclear NMR techniques.197 The ﬁrst complex of triphenylphosphine oxide with a chiral substrate has been obtained by crystallising the phosphine oxide in the presence of S-()-1,1 0 -bi-2,2 0 -naphthol (BINOL), resulting in the formation of a 1:2 (BINOL): (Ph3PO) complex, the structure of which has been determined by X-ray crystallography. A complex of the same

113

Organophosphorus Chem., 2006, 35, 92–126

stoichiometry has also been isolated by the use of racemic BINOL. In the homochiral complex, the phosphine oxide molecules appear to exist in only one enantiomeric form.198 Interactions between b-cyclodextrin and a monosulfonated triphenylphosphine oxide have been investigated in aqueous solution by NMR, UV-visible absorption and ESMS techniques. Titration and continuous variation plots point to the formation of 1:1 inclusion complexes.199 Solid state X-ray structural studies have been reported of the adduct of cyclohexylamine hydrochloride and the tris(phosphine oxide) (149), and also of the di(phosphine oxide) (150), in which weak C(phenyl)–H O(oxide) hydrogen bonds are identiﬁed.200 Phosphorus-oxygen coordination leading to pseudotrigonal bipyramidal geometries in the anionic phosphine oxide (151) and hydrogen bonding interactions with tris(2-hydroxy-3,5-dimethylbenzyl)amine have also been the subject of a structural study.201 A structural study of the phosphine oxide (152), obtained by hydrogen peroxide oxidation of tris(o-dimethylaminomethylphenyl)phosphine, has shown that the geometry about phosphorus is tetrahedral, no intramolecular coordination to phosphorus from the N-oxide units being apparent.202 Among other phosphine chalcogenides which have been the subject of X-ray crystallographic studies are the thioxo-phosphorinane (153),203 tris(2pyridyl)phosphine oxide,204 and the ionic system (154) which involves an unusual anion.205 The gas phase structure of tris(t-butyl)phosphine oxide has been determined by a new method which links the gas-phase electron diffraction reﬁnement process with computational methods in a dynamic interaction of theory and experiment. This approach has revealed a shorter phosphorus-oxygen distance than was found by a less sophisticated analysis, and is consistent with the molecule being regarded as But3P¼O rather than But3P1–O.206

P X

Ph

(139) X = O, S or Se

Ph

P

Ph

R

O

MeO

(140) R = Ph, PhCH2,

CH2

or Me

X X

Ph

P

But

Ph P But

S

Ph But

(141) O

P

CO2Me

(144)

t

Bu

Ph

P

But

X

OH

O

O

(143)

Ph2P

P Me

H

(142)

P Ph

Ph

P

OAc

(145)

(CH2)nOH

(146) X = O or S; n = 1-3

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Organophosphorus Chem., 2006, 35, 92–126

O

O

Ph

PR2

Ph P

Ph

P

N

O

H

Ph

OH

Ph X

O

(147)

(148) X = Br or BF4

O

O

Ph2P

Ph2P CO2 O O

PPh2 Ph2P

PPh2

O O

O

PPh2 O (149)

(151)

(150)

O O NMe2

Ph

O

P

O F3B

Ph2PCH2 NH

P O 3 (152)

H MeN

BF3

N Me

O (153)

(154)

2.4 Phosphine Chalcogenides as Ligands. – This continues to be an active area, although few applications of these ligands in catalysis have been noted. Significant interest, however, continues to be shown in the use of phosphine oxides as selective extraction agents for various metal ions. This is particularly evident in the design and complexing abilities of calixarene systems bearing several phosphine oxide groups. The secondary phosphine oxide-functionalised calix[4]arene (155) is an easily accessible key intermediate for the synthesis of the upper rim carbamoylmethylphosphine oxide (156) and diphosphine dioxide (157) systems, both of which have useful binding properties for lanthanide and actinide ions.207 Related calix[4]arenes bearing diphenylphosphine oxide substituents at the upper rim demonstrated high selectivity for iron (III).208 Lower rim poly(phosphine oxide)-functionalised calix[4]arenes (158, n ¼ 4, R ¼ Ph or Me) have also been prepared, and shown to have uses as extraction agents for thorium(IV) and europium(III) ions209 and also for complex formation with cobalt(II), nickel(II), copper(II) and zinc(II).210 A related p-t-butylcalix[6]arene bearing dimethylphosphinylmethyloxy-substituents (158, n ¼ 6, R ¼ Me) has also been prepared and shown to complex strongly to lanthanide ions.211 The donor properties of bis(diphenylphosphinoyl)alkanes have continued to attract

115

Organophosphorus Chem., 2006, 35, 92–126

attention. Complexes of bis(diphenylphosphinoyl)methane with the uranyl ion212 and also scandium and various lanthanide ions213,214 have been characterised in the solid state and in solution. The donor properties of 1,2-bis(diphenylphosphinoyl)ethane and the chiral dioxides (159) and (160) towards a di(rhodium) carboxylate have been compared using low-temperature 1H and 31 P NMR spectroscopy. The dioxide (160) shows a distinct preference for binding through Ph2P(O) rather than Ph(But)P(O), presumably due to the bulky t-butyl group.215 Two-dimensional coordination polymers of praseodymium(III) with 1,2-bis(diphenylphosphinoyl)ethane and the pyridine-based dioxide (161) have also been characterised.216 Considerable interest has been shown in the ligand properties of the anionic bidentate sulfur and selenium donors (162), complexes of indium(III),217 arsenic(III), antimony(III), bismuth(III),218 mercury,219 and gold(III) and silver(I)220 having been investigated. Palladium(II) complexes of the neutral mono- and di-disulfides (163, E ¼ lone pair) and (163, E ¼ S), respectively, have also been studied.221 Further work has appeared on the properties of rhodium(I) complexes of the anionic disulﬁde (164) with regard to their ability to carry small molecules such as CO, O2, CO2, CS2 and SO2.222 A variety of (phosphine selenide)-carbonyl cluster complexes has been isolated from the reactions of the diselenide (165) with ruthenium- and iron- carbonyl complexes of the type [M3(CO)12].223 Unusual polynuclear copper(I) complexes have been obtained from the reactions of a series of bis(diphenylselenophosphinoyl)alkanes (166) with copper(I) halides in acetonitrile, the length of the alkane spacer and the nature of the halide ion inﬂuencing the structure of the resulting complexes.224 Tetraalkyldiphosphine disulfides (167) have continued to attract interest as ligands, complexes with silver(I) and copper(I),225 and a rhenium bromocarbonyl acceptor,226 having been characterised. Sulﬁdo(carbonyl)rhenium clusters have been obtained from the ditertiary diphosphine disulﬁde (168) and the crowded but electron rich monosulﬁde (169).227

O O O n O

4 4

Ph

4

Ph O

Me2N (155)

O

O

Ph

(156)

O

O

PPh2

Ph2P

PR2

P

O

P H

Ph

P P

O

O H (158)

(157) O But Ph

PPh2 P

O

O Ph2P

N

O (159)

(160)

(161)

PPh2

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Organophosphorus Chem., 2006, 35, 92–126

R2P

N

X

Pri PR2

R2P

X

E

N

Ph S

PR2

Ph2P

S

Ph S P

PPh2

Me (162) X = S or Se; R = Ph or Pri

Se Ph2P Ph2P Se Se

(164)

(163)

Se (CH2)n

S S

PPh2

R2P PR2

PPh2 (167) R = Me, Et, Prn,Bun or Ph

(166) n = 1-4

(165)

OMe

Ph2P S

S

PPh2

MeO

P 3 OMe

(168)

(169)

NHPPh2 S PPh2 S (170)

Among other monotertiary triarylphosphine chalcogenide ligands studied are triphenylphosphine oxide, triphenylphosphine sulﬁde and triphenylphosphine selenide, from which a series of tungsten carbonyl complexes has been prepared.228 This family of ligands has also found application in the formation of complexes with rhodium (I) cyclooctadiene, which catalyse the efﬁcient carbonylation of methanol.229 The reactions of a series of monodentate tertiary phosphine selenides with [Ru3(CO)12] have been shown to involve cleavage of the phosphorus-selenium bond, the selenium being transferred to the metal. In contrast, normal mononuclear phosphine selenide complexes have been obtained from the reactions of diphenyl(2-pyridyl)phosphine selenide with palladium(II) and platinum(II) acceptors.230,231 Complexes of the phosphinoaminoarylphosphine sulﬁde (170) with ruthenium, rhodium and iridium acceptors have been characterised. Not surprisingly, the aminophosphine moiety coordinates preferentially to these metals, but complexes involving additional coordination from the phosphine sulﬁde group were also prepared.232 Monotertiary phosphine oxides bearing other donor groups have also been prepared and their coordination chemistry studied. The ﬁrst bis(phosphine) monoxide complexes of copper(I) have been prepared from bis(diphenylphosphino)methane monoxide and bis(diphenylphosphino)ethane monoxide. Coordination from both phosphorus and phosphine oxide oxygen was observed in one case, the expected preferential coordination of the softer phosphorus donor to copper(I) dominating behaviour in solution.233 Cobalt(II) and cobalt(III) complexes of the terpyridylphosphine oxide (171) have been characterised.234 The bis(bipyridyl)phosphine oxide (172) forms luminescent complexes with

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Organophosphorus Chem., 2006, 35, 92–126

lanthanide ions, which can be used for the detection of anions.235 A new triphenylphosphine oxide complex of terbium(III) has been shown to exhibit strong electroluminescence properties.236 Other reports of lanthanide (and actinide) complexes involving triphenylphosphine oxide as a ligand have also appeared.237,238 Among other complexes of triphenylphosphine oxide recently described are molybdenum complexes involving dithiophosphates as co-ligands,239 stable complexes of diorganotin cations,240 and salts of polyhalotellurate anions involving protonated phosphine oxide units, formed from the reactions of triphenylphosphine with tellurium tetrahalides under ambient conditions in THF.241 Tris(4-ﬂuorophenyl)phosphine oxide has been shown to have a remarkable co-ligand effect for the stabilisation of chiral lanthanum complex catalysts used in a highly selective epoxidation of conjugated enones.242 A series of complexes of oxodiperoxomolybdenum with trialkylphosphine oxides and triphenylphosphine oxide has been prepared and shown to oxidise indoles to various indolone products.243 The chiral hydroxymethylphosphine oxide (173) has been prepared in 67% yield by the reaction of diphenylphosphine with benzaldehyde in THF in air at 401C and used as a ligand in a rhodium(I)-catalysed hydroformylation of alkenes. It has also been partially resolved using an enzyme, and used in an enantioselective hydroformylation.244 Triethylphosphine oxide and tri(n-propyl)phosphine oxide have been used as ligands in the synthesis of various hexanuclear halomolybdenum cluster complexes.245 Trialkylphosphine oxides have also been used as co-ligands for the stabilisation of silver nanaocrystals.246 Tris(t-butyl)phosphine oxide has found use as a bulky ligand for the stabilisation of a new family of monocyclopentadienylscandium bis-alkyls.247 Scandium(III) halide complexes of a range of phosphine- and arsine-oxides have been studied in solution and in the solid state.248 Lanthanide complexes of the ﬂuoroalkylphosphine oxide (174) have been characterised.249 Various metal complexes of the carboxyalkylphosphine oxide (175) have been characterised in solution, some being accessed by in-situ oxidation of the parent trialkylphosphine.250

P

P

O

N

N

N N

O

N

N

N (171)

(172)

O H

PPh2

(CF3CH2CH2)3

P

O

O

P (CH2CH2COOH)3

OH

(173)

(174)

(175)

118

Organophosphorus Chem., 2006, 35, 92–126 O R1

O

R1

P R2

OH

H

(176)

R2 (177)

P

Ph

P Bu

H t

(178)

The properties of secondary phosphine oxides and sulfides as ligands have also been the subject of recent papers. In solution, these compounds exist in equilibrium between the pentavalent phosphine oxide form (176) and the trivalent phosphinite form (177). It is the phosphinite form that coordinates (via phosphorus) to a transition metal ion. Air-stable P-stereogenic secondary phosphine oxides and sulfides are conﬁgurationally stable in the presence of metal ions both in solution and in the solid state, and have the potential to act as chiral monodentate ligands for asymmetric catalysis. It has now been shown that both chiral forms of the secondary phosphine oxide (178) are useful ligands for asymmetric palladium-catalysed carbon-carbon bond formation.251 In a similar vein, a series of chiral secondary phosphine oxides of the type (176) has been prepared from the reactions of Grignard reagents with bulky dichlorophosphines and resolved into their enantiomers by preparative chiral HPLC. These ligands have been applied in an iridium(I)-catalysed asymmetric hydrogenation of imines, with good enantioselectivities.252 References 1. M. Stivanello, L. Leoni and R. Bortolaso, Org. Proc. Res. Dev., 2002, 6, 807. 2. L. Porre`s, B.K.G. Bhatthula and M. Blanchard-Desce, Synthesis, 2003, 1541. 3. S. Harusawa, M. Kawamura, S. Koyabu, T. Hosokawa, L. Araki, Y. Sakamoto, T. Hashimoto, Y. Yamamoto, A. Yamatodani and T. Kurihara, Synthesis, 2003, 2844. 4. T. Hanamoto, N. Morita and K. Shindo, Eur. J. Org. Chem., 2003, 4279. 5. A.B. Smith (III), B.S. Freeze, I. Brouard and T. Hirose, Org. Lett., 2003, 5, 4405. 6. F. Meyer, A. Laaziri, A.M. Papini, J. Uziel and S. Juge´, Tetrahedron: Asymmetry, 2003, 14, 2229. 7. C. Gracia, G. Marco, R. Navarro, P. Romero, T. Soler and E.P. Urriolabeitia, Organometallics, 2003, 22, 4910. 8. A. Hamdi, K.C. Nam, B.J. Ryu, J.S. Kim and J. Vicens, Tetrahedron Lett., 2004, 45, 4689. 9. E.E. Bonfantini, A.K. Burrell, W.M. Campbell, M.J. Crossley, J.J. Gosper, M.M. Harding, D.L. Ofﬁcer and D.C.W. Reid, J. Porphyrins and Phthalocyanines, 2002, 6, 708. 10. R. Weiss, F. Pu¨hlhofer, N. Jux and K. Merz, Angew. Chem. Int. Ed., 2002, 41, 3815. 11. F.G. Pu¨hlhofer and R. Weiss, Eur. J. Org. Chem., 2004, 1002. 12. H. Danjo, W. Sasaki, T. Miyazaki and T. Imamoto, Tetrahedron Lett., 2003, 44, 3467. 13. K. Ohsaki, K. Konishi and T. Aida, Chem. Commun., 2002, 1690. 14. U.V. Monkowius, S.D. Nogai and H. Schmidbaur, J. Am. Chem. Soc., 2004, 126, 1632. 15. S. Ito, S. Moriyama, M. Nakashima, M. Watanabe, T. Kubo, M. Yasunami, K. Fujimori and N. Morita, Heterocycles, 2003, 61, 339. 16. R. Mazurkiewicz, B. Fryczkowska, R. Gaban´ski, R. Luboradzki, A. Wzochowicz and W. Mo´l, Phosphorus, Sulfur, Silicon, 2002, 177, 2589.

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168. R.I. Vasil’ev, N.V. Durmanova, A.R. Garifzyanov and R.A. Cherkasov, Russ. J. Gen. Chem., 2003, 73, 994. 169. K. Shioji, S. Tsukimoto, H. Tanaka and K. Okuma, Chem. Lett., 2003, 32, 604. + 170. G. Keglevich, H. Forintos, A. Ujva´ri, T. Imre, K. Luda´nyi, Z. Nagy and L. Toke, J. Chem. Research, 2004, 432. 171. G. Keglevich, T. Ko¨rtve´lyesi, H. Forintos and S. Lovas, J. Chem. Soc., Perkin Trans. 2, 2002, 1645. 172. K. Izod, W. McFarlane and W. Clegg, Chem. Commun., 2002, 2532. 173. E. Krawczyk, A. Skowron´ska and J. Michalski, J. Chem. Soc., 2002, 4471. 174. S. Makowiec and J. Rachon, Heteroatom Chem., 2003, 14, 352. 175. Y. Uchida, M. Matsumoto and H. Kawamura, Heteroatom Chem., 2003, 14, 72. 176. Y.S. Li, X.R. Liang and W.K. Su, Org. Prep. Proc. Int., 2003, 35, 613. 177. S.-L. You, H. Razavi and J.W. Kelly, Angew. Chem. Int. Ed., 2003, 42, 83. 178. S.-L. You and J.W. Kelly, J. Org. Chem., 2003, 68, 9506. 179. S. Caddick, J.D. Wilden and D.B. Judd, J. Am. Chem. Soc., 2004, 126, 1024. 180. K.E. Elson, I.D. Jenkins and W.A. Loughlin, Tetrahedron Lett., 2004, 45, 2491. 181. K.E. Elson, I.D. Jenkins and W.A. Loughlin, Org. Biomol. Chem., 2003, 1, 2958. 182. T.A. Khan, R. Tripoli, J.J. Crawford, C.G. Martin and J.A. Murphy, Org. Lett., 2003, 5, 2971. 183. V.D. Kolesnik and A.V. Tkachev, Russ. Chem. Bull., Int. Ed., 2003, 52, 624. 184. (a) C.S. Colley, D.C. Grills, N.A. Besley, S. Jockusch, P. Matousek, A.W. Parker, M. Towrie, N.J. Turro, P.M.W. Gill and M.W. George, J. Am. Chem. Soc., 2002, 124, 14952; (b) M. Weber and N.J. Turro, J. Phys. Chem. A, 2003, 107, 326. 185. C. Dursun, M. Degirmenci, Y. Yagci, S. Jockusch and N.J. Turro, Polymer, 2003, 44, 7389. 186. C. Ogawa, H. Konishi, M. Sugiura and S. Kobayashi, Org. Biomol. Chem., 2004, 2, 446. 187. S. Bhattacharya, S. Banerjee, S.K. Nayak, S. Chattopadhyay and A.K. Mukherjee, Spectrochim. Acta A, 2004, 60, 1099. 188. Y. Sakamoto, K. Kondo, M. Tokunaga, K. Kazuta, H. Fujita, Y. Murakami and T. Aoyama, Heterocycles, 2004, 63, 1345. 189. D. Magiera, S. Moeller, Z. Drzazga, Z. Pakulski, K.M. Pietrusiewicz and H. Duddeck, Chirality, 2003, 15, 391. 190. Z. Pakulski, O.M. Demchuk, R. Kwiatosz, P.W. Osin´ski, W. S´wierczyn´ska and K.M. Pietrusiewicz, Tetrahedron: Asymmetry, 2003, 14, 1459. 191. M. Rivard, F. Guillen, J.-C. Fiaud, C. Aroulanda and P. Lesot, Tetrahedron: Asymmetry, 2003, 14, 1141. 192. J. Omelan´czuk, A. Karac¸ar, M. Freytag, P.G. Jones, R. Bartsch, M. Mikozajczyk and R. Schmutzler, Inorg. Chim. Acta, 2003, 350, 583. 193. F. Wang, Y. Wang, P.L. Polavarapu, T. Li, J. Drabowicz, K.M. Pietrusiewicz and K. Zygo, J. Org. Chem., 2002, 67, 6539. 194. P. Kiezbasin´ski, R. ’urawin´ski, M. Albrycht and M. Mikozajczyk, Tetrahedron: Asymmetry, 2003, 14, 3379. 195. R.R. Shagidullin, A.V. Chernova, S.A. Katsyuba, L.V. Avvakumova and Rif. R. Shagidullin, Russ. Chem. Bull., Int. Ed., 2004, 53, 55. 196. A. Kolbe, M. Plass, R. ’urawin´ski, P. Kiezbasin´ski and M. Mikozajczyk, Spectrochim. Acta A, 2003, 59, 2875. 197. C. Lo´pez-Leonardo, M. Alajarin, P. Llamas-Lorente, D. Bautista, M.L. Jimeno, I. Alkorta and J. Elguero, Structural Chem., 2003, 14, 391.

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198. S. Chandrasekhar, G. Kulkarni, B. Muktha and T.N.G. Row, Tetrahedron: Asymmetry, 2003, 14, 3769. 199. M. Canipelle, L. Caron, H. Bricout, S. Tilloy and E. Monﬂier, New J. Chem., 2003, 27, 1603. 200. R. Kruszynski and W. Wieczorek, Heteroatom Chem., 2004, 15, 233. 201. A. Chandrasekharan, N.V. Timosheva, R.O. Day and R.R. Holmes, Inorg. Chem., 2003, 42, 3285. 202. A. Chandrasekharan, N.V. Timosheva, R.O. Day and R.R. Holmes, Inorg. Chem., 2002, 41, 5235. 203. (a) A.A. Espenbetov, A.P. Logunov, G.T. Maishinova and B.M. Butin, Izvest. Nat. Akad. Nauk Respub. Kazakhstan, Ser. Khim., 2003, (5), 17; (b) A.A. Espenbetov, A.P. Logunov, G.T. Maishinova and B.M. Butin, Chem. Abstr., 2003, 141, 260811. 204. R.J. Bowen, M.A. Fernandes, P.W. Gitari and M. Layh, Acta Cryst.C: Cryst. Struct. Commun., 2004, 60, o–258. 205. N. Kuhn, M. Go¨hner and M. Steimann, Z. Anorg. Allg. Chem., 2003, 629, 595. 206. S.L. Hinchley, M.F. Haddow and D.W.H. Rankin, Dalton Trans., 2004, 384. 207. L. Atamas, O. Klimchuk, V. Rudzevich, V. Pirozhenko, V. Kalchenko, I. Smirnov, V. Babain, T. Efremova, A. Varnek, G. Wipﬀ, F. Arnoud-Neu, M. Roch, M. Saadioui and V. Bo¨hmer, J. Supramol. Chem., 2002, 2, 421. 208. (a) M. Kyoda, H. Maekawa, Y. Sadai and I. Nishiguchi, Advances in Technology of Materials and Materials Processing Journal, 2004, 6, 29; (b) M. Kyoda, H. Maekawa, Y. Sadai and I. Nishiguchi, Chem. Abstr., 2004, 141, 332253. 209. M. R. Yaftian, R. Taheri and D. Matt, Phosphorus, Sulfur, Silicon, 2003, 178, 1225. 210. V. Videva, A.-S. Chauvin, S. Varbanov, C. Baux, R. Scopelliti, M. Mitewa and J.-C.G. Bu¨nzli, Eur. J. Inorg. Chem., 2004, 2173. 211. F. de M. Ramı´ rez, S. Varbanov, C. Ce´cile, G. Muller, N. Fatin-Rouge, R. Scopelliti and J.-C.G. Bu¨nzli, J. Chem. Soc., Dalton Trans., 2002, 4505. 212. S. Kannan, N. Rajalakshmi, K.V. Chetty, V. Venugopal and M.G.B. Drew, Polyhedron, 2004, 23, 1527. 213. J. Fawcett and A.W.G. Platt, Polyhedron, 2003, 22, 967. 214. A.M.J. Lees and A.W.G. Platt, Inorg. Chem., 2003, 42, 4673. 215. T. Ga´ti, A. Simon, G. To´th, A. Szmigielska, A.M. Maj, K.M. Pietrusiewicz, S. Moeller, D. Magiera and H. Duddeck, Eur. J. Inorg. Chem., 2004, 2160. 216. Z. Spichal, M. Necas, J. Pinkas and J. Novosad, Inorg. Chem., 2004, 43, 2776. 217. G.L. Abbati, M.C. Aragoni, M. Arca, F.A. Devillanova, A.C. Fabretti, A. Garau, F. Isaia, V. Lippolis and G. Verani, Dalton Trans., 2003, 1515. 218. D.J. Crouch, M. Helliwell, P. O’Brien, J.-H. Park, J. Waters and D.J. Williams, Dalton Trans., 2003, 1500. 219. D.J. Crouch, P.M. Hatton, M. Helliwell, P. O’Brien and J. Raftery, Dalton Trans., 2003, 2761. 220. S. Canales, O. Crespo, M.C. Gimeno, P.G. Jones, A. Laguna, A. Silvestru and C. Silvestru, Inorg. Chim. Acta, 2003, 347, 16. 221. S.K. Mandal, G.A.N. Gowda, S.S. Krishnamurthy, C. Zheng, S. Li and N.S. Hosmane, J. Organomet. Chem., 2003, 676, 22. 222. M. Doux, N. Me´zailles, L. Ricard and P. Le Floch, Organometallics, 2003, 22, 4624. 223. D. Belletti, C. Graiﬀ, C. Massera, A. Minareelli, G. Predieri, A. Tiripicchio and D. Acquotti, Inorg. Chem., 2003, 42, 8509. 224. T.S. Lobana, Rimple, A. Castineiras and P. Turner, Inorg. Chem., 2003, 42, 4731. 225. H. Liu, M.J. Calhorda, M.G.B. Drew and V. Fe´lix, Inorg. Chim. Acta, 2003, 347, 175.

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226. O.S. Sentu¨rk, H.A. Shekhel, B.T. Sterenberg, K.A. Udachin, S. Sert, U. O¨zdemir and F.U. Sarikahya, Polyhedron, 2003, 22, 1659. 227. D. Belletti, C. Graiﬀ, V. Lostao, R. Pattacini, G. Predieri and A. Tiripicchio, Inorg. Chim. Acta, 2003, 347, 137. 228. J.B. Cook, B.K. Nicholson and D.W. Smith, J. Organomet. Chem., 2004, 689, 860. 229. P. Das, P. Chutia and D.K. Dutta, Chem. Lett., 2002, 31, 766. 230. D. Belletti, D. Cauzzi, C. Graiﬀ, A. Minarelli, R. Pattacini, G. Predieri and A. Tiripiccio, J. Chem. Soc., Dalton Trans., 2002, 3160. 231. D. Belletti, C. Graiﬀ, C. Massera, G. Predieri and A. Tiripiccio, Inorg. Chim. Acta, 2003, 350, 421. 232. S.M. Aucott, A.M.Z. Slawin and J.D. Woollins, Polyhedron, 2003, 22, 361. 233. D. Saravanabharathi, M. Nethaji and A.G. Samuelson, Polyhedron, 2002, 21, 2793. 234. E.C. Constable, C.E. Housecroft, M. Neuburger and A.G. Schneider, Inorg. Chem. Commun., 2003, 6, 912. 235. L.J. Charbonnie`re, R. Ziessel, M. Montalti, L. Prodi, N. Zaccheroni, C. Boehme and G. Wipﬀ, J. Am. Chem. Soc., 2002, 124, 7779. 236. H. Xin, F. Y. Li, M. Shi, Z.Q. Bian and C.H. Huang, J. Am. Chem. Soc., 2003, 125, 7166. 237. J.-C. Berthet, M. Nierlich and M. Ephritikhine, Polyhedron, 2003, 22, 3475. 238. M.J. Glazier, W. Levason, M.L. Matthews, P.L. Thornton and M. Webster, Inorg. Chim. Acta, 2004, 357, 1083. 239. N. Manwani, M.C. Gupta, R. Ratnani, J.E. Drake, M.B. Hursthouse and M.E. Light, Inorg. Chim. Acta, 2004, 357, 939. 240. J. Beckmann, D. Dakternieks, A. Duthie and C. Mitchell, Dalton Trans., 2003, 3258. 241. S.M. Na¨rhi, R. Oilunkaniemi, R.S. Latinen and M. Ahlgre´n, Inorg. Chem., 2004, 43, 3742. 242. R. Kino, K. Daikai, T. Kawanami, H. Furuno and J. Inanaga, Org. Biomol. Chem., 2004, 2, 1822. 243. C.I.A. Kiraz, T.J. Emge and L.S. Jiminez, J. Org. Chem., 2004, 69, 2200. 244. H.J. Clark, R. Wang and H. Alper, J. Org. Chem., 2002, 67, 6224. 245. L.F. Szczepura, B.A. Ooro and S.R. Wilson, J. Chem. Soc. Dalton Trans., 2002, 3112. 246. M. Green, N. Allsop, G. Wakeﬁeld, P.J. Dobson and J.L. Hutchison, J. Mater. Chem., 2002, 12, 2671. 247. L.D. Henderson, G.D. MacInnis, W.E. Piers and M. Parvez, Can. J. Chem., 2004, 82, 162. 248. N.J. Hill, W. Levason, M.C. Popham, G. Reid and M. Webster, Polyhedron, 2002, 21, 1579. 249. V.V. Semenov, N.F. Cherepennikova, L.G. Klapshina, M.A. Lopatin, T.G. Mushtina, N.P. Makarenko, S.Ya. Korshev, G.A. Domrachev, W.E. Douglas and B.A. Bushuk, Russ. J. Coord. Chem., 2004, 30, 435. 250. A. Kr˛e(el, R. Latajka, G.D. Bujacz and W. Bal, Inorg. Chem., 2003, 42, 1994. 251. W.-M. Dai, K.K.Y. Yeung, W.H. Leung and R.K. Haynes, Tetrahedron: Asymmetry, 2003, 14, 2821. 252. X.-B. Jiang, A.J. Minnaard, B. Hessen, B.L. Feringa, A.L.L. Duchateau, J.G.O. Andrien, J.A.F. Boogers and J.G. de Vries, Org. Lett., 2003, 5, 1503.

Tervalent Phosphorus Acid Derivatives BY D.W. ALLEN Biomedical Research Centre, Shefﬁeld Hallam University, City Campus, Shefﬁeld, S1 1WB, UK

1

Introduction

As this chapter covers two years of the literature relating to the above area, it has been necessary to be somewhat selective in the choice of publications cited. Nevertheless, it is hoped that most significant developments have been noted. As in previous reports, attempts have been made to minimise the extent of overlap with other chapters, in particular those concerned with the synthesis of nucleic acids and nucleotides to which the chemistry of tervalent phosphorus esters and amides contributes significantly, the use of known halogenophosphines as reagents for the synthesis of phosphines (see Chapter 1), and the reactions of dialkyl- and diaryl-phosphite esters in which the contribution of the phosphonate tautomer, (RO)2P(O)H), is the dominant aspect, which are usually covered elsewhere in these volumes. The period under review has seen the publication of a considerable number of review articles, and most of these are cited in the appropriate sections. Once again, there has been considerable interest in tervalent phosphorus-ester and -amide chemistry that relates to the preparation of new, often chiral, ligand systems for use in metal-catalysed homogeneous catalysis. Several major reviews of this area have appeared, covering recent developments in the area of asymmetric catalysis using organometallic complexes of ligands which contain two or three P–O or P–N bonds,1 the use of chiral ferrocenylphosphorus(III) ligands involving phosphite, phosphoramidite and aminophosphine donor groups,2,3 and the use of chiral phosphites and phosphoramidites in a wide range of asymmetric syntheses.4 A new approach in combinatorial asymmetric transition metal-catalysed synthesis relates to the use of mixtures of chiral monodentate phosphites, phosphonites and phosphoramidites derived from BINOL and related systems as ligands and work in this area has also been reviewed.5,6 Another major review covers the synthesis and reactivity of diphosphines in which the phosphorus atoms are bridged by heteroatoms such as oxygen, nitrogen, sulfur and selenium, compounds which hitherto have received little coverage compared with that of their

Organophosphorus Chemistry, Volume 35 r The Royal Society of Chemistry, 2006 127

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carbon-bridged analogues such as bis(diphenylphosphino)methane.7 The applicability limits of calculation methods for estimating the enthalpy of vaporisation of organophosphorus compounds, including tervalent phosphorus acid derivatives, have been reviewed.8 Research into the mechanisms of nucleophilic substitution reactions of tervalent phosphorus acid derivatives has been reviewed with emphasis on the reactions of phosphoramidites.9

2

Halogenophosphines

A clean route to dichlorophenylphosphine is provided by carrying out the longestablished Friedel-Crafts reaction of benzene and phosphorus trichloride in ionic liquid media derived from butylpyridinium chloride and aluminium trichloride, the system allowing an easy product isolation procedure.10 New simple high yield procedures for the synthesis of the heterocyclic halophosphites (1, X¼Cl or F) have been developed. The chlorophosphite was obtained via the reaction of 2,2-dimethyl-1,3-propanediol with phosphorus trichloride at room temperature, in the absence of base or solvent, and was converted into the ﬂuorophosphite by treatment with antimony pentaﬂuoride.11 Chlorophosphites (RO)2PCl have also been obtained, in quantitative yield, by treatment of secondary phosphites (RO)2P(O)H with dichloro(2,4,6-tribromophenoxy)(1,2-diphenoxy)phosphorane.12 Treatment of the ephedrine-derived aminophosphine-boranes (2) with a solution of hydrogen chloride in toluene provides a route to highly enantiomerically-enriched chlorophosphine-boranes (3), the cleavage of the P–N bond proceeding with inversion of conﬁguration at phosphorus. These compounds are important new electrophilic building blocks for the stereoselective synthesis of chiral phosphorus compounds.13 They can also be reduced using a variety of complex hydride reagents to the related secondary phosphine-boranes.14 The heterocyclic bromophosphines (4) and (5) have been obtained via the reactions of various indoline derivatives with phosphorus tribromide and used as intermediates for the synthesis of a range of heterocyclic phosphorus compounds.15 The reactions of bulky organometallic reagents with simple halogenophosphine precursors have been widely employed in the synthesis of new halogenophosphines. Among new arylhalogenophosphines bearing triﬂuoromethyl substituents in the aryl rings prepared in this way and characterised by X-ray crystallography are the primary dibromophosphine (6) and the secondary halogenophosphines (7) and (8).16 The 9-triptycenyldichlorophosphine (9) has been obtained from the reactions of 9-triptycenyllithium (one equivalent) with phosphorus trichloride, the related reactions with AsCl3, SbCl3 and BiCl3 yielding the heavier Group 15 congeners.17 Treatment of indenyllithium with di(isopropyl)aminodichlorophosphine yields the monochloro(amino)phosphine (10), subsequently converted into the chiral dicarboranyl(amino)indenylphosphine (11) from which a series of rare-earth complexes has been prepared.18 The ketiminylchlorophosphine system (12) has been obtained from the reaction of a lithiated b-diketimine with dichlorophenylphosphine. Reduction of (12) with potassium

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129

naphthalenide provides the heterocyclic dihydroazadiphosphole (13).19 Treatment of a magnesium salt of the linked silylamido(cyclopentadienyl) ligand [Me2Si(C5Me4)NBut]2 with phosphorus trichloride results in the initial formation of the bicyclic chlorophosphine (14) which rearranges to give (15) as the ﬁnal product. The corresponding reactions with arsenic- and antimony-trichlorides result in the isomeric systems (16). Chloride abstraction from (15) and (16) provides the related phosphenium, arsenium and stibenium cations which again reveal interesting structural differences.20 Dilithiation of 2,2 0 -dimethyl-1,1 0 binaphthyl, followed by treatment with phosphorus trichloride (or Et2NPCl2 followed by hydrogen chloride) yields the chiral phosphinous chloride (17), a key intermediate for the synthesis of a range of chiral tervalent phosphorus acid derivatives, and tertiary phosphines.21,22 The chiral phosphinous chloride (18, R¼Me) has been obtained from the reaction of an ortho-lithiated chiral benzylamine with the reagent (Me3Si)2CHPCl2, reduction with LiAlH4 giving the related secondary phosphine.23 In related work, it has been shown that whereas LiAlH4 reduction of (18, R¼H) under reﬂux conditions in ether-THF yields the expected secondary phosphine, when the reduction is carried out at lower temperatures, the P,P-diphosphine (19) is formed as a significant biproduct. The latter may be obtained in much higher yield from the reaction of the lithiated secondary phosphine with lead(II) iodide. This study also reports that LiAlH4 reduction of the crowded phosphonous dichloride (Me3Si)2CHPCl2 yields the diphosphine (20).24 The thioether-functionalised chlorophosphine (21) has been prepared from (Me3Si)2CHPCl2 by treatment with ortho-lithiated thioanisole, and reduced, in situ, to the related secondary phosphine.25 Treatment of 1,2-bis(dichlorophosphino)ethane with the bulky Grignard reagent (Me3Si)2CHMgCl generates the bis(chlorophosphine) (22). This has been shown to react with the base DBN (1,5-diazabicyclo[4,3,0]non-5-ene) to give an adduct which, on deprotonation with t-butyllithium, generates the anionic species (23), isolated as a magnesium-DBN complex.26 The bis(trimethylsilyl)phosphine (24, X¼tms) is converted into the chlorophosphine (24, X¼Cl) on treatment with hexachloroethane. Controlled thermolysis of the latter at 901C in toluene results in the clean formation of the dibenzophosphasemibullvalene (25), probably via an intermediate phosphinidene.27 Heating a solution of the 2H-azaphosphirene complex (26) in carbon tetrachloride at 701C results in the selective formation of the complexed dichlorophosphine (27).28 Woollins’ group has continued to explore the chemistry of the peri-bis(dichlorophosphino)naphthalene system (28). A new synthetic pathway to this compound starts with chlorination of the thiophosphonic anhydride (29), which provides the dipolar adduct (30), involving an intramolecular P(III)–P(V) interaction.29 Treatment of the latter with methyldichlorophosphite provides the bis(dichlorophosphine) (28) in almost quantitative yield. On subsequent treatment with magnesium, the bis(dichlorophosphine) is converted into the polymeric diphosphine (31), insoluble in common organic solvents. Halogenation of (31) with bromine and iodine gave the bis(dibromophosphine) (32) and the diiododiphosphine (33), respectively.30 Treatment of the bis(dichlorophosphine) (28) with oxygen (in excess, for prolongued

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periods) yielded mainly the monoxide (34), with only ca 10% of the corresponding dioxide. Also isolated in small amounts was the partial hydrolysis product (35).31 The outcome of the reaction between 1,8-dilithionaphthalene and dichlorophosphines RPCl2 is dependent on the nature of the R group at phosphorus. Thus, the reaction with phenyldichlorophosphine leads to the diphosphine (36) whereas with iPr2NPCl2, the naphtho[1,8-bc]phosphete (37) is formed.32 BH3

O P X O

P R Ph N Me

(1)

BH3

OH Ph

P R Ph

Cl

(3)

(2) R = e.g., Me, But, Cy, o-Tol, o-An, 1-Naphthyl, 2-Naphthyl

O

O

NMe2

N Ph N P O Me Br

N

P

Me

Br

(4)

(5)

CF3

CF3

CF3 X P

Cl CF3 PBr2

F3C

P

F3C

F3C

CF3 F3C

CF3 (6)

CF3

CF3

CF3

(7)

(8) X = Cl or Br

Pri2N P

Pri2N

Cl

P

C2B10H11

Cl2P (9)

(10)

Ph

Cl

(11) Ph

P R

R

N

NHR (12)

Ph

P P N N (13)

R

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Organophosphorus Chem., 2006, 35, 127–168

Me2Si

Me2Si ButN PCl

PCl N But

Me2Si

(15)

(14)

ECl NBut

(16) E = As or Sb

NMe2 (Me3Si)2HC

R PCl (Me3Si)2HC

P

Cl

P P

NMe2

CH(SiMe3)2

(Me3Si)2HC P P CH(SiMe3)2 H H

NMe2 (17)

(18)

(19)

CH(SiMe3)2

(Me3Si)2HC P

SMe (Me3Si)2HC

P

P

Cl

(20)

CH(SiMe3)2

(Me3Si)2HC P

P

N

N

Cl N

Cl

(21)

(22)

(23)

P H PSiMe3 X (24)

(OC)5W CH(SiMe ) 3 2 P N Ph

(25)

(OC)5W CH(SiMe ) 3 2 P Cl Cl

(26)

(27)

S Cl2P

PCl2 (28)

P S

N

P S (29)

S

Cl2P (30)

PCl4

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Organophosphorus Chem., 2006, 35, 127–168

P

P

Br2P

IP

PBr2

n (31)

(33)

(32)

Cl

PCl2 PCl2

P O

O

O

P

(34)

PI

O Cl

Ph

P

P

P Ph

NPri2

(36)

(35)

(37)

Among a miscellany of other studies of the reactivity of halogenophosphines reported in the period under review are the derivatisation of free OH groups of acylglycerols in vegetable oils using chlorophosphines, followed by detection using 31P NMR,33 the reactions of chlorodiphenylphosphine with enamine derivatives of b-aminocrotonic acid giving, e.g., the enaminophosphines (38),34 the opening of the epoxide ring of oxiranes bearing 2,2-dichlorocyclopropyl substituents to give P(III)-esters of type (39),35 the reactions of chlorophosphites with b-aldiminoalcohols to give heterocyclic phosphonates, e.g., (40),36 and a Mannich-type reaction involving p-tolyldichlorophosphine, methyl ethyl ketone and 1,2-diaminopropane, which results in the formation of a new 1,4,2-diazaphosphorine-2-oxide.37 The cyclic bis(phosphinous chloride) (41) has been shown to react with N,N 0 -dimethyl-N,N 0 -bis(trimethylsilyl)urea to form initially the bicyclic system (42), which gradually rearranges to form the more thermodynamically stable urea-bridged diphosphine (43).38 Cyclic chlorophosphites and related isothiocyanato-, azido-, and amido-phosphites (44) undergo a cycloaddition reaction with diisopropyl azodicarboxylate to form new stable crystalline pentacoordinate phosphoranes, e.g., (45), in which the nitrogen atom, rather than the oxygen, occupies an apical position of the trigonal bipyramid.39 CH2Cl O

CN

R2N

RnP

PPh2 N

(38) R2N = or

O

Cl x

Cl

3-n

(39) R = Ph, p-Tol or ClCH2CH2 ; n = 1 or 2; x = 0 or 1 N

O

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Organophosphorus Chem., 2006, 35, 127–168

NMe Cl

Cl

Cl

O O

P

O

Cl

P Cl

P

N H

O

MeN

P

P

P

Cl

Cl

Cl

Cl

Cl

Cl

O

MeN

Cl

NMe P Cl

Cl

Cl

Ph (40)

(41)

(42)

(43)

But

But

O

O

P Me

P

P X

O

R

OPri O N PriO2C But

O But (44) X = Cl, N3, NCS or NHMe

Cl

Ph X

N

R R

N

(45)

(46) R = H or Me

Halogenophosphines have also attracted a number of structural, physicochemical, and theoretical studies. Rotational barriers in a series of methylsubstituted piperidinochlorophosphines (46) have been measured by variable temperature NMR studies.40 NMR techniques have also been used to study the mechanism of halogen exchange in the phosphorus(III) halide (47).41 The conﬁgurational stability of chlorophosphines has been investigated by density functional theory studies, together with experimental studies. The presence of HCl in the medium was found to catalyse the P-centre chiral inversion at room temperature, the reaction involving a two-step mechanism. The conﬁgurational stability of chirogenic chlorophosphines can be protected using borane adducts.42 Quantum chemical calculations and 35Cl NQR techniques have been used to probe structural features of alkyldichlorophosphines.43 Theoretical methods have also been applied to the study of the molecular structure and conformational preferences of a wide range of halogenophosphines, including 1,3,2-diheterophospholenes,44,45 P-chloro- and -isocyanato-1,3,2-benzodioxaphosphinan-4-ones, (48),46 the chlorodithiophosphite ClP(SMe)2,47 and also various cyanophosphines.48 Y X X N X

P N

Cl

O

P

X

O X

O

Y (47) X = H, F, Cl, Y = H, But or CN

(48) X = Cl or NCO

134

3

Organophosphorus Chem., 2006, 35, 127–168

Tervalent Phosphorus Esters

3.1 Phosphinites. – As in recent years, most of the interest in this area has centred around the synthesis and evaluation of new ligand systems for use in homogeneous catalysis, in which phosphinite donor centres either replace or complement conventional phosphino or other donor centres in previously designed systems, many of which are chiral. In most cases, the phosphinite centre is introduced via the reaction of an alcohol or phenol with a chlorophosphorus(III) precursor, in the presence of a base. However, the synthesis of vicinal bis(diphenylphosphinites) derived from chiral vicinal diols by this classical approach tends to give impure products, probably as a result of traces of water in the diols. These problems have now been overcome using a metal-template procedure in which the diol is added to palladium(II)- or platinum(II)-complexes of diphenylchlorophosphine in anhydrous THF.49,50 The conventional approach, however, has continued to be widely applied in the synthesis of new phosphinites. Among these are the chiral bis(phosphinites) (49),51 the ferrocenylglucose bis(phosphinite) (50),52 the long chain asymmetric bis(phosphinite) (51) (and a related bisphosphite),53 the ‘large bite’ bis(phosphinite) (52),54 the reduced BINAP bis(phosphinite) system (53),55 and the pincer ligand bis(phosphinites) (54).56 Conventional phosphinylation methods have also been used to prepare the silica-linked tris(diphenylphosphinite) (55).57 The reactions of silanols with chlorophosphines in the presence of a base have been used in the synthesis of a bis(diphenylphosphinite)-derivatised silsesquioxide.58 Puddephatt’s group has continued to explore the synthesis59 and coordination chemistry60,61 of resorcinarenes bearing four or eight diphenylphosphinito groups, e.g., (56). Among new chiral monophosphinite systems prepared conventionally are a range of aminoacid based diphenylphosphinites, e.g., (57),62 the cinchonidine- and quinine-based phosphinites (58), subsequently used for the asymmetric desymmetrization of meso1,2-diols,63 and the complexed cyclopentadienyl phosphinite (59).64 Mathey’s group has described interesting new approaches to the synthesis of chiral phosphinites. Treatment of 1-cyanophospholes with lithium alkoxides of allylic alcohols results in the initial formation of the corresponding 1-allyloxyphospholes, which rearrange at 251C to form tricyclic phosphinites, e.g., (60).65 The reaction of 1-cyano-3,4-dimethylphosphole with the dilithium salt of (R,R)-1,2diphenyl-1,2-ethanediol gave the diphosphinite (61), which then underwent a cycloaddition reaction with N-phenylmaleimide to give the chiral system (62).66 In yet another approach, treatment of the phosphonium salt (63) with thallous ethoxide gave the mixed phosphinite-phosphine (64).67 Considerable interest has been shown in the synthesis of phosphinites which bear other non-phosphorus donor atoms or groups. Among these are a series of phosphinite-oxazolines, e.g., (65),68,69 various sulfur-phosphinite donors, e.g., (66),70,71 aminophosphine-phosphinites, e.g., (67),72,73 and a variety of phosphine-phosphinites, e.g., the unsymmetrical pincer ligand (68),74 the camphane system (69),75 and the aa-trehalose derivative (70).76 The phosphine-phosphinite (71) also has a nitrogen donor centre.77 Among other new phosphinites also bearing a nitrogen

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Organophosphorus Chem., 2006, 35, 127–168

donor atom are the aminoalkynylphosphinite (72),78 various pyridine-based systems, e.g., (73) (together with related phosphite esters),79 the bis(phosphinite) (74),80 and the 3-pyridylmethylphosphinite (75).81 The synthesis, structure and properties of the cyclic thiaphosphinites (76) have been reviewed.82 Ph2PO Ph2PO

OPR1R2 1 2

O

Ph2P O

O

OPR R

O O

O O (49) R1,R2 = Ph, Cy or But

OCH3 O

Ph2P

O O

Fe (50)

(51)

X OPAr2 OPAr2 Ph2PO

But2PO

OPPh2 (52)

(53) Ar = 3,5-Me2C6H3

(54) X = H, MeO, Me, C6F5 or 3,5-(CF3)2C6H3 R1COO

OPPh2 O

OPPh2 OPPh2

O Si

OPBut2

N H

Si

O

N H

Ph2PO

O Ph2PO

COOR1

2 R2 R

R2

OPPh2

R2

OPPh2

(55) R1COO

COOR1

(56) R1 = e.g., OCH2Ph, Cy, 2-thienyl; R2 = CH2CH2Ph

N

Ph2PO

Ph

OPPh2

(FeCO)3 BocNH

COOMe (57)

O P

R2

R OPPh2

R1 R

1

N (58) R = H or Me

(59)

(60) R1 = H or Me; R2 = H or Ph

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Organophosphorus Chem., 2006, 35, 127–168

O

P

Ph

O

O

O

N

Ph

Ph

Ph O

Ph

P

P

N Ph

O

O P

O

(61) (62) Ph

Ph Ph P

Ph

P Me

Ph P

I

Ph EtO Me

R2

P

R2

O

O P

N R1

Ph

Ph

(65) R1 = Pr i or But; R2 = Ph or o-tol

(64)

(63) SMe

Y

PCy2 OPPh2

O

N

O But2P

PCy2

(68)

(67)

(66) Y = H or NMe2 HO

OH

HO O

HO O

PPri2

Me OH

O

OPPh2

N

O O

PR2

PPh2

PPh2

OH

PPh2

PPh2 (69) R = Ph, Mes or Cy

(70)

(71)

NMe2

OPPh2 (72)

O R

N Ph2PO

N H

(73)

Ph2P

N

O

O

PPh2

PPh2 (74)

(75)

Apart from their properties as ligands, other aspects of the reactivity of phosphinite esters have been of interest. It has been shown that phosphinite esters (77) undergo the Michaelis-Arbuzov rearrangement to give the phosphine oxides (78) between room temperature and 801C in the presence of trimethylsilyl halides, the reaction not needing the presence of any alkyl halide.83 The rearrangement proceeds even more efﬁciently at room temperature in the

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Organophosphorus Chem., 2006, 35, 127–168

presence of stronger Lewis acids such as trimethylsilyl triflate or boron triﬂuoride etherate.84 Allylic phosphinites (79) have been shown to undergo a stereoselective [2,3]-sigmatropic rearrangement on heating to form the (E)-allylic phosphine oxides (80).85 R1

S R P

n (76)

R3 R

R2

Me3SiX P O

OPPh2

X = Br or I

R3

O P

R3

(78)

But

R3 R1 R2 PPh2

R H O

(79) R1 = Me, Bu, 2-Py or H; R2, R3 = H or Me

R2

(77)

R1 R2

R1

(80)

But

O P Bu

t

H R

(81) R = H or Ph

The synthesis, characterisation and thermolysis of a new class of phosphiniteborane adducts derived from the bulky phosphinites (81) has been investigated. The borane adducts undergo an unusual thermally-induced phenol-elimination reaction when heated to between 100 and 1401C to give highly cross-linked phosphorus-boron polymeric materials.86 Phosphonium salts formed in situ from sugar-derived alkyl diphenylphosphinite esters are key intermediates in a new method for the a-selective glycosylation of glycosyl acceptors, forming a-disaccharides in high yield without the assistance of any acid catalysts.87 Methylphosphonium salts derived from alkyl diphenylphosphinites formed in situ from lithium alkoxides ROLi and chlorodiphenylphosphine have been shown to react with Grignard reagents R 0 MgX to form the cross-coupled products R–R 0 in a one-pot procedure.88 The reaction between alkyl diphenylphosphinite esters and 1,4-quinones leads to the intermediate betaines (82). In the presence of carboxylic acids, alcohols or phenols, these are protonated and are then subject to nucleophilic attack (with inversion of conﬁguration) at the alkoxy group by carboxylate, alkoxide, or phenate anions to form esters or ethers, together with a p-hydroxyphenyl diphenylphosphinate, under mild and neutral conditions. This approach has been reported in a series of papers by Mukaiyama et al. for the synthesis of esters of primary, inverted secondary- and tertiary-alcohols,89,90 and benzylic alcohols,91 and also for the synthesis of alkyl-aryl and diaryl ethers.92,93 In these reactions, the initial diphenylphosphinite is formed in situ, usually from an alcohol and chlorodiphenylphosphine in the presence of a base. An alternative access to the phosphinite esters is provided by the reaction of N,Ndimethylaminodiphenylphosphine with the alcohol in dichloromethane at 401C.94 Ether formation by this approach has also been described using tetraﬂuoro-1,4-benzoquinone instead of the more commonly employed 2,6-dimethyl1,4-benzoquinone.95 Arising from their involvement as ligands in metal ioncatalysed reactions, studies have been made of ortho-metallation reactions

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Organophosphorus Chem., 2006, 35, 127–168

undergone by aryl phosphinite (and phosphite) esters in the presence of palladium complexes.96,97 R O

Ph

O

P Ph

O R

R1 R2

R3

BH3

R1 P R2

OH

(83)

(82) R = H or Me

The chemistry of secondary phosphine oxides, R2P(H)O and their phosphinous acid tautomers, R2POH, has continued to attract attention. The study of the phosphinous acid tautomers has been aided by the development of stereoselective procedures for direct conversion of secondary phosphine oxides to the phosphinous acid-boranes (83). Treatment of the secondary phosphine oxide with either a base-borane complex or boron triﬂuoride and sodium borohydride provides the phosphinous acid-borane with predominant inversion of conﬁguration at phosphorus.98 The phosphinous acid tautomers are usually trapped as ligands in metal complexes and further examples of this behaviour have been noted.99 Discrimination of enantiomeric forms of chiral phosphinous acids, Ph(R)OH, coordinated to a chiral rhodium complex, has been studied by NMR.100 Palladium complexes of di(t-butyl)phosphinous acid have found application as homogeneous catalysts.101,102 A lithium salt of the tellurophosphinite Ph2PTeH has been prepared and structurally characterised.103 3.2 Phosphonites. – Compared to other phosphorus(III) acid esters, relatively little well-deﬁned work has appeared on the synthesis and reactions of phosphonites. Routes to these compounds are often described in papers which are mainly concerned with work on related phosphite esters. Radical addition of bis(trimethylsilyloxy)phosphine to indene has given the phosphonite (84).104 A series of new phosphonites and diphosphonites bearing perﬂuoroalkyl substituents, e.g., (85) and (86), has been described, together with related phosphites.105,106 Among a new series of ‘short-bite’ chiral phosphorus(III) ester ligands prepared is the diphosphonite (87)107 Selective ortho-lithiation of 9,9-dimethylxanthene or 2,7dimethylphenoxathiin, followed by treatment with (Et2N)2PCl gave bis(diethylamino)phosphines, which were then treated with the appropriate bis(phenol) to give new chelating bis(phosphonites), e.g., (88).108,109 The synthesis of phosphinites bearing other donor centres has also developed. Among new systems of this type described recently are the ferrocenylphosphino-menthylphosphonite (89)110 and the bis(phosphinoalkyl)phosphonites (90).111 Also reported are phosphonites containing nitrogen donor centres, including the chiral systems (91),112 (92),113 and (93).114 Studies of the reactivity of phosphonites have also been few and far between. Woollins’ group has explored the reactivity of the bis(phosphonite) (94) towards oxygen, sulfur and selenium, a complete series of mono- and di-oxidised

139

Organophosphorus Chem., 2006, 35, 127–168

derivatives having been prepared and fully characterised by NMR and X-ray crystallography, providing much new data on structural aspects of peri-disubstituted naphthalene diphosphorus compounds.115 A variety of products has been obtained from the action of hydrogen chloride on the cyclic phosphonite ester (95).116 The cyclic hydroxyaryl phosphonite (96) has been shown to be transformed into the phosphite (97) and other phosphite transformation products in the presence of rhodium(I) during the course of a rhodium-catalysed hydroformylation reaction.117 The bis(phosphonite) (98) has also found use as a ligand in rhodium-catalysed hydroformylation reactions.118 Applications of chiral phosphonites (and related phosphites and phosphoramidites) derived from BINOL as ligands in asymmetric catalysis have been reviewed.119 R

F13C6

R

O P Ph O

P(OSiMe3)2

O O

F13C6

P

O

R

(84)

R

(85)

(86) R = C6F13

R1 O

O P

P O

P O

R

O

R1

X

2

O

O

P O

R3

R2 PPh2

P O O

Fe

R3

P(OMenthyl)2

R2 R2 R3

R3

(88) R1 = H or Me; R2, R3 = H, But or OMe; X = S or CMe2

(87)

(89)

N N

PPh2 n P O

O Ph P O

O

O

P

O

O

N

P O

n PPh2 (90) n = 1 or 8

(MeO)2P

P(OMe)2 (94)

(91)

O P Ph O

(92)

(93)

O P O

OH

But

But

t

Bu

O

P

O O

But

(95) MeO

OMe (96)

MeO

OMe (97)

140

Organophosphorus Chem., 2006, 35, 127–168 But

But

But

But

O P O

O P O

But

But

But

But

(98)

3.3 Phosphites. – The synthesis of new phosphite esters remains a significant area of activity, much of it directed towards the synthesis of phosphite ligands of interest in metal-catalysed reactions. The chiral BINOL-derived chlorophosphite (99) has again been widely used in the design of new mono-, di- and polyphosphite ligands. Among new monophosphite systems derived from phosphitylation of BINOL are (100),120 (101),121 and a series of acylphosphites.122 BINOL phosphites derived from the steroidal alcohol deoxycholic acid123 and various carbohydrate alcohols124,125 have also been prepared. The partially reduced H8-BINOL monophosphites (102) are also easily accessible and have shown good performance in rhodium-catalysed hydrogenation reactions.126 Routes to other new axially chiral biphenyls have enabled the synthesis of the atropisomeric phosphites (103)127 and (104).128 Among other new cyclic monophosphite esters reported are the chiral ligand (105),129 the phosphitylated dihydroquercitin (106),130 and the benzodioxaphosphorin (107).131 A new route to ﬂuorous phenols has given access to the triarylphosphites (108).132 Established routes to phosphites have been exploited in the synthesis of a wide range of new cyclic phosphites having two or more phosphite units. The reactions of chlorophosphites with bisphenols have given macrocyclic bis-, tris- and tetrakis-phosphites, e.g., (109),133 and related macrobicyclic systems.134 Phosphitylation of 2,2 0 -dihydroxybiphenyls and related BINOLs is key to the synthesis of a variety of cyclic bis(phosphites), e.g., (110),135,136 furanoside bis(phosphites), e.g., (111),137 and chiral pyrophosphites, e.g., (112).138 Transesteriﬁcation of triphenylphosphite with pentaerythritol and dipentaerythritol provides a route to a variety of bicyclic phosphites, e.g., the bis(phosphite) (113) and the mixed donor pyridine-functionalised phosphite (114).139 The synthesis of mixed donor P,N-bidentate ligands by Russian workers has been reviewed.140 Among new phosphites also bearing nitrogen donor centres are the pyridinoamides (115),141 the phosphito-isoquinoline (116),142 various amino-, imino-,143 and oxazolinophosphites,144,145 and the tripodal N-centred tris(phosphites) (117).146 The tris(zinc(II) porphyrinyl)phosphite (118) has been prepared and shown to form supramolecular multicomponent assemblies with quinuclidine and acceptor metal ions.147 In related work, zinc-complexed tetraarylporphyrins bearing a single diorganophosphito substituent in one of the aryl groups have also been prepared and shown to assemble with a series of pyridylphosphines via coordination of the pyridine nitrogen to the zinc atom, giving new, unsymmetrical bidentate P–P 0 ligand systems.148 Other phosphine-phosphite149,150 and also phosphite-thioether151 systems have been described. Phosphites derived from

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Organophosphorus Chem., 2006, 35, 127–168

incompletely condensed silsesquioxanes,152 b-cyclodextrins,153 calixarenes,154 and calix[4]resorcinarenes155 have also been prepared. The synthesis of a series of phosphite dendrimers has also been achieved, these compounds forming metal complexes in which the metals are attached to the branching points within the dendrimer.156

Ph O P O O

O P Cl O

(99)

Ph O P O O

OMe

(100)

Ph OCH2Ph

(101)

R O P O Ph R

O P OR O

(104)

(103) R = H, Me, Br or But

(102) R = Pri or CH(Me)Ph

O P OPri O

O O

But

OMe O MeO O

O P

O

O MeO

Pri (105)

O

O O P O

OMe

(106)

CH2CH2CH2RF8 3

Ar O P

O

O (107)

But P O

P O

O

O

O

O

P O Ar

(108) RF8 = (CH2)7CF3

(109) Ar = 2,6-But2-4-MeC6H2

But O O O O P P O O But But

(110)

But

142

Organophosphorus Chem., 2006, 35, 127–168 R1

O O P O

O P O

O P

O

R1

O

O O O

R1

or

O O P O P O O

R2

R2

O

R

R

=

O

R1

O

O

R

R

(112) R = H, Me or Br 1

2

(111) R , R = H, SiMe3, or Bu

t

O O P

O O

O

O

O

O

O

P

O

O

P

O

O O

N

O (113)

(114)

O

But

N H O

P O

But

N

N R O

O O P O

N

O O P 2 O R1 R

3

But 1

But 2

(117) R , R = H or Me (115) R = H or Me

(116)

Apart from their behaviour as ligands in metal catalyst systems, studies of the reactivity of phosphites towards a wide variety of other substrates have attracted attention. New aspects and applications of the classical MichaelisArbuzov reaction and its variants continue to appear. Evidence of the thermal disproportionation of methyltriaryloxyphosphonium halides formed in the reactions of triarylphosphites with alkyl halides, together with the formation of P–O–P intermediates, has been reported.157 The Michaelis-Arbuzov reaction has been used in the synthesis of phosphonate-based styrene-divinylbenzene resins158 and polyphosphonated chelation therapy ligands.159 Treatment of electron-rich benzylic alcohols dissolved in triethylphosphite with one equivalent of iodine affords a low-temperature one-pot route to the related benzylic phosphonates, compounds which are otherwise difﬁcult to prepare.160 Upperrim chloromethylated thiacalix[4]arenes have also been shown to undergo phosphonation on treatment with a phosphite ester in chloroform at room temperature.161 The nickel(II)-catalysed reaction of aryl halides with phosphite esters in high boiling solvents, e.g., diphenyl ether, (the Tavs reaction), has also

Organophosphorus Chem., 2006, 35, 127–168

143

found application in the synthesis of upper-rim calix[4]arene phosphonates162 Diethyl arylphosphonates are rapidly accessible in good yield from nickel(II) and palladium(II)-catalysed reactions of aryl halides with triethylphosphite under microwave radiation.163 No metal ion catalyst is needed in the reaction of nitro-activated chlorothiophenes with triethylphosphite, which proceed in the absence of a solvent under mild conditions to give the related nitrothienylphosphonates.164 g-Azido-a-diazo-b-ketoesters have been shown to react with trimethylphosphite under mild conditions in a tandem StaudingerArbuzov rearrangement sequence to form g-(dimethylphosphorylamino) -a-diazo-b-ketoesters, e.g., (119).165 Reactions of phosphite esters with a-halocarbonyl and related compounds have also continued to be reported. Both Arbuzov and Perkow pathways have been observed in the reactions of trialkylphosphites with mono-and di-acylals of halo-substituted acetic acids.166 Aza-Perkow pathways are involved in the reactions of trihaloacetimidoyl chlorides with trialkylphosphites.167 The reaction between triethylphosphite and 2-bromo-1,3-dicarbonyl compounds has been used to generate enolphosphate intermediates, subsequently alkylated to form b-substituted-ab-unsaturated carbonyl compounds.168 Mechanistic and synthetic aspects of the reactions of g-halogeno-ab-unsaturated carbonyl compounds with trialkylphosphites, leading to a variety of functionalised phosphate esters, have also been explored.169 A reductive methylation/phosphorylation pathway is involved in the reaction of trimethylphosphite with 3,4-diazacyclopentadienone N-oxides, which results in the phosphate (120).170 A new protocol has been developed for the O-methylation of phenolic compounds using trimethylphosphite (or trimethylphosphate) under solvent-free and microwave conditions.171 Conditions have been established for the selective hydrolysis of the bicyclic phosphites (121) to give the related dihydrogen phosphites (122).172 A study of the hydrolysis of the cyclic phosphites (123, X¼OPh) (and the related phosphoramidites, X¼NMe2) to the cyclic phosphites (124), in the presence of intentionally added water, has shown that hydrolysis is inhibited by the addition of simple additives such as KF, K2CO3, or Et3N.173 Further examples of the formation of glycosydic linkages via the intermediacy of glycosylphosphites have appeared.174,175 The reaction of a protected glucopyranoside with triethylphosphite and trimethylsilyl triﬂuoromethanesulfonate has been shown to lead to the formation of the seven-membered phostone system (125).176 A new reaction of vicinal sulfonyliminocarboxylates (126) with phosphite esters involves a chelotropic 1,4-cycloaddition of the phosphite to form an intermediate cyclophosphorane, followed by a 1,2-shift of the sulfonyl group, resulting in the iminophosphoranes (127).177 A new class of semistabilised phosphorus ylides (128) derived from phosphites is accessible in-situ from the reaction of trialkylphosphites with a carbene-transfer reagent system, affording high Eselectivities in Wittig oleﬁnation reactions.178 A route to stabilised ylides derived from phosphites is afforded by the reactions of phosphite esters with electronwithdrawing acetylenes such as dibenzoylacetylene or dimethyl acetylenedicarboxylate, the resulting 1:1 intermediate ylides then being trapped with a variety

144

Organophosphorus Chem., 2006, 35, 127–168

of reagents.179,180 Nucleophilic attack of phosphite esters at carbon is also the key step in reactions with a benzylidenemalonitrile, giving the phosphonates (129),181 with a-ketoallenes, initially giving the cyclic phosphoranes (130),182 and with various benzoxazinones, giving phosphonated isoindolines and indoles.183 The reactions of trialkylphosphites with the naphtho[2,1-b]furanylium cation184 and 3-acetylcoumarin185 have also been explored. Oxidation reactions of phosphites have also attracted attention. Sterospecific oxidation of trialkylphosphites obtained enantioselectively by the condensation of racemic dialkylphosphorochloridites with an alcohol in the presence of a chiral amine has provided the ﬁrst asymmetric synthesis of trialkylphosphates.186 Whereas arylphosphites are normally unreactive towards singlet oxygen, indirect oxidation to the phosphates occurs in a dye-sensitized co-photooxidation in the presence of dimethylsulﬁde.187 Triarylphosphites are also oxidised by diarylselenoxides by a concerted oxygen-transfer mechanism.188 Trimethylphosphite has found use as a trap for alkoxy radicals formed from the ring-opening of oxiranylcarbinyl radicals formed from haloepoxides in the presence of free-radical initiators.189 The reaction of epoxides with trialkylphosphites in the presence of trimethylsilyl chloride and lithium perchlorate in diethylether occurs regioselectively to form the phosphonates (131).190 Combinations of trimethylphosphite with trimethylsilyl chloride or acetic acid, again in the presence of lithium perchlorate in diethylether, have found use in the synthesis of a-hydrazinophosphonates and N-hydroxy-a-aminophosphonates.191 a-Aminophosphonates have also been prepared by the reactions of aldehydes, secondary amines and trialkylphosphites in the presence of ethereal lithium perchlorate192 or aluminium trichloride.193 Further applications have been described of the use of triethylphosphite as a coupling reagent in the synthesis of new extended analogues of tetrathiafulvalene,194 and heterohalogenated tetrathiafulvalenes.195 Anomalous ring cleavage of 1,3-dithiole- and 1,3-diselenole-2-thiones has been observed under cross-coupling conditions using triethylphosphite.196 Organophosphites continue to be of interest as stabilisers in PVC formulations197 and as ligands in asymmetric transition metal catalysis, where again the utility of mixtures of different monodentate phosphites (and phosphonite) esters has been noted.198 Bulky triarylphosphite ligands have been shown to undergo ortho-metallation reactions in the presence of platinum and palladium salts, the resulting complexes having significant catalytic activity in Stille and Suzuki coupling reactions.199 The tricyclic phosphite (132) has also shown superior properties as a ligand in metal-catalysed oleﬁn hydrogenation and hydroformylation reactions.200 Interest in the chemistry of secondary phosphites has also continued, with particular reference to their tautomerism and the involvement of the P(III) hydroxyphosphite tautomers as intermediates in reactions. A novel double dealkylation of a trialkylphosphite in the presence of acid and a ruthenium salt has enabled the characterisation of the monoester MeOP(OH)2 as a ligand.201 When dimethylphosphite (normally viewed as dimethyl phosphonate) is used as the phosphorus component of the Mitsunobu reaction, the course of the reaction changes and leads to products arising from free-radical pathways.202 The reaction of diallylphosphite with bis(trimethylsilyl)acetamide or trimethylsilyl chloride yields

145

Organophosphorus Chem., 2006, 35, 127–168

the phosphite (133), which, on exposure to phosgene in toluene, is converted into the bis(phosphonomethyl)phosphoric acid ester (134).203 Treatment of the bicyclic thiophosphite (135) with di(Grignard) reagents derived from ao-dibromoalkanes, followed by a further Grignard reagent or sodium alkoxide, and ﬁnal treatment with sulfur and water, provides a simple route to the dithiaphosphepin system (136).204 Among theoretical treatments of phosphite esters reported are studies of the molecular and conformational preferences of trimethylphosphite, both as a free ligand and also in the metal-coordinated state,205 the estimation of barriers to atropisomerism of dibenzo[d,f][1,3,2]dioxaphosphepin moieties of bis(phosphite) ligands,206 and the ring closure of 2-hydroxyethyl ethylene phosphites to form bicyclic spirophosphoranes, a new P(III) insertion reaction.207 A structural and microstructural description of the glacial state of triphenylphosphite has been achieved from powder synchrotron X-ray diffraction data and Raman scattering studies.208 Ph

Ph

N N

O

Zn N (MeO)2P

P O

O

H N

(MeO)2P OEt

Ph

O

Ph

Ph

N2

O

N

O

N

NMe

3 (118)

(119)

R

O P O

R

EtO

O P

Ph

O

O BnO

R

RO

O

(124)

NSO2R

SO2R N P(OR)3

F3C

F3C

(126)

Ar

(127)

(128)

P CH3(CH2)5

X (CH2)7COOMe

(129)

(RO)3P

OMe

OMe OMe

C(CN)2 R

O P O H

2

O

O

(125)

(RO)2P O

2

O

R1

P X O

(123) R1 = Me or Et; R2 = Me, Et or Pr; X = OPh or NMe2

RO

BnO

MeO

R

(122)

(121) R = Me or Et

O

R1

OH O O P H OH OH

O

(120)

O P MeO OMe OMe

(130) X = H or Cl

R1

OSiMe3

O

O

O

P(O)(OR2)2 (131) R1 = alkyl or aryl; R2 = Me or Et

Me

Me (132)

Me

146

Organophosphorus Chem., 2006, 35, 127–168 Me

Me O P OTms O (133)

4

Me

P(O)(OR)2

(RO)2P(O) O

P(O)(OR)2

(134) R = alkyl

P S P S (135)

R

P

S

Me

S S (136) R = alkyl. aryl, alkenyl or alkoxy

Tervalent Phosphorus Amides

4.1 Aminophosphines. – The synthesis and use of aminophosphines as ligands have been reviewed.209 Racemic chlorophosphines of the type R1R2PCl have been shown to react stereoselectively with chiral amines (1-phenylethylamine or aminoacid esters) in the presence of triethylamine to give the diastereomerically enriched aminophosphines (137), which were isolated as diastereomerically pure crystalline borane complexes.210,211 This approach has also been used in the synthesis of chiral t-butylphenylphosphine oxide, via the acid hydrolysis of an intermediate chiral aminophosphine.212 Among other new monoaminophosphines prepared by treatment of primary or secondary amines with chlorophosphines in the presence of a base are the adenine derivatives (138),213 the phosphinoalkylaminophosphines (139),214 the aminophosphine-phosphine sulﬁde (140),215 and the hydrazinophosphines (141)216 and (142).217 New aminophosphines and amino(chloro)phosphines bearing trialkylsilyl and other sterically bulky substituents at nitrogen have been prepared via treatment of Nlithiated amines with chlorophosphines and characterised by X-ray crystallography and NMR studies.218,219 The ﬁrst fully-characterised NH-functional monophosphinourea derivative (143) has been obtained as a crystalline solid in almost quantitative yield from the reaction of N,N 0 -dimethylurea with chlorodiphenylphosphine in the presence of triethylamine in THF.220 A detailed study of the reactions of anilines, bearing electron-withdrawing substituents in the benzene ring, with chlorodiphenylphosphine and inorganic or organic bases in different solvents and in varying stoichiometry has shown that, in addition to the aminophosphines (144), both diphosphinoamines (145) and the phosphinophosphazenes (146) can be isolated in varying amounts. In the case of the reaction of pentaﬂuoroaniline with chlorodiphenylphosphine and butyllithium in equimolar amounts, the phosphazene is the sole product. The latter compounds arise from the intermediacy of a P-lithiophosphazide anion, a tautomer of the N-lithioamide expected to be formed in the reaction mixture.221,222 The perﬂuoroalkylaminophosphine (147) has been prepared for ligand applications in ﬂuorous biphasic solvent systems.223 Polymer-bound aminoalcohols have been transformed by conventional chemistry into a series of polymer-supported aminophosphine-phosphine and -phosphinite ligands, e.g., (148).224 The anticipated high basicity of the tris(guanidyl)phosphine (149) stimulated several attempts to prepare it. However, these only led to the isolation of the corresponding phosphine oxide.225 Considerable interest has been shown in the synthesis of bis(aminophosphines) and many new examples have been described. These include the simple benzene- and pyridine-bridged systems

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Organophosphorus Chem., 2006, 35, 127–168

(150)226,227 and (151),228 the bis(phosphinoamides) (152),229 the alkylenebridged system (153)230 various phosphinoamines derived from atropisomeric 2,2 0 -diamino-1,1 0 -binaphthyl and related partially-reduced systems,231,232 and the arene sulfonylaminophosphines (154) and (155).233 Also described are bis(aminophosphines) (and related phosphoramidites) derived from heterocyclic secondary amines such as phenazine, piperazine and homopiperazine, e.g., (156),234 (157)235,236 and (158).237 N-Pyrrolylaminophosphines have also attracted attention. Among new pyrrolyl- (and related indolyl)-phosphines described is the chiral sulfonylated derivative (159),238 the 7-aza-N-indolylphosphines (160),239 the cyanopyrrolylphosphines (161),240 the unsymmetrical di(N-pyrrolyl)phosphino-functionalised dppm analogue (162),241 and the heterocyclic aminophosphine (163).242 Other heterocyclic aminophosphines prepared include chiral diazaphospholidines, e.g., (164),243 (165),244 and (166), the latter resulting from a ring-contraction of the diazadiphosphocine (167) on treatment with phenylmagnesium bromide,245 and also the atropisomeric system (168).246 A crowded diazaphospholidine system has also been used for the stabilisation of the optically pure phosphino(silyl)carbene (169).247 Aminophosphine-stabilised C-phosphanyl-C-chloroiminium salts (170) have been prepared as electrophilic carbene synthetic equivalents.248 In addition to the ferrocenylbis(diazaphospholidine) (165) noted above, other new ferrocene-based chiral aminophosphines, e.g., (171)249 and (172),250 have also been prepared. Chiral aminophosphine-oxazoline hybrid ligands have continued to attract attention, new examples including (173)251,252 and (174).253 Routes to fourmembered ring aminophosphines (diphosphazanes) have undergone further development, new systems reported including (175),254 (176),255 and (177).256 The pyridyl-functionalised diphosphazane (178) has been prepared as part of a study of the oligomerisation of phospha(III)zanes.257 Both diphosphazanes and triphosphazanes (179) have been identiﬁed as products of oligomerisation of the iminophosphines R–N¼P–X.258 The 1,2-bis(diazasilaphosphetidino)ethane chelating ligand (180) has also been prepared.259 R R1 R2

N

H P N CHR3R4

N

(137) R1 = But or Ph; R2 = Ph or Mes; R3 = Ph, Bui or Pri; R4 = Me or CO2Me

H2 N

PPh2

N

Ph2P

(CH2) n NHPPri2

N N

(139) n = 2 or 3

(138) R = H or Pri

O NHPPh2

Me Pri2P NH N

Ph2PNHNH

PPh2 S (140)

(141)

(142)

N

Me N H

N PPh2 (143)

148

Organophosphorus Chem., 2006, 35, 127–168 NHPPh2

Ar N

Ph2P

Ar PR2

X

PPh2 N P Ph Ph

(CF2)6CF3 N H

(147)

(146)

(145)

(144) X = o-, m-, p-CN, o -C6H5 or o -CF3

(C6F5)2P

N(PPh2)2 n R2

NMe2

R3 P N X

NMe2

3

Ph2PNH

R1 (149)

(148) R1 = H, Me or Ar; R2 = H, Me or Pri; X = PPh2 or OPPh2

N

R2 P

N

N PPh2

PR2

Ph

N

n N(PPh2)2 (151) n = 0 or 1

SO2Bu

SO2Bu N P Et N SO2Bu

Ph

PPh2

O

NHPPh2

(150) X = CH or N

Ph

O

X

N N

SO2Bu

Ph (155)

(154)

(153) R = Ph or Pri

(152)

PPh2

R2

N

N N

N

Ar N

PPh2 N

PPh2 (157)

(156)

CN N

R2P

(160) R = Ph or N-pyrrolyl

N

Ph2P

S N

P N

O

PPh2 1

2

(159) R , R = H or Me

(158)

2

Ph

Ph

N

N P

O

PR2

(161) R = Ph or N-pyrrolyl

PPh2

R1

PPh2

PPh2

N

PPh2 PPh2

N

O S

N

Pr i (162)

Pr i (163)

149

Organophosphorus Chem., 2006, 35, 127–168

MeO

N P N

NPh N P

PPh2 Pri P N

N P N Ph Pri

Fe

N

X (164) X = Ph, OMe or Br Cl Pri P N

(167)

But N

Ph

NR PR NR

P N Pri Cl

SiMe3

P

(R12N)2P

N But

Ph

(168)

R2 N

Cl

CF3SO3

R2

(170) R1 =Pri; R2 = Me or Pri

(169)

Me

NR2 P Fe

Fe

(166)

(165)

PPh2

N R1 PR

2

O

O N

2

Ph2P

P

N N

N

Ph2P

R

Pri

NR2 (172) R1 = H, Me, Et or Pr; R2 = Ph or Cy

(171)

(173) R = Pri or But; Ar = e.g.,Ph, o-Tol, 2-EtPh

But

But

But

N

N ButNH P

(174)

ArNH P

P H

N

ButNH P NHAr

N

N

But

But

(175)

(176)

P NHBut

P Se

N But (177)

But R

N

X

t

Bu

N P N Cl

P

X P P Cl

N P R

N N

(178)

N R X

(179) R = Mes* or 2,6-Pr i2C6H3; X = Cl or OSO2CF3

N Me2Si

N SiMe2

P P

N But

N But (180)

150

Organophosphorus Chem., 2006, 35, 127–168

Treatment of the crowded amino(chloro)phosphine (181) with aluminium chloride results in chloride abstraction to yield the phosphenium salt (182). With potassium-graphite in THF, (181) is converted into the diphosphine (183), which undergoes reversible dissociation on heating in vacuo to form the stable radical (184), which reverts to the diphosphine on cooling. The structure of the radical has been determined in the gas phase by electron diffraction.260,261 In contrast, the reaction of o-cyanophenylamino(diphenyl)phosphine with potassium-graphite proceeds with proton-abstraction to give a ‘free’ phosphinamide anion, isolated as a potassium complex.262 The ligand donor properties of P–N bonded phosphinoamides have been reviewed.263 A new route to iminophosphoranes (185) is provided by alkylation of arylaminophosphines, followed by deprotonation with triethylamine.264 Surprisingly, protonation of diphosphinoamines attached to pyridine at the ortho-position, e.g., (186), results in a quantitative transformation to iminophosphoranes, e.g., (187), which is reversed on treatment with base, the system therefore having potential as a new type of molecular switch.265 Iminophosphorane tautomers have also been recognised as intermediates in the reactions of the aminophosphine ButP(NH2)2 with Group 13 metal trialkyls, which result in the formation of the eightmembered ring heterocycles (188).266 In contrast, the reactions of ButP(NHBut)2 with base-stabilised aluminium hydrides proceed via the aminophosphine form at the ‘hard’ nitrogen atoms with elimination of dihydrogen to give the H-bridged dimer (189). Related reactions with boranes, gallanes and indanes take place at the softer phosphorus atom to give simple adducts.267 Aminophosphines of the type Ph2PNHAr have been shown to act as iminophosphoranyl synthons, undergoing addition of the P–H bond of the iminophosphorane tautomer to the vinyl group of P-vinyliminophosphoranes to give the bis(iminophosphoranes) (190).268 Treatment of the borane adduct of the diazaphospholidine (164, X¼Ph) with phenyllithium results in an unusual addition/nucleophilic aromatic substitution reaction, to give the diazaphosphaazulene (191).269 Insertion of carbon fragments into the P(III)–N bond of aminophosphines and aminobis(phosphines) occurs on treatment with paraformaldehyde, resulting in the insertion of a methylene group, followed by oxidation at phosphorus to give, e.g., the phosphine oxides (192). Similarly, the reaction of aromatic aldehydes with aminophosphines results in insertion of ‘ArCH’ into the P–N bond to give the phosphine oxides (193), whereas with aliphatic aldehydes, P–N bond cleavage occurs, giving a-hydroxyalkylphosphine oxides.270 Treatment of bis[bis(dialkylamino)phosphino]methanes (194) with bis(triﬂuoromethyl)acrylonitrile results in the formation of the ylides (195), which gradually decompose at room temperature to form the amino(ﬂuoro)phosphinoiminophosphorane (196).271 A procedure has been developed for the determination of the absolute conﬁgurations of chiral phenylcarbinols from the 31P-NMR spectra of the diastereoisomers formed in the reactions of the alcohol with the chiral phospholidine derivatising agents (197), formed in situ from chiral diamines of known absolute conﬁguration.272 The diselenide (198) has been obtained in good yield and on a large scale from the reaction of the

151

Organophosphorus Chem., 2006, 35, 127–168

parent bis(phosphino)amine with selenium in concentrated solutions in toluene.273 The reaction of tris(dimethylamino)phosphine with a rotaxanated disulﬁde has been shown to lead to cleavage of the S–S bond, resulting in the formation of a stable tris(dialkylamino)thiophosphonium salt in rotaxane form.274 The synthesis, reactions, and catalytic applications of the bicyclic triaminophosphines (proazaphosphatranes) (199) have continued to attract attention and this area has been reviewed.275 Among new catalytic applications of these compounds reported by Verkade’s group is their use in various palladium-catalysed procedures, including the Stille cross-coupling of aryl chlorides,276 amination reactions of aryl halides,277,278 and the direct a-arylation of nitriles with aryl bromides.279 Proazaphosphatrane ligands have also found use in the Bayliss-Hillman reaction,280 the dimerisation of allyl phenyl sulfone,281 the head to tail dimerisation of methyl acrylate,282 and for the regioselective Michael addition of a bg-unsaturated ester and a nitrile to a variety of ab-unsaturated ketones.283 Verkade has also reported the Staudinger reactions of (199, R¼Me or Pri) with various arenesulfonylazides, which lead to the ionic phosphazides (200) and (201), together with other products, depending on the initial triaminophosphine structure.284 Alkyldiaminophosphines, in particular (202), have shown promise as ligands in expanding the scope of the Stille crosscoupling reaction to alkyl halides.285 Interest in the coordination chemistry of aminophosphines has also continued, recent reports including studies of Group 6 transition metal carbonyl complexes286 and the reactivity of dialkylamino- and bis(dialkylamino)-phosphines in the coordination sphere of metals.287 Al2Cl6

(Me3Si)2N Pri2N

P Cl

(Me3Si)2N

(Me3Si)2N

P AlCl4

Pri2N

(181)

Pri2N

P

(182)

P

N PPh2

H

N

(Me3Si)2N

N(SiMe3)2

cool

Pri2N

N PPh2

(184)

PPh2 N PPh2

N PPh2 PPh2

Ph2P (186)

But

H H P N

HN Me M Me HN

M

Me

Me NH

P H

Bu

t

(188) M = Al, Ga or In

But

(187) But

But

HN N H H Al P But Al P NH H H N But

But (189)

P

NH

H (185)

heat

(183)

Ph2P R1R22P NAr

NPri2

MeO

X

N P P N Ph Ph Ph Ph (190)

152

Organophosphorus Chem., 2006, 35, 127–168

H3 B

Ph R N

O

P N

O

Ph2P

(192) R = Me, Pr or Bu (R2N)2P

(193) F

P(NR2)2

(R2N)2P

P(NR2)2 NC

(194)

CH(CF3)2

NC

(195)

i

R1N

N

(199)

(200)

NR2

CH(CF3)2

PPri2

Se Se

P X

(198)

(197) X = NMe2 or Cl; R1 = Me or CH2tms; R2 = Ph or -(CH2)4-

N

H N

Pr 2P

NR1

N3 ArSO2 P RN NR NR

P

(196)

R2

R2

P RN NR NR

Ar

Ph2P NHPh

N Ph (191)

(R2N)2P

O

PPh2

NR N

P N3 NR NR (201)

RN RN P N RN

ArSO2

CyP N

2

(202)

4.2 Phosphoramidites and Related Compounds. – The synthesis of phosphoramidites has continued to be a very active area, being driven by the need to develop new, more effective, chiral ligands for use in metal-promoted homogeneous catalysis. Phosphoramidites derived from BINOL continue to dominate the ﬁeld, and although many of the publications noted are now mainly concerned with applications in catalysis, the synthesis of new BINOL-derived compounds has also been reported, including schemes for the parallel synthesis of ligand libraries of monodentate BINOL-phosphoramidites (203), linked to in situ screening for catalytic activity.288,289 New polymer-bound BINOL-phosphoramidites have also been described, including (204)290 and (205),291 and compounds derived from the free-radical polymerisation of phosphoramidites bearing a p-styrylamino substituent.292 New monomeric BINOL-phosphoramidites have also been prepared, including (206)293 and mixed phosphoramidite-phosphite and -phosphinites, e.g., (207).294 Applications in catalysis of BINOL-phosphoramidites have attracted much interest. Monodentate BINOL-phosphoramidites offer a breakthrough in rhodium-catalysed asymmetric

153

Organophosphorus Chem., 2006, 35, 127–168

hydrogenation of alkenes295 and a- or b- dehydroaminoacid derivatives,296,297 acting as more accessible, effective replacements for bidentate chiral phosphines, and affording high enantioselectivities. Other applications include their use in promoting highly enantioselective conjugate additions of dialkylzinc reagents to acyclic nitroalkenes,298 asymmetric allylic-substitution,299 -amination,300 and -alkylation,301 conjugate addition reactions of arylboronic acids302 and Meldrum’s acid,303 the enantioselective desymmetrization of meso-cyclic allylic bisdiethylphosphates,304 and the asymmetric borane reduction of the Nphenylimine of acetophenone.305 New phosphoramidites (208) derived from H8-BINOL have been prepared and applied as ligands for the catalytic hydrogenation of enamides306 and a-dehydroaminoacids.307 Also reported is a series of new chiral phosphoramidites based on 2,2 0 -dihydroxybiphenyls, e.g., (209),308 and (210).309 In addition to these atropisomeric systems, the synthesis of a wide variety of new phosphoramidites, many of which are chiral, has been reported. Among new chiral monodentate systems is a range of heterocyclic compounds derived from 2-(2-hydroxyphenyl)-1H-benzimidazole, e.g., (211) (from which a series of stable pentacovalent phosphoranes has also been obtained via reactions with 3,5-di-t-butylcatechol),310 the phospholidines (212),311 a series of spirophosphoramidites (213)312,313 which also have applications in catalysis,314,315 the 1,3,2-oxazaphospholidinones (214),316 the protected pentaerythritol derivatives (215),317 the D-mannitol derivatives (216),318 and the P-chirogenic diaminophosphine oxide (217), this representing a new class of chiral phosphorus ligand which displays its activity via the P(III) tautomer.319 The selective phosphitilation of dihydroquercitins has been explored and a number of new phosphoramidites described.320,321 A silsesquioxanylphosphoramidite has also been prepared.322 Various monodentate and bidentate phosphoramidites involving the same phosphoramidite unit have been prepared. Included among these are pyrrole-based phosphoramidites, e.g., (218),323 various catechol-based phosphoramidites, e.g., (219),324 and the ethylene-bridged oxazaphosphorinanones (220).325 Among large ring heterocyclic phosphoramidites prepared are ten-membered ring systems, e.g., (221),326 and the 16-membered macrocycle (222).327 New phosphoramidite ligands bearing additional donor centres have also attracted interest and among these are the urea derivative (223)328 and a series of phospholidines of type (212) which bear a chiral aminoalkoxy substituent at phosphorus.329 O N

O O O R1 P N 2 R O

O

N

P O

O

O

O

(203)

(205) (204)

P

Ph O

154

Organophosphorus Chem., 2006, 35, 127–168 R1 R2

O

N P

O O

P O

O O R1 P N 2 R O

O P NH O

(207) R1, R2 = (CH2)2; R1 = H, R2 = Et

(206)

(208) R1,R2 = (CH2)4; R1,R2 = Me or Et; R1 = (R )-CH(Me)Ph, R2 = H or Me

NHR R1

NR

O R2 P N R2 O

But

O

P

N

O

But

N P O Y

R1

OMe

MeO

1

t

(210) R = Me, Et, Bz or Pri

(209) R = H, Me, Bu , Ph or Br; R2 = Me or Pri

NR2 O

N X P PhN

P

(211) Y = NMe2,Cl or Ph

O

O

O

R

P

NSO2tol

Ph X

X

(213) R = Me, Et, Pri, Cy or (R )-CH(Me)Ph; X = H or OMe

(212) X = e.g., OPh, O-Ad, O-Men, OMe

(214)

R CN

RO RO

O O

P

NPri2

O PNMe2 O

O O

RO

PhNH

H

Ph N H P N O Ph

R (215) R = DMtr, Lev or TBDMS

(216) R = Me, Et, Bui or Ph

(217)

155

Organophosphorus Chem., 2006, 35, 127–168

n N

O N

P

O

O

N

P

N

N

O P

O

P

O

Ph

Ph

N

(219) n = 1 or 2

(218)

O

O N

N

O

P P O O NR2 R2N

O

P

Cl

P

(221)

(220) R2N = NMe2, NEt2, N-morpholinyl or NHPh R2

O

O

R12NP

R N O P Et Et

O P

R N

Et Et

P O N R (222) R = But

N Ph2P

PNR12

O

O

P O N R

N P

Bu O

t

1 R1 R

O R2

R2 But

1

R

O

R

1

O

2

PNR12

R12NP O (223)

Cl

N Ph

R2

O

(224) R1 = alkyl; R2 = H or CH2NR2

The reactions of triaminophosphines and diamidoarylphosphites with macrocyclic phenolic compounds have continued to be applied in the synthesis of cyclic phosphocavitand amidophosphite derivatives (224) of calix[4]resorcinarenes.330,331 The ﬁrst heterobimetallic complexes of such ligands have been prepared.332 Also reported is a study of the selective oxidative imination of these phosphocavitands with phenyl azide, only three of the four phosphorus atoms undergoing the reaction.333 The amidophosphitylation of phenols has also been used to prepare new phosphoramidite derivatives, e.g., (225), of calix[5]arenes, the larger cavity, compared to calix[4]arenes, providing greater ﬂexibility in interactions with metal ions.334 Further work has appeared on the spontaneous dismutation of diamidoarylphosphites, to form cyclo(bis-amidoarylphosphites) (226) and phosphorus triamides, that occurs in solution at room temperature. Substituent and solvent effects have now been explored.335 The naphthylene bis(diamidophosphite) (227) undergoes a similar dismutation to

156

Organophosphorus Chem., 2006, 35, 127–168

form the unsymmetrical diphosphacyclophane (228).336 The reactions of cyclic phosphoramidites with dialkyl azodicarboxylates lead to products that are quite different to the familiar phosphoniobetaines involved as the key intermediates in related Mitsunobu reactions of tertiary phosphines. Thus, e.g., treatment of the cyclic phosphoramidites (229) with a dialkyl azodicarboxylate results in the formation of the phosphinimines (230). The mechanism of these reactions has been investigated by solution NMR studies, revealing the involvement of pentaand hexa-coordinate phosphorus intermediates.337 The chiral oxazaphospholanes (231) have been shown to undergo a stereoselective redox addition reaction with aromatic aldehydes to form the cyclic phosphinimines (232), potential precursors of a-hydroxyphosphonate esters of medicinal interest.338 The reactions of the oxazaphospholanes (233) with carboxylic acid chlorides also result in oxidation at phosphorus, with the formation of the cyclic phosphonamidates (234).339 On treatment with azides, the allyloxydiazaphospholidines (235) form the expected phosphinimines (236). These undergo a palladium-catalysed [3,3]sigmatropic rearrangement to form the phosphoramidates (237), precursors of allylic amines.340 Phosphoramidites have been shown to be efﬁcient, ‘green’ organocatalysts for the Michael reaction.341 They have also found use in the synthesis of phosphito-alkoxytitanium gel materials,342 and as reagents in a phosphoramidite approach to the phospholipid ‘cardiolipin’.343

But

But

OH

But

O

O P

Me2N O

P NMe 2 O

O Ar O R2 N P P NR2 O Ar O But

But

O

(226)

O

O

NPri2 or N-morpholinyl

But

But

O

O

P NR 2

R2 N P

Y

P

NHBut

Y

But (229) Y = S or CH2

P O

O

(228)

P(NR2)2

(227) R2N = NMe2, NEt2,

(225)

O

O

(R2N)2P O

But (230)

CO2R N NHCO2R NBut

157

Organophosphorus Chem., 2006, 35, 127–168 R2 Ph

Ph

O

Me

P N(SiMe3)2 NR1

Me

(231) R1 = Me or Pri

Ph

N

N

OBut

O

(233)

NMe P

R1

R2

(235) R1 = H, Et or Ph; R2 = H or Me

COR

(234)

MeN R3N

O

O P

O

MeN

OSiMe3 P NR1 NSiMe3

(232) R2 = -C6H4X

Ph

P

O

R1

NMe P

MeN R3

O R2

(236) R3 = Tos or P(O)(OPh)2

NMe P

N

O

R1

R2 (237)

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3 Tervalent Phosphorus Acid Derivatives BY D. W. ALLEN

1

Introduction

As in previous reports, attempts have been made to minimise the extent of overlap with other chapters, in particular those concerned with the synthesis of nucleic acids and nucleotides to which the chemistry of tervalent phosphorus esters and amides contributes significantly, the use of known halogenophosphines as reagents for the synthesis of phosphines (see Chapter l), and the reactions of dialkyl- and diaryl-phosphite esters in which the contribution of the phosphonate tautomer, (ROhP(O)H),is the dominant aspect, which are usually covered elsewhere in these volumes. Once again, there has been considerable interest in tervalent ester and amide chemistry that relates to the preparation of new, often chiral, ligand systems for use in metal-catalysed homogeneous catalysis.

2

Halogenophosphines

Relatively few papers have appeared which are predominantly concerned with the synthesis of new halogenophosphines. The dichlorophosphine (1)has been obtained from the reaction of the Grignard reagent derived from 4-chlorohepta1,6-diene with phosphorus trichloride. Subsequent reduction with lithium aluminium hydride gives the primary phosphine (2), which undergoes a radicalpromoted double intramolecular addition of P-H to double bonds to give 1-phosphabicyclo [3,2,lloctane (3).' The reactions of 1-1ithio- and 1,2-dilithio1,2-dicarba-closo-dodecaboranewith t-butyldichlorophosphine have given the mono-and di-halophosphinodicarba-closo-dodecaboranes(4), the latter being isolated as a mixture of diastereoisomers, separable by chromatography? In the in reaction of phosphorus trichloride with 2,4,6-tri-t-butyl-N-methylaniline dimethoxyethane, one of the o-t-butyl groups is eliminated to give the sterically crowded aminodichlorophosphine (5), subsequently used to prepare the new unsymmetrical diphosphene, (6).3Direct introduction of halophosphine moieties into substrates having reactive C-H bonds has been used to prepare a number of new systems, including further examples of pyridine dichlorophosphinoylides (7), subsequently transformed into the phosphaindolizines (8); and the Organophosphorus Chemistry, Volume 34 0 The Royal Society of Chemistry,2005

163

164

Organophosphorus Chemistry

v -

CH2=CHCH2

MesZ

dibromophosphinophospholes (9), the position of substitution being dependent on the bulk of the substituents in the aryl ring attached to the phosphole phosphorus. When R = Pr', substitution occurs at the 2-position, whereas when R = But, the 3-position is involved. A wide range of phosphorus-functionalised phospholes has been obtained from these intermediate^.^ The phosphorylation of N-arylpyrroles using phosphorus tribromide takes place regioselectively in the 2-position of the ring, although a 2- to 3- migration of the dibromophosphino group has also been observed, the ease of which depends on the nature of the substituents in the aryl ring, and the solvent polarity. Subsequent dibromophosphination of 2- and 3- mono(bromophosphino)-N-arylpyrrolesagain occurs regioselectively in the respective 4- or 5- positions of the ring, being governed by the electron-withdrawing nature of the dibromophosphino substituent.6 The related reaction of phosphorus tribromide with a compound containing two N-arylpyrrol-3-yl residues bound to a phosphorus atom gives rise to 1,4-diphosphinines, e.g., (10), a new heterocyclic system, via cyclisation of bromophosphino intermediate^.^ Among other new heterocyclic phosphorus systems isolated from the direct reactions of phosphorus tribromide with nitrogen-containing substrates are various ring-fused [1,4,2]-diazaphosphinineskg the hetero-fused 1,2,3-diazaphosphorine system (1l)," and various 1,2-dihydrobenz[c]-[ 1,2]azaphosphol-3-0nes.~'Also reported are the direct phosphination reactions of 5,lOdimethyl-5,lO-dihydrophenazineand related heterocyclic systems, giving the bromophosphine derivatives ( 12),12 and the halophosphination of 2,3-disubstituted thiophenes in the 5-~0sition.l~ A new approach to P-chiral phosphinoyl- and thiophosphinoyl- halides is provided by the reactions of racemic t-butylphenylchlorophosphine with enantiomerically pure bis-phosphoryl and bis-thiophosphoryl disulfides under kinetic resolution conditions in a 2:l mole ratio.14 Chlorophosphine-borane reagents have found use in the synthesis of P-stereogenic phosphine ligands bearing 2,6-disubstituted phenyl groups." In the presence of aluminium trichloride, organodichlorophosphines have been shown to insert into the O-CH3bond of anisoles to give a one-pot synthesis of unsymmetrical aryl methylphosphinates (13),products that are difficult to access by other reported routes.16A novel access to P-phosphorylated ketones is provided by the reaction of diorganomonochlorophosphines with imines.17 Oxidation of bis(trimethylsily1)aminodichlorophosphine with sulfuryl chloride in ether results in the formation of the phosphoranimine (14),a valuable precursor for polyphos-

3: Tervalent Phosphorus Acid Derivatives

165 Me

\

R

i

5

0

v

R

4

-6 ~

'P ~ CI~

-C02R R

'

(7) R'-R5 = H, Me or Et

(8) R = H, Me or Et

(9) R = Pr' or BU'

Ph Me

R2N,

,s

Me

N-N,

//

- -

I

Ar (10) Ar = ptolyl

(1 1) Ar = ptolyl

I

Me (12) X = NMe, 0, S or CH2CH2, Y = H or PBr2

phazene synthesis, in 80% yield.'* The reactions of chlorophosphines with the 2-pyridylselenide anion have given the related (2-pyridyl)selenophosphorus(III) esters, e.g., (15).19 The formation of the diaminochlorophosphines (16), by treatment of secondary allylamines with phosphorus trichloride, provides an easily removeable phosphorus tether which enables a rhodium-promoted transformation of the double bonds, leading eventually to a range of chiral functionalised 1,4-diamines?' A range of chiral phosphorus(II1) triflates (17) has been obtained by treatment of the related diaminochlorophosphines with trimethylsilyl triflate, and their ability as electron-acceptors explored through their interactions with 4-phen~lpyridine.~'The stoichiometric reaction of N,N-bis(dich1orophosphino)aniline with 2,2'-thiobis(4,6-di-t-butylphenol) in diethyl ether at room temperature affords the 10-membered cyclic bis(ch1orophosphine)(18, X = C1) in 89% yield. Treatment of the latter with antimony trifluoride results in conversion to the related difluorophosphorus(II1) system (18, X = F).22Fluorophosphorus(II1) compounds have been shown to react with the Ruppert reagent, (trifluoromethyl)trimethylsilane, to form the related trifluoromethylphosphorus ~ystems.2~ Fluorophosphorus(II1) compounds can also be activated by chlorotrimethylsilane, and this is the basis of a new approach for the stepwise replacement of amino and fluoro substituents at trivalent phosphorus, having applications in the synthesis of nucleosidyl ph0sphites.2~ The utility of diethyl chlorophosphite as a reagent for the deoxygenative transformation of a wide range of functional groups has been e~plored.~' The reduction of thiophosphorus acid chlorides with alkali metals in liquid ammonia-THF solutions results in the formation of >P-S- anions, which, with elemental sulfur, yield the P(V) anions >P(s)-s-.26 A theoretical study of nucleophilic substitution of halophosphines by halide anions indicates the involvement of an anionic tetra-coordinated intermediate species (X-PH2-Y)-, rather than a transition state structure. The authors predict that this intermediate should be detectable, and that the SN2reaction at trivalent phosphorus is exothermic when the reactant halide anion is more electronegative

166

Organophosphorus Chemistry

Me3SiN= PCI3 (13) R = Ph or Cy X = Me or H

(14)

9

\ /

F3c@

cF3

x X (17) X = H, hal, Me, But, CN or NO2

than the product halide anion, and v i c e - ~ e r s aA. ~detailed ~ solid-state and solution-state multinuclear NMR study of the unsymmetrical diarylchlorophosphine (19) has been reported.28The molecular structure of dimethylaminodichlorophosphine in the gas phase has been studied by electron diffraction and density functional theory meth0ds.2~The conformational stability of (methylthio)dichlorophosphine, dissolved in liquid krypton, has been studied by temperature-dependent infrared techniques and ab initio calculations.30Chlorine-35 NQR spectroscopy has been used to study the influence of steric effects on the molecular conformations in the solid state of a series of alkyl- and aryl- dichlorophosphines?' and also the conformational isomerism and chlorotropy mechanisms of chloromethyl- and trichloromethyl- dichloroph~sphines.~~

3

Tervalent Phosphorus Esters

3.1 Phosphinites. - As in recent years, most of the interest in this area has centred around the synthesis and evaluation of new ligand systems for use in homogeneous catalysis, in which phosphinite donor centres either replace or complement conventional phosphino or other donor centres in previously designed systems, many of which are chiral. In most cases, the phosphinite centre is introduced via the reaction of an alcohol or phenol with a chlorophosphorus(II1) precursor, in the presence of a base. A range of 'tunable' carbohydrate-derived diarylphosphinites, e.g., (20), has been developed, which show high selectivity in the catalytic hydrovinylation of styrene derivative^.^^ The chiral binaphthyl bis(phosphinites) (21) have been prepared and shown to be effective ligands in the ruthenium-catalysed asymmetric hydrogenations of fl-aryl-substituted f3(acy1amino)acrylatesand P-ket~esters.~~ Two groups have reported the synthesis of phosphinite-oxazoline ligands, e.g., (22), from L-serine methyl ester, which offer the possibilty of considerable variation in the nature of substituents and

3: Tervalent Phosphorus Acid Derivatives

167

9 ; YN

0

PPh2

PPh2

R1 (22) R1 = ferrocenyl, 3,5-BUt2C6H3,naphthyl, biphenyl-Cyl, H, Ph or But R2 = Pr', Bu' or PhCH2

(23) R = Ph, Mes or Cy

consequent catalytic effecti~eness.~~>~~ A related series of ligands has also been prepared from threonine methyl ester.37A route to a series of phosphinoalkylphosphinite ligands, (23), derived from (1s)-(+)-camphor sulfonic acid, has been developed, these being effective in the rhodium-catalysed asymmetric hydrogenation of a-dehydroaminoacid~.~~ Further examples of phosphinites derived from the reaction of chlorodiphenylphosphine with 1,2-diphenyl2-aminoethanols in the presence of triethylamine and a trace of 4dimethylaminopyridine as a catalyst, e.g., (24), have been prepared and found to be effective for highly enantioselective palladium-mediated allylic a l k y l a t i ~ n . ~ ~ pol yether-linked phosphinites have also been described which are effective in a one-phase rhodium-promoted hydroformylation of higher alkenes, coupled with a two-phase recovery of the catalysta The Arbuzov reactions of ethyl diphenylphosphinite with 1,3,5-tris(bromoalkyl)benzenesare the key to a synthesis of a range of trifunctional phosphine ligands (25), of interest for the self-assembly of cage-and chain-like platinacyclophane complexes!' Thermolysis of the bis(phosphinites) (26) at 190-260°Cfor 24 hours has given the bis(phosphine oxides) (27), in yields which varied from 9%, for R = Ph, to >90% for R = Pr' or

(24) R = Pr', Bu or CH2Ph

(25)n = 1-4 0

0 II

R2P-0,

CH2-CH2 ,O-PR2

(26) R = Ph, P i or Cy

R2P,

II

, PR2 CH2-CH2 (27)

3.2 Phosphonites. - A wide variety of chiral monodentate phosphonite ligands derived from binaphthol and biphenanthrol, e.g., (28), has been obtained from the reactions of a dichlorophosphine with the corresponding biphenol, and used

168

Organophosphorus Chemistry

to promote the enantioselective copper(1)-catalysed conjugate addition of diethylzinc to en one^.^^ The new hemilabile bis(oxazo1ine)phenylphosphonite (29) has also been prepared.44The reactions of dichlorophosphines with the aminotriphenol (30), in the presence of triethylamine, give phosphonites that, depending on the nature of the organic substituent at phosphorus, can undergo conversion to a six-coordinate phosphorus system. Thus, whereas the reaction of phenyldichlorophosphine gives the phosphonite (3 l), (solid state h3’P = 173 ppm), that of ethyldichlorophosphine results in the isolation of the six coordinate system (32), (solid state h31P = -96 ppm). Solution NMR studies reveal that phosphonite (31) also exists in equilibrium with a six coordinate form, the

(28) R = Me, Bu‘, Ph, o-anisyl or Cy

(29)

tricoordinate molecule predominating, whereas the six coordinate structure (32) is predominant with respect to its tricoordinate ‘tautomer’. Such interactions have also been investigated for a wider range of phosphonite structures of the above type.45Another, similar, system has also been d e ~ c r i b e dThe . ~ ~monophosphonite (33) is easily accessible from a radical-promoted reaction of bis(trimethylsi1oxy)phosphine with N-vinyl~arbazole!~A range of phosphonous acid- esters and -amides having a 1- or 3- indolyl substituent, e.g., (34), has also been prepared and used as stationary phases in gas chromatography!* A living

3: Tervalent Phosphorus Acid Derivatives

169

cationic ring-opening polymerisation of a six-membered cyclic phosphonite has been achieved using a new catalyst system consisting of a halobenzene and nickel(I1) br0mide.4~ Several new diphosphonite ligand systems have also been devised. The ferrocenyl diphosphonite (35) represents a new class of sterically congested ligand, being obtained from the reaction of 1,l’-dilithioferrocene with the crowded phosphorochloridite (36).50The related ferrocenyl system (37), originally reported in 1998, has now been shown to act as an excellent chiral ligand in the copper-catalysed enantioselective conjugate addition of diethylzinc to a$unsaturated carbonyl compounds, enantioselectivities of up to 99 % being A route to the chiral phosphonite-phosphite (38) has also been devobser~ed.’~

‘8a /

(Me3Si0)2P-

H

(34) R = Et, Pr or Ph

(33)

Fe

‘R

(37) R = H, Me or Ph

O

m

170

Organophosphorus Chemistry

eloped, and the various diastereoisomers evaluated as ligands in several metalcatalysed reaction^.'^ A range of enantiopure C1-symmetric phosphino-phosphonites having an o-phenylene backbone has been prepared by treatment of the o-phosphinoarylphosphonamidite(39) with chiral alcohols, e.g., ( +)-menthol, from which (40) is derived.53 Chiral phosphonites having a paracyclophane backbone, e.g., (41), have also been prepared and applied in the rhodiumcatalysed asymmetric hydrogenation of dehydroamino-acids and -estersSs4The bis(phosphonite) (42),having the rigid 1,8-naphthyl backbone, has been obtained by treatment of a related bis(phosph0namidite) with methanol. This molecule behaves as a normal bidentate ligand towards Mo(0) and Pd(II), but attempts to reduce it to the corresponding bis(primary phosphine) failed.” New bis(phosphonites) and bis(phosphites) based on the calixC41arene backbone have also been ~repared.’~

pLoto

($

/

/

P/O

‘ 0 a p ( N M PPh2 e 2 ) 2

(39)

3.3 Phosphites. - The synthesis of new phosphite esters continues to be a significant area of activity, much of it again directed towards the synthesis of phosphite ligands of interest in metal-catalysed reactions. The effectively achiral, conformationally flexible, biphenylylphosphorochloridites(43) have been converted into a series of diastereoisomeric phosphites (44) on treatment with a range of chiral alcohols, in the presence of triethylamine.” The chiral ferrocenylphosphite (45) has been obtained from the reaction of hydroxyferrocene with the phosphorochloridite derived from the chiral 1,3-dihydroxybutane.5’ The reaction of racemic 2,2‘-dihydroxy-l,l’-binaphthalene (BINOL) with the phosphorodichloridite derived from (-)-menthol results in the formation of the diastereoisomers of the cyclic phosphite (46).Their separation by fractional crystallisation, followed by aqueous hydrolysis, yields the respective enantiomers of the dihydroxybinaphthalene, thereby providing a practical resolution of this comp ~ u n d . ’The ~ phosphoramidite route to phosphite triesters has been used in

3: Tervalent Phosphorus Acid Derivatives

171

the synthesis of dendrimers possessing three different branching units (P = Se, P = 0,and P = S) within the same molecule,6' and in the synthesis of cyclic- and acyclic-phosphites derived from dipalmitoylglycerol (and subsequently a phosphatidylinositol-4-phosphate)!' Hemiacetals and hemithioacetals of a-halo+oxoaldehydes have been treated with phosphorochloridites in the presence of a base to give a-heterosubstituted phosphites, e.g., (47). Depending on the nature of the carbonyl fragment and the heteroatom, these undergo either an intramolecular Perkow reaction or decompose to give unsaturated thioethers and a chlorophosphate.62 A series of calixC41arene-based phosphites (and diaminophosphines) has also been de~cribed.6~ New chiral phosphite ligand systems bearing either an sp3-or sp2-hybridisednitrogen atom have been prepared by the 67 with phosphorochloridites reactions of aminoalcohols64~650r iminoalcohols66$ or phosphoramidites. Thus, e.g., phosphorylation of (2R)-2-pyrrolidin-l-yl-b~tan-1-01 has given a series of chiral aminoalkylphosphites, e.g., (48),64and that of (2R)-2-{ N-(benzy lideneamino)}-3-methylbut an- 1-01 has given esters of type (49).66967 Phosphino-phosphite ligands have also received further attention. A convenient synthesis of new, chiral phosphino-phosphites is afforded by the demethylation of o-anisylphosphines, using boron tribromide, to give the related o-hydroxyphenylphosphines(50), which undergo phosphorylation on treatment with phosphorochloridites to give, e.g., (51).68Also reported are (52) and (53),69 (54);' and a range of phosphino-phosphites derived from carbohydrates (55).71,72 The synthesis of chiral, chelating diphosphite ligands has also been an area of considerable activity. Among new systems of this type are (56),70(57),73(58),74and (59);' all of which have been applied as ligands in catalysis, as have other sterically congested bisph~sphites.~~ Diphosphites derived from carbohydrates, e.g.,(60, X = 0),have also attracted considerable attention, having been applied in asymmetric catalytic hydrogenati~n?~ hydrof~rmylation,'~~~~ hydrosilylation:' allylic substitution,8l and the conjugate addition of diethylzinc to cyclo-

172

Organophosphorus Chemistry

0 II R-C-CH-CH I

CI

OEt '

O-P(OR)2 (48)

(47)

(49) X = H or NMe2

(50) R' = R2 = Ph, Me or Pr' R' = Me, R2 = Ph

Me0

OMe (52)

c:= hexenone.82 Related carbohydrate-derived chiral phosphite-phosphoramidite ligands, e.g., (60, X = NH), have also been prepared and their effectiveness explored in asymmetric catalytic h~drogenation,8~ hydr0formylation,8~and the conjugate addition of diethylzinc to cycl0hexenone.8~A range of phosphite ligands bearing fluoroalkyl substituents, facilitating their application in fluorous biphase systems, has also been described. The perfluoroalkyl-substituted triarylphosphites (61) have been prepared, and their ligand donor properties studied. Spectroscopic and structural data have shown that, even with the presence of the phosphite ester oxygen atom, the electronic effects of the fluoroalkyl substituent are still experienced at phosphorus.86Applications of these ligands in catalytic hydroformylation procedures conducted in fluorous solvents have also been r e p ~ r t e dIn . ~related ~ ~ ~ work, ~ a series of triarylphosphites (62) has been prepared in which an 'insulating' ethylene segment separates the perfluoroalkyl group from the aryl group. The effectiveness of such ligands in the catalysis of olefin

173

3: Tervalent Phosphorus Acid Derivatives Ph I

Do\ r> - -Ph

(56)

Ph

% \ /

MeM *e

R (58)

R

(59) R = OMe or But

hydroformylation has also been ~ t u d i e d . *Among ~ * ~ ~ other fluoroalkyl-functionalised phosphite systems prepared are the phosphino-phosphite (63) and the diphosphite (64);' and various bis(fluoroalkyl)phosphites92and 2-polyfluoroalkoxy- 1,3,2- dioxapho~phorinanes?~

R2 = H,But or SiMe, R3 = H or OMe

R4 = H or SiMe,

(60) R' = H or Me

P [ O b R ] , (61) Rf = 2-,3- or 4-C6Fj3

(62) R' = CH2CH2C8F17, R2 = H R' = H, R2 = C H ~ C H ~ C ~ F ~ T R',R2 = CH2CH2CBF1,

Studies of the reactivity of phosphite esters towards substrates other than metal ions also continue to be of wide interest. Aspects of the reactivity of phosphites, e.g., trimethyl phosphite, towards a-diketones and o-quinones have been re~iewed.9~ The Michaelis-Arbuzov reaction has found further applications in synthesis. An efficient synthesis of a phosphonoacetate-trilactoside conjugate relies upon the Michaelis-Arbuzov reaction of bromoacetamide with

",p

174

Organophosphorus Chemistry

R1O

.R2 R'0

-

\ / -Rz

R2

(64)R1,R2= H or Rf (CH2)n

(63)R' ,R2 = H or R, (CH2),,

tris(trimethylsilyl)phosphite?5 Conventional Michaelis-Arbuzov procedures have also been used in the synthesis of methyl 4-(dimethoxyphosphoryl)-3oxobutanoateP6 the P-ferrocenylethylphosphonate ester (65):' and the bis(phosphonate) (66), (subsequently used in Wadsworth-Emmons procedures for the synthesis of distyrylbenzenes)?* Microwave-assisted Michaelis-Arbuzov reactions, under solvent free conditions in the presence of aluminium oxide, have been shown to result in high yields of dialkyl alkylpho~phonates.9~ Various acylated o-haloanilides have been shown to undergo the Tavs reaction with trialkylphosphites in the presence of a nickel(I1) halide to form the phosphonates (67), halogens ortho to the acylamino group being preferentially replaced, indicating the operation of a coordination template effect involving the metal ion. The phosphonates (67) are intermediates for the synthesis of 1H-1,3-benzazaphospholes.lWThe prolonged photo- Arbuzov reaction of 1,3,5-trichlorobenzenewith trimethylphosphite (as reactant and solvent) results in the formation of a mixture of the three possible arylphosphonate esters (68), separable by fractional distillation, from which a range of aryl primary phosphines has been obtained by reduction.101Seven- (and eight)-membered ring cyclic phosphites, e.g., (69), undergo a photo-Arbuzov ring contraction rearrangement on uv-irradiation in solution in the absence of air, with formation of cyclic phosphonates, e.g., (70).Io2 The benzodioxaphosphorin ester (7 1)also undergoes a related ring contraction 0

R2v EtO, ,OEt

I

dj

R3

&

(67) R1 = Me, Bu', Ph or 2-pyridyl R2 = H, F or Me, R3 = H or F

(65)

@?

dP-OMe

X

(68)X = CI or P(O)(OMe)2

NHCOR'

(69)

3: Tervalent Phosphorus Acid Derivatives

175

to form the benzooxaphosphole oxide (72).'03 Phosphito-phosphonate rearrangements have also been observed in the chemistry of a-(N-sulfony1amino)alkyl phosphites.'04 A number of other reactions involving nucleophilic attack of a trialkylphosphite at carbon, followed by a Michaelis-Arbuzov finish to give an alkylphosphonate ester, have also been described. Thus, a vastly improved route to 2-phosphonothiolanes (73)is afforded by nucleophilic attack by the phosphite on the Pummerer sulfonium ion derived from treatment of thiolane S-oxide with triflic anhydride.lo5In addition, Katritzky's group has published a series of papers describing nucleophilic displacement of a benzotriazolyl group from a heterocycloalkylmethyl unit by a variety of nucleophiles, including triethylphosphite, the latter leading to the related heterocycloalkylmethylphosphonates derived from hexahydropyrimidines and tetrahydroquinazolines,lo6 imidaz~lidines,'~~ 2-ben~azepines,''~ 2,3,4,5-tetrahydro-l,Q-benzothiazepines and related oxazepines, diazepines,lWand tetrahydroisoquinolines."' Triethylphosphite continues to find application in the synthesis of tetrathiafulvalenes and related compounds via C = C coupling reactions of 1,3-dithiolane-2-0nes and -thiones.11'*''2Attempts to prepare halogenated versions of tetrathiafulvalenes by these reactions found that whereas brominated products were accessible, some loss of iodine occurred in the reactions of iodo-substituted substrates with triethy1pho~phite.l'~ The application of the phosphite coupling reaction to the synthesis of selenium-and tellurium variants of tetrathiafulvalene systems has been reviewed.' l4 Whereas thiazoline-2-thiones are inert to trivalent phosphorus esters, the related 2-selenones undergo the expected C = C coupling reaction. An attempted triethylphosphite-induced cross-coupling reaction between a thiazoline selenone and a dithiol-2-thione gave unexpected products, arising from 1,3-dipolar cycloaddition reaction^."^ The reactions of acenaphthene quinones with trimethylphosphite (and a cyclic phosphinamidite) have been reviewed.' l 6 Several products arising from nucleophilic attack at carbon have been identified in the reaction of triethylphosphite with l-phenyl-3,4-dichloro-2-aza-1,3-pentadiene."' In the presence of hydrogen chloride, the iminoalkylphosphite (74) undergoes a stereospecific intramolecular cyclisation to form the oxazaphosphorinane system (75)."8,"9 Nucleophilic attack at carbon is also involved in the reaction of triethylphosphite with a-nitrohydrazones, yielding the phosphonates (76),120in the reaction of acyl chlorides with tris(trimethylsilyl)phosphite, giving the bis(phosphonic acids) (77),121in the reactions of phosphites with 2-polyfluoroacylcycloalkanones,'22and in the microwave-induced Abramov reaction of 3-formylchromones with trialkylph~sphites.'~~ The first example of a stereoselective aza-Perkow reaction is provided by the reaction of the imidoyl chloride (78) with two moles of triethylphosphite, which gives the phosphonylated alkenylphosphoramidate (79) in only one isomeric form.124When N-phthalylamino acid chlorides were treated with commercially available triethylphosphite, up to seven products were observed. However, using the purified phosphite, the reaction led only to the isolation of acylphosphonates of type (80).Many of the side products in the reactions of the commercial phosphite have been shown to arise from the presence of diethylphosphite, and also subsequent rearrangement reactions of (80).'25The reactions of trialkylphos-

Organophosphorus Chemistry

176

0 It

0 0

N

NHAr

U

Et

(W2P,

;(OH),

R-C-OH ;(OH), 0

H

+\

C12CH CI

CH2Ph

CI

P(OEt)2

d'

phites with monoacylals of dichloro- and trichloro-acetic acids have also been investigated.'26 Iminophosphoranes have been isolated from the reactions of trialkylphosphites and azido-p-q~inones.'~~ Further applications of glycosylphosphites in the formation of glycosidic linkages have been d e s ~ r i b e d . ' ~ * ~ ' ~ ~ Trialkylphosphites have been used as reagents in the synthesis of a variety of phosphorylated heterocyclic compounds, including o x a z ~ l e s , ~1,3,4~~ thiadia~oles,'~~ and p y r a z ~ l o n e s . Trimethylphosphite '~~ has also been used to New high molecular weight arylphosdeoxygenate isoxaz~line-N-oxides.'~~ phites, e.g., (81)'34and (82),135 continue to be developed as antioxidant additives 0

Ard

O R (80)

for use in polymers'36and An efficient route to substituted benzylic bromides is afforded by polybromination with an excess of N-bromosuccinimide, followed by selective debromination of the polybrominated mixture with diethy lpho sphite and N,N-diiso p ro p ylethylamine, to give the desired monobromo compounds in high Dialkylphosphites (and hypophosphorous acid) also act as efficient radical reducing agents for thiocarbonyl or halide groups in the sugar part of nucleosides, giving the respective hydrocarbons in high yield.'39Combination of diethylphosphite with carbon tetrachloride results in dehalogenation with formation of the trichloromethyl radical, capable of

3: Tervalent Phosphorus Acid Derivatives

177

adding to alkenes, the phosphite also functioning as a hydrogen atom donor and promoting an intermolecular chain reaction." An infrared study of the adsorption of trimethylphosphite on a zeolite indicates that the phosphite reacts readily with surface silanol groups, with the formation of free dimethy1pho~phite.l~' Electrolytic oxidation reactions of alkylphosphite esters have been investigated using cyclic ~oltammetry.'~~ The products of the gas-phase reaction of trimethylphosphite with the OH radical, and with NO2 and 03, have been investigated by FTIR spectrometry and atmospheric pressure ionization mass spectrometry. The kinetics of the reaction with the OH radical have also been studied.'43Mass spectrometry techniques have also been used to study other gas-phase reactions of phosphite e ~ t e r s . ' Phosphites ~ ~ ' ~ ~ and their derivatives have also attracted a range of structural studies. Crystal structures of a bicyclic phosphite-ozonide complex'46and an azidoalkyl p h ~ s p h i t e have ' ~ ~ been described. Structural studies of triphenylphosphite in the and solid ~ t a t e ' ~have ~ , ' been ~ ~ made using various spectroscopic and diffraction techniques. Structural and spectroscopic studies of the conformational behaviour of cyclic phosphites have also been r e p ~ r t e d . ' ~ ' , ' ~ ~

4

Tervalent Phosphorus Amides

4.1 Aminophosphines. - The reactions of phosphorus trichloride with a series of bulky primary amines have given the aminophosphines (83), which have been shown to exist in equilibrium with the tautomeric form (84).'53 The direct reactions of organodichlorophosphines with secondary amines have given the amino(ch1oro)phosphines (85), from which a range of cyclopentadienyl(amin0)phosphineshas been prepared.154Woollin's group has published full details of the synthesis of alkyl-and dialkyl-N-pyrrolidinylphosphines(86). These have been shown to be unusually electron rich donor ligands compared to tris(N-pyrrolidiny1)phosphine(or trialkyl- or triaryl-phosphines), the greatest effect being for the bis(N-pyrrolidinyl) systems.'55 Related aminophosphine ligands, e.g., (87)156and (88),157have also been prepared from piperazines. A series of chiral oxazoline-functionalised N-pyrrolidinylphosphines, e.g., (89), has been prepared from pr01ine.l~~ A related series of chiral 2-(N-phosphinopyrrol-2-y1)oxazolines (90)has been obtained from 2-cyanopyrrole by condensation with a

PfNHR13 (83)R = Pr', But or Ph(Me)CH

H (RHN~+=NR (84)

R:

P -NR2R3 CI' (85) R' = But, Me or Ph, R2 = Et or But, R3 = H or Et, R2,R3 = (CH2CH2)20

178

Organophosphorus Chemistry

chiral aminoalcohol and a subsequent reaction with a dialkyl-or diarylchloropho~phine.'~~ A wide range of macceptor aminophosphines bearing N-pyrrolyl, -indolyl, and -carbazolyl substituents has also been described, including mixed systems derived from the chlorophosphine (91), which is accessible in 96% yield from the reaction of pyrrole and phosphorus trichloride.16' Other new mono(aminophosphines) have been described which bear unusual substituents, e.g., the N-phosphinodi(pyridy1)amine (92),161 the

PPh2

R (89) R = Pr' or Ph

(90) R = alkyl or aryl

(911

C=CR' NH I

( Me3Si)2N-P,

R2

Ph2P' (93)

(94) R1 = SiMe3 or CH2COMe R2 = Ph, Pr', CH2SiMe3or CGCR'

N-phosphinohydrazinopyridine (93),162 the P-acetylenic (sily1amino)phosphines (94),'63and a range of aminophosphines bearing 2-imino-1,3-thiazolidines, e.g., (95). Of particular interest in the latter case is the use of "N-NMR spectroscopy for the determination of 1J(31P,'5N) data, of which there are few examples for systems having two coordinate sp2-hybridisednitrogen linked to p h o s p h ~ r u s . ' ~ ~ Various acyclic bis(aminoph0sphines) have also been reported, including the imino-functional system (96),'65the bis(phosphin0)-hydrazines (97)166 and -ureas (98),167and the 1,8-bis[bis(dialkylamino)phosphino]naphthalenes (99).168There has also been significant activity in the synthesis of cyclic aminophosphines. An improved route to the four-membered ring system (100) is afforded by the reaction of phosphorus trichloride with t-butylamine in a 1:3 mole ratio in THF. Treatment of this with ammonia in THF/triethylamine at -78°C gives (101),

Me Ph

7 ];'"".'%" ; b N Me

(95) n = 1-3

(98) R = Me or Et

A+

(Pi2NI2P

R\ N-N,

P(NPT'~)~

(96)

(99) R = Me or Et

Ar2P

? PAr2

(97) R = Me or Et, Ar = Ph, etolyl or eanisyl

(100)

3: Tervalent Phosphorus Acid Derivatives

179

which, when combined with (100) in a 1:l mole ratio in the presence of triethylamine, gives a tetrameric macrocyclic system consisting of four fourmembered rings linked by endo NH groups, as shown by a low-temperature X-ray structural Treatment of the diastereoisomeric 1,3,2-oxazaphospholidine system (102) with t-butyllithium results in a novel intramolecular rearrangement, giving the chiral, non-racemic dihydrobenzazaphosphole system (103), which is capable of further elaboration uia phosphinylation of the alcohol group to afford a series of 'tuned' chiral ligands.ImSeveral groups have reported the synthesis of new diazaphospholidines, including the new chiral quinoline derivative (104),17' the closely related mono- and bis-(diazaphospholidine) ligands (105) and (106),17' various N-tosylated diazaphospholidines, e.g., ( 107),173 and a series of P-chirogenic o-trimethylsiloxyaryl diazaphospholidines (108).

Br I

R3 Me3Si, Ts I N:P-(cH.)"-P:) N

Ts I

I Ts

N I Ts

[

(107) n = 2 o r 4

0

M e N q

(108) R' = H, Me or But, R2 = H, Me, Ph or CI, R3 = e.g. Ph

Complexation of the latter at phosphorus with borane, followed by methanolysis of the siloxyether function, gives the related o-hydroxyaryl diazaphosph~lidines.'~~ The cage-like triaminophosphine (109) has been obtained from the reaction of tri(2-pyrroly1)methanewith phosphorus trichloride, in the presence of triethylamine. This compound is stable to methanolysis, hydrolysis, and aerial oxidation at room temperat~re.'~~ Phosphorylation of various 1,2,4-triazoles with halophosphines has given a route to the heterocyclic system (1 and routes to various [2,4,1]benzodiazaphosphinines, e.g., (11l), have also been de~eloped.'~~~'~~ Apart from studies of their properties as ligands in metal-catalysed processes in homogeneous solution, there have been other studies of the reactivity of aminophosphines in the past year. The first example of the insertion of a methylene group into a phosphorus(II1)-nitrogen bond has been recorded. Treatment of the aminophosphine (112) with paraformaldehyde leads to the insertion of a methylene group into the P-N bond with subsequent oxygenation

180

Organophosphorus Chemistry

at phosphorus to give the phosphine oxide (113). The mechanism is assumed to follow a Staudinger-Wittig route to form an imine and diphenylphosphine oxide, the latter then adding to the imine to give (113).'79The reactions of tris(dialky1amino)phosphineswith a 1,3-diphenylpropanetrionederivative in refluxing toluene resulted in the new oxazaphospholenes (114). However, when the reaction was conducted in the absence of a solvent, the aminophosphoranes (115) were isolated instead.18' The reactions of the N,N'-bis(phosphin0)diaminoethanes (116)with sulfur and selenium have given the corresponding disulfides and diselenides in good yield."' Bis(cha1cogen) derivatives have also been

O A *r' (110) X = B r o r P h

(111)

obtained from the unsymmetrical diphosphine (117).'82The ionic system (118) has been isolated from the reaction of tris(dimethy1amino)phosphinewith the diiodine adduct of diphenyldi~elenide.'~~ The P-coordinated trans- phosphinoiminophosphine (119) has been shown to undergo an unprecedented rearrangement to form the N-coordinated cis- system ( Rearrangement reactions of diphosphazanes similar to (101), in the coordination sphere of zirconium, have also been inve~tigated.'~~ Further studies of the reactions of biscbis(dialkylamino)phosphino]methanes with hexafluoroacetone and related systems, giving carbodiphosphoranes, e.g., (12l), have appeared.ls6 In related work, the reaction of bis[bis(diethylamino)phosphino]methane with methyl 2[bis(trifluoromethyl)]vinyl ketone results in the unexpected formation of the unusual zwitterionic system (122), containing two phosphorus atoms of opposite 0 II

PhNH-pPh2

Ph-NH-CH2-PPh2

(112) CHC02Me

Ph-C

//

MPh

PhN,

(113)

fC

,O

z\

R2N 0 (114) R = Me or Et

R\ PhC ph)fP(NR2)3 Ph

; (115)

n?

N , Ph2P

N\ PPh2 (116) R = Me, Ph or PhCH2

charge and different coordination number, and also having a direct P-H bond at the hexacoordinated pho~phorus.'~'A range of stable amino(phosphin0)carbenes has been obtained by deprotonation of the phosphinoiminium salts (123), giving (124).NMR studies indicate that only the amino substituent interacts with the carbene centre, the phosphino group remaining as a spectator. The reactivity of such systems having dialkylamino groups present at phosphorus has been

3: Tervalent Phosphorus Acid Derivatives

181

compared with that of those having conventional alkyl or aryl substituents.lsX The bicyclic triaminophosphines (125) have continued to find application as catalysts in a wide range of reactions, the past year having seen their use in promoting 1,2-addition reactions of activated allylic s y n t h ~ n s ,1,4-additions '~~ to a#-unsaturated substrate^,'^^ the direct synthesis of (E)- a$-unsaturated esters,"'and the trimethylsilylcyanation of aldehydes and ketones.l9*These compounds have also found use as dehydrobromination reagents in the synthesis of Vitamin A derivative^.'^^

Ph2Pibl

PPh2

(123) R2N = Cy2Nor Pi2N

((Me2N)3P-SePh]+ I-

(125) R = H, Me, P i or BU'

4.2 Phosphoramidites and Related Compounds. - The synthesis of a wide range of new chiral cyclic phosphoramidites has been described in the past year, the underlying theme again being their effectiveness as ligands in metal ion-catalysed reactions. The monodentate phosphoramidites (126) have been prepared in high yields in an ex-chiral-pool synthesis starting from D-mannitol, and their palladium(I1)- and rhodium(1)-complexes studied.194Both enantiomers of the new chiral phosphoramidite (127), involving the 1,l'-spirobiindane backbone, have been characterised as air stable solids, and used in rhodium-catalysed hydrogenation reaction^.'^^ A series of chiral phosphoramidites (128) bearing the 8-oxyquinolyl substituent has been prepared.196The phosphoramidite (129) derived from a partially hydrogenated BINOL has also been prepared, and shown to promote extremely high enantioselectivities in the rhodium-catalysed asymmetric hydrogenation of a-dehydroamino However, phosphoramidites derived from BINOL continue to dominate this group of ligands. Among new systems prepared are (130),19' the bispidine-linked system (13l), from which a combinatorial library of chiral ligands has been assembled,199and the bidentate bis(phosph0ramidites) (132). The latter paper also includes related systems

182

Organophosphorus Chemistry

me\^

R-CH2 Mexo<:

P-NMe2

0

Me

M

Me

DI

\

/ I -

-0

R-CH2 (126) R = Me, Et, Bu’or Ph

(127)

R

0 R3

R R (132) n = O o r l R = Me, Pr‘ or CH(Me)Ph

(131) R’ = Me or methylpolystyrene R2 = acyl, alkyl or arylsulfonyl R3 = H, Me, Br or Ph

1

-P-N

(133)

(134) X = CH2 or CO

3: Tervalent Phosphorus Acid Derivatives

183

0

\

R (136) R = al kyl

(135)

derived from the chiral diol TADDOL.200Two groups have described the synthesis of the chiral phosphoramidites (133), together with other closely related systems.201~202 The hybrid phosphoramidite-phosphite (134), based on (S)-prolinol and (S)-oxoprolinol, have also been reported.203The unsymmetrical bisphosphoramidite (135) has been obtained from the reaction of a precursor bis(phosphorus(II1) chloride) with (N-trimethylsilyl)morpholine.2°4The cyclohexadienylfused heterocyclic system (136) is formed in the reaction of diimines of 1,2Considerable interest has cyclohexanedione with ethyl phosphorodichloridite~05 been shown in the synthesis and reactivity of tervalent phosphorus(II1) derivatives of calix[4]resorcinarenes. Treatment of calix[4]resorcinarenes with the cyclic phosphonamidite (137) has given a range of phosphorylated products, including the tetraester (138, X = Et).206Amore direct route is offered by the

(138) R = alkyl

(137)

0

0

(139) R = Me or Et

(140) R = Me or Et

direct chlorophosphorylation of calix[4]resorcinarenes with phosphorus trichloride, giving the related cyclic phosphorochloridites (138, X = Cl),2°77208 from which a range of phosphoramidites (138, X = NR2)209(and other derivatives)210 have been prepared by conventional chemistry. The reactions of triaminophosphines with diphenols have given a series of macrocyclic cavitand phos-

184

Organophosphorus Chemistry

phoramidites, e.g., ( 139)211 and ( 140).2’29213 Phosphoramidite cavitands have also been of interest as ligands in the design of bimetallic complexes.214Thermal decomposition of 2H-azaphosphirene metal complexes in the presence of 1piperidinecarbonitrile and heterocumulene derivatives has enabled the isolation The N-sulfonylated cyclic of metal complexes of the heterocyclic systems ( 141).215 phosphonamidite (142) has also been prepared and used as a chiral ligand in homogeneous ~ata1ysis.l~~ The chiral BINOL-derived phosphoramidite (143)has been used together with diethyl azodicarboxylate in a Mitsunobu procedure for the enantioselective reaction of secondary alcohols with phthalimide.216Nucleophilic- and acid-catalysis of the alcoholysis of phosphoramidites has been inve~tigated.~~’ New modes of 1,3-dipolar cycloaddition reactions have been uncovered in a study of the reactions of the cyclic phosphorus(II1)-azides and -isocyanates (144) with dimethyl acetylenedicarboxylate?l8

CH(SiMe&

h

I

Xxp\N

HN

Ph- -N

-NMe2

7

0’ N

_I _

SO2tol-p

(141) X = O o r S

(142)

‘ ’ (143)

(144) X = N3or NCO

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3: Tervalent Phosphorus Acid Derivatives

185

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Organophosphorus Chemistry

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3: Tervalent Phosphorus Acid Derivatives

187

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Quinquevalent Phosphorus Acids ´ SKAa AND R. BODALSKIb BY A. SKOWRON a Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, 90-363-Lodz, Sienkiewicza 112, Poland b Technical University, 90-924-Lodz, Zeromskiego 116, Poland

1

Introduction

The current review is of necessity selective. Over the two year period covered, there has been impressive advances in several areas of P(V) chemistry. For example, biological aspects of quinquevalent phosphorus acids chemistry continue to increase in importance. A wide variety of natural and unnatural phosphates including inositols, lipids, some carbohydrates and their phosphonates, phosphinates and ﬂuorinated analogues has been synthesized. Special attention has been paid to the synthesis of phosphorus analogues of all types of amino acids and some peptides. Numerous investigations of phosphate ester hydrolysis and related reactions continue to be reported. Interest in approaches to easier detoxiﬁcation of insecticides continues. A number of new and improved stereoselective synthetic procedures have been elaborated. The importance of enantioselective and dynamic kinetic asymmetric transformations is illustrated in many publications.

2

Phosphoric Acids and Their Derivatives

Asymmetric synthesis with chiral cyclic phosphorus auxiliaries has been the subject of a review.1 2.1 Synthesis of Phosphoric Acids and Their Derivatives. – A selective and mild synthetic route to long or functionalized chained dialkyl phosphates (1)–(5) has been reported (Figure 1).2 Trimethylsilyl phosphorohalidates (6) and (7) have been synthesized from phosphoryl dihalogenoﬂuoride (8) and hexamethyldisiloxane (9). An alternative approach to (7) using bis(trimethylsilyl) phosphoroﬂuoridate (10) has been also elaborated (Scheme 1).3 Compounds (6) and (10) are involved in a new synthesis of bis(trimethylsilyl) diphosphorodiﬂuoridate (11).3 Organophosphorus Chemistry, Volume 35 r The Royal Society of Chemistry, 2006 169

170

Organophosphorus Chem., 2006, 35, 169–264 RO

O P

RO (1) R =

OH

N

(CH2)8 N

O

(2) R = oleyl (3) R = ethyl (4) R = CH3(CH2)3

N

(CH2)4 N

(5) R = CH3(CH2)3

O

N

(CH2)5 N

O

Figure 1

Me3SiO POFX2

+

(Me3Si)2O (9)

(8) Me3SiO

X

O P

Me3SiX

(6) X = Cl (7) X = Br

F

Me3SiO PCl5

O Me3SiCl

P

F

Me3SiO

O P

Cl

(10)

POCl3

F (6)

O Me3SiO

P

O O

F

P

OSiMe3

F (11) Scheme 1

The ﬁrst example of the asymmetric synthesis of P-chiral trialkyl phosphates (12) via trialkyl phosphite, in which the keystone is dynamic kinetic resolution in the condensation of a dialkyl phosphorochloridite (13) and an alcohol by the catalytic assistance of a chiral amine has been reported (Figure 2).4 2,4-Dinitrophenol (DNP) was employed as an activating reagent with benzyloxy-bis-(diisopropylamino) phosphite to synthesize the cyclic phosphate derivatives (14) from a series of alkane diols HO–(CH2)n–OH (n¼2–6). Included was a cyclic phosphate derivative of carbohydrate (15). The mechanism of activation by 2,4-DNP and cyclization was also described (Figure 3).5 A convenient approach to a variety of cyclic enol phosphates (16) and (17) via ring-closing methathesis (RCM) using the second generation Grubbs catalyst (18) has been elaborated (Figure 4).6

171

Organophosphorus Chem., 2006, 35, 169–264 R1O P

Cl

1) chiral amine (cat.) R3OH, Pr i2NEt t

2) Bu OOH

R2O

O P R1O R2O

OR3

(12)

(13) racemic

optically active

Figure 2

O OH HO

n

BnO

1) BnOPN(Pr i2)2 BnO O 2) 2,4-DNP t P 3) Bu OOH O O

P

BnO BnO

R R (14)

O

O

BnO

O

OBn (15)

Figure 3

Reactions of alkyl halides with diethyl phosphite in the presence of ammonium acetate/sulfur and acidic aluminia using microwave irradiation provide a simple and general route to thiophosphates.7 Two diastereoisomers of 1,3,2dithiadiphosphetane 2-sulﬁde (19) have been isolated for the ﬁrst time via the reaction of thioketones (20) with Lawesson’s reagent (Figure 5).8 The ring-closure reactions of isoquinoline derivatives (21) with phenylphosphonyl chloride afforded a new ring system (see 1,3,2-diazaphosphorinano [6,1a] isoquinolines (22) and (23) in Scheme 2). Their conformational analysis was performed by 1H, 13C, 31P-NMR.9 A simple method for the synthesis of polyfunctional phosphorodithioates (and structural analogues) (24) based on the nucleophilic ring opening reactions of N,N-dialkyl-3-hydroxy(benzyloxy) azetidinium salts (25) and N,N-dibenzyl2,3-epoxy-propylamine with anions of mono- and dithioacids of phosphorus (26) has been reported (Scheme 3).10 A new reaction of vicinal sulfonyliminocarboxylates (27) with phosphite occurs with N-C transfer of the RSO3 group and leads to sulfonyl-substituted triﬂuorophosphazene derivatives (28) (Scheme 4). The novel rearrangement is interpreted as cheletropic 1,4-cycloaddition and subsequent 1,2-shift of the sulfonyl group in the intermediate phosphorane.11 A significant advance in the synthesis of phosphorylated prodrugs has been described. The preparation of various bis-pivaloyloxymethyl (POM) phosphate triesters (29) was accomplished with the use of bis(POM) phosphoryl chloride (30) under mild conditions (Scheme 5).12 Phosphorylated 1,6-diphenyl-1,3,5-hexatriene (DPH) (31), a lipophilic dye consisting a ﬂuorophore attached to a phosphate diester was prepared and its

172

Organophosphorus Chem., 2006, 35, 169–264 O OEt

P O

OEt

N Mes

Mes N O

and

Cl

O P

X O

X = O, S, SO2, NTos

(17)

enol phosphates

Ru

Cl

(18)

PCy3 Ph

OPh OPh

ketene acetal phosphate

(16) O OEt P O

OEt

O

O

OPh P

and

O

OPh

X

Figure 4

S Ans

S

P

P

Ans

S

Ph S R (20)

S Ans = p-MeOC6H4

Ph

R = 1-Ad, But

R

S P

Ph

Ans

S

S P

P R

S

S P

S

Ans

(19)

Figure 5

ﬂuorescence behavior in different solvent systems and in a liposomal membrane bilayer was examined (Figure 6a).13 The eight-step synthesis of the ﬂuorescent porphyrin conjugate (32) featuring a carboranyl phosphate ester attached to the porphyrin via an amide linkage has been disclosed (Figure 6b).14 Catalytic asymmetric total synthesis of a promising anticancer agent Fostriecin (33) has been performed using method that combined several catalytic asymmetric reactions as shown in Scheme 6.15 A convenient synthesis of (E)-4-hydroxy-3-methyl-2-butenyl pyrophosphate (34), an intermediate in the deoxyxylulose pathway of isoprenoid biosynthesis, was accomplished by pyrophosphorylation of (E)-4-chloro-2-methyl-2-butene1-ol (35) (Scheme 7). This route enables convenient access to isotopically

173

Organophosphorus Chem., 2006, 35, 169–264 MeO Ph

N MeO

P H

NH H

R

PhPOCl2

2 HX

O

NHR1

3

R2

Et3N / CH2Cl2

(22)

NHR1

R3 R2

MeO

(21) R1 = H, Me, Ph R2 = H, Me R3 = H, Me

O

N MeO

P H

Ph

NHR1

R3 R2 (23)

Scheme 2

Y

Y O

OR1

N X (25)

R2R3P

X M

O

N

Z

R1= H, Bn; X= Cl, Br

P

OR1

(26)

R2 R3

(24)

R2= OCH2CMe3, OEt, But R3= OCH2CMe3, OEt, Ph Y= S, O; Z= S M= NHEt3, Na Scheme 3

O

O

AlkO NSO2R1

(R2O)2POR3

rt

SO2R1

AlkO F3C

F3C (27)

N

P(OR2)2OR3

(28) Scheme 4

labelled product [4-13C] (34) from commercially available [1-13C]-2-propionic acid.16 Farnesyl diphosphate analogues (36)–(40) modiﬁed in the central isoprene unit have been prepared via the authors stereoselective vinyl triflate-mediated route to isoprenoids. The 7-allyl compound (38) is a modest inhibitor of

174

Organophosphorus Chem., 2006, 35, 169–264 O NH

ClP(O)(OPOM)2 (30)

ROH Et3N, Et2O

ROH BunOH BuiOH BnOH

ROP(O)(OPOM)2 (29)

HO

O

N

O

N3

AcO AcO

OAc OAc O OH

Scheme 5

O (BnO)2P

O

(31)

Figure 6a Ph

O

N

H N

C

Ph

O H

CH3 O

+

P O OR

R

HN N

NH H

+

R

Ph

(32) R= [iPr2EtNH] , Na

Figure 6b

mammalian protein-farnesyl transferase, but surprisingly the other analogues are effective alternative substrates for this enzyme (Figure 7).17 The ﬁrst catalytic methodology to convert glycals (41) into glycosyl phosphates (42) employing safe, commercially available reagents has been presented (Scheme 8).18 A novel and practical synthesis of S-(1- and 2-halogenoalkyl) sugars (43), including some at the anomeric center, has been developed. The synthesis consists of reactions of readily available S-(O,O-dialkyl)phosphorodithioates

175

Organophosphorus Chem., 2006, 35, 169–264 direct catalytic asymmetric aldol reaction Noyori reduction HO

O P

OH

HO O

O

OH

O Me

OH catalytic asymmetric cyanosilylation of ketone

catalytic asymmetric allylation

(33) Scheme 6

O (i)

OH Cl

80%

-O O

(35)

O-

O

P

P -

O

OH O (34)

Reagents: (i) (Bu4N+)3 pyrophosphate (1.35 equiv.), MeCN Scheme 7

R

O

O

P O

O-

P O

O-

O-

(36) (R= Et); (37) (R= vinyl); (38) (R= allyl); (39) (R= Pri); (40) (R= Bui)

Figure 7

R2

OR1 O

R3 R1O

R2 (i) (ii)

R3 R1O

OR1 O

R3 R1O

O OAc OP(OBu)2

(41)

1 R2 OR OAc O

O OP(OBu)2

(42) selectivities: from 1.8 : 1 to 50 : 1

Reagents: (i) methylrhenium trioxide (MTO), urea hydrogen peroxide (UHP), HOP(O)(OBu)2, (DBT), (BMM)BF4; (ii) Py, AcO Scheme 8

176

Organophosphorus Chem., 2006, 35, 169–264

(44) or monothioates at various positions in the carbohydrate ring with ﬂuoride anions. In this reaction the halogenoalkanes play the role of both reactants and solvents. (Scheme 9).19 The preparation of inositol and structurally related phosphates continues to be explored. Examples include the synthesis of the enantiomers D- and L-myoinositol 1,3,4,6-tetrakisphosphate (45) and (46) regioisomers of myo-inositol 1,3,4,5-tetrakisphosphate. Both D- and L-isomers are Ins (1,4,5)P3 5-phosphatase inhibitors, but not of Ins (1,4,5)P3 3-kinase (Figure 8).20 The synthesis and properties of a malaria candidate glucosyl phosphatidyl inositol (GPI) prototype (47), and one variant, i.e., (48), of the candidate structure has been reported. The approach elaborated addresses the crucially important (vide infra) 0–2 acylation of the inositol moiety, an unusual feature which also occurs in other heavily lipidated GPIs such as CD52 and AchE (Figure 9).21 A variable concept for the synthesis of branched glucosyl phosphatidyl inositol (GPI) anchors was established. Its efﬁciency could be shown by the successful synthesis of the GPI anchor of rat brain Thy-1 (49), and of the scrape prion protein (Figure 10).22 A synthetic strategy has been developed that allows reconstruction of the protein – GPI anchor linkage motif (50) (Figure 11).23

O

O Gl

OCOMe

(i)

Gl

S

(ii)

(44)

O

n= 1, 2; X= Cl, Br

Gl= per-O-acetylglycosyl O Reagents: (i) HS P S O

P S

(43)

O

S

F

Gl S(CH2)nX

P

, BF3 Et2O; (ii) F , (CH2)nX2

Scheme 9

O

2-

O2PO O2PO

2-

O

2

1 6

3 5

4

OH OPO22-

OH OPO22O

O (45) D-Ins(1,2,4,6)P4 IC50= 3.8 M for Ins(1,4,5)P3 5-phosphatase

Figure 8

OPO22-

O

O 2-

5

1

O2PO

6 2

3

4

OH 2-

O2PO

OH OPO22O

O (46) L-Ins(1,2,4,6)P4 IC50= 14 M for Ins(1,4,5)P3 5-phosphatase

177

Organophosphorus Chem., 2006, 35, 169–264 O

OH P

NH2

O

O OH O HO HO O

HO

O

HO HO

O OH O

HO HO

OH O

O

O HO

BnO H2N

R2

O

O

O

H

O P R2

OCOR1 OH OH

OH

O

O

(47) R1= C4H9; R2= C6H11 (48) R1= C13H27; R2= C17H36

O

Figure 9 HO

O

-O P O

...Lys-Leu-Val-Lys-Cys

OH O

HO HO

rat brain Thy-1 O

O

O

HO HO

NH3+

HO HO + HO NH3

OO

O O

P

HO O

OH OH

-O

O NHAc

O

HO HO

O O HO

HO

OH OH

+H3N

O

O O O O

OH

-O

P

O O O

(CH2)16CH3

O(CH2)17CH3

(49)

Figure 10

The total synthesis of a novel hybrid lipid Pea-PIP2 (51), possessing a phosphatidyl ethanolamine (PE) headgroup at the 1-position and a phosphatidyl inositol 4,5-bisphosphate [PtdIns(4,5)P2] headgroup at the 4-position has been elaborated. Reporter groups (biotin, ﬂuorophores, spin label) were

178

Organophosphorus Chem., 2006, 35, 169–264 H N

O

O P

AcNH-Gly-Gln-Asn-Asp-Thr-Ser-Gln-Thr-Ser-Ser-Pro-Ser-Gly-Cys

NaO

O HO HO HO HO HO

HO O O O

(50) O

Figure 11

C15H31 O

-

O

-

O

-

O

-

O

OH

PO

O

OO

O O

O

P

P

O

O O PO

O

NHR O

O-

O

OH C15H31

OH

R= reporter

(51)

Figure 12 O

OTBDMS

N O

O TBDMSO

P

O

O-

O OCC15H31 O

O O

O

C14H29

(52)

Figure 13

covalently attached to the free amino group of the PE, such that the reporter groups were attracted to the lipid-water interface (Figure 12).24 The most efﬁcient method for the synthesis of racemic plasmenylcholines (52), an important class of glycerophospholipids, requires only six steps beginning from the inexpensive starting materials solketal or glycerol and acrolein. This method may also be applicable to the synthesis of chiral plasmenylcholines (Figure 13).25 A series of phospholipid analogues (53)–(56) have been prepared and evaluated for their water solubility and inhibition of PLCBC. Their water solubility was enhanced by shortening the acyl side chains, reducing the number of acyl side chains, and by the introduction of a hydroxyl group on the termini of the acyl side chains. The key structural feature that conferred inhibitory activity on

179

Organophosphorus Chem., 2006, 35, 169–264

the compounds was the replacement of the two non-bridging oxygen atoms of the phosphodiester group with sulfur atoms (Figure 14).26 Practical and versatile routes have been developed to produce structurally related phospholipids that are conformationally restricted or ﬂexible (57) and (58), respectively. The conformationally restricted structures have a cyclopropyl ring in the interfacial region of the phospholipids (Figure 15).27 (R)- and (S)-enantiomers of novel lysophosphatidylcholine analogues (59) and (60) have been synthesized from commercially available L- and D-serine as starting materials by a short and efﬁcient method (Scheme 10). These newly designed and prepared lyso PC analogues exhibited much enhanced hyphal transition inhibitory activity against Candida species as compared to the natural lyso PC.28 The synthesis and biological activities of sphingosine-1-phosphate stereoisomers and analogues have been reported, e.g. D-erythro-S1P (61) (Figure 16).29,30

O

R1

S

O

O P O S

O NMe3

-

R1

O

1

O

+

R

S O P

(53) O

O R2

inhibitors of PLC

S-

(54) R2= -CH2CH2NMe3 (55) R2= -CH2CH2NH3 (56) R2= -CH2CNH3 (S) CO2-

Figure 14

O

O O

P

O

OX

O-

O

O

R

R

O

Figure 15

O

O

(57)

P

O

O

R

R

O

OX -

O

(58)

180

Organophosphorus Chem., 2006, 35, 169–264

Another report involves the ﬁrst total synthesis of two photoactivatable analogues of the growth-factor-like mediator sphingosine-1-phosphate (62) and (63) and their differential interaction with protein targets.31 Benzyl or cyanoethyl phosphochloroamidites (64) and (65) and D-mannose (66) are convenient starting materials for the preparation of a wide range of a-D mannosylphosphate serine derivatives (67) a new class of synthetic glucopeptides (Scheme 11). The best results were obtained with serine derivatives modiﬁed by amino protecting or masking groups that provide favorable hydrogen bonding.32 Three 1-(2-nitrophenyl)ethyl phosphoroamino acid building blocks (68), (69) and (70) for solid-phase peptide synthesis have been described (Figure 17).33 A new straightforward method of synthesis of dendrimers, using two branched monomers (CA2 and DB2) has been desribed (Figure 18).34 A new illustration of the strong synthetic interest in compounds possessing the P¼NP¼X (X ¼ O,S) group has been reported. Besides its reactivity with

O NH2 O

HN

OH

O O R

O

O P

NMe3

O L-serine R= CO2Me (S) (59) R= CH2OH (R) (60)

Scheme 10

O

OH

P HO

O

O-

C13H27 NH3+

D-erythro S1P (61) O

OH

P*

OAr

HO

O 9

OH

* = 32P

NH2 N or

Ar =

N CF3

O (62)

Figure 16

(63)

181

Organophosphorus Chem., 2006, 35, 169–264 Ac O

AcO AcO

OH (66) OAc (i), Pri2NPCl(OR) R= Bn (64) R= (CH2)2CN (65)

AcO

OAc O

AcO AcO

AcO

NHFmoc HO

O

OAll

(ii)

AcO AcO

OAc O NHFmoc OR

O

OR

O

O

P

OAll

P

NPri2

O

(67)

O

Reagents: (i) DIPEA, CH2Cl2; (ii) 1H-tetrazole, CH3CN followed by addition of ButOOH

Scheme 11 NO2 NO2 O

O

O

O P

O

O

P O

O

NO2

O

CN

P O

O

O

CN

CN OH

OH

FmocHN

OH

FmocHN O

FmocHN O

(68)

O

(69)

(70)

Figure 17

PPh2 Me S A C A

N3

N

S

NH2

P

B

OHC

D

N

NH2

B

O

O

P O

Me CA2 DB2

PPh2

Figure 18

electrophiles, this group is able to activate vinyl groups when included in heterohexatriene H2C¼CHP(R)2¼NP(R1)2¼X linkage. It has been shown that this linkage reacts readily and cleanly with variously functionalized primary or secondary amines and methylhydrazine.35

182

Organophosphorus Chem., 2006, 35, 169–264

2.2 Reactions of Phosphoric Acids and Their Derivatives. – Numerous investigations of phosphate ester hydrolysis continue to be reported. The hydrolysis between 1.5 o pH o 4 of ﬁve- and six-membered cyclic phosphoramides (71) has been followed by UV and 31P NMR spectroscopy. Small differences in hydrolysis reactivity for n ¼ 5 and n ¼ 6 constitutes evidence for syn lone pair catalysis. The product ratios from the hydrolysis shows that in the ﬁvemembered rings the main product is the one produced by endocyclic cleavage; meanwhile, in the six- membered cyclic phosphoramide the kinetic product is the one produced by exocyclic cleavage. The syn orientation of two electron pairs on nitrogen stabilizes the transition state of water approach to the phosphoramides by ca. 3 kcal/mol1 when compared to the orthogonal attack. (Scheme 12).36 The hydrolysis of diethyl 8-dimethylaminonaphthyl-1-phosphate (72) is catalysed by the neighboring dimethylammonium group, with a rate acceleration, compared with diethyl naphthyl-1-phosphate, of almost 106. The reaction is catalysed by oxyanion nucleophiles, and it has been shown that a common nucleophilic mechanism, enhanced by general acid catalysis by the neighbouring dimethylammonium group, accounts for all the observed reactions. The efﬁciency of general acid catalysis depends on the extent of negative charge development on the leaving group oxygen in the transition state for P–O cleavage, and the strength of the intramolecular hydrogen bond in reactant and transition state. (Scheme 13).37 The hydrolysis of the phosphate monoester of 8-(dimethylamino)-1-naphthol (73), involves nucleophilic attack by oxyanions on a phosphate monoester

NHR2 P

N n-5

n= 5

O

OH2

slow

Endo cleavage: (n=5) and phosphonamides Exo cleavage: (n=6)

TBP

N n=6 (71)

Scheme 12

RCOO-

O EtO EtO

ORCOO

P O

EtO

NHMe2

P EtO

± RCOO-

(72) Scheme 13

H O

NMe2

183

Organophosphorus Chem., 2006, 35, 169–264

dianion. This is a system known to support efﬁcient intramolecular general acid catalysis (Scheme 14).38 New ﬂuorescent probes have been synthesized for monitoring the cleavage of phosphodiesters and of carboxylic esters.39 Significant and differential acceleration of the dephosphorylation of the insecticides, paraoxon (74) and parathion (75), caused by alkali metal ethoxides has been observed. Paraoxon (74) is ca. 20–30 times more reactive than parathion (75) toward dissociated EtO but ca. 2 103 times more reactive toward ion-paired EtOLi1 in anhydrous EtOH (Scheme 15).40 It was found that La31-catalysed methanolysis of hydroxy-p-nitrophenyl phosphate (HPNPP) (76) is a model for the RNA transestriﬁcation reaction (Scheme 16).41 The same authors proposed catalytic methanolysis promoted by La31 as a new method for controlled decomposition of paraoxon (74) (Scheme 17). They found that methanolysis of (74) promoted by La(OTf)3 (Tf¼OS(O)2CF3) in a methanol medium is billion-fold accelerated.42 Investigation of the reaction of oximate a-nucleophiles with diisopropylphosphoroﬂuoridate (DFP) (77) and two model phosphonates (78) and (79) has been

O AcO-O -O

P

H

H

O

O

NMe2 O pH 4-9

P AcO

NMe2

OO-

(73) Scheme 14

X (EtO)2P O

NO2

EtO-M+

M+O-

(EtO)3P=X

NO2

X= O (74), X= S (75), M= Li, Na, K

Scheme 15

OAr HO

O

P

-

O

La3+

OAr

Kd HO

O

P -

O

-

P OAr

Scheme 16

HO

O

O La3+ O

(76)

CH3O-

La3+

O

O

P

184

Organophosphorus Chem., 2006, 35, 169–264 O O (EtO)2P

(EtO)2P

(La3+)2(OMe)1,2,3 O

NO2

OMe

+

MeOH, rt, buffer HO

(74)

NO2

Scheme 17

O 1

R

P

O X

+

k

Ox-

R1

R2

P

Ox

+

X-

R2 1

2

i

(77) R = R = OPr ; X = F (78) R1 = Ph, R2 = X = O

NO2

(79) R1 = Me, R2 = X = O

NO2

Scheme 18

(Me2N)2POCl

SOH/H2O

(Me2N)2POOS

+

(Me2N)2POOH

(80) log(k / k0) = 1.14NT + 0.63YCl + 0.17 Scheme 19

revealed either a leveling oﬀ in reactivity or a bell-shaped behavior in accordance with a critical decoupling of desolvation and bond formation. The relevance of these results to detoxiﬁcation is also emphasized (Scheme 18).43 A detailed study of the speciﬁc rates of solvolysis of N,N,N 0 ,N 0 -tetramethyldiamidophosphorochloridate (80) (TMDAPC) with analysis in terms of the extended Grunwald-Winstein equation has been reported (Scheme 19). The stereochemistry of nucleophilic attack at tetracoordinate phosphorus was also discussed.44 The initial reaction of bis (2,4-dinitrophenyl) phosphate (BDNPP) (81) with hydroxylamine involves release of 1 mol 2,4-dinitrophenoxide ion and formation of a phosphorylated hydroxylamine (82), which reacts readily with further NH2OH, giving the monoester (83). The intermediate (82) also breaks down by two other independent reactions; one involves intramolecular displacement of aryloxide ion (83) and the other involves migration of the 2,4-dinitrophenyl group from O to N and formation of phosphorylated 2,4dinitrophenylhydroxylamine (84) (Scheme 20).45

185

Organophosphorus Chem., 2006, 35, 169–264

Various Lewis acids MXn have been evaluated as catalysts for the phosphoryl transfer, the most efﬁcient being TiCl4 (Scheme 21). Application of this methodology to the phosphorylation of representative target alcohols is presented.46 A number of N-phosphoryl oxazolidinones (85) have been prepared and developed as alternative phosphorylating agents suitable for a variety of representative alcohols. (Scheme 22). The 5,5-diphenyl oxazolidinones were determined to be the best framework for such reagents.47 The oxathiaphospholane methodology has been applied to the synthesis of N-phosphorothioylated amino acids as well as O-phosphorothioylated derivatives of hydroxyamino acids, i.e., serine, threonine and tyrosine. N- and O-(2-thiono-1,3,2,-oxathiaphospholanyl) amino acids methyl esters (86) were prepared in high yield by the reaction of amino acids esters (87) with 2-chloro-1,3,2-oxathiophospholane (88) in pyridine in the presence of elemental sulfur. Compounds (86) were converted into the corresponding methyl or benzyl phosphorothioamides (89) by DBU-assisted treatment with methyl or benzyl alcohol. The DBU-assisted oxathiaphospholane ring opening process did not cause any measurable NO2 O O2N NO2

NO2

NH2OH

O O2N

O

P

O-

O

O

NH2OH O2N

O

P

O-

(83) O

NH2

O-

2

NO2

(82)

(81)

P O-

O H N

O2N

O

O-

P O-

(84)

Scheme 20

O OH

O +

R1

R2

MXn

O

P(OPh)2

ClP(OPh)2 R1

R2

Scheme 21

O O

O

O N

1

O

P(OEt)2

OH

BuLi

+

R

R2

R

O

OP(OEt)2 +

NH

1

R2 R1 R2

R1 R2 (85)

Scheme 22

186

Organophosphorus Chem., 2006, 35, 169–264

C-racemization of phosphorothioylated/phosphorylated amino acids (Scheme 23).48 An oxathiaphospholane approach to one-pot phosphorothioylation of isoprenoid alcohols such as allyl, geranyl, isopentenyl, citronellyl, farnesyl, and phytyl alcohols has also been reported (Scheme 24).49 Non-enzymatic systems were used to show that vibrational spectroscopy can provide a sensitive probe of the environment of the phosphoryl group, a group commonly transferred in enzymatic catalysis. The results described provide a foundation for understanding both the bonding behavior of monosubstituted phosphates and the electrostatic environment of the phosphoryl group, including that within enzyme active sites.50 Physical and kinetic analysis of the cooperative role of metal ions in the catalysis of 2-hydroxypropyl-4-nitrophenyl phosphate (HPNP) cleavage by a dinuclear Zn(II) complex (90) have been reported.51 Non-coordinating amino H-bond donors adjacent to a zinc (II)center enhance the afﬁnity of phosphates to the zinc (II) center (Scheme 25).52 Unusually high phosphodiesterolytic activity of La(III) hydroxide complexes stabilized by glycine derivatives (91) that surpass all currently known catalytic systems based on trivalent lanthanides was observed (Figure 18a).53 O R

R

P

O

O O-

O

OH-

O

O

La

La O

N H2

H C

O

H

O (91)

Figure 18a

H2N

H2 N

H

S COOMe +

P

Cl

(i)

H N

P

O

R (87)

S-

S S O

(88)

H C

COOMe

(ii)

1

R O

R

P

H N

H C

O

COOMe

R (89)

(86)

Reagents: (i) S8, pyridine; (ii) R1OH, DBU

Scheme 23 S O ROH + NC

S-

S

P O

S-

O

DBU MeCN

CN CN

P S

O OR

RO S

P

O

O NH4OH/ dioxane 40 h, r.t. SRO

P O

Scheme 24

O-

187

Organophosphorus Chem., 2006, 35, 169–264 O -

H2N

O P OO

X

O

N N

O

Zn

O-

H2N

O H2O, pH 7

N

N

H2N

P

N

N

Zn

H2N

(90)

N

N X= H2O:OH; 1:2 Scheme 25

N N H3N NH3

H3N

O

HO

H

N

O P

HN

O Cu2+ N N H

N

O P

H N

entropy driven binding

N

H

H

O NH

N

N

(92)

NH

H

N H HO

H

O Cu2+ H

N

N N

enthalpy and entropy driven binding (93)

Figure 19

The energetics of phosphate binding to ammonium- and guanidiniumcontaining metallo-receptors in water has been studied. It was proposed that the binding of the host-guest pairs proceeds through ion-pairing interactions between the charged functional groups on both the host and the guest. The differences in the entropy and enthalpy driving forces for the ammonium (92)and guanidinium (93)- containing host were postulated to come primarily from differences in the solvation shell of these two groups (Figure 19).54 TMSOTf – promoted glycosidations of 2-azido-2-deoxyglycopyranosyl diphenyl phosphates (94) with a variety of glycoside alcohols afforded 1,2-transb-linked disaccharides (95) in high yield. Furthermore, these reactions proceed with the highest levels of stereoselectivity reported to date for this type of glycosidation (Scheme 26).55 Organophosphorus and nitro-substituted sulfonate esters of 1-hydroxy-7-azabenzotriazole (96), (97) and (98) are highly efﬁcient fast-acting peptide coupling reagents (Figure 20).56

188

Organophosphorus Chem., 2006, 35, 169–264 O O

ROH, TMSOTf N3

OP(O)(OPh)2

(95)

N3 α : β = ~ <1:>99

(94) OH ROH=

OR

EtCN, -78 ˚ C

OBn

O

BnO BnO

BnO

O

HO BnO

BnO

OMe

OMe

Scheme 26

N

N N

X

O

O

P(OR)2

X= CH, N

(96)

N

N

X

O

X= CH, N

N N

N

O

O

S

X PAr2 O

Y

N

Z

O X= CH, N Y, Z= H, NO2 (98)

(97)

Figure 20

O

O

H

HO

P

H

HO

HO

HO

OH

P

OH

H2N

H2N OH

OH OH

O

O

H

H O

O O

O Leustroducsin H (99)

Leustroducsin B (100)

Figure 21

Chemical transformation of Leustroducsin H (99) to Leustroducsin B (100) having various biological activities has been successfully accomplished in 11 steps including enzymatic hydrolysis of phosphate ester (Figure 21).57 Zn-chelated glycine ester enolates (101) are highly efﬁcient nucleophiles with respect to Michael acceptor phosphate (102) in the synthesis of trans-methoxycarbonylcyclopropyl- and cycloacetyl-glycines (103) by domino sequences of Michael additions and subsequent ring closures. They react to give the anti

189

Organophosphorus Chem., 2006, 35, 169–264

isomers with high yields and excellent diastereo- and enantio-selectivities (e.g. Scheme 27).58 A highly regio-, diastereo-, and enantioselective desymmetrisation of ﬁve-, six-, and seven-membered meso-cyclic allylic bis-diethyl phosphates (104), (105) and (106), was achieved with diethylzinc using catalytic amounts of [Cu(OTf)]2, C6H6 and phosphoramidite ligands (107). The addition of diethylzinc to cyclopentene, cyclohexene, and cycloheptene bis-diethyl phosphates, provided allylic monophosphates (108), (109) and (110) with enantiomeric excess of up to 87, 94 and 498%, respectively (Scheme 28).59 Enantiomerically enriched b-(diphenylphosphatoxy)nitroalkanes (111) undergo radical ionic fragmentation induced by tributyltinhydride and AIBN to give alkene radical cations in contact radical ion pairs. These ion pairs are trapped intramolecularly by the amino groups to give pyrrolidines (112) and piperidines with significant enantioselectivity (B60% ee), indicative of cyclization competing effectively with equilibration within the ion pairs (e.g. Scheme 29).60 The diastereoselective synthesis of an optically pure spiroketal (113) via an intramolecular tandem hydrogen abstraction reaction, promoted by an alkoxy radical, has been reported (Scheme 30). This methodology can be applied to the generation of radical cations under non-oxidizing conditions.61 It was shown that both the nature of the substituent at phosphorus atom and the base used in the deprotonation step have a significant inﬂuence on the alkylation of perhydro 1,3,2-benzoxaphosphorinane-2-oxides (114) derived from ()-S-benzylamino menthol (Scheme 31).62 Palladium-catalysed [3,3] sigmatropic rearrangement of (allyloxy)- iminodiazaphospholidines (115) and (116), involving transposition of C–O and C–N

S

Tfa-GlyOBut (101)

(EtO)2(O)PO

COOMe

R

MeOOC R

R

COOBut 96% ds > 98% ee

LHMDS, ZnCl2 86%

R

(102)

NHTfa

(103)

Scheme 27

O OP(OEt)2 Et2Zn [(CuOTf)2 benzene], (107) n

Toluene, -60˚C/-40˚C

O

n

Et

O OP(OEt)2

OP(OEt)2 O (104) n= 1 (105) n= 2 (106) n= 3

O (108) n= 1 (109) n= 2 (110) n= 3

Scheme 28

R1

(107)

P

N R2

R1= R2= Me R1= R2= (R)-CH(Me)Ph R1= R2= (S)-CH(Me)Ph R1= (R)-CH(Me)Ph; R2= Pri R1= R2= Pri R1= (R)-CH(Me)Ph; R2=H

190

Organophosphorus Chem., 2006, 35, 169–264

H NH

NO2

Bu3SnH, AlBN

O O

C6H6, 80 ˚ C

N

P(OPh)2

64%, 60% ee

85% ee

(112)

(111) Scheme 29

O O O P OEt

EtO

O

Ph3SnH/AlBN Benzene

O

O

O O

O

O (113) Scheme 30

Me O

1. LDA 2. BnBr 3. H3O+

N P

R= Et

O N

R

P O Ph (114) R= Et, Bn

Me Bn

O

+

P

O

Ph

O

Et

N

R= Et

H O

Ph

1. BuLi 2. BnBr 3. H3O+

Bn

N

H

P

1. LDA or BuLi 2. BnBr 3. H3O+

Ph

H Bn

R= Bn

O

Ph O

Bn

N P Ph

Ph O

+

O

Bn

N P

H Ph

H O

Scheme 31

functionality, has been developed for the synthesis of allylic amines (117) and tosylamines (118) via phosphoroamides (119) and (120) (Scheme 32).63 The same phosphorimidate phosphoramidate rearrangement has been applied to the preparation of allylic amines starting from the phosphoroimidate (121) (e.g. Scheme 33).64

191

Organophosphorus Chem., 2006, 35, 169–264 Me N

Me N

NR1

[PdCl2(MeCN)2] (5 mol%)

P N Me

O

R HCl

P

CH2Cl2

R

R O

N Me

HN N R1

R1 (117) R1= H HCl (118) R1= Ts

(119) R1= P(O)(OPh)2 (120) R1= Ts

(115) R1= P(O)(OPh)2 (116) R1= Ts

Scheme 32

O

O

O

P O

O P

N

Ph

Ph

N

O

Ph

EtSH, NaH

NH

HCl/MeOH 80-20%

(121) Scheme 33

SN2P

O (EtO)2P

Cl

+

(EtO)2P O-

(EtO)2P

O- + (EtO)2P

O Cl

(122)

(123)

SET

O O (EtO)2P

P(OEt)2

Scheme 34

Alkali metal salts of diethyl phosphite (122) act as nucleophiles or electron donors in their reaction with diethyl phosphorochloridate (123). Evidence was provided that formation of the direct P(IV)-P(IV) bond proceeds via a single electron transfer process (SET) from phosphite anion to phosphorochloridate (Scheme 34).65 Readily available N-(diethoxyphosphoryl)-benzylhydroxyamine (124) with primary and secondary halides as well as with bis-halides under basic conditions lead to N-alkylated derivatives (125). Facile dephosphorylation afforded appropriate N-substituted O-benzylhydroamines (126) (Scheme 35).66 The lithiated anions derived from (1-alkyl-) or (1-phenyl-2-propenyl)- phosphoric triamides (127) can be used as new ketone homoenolate equivalents. The proposed route gives various ketones (128) using an umpolung strategy in contrast to other known routes (Scheme 36).67 It was shown that isocyanatophosphoryl dichloride (129) is a convenient reagent for the introduction of a carbamoyl group into molecules with p-excessive heterocycles and enamine groups (Scheme 37).68

192

Organophosphorus Chem., 2006, 35, 169–264 O O

O

P(OEt)2

N H

O

56-95%

N

P(OEt)2

O

61-92%

NH2Cl

R (124)

R

(125)

(126)

R= Et, Me, Pri, Bu, Allyl, Bn, (CH2)3Br, (CH2)4Br, (CH2)3P(O)(OEt)2

Scheme 35

Me

1. BuLi, THF, -50 ° C 2. E

N (Me2N)2P O

R

3. H3O

R

E

E = electrophile

O

(127)

R= Me, Prn, Ph

67-93% (128)

Scheme 36

O Het

H

O

O C N PCl2 (129)

Het

C

O

O H N

PCl2

H2O

Het

C

O H N

P(OH)2

∆ , H2O

O Het

C

NH2

Het = indoles, pyrroles, indolizines, enamines

Scheme 37

Nu

Nu

N P RO RO (132)

O

R1O

N P RO RO (130)

O

N P RO RO

O

(131)

Scheme 38

The synthesis of allylic and non-allylic cyclic N-phosphoryliminium ions (130) based on N,O-acetals (131) and their application in C-C bond formation (132) has been reported. In addition, the inﬂuence of a chiral auxiliary on the phosphorus atom has been also investigated (Scheme 38).69 A new cyclising reagent is proposed for the synthesis of 5-unsubstituted 1,3,4-thiadiazoles (133). The latter are formed in good yield by the reaction of thiohydrazides (134) with diethyl chlorophosphate (Scheme 39).70 A useful, one-pot protocol has been developed for the conversion of enolizable ketones (135) to alkylated or arylated oleﬁns (136) by Pd-catalysed cross coupling of insitu generated enol phosphates (137) with Grignard reagents (Scheme 40).71

193

Organophosphorus Chem., 2006, 35, 169–264 O

S

N (EtO)2P

R

N

Cl

DMF

NHNH2

S R

(134)

(133)

Scheme 39

O R1 R

OPO(OPh)2

R2MgX

R1

ClPO(OPh)2

Pd Catalyst

R

(135)

R3

R3MgX

R1 R (136)

(137) Scheme 40 R6 R1

R5 R2

O

R1

S

P(OEt)2

Na 4

R

R

4

THF:Et2O = 1:1

R1

R2 R3

(140)

3

O

S

R2

∆

R3 4

R

R

(138) R5

R6

R5

R6 (139)

Scheme 41

Further examples of the applications of thiophosphates in organic synthesis have been reported. The methodology based on intermediate thiophosphates (138) constitutes a general and convenient route to a wide range of conjugated non-linear trienynes (139). Thiophosphate (138) reacts readily with sodium derivative of dienynes to form (139) in one operation via single and double carbon-carbon bond formation (Scheme 41).72 Several new thiophosphates (140) have been prepared. They are useful precursors of novel cyclic compounds (141) which have similar structures to Baylis-Hillman adducts. The synthetic approach to these compounds involves reduction of the carbonyl group by NaBH4 in the presence of methyl iodide which exhibit full axial selectivity. Subsequent oxidation of intermediate sulphides (142) to sulphoxides (143) and cis elimination of the latter affords the desired compounds (141) of deﬁned stereochemistry (Scheme 42). Multifunctionality of the compounds makes them attractive for numerous further important transformations.73 A convenient, general and stereoselective synthesis of trisubstituted and tetrasubstituted alkenes (144), which may contain a cyanide function, as well as trisubstituted episulphides (145) have been elaborated. The method makes use of readily available thiophosphates and selenophosphates (146) (Scheme 43).74

194

Organophosphorus Chem., 2006, 35, 169–264 O (i)

SP(O)(OEt)2

R

OP(O)(OEt)2 C(O)OEt

H C(O)OEt

(140)

(ii)

SMe

R

(CH2)n

OP(O)(OEt)2 C(O)OEt

H

S(O)Me (CH2)n

R

(CH2)n (142)

(143) - HOSMe

n = 1, 2, 3; R = H n = 2; R = H, 3-Me, 4-Me, 5-But, 5-Ph, 4,4',6-Me

OP(O)(OEt)2 C(O)OEt R (CH2)n (141) Reagents: (i) NaBH4, MeI, MeOH; (ii) MCPBA Scheme 42

H(CN) (i)

O

O

2

2

R

R1

R

R1

X

O

(144)

R3

P(OEt)2

R3

R3

R2

R1

H

(ii)

S

(146)

R2

R1

(145)

R3 Reagents: (i) X = Se, NaBH4, MeOH or KCN, 18-crown-6, DMF; (ii) X = S, NaBH4, MeOH Scheme 43

S S

P(OEt)2 O

H

Nu 2-4 min, 77-92%

R1

R2

S

S

Nu +

R1

O

P(OEt)2

R2 (147)

(148) Nu = CN , RS Scheme 44

An expedient solvent-free synthesis of functionalized thietanes (147) by nucleophilic-induced cyclization of phosphorodithioates (148) has been reported (Scheme 44).75 The reaction of 16-dehydropregnenolone acetate (16-DPA) (149) with P4S10 afforded a novel adduct 16-DPA-P2S5 (150). The adduct undergoes

195

Organophosphorus Chem., 2006, 35, 169–264

[4þ2]-cycloaddition with alkyne dienophiles to give steroidal (17,16-c) pyrans (151) under thermal conditions (Scheme 45). The reaction provides a new strategy for the activation of conjugated enones towards unreactive dienophiles. 76 Triaryl phosphites selectively reduce aryl selenoxide (152) to selenides (153) via a concerted mechanism for the oxygen transfer from Se to P (Figure 22).77 Regio- and stereoselective ring-opening reaction of epoxides (154) using organic dithiophosphorus acids (155) as nucleophiles constitutes a practical method for the synthesis of b-hydroxymercaptans (156) (Scheme 46). Furthermore, an enantioselective ring-opening reaction was accomplished with an ee value of 73% in the presence of a chiral (salen)Ti(IV) complex (157).78 The functionalization of the periphery of dendrimers continues to attract attention because the properties and applications of these compounds mainly depend on the type of functional end groups they bear. The functionalization of phosphorus-containing dendrimers was easily achieved through thioacylation reactions involving new dendrimers capped with dithioester end groups and various functionalized amines. These reactions were successfully applied to the ﬁrst generation (12 end groups) (158) and the third generation of the dendrimer (48 end groups) and allowed their functionalization by various amines, alcohols, glycols and azides (e.g. Scheme 47).79

O H

H

P

P2S5

2

S

O

S S

O

H

P

S

S

H

H (150)

(149)

DMAD

H

O C(O)OMe

H

C(O)OMe

(151) Scheme 45

O (ArO)3P

+

Ar (152)

Figure 22

(ArO)3P

Se Ar

O +

Ar Se Ar (153)

196

Organophosphorus Chem., 2006, 35, 169–264 S O

H

S

OH

R2PS

H

R2PSH

+

OH

HS LiAlH4

0 ˚ C, 0.5 h toluene

(155)

n

n= 0, 1

n

n

(156)

(154)

t

Bu

N

N

OH

HO

But

t

But

Bu

(-)-(R,R) (157) Scheme 46

R1 N C S N3P3 O

C H

N

N Me

1-G1

S

Cs2CO3

PCl2

S

6

HO

N3P3 O

R2 S

O

C N N P O H Me

C SMe

S C N R1 R2

2-G1

6

(158)

Scheme 47

Analysis of 24 phosphorus-containing dendrimers and dendrons allows conclusions to be drawn about the thermal stability of these compounds. The internal structure of these dendrimers is stable up to very high temperature. The most important factor concerning their stability is the nature of the end groups.80 Acyclovir was successfully grafted on the surface of thiophosphate dendrimers via thio- and phosphodiester linkages, providing water-soluble prodrug candidates (159) (Figure 23).81 In four dendrimers terminated by 12 electroactive tetrathiafulvalenyl substituents (160), the three dimensional character of the inter- and intra-dendrimeric charge and electron transfer, and hence of the electroconductivity, has been assessed by examination of the electronic spectra of their corresponding neutral state and cation, radical, dication, and mixed-valence salts, including a closed – shell anion (Figure 24).82 The N3 groups linked to thiophosphoryl functions are good leaving groups for regioselective nucleophilic substitutions on macromolecules such as phosphorus macrocycles (161) (e.g. Scheme 48).83

197

Organophosphorus Chem., 2006, 35, 169–264 O

Pacv

acvP

R

R

N

S

R Pacv acvP R P S S acvP R SS R Pacv P P P P R Pacv P S acvP R S S P S P R S Pacv R R R Pacv acvP Pacv P

P

NH

O Pacv=

P

O

N

O

N

NH2

O NH4 =

O(CH2)5O

= R=

O(CH2)3O O(CH2)6O

(159)

Figure 23 R S

N N3P3

N

O

P

R

S

er ac sp

O

S S

R

O

S

2

6

O (160)

Figure 24 Cl

S

Cl

P N S

N

O

N N3

O

P N3

P O

O

2 ArO

S

O

S

- 2 N3

ArO

OAr

O P

O

O

S

N

N

P S

N

P

N

N

S P

P Cl

S

Cl (161)

Scheme 48

2.3 Selected Biological Aspects. – Water soluble phosphate prodrugs of buparvaquinone (162) and (163) containing a hydroxynaphthoquinone structure, were synthesized and evaluated in vitro for improved topical and oral drug delivery against cutaneous and viscelar leishmaniasis. The investigation also showed that buparvaquinone permeation through human skin can be signiﬁcantly improved by using phosphate prodrugs (Figure 25).84

198

Organophosphorus Chem., 2006, 35, 169–264 O

O O

HO

P

OH

O Enzymatic hydrolysis

O

(162) O

OH O O O O HO

P

OH

O (163)

Figure 25

The physiochemical properties of noladin ether (164) were successfully improved by introducing a phosphate moiety to the structure. High water solubility and chemical stability, together with a rapid quantitative enzymatic hydrolysis in vitro and the ability to reduce IOP in vivo, prove that the phosphate esters (165) and (166) are promising prodrug candidates of endocannabinoid noladin ether (Figure 26).85 A superior class of nitroaryl phosphoroamides (167), (168) and (169) as potential prodrugs for nitroreductase-mediated enzyme-prodrug therapy has been developed. These nitroaryl phosphoroamides have low cytotoxicity before reduction and are converted to phosphoroamide mustard or similarly reactive species upon bioreduction. The excellent biological activity of these compounds correlates well with their substrate activity for E coli nitroreductase.86 A novel series of phosphate esters (170), (171) and (172), small molecule tags with high afﬁnity for serum albumin, reduce clearance and increase the circulating half life of bioactive peptides administered to rabbits (Figure 27) (Figure 28).87 A new enantioselective synthesis of both (2R)-OMPT (173) and (2S)-OMPT (174) has been described (Scheme 49). Calcium release assays in both LPA3transfected insect Sf9 and rat hapatoma Rh 7777 cells showed that (2S)-OMPT was 5- to 20-fold more active than (2R)-OMPT. Similar results were found for calcium release, MAPK and Akt activation, and IL-6 release in human OVCAR 3 ovarian cancer cell.88 Synthetic and biological evaluations of new diadenosine polyphosphate (175) analogues on blood platelet aggregation have been reported. The most active are compounds with sulphur replacing one or both non-bridging oxygens at

199

Organophosphorus Chem., 2006, 35, 169–264 OH O OH (164)

OH O O O P

OH OH

(165)

OH

HO P O

O

O O O P

OH OH

(166)

Figure 26

H N

O2N

NH

O

P

P O

O

N(CH2CH2Cl)2 O2N

(167) H2N

O N(CH2CH2Cl)2

(168)

O P

O O2 N

N(CH2CH2Cl)2

(169)

Figure 27

phosphorus bound to adenosyl residues and hydroxymethyl group of bis(hydroxymethyl)phosphinic acid (Figure 29).89 cyclo-Saligenyl-mannose-1-monophosphates (176), a new strategy in CDG1a therapy, have been described.90 The modiﬁed receptor antagonist (177) has been synthesized. This study has resulted also in the discovery of a high-afﬁnity LPA/LPA3 of (177), which exhibits a K1 value of 18mM at the LPA1 receptor and is significantly more potent than (178) at the LPA3 receptor.91 It was found that the Z-isomer of triphosphate (179) is a potent competitive inhibitor of

200

Organophosphorus Chem., 2006, 35, 169–264

O N H

ALCDNPRIDRWYCQFVEG-CONH2 R= R=

R=

4

O

O P

O

(171)

R

(172)

OH (170)

Figure 28

wild-type HIV-1 reverse transcriptase with Ki close to ddATP. The E-isomer (180) is about 30-times weaker (Figure 30) (Figure 31).92 A new and efﬁcient route to enantiomerically homogenous lysophospholipid analogues from (S)-1,2,4-butanetriol (181) has given two 3-diﬂuoromethyl substituted analogues of 2-acyl-sn-glycerol-3-phosphate (182). These compounds are migrated-blocked analogues of the labile sn-2 LPA species. It was shown that esters (182) are as fully active as natural LPA (Figure 32).93 Potent and subtype-selective agonists (183), (184) and (185) for LPA1 and LPA3, were developed by using carbohydrates as a core structure.94 Two ﬂuorescently-labelled, activity-based probes, Probe A and Probe B have been successfully designed and synthesized. They were shown to label selectively different types of phosphatase over other enzymes (Figure 33) (Figure 34).95 For the purpose of cancer antineovascular therapy, a novel angiogenesistargeted peptide, Ala-Pro-Arg-Pro-Gly (APRPG) was attached to hydrophobized polyethylene glycol (distearoylphosphatidylethanolamine [DSPE]-PEG). Liposomes modiﬁed (186) with this DSPE-PEG-APRPG conjugate strongly accumulate in tumors of tumour-bearing mice (Figure 35).96

3

Phosphonic and Phosphinic Acids

3.1 Synthesis of Phosphonic and Phosphinic Acids and Their Derivatives. – New synthetic approaches to phosphonic and phosphinic acids and their derivatives are still being developed because of their speciﬁc biological properties particularly as natural products and as analogues of phosphates, phosphono- and phosphino-peptides, amino-acid analogues and pro-drugs.

3.1.1 Alkyl, Cycloalkyl, Arylalkyl and Related Acids. New selenophosphates, selenophosphorothioates, selenophosphorodithioates and selenophosphorotrithioates are easily generated from readily available starting reagents, by a three or four-step sequence of reactions. These compounds (187) have been used as precursors of the corresponding phosphorus-centered radicals by homolytic cleavage of the P–Se bond. When radicals are produced in the presence of a range of alkenes (188) most of the expected adducts (189) are

(2S)

OH

O

O

(i)

O

(174)

O

P(OH)2

S

OMe O

(ii)

P(OH)2

S

(iv)

P(OCH2CH2CN)2

P(OCH2CH2CN)2

S

O

S

(2S)-OMPT

C17H33

O

O

OMe

OH

O

C17H33

HO

O

OH

O

O

OMe O

P(OCH2CH2CN)2

S

P(OCH2CH2CN)2

S

Scheme 49

Reagents: (i) (CNCH2CH2O)2PN(Pri)2, 1H-tetrazole, S,CS2/pyridine, 86%; (ii) p-TsOH, MeOH, 67%; (iii) oleoyl chloride, 2,4,6-collidine, -78 ˚ C, 87%; (iv) TMSCHN2, HBF4, 58%; (v) ButNH2, BTMSA, 84%

OH

O

(173)

O

O

5 steps

(2R)-OMPT

C17H33

C17H33

O

O

(2S)

(v)

(iii)

O

O

Organophosphorus Chem., 2006, 35, 169–264 201

202

Organophosphorus Chem., 2006, 35, 169–264 S

AdeO

P

O O

S

CH2 P

CH2 O

P

O-

X

OAde

X

(175)

X = O, S

AcO

OAc O

AcO AcO

O

Man-1-P

O P

O

X O CDG-la correction

cycloSal-Man-1-P (176)

Figure 29

O HO

P

HO

O

Ar

O R1

R2

(178) R1 = H; NHC(O)C17H33; Ar = Ph (Ki = 137 nM LPA1) (177) R1 = NHC(O)C17H33; R2 = H; Ar = 2-pyr (Ki = 18 nM LPA1)

Figure 30

O HO

P

O O

OH

P OH

O O

P

O

Ade

OH (179) Z-isomer (180) E-isomer

Figure 31

O OH

O

HO OH (181)

Figure 32

HO HO P O

R F

O F (182)

203

Organophosphorus Chem., 2006, 35, 169–264 O

O

O

oleoyl

oleoyl

oleoyl O

O

O O

OH ONa P

O

O

OH SNa P

O

O (184)

(183)

OH ONa P

O

(185)

Figure 33 F

O

O (HO)2P

H N

O

O

O

N H

Cy3

O Probe A F2C

O

O (HO)2P

O

H N O

N H

Cy3

O Probe B

Cy3=

+ N I

N COOH

Figure 34

formed in high yields (Scheme 50).97 AIBN-initiated free radical addition of dialkyl phosphites to various 1,6- and 1,7-dienes and heterodienes containing oxygen or nitrogen atoms (190) affords the corresponding 5- and 6-membered ring carbocyclic and heterocylic derivatives of dialkyl methylphosphonates (191) (Scheme 51). Similar transformations using diphenylphosphine oxide and diethyl thiophosphite have also been performed.98 Rhodium prolinate second generation complex Rh2(S-TISP)2 has been used as a very effective catalyst promoting conversion of dimethyl aryldiazomethyl phosphonates (192) into the stereochemically deﬁned donor/acceptor substituted rhodium carbenoid intermediates. The latter are capable of cyclopropanation of various styrene derivatives affording cyclopropylphosphonates (193) in high yields (85–96%), diastereoselectivity (>98% de), and enantioselectivity (76–92% ee) ( Scheme 52).99 A

204

Organophosphorus Chem., 2006, 35, 169–264 O R1

O O

R2

O O

P

O

NH3+

O

O+ PEG + APRPG peptide

O R1

O O O

R2

O O

H N

P

O

APRPG

O

O n

O

O-Na+

O

O

(186) R1, R2 = Alkyl

Figure 35

X R1Y

P

SePh

TTMSSH

+ R3

YR1 (187)

R1Y

P

R2

R3

R4

AIBN

R4 (188)

X

R1Y

R2

(189)

X, Y = O and/or S

Scheme 50

X

R R1 R

(R1)2P(X)H

R

P R

R1

AIBN or Et3B/O2 X = O, S (190)

(191) Scheme 51

205

Organophosphorus Chem., 2006, 35, 169–264 O

O

Ar

P(OMe)2 N2

H

Rh2(S-biTISP)2 2,2-dimethylbutane

Ar

P(OMe)2 Ar

Ar

(192)

(193) Scheme 52

O O HO

P

HO

O

O

P

P

ONa

OH

ONa

ONa

OH

O

P

OH

ONa

HO O

N N N N

(194)

Figure 36

new water-soluble calix[4]-arene-based bipyridyl podand (194) has been elaborated by incorporation at the upper rim of four phosphonate groups. The association of its hydrophilic and chelating properties in the complexation of copper (I) in water is positively evaluated (Figure 36).100 A series of tetrahydroxythiacalix[4]arenes of the cone conformation with phosphonate and phosphine oxide groupings on the upper rim (195) has been synthesised (Figure 37).101

3.1.2 Alkenyl, Alkynyl, Aryl and Heteroaryl Acids. Treatment of readily accessible (E)- and (Z)-alkyl and aryl substituted vinyl boronates (196) with triethyl phosphite in the presence of lead diacetate results in their stereospecific transformation into (E)- and (Z)-vinylphosphonates (197) (Scheme 53).102 Palladium acetate catalysed Mizoroki-Heck reaction of arylboronic acids (198) with diethyl vinylphosphonates (199) is an effective synthetic approach to

206

Organophosphorus Chem., 2006, 35, 169–264 O O R1

R1

P

O

O

P R

R2

R2

R2

R1

P

R1

P

2

S

S S OH

S

OH

HO OH

(195)

Figure 37

O

O

Pd(OAc)2[4 mmol%]

R1CH=CR2B

R1CH=CR2P(OEt)2

P(OEt)3[2 equiv.] O2, 95 ° C

O

(E) or (Z) (197) Stereospecifically

(196) Scheme 53

RB(OH)2 + (198)

P(OEt)2 (199)

O

Pd(OAc)2 Na2CO3

O

DMF, O2 60 ˚ C

R

P(OEt)2 (200)

Scheme 54

aryl substituted a,b-unsaturated phosphonates (200) of (E) stereochemistry (Scheme 54).103 A simple procedure for the preparation of triﬂuoromethylated vinyl- and dienyl-phosphonates with g-alkoxycarbonyl moiety of exclusively or predominantly (Z)-conﬁguration (201) has been described. It involves acylation of ethyl-1,1-bisphosphonate (202) with triﬂuoroacetic anhydride, addition of selected Reformatsky reagents to the resulting 1-triﬂuoroacetyl-1,1-ethyl bisphosphonates (203) and ﬁnally spontaneous Horner-Wadsworth-Emmons (HWE) oleﬁnation of the adducts (Scheme 55).104 Differently substituted 1,3-dienes (204) readily add to vinylidene bis-phosphonate (205) to give the corresponding cyclohex-3-ene-1,1-bis-phosphonates (206). With unsymetrically substituted dienes mixture of regioisomers are obtained. In some cases migration of the double bond in the primary adducts is observed (Scheme 56).105 It has been demonstrated that under specially selected conditions the monoalkylation of triethyl phosphonocrotonate (207) with a number of halides or

207

Organophosphorus Chem., 2006, 35, 169–264

O (EtO)2P

(EtO)2P

(i), (ii)

P(OEt)2

O

O

O

O

P(OEt)2

F3C

(iii)

F3C

P(OEt)2

RO2C O (203)

(202)

(201)

Reagents: (i) BuLi, (ii) (CF3CO2)O, (iii) BrZnCH2CO2R

Scheme 55

O O R

+

O

(EtO)2P

P(OEt)2 90-140 ° C

P(OEt)2

P(OEt)2

R

O (204)

(206)

(205) Scheme 56

O

O (i), (ii) (EtO)2P

(EtO)2P

CO2Et

CO2Et

THF (207)

R

X = Br, I, OTf R = Alk, Ar, Bn

(208)

Reagents: (i) LLiHMDS or NaHMDS, (ii) RX Scheme 57

O

O

P(OEt)2

P(OEt)2

(i), (ii) THF -78 ° C

EtO (211)

EtO

O

OMe (210)

(iii) >99%

P(OEt)2 CHO (209)

Reagents: (i) LDA, (ii) MOMCl, (iii) CF3CO2F Scheme 58

triflates is an efﬁcient method for the synthesis of a-substituted phosphonates (208). The alkylation is fully regio- and stereoselective (Scheme 57).106 The ﬁrst synthesis of phosphonoacrolein (209) was achieved by acid decomposition of b-ethoxy-a-(methoxymethyl)vinylphosphonate (210) derived from lithiated phosphonate (211) and chloromethyl methyl ether (MOMCL) (Scheme 58). The phosphonoacrolein (209) appeared to be a particularly active heterodiene in the Diels-Alder additions with electron rich alkenes and alkynes.

208

Organophosphorus Chem., 2006, 35, 169–264

New families of dihydropyrans (212), (213), (214) and pyranopyrans (215) have been obtained in this way (Figure 38).107 The preparation of a novel phosphonate containing 3,4-dihydro-2-H-pyrrole-1-oxide residue (216) has been reported. The synthesis of this solid and highly lipophilic spin trap is based on the addition of diethyl phosphite to pyrroline (217) and subsequent m-CPBA oxidation of phosphonate (218). (Scheme 59). The structure of the (218) was assigned using X-ray diffraction techniques. Its ability to react with different free radicals especially hydroxyl and superoxide was evaluated.108 Successive treatment of diethylphosphonylalkyl a-aminonitriles (219) with 1,1 0 -carbonylimidazole (CDI) or 1,1 0 -carbonyl-di-(1,2,4-triazole) (CDT) and O-substituted hydroxylamines has proven useful as a convenient protocol for the preparation of new 5-diethoxyphosphorylalkyl derivatives of 3-aralkoxy-4imino-imidazolidine-2-ones (220) and 4-alkoxy (aralkoxy) imino-imidazoline2-ones (221) (Scheme 60).109 A series of heterocycle derivatives of 1,1-bis-phosphonate (222), (223), (224) and (225) has been synthesized by Michael addition of 1,1-methylene bisphosphonate to acceptors such as: 5-arylidene rhodamines, 5-benzylidene-2thiohydantoin, benzylidene or 2(2 0 -furyliden)-cyanomethyl-1,3-benzothiazoles

O

O

O

P(OEt)2

P(OEt)2

P(OEt)2

R2 H R1

EtS O

H

H O

EtS

(212)

HO

(213) O

O (214)

O

R2

(EtO)2P

P(OEt)2

O

R1

O

(215)

Figure 38

O P(OEt)2

(EtO)2POH Ph

N (217)

90%

N H

(218)

O MCPBA Ph 34.7%

P(OEt)2 Ph

N O

-

(216)

Scheme 59

209

Organophosphorus Chem., 2006, 35, 169–264 NH

O 3. EtOH/HCl

R3

(EtO)2P N

K2CO3

O

HN

(220)

R3

(EtO)2P

CN n 1

2

R

R

NH2

R4

O

O 1. CDI or CDT

NEt3

2. H2NOR4

R4

O

(219) 3. NEt3

N

O

R3

(EtO)2P

n

R1

R2

NH HN

(221) O

Scheme 60

O

O

HN

NH

(EtO)2P(O) (EtO)2P(O)

S

S

(EtO)2P(O) (EtO)2P(O)

Ar

Ph

S

N H

(223)

(222) Ar = Ph, Me2NC6H4 Y

(EtO)2P(O)

N

(EtO)2P(O) S

CN (EtO)2P(O)

Y

(EtO)2P(O) S

(224) Y = Ph, 2'-furyl

(225) Y = CN, CO2, Et

Figure 39

and ethyl 3-(2-thienyl)acrylocyanoacetate or related nitrile respectively (Figure 39).110 Alkenylphosphonates (226) can be prepared by regioselective addition of monoesters of phosphonic acid (227) to alkynes in the presence of Hg(OAc)2/ BF3 OEt2 (Scheme 61).111 The cinchona alkaloids are particularly valuable ligands in asymmetric addition of diethylzinc to a N-diphenyl phosphinoylimine (228) leading to enantiomerically enriched (R)- and (S)-N-(1-phenylpropyl-diphenylphosphinic amide) (229). Cinchonine and cinchonidine were found to be the pseudoenantiomeric pair which gave the adduct in highest enantiomeric excess (up to 93% ee) (Scheme 62).112

210

Organophosphorus Chem., 2006, 35, 169–264 O

O

R2P(OEt)2

1

+

R

OEt

H

P

R1

(227)

O

R2

(226) Scheme 61

Cinchona alkaloid Ph

N PPh2

Et2Zn

Ph

O

H N

*

O PPh2

Et

(228)

(229) Scheme 62

O O ArCH

O

+

O TiCl4

NH2PPh2 +

Ph2P

PPh3, NEt3 CH2Cl2

NH

O

Ar (230)

Scheme 63

O Ph

P H (232)

O OH

O Pyr.

+ RO

Cl

CH2Cl2 rt

Ph

P

OR

H (231)

Scheme 64

One pot, three component reactions of a variety of arylaldehydes, diphenylphosphinamide and methyl vinyl ketone catalysed by TiCl4, PPh3 and Et3N have been found to give the aza-Baylis-Hillman adducts (230) (Scheme 63).113 Monoesters of phenylphosphinic acid (231) can be easily prepared in high yield from the reaction of phenylphosphinic acid (232) and the corresponding chloroformates (Scheme 64).114 3.1.3 Halogenoalkyl and Halogenocycloalkyl Acids. A couple of novel 6(phosphonodiﬂuoromethyl)-2-naphthoylosulfonamides (233) have been obtained in a conventional manner. The amides represent a structure-based extension in the design of inhibitors that may have broader utility in the development of protein-tyrosine phosphetase (PTB1B) inhibitors. The ability

211

Organophosphorus Chem., 2006, 35, 169–264

of sulfonamido functionality to mimic carbonyl-H2O motifs may be useful in other systems (Figure 40).115 A series of (3-alkenylphenyldiﬂuoromethyl)phosphonic acids (234), has been synthesized on non-crosslinked polystyrene (NCPS) support and examined for inhibition with protein tyrosine phosphatase 1B. Phosphonic acid (234) was the most potent of this series of compounds being a reversible, competitive inhibitor with a Ki of 8.0 1,4 mM (Figure 41).116 Diethyl diﬂuoroalkylphosphonates (235), when subjected to chlorination by thionyl chloride, are smoothly transformed into diﬂuoroalkylphosphonyl dichloride (236). Esteriﬁcation of the latter with different thiols under basic conditions delivers new diﬂuoroalkylphosphonodithioates (237) in good yield. Exposure of these compounds to Lawesson’s reagent converts P¼O into P¼S giving new diﬂuoroalkylphosphonotrithioates (238) (Scheme 65).117 Palladium catalysed cross-coupling reactions of a-phosphonylvinyl nonaﬂuorobutanesulfonates (nonaflates Nf) (239) with dialkyl phosphite result in the formation of gem-bis(phosphono)ethylenes (240) (Scheme 66). It was shown that (240) is a promising and versatile reagent for the synthesis of gem-bisphosphono substituted compounds (241),(242) and (243) expecting to exhibit not only biologically active but also other interesting properties (Figure 42) (Figure 43) (Figure 44).118 A convenient synthetic approach to highly reactive N-(arylsulfonyl)trichloro- and triﬂuoroacetimidoyl chlorides (244) by reacting the corresponding N-acylsulfonamides with PCl5 has been elaborated. The interaction of (244) with phosphites proceeds through different pathways depending on the substituents in the reagents, and leads to compounds (245), (246), (247) and (248) (Figure 45).119 O

O

O S

O

N H

R

(HO)2P F

F (233)

Figure 40

O OAllyl O -

O

P O

CF2 -

(234)

Figure 41

212

Organophosphorus Chem., 2006, 35, 169–264 O 1

F2R

O

P

(i)

OEt

1

F2R

OEt (235)

P Cl (236)

O 1

F2R

(ii)

Cl

S (iii)

2

P

SR

1

F2R

SR2

P

SR2

SR2

(237)

(238)

Reagents: (i) SOCl2, (ii) RSH, NEt3, (iii) Lawesson's reagent Scheme 65

P(O)(OEt)2 R1

P(O)(OEt)2

(i), (ii), (iii) DMF

ONf

R1

(239)

P(O)(OR2)2 (240)

Reagents: (i) HP(O)(OR2)2, (ii) Pd(PPh3), (iii) EtNPri2 Scheme 66

Br

Br P(O)(OEt)2 P(O)(OEt)2 (241)

Figure 42

P(O)(OEt)2

N N

X

P(O)(OEt)2

(242) X = Cl, F

Figure 43 P(O)(OEt)2 X N (243) X = Cl, F

Figure 44

P(O)(OEt)2

213

Organophosphorus Chem., 2006, 35, 169–264 P(O)(OEt)2 F3C

Cl

Cl

Cl

N

Tos N H

(EtO)2(O)P (245)

X3C

N

SO2Ar

P(O)(OEt)2 Cl

(244)

Tos N H

F3C

P(O)(OAlk)2

(247)

Cl

SO2Ph

X = F, Cl

X

P(O)(OEt)2

X

N

(246)

(248)

SO2Ar

P(O)(OEt)2

Figure 45

O EtO

O

OH

P

R

Ph

+

H (249)

OH

O

P Ph H EtO R (250)

Lipase OAc

P

EtO

Ph

O

OAc

P Ph H EtO R (250) (RP, R)

+

R

OH

H (251)

(SP, S)

Figure 46

H +

R

X

O

X CHO

(254) X = TBDPSO (255) X = NBn2

P EtO

PhOLi (20 mol%)

P R OEt

(256)

X

O

OH syn (252)

+

O P

R OEt OH anti (253)

Figure 47

3.1.4 Hydroxyalkyl and Epoxyalkyl Acids. Lipase-catalysed acylation of ethyl(1-hydroxyalkyl)phenylphosphinates (249) and (250) afforded a single diastereoisomer of the corresponding acetates (251) in high enantiomeric excess (>98%) (Figure 46).120 Diastereoselective synthesis of b-substituted a-hydroxyphosphinates (252) and (253) by hydroxyphosphinylation of a-silyloxy aldehydes (254) and aamino aldehydes (255) with ethyl allylphosphinate (256), catalysed with lithium phenoxide, has been reported (Figure 47).121 Two methods for the ﬁrst synthesis of partial amides (257), (258) and a partial amide ester (259) of etidronate have been developed (Figure 48).122 The preparation of 1,1-bisphosphonates from tris(trimethylsilyl)phosphite (260) and acid anhydrides (261) has been described. This synthesis allows a

214

Organophosphorus Chem., 2006, 35, 169–264

O HO

O

N HO

P O N

P O N

ZO

N P O N

HO

P

P + -

O

N

+ -

ZO

- +

OZ

P + -

N

ZO

(257)

OMe (259)

(258)

Figure 48

O

n

1. 2equiv. P(OSiMe3)3 (260) 2. MeOH

O

O

OH P(O)(OH)2

HO

n

O

P(O)(OH)2

(262)

n = 0, 1 (261) O

O

O

1. P(OSiMe3)3 20 ° C, 1h

OK

2. MeOH 3. H2O/K2CO3

P(O)(OK)2

O

HO

(261)

P(O)(OK)2

(263) Scheme 67

direct access to 1-hydroxymethylene 1,1-bis(phosphonic) acids functionalyzed by a carboxylic function in the side chain (262) and (263) (Scheme 67).123 Alternative routes to acetylated etidronic acid derivatives have been investigated. (1-Acetoxyethylidene)-1,1-bisphosphonic acid (264) and its P,P-dimethyl (265), trimethyl-(266) and tetramethyl esters (267) were prepared (Figure 49).124 Candida antractica lipase B- and immobilised Mucor miehei lipase- catalysed alcoholysis and C-rugosa lipase- catalysed hydrolysis have been successfully used for the highly effective synthesis of optically active triﬂuoromethylated 1and 2-hydroxyalkane-phosphonates (268) and (269) from their racemic Oacylated precursors (270) and (271) (Scheme 68).125 It has been found that reactions of diethyl mesyl- or tosyloxybenzyl-phosphonates (272) with sodium diethyl phosphite give the corresponding

215

Organophosphorus Chem., 2006, 35, 169–264 AcO

P(O)(OMe)2

AcO

P(O)(OMe)2 OMe

P(O)(OMe)2

P O

(267) OMe

O

AcO

P O-Z+

AcO

O-Z+ (266) P(O)(OH)2

OMe P O

P(O)(OH)2

O-Z+

(264)

(265)

Figure 49

OCOR2

OCOR2 1

F3C

P(O)(OR )2 n

lipase/BuLi solvent

OH 1

P(O)(OR )2 +

F3C

n

P(O)(OR1)2

F3C

n

(270)

(268)

n = 0, 1

OCOPrn

OCOPrn

P(O)(OR)2

F3C

CRL DIP-H2O

OH

P(O)(OR)2 +

F3C

F3C

(271)

P(O)(OR)2 (269)

Scheme 68

OR

OP(O)(OEt)2

X P(O)(OEt)2 + NaP(O)(OEt)2

(272)

X = H, NO2 R = MeSO2, p-TolSO2

THF

X P(O)(OEt)2

(273)

Scheme 69

phosphono phosphates (273). Formation of the desired bisphosphonates was not observed (Scheme 69).126 A facile procedure for highly regioselective and efﬁcient synthesis of a-hydroxyphosphonates (274) and (275) based on the reaction of trialkyl phosphites with epoxides in LiClO4/Et2O has been presented (Scheme 70).127 b-Hydroxyalkylphosphonates (276) have been prepared under neutral conditions by reaction of diethyl iodomethylphosphonates (277) and carbonyl

216

Organophosphorus Chem., 2006, 35, 169–264 P(OR2)3/TMSCl

O

OSiMe3

R1

LPDE, 5 to 45 min, rt

P(O)(OR2)2

1

R

(274)

O

P(O)(OR)2

P(OR)3 TMS, LPDE

OSiMe3 (275)

Scheme 70

O

O (EtO)2P

I

+

SmI2

R1R2CO

R1

HO

(EtO)2P

THF

(277)

R2 (276)

O

O (EtO)2P

I

1

2

+ R COOR

SmI2

O

(EtO)2P

THF

(277)

R1 (278)

Scheme 71

O

OH

O BnO

P(O)(OEt)2

BnO

BnO

P(O)(OEt)2

BnO

OBn

OH

OBn OBn

(279) O

(280)

OH P(O)(OEt)2

BnO

OBn OBn (281)

Figure 50

compounds (aldehydes and ketones) in the presence of samarium iodide. Similar reaction of iodomethylphosphonate (277) with esters leads stereoselectively to 2-oxoalkylphosphonates (278). The above protocol has also been applied to convert D-arabinonono-1,4-lactone, D-mannono-1,5-lactone and L-rhamnono-1,5-lactone into the 2-hydroxyphosphonates (279), (280) acid (281) respectively (Scheme 71) (Figure 50).128,129

217

Organophosphorus Chem., 2006, 35, 169–264

(3R,4S)-3,4-Dihydroxy-5-oxohexylphosphonic acid (282), an isosteric analogue of 1-deoxy-D-xylulose-5-phosphate (DXP), the ﬁrst C5 intermediate in the MEP pathway for isoprenoid biosynthesis has been synthesized from (þ)2,3-O-benzylidene-D-threitol (283) by a seven step reaction sequence. This phosphonate (282) was next enzymatically converted into (3R,4R)-3,4,5-trihydroxyphosphonic acid (284), an isosteric analogue of 2-C-methyl-D-erythritol4-phosphate (Scheme 72).130 Enzymatic alcoholysis of 3-chloro-2-chloroacetoxy, 3-azido-2-chloroacetoxy and 1-chloro-2-chloroacetoxypropyl phosphonates (285), (286) and (287) catalysed by immobilized mucor miehei lipase (IM) and candida antarectica lipase B was a particularly effective method for the formation of the corresponding highly enriched enantiomerically chloroacetoxyphosphonates (288), (289) and (290). Kinetic resolution by specially selected reaction sequences led to phosphocarnitine (291), phosphogabob (292) and phosphomycin (293) respectively (Scheme 73).131

3.1.5 Oxoacids. It has been shown that Cobalt(0) or magnesium-mediated reactions of a-halomethylphosphonates (294) with esters constitute a novel approach to 2-oxoalkylphosphonates (295) (Scheme 74).132 A versatile method for the preparation of diverse range of a-ketophosphonates (296) involves the alkylation of 2-(diethoxyphosphonyl)- 1,3-dithiane (297) followed by hydrolysis of the resulting 2-alkyl-2-phosphonyl- 1,3-dithianes (298) (Scheme 75).133 Acylation of methythio-1-lithiomethylphosphonate (299) with 2 0 - and 3 0 substituted benzoyl chlorides (300) constitutes an efﬁcient synthesis of diethyl 1-methylthio-2-oxo-2-phenylethylphosphonates (301) (Scheme 76).134 Phosphonoformic acid (PFC) – amino acid P-N conjugates (302) have been obtained via coupling of C-methyl PFA dianion (303) with C-ethyl-protected amino acids which gave stable monoanionic intermediates (304) that resisted PC cleavage during subsequent alkaline deprotection of the two carboxylate ester groups (Scheme 77).135 An a-phosphono lactone derivative of farnesol (305) has been prepared in both optically-inactive and -active forms to provide new analogues of farnesyl O

OH synthesis

O

OH

(283) OH P(O)(OH)2

O OH

DXP reductoisomerase

OH P(O)(OH)2 OH

(282) Scheme 72

OH

(284)

(285)

P(O)(OEt)2

IM/BuOH Cl (288)

P(O)(OEt)2

OCOCH2Cl

(286)

P(O)(OEt)2

CALB/BunOH N3 (289)

benzene

CALB/BuOH

(290)

Cl

P(O)(OEt)2

OCOCH2Cl

Scheme 73

Reagents: (i) K2CO3/MeOH, (ii) Me3SiBr/MeOH, (iii) K2CO3/H2O

Cl (287)

P(O)(OEt)2

OCOCH2Cl (i), (ii), (iii)

P(O)(OEt)2

OCOCH2Cl

Reagents: (i) K2CO3/MeOH, (ii) Pd/C, (iii) Me3SiBr/MeOH

N3

OCOCH2Cl

H

H

H3N

ClMe3N

P(O)(ONa) (293)

O

(i), (ii), (iii)

(i), (ii), (iii)

Reagents: (i) K2CO3/MeOH, (ii) aq NMe3/MeOH, (iii) Me3SiBr/MeOH, dowex

Cl

OCOCH2Cl

(292)

OH

(291)

OH

P

O O-

OH

P(O)(OH)2

218 Organophosphorus Chem., 2006, 35, 169–264

219

Organophosphorus Chem., 2006, 35, 169–264 O

O +

R1

OR2

L4Co(0) or Mg THF, rt

XCH2P(O)(OEt)2 (294)

L = Me3P, Ph3P X = Cl, I R1 = Alk, Ar, Heteroaryl R2 = Me, Et

P(O)(OEt)2

R1 (295)

Scheme 74

H

R (i), (ii)

S

P(O)(OEt)2

S

O

S

P(O)(OEt)2

S (298)

(297)

(iii) or (iv) R

P(O)(OEt)2 (296)

Reagents: (i) LDA, THF, -78 ° C, (ii) R-Hal, (iii) AgNO3, Br2, MeCN, H2O or (iv) AgNO3, NBS, MeCN/H2O

Scheme 75

O

S

O Cl

P(O)(OEt)2 + R

1. BuLi 2. LDA

P(O)(OEt)2

THF, -78 ˚ C to rt

R S

(299) (300)

(301)

R = 2'-MeO, 2'-Me, 2-F, 2-Cl, 2-Br, 3-MeO, 3-Me, 3-F, 3-Cl, 3-Br, 3-NO2

Scheme 76 CO2Et O

O

O 1. BTMS

MeO

P OMe

2. NaOH OMe

-

O

O

R

P O(303)

OMe

CO2Et

NH3Cl-

EDC, NaOH

R

N H

O

O

P

O(304)

OMe

NaOH CO2i

i

R = Pr , Bu , Bz

R

N H

O

O

P O-

O-

(302)

Scheme 77

pyrophosphate. The best of the examined synthetic strategies appeared to be that based on generation of enolate from racemic or enantiomerically enriched farnesyl lactone (306) followed by trapping the enolate with diethyl phosphonochloridate and oxidation (Scheme 78).136

220

Organophosphorus Chem., 2006, 35, 169–264 O

O

(i), (ii), (iii)

O

O

2

2

(305)

(306)

P(O)(OEt)2

Reagents: (i) LDA, (ii) ClP(OEt)2, (iii) [O]

Scheme 78

O

O R N

1. base 2. ClP(O)(OEt)2 3. H2O2

P(O)(OEt)2

R N (308)

(307)

R= 2

Scheme 79

O R N (307)

O 1. LDA (2.2 eq)

P(O)(OEt)2

R N

2. ClP(O)(OEt)2 (2.3 eq) 3. H2O2 94%

P(O)(OEt)2 (309)

R = n-Octyl, 2

Scheme 80

It has been demonstrated that the reaction of a lactam enolate with diethyl phosphoro-chloridate and subsequent oxidation is an equally attractive method for transformation of different N-farnesyl lactams and imides (307) to the corresponding a-phosphono lactams (308) (Scheme 79).137 Analogous reaction sequences performed in the presence of excess base and phosphonylating reagent diethyl phosphorochloridate provided a series of new a,a-bisphosphonates (309) (Scheme 80).138 A method for the simple synthesis of phosphonothioates (310) or phosphonothioic acids (311) has been reported. It uses standard reagents and should be applicable to the preparation of phosphonothioic acids bearing a range of functional groups (Scheme 81).139 Catalysed by Cs2CO3 and TBAI a mild and efﬁcient one pot three component coupling was performed using dialkylphosphite, CS2 and alkyl halide leading to phosphonodithioformates (312) (Scheme 82).140

221

Organophosphorus Chem., 2006, 35, 169–264 O

S R

P

OMe

(i), (ii)

R

P

SMe

R

OMe

OMe

O-

O (iii), (iv)

S-

P

R

OH

P

S

OH (311)

(310) R = Pr, Bz, -(CH2)5CO2H, -(CH2)5CO2Me Reagents: (i) NMe3, (ii) MeI, (iii) Me3SiI, (iv) H2O/base Scheme 81

O (R1O)2P H

Cs2CO3, CS2, R2X TBAI, DMF, 23 ˚ C

R1O

O S

P C

R1O

R2

S

O

X

S

1

(R O)2P SR2 (312) Scheme 82

3.1.6 Aminoalkyl and Related Acids. Various 1-aminoalkylphosphonic acids (313) have been obtained in high yield by microwave assisted reaction of ammonium hypophosphites (314) with aldehydes (Scheme 83).141 The same methodology has been successfully used in a simple synthesis of 1aminoalkylphosphonates (315) from 1-hydroxyalkylophosphonates (316) and amines (Scheme 84).142 1,2-Diamino-, 1-amino-2-hydroxy and 1-amino-2-chloro-2-phenylphosphonates (317) have obtained in a stereo- and regio-selective manner from 2-amino1-hydroxy-2-phenylethylphosphonate (318) through the intermediacy of an aziridinium ion (Scheme 85).143 The ﬁrst enantioselective synthesis of 1-aminoalkylphosphinic acids (319) based on the addition of phenylphosphinate (320) to chiral imines (321) and standard removal of protecting groups from the adducts (322) has been realized (Scheme 86).144 It has been found that addition of metalated isothiocyanomethylphosphonate (323) to aldehydes is a convenient route to diastereomeric, cis- and trans-5substituted-(2-thio-oxazolidin-4-yl)phosphonates (324) which can be smoothly converted by a three step reaction sequence into syn- and anti- N-Boc 1-amino2-hydroxyalkylphosphonates (325) respectively (Scheme 87).145 Condensation of the new pentacoordinate oxaphospholene (326) with azadicarboxylate, followed by reduction of the resultant ketone (327) produce cis- and/or trans-oxazolidones (328), potential precursors to phosphonate

222

Organophosphorus Chem., 2006, 35, 169–264 O

O R1NH3O

P

H +

R2

CHO

H C

R2

MW 0.5-2 min

P

OH

NH H

H (314)

R1 (313) Scheme 83

H C

R

P(O)(OEt)2

R1NH2/Al2O3 MW / 3-7 min

R

OH (316)

H C

P(O)(OEt)2

NH R1

R = Ar, Alkyl, Alkenyl R1 = Ar, c-Hex

(315)

Scheme 84

Bn2N Ph

H P(O)(OMe)2

H

OR (318)

(ii)

Ph

H

NBn2 P(O)(OMe)2 H

X (317)

R=H (i) R = Ms Reagents: (i) MsCl, NEt3, CH2Cl2, (ii) BnNH2, NEt3; or Bn2NH, NEt3; or Et4N+Cl- ; or H2O-SiO2

Scheme 85

analogues of sphingomyelin, sphingosine 1-phosphate and ceramide 1-phosphate (Scheme 88).146 Catalytic hydrogenation of cis N-Boc aziridine 2-phosphonates (329) derived from 3-amino-2-hydroxyalkyl phosphonates affords N-Boc a-amino-2-phosphonic esters (330) regioselectively (Figure 51).147 The reaction of oxazolines (331) derived from L-serine with diethylphosphite leads to a mixture of racemic a- and b-phosphono alanines (332) and (333). This new reaction proceeds without the use of any halogenated intermediate, and offers a simple route for various phosphonoamino acids bearing suitable protecting groups (Scheme 89).148 A modular method for the construction of polypeptides (334) containing the Phe-Arg phosphinic acid isostere has been reported (Figure 52).149 A new and facile synthesis of various 2[alkylamino(diethoxyphosphonyl)methyl] acrylic esters (335) has been developed. They constitute intermediates of choice to each a-methylene-b-functional azetidinones (336) through a tandem: hydrolysis-intramolecular lactamization (Figure 53).150

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Organophosphorus Chem., 2006, 35, 169–264

O P EtO

toluene 60-70 °C

R1 +

H

N

O *P

S

H

*

EtO R2

(320)

H N

R1

(321)

S R2

(322)

(i), (ii), (iii) R1 = Ar, Bui R2 = Me, CH2OMe O P

NH2

*

EtO

(319)

R1 Reagents: (i) HBr-AcOH, (ii) propylene oxide, (iii) H2, Pd/C

Scheme 86

P(O)(OEt)2

R

R

P(O)(OEt)2

O (EtO)2P

NCS

(i), (ii)

(iii) NH

O

NBo c

O

(323) S cis- (324)

S (iv)

OH

R P(O)(OEt)2

R

P(O)(OEt)2

(v) NBoc

O NHBoc anti- (325)

O

R = But, Pri, Ph-CH=CH, 2-Furyl, Ph Reagents: (i) NaH, (ii) RCHO, (iii) Boc2O, DMAP, (iv) H2O2, HCO2H, (v) Cs2CO3, MeOH/H2O

Scheme 87

C13H27

O C13H27 H (i)

C13H27

P(O)(OEt)2 N

O P(OEt)3

Cl3CH2CO2C

NHCO2CH2CCl3 (327)

(ii)

O O (EtO)2P

O N H H (328)

(326)

Reagents: (i) Cl3CCH2CO2N=NCO2CH2CCl3, ZnCl, (ii) [H], Zn/AcOH, [H] = NaBH4, ZnBH4, LiBH4, BH3-DMS

Scheme 88

224

Organophosphorus Chem., 2006, 35, 169–264 Boc

Boc

N

HN

H2, Pd R1

R1

P(O)(OEt)2

P(O)(OEt)2 (329)

(330)

Figure 51

CO2R

O

O

(EtO)2P

HPO(OEt)2

CO2R

N

O

R = Me, Pri, All, Bn

(EtO)2P

+

CO2R

NHBz

Ph (331)

NHBz

( )- α

( )-β

(332)

(333)

Isolated yields α+β: 46-77 %; Ratio α/β ∼ 1:2 Scheme 89

Ph NH NHAc Tyr

N H

P O

N NHMe H

OH O

N H

NH2

Nap

(334)

Figure 52

P(O)(OEt)2 P(O)(OEt)2

EtO2C

NHR (335)

NR

O (336)

Figure 53

A number of 1- and 2-aminoalkanephosphonates (337) were successfully resolved by enzymatic, Candida antractic lipase B-catalysed acylation. The high enantioselectivity and preparative simplicity of these reactions makes them an attractive alternative for the preparation of optically pure aminoalkylphosphonates (Scheme 90).151

225

Organophosphorus Chem., 2006, 35, 169–264 NH2 R1

NH2

NH2 2

( )n

P(O)(OR )2

CALB, AcOEt

2

diisopropyl ether

R1

( )n

P(O)(OR )2 +

R1

( )n

P(O)(OR2)2

R1 = Me, Et R2 = Et, Prn, Pri n = 0, 1

(337)

Scheme 90

NHAc P(O)(OR)2

Ar

(i), (ii)

NHAc P(O)(OR)2 +

Ar Br

(338)

P(O)(OR)2

Ar Br

(339)

Reagents: (i) BrNHCOMe (2.3 equiv.); 5% (DHQ)2PHAL or (DHQD)2PHAL; 4% K2OsO2(OH)4; LiOH H2O (1.02 equiv.), 0-4 ˚ C; 71 mM in olefin; 1:1 MeCN/H2O, (ii) Na2SO3, 1h Scheme 91

R1

R2 P(O)(OEt)2

R3

R1

H2, Pd/C MeOH

R2 P(O)(OEt)2

R3

(341)

(340)

R1= H, CF3 R2= CF3, OH, CO2Me, CO2Et R3= CO2Me, CO2Et, NHCOPh, NHCO2But X R

P(O)(OEt)2 CF3

BunLi THF

R

CF3 P(O)(OEt)2

HX

(342) (340) R= CF3, CO2Me X= NCOPh, NCO2But, O Scheme 92

An original modiﬁcation of the Sharpless AA reaction using excess of Nbromoacetamide as nitrogen/bromine source appeared particularly useful method for the transformation of 2-aryl-vinylphosphonates (338) into syn-2aryl-2-amino-1-bromoethyl phosphonates (339) (Scheme 91).152 Two alternative routes to methyl- and triﬂuoromethyl- substituted b-amino and b-hydroxy phosphonates (340) via hydrogenation of vinylphosphonates (341) followed by aldol-type addition of ethylphosphonate to triﬂuoromethyl substituted imines (342) and carbonyl compounds have been elaborated (Scheme 92).153

226

Organophosphorus Chem., 2006, 35, 169–264

Oleﬁnation of aldehydes with a-silyl- and a-stannyl-stabilized phosphonate carbanions derived from cyclo-[L-AP4-D-Val] allow a (Z)-selective access to a,b-substituted vinyl phosphonates (343) that have been transformed into enantiomerically pure 4-alkylidene 4PA derivatives (344) (Figure 54).154 Electrophilic ﬂuorination of lithiated bis-lactim ethers derived from cyclo-[LAP4-D Val] (345) with commercial NFSi allow direct access to a-monoﬂuorinated phosphonate mimetics of naturally occurring phosphoserine (346) and phosphothreonine (347), in enantiomerically pure form and suitably protected for solid-phase peptide synthesis (Figure 55).155 A novel preparation of racemic and enantiopure forms of phosphocarnitine (348) from easily available 3-chloro-2-oxopropylphosphonate (349) has been accomplished. The Baker’s yeast catalysed reduction of (349) followed by kinetic resolution of the reduction product using AH-S AMNO lipase-catalysed acylation and ﬁnally standard exchange of chlorine atom for trimethylamine group are the key steps in the synthesis of enantiomers of phosphocarnitine (Figure 56).156 A general method based on sequential reactivitives of bis-bromocycloalkenes (350) has been elaborated for the synthesis of phosphonocycloalkenes (351), the

OEt

OEt

R

(EtO)2(O)P

N

N

2

2'

R

5

N

N (EtO)2(O)P

OEt

OEt

(343) R

R

NH2

NH2 (EtO)2(O)P

(EtO)2(O)P

CO2Et

CO2H

(344)

Figure 54

O

OEt

O

H2N

H2N OX

N N

F

F R

(EtO)2(O)P R

OEt (345)

Figure 55

OX

P(O)(OEt)2 (346)

R P(O)(OEt)2 (347)

227

Organophosphorus Chem., 2006, 35, 169–264 HO P

(EtO)2(O)P

Cl

NMe3

O

Bioreduction Enzymatic Kinetic Resolution

O

OH

(S)-(-) Phosphocarnitine HO

O

NMe3

P

(349)

O O

OH

(R)-(+) Phosphocarnitine (348)

Figure 56 AcHN

Br Br

(i), (ii)

( )n

CO2Et

1

AcHN

CO2Et

AcHN

2'

CO2H

(iv), (v)

(iii) Br

P(O)(OEt)2

( )n

P(O)(OH)2

( )n

( )n

(350)

(351)

Reagents: (i) diethylacetamidomalonate, NaH, (ii) LiBr, H2O, (iii) (EtO)2P(O)H, DABCO, (iv) Pd(PPh3)4, (v) HCl O H2N

H (Me2O)(O)P

CHN2

(353)

(i)

CO2H

(ii), (iii) H

O

P(O)(OMe)2 H

H

P(O)(OH)2

(352) H

Reagents: (i) [RhOAc2]2, (ii) KCN, (NH4)2CO3, (iii) HCl 6N

Scheme 93

O R

OH P(O)(OMe)2

NHBn R= Me, Pri, Bui, Bn, Ph

Zn(BH4)2 THF, -78° C 70-95 %

R

P(O)(OMe)2 NHBn (354) anti: 34-92 % de

Figure 57

constrained analogues of AP4. An additional congested AP4 analogue (352) has also been obtained by a Rh(OAc)2 catalysed intramolecular cyclopropanation of alkenylphosphonate (353) (Scheme 93).157 The reduction of N-benzylamino-b-ketophosphonates with Zn(BH4)2 shows excellent levels of anti-stereoselectivity to give preferentially anti- a-benzylamino-b-hydroxyphosphonates (354) (Figure 57).158

228

Organophosphorus Chem., 2006, 35, 169–264

Palladium-catalysed addition of amines to 2-vinyl-1,1-cyclopropane bisphosphonate (355) has proven useful as a simple way to a new class of 5-amino-3pentenyl-1,1-bisphosphonates (356) (Figure 58).159 An optimized protocol for the preparation of diﬂuoromethylene phosphonate (357) an analogue of b-aspartyl phosphate based on the coupling of protected aspartic acid chloride (358) with diﬂuoromethylphosphonate zinc reagent (359) has been described (Figure 59).160 A two step synthesis of the ﬁrst b-aminophosphotyrosyl mimetic (360) was carried out. Addition of ()(R)-tert-butanesulﬁnylamide to 4-phosphonomethyl benzaldehyde (361) gave chiral aldimine (362) which under treatment with the titanium enolate of methyl acetate produced the target compound with high diastereoselectivity (Figure 60).161 A convenient synthesis of new 2-substituted-2-(diethyl phosphono)-3-isopropenyl-2H-azirines (363) starting from phosphorylated allenes (364) has been developed (Figure 61a).162 Dimethyl thiophosphite was found to undergo diastereoselective addition to imines containing N-chiral auxiliaries derived from (S) and (R) phenylglycine and esters of different a-amino acids. This reaction gives ready access to a range of new a-aminophosphonothionates (365). Absolute stereochemistry of adducts resulting from the reaction conducted with (S)- and (R)-phenylglycine was unequivocally conﬁrmed by conversion to known enantiomeric phosphonophenyl glycines (Figure 61b).163 New g-ethoxycarbonyl- and a-amino-alkyl-hydroxyphosphinic acid derivatives (366) and (367) were conveniently prepared by Michael addition or Kabachnik-Fields reaction of a new precursor, benzyloxymethyl hydrogenphosphinate (368), with a,b-unsaturated esters or imines (Scheme 94).164 Phosphinic acid inhibitors (369) of Cathepsin C were synthesized by addition of methyl acrylate to the appropriate a-amino phosphinic acid and by

P(O)(OEt)2 +

R2NH

Pd(PPh3)4 2.5 mol%

R2N

P(O)(OEt)2

THF, rt

P(O)(OEt)2

P(O)(OEt)2

(355)

(356)

Figure 58

O

O

O Cl

O NH3 (358)

Figure 59

O

+

O

P

CF2ZnBr

F2 C O

O P O

O (359)

NH3

O

(357)

O

229

Organophosphorus Chem., 2006, 35, 169–264 O O

X

S

But

N

S

But

NH2

(BnO)2(O)P

H (BnO)2(O)P (362)

(361)

MeCO2Me, BunLi ClTi(OPri)3 O But

S NH

O OR

(BnO)2(O)P (360)

Figure 60 H R

Cl

R

1. NaN3

N

H

2. 80 ° C

(EtO)2(O)P

(EtO)2(O)P

(364)

(363)

R= H, HOCH2, Bun, n-C5H11

Figure 61a S

R

R2

N

(MeO)2P H R1

H

H N

(MeO)2(S)P R

R2

H N

(MeO)2(S)P

R1

R2 R1

R (365)

Figure 61b CO2Et

R2 H

O

N

P

N OEt

R2

R1

(367)

O

Ph

R

O

R1 EtOH 80 ° C, N2, 12h

P

O

R

OEt H

O

Ph

(368)

ButOK (0.2 equiv.) anh. THF

OEt P EtO2C

O

Ph

(366)

Scheme 94

N-terminus elongation of the adduct using the mixed anhydride procedure. The latter step appeared to be a suitable method for N-terminal extension of phosphinic pseudopeptide analogues without rearrangement during the hydroxyphosphinyl protection (Figure 62).165

230

Organophosphorus Chem., 2006, 35, 169–264 O

H N

OH P

HCl H2N

COX O

R

Non-competitive inhibitors

(369) R= CH2CH(CH3)2, Ph, Bz, PhCH2CH2 X= OH, OMe

Figure 62 O

O N Ar

P

O

Ph (374) 10 mol%

H

O

R

Ar

O O

Et2O

H

Ar

O R

P HN

(370)

Ar = 2-nitrophenyl (371)

But

Ar

(372) 81-99 ee

H2, Pd/C Ph

HO HO

R

P NH2 (373)

S

N O

N H

N H

N HO O

(374) But

O

But

Scheme 95

Ar Ar

N

P(O)(OEt)2

(375)

Figure 63

Thiourea-catalysed enantioselective hydrophosphonylation of imines (370) using phosphite (371) provides a general and convenient route to a wide range of highly enantiomerically enriched a-amino phosphonates (372). The deprotection of these products yields the corresponding a-amino phosphonic acids (373) (Scheme 95).166 It has been reported that 1-arylidene-1-amino-1-arylmethylphosphonates (375) can be conveniently prepared by direct reaction of hydrobenzamides with diethyl phosphite (Figure 63).166,167 1.3.7 Phosphorus Containing Ring Systems. 1-Acyl allyl phosphonates (376) exposed to the action of m-CPBA in the presence of MgSO4 are readily cyclized

231

Organophosphorus Chem., 2006, 35, 169–264

to provide 3-acyl-1,2-oxaphosphol-3-enes (377). Addition of alkyl cuprates gives rise to the corresponding trans-3-acyl-4-1,2-oxaphospholanes (378) stereoselectively (Scheme 96).168 The ﬁrst successful preparation of phosphorus-containing heterocyclic fatty acid derivatives has been presented. Reaction of a-keto allene (379) with trimethyl phosphite gave oxaphosphole derivative (380). Similar transformations with a-keto and a-chloro-a-ketoallenes (381) and (382) led to the formation of alkenylphosphonates (383) and (384), respectively (Figure 64).169 4-Iodophosphaisocoumarins (385) were obtained in good yields and with high regioselectivity by the reaction of 2-(1-alkynyl)phenylphosphonates (386) with I2 or ICl. This reaction represents the ﬁrst example of a phosphono iodocyclization onto a C-C triple bond (Figure 65).170 O

R1

(EtO)2(O)P

EtO

MCPBA, MgSO4

O O

O

CH2Cl2

R2

O

P

(376)

1. R2CuLi2I R1

R2

EtO

2. H3O+

P

O

O

R1 R

(377)

2

3

R

(378)

Scheme 96

Cl

OMe

O

O

P

O

P(OMe)3

H3C(CH2)5 (CH2)5CH3

toluene, ∆, 5d

(CH2)4CH3

H3C(CH2)5

(CH2)7COOMe

(CH2)7COOMe

(379)

(380) O O

O 1. P(OMe)3

MeOOC(CH2)7 (CH2)5CH3

P

O O

MeOOC(CH2)7

2. H2O

(CH2)5CH3

X

X X= H (383) X= Cl (384)

X= H (381) X= Cl (382)

Figure 64 R2

I R2 I2 or ICl

R1

P(O)(OEt)2 (386)

O

R1

P O (385)

Figure 65

OEt

232

Organophosphorus Chem., 2006, 35, 169–264

Conformationally constrained a-Boc-aminophosphonates (387), (388) (389), (390) and (391) were made via a transition metal catalysed Curtius rearrangement. The conformational constraint involved either a ring-closing metathesis reaction catalysed by the ﬁrst generation Grubbs catalyst or intramolecular cyclopropanation mediated by Rh2(OAc)4 (Figure 66).171 A two step synthesis of 2-oxo-2-vinyl-1,3,2-dioxaphospholanes and dioxaphosphorinane (392) involves transesteriﬁcation of diethyl phosphite with selected diols followed by palladium catalysed coupling of the resultant cyclic phosphites (393) with vinyl bromide (Figure 67).172 It has been observed that the reaction of methyl 2,3-di-O-benzyl-4,6-benzylidene-a(b)-D-glucopyranoside with triethyl phosphite and trimethylsilyl triﬂuoro-methanesulfonate leads unexpectively to seven-membered phostone (394). Removal of protecting groups from the phostone is also reported (Figure 68).173 The simple transformation of carbohydrate-derived g-hydroxyphosphonic acids (395) into the corresponding phostones (396) using standard acylation conditions has been described (Scheme 97).174

O

O

O

P O BocHN

O

BocHN

P(O)(OMe)2

P O

NHBoc (389) a

a (390)

a

(388) "potential" amine

ButO2C

P(O)(OR)2

tetrahedral carbonyl surrogate

R= Me, Allyl b Cl

P O

H O

b, a Ph BocHN

Ru

a=

NHBoc

O

PCy3

Cl PCy3 b = Rh2(OAc)4

P(O)(OMe)2 SO2

(387)

(391)

Figure 66 OH

O

EtO P

+ OH

EtO

H

130-140 ° C p= 150 Torr

O

O Pd(PPh3)4, (5 mol%) P

O (393)

Figure 67

H

vinyl bromide, NEt3 toluene, 70-100 ° C

O

O P O (392)

233

Organophosphorus Chem., 2006, 35, 169–264 EtO

O P

7

Ph

6

O

4

O BnO

5

O

2

1

3

BnO

OMe

(394)

Figure 68 OC20H41 P

HO

(i), (ii)

OH

OC20H41

HO

P

O HO

OR

O

HO

(395)

O

(396)

Reagents: (i) NEt3, (ii) Ac2O, Py Scheme 97 BnO

BnO

OH O

O

OH

6

BnO

P

(ii)

H (399)

BnO

OH

4

BnO

(398)

BnO

O P

5

P(O)(OEt)2 BnO

1

O

OH

(i)

P(O)(OEt)2

2 3

7

8

OAc

P(O)(OEt)2

O P

+

O BnO

OAc

(397)

Reagents: (i) (H)(OEt)P(O)CH2P(O)(OEt)2, (ii) Ac2O, Py

Scheme 98

The ﬁrst synthesis of arabino-conﬁgured cyclic phosphonomethylphosphinates (397) has been accomplished. The crucial step of this synthesis consisted in the condensation of H-phosphinylphosphonate (398) with hydroxyaldehyde (399) derived from D-arabinol derivative followed by cyclization of (398) induced under acylation conditions (Scheme 98).175 Intramolecular transesteriﬁcation of aminoalkylphosphinate (400) and direct intramolecular esteriﬁcation of the related phosphinic acid (401) provided a simple route to a new 2-oxo-1,4,2-oxazephosphinane (402) (Figure 69).176 Dimethylsulfonium methylide opening of the oxirane ring of erythrophospholane epoxides (403) constitutes a simple approach to the synthesis of one carbon atom homologated allylic alcohols of phospholane oxide (404) (Figure 70).177 A convenient preparation of a new class of 1-L-a-amino acid derivatives of 2-phospholene oxides (405) involves amination of () 1-chloro-2-phospholene oxides (406) with enantiomerically pure L-a-amino acid esters (407) (Figure 71).178 New phosphono containing pyrimidine analogues, diazaphosphinine oxides (408), were obtained by cyclization of metalated primary enamine phosphonates with nitriles (Figure 72).179

234

Organophosphorus Chem., 2006, 35, 169–264

O OH P

O O

OR

P

H

N H

N H

R= Me, H (401)

(402)

H

Figure 69

O

R

O

S

OR P

P THF, -20 ° C to rt (403)

O

OH (404)

Figure 70 O O

R1

O

Cl P +

R1

-78 ° C to rt

H (406)

R

O

Et3N, CH2Cl2 O

H O

NH P

NH3Cl (407)

(405) R

Figure 71

O OEt P N N H

R2

(408)

Figure 72

The eight membered 1,5,3,7-diazadiphosphocine-1,5-diacetic acid (409) was synthesized in a one pot reaction of glycine, formaldehyde and hypophosphorous acid in acidic aqueous medium (Figure 73).180

235

Organophosphorus Chem., 2006, 35, 169–264 O

OH P

HOOC N

N COOH

P HO

O (409)

Figure 73

( )n

( )n N

(EtO)2P(O)CH2CONHNH2 (410) OMe

N

NaOEt/EtOH, ArCHO toluene, reflux

N N

(411) Ar

n= 0, 1, 2 (412)

Figure 74

O

O

O

ROMP

P O EtO N2

R

H

R= Alkyl, Ar

(413) R

K2CO3, MeOH

H (414)

63-91% yield (87->95% purity)

Figure 75

3.2 Reactions of Phosphonic and Phosphinic Acids and their Derivatives. – Diethoxyphosphinyl acetic acid (410) has been used as a unique reagent for a one-pot transformation of aldehydes and alkoxyimines (411) into fused [5,5][5,6]- and [5,7]-3[(E)-2-arylvinyl] 1,2,4-triazoles (412) (Figure 74).181 ROMP gel supported 1-azo-2-oxopropylphosphonate (413) has been synthesized and the immobilized reagent successfully employed to convert a number of aldehydes possessing different substitution patterns into the corresponding terminal alkynes (414) (Figure 75).182 The [Rh2(OAc)4] catalysed cyclization of a-diazo-a-(diethoxyphosphonyl)acetamides (415) led to a- and g-lactams (416) and (417). Conformational and electronic effects responsible for trans-stereochemistry of the g-lactam ring

236

Organophosphorus Chem., 2006, 35, 169–264

closure were studied. It was found that the steric effect exerted by the Nsubstituent of the amide determined the stereoselectivity of the b-lactam formation. A similar reaction of diazo-a-(dialkoxyphosphoryl)acetate was not so effective (Figure 76).183 The feasibility of the use of acylphosphonates as a carbonyl group radical acceptor have been demonstrated. Radical cyclization of the acylphosphonate (418) in the presence of hexamethylditin gave the cyclopentanone (419) in 91% yield. Additionally, various electrophilic alkyl radicals from activated oleﬁns bearing a-electron-withdrawing groups smoothly reacted with alkenyl acylphosphonates (420). Furthermore, similar results were obtained with alkynylarylphosphonates (421) (Scheme 99).184 Arylphosphonic acids (422) have been discovered to react with a variety of alkenes in the presence of Pd(OAc)2 and Me3NO providing Heck-type adducts (423). The reaction requires TBAF as the activator (Figure 77).185 The ﬁrst example of the NaIO4 promoted oxidative C-P bond cleavage in a-aminophosphono acids has been observed. Strong evidence on its reaction mechanism was obtained from NMR, EPR and UVvis data collected by spectroscopic monitoring of the reaction.186 It has been demonstrated that under treatment with EtSLi diﬂuorophosphonomethyldithioacetate (424) undergoes clean monodeﬂuorination. Thioacylation of amines, aminoesters and aminoalcohols of the resultant ﬂuoromethyldithioacetate (425) led to ﬂuorophosphonothioacetamides (426)-both potential HWE reagents (Scheme 100).187 Self-catalysed Michael Addition reactions of selected nitroalkanes (427) with dicyclohexylammonium 2-(diethoxyphosphoryl)acrylate (428) afforded 4-nitroalkanoates (429) (Scheme 101). It was also demonstrated that the Nef reaction on the resulting primary and secondary 4-nitroalkanoates involved intramolecular catalysis by the carboxylic acid group.188 The conjugate addition of enolisable carbonyl compounds (430) to indoles appeared useful as a source of the phosphonates (431) and (432) (Figure 78).189,190 O-Phenylphosphonoamidates (433) including optically pure isomers were obtained according to a strategy based on hydrolytic removal of the phenoxy substituent from routinely accessible common precursor (434) and nucleophilic

O

O X (EtO)2(O)P

R (415)

X= P(O)(OEt)2 Y= O, NR1

Figure 76

Rh2(OAc)4

Y N2

O

X Y

+

(cat.)

Y R (416)

R

(417)

237

Organophosphorus Chem., 2006, 35, 169–264 EtO2C

CO2Et

EtO2C

EtO2C

CO2Et

CO2Et

- P(O)(OEt)2

(Me3Sn)2 hν I

O

O P(O)(OEt)2

P(O)(OEt)2

(418)

O

(419) (91%)

E

E

E

E

E

E

- P(O)(OEt)2

X X O

O

P(O)(OEt)2

P(O)(OEt)2

X

O

(420)

E

E

O

E

O

P(O)(OEt)2

(421)

E

E

E

O

P(O)(OEt)2

X

X

PhSH/AlBN PhSO2Br/AIBN

E= CO2Et X= SPh: E/Z= 1:12, 86% X= SO2Ph: E/Z= 1:32, 90%

Scheme 99

MeO MeO

P(O)(OH)2 +

Pd(OAc)2 Ar

Me3NO TBAF

Ar

(422) (423)

Figure 77 F

F SMe

(EtO)2(O)P

1. 2 equiv. EtSLi/THF -78 ° C to rt / 15h

S

H

F SMe

92% (425)

F

RNH2/NEt3 CH2Cl2 15h / 25 ° C

(EtO)2(O)P

2. H3O+ (424)

H

NHR (EtO)2(O)P S

S (426)

Scheme 100

exchange of a chlorine atom for the amine or amino acid ester moiety. (Scheme 102). The results of a study on the chemical behavior of (433) indicate that they may represent a new promising class of compounds useful for the design and construction of effective and speciﬁc inhibitors for serine protease family members.191

238

Organophosphorus Chem., 2006, 35, 169–264 R1

CO2-NH2(c6H11)2

(EtO)2(O)P

CO2-NH2(c6H11)2

(EtO)2(O)P

+

NO2 R2

(428)

NO2 (427)

R1= H, Me R2= H, Me, Et

R1

R2

(429)

Scheme 101 (EtO)2(O)P

O

CO2H R2

R3 2

R

1

R

(EtO)2(O)P

P(O)(OEt)2

R1

N H

O (430)

O

CO2H

R1 R3

(431)

R2

(432)

Figure 78

H N

O

O

P(O)(OPh)2

H N

O

(i), (ii), (iii), (iv)

O

Ph

P X

O

R

O

(434) (433)

X= NH R= Ph, Bz, (CH2)2CH(CH3)2 X-R = L-ValoMe Reagents: (i) 1M NaOH/dioxane/KF, (ii) SOCl2, (iii) nucleophile, NEt3, (iv) pH1

Scheme 102

O

R

P

N

1. base 2.E

O (435)

R= Bn, Pri

O

R

P

N O

E de up to 90%

Figure 79

The diastereoselectivity in the alkylation of N-substituted 2-oxo-2-propyl1,3,2-oxazaphosphorinanes (435) is inﬂuenced by the bulkiness of the nitrogen substituent. The a-carbanion derivatives of (435) when R ¼ CHPh2 and R ¼ CPh3 are unstable in the presence of DMPU and afford unexpected products (Figure 79).

239

Organophosphorus Chem., 2006, 35, 169–264

Studies of structurally related phosphonoamidates possessing P- and C-stereogenic centers indicated that the alkylation of diastereoisomer (436) is mostly inﬂuenced by the chirality of the asymmetric phosphorus atom, while the alkylation of l diastereoisomer (437) depends on a combination of both the chirality of phosphorus and carbon atoms (Scheme 103).192,193 It has been demonstrated that methylsulfanyl diﬂuoromethyl phosphonate (438) has an excellent potential as a freon-free source of phosphonodiﬂuoromethyl carbanion. A simple preparative procedure involving sequential treatment of the former with butyl lithium and different electrophiles allowed the preparation of a wide range of new ﬂuorinated building blocks (439) (Figure 80).194 Acylation of a-lithio-a-phosphonylalkyl sulfides (440) with carboxylic acid esters was utilized as a facile route to a-alkylsulfenyl substituted b-ketophosphonates (441). Keto-enol tautomerism of these new compounds in different solvents as well as regiochemistry of alkylation and acylation reactions and usefulness for HWE oleﬁnation reactions were studied (Scheme 104).195 It has been reported that xanthane derivatives of tetraalkylmethylene-1, 1-bisphosphonate (442) are smoothly added to different oleﬁns to give various functionalised geminal bisphosphonates (443) via a radical chain reaction initiated by lauroyl peroxide (Figure 81).196

Ph P

O N

O

E

E

Ph P

O N

CH2Ph

Ph +

O

P

O N

CH2Ph

O CH2Ph

(436) major

Ph P

O N

O CH2Ph

minor

E

E

Ph P

O N

O CH2Ph

+

Ph P

O N

O CH2Ph

(437) Scheme 103

(Pr iO)2(O)PCF2SCH3 (438)

Figure 80

1. ButLi, THF, -78 °C, 5 min. inverse addition 2. electrophile, -78 ° C, 1h 3. NH4Cl

(PriO)2(O)PCF2-E (439)

240

Organophosphorus Chem., 2006, 35, 169–264 O (R1O)2(O)P

R 2

BuLi

2

(R O)2(O)P

SR

base

RC(O)OR (440)

(R1O)2(O)P

OH (R1O)2(O)P

C,O-methylation

MeI

O

SR 1

AcX R

O-acylation

ArCHO

SR2

RC(O)C

R

CHAr 2

SR

SR2 (441)

Scheme 104 (R1O)2(O)P

(R1O)2(O)P

P(O)(OR)2

P(O)(OR)2

2

R S

OEt S

S

Lauroyl Peroxide (cat.) 1,2-dichloroethane

OEt

R2

71-82%

S

(443)

(442) 1

R = Me, Et R2= PivO(CH2)9, AcOCH2, CH3CO(CH2)2, TMSCH2, NCCH2, 4-ClC6H4OCH2, 4-BrC6H4N(SO2Me)CH2

Figure 81 R4

R2 R1

(EtO)2(O)P

+ O (444)

R3

Br R4

In THF HOAc

(EtO)2(O)P HO

R3 1

R

R2

(445)

Figure 82

Acyl phosphonates (444) have been converted into tertiary a-hydroxy alkenylphosphonates (445) through an indium mediated allylation. The allylation proceeds equally well with different allylic bromides and does not appear to be sensitive to steric hindrance at the b-carbon atom (Figure 82).197 The particularly high reactivity of N-benzyloxycarbonyl a-aminophosphonochloridate (446) has been shown to arise from intramolecular catalysis by the carbonate group. This reactivity is not diminished when the hydrogen of the NH moiety is replaced by an alkyl group or when alkylation of a-carbon impedes intramolecular nucleophilic attack at the phosphoryl center (Figure 83).198 Bacterial phosphonotriesterase has proven to be a useful catalyst in enzymatic hydrolysis of () aryl methyl phenylphosphonates (447). Stereoselectivity of the natural phosphonotriesterase can be manipulated by alternation of the pKa value of the leaving phenol. For the wild-type enzyme the stereoselectivity has been enhanced in excess of 3 orders of magnitude (Figure 84).199

241

Organophosphorus Chem., 2006, 35, 169–264 O BnO

O

O O

N H Cl (446)

P

O

- Cl

P

PriOH fast

OMe

BnO

O N P H PriO OMe

BnO

N H

OMs

Figure 83 O Ph

O

P

OMe

O

Ph PTE

P

O OMe

Ph

O

OH

+

H2O

OMe

P

X X

OH

X

(447)

Figure 84

R

P(O)(OEt)2

PPh3/DDQ/NH4SCN

R

P(O)(OEt)2

CH2Cl2, rt OH (448)

SCN (449)

Figure 85

Diethyl a-hydroxyphosphonates (448) were converted into the corresponding a-thiocyanatophosphonates (449) using triphenyl phosphine, 2,3-dichloro-5,6dicyanobenzoquinone and ammonium thiocyanate under neutral conditions (Figure 85).200 The ﬁrst aza-Perkov reaction between N-sulfonyltrichloroacetimidoylphosphonates (450) and hydrophosphoryl nucleophilic reagents led to C,N-diphosphorylated dichlorovinylsulfonamides (452). Intermediacy of the bis-phosphonates (451) in this transformation has been unequivocally corroborated (Scheme 105).201 A concise and straightforward hydrolytic kinetic resolution of () 1,1diﬂuoro-3,4-epoxybutylphosphonate (453) using a chiral Salen-Co complex was employed as a key step to obtain enantiomeric diols in 99% ee as important intermediates. The enantiomerically homogenous 1,1-diﬂuoro-2,3-dihydroxypropylphosphonates (454) and (455) were converted by stereoselective esteriﬁcation and deprotection into the novel phosphatase resistant analogues of lysophosphatidic acid and phosphatidic acid (456) and (457), respectively (Figure 86).202

242

Organophosphorus Chem., 2006, 35, 169–264

P(O)(OEt)2

P(O)(OEt)2 Cl3C

N

R2P(O)H

SO2Ar

N H (451)

(450)

P(O)(OEt)2

Cl

N

1,2-P

SO2Ar

Cl3C R2(O)P

Cl

SO2Ar

P(O)R2

- HCl

R= OEt, OPh

Cl

P(O)R2

Cl

N

SO2Ar

P(O)(OEt)2 (452)

Scheme 105 (S,S)-cat. (0.5 mol%)

OH F2 C

HO

P(O)(OEt)2

(R,R)-cat. (0.5 mol%)

F2 C

O

OH

P(O)(OEt)2 0.45 eq. H2O

0.45 eq. H2O (453)

(454)

F2 C

HO

P(O)(OEt)2 (455)

cat.: Salem. CoOAc O

O C17H33

O

C F2

OH (3S) and (3R) (456)

P(O)(ONa)2

C17H33

O O

C F2

O

P(O)(ONa)2

LPA analogue C17H33 PA analogue

(3S) and (3R) (457)

Figure 86

1. Pd(OH)2/C, H2 HCl-MeOH

R (EtO)2(O)P

1. BuLi N

O

2. Electrophile

N

(EtO)2(O)P

O 2. NaOH

R= Me, Prn, Bu Ph (3R, 5S, 7aS) (458)

R= Me Ph

Me (EtO)2(O)P

N H

(2S) (460)

(3R, 5S, 7aS) (459)

Scheme 106

Stereoselective alkylation of chiral oxazolopyrrolidine phosphonate (458) occurred with a complete retention of stereochemistry on the a-stereogenic center. Removal of the chiral auxiliary from the resultant diastereomerically pure phosphonates (459) by catalytic hydrogenolysis gave rise to enantiomerically homogenous a-substituted pyrrolidin-2-yl-phosphonates (460) (Scheme 106).203 Di- or tri-substituted vinylphosphonates (461), (462), (463) and (464) were selectively synthesized from 1-alkynylphosphonates (465) via intermediate phosphonates containing titanacycle (466), manipulated by Ti(O-iPr)4/2i-Pr MgCl (Scheme 107).204

243

Organophosphorus Chem., 2006, 35, 169–264 R1

P(O)(OEt)2

R2

H

(461) R1

R

i

Ti(OPr )2

P(O)(OEt)2

R3

1

R

P(O)(OEt)2

Pri

R3

R1

(465)

(462)

HO

(EtO)2(O)P 1

P(O)(OEt)2

H

R2

(463)

(466)

R1

O

P(O)(OEt)2 (464) R3

Ph HO

Scheme 107

Bun

P(O)(OEt)2

O

O M L2

Bun

P(O)(OEt)2

Bun

P(O)(OEt)2

H H OH

ML2= Ti(OPri)2

ML2= ZrCp2

OH

(467)

(468)

Scheme 108

Addition of zircona- and titanacyclopropane metallocenes to conjugated enones was investigated. Analysis of the products shows that the reaction course is strongly controlled by both the metallocyclic and the enone moiety. The zirconacycle affords the rearranged (467). On the other hand, rearranged adducts, 1,3-butadienylphosphonates (468) are formed when titanacycles are used (Scheme 108).205 a-Keto-b,g-unsaturated phosphonates (469) undergo Lewis acid catalysed cyclocondensation reactions to give hetero Diels-Alder products with cyclopentadiene, cyclohexadiene, dihydrofuran and dihydropyran with high endo stereoselectivity. Diels-Alder cycloadducts with cyclopentadiene (470) appear to be initially formed and undergo [3þ3] Claisen rearrangement in the presence of Lewis acid. These cyclocondensations are further examples of inverse electron demand hetero Diels-Alder additions where the diene acts as a 2p component (e.g. Scheme 109).206

244

Organophosphorus Chem., 2006, 35, 169–264

O

P(O)(OEt)2

O SnCl4

+

P(O)(OEt)2

SnCl4 O

(469)

P(O)(OEt)2 (470)

Scheme 109

(RO)2(O)P

R1

Ar-B(OH)2, Pd(PPh3)4 cat. or

R1

(RO)2(O)P

Br O

(Z and E)-isomers

Li

B

R= Aryl, Alkenyl

R2

O

(471)

R

NiCl2(dppf) (cat.)

Figure 87

But

But O

O P R

But (472)

O ButOOBut hν

O P R

But

Ar (473)

Ar

low reactivity towards O2

Figure 88

Synthetically attractive arylation and alkenylation of a-bromoalkenyl phosphonates (471) with organo-boranes and -borates have been performed. Arylation was successful with the aryl boronic acids and a palladium catalyst, while alkenylation proceeded best with alkenyl borates, and a nickel catalyst (Figure 87).207 Several benzo[d]-1,2-oxaphosphole 2-oxides (472) were examined as potential precursors of stabilized C-centered radicals (473) (Figure 88).208 The formation of phosphonates RP(X)(OH)OR 0 (R ¼ iPr, t-Bu, R 0 ¼ Me or i-Pr) from RP(X)(OH) NH t-Bu and R 0 OH in CDCl3 is non-sensitive to steric effects when X ¼ S but not when X ¼ O (>103 times slower with R ¼ t-Bu, R 0 ¼ i-Pr than R ¼ i-Pr, R 0 ¼ Me), pointing to a dissociative elimination – addition mechanism via metathiophosphonate intermediate (474) when X ¼ S but the usual associative SN2(P) mechanism when X ¼ O (Figure 89).209

245

Organophosphorus Chem., 2006, 35, 169–264 S R

S NHBut

P

R

P

OH

S NH2But

R

P

S R1OH

R

O

O

P

OR1

OH

(474)

Figure 89

O

O

O

Ar

Ar

P

P

O

Ar

ROH

P

O

O Ar OR HO O P Ar

ROH

(475)

P

OH

OR

Figure 90

O PhMeHC

O

P

NHOSO2Bn

PhMeHC

Ph

P

OSO2Bn

NHPh (476)

(477) Attack at P Attack at S ButNH2

ButNH2 O

O BnSO2O

-

+

PhMeHC

P

NHBut

NHPh (479)

PhMeHC

P

O- +

BnSO2NHBut

NHPh (478)

Scheme 110

Thermally induced and UV-light mediated alcoholysis reactions of 2,3oxaphosphabicyclo [2.2.2] octenes bearing sterically demanding substituents at the P-atom (475) with different alcohols were studied. The observed sensitivity to steric effects suggests that phosphonylation of alcohols follows two parallel pathways which are consistent with EA and SN(2)P (or AE) mechanisms (Figure 90).210 The intermediacy of phosphonoamidic-sulfonic anhydride (476) in the rearrangement of O-sulfonyl-N-phosphinoylhydroxylamine (477) with tert-butylamine was conﬁrmed. The observed products, phosphonoamidate anion (478) and phosphonic diamide (479) correspond to attack of tert-butylamine at sulphur and phosphorus atoms of the anhydride (Scheme 110).211

246

Organophosphorus Chem., 2006, 35, 169–264

It has been discovered that the one-pot reaction of alkynylzirconocenes with alkynyl imines (480), dimethylzinc and a zinc carbenoid, leads to unprecedented C,C-dicyclopropylmethylamines (481) as single isomers. This reaction proceeds via the rare bicyclo[1.1.0]butane intermediates (482). This novel methodology tolerates a number of common protecting groups used in synthesis (Scheme 111).212 Both Me-DuPHOS (483) and Me-DuPHOS monoxide (484) have been successfully used as chiral ligands in the copper catalysed highly enantioselective addition of dialkylzinc to N-phosphinoyl imines (485). A simple deprotection of N-protecting group from (486) provided a-chiral amines (Figure 91).213,214

R1

R

NHP(O)Ph2

1. Cp2ZrHCl 2. ZnMe2 3.

Ph

R1 (481)

NP(O)Ph2 Ph

R

(480)

4. Zn(CH2I)2 NHP(O)Ph2 R1 R

Ph

intermediate (482)

Scheme 111

O P

P

P

P

(484)

(483)

Me-DuPHOS (483) or Me-DuPHOS-oxide (484) N R1

R22Zn (2 eq.), toluene, 0 ° C

P(O)Ph2

HN

Cu(OTf)2 (10 mol%) H

(485)

Figure 91

P(O)Ph2

R1

R2 (486)

247

Organophosphorus Chem., 2006, 35, 169–264

The highly enantioselective and diastereoselective asymmetric Mannich–type reaction of N-phosphinoylimines (487) with hydroxyketone (488) was catalysed by (S,S) linked BINOL, affording N-phosphinylated aminoalcohols (489). The observed complementary anti-selectivity, in combination with the facile removal of diphenylphosphinoyl group make this reaction synthetically attractive (Figure 92).215 Systematic studies on the asymmetric Strecker reaction of N-diphenylphosphinoyl imines (490) catalysed by Gd(O-iPr)3 complexes with Dglucose derived ligands has been reported. A wide range of aliphatic, alicyclic, aromatic and heterocyclic imines were investigated. Particularly high enantioselectivity was obtained with the combined use of a catalytic amount of TMSCN and a stoichiometric amount of HCN as reagents and with a chiral gadolinium complex of (491) as the catalyst. The products were converted to disubstituted a-amino acids and their derivatives (Figure 93).216–218 The most effective route to aminoalcohol (493) was established by screening various stereochemically homogeneous N,N-disubstituted-, N-monosubstituted-amino alcohols and iminoalcohols as chiral additives to promote asymmetric addition of alkylzinc to N-diphenylphosphinoyl imine (492). The addition reactions that were performed in the presence of this compound resulted in excellent enantioselectivity (Figure 94a).219 Three deuterated analogues of 5-diethoxyphosphonyl-5-methyl-1-pyrrolidine N-oxide (DEPMPO) (494), (495) and (496) were synthesised and used to trap tert-butylperoxide radical (Figure 94b).220

Ph2(O)P O N

OMe

P(O)Ph2

cat. Et2Zn (4x mol%) cat. (S,S)-linked-BINOL (x mol%)

+ THF, MS 3A

OH

R

R

NH R

O

OMe

R OH

(x= 0.25 - 1 mol%)

(487)

(489)

(488)

(12 examples) yield: up to 99% ee: up to >99.5% dr: up to >98/2

Figure 92

N R1

P(O)Ph2 Gd catalyst (0.1-1 mol%) TMSCN (2.5-5 mol%) HCN (1.5 eq.) R2

(490)

EtCN, -40 ˚ C

O NC R1

HN

P(O)Ph2

R2

Ph2(O)P HO

up to 99% ee

O

F

HO

F

(491)

Figure 93

248

Organophosphorus Chem., 2006, 35, 169–264

Ar

N P(O)Ph2

chiral ligand (493)

R2Zn

Ar

toluene, rt, 48h

(492)

Ph

H N

*

N H

P(O)Ph2

OH

(493)

R

(a)

Ph

R= Et, 96-98% ee R= Bu, 95-97% ee

D

D D

(EtO)2(O)P N

D3C

O

(b)

D

D (EtO)2(O)P N

D

N

D3C

O

(494)

D

D (EtO)2(O)P

O

(495)

(496)

Figure 94 O

O

O

1

2

R OPCH2COR

O

ArOPCH2COR

OLi

OLi

(497)

(498)

Figure 95

H

(499)

P(O)(OEt)2

(EtO)2(O)P

(500)

P(O)(OEt)2

EtOOC

P(O)(OEt)2

(501)

Figure 96

It has been observed that the lithium salts of phosphono acetates (497) and (498) undergo base catalysed D/H proton exchange and C-OR esterolysis as well as acidic hydrolysis mediated by Th41 and Zn41 (Figure 95).221 Three new phosphonate derivatives of C60 methanofullerenes (499), (500) and (501) were synthesized. Their electrochemical behavior and the pathways involved in the retrocyclopropanation reactions were also investigated (Figure 96).222 Acid-base properties of (1H-benzimidazol-2-yl-methyl)phosphonate 2 (Bimp ) (502) were investigated. Evidence for intramolecular hydrogen bond formation in aqueous solution between (N-1)H and the phosphonate group was presented (Figure 97).223

249

Organophosphorus Chem., 2006, 35, 169–264 O

N

O-

P O-

N H Bimp2(502)

Figure 97 OR RO

P

O RO O

P* O

Ph

But

M Ph RO

P

Ph

But

M Ph

O RO

OR (503)

P

O

OR M= Sn, Si R= Pri, Et

(504)

Figure 98 O P(OPh)2 [Pd] Me (505)

O R.E.

MeP(OPh)2 (506)

Figure 99

The cyclization reaction of organosilicon and organotin compounds containing the O–C–O coordinated Pincer-type ligand {4-tertBu-2,6-[P(O)(OR)2]2C6H2} (R ¼ i-Pr,Et) has been studied. O18-labeling experiments revealed a mechanism according to which hypercoordinated trioganoelement cations (503) were transformed into benzoxaphosphastannols and benzoxaphosphasilole (504) respectively, depending on the identity of M (Figure 98).224 Transformation of intermediate complexes L2PdMe[P(O)(OPh)2] (505) into diphenyl methylphosphonate (506) has been studied using discrete model substrates. The electronic and steric effects of the supporting ligands were characterized by measurements of the reductive elimination rates from a series of complexes containing nitrogen- or phosphine-based ligands (Figure 99).225 The cycloisomerization of various 1,6-enynes containing a modiﬁed chain has been investigated to provide cyclopentanes (507) with a great potential as novel conformationally – restricted analogues of farnesyl diphosphate FDP (508) (Figure 100).226

250

Organophosphorus Chem., 2006, 35, 169–264 O

O

P

P

O O

O O

O (508)

FDP

O Z= O O

P or

O

Z van der Waals "hydrophobic" interactions

Z O

(507) FDP analogue

Electrostatic "hydrophilic" interactions

Figure 100

CONHOH

CF3

O OMe

N

NH

N O

P O

P

OEt

O

O (509) (510) N MTP EC50= 0.011 nM Hamster cholesterol lowering: -35% at 15 mg/kg/day

Figure 101

3.3 Selected Biological Aspects. – A novel series of phosphonamide based TACE inhibitors were discovered. The (S)- form of D-leucine derivative (509) showed potent inhibitory activity against TACE with a highly selective proﬁle. The different binding mode of this type of compound is likely to enhance its selectivity for TACE. The study reveals the potential of the phosphonamide derivatives as a new type of MP inhibitor, and provides a novel concept for the design of selective inhibitors.227 A number of newly synthesized (Figure 101) phosphonate esters were evaluated for their effects on microsomal triglyceride transfer protein activity (MTP) e.g. (510).228 A series of phosphonothioic acids (511) and corresponding phosphonic acids (512) have been synthesized and their inhibitory properties were compared towards human placental and E. coli alkaline phosphatases, the protein-tyrosine phosphatase from Yersinia, and the serine/threonine protein phosphatases PP2C and lambda. It was found that,

251

Organophosphorus Chem., 2006, 35, 169–264 O R

O

P

OH

R

OH

S OEt

P

R

OEt

P

O OH

HO

OH

O H N

P OH

phosphonic acid

phosphonothioic acid

(512)

(511)

N-cyclopentylcarbamoylphosphonic acid 3m IC50= 80nM on MMP-2 (513)

Figure 102 P(O)(OH)2 OH N

P(O)(OH)2

(HO)2(O)P R

HN (514)

P(O)(OH)2 CH3 (CH2)n (515)

COOH (HO)2(O)P NH2

IC50= 10 nM

(516)

R= OH, H

Figure 103

with some exceptions, differences in inhibitory properties were modest.229 Several alkyl- and cycloalkylcarbamoylphosphonic acids have been obtained which (in vitro) inhibit selectively MMP-2 and are effective in preventing tumor cell dissemination in vivo. Further, some of these compounds showed enhanced anticancer properties. It was found that N-cyclopentylcarbamoylphosphonic acid (513) is the most active compound in the series studied (Figure 102).230 The activities of bisphosphonates as inhibitors of the Leishmania major mevalonate/ isoprene biosynthesis pathway enzyme, farnesyl pyrophosphate synthase, have been reported. The results obtained represent the ﬁrst detailed quantitative structure-activity relationship study of the inhibition of an expressed farnesyl pyrophosphate synthase enzyme by bisphosphonate inhibitors and show that the activity of these inhibitors can be predicted within about a factor of 3 by using 3D-QSAR techniques.231 The bisphosphonate (514) was the most active (Figure 103).231–233 Bisphosphonates, e.g. (515), derived from fatty acids were shown to be potent inhibitors of Trypanosoma cruzi farnesyl pyrophosphate synthetase.234 2-Amino-3-phosphono propionic acid (AP3) (516) is a potent multisubstrate inhibitor of GFAT.235 Phosphonate substrates (517) were prepared and shown to act as competitive inhibitors of IM Pase, while product mimics (518) showed various inhibitory modes of action (Figure 104).236 The diastereoselective synthesis of a new class of potent phosphinic pseudopeptide metalloprotease inhibitors has been reported. A strategy to produce rapidly P01deversiﬁed phosphinic pseudopeptides (519) led to the identiﬁcation of inhibitors able to discriminate MMP-11 from other MMPS with a two-order magnitude of selectivity. This results conﬁrm the efﬁciency of phosphinic peptide chemistry for the development of highly selective inhibitors of zinc-metalloproteases (Figure 104a).237,238 The synthesis of phosphonate (520) and its use for

252

Organophosphorus Chem., 2006, 35, 169–264 O

R1 P

O

OH

OH 2

HO

XR

OH

XR2

HO

R1 and R2= alkyl X= O or NH

OH (518)

(517)

Figure 104 S

O H N Cbz

R

O

P

TrpNH2

OH O Ph R1 and R2= alkyl, X= O or NH

Diversification

H N Cbz

R

P

R TrpNH2

*

OH O Ph (519) Selective inhibitors of MMP-11

Figure 104a

the preparation of a Grb2 SH2 domain-directed tripeptide (521) has been reported. In extracellular ELISA-based assays (521), exhibits potent Grb2 SH2 domain binding afﬁnity (IC50 ¼ 8nM) (Figure 104) (Figure 105).239 The ﬁrst Grb2 SH2 domain binding ligands derived from carboxamidobased macrocyclization of the pTyr mimetic b-position (522) have been presented (Figure 105a).240 The enantiomers of a novel unsaturated phosphonocholine antitumor ether lipid (523) were synthesized and found to have differential antiproliferative effects against epithelial cancer cell lines. The basis of the enantioselective effects on the cells was investigated in SK-N-MC and SK-N-SH neuroblastoma tumor cells (Figure 106).241 The immunological characterization of (E)-4hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP) (Figure 106) (524) and its methylenediphosphonate analogue, HMB-PCP (525) has been described. With an EC50 of 0.10.2 mM, HMB-PP is significantly more potent in stimulating human Vg9/Vd2T cells than any other compound described so far. However, replacing the pyrophosphate by a P-CH2-P function abrogates the bioactivity drastically, with HMB-PCP having a EC50 of only 5.3 mM (Figure 107).242 An antigenic peptide analogue consisting of HIV gp 120 residues 421–431 (an antigen recognition site probe) with diphenyl amino(4-amidinophenyl)- methanephosphonate located at the C-terminus (a catalytic site probe) (526) was synthesized and its trypsin and antibody reactivity characteristics were studied (Figure 108).243

253

Organophosphorus Chem., 2006, 35, 169–264 O O

NH2

N H HN

OH H N

t

(Bu O)2(O)P

(HO)2(O)P

CO2But (520)

X

(a)

X= CH2CO2H

O O

O (521)

O NH2

H2N (HO)2(O)P

HN H N O

NH

O

(522)

O

(b)

O O

IC50= 600 µM

Figure 105 OC16H33 MeO

OC16H33

H

H

O

OMe

NMe3

P O

P O

O (S)

NMe3

O

(523)

O (R)

Figure 106

Prodrugs of FR900098 with increased oral anti-malarial efﬁcacy were obtained by masking the polar phosphonate moiety as acyloxyalkyl esters. The acyloxyethyl ester (527), which is expected to release only acetic acid and acetaldehyde upon hydrolysis in addition to the active compound, was at least twice as active as FR900098 (Figure 109).244 The metabolically stabilized LPA analogue, 1-oleoyl-2-methyl-rac-glycerophosphothioate (OMPT) is a potent agonist for the LPA3G-proteincoupled receptor. A new enantiospecific synthesis of both (2R)-OMPT and (2S)-OMPT has been described (Figure 109b).245

254

Organophosphorus Chem., 2006, 35, 169–264 O

O

HO O

P

P

O

O (524)

O P

O H2 C P

O

O

HO O

O

O

HMB-PP EC50= 0.1 nM

O

HMB-PCP EC50= 5.3 µM

(525)

Figure 107

H2N

R-Lys-Gln-IIe-IIe-Asn-Met-Trp-Gln-Glu-Val-Gly

antigen-recognition site probe detection tag or carrier-conjugation site

N H

NH2

P(O)(OPh)2

catalytic site probe

(526)

Figure 108

4

Structure

2-Ethoxy-2-oxo-1,4,2-oxazaphosphinanes (2S,5S)- and (2R,5S) (528) were synthesized. Both diastereomers were used in NMR and X-ray crystallographic studies that permitted unequivocal conﬁgurational assignment, as well as examination of the consequence of nO-O*PO stereoelectronic interactions on structural properties (Figure 110).246 1,3,2-Dioxaphosphorinane derivatives containing a substituent with different steric arrangement at the C5 position (529)–(532) have been prepared. Their conformations and conﬁgurations were determined by 1H, 31P NMR and X-ray crystallographic techniques. Both chair-twisted-chair and chair-boat equilibra were observed in solution. X-Ray analysis revealed in one case two independent molecules per asymmetric unit, one with chair and the other one with a boat conformation (Figure 111).247

255

Organophosphorus Chem., 2006, 35, 169–264 OH N

P(O)(OH)2

OH

O

N

P

O O

O

O O

O

O FR900098

O (527)

Figure 109a O C17H33

O

OCH3 S

O P

OH

HO

OMPT

Figure 109b

H

N

Ph

H

CH2Ph O

P

O

CH2Ph N

Ph

O

OEt P O

OEt (528)

Figure 110

R

R O

O O

O

P O OPh

O

O OPh

O

R O

O

O

O O

P O OPh

O (530)

Figure 111

O

(531)

R

O

O

P

(529)

R= Me, Ph, vinyl

O

O

O

O

P O OPh (532)

O

256

Organophosphorus Chem., 2006, 35, 169–264

Diastereomeric 5-tert-butyl-4-methyl-2-phenoxy-2-oxo-1,3,2-dioxophosphorinanes were synthesized and studied by NMR and computational methods, assuming a novel criteria in which the conformations and conﬁgurations depend upon the conformation and conﬁguration of the corresponding diol

GlcN I

GlcN II OH (HO)2(O)P

O

O

O

O

HO

O

O NH

O

O

O

O

OH

NH O P(O)(OH)2

OH O

O O

O OH

C10:0 (3-OH)

C10:0 (3-OH)

C12:0 (3-OH)

C12:0 (3-OH)

C12:0

C12:0 (2-OH) (533)

Figure 112 OR

OR RO

RO

P

P

O Cu

Cu

O H

O

O

N H

N P OR

Cu

O H

O P OR

H

O O RO

P OR

H

O

N

O RO

(534)

Figure 113

O O

N H

N

O RO

P

O

O N

OR RO

Organophosphorus Chem., 2006, 35, 169–264

257

precursors.248 The chemical structure of lipid A from the lipopolysaccharide of the plant-associated bacterium Pseudomonas cichorii (533) was elucidated by compositional analysis and the spectroscopic methods MALDI-TOF and 2D NMR (Figure 112).249 The synthesis and structural elucidation of a copper mononuclear complex (534) at three different temperatures 293, 203 and 93 K provides evidence for the involvement of phosphoryl oxygen in the activation of the O–H bond of the coordinated water molecule through intramolecular hydrogen bonding while additional intermolecular C–H–O interactions shed light on the role of natural ligands in the activation of phosphate ester linkages and provide useful snap-shots of various steps in metal-catalysed phosphate ester hydrolysis (Figure 113).250 References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.

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4 Nucleotides and Nucleic Acids; Mononucleotides BY M. MIGAUD

1

Methodologies

Despite rapid advances, the chemical synthesis of oligoribonucleotides remains a challenge as the perfect combinations of compatible protecting groups still wait to be established. Consequently, new protecting groups are being designed to facilitate oligoribonucleotide syntheses on solid supports. Pfleiderer has reported the use of acetals as new 2’-O-protecting groups suitable for the synthesis of monomeric building units (la-1) and their incorporation into oligoribonucleotides.’ 0

U

npeocGp

C-

n

A-

R= H, R1= ti

NCJ

R=OCOOnpe. R1= H R=OCOOnpe. R1= F

1 a4

DMTO

-Lo< 2a, B= Thy, R= H 2 b B= “Ade, R= H 2c, B=’‘Cyt.

R=H

2d, B=IbuGua. R = H 2e, B= T h y , R = OCHflHflCHa

OMe

He also used the 2-cyanoethoxy carbonyl group in the protection of 2’-deoxyribo- and ribo-nucleosides and described comparative kinetic studies that revealed valuable information about the ease and sequential deprotection of various blocking groups at different sites of the nucleobases.2 Guzaev has described the use of 2-(N-isopropyl-N-anisoylamino)ethylas an alternate phosphate triester protecting group to 2-cyanoethyl in the stepwise coupling of phosphoramidite nucleoside building blocks. While the phosphoramidite buildOrganophosphorus Chemistry, Volume 34

0The Royal Society of Chemistry, 2005 192

4: Nucleotides and Nucleic Acids; Mononucleotides

193

ing blocks (2a-e) were stable compounds with high hydrolytic stability, the phosphate triester could be quantitatively deprotected either on solid support by treatment with a polar organic solvent or under standard deprotection condition~.~

0 X= y-OAr

03a; B= T, At= Ph, X= 0 3b; B= T, AF 261-Ph, X= 0 3 ~ B= ; T, AF 4CI-Ph, X= 0 3d; B= T, At= 2 , 4 C l ~ P h , 0 3e; B= T, At= 3,4CIrPh, 0 3f; B= T, Ar= 3 , X l ~ P h X= , 0 3g; B= T, At= 2,4,6-CI-Ph, X= 0 3h; B= T, AF 4-N*Ph, X= 0 3i; B= T, At= 2,3,4,5,6-Cl~-Ph,% 0 3j; B= T, At= 2,3,4,5,6-F~-Ph,X= 0

*

*

4a; B= T, AF Ph, S S 4b; B= T, AF 2-CI-Ph, S S 4 ~ B= ; T, AF QCI-Ph, Xi S 4d; B= T, AF 2,4CIrPh, X= S 4e; B= T, AF 3,4-C1rPh, X= S 4f; B= T, AF 3,56IrPh, X= S 49; B= T, AF 2,4,6-CI-Ph, YF S 4h; B= T, At= QN+Ph, Xi S 4i; B= T, AF 2,3,4,5,6ClgPh, S S 4j; B= T, Ar= 2,3,4,5,6-Fs-Ph, X= S

B= N6-Bz-A, AF 4CI-Ph, X= 0

4k; B= N6-Bz-A, AF 4CI-Ph, X= S

31; B= N2-iBu-G, AF 461-Ph, X= 0

41; B= N2-iBuG, At= 4-CI-Ph, X= S

3m; B= N’-Bz-C, AF 4-CIPh, S 0

4m; B= N’-Bz-C, At= 4-CI-Ph, Xi S

3n; B= N6-Bz-A, At= 4-N*Ph,

4n; B= N6-Bz-A, AF 4-N%Ph,

3k;

X= 0

30; B= N2-iBuG, At= 4-NO;rPh, Xi 0 40; B= N2-iBu-G, At= 4-N+Ph, 3p; B= Nl-Bz-C, At= 4-NO;rPh, X= 0

X+ S X= S

4p; B= Nl-BzC, At= 4 - N q P h , X= S

A new one-pot method has been developed by Kraszewski for the synthesis of aryl nucleoside phosphate (3a-p) and phosphorothioate (4a-p) diesters! This method, based on H-phosphonate chemistry, employed diphenyl phosphorochloridate and a series of phenols. Depending on the substituents present on the phenols, oxidation conditions were optimized to avoid competing hydrolysis. A versatile procedure that permits easy access to H-phosphonoselenoate monoesters (5) has been developed by Stawinski. These monoesters, obtained by selenisation of a phosphinate using triphenylphosphine selenide in combination with trimethylsilyl chloride, reacted with a suitable nucleoside in pyridine/acetonitrile in the presence of diphenyl phosphorochloridate to yield

?

Se= P-

H

?

O=P-H I Se-

5

O RO w 6

194

Organophosphorus Chemistry

the H-phosphonoselenoate diesters This report complements the H-phosphonate and H-phosphonothioate methodologies for the preparation of biologically important phosphate analogues. Stawinski and Kraszewski have also developed a new procedure to prepare 2’,3’-O,O-cyclicphosphorodithioates via cyclic 4-nitrophenyl phosphite triesters, formed by reacting 5’-protected nucleosides with tri-(4-nitrophenyl)phosphite and pyridine in DMF. Subsequent stepwise sulfurisations yielded the cyclic H-phosphonothioates (7)and the cyclic phosphorodithioates (8).6A series of nucleoside-3’-0- (9a-h) and 5’-0- (10a-d) phosphorothioates have been prepared by Stec using 2-alkoxy-2-thiono-l,3,2oxathiaphospholanes. These phospholanes are readily converted into phosphorothioate monoesters via a one-pot procedure, by reacting a suitably protected nucleoside in the presence of 3-hydroxypropionitrile and DBU, with subsequent treatment with aqueous a m m ~ n i a . ~

Dmow DmoY7 9?

0 0

8a, B= U 8b, B= A 8 c , B= C 8d, B=G

7a, B= U

7b, B = A 7 c , B= C 7d, B= G

ROH

0, CS,P-Nk

1 Tetrazole

[’;<

2. Sa

R=

v

OR

2 NH40H

: 0-

“OV 0

z y

ga, B= N ~ - AY, = H,

-

1. H O C H S H S N DBUICH3CN -S-Y-OR

z=OAC

9b, B= NI-BZ-C, Y = H, Z= OAc 9c, B= N2-t-BUG, Y= H, Z= OAc 9d, B= T, Y= H, Z= OAc , = OH, ge, B= N ~ - AY

z=OAC

3, B= N’-BzC, Y = OH, Z= OAc 9g, B= N2-t-Bu-G, Y= OH, Z= OAc 9h, B= U, Y = OH, Z= OAc

o=p-sI

0lea, B= N ~ - A , lob, B= N’-Bz-C IOc, B= N2-t-Bu-G IOd, B= T

Acid salts of imidazole- and benzimidazole-related compounds have been evaluated as alternative promoters to the various activators developed for the condensation of a nucleoside phosphoramidite and a nucleoside. The acid/azole complexes were developed to circumvent some of the disadvantages most commonly encountered in both solution- and solid-phases. Azolium promoters were shown to achieve high yielding coupling reactions even with nucleosides of low reactivity.’ Hayakawa has also reviewed and broadened the recent phosphoramidite methodologies by describing the versatility of ally1 and allyloxycar-

195

4: Nucleotides and Nucleic Acids; Mononucleotides

bony1 groups for the protection of nucleoside bases and internucleotide linkages, respectively. Use of these protecting groups in combination with azolium promoters was reported to be beneficial in large-scale syntheses? In addition, he demonstrated that addition of 381 or 481 molecular sieves to a liquid-phase mixture of stoichiometric amounts of nucleoside phosphoramidite, nucleoside and appropriate promoter resulted in high yields and levels of purity.1° 2

Mononucleotides

2.1

Nucleoside Acyclic Phosphates.- 2.1 .I Mononucleoside Phosphate Derivatives. Zemlicka has reviewed recent progress achieved in delivering antiviral and

antitumor nucleoside analogues to their site of action by using lipophilic pronucleotides such as the phenyl phosphoralanilate derivatives." The syntheses and biological activities against HIV-1 replication of three novel AZT-phosphotriesters bearing an N-substituted L-tyrosine residue and a S-pivaloyl-2-thioethyl (SATE) group (lla-c)have been reported. These compounds were able to deliver the parent 5'-nucleotide efficiently via a mechanism that involves successively an esterase and a phosphodiesterase step.12 Mononucleoside phosphoramidate diesters (12a-b) bearing a SATE group and an alkylamino residue have been synthesised by the same laboratory from isopropylamine and the appropriate H-phosphonate diesters. While (12a)exhibited a significant anti-HIV effect, (12b) only displayed a moderate effect. This latter observation could be related to a Balzarini has reported the slower rate of decomposition of the pronu~leotides.'~ synthesis of a number of lipophilic, masked phosphoramidate derivatives (13a-d) of the antiherpetic agent (E)-5-(2-bromovinyl)-2'-deoxyuridine,designed to act as membrane-soluble prodrugs of the free nucleotide. The phosphoramidates were prepared from the nucleoside and the aryl-(aminoester)-phosphorochloridate in the presence of N-methylimida~ole.'~ RHN

0

n

N l 12a; R=H 12b; R=OH

I l a ; R= fBoc, Rq= tsu I l b ; R= H, Rq= tBu

.

COOR2 OH

13a; X= H, R=CH3, RI= H, R y CH3 13b; X= H, R=CH3, Rq= H, R p C H P h 1%; X= H, R= CH3, R1= CH3, R y CH3 13d; X= CI, R= CH3, Rq= H, RF CH3

196

Organophosphorus Chemistry

2’,3’-O-Ethoxymethylidene adenosine 5’-thiophosphoramidate (14) was synthesised, as a potential pro-drug, by reacting threonine, thiophosphoryl chloride, 2’,3’-ethoxymethylidene adenosine and triethylamine in a THF/pyridine mixture.15 As an alternative to the unsuccessful aromatic amino acid phosphoramidate pro-drug approach for the anticancer agent FdUMP, Borch reported the synthesis of phosphoramidates (15a-g), containing a labile aromatic group that undergoes intracellular enzymatic activation. Compound (15b)is a potent prodrug as it delivers FdUMP after enzymatic reduction and expulsion of the aromatic moiety, thus liberating the phosphoramidate anion, which spontaneously cyclises to cleave the P-N bond and yield the nucleoside monophosphate q~antitative1y.l~

15e; Rj=CH& R= 0

0

15f; Rj=F.

R=

4J-J 0

15g; R j = C H S R=

Methodologies to create functional and topological diversity in libraries of nucleoside phosphoramidates have been improved by the use of parallel solidphase synthesis. A representative 600-member library of dinucleoside phosphoramidates (16) and tri-nucleoside phosphoramidates (17) was synthesised from CGP-support-bound di- and tri-nucleoside H-phosphonates (5’-DMTprotected) and selected amines. The library was screened for antiviral activity against HBV and some of its members showed potent activity.” Sekine has reported the synthesis and anticancer activity of Phosmidosine (18) and its demethylated parent (19).The Phosmidosines were obtained by reaction of an appropriately protected 8-oxoadenosine 5’-O-phosphoramidite and N protected prolinamide in the presence of 5-(3,5-dinitrophenyl)-lH-tetrazole, followed by in situ oxidation with t-BuOOH to form the N-acyl phosphoramidate linkage. These syntheses required extensive work with regard to the choice of protecting groups on the adenine moiety, as this was crucial for successful P-N bond formation.’*

4: Nucleotides and Nucleic Acids; Mononucleotides

197 16 3'w-N~ 3'CA-Nx 3'GA-Nx 3'AC-Nx 3'CCNx 3'GCNx 3'TC-Nx 3'AG-Nx 3'CGNx 3GGNx 3'AT- Nx 3'CT-Nx S'GT-NK

3'AA-Nx 3'CRNX

3Il-Nx

3 UT-Nx

3'GkNx 3'AC-Nx 3'CC-Nx

3GCNX 3UCNX

3AG-Nx 3'CGNx 3GGNX 3AT-Nx

3CT-Nx 3GT-Nx

A, C . G . T deoxynbonucleosides

A, C, G, U 2 4 M e nbonucleosides

17

19

18

Ph..../O-; 0

1

0

20 sp

'OMe

ll 0

'OMe

20 Rp

M-GOESY was employed to establish unequivocally an S N 2 mechanism by which deoxyribonucleoside cyclic N-acylphosphoramidites (20Sp, 20Rp) condense with base-activated nucleosidic 5'-hydroxyls. This mechanism was consistent with the P-stereochemistry of related dinucleoside phosphorothi~ates.~~ Stawinski has investigated the configurational stability of dinucleoside H-phosphonates and the stereochemical course of their sulfurisation in the presence of diazabicyclo[5,4,0]undec-7-ene (DBU) using 31PNMR and found that, under the reaction conditions and irrespective of the type of protecting groups present on the nucleoside moieties, the H-phosphonate diesters did not undergo any

198

Organophosphorus Chemistry

detectable epimerisation at the phosphorus centre and the sulfurisation with elemental sulfur proceeded stereoselectively.2° Zhao has reported the preparation of alkyl thiophosphoramidate derivatives of 2',3'-protected adenosine (21a-d)and uracyl(22a-d) starting from 0-isopropyl phosphorodichloridothioate. The key step was the coupling of the protected nucleosides with alkyl methoxyaminoacyl thiophosphorochloridate in the presence of triethylamine?' Shaw has reviewed the various approaches to the synthesis of organophosphate-oligonucleosides and has further commented on their chemical and biophysical properties along with their interactions with various enzymes such as DNA-polymerases, and compared them to other members of the family of phosphorus modified nucleic acids.22She also reported the synthesis of Ptyrosinyl(P-0)-5'-P-nucleosidylboranophosphates (23a,b), as antiviral and anticancer prodrug candidates. The P-boranophosphates were prepared by reacting a phosphoramidite intermediate obtained from protected tyrosine and the protected nucleoside in the presence of lH-tetrazole, followed by in situ boronation of the phosphite triester intermediate. The two diastereomers were then separated by reverse-phase HPLC.23

s

S

0

21a: B= A, R= H 21b: B= A, R= CH3 21c: B= U, R= H 21d: B= U, R= CH3

22a: 22b: 22c: 22d:

B= A, R= H B= A, R= CH3 B= U, R = H B= U, R= CH3

2%: R'= OH, R"= H, B= 6-FU 23b: R'= N3, R"= H, B= T

0

H 24

25

The S-pivaloyl-2-thioethyl5-fluorophosphate derivative of 3'-azido-3'-deoxythymidine (24) was synthesised by Perigaud and evaluated for anti-HIV activity in an attempt to improve the biological activity of the mononucleoside 5'fluorophosphate parent. The fluorophosphotriester was obtained by treating the H-phosphonate diester in pyridine with iodine and triethylamine trihydrofluoride.24 Treatment of bis-(trimethylsilyl) hypophosphite with 3'-deoxy-3-C-(iodomethyl)- uridine resulted in substitution to give the corresponding 3'-C-methyl-

4: Nucleotides and Nucleic Acids; Mononucleotides

199

enephosphinate (25), a building block for oligo(ribonuc1eoside methylenephosphonate)s. Conditions to minimise competitive reduction of the iodomethyl group, which yields the 3’-deoxy-3’-C-methyl uridine derivative, were optimized via solvent and temperature conditions and gave a substitution/reduction ratio of 5:4 at best. Alternatively, the use of a trifluoromethanesulfonyl leaving group instead of iodide resulted in the formation of triethylammonium 2‘-0(tert-butyldimethylsilyl)-3’-deoxy-5’-O-(4-methoxy-triphenylmethyl)uridine 3’C-methylene-phosphinate in 93% isolated ~ield.~’In an attempt to bypass viral resistance to cytosine arabinoside (ara-C), believed to follow from mutational loss of ability to convert this pro-drug to the corresponding monophosphate, a-hydroxy phosphonate derivatives of cytosine and ara-C have been prepared. The 5-a-hydroxy phosphonate derivatives (26a-c)were either synthesised via an Abramov addition of diethyl phosphite on a suitably protected C-5’-aldehyde while the 6’-hydroxyphosphonates (27a,b) were obtained via a HornerWadsworth-Emmons condensation with subsequent AD-mix a oxidation.26 Agrofoglio has reported the syntheses of carbocyclic analogues of phosphononucleosides (28a-e).Compound (28a) was synthesised by introducing the heterocycle under Mitsunobu conditions, while compounds (28b-e) were obtained by building up the base around a cyclopentylamine moiety.27O-Alkyl-Hphosphonates of AZT (29a-e)and D4T (30a-e)have been prepared via a simple one-pot route under mild conditions and in reasonable isolated yields using phosphorus trichloride, followed by alcoholysis and dealkylation by triet hylamine.2’ Ismail reported the synthesis of the 1,2-unsaturated pyranosylphosphonates (31a-c) which are cyclic nucleotide analogues of 9-[2-(phosphonylmethoxy)ethyl] adenine (PMEA) and 1-[3-hydroxy-2(phosphonomethoxy)propyl]adenine (HPMPA). The 2,3-unsaturated pyranose precursor, obtained via a Ferrier rearrangement of 3,4,6-tri-O-acetyl-~-glucalin the presence of triethylphosphite, underwent deacetylation, double bond migration and tosylation to afford the intermediate which upon treatment with a nucleobase in the presence of NaH/DMF and deprotection, yielded ( 3 1 a - ~ )It. ~ ~ was also reported that, in addition to (31a),the 1,3-bis-alkylated nucleoside (32) was isolated in a 3:2 ratio. The methodology to prepare triazole analogues of Prepared from the novel phosphasugar nucleosides (33a-o)has been de~cribed.~’ bromination of 3-methyl-1-phenyl-2-phospholene 1-oxide, followed by treatment with sodium azide, the azidophospholane intermediate was then reacted via a 1,3-dipolar cycloaddition with various alkynes to yield the triazole derivatives. Nifantiev reported the preparation of (35a,b) from the nucleoside phosphites (34a,b),obtained by treatment of a chlorophosphite with d4T at 0°C in the presence of diisopropylethyl amine.31The phosphites (34a,b)underwent spontaneous rearrangement when warmed to RT, though in low yield, to yield (35a,b). The proposed mechanism for this new rearrangement would involve the possibility of an Arbuzov-Michaelis-type isomerisation. Colman has reported the synthesis of a nonhydrolysable reactive CAMP derivative (Sp)-adenosine-3‘,5’-cyclcic-S-(4-bromo-2,3,-dioxobutyl)phosphorothioate (36), which contains both reactive bromoketo and dioxo groups.

200

Organophosphorus Chemistry

HO OH

HO

26a

&

OH

26b

26c

NH2 I

NH2 I

6H

HO OH

2 7a

27b 0 II

Y\//N\

28a

OH

28b: 28c: 28d: 28e:

0

(+), X+ NH2, Y= N q (-), X= NH2, Y= NO;! (+), X= Y = NH2 (-), X= Y = NH2

0

RO--P-H

RO-P-H

0Y N3

2%: 29b: 29c: 29d: 2%:

B

R= Et R= iPr

30a: R= Et 30b: R= iPr 3 0 ~ R= : t-BU 30d: R=C& 30e: R= Cg15CH2

R= t-Bu R=C&I5 R= Cg15CH2

\I OH OEt

HO

31a: B=T 31b: B= N4-iPrCO-C 31c: B = A

32

4: Nucleotides and Nucleic Acids; Mononucleotides

20 1

33a: R1= CooMe, RF COOMe 33b: RI= COOEt, RF COOEt 3 3 ~Rq= : C H S H , R y CH+H 33d: R1= COOH,RF COOH

R1

OH

33e: R1= H,R y TMS 33f: R1= H, RF C(CH3)SH 33g: R1= C(CH3)$IH, RF H 33h: R1= H, R p C H m 33i: RI= CHflH, RF H 33j: RI= H, RT COOMe 33k: R1= CooMe, R y H 331: Rq= H, RF Ph 33m: R1= Ph, RF H 33n: R1= H, RF C(CH3)3 330: Rq= C(CH-j)3, R y H

This reagent was used as an effective affinity label of the catalytic site of the cGMP-inhibited CAMPphosphodiesterase. Compound (36)was prepared by the reaction of Sp-CAMPS, the S-isomer of the non-hydrolysable adenosine 3’3‘cyclic monophosphorothioate, with dibromobutanedione in methanol in the presence of t r i e t h ~ l a m i n e . ~ ~ 5-Fluoro-2‘,5’-dideoxyuridine-5’-S-thiosulfate (37) was synthesised from 5fluoro-5’-0-tosylo-2’-deoxyuridine and sodium thiosulfate pentahydrate in ethanol at reflux. This compound is a member of a larger family of analogues of dUMP, dTMP and 5-fluoro-dUMP which have been used to probe interactions with thymidylate s y n t h a ~ eEthyl . ~ ~ chloroformate was shown to be an effective promoter as an alternative to DCC in the preparation of l-[((S)-2-hydroxy-2oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine (cyclic HPMPC) from HMPC in large scale quantities and in high isolated yield as well as Hammer has reported the synthesis of nucleoside phosphoramidite derivatives bearing thiazole and thiazole N-oxide as the heteroaromatic base (38a,b).35 The thiazole derivative obtained by a Hantzsch cyclisation method was converted to the N-oxide C-nucleoside by peracid oxidation. Incorporation of the N-oxide thiazole phosphoramidite into DNA resulted in significant deoxygenation of the N-oxide heterocycle. A mechanism accounting for this reaction has been proposed and involved the formation of an N-oxide phosphite triester. To investigate whether 5-formyl-2‘-deoxycytidine(39)formation might be one cause of the C + T transition mutation frequently found in cytosine methylation sites, Matsuda has synthesised oligonucleotides containing (39) at specific sites and examined its miscoding proper tie^.^^ Oligonucleotides incorporating (39) were obtained from the parent oligonucleotides containing 5-( 1,2-dihydroxyethyl)-2’-

202

Organophosphorus Chemistry

deoxycytidine (40) by oxidation with sodium periodate. The phosphoramidite (40), incorporated into oligonucleotides by the phosphoramidite method with a DNA synthesiser, was synthesised by dihydroxylation of the S’DMT, 3’TBDMS-protected 5-vinyl-2’-deoxycytidine obtained after vinylation and amination of a protected 5-iodo-2’-deoxyuridine.

Dmo .N ‘X

0

0

NCCH~H+~

NiPr2 HO

38a;X= H 386;XF 0

6H

kH2XHAC DmvN” OAc

ZI

?

O V N d o

? -O-p=o c,

1 ,

O h

NCCHgHfl-P NiPr2

40

Thomas has described a general synthetic methodology to prepare 5’,6oxomethylene-tethered 5’-uracyl monophosphate (41) and 2’-deoxy 5’-uracyl monophosphate (42).37Such compounds could be used to probe the requirements that biomacromolecules have for binding their 5’-nucleotide ligands. The tether introduced low structural and electronic disturbance, preserved all the hydrogen bond donating and accepting recognition sites and reinforced the conformational restriction about the glycosidiclinkage most commonly found in the bioactive anti-form. 5’-0- (benhydryloxy- bis - trimethylsilyloxy) silyl -2’- bis- (2-acetoxyethoxy) methyl-3-methyl uridine-3’-phosphoramidite (43) has been prepared to probe the specific structural and stabilizing role of the natural base modification 3-methylpseudouridine in a specific loop of the 23s ribosomal RNA.38The choice of protecting groups was based on compatibility issues related to solid-phase RNA synthesis. The phosphoramidite derivative of N-nitrothymidine (44) has been synthesised and found suitable for oligonucleotide synthesis using a standard phosphite triester solid phase approach.39The N-nitrothymidine residues could be converted into a range of N3-modifiedthymidines by reaction with primary alkyl amines. Phosphoramidite derivatives of 4-nitroindazole N’ and N2-(2’-deoxy-PD-ribofuranosides) (45, 46) have been synthesised, their base pairing properties investigated and found to show ambiguous base pairing.40Seela has also reported the syntheses of the phosphoramidite derivatives of 8-aza-7-adenine

203

4: Nucleotides and Nucleic Acids; Mononucleotides

Ns-(2’-deoxy-ribonucleoside) and the 7-deazaguanine C8-(-2’-deoxyribonucleoside), compounds (47) and (48), respectively. Compound (47) was obtained from the glycosylation of 8-aza-7-deaza-6-methoxypurine with an appropriately protected a-halogenose while (48) was prepared from the reaction of 7-deazaguanine with 1-O-acetyl-2,3,5-tribenzoyl-~-~-ribofuranose in the presence of tin tetrachloride.“l

NiPq

0

O - d0

yo 0 43

Another type of convertible nucleoside phosphoramidite, a derivative of (5’s)5’-C-(5-bromo-2-penten-1-yl)-2’-deoxyribosylfuranosylthymidine (49), has been reported. The synthesis of this phosphoramidite was stereoselectiveand involved a Sakurai reaction between 5’-C-thymidine aldehyde and allyltrimethylsilane?2 Seela has reported the synthesis of the ribosyl-phosphoramidite derivatives of 7-bromo- and 7-iodo-8-aza-7-deazapurine-2,6-diamine (50a,b) from advanced synthetic precursors and of the bromo- and iodo-derivatives at the 5-position of uracyl phosphoramidite (51a,b). He further described the effect on base-pair stability due to their incorporation into oligonucleotide duplexed3 N’, 06-ethano-5’4- dimethoxytrityl-3’-0- (P-cyanoethyl-N, N-diisopropyl) phosphoramidite -2’-deoxyxanthosine (52) was prepared from 2’deoxyguanosine and incorporated into oligodeoxynucleotides in order to trap 06-alkylguanine alkyltransferase covalently bound to DNA. This deoxyxanthosine behaves as a very effective mechanism-based crosslinker between the human protein involved in DNA repair and the oligodeoxynucleotide strands.44 A palladium-catalysed cross-coupling reaction between a protected 8-bromo-2’deoxyguanosine and arylamines was employed for the synthesis of 5’-O-DMT3’-O-phosphoramidite-C8-arylamine-2’-deoxyguanosine (53a,b).45

204

Organophosphorus Chemistry

0

NCCHSHfl-y’

NCCHSHfl-

NiPr2

7‘ 0

NCCHSHfl-7

NiPr2

NiPr2

45

44

0

46

i-BuHN ,

NHi-Bu

DMIT)

47

51a; R= Br 51b; R= I

50a: R= Br; Rq= iBu 50b: R= I ; R1= BZ

49

NCCH$H$3-7’

48

N1Pr2

0

NiPq

52

53a; R= Bn, At= pC$14CH3

53b: R= CPE, AF pC914CH3

Seela has reported the syntheses of 2’-deoxyribosylphosphoramidites (54a-d) containing 7-deazapurines and pyrimidines carrying aminopropargyl side chains. The amino group of the side chain was protected by phthaloyl residues that are less labile than trifluoroacetyl and yet can be removed with ammonia under standard N2-alkylated and 06-allyl protected deoxyguanosine phosphoramidites, building blocks for oligodeoxynucleotide synthesis, were derived from cis- and trans- opened ( *)-7p, 8a-dihydroxy-9a,

205

4: Nucleotides and Nucleic Acids; Mononucleotides

lOa-epoxy-7,8,9, 10-tetrahydrobenzo(a)pyrene,(55,56), and ( -t)-7p, 8a-dihydroxy-9a, l0a-epoxy-7, 8, 9, 10-tetrahydrobenzo(a)pyrene (57, 58) and from trans-opened ( +)-3a, 4P-dihydroxy-la, 2a-epoxy-1, 2, 3, 4-tetrahydrobenzo(a)phenanthrene (59, 60). These protected phosphoramidites were obtained from the initial reaction of the diol epoxides with 06-allyl-3’,5’-di-0-(tertbutyldimethylsilyl)-2’-deoxyguanosine.Palladium-catalysed deprotection of the ally1 protecting group was carried out prior to release of the constructed oligonucleotides from the solid supp0rt.4~

DMTO

@:

R

‘NA R2

0

NCCH$2H$-Y’

NCCHSHfl-7 NiPq

0 N iPq

54a: R= CCCH2NHPth, R i = OH, RF NH(i-Bu) 54b: R= CCCH2NHPth, R i = N H k , R F H

5 4 ~R= ; CCCHzNHPth, R i = OH 54d; R= CCCH2NHPth, R i = NHBz

OAc

OAc

56

55

OAc

OAc

58

57

OAc

OAC

58

60

Tor has reported a versatile method for the site-specific incorporation of polypyridine Ru” and 0 s ” complexes into DNA oligonucleotides using solidphase phosphoramidite chemistry. Nucleoside phosphoramidites containing a [(b~y)~M(3-ethynyl1,10-phenanthroline)12 metal center covalently attached to +

206

Organophosphorus Chemistry

the 5'-position in 2'-deoxyuridine (61a,b) have been synthesised. The nucleosides incorporating the metal complex were prepared from 5-ethynyldeoxyuridine via a Sonogashira cross-coupling reaction with the coordination complexes [(bpy)2M(3-bromo-1,1O-phenan-throline)]2+(PFg')2.48 Hawkins has reviewed the various approaches to monitor subtle DNA interactions with other molecules through the use of pteridine nucleoside analogue probes.49She has also reported the synthesis of the phosphoramidite derivatives of two fluorescent adenosine analogues, 4-amino-6-methyl-8-(2-deoxy-~-~-ribofuranosyl)-7-(8H)-pteridone (62a) and 4-amino-2,6-dimethyl-8-(2'-deoxy-~-~-ribofuranosyl)-7(8H)-pteridone (62b). These compounds were selectively incorporated into oligonucleotides and used as fluorescent markers, providing information on DNA structure as it responds to binding or catalysis through interaction with other molecules.50

NCCHflHfl-y'

62a; R= H 62b; R= CH3

0 NiPq 61a; M= Ru 61b; M= 0 s

iPqN-

7 0

NiPr2

N-

/

0

ma: B= sMeU

6 4 : B= T

63b: B= Am

64b: B=

63c: B= GiBU

64c: B= @'A

63d: B= sM'%Bz

6 4 : B= hcG

Monaharan has developed a versatile synthetic route for the synthesis of 2'4[ ( N , N-dimethylamino)-oxyethyl] modified purine and pyrimidine nucleoside

phosphoramidites (63a-d) to be used as antisense oligonucleotide building blocks. In the syntheses of the purine-based analogues, the ( N , N dimethylamino)-oxyethyl group was introduced via a 2'-allyloxy nucleoside intermediate, while the pyrimidine-based nucleosides were obtained from the TBDMS-protected 2,2'-anhydro-5-methyluridinevia ring opening reaction in the presence of borane and ethylene glycol. The aminoxy derivatives were

4: Nucleotides and Nucleic Acids; Mononucleotides

207

prepared under Mitsunobu conditions with N-hydroxyphthalimide from the primary alcohols to yield the phthalimido derivatives that were subsequently deprotected with N-methylhydrazine. Subsequent reductive amination yielded the monoalkylated and the bis-alkylated aminoxy derivatives, which were subsequently converted to their phosphoramidite parents.51 Four 3’-0-([2-(2-nitropheny1)propoxy]carbonyl)-protected 5’-phosphoramidites (64a-d) were synthesised as building blocks for photolithographic in situ DNA synthesis occurring in the 5’- 3’ direction, thus allowing attachment of the oligonucleotides to the surface via their 5’-termini, while the 3’-hydroxyl groups were available as substrates for enzymatic reactions. The carbonates were prepared from the 5’-0-DMT, N - [4-( ter-but yl)phenoxy] acetamide protected 2'-deox ynucleosides by treatment with 2-(2-nitrophenyl)propylcarbonochloridate in the presence of 1-methyl-1H-imidazoleand molecular sieves. After 5’-0-DMT-deprotection, the terminal hydroxyls were converted to the phosphoramidites (64a-d)by reaction with cyanoethyl tetraisopropylphosphorodiamiditein the presence of pyridine hydrochloride.s2 Fidanza has also reported the synthesis of photolabile phosphoramidite reagents (65a-b, 66a-b, 67a-g, 68a-c) for applications in photolithographic synthesis of high-density oligonucleotide arrays. In their preparation, a series of purine and pyridine nucleoside derivatives reacted with 1-(3,4-methyledenedioxy-6-nitropheny1)ethylchloroformate either via the 3’- or the 5’- free hydroxyl group while the remaining alcohol was phosphitylated with cyanoethyl tetraisopropylphosphorodiamiditein the presence of diisopropylammonium tetra~olide.~~ OCHGHSN

{o O \O N O *

iR$-P

0

iPr$”‘OCHflHflN

x

0 R

‘

X

67a;R= NHPAC,X= H, Y= H 67b, R= NHpAc,X= NHpAc,Y=H 67c, R= OH. XABkH, Y=H

N A O

68a, R= H, X=NHPAC,Y= H 68b.R= CH3, X=OH, Y 4 68c.R= H, X S H , Y=OMe

67d,R=OH, X= ’*‘G, Y=H 67e.R= OH. X-H, Y= H

m, R= NHPAC, x= N

H ~Y=OW ~ ~ ,

w g , R= N H ~ & , H , Y= o ~ e

The syntheses, from glucose, of the phosphoramidite analogues of a 2-deoxyD-erythrose-derived adenosine carrying a C8-CH20-DMTgroup (69) and of a 2-deoxy-~-erythrose-derived uridine possessing a C6-CH20-DMTgroup (70) have been reported by V a ~ e l l a Pitsch . ~ ~ has described highly convergent syntheses of the phosphoramidite derivatives of a series of 2’-O-acetate-[3’-deoxy4’-O-(4,4’-d~methoxytrityl)-~-~-r~bopyranosyl]-pur~ne and pyrimidine ana-

208

Organophosphorus Chemistry

logues (71a-d) and their assembly using a DNA synthesizer into the corresponding p-DNA oligonucleotides. 55 0

0

0

iPr2N’ pxOCH-$H$N

iPr2N’

69

71a; B=T

72a; B= T

71a; B= 5CH3-CAC

72b; B= B#A

71c; B= GAC 71d; B= 2-NHiBU,6-NHmac-Purine

P-OCHGHSN iPr2N

Numerous novel conformationally constrained nucleoside analogues and their phosphoramidite derivatives have been reported. Leumann has described the synthesis and incorporation into a-DNA of fixed nucleoside analogues (FNA) (72a,b). The modified nucleosides were prepared from a tricyclic sugar surrogate via the classical Vorbruggen one-pot procedure, which mainly yielded the a-isomer. Protecting group manipulations were followed by conversion of the nucleoside analogues into their respective phosphoramidites in the presence of chlor o(diisopropy1amino)-P-cyano-ethox yphosphine and diisopropylet hyl amine.s6The synthesis of a locked tricyclic thymidine phosphoramidite (73), in which the furanose ring of this nucleoside adopted a perfect S-type conformation, has been described by Nielsen. 57 The phosphoramidite (1S, 3R, 4S)-3-(2-cyanoethoxy(diisopropylamino)-phosphinoxymethyl)-5-N-(4-monomethoxytrityl)-uracill-yl)-5-aza-2-oxabicyclo[2,2,1] heptane (74) was synthesised from the known 1-(3’-deoxy-@-~psicofuranosy1)uracyl in eight steps. This nucleoside derivative adopted an Stype furanose conformation and the secondary amino acid in the 4’-position allowed for incorporation into oligonucleotides using 5’+ 3’ directed oligonucleotide synthesis.58To evaluate the relationship between furanose conformation and anti-HIV activity, a series of analogues of known anti-HIV active nucleosides with the furanose locked in the N-type or in the E-type conformation have been synthesised. Masked 5’-0-monophosphate derivatives were prepared in order to see if the first phosphorylation step was a major obstacle for in vivo activity. The benzodioxaphosphoryl derivatives (75a-c)were prepared by treatment of the appropriately protected nucleoside parent with 2-chloro-4H-1,3,3benzodioxaphosphorine in the presence of diisopropylethylamine, and subsequent oxidation with tert-butyl peroxide. The 5’-0-(phenoxy-[ 1-(methoxycarbonyl)ethylamino]phosphoryl} derivatives (76a-c) were synthesised from the

4: Nucleotides and Nucleic Acids: Mononucleotides

209

0

0

74

cd@p

76a; R= N3, B= T 75c

R O '

76b; R= N3, B= A 76c; R= H; R= T

77 NHBz

\

Dm & )

0 78

79

nucleoside and a phosphorochloridate with N-methylimidazole as base.59The syntheses of 3'-O-phosphoramidites of bicyclic a-L-ribo-configured thymin- 1-yl (77), 5-methylcytosin-1-yl(78) and adenin-9-yl (79) nucleoside derivatives have been reported by Wengel. These building blocks have been used in automated oligomerisation for the production of a-L-ribo-configured locked nucleic acid oligomers.6' Wengel has also reported the synthesis of (lS, 5S, 6S)-6-hydroxy-5hydroxymethyl-1-(uracyl-l-yl)-3,8-dioxabicyclo-[3.2.l]-octaneand its conversion into the phosphoramidite derivative (80)that was used as building block for incorporation into oligodeoxynucleotides. Compound (80), expected to be re-

Organophosphorus Chemistry

210

stricted into a 04’-endo furanose conformation, was also prepared from 1-(3’deoxy-P-D-psicofuranosy1)uracylin 13 steps.61No serious steric constraints upon duplex formation were observed when such a bicyclic monomer was introduced into an oligonucleotide. A critical step in locked nucleic acid (LNA) monomer synthesis is the final phosphitylation of the 3’-hydroxyl group, for high purity and high yields are necessary for subsequent oligomerisation. Koch has reported that 4,5-dicyanoimidazole is an improved activator to 1H-tetrazole and pyridinium trifluoroacetate for the phosphitylation of LNA. It catalytically activates 2-cyanoethyl N,N,N’,N’-tetraisopropylphosphorodiamite in acetonitrile to yield the locked nucleoside phosphoramidite derivatives in quantitative yields. 62

N3

xAN N\ z/\/ovp~~~~w2

XAN

0

(W2(0)P,O~ 81a; X= H, Y= NH2, Z= 0 81b; X= NH2, Y= NH2, Z= 0 S I C ; X= NH2, Y= OH, Z= 0 81d; X= NH2, Y= CH3, Z= 0 81e; X= NH2, Y= NHCH(CHd2, Z= 0 81f; X= NH2, Y= N(CHd2, Z= 0 81g; X= NH2, Y= O C H $ H ~ H ~ ( O ) ( O H ) 2 ,Z= 0 81h; X= SCH3, Y= NH2 81i; X= NH2, Y= NH2, Z= S 81j; X= NH2, Y= OH, Z= S

83a; R= NH2 83b; R= CI

82a; XF H, Y = NH2 82b; X= NH2, Y= NH2 8 2 ~X;F CH3, Y= NH2 82d; X= NH2, Y= NHCH(CHd2 82e; X= NH2, Y= N(CH& 82f; XF NH2, Y= OCH$H$XH2P(O)(OH)2

83c;R= NH2 83d; R= CI

Balzarini and De Clercq have reported a novel subclass of acyclic pyrimidine nucleoside phosphonates (8la-j) and (82a-f) that are endowed with inhibitory activity against both DNA and retroviruses. Extensive SAR studies indicated that the 6-[2-(phosphonomethoxy)ethoxy] pyrimidines must bear an unsubstituted amino group concomitantly on both C2 and C4,or an amino on C2and an OH group on C4in order to display antiviral activity. In addition it was found that alkyl ether derivatives are preferred over alkyl thioethers. 63 The reaction of the acyclic 6-chloropurine nucleoside derivatives with guanidine in a DMF solution in the presence of BABCO yielded the 6-guanidinopurine parents, which were subsequently alkylated with diisopropyl2-chloroethoxymethylphosphonate in the presence of Cs2CO3 to yield the acyclic nucleoside phosphonates

4: Nucleotides and Nucleic Acids; Mononucleotides

211

(83a-d).64 Rosenberg has described the synthesis of 2’-C-alkoxy (84a-y) and 2’-aryloxy (85a-g) derivatives of N-(2-phosphonomethoxyethyl)-purinesand pyrimidines and reported on their biological activity to inhibit DNA viruses and retroviruses. These acetals were prepared from the diisopropyl vinyloxymethanephosphonate, yielding either 1-(2-bromo- 1-aryloxy)- or 1-(2iodo- l-alky1oxy)ethoxymethanephosphonates.Displacement of the halogen by the nucleobase under basic conditions generated the phosphonate nucleoside derivatives.65

HO B, , ) X

84a; B= A, R= l-Adamantanyl 84b; B= A, R= 2-Anidoethyl 84c; B= A, R= Elenzyl 84d; B= A, R= f-Butyl 84e; B= A, R= 2-Fluoroethy I 84f; B= A, R= Cy clohexy I 84g; B= A, R=8Nydroxy-3,6dioxaocty I 84h; B= A, R= 2-Hy droxy ethy I 84i; B=A, R= Methyl 84j; B=A, R= n-OctyI 84k; B=A, R= Phosphonomethyl 841; B= A, R= 2,2,2-trifluomethy I 84m; B= C, R= Ally1 84n; B= C, R= 2-Fluoroethy I 840; B= C, R= Methyl 84p; B= 2,6diaminopurine, R= 2-Azidoethy I 84q; B= 2,6diamino-purine, R= 2-Benmy loxy ethy I 84r; B= 2,6diamino-purine, R= 2-FluoroethyI 84s; B= 2,6diamino-purine, R= 2-Hy droxy ethy I 84t; B= 2aminebbromopurine, R= Ally I 84u; B= 2-amino-bbromopurine, R= 2-Benzoy loxy ethy I 84v ; B= 2aminob-brornopurine, R= 2Fluoroethy I 84w; B= G, R= Ally1 84x; B= G, R= 2-Fluoroethy I 84y ; B= C, R= 2-Hy droxy ethy I

85a; B= A, X= S 85b; B= A, X= 0 85c; B=c,x=o 85d; B= 2,6diaminopurine, X= 0 85e; B= G, X= 0 85f;B=T,%O 85g; B= u, x= 0

The synthesis of a number of phosphonate derivatives of methylenecyclopropane nucleoside analogues (86a-1) has been reported by Zemlicka.66Most were obtained by an alkylation-elimination approach. Starting from a methanesulfonate, methylenecyclopropane phosphonates were obtained by Michaelis-Becker reaction with alkyl phosphites and converted to vicinal dibromides, subsequently used for alkylation-elimination of nucleic acid type bases. All compounds were evaluated against herpes viruses, hepatitis B and HIV and were found to be inactive except for (86b), which was found to inhibit VZV proliferation. The synthesis of novel HBV-specific antiviral agents, the 2-amino-6-arylthio9-[2-(phosphonomethoxy)ethyl]purine bis (2,2,2-trifluoroethyl) esters (87a-r) has been reported. These phosphonate diesters were prepared by the reaction of substituted purines with bis-(trifluoroethyl) (2-iodoethoxy)methylphosphonate in the presence of DBU.67

Organophosphorus Chemistry

212

Racemic or chiral p-amino alcohols and diols were coupled with methyl difluoro(diethoxyphosphono)dithioacetate to give the corresponding P-hydroxythioaminides. These intermediates were then cyclised under Mitsunobu conditions in the presence of either 6-chloropurine or 3-benzoylthymine to yield nucleosidic base-derived thiazolines linked to a difluoromethylphosphonate diester (88a, b). 68

86a; B= A 86b; B= G 86c; B= C

86d; B=A 86e; B=G 86f;

86g; B=A 86h; B= G 86i; B= C

B=c

87a; R= SPh 87b; R= SPh(4-h) 87c; R= SPh(34e) 87d; R= SPh(2-h) 87e; R= SPh(4-Et) 87f; R= SPh(4-iPr) 879; R= SPh(4-NOi) 87h; R= SPh(4Cr) 87i; R= SPh(4-OMe)

86j; B= A 86k; B=G 861; B= C

87a; R= SPh(3-OMe) 87b; R= SPh(2-OMe) 87c; R= SPh(4-OEt) 87d; R= SPh(4-nPr) 87e; R= SPh(4-fPr) 87f; R= SPh(4-nBu) 87g; R= SPh(4-iSu) 87h; R= SPh(4-OCF3) 87i; R= S-O-naphty r)

0 HN-~

88a

88b

Bis(hydroxymethy1)phosphonic acid esters that incorporated thymine were employed as a backbone to prepare short oligonucleotide chains. This chain was prepared by condensation of the bis(4,4’-dimethoxytrityl) protected phosphonic acid and N’ or N3-(2-hydroxyethy1)thyminein the presence of 1-(2-mesitylenesulfonyl)-3-nitro-l,2,4-triazoleor by an Appel reaction with N’ or N3-(2aminoethy1)thymine (89a-b). Selective removal of one DMT-group and phosphitylation yielded the building blocks for solid supported synthesis of the short oligomers by the phosphoramidite approach.69Holy has reported the synthesis of 8-amino and 8-substituted amino derivatives of acyclic purine nucleotide analogues. The 8-amino, 8-methylamino- and 8-dimethylamino-adenine and -guanine analogues of N-(2-phosphonomethoxyethyl) and (S)-N-(3-hydroxy-2phosphono-methoxy-propyl) derivatives of purines (90a-i), were prepared by

213

4: Nucleotides and Nucleic Acids; Mononucleotides

either direct modification of the 8-bromopurine acyclic nucleotide analogues or by alkylation of the 8-modified purine bases with alkylating reagent^.^'

DMl-o-l o=P-x

(

& = o

O=P-X

-

0

N

0 RO-7 NiPr2

RO-P NiPr2 89a; R= C H S H S N ; % 0 89b; R= C H S H S N ; % NH 8 9 ~R=CH3% ; 0 89d; R= CH3; % NH

89e;R= C H S H S N ; % 0 89f; R= C H S H S N ; X= NH 89g; R= CH3 % 0 89h; R= CH3; X= NH

X

0 -

P(O)(OiPr)2

90a; X= NH2, Y= H, R73CH3, RF H 90b; X= OH Y= NH2, R13CH3, RF H 9 0 ~X= ; NH2, Y= H, R1=CH3, RF CH3 90d; X= OH, Y= NH2, Rq=CH3, RF CH3

2.1.2 Polynucleoside Monophosphate Derivatives. - Imanishi has reported the synthesis, hybridisation properties and enzymatic stability of novel oligodeoxynucleotide analogues that incorporated a 3‘-amino-2’,4’-bridged nucleic acid monomer nit.^' This modified nucleoside was introduced into the oligonucleotides as a heterodimer unit (91)composed of the protected 3’-amino2 ’ 4 , 4’4-C-methylene bridged nucleic acid and a phosphitylated thymidine moiety linked via a methyl phosphotriester linkage. In addition to some enhanced hybridisation properties towards complementary ssDNA, ssRNA and dsDNA, oligonucleotides incorporating this heterodimer unit were found to be more resistant to nuclease activity than phosphorothioate-modified oligonucleotides. Hakimelahi has reported a novel strategy for the synthesis of ”-purine acyclic nucleosides, in which the key step involves the reaction of [2-(pmethoxyphenyloxy)ethoxyl]methyl chloride and N9-tritylated nucleobases, followed by concomitant self-detritylation. 7-[(2-Hydroxyethoxy)methyl] guanine was phosphorylated by both HSV- and Vero-cell thymidine kinases to yield (92), and was found to have more potent cellular toxicity than acyclovir, while the adenine parent was phosphorylated by neither kinase. In addition, the N7adenine acyclic nucleoside phosphonate (93) was synthesised by alkylation of adenine with 3-bromopropionitrile to yield N9-(cyanoethyl)adenine,which upon

214

Organophosphorus Chemistry

treatment with methyl iodoacetate and 2,2,6,6,-tetramethylpiperidine, afforded the N7-alkylated isomer precursor. After reduction of the ester product, the phosphonate (93) was obtained by treating the terminal alcohol of the precursor with diethyl(p-to1uenesulfonyloxymethane)-phosphonatein the presence of sodium ter-butoxide. The dinucleotide 5’-monophosphate derivative of this acyclic nucleoside (94)and the butenolide ester (95)were synthesised in three steps from adenosine 5’-monophosphate by condensation of the silylated adenosine phosphate triester with (93) in the presence of trichloromethansulfonyl chloride in collidine and THF. After desilylation, the resulting dinucleotide (94)was treated with (Z)-4-(2-chloroethylideny1)2,3-dimethoxy-A-~~~-butenolide in the presence of base to afford (95).Both dinucleotides exhibited notable activity against DNA

Kinetic data for the cleavage of the 2-cyano-2-(hydroxymethyl)-3-methoxy-3oxopropyl group from the inter-nucleosidic phosphodiester bond of thymidylyl(3’+5’)-thymidine (96a) and its phosphorothioate analogue (96b) have been reported. The 3-(alkylamino)-3-oxopropylphosphorothioate analogue (96c), also prepared, showed that an aminocarbonyl substituent was able to induce cleavage of the conjugate group but at a rate 100-fold slower.73Scott has improved the synthetic route for the one-pot preparation of the dinucleotide hybrid 5’-O-phosphoryl-2’-deoxycytidylyl-(3’-+ 5’)adenosine.It involves the successive 1H-tetrazole-catalysed coupling of 2-cyano N,N,N’,N’-tetra-isopropylphosphorodiamidite with 4-N-benzoyl 5’-(4,4’-dimethoxytrityl)-2’-deoxycytidine and 6-N, 6-N, 2’-0,3’-0-tetrabenzoyladeno~ine?~ The synthesis of diastereomeric dinucleotides in which the phosphodiester linkages have been confor-

4: Nucleotides and Nucleic Acids; Mononucleotides

215

mationally restricted as a seven membered phosphepine ring (97a-d), has been reported by Nielsen. These analogues were synthesised from epimeric 5'-C-vinyl thymidine derivatives, which were used to access dinucleotides containing two terminal alkene moieties by standard phosphoramidite chemistry. These dinucleotides were then employed as substrates in ring-closure metathesis Stawinski has described synthetic methods for the preparation of dinucleoside 4-pyridyl-, 3-pyridyl- and 2-pyridyl- phosphonates and phosphonothioates. He showed that dinucleoside H-phosphonates and dinucleoside H-phosphonates could be efficiently converted into 4-pyridyl-phosphonothioates (98a)in pyridine in the presence of trityl chloride and DBU. 2-Pyridylphosphonates and their thio analogues (98b,c)could be obtained by treating the corresponding H-phosphonate or H-phosphonothioate derivatives with N-alkyloxypyridinium salts in the presence of DBU. Finally, the dinucleoside 3-pyridyl-phosphonates and phosphonothioates (98d,e) were formed in a palladium catalysed cross-coupling reaction of H-phosphonate and H-phosphonothioate diesters with 3-bromopyridine?6

?

97a

97b

0

97c

I

? Y-P=X I

w

0,

98a; X= S, Y = 4-Py ridy I 98b; X= 0, Y= 2-hridyI 98c; X= S, Y= 2-Pyridyl 98d; X= 0, Y = 3-FyridyI 98e; X= S, Y = 3-Py ridy I

97d

216

Organophosphorus Chemistry

Stromberg has investigated the mechanism of the coupling step of the H phosphonate approach to oligonucleotide synthesis by providing detailed kinetic studies of the pivaloyl chloride-promoted H-phosphonate condensation step in the presence of differently substituted pyridines. An intermediate, suggested to be a pyridinium adduct, was formed by the attack of the pyridine derivative on the initially formed mixed phosphonic carboxylic anhydride.77He also investigated the mechanism of iodine oxidation of protected 5’-(uridine3’-deoxy-3’-Cmethylenephosphinate) to the corresponding thymidine 5’-(uridine 3’-deoxy-3’C-methylene-phosphonate). The reaction, which occurred via a tricoordinated form of the phosphinate, proceeded either via an anion intermediate in the presence of triethylamine or via the neutral tautomer in the presence of pyridinium The synthesis and biological activity of dithymidylyl-3’,5’-phosphorofluoridate (99a) and dithymidylyl-3’,5’-phosphorothiofluoridate(99b) have been reported. Both fluoridates were obtained by fluorinolysis of the P-Se bond in appropriate dimethoxytrityl selenoesters. These compounds were found to be hydrolytically unstable and to be inactive as inhibitors of phosphodiesterases and alkaline pho~phatases.7~ Stec has described the synthesis of dithymidine boranophosphates by the oxathiaphospholane approach. The two diastereomers of the nucleoside-3’-O-oxathiaphospholane-borane (1OOa) complex could not be separated by chromatography but the mixture could be used for the non-stereocontrolled formation of the internucleosidic boranophosphonate bond by reaction of 5’-OH-nucleoside in the presence of DBU (scheme 1). A similar approach to dithymidine boranophosphorothioate from the dithiaphospholane (100b) was reported to be

9

F- P= X I

99a, X= 0

DMTov Dmov HO

0 I

+

‘H3B-P=X

AcO 100a, X=O IOOb, % S HO SCHErVE 1

Oligonucleotides with extended zwitterionic internucleotide linkages have been synthesised using two non-natural nucleosidic analogues, N 4 2 - h ~ -

217

4: Nucleotides and Nucleic Acids: Mononucleotides

droxyethyl)-2’,5’-dideoxy5’-aminoth ymidine and N-(2-h ydrox yet hy1)-Nmet hyl-2’,5’-dideoxy-5’-aminot h ymidine. The respective phosphor amidites (101a) and (1Olb) were prepared and used without isolation for the synthesis of the modified oligodeoxynucleotides.81Another type of internucleosidic linkage, in which the natural phosphodiester linkage has been replaced by a 2,5-disubstituted tetrazole ring, has been reported by Pedersen. The synthesis was based on an alkylation of 5’-O-trityl-on and 5’-O-trityl-off 3’-deoxy-3’-(lH-tetrazol-5y1)thymidines with 5’-iodothymidine in the presence of triethylamine. The 5’protected dinucleoside phosphoramidite (102) was obtained by treatment with 2-cyanoethyl tetraisopropyl-phosphorodiamiditein the presence of N,N-diisopropylammonium tetrazolide.82 Shaw has reported the first syntheses of thymidine- and 2’-deoxy-5fluorouridine - 3’,5’- cyclic boranophosphorothioate (103a,b).These analogues, displaying increased lipophilicity, were prepared from a key intermediate, a cyclic phosphoramidite obtained by heating a thoroughly degassed HMPA solution of the nucleoside. This phosphoramidite was then converted to a cyclic phosphite triester in the presence of 4-nitrophenol and 5-ethylthio-lH-tetrazole, and converted to the boranated complex in situ. The cyclic boranophosphite was then converted to the 3’,5’-cyclic boranopho~phorothioate.8~

DMTO

\ \

0

-

0

101a; R= H 101b; R= CH3

$

DMTow b Y,N-A“ N’

102

7 y B

- H3B-P\0 S

103a, E T 103b, E 5F-U

2.2 Nucleoside Pyrophosphates. - 2.2.1 Nucleoside Pyrophosphonates. Numerous analogues of natural nucleotides modified at the phosphate moiety have been reported. The chemistry of these modified nucleotides has been extended to the synthesis of polyphosphate derivatives. Alexandrova has described the synthesis of P-H-phosphonomethyl analogues of thymidine (104a)

Organophosphorus Chemistry

218

and 9-(2-hydroxyethyl)adenine (104b) diphosphate. These derivatives were obtained by phosphonylation of 5’-O-phosphonomethylthymidine and 9-[2-(phosphonomethyloxy)ethyl] adenine with sodium p y r o p h o ~ p h i t e . ~ ~

2.2.2 Nucleoside Diphosphosugars. Pyrimidine nucleotide transglycosidases have been employed in the synthesis of pyridine nucleotide analogues incorporating nicotinoylamino acids. Twenty two pyridine nucleotide cofactors, derivatives of nicotinamide mononucleotide and nicotinamide adenine dinucleotide (phosphate), that have an amino acid residue at the carbonyl carbon of the nicotinamide moiety (105a-v),have been prepared by means of transglycosidation reactions.85Matsuda has reported extensive work on the preparation of

0-

0-

I

0-

HO 104

105a, RI= Gly 105b, RI= Leu 105c, R1= Ser 105d, Rq= Asp

HO

105f, R1= 105e, RI= Asn Glu H o e 0

I

0104b

1051, Rq= Gly, R2= H 105m, RI= Ala, R y H 105n, R1= Ser, RF H 1050, R1= ASP, R y H

105g, RI= Gln 105h, RI= QAla /’ 0 1051,R1=GABA I OH 105j, RI= 6HA OXp’, 105k, RI= GlyGly OH 105~1, RI= GABA, R y P@H2 105v, RI= GlyGly, RF PO3H2

HO

carbocyclic analogues of cyclic adenosine diphosphate ribose. Cyclic ADPcarbocyclic-ribose (106a) was described as a hydrolytically stable mimic for the cyclic NAD-metabolite. Its synthesis and that of its brominated parent (106b) was achieved by treatment of a protected N ‘-carbocyclic-ribosyladenosine bisphosphate with silver nitrate in the presence of molecular sieves in pyridine. The yield was optimized to become quantitative when the cyclisation took place between the 5”-phosphate of the carbocycle and the 5’-phenylthiophosphate while the Cs adenine position had been substituted with a halogen.86-88 In addition to the carbocyclic adenosine derivatives, Matsuda has also reported an improved synthesis of the inosine congeners, previously de~cribed.’~ Rutherford has carried out NMR and semi-empirical energy calculations on cyclic adenosine diphosphate ribose, which showed that the previously reported hypothesis of pH-related conformational control via intramolecular hydrogen bonding between a protonated N 3 and phosphate in cADPR is not s u p p ~ r t e d . ~ ~ Borch reported the synthesis of thymidine diphosphate glucose (107)via a new method that employs a highly reactive zwitterionic phosphoramidate intermediate as the phosphorylating species (Scheme 2). This methodology was also used

219

4: Nucleotides and Nucleic Acids; Mononucleotides

0

qpT I,

Bno-P-0

OH

H2, WM:

HO

b

HO

0 0 O0-P-0H O P-0 H

OH

p

T

HO 107

106a; X= H 106b; X= Br

Scheme 2

for the facile preparation of thymidine diphosphate rhamnose. N-methyl-N-(2chlorobutyl) thymidyl phosphoramidate (lOS), prepared from N-methyl-N-(2chlorobuty1)amine hydrochloride and benzyloxy phosphorus dichloride, was activated by hydrogenolysis and subsequently reacted with the sugar monophosphate in the presence of pyridine and tetrabutylammonium chloride to yield the sugar nucleoside diphosphates.” Uridine diphosphate galactose (109) was prepared using seven enzymes involved in three biosynthetic pathways, immobilised on super-bead columns. This method, which converted 50% of uracyl monophosphate into UDP-galactose (109),was superior to the solution approach as enzyme stability was improved?’ To study the biosynthesis of the pseudosaccaharide acarbose, thymidine 5’diphospho-4-amino-4,6-dideoxy-a-~-glucopyranose (110) was synthesised from galactose in sixteen steps.

111

HO

n

The sugar-nucleotide phosphate linkage was accomplished using the morpholidate monophosphate derivative of thymidine and the fully deprotected monophosphorylated amino-sugar in the presence of 1H-tetrazole and pyridine?’ Poulter has reported the synthesis of 4-diphosphocytidyl-2-C-methyl-~erythritol (lll),a metabolite occurring in the biosynthesis of isoprenoid compounds. The free phospho-acids were coupled to cytidine 5’-monophosphate using a protocol initially developed for the synthesis of base-sensitive nucleoside diphosphate sugars for which the thymidine monophosphate was activated as a trifluoroacetate mixed anhydride.93Shibaev has described a novel synthesis of uridine 5’-(2-acetamido-2,6-dideoxy-a-~-galactopyranosyl diphosphate) (112)

220

Organophosphorus Chemistry

for which 2-azido-3,4-di-0-acetyl-2,6-dideoxy-cr-~-galactopyranosyl nitrate was the key ir1termediate.9~ NHR

Hcj O ‘ W 113b R=BI@TIN

HO

113c R=FLUORESCEIN

1131 R= BIOTIN 1139. R=FLUORESCEIN

3

113d. R = X-BIOTIN 113e. R=X-FLUORESCEIN

113h R=K-BIOTIN 1131 R - WLUORESCEIN

Nucleoside Polyphosphates

Barone reported the use of several novel nucleotide analogues (113a-i) for the enzymatic labeling by T7 RNA polymerase of nucleic acid targets for a variety of array-based assays.95The synthetic routes to prepare these compounds have not yet been reported. In order to access new probes for efficient fluorescent labeling of nucleic acids, Cummins synthesised the fluorescein conjugate (114a,b) of the bicyclic nucleobase analogues (R- and S-) 6H, 8H-3,4-dihydropyrimido[5,4-c][1,2]-oxazin-7-one, which could mimic both cytosine and thymidine and competed with the natural thymidine triphosphate natural substrate for enzymatic incorporation into the nucleic acid chain.96 The synthesis of the triphosphate derivative of 1-(2-deoxy-P-~-erythrofuranosyl)-imidazole-4-hydrazide (115a) has been described by Pochet. I n vitro, it behaved as substrate for several DNA polymerases. The phosphoramidite derivative of 1-(2-deoxy-~-~-erythrofuranosyl)-imidazole-4hydrazide (115b) was also prepared for synthetic incorporation into oligodeoxynucleotides~7The nucleoside precursor was obtained by enzymatic transglycosylation using N-deoxyribosyltransferase, which after appropriate protection steps was phosphorylated with 2-cyanoethylphosphate in the presence of DCC and pyridine. After removal of the cyanoethyl group, the phosphate monoester was converted to the morpholidate analogue, which then reacted with bis-tributylammonium pyrophosphate. Jacobson has described the synthesis of the triphosphate esters of adenine nucleotide analogues locked in a northern methanocarba conformation (116a-9. Such a ring-constrained conformation results in enhanced stability and potency for P2Y1 receptors. The triphosphate monoesters were prepared in a stepwise manner, involving the formation of a monophosphate di-t-butyl triester using the Sphosphoramiditemethod followed by condensation of additional phosphate or pyrophosphate groups using carbodiimidazole after removal of the alkyl protecting group of the triester by treatment with l H - D o ~ e x - 5 0 . ~ ~

4: Nucleotides and Nucleic Acids; Mononucleotides

22 1

0

1 1 4 ; (R), Rq=FLUORESCEIN 114b; ( S ) , RI= FLUORESCEIN

HO, 0’ I

o= P’,

HO

V 11

P- OH OH

iPr2P.J’ p, OCH2CH2CN I HO 115a

H 115b

Shaw has described the first synthesis of ribo- and deoxyribonucleoside (a-Pborano, a-P-thio) triphosphates (117a,b) and investigated the chemical and biochemical properties of the adenine and thymidine derivatives. The suitably protected nucleoside was phosphitylated and subsequently treated with tetrabutylammonium pyrophosphate to form a cyclic intermediate. Reaction with borane, followed by ring opening of the cyclic boranated triphosphate with lithium sulfide, afforded compounds (117a) or (117b)corresponding to the starting n u c l e o ~ i d e . ~ ~ The first examples of nucleoside di- (1 18a)and tri-phosphate (118b)containing the electrophilic and potentially reactive carbonyl group in place of a phosphoanhydride oxygen have been reported. The guanosine triphosphate derivative (118b)was obtained by reaction of the phosphoro-N-methylimidazolidate of the N-(p-n-buty1)-benzyl 2-deoxyguanosine monophosphate with carbonyldiphosphonic acid. The carbonyl diphosphonate analogue (118a) was obtained by displacement of the mesyl group of the corresponding 5’-mesyl nucleoside with carbonyldiphosphonate. The guanosine diphosphonate analogue was found to be stable to hydrolysis while the nucleoside carbonyl triphosphate homologue was rapidly hydrolysed in aqueous conditions. Both were reported to be potent inhibitors of human DNA po1ymerase.’O0 The synthesis of dinucleotide polyphosphate analogues incorporating a cyclopentenyl residue as a glycone and phosphonate residues in place of phosphate residues has been described. In addition, these compounds were evaluated for their potency at inhibiting HIV reverse transcriptase in comparison to their triphosphate mimics. The carbocyclic a,6-bis(nucleoside)-5,5’-tetraphosphonates(119a-f) were prepared from the parent monophosphonates and 1,l’-carbonyldiimidazoleas an activating agent. lo1>’O2 In order to investigate the in-vivo phosphorylation and dephosphorylation process in a series of L-pyrimidine nucleosides, known to be active antiviral and anticancer agents, Cheng has prepared the polyphosphate analogues either

222

Organophosphorus Chemistry

enzymatically, by the action of a recombinant cytidine monophosphate kinase, or chemically. In the chemical approach, these diphosphate and triphosphate esters were prepared via a multistep one-pot procedure from the L-nucleoside, phosphorus oxychloride and phosphoric a ~ i d . " ~ . ' ~

0' I

O=P(

OH

0

116a, X= 0, R1= NH2, R y CI, n= 2 116b, X=0, R1= NH2, RF MeS, n= 2 116c, X= 0, R1= NH2, RF CI, n= 1 116d, X= 0, R1= NHCH3, R y H, n= 2 116e, X= 0, R1= NH2, R y CI, n= 2 116f, X= CH2, RI= NHz, R y H, n= 2

HO 117a, B= T, R= H 117b, B=A, R=OH

Xf\-O--I

0

OH

OH

HO 118a, n=O 118b, n= 1

OH

0

B12

H A b 0 a

119a, B= G, X= 0 119b, B= G, X= CF2 1 1 9 ~B= , G, X= CBr2 119d, B = A YFO 119e, B= A, YF CF2 113, 5 A, X= CBr2

Reference 1. 2. 3.

4. 5. 6. 7.

8. 9. 10.

S. Matysiak and W. Pfleiderer, Helu. Chim. Acta, 2001,84,1066. C. Merk, T. Reiner, E. Kvasyuk, and W. Pfleiderer, Helv. Chim. Acta, 2000,83,3198. A. P. Guzaev and M. Manoharan, Nucleosides Nucleotides & Nucleic Acids, 2001, 20, 1011. J. Ciesla, J. Jankowska, M. Sobkowski, M. Wenska, J. Stawinski, and A. Kraszewski, J . Chem. SOC.,PT1,2002,31. M. Bollmark, M. Kullberg, and J. Stawinski, Tetrahedron Lett. 2002,43,515. M. Wenska, J. Jankowska, J. Stawinski, and A. Kraszewski, Tetrahedron Lett. 2001, 42,8055. M. Olesiak, D. Krajewska, E. Wasilewska, D. Korczynski, J. Baraniak, A. Okruszek, and W. J. Stec, Synlett, 2002,6,967. Y. Hayakawa, R. Kawai, A. Hirata, J-I. Sugimoto, M. Kataoka, A. Sakakura, M. Hirose, and R. Noyori, J . Am. Chem. SOC.2001,123,8165. Y. Hayakawa, Bull. Chem. SOC.Japan, 2001,74,1547. Y. Hayakawa, A. Hirata, J-I. Sugimoto, R. Kawai, M. Kataoka, and A. Sakakura,

4: Nucleotides and Nucleic Acids; Mononucleotides 11. 12.

13.

14. 15.

16. 17. 18.

19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.

32. 33.

34. 35. 36. 37. 38.

39.

223

Tetrahedron, 2001,57,8823. J. Zemlicka, Biochim. Biophys. Acta, 2002,1587,276. S. Peyrottes, S. Schlienger, T. Beltran, I. Lefebvre, A. Pompon, G. Gosselin, A. M. Aubertin, J. L. Imbach, and C. Perigaud, Nucleosides, Nucleotides & Nucleic Acids, 2001,20, 315. D. Egron, C. Perigaud, G. Gosselin, A. M. Aubertin, and J. L. Imbach, Nucleosides Nucleotides & Nucleic Acids, 2001,20,751. S. A. Harris, C. McGuigan, G. Andrei, R. Snoeck, E. De Clercq, and J. Balzarini, Antiuir. Chem. Chemoth. 2001,12,293. Z-W. Miao, H. Fu, and Y. F. Zhao, Phosphorus Sulfur and Silicon and the Related Elements, 2002,177,2089. S. C. Tobias and R. F. Borch, J . Med. Chern. 2001,44,4475. Y. Jin, X. Chen, M-E. Cote, A. Roland, B. Korba, S . Mounir, and R. Iyer, Bioorg. Med. Chem. Lett. 2001,11,205. T. Moriguchi, N. Asai, K. Okada, K. Seio, T. Sasaki, and M. Sekine, J . Org. Chem. 2002,67,3290. A. Wilk, A. Grajkowski, T. E. Bull, A. N. Dixon, D. I. Freedberg, and S. L. Beaucage, J . Am. Chem. SOC.,2002,124,1180. T. Johansson and J. Stawinski, Bioorg. Med. Chem. 2001,9,2315. Z-W. Miao, H. Fu, B. Han, Y. Chen, and Y. F. Zhao, Syn. Commun. 2002,32,1159. J. S. Summers and B. R. Shaw, Curr. Med. Chem. 2001,8,1147. P. Li and B. R. Shaw, Organic Letters, 2002,4,2009. D. Egron, A. A. Arzumanov, N. B. Dyatkina, A. M. Aubertin, J. L. Imbach, G. Gosselin, A. Krayevsky, and C . Perigaud, Bioorg. Chem. 2001,29,333. A. Winqvist and R. Stromberg, Eur. J . Org. Chem. 2002,1515. X . Chen, K-Y. Jung, D. F Wiemer, A. J. Wiemer, and R. J. Hohl, Phosphorus Sulfur and Silicon and the Related Elements, 2002,177, 1783. B. Legeret, Z. Sarakauskaite, F. Pradaux, Y. Saito, S. Tumkevicius, and L. A. Agrofoglio, Nucleosides, Nucleotides & Nucleic Acids, 2001,20,661. X . B. Sun, J. X. Kang, and Y. F. Zhao, Chem. Commun. 2002,2415. A. El-Hamid and A. A. Ismail, Pharmazie, 2001,56, 534. M. Yamashita, P. M. Reddy, Y. Kato, V. K. Reddy, K. Suzuki, and T. Oshikawa, Carbohydr. Res. 2001,336,257. E. E. Nifantiev, S . B. Khrebtova, Y. V. Kulkova, D. A. Predvoditelev, T. S. Kukhareva, P. V. Petrovskii, R. Rose, and C. Meier, Phosphorus Sulfur and Silicon and the Related Elements, 2002, 177,25 1. S. H. Hung, K. S. Madhusoodanan, J. A. Beres, R. L. Boyd, J. L. Baldwin, W. Zhang, R. W. Colman, and R. F. Colman, Bioorg. Chem. 2002,30, 16. B. Golos, J. M. Dzik, Z. Kazimierczuk, J. Ciesla, Z. Zielinski, J. Jankowska, A. Kraszewski, J. Stawinski, W. Rode, and D. Shugar, Biol. Chem. 2001,382,1439. M. S . Louie and H. Chapman, Nucleosides Nucleotides & Nucleic Acids, 2001,20, 1099-1102. T. J. Miller, H. D. Farguar, A. Sheybani, C. E. Tallini, A. S. Saurage, F. R. Fronczek, and R. P. Hammer, Org. Lett. 2002,4,877. N. Karino, Y. Ueno, and A. Matsuda, Nucleic Acids Research, 2001,29, 2456. M. P. Groziak and D. W. Thomas, J . Org. Chem. 2002,67,2152. H. M-P. Chui, M. Meroueh, S. A. Scaringe, and C . S . Chow, Bioorg. Med. Chem. 2002,10, 325. 0.Gorchs, M. Hernandez, L. Garriga, E. Pedroso, A. Grandas, and J. Farras, Org. Lett. 2002,4, 1827.

224 40. 41. 42. 43. 44. 45. 46.

47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72.

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F. Seela and A. Jawalekar, Helv. Chim. Acta, 2002,85, 1857. H. Debelak and F. Seela, Nucleosides Nucleotides & Nucleic Acids, 2001,20, 577. V. Banuls, J-M. Escudier, C. Zedde, C. Claparols, B. Donnadieu, and H. Plaisancie, Eur. J . Org. Chem. 2001,4693. G. Becher, J. He, and F. Seela, Helv. Chim. Acta, 2001,84, 1048. D. M. No11 and N. D. Clarke, Nucleic Acids Research, 2001,29,4025. C. Meier and S. Grasl, Synlett, 2002,5,802. F. Seela, N. Ramzaeva, P. Leonard, Y. Chen, H. Debelak, E. Feiling, R. Kroschel, M. Zulauf, T. Wenzel, T. Frohlich, and M. Kostrzewa, Nucleosides, Nucleotides & Nucleic Acids, 200 1,20, 1421. H. Kroth, H. Yagi, J. M. Sayer, S. Kumar, and D. M. Jerina, Chem. R e x Toxicol. 2001, 14,708. D. J. Hurley and Y. Tor, J . Am. Chem. SOC., 2002,124,3749. M. E. Hawkins, Cell Biochem. Biophys. 2001,34,257. M. E. Hawkins, W. Pfleiderer, 0.Jungmann, and F. M. Balis, Anal. Biochem. 2001, 298,23 1. T. P. Prakash, A. M. Kawasaki, A. S. Fraser, G. Vasquez, and M. Monaharan, J . Org. Chem. 2002,67,357. M. Beier, A. Stephan, and J. D. Hoheisel, Helv. Chim. Acta, 2002,84,2089. G. H. McGall and J. A. Fidanza, Meth. Mol. Biol. 2002,170,71. W. Czechtizky and A. Vasella, Helv. Chim. Acta, 2001,84, 1000. D. Ackermann and S. Pitsch, Helv. Chim. Acta, 2002,85, 1443. B. Keller and C. J. Leumann, Synthesis-Stuttgart, 2002,6,789. J. Ravn, N. Thorup, and P. Nielsen, J . Chem. SOC.P T l , 2001, 1855. Kvaerno, L., Wightman, R. H., and Wengel, J. J . Org. Chem. 2001,66,5106. T. Bryld, M. H. Sorensen, P. Nielsen, C. Nielsen, and J. Wengel, J . Chem. SOC.,P T I , 2002,1655. M. D. Sorensen, L. Kvaemo, T. Bryld, A. E. Hakansson, B. Verbeure, G. Gaubert, P. Herdewjin, and J. Wengel, J . Am. Chem. SOC.2002,124,2164. L. Knaervo and J. Wengel, J . Org. Chem. 2001,66,5498. D. S. Pedersen, C. Rosenbohm, and T. Koch, Synthesis-Stuttgart, 2002,802. A. Holy, I. Votruba, M. Masojidkova, G. Andrei, R. Snoeck, L. Naesens, E. De Clercq, and J. Balzarini, J . Med. Chem. 2002,45, 1918. M. Cesnek, A. Holy, and M. Masojidkova, Tetrahedron, 2002,58,2985. D. Rejman, M. Masojidkova, E. De Clercq, and I. Rosenberg, Nucleosides Nucleotides & Nucleic Acids, 2001,20, 1497. H-P. Guan, Y-L. Qiu, M. B. Ksebati, E. R. Kern, and J. Zemlicka, Tetrahedron, 2002,58,6047. K. Sekiya, H. Takashima, N. Ueda, N. Kamiya, S. Yuasa, Y. Fujimura, and M. Ubasawa, J . Med. Chem. 2002,45,3138. E. Pfund, T. Lequeux, S. Masson, and M. Vazeux, Org. Lett. 2002,4,843. B. Nawrot, 0. Michalak, M. Nowak, A. Okruszek, M. Dera, and W. J. Stec, Tetrahedron Lett. 2002,43, 5397. Z. Janeba and A. Holy, Nucleosides Nucleotides & Nucleic Acids, 2001,20, 1103. S. Obika, M. Onoda, K. Morita, J-I. Andoh, M. Koizumi, and T. Imanishi, Chem. Commun. 2001,1992. G. Hakimelahi, T. W. Ly, A. A. Moosavi-Movahedi, M. L. Jain, M. Zakerinia, H. Davari, H-C. Mei, T. Sambaiah, A. A. Moshfegh, and S. Hakimelahi, J . Med. Chem. 2001,44,3710. P. Poijarvi, E. Maki, J. Tomperi, M. Ora, M. Oivanen, and H. Lonnberg, Helv.

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Chim. Acta, 2002,85, 1869. 74. Zhu, X-F and Scott, A. I. Nucleosides Nucleotides & Nucleic Acids, 2001,20, 197. 75. A. M. Sorensen, K. E. Nielsen, B. Vogg, J. P. Jacobsen, and P. Nielsen, Tetrahedron, 2001,57,10191. 76. J. Stawinski and T. Johanssen, Phosphorus SuEfur and Silicon and the Related Elements, 2002,177, 1779. 77. S. Sigurdsson and R. Stromberg, J . Chem. SOC.- PT 2,2002,1682. 78. A Winqvist and R. Stromberg, Eur. J . Org. Chem. 2002,3140. 79. K. Misiura, D. Szymanowicz, and H. Kusnierczyk, Bioorg. Med. Chem. 2001, 9, 1525. 80. A. Okruszek, A. Sierzchala, K. Zmudzka, and W. Stec, Nucleosides Nucleotides & Nucleic Acids, 2001,20, 1843. 81. S. Kochetkova, E. Timofeev, E. Korobinikova, N. Kolganova, and V. Florentiev, Tetrahedron, 2001,57,10287. 82. V. V. Filichev, A. A. Malin, V. A. Ostrovskii, and E. B. Pedersen, Helv. Chim. Acta, 2002,85,2847. 83. P. Li and B. R. Shaw, Chem. Cornrnun. 2002,2890. 84. A. V. Ivanov, M. V. Jasko, and L. A. Alexandrova, Russ. J . Bioorg. Chem. 2001,27, 264. 85. T. Imai and M. Hatori, J . Nutri. Sc. Vitam. 2002,48, 177. 86. M. Fukuoka, S. Shuto, N. Minakawa, Y. Ueno, and A. Matsuda, Nucleosides Nucleotides & Nucleic Acids, 2001,20, 1355. 87. S. Shuto, M. Fukuoka, H. Abe, and A. Matsuda, Nucleosides Nucleotides & Nucleic Acids, 2001,20,461. 88. S. Shuto, M. Fukuoka, A. Manikowsky, Y. Ueno, T. Nakano, R. Kuroda, H. Kuroda, and A. Matsuda, J . Am. Chem. SOC.2001,123,8750. 89. T. Rutherford, J. Wilkie, C . Q. Vu, K. D. Schnackerz, M. K. Jacobson, and D. Gani, Nucleosides, Nucleotides & Nucleic Acids, 2001,20, 1485. 90. C. L. Free1 Meyers and R. F. Borch, Org. Lett. 2001,3, 3765. 91. Z. Liu, J. Zhang, X. Chen, and P. G. Wang, ChemBioChem, 2002,3,348. 92. S. G. Bowers, T. Mahmud, and H. G. Floss, Carhohydr. Res. 2002,337,297. 93. A. T. Koppisch and C. D. Poulter, J . Org. Chem. 2002,67,5416. 94. P. A. Illarionov, V. I. Torgov, I. I. Hancock, and V. N. Shibaev, Russ. Chem. Bull. Intl Ed, 2001,50, 1303. 95. A. D. Barone, C. Chen, G. H. McGall, K. Rafii, P. R. Buzby, and J. J. Dimeo, Nucleosides Nucleotides & Nucleic Acids, 2001,20, 1141. 96. W. J. Cummins, A. 1 Hamilton, C. L. Smith, and M. S. Briggs, Nucleosides Nucleotides & Nucleic Acids, 2001,20, 1049. 97. H. Strobel, L. Dugue, P. Marliere, and S. Pochet, Nucleic Acids Research, 2002,30, 1869. 98. R. G. Ravi, H. S. Kim, J. Servos, H. Zimmermann, K. Lee, S. Maddileti, J. L. Boyer, T. K. Harden, and K. A. Jacobson, J . Med. Chem. 2002,45,2090. 99. J. Lin, K. W. Porter, and B. R. Shaw, Nucleosides Nucleotides & Nucleic Acids, 2001,20,1019. 100. I. B. Yanachkov, J. M. Stattel, and G. E. Wright, J . Chem. SOC.PT. 1,2001,3080. 101. E. A. Shirokova, A. L. Khandashinskaya, Y. S. Skoblov, L. Y. goryunova, R. S. Beabealashvilli, and A. Krayevsky, Nucleosides Nucleotides & Nucleic Acids, 2001, 20, 1033. 102. A. L. Khandashinskaya, E. A. Shirokova, Y. S. Skoblov, L. S. Vistorova, L. Y. goryunova, R. S. Beabealashvilli, T. R. Pronyeava, N. V. Fedyuk, V. V. Zolin, A. G.

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Pokrovsky, and M. K. Kukhanova, J. Med. Chem. 2002,45,1284. 103. P. Krishnan, J-Y. Liou, and Y-C. Cheng, J. Biol. Chem. 2002,277,31593. 104. P. Krishnan, Q. Fu, J-Y. Liou, W. Lam, G. Dutschman, and Y-C. Cheng, J . B i d . Chem. 2002,277,5453.

5 Nucleotides and Nucleic Acids; Oligo- and Polynucleotides BY DAVID LOAKES

1

Introduction

As the field of oligonucleotides has developed over the past years, so there has been a large increase in the number of publications. This review covering one year details the many new analogues and applications that have been reported. The two most dominant fields of research are base analogues and NMR solution structures, driven by advances in chemistry and NMR methodology. Within the new base analogues described, most have been used in hybridisation studies, but a number of new and exciting applications are developing. Electron transport within oligonucleotide duplexes and the synthesis of oligonucleotides bearing clinically significant modifications are two such areas that have been widely studied. Many of these are aimed at tuning oligonucleotide structures and their application by the inclusion of appropriate functional groups. A number of the modifications described in this review have also been the subject of NMR or X-ray structure determination. Developments in the synthesis of RNA and DNA oligonucleotides have declined, in part because fully automated synthesis is now routine, and the number of commercially available modifications grows each year. However, this is now developing in new directions, in particular in the synthesis of oligonucleotides attached to alternative surfaces such as metals and glass, and in the synthesis of oligonucleotide-conjugates. Both these two areas have seen many new developments. Many new sugar-modified oligonucleotides have been reported, in particular with locked nucleic acids. One of the main growth areas in oligonucleotides with modified internucleotide linkages has been in novel PNA backbones and in their applications. 1.1 Oligonucleotide synthesis. - 1.1.1 D N A Synthesis. There have been few publications on improvements to DNA synthesis, and the main area of development has been in the development of modified oligonucleotides (ODNs). There have, however, been some improvements in the use of supports, reagents and protecting groups. Two new thymidine modified solid supports have been prepared suitable for oligonucleotide synthesis in which the support is attached via the thymine N3 position.' These modified supports allow for ODN synthesis Organophosphorus Chemistry, Volume 34 0 The Royal Society of Chemistry, 2005

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from the thymidine residue in either 3’- or 5’-directions. Various acid salts of imidazole and benzimidazole were examined as promoters for the condensation of phosphoramidites with nucleos(t)ides.2 Amongst these, N (pheny1)imidazolium triflate, N-(p-acetylpheny1)imidazolium triflate, N (methy1)benzimidazoliumtriflate and N-(pheny1)imidazolium perchlorate were shown to be powerful activators for phosphoramidite coupling reactions for DNA and RNA synthesis. A new protecting group for the internucleotidic phosphate or phosphorothioate group has been used. Use of the 2-(N-isopropy-N-anisoylamino)ethyl group (1) demonstrated high coupling yields, favourable deprotection kinetics and stability of the phosphoramidite building block^.^ An alternative phosphate/thiophosphate-protecting group is described for ODN synthesis via phosphoramidites. The 4-oxopentyl group has been shown to be as effective a protecting group as the cyanoethyl group, and is readily removed after ODN synthesis using ammonia gas or concentrated a m m ~ n i a Finally, .~ the use of 4-monomethoxytritylthio as a 5’-OH protecting group allows DNA synthesis without requiring acid deprotecti~n.~It is cleaved using 0.1M I2 in MeCN:pyridine:H20, 10:9:1. There are new methods for oligonucleotide synthesis using the Q-linker (hydoquinone-0,O’-diacetic acid) (2). Conjugation of the Q-linker to the 3’-end of a nucleoside allows the linker to be attached to underivatised amino or hydroxyl supports.6 After ODN synthesis the linker is removed from the support and the oligonucleotide by treatment with ammonia. By this method, the solid support can be re-used, which will lower the cost of large-scale ODN synthesis. A variety of supports were used to determine the efficacy of this process, with successive syntheses carried out on a number of them.7 The Q-linker was also used to synthesise ODNs end-to-end, using the linker as a spacer group between each oligonucleotide?,

DMToTB Q OAC02H

I

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The commercially available 3-amino- 1,2,4-dithiazole-5-one,(3), has been attached to a hydroxyl resin via a succinic acid linker, and has been used as an efficient sulfur-transfer reagent for the solution-phase synthesis of phosphorothioates." DNA synthesis scale-up to lOOg of a 20-mer phosphorothioate has been examined;" key to this was the purification of the product, which was carried out using a high efficiency polymeric anion exchange chromatographic media. ODNs bearing a 3'-phosphate protected with S-pivaloyl-2-mercaptoethyl (SPME) groups have been used as a bio-reversible protecting group.12To maintain the SPME group after ODN synthesis, 1M piperidine was used to cleave the phenoxyacetyl protecting groups, and then 0.01M K2C03in methanol to cleave the oligonucleotide from the solid support. The synthesis of ODNs free from aldehyde abasic sites may be carried out using the hydroxylamine derivative (4). The reaction leads to a product that has a significantly increased retention time on RP-HPLC allowing separation from the desired p r o d ~ c t . ' ~ The synthesis of 2-(acety1thio)ethyl (MeSATE) pro-oligonucleotides has been reported using allyloxycarbonyl (AOC) protection for the nucleobases and allyl protection of the internucleotide phosphate groups.l4?l 5 The use of allyl protecting groups is particularly useful for base-sensitive analogues, and all allyl protecting groups are removed using palladium(O), with dimedone as an allyl scavenger. The authors also discuss the use of a l-(O-nitrophenyl)-l,3-propanediol photocleavable solid support. The T2' pro-oligonucleotide Me-SATE bearing a fluorescein residue was taken up into HeLa cells as confirmed by fluorescence microscopy and flow cytomet ry.I6 I .I .2 D N A microarrays. The synthesis and applications of oligonucleotide microarrays is a rapidly expanding area. A variety of solid supports have been examined to attach principally ODNs, but also RNA. There have been improvements to attachment, synthesis and analysis of the resultant arrays, and a variety of methods for labelling have been examined. There are also many methods described for the attachment to metal surfaces, especially gold, but also silver and quantum dots. These latter reports are covered in the section on oligonucleotide conjugates. A new method for the removal of the 5'-0-DMT group during the synthesis of ODNs on a microarray has been studied17 which uses all the steps involved in phosphoramidite synthesis, but uses a photogenerated acid (PGA) rather than trichloroacetic acid to deprotect. The photolabile 3'-0-{ [2-(2nitrophenyl)propoxy]carbonyl}-protected 5'-phosphoramidites ( 5 ) have been prepared for the 5'+ 3' light-directed synthesis of DNA on microarrays.'' Developments for the synthesis of high-density DNA probe arrays employ nucleoside monomers protected with 5'-(a-methyl-6-nitropiperonyloxycarbonyl)(MeNPOC) with proximity photolithography, which is currently capable of printing 10 pm2 probe features at a density of lo6probes/cm2.19 A strategy for the labelling of RNA prior to hybridisation on high-density DNA chips has been developed.*' RNA targets need to be fragmented to an average of
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imidazole. Cleavage results in a 2’,3’-cyclic phosphate which is then reacted with an aromatic methyl halide (such as 5-(bromomethyl) fluorescein) as previously described.21The method is reported to be more sensitive than using labelled nucleotides used in transcription. Glass has become a common surface for the attachment of ODNs. A glass coating consisting of polyethylenimine and reactive cyanuric chloride residues has been developed for the production of spotted oligonucleotide arrays.22The surface binds ODNs through both covalent and non-covalent interactions. Surface density of the probe strand in DNA microarrays is a key factor that determines the extent to which immobilised probes are able to capture solution phase targets. Using surface plasmon resonance with DNA films, the effect of surface probe density on DNA hybridisation has been studied.23It was found that the hybridisation isotherms were complex, and could not be fitted to a simple kinetic model. At low density, 100% of the probes may be hybridised, but at higher probe concentrations the efficiency drops and the kinetics are slower. Demers et ~ 1 have . ~described ~ the use of direct-write dip-pen nanolithography (DPN) to develop covalently bound nanoscale patterns of oligonucleotides on metallic and insulating materials. DNA derivatised with hexanethiol groups were used for patterning on gold surfaces, and with 5’-acrylamide groups on derivatised silica. I n situ synthesis of oligonucleotide arrays on glass has been examined, with the surfaces defined and separated by differential surface tension.25Appropriately cleaned and masked glass surfaces are treated with 3-aminopropyldimethylethoxysilane (APDMS) which reacts with the glass surface via a single siloxane bond. The rest of the surface is treated with the perfluorosilane (tridecafluoro-l,1,2,2-tetrahydrooctyl)trichlorosilane,leading to a surface akin to Teflon, and therefore resistant to chemical synthesis. Coupling to the modified glass surface has been examined to determine yields and coupling efficiencies.An alternative approach to the functionalisation of glass surfaces is to treat the glass with 3-aminopropyltriethoxysilane, which again generates an amino-modified surface. This is then treated with a homobifunctional linker, such as disuccinimidyl glutarate or 1,4-phenylenediisothiocyanate,which leaves a chemically reactive surface film for functionalisation.26This method was then used to attach ODNs by coupling to the linker. In addition, ODNs have been attached to semicarbazide-coated glass for the synthesis of microarrays. A benzaldehyde

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23 1

unit, incorporated during oligonucleotide synthesis as an acetal-protected phosphoramidite, may be used to modify the oligonucleotides~7 A number of novel methods of detection of oligonucleotides on microarrays have been developed. The amplified detection of viral DNA by the generation of a redox-active replica and subsequent bioelectrocatalysed oxidation of glucose has been reported as a method for the detection of pathogens.28An oligonucleotide containing a 5’-thiol group was assembled onto a gold electrode, which is complementary to a region of the M13$ cyclic DNA. The process is monitored using a microgravimetric quartz crystal microbalance. In the presence of Klenow fragment, the target DNA is amplified using the dNTP (6) incorporating the redox-label ferrocene. The resultant DNA may be electrochemically analysed, and in the presence of glucose oxidase, the ferrocene acts as electron-transfer mediator for the oxidation of glucose to gluconic acid on a bioelectrode. 0,’ Me. I

dRTP

I Me

(6) (7) Another electronic method for the detection of hybridisation events has been carried out using 2‘-O-ferrocenyl derivatives in ODNs. 2I-O-ferrocene and the modified ferrocene derivative (7) were incorporated into ODNs. Thermal melting experiments demonstrated that there was little duplex destabilisation, and alternating current voltammetry showed that the two ferrocene derivatives could be di~tinguished.2~ A DNA array on gold electrodes coupled to an electronic detection system showed that dual signalling probes containing the two ferrocene derivatives could be used to detect single base mismatches. A method that uses ODNs as biochemical barcodes for the detection of protein structures in solution has been rep~rted.~” 31 Each protein recognition element (e.g. biotin, dinitrophenyl) may be encoded with a different ODN bound to a solid surface, such as gold nanoparticles. Each ODN has a different melting temperature, and a spectroscopic signature associated with the nanoparticles that changes on melting to decode a series of protein elements in a multi-protein solution assay. A complex method for magnetically induced solid-state electrochemical detection of DNA hybridisation has been developed.32The method involves hybridisation of oligonucleotides to coated magnetic beads, followed by binding of streptavidin-coated gold nanoparticles to the captured target. Catalytic silver precipitation (Ag+/hydroquinone)on the gold nanoparticles, followed by magnetic collection of the particle assemblies allows detection using tunnelling electron microscopy. A method for the detection of single base mismatches (single nucleotide polymorphism, SNPs) with DNA microarrays is described that does not require labelling of the sample DNA.33The method is based on the disruption of FRET between a fluorophore attached to the immobilised probe, and a quencher sequence complementary except for an artificial mismatch. Typically, a universal

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base, such as 5-nitroindole or 3-nitropyrrole, or an abasic site, is used as the artificial mismatch. The analysis of the mismatch is based on differences in the extent of disruption of FRET on hybridisation between a perfect match complement and a mismatch or SNP.

1.2 RNA Synthesis. - As with DNA synthesis, there have been very few new developments in RNA synthesis. There have been new protecting group strategies described, in particular with the now widely used TOM chemistry. The synthesis of RNA using 2’-0-[(triisopropylsilyl)oxy]methyl] (2’-0-TOM) protected phosphoramidites has been described.34RNA synthesis uses N-acetyl protected nucleobases, and using 5-benzylthio- 1H-tetrazole as activator, coupling yields of 99.4% are reported. Deprotection of the oligoribonucleotides requires first MeNH2in EtOH/H,O then Bu4NFin THF. A new method for the synthesis of 2’-O-protected ribonucleoside phosphoramidites for RNA synthesis is described. The synthesis uses di-t-butylsilylene to prepare a cyclic 3’,5’-protected nucleoside, then the 0 2 ’ position is protected as its TBDMS ether. Selective removal of the di-t-butylsilylene group is carried out by treatment with HF-pyridine at 0°C.35 There have also been new reagents used for RNA synthesis. A novel activator for the synthesis of the inter-ribonucleotide bond using phosphoramidite chemistry has been reported.36N-phenylimidazolium triflate (PhIMT) has been used very effectively with ally1 protection to prepare Uloin 99.6% average coupling yield. The use of 5-(benzylmercapto)-lH-tetrazole as activator for RNA synthesis using 2’-O-TBDMS phosphoramidite monomers is reported to yield superior coupling effi~iency.~~ Lower coupling times (3 minutes) and higher yields are reported. 1.3 The Synthesis of Modified Oligodeoxyribonucleotides and Modified Oligoribonucleotides. - 1.3.1 Oligonucleotides Containing Modified Phosphodiester Linkages. Amongst the most common backbone modifications are phosphorothioates and methylphosphonates. These have been widely used, and have been particularly beneficial for stabilising oligonucleotides in in vitro and in vivo studies. Whilst both these modifications have been further studied, there are very many more modifications that have been developed. These have been classified here into three categories. The first is those modifications which involve changes to the phosphodiester linkage, and include phosphoramidates, alkyl phosphonates and also a variety of analogues involving mixed backbone modifications, as well as branching and polarity reversal. The second category is a number non-natural backbone linkages. Amongst this could be included PNA analogues, but as there are many new PNA derivatives reported, these are discussed separately. As phosphorothioate oligonucleotides are widely used as antisense agents, there have been a number of reports on their mode of action. Using Rp and Sp phosphorothioate internucleotide linkages in ODNs, it was shown that Serratia marcescens endonuclease hydrolyses the Rp phosphorothioate bond with inversion of configuration at p h o s p h ~ r u sThe . ~ ~ presence of an Sp phosphorothioate

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linkage downstream of the cleavage site reduces the rate of hydrolysis, suggesting the participation of the pro-Sp oxygen atom of that phosphate in the cleavage mechanism. A significant problem with the development of antisense ODNs is the non-specific binding of oligonucleotides to cellular proteins. Mou et have used the Ff gene 5 protein (g5p) as a model for a ssDNA binding protein. The affinity for g5p binding to phosphorothioate-DNA binding is 300-fold higher than for unmodified DNA. They have demonstrated that ODNs containing propynylated pyrimidines, or 2’-0-Me modified oligonucleotides, however, have a 2-fold reduced affinity for g5p. The mechanism of action of human plasma 3’-exonuclease has been investigated using 5’-0-[’s0]phosphorothioates~o5’-O-cc-[’*O]thiotriphosphates were synthesised, and incorporated into an oligomer with terminal deoxyribonucleotidyl transferase (TdT), and the digestion of the primer was followed using MALDI T O F mass spectrometry. It was found that retention of configuration at phosphorus occurs, and this implies a two step mechanism resulting in a double inversion. Phosphorothioate derivatives have also been used in ligation and conjugation reactions. Oligonucleotides containing a single monophosphoryldithio internucleotide linkage have been introduced by a ~ t o l i g a t i o nThe . ~ ~ modified internucleotide linkage resembles the natural phosphodiester linkage in size and charge density, is stable in water, and undergoes thiol-disulfide exchange reactions. A convenient method for detecting autoligation using a molecular beacon approach has been developed.42Using an ODN bearing a 3’-thiophosphate and a second ODN bearing a 5’-dabsyl group (8), autoligation could be readily monitored when the two ODNs were brought together on a complementary ODN. The 5’-modified ODN also carries a fluorescein labelled nucleotide three bases away from the 5’-terminus,which acts as a quencher until the dabsyl group is removed on ligation. 5’-Deoxy-5’-thioguanosine-5’-monophosphorothioate and 0-[o-sulfhydryl-tetra(ethy1eneglycol)]-0-(5’-guanosine) monophosphate have both been used as the initiator nucleotide for T7 RNA polymerase transcription reactions.43The RNA from these reactions bears a 5‘-terminol thiol group, and these modified oligoribonucleotides have been used in conjugation reactions with thiophilic biotin reagents, e.g. biotin-PEG-maleimide. “0

234

0rganop hosphorus Chemistry

Phosphoramidate linkages have been shown to have a number of beneficial properties due to the properties of the P-N linkage. A number of ODNs containing N3’+ P5’ phosphoramidate linkages of 2’-modified ribonucleotides have been evaluated as potential inhibitors of human telomerase.4!45 These include the 2’-deoxy-, 2’-hydroxy-, 2’-methoxy-, 2’-ribo-fluoro-, 2’-arabino-fluoro- and 2’-deoxy-N3’+P5’ thio phosphoramidates. The substitution of the phosphate diester in ODNs by N-(2-methoxyethyl)phosphoramidate linkages leads to a non-ionic internucleotide linkage. In short homopyrimidine oligonucleotides this was found to lead to a significant increase in duplex stability with complementary DNA.“6The further introduction of 2-amino-a-2’-dA into this modified oligonucleotide showed moderate increase in stability with complementary DNA, but enhanced stability with RNA. The inhibition of telomerase is dependent on the ability of the modified ODN to form a stable duplex with the RNA target and not on the nature of the sugar phosphate backbone. The most active ODNs were in the sub-nM to pM range of concentrations. a-ODNs containing a mixture of phosphodiester and cationic phosphoramidate (N-dimethylaminopropylphosphoramidate)linkages were prepared and evaluated as T F O S .Such ~ ~ ODNs were found to be superior third strands in triplexes compared to P-phosphodiester ODNs over a 5.5 - 7.0 pH range. The enzymatic incorporation of 5’-deoxy-5’-amino5‘-triphosphates was demonstrated using the DNA polymerase Sequenase ~ 2 . 0 The . ~ ~newly formed P3’-N5’ internucleotide linkage is acid labile, and a MALDI-TOF mass spectrometry method was used to examine oligonucleotides in which P3’-N5’ internucleotide linkages were introduced, either chemically or enzymatically.The two modified nucleosides (9) have been introduced into ODNs having a 5’-amino group available for charge interaction with the adjacent phosphate ODNs containing either nucleoside (9) had reduced electrophoretic mobility by PAGE, showing that a new zwitterionic amine-phosphate pair is formed. No stability data were presented. The introduction of a methylphosphonate linkage removes a negative charge from the oligonucleotide backbone. Such analogues are also more resistant to nuclease degradation, but too many substitutions leads to solubility and aggregation problems. An important component of pro tein-DNA recognition is the charge neutralization of DNA backbone phosphates and subsequent proteininduced DNA bending. Replacement of phosphates by neutral methylphosphonates has been shown to be a model for protein-induced bending and may change the inherent flexibility of the DNA. Okonogi et aLS0have developed a model to measure the differential flexibility of duplex DNA when methylphosphonate substitutions are made. They found that the local flexibility is increased by up to 40%,which implies that backbone neutralization and DNA flexibility augments DNA-binding motifs. ODNs containing CpG motifs in a particular sequence context activate the vertebrate immune system. The significance of negatively charged internucleotidic linkages in the flanking sequences 5’- and 3’- to the CpG-motif on immunostimulatory activity has been examined.51Secretion of IL-12 and IL-6 in mouse spleen cell cultures increased significantly when a

235

5: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

methylphosphonate linkage was placed four or more internucleotide linkages from the CpG-motif in the 5'-flanking sequence. Within the first three internucleotide linkages in the 5'-flanking sequence, immunostimulatory activity was suppressed. The placement of methylphosphonate linkages in the 3'4anking sequence to the CpG-motif either did not affect or only slightly increased immunostimulatory activity compared with the parent ODN. The effect of an abasic site in either 3'- or 5'-flanking region of a CpG motif has also been in~estigated.~~ One or two base deletions in the 3'-flanking sequence was found to have very little effect on immunostimulatory activity, but in the 5'-flanking sequence immunostimulatory activity increases. As well as methylphosphonates, a number of other alkyl phosphonate derivatives have been used. Commercial phosphoramidites have been hydrolysed to their H-phosphonates, which were then coupled with thymidine-C5-vinyl bromide using Pd(0) catalysed cross coupling to give the dinucleotide (lo), which was then used to synthesise O D N S . The ~ ~ effect of (10) in ODNs on the monomeric 3'+5' DNA helicase PcrA demonstrated that a single modification in the backbone of the translocating strand was sufficient to inhibit the activity of P c ~ AThis . ~ ~leads to the suggestion that rotational flexibility of the backbone is essential for efficient unwinding. To obtain further information for the mechanism of reaction of the Tetrahymena ribozyme, the 5'-bridging oxygen of the scissile phosphate was replaced with a methylene giving a 5'-methylene phosphonate m ~ n o e s t e rIt. ~was ~ found, unexpectedly, that the reaction was 1000fold faster than un-modified control. Using DNA-RNA chimeras, it was shown that the methylene group enhances docking of the substrates into the catalytic core by 10-fold, and cleavage 100-fold.ODNs containing phenylalkyl modified backbones (11),n = 1-3,5, have been synthesised and the Rp and Sp isomers ~ e p a r a t e dIn . ~hybridisation ~ studies it was found that increasing the alkyl chain led to greater destabilisation. For ODNs with n = 1 the most stable duplexes were formed with the Rp isomer, similar to that found with methylphosphonate

-

-

-

derivative^.^^

Oligonucleotides have been modified to incorporate histamine residues to aid cellular The histamine was incorporated at sites where H-phosphonate monomers were used. It was shown that such modified oligonucleotides with six histamine residues were readily taken into nuclei in HeLa cells, but further

236

Organophosphorus Chemistry

substitutions led to lower uptake. A series of oligothymidylates and oligoadenylates were prepared in which the -0-P-CH2-0internucleotide linkage (CH2 at either 3’- or 5‘-end) was ~ubstituted.’~ The additional methylene group caused considerable duplex instability, though they were resistant to nucleases. The binding properties of ODNs containing the fluorescent label thiazole orange (12) attached by various linkers to the internucleotide phosphate via a phosphoramidate linkage have been examined.60During phosphoramidite ODN synthesis (12) was introduced into ODNs using an H-phosphonate monomer. In an oligoadenylate, (12) stabilised duplexes with DNA and RNA targets. However, when incorporated into either oligo-a- or oligo-P-thymidylates there was no stabilisation with poly r(A). Oligodeoxythymidylate 14-mers containing combinations of phosphate and boranophosphate linkages have been synthesised.6l By introducing the boranophosphate into every other or every third internucleotide linkage, higher binding affinity as well as RNase H activation was achieved over fully modified boranophosphate linkages. Short mixed-base sequence boranophosphate (BH33 ODNs (13) were synthesised and characterised.62 Base modifications during boronation were avoided by using base-unprotected H-phosphonate monomers. The treatment of N-acylated nucleobases during DNA synthesis with boraneamine complexes leads to the corresponding N-alkylated derivativest3 for example, N-acetyl cytosine is reduced to the ethylamine derivative. A new reagent for the synthesis of terminal phosphates or thiophosphates has been prepared which is compatible with phosphoramidite chemistry. The reagent (14) is introduced during oligonucleotide synthesis. For phosphorothioates, 3H-1,2-benzodithiol-3-one 1,l-dioxide is used as a sulfur-transfer agent, and other internucleotide linkages are oxidised with L - B u O O H . ~ ~ Oligonucleotides have been converted to their 5’-triphosphate derivatives on solid supports by reaction with the phosphitylating agent (15), followed by reaction with pyrophosphate and then iodine 0xidation.6~

(13)

(14)

TMT = trimethoxytrityl

(15)

R = phosphoramidite or linker to CPG

The synthesis of ODNs bearing two pyrene residues attached to the 5’phosphate has been investigated.66Excimer fluorescence intensity is highly sensitive to duplex formation, such that on hybridisation with either DNA or RNA the fluorescence intensity increases ten-fold. Changes in excimer fluorescence are also dependent on the structure of the binding site. Hybridisation to structured targets leads to a quenching of the fluorescence, and therefore these probes may

5: Nucleotides and Nucleic Acids: Oligo-and Polynucleotides

237

be used to probe RNA s t r u c t u r e ~ . ~ ~ The use of chimeric oligonucleotides has a number of advantages, especially in antisense therapy. A number of backbone modified chimeric oligonucleotides have been studied as well as sugar modified chimeras, the latter being discussed in section 1.3.2.The antisense effects of neutral (morpholino),cationic (PNA) and anionic (2’-0-Me and 2’-0-MOE) oligonucleotide analogues have been studied.68 The effects were carried out using a splicing assay in which oligonucleotides blocked aberrant and restored correct splicing of enhanced green fluorescent protein (EGFP)precursor to mRNA, generating properly translated EGFP. The data showed that the uptake and antisense effects of neutral and cationic oligonucleotides were much higher than that of negatively charged ones. A study of phosphodiester and morpholino TFOs directed towards the human HER2/neu promoter showed that morpholino TFOs had many advantage^.^^ They are nuclease resistant, and form triplexes in the absence of magnesium ions. However, targeted towards the HER-2/neu promoter, it was found that a pyrimidine motif was necessary for triplex formation, and that low pH (- 5) was required. Exposure to dsRNA leads to post-transcriptional gene silencing, a phenomenon known as RNA interference (RNAi).Gene silencingmay also arise from cosuppression, in which transgenic DNA leads to silencing of both the transgene and the endogenous gene. To study the role of such short RNA molecules in vivu, Tijsterman et ~ 1 . ~ ’examined whether gene silencing could be triggered by injecting either single- or double-stranded RNA, DNA or morpholino oligonucleotides into C . elegans. It was shown that ssRNA is also a potent inducer of gene silencing. DNA or morpholino oligomers were found to be inactive. Oligonucleotides have been used to direct base-exchange and gene repair in a variety of organisms. A chimeric RNA-DNA oligomer which folds into a double hairpin structure was found to be amongst the most promising c a n d i d a t e ~ It .~~ was shown that the chimera directed nucleotide exchange by using the cell’s DNA repair machinery. It was demonstrated that the DNA region was the active component in the repair process. A series of homopyrimidine oligonucleotides was prepared by solid phase synthesis, in which there was a central N-acyl-N-(2-hydroxyethyl)-glycineresidue (16). These were used as TFOs in which the modification faces an interrupting T:A base pair. Amongst the acyl moieties tested, an anthraquinone carboxylic acid gave the most stable

There have been two reports on branched or cyclic oligonucleotides. A series of ‘V’ and ‘Y’ shaped DNA and RNA oligonucleotides related to splicing intermediates of S . cerevisiae actin pre-mRNA has been used to study the effects

238

Organophosphorus Chemistry

of branched nucleic acids on in uitro pre-mRNA splicing in yeast.73It was found that the branched RNA’s (‘Y’ shaped) were best at inhibiting RNA splicing. Circular ODNs have been prepared using the new structural i-rn0tif.7~The i-motif is composed of two parallel-stranded duplexes held together in an antiparallel orientation, and the structure is stabilised by hemiprotonated C:C+ base pairs. It can also be prepared unimolecularly using 5’-(CCCTAA)3TAACC, which is a portion of vertebrate telomeric DNA, under acidic conditions. In the i-motif, the 3‘- and 5’-ends are proximal to each other, and the termini have been chemically ligated by the addition of N-cyanoimidazole. Two papers have detailed oligonucleotides containing 2’,5’ phosphodiester linkages. A comparative study of hairpin loops differing in the connectivity of phosphodiester linkages (3’,5’- and 2’,5’-)revealed that the tetraloop UUCG with 2’,5’-linkage is as stable as that with a 3’,5’-linkage.75y76 Additionally, the stability of the 2’,5‘-tetraloop was found to be independent of the nature of the stem (DNA, RNA or 2’,5’-RNA) whilst the native RNA tetraloop is most stable with a RNA stem. Synthetic ODNs, which contain a CpG-dinucleotide step in specific sequence contexts, activate the vertebrate immune system. The introduction of a 2‘,5’-internucleotide linkage within 3-5 nucleotides in either 3’- or 5’-flanking sequence does not interfere with the immunostimulatory effects of the CpG. Within the 5’-flanking sequence, it potentiated the immunostimulatory effects of the C P G . ~The ~ introduction of a 2’,5‘-linkage within the 3’-flanking sequence may be effective to induce specific cytokines as desired. A series of ODNs containing a mixture of a-and p-anomeric nucleotides as well as 5’3’ or 3’,3’ polarity reversal gapmers were targeted to the erbB-2 oncogene to examine RNase H It was found that a p-anomeric window of three nucleotides was sufficient to allow RNase H activity despite the reversal of polarity within the ODN. 2’4-modified oligonucleotides containing an inverted 3’-3’ thymidine at the terminus have been shown to lead to higher duplex stabilities and resistance to n u ~ l e a s e s . ~ ~ ODNs with a 3’-3’-inversion site have been synthesised using a lysine residue to conjugate the two ODN strands. Such modified oligonucleotides were designed to support triplex formation with the two halves of the ODN forming a triplex with opposite strands of the duplex, and the lysine residue spanning the duplex.80 Hybridisation studies confirmed that a triplex was formed at acidic pH, but not under neutral conditions. It has been shown that these ODNs with a 3’-3’ linkage, designed as alternate-strand TFOs, are more stable with the anthraquinonyl group (17) at the junction.8’These TFOs showed enhanced hybridisation properties and protected the target DNA duplex from digestion by the restriction enzyme Hind 111. The second category of internucleotide linkages is a series of backbone analogues in which the phosphodiester linkage is completely replaced. Various nitrogenous units have been used to replace the phosphate. The synthesis of oligonucleotides containing amide bond internucleotide linkers has been reported using commercially available 5’-amino-modifiers and two new solid supports that provide, after photochemical cleavage, either a 3’-carboxylicacid or a 3’-amino functional group.82Short oligonucleotides synthesised from these

239

5: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

new supports were prepared, and coupled together under mild conditions to yield up to 40-mers by this segment assembly approach. Oligonucleotides could be coupled to give either 5'+3' or 3'+3' linkages. A series of five-atom amide bond internucleotide linkages have been assessed for their ability to bind to RNA complements. In most of the examples it was shown that there was an increase in Tm of up to 2"C, though only single substitutions were made.83CD measurements revealed that there was little effect on the structure of the DNA/RNA duplexes.

DNA-3-phosp hate-0

&

0-3-phosphate-DNA

OA0 N-(CH2)n." H

N H

0

0

I Q..

(18)

R = H or Me

(20)

R = M e or Bn

The ribonucleoside derivative containing the MMI linkage84(18) has been used in oligonucleotides in comparison to the deoxynucleoside analogue against RNA complements.8' In all cases it was found to give rise to superior Tms in hybridisation studies ( + 3"C/modification). Template-directed polymerisation of a modified nucleoside has been demonstrated with the thymine monomer ( 19).86 Using a poly-dA template, synthesis of an octamer of (19) linked via imine bonds was performed. The presence of imine bonds was confirmed by NMR spectroscopy. Oligonucleotides containing the hydroxamate linkages (20), introduced via phosphoramidite chemistry as a dimer, have been assessed in hybridisation st~dies.8~ The methyl hydroxamate showed little difference on duplex stability towards either DNA or RNA compared to DNA, but the benzyl derivative was found to be destabilising. The solution phase synthesis of short polynucleotides in which the negatively charged phosphate backbone is replaced by the positively charged guanidine linkage has been described.88Polynucleotides in both the 2'-deoxyribose and ribose (21) have been described, and preliminary work on solid phase synthesis has been developed. The effect of introducing a sulfamate or sulfamide internucleotide linkage has been examined using the thymidine dimers (22).89When incorporated into du-

240

Organophosphorus Chemistry

plex DNA, the sulfamide linkage was found to be significantly destabilising, whilst the 3’-N-sulfamate linkage had little effect on duplex stability, and was slightly stabilising at low salt concentrations. The effect of using bridging dimethylene sulfide, sulfoxide and sulfone groups (23) in short homopolymeric oligodeoxynucleotides has been studied. The oligonucleotides are synthesised by coupling together dinucleoside units. It was found that self-structure and selfaggregation increased with the length of the oligonu~leotide.~~ Incorporation of the positively charged S-methylthiourea linkage (24) into DNA has been carried out and the stability of these chimeric oligonucleotides studied. The presence of an S-methylthiourea linkage is generally destabilising, though this effect decreases with decreasing salt concentration?’ Oligonucleotides with this linkage were found to have enhanced nuclease resistance.

HN

OH 0,S-J

”Y HO

(21)

0

OH

B=UorA

(”)

X = N, sulfamide

x = 0 ,suKamate

ic,J ----J

(23) n = 0 , 1 , 2

A novel class of nucleic acid mimics has been described which possess two ethylenediamine moieties for intermolecular metal co-ordination (25).In the presence of Zn2+ ions and template DNA, the analogues (25) form relatively stable structures, stabilised by the co-ordination of adjacent chelating moieties with zinc ions.92It was shown that with an oligothymidine template and the adenine derivative of (25) that a 2:l complex was formed, which showed a biphasic melting transition. Short RNA duplexes (3-4 bp) are considerably stabilised if both termini of the duplexes are bridged by non-nucleotidic For example, the pairing of rGAA with rUUC in such a cyclic system exhibits a T, of 36°C in 1M salt solution. This final section will detail the many new PNA derivatives that have been

5: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

24 1

prepared and targeted towards oligonucleotides. The use of PNA still attracts much interest, in particular to determine its mode of action and in vitro applications. The thermodynamic behaviour of PNA/DNA duplexes with identical nearest neighbours but with different sequences and chain lengths has been examined to determine whether the nearest-neighbour model is valid for PNA/DNA duplex ~tability.9~ The average difference for short duplexes was 3.5%, but increased to 16.4% for 10- to 16-mers. Also, the effect of a base bulge is different in PNA/DNA than DNA/DNA duplexes. When PNA is present at relatively high concentrations, aggregation and non-specific interactions with ssDNA occur.95This phenomenon has been used to inhibit the ATPase activity of T4 Dda helicase. The PNA aggregates bound non-specifically to the ssDNA and inhibited ATPase activity by depletion of ssDNA. This was confirmed by the use of an alternative PNA sequence, in which similar results were observed. PNA has previously been shown to strand-invade duplex DNA, and the resulting single-stranded D-loops were able to induce transcription both in vitro and in viv0.9~Further studies have now shown that the optimum length of PNA is 16-18 units, and these were able to induce transcription of target genes in vitro in HeLa cells at high levels.97Stable DNA tetraloop hairpin structures may be strand-invaded by DNA or PNA probes to give DNA:DNA or DNA:PNA duplexes, even when the new duplex structure has a lower T, than the hairpin.98 Secondary structure in the probe and/or target lead to duplex destabilisation, and PNA probes have a higher affinity than DNA probes. A DNA hairpin with a GAAA loop and four G:C base-pair stem is readily strand-invaded by an 8-mer PNA probe, whilst the corresponding DNA probe does not. However, a DNA 10-mer probe provided sufficient enthalpic stabilisation to overcome the entropic loss of hybridisation. Mixed thymine/guanine PNA oligomers form DNA/(PNA), triplexes with complementary dA/dC O D N S . ~ The ~ PNA oligomer targets dsDNA, and triplexes are formed by strand invasion. The photooxidation of DNA/PNA duplexes, and DNA/(PNA)2triplexes has been examined using riboflavin.lmIt was found that DNA/PNA duplexes were cleaved at GG steps with similar efficiency as is observed with DNA duplexes, though the selectivity for 5'-GG oxidation was reduced, and remote oxidation was considerably suppressed. In the DNA/(PNA)2 triplexes, remote oxidation was completely inhibited. It has been shown that the quadruplex structure of a thrombin binding aptamer is disrupted by short PNA sequences at 37°C.'01Under these conditions, the corresponding DNA probe does not bind to the aptamer. The stability of the PNA-DNA structures was attributed to overhanging DNA bases, which stabilised the duplex structure and prevented the DNA from adopting a quadruplex. Applications of PNA include the development of a novel method for multiplex detection of DNA single nucleotide polymorphisms (SNPs) using MALDI-TOF monitoring.'02The method makes use of a PNA ligation reaction, in which an 'abasic site' is generated (26) on a DNA tem~1ate.l'~ The ligation process is dependent on the target sequence, and the authors claim that no ligation products are detected with a mismatch site in the PNA. After ligation, the DNA is digested with trifluoroacetic acid and the products examined by MALDI-

Organophosphorus Chemistry

242 ‘H-CCT ACA G-Gly ‘H-CCT CCA G-Gly ‘H-CCT TCA G-Gly

EDC, irnidazole

+

I

GlyG CCC ACC AHHN-Ac

SGGA XGT CGC GGG TGG T-3’

‘H-CCT ACA G-GlyGlyG CCC ACC A-HHN-Ac ‘H-CCT CCA G-Gly-GlyG CCC ACC A-HHN-Ac ‘H-CCT TCA GGlyGlyG CCC ACC A-HHN-Ac

TOF. The authors claim that, from their preliminary results the method is effective down to 5 nM concentrations of DNA. A method for the attachment of fluorescent groups to PNA in solution and on solid phase has been reported for use in FRET analysis.1o4Like fluorescently labelled DNA, in the single-stranded state the fluorescence is only weak, but on hybridising to DNA, fluorescent enhancement occurs. A study of DNA and PNA molecular beacons has been carried out with stem-less and stem-containing structures, and at various salt concentration^.'^^ The authors found that stemless PNA beacons hybridise rapidly to complementary ODNs, and that they are less sensitive to changes in salt concentration than analogous DNA beacons. Whilst stem-less DNA beacons are inappropriate for diagnostic purposes due to the high background fluorescence, they do have applications for studying the conformational flexibility of single-stranded nucleic acids. PNA has been useful in a number of cellular systems. Antisense ODNs, which bind mRNA, have been shown to alter splicing patterns that may have therapeutic effects. 2’-O-Methoxyethyl(2’-0-MOE) oligonucleotides have been shown to redirect constitutive and alternative splicing of the murine interleukine-5receptor-a chain pre-mRNA in cells.’06Antisense PNA has now been used to alter splicing of the pre-mRNA in a similar manner to 2’-0-MOE modified oligonucleotides.107Also, the length of the antisense PNA could be shortened from 20 to 15 units compared to 2’-O-MOE oligonucleotides. Measurement of unwinding of dsDNA by helicases is hampered due to the rapid reannealing of the ssDNA products. The use of an ODN to trap the ssDNA to prevent reannealing sequesters the helicase, and leads to lower rates for unwinding. The use of PNA, however, has proved successfulfor rate measurements of helicases as it was shown that the PNA does not bind to the bacteriophage T4 Dda helicase.’ox Initiation of HIV-1-RT occurs by extension of the cellular tRNA3LYsthat anneals to the primer-binding site on the 5’-non-translated region of the viral genome. The A-rich sequence (A-loop) upstream of the primer-binding site interacts with the anticodon loop of tRNA3LYs,and it has been suggested that this is essential for priming the initiation of RT. A PNA sequence targeted to the A-loop exhibited specific high binding, and blocked in vitro initiation of reverse

5: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

243

tran~cription."~ It also disrupted the pre-formed [tRNA3LYs-viralRNA] complex, rendering it non-functional for reverse transcription. A synthetic transcription activator has been prepared using a PNA-peptide chimera."O A short peptide known to support activation in yeast"' was coupled to a bis-PNA targeted towards a homopurine DNA site. When this complex was targeted towards DNA containing (multiple) DNA binding sites, it was found that it could recruit transcription factors, thus mimicking a fundamental property of native activators. The non-coding RNA Xist has been shown to be essential for X-chromosome inactivation and to coat the inactive X-chromosome (Xi). The chromatin-binding region was functionally mapped and evaluated by using an approach for studying non-coding RNA function in living cells called PNA interferencemapping. A single 19-bp antisense cell-permeatingPNA targeted against a particular region of Xist RNA caused the disruption of the RecA protein-coated ssDNA probes bind specifically to DNA sequences within dsDNA targets, giving multi-stranded probe-target DNA hybrids, which can be used for sequence specific gene capture, modification and regulation. Hybridization of PNA within, or adjacent to, the probe-target region significantly enhances the yield of hybrid DNA.'13 In an attempt to expand the properties of PNA there have been many attempts to modify the backbone. Modification from aminoethyl-glycyl units to a ring system was expected to impose additional constraints to the PNA. The synthesis and hybridisation properties of chiral PNA based on N-aminoethyl-cis-4-nucleobase-L-proline (27) have been s t ~ d i e d . "Whilst ~ all four monomer units were prepared, only the adenine derivative was incorporated into PNA and hybridised to DNA. It was shown that this PNA is more stable in a duplex with DNA than the corresponding DNA:DNA duplex. Homothymine PNA probes composed of trans-4-hydroxy-~-prolineand phosphono monomers exhibit strong binding to poly-A RNA."' Using a mixture of linear and bis-PNA composed of these monomers, a method for the isolation of RNA with secondary structures at the 3'-end and with short poly-A tails was developed.'16 Carbamate linked prolyl nucleic acids (PrCNA) have been examined as probes for DNA as carbamate linked nucleic acids bind to complementary DNA.'17 However, homopolymers of PrCNA do not bind to DNA and are destabilising in triplexes."* Modification of the backbone to a six-membered aminopipecolyl (pipPNA) was expected to introduce constraints to the PNA backbone. The introduction of a pipPNA monomer at the C-terminus was tolerated as determined by its melting temperature with a DNA target, but when introduced into the central portion of PNA, it was quite destabilising.' l9 The conformationally restricted piperidinone PNA adenine monomers 3R,6R pip-PNA (28) and its 3s-isomer have been incorporated into PNA for hybridisation studies.'20Introduction of the pip-PNA was found to be detrimental to duplex stability. PNA units consisting of either R- or S-N-(2-pyrrolidine-methyl)-N-(thymine1-acety1)-glycine were synthesised, and targeted towards complementary RNA.12' It was found that the R-isomer bound with higher affinity to RNA than the S-isomer. The positively charged (at physiological pH) and conformationally

244

Organophosphorus Chemistry

constrained pyrrolidyl PNA monomer (29) shows high selectivity for DNA rather than RNA.'22It is considerably stabilising compared to PNA when in a duplex with DNA, but destabilising when in a triplex. Pyrrolidinyl PNA monomers of alternate sequences of thymine modified D-proline and P-aminoacid spacers of ~-aminopyrrolidine-2-carboxylic acid, ~-aminopyrrolidine-2-carboxylic acid, (1R,2S)-2-aminocyclopentanecarboxylicacid and p-alanine were prepared. Gel-shift assays showed that only the homothymine PNA oligomer from the ~-aminopyrrolidine-2-carboxylicacid spacer binds with p~ly(dA).'*~ Hybridisation studies with complementary DNA or RNA were carried out with PNA containing the aromatic peptide nucleic acid (APNA) derivative (30).'24It was found that with both triplexes and duplexes (parallel and antiparallel) APNA behaved similar to PNA, though a single incorporation of APNA was destabilising. Further substitutions of APNA results in further destabilisation. A homopolymer of APNA was too insoluble in aqueous solution to be studied. PNA containing either a thiazolidine (3 1)or thiazine ring (32)were prepared, and the PNA targeted towards DNA.'25,126 Whilst still maintaining base-pairing selectivity, either PNA monomer was found to be destabilising in PNA:DNA duplexes or PNA:RNA triplexes.

H

Base

I

OH

Finally, new base analogues of PNA have also been investigated. A series of 1,8-naphthyridin-2-(1H)-ones were investigated as PNA analogues to examine the effect of increasing the surface area of a Watson-Crick (or Hoogsteen) base pair. Of the analogues studied, only the 7-chloro-derivative (33) led to consistent increase in duplex and triplex ~tabi1ity.l~~ The increased size gave rise to higher duplex stability when contained at the end of the helix than in the middle. Stabilisation was greater in PNA:DNA duplexes and triplexes than in PNA:RNA duplexes. The substitution of adenine and thymine with dia-

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245

minopurine and thiouracil, respectively, in complementary mixed-base PNA oligomers, have been termed pseudo-complementary PNAs (pcPNAs).12*Pairs of pcPNAs have been used to demonstrate an ability to highly selectively target any designated site on double-stranded DNA (dsDNA) by forming very stable PNA-DNA strand-displacement complexes via double duplex invasion. They have been used to study the kinetics of the formation of corresponding PNADNA complexes at various temperatures by a gel-shift assay. 1.3.2 Oligonucleotides Containing Modijied Sugars. Developments in oligonucleotides with modified sugars have generally been aimed at two particular areas. Firstly, the development of analogues that have some improved physical or biological property, usually for enhancing the stability of structured oligonucleotides or improving the nuclease stability for cellular activity. These modifications have mostly involved 2’-modifications either by 2’-0- or with 2’-aminoanalogues. The second, and major development, is the study of a number of different sugar residues, in particular a variety of hexose sugars. Whilst one objective for the study of these modified sugar oligonucleotides is enhanced cellular stability and the ability to induce RNase H activity for antisense studies, a number of modifications have been prepared to investigate the binding properties of the analogues. The most common sugar modification is 2’-0-Me. An approach to promote sequence specific cleavage of RNA by an antisense 2’-0-Me oligonucleotide makes use of nucleoside analogues bearing terpyridine units (34) and (35).’29 RNA cleavage was observed with a 5’-terpyridine unit in the presence of Cu(II), and when two such units are used in tandem the cleavage efficiency is greatly enhanced. The Trm7p methyltransferase of Saccharomyces cerevisiae, a homologue of the E . coli 2’-O-rRNA methyltransferase FtsJ/RrmJ, has been confirmed as the enzyme that methylated the 2’-0-ribose nucleotides of the tRNA anticodon loop, both in vitro and in v i ~ o .A’ ~class ~ of human small nuclear RNAs that localise to Cajal bodies (scaRNAs) has been demonstrated to act as guide RNAs in the site-specific synthesis of 2’-O-methylated nucleotides and pseud~uridines.’~~ There are a number of other 2’-0-modifications designed either to enhance stability or to introduce a positive charge into the oligonucleotide. Oligonucleotides containing the 2’-methoxyoxalamido(MOX) (36) and 2’-succinimido (SUC) (37) convertible groups have been prepared.’32* 133 After synthesis, the oligonucleotides were treated with various modifiers, such as imidazole, for further study. All modifications used were found to be detrimental to duplex stability. Some modifications were used in primers in sequencing reactions. 2’-0dimethylaminooxyethyl (2’-0-DMAOE) oligonucleotides have been further examined for their nuclease resistance and pharmacological properties.134.135 2’-O-DMAOE ODNs were found to be highly nuclease resistant, and in an inhibition assay of IL-1p stimulated ICAM-1 protein in HUVEC cells they exhibited an ICsOof 2 nM in a non-RNase H mediated mechanism. TFOs containing the sugar modification 2‘-0-(2-aminoethyl) (2’-AE) have previously been shown to enhance triplex stability at physiological condition~.’~~ Further

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Organophosphorus Chemistry

work with 2’-AE modified TFOs showed that the triplexes were more stable than the underlying duplex, and more stable than 2’-0-Me modified T F O S . ’In ~ ~a gene knockout assay, the incorporation of 3-4 2’-AE modifications was found to be at least 10-fold more active than two 2’-AE modified TFOs.

The effect of introducing the 2’-O-carbamate derivatives (38)in DNA duplexes revealed that they are significantly destabili~ing.’~~ Molecular modelling suggests unfavourable steric interactions between the carbamate NH and the anomeric proton of the neighbouring sugar residue. A separate study investigated a large range of 2’-O-carbamate derivative^,'^^ and it was found that apart from a pyrene derivative, all other 2’-O-carbamate derivatives were destabilising. Other 2’-O-modificationsinclude phenanthroline linked oligonucleotides (39) which have been prepared as artificial ribon~cleases.’~~ When targeted towards complementary RNA in the presence of zinc ions, cleavage of the RNA was achieved, albeit with low selectivity. ODNs containing 2’-0-p-Dribofuranosyladenosine were prepared and used as modified primers in RNAtemplated DNA synthesis catalysed by HIV RT. It was shown that the additional 2’-O-ribofuranosyl group within the first seven positions of the 3’-end of the primer prevents its e10ngation.l~’ There have also been 2’-amino-modified oligonucleotides investigated. The hammerhead ribozyme is an efficient ribonuclease but can carry out the reverse RNA ligation reaction, though typically the ribonuclease reaction is 100-fold faster. The introduction of a cross-link, away from the catalytic core, between C11.5and C2.6 introduced through a disulfide linkage via 2’-amino-2’deoxycytodine (40), dramatically increases the ligation reaction 143 Whilst

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the cleavage rate is unaffected, the ligation rate is increased, making the ribozyme an efficient RNA ligase. It has been demonstrated that 2’-amino-modified nucleotides within an oligonucleotide duplex are susceptible to acylation when the nucleotide is part of a mismatch.lMUsing either DNA or RNA as the target, all mismatches were interrogated using 2’-amino modified cytidine. The two 2’modified nucleosides with bidentate ligands (41-42) have been synthesised into ODNs for the incorporation of transition metal complexes.145 When present in a DNA duplex, (41-42)were found to be destabilising, though this effect was less at the termini. No data for binding to transition metals are provided. Other 2’-modifications include 2’-seleno- and 2’-selenomethyl-modified uridine phosphoramidites prepared and incorporated into oligonucleotides for phase and structure determination in X-ray crysta110graphy.l~~ Oligonucleotides containing the C2’- or C3’-difluoromethylene uridine analogues (43) and (44), respectively, have been incorporated into oligonucleotides, though no data concerning the oligonucleotides are p r 0 ~ i d e d . l ~ ~

There are two reports that deal with 3’- and 4‘-modified oligonucleotides. A study of T, and CD properties of ODNs having 2’,5’-linked 3’-deoxynucleotides showed that whilst they do form duplex structures, they are thermodynamically much less stable than the usual 3’,5’-linked 2’-deoxy ODNs.14’ This reduced stability is due to much more rigid phosphodiester backbones in 2’,5’-linked ODNs than 3’,5’-linkages. The introduction of 3’-S-phosphorothiolate linkages has been studied. The use of 3’-S-phosphorothioamidates has proved unsuccessful due to the poor reactivity of the phosphorothioamidates. However, the use of extended coupling times with either 5-ethylthiotetrazole or 43dicyanoimidazole as activators led to coupling yields of 80-90%.’49 The effect on DNA synthesis with Klenow fragment using C4’-alkyl (H, Me, Et and ‘Pr) modified ODNs has been studied.15’When at the 3’-end of the primer, such modifications resulted in inhibition of chain extension. However, at positions + 2 to +4, the larger the alkyl group, the lower the efficiency for chain extension. In the template, strand inhibition of extension occurs at + 2 and + 4 positions even with the smaller alkyl chains. Thus these analogues have been

248

Organophosphorus Chemistry

used as probes for steric constraint within the enzyme active site. The direct observation of hole transfer through DNA between guanine residues has been studied using 4’-acylated dG residues, which on photolysis generate a sugar radical cation to inject the positive charge into the DNA duplex.’51The rate of charge transfer between guanine residues decreases with increasing separation of the guanine bases if they are separated by no more than three base pairs. At longer separations, the process is mediated by thermally induced hopping of charges between adenine bases. Modifications at C5’ have been used for the attachment of labels during or after oligonucleotide synthesis. To aid the NMR solution structure of oligoribonucleotides, a method for the synthesis of C5”-deuterated NTPs has been reported,152and the NMR of oligomers containing the deuterated nucleotides studied. New phosphoramidite monomers have been prepared in which phenothiazine is incorporated via a linker to either 5’-deoxy-5’-amino- dT or dA.153The physical properties of ODN duplexes containing them have been studied, and it was found that although the duplexes were slightly destabilised, the duplexes were otherwise unchanged, and the photophysical properties of pheno thiazine retained. ODNs containing the convertible analogue (S’S)-5’-C-(5-bromo-2-pentenyl)2’-deoxythymidine (45) have been synthesised, and, prior to cleavage from the solid support, treated with ethylene diamine (which displaces Br).154The T,s of duplexes containing the diamine derivative were not substantially altered, and modelling suggests the side chain is in the minor groove. ODNs containing a 5’-deoxy-5’-methylseleno modification have been reported to enable MAD phase determination in nucleotide X-ray crystal10graphy.l~~

(45) In addition, C5’ modifications have been used for ligation and cleavage reactions. The non-enzymatic template-directed synthesis of oligonucleotides has often been investigated. One approach has been the use of 3’-deoxy-3’-amino nucleosides reacting with activated 5’-nucleotides,such as (46).By this approach it has been possible to prepare short oligonucleotides, but a major problem with non-enzymatic oligonucleotide synthesis is the lack of selectivity. Stutz and Richert have demonstrated that the specificity can be significantly enhanced by the attachment of a 5’-acylamido cap on the template strand.156A number of capping reagents were used, and the group that gave the highest selectivity was cholic acid. In an attempt to mimic the action of RNase A, a variety of diimidazole constructs was synthesised. These were attached to oligonucleotides containing 5’-deoxy-5’-aminomodified nucleotides. Unfortunately, using a variety of conditions, no cleavage was 0 b s e r ~ e d . l ~ ~

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Modification of the ribose sugar by inversion of configuration at C2’ gives arabinose, and this is one of the most common pentose modified sugars used in oligonucleotide synthesis. Antisense oligonucleotides comprised of 2’-deoxy-2’fluoro-D-arabinose nucleotides (FANA) are known to exhibit high binding to complementary RNA and to elicit the action of RNase H. As phosphorothioate ODNs are widely used as antisense agents, the phosphorothioate derivatives of FANA ODNs have been synthesised and studied in an antisense assay.15*Fully modified phosphorothioate FANA ODNs showed only weak cellular inhibition, and were less effective in inducing RNase H activity. However, using gapmers with DNA in the core, they had potent antisense activity, and were substrates for RNase H. The effect did not decrease with decreasing DNA core size in the manner observed for analogous 2’-O-methyl gapmers. 2’-Arabino- and 2’-arabino-fluoro nucleic acids (ANA and 2’-F-ANA, respectively) have been demonstrated to form hybrids with RNA that are capable of activating RNase H. The properties and potential applications of such modified oligonucleotides have been r e ~ i e w e d .The ’ ~ ~effect of substituting arabinonucleosides into the DNA priming site of the HIV-1 RT has been examined.16’ The introduction of AraC at the 3’-end of the primer resulted in stalling after the addition of four nucleotides, whereas dC or riboC had no effect. The effect was observed for arabinonucleotides at the first five positions of the primer. The effect of a 2’R- (= arabino) and 2’s- (= ribo) C-methyl group in oligonucleotides has been assessed.16’ Each C-methyl analogue of uridine and cytidine was incorporated into a homopyrimidine RNA oligonucleotide, and hybridisation studies with complementary RNA or DNA conducted. It was found that the arabino derivatives do not hybridise to either DNA or RNA. The ribo-analogues did hybridise with DNA and particularly well with RNA, though the melting curves showed some non-cooperativity. It is suggested that the 2’s-methyl oligonucleotides have the correct pre-organisation for pairing with complementary RNA. The incorporation of 2’-arabino-ethynyl modified nucleosides into ODNs has been studied.16*Strong destabilisation was observed when 2’-ethynyl pyrimidines were incorporated in DNA duplexes, but with the purine analogues there was little effect. Homo-dA polymers form stable duplexes with DNA, but strong destabilisation with RNA. When alternating dC-dG oligonucleotides are made, they form left-handed duplexes regardless of the salt concentration. It was proposed that the arabino-ethynyl group locks such duplexes in a left-handed conformation. The incorporation into ODNs of 2’-O-(~-arabinofuranosyl), 2’-O-(~-arabinofurnaosyl), 2’-O-(~-ribopyranosyl)and 2’-O-(~-erythrofuranosyl)modifications has been shown to be well tolerated in duplexes with complementary RNA (ATm +0.5 to - 1.4”), but less so with DNA (ATm -0.8 to -4.7”).’63The incorporation of a 5’-amino group in the 2’-O-sugar increased duplex stability. (~)-a-Lyxopyranosyl-(4’+3’) oligonucleotides (47) contain a shortened, 5bond backbone, but are capable of cross-pairing with both DNA and RNA.’64 The (~)-P-ribopyranosyl-(4’+3’) oligonucleotides (48), however, do not show base pairing under these conditions. The authors conclude that shorter backbones may be tolerated if their vicinal bound phosphodiester bridges can assume

Organophosphorus Chemistry

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an antiperiplanar conformation.

‘P’ HO’ ‘ 0

,,,,o L-a-lyxopyranosyl

(3’-NH)-TNA

,,,*NH

(2’-NH)-TNA

D-p-ribopyranosyl

(47) (48) (49) (50) The 3’-NH and 2’-NH phosphoramidate derivatives of a-threofuranosyl(3’+2’) oligonucleotides (TNA) (49) and (50), respectively, were incorporated into duplexes with complementary DNA, RNA or TNA.16’ Both analogues form stable base pairs with each of the oligonucleotides, though 3’-NH-TNA forms the most stable duplexes with 3’-NH-TNA and then with RNA, whilst 2’-NHTNA forms the most stable duplexes with RNA. The replacement of adenine by 2,6-diaminopurine in TNA oligonucleotides strongly enhances the stability of TNA:TNA, TNA:RNA and TNA:DNA duplexes.’66In addition, it was shown that 2,6-diaminopurine-TNA accelerates the template-directed ligation of TNA with TNA, DNA or RNA templates. The substitution of pentose by hexose sugars has received much attention because oligonucleotides containing hexose sugars have many useful properties. The first hybridisation system between pyranose and furanose nucleic acids has been r e ~ 0 r t e d . a-Pyranose l~~ oligonucleotides (a-homo-DNA) forms stable duplexes with RNA in a parallel orientation. NMR studies show that the a-homoDNA bases (in a-homo-DNA:RNA duplexes) are equatorially arranged, whilst in the RNA strand they are pseudoaxial. The helical structure does not conform to either A- or B-forms. A study of the pentopyranosyl-(4’+2’) family (P-D-ribo- (pyranosyl-RNA), a-L-lyxo-, p-D-xylo- (51) and a-L-arabino-) was carried out and has shown that the p-D-xylo oligonucleotide duplexes are as stable as that observed with pyranosyl-RNA.16*It had been assumed that P-D-xJ~o-RNA would be less stable due to ring strain in the sugar. A comparison of the duplex stabilities of oligonucleotides derived from ribopyranosyl- (p-RNA), 3’-deoxyribopyranosyl- (p-DNA) and 3’-O-methylribopyranosyl- (3’4-Me-RNA) (4’-+2’) oligonucleotides has been carried p-DNA, like p-RNA, forms antiparallel Watson-Crick duplexes that are more stable than DNA duplexes. p-RNA forms the most stable duplexes, followed by p-DNA, and then 3’-O-Me-RNA. Chimeric oligonucleotides have also been prepared from p-DNA and RNA or (2’+5’)-RNA.l7’ These chimeric oligonucleotides were used to prepare an aptamer binding to flavin mononucleotide and the hammerhead ribozyme. Anhydrohexitol nucleic acids (HNA) have received much attention, but the synthesis of the monomers is difficult. In search for better and synthetically easier

25 1

5: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

(51)

B=AorT

(52)

(53)

(54) R = H, hNTP

R = OH, aATP

analogues, the two methylated derivatives (52) and (53) were prepared and incorporated into oligonucleotides.'71Both derivatives gave a small increase in thermal stability compared to HNA, particularly towards complementary RNA. However, the methyl glycosidicderivative (53),when in homopolymers showed a preference for self-pairing. The template-directed synthesis of anhydrohexitol nucleic acids was studied using a variety of reverse trans~riptases.'~~ Whilst a number of RTs were able to incorporate one anhydrohexitol nucleoside triphosphate (hNTP) (54) R = H, only RAV2 and HIV-1 RT were able to incorporate a second hNTP. Several HIV-1 RT mutants were examined, and the M184V mutant was able to incorporate several hNTPs. The presence of an adjacent hydroxyl group (aATP), (54)R = OH, had a detrimental effect on substrate activity of all the RTs examined. Short mRNAs with hexitol residues (HNA) in two codons have been studied in an E. coli in vitro translation system.173The replacement of HNA residues in the AUG start codon and UUC second codon did not influence the translation. Peptide formation and translocation took place with the HNA codons. The hybridisation properties of various 6-membered nucleic acid derivatives with complementary RNA have been studied. The 6-membered nucleic acid derivatives studied are a- or P-hexitol nucleic acid, HNA, cyclohexene nucleic acid, CeNA, (55), cyclohexane nucleic acid, CNA, and a- or P-homo-DNA, (56-58).174Considerable cross-pairing of the nucleic acid derivatives was observed, and apart from P-homo-DNA, all analogues bound to RNA with generally greater stability than RNA:RNA in a po1yA:polyT duplex. The most stable duplex was P-HNA:P-HNA. The cyclohexene nucleoside (CeNA) derivative of adenine (55) was incorporated into ODNs using standard phosphoramidite chemistry.175 Incorporation of (55)into a mixed DNA sequence resulted in a slight decrease in stability opposite a DNA target, but an increase opposite RNA, similar to results found for anhydrohexitol (HNA) derivatives. However, unlike HNA, CeNA was able to activate RNase H activity.The nucleoside (55)forms duplexes with RNA that are more stable than DNA:RNA duplexes. In NMR studies, it was shown that the cyclohexenyl A nucleotide adopts a 3'-endo conformation in ~ s - D N A . A '~~ CeNA:RNA duplex is cleaved by RNase H, with Km and Vm,, in the same order as DNA:RNA, but the Kcatis 600-fold lower for CeNA:RNA. Oligonucleotides containing the isonucleoside (59), that has an extended phosphodiester linkage were prepared by the phosphoramidite a p p r 0 a ~ h . I ~ ~ Such homo-oligonucleotidesadopt an A-form conformation as demonstrated by

252

Organophosphorus Chemistry

C D measurements, and whilst forming duplexes with both DNA and RNA, the duplexes are destabilised by 0.5"C/modification.

(60)

R = H, L-threoninol R = CH3, L-serinol

Acyclic sugar modifications derived from L-threoninol and L-serinol (60) have been incorporated into ODNs for hybridisation The presence of the acyclic sugar, as expected, causes some destabilisation to the duplex, though the extent of destabilisation is dependent on sequence and the number of modifications. This final section deals with the many reports that deal with locked nucleic acids which were first jointly prepared by I m a n i ~ h iand ' ~ ~Wengel.18' Since then, there have been a number of advances in the applications of LNA as well as a number of new analogues. Steric blocking antisense oligonucleotides have been used to target the HIV-1 TAR apical stem loop.'8', 182 2'-O-Methyl oligoribonucleotides effectively block Tat binding to TAR in uitro, whilst substitution by 5-propynylC or 5-methylC LNA into a 12-mer 2'-O-methyl oligoribonucleotide and a 12-mer PNA leads to stronger inhibition. It was found that 10-16-mer 2'-O-methyl oligoribonucleotides gave a sequence- and dose-dependent inhibition of Tat-dependent transcription of an HIV DNA template in HeLa cell nuclear extract. LNA oligonucleotides were assayed as anti-mdr 1 agents. One such oligonucleotide was shown to strongly inhibit mdrl induction in HeLa cells, and completely inhibited activation of mdrl in K-562 cells.'83 The transfection of cis-element dsDNA, decoy ODNs, have been reported as powerful tools for gene therapy.ls4Delivered to cells, decoy ODNs containing a

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253

recognition sequence for transcription factors are recognised and bind to the transcription factor, resulting in reduction of transcriptional activation. However, a major limitation of this approach is the rapid degradation of phosphodiester ODNs. Crinelli et a1.’85have used LNA to protect ODNs from nuclease degradation. The addition of LNA to the termini of DNA was sufficient to protect the ODN. Insertion of LNA into the binding site, whilst enhancing protection, was found to reduce the binding affinity for the target transcription factor (NH-KB).Similar findings were made by Kurreck et a1.,186who examined the design of antisense oligonucleotides. They report that the inclusion of three LNA nucleotides at each termini of oligonucleotides is sufficient to increase stability to nuclease degradation 10-fold.They also observe that for DNA/LNA oligonucleotides a minimum of eight consecutive DNA monomers is required for full activation of RNase H. This is reduced to six DNA monomers in DNA/2’-OMe oligonucleotide chimeras. BNA (also known as LNA) has been used in TFOs in a pyrimidine motif at neutral pH. The binding constant of the BNA TFO was about 20 times larger than that of DNA as a result of a large decrease in the dissociation rate ~0nstant.A l ~ 3’-amino-2’,4’-BNA ~ nucleotide has been prepared to introduce N3’-P5’ phosphoramidate linkages.18’ It is introduced as a dinucleotide unit (61), and in thermal stability studies was shown to exhibit superior duplex and triplex stability compared to either BNA or DNA, and shows enhanced resistance to digestion by SVPDE. These properties have previously been observed for N3’P5’ phosphoramidate linkages in DNA.189 Three dinucleotide thymine building blocks having 5’-LNA-DNA-3’,5’-LNALNA-3’ or 5’-DNA-LNA-3’ sugar residues connected by the amide linkage (62) have been synthesised and incorporated into oligonucleotides to study their duplex stabilitie~.’~~ An LNA residue at the 5’-end was found to be quite destabilising, but at the 3’-end was more stable than LNA with the normal phosphodiester backbone, despite the increased length of the internucleotide chain. The incorporation of ~ - D - L N Aanalogues (thymine and 5-methylcytosine) into oligonucleotides has been r e p ~ r t e d . ’ ~a-D-LNA ~ - ’ ~ ~ locks the nucleotide into N-type conformation. In a mixed sequence, CX-D-LNA exhibits a preference for parallel stranded duplexes, and shows selectivity for RNA over DNA. When a-LNA oligonucleotides prepared with 3’-3‘ or 5’-5’ polarity reversal are incorporated into P-DNA, there is then a large destabilisation with complementary DNA or RNA. However, polarity reversal of P-LNA in a-DNA with complementary RNA is not de~tabi1ised.l~~ a-L-LNA phosphoramidite monomers (5-methylcyosine and adenine) have been incorporated into mixed DNA-a-L-LNA oligonucleotides. In hybridisation studies the presence of the CX-L-LNA units increased the T, against both DNA and RNA complements, but greater stability was observed with RNA.’95A duplex against RNA was also able to induce RNase H activity though at a very slow rate. a-L-Ribothymidine has been incorporated into chimeric oligonucleotides with DNA or ~ - L - L N A .c~-L-RNA/DNA ’~~ and ~ - L - R N A / ~ - L - L N chimA eras were both found to have enhanced affinity towards complementary RNA,

Organophosphorus Chemistry

254

and the a-L-RNA/a-L-LNA chimera was more stable than the control DNA duplex with complementary RNA.

mTok2Ho,,,p ?& "0

N I-0

B

-0-

MeO-P=O

Okay I

0

'

0 I

o=p-oI 0.. ..

0 I . P(N'Pr2)OCE

(64)

The conformationally locked tricyclic LNA derivative (63) has been synthesised and incorporated into DNA.'97 The analogue displayed a marked decrease in affinity for either DNA or RNA than unmodified sequences. Oligonucleotides containing a tricyclic sugar residue (64) have been prepared as conformationally restricted DNA analogues. The presence of the cyclopropane ring enhances structural rigidity.19*The analogue stabilises both DNA and RNA duplexes, and shows a preference for RNA, a fact confirmed by CD measurements which indicates A-form duplexes. The tricyclic analogue, however, is most stable when self-paired. The binding properties of 2'-0,-4'-Gethylene bridged nucleic acids (ENA) (65) have been examined and compared with LNA.'99NMR demonstrated that ENA adopts the N-conformation, as does LNA. In hybridisation studies, ENA showed an enhanced affinity towards RNA, but was slightly less stable than the corresponding LNA analogues. However, it was reported that ENA exhibits superior nuclease resistance to LNA. The bicyclic uridine nucleoside (1S,5S,6S)6-hydroxy-5-hydroxymethyl- 1-(uracil-1-yl)-3,8-dioxabicyclo[3.2.11octane (66) has been incorporated into ODNs where it was expected to restrict the sugar moiety into an 04'-endo conformation.200It was found that the presence of the analogue caused some destabilisation in duplexes with either DNA or RNA, thus a locked nucleic acid does not always lead to duplex stability. The conformationally restricted S-type uracil nucleoside (67) bearing nitrogen at C3' was synthesised and incorporated into oligonucleotides. It was found that the analogue introduced quite large destabilisation in duplexes with both DNA and RNA.201Novel nucleosides containing a W-shaped bicyclic nucleoside (WNA) bearing an aromatic ring as a stacking motif (68) have been studied in purine rich anti-parallel T F O S . ~ The ' ~ aromatic ring aids stabilisation of the duplex by stacking interactions, whilst the guanine residue provides sites for Hoogsteen hydrogen bonding. The analogue was shown to have high selectivity for a TA site. Pseudorotationally locked abasic site analogues were incorporated into the

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recognition sequence of M.Hha1 (5'-GXGC). The binding affinity of M.HhaI increased when the abasic site is constrained in the South conformation (69), but decreased when constrained to the North c o n f ~ r m a t i o n ?A~new ~ pyrene LNA nucleotide has been synthesised and incorporated into either DNA or a 2'-0-MeRNA/LNA chimeric oligonucleotide?MIn either case the pyrene nucleotide was shown to exhibit universal behaviour in hybridisation studies, and it did not affect the base-pairing properties of neighbouring nucleotides.

0...

1.3.3 Oligonucleotides Containing Modified Bases. By far the greatest number of publications of modified oligonucleotides involve base modification. This section will deal with these modifications, first with modifications to pyrimidines, then purines and finally with a number of artificial nucleoside analogues employed for a particular property of the nucleobase. For the pyrimidine analogues, uracil analogues will be discussed first, and then cytosine analogues. With uracil analogues, the most common modification point is C5, though a few other modification sites are reported. The effect of binding of Sm proteins to human U4 snRNA was investigated to determine whether the Sm site was a likely target for the RNA-mediated effects of the anti-cancer drug Sfluorouridine (5-FU).205These effects were studied by including 5-FUTP in the in vitro transcription reactions, but it was found that the presence of 5-FU did not inhibit Sm protein binding. Fluoropyrimidines have found use in chemotherapy treatments, but their use is limited due to the onset of chemoresistance. Liu et aZ.206have studied the use of short ODNs consisting entirely of the analogue 5-fluoro-2'-dU. They report that such homoODNs with 5'-folic acid conjugated show improved cytotoxicity in human tumour cells and in 5-fluorouracil resistant cell-lines. In particular, the 10-mer folic acid conjugate was more effective, and showed enhanced cellular uptake compared to the ODN lacking folic acid. At a pH of -8.5, in the presence of divalent metal ions such as Zn2+,Ni2+ and Co2+,DNA adopts a structure in

256

Organophosphorus Chemistry

which it is proposed that the metal ion is interposed in the base-pair. This complex is known as M-DNA, and occurs principally in poly(dG):poly)dC or poly(dA):poly(dT) tracts. Replacement of d G by dI or dT by 5-fluoro-2’deoxyuridine allows formation of M-DNA at lower pH.’07 It was found that the lower the pK, of the imino proton, the lower the pH at which M-DNA forms. One problem for targeting RNA is that the A:U and G:U base pairs have similar stability, and G:U wobble pairs account for almost half of known non-Watson-Crick pairs. 2-Thiouridine will increase the specificity for pairing with adenosine by a factor of 10. It has been reported that the complete substitution of pyrimidines by C5-propynyl pyrimidines enhances this specificity ’09 100-fold without altering base pairing specificity.208* Oligonucleotides containing 5-formyl-dU have been used to form cross-links via a Schiff base with peptide fragments.210Using peptides derived from Rec A protein it was shown that 5-formyl-dU will cross-link with a lysine residue at either the 6th or 8th position from the N-terminus. The synthesis of ODNs containing 5-trifluoromethyl-dU, using standard phosphoramidite synthesis, leads to conversion of the trifluoromethyl group to cyano. However, using acetyl-protected dC and PAC-protected purine amidites, the 5-trifluoromethyldU can be incorporated.211The presence of the 5-trifluoromethyl-dU derivative in a self-complementary dodecamer led to a 3°C destabilisation. Laterally asymmetric charge neutralisation along the DNA helix can induce bending towards the neutralised surface. C5-amino-modified nucleosides (e.g. propylamino and propynylamino) have been incorporated into DNA duplexes, and the degree of bending determined by electrophoretic mobility.212It was found that six flexible ammonium ions (propylamino) within the duplex caused detectable curvature whereas the rigid linker (propynylamino) had no effect. The physicochemical properties of short DNA hairpins containing a cationic 5-(3aminopropyl) side chain have been examined to study the melting properties of the hairpins and their interaction with Mg’+ ions.213The presence of the chain in the major groove effectively neutralises a high degree of negatively charged phosphate groups, yielding a hairpin with a lower charge density. The synthesis of positively charged and mass tagged nucleosides bearing a quaternary ammonium function at the penultimate position of a primer has been described.214 Neutralisation of the phosphate backbone by means of the quaternary ammonium salts increases the detection sensitivity in MALDI-TOF mass spectrometry by two orders of magnitude. The effects of base (5-propynyl-dU, 5-bromo-dU and 5-methyl-dC) and sugar (phosphorothioate, methylphosphonate and 2’-O-methyl) in TFOs has been studied.’I5 For most modifications, the AHo for purine triplex formation is almost zero, suggesting a temperature-independent affinity constant. However, for the pyrimidine modifications, the triplex formation is strongly favoured at lower temperatures. The use of 5-propargylamino-dU has been shown to be effective at enhancing triplex stability when incorporated into the TFO. It has now been demonstrated that further modification of the sugar with 2‘-aminoethoxy infers even greater stability across a broad pH A modified dU analogue was designed to incorporate a thymine group linked

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to C5 of dU, such that within an ODN duplex the thymine would act as a ‘clamp’ forming a Hoogsteen base-pair with the dA complementary to the d U as shown in (70).217The Hoogsteen base-pairing properties of the analogue were confirmed when based paired opposite 7-deaza-dA, where duplex stability was reduced. However, the analogue was significantly destabilising when in a duplex. A phosphoramidite monomer derived from (71) has been introduced into ODNs for post-synthesis modification.218The ketone was treated with a number of aminooxy derivatives, and it was shown that the modification had little effect on duplex stability. This may be used to ‘decorate’ DNA for a number of DNA applications. A series of modified dUTP analogues (72) which can incorporate a variety of amine derivatives, including biotinylated and fluorescent derivatives, has been prepared for study in PCR It was found that K O D Dash DNA polymerase was able to incorporate the modified triphosphates during PCR whilst other conventional DNA polymerases would not. 0

dR 0

dRTP

The incorporation of the 2’-dU phosphoramidite bearing the nitroxide 3ethenyl-2,2,5,5-tetramethyl-pyrrolin1-yloxy group (73) has been shown to be a convenient method to introduce a spin-label into oligonucleotides.222ODNs containing spin-labels, e.g. (73), may be used with EPR detection to detect oligonucleotide binding.223Spin labels show a change on binding, and are highly sequence selective. They may also be used to optimise annealing conditions, and may be used to investigate the binding of oligonucleotides to DNA chip surfaces. A number of analogues has been prepared for photochemical studies. The photochemical reaction of 5-halouracil derivatives in DNA has been investigated for some time. Hydrogen abstraction of the sugar moiety from the 5’ side by dU is largely conformation-dependent. Competitive C1’ and C2’p H abstractions are observed in B-DNA:24 predominant C1’ H abstraction occurs in DNA-RNA and stereospecific C2’a-hydroxylation occurs efficiently in Z-DNA.226In a more recent the photoreaction of 5-iodouracil con-

258

Organophosphorus Chemistry

taining DNA in the presence of Sso7d protein is studied. Sso7d protein causes a 60" kink in DNA at TpT steps. In the photochemical reaction, 5-iodo-dU is substituted for a dT, and the products of the reaction were found to be a mixture of 5-formyl- and 5-carboxyl-dT. The analogue 5-(phenylthiomethyl)-2'-dU was incorporated into DNA via its phosphoramidite derivative. Exposure of the ODN to UV light leads to photolysis of the phenylthiomethyl group to generate a radical that reacted further to give a variety of lesions. The most abundant lesion formed was found to be the thymine-guanine analogue (74).228Mechanistic studies on the formation of deoxyribonolactone by UV irradiation has been studied. In a hexamer duplex containing 5-bromo-2'-dU adjacent to l'-deutero-2'-dA, photoreaction gave rise to deoxyribonolactone. It was found that, during the reaction, the 1'-deutero group is transferred from the adenosine sugar to give 5-deuter0-2'-dU.~~~

I dR

(73)

(74)

O=..

Oligonucleotide duplexes containing the benzophenone-modified nucleoside (75) have been shown to undergo a reversible photochemical cross-linking reaction.230The benzophenone is located in the major groove. On photolysis, a new product is formed, which the authors were unable to characterise, but, based on model reactions, the benzophenone modified thymidine derivative (76) is postulated. On heating at 90°C the cross-link is reversed. Various methods have been described for the introduction of metals into oligonucleotides. A method for the incorporation of Ru" and 0s" complexes into ODNs attached to C5 of dU (77)has been The presence of the metal centre does not cause a decrease in duplex stability, and CD shows that duplexes

5: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

259

containing the analogues adopt the usual B-form. Duplexes containing the ruthenium analogue are luminescent, and may be used to study energy and electron transfer processes through the DNA base stack. A variety of novel phosphoramidite monomers were prepared by Mitsunobu reaction with alcohols and 5’-O-DMT-protected 2’-dU. Surprisingly, the alcohol ligands were attached to the N3 position of the uracil base.232This methodology was used to introduce chelating groups into oligonucleotides for the introduction of lanthanide(II1) ions. A method for the sequence-specific cleavage of RNA has been examined using the Cu(I1) complex of the terpyridine-modified analogue (78).233 Analogue (78) was incorporated into an ODN, and targeted towards RNA in such a manner that it was opposed to an unpaired RNA residue. To generate an unpaired RNA residue, a 1,3-propanediol linker was incorporated next to (78), thus creating artificial mismatches. RNA cleavage correlated with the number and location of the linkers in the DNA strand. 0

dR

0

bpy = bipyridyl

There are also various other dU analogues described, modified at positions other than C5. 2’-O-Methyl-6-oxocytidine-containing oligonucleotides were found to be sequence specific inhibitors of HIV-1 integrase in vitro.2343235 The presence of the 6-oxocytidine was found to be essential for inhibition, though the precise mechanism of action was unknown. N3-Nitrothymidine has been used as a convertible nucleoside for post-synthesis modifi~ation.2~~ N-Nitrothymidine reacts with primary amines yielding N3 substituted ODNs. The stability towards oxidation and the oxidative desulfurisation of 2-thiouridine during oligonucleotide synthesis has also been It was found that a mixture of CC&/H20 in the presence of a basic catalyst was superior in maintaining the thiocarbonyl function, whilst 2-phenylsulfonyloxaziridine was a very effective reagent for desulfurisation. A series of TFOs containing a- and P-thymidine, a- and P-N7hypoxanthine and a- and P-N7- and N9-aminopurine nucleosides, designed to bind to T-A inversion sites in DNA duplexes, has been assessed.238Using gel mobility shift assays, the recognition of T-A in an antiparallel triplex binding motif is observed using the a-N9-aminopurine modification. Three NifS-like proteins, IscS, CSD, and CsdB, from E . coli catalyse the removal of sulfur and selenium from L-cysteine and L-selenocysteine, to form L-alanine. These enzymes are proposed to function as sulfur-deliveryproteins for iron-sulfur clusters, thiamin, 4-thiouridine, biotin, and molybdopterin. Mihara et al.239have reported evidence that a strain lacking IscS is incapable of synthesiz-

260

Organophosphorus Chemistry

ing 5-methylaminomethyl-2-selenouridine and its precursor 5-methylaminomethyl-2-thiouridine (mnm5s2U)in tRNA, suggesting that the sulfur atom released from L-cysteine by the action of IscS is incorporated into mnm5s2U. Neither CSD nor CsdB were essential for production of mnm5s2Uand 5-methylaminomethyl-2-selenouridine. The tRNA analogue 3-methyluridine (m3U)has been incorporated into RNA hairpin structures as analogues of the natural base modification 3-methylpse~douridine.~~~ Analogue m3Uwas incorporated as the 2’-O-ACE protected phosphoramidite. In an RNA hairpin corresponding to the 1920-loop region of 23s ribosomal RNA, it was shown that the incorporation of m3U in place of U had little effect on the hairpin stability. The HDV ribozyme catalyses its self-cleavage by a proton transfer mechanism such that N3 (C75) acts as a general acid. C75-U mutation abolishes enzyme activity. To test whether the activity of the C75-U mutation could be restored, 6-azauridine (n6U)was incorporated into the HDV ribozyme active site, as the pK, of n6U N3 is 6.7 (9.7 for U).241Self-cleavage activity was not restored, suggesting that C75 has other functions in the self-cleavage reaction centre. The final uridine-modified analogues are those associated with damaged bases, the most common being the thymine dimers and glycols. Translesion synthesis using the yeast DNA polymerase 1; has been studied with the UV . ~ ~ incorpor~ damaged lesions TT (6-4) (79) and the cis-syn thymine d i m e r ~Pol ated A or T with similar efficiencies opposite the 3’-T and predominantly A opposite the 5’-T of the (6-4) photoproduct. With the cis-syn thymine dimer, Pol 1; was able to bypass the 5’-T, but the 3’-T blocked synthesis. Human DNA polymerase q (pol q) has been shown to efficiently and accurately catalyse translesion synthesis past the cis-syn thymine dimer. In addition, pol q will catalyse insertion opposite the 5R- or 5s-thymine glycol lesion, but extension was inhibited to a large extent by the 5S n ~ c l e o t i d e . ~ ~ ~ Oligonucleotides containing the oxidatively damaged thymine glycol building block (80) (5R6S isomer shown) were Using silyl protection of the glycol unit results in silyl group migration for the (5s)isomer, which was therefore incorporated without protecting groups. The thymine glycol is slightly destabilising when present in a DNA duplex. The rates and site of digestion of RNA:DNA duplexes containing the lesions thymine glycol and urea have been examined.245Using E.coli RNase H with unmodified RNA:DNA duplex, there is one major product. However, with DNA containing the two lesions there are three products, with cleavage occurring adjacent to the lesions.

HO

OH

5: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

26 1

Two diastereoisomers have been identified as radiation induced decomposition products of dC. The synthesis of one of these isomers, (5’S,5S,6S)-5’,6-cyclo5-hydroxy-5,6-dihydro-2’-deoxyuridine (8 l), and its incorporation into DNA, has been reported.246The presence of the lesion causes a marked destabilisation of DNA duplexes. The nucleases P1,calf spleen phosphodiesterase and bovine intestinal mucosa phosphodiesterase failed to cleave the lesion, nor was it a substrate for a number of repair enzymes, and it acted as a block to Klenow fragment and Taq polymerases. It has been shown that when DNA from salmon milts is irradiated with UV light, the molecular weight of the DNA is greatly The reaction is inhibited by radical scavengers, strongly suggesting that there is a radical reaction. It is proposed that the cross-linking reaction occurs uia thymine dimer formation. The resulting DNA films retain a B-form duplex, are able to accumulate DNA-intercalating compounds (such as ethidium bromide) and are resistant to hydrolysis by nucleases. There are fewer modified cytidine oligonucleotides than for uridine. The most common point of modification for these analogues is N4. The incorporation of a series of N4-acyl-2’-deoxycytidinederivatives has been reported, and the duplex stability of ODNs containing the modifications In order to obtain ODNs containing N4-acyl modifications, a new solid support (82), where the support is a highly cross-linked polystyrene resin, was prepared. The analogues were incorporated into a thymidine ODN, and the oligo removed from the support using DBU. It was found that the acyl groups were destabilising when in a DNA duplex. Oligonucleotides containing N4-alkoxycarbonyl-dC derivatives (83) have been synthesised on polystyrene resins having a silyl linker. The use of the silyl linker allowed for cleavage of the oligonucleotides from the support with TBAF under neutral conditions.249Generally these analogues were destabilising in a duplex with DNA, but they were more stable than the corresponding N4-acyl-dC analogues. In addition, it was found that the analogues (83) also formed more stable duplexes when base paired with dA. The novel 5’-triphosphate derivative (84) has recently been used for in vitro labelling and detection of DNA.250Curiously, the analogue behaves as both a dTTP and a dCTP analogue and is therefore potentially mutagenic. DNA containing a N4-dC-ethyl-N4-dCcrosslink via a convertible nucleoside, or by a protected cross-linked phosphoramidite, has been reported.251The cross-linked analogue was incorporated into DNA duplexes such that the C-C formed a mismatch or was staggered between two CG steps. In the mismatch duplexes, the T, was found to be considerably higher (25°C in an 11-mer), whilst in the staggered configuration, an 8-mer duplex was stabilised by 49”C.252 The reaction of dC with glycidaldehyde leads to the lesion 8-(hydroxymethy1)3,N4etheno-dC (8-HM-S), (85). The miscoding properties of this lesion have been studied with various DNA polymerases. Calf thymus DNA polymerase a and human pol K did not extend the DNA, human pol p was able to extend beyond the lesion, and human pol q catalysed the most efficient bypass.253dC and dA were most efficiently incorporated opposite ~-HM-EC, though with pol K some incorporation of dTTP occurred. 8-HM-EC is also a substrate for the

Organophosphorus Chemistry

262 H

O

W

T

0

0

I CI CI'

dR

(83)

dR

R = Me, Bu, EtOMe

dR

~RTP

(84)

NA0\

I I V

repair enzyme mismatch uracil-DNA glycosylase (Mug), though the efficiency of binding and repair is 2.5-fold lower than for e t h e n ~ - d C . ~ ~ ~ There are a few cytidine analogues that have also been incorporated into oligonucleotides. The analogue pseudoisocytidine (86) has been incorporated into ODNs as its 5'-triphosphate using Klenow fragment, where it was incorporated opposite dG.255The chemical stability of ODNs containing 2'-deoxy-5methylisocytidine during ODN synthesis and deprotection has been investigated. It was shown that de-pyrimidination during alkaline deprotection occurred to a lesser extent than had been previously s ~ g g e s t e d . 2The ~ ~ cytosine mimic, 5-methylpyrimidin-2-one, has been prepared and incorporated into ODNs to study RecA-DNA complexes.257 The presence of the analogue had little effect on RecA binding, but there is a concentration dependent increase in polarised emission from the analogue on binding with RecA. The mutagenic ribonucleotide rPTP (87) has been used in an in vitro retroviral replication model.25sAfter four rounds of replication the mutation frequency was per nucleotide, with C+U and U+C mutations observed. It raised to 3.8 x was suggested that such an analogue could induce mutations in a retroviral target beyond its error threshold. The tricyclic cytosine analogues phenoxazine and 9-(2-aminoethoxy)-phenoxazine (g-clamp, see (141))have been incorporated into ODNs to study their effect with exonuclease. It was found that a single substitution at the 3'-terminus afforded complete protection of the ODN with snake venom phosph~diesterase.~~~ Amongst the most widely used purine derivatives are 8-0x0-dG and 2aminopurine (2AP). As the persistence of damaged DNA/RNA bases could lead to transcriptional/translational errors, organisms have evolved mechanisms to recognise such lesions. E . coli possesses proteins that specifically bind to RNA carrying 8-0xoguanosine.2~~ The effect of introducing 8-0x0-dG into telomeric

5: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

263

DNA showed that there might be a biological consequence to oxidation of telomeric DNA.261Telomeric DNA contains GGG sequences, and telomeres adopt a quadruplex structure. Oxidation of the 5’-G resulted in a quadruplex structure, but oxidation in the middle of the GGG triplex led to multiple structures. Telomerase activity was significantly reduced when 8-0x0-dG was at the 5’-end of the triplet, but not in the middle where multiple structures were formed. The introduction of 8-(hydroxymethyl)-2’-dA into a DNA duplex causes a considerable decrease in duplex stability. The effect of the modification has been studied by molecular dynamics simulation, where it was found that the analogue causes stretching of the double helix, opening of the grooves and exposure of the core to the buffer.262Parallel-stranded hairpin duplexes (po1ypurine:polypyrimidine) containing 8-aminopurine (adenine, guanine or hypoxanthine) bind to single-stranded polypyrimidine targets via triplex formation.263* 264 The binding is stronger when 8-aminopurine derivatives are present compared to guanine or adenine hairpin structures, and 8-aminoguanine showed the strongest stabilisation, though 8-aminohypoxanthine was the most stable at neutral pH. The use of 8-aminopurine derivatives in parallel stranded duplex structures has been shown to adopt Hoogsteen base-pairing motifs rather than reverse Wat~on-Crick.~~’ The adenosine isostere, 2-aminopurine (2-AP), has been used to probe cleavage of the hammerhead ribozyme?662-AP was incorporated into the hammerhead ribozyme proximal to the cleavage site, and it was shown that it did not interfere with ribozyme folding or catalysis. The fluorescence of 2-AP is sensitive to environmental changes, and changes dramatically during cleavage of the substrate. Physical changes in the template strand during primer extension with the T4 DNA polymerase were monitored using the fluorescent analogue 2aminopurine 2-AP was positioned in the template strand opposite the primer terminus (n) and at n + 1 and n + 2 positions 5‘ to the primer terminus. At the n-position, fluorescence enhancement occurred due to the formation of an editing complex, but at 5’ positions, enhancement was a measure of interactions of the DNA with the polymerase induced by intrastrand base unstacking. The fluorescent analogue 2-aminopurine has also been used to measure the translocation of PcrA helicase towards the 5’-end of ssDNA as a fluorescent signal is observed when PcrA reached 2-AP.268Random binding of PcrA to ssDNA is followed by an ATP-dependent translocation towards the 5’-terminus at a rate of 80 bases per second at 20°C. A-tract DNA duplexes exhibit high propeller twist and rigidity, which makes A-tract DNA unfavourable for triplex formation. It has been demonstrated that the introduction of a single central GC pair into the duplex significantly enhances the stability of the resulting triplex, as does the introduction of diam i n ~ p u r i n eIn . ~both ~ ~ cases, the stabilisation occurs due to the disruption of the intrinsic properties of A-tract DNA. There have been reports on 6-substituted purine analogues and, in particular, C6-vinyl modified nucleosides have been studied in oligonucleotides. The incorporation of the 2-amino-6-vinyl purine analogue (88) into oligonucleotides has been carried out, using methylsulfide protection of the vinyl group. Oxidation

264

Organophosphorus Chemistry

after ODN synthesis with magnesium monoperphthalate regenerated the vinyl group.27oWhen incorporated into TFOs it was shown to be a selective crosslinking agent to the adenine of a T:A interruption in the duplex. The 2-amino-6vinylpurine derivative (89) has been incorporated into ODNs and shown to be an efficient agent for interstrand cross-linking to cytidine ~ p e c i f i c a l l y272 . ~The ~~~ reaction occurs under neutral conditions, and it is suggested that such analogues would have use in antisense strategies.

I

dR

dR

(90) x = o , s (89) The base analogues 2-amino-6-(2-thienyl)purine and 2-amino-6-(2fury1)purine (90) have been incorporated into ODN duplexes as potential nonhydrogen bonding base pairs with pyridin-2-one n~cleoside.~’~ The thienyl derivative opposite pyridin-2-one was more stable than the N6dimethylaminopurine. The 5’-triphosphate derivative of the pyridin-Zone nucleoside was inserted opposite the thienylpurine derivative more efficiently than the natural dNTPs. RNA oligomers have been prepared using the phosphoramidite monomer derived from 6-trifluoromethylpurine ribonucleoside as potential inhibitors of adenosine d e a m i n a ~ eThe . ~ ~presence ~ of the modification was destabilising in an RNA duplex, equivalent to an A-A mismatch. Another common position to modify purines is the N2 or C2 position. 2Fluoro-modified deoxyinosine derivatives have been used to site-specifically introduce cross-links between adjacent guanine residues in oligonucleotides. Reaction of the 2-fluoro-dI containing ODNs with various chain length diamines was found to be an efficient method of cro~s-linking?~’ These cross-linking agents have been used to induce bending in DNA. The synthesis and incorporation into DNA of the 2’-deoxy-2- and 8-deuteroadenosine derivatives has been The synthesis of the 2-deutero derivative is reported to be an improvement on previously published procedures. Such modifications would be of particular interest in NMR solution studies. Oligonucleotides modified by the addition of spermine to the N2 of G residues have been shown to have increased binding affinity to DNA.277These ODNs were shown to be taken up by a supercoiled plasmid three fold higher than for un-modified DNA, and it is demonstrated that the spermine-modified ODNs bind within superhelical double-stranded DNA by strand invasion. 2-Azido-2’-dA was synthesised from 2’-dG and incorporated into ODNs using H-phosphonate chemistry without reaction of the azido gro~p.2~’ When incorporated into duplexes, the presence of 2’-azido-2’-dAwas found to be significantly destabilising, and it is suggested that this is due to electrostatic repulsion.

5: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

265

There are a number of pyrrolo- and pyrazolo-pyrimidine analogues described, especially by Seela and co-workers. These analogues have mainly been used in hybridisation studies. The 9-deaza N7-purine nucleosides (91) were synthesised and incorporated into ODNs for comparison with 7-aza~urine.2~~ The 7-azapurine derivative forms a stable base pair with “OdC in antiparallel duplexes. The analogues (91) also form stable base pairs with isodC,with the halogenated derivatives being most stable. The analogue 2-amino-7-deazaadenine was incorporated into O D N duplexes, where it was shown that it formed stable base pairs with both dT and dC.280However, in primer extension assays with the analogue in the template strand, the ratio of incorporation of dTTP:dCTP was 100:2, and thus is recognised by a polymerase as an adenine derivative. 7-Deaza- 2’-dA and -2’-dG as well as C5-dT and -dC nucleosides bearing propargylamine side chains have been incorporated into ODNs for hybridisation studies.281In each case, the presence of the propargyl side chain led to higher duplex stability. The 8-aza-7-deazaadenine and 7-deaza-C8-guanine C-nucleoside derivatives (92)and (93), respectively, have been prepared as their phosphoramidite building blocks and incorporated into ODNs for hybridisation studies.282(92) hybridised to each of the four natural DNA bases, thus behaving as a universal base analogue. (93), however, showed base pairing properties similar to 2’deoxyisoguanosine. The 7-deaza-8-aza-2’-deoxyisoguanosine derivatives (94) were incorporated into parallel stranded DNA duplexes for hybridisation stuBoth analogues give rise to higher duplex stabilities compared with 2’-deoxyisoguanosine, and the brominated derivative is considerably more stabilising. PyrazoloC3,4-d]pyrimidines related to 2’-dA, 2’-dG and 2’-deoxy-2aminoadenosine exhibit greater stability with dT and 2’-dC, respectively, than with the natural purines. This stability is further enhanced by the addition of halogen or propynyl substituents to C7.284The N8-glycosylated derivative of pyrazolo[3,4-d]pyrimidine-4,6-diamineshowed ambiguous base pairing properties. Whilst showing a preference for base pairing with thymidine, it still formed stable base pairs with each of the other natural nu~leotides.~’~ It is well known that ODNs containing runs of thymidine and guanosine can form quadruplex structures. It has now been shown that the guanosine analogues, 2’-deoxyisoguanosine and 8-aza-7-deaza-2’-deoxyisoguanosine can form mixtures of quadruplex and pentaplex (95) assemblies, depending on the counter ion.286The ODNs 5’-d(T4X4T2) were studied. When X is 8-aza-7-deaza-2’deoxyisoguanosine then quadruplex structures are formed in the presence of Na+ or Rb+, but in the presence of Cs+ pentaplexes are formed. When X is 2’-deoxyisoguanosine a mixture of quadruplex and pentaplex structures are formed in the presence of Rb+ ions. The base pairing properties of the a- and P-anomers of the imidazo[1,2-a]1,3,5-triazine nucleoside (96) have been Both anomers are more stable than duplexes with dG, though the a-anomer is most stable. When the p-anomer alternates with dG, antiparallel duplexes (aps) are observed, but parallel duplexes (ps) are formed with the a-anomer. A reversal of the chain orientation (ps-+aps) occurs when the p-anomer pairs with 2’deoxyisoguanosine.

Organophosphorus Chemistry

266

dR

(96)

a-and p-anomer

(95)

As guanine is the nucleobase with the lowest oxidation potential, it is the base most likely to be damaged by an electron transport process, and there have been many reports on this topic. Lewis et d2** have examined the dynamics of hole transport from positively charged guanine radicals to a GG site. Using modified hairpins in which a stilbene dicarboxamide acceptor forms the 'loop' region, hole transport has been examined for a variety of hairpin duplex structures. 7Deazaguanine has also been used as a hole trap in strand cleavage studies because it has a lower oxidation potential than guanine. It was shown that 7-deazaguanine is a much deeper hole trap than GG or GGG, and that hole transfer is strongly dependent upon the number of A:T base pairs separating the hole donor and acceptor.289Altering the potential energy gap between the hole donor and acceptor may attenuate the rate of hole migration. The modulation of hole-transport by altering the rate of hole trapping has been The introduction of N2-cyclopropyl-dG has been used to act as a radical trap, and one electron oxidation causes homolytic cyclopropane ring opening. Thus the analogue terminates DNA-mediated hole transport. The introduction of N2-phenyl-dG into duplex DNA has been shown to dramatically suppress oxidative decomposition, not only at the N2-phenyl-dG site, but also at remote d G sites.291 The oxidative effect of long-range charge transport in RNA and mixed

5: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

267

RNA:DNA duplexes has been examined using oligonucleotides conjugated at the 5’-end with either ethidium or a rhodium complex as the photo-o~idant.2~~ Photo-excitation leads to radical hole migration to the nearest susceptible guanines. It was found that with the ethidium bound duplexes that the ribosecontaining strands were oxidised at long range (- 3581), whilst the rhodium complexes were not susceptible. This was attributed to poor coupling of the rhodium complex with the A-form duplexes. To investigate the driving force dependence of hole transfer from guanine radicals in DNA, pulse radiolysis of phenothiazine conjugated ODNs has been measured.293Using T12S04 as an oxidant source, radiolysis generates T12+which can oxidise all four of the DNA bases, but the guanine with the lowest oxidation potential is oxidised. Hole transfer from the guanine radical to the phenothiazine moiety was observed in the range of loops. Similar results were observed when pyrene was used, and monitored by the formation and decay of the pyrene radical cation, which has a large molar extinction coefficient?94 The one-electron oxidation rate of guanine derivatives (8-bromo- and 7,8dihydro-guanine) may be controlled by base pairing with cytosine derivatives.295 Oxidation using N,N’-dibutylnaphthaldimidide(NDI) or fullerene in their triplet states was measured by triplet-quenching experiments. It was shown that the introduction of 5-Br or 5-Me groups to cytosine accelerated or suppressed the oxidation of the guanine derivatives, respectively. Using transient absorption spectroscopy, the distance dependence of charge-shift dynamics between the covalently attached, photoexcited electron acceptor 9-alkylamino-6-chloro-2methoxyacridine (97), intercalated into a DNA duplex at an artificial abasic site, and either dG or 7-deazadG as electron donor, with variable numbers of A:T base pairs between the donor and acceptor, has been e ~ a m i n e d .The 2 ~ ~absence of distributed kinetics even on the sub-picosecond time scale shows that structural fluctuations on any longer time scale are not reflected by a distribution of electronic couplings between (97) and the nucleobases within the duplex. In an independent paper, the analogue (97) has been used in conjunction with various lanthanide(II1) or divalent metal ions to act as a site-selective RNA r i b o ~ y m e . ~It~is~ reported , ~ ~ * that RNA scission occurs opposite the site of (97), and although metal ions are involved, it is shown that they are not fixed anywhere specifically. There are many reports regarding purine lesion analogues. Guanine lesions are the most common, usually from oxidative damage. There are also reports on polyaromatic hydrocarbon (PAH) modified purine analogues. Further work on such damaged analogues is found in the section on nucleic acid structures. A thermodynamic and kinetic study of the effectiveness of the repair of 8-0x0-dG It was found for the first by the E. coli repair enzyme Fpg has been carried time that recognition by Fpg protein of specific DNA is additive in terms of Gibbs free energies. Fpg protein interacts effectively not only with specific ss and ds ODNs but also with nonspecific ones. Oligonucleotides containing 8-0x0-dG were treated with peroxynitrite to give the oxidation products oxaluric acid (98), oxazolone (99) and cyanuric acid (100). After purification, these ODNs were ligated into bacteriophage DNA and transfected into E . coli, and the efficiency of

268

Organophosphorus Chemistry

translesion synthesis studied.300It was found that all three lesions were readily bypassed yielding G +T transversions at frequencies an order of magnitude higher than that caused by 8-0x0-dG. Me0

\

HN I

dR oxaluric acid

dR oxazalone

dR cyanuric acid

The synthesis of DNA containing the analogue Fapy-dG (N6-(2-deoxy-a,P-~erythro-pentofuranosyl)-2,6-diamino-4-hydroxy-5-formamidopyrimidine(101) has been Fapy-dG is a major lesion found in DNA due to the effects of ionising radiation and oxidative damage. The yield of Fapy-dG formed by y-radiolysis is more prevalent than the well-studied lesion 8-0xo-dG.~'~ The analogue instructs Klenow Exo-to misincorporate dA at a significant rate, giving rise to G + T t r a n s ~ e r s i o n sThe . ~ ~ C-nucleoside ~ derivative of Fapy-dA has also been incorporated into ODNs via its phosphoramidite derivati~e.~"FapydG:dC-containing duplexes melted at lower temperature than the corresponding duplex with dG:dC, though Fapy-dG:dA duplexes melt significantly higher than dG:dG duplexes. Fapy-dA or its C-nucleoside was found to be destabilising opposite any of the four natural DNA bases. When Fapy-dA or its C-nucleoside were in a template for primer extension by Klenow fragment, it was found that the most common dNTP incorporated was TTP.305However, compared to when dA was in the template, there was a 50% chance of misincorporation of dATP or dGTP. The reaction of peroxynitrite with guanine-containing oligonucleotides also leads to the formation of 5-guanidino-4-nitroimidazole (102). It was shown that ssDNA reacts 10 times faster than dsDNA to yield the lesion, and that DNA containing (102) is a poor substrate for cellular repair enzymes.306When (102) is in a template for primer extension, it behaves as a replication block. A nearest-neighbour analysis was used to address the contribution of sequence context on 06-methylguanine(m6G)repair by the E. coli methyltransferases Ada or Ogt, with m6G flanked by all permutations of G, A, T, or C.307The Ada methyltransferase demonstrated strong 5' and 3' sequence-specific repair of m6G in vivo. The Ada 5' preference decreased in the order Gm6GN >Cm6GN >

5: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

269

Tm6GN > Am6GN, while the Ada 3’ preference decreased Nm6G(T/C) > Nm6G(G/A). The Ogt methyltransferase repaired m6G poorly in an Am6GN context. The kinetics of primer extension reactions with T7 DNA polymerase and HIV-RT have been measured for ODNs containing the mutagenic lesions @-methyl-dG and 06-benzyl-dG.308It was found that both polymerases preferentially incorporated dTTP opposite both lesions, though the efficiency of incorporation was less for 06-benzyl-dG.The Kdfor binding dCTP or dTTP to a duplex containing 06-methyl-dG was 8-fold higher than for un-modified DNA, and 50-fold higher for 06-benzyl-dG.Thus 06-benzyl-dG is a greater steric block to chain extension with both polymerases than 06-methyl-dG. Various experiments were carried out to address the mechanism of stalling by the polymerases and concluded that a non-productive polymerase complex explains the kinetics of misincorporation opposite the 06-alkyl-dG analogues.3o9 The DNA lesion 8,5’-cyclo-2’-dG, formed by attack of hydroxyl radicals, contains damage to both base and sugar, and is therefore repaired by nucleotide excision repair enzymes, and is involved in diseases with defective nucleotide excision repair. A mass spectroscopic assay has been developed for the quantitation of the lesion after enzymatic separation of the 5’ ( R )and 5’ ( S ) isomers.31o The thermodynamic stability of ODNs containing the oxidative lesion, 2hydroxy-dA has been e~amined.~” It was shown that when the lesion was in the middle of a DNA duplex it behaved as a universal base, in that there was no difference in T, when opposite any of the canonical bases. On the other hand, when it was near the termini, there was a preference for base pairing with thymidine, but it also formed base pairs with other nucleotides which was sequence dependent. The extent of oxoprenylation by malondialdehyde or adenine propenal has been investigated in DNA, see ( 139).312 ssDNA was found to be more sensitive to oxoprenylation, and supercoiled-DNA more susceptible than linearised plasmid DNA. A variety of intercalators were used, some of which inhibit oxoprenylation, e.g. netropsin, whilst others, like ethidium bromide, caused enhanced oxoprenylation. dR

o...

BenzoCalpyrene diol epoxides react with adenine residues in DNA to give 1OS(+)- and lOR(-)-trans-anti-benzo[a]pyrene-N6-dA adducts (103), 10R(-) shown, which give rise to mutational hot spots. The solution structure of an 11-mer duplex in which there is a modified adenine has been studied, and it was

270

Organophosphorus Chemistry

shown that whilst the lOR(-) adduct intercalates on the 5'-side of the adenine, the 1OS(+) is disordered, and the adduct is on the 3'-side of the adenine.313Molecular mechanical calculations show that the 1OR(-)is more stable than the lOS(+), with most of the stabilisation being enthalpic. The translesional DNA synthesis past the lesion C8-2-acetylaminofluorene-dG (dG-AAF) and C8-2-aminofluorene-dG (dG-AF) has been investigated with the human DNA polymerase K (pol K) and E. coli DNA polymerase IV (pol IV).314With dG-AAF in the template, and at high enzyme concentrations, dTMP followed by much smaller amounts of dAMP, dGMP and dCMP were incorporated. With templates containing dGAF, all four of the natural triphosphates were incorporated with equal efficiency. The effect on duplex bending of the mutagenic lesions (+)- and (-)-anti-7,8diol-9,lO-epoxidederivatives of benzo[a]pyrene (BPDE)have been examined by a gel mobility assay. The (+)-isomer has previously been shown to be tumorigenic whilst the (-)-isomer is not. It has been shown that (+)-trans-antiBPDE-N2-dG adducts cause considerably more bending in DNA than the (-)-isomer regardless of the neighbouring sequence.315All four isomers of BPDEN2-dG have been site-specifically incorporated into ODNs to monitor the translesion synthesis using a truncated form of human pol K (pol K A C ) . ~It' ~was found that each isomer preferentially directed the incorporation of the correct nucleotide (dCMP), although ( + )-trans-anti-BPDE-M-dG did misincorporate small amounts of each of the other nucleotides when high levels of the polymerase were used. With Klenow fragment, it was found that the (+)-trans- and (+)-cis- derivatives caused a strong steric block to primer extension when the lesion was within five positions of the primer t e r m i n u ~ , 3the ~ ~(+)-cis-isomer showing the most inhibitory effect. The final examples of purine lesions are those derived from platination reactions, which frequently occur with guanine residues with anti-cancer agents like cisplatin. Cisplatin may form two different cross-links with DNA: intrastrand occurring at GG sites and interstrand at G C sites. Intrastrand cross-links are usually more abundant. Kinetic measurements between two hairpin DNA structures and cisplatin showed that the interstrand cross-link is as fast or faster than the intrastrand ~ross-link.~'~ The authors suggest that the low occurrence of interstrand cross-linkage is due to a slow initial platination reaction at GC sequences. A non-histone chromatin-associated protein in S. cerevisiae, Nhp6A, contains a HMG box DNA minor groove binding motif. Nhp6A was shown to bind to cisplatin-modified DNA with 40-fold greater affinity than to un-modified although it readily exchanges onto un-modified DNA. A surface-exposed phenylalanine on Nhp6A promotes bending of the DNA by insertion into the helix from the minor groove. It was suggested that this phenylalanine can also intercalate into cisplatin-modified DNA, binding in either orientation. The rate of adduct formation between C ~ ~ - [ P ~ ( N H ~ ) ( ~ - N H ~ C ~ H ~ JofC I ( O H ~ ) ] a single stranded ODN d(T,GTl6-Jhas been studied.320The shape of the reaction profile showed that platination is kinetically favoured when the guanosine N7 is located at the centre part of the ODN, with the rate decreasing to similar values as the guanosine is located towards either end. The platination reaction of the telomeric sequence (T2G4)4was studied in salt solutions containing Li+, Na+ or +

5: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

27 1

K + to identify which guanine residues are platinated in the presence of these The platination reaction showed that the same quadruplex folding was observed with each of the cations, and the cations determine the stability of the quadruplex in the order K+>Na+>>Li+.

/co2H

I

dRTP

dRTP

~RTP

I

dRTP

The synthesis of fully modified DNA would have uses, particularly in the newly developing area of single molecule sequencing. The first example of enzymatic synthesis of DNA using four modified dNTPs (104-107) has been In a primer extension reaction using Thermus thermophilus (Tth), a 79-mer DNA was prepared using the four modified dNTPs. To demonstrate that the fully modified DNA could serve as a template in PCR with natural dNTPs it was found necessary to increase the PCR denaturing to 100°Cand to use the extremely thermostable DNA polymerase from Pyrococcus woesei (Pwo). In addition a commercial additive for improved amplification of GC-rich regions of dsDNA (GC-Rich solution, Roche) was added. It has also been shown that the large fragment of E. coli DNA polymerase I is capable of synthesising 58-mers comprised of tetramethylrhodamine-labeleddU residues.323Other polymerases also capable of synthesising homopolymeric DNA from fully dye-labelled dNTPs included Vent exo- and some mutant Klenow fragment DNA polymerases which had been evolved to accept dye-labelled dNTPs. The meth ylated t RNA analogues 1-meth ylguanosine (m'G), N2,N2-dimethylguanosine (m22G),N6,N6-dimethyladenosine(m62A)and 3-methyluridine (m3U) are all required for the correct cloverleaf folding of tRNA. A NMR study of RNA containing the analogues m22Gand m62Ahas demonstrated the stabilising effect of these methylated derivatives.324A RNA sequence corresponding to the 3'-end of the small ribosomal subunit containing only the four canonical RNA analogues exists as an equilibrium mixture of two hairpin-loop structures. The substitution by m22Gand m62Aalters the equilibrium such that only one of the

272

Organophosphorus Chemistry

hairpin structures is formed. Finally, there are two reports of 1-modified purine derivatives, and one on a pteridine derivative. 1-Methyladenosine has successfully been introduced into DNA and RNA by protection of N6 with a chloroacetyl group ( 1 0 ~ 9 . Carefully ~~’ controlled anhydrous conditions were required for the deprotection of the oligonucleotides using 2M NH3 in methanol. The presence of the analogue was found to be destabilising in a duplex, but in the loop of a hairpin structure a slight stabilisation was observed. Amphipathic oligo and polyribonucleotides that exhibit secondary structure in solution may be potent inhibitors of HIV and HCMV replication and cytopathicity in tissue culture. Poly (1-propargylinosinic acid) (109), polymerised using E . coli PNPase, has been shown to lack such secondary structure but found to be active against both HIV and HCMV.326The fluorescent isoxanthopterin nucleosides (110) have been introduced into DNA using npe/npeoc protected pho~phoramidites.~~’ In duplexes, the presence of the isoxanthopterin nucleosides was found to be slightly destabilising (- 1OC). 0

Before considering the final section on artificial base analogues in oligonucleotides, there are a few reports on abasic sites. Translesional synthesis of DNA containing the 2’-deoxyribonolactone lesion with M-MuLV RT and with Klenow fragment has been examined. It was found that with the reverse transcriptase, the lesion acted as a complete block, with no dNTP added opposite it. With Klenow fragment it was observed that there was a sequence context effect, but that the polymerase appeared to follow the A-rule by preferentially adding dAMP opposite the lesion.328To examine the role of conserved nucleobases in the hairpin ribozyme, abasic sites were introduced instead. It was found that the cleavage rate was significantly reduced, but that the rate could be enhanced in the presence of various heterocyclic amine The apurinic/apyrimidinic endonuclease (AP endo) is a key enzyme in the repair of oxidatively damaged DNA and is used in repairing abasic sites. The effect of multiple abasic sites, including two complementary abasic sites, has been studied by steady state and single turnover experiments, and it was shown that multiple abasic sites interfere with substrate binding and catalysis.330Endonuclease VIII from E . coli has also been used to study a variety of DNA lesions generated from y-irradiati~n?~~ and the uvrC genes of E . coli, which control the initial steps of nucleotide excision repair, have been studied in the repair of N3-adenine ad duct^.^^* A large number of artificial base analogues has been incorporated into

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oligonucleotides to fulfil a specific task. Applications include stabilising a base pair in triplexes, investigation of stacking interactions and the search for new base pairs to expand the genetic code. Many of the analogues used are aromatic, planar and often non-hydrogen bonding, for example to search for new universal base analogues. A set of ribonucleoside derivatives which are isosteres of the natural RNA nucleosides have been used to study duplex stabilising forces. The C-ribonucleoside derivatives, phenyl, 2-, 3- and 4-fluorophenyl, 2,4-difluorophenyl and the ribonucleoside derivatives of benzimidazole and 4-fluoroand 2,4-difluoro-benzimidazolewere prepared and incorporated into RNA.333i 334 Once incorporated into RNA duplexes, the effects of base stacking and solvation were studied. The 2,4-difluorophenyl- and 2,4-difluorobenzimidazole analogues were found to behave as universal bases.335It was further shown that the fluorinated analogues showed enhanced duplex stabilisation, and this was proposed to be due to C-F-H-C hydrogen bonding. The incorporation of the nucleoside derivative of 3-formylindole has been to introduce into ODNs an aldehyde function for post-synthesis modification. The analogue itself behaved as a universal base, though was less stable than an AT base-pair. The formyl group was also treated with hydrazino derivatives to give a range of products. The 5’-triphosphate derivative of the pyrrole carboxamide analogues (111) and (112) have been prepared, and their incorporation into ODNs The monocarboxamide derivative (111) was shown to behave as a thymidine analogue, whilst the dicarboxamide derivative (112) incorporated as both dA and dC. The reactive nucleoside 5’-triphosphate (113)has been examined as a substrate for various DNA p~lymerases.’~~ It was found that Klenow fragment (exo-)and Vent (exo-)DNA polymerases were best able to incorporate (113), which was best incorporated as either dATP or dGTP, and led to a mutation rate of 2 ~ 1 0 per ’ ~ base per amplification during PCR. The reactive hydrazide group was further treated with various aldehydes to modify DNA containing it. 0

0

dR

I

dR

I dRTP

A series of aromatic C-nucleosides (pyrene, naphthalene, acenaphthene and biphenyl) were incorporated into ODNs to study their effect on base

274

Organophosphorus Chemistry

This effect was studied using the fluorescent properties of the modified base 2-aminopurine (2-AP), which forms stable base-pairs with thymine, and results in a decrease in fluorescence attributable to base stacking. Each of the aromatic nucleosides showed an increase in fluorescence from 2-AP, suggesting that there is a local disruption in base stacking with it. The non-hydrogen bonding, non-shape-complementary base analogue derived from bipyridine (114)has been found to form stable self-pairs in duplex DNA.340The self-pair was found to be similar in stability to a G:C pair. When (114) is opposite an abasic site it was found to be quite destabilising. ODNs containing thiazole (115) and its corresponding N-oxide have been prepared.341Significant deoxygenation occurred during DNA synthesis involving an N-oxide phosphite ester. In efforts to extend the genetic alphabet to three base pairs, the self-pairing of the deoxyribosyl derivative of 7-azaindole (7-AI) has been examined.342Klenow fragment will efficiently incorporate the 5’-triphosphate derivative of 7-A1 opposite 7-A1 as a template base, but thereafter there is no further chain extension. The Pol fi polymerase is approximately 100-fold less effective than Klenow fragment, but when used together, the two polymerases are able to efficiently chain extend to full length DNA containing a 7-AI:7-AI base pair. A series of thiophene or furan heterocycles (116) has been examined as nucleobases as orthogonal third base-pairs for the development of the genetic The compounds when paired opposite each other are too small to allow for stable duplex formation, but higher stability was obtained when paired with larger hydrophobic nucleobases, such as MICS344. The artificial nucleobase (117), when incorporated into TFOs, was found to form stable triplexes with duplex DNA containing a pyrimidine within an oligo-purine sequence.345The analogue provided 5-8°C of stabilisation compared to natural base triplets, yielding T,s similar to triplexes without the pyrimidine insertion. DNA triplex formation is reversibly modulated by the presence of the azobenzene derivative (118) in the third ~ t r a n d .In ~ the ~ ~trans i~~~ form, the triplex is stabilised by intercalation of the planar unit into the DNA duplex. In the presence of UV light the azobenzene isomerises into the cis form which is generally destabilising. The trans form in some sequences was 40°C more stable than the cis form. The purine-like analogues (119-121) have been designed to selectively recognise a C:G base pair when incorporated into a TFO in parallel binding mode.348(121) was found to be incompatible with ODN synthesis, but (119) was found to exhibit a preference for triplex formation with G:C z C:G, and does not involve protonation of (119). The unexpected binding to G:C base pairs was explained by intercalation of (119). Perylene has been incorporated at both 5’- and 3’-ends of an oligopyrimidine sequence via polymethylene linkers.349The presence of the ligand led to quite substantial increases in both duplex and triplex stability, particularly when incorporated to the 5’-end. Aromatic modified oligonucleotides have been used in photochemical reactions, in one case to act as a photochemical switch, in other cases for cleavage reactions. Azobenzene derivatives in ODNs have been used as a molecular switch by taking advantage of the cis-trans isomerisation by UV light. The azobenzene moiety has now been introduced into ODNs on an enantioselective-

5: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

I

275

dR

dR

R, = H or Me

''

( I 18)

(1 19) (120) (121) ly pure linker.350 Using D- or L-threonine as the linker, azobenzene was incorporated into DNA duplexes. It was shown that the D-form gave significantly higher T,s. The introduction of the o-nitrobenzyl-modified nucleoside (122)into DNA generates a site that can be cleaved on irradiation with 360nm light.35'Both the R and S isomers were prepared, and hybridisation studies showed that the modifications were only slightly destabilising. Using a caged phosphoramidite monomer bearing a C1' nitrobenzyl cyanohydrin, ODNs were prepared (123), which upon UV irradiation give rise to a deoxyribonolactone

. ~ There are a few new developments in molecular beacons. Antony et ~ 2 have studied the effects of various polyamines on the stabilisation of triplexes using a molecular beacon strategy. Using the purine-pyrimidine-rich promoter site sequence of cyclin D l , an 18-mer G-rich molecular beacon TFO was used, and

~

~

276

Organophosphorus Chemistry

triplex formation monitored by enhanced fluorescence on binding due to the weakened FRET from the beacon. A modified molecular beacon containing a stem hairpin structure similar to conventional molecular beacons has been used as a probe in PCR.354The modified beacon is cleaved upon hybridisation by the polymerase 5‘-3‘exonuclease, thus combining the advantageous properties of TaqMan probes with molecular beacons. There are also a number of new dye-modified analogues for use in FRET analysis. A new four colour set of FRET dideoxy 5’-triphosphate terminators has been developed involving a rigid, linear ET cassette linker chemistry, and formulated with Thermo Sequenase I1 DNA polymerase.355, 356 An alternative approach for a four colour set of FRET dyes has been reported where the dyes are incorporated into ODNs as phosphoramidite derivatives.357 Fluorescence resonance energy transfer (FRET) has been used to study the structural features of ODN duplexes containing the pyrimidine(6-4)pyrimidone photoproduct (79).358Compound (79) is a major lesion formed at dipyrimidine sites by UV light. Using 32-mer duplexes, FRET labelled duplexes containing (79) showed that the duplex was almost identical to the undamaged duplex. FRET revealed a slight unwinding of the duplex at the damage site, but did not suggest a kinked structure. ssDNA primers incorporating a fluorescein (F)at the 5’-end, a rhodamine dye (R) 4nt from F and a cyanine dye (Cy) 6nt from R, with 13nt to the 3’-end, were used. In this manner, F acted as a donor for R and Cy, R acted as an acceptor for F and a donor for Cy whilst Cy acted as an acceptor for both. This assembly of a triple fluorescence ET system has been constructed to enhance acceptor emission and a large Stokes shift.359

2

Aptamers

Since it was first shown that functional nucleic acids could be selected from randomised libraries360,361 there have been many examples of aptamers and ribozymes selected for a variety of applications. There are a number of new reports on various aspects of aptamers, due in part to a special issue on this subject (Bioorganic and Medicinal Chemistry, 2001, volume 9, issue 10).Whilst most of the new aptamers that have been described are designed for binding to a given target, the number of aptamers that have catalytic activity is increasing. There are also examples now of allosteric aptamers, both for binding and with catalytic activity, that function only in the presence of a ‘co-factor’. There are a number of new methodologies associated with the selection and applications of aptamers. The process of in uitro selection is a repetitive and time-consuming process. Cox and E l l i n g t ~ nhave ~ ~ ~adapted automated workstations to select anti-protein aptamers. As an example, they selected antilysozyme aptamers that inhibit cell lysis. Brunel et have developed an in uitro screen which they call SETIS (SElection of genomic Target RNAs by Iterative Screening). It allows for screening of major portions of the genome to identify potential targets for RNA binding proteins. SETIS is a useful strategy to screen for parts of biological networks of RNA-protein interactions, and it

5: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

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provides a tool to investigate arrays of processing and translational regulation events. H

H3c02cv NlC02CH3

CH3

wybutine

A method for developing libraries of mRNA-encoded peptides has been developed which uses a modified tRNA as a bifunctional linker to attach both an mRNA and its translation product. During translation, the growing peptide chain is transiently linked to a tRNA by a labile ester bond. By using a 3’-amino3’-deoxyadenosine, the ester linkage is replaced by a stable amide bond. The yeast tRNAPhecontains the modified nucleoside wybutine (124) in the anticodon loop which was used to photocrosslink with the translation product. It is suggested that this method could be used to generate libraries for in vitro A new concept for the targeting and release of therapeutic agents has been A prodrug-metabolising catalyst consisting of a catalytic group attached to an oligonucleotide analogue that binds specifically to a unique site on a disease-specificnucleic acid sequence, such as an overexpressed mRNA, has been developed. The prodrug in turn consists of a cytotoxic drug attached via a cleavable linker to an ODN that binds adjacent to the catalytic component binding site. When the catalytic component binds to the disease-specific oligomer, a prodrug metabolising enzyme-like species is created which contains both a prodrug binding site and a catalytic site. This enzyme-like catalyst then catalyses release of the cytotoxic drug from the prodrug. This review will detail aptamers for binding, with catalytic activity and allosteric aptamers discussed separately. Both DNA and RNA aptamers have been found for binding to a variety of targets. Aptamers targeted at protein or amino acid groups are the most common. A DNA aptamer that binds L-tyrosinamide was selected using SELEX.366Using a randomised 60-mer, after 15 rounds of selection several aptamers were isolated and identified. The aptamers showed a highly conserved ssDNA sequence that bound L-tyrosinamide with a Kd of 45pM. Using a randomised 59-mer region, and 20 rounds of selection, DNA aptamers binding to calf brain tubulin were identified.367The aptamers were found to be T-rich, and the dissociation constants of the best two aptamers were 45.0 and 19.4pM.DNA aptamers were selected for binding to the Ff phage gene 5 protein (g5p), which is a ssDNA-binding protein.368Aptamers were isolated from a library of 58-mers containing a randomised 26nt region after eight rounds of selection. Protein g5p has a high binding affinity for polypyrimidine sequences, so surprisingly the aptamers isolated were mostly G-rich. In 10mM NaCl, the

278

Organophosphorus Chemistry

most abundant aptamer was single-stranded and was saturated by g5p. In 200mM NaCl, the aptamer adopted a quadruplex structure, and the binding affinity for g5p was 100-fold higher. DNA ligands with a high affinity for the RNase H domain of the HIV-1 RT were isolated by SELEX,369which were able to inhibit the RNase H activity in vitro. No such effect was observed with the cellular RNase H. These ligands were also able to strongly reduce the infectivity of HIV- 1 infected human cells. The in vitro selection of an RNA aptamer binding to an Args peptide as a model of the HIV-1 Rev peptide was carried out with the peptide immobilised on a quartz-crystal microbalance (QCM).370 The selection process was monitored by mass changes using the QCM. After seven rounds of selection the mass changes were found to be constant and selection terminated. The association constant of the selected aptamer was found to be 7.2 x lo7M-’, similar to that found for the binding of Rev to RRE (2.3 x lo7 M-*).Using an aptamer evolved to bind to the Tat protein of HIV-l,371a method of coupling of genotype with phenotype was developed to obtain extremely tight binding a p t a m e r ~The . ~ ~process ~ used three units of the aptamer coupled in tandem with three units of a Tat-derived peptide. The binding of the resultant RNA was one of the strongest reported, with an apparent Kd below 16pM. Two RNA aptamers have also been selected for binding to oligonucleotides. RNA aptamers were selected that bind to the loop region of HIV-1 TAR RNA.373 The aptamers were found to be RNA hairpins which gave rise to kissing complexes with TAR, and bound with Kd of 5 nM in the presence of magnesium ions. The aptamers were further modified by preparing the N3’+P5’ phosphoramidate ligand which were as effective but also resistant to nuclease degradation. Using a DNA template containing 40 random nucleotides, a library of RNA transcripts was prepared which was used in an in vitro selection targeted at RNA hairpins from HCV mRNA.374After eight rounds of selection, RNA aptamers were isolated that bound to the SL1 apical loop of HCV mRNA with a Kd of 70nM under physiological conditions. Other targets include binding to an antibiotic and to the cofactor FAD. Using a moenomycin-sepharose affinity column, a randomised 40-mer RNA pool was used to select aptamers to bind to the antibiotic moenomycin A.375After 12 rounds of selection, aptamers were identified with dissociation constants in the range 300-400nM. A majority of the aptamers were greater than 50% G-rich. Another RNA antibiotic binding aptamer was reported by Berens et ~ 2 1 . Using ~ ~ ~ . a randomised 74-mer region and 15 rounds of selection, a number of aptamers binding to tetracyclin were identified. One of these was further characterised, and shown to have a Kd of lpM, which is an affinity comparable to the binding of tetracyclin to the small ribosomal subunit. Atypical tetracyclin analogues were not recognised by these aptamers. RNA aptamers binding to the cofactor flavin adenine dinucleotide (FAD) have been selected and characterised. They were shown to bind to the isoalloxazine nucleus of FAD, but did not distinguish between FAD and FADH2,and could not be removed from an FAD resin using UMP. This new class of FAD aptamers has been shown to be structurally and functionally different from other known FAD a p t a m e r ~ . ~ ~ ~

5: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

279

One example of a deoxyribozyme with ligase activity has been presented, but most aptamers with catalytic activity are RNA. A deoxyribozyme ligase has been selected to catalyse the joining of a 3’-phosphorothioate to a 5’-iodo-5’deoxyn~cleotide.~~~ Using a randomised 90nt region and 11 rounds of selection, deoxyribozymes were selected, though they showed a sequence dependence. In contrast, a DNA-cleaving deoxyribozyme has been selected and c h a r a c t e r i ~ e d . ~ ~ ~ This deoxyribozyme is copper-dependent, and the minimised structure is 46nt forming duplex and triplex structures flanking a highly conserved core. The hc ligase ribozyme catalyses the joining of the 3’-end of an oligonucleotide substrate to its own 5’-triphosphate within a helical context of an RNA hairpin. This was used as a starting point to evolve ribozymes that catalyse RNA ligation to the 5’-triphosphate of a hairpin structure. It also ligated two oligonucleotides bound at adjacent positions on a template, and the addition of 5’-triphosphates to the 3’-end of an oligonucleotide in a template-dependent manner.38oA continuous in vitro evolution process has been carried out to catalyse three successive nucleotidyl addition reactions. Using a chimeric DNA/RNA template, a ribozyme has been evolved that is required to catalyse the addition of two monophosphate units to complete the synthesis of the T7 RNA polymerase promoter, followed by a RNA-catalysed RNA ligation. These three steps give the same product as that obtained by the RNA polymerase.381The evolved ribozymes were able to operate in either 3’45’ or 5’43’ direction. An RNA Diels-Alderase ribozyme recently developed that catalyses the formation of carbon-carbon bonds between a tethered anthracene diene and a biotinylated maleimide d i e n ~ p h i l eThe . ~ ~ ribozyme ~ active site has been further characterised by chemical substitution of the diene and d i e n ~ p h i l e It . ~ was ~~ shown that the diene must be an anthracene, and substitution only at specific sites is permitted. The dienophile must be a maleimide with an unsubstituted double bond. The RNA-diene interaction was found to be governed preferentially by stacking interactions. A ribozyme has been selected that catalyses the synthesis of dipeptides using an aminoacyl-adenylate The ribozyme catalysed the formation of 30 different dipeptides, many with rates similar to that of the Met-Phe dipeptide used in the selection process. New allosteric aptamers and ribozymes have been detailed. DNA aptamers have been used as conformational switches. An ATP binding aptamer was prepared to which anthraquinone was additionally attached. Within the aptamer were two pairs of guanosine residues. In the absence of the binding element (adenosine was used in place of ATP) there is an ‘impaired’region which prevents electrical conductance through the structure. In the presence of the analyte, the ‘impaired’ region is closed and electron transfer is facilitated. This was demonstrated by the cleavage of the aptamer at specific sites only in the presence of the a n a l ~ t eDNA . ~ ~ ~aptamers selected to bind simultaneously to cytochrome c and the metalloporphryin hemin were found to have a conserved guanine-rich core. A deletion mutant CH6A was found that in the presence of hemin formed a quadruplex structure. The binding of cytochrome c to the CH6A-hemin complex was tighter than its binding to CH6A The in vitro selection of self-cleaving ribozymes which are dependent on the

280

Organophosphorus Chemistry

quinolone derivative pefloxacin and derivatives has been studied, using a theoretical model which was validated e~perimentally.~'~ After 16 rounds of selection, allosteric ribozymes were isolated which were effective at sub-micromolar concentrations of the drug. An in uitro selection method has been reported in which an aptamer was isolated that bound ATP only in the presence of a specific pr~tein.~" An RNA unit which bound the HIV-1 RRE was used which also contained a 20-mer random region. In the presence of RRE, selection was carried out using an immobilised ATP for binding. The aptamer was found to bind to ATP when RRE was present, but not in its absence. An effector-activated ribozyme has been selected that requires the presence of ATP to catalyse DNA ligation reaction~.~'~ Using an anti-adenosine aptamer appended to a selected deoxyribozyme ligase it was shown that ATP specifically activates the constructs. Base analogues have also been used in the selection of aptamers. Using 5'-(cr-P-borano) triphosphate derivatives of GTP and UTP, cf compound (13), Lato et ~ 1 . ~have ~ ' examined the effect of boranophosphate groups in aptamers binding to ATP. It was found that aptamers containing the C - f ~ l dwere ~ ~ l inactive when borano-guanosine was substituted. However, selections were made that were dependent on the presence of boranophosphate derivatives, and were specific in that substitution of borano-guanosine with borano-uridine led to loss of binding to ATP. N4-Biotinylated dCTP was used in SELEX to develop aptamers bearing multiple biotin residues.392Using a randomised region of 59nt in a DNA template, transcripts were prepared using T7 RNA polymerase, substituting CTP with the biotinylated-CTP. Aptamers binding to ATP were selected after eight rounds, and the dissociation constants of the best two aptamers were 10 and 15pM. Since these aptamers carried multiple biotin residues, the sensitivity in a ATP-binding assay was high. The final examples describe two aptamers acting inside cells. A malachite green binding motif was inserted upstream of the cyclin B2 (CLB2) start codon in the 5'-UTR of a cyclin transcript in S. c e r e u i s i ~ eProgression .~~~ through the cell cycle is dramatically slowed, with elongated bud morphology, in the presence of the fluorescent malachite green analogue, tetramethylrosamine. Quantification of CLB2 expression is consistent with a model in which translational initiation is blocked by ligand-induced conformational changes in the 5'-UTR. In the second example, aptamers have been used to transport RNA-conjugated compounds to intracellular compartments in African trypanosomes to target the lysosome of the parasite. Human serum contains lytic factors (TLFs),which are taken up by receptor mediated internalisation of the high-density lipoprotein fraction, and transported to the lysosome. Within the lysosome the TLFs are activated leading to lysis and as a consequence the destruction of the 3

OligonucleotideConjugates

The range of compounds that have been attached to oligonucleotides is quite exceptional. The two main areas are the attachment to metal surfaces for a range

5: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

28 1

of applications from microarrays (see also section 1.1.2)to various nanoparticles, and the synthesis of peptide-oligonucleotide conjugates. However, there are a large number of other conjugates, including sugars, dyes (see also section 1.3.3) and reactive groups. The first group describes methods for the synthesis of various oligonucleotide conjugates, and then specific conjugates will be covered. Polymer-oligonucleotide conjugates were obtained using ODN synthesis on poly(ethy1ene-alt-maleic anhydride, PMEA) attached to the surface of glass beads. The effect of the number of ODNs per polymer chain was measured by both T, experiments, and with enzyme linked oligosorbent assays (ELOSA) using the conjugates captured on a solid phase receptacle with a HBV DNA target.395The data showed that whilst the higher loading polymers gave the highest Tms,this did not correlate with the ELOSA assay, where lower loadings were found to give better results. The synthesis of (N-4) peptide (3'+5') DNA conjugates has been described using CPG as solid support. The first amino acid was attached to the CPG via an ester linkage, and peptide couplings carried out using Boc protection, and a p-hydroxybenzoic acid group was used as linker to DNA.396 The synthesis of oligonucleotide-amino acid/peptide conjugates has been demonstrated by direct coupling of either an amino acid or a peptide to an oligonucleotide which has been modified to carry a 5'-10 atom spacer aminomodifier.397Coupling reactions were carried out using EDC at high concentrations. The synthesis of oligonucleotide-peptide conjugates has been achieved on a CPG support. The ODN synthesis is terminated by an amino-linker, which is treated with an alkyl diisocyanate, and then with a peptide, coupling through a terminal a-amino The conjugation of a trilysyl group, during ODN synthesis, to an oligonucleotide is shown to increase resistance to nuclease Sl.399 Of particular interest is a paper by Gartner et aZ.4(" who have carried out a large range of template-directed chemical syntheses. Using two complementary ODNs, each carrying a different reagent, it was shown that on hybridisation, and in the presence of other water-soluble reactants where appropriate, that various synthetic reactions occurred, including carbon-carbon bond formation. If a reagent was present on a non-complementary ODN then no reaction occurred. Examples include reaction between amines and aldehydes, amide bond formation and a number of different carbon-carbon bond formation reactions. A method for the double-labelling of oligonucleotides has been described for the conjugation of two different reporter groups."01The oligonucleotide is synthesised with two phosphorothioate groups, each having a different protecting group. The 3'-terminal phosphorothioate is protected with the base-labile 2-(Nisopropyl-4-methoxybenzamido)-ethylgroup, which is removed during the basedeprotection at room temperature of the oligonucleotide. The 3'-terminal phosphorothioate is then treated with an iodoacetamide derivative (e.g.of pyrene). An internal phosphorothioate is protected with the stable 2-(methoxybenzamido)ethyl group, which is removed with concentrated ammonia at 55"C,and is then treated with various thiophilic reagents to introduce the second reporter group. The synthesis of short oligoribonucleotides bearing a 5'-phenylalanine residue

282

Organophosphorus Chemistry

has been carried The synthesis involved the use of an acid labile phosphoramidate linker, though this leaves the oligomer with a 3'-phosphate group, and the Phe group was introduced using amino acid synthesis conditions. The final oligomer had a Phe group attached via an ester linkage. The templatedirected assembly of DNA conjugates has been studied using a salicylaldehyde modified ODN (125).403In the presence of complementary template DNA, the two salicylaldehyde groups are brought together, and in the presence of metal ions and a diamine, a conjugate is formed. Reactive groups have a number of uses when attached to oligonucleotides, for example, for cleavage reactions. Antisense ODNs bearing a 5'-conjugated psoralen group have been targeted at a homopurine region of the c-Myc protooncogene. The ODNs form a triplex structure with the target, and act as a ~lamp.4'~ In an in vitro translation assay, the presence of such ODNs when activated by UV light reduced expression of c-Myc by >99%. Dienes (126) have been incorporated into oligonucleotides via phosphoramidite building blocks to allow for conjugation with various dien0philes.4~~9~~~ After oligonucleotide synthesis the dienes were allowed to react with maleimide-modified derivatives to yield Diels-Alder modified conjugates. Modified maleimide derivatives include a biotin derivative as well as a bismaleimide derivative, which conjugated with two oligonucleotides. The silyl protected phenol derivative (127) serve as precursors for the electrophilic quinone methide under biological conditions.407When incorporated into the third strand of a triplex and treated with fluoride, the quinone methide is unmasked and both oligonucleotides in the target duplex are selectively modified by the conjugate within two residues of the triplex-forming region.

DNAa*OH

,

H

H O N -

A

K0O R

-0. /O

t

P 09 \ 0-Oligo

/-7

OTBDMS OAc fluoride

N-DNA H

(1 27) One of the most common metal surfaces that oligonucleotides have been attached to is gold, which is readily conjugated with thiol-modified materials.

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Novel bioinorganic materials have been prepared using protein and ODNmodified gold nanoparticles.408A mixture of streptavidin complexed to four biotinylated ODNs, ODN modified gold nanoparticles and ssDNA part-complementary to the streptavidin-bound DNA and part-complementary to the nanoparticle-bound DNA, was found to form micrometer-sized aggregates. These aggregates do not form at room temperature but just below the melting temperature of the duplex region. A similar, earlier report demonstrated the use of bis-biotinylated ODNs and streptavidin to generate nanostructured DNAprotein conjugate^.^^ This group has modified these DNA-protein conjugates by the addition of biotinylated hapten The complexes were used in a novel PCR-based immunoassay, which they term competitive immuno-PCR (cIPCR). They report that cIPCR allows for around a 10 to 1000-fold improvement in the detection limit of conventional antibody-based assays. The use of a new trithiol dendrimer attached to the 5'-end of an oligonucleotide has been shown to form more stable DNA-gold nanoparticle conjugates.411 The stability of probes is essential for diagnostic applications, and the trithiol capped DNA showed stability using 100nm diameter nanoparticles even in high salt. The thiol cap, however, had no effect on hybridisation properties. Enzymatic extension of gold nanoparticle-bound primers has been observed. However, the efficiency of the reaction was strongly affected by linker length and primer coverage. Extension of primers attached by the longest linker was as efficient as a solution phase reaction.412 The orientation of thiol-modified DNA on a gold single crystal surface has been examined using electrochemical scanning tunnelling microscopy. It was found that at potentials negative of the potential of zero charge (pzc), the DNA stands vertically, and as the potential shifts positively the DNA lies on the surface.413A quartz-crystal microbalance (QCM) has been used to measure the kinetics of DNA polymerase reactions.414The primer/template immobilised onto the quartz-crystal microbalance, and the kinetics of (i) binding of the polymerase to the primer (mass increase), (ii) primer extension (mass increase) and (iii) enzyme release could all be measured using this sensitive technique. There are many reports of the use of gold nanoparticles to attach biological molecules, such as oligonucleotides. Gold particles are easy to modify because they are usually stabilised by weakly binding ligands that are readily displaced by functional groups that bind strongly, such as thiols. Silver particles have, to date, had limited use because they tend to degrade under conditions used in DNA hybridisation, but silver particles exhibit a distinct surface plasmon band, and the extinction coefficient is four times higher than that of gold. Cao et aL415 have developed silver nanoparticles with a monolayer of gold that exhibit the desirable properties found for silver particles, whilst having the stable surface chemistry of gold. Large-scale uniaxial organisation of metallic nanorods may be tailored by using specific DNA duplex formation."16Two non-complementary strands of DNA were immobilised onto the surface of two batches of gold nanoparticles. On mixing, no recognition occurs, but the addition of a third strand half-complementary to each of the immobilised ODNs induces hybridisation which drives self-assembly of the nanorods.

284

Organophosphorus Chemistry

In a recent development, magnetic nanoparticles were conjugated to oligonucleotides which, on hybridisation, assembled into stable n a n o a ~ s e m b l i e As s ~ ~a ~ result of the formation of these clusters, there was a decrease in the spin-spin relaxation time (T2) of adjacent water protons. The magnetic nanoparticles have been referred to as magnetic relaxation switches (MRS). This group has further developed these MRS's that are capable of detecting DNA cleaving and methylating enzymes.418Two self-complementary probes which contain a restriction enzyme site (BamH1 or EcoRl) hybridise to form a MRS nanoassembly which exhibits a pronounced effect on T2. On treatment with a restriction enzyme, the nanoassemblies switch to a dispersed state with an increase in T2. In the case of methylation, the duplex is cleaved after treatment with a methyltransferase, and methylated DNA is cleaved with a restriction enzyme. The hybridising behaviour of duplex DNA covalently linked to metal nanocrystals may be controlled by inductive coupling of a radio-frequency magnetic field to the nanocry~tal.4'~ Inductive coupling to the nanocrystal increases the local temperature of the bound DNA, which causes the DNA to denature without affecting surrounding duplexes. Quantum dots are CdSe/ZnS semiconductor nanocrystals which have robust fluorescent properties with size-tunable emission properties. By using hydroxylated nanocrystals, oligonucleotides may be conjugated. When four different sequences attached to four different size quantum dots are mixed, it was shown that it was possible to separate each type of quantum dot by hybridisation to a complementary sequence on a defined micrometer-size surface.420 A number of ODNs have been hybridised to complementary probes which are immobilised on microscopic polymer particles. The hybridisation was assayed by a mixed-phase hybridisation using time-resolved fluorimetry by a photoluminescent europium(II1) A DNA hybridisation assay based on luminescence resonance energy transfer (LRET) has been described using the "~~ with the Tb3+ is terbium ligand BPTA, (128), to the dye C Y ~ .Labelling achieved using a biotin-labelled probe, which is then bound to BPTA-labelled streptavidin. Strong sensitised emission of Cy3 was observed when the Tb3+ chelate was excited at 325nm when the two probe ODNs were hybridised to complementary DNA. The sensitivity of this assay is very high, with detection limits of up to about 30pM target DNA. A number of different metal ions have also been attached to oligonucleotides using various chelating ligands. A novel branched oligonucleotide synthesis has been described using a transition metal complex as the vertex.423Transition metal centers occur in a range of geometries, coordination numbers, and bond angles, e.g. octahedral, square planar, trigonal bipyramidal. Two parallel (5'-3') homothymidine ODNs were synthesized, linked to a ci~-[(bpy)~Ru(imidazole)~] 2 + moiety via hexyl spacers (129). It was shown that in the presence of one equivalent of the corresponding homo-dA ODN that the T, was the same as the non-conjugated duplex. The addition of a second equivalent showed the same T,, but the hyperchromicity increased from 13% to 17%. The naphthyridine dimer (130) has been used to stabilise G:G mismatches (arrows show hydrogen bonding residues)."24The ligand has been used to induce hairpin structures in

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DNA monolayers conjugated to gold surfaces, which occur only in the presence of the ligand.

INA

I

0-

A series of oligonucleotides conjugated to intercalators, fluorophores, minor groove binders and photoreactive groups have been studied for their ability to form stable triplexes.42s-426 Of particular interest was a conjugate with a dipyrido[ 3,2-a:2’,3’-c]phenazine-ruthenium(II) complex which forms a particularly stable triplex, is highly fluorescent and increases the residence time of the third strand of the triplex. Metallophthalocyanines (Co(II), Al(II1) and Zn(I1)) have been conjugated to short ODNs via an amino linker. These were found to modify complementary strands of DNA under prolonged photolysis (Hg-lamp or He/Ne laser) in low to moderate yields in the presence of reactive oxygen ~pecies.4~~ Peptide-oligonucleotide derivatives are an important class of conjugate because they are widely used to aid the delivery of modified oligonucleotides into cells for antisense or antigene therapies. A number of new methods for the synthesis of these conjugates have been published, and there are also a number of publications detailing cellular delivery and effects of them. The solid phase synthesis of 3’-conjugates of ODNs has been shown using a L-homoserine branching The homoserine allows for attachment of a variety of labels, then deprotection of the hydroxyl group generates a start-point for O D N synthesis. Oligonucleotide-peptide conjugates have been synthesised using hydrazone formation as the ligation ~ t e p . Oligonucleotides 4~~ are synthesised bearing a terminal amino group which is treated with diacetyl-L-tartaric anhydride. After deprotection of the oligonucleotide, treatment with iodine yields a glyoxylyl group, which readily reacts with an a-hydrazino acetyl peptide. The stepwise synthesis of peptide-oligonucleotide conjugates has been rep0rted.4~’.431 The synthesis makes use of ( f)-3-amino-1,2-propanediolwhich is tethered to a solid support through the central hydroxyl group, with Fmoc

286

Organophosphorus Chemistry

amino and DMT hydroxyl group protection. The peptide synthesis is carried out using Fmoc chemistry, and non-acid labile side chain protecting groups. The synthesis of a suitable arginine derivative is described. After peptide synthesis the DMT group is removed from the linker and the oligonucleotide synthesised in the usual manner. Finally all base labile protecting groups are removed with ammonia, and silyl protecting groups with triethylamine trihydrofluoride. A convergent synthesis of peptide-oligonucleotide conjugates has been reported. The conjugation is accomplished via either thiazolidine or oxime formation (131).4323433 Thiazolidine formation is achieved by coupling a peptide with a cysteine residue to an oligonucleotide bearing an aldehyde function. The aldehyde function on either the oligonucleotide or peptide may be ligated with a peptide or oligonucleotide containing an oxyamino function. Either conjugation proceeded in good yield under mild aqueous conditions. Peptide

X

X = CHO, Y = ONH, or X = ONHZ, Y = CHO

y

I

2 = -0-N=CH- or -CH=N-0-

vCsH -1 1 OHC

Oligonucleotide

1

Oligonucleotide

The solid phase synthesis of (C)-PNA-(N)-3’-DNA-5’conjugates has been described using commercially available Bhoc/Fmoc PNA rnon0mers.4~~ After PNA synthesis, the protecting groups are removed with TFA and the nucleobases are reprotected using benzoyl chloride. Following this, ODN synthesis is carried out using standard DNA synthesis. The large-scale synthesis of phosphorothioate oligonucleotides conjugated with antennapedia peptide up to 15pmole scale has been demon~trated.~~’ Using equimolar amounts of ODN and peptide, conjugation using disulfide coupling in 60% yield was attained. To aid hepato-cellular uptake of antisense ODNs, the phosphoramidites of cholic and taurocholic acids were prepared and added to the 5’-end of antisense 0ligomers.4~~ The oligonucleotides were further modified by the inclusion of phosphor0 thioa te and benzylphosp hona te int ernucleot ide linkages. The bile acid conjugated oligomers exhibited enhanced lipophilicity as determined by HPLC, and when incorporated into duplexes no destabilisation was observed. An antisense phosphorothioate ODN targeted to the HIV-1 gag-mRNA was

5: Nucleotides and Nucleic Acids; Oligo-and Polynucleotides

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found to be slightly more effective in vitro when conjugated with a 5’-unit containing an imidazole and primary amine ( 132).437 The 5’-conjugate was designed to act as an RNA cleaving agent, where it cleaves CpA when bound opposite it. E . coli RNase H has been conjugated to an antisense ODN using a water soluble linker. The ODN was designed to target the DR1 region of hepatitis B viral (HBV) mRNA. When the conjugate was incubated with HBV mRNA it was found that 85% of the DR1 substrate was cleaved by the conjugated RNase H.438 Me0

I NH2

(132)

(133) The use of TFOs as therapeutic agents is limited by their poor cellular uptake. Rapozzi et have shown that a 13-mer purine T F O conjugated to a high molecular weight PEG (9000 Da) was efficiently internalised, and specifically downregulated the transcription of bcrlabl mRNA by 65%. Three indolocarbazole topoisomerase I poisons have been attached to the 3’-end of TFOs. These TFOs were shown to direct cleavage by topoisomerase I at specific sites depending on the triplex recognition sequence, though the efficacy of cleavage was dependent on the length of the linker arm between the ODN and the indolocarb a z 0 1 e . ~These ~ ~ conjugates at 10nM induced cleavage two-fold better than the free indolocarbazole at 5p.M. Polypurine antigene effectors were found to be more effectively transported into cell nuclei when conjugated to high molecular weight monomethoxy poly(ethy1ene glycols) MPEG.441Using 9000 Da MPEG, various ODNs were prepared with phosphorothioate linkages, and a fluorescent marker to monitor cellular uptake. Helicases unwind dsDNA and are classified 5’+3’ or 3’+5’ according to their ability to unwind DNA adjacent to either a 5’ or 3’ ssDNA overhang. An assay has been developed to determine whether this preference also indicates unidirectional translocation on ssDNA. Using oligonucleotides which have either a 3’- or 5’-biotin bound to streptavidin, it was found that 5’+3’ helicases displaced streptavidin from the 3’-end but not from the 5’-end. Similarly, 3/45’,such as the helicase NS3 from HCV, displaces streptavidin from the 5’-end Poly-(D,L-lactic-co-glycolic acid) (PLGA) was conjugated with 5’-aminomodified ODNs to form amphiphatic structures. In aqueous solution, the conjugates aggregated to give micellar structures with the PLGA forming the hydrophobic core, and the ODNs forming the hydrophilic corona.443These micelles released the ODNs in a controlled manner via degradation of the biodegradable PLGA units. As the micelles were efficiently transported into cells, they were proposed to be delivery vehicles for ODNs. The fluorescence intensity, polarisation and lifetime of commonly used fluorophores conjugated to oligonucleotides has been examined. The fluor-

288

Organophosphorus Chemistry

escence intensity has a dependence on the oligonucleotide sequence, and its position within the sequence.u If a dye is close to the 3’-end with a terminal d G or dC there was found to be a 10-fold quenching of fluorescence. No such effect was observed at the 5’-end. A guanosine overhang acts as a quencher, whilst a dG:dC base pair quenches fluorescence much less efficiently. Two new fluorescent dyes have been incorporated into ODNs, and quenching of them monitored during hybridisation. Flavins and deazaflavins exhibit a bright blue or green fluorescence at 520-540 and 450-460nm, respectively, in aqueous solutions, with deazaflavins having larger fluorescence infen~ities.4~~ Incorporation of the dyes into ODNs was shown to have little effect when in a duplex. Single stranded probes incorporating consecutive fluorophore and acridine moieties are weakly fluorescent until hybridisation to a complementary nucleic Upon hybridisation, fluorescence increases due to reduced quenching. The ligation of carbohydrates to ODNs was achieved using an oxyamino modified sugar and DNA containing an aldehyde moiety, introduced using the phosphoramidite (133).447The presence of the carbohydrate had little effect on duplex stability. Glycopolymers derived from a-mannosides and f3-galactosides were conjugated to ODNs using a 5’-thiol modifier. When the O D N is halfcomplementary, self-organisation with a complementary ODN leads to macromolecular gapped duplexes bearing the glycopolymers at regular intervals.448 The binding affinity to these macromolecular conjugates to lectins was investigated using fluorimetry. The synthesis of conjugates containing fullerene (C60)-modifiedtrimethoxyindole groove binders were prepared for studying photochemical reactions in triple~es.4~~ The conjugate was attached to a TFO, but the presence of the fullerene residue caused considerable instability of the triplex strand. When attached to the 5’-end of a pyrimidine-rich TFO, naphthalene diimides (NDI) stabilise triplexes by intercalation. The strength of this stabilisation can be altered by changes to the linker between the oligomer and the NDI. More rigid linkers, particularly with a phenyl ring present, result in enhanced stabilisation; for example, the phenyl linker increased the T, by 28°C compared to the unconjugated TFOs conjugated at the 5’-terminus via a phosphorothioate to the anthracyclin derivative carminomycinone were shown to give enhanced stability, though further stability would be required to obtain triplexes under physiological condition^.^^' Xia et ~ 1have . developed ~ ~ ~an activity-based selection method to evolve DNA polymerases with RNA polymerase activity. Stoffel fragment (SF) of Therrnus aquaticus DNA polymerase is displayed on a filamentous phage by fusing it to a coat protein, and the substrate DNA template/primer duplexes are attached to other adjacent coat proteins. Phage particles displaying SF polymerases, which extend the attached primer by incorporating ribonucleoside triphosphates and biotinylated UTP, are immobilized on streptavidin-coated beads. After four rounds of screening a SF library, three mutants were isolated and shown to incorporate ribonucleoside triphosphates virtually as efficiently as the wild-type enzyme incorporates dNTP substrates.

5: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

4

289

Nucleic Acid Structures

After oligonucleotides containing modified bases, the area of oligonucleotide research that has developed the most is nucleic acid structures. Advances in NMR techniques means that the number of solution structures has grown significantly. In particular, there are many structures that have now been solved of oligonucleotides with some modification, and many sugar-modified oligonucleotides have been studied. Duplexes containing WL-LNA (134) have been studied by NMR and molecular dynamics.453 Duplex (134) was incorporated into the sequence d(CTGATATGC) at all T sites and hybridised to a complementary RNA target, The data showed that a-L-LNAbehaves as a B-type mimic, whereas LNA (P-D-rib0 configuration) is an A-type mimic. NMR structures for duplexes of d(CTGATATGC), where the central or all three of the thymidines are substituted by LNA, against complementary RNA have been rep0rted.4’~It was found that with one LNA residue, around the LNA the duplex geometry was more A-form, and with three LNA residues, the whole duplex adopted A-form. This indicated that three residues were sufficient for the duplex to adopt A-form, and the addition of further LNA residues would only introduce minor changes. -0

T

a-L-LNA

The structure of the self-complementary pyranosyl-RNA duplex (CGAATTCG) has been solved by NMR and shown to be in a left-handed double helix. Due to a strong inclination of -50°, bases on opposite strands are positioned on top of each other, presumably stabilised by interstrand stacking. Intrastrand stacking interactions between neighbouring bases is almost negligible!” The solution structure of the hairpin r(GGAC)d(TTCG)ara(GUCC), which has a RNA:arabinonucleic acid (ANA) stem, has been in~estigated.4~~ Whilst the RNA sugars adopt the C3’-endo (north) conformation, the ANA sugars adopt a more rigid 04’-endo (east) conformation. In comparison to a DNA:RNA stem structure, the RNA:ANA structure parameters are more like the DNA:RNA parameters. The minor groove in both structures is intermediate between that of A- and B-form duplexes, and may explain why ANA:DNA duplexes activate RNase H activity. Structures of oligonucleotides with modified backbone include an NMR study of the duplex d(TGTTTGGC)with diasteromerically pure R, or S, methylphosphonates of the duplex d(CCAAACA).Substitution was carried out using either all R, or a single central S, in an otherwise R, o l i g o n ~ c l e o t i d eThe . ~ ~ ~methylphosphonate strand showed increased dynamics relative to the phosphodiester strand, and whilst sugars in the phosphodiester strand are CT-endo, in the methylphosphonate strand they are an intermediate C4-endo. The introduction

290

Organophosphorus Chemistry

of a single S, diastereoisomer has a marked negative effect on the duplex stability . Substitution of a phosphate linkage in an oligonucleotide to an alkyl phosphonate leads to a neutral linkage. The effect on the structure of a decamer duplex containing an alkyl phosphonate group (both diastereoisomers) has been studied by NMR.458Both structures adopt a B-form duplex, though at the modification site there is some displacement to A-form and moderate bending of the duplex. The effect is more pronounced with the S-diastereoismer, as the alkyl group points into the double helix. The stability of a triplex oligonucleotide in which the third strand contains 2’-aminoethoxy substituted ribose sugars has been examined by NMR.459It was shown that the enhanced duplex stability is attributed to the interaction of the positively charged side chain with the phosphate backbone of the duplex. Of the structures of modified nucleic acids, the greatest number involve base modification, and these may be useful to understand a number of medical conditions and treatments. These fall broadly into two categories, lesions involving polyaromatic hydrocarbon (PAH) modifications, many of which are mutagenic, and lesions generated by other smaller reactive species. The carcinogenic heterocyclic amine (HA) 2-amino-l-methyl-6-phenylimidazo[4,5-b]pyridine, PhIP, (135) is formed during the cooking of various meats. The solution structure of an 11-mer duplex containing the C8-dG adduct formed by reaction with N-acetoxy-PhIP has been A slow conformational exchange is observed in which the PhIP ligand intercalates into the DNA helix by displacing the modified base pair (major form) in which the minor groove is widened, and the major groove is compressed at the lesion site. In the alternative minor form the ligand is located outside the helix in a minimally perturbed B-DNA duplex. The solution structure of the duplex d(ACATCG*ATCT).d(AGATAGATGT), where G* is the cationic lesion trans-8,9-dihydro-8-(N7-guanyl)-9hydroxy-aflatoxin B1 (136), a mutagenic metabolite from several species of the genus Aspergillus, has been reported.46’In the duplex, G* is mismatched with dA. The aflatoxin group intercalates 5’ to G*, and the mismatched dA was in the anti-conformation, extruded into the major groove. The same duplex with the mismatched G:A without the aflatoxin moiety showed that the mismatch is involved in a Watson-Crick base pair unlike the G*:A pair. The conformations of the (R)- and (S)-P-(N6-adenyl)styrene oxide adducts in the duplex d(CGGACA*AGAAG).d(CTTCTTGTCCG), corresponding to codons 60-62 of the human N-ras protooncogene, have been solved by NMR.462The increased tether length of the P-adducts results in reduced distortion to the duplex and mutes the stereochemical influence at the a-carbon, such that both adducts exhibit similar conformation, compared to the corresponding a-styrenyl add ~ c t s . In 4 ~both ~ P-adducts the styrenyl group lies in the major groove with little steric hindrance. Quinolones have been shown to act as gyrase inhibitors, and are clinically used as antibiotics. A series of quinolones has been conjugated to the 5’-end of short ODNs as 5’-acylamido derivatives using 5’-arnin0-5’-deoxythymidine!~~ The presence of the quinolone at the 5’-terminus was shown to greatly enhance

29 1

5: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

0

II

0

II

H

(136)

H a

(137)

R = 5’-amino-5’-dT

dR

duplex stability. In the case of the quinolone oxolinic acid (oa) (137) the NMR structure of the duplex (oa-TGCGCA)2 has been solved. The oxolinic acid displaces the terminal T:A base pair and stacks on the G:C pair. The displaced adenosine binds in the minor groove, whilst the thymidine residue packs against the oxolinic acid, forming a molecular cap. 2,7-Diaminomitosene (DAM) is a major metabolite of the antibiotic mitomycin which forms DNA adducts in tumour cells. The duplex d(GTGG*TATACCAC), where G* is the N7-adduct linked to C10 of the mitosene (138) has been studied by NMR?65Unlike many major groove alkylating agents which intercalate into the duplex, the DAM molecule is anchored in the major groove oriented 3’ to the adducted guanine, and does not perturb the B-form structure of the duplex. It is suggested that the low cytotoxicity of DAM may be because of the major groove alignment of the adduct. An intrastrand cross-link formed by cisplatin and adjacent guanine residues causes an unusally distorted base pair (bp) step, known as the Lippard bp step. A study of the effects of neighbouring nucleotides to the cross-linked G:G has shown that the 3’-nucleotide has little effect, but the 5’-nucleotidehas a dramatic effect!66 The 5’ residue always maintains an S pucker, but the canting varies, depending on the substituent. Bleomycin causes two major lesions to DNA, formation of a 4-keto abasic site and strand cleavage to yield a 3’-phosphoglycolate and a 5’-phosphate. As a model for the 4’-keto abasic site, an NMR structure of a 13-mer DNA duplex containing an abasic site has been reported.467 It was found that for both the a-and P-anomers, the abasic site was extrahelical, and that the duplex showed very little distortion to the backbone. This was discussed in terms of repair of such lesions in vivo. The action of ethylene oxide with DNA leads to N-3-hydroxylethyl cytosine (HE), which may lead to mutations, as the most frequent base inserted opposite it is adenosine. The solution structure of a 14-mer DNA duplex incorporating an internal HE:dA base pair has been Both HE and the adenosine are intrahelical, and do not perturb the adjacent base-pairs significantly. The C1’C1’ distance is greater than that for an A:T pair, and this leads to a bulge in the duplex structure. The bulky chain is positioned close to the centre of the helix, and thus it does not disturb the hydrogen-bonding face sufficiently for it to interfere with polymerase replication. The reaction of guanosine with malondialdehyde or base propenals leads to the pyrimidoc 1,2-a]purin- lO(3H)-oneadduct (139). When (139) is opposite dC in a duplex at neutral pH it spontaneously but

292

Organophosphorus Chemistry

reversibly ring opens to give N2-(3-0xo-l-propenyl)-dG(OPG).Adduct (139)was incorporated into a duplex which also contained a two nucleotide bulge as a model for the -2bp strand slippage deletions associated with the (CpGh-iterated repeat hotspot for frameshift mutations for the Salmonella typhimurium hisD3052 gene, and the structure studied by NMR!69 The structure showed that the two-base bulge consisted of (139) and the neighbouring 3'-dC, rather than the open chain OPG. When (139) was incorporated into the fully complementary duplex it gave the ring-opened OPG. The remaining solution structures do not contain modifications, though there are structures that involve a bound ligand. DNA structures will be reported first, followed by RNA structures. A series of DNA duplexes which contain a 4x4 internal loop sequence has been examined by NMR. Of the structures studied, one duplex was observed to contain five non-Watson-Crick base pairs, four of which were consec~tive.4~~ Whilst the loop structure fitted into a B-DNA helix with good thermal stability (T, = 52"C), the duplex incorporated wobble C:A, sheared A:C, sheared A:G and wobble G:T base pairs. The solution structure of the duplex d(CGATCG)2 with the antitumor drug 2-(pyrido[1,2-e]purin-4yl)amino-ethano1(140) has been rep0rted.4~'The drug intercalates between the two CpG steps with its side chain in the minor groove. There are only weak stacking interactions between (140) and the DNA bases, but the affinity is enhanced by a hydrogen bond from the hydroxyl group to the amino group of G6.

(138) (139) (140) A stem loop DNA duplex containing either a d(AATAA) or d(AAUAA)bulge has been studied by NMR.472The five nucleotides are unpaired and induce a kink into the duplex. The d(AATAA) bulge induces a kink of 104", with the kink occurring between the third and fourth nucleotides. Similar results were observed for the d(AAUAA)bulge, though the kink angle was 87". These results are discussed in connection with a r(AAUAA)bulge found in group I introns, where the DNA structure was found to be more rigid than the RNA duplex. The solution structure of the duplex d(CCATAATTTACC):d(CCTATTAAATCC) has been solved, showing that the duplex is parallel-~tranded.4~~ The structure is stable at neutral to acidic pH, and is stabilised by C:C+pairs. It adopts a B-form duplex, though there is some distortion, and all A:T base pairs are reverse Watson-Crick. The K homology (KH) repeats of the FUSE-binding protein (FBP) is a

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regulator of c-myc expression, and binds to a single-stranded far upstream element (FUSE). The solution structure of KH3 and KH4 domains of FBP bound to a 29nt ssDNA from FUSE has been rep0rted.4~~ The KH domains recognise two 9-10nt sites separated by five bases. KH4 binds to a 5' site, and KH3 to a 3' site. Polyamides derived from N-methylpyrrole (Py), N-methylimidazole (Im) and N-methylhydroxypyrrole (Hp) have been shown to bind in the minor groove of DNA in both 1:l and 2:l (1igand:DNA) stoichiometry, and whilst the structures of 2:l complexes have been reported, there is little information on the 1:l complexes. The solution structure of the polyamide ImPy-P-Im-PImPy-P-Dp, where P is p-alanine and Dp is dimethylaminopropylamine bound to a purine tract DNA in 1:l complex has been The ligand lies in the minor groove of a B-form duplex for a full turn of the helix, with each amide NH group forming bifurcated hydrogen bonds to the purine N3 and pyrimidine 0 2 atoms on the floor of the minor groove. Two DNA quadruplex structures have also been reported. The solution structure of the dimeric quadruplex d(G3AG2T3G3AT) has been shown to contain new topological f e a t ~ r e s . 4The ~ ~ sequence exhibits three sharp turns. The first is a double chain reversal, the second is of the edgewise type, and the third is a new form called the V-shaped type. The dimeric quadruplex has two G-tetrads and a novel AGGGG pentad, formed through a sheared G:A mismatch. This group has also shown, amongst others, that DNA quaduplexes are not confined to G, repeat sequences. In a further they have shown that the sequence d(GAGCAGGT) in high salt forms a dimeric quadruplex with GGGC, GGGG and ATAT tetrad motifs. The solution structure of d(GGAGGAGGAGGA) containing four tandem repeats of GGA triplets has been rep0rted.4~' The sequence forms an intramolecular quadruplex consisting of a G:G:G:G tetrad and G(:A):G(:A):G(:A):Gheptad. Two quadruplexes were found to form a dimer stabilized by stacking interactions between the heptads. The solution structure of the U6 RNA intramolecular stem loop of the spliceosome has been solved showing the metal-binding site that is required for the first catalytic step of pre-mRNA spli~ing.4~~ The structure binds Cd2+at the U80 site, which is adjacent to a readily protonated C:A wobble pair. Protonation of the wobble pair and metal binding are mutually antagonistic. The structure of the RNA stem-loop 4 (SL4) of the HIV-1 major packaging domain has been solved by NMR.4" The GAGA tetraloop adopts a classical GNRA form with only slight difference in detail. The tandem G:U pairs form a combination of wobble and bifurcated hydrogen bonds, and a continuous stack of five bases extends over most of the stem to the base of the loop. Residues G2 to G5 (gGGUG) show broadened resonances suggesting enhanced mobility on the 5'-side of the stem. NMR was used to solve the structure of an oligonucleotide from the helix I11 sequence of Xenopus oocyte 5s rRNA. The structure includes two unpaired adenosine residues flanked by G:C base pairs which is required for binding of ribosomal protein L5. The adenosine residues are located in the minor groove stacked onto the 3' guanine bases. The major groove is widened at the site of the adenosines, and the helix is substantially E-motifs are secondary struc-

294

Organophosphorus Chemistry

tural elements found in rRNA, and have an asymmetric 4x3 internal loop. A series of DNA duplex analogues of RNA E-motifs containing the sequence 5’-d(GXA):(AYG),where X and Y are a complementary base pair, have been studied by NMR, and were found to adopt a zipper-like conformation. The X:Y base pair did not form the canonical Watson-Crick structure, but instead formed interstrand stacks surrounded by G:A sheared pairs.482 The simian retroviral type-1 (SRV-1) pseudoknot is responsible for programmed ribosomal frameshifting. The solution structure of a modified SRV- 1 pseudoknot has been reported, and shown to adopt the classical H-type fold, and forms a triple helix motif as well as a ribose-zipper motif.483The ribose-zipper motif has not been previously observed in pseudoknot structures. Hepatitis C virus (HCV)internal ribosome entry site (IRES)is required for recognition by the small ribosomal subunit and eukaryotic initiation factor 3 (eIF3) for viral translation initiation. The solution structure of the RNA eIF3 binding domain of the HCV IRES has been solved, showing the internal loop and adjacent mismatched helix which are important for IRES-dependent translation of initia t i ~ nThe . ~ structure ~~ of a 23nt RNA sequence derived from residues 612-628 of the E . coli 16s RNA has been determined by NMR:*’ The structure is an A-form hairpin duplex with a CUCAA pentaloop, with a A G A base triple stabilising the loop structure, and the A functional groups exposed in the minor groove. The structure of the loop region facilitates minor groove interactions with other 16s rRNA helices. Long-range interactions of the P5.1 RNA hairpin of Bacillus RNase P have been suggested to form a scaffold to support RNA folding and activity. The solution structure of the P5.1 hairpin has been solved, and shows that the UGAGAU hexaloop contains two stacks of bases on opposite sides of the 100p.4~~ This structure distinguishes this type of hairpin loop from the GNRA tetraloops. The binding region of the E . coli S2 ribosomal protein contains the conserved r(UUAAGU) hairpin loop, the structure of which has been solved by NMR for the sequence r(GCGUUAAGUCGCA).487The uridines at the base of the loop form a single hydrogen bond pair, and the loop uridine makes contact with the neighbouring adenosines consistent with the formation of a U-turn. The guanine base is looped out into the solvent. The 5’ non-coding region of the picornaviral genome begins with a cloverleaf that is required for viral replication. A highly conserved stem-loop has been shown to be a necessary region of the cloverleaf. The solution structure of a 14-mer RNA hairpin, part of the conserved stem-loop from human rhinovirus, has been A five base pair stem is bounded by a UAU triloop, with the second loop base stacking onto the closing base pair of the stem, which results in deviations from the A-form, particularly on the 3’ side of the stem. The yeast orthologue of Rnase 111, Rnt lp, cleaves rRNAs, snRNAs and snoRNAs at a stem capped with a conserved AGNN tetraloop. Nine base-pair stems ending with AGAA or AGUC tetraloops bind to Rntlp and direct specific but sequenceindependent RNA cleavage. The solution structures of the two tetraloops revealed a common fold for the terminal loop which is stabilised by A:A or A:C base ~ a i r s . The 4 ~ ~results suggest that Rnase I11 recognises the fold of a conserved

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single-stranded tetraloop to direct dsRNA cleavage. There are a number of significant X-ray and NMR structures of oligonucleotides that are beyond the scope of this review to discuss in detail, but are clearly worth noting. These include: the crystal structure of the 30 S ribosomal subunit from Therrnus therrnophilus interactions with 16 S RNAt9' and the high resolution crystal structure of the large ribosomal subunit from Deinococcus radiodurans (D50S)t9' a 1.66A crystal structure of TraR from Agrobacteriurn tumefaciens in a complex with the pheromone N-3-oxooctanoyl-~-homoserine lactone and a self-complementary DNA duplex containing the Tra the crystal structure of Therrnus aquaticus RNA polymerase holoenzyme complexed with a fork-junction promoter DNA the crystal structure of the human Ku heterodimer alone and bound to a 55nt DNA the X-ray structure of the Oxytrich nova telomere end-binding protein a-subunit bound to SSDNA!~~ the 1.8A crystal structure of the human signal recognition particle (SRP) complex with its primary binding site on helix 6 of SRP RNA;496the 2.3A crystal structure of the signal recognition particle (SRP19) and 7S.S RNA from ~ ~ 2.6A crystal structure of yeast the archaeon Methanococcus j a n n a ~ c h i i tthe tRNAAsPcomplex with E . coli aspartyl-tRNA s y n t h e t a ~ e the t ~ ~DNA endonuclease NaeI bound to its cognate DNA that shows two copies of DNA by two different amino acid the crystal structure of an RNA tertiary domain critical to hepatitis C virus internal ribosome entry site-mediated translation the structure of a TonEBP-DNA complex encircling its DNA target?'' a 1.8A crystal structure of the Oxytricha nova telomere end binding protein (OnTEBP) bound to 3'-terminal SSDNA.~'* A number of oligonucleotide hairpin, quadruplexes and other higher ordered tertiary structures have also been reported: the solution structure of the transcriptional antiterminator LicT from Bacillus subtilis bound to a 29 bp ribonucleic antiterminator RNA hairpin;503a crystal structure of a kissing complex of the HIV-1 RNA dimerisation initiation site;504,505 the crystal structure of the Z a high affinity-binding domain of the RNA editing enzyme ADARl bound to lefthanded Z-DNA;506the crystal structure of parallel quadruplexes from human telomeric DNA.507 Two structures incorporating modified nucleotides include the co-crystal structure of pseudouridine synthase TruB with a T stem-loop of tRNA in which the modification site (U55)is modified with 5-fluor0uridine,5'~and the crystal structure of the Lactococcus Zactis formamidopyrimidine-DNA glycosylase bound to DNA containing an abasic This final section deals with the fewer crystal structures of oligonucleotides that have been reported. Most of these include some modification. One of the strongest nucleic acid duplex structures is that formed by hexitol nucleic acid (HNA), cf (57). A crystal structure of the HNA duplex h(GTGTACAC) showed two different double helical conformations. Both had similarities with the normal A-type duplex, with the anhydrohexitol chair conformation mimicking the furanose C3'-endo form observed in RNA.'l' Both crystal forms had very wide major grooves, with increased hydrophobicity in the minor groove. One crystal form had a major groove wide enough to accommodate a second HNA double

296

Organophosphorus Chemistry

helix, thus resulting in a double helix of HNA double helices. A crystal structure of the duplex d(GC*GTAT*ACGA)2, where T* is a 2'-@methoxyethyl thymidine, and C* is the guanidino G-clamp ( 1 4 1 y has been solved, and which confirms the presence of five hydrogen bonds to dG.512Due to the presence of the methoxyethyl-dT derivative, the duplex was A-form. The structure shows two Hoogsteen-type hydrogen bonds between the guanidinium group and the guanosine 0 6 and N7. A crystal structure of the 2'-O-Me(CGCGCG)2 duplex has been solved, in which 2-methyl-2,4-pentanediol used as a precipitant is bound to the RNA in the minor groove.513The structure shows a deviated A-form, and the duplex is overwound with an average 9.7 bp per turn. The two pentanediol residues intrude into the hydration network in the minor groove, forming hydrogen bonds between their hydroxyl groups and the exocyclic amino groups of the guanosine residues.

The novel base pair between pyridine-2,6-dicarboxylate (Dipic) and pyridine (Py), (142), which is stabilised by co-ordination to copper ions was recently reported.514A crystal structure containing this base pair in a ODN duplex has now been solved in a self-complementary d ~ d e c a m e r . ~Whilst '~ well accommodated within the duplex, the presence of the Dipic:Py base pair causes the duplex to adopt a Z-form duplex rather than the expected B-type. An X-ray crystal structure of the Dickerson dodecamer in which an internal dC is substituted for the mutagenic analogue N4-methoxy-dC showed that the analogue was in the imino tautomeric This is in contrast to an earlier report5" in which the analogue was in the amino tautomeric state, and therefore confirms that the analogue may adopt two alternate hydrogen bonding faces. An X-ray crystallography structure of the duplex from d(ATABrUAT)and d(ATATAT) demonstrates that an alternative to the classical B-DNA double helix is possible.518This sequence is found not only in TATA boxes, but also in other regulatory regions of DNA. The structure is not related to those found in triplexes or to parallel DNA duplexes, though its conformational parameters are very similar to those of B-form DNA. Bases of the two antiparallel strands form Hoogsteen pairs, with adenines in the syn conformation. Some pathogenic viruses use - 1 ribosomal frame-shifting to regulate transla-

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tion of their proteins from mRNAs. Frameshifting is commonly stimulated by a pseudoknot located downstream from a slippery sequence. The structures of two crystal forms of the frameshifting RNA pseudoknot from beet western yellow virus have been reported.519At a resolution of 1.25 A,ten mono and divalent metal ions per asymmetric unit could be identified, giving insight into potential roles of metal ions in stabilizing the pseudoknot. A magnesium ion located at the junction of the two pseudoknot stems appears to play a crucial role in stabilising the structure. The structure of the RNA duplex r(GUGgCGCAC)2,which has a bulged uridine in each strand 0, has been solved by X-ray c r y ~ t a l l o g r a p h y . ~ ~ ~ The duplex is A-form, and the uracil residues in each strand protrude into the minor groove. The resulting bulge induces large twist angles between the base pairs flanking the bulge and large kinks in the helix at the bulges. The result of the large kink and twist is a narrowing of the major groove in the middle of the duplex. The 2.54A crystal structure of an RNA oligonucleotide from the ribosomal decoding A site in a complex with the antibiotic tobramycin has been A self-complementary RNA duplex was used containing two A-sites. The tobramycin three aminosugar rings interact directly or via water molecules with the deep groove and stabilise a bulged-out conformation of two adenines. This is the first crystal structure of the A-site bound to an aminoglycoside of the 4,6-disubstituted 2-deoxystreptamine family. The crystal structure of the duplex d(CGTACG)* bound to 9-amino-N-[2-(4-morpholinyl)ethyl]-4-acridinecarboxamide, an inactive derivative of the antitumor agent DACA, has been sol~ e dIt .was ~ shown ~ ~ that the drug intercalates between each of the CpG dinucleotide steps, with the side chain in the major groove, as well as a molecule at each end of the duplex linking it to the next duplex. The intercalation causes the helix to unwind at CpG steps compared to B-DNA, whilst the central TpA step is overwound. Finally, there are two reports that deal with nucleic acid structures using techniques other than NMR or X-ray crystallography. The structure of an intramolecular DNA triplex (H-DNA), formed by mirror-repeated purine-pyrimidine repeats and stabilised by supercoiling, has been studied using atomic force H-DNA results in a kink in the double-helix path which forms an acute angle such that the flanking regions are brought into close proximity. G-tract DNA has been studied using C D and FTIR to determine the structural and conformational effects in Of the duplexes studied, all were shown to adopt the B-form double helix, but the sugar pucker varied depending on the DNA sequence.

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Pentacoordinated and Hexacoordinated Compounds BY C.D. HALL Department of Chemistry, University of Florida, Gainesville Fl 32611, USA

Summary The three years since SPR 33 have seen considerable activity in the ﬁeld of hypervalent phosphorus chemistry especially in the area of hexacoordinate and pseudo-hexacoordinate phosphorus compounds. In this respect, the Holmes’ group have made further, substantial contributions to the subject of N, O and S donor interaction at hypervalent phosphorus and the relevance of such interactions to the mechanism of phosphoryl transfer enzymes. The utility of proazaphosphatranes as catalysts (or co-catalysts) has been established by Verkade et al. in an impressive range of synthetic procedures and both Kawashima and Akiba have reported outstanding work on bicyclic phosphorane systems, carbaphosphatranes and the relevance of anti-apicophilic phosphorane systems to the mechanism of the Wittig reaction. The Lacour group has detailed the use of C2-symmetric hexacoordinated phosphate anions for enantiodifferentiation of organic and organometallic cations and last, but not least, Gillespie et al. have produced a thought-provoking review on bonding in pentaand hexacoordinated molecules. Regrettably, this contribution must be my swan song. After 25 years, age, the call of the golf course, choral singing, bridge and a part-time involvement with the Katritzky group in Gainesville, Florida (home of the Gators) persuades me that it is time to hand over the reins to a younger, more perceptive mind. I should add, however, that it has been a great pleasure to work with a number of patient and highly dedicated senior reporters plus of course, the talented technical editing staﬀ of the RSC. I am also indebted to Profesors Donald Denney and Alan Katritzky for reading and commenting on the manuscript. Finally, my sincere thanks are due to my wife, Jean Hall, who has typed all of these articles (and quite a few more over the years) without, as she plainly says, understanding a word. This, I am sure you will agree, is well above and beyond the call of duty.

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Introduction

The three years since June 2001 have seen a mini-revival of interest in penta- and hexacoordinated phosphorus chemistry. Several important reviews have appeared, the ﬁrst of which by Gillespie and Silvi,1 shows that there is no fundamental difference between bonds in hypervalent and non-hypervalent molecules and hence challenges the usefulness of the term ‘‘hypervalency’’. An accompanying paper by Gillespie et al.2 emphasizes this point and shows that the total population of the valence shell in phosphorus compounds varies from 9.44 (PMe5) through 7.15 (PCl5) to 5.37 (PF5) indicative of something close to ﬁve pure covalent bonds in PMe5 but the equivalent of only ca. 2.5 covalent bonds in PF5. Thus the latter molecule is largely ionic and could be represented approximately by two resonance structures (1a and 1b) with either three or two covalent bonds respectively. Group 16 (S, Se and Te) and Group 17 elements were subjected to the same topological analysis of the electron localization function (ELF) and although examples from the Group 17 elements were limited, similar overall conclusions were reached. These important papers make a substantial impact on the understanding of bonding in ‘‘hypervalent’’ molecules. The synthetic utility of proazaphosphatranes, so admirably exploited by Verkade and co-workers (vide infra), is reported in three comprehensive reviews.3–5 Overall they deal with the synthesis, structure and basicity/nucleophilicity of the proazaphosphatranes and then cover a wide range of synthetic applications including synthesis of heterocycles (e.g. oxazoles), ylid generation, cyclizations and base, nucleophilic or metal-catalyzed cross coupling (e.g. Suzuki) reactions. Holmes has provided another substantial review, this time on the role of hypervalent phosphorus chemistry in the mechanism of phosphoryl transfer enzymes and cAMP.6 The article delineates the tendency of phosphorus to form the hexacoordinated state from a pentacoordinated one and the inﬂuence of such a change on the mechanism of phosphoryl transfer enzymes. Factors that are discussed include transition state or intermediate anionicity, hydrogen bonding, packing effects (van der Waals forces), the ease of formation of hexacoordinate phosphorus from lower coordination states and the problem of pseudorotation as part of the mechanistic process. The fact that X-ray crystallography of isolated intermediates in displacement reactions at phosphorus does not necessarily represent the situation in solution is emphasized and the author concludes that donor bonds are likely to play a significant role in determining active site interactions. Density function calculations on metaphosphate, acyclic and cyclic phosphates and phosphoranes have been reported. Solvent effects calculated with three well established solvation models were also analyzed and compared. The results showed that microscopic solution pKa values increased in the order, metaphosphates [P(O)2OH]ophosphates [P(O)(OH)n(OR)3n, n ¼ 1–3, R¼H or Me]ophosphoranes [P(OH)n(OR)5n, n ¼1–5, R ¼H or Me] with values for cyclic phosphates and cyclic phosphoranes lower than the respective acyclic molecules. Furthermore protonation of the equatorial position in phosphoranes is about 4 pKa units lower than that found for the axial positions. Finally in

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terms of bond energies, P–O single bonds in phosphates were found to be stronger than in phosphoranes, axial P–O bonds in phosphoranes were weaker than equatorial bonds by ca. 10 kcal mol1 and P–OC bonds were more apicophilic than P–OH bonds. The authors anticipate that the results may afford quantitative insight into the structure and stability of phosphorus compounds relevant to RNA catalysis.7

An account has appeared on the preparation, structure and reactivity of a series of metallaphosphoranes.8 For example, the transition metal complex (2) reacts with (3ab) to form (4ab). X-ray crystallographic analysis and spectroscopic data for these metallaphosphoranes reveal that the transition metal fragment serves as a strong p donor towards the phosphorane fragment. The account also reports the activation parameters for pseudorotation about phosphorus in several metallaphosphoranes with values ranging from 67.8 to 89.7 kJmol1 dependent upon the metal centre (Co, Ru or Fe) and the substituents in the Cp ring. 2

Acyclic Phosphoranes

Ab initio quantum calculations and 35Cl NQR spectra show that chlorophosphoranes (5) and (6) have tbp structures with the pentaﬂuorophenyl groups located in equatorial positions9 consistent with the electronegativity of the respective groups but contrary to earlier claims regarding the same molecules.10,11 The structure of Me4PF has been investigated in the solid state, gas state and in solution.12 In the solid state vibrational spectra (IR and Raman) and a single crystal X-ray structure show an ionic tetramethylphosphonium ﬂuoride structure with the ﬂuoride ion in an almost planar trigonal conﬁguration surrounded by three Me4P1 cations. NMR spectra in a range of solvents (water-benzene) again show an ionic structure (d31P NMR, þ 23.1 to þ 31.3 dependent on solvent) with 19F values matching those of tetramethylammonium ﬂuoride. In the gas phase, however, vibrational spectra, quantum mechanical calculations using a variety of basis sets and gas electron diffraction (GED) studies reveal a tbp structure with one methyl group and the ﬂuorine in apical positions. Thus in solution (e.g. in CH3CN) the salt may serve as an excellent source of ‘‘naked’’ ﬂuoride.

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The P–Cl bond strengths in hypervalent tetrahalophosphorus anions, 1 PF2Cl 2 , POCl4 and PSCl4 (41–99 kJmol ) were determined by measuring thresholds for collision-induced dissociation in a ﬂowing afterglow mass spectrometer and the differences attributed to rearrangement energies of the dissociation products. Computational results gave generally good agreement with experiment.13 Pentaphenylantimony (7) and pentaphenylphosphorus (10) react with phenylmercuric chloride (8) to form (9) and (11) respectively with diphenylmercury as the byproduct.14 A similar but slightly more complex reaction occurs between (7) and ferrocenylmercuric chloride (C5H5FeC5H4HgCl).

The reaction of triphenylbismuth dichloride with sodium ﬂuoride in acetone led to the formation of Ph3BiF2 and an X-ray crystal analysis of the product showed a tbp structure with both ﬂuorines in axial positions.15 It should be noted that the abstract in this paper states, erroneously, that the ﬂuorine atoms are in equatorial positions. Gloede has shown that the reaction of 2,4,6trichlorophenol with PCl5 in CH2Cl2 gives a mixture of aryloxychlorophosphoranes (C6H2Cl3O)nPCl5n, n ¼ 1–4) depending on the ratio of reactants.16

3

Monocyclic Phosphoranes

Triphenylphosphine oxide has been shown to react with o-dihydroxyaromatic compounds (e.g.12) to form (o-naphthalenedioxy)triphenylphosphorane (13) showing that the phosphoryl group is, in fact, quite reactive towards acidic

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dihydroxy compounds probably as a result of the formation of a stable, ﬁve-membered ring within the pentacoordinate structure.17

In a paper dealing with the reaction of dihydroxyarenes with PCl5, Gloede et al. mention the formation of (15) from the reaction of (14) with phenol.18 The compound was identiﬁed by its 31P NMR signal at – 48 ppm. A companion paper19 deals with the reaction of bis(2-hydroxyphenyl)methane (16) with PCl5 and PCl3 yielding (17) and (18) respectively, with the latter forming (19) on reaction with Cl2. There was no mention of pentaoxy phosphoranes analogous to (15).

The phenylenedioxyphosphorane (20) does not react with benzonitrile but interestingly, reacts with benzoisonitrile in the presence of HCl, albeit in low

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yield, to give a tetrameric dication (21) with two tetrachloro(phenylenedioxy)phosphorate counterions.20 The structure of the product was established unequivocally by X-ray crystallography.

Further data has appeared on the reaction of arylenedioxy trihalogenophosphoranes (e.g. 20) with alkyl and aryl acetylenes.21 To give but one example, (22) reacts with arylacetylenes to give a mixture of the expected product (23) and two quinonoid-type structures (24a, cis) and (24b, trans). The same products are obtained by the reaction of chloranil with PCl3 and arylacetylenes. Full spectroscopic and X-ray crystallographic details of the products of these reactions have also been published.22

The reaction of ﬂuorinated halogenophosphoranes (25) with the silyl epoxide (26) gives a mixture of (27, 70%) and (28, 15%) with X¼Cl and a lower yield of (27, 27%) with X ¼ Br. The products were characterized by 13C and 31P NMR and evidence is presented to suggest that the mechanism involves ring opening of the epoxide to give (30) via (29) followed by cyclisation to (27).23

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The reaction of 1-phosphaindene (31) with arylacetylenes leads to the formation of (32) and a single crystal X-ray diffraction study reveals an almost regular tbp with axial chlorines and the benzophosphole ring in a diequatorial conﬁguration.24 Kawashima et al. have devised a new method for the synthesis of monocyclic phosphoranes by the reaction of the thiophosphinate (33) with triethyloxonium tetraﬂuoroborate to form the phosphonium salt (34) which, on exchange of the CH2Cl2 solvent for Et2O, was converted quantitatively to (35) by ﬂuoride abstraction from the counterion.25

In a study of ylides containing bis(triﬂuromethyl) groups Ro¨schenthaler et al. also reported an unusual method for the formation of monocyclic phosphoranes (37ab) by the reaction of ylide (36ab) with hexaﬂuoroacetone.26 The products were characterized by 1H, 19F, 31P NMR, mass spectrometry and elemental analysis.

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In an elegant extension of their pentacoordinate oxaphospholene methodology which uses the phosphorane as an enolate equivalent, McClure and Mishra synthesized (39) from (38) and triethyl phosphite and then proceeded to show that (39) could be converted to (40) a potential precursor to the biologically important sphingosine-1-phosphate (41).27

Allen et al. describe the synthesis and X-ray crystallographic studies of (42) and (43) in which there appears to be hypervalent interaction between the carbonyl oxygens and either the phosphonium or stibonium centres. The conclusion relies largely on the oxygen ’onium center bond distance at 2.661A˚ for (42) and 2.497A˚ for (43), both well within the respective van der Waals radii of 3.35A˚ and 3.75A˚. In both structures, the Group 15 element and the carbonyl oxygen are bent out of the plane of the anthraquinone system but the extent of the deformation is less with (43) suggesting a genuine hypervalent interaction.28

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The reaction of (44) with two equivalents of diethylaminotrimethylsilane (45) gave (46) whereas use of excess (45) gave (47) which was hydrolysed to (48) in the absence of base.29 All the products were characterized by single crystal X-ray structure determinations.

A series of tetracoordinate and pentacoordinate heterocyclic compounds containing P, S or Si within three-membered rings has been investigated by applying an electron-pair bond model for hypervalent molecules.30 In the case of pentacoordinated phosphorus, axial-equatorial conﬁguration of the threemembered ring (49a) is at a local minimum whereas the di-equatorial isomer (49b) is a T.S. on the pseudorotation pathway. The same holds true for (50) but with N in the three-membered ring, diequatorial disposition of the ring (as in 51) is preferred and the bond model analysis shows that the lone pairs on the N atom in the equatorial position delocalize more than those in the apical position into the equatorial P–F bonds. Hypervalent tetracoordinate three-membered heterocycles containing P, S and Si are also discussed within this paper.

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Bicyclic Phosphoranes

Although strictly outside the realm of phosphorus chemistry, reaction of (52) with benzylmagnesium bromide followed by treatment with lithium 2,2,6,6,tetramethylpyridine (LiTMP), triﬂuoroacetophenone and aqueous NH4Cl gave (53ab) which reacted with bromine to form (54ab). The bromostiboranes were then cyclised to (55a) and (55b) and although (55b) was unstable to moisture, (55a) was isolated as a colourless crystals from hexane. X-ray crystallographic analysis of (55a) revealed a distorted tbp with both oxygen atoms in apical positions and the phenyl group at position 3 of the oxastibitane ring cis to both the aryl group on antimony and the phenyl group at position 4. Thermolysis of (55a) in o-xylene-d10 at 2201C gave (56) with retention of conﬁguration plus the stibine (57) but there was no sign of the expected oleﬁn (60). On the other hand, thermolysis of (55a) in the presence of LiBr in CD3CN at 1401C gave a mixture of (56), (57) and (58). Interestingly, thermolysis of (55a) in the presence of lithium tetraphenylborate.3DME gave (60) in 85% yield together with trace amounts of (56–58). It was suggested that the reaction proceeded through a hexacoordinate antimonate (59) which collapsed to the oleﬁnic product.31,32

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The utility of the Martin ligand has been exempliﬁed once again in the synthesis of the ﬁrst 1,2-s5-selenaphosphirane (62) from (61), Scheme 1,33,34 and the ﬁrst 1,2-s5-thiaphosphirane (64) from (63).35 An X-ray crystallographic study of (62) showed a highly distorted tbp with O and Se in apical positions and an O1-P-Se bond angle of 155.82(6)1 indicating a distortion from tbp to sp of 56%. In the solid state, (62) had d31P 26.1 but in solution the d31P value varied from 26.6 (C6D6) to 13.6 (CDCl3) over a range of solvents and the values showed an approximate correlation with the acceptor number of the solvent used. A similar correlation was found with Ha of the phenyl ring and the 77Se NMR signal moved to higher ﬁeld in line with the acceptor number of the solvents. The results were consistent with increasing polarity of the P-Se bond with increasing solvent acceptor number.

A very similar X-ray crystallographic structure was obtained for (64) with an O1-P-S angle of 155.60 (7)1 indicating a highly distorted tbp and a P–S bond length of 2.2553 (13)A˚, significantly longer than the sum of the corresponding covalent radii (2.14A˚). Thus the P–S bond is also polar as reﬂected in the downﬁeld shift of the Ha proton to 8.73 (cf 7.53 in 63) and a 3lP NMR signal

Scheme 1

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which again responds to the acceptor number of the solvent from 48.8 in C6D6 to 40.4 in CDCl3. Iminooxaphospholens (65ab) can be stabilized by reaction with hexaﬂuoroacetone to form (66ab).36 X-ray crystallography of (66a) showed that both rings were disposed axial-equatorial with the oxygen atoms in axial positions within a slightly distorted tbp.

During a study of spirocyclotetraalkylphosphonium salts, Schmidbaur et al. reacted (67) with a series of organolithium reagents (RLi, with R ¼ Me, Et, Bun, Vi (vinyl) and Ph) to form (68) in good (R ¼ Me, Et, Bun) to low (R ¼ Vi, Ph) yields Single crystal X-ray analysis of (68) with R ¼ Me showed a tbp conﬁguration with the rings axial-equatorial and the methyl group in an equatorial position. All the pentacoordinate structures showed ﬂuxional behaviour in solution with a very low energy barrier to pseudorotation as evidenced by low temperature NMR.37

In a short review of compounds containing the P–CH2–P fragment,38 Shevchenko et al. mention the reaction of (69) with alkyl isocyanates,39 azides40 and hexaﬂuoroacetone,41 all of which give penta- or hexa-coordinate phosphorus compounds. (e.g.70). An unusual reaction of (71) with (72) gave a similar zwitterionic structure (73).38

By further exploitation of the Martin ligand, Akiba et al.42ab have extended their work on the preparation of conﬁgurationally stable enantiomeric pairs of

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optically active phosphoranes43 and the isolation and characterization of an ‘‘anti-apicophilic’’ (O-cis) phosphorane44 to explore the reactivity of O-cis phosphoranes. Thus the reaction of (74) with TBAF (Bu4N1 F) gave the hexacoordinate structure (75) presumably by attack of the ﬂuoride anion anti to the P-O equatorial bond. Although the structure of (75) was not established unequivocally a parallel was drawn with the X-ray structure of the antimony analogue.45 The O-trans isomer (76) did not react with TBAF thus enhancing the view that reaction with the ﬂuoride ion occurs through the low lying O-cis s* P–O orbital. Deprotonation of (77) followed by reaction with benzaldehyde over a prolonged period produced diastereomer (78) as the only product, presumably by equilibration of the stereoisomeric mixture and this, on reaction with KH in the presence of 18-C-6 gave the isolable phosphate (79) whose structure was determined by X-ray crystallography and shown to be the ﬁrst phosphate bearing an oxaphosphetane ring system.42aThermal decomposition of (79) to trans stilbene required 4 days at 601C whereas decomposition of the O-trans isomer was shown to be very much faster.42b

Several new spirocyclic phosphoranes (80a–e) have been isolated and examined by X-ray crystallography. For (80a–c), X was found to be apical but for

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X ¼ NH2 or NHPh (80d,e) the equatorial position was preferred. The possible reasons for this are discussed and variable-temperature (1H, 31P) NMR spectra reveal some unusual intramolecular processes within these compounds.46

In a related paper, Swamy et al. report the reaction of (81a–e) with diisopropyl azodicarboxylate (DIAD) which in four of the ﬁve cases generates pentacoordinate structures (82a–d) with nitrogen, rather than the expected oxygen, in an apical position, i.e. a ‘‘reversed’’ apicophilicity. X-ray crystallography reveals that in (82a-c) the group X is apical but in (82d) the NHMe group is equatorial. In the case of (82e) oxygen is found in the expected apical position but now the phenyl group is forced into an apical position.47

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Several macrocyclic bisphosphoranes (e.g. 83) have been prepared by condensing tris(dimethylamino)phosphine with isopropylidene-mannitols and their structures determined by elemental analysis, MS, NMR, cryoscopy, polarimetry and AM1 calculations.48

The reaction of 2-ketoglutaric acid (84) with phosphorus trichloride in THF gave a mixture of three enantiomeric pairs (85a–c), as evidenced by 1H and 31P NMR, which crystallized as (85c) identiﬁed by single-crystal X-ray analysis (Figure 1). After several hours in acetonitrile solution the crystals (with d 31P, 49.3) reverted to a mixture of the three isomers. The open enolate forms of the lactone rings (e.g. 85c/) were also detected in solution. The reaction of the spirophosphoranes with S8 in the presence of triethylamine to form (86), was also described.49

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Figure 1

The crystal structure of the hydroxyphosphorane (88) prepared by N2O4 oxidation of (87) showed an almost perfect tbp structure with the unit cell containing two molecules of the same helicity connected by H-bonds between the P–OH and carbonyl groups.50 The phosphorus ester (89), fashioned from two n-butyl tartrate moieties exists in solution due to intramolecular hydrogen bonds. On treatment with triethylamine, however, it forms the triethylammonium salt (90) of the corresponding hydroxyphosphorane. The pKa value of (89) was determined to be 7.7 in DMF and 4.4 in DMSO, similar to values for dichloroacetic acid in the same two solvents.51

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With trihydroxyethylenephosphorane (91) as a model for RNA hydrolysis, Karplus et al. developed a protocol for calculating the values of pKa1 and pKa2 of (91) based on estimates of the pKa for phosphoric acid. The protocol used density functional theory to calculate gas-phase protonation energies and continuum dielectric methods to determine solvation corrections and arrived at values of 7.9 and 14.3 for pKa1 and pKa2 respectively.52 These values are within the experimental ranges of 6.5–11.0 for pKa1 and 11.3–15.0 for pKa2 proposed for the molecules.53 Novel bicyclic (92) and tricyclic (93ab) hydrophosphoranes have been synthesized and shown to form complexes with PdCl2(COD), PdCl2(RCN)2, and Pd(allyl)Cl2 containing an ‘‘open’’ form of the phosphoranes.54 The Pd-catalyzed alkylation of 1,3-diphenylallyl acetate (94) with dimethyl malonate gave (95) in up to 74% ee using complexes of (92) or (93ab).54

The reaction of (93b) with Pt(COD)Cl2 gave (96) and when the reaction was carried out in the presence of silver tetraﬂuoroborate, the crystalline salt (97) was formed. An X-ray crystallographic structure determination of (97) showed a distorted tbp around phosphorus with the platinum fragment in an equatorial position and a near square-planar coordination geometry around the Pt atom.55 On heating to 601C, (97) lost cyclooctadiene to form (98). Variable temperature 31P NMR studies were reported for (96) and (97). This work, using ligands (92) and (93a), was extended to complexes of Pt and Rh with similar results.56

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The inﬂuence of the transition metal fragment on the activation barriers for Berry pseudorotation have been determined for (99a–d) and (100ab).57ab Both the 31P and 13C NMR of (99b–d) showed that the metal fragment was in an equatorial position and the three possible pairs of enantiomers with the metal fragment equatorial (0101, 0101, 0102, 0102, and 0202, 0202), were only interconvertible via high energy isomers (MO1, MO2) with the metal fragment apical (Scheme 2).57b The energy barriers (DG#) for the interconversion in (99a), (99b) and (99c) were 84.2, 89.7 and 73.1 kJmol1 respectively showing that changing the substituent from Cp to pentamethyl Cp (Cp*) increased the barrier. With (100ab), the DG# values were 67.8 and 67.9 kJmol1 respectively.

The cycloaddition of an alkyne (102) to the iminophosphorane (101) gave the ﬁrst stable l,2-l5-azaphosphetene (103) whose structure, as determined by X-ray crystallography, showed a distorted tbp with N and O atoms at the apical positions.58 The variable temperature 31P NMR spectrum of (103) in C7D8 or CD3CN showed a shift to lower ﬁeld with decreasing temperature indicating that (103) was in equilibrium with the corresponding ylid structure (104).

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Scheme 2

283

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In a related study,59 (101) was shown to give cycloadducts (103) when reacted with (102), and it gave (105) with hexaﬂuoroacetone, (106) with phenylisothiocyanate and interestingly, (107) was obtained with dimethyl acetylene-dicarboxylate and water. The structures were all conﬁrmed by Xray crystallography.

In a sequel to the synthesis of 5-carbaphosphatrane (108),60 reported in SPR 33, Kawashima et al. described the oxidation, sulfurization and selenation of

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(109) to give (111), (112) and (113) respectively.61 The authors consider that the reactions occur through the tautomeric cyclic phosphonate (110) although the latter was not detectable by 31P NMR.

There follows a section on the synthetic applications of proazaphosphatranes (PAP) developed extensively over the past few years by Verkade et al. The semistabilized ylid (114) reacts with aldehydes to give alkenes in high yield with quantitative selectivity despite changes in temperature, solvent polarity and the metal ion of the base used to generate (114).62 It was suggested that the tricyclic cage structure of the ylid played a pivotal role in affording a dominant l,2 interaction between the Ph and R1 groups of the T.S. (or intermediate, 115) leading to the E oleﬁn. Activated allylic compounds (116a-d) react with aromatic aldehydes in the presence of proazaphosphatranes, specifically P(PriNCH2CH2)3N, as catalyst at 93 to 631C to give a addition products. When R ¼ H and Z ¼ CN, an allylic transposition occurs to give a BaylissHillman adduct as the only product. (Scheme 3).63

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The proazaphosphatrane sulﬁde (117) has been shown to facilitate rapid and highly selective Bayliss-Hillman reactions between aromatic aldehydes and a,bunsaturated ketones in the presence of suitable Lewis Acids, with TiCl4 affording the best results. Thus p-nitrobenzaldehyde (118, 1mmol) reacted with cyclohexenone (3mmol) catalyzed by (117, 0.05 mmol) and TiCl4 (1.0 mmol) in CH2Cl2 under argon at room temperature to give a 94% yield of (119).64 The yields from a wide range of aromatic aldehydes and activated alkenes were in the region of 81-95% under extremely mild conditions.

Scheme 3

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Michael additions of a b,g-unsaturated ester (120a) or nitrile (120b) to a,b unsaturated ketones (121a–e) were also catalyzed by P(PriN CH2CH2)3N to give (122a–e) or (123d,e) in high yield but low diastereomeric selectivity. In one case, however, using (120a) and (124) a diastereomeric ratio of 91: 9 was found in the product (125) by NMR.65

Head-to-tail dimerisation of methyl acrylate to the dimethyl ester of 2methylenepentane-dioic acid (126) occurred in 82–85% yield in the presence of catalytic amounts of P(RNCH2CH2)3N with R ¼ Pri, Bui, or Bz but the less sterically hindered proazaphosphatrane with R ¼ Me, gave oligomer or polymer.66 The proazaphosphatrane, P(RNCH2CH2)3N with R ¼ Bui also acts as an effective ligand for the palladium-catalyzed direct arylation of ethyl cyanoacetate (127) with aryl bromides (e.g. 128) to form (129) in high yield.67

Proazaphosphatrane ligands in combination with Pd2(dba)3 also generate highly active catalysts for Buchwald-Hartwig amination of aryl chlorides, e.g. (132) from (130) and (131). The PAP ligand with R ¼ Bui was particularly effective and the catalyst performed extremely well with sterically hindered substrates.68

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A family of proazaphosphatranes [P(R1NCH2CH2)2N (R2NCH2CH2)] with R ¼ R2 ¼ Bui, and R1 ¼ Bz, R2 ¼ Bui and R1 ¼ R2 ¼ Bz have also been shown to be effective ligands in the palladium-catalyzed Stille cross coupling of aryl halides (ArX, 133) with aryl-, vinyl- and allyl-tri-n-butyltin (Bu3SnR,134) to give (135) thus illustrating, once again, the versatile synthetic utility of these powerful phosphorus ligands.69,70 1

The reaction of S,S,S-(136) with tris-dimethylaminophosphine/PCl3 in CH3CN at 01C gave the chiral azaphosphatrane (137) in overall 56% yield. Unfortunately (137) did not induce asymmetry in mandelonitrile formed from the catalyzed reaction of Me3SiCN with PhCHO. It was also inefﬁcient in catalyzing the addition of alkyl cyanide to benzaldehyde, and was not suﬃciently basic to effect rearrangement of cyclohexene oxide to 2-cyclohexenol.71 Further experiments with analogues of (137) are promised for future publications.

A new class of main group atranes has been afforded by the synthesis of carbophosphatranes (141) and (142) from (138) via (139) and (140),- Scheme 4.72 X-ray crystallography of (141) reveals a typical tbp structure with hydrogen and carbon atoms in the apical positions and three oxygen atoms equatorial indicating that (141) is an example of an ‘‘anti-apicophilic’’ arrangement. The 1JPH of (141) and 1JPC values of (141) and (142) were 852 and 215 Hz respectively, large for apical coupling constants of phosphoranes in general but close to those reported for 5-azaphosphatranes (e.g. 143). Force constant calculations indicate that the transannular bond in (141) is about twice as strong as that in (143) and three times stronger than that of the silatrane (144) reﬂecting the difference between a substantially covalent C-P bond in (141) and the more ionic N-P and N-Si dative bonds.

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In a discussion of the role of pentacoordinate phosphorus compounds in biochemistry, Zhao et al. reported the isolation of a silicon-protected pentacoordinate phosphorus compound (148) by the cyclisation of (147) formed from (145) and (146). Phosphorane (148) was then discussed as a model for the involvement of pentacoordinate phosphorus in activating the formation of peptides from amino acids such as histidine, serine, threonine and a-alanine but not b- alanine.73

In an extension of their studies on oxygen donor action at phosphorus, Holmes et al. examined (149–153) as mimics for amino acid residues, especially those containing carbonyl (Asn, Gln) or carboxylate (Glu, Asp) groups. Phosphorane (153), without a donor group, was included for comparison purposes. The structures of all ﬁve compounds were determined by X-ray crystallography which revealed that P–O coordination occurred for (149–151) in the presence of H-bonding and also in (152) where H-bonding is not possible, leading to tbp geometry in all four cases. Evaluation of the energies associated with both bonding types indicated a range for P–O coordination above and below the hydrogen bond energy. It was concluded that phosphoryl transfer enzyme mechanisms should beneﬁt by donor interaction at P and also by H-bonding interactions.74

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Scheme 4

A similar conclusion was reached in a sequel to this paper in which (154ab, 155, and 156) were prepared from the respective neutral species by treatment with di- or triethylamine.75 X-ray crystallography revealed hexacoordinated

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anionic phosphoranates (154 ab), pseudo-tbp anionic phosphine (155) and tbp anionic phosphine oxide (156). All three had stronger P–O bond interactions than the corresponding neutral species as judged by P-O bond distances and all three showed the energy of donor interactions exceeding those of the H-bonds present. The basic coordination geometries were retained in solution as evidenced by 31P data.

The whole concept of P-donor interaction in the presence of a H-bonding network and its relevance to the active site of phosphoryl transfer enzyme mechanisms was also discussed in two companion papers 76,77 which reached the conclusions that P-O donor interactions leading to hexacoordinate states, hydrogen bonding, and conformational distortions due to van der Waals forces, are all important in structuring the active site. Reaction of RPCl2 (R ¼ Ph or Et) with (157) gave tricoordinate (158a) with R ¼ Ph but hexacoordinate (159b) products with R ¼ Et and both structures were conﬁrmed by X-ray crystallography (Scheme 5). In addition, 31P NMR showed that in solution the tricoordinate and hexacoordinate forms of both compounds existed in equilbrium, an unprecedented interchange between tricoordinate and hexacoordinate phosphorus (Scheme 6). Solid state 31P NMR showed that (158) was in the tricoordinate state and (159) was hexacoordinate in agreement with the X-ray data.78 As part of a study of the reaction of aminotriphenols with phosphites or phosphonites, Holmes et al. reported the reaction of (160) with triphenyl phosphite or diphenoxyphenylphosphonite in the presence of N-chlorodiisopropylamine to give a mixture of (161a, isolated) or (161b, not isolated) both of which lost phenol to form (162a) or (162b) respectively with (163a) detected as a minor, unisolated product. X-ray crystallography and NMR data support the proposed structures and (162b) represents the ﬁrst hexacoordinated tetraoxyazaphosphatrane; both (163a) and (163b) have pronounced P-N coordination.79 The results were used yet again to support the concept of amino acid donor interaction at active sites of phosphoryl transfer enzymes.

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Scheme 5

Scheme 6

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Research on sterically imposed hypercoordination by Woollins et al. revealed that (164) collapsed its steric strain to form (165)80, found in both the solid state and solution. Further to this work, (167) was prepared by the addition of chlorine to (166) and shown by X-ray crystallography to adopt a near perfect pseudo-octahedral coordination at P(2).81 Despite the relatively long P(2)-O bond distance of 1.842A˚, the data favour bonding in (167) as ‘‘sterically imposed interaction of peri-substituents via a bridging O atom.’’ The interpretation is supported by 31P{1H} which shows d31P(1) ¼ 63.5 and d31P(2) ¼l82.7 with 2JPP ¼ 64 Hz. The chemical shift of P(2) clearly belongs in the hexacoordinate region and the 2JPP value indicates significant electronic P–P interation in (167).

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In an effort to determine whether apical oxygen or apical carbon (as represented by (168ab) is the reactive intermediate in the Wittig reaction, Akiba et al. synthesized and characterized (170a) by reaction of (169) with BuLi followed by I2. The compound was formed as a mixture of (170a) and (170b) but (170a) crystallized from the reaction mixture and its structure was determined by X-ray crystallography. Heating a sample of (170a) at 1201C for 5 min. converted it to (170b, O-apical) whose structure was also deﬁned by X-ray crystallography. Prolonged heating of (170b) at 1401C eventually gave oleﬁn and phosphine oxide and and thus the strength of the apical P–C bond in (170a) makes bond cleavage a much higher energy process than stereomutation.82

5

Hexacoordinate Phosphorus Compounds

The oxidation of (171) with (172) gave the zwitterionic compound (173) that was analyzed by X-ray crystallography and shown to contain both l4P1 and l6P atoms and a P–H bond. The 31P{1H} NMR data on (173) in CDCl3 showed a high ﬁeld doublet of triplets at 134.2 ppm, characteristic of hexacoordinate phosphorus with the splitting pattern due to one nonequivalent and two equivalent ﬂuorines.83

The benzylic anion (175) generated from (174) reacted with N-a-diphenylnitrone (176) to give the phosphorate (177), characterized by 31P NMR, and subsequent protonolysis products. A similar reaction of the O-trans isomer of

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(174), compound (178), led to the formation of the O-trans phosphorate (179) which proved to be less stable than (177) mainly due to the stabilizing inﬂuence of the s* orbital of the trans P–O bond in (177)84, c.f. reference 42ab.

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The work of Lacour et al. has focused attention on the use of C2-symmetric hexacoordinated phosphate anions for enantio differentiation of chiral cationic dyes85and chiral quaternary ammonium cations.86 Thus the BINPHAT anion (180) whose conﬁguration is controlled by the BINOL ligand, behaves as an efﬁcient NMR shift reagent and chiral inducer of monomethinium dyes (181) as determined by CD and 1H NMR.85

Likewise, the same BINPHAT anion acts as an efﬁcient NMR shift reagent for quaternary ammonium cations (182–186) including the biologically active methacoline (187).86,87 Furthermore, the BINPHAT anion has been shown to be an efﬁcient NMR chiral shift reagent for triphenylphosphonium salts containing stereogenic centres on an aliphatic side chain, e.g. (188ab) and (189).88

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Figure 2

In a variation on the same theme, a novel C2-symmetric hexacoordinated phosphorus cation (191) was synthesized from tropolone (190), R-BINOL and PCl5 and shown to be an efﬁcient NMR shift reagent for chiral anionic phosphate (e.g. BINPHAT, Figure 2) and borate anions.89

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The one-pot synthesis of a series of C2-symmetric hexacoordinated phosphate anions (192a–d, D or L isomers) containing tartrate esters as chiral auxiliaries, has been described.90 The presence of the chiral tartrato ligands (usually 2R,3R) led to the formation of diastereomeric anions (D2R,3R/ L2R,3R) with significant, but variable control over the D or L conﬁguration depending on the nature of the ester chains and the solvent. The asymmetric induction improved with increasing size of the group R from a diastereomeric ratio of 65: 35 for Me to 84: 16 for But (D: L).

The search for an enantiopure hexacoordinated phosphorus anion that would be highly stable, easily and stereoselectively synthesized and asymmetrically efﬁcient with both organic and organometallic cations was ﬁnally satisﬁed by the synthesis of (194) from tetrachlorocatehol and the a-D-mannopyranoside (193).91 Multinuclear NMR data (1H,13C and 31P) suggested the presence of only one diastereomer in the crystalline precipitate of the product and this was conﬁrmed as the L isomer by X-ray crystallography and circular dichroism. The asymmetric efﬁciency of (194) was tested with organic (195) and organometallic (196) cations and compared with the asymmetric efﬁciency of D-1 TRISPHAT and D-2-BINPHAT. A modest diastereomeric excess of 34% was found with (195) by NMR and CD analysis, but better results were obtained with (196) for which the de varied from 89–30% as the polarity of the solvent was increased. A useful review on hexacoordinated phosphate anions as chiral auxiliaries has appeared recently.92

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Reaction of the p-t-butylcalixarene (197) with PCl5 forms the hexacoordinate structure (198) with two S–P donor bonds.93,93 Although not isolated, the compound was characterized by a 31P NMR signal at 133 ppm and by hydrolysis to (199).

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A substantial paper by Akiba et al. describes the synthesis and characterization of a series of phosphorus (V) octaethylporphyrin derivatives of the type [P(OEP)(X)(Y)]1Zwhere OEP ¼ octaethylporphyrin; X ¼ Me, Et, Ph or F; Y ¼ Me, Et, OH, OMe, OEt, OPr, OPri, OBusec, NHBu, NEt2, Cl, F, O; Z¼ClO4, PF6. X-ray crystallographic analysis of eleven of these compounds revealed octahedral geometry about phosphorus, but a greater degree of ‘‘rufﬂing’’ in the porphyrin core coupled with shorter P–N bond distances as the electronegativity of X and Y increased. Comparison with arsenic analogous95 showed a much smaller ring current in the phosphorus compounds due, at least in part, to the rufﬂing. Features of these unique hexacoordinate compounds were also investigated by density functional calculations on two models, (Por)P(Et)(O) and (Por)P(F)(O) where Por refers to unsubstituted porphyrin. Ab initio density functional calculations afford theoretical evidence of hexacoordinate main group atoms, Si, P, and As centred in planar, hexagonal hydrocopper complexes, Cu6H6X where X ¼ S, P or As.96 Finally, as a further contribution to understanding of bonding in hypervalent molecules, Sun has offered an alternative model of bonding in hexacoordinated molecules, eg SF6 and PF 6 , which does not involve d-orbital participation but employs the concept of the three center, four electron bond.97 The model was supported by the use of a partial charge analysis using Allen’s electronegativity approach.98

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45. S. Kojima, Y. Doi, M. Okuda and K.-y. Akiba, Organometallics, 1995, 14, 1928. 46. P. Kommana, S. Kumaraswamy, J.J. Vittal and K.C. Kumara Swamy, Inorg. Chem., 2002, 41, 2356. 47. N.S. Kumar, P. Kommana, J.J. Vittal and K.C. Kumara Swamy, J. Org. Chem., 2002, 67, 6653. 48. A. Munoz and A. Rochal, Phosphorus, Sulfur Silicon Relat. Elem., 2001, 174, 177. 49. A. Munoz, H. Gornitzka and A. Rochal, Phosphorus, Sulfur Silicon Relat. Elem., 2002, 177(5), 1255. 50. A. Munoz and H. Gornitzka, Phosphorus, Sulfur Silicon Relat. Elem., 2003, 178(1), 5. 51. D.G. Boyer, M-T. Boisdon, A. Rochal and A. Munoz, Phosphorus, Sulfur Silicon Relat. Elem., 2003, 178(10), 2117. 52. X. Lopez, M. Schaefer, A. Dejaegere and M. Karplus, J. Am. Chem. Soc., 2002, 124, 5010. 53. D.M. Perrault and E.V. Anslyn, Angew Chem., Int. Ed., 1997, 36, 432. 54. K.N. Gavrilov, A.I. Polosukhin, O.G. Bondarev, S.E. Lyubimov, K.A. Lyssenko, P. Petrovski and V.A. Davankov, J. Mol. Cat. A: Chemical, 2003, 196(1-2), 39. 55. I.S. Mikhel, O.G. Bondarev, V.N. Tsarev, G.V. Grintselev-Knyazev, K.A. Lyssenko, V.A. Davankov and K.N. Gavrilov, Organometallics, 2003, 22, 925. 56. O.G. Bondarev, I.S. Mikhel, V.M. Tsarev, P.V. Petrovskii, V.A. Davankov and K.N. Gavrilov, Russ. Chem. Bull., Int. Ed., 2003, 52(1), 116. 57. (a) H. Nakazawa, T. Ogawa, K. Kawamura and K. Miyoshi, Phosphorus Sulfur Silicon Relat. Elem., 2002, 177(8-9), 2163; (b) H. Nakazawa, K. Kawamura, T. Ogawa and K. Myoshi, J. Organometallic Chem., 2002, 646, 204. 58. N. Kano, A. Kikuchi and T. Kawashima, Chem. Commun., 2001, 2096. 59. N. Kano, J.-H. Xing, A. Kikuchi, S. Kawa and T. Kawashima, Phosphorus, Sulfur Silicon Relat. Elem., 2002, 177(6-7), 1685. 60. J. Kobayashi, K. Goto and T. Kawashima, J. Am. Chem. Soc., 2001, 123, 3387. 61. J. Kobayashi, K. Goto and T. Kawashima, Phosphorus, Sulfur Silicon Relat. Elem., 2002, 177(6-7), 1405. 62. Z. Wang, G. Zhang, I. Guzei and J.G. Verkade, J. Org. Chem., 2001, 66(10), 3521. 63. P.B. Kisanga and J.G. Verkade, J. Org. Chem., 2002, 67, 426. 64. J. You, J. Xu and J.G. Verkade, Angew. Chem. Int. Edn., 2003, 42(41), 5054. 65. A.E. Wro´blewski, V. Bansal, P. Kisanga and J.G. Verkade, Tetrahedron, 2003, 59(4), 561. 66. W. Su, D. McLeod and J.G. Verkade, J. Org. Chem., 2003, 68(24), 9499. 67. J. You and J.G. Verkade, J. Org. Chem., 2003, 68(21), 8003. 68. S. Urgaonkar and J.G. Verkade, J. Org. Chem., 2004, 69(26), 9135. 69. W. Su, S. Urgaonkar and J.G. Verkade, Organic Letters, 2004, 6(9), 1421. 70. W. Su, S. Urgaonkar, P.A. McLaughlin and J.G. Verkade, J. Am. Chem. Soc., 2004, 126(50), 16433. 71. J. You, A.E. Wro´blewski and J.G. Verkade, Tetrahedron, 2004, 60(36), 7877. 72. J. Kobayashi, K. Goto, T. Kawashima, M.W. Schmidt and S. Nagase, J. Am. Chem. Soc., 2002, 124, 3703. 73. Y.-F. Zhao, B. Han, J. Chen and Y. Jiang, Phosphorus, Sulfur Silicon Relat. Elem., 2002, 177(6-7), 1391. 74. A. Chandrasekaran, R.O. Day and R.R. Holmes, Inorg. Chem., 2001, 40(24), 6229. 75. A. Chandrasekaran, R.O. Day and R.R. Holmes, Inorg. Chem., 2002, 41(6), 1645. 76. R.R. Holmes, A. Chandrasekaran, N.V. Timosheva and R.O. Day, Phosphorus, Sulfur Silicon Relat. Elem., 2002, 177(6–7), 1397.

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77. A. Chandrasekaran, N.V. Timosheva, R.O. Day and R.R. Holmes, Inorg. Chem., 2003, 42, 3285. 78. N.V. Timosheva, A. Chandrasekaran, R.O. Day and R.R. Holmes, J. Am. Chem. Soc., 2002, 124(24), 7035. 79. N.V. Timosheva, A. Chandrasekaran and R.R. Holmes, Inorg. Chem., 2004, 43(23), 7403. 80. P. Kilian, D. Philip, A.M.Z. Slawin and J.D. Woollins, Eur. J. Inorg. Chem., 2003, 249. 81. P. Kilian, A.M.Z. Slawin and D.J. Woollins, Chem. Commun., 2003, 1174. 82. S. Kojima, M. Sugino, S. Matsukawa, M. Nakamoto and K.-y. Akiba, J. Am. Chem. Soc., 2002, 124, 7674. 83. I. Shevchenko, V. Andrushko, E. Lork and G.-V. Ro¨schenthaler, Chem.Commun., 2002, 120. 84. S. Matsukawa, Y. Yamamoto and K.-y. Akiba, Heterocycles, 2003, 59(2), 707. 85. J. Lacour, A. Londez, C. Goujon-Ginglinger, V. Buss and G. Bernardinelli, Org. Letters, 2000, 2(26), 4185. 86. J. Lacour, L. Vial and C. Herse, Org. Letters, 2002, 4(8), 1351. 87. J. Lacour and A. Londez, J. Organomet. Chem., 2002, 643–644, 392. 88. V. Hebbe, A. Londez, C. Goujon-Ginglinger, F. Meyer, J. Uziel, S. Juge´ and J. Lacour, Tetrahedron Lett., 2003, 44(12), 2467. 89. J. Lacour, L. Vial and G. Bernardinelli, Org. Letters, 2002, 4(14), 2309. 90. J. Lacour, A. Londez, D.-H. Tran, V. Desvergnes-Breuil, S. Constant and G. Bernardinelli, Helv. Chim. Acta., 2002, 85, 1364. 91. C. Pe´rollier, S. Constant, J.J. Jodry, G. Bernardinelli and J. Lacour, Chem. Commun., 2003, 2014. 92. J. Lacour and V. Helbe-Viton, Chem. Soc. Rev., 2003, 32(6), 373. 93. J. Gloede, S. Ozegowski, D. Weber and W.D. Habicher, Phosphorus, Sulfur Silicon Relat. Elem., 2003, 178, 923. 94. K.-y. Akiba, R. Nadano, W. Satoh, Y. Yamamato, S. Nagase, Z. Ou, X. Tan and K.M. Kadish, Inorg. Chem., 2001, 40(2), 5553. 95. W. Satoh, R. Nadano, G. Yamamoto, Y. Yamamoto and K.-y. Akiba, Organometallics, 1997, 16, 3664. 96. S.-D. Li, G.-M. Ren and C.-Q. Miao, Inorg. Chem., 2004, 43, 6331. 97. X. Sun, Chemical Educator, 2002, 7(5), 26l. 98. L.C. Allen, J. Am. Chem. Soc., 1989, 111, 9115.

Nucleic Acids and Nucleotides: Mononucleotides BY M. MIGAUD Department of Chemistry, David Keir Building, Queen’s University, Belfast, Stranmillis Road, Belfast, BT9 5AG, UK

1

Introduction

Extensive work has been reported on the chemistry of polyphosphates, in particular that of dinucleoside and sugar nucleoside pyrophosphates. This reﬂects the reliability and ﬂexibility of the phosphoramidate methods which have been developed over the past few years. Similarly, a wide range of oligonucleotide building blocks, incorporating extensive structural modiﬁcations when compared to the natural nucleoside structures, have been described. 2

Mononucleotides

2.1 Nucleoside Acyclic Phosphates. – 2.1.1 Methodologies. A scaleable one-pot method to access H-phosphonate derivatives of 20 ,30 -dideoxy-2 0 ,30 -didehydrothymidine (d4T) and AZT that employs PCl3 as reagent and an acid catalysed Arbuzov dealkylation subsequent to a bis-alcoholysis, has been reported by Zhao.1 While developing a method for the direct thiation of 2 0 -deoxy-5,6dihydropyrimidine nucleosides with Lawesson’s reagent, Clivio has identiﬁed a number of oxathiaphosphepane intermediates (1) which resulted from the heat reversible incorporation of an AnPS2 moiety within the 2 0 -deoxyribose unit (Scheme 1).2 Wolter reported the synthesis in four steps from 50 -O-DMT-thymidine of a ‘‘user-friendly’’ solid reagent, the phosphoramidite (2), that converts terminal hydroxyl groups of oligonucleotides into phosphate monoesters.3 DMTO O

NH

O

O O

O N

N H

O N H

(2)

Organophosphorus Chemistry, Volume 35 r The Royal Society of Chemistry, 2006 304

N O

P

O CN

CN

305

Organophosphorus Chem., 2006, 35, 304–354 CH3O TBDMSO

S TBDMSO

O

P

S

O

S

N

NH

dioxane 85oC N

TBDMSO

O

O

TBDMSO

S

N H

(1) Scheme 1

2.1.2 Mononucleoside Phosphate Derivatives. To identify potential leads for new anti-mycobacterium tuberculosis treatment, Van Calenberg synthesized a number of 2 0 - and 3 0 -modiﬁed thymidine 50 -O-monophosphate analogues (3–6). These were evaluated amongst other known inhibitors of the mycobacterium thymidylate kinase.4 Compound (7) was prepared in four steps from 2 0 -deoxyguanosine as a suitable building block for DNA synthesis.5 Similarly, Beigelman reported the scaleable preparation of the 20 -deoxy-20 -N-phthaloyl nucleoside phosphoramidites (8–10) for use in oligonucleotide synthesis.6 Eschenmoser described the synthesis of the a-threofuranosyl nucleoside phosphoramidites (11–14), starting either from 1,2,3-tri-O-acetyl erythrose or from a-L-threofuranosyl thymine.7 20 -Fluoro-Luridine and 20 -ﬂuoro-L-cytidine phosphoramidites, (15) and (16) respectively, were synthesized from L-arabinose and used as building blocks in the synthesis of 2 0 ﬂuoro-Spiegelmers binding to a D-neuropeptide.8 To facilitate phase determination in X-ray crystallography and the 3-D-structure identiﬁcation of nucleic acids, the selenium containing phosphoramidite (17) was prepared from the 2-Se-uridine and incorporated in DNA and RNA oligonucleotides.9 Similarly, to further investigate the role played by the 2-hydroxyl group in RNA, the phosphoramidite derivative of 2 0 -deoxy-2 0 -C-b-methylcytidine (18) was prepared from 1,2,3,5-tetraO-benzoyl-2-C-b-methylribofuranose.10

O O

N

N

HO P O

O

O

HO

X (3) (4) (5) (6)

N Y

MMT

H N O

NH

N

Ndbf

N

O

X= Cl; Y= OH X= F; Y= OH X= OH; Y= NH2 X=NH2; Y= OH

O

P O CN

iPr2N (7)

306

Organophosphorus Chem., 2006, 35, 304–354 CN

DMTO O

B

O

MMT

NH

B O

O O NC

iPr2N

P

O

B O

N O

O P O iPr2N

P O

iPr2N

(8) B= Ura (9) B= N4-Ac Cyt (10) B= N-Bu, N-Bz Ade

NH MMT

CN

(13) B= T (14) B= ABz

(11) B= T (12) B= ABz

NHBz N

B

DMTO

ODMT

O

O

F O

O NC

P O

iPr2N (15) B = Cyt (16) B = N4-AcThy

CN

O P iPr2N (17)

DMTO

Cac

SeCH3

O NC

O

N

O

CH3 H

O P iPr2N (18)

Leumann has reported the synthesis of various types of modiﬁed phosphoramidites. He described the synthesis of pyrrolidino-C-nucleoside phosphoramidites incorporating a pseudo-uracyl, pseudo-thymine or pseudoisocytosine, (19), (20) and (21), respectively.11 He also reported the preparation of the enantiomerically pure adenine and thymine cyclopentane amide phosphoramidites (22) and (23).12 Herdewijn reported the use of lipases for the preparative scale resolution of (þ/) (4aR, 7R, 8aS)-2-phenyl-4a,7,8,8a,tetrahydro-4H-1,3-benzodioxine and the synthesis of eight enantiomerically pure phosphoramidites of D- and L-cyclohexyl nucleosides (24(þ), 24(), 25(þ), 25(), 26(þ), 26(), 27(þ), 27()).13 The phosphoramidite derivatives (28) and (29) were synthesized from 1-(5,6-di-O-acetyl-2,3-dideoxy-3-phthalimido-a-Darabino-hexofuranosyl)thymine and incorporated into oligodeoxynucleotides as putative conformationally restricted acyclic nucleosides.14 Starting from adenine b-D-nucleosides with ribo-, xylo- and arabino- conﬁgurations, the phosphonate derivatives (30-35) were synthesized after phosphonomethylation with diisopropyl tosylmethylphosphonate of the suitably protected nucleoside precursors. The phosphonomethyl derivatives were then incorporated into oligonucleotides using solid phase synthesis protocols.15

307

Organophosphorus Chem., 2006, 35, 304–354

DMTO

fmoc B

N

O NC

O P iPr2N (19) B= pseudo-Ura (20) B= pseudo-Thy (21) B= pseudo-isocytosine

O

MMTO O

B H N

O

B O NC

NC

O

O P iPr2N

O P iPr2N

(24) (+) and (-) B= N6-Bz Ade (25) (+) and (-) B= N2-iBu Gua (26) (+) and (-) B= N4-Bz Cyt (27) (+) and (-) B= Thy

(22) B= Thy (23) B= N6-anIsoyl-Ade

X Y Phth

O T

(28) X= ODMT; Y= OP(NiPr2)(OCH2CH2CN) (29) X= OP(NiPr2)(OCH2CH2CN); Y= ODMT O

O iPrO

O

P

O OiPr BzO

Abz iPrO

P

O OiPr ODMT

ODMT (31)

(30) DMTO O

BzO (32)

Abz

DMTO O

O

OBz Abz O

P OH O OMOP

Abz O

OBz

O (33)

P OH OMOP

308

Organophosphorus Chem., 2006, 35, 304–354 DMTO

ODMT Abz

BzO O

ODMT Abz O

O

HO P MOPO

O O

O

P OH OMOP

(35)

(34)

Extensive work has been reported with regard to the synthesis of phosphoramidites, building blocks for the synthesis of locked nucleic acids. For instance, Koch has developed a synthesis of the 2 0 -thio-LNA ribothymidine phosphoramidite (36), which is convergent with the previously reported procedures to access LNA and 2 0 -amino-LNA.16 However, Wengel has been the most proliﬁc in this area. He has reported the synthesis of four conformationally restricted bicyclic 2 0 -spiro nucleoside phosphoramidites (37–40). The nucleoside precursors showed no anti-viral activities and their introduction into oligonucleotides induced decreased duplex thermostabilities compared with the corresponding DNA:DNA and DNA:RNA duplexes.17 He also described the syntheses and antiviral activities of conformationally locked 3 0 -deoxy and 3 0 -azido-3 0 -deoxynucleoside derivatives (41–46) as pro-drugs of potential 5 0 -O-triphosphorylated anti-HIV drugs.18 In addition to reporting the syntheses of locked nucleosides based on natural nucleobases, he has described the synthesis of conformationally locked aryl C-nucleoside phosphoramidites, either in a Dribo conﬁguration (47–51)19 or in a b-L-ribo conﬁguration (52), (53).20 He has also prepared the non-locked a-L-ribofuranosyl phosphoramidite (54) for incorporation in a-L-RNA/DNA; a-L-RNA/a-L-LNA chimeras.21 Finally, he has described the synthesis of a methylphosphonamidite locked nucleic acid thymine derivative, (55). The two diastereoisomers of this phosphonamidite were obtained by treating the locked thymidine nucleoside suitably protected with bis(diisopropylamino)methylphosphine in the presence of 1H-tetrazole.22

O NH DMTO O

O NC

N

S

O P iPr2N (36)

O

309

Organophosphorus Chem., 2006, 35, 304–354

O

O NH

DMTO

O

N

O

NH DMTO O

O O NC

O

N

O O NC

O P iPr2N

O P iPr2N

(37)

(38)

O

O NH

DMTO

O

N

O

NH DMTO O

O

O

O NC

O

N

O NC

O P iPr2N

O P iPr2N

(39)

(40)

O NH

O

NH

O

P O

O

N

O

O O

O

O

O

O

P O O

O

(42)

N3 O

O (41)

O

N

O NH

O

O

P O O O

O

O

O HN

N3 (43)

N O

O

P O O

O

CH3 OMe

R

B

O

(44) B= Ade; R= N3 (45) B= Ade; R= H (46) B= Thy; R= N3

310

Organophosphorus Chem., 2006, 35, 304–354

DMTO O

Ar RO

O

O Ar

DMTO

O O N P CN

O

(47) (48) (49) (50) (51)

Ar= phenyl Ar= 4-fluoro-3-methylphenyl Ar= 1-naphthyl Ar= 1-pyrenyl Ar= 2,4,5-trimethylphenyl

(52) Ar= phenyl; R= P(OCH2CH2CN)(NiPr2) (53) Ar= 1-pyrenyl; R= P(OCH2CH2CN)(NiPr2)

O NH DMTO O

O

N

CNCH2CH2O P

O

iPr2N

O

Thy OTBDMS

O O

H3C P N

DMTO

(55)

(54)

The Lewis acid-mediated N-glycosylation of 2,3-dideoxyribofuranosides having a (diethoxyphosphorothioyl)diﬂuoromethyl group at the 3a-position with silylated nucleobases has been reported to be successful for the diastereoselective synthesis of b-N-pyrimidine-nucleotide analogues, (56–59).23 O

NHBz R

NH

N TBDPSO

TBDPSO O

N

O

O

N

CF2

CF2

S P OEt

S P OEt

OEt

OEt

(56)

O

(57) R= H (58) R= F (59) R=CH3

The a-phosphonolactones, (60) and (61), analogues of cytidine and cytosine arabinoside diphosphates, have been synthesized in an attempt to bypass

311

Organophosphorus Chem., 2006, 35, 304–354

metabolic adaptations and resistance known to be occurring during the treatment of myeloid leukemias by cytosine arabinoside.24 These phosphonates were prepared via ring closing metathesis on acrylate esters of homoallylic alcohols and reduction of the a,b-unsaturated lactones followed by a base-catalysed carbon-phosphorus bond formation using chlorodiethylphosphite. Chan has reported a novel class of tetrahydrofuran phosphonates with potential antiviral activity (62) and (63).25 His work further extended to the preparation and evaluation of a series of substituted tetrahydrofuran derivatives (64–73).26 O EtO

NHAc

O

P

N

O

OEt

O

O

N

EtO

NHAc

O

P

N

O

OEt

O

O

O

N

OR OR

OR OR R= TBDMS (60)

(61)

HO

HO N

N N

N

O

HO P O

O

X Y

z

R (63) R= H (69) R=OH

(62) X= Y= Z= H (64) X= OH; Y= H; Z= H (65) X= F; Y= H; Z= H (66) X=H; Y= F; Z= H (67) X=OCH3; Y= Z= H (68) X= OH; Y= H; Z= OH

HN

HN N

N N

O HO P O

NH2

N

N

O

O

HO P O

N

N NH2

O

N

NH2 N

O HO P O

O

R (70) R= H (71) R= OH

N

N

(72)

N

NH2

312

Organophosphorus Chem., 2006, 35, 304–354

H2N N

N N

O

N

NR

Ph

NH2

P

O

HO P O

O

X

N

O

O OH

OH

(74) X= CN; R= CH3 (75) X= CN; R= p-Cl-Bn (76) X= CN; R= H (77) X= COCH3; R= H (78) X= COOEt; R= H (79) X= CH3; R= H (80) X= H; R= H

(73)

Oshikawa described an efﬁcient method for the synthesis in racemic form of several deoxyphosphasugar pyrimidine nucleosides (74–80). The synthetic route involved the treatment of 2-aminophospholane 1-oxide with several acyano, acetyl, ethoxycarbonyl-b-ethoxy-N-ethoxycarbonylacrylamides, precursors of the substituted uracyl ring systems.27 The phosphonate derivatives of methylenecyclopropane nucleoside analogues (81–92) have been synthesised by Zemlicka via an alkylation-elimination method.28 Stec reported the synthesis of novel acyclic nucleosides (93–100) based on a bis(hydroxymethyl)phosphinic acid backbone and obtained by condensation of its bis-(4,4 0 -dimethoxytrityl) derivative with N-1 or N-3-(2-hydroxyethyl)thymine in the presence of 1-(2mesitylensulfonyl)-3-nitro-1,2,4-triazole as activator.29 Balzarini reported the synthesis and biological activity as antiproliferative agents of a series 2,4diamino-6-[(2-phosphonomethoxy)ethoxy]pyrimidine derivatives (101–108).30 Stang described the reaction of (1-chloro-4-diethoxyphosphonyl)alka-2,3-dienes with purine and pyrimidine heterocyclic bases in the presence of cesium carbonate. This afforded acyclic nucleoside analogues (109–120), containing a 1,2-alkadiene skeleton.31

PO3H2

PO3H2

PO3H2

B

B B

(81) B= Ade (82) B= Gua (83) B= Cyt

PO3H2

(84) B= Ade (85) B= Gua (86) B= Cyt

B (87) B= Ade (88) B= Gua (89) B= Cyt

(90) B= Ade (91) B= Gua (92) B= Cyt

313

Organophosphorus Chem., 2006, 35, 304–354

ODMT

B X P

R

N R

NH2

NH2

O

R

N

O O P

N

H2N

N

H2N

O

N

O

O O

(93) R= CH2CH2CN; X= O; B= N1-Thy (94) R= CH3; X= O; B= N1-Thy (95) R= CH2CH2CN; X= NH; B= N1-Thy (96) R= CH2CH2CN; X= O; B= N3-Thy (97) R= CH3; X= O; B= N3-Thy (98) R= CH2CH2CN; X= NH; B= N3-Thy

(HO)2OP X

B Y

PO(OH)2

(OH)2OP

(101) R= Allyl (102) R= Benzyl (103) R= CH2CN (104) R= CH2COOH

O

(105) R= Allyl (106) R= Benzyl (107) R= CH2CN (108) R= CH2COOH

(109) X= Y= H; B= Ade (110) X=H; Y= n-C4H9; B= Ade (111) X=CH3; Y= n-C3H7; B= Ade (112) X=CH3; Y= n-C4H9; B= Ade (113) X= Y= H; B= Ura (114) X=H; Y= n-C4H9; B= Ura (115) X=CH3; Y= n-C3H7; B= Ura (116) X=CH3; Y= n-C4H9; B= Ura (117) X= Y= H; B= Thy (118) X=H; Y= n-C4H9; B= Thy (119) X=CH3; Y= n-C3H7; B= Thy (120) X=CH3; Y= n-C4H9; B= Thy

Extensive work has been reported on the synthesis of nucleoside phosphoramidite and H-phosphonate derivatives incorporating modiﬁed-nucleobases. To target the stabilization of RNA bulges, Stromberg synthesized the Hphosphonate derivative of 2 0 -naphthylmethyl-2 0 -deoxytubercidine, (121).32 Lonnberg developed the synthesis of the phosphoramidites (122) and (123) to learn more about the effects that the in vivo base modiﬁcation of adenosine to the 11-carboxy-1, N6-etheno adduct exerts on the duplex stability and coding properties of DNA.33 To similar ends, Cadet synthesized the phosphoramidite derivative of 1-hexanol-1, N6-etheno-2 0 -deoxyadenosine, (124) and incorporated it into modiﬁed oligonucleotide chains.34 Yaekura has shown that the treatment of guanine nucleotides with an excess of crotonaldehyde in pH 8 phosphate buﬀer containing an equimolar amount of arginine at 501C for 2h resulted in the selective formation of the corresponding cyclic 1, N2-propano adducts (125–127).35,36

314

Organophosphorus Chem., 2006, 35, 304–354

O

O

N

HN

N

N

OR

N DMTO

MMTO

N

O

N

N

O

N NC

O OTBDMS O P

O O P O

N

H

(122) R= CH3 (123) R= CH2CH3

(121)

N N

N DMTO O

O

N

N HO

N

N

HO

O

O

O

N H

N

N

CH3

NC O

O

O P

O P

N

O

O

(124)

O

O P O O

HO

O

N

O

N

N

O

(125)

N

N H

CH3

O

O

N

N

N H

CH3

OH OH

OH (126)

N

N

O O P O

HO

(127)

In order to expand on the number of thioguanosine-modiﬁed building blocks for the synthesis of RNA-type oligonucleotides, Zheng has developed a synthetic route to (128), which employs 2,4-dinitrophenyl as thiol protecting group for the starting material 6-thioguanosine. The 2,4-dinitrophenyl group was subsequently removed in high yield using mercaptoethanol under very mild alkaline conditions once the oligonucleotides had been synthesised.37 Seela reported the syntheses of the phosphoramidites of 8-aza-7-deazaguanine N8-(2 0 -deoxy-b-D-ribofuranoside) (129),38 the halogenated 7-deaza-2 0 -deoxyxanthosine derivatives (130– 132)39 and the N7-(2 0 -deoxy-b-D-erythro-pento-furanosyl) isoguanine (133).40

315

Organophosphorus Chem., 2006, 35, 304–354

(CH3)2N NO2

O2N

N S

O

O

N

N MMTO

H N

N H N

N

N

N

DMTO

N

O

O

NC

O O OTBDMS

NC Ph

O O P

O P

N

N

(129)

(128)

O O

NH DMTO

N

O

N H

N

O

DMTO

NC

O

O

Y

NC

N

O P N

DMTO O

N

N

N

N

O

O O

O P N

X

NC

(130)

O

(132)

O P N

(131a) X= H; Y= DPCO (131b) X=DPCO; Y=H

O

O N

N S

ODPC

N

CH3

N N

DMTO O

N N

N

DMTO

NC O O P N

O

N(CH3)2

N

SO2N(CH3)2

NC O O P N

(133)

(134)

O

316

Organophosphorus Chem., 2006, 35, 304–354

Benhida described the synthesis of a 2-deoxy-C-nucleoside analogue and its phosphoramidite derivative featuring 6-(thiazolyl-5)-a-benzimidazole nucleobase (134).41 A more efﬁcient route to the expanded adenosine analogue (135) was developed by Kool, who also described the synthesis of the expanded thymidine analogue (136) starting from 5-methylanthranilic acid. Both nucleosides were found to be efﬁcient ﬂuorophores.42 3 0 -Cyanoethyl phosphoramidites of 6-methyl-3-(2 0 -deoxy-b-D-ribofuranosyl)-3H-pyrrolo[2,3-d]pyrimidin-2-one (137) and of 6-methyl-3-(b-D-ribofuranosyl)-3H-pyrrolo[2,3-d]pyrimidin-2-one (138) were synthesized and used as ﬂuorescent analogues for deoxycytidine and cytidine in oligonucleotides, respectively.43 H2N N

O

N N

DMTO O

N

NH

DMTO N H

O

O

NC

NC

O

O O P

O P

N

N

(135)

(136)

NH N DMTO O

N

O

NC

(CH3)3Si

R

O P

O HN

OO Si O

O

O (CH3)3Si NC

O

Ph

Ph

H3C

O O O P

NCH3 O O

O O

O

N O

N

O (137) R= H (138) R= OTOM

(139)

A selective method which involves the selective pivaloyloxymethyl protection of the N1 of pseudouridine followed by methylation at N3 was developed to prepare the 5-benzhydryloxybis(trimethylsilyloxy)silyl, bis(2-acetoxy-ethoxy)methyl- protected phosphoramidite derivative (139) of the nucleoside 3-methylpseudouridine. The methylated pseudouridine phosphoramidite was successfully used in oligonucleotide synthesis for the NMR study of helix 69 of E. coli 23S rRNA.44 2-Thiouridines incorporating 2 0 -modiﬁed nucleoside phosphoramidites

317

Organophosphorus Chem., 2006, 35, 304–354

(140) and (141) have been synthesized from the 2 0 -modifed uridine via a 5-ODMT-2-O-MOE-2-O-ethylthymidine prepared from a 5 0 -mesylate precursor.45 Richert described the synthesis of the 5 0 -protected 3 0 -phosphoramidite of 1-(2 0 deoxy-b-D-ribofuranosyl)-2-ethynyl-4-ﬂuorobenzene, (142).46 The C-nucleoside was obtained from the a-chlorosugar and a cadmium-activated arene anion as a mixture of a and b diastereoisomers, with the undesired a-anomer formed in excess. Harusawa reported the synthesis of the C4-linked imidazole ribonucleoside phosphoramidite (143). This C-nucleoside, prepared from tribenzylribofuranosylimidazole, was incorporated into an RNA sequence to study its capacity as a general acid and base catalyst of ribozymes.47 F

O NH DMTO

N

O

DMTO O

S

NC

NC O

O

R

O P

O P

N

N

(140) R= OCH2CH2OCH3 (141) R= F

O

(142)

O P OR HN OR

O N

DMTO

N

N

DMTO O

O

N

O

NC

NC

O

O OTBDMS O P

O P N

(143)

N

(144) R= CH2CH2CN (145) R= CH2CH3

The synthesis and incorporation into oligonucleotides of the N-phosphorylated deoxycytidine 3 0 -phosphoramidites (144) and (145) obtained either from the O-protected 2 0 -deoxycytidine and bis(2-cyanoethyl) N,N-diisopropyl phosphoramidite or diethylphosphorochloridite, respectively, was described by Sekine.48 Sekine also reported that the N-phosphorylated derivatives of 2 0 deoxy adenosine decomposed readily and were unsuitable for incorporation into oligodeoxynucleotides.

318

Organophosphorus Chem., 2006, 35, 304–354

Kool described the synthesis of the phosphoramidite derivative of a Cnucleoside incorporating a porphyrin moiety, (146).49 His approach was to assemble the porphyrin de novo on the sugar moiety starting from 3,5-bisO-toluoyl-protected deoxyribose-C1-carboxaldehyde, benzaldehyde and dipyrromethane under Lindsey conditions. Similarly, to ﬂuorescently label oligonucleotides, Burgess reported the synthesis of phosphoramidite (147), for which the nucleoside precursor was prepared from 5-ethynyl thymidine and iodoﬂuorescein via Sonogashira’s coupling procedure.50 AcO O O Ph

N NH DMTO

HN

O

O

AcO

NH

N

DMTO O

O

N

O

NC

NC

O

O

O P

O P

N

N

(146)

(147)

Methoxyoxalamido and succinimido precursors were used in conjunction with ETT as catalyst in the synthesis of the uridine phosphoramidites (148a) and (148b). Both compounds possess a biotin moiety linked via a long and uncharged tethering arm at the 2 0 -position.51 The 3 0 -O-lysophosphatidyl-2 0 nucleosides (149–152) were synthesized from the regioselective lipase-catalysed transacylation at the C1-hydroxyl of the glycerol moiety with activated palmitic acid ester in an organic solvent. The glycerol phosphate diester substrate was prepared from the protected nucleoside phosphoramidites and [(4S)-2,2dimethyl-1,3-dioxolan-4-yl]methanol.52 Shirokova reported the synthesis of uncharged 5 0 -aminocarbonyl and 5 0 -aminocarbonylmethylphosphonate derivatives of AZT and d4T, (153–162) and their activity in cell cultures infected with HIV-1. These compounds were prepared by treatment of the corresponding 5 0 -ethoxycarbonylphosphonyl nucleosides with primary amine followed by esteriﬁcation.53 Synthesis and cytotoxic activity of 1-dodecylthio-2-decyloxypropyl-3-phosphatidic acid conjugates of gemcitabine (163) and cytosine arabinoside (164) have been reported.54 These compounds were prepared by direct conjugation of 1-S-dodecyl-2-O-decylthioglycero-3-phosphatidic acid to the 5 0 -OH of the nucleosides in the presence of 2,4,6-triisopropylbenzenesulfonyl chloride in pyridine. Waldmann has developed a mild enzymatic deprotection method using penicillin G acylase for the synthesis of the nucleopeptides

319

Organophosphorus Chem., 2006, 35, 304–354

(165–168). This enzyme catalyses hydrolysis of the N-phenylacetoxybenzyloxycarbonyl group from the terminus amine.55 O N H

NH

HN

O O

O NC O

S HN NH

O P

O

H

N

H N

H

O

O

(148a)

O NH

DMTO O

N

O O

NC O HN

N H

O P O

N

O

O S

O

H HN NH

H

H N O

O

HO O

O O P O OH OH O O

O

O

B

(149) B= Ade (150) B= Gua (151) B= Thy (152) B= Cyt

(148b)

N

O

320

Organophosphorus Chem., 2006, 35, 304–354 O

R

N H

O

O

O R

P ONu

X (153) R= H; X= OCH2CH3; Nu= AZT (154) R= CH3; X= OCH2CH3; Nu= AZT (155) R= CH2CH2Ph; X= OCH2CH3; Nu= AZT (156) R= H; X= OCH2CH3; Nu= d4T (157) R= CH3; X= OCH2CH3; Nu= d4T (158) R= CH2CH2Ph; X= OCH2CH3; Nu= d4T

P

N H

X

ONu

(159) R= H; X= OCH2CH3; Nu= AZT (160) R= H X= OC6H11; Nu= AZT (161) R= CH3; X= OCH2CH3; Nu= AZT (162) R= H; X= OCH2CH3; Nu= d4T

NH2

NH2 N

OH C12H25S

O P O OC10H21 O

O

O P O OC10H21 O

C12H25S

O

N

N

OH

F

O

(163)

(164)

NH2

NH2 N

OH

O P O O AA

OH

OH

OH F

Ala

N

Ser

O

Ala

O P O O AA

Ser

O

N

N

OH O

N

O

1

AA2

OH

OH (165) AA= Val (166) AA= Phe

(167) AA2-AA1= Pro-Val (168) AA2-AA1= Ala-Phe

Perigaud reported the synthesis of the H-phosphonamidate of AZT (169). It was synthesized by the successive coupling of AZT to bis(diisopropylamino) chlorophosphine and in situ hydrolysis in the presence of tetrazole and water.56 Phosphorodiamides (170–179) have also been reported as prodrugs for antiviral nucleosides.57 These were prepared by quenching the reaction between phosphorus oxychloride and the nucleoside with an excess of amine in methanol or dioxane. O O

N H N P O O

NH O

N3 (169)

N

O

N P OR O (170) R= AZT (171) R= d4T (172) R= d2T (173) R= acyclovir (174) R= ara-A (175) R= ribo-A

O

O

321

Organophosphorus Chem., 2006, 35, 304–354 O

O

O

O N O N P O

O

O

NH

H

O

N P O O

O

N

O

NH

O

O

O

N

N3 (176)

Ph Ph Ph

(178)

O

Ph

Ph Ph

NH

NH O

N

NH

NH

Ph

N P O H O

O

Ph

N P O H O

O

O

N

O

N3 (179)

(177)

Meier reported two improved cycloSal-masking phosphate groups which once attached to the anti-HIV drug d4T (180a, 180b), possessed a reasonable chemical half-life and high cell selectivity, achieved TK-bypass and had no inhibitory effect on butyryl-cholinesterase.58 He also described the synthesis, hydrolytic properties and biological activities of 3-unmodiﬁed and 3-O-esteriﬁed cycloSal-5-[(E)-2-bromovinyl]-2-deoxyuridine derivatives (181a–f ), (182a–g) and (183a–g).59 Other analogues containing benzyl-substituted monophosphates of cycloSal-d4T (184a–g) were prepared and evaluated for their ability to release d4T selectively and were found surprisingly stable.60 Cyclosaligenyl-tiazofurin monophosphate (185) has also been synthesized and its biological activity as pronucleotide against human myologenous cell line has been conﬁrmed despite being four-fold less active than its nucleotide parent.61 However, it was also found to be A1 adenosine receptor agonist.

F

X

O NH

O Y

O O P O

(180a) X=Y= H (180b) X=Y=tBu

O

N

O

322

Organophosphorus Chem., 2006, 35, 304–354 (182a) X=3-Me; R=Ac (182b) X=3-Me; R=C2H5CO (182c) X=3-Me; R=i-C3H7CO (182d) X=3-Me; R=t-C4H9CO (182e) X=3-Me; R=C5H11CO (182f) X=3-Me; R=C10H21CO (182g) X=3-Me; R=Lev (183a) X=3-Me; R=Gly (+/-183b) X=3-Me; R=Ala (+/- 183c) X=3-Me; R=Val (+/- 183d) X=3-Me; R=Leu (+/- 183e) X=3-Me; R=Ile (+/- 183f) X=3-Me; R=Phe (+/- 183g) X=3-Me; R=Pro

O X

NH

O O O P O (181a) (181b) (181c) (181d) (181e) (181f)

O

N

O

OR X=5-Cl; R=H X=H; R=H X=5-OMe; R=H X=3-Me; R=H X=3,5-diMe; R=H X=3-tBu; R=H Y

O

R

CONH2

O O P O O

X

NH N

O

O O P O O

O

OR (184a) R= CH3, X=Y=H (184b) R= CH3, X=CH3; Y=H (184c) R= CH2Cl, X=Y=H (184d) R= CHCl2, X=Y=H (184e) R= CCl3, X=Y=H (184f) R= CH3, X=H; Y=Cl (184g) R= H, X=H; Y=Cl

S

N

O

OH OH (185)

Perigaud reported an extensive amount of work on the synthesis of phosphodiester and triester derivatives and their ability to act as pro-drugs. For instance, the S-acyl-2-thioethyl phosphoramidate diesters of AZT (186a–m) were prepared by a one-pot procedure via the hydrogenphosphonates, which underwent oxidative coupling with the corresponding amines.56 Similarly, he reported the synthesis, antiviral activity and stability study of phosphotriester derivatives of AZT bearing modiﬁed L-tyrosinyl residues where the carboxylate group of L-tyrosine has been replaced by an alcohol (187a,b) or an amide (187c–f) function.62 They were synthesized via the phosphoramidite AZT derivative and showed potent antiviral activity in particular against TK-deﬁcient cell lines. Mononucleoside SATE glucosyl phosphorothiolates (188a,b) were also found to be potent antiviral agents in TK-deﬁcient cell lines.63 O

But

S O

NH

O O HN P R' O n R COOCH3

O

N3

N

O

(186a) (186b) (186c) (186d) (186e) (186f) (186g) (186h) (186i) (186j)

n=1 R=H, R'= CH3 n=1 R=H, R'= H n=1 R=H, R'= CH2Ph n=1 R=H, R'= CH2PhOH n=1 R=H, R'= C2OTBDMSH n=1 R=H, R'= CH2OAc n=1 R=CH3, R'= H n=1 R=CH3, R'= CH3 n=2 R=H, R'= H n=3 R=H, R'= H

323

Organophosphorus Chem., 2006, 35, 304–354 O

But

S NH

O

O

O HN P O R

O

(186k) R=NHiPr (186l) R= pyrimidine (186m) R= CH2Ph

O

N

N3

O

But

S NH

O

O

O O P O

OH RNH

O

(187a) R=tBoc (187b) R=H

N3

O

But

S NH

O

O

R"2N

O

N

O O P O

O

O

(187c) R=H; R'=R"=tBoc (187d) R=Ac; R'=R"=tBoc (187e) R=R'=R"=H (187f) R=Ac; R'=R"=H

O

N

N3 RR'N

O

But

S O S P O

RO

O O OR OR

NH

O

O

O

N3

N

O

(188a) R=H (188b) R=Ac

OR

The syntheses of the 5 0 -hydrogenphosphonothioate derivatives of AZT, d4T and ddI (189a–i) have been reported.64 They were prepared through sequential one-pot reactions, i.e. coupling of triethylammonium phosphinate with diﬀerent alcohols in the presence of pivaloyl chloride, following oxidation with elemental sulfur and further condensation with the nucleoside analogues in the presence of pivaloyl chloride.

324

Organophosphorus Chem., 2006, 35, 304–354

NH

OR H P O S

O

O

O

O

H P O S

O

N

NH

OR O

N

OR H P O S

O

H N

N N

O

N

N3 (189a) R=hexadecanyl (189b) R= isopropyl (189c) R=cyclohexyl

(189g) R=hexadecanyl (189h) R= isopropyl (189i) R=cyclohexyl

(189d) R=hexadecanyl (189e) R= isopropyl (189f) R=cyclohexyl

Shaw reported the synthesis of P-tyrosinyl-(P-O)-5-P-nucleosidyl boranophosphates (190a,b) obtained in a one-pot synthetic procedure via a phosphoramidite65 and that of the nucleoside 30 ,5 0 -cyclic boranophosphorothioates (191a,b) prepared from a cyclophosphoramidite intermediate.66 The cyclophosphoramidite, obtained by heating the nucleoside with HMPA was transformed to the phosphite triester by reaction with 4-nitrophenol in the presence of 5-ethylthio-1H-tetrazole. The boranophosphite was oxidized with Li2S after boronation with BH3.SMe2. NH2

NH2

COOH

COOH

O

O NH

O -H3B P O O

O

N

O

F -H3B P O O

O

(190a)

O

O NH N

O S P O BH3(191a)

O

N

OH (190b)

N3

O

NH

O

F

O

NH O

N

O

O S P O BH3(191b)

3-Phosphonodiﬂuoromethylene analogues of nucleoside 3 0 -phosphates (192a–e) were synthesized from readily available ketones. Their syntheses involve addition of the lithium salt of diﬂuoromethylphosphonothioate. The beneﬁcial presence of the sulfur atom in this reagent translates into increased

325

Organophosphorus Chem., 2006, 35, 304–354

yields, reproducibilities, and ease of puriﬁcation.67 Wiemer reported the synthesis of the 5-amino-5-phosphonate analogues of uracyl, cytidine and cytosine arabinoside monophosphates, (193a–d).68 These were synthesized via the addition of phosphite to an imine intermediate. He also reported the synthesis of the alcohol analogues of cytidine and cytosine arabinoside (194a–d), prepared via phosphite addition or a Lewis acid mediated hydrophosphorylation of the appropriately protected 5 0 -nucleoside aldehydes.69 HO O

AcO

B

O (192a) B=Thy (192b) B=Ura (192c) B=Cyt

CF2 OH O P ONa ONa

CF2 OAc O P ONa ONa (192d) B=Ade (192e) B=N2-Ac-O6-(Ph2NCO)-Gua

NH2

O O

NH3+

O P O

NH O

O

O

N

NH3+

O P O

N O

(193b)

(193a)

NH2

NH2 NH3+

O P O

N O

O O

N

NH3+

O P O

N O

OH OH (193d)

(193c)

NH2

NH2

O P O

OH

N O

O

N

OH OH

O

O

N

OH OH

OH OH

O

B

N

OH OH (194a)

O O

O P O

OH

N O

N

OH OH (194b)

O

326

Organophosphorus Chem., 2006, 35, 304–354 NH2

NH2 O

OH

N

O P O

OH

O P O

O

N

O

O

N O

O

N OH

OH OH

OH

(194d)

(194c)

A procedure, which involved the highly b-stereoselective sialylation of the peracetylated sialic acid methyl ester with mercaptoalkyl- and mercaptoaryltrichloroacetate, followed by removal of the trichloroacetate protecting group and phosphitylation of the 5 0 -nucleoside phosphoramidites, was developed to prepare cytosine monophosphate-N-Ac-neuramic acid derivatives containing tethered alkanes and arenes (195a–d).70 Schmidt reported the asymmetric synthesis of the potent phosphoramidate a(2-6)sialyltransferase transition state analogue inhibitors, (196a,b). These were synthesized by condensation of cytidine phosphitamide with the non-racemic a-aminophosphonates, prepared by Mitsunobu azidation followed by Staudinger reduction of the corresponding chiral a-hydrophosphonates.71 The bisubstrate-type inhibitors of sialyltransferases, (197a–c), reported by Ito, have CMP-NeuAc and lactose moieties connected by an alkanedithiol linker.72 Sekine has furthered his work on phosmidosine by reporting the synthesis of chemically stabilized analogues (198a–c) and establishing phosmidosine’s structure-activity relationship.73

NH2

OH OH

HO

O

O

S n

O P O

N O O

O

N

COO-

AcN

OH OH

HO

(195a) n=1 (195b) n=2

NH2

OH O

OH

HO

O

O P O

S

N O O

N

COO-

AcN HO

OH OH (195c)

O

327

Organophosphorus Chem., 2006, 35, 304–354 NH2 OH N

O OH

HO

O P O

S

O

O O

COO-

AcN

O

N

OH OH

HO

(195d)

NH2

NH2 N

O NaO P NH

O O

PO3Na2

O

NaO P NH

O

N

N

O

O

PO3Na2 OH OH

NH2

OH

N

O O P O O

OH O

O

COO-

AcHN HO

OH OH

(196b)

(196a)

HO

N

N

O (197a) (197b) (197c) (197d) (197e)

OH OH

S [ ]n S

OH O

O

HO

OH

OH OH

O

OMe

OH

H2N NH OR H O

H N

O N P O N H O O OH OH (198a) R= Et (198b) R= iPr (198c) R= Bu

N N

n= 1 n= 2 n= 3 n= 4 n= 5

O

328

Organophosphorus Chem., 2006, 35, 304–354

2.1.3 Polynucleoside Phosphate Derivatives. Saigo has developed novel dialkyl(cyanomethyl)-ammonium tetraﬂuoroborate activators to be used in the diastereocontrolled cyclic-phosphoramidite-based syntheses of oligodeoxyribonucleoside phosphorothioates (Scheme 2).74 He further developed the stereocontrolled syntheses of such oligodeoxynucleotide derivatives by investigating the reaction conditions for the preparation of the 5 0 -TBDPS-thymidine-3-O-oxazaphospholidines (199) and proposed a mechanism for the diastereoselective formation of nucleoside 3-O-oxazaphospholidine derivatives on the basis of ab initio molecular orbital calculations.75 To achieve best selectivity in the synthesis of thymidyl(5-3)thymidine phosphorothioate, Sekine developed new thymidine 3phosphoramidite building blocks having a covalent linker between the trityl type 5 0 -hydroxyl protecting group and the phosphorus atom attached to the 3 0 hydroxyl group of thymidine (Scheme 3). The ring structures were designed to reduce the conformational freedom around the phosphorus center (200a–c). The cyclic phosphoramidite gave preferentially the Rp diastereoisomer. This stereoselectivity was achieved without any chiral sources other than the 2-deoxyribose moiety itself.76 Stawinski’s approach to achieve diastereoselectivity was based on intramolecular nucleophilic catalysis. To this end, he developed the thiophosphorylating reagent (201), prepared by condensation of 9-ﬂuorenemethyl phosphonate with 4-methoxy-2-pyridinemethanol 1-oxide followed by in situ sulfurisation with elemental sulfur. Compound (201) was then coupled to a 5 0 protected thymidine in the presence of 2-chloro-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphinane (Scheme 4) and subsequent removal of the Fmoc group yielded (202) which was then coupled to a 3 0 -protected thymidine using the same coupling reagent.77 Vigroux reported the synthesis of a diastereopure dinucleotide (203) O

OH

NH

N TBDPSO

3'-TBDMS-Thy

O

N

O

TBDPSO

N

O

O

activators:

O

NC

O P*

R2

CN

+

N H

O * P

CH3HN

CN

N * *

R1

N+

O

H HBF4−

HBF4–

+

N

R2

H

HBF4−

* * R1

O

NH O O

(199)

N

OTBDMS phosphoramidites:

O

OR

OR

OR

P*

P*

P*

N

O

* * Ph

O

N

O

* *

* * Ph

N

OR

Ph Scheme 2

P* N * *

Ph

Ph

O

329

Organophosphorus Chem., 2006, 35, 304–354 MeO MeO O O MeO

MeO

NH

O O

tetrazole type activators O O

2. (Et 2 NC(S)S-)2

O

S O

O

1. 3'-TBDMS-Thy

O

N

NH

O

O

O O

O

N

O

S O

P

P S

NH

O

N

O

O

N

(200a) MeO

OTBDMS

O MeO

NH

O O

O

N

O O

S O R R

O

P N

(200b) R = H (200c) R = Me

Scheme 3

O O OMe

N

S O P O O

NH

TBDPSO 3'-TBDMS-Thy

O

N

(201)

N

O

O

O

N

1. 5'-TBDMS-Thy 2. TEA-PhSH

OMe

O

NH

TBDPSO

O S

O NH

P S O P O O

O

O O

N

OTBDMS

O (202)

Scheme 4

O

330

Organophosphorus Chem., 2006, 35, 304–354

incorporating a 1,3,2-dioxaphosphorinane linkage in which two out of the six torsion angles of the natural phosphodiester backbone have been constrained.78 O NH HO O

O

N

O O PR O O

NH O

S

N

O

O

O

NH

DMTO

O

O

O

N

O

O

O

OH

NH

P S N

O

N

O

O

(203)

NH

DMTO

N

NH

P S O

O O

N

ODMT (204a)

O

O

N

O

ODMT (204b)

Stromberg has reported a detailed kinetic study of the pivaloyl chloridepromoted nucleoside H-phosphonate condensation step with a suitably protected nucleoside in the presence of differently substituted pyridines.79 He also investigated the stability of H-phosphonate nucleosidic dimers under various organic and aqueous basic conditions. Strong bases such as DBU and ﬂuoride ions cleaved the dinucleoside H-phosphonates rapidly, as also did a combination of protic solvent and a base.80 The base-promoted reaction of a suitably protected dithymidine Hphosphonothioate with N-methoxypyridinium tosylate in acetonitrile or with trityl chloride yielded the dithymidine analogues incorporating a 2-pyridyl or a 4-pyridyl moiety directly attached to the phosphorus center, (204a–b), after treatment with iodine.81 Stawinski also described the synthesis of the arylphosphonates (204c,d) possessing metal complexing properties and prepared by palladium-catalysed coupling reaction between the bromopyridine derivatives and the dithymidine H-phosphonate precursor.82 Nawrot reported the diastereoselective synthesis from the H-phosphonate dimer of the parent dinucleoside pyridinyl-phosphonates (205a–c) for use in oligonucleotide synthesis.83 Meier used similar chemistry to synthesize a phthalidyl-phosphonate thymidine-thymidine dimer (206) and established its absolute P-conﬁguration.84 Saigo reported the use of the BH3 group as an effective protecting group for phosphonic acid diesters. Starting from the dithymidine boranophosphate diester derivative, the dithymidine H-phosphonate was obtained by removal of the BH3 group in the presence of triarylmethyl cations.85 He also described the synthesis of compounds (207a–d) which were obtained from the appropriately protected nucleobases after condensation with dialkylboranophosphate in the presence of N,N 0 -bis-(2-oxo-3oxazolidinyl) phosphinyl chloride, 3-nitro-1,2,4-triazole and Hunig’s base.86

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Organophosphorus Chem., 2006, 35, 304–354

O

O NH

DMTO O

O

N

N

O

O

O

O NH

P S O O

N

O

O

N

NH

P S

N

O

ODMT

(204d)

O

O

O

O NH

NH

DMTO

O

N

O

N

O

NH

O

O O

O N

N

O

N

NH

P S

N

NH

P S O

O O

O

N

O

CN

P O

O

N

O

O O

P S

NH

DMTO

O

N

O O

O

N

ODMT

(204c)

DMTO

O

N

O

N N

NH

DMTO

N

O

O

N

O

CN

P O

P O

N CN

(205b) Sp and Rp

(205a) Sp and Rp

(205c) Sp and Rp

O NH

DMTO O

HO

O

N

O

B

O

O

O

O

NH

P S O

O

O O

(206)

N

OTBDPS

O

BH3

P

O

NH

O O

OH

N

O

(207a) (207b) (207c) (207d)

B= Ade B= Gua B= Thy B= Cyt

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Organophosphorus Chem., 2006, 35, 304–354

Ora reported kinetic and mechanistic studies on hydrolytic reactions of di-ribonucleoside 3 0 ,5 0 -(3 0 -N-phosphoramidates) and 3 0 ,5 0 -(3 0 -N-thiophosphoramidates).87,88 Sequential esteriﬁcation of diphenylphosphite with 5 0 -O-DMT-thymidine and hydrogen sulﬁde yielded the H-thiophosphonate derivative of thymidine which was subsequently condensed with AZT or d4T in the presence of diphenyl chlorophosphate and offered compounds (208a–f) as new anti HIV-prodrugs after treatment with L-amino acid methyl esters.89 Nawrot described the synthesis of the dinucleoside (N3 0 -MeP5 0 )-methanephosphonamidates (209a,b) starting from the appropriately protected amino-nucleobase and either dichloromethylphosphine or dichloromethanephosphonate.90

HO

DMTO O

T

R

O S

O

P O

N H

C H O

COOCH3 T

(208a) (208b) (208c) (208d) (208e) (208f)

R= H R= CH3 R= CH2Ph R= CH(CH3)2 R= CH2CH(CH3)2 R= CH(CH3)CH2CH3

B

NH P

O

(209a) B= Thy (209b) B= Cyt

O O

B

OTBDMS

Mickelﬁeld reported a new route to prepare sulfamide- (210a) and 3 0 -Nsulfamate- (210b) modiﬁed dinucleosides.91 For this synthetic approach, the 4-nitrophenyl 3 0 - or 5 0 -sulfamates, prepared from 4-phenyl chlorosulfate, were coupled with alcohol and amine functionalities of other nucleosides. Benner reported the synthesis of two bis-methylene sulfone dinucleoside derivatives, (211a) and (211b).92 These were synthesized from 3 0 -carboxaldehyde nucleoside starting materials, which after reduction to the corresponding alcohols, were thioacetylated under Mitsunobu conditions and hydrolysed to the corresponding thiols. These were then reacted with the 5 0 -monohalogenated thymidine and oxidized with Oxones. The synthesis of thymidine dimers (212) in which the natural phosphodiester linkage has been replaced by a 2,5disubstituted tetrazole ring has been described by Pedersen93 while Vanek reported the synthesis of nucleotide analogues and the related dimers (213a,b), mimics of the a- and b-D-2 0 -deoxyadenosine 3 0 -phosphate, containing a pyrrolidine ring instead of the sugar unit.94 Cyclic dinucleotides (214a–d), containing a butylene nucleobase-phosphotriester connection, synthesized by a tandem ring-closing metathesis and hydrogenation reaction, have been reported by Nielsen.95,96 However, these cyclic dinucleotides are not compatible with standard solid phase oligonucleotide synthesis as they are reactive towards bases.

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Organophosphorus Chem., 2006, 35, 304–354

DMTO DMTO O

DMTO

T

O T

O NH O

NH

S O NH

O

S O

O

S O O

O T

O O

B

T

N P O

T

O

DMTO

OTBDMS

(210a)

NC

(210b)

DMTO

(211a) B= Thy (211b) B= Ade

HO

HO O

T

A

O

A

N N N N N O

O O HO P

HO P O

T

A

O

N

O

N

A

P O O

OTr

HO

NC

(213b)

(213a)

(212) HO

HO T O

O

T

O O O

O

O O

N

P O

N

O

O

OH

O

O

N

P O

N

O

O

R

(214a) R=OH (214b) R= H

OH

R

(214c) R=OH (214d) R= H

Kool reported the synthesis of macrocyclic nucleotide-hybrid compounds (215a–h), putative inhibitors of the HCV polymerase, polymerase C NS5B. The compounds were prepared by solid phase synthesis on controlled pore glass.97

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Organophosphorus Chem., 2006, 35, 304–354

Clivio described the synthesis of an oligonucleotide building block containing a syn-cis thymine cyclobutane dimer photoproduct (216)98 and that of the phosphoramidite (217), and the thio analogue at the 5,6-dihydropyrimidine C5 position of the thymidyl(3 0 -5 0 )thymidine (6–4) photoproduct (218).99 HO

O P

R

(215a) B=B'=H; R=R'= H (215b) B=U; B'=T; R= OMe; R'=H (215c) B=T; B'=U; R= H; R'=OMe (215d) B=C; B'=C; R= OMe; R'=OMe (215e) B=C; B'=U; R= OMe; R'=OMe (215f) B=C; B'=G; R = OMe; R'=OMe (215g) B=C; B'=A; R= OMe; R'=OMe (215h) B=H; B'=C; R= H; R'=OMe

B'

O

O

O

O R' O P HO O

B

O HN

O

O

O

HN

SSCH3

LevO

NH

O

N N

LevO O NC

O

N O

N

O

O O P H3C O O

O O P O O

O

O

P O

N

O

CN

O

P O

N

(216)

N

CN

(217) O HN S

LevO O

O

N

O P -O O O

NH N

O

O

OH (218)

3

Nucleoside Polyphosphates

3.1 Polyphosphorylated Nucleosides. – The ﬁrst C-nucleotide analogue (219) to be reported as displaying P2Y1-receptor antagonist activity and being stable

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Organophosphorus Chem., 2006, 35, 304–354

in vivo has been synthesized by Bourguignon. This compound is a C-nucleoside pyrazolo[1,5-a]-1,3,5-triazine 3 0 ,5 0 -bisphosphate and its synthesis involved, amongst the crucial steps, a regio- and stereo-speciﬁc palladium-mediated coupling reaction of the unprotected glycal 1,4 anhydro-2-deoxy D-erythropent-1-enitol and the 8-iodo-2-methyl-4-(N-methyl-N-phenylamino)-pyrazolo[1,5-a]-1,3,5-triazine.100 Similarly, Jacobson reported the preparation of P2Y1-receptor antagonists with enhanced potency, which incorporated substitution at the 2-position of the adenine ring of the parent nucleotide and contained a bicyclo[3.1.0]hexane ring system locked in a northern conformation, (220a–j).101 Two cyclic nucleotide analogues of adenosine diphosphate, (221a–b), thought to be putative P2Y1 antagonists, were reported by Shibuya and incorporated an isosteric diﬂuoromethylene phosphonyl group.102 CH3NH

CH3NH

N

N

N

N (HO)2(O)PO

(220a) R= F (220b) R= Br (220c) R= I (220d) R= CH3 (220e) R= C6H11 (220f) R= 1-C6H9 (220g) R= 1-C6H7 (220h) R= SCH3

R

N

N N

N

(HO)2(O)PO

O

OP(O)(OH)2

OP(O)(OH)2 (219) H2N N R

N N N

(HO)2(O)PO

(220i) R= I (220j) R= SCH3

OP(O)(OH)2 CH3NH

CH3NH

N

N N

N N

(HO)2(O)PO

N

CF2P(O)(OH)2 (221a)

N

(HO)2(O)PO

N

CF2P(O)(OH)2 (221b)

Potter described the synthesis and Ca21-mobilizing activities of purinemodiﬁed mimics of adenophostin A incorporating modiﬁcations at the C-6

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Organophosphorus Chem., 2006, 35, 304–354

and C-2 of adenine, (222a–g).103 These compounds were synthesized via a + convergent route involving a modiﬁed Vo´rbruggen condensation of either 6-chloropurine or 2,6-dichloropurine with a protected disaccharide. R N N N

HO O

N

O

O

(222a) R= OMe (222b) R= BNHcyclopentyl (222c) R= NHMe (222d) R= NMe2 (222e) R= NHC6H11 (222f) R= NH-(3-noradamantantyl)

OPO(OH)2

HO (HO)2OPO

OH OPO(OH)2

MeHN N OMe

N N

HO O

O

O

N

(222g)

OPO(OH)2

HO (HO)2OPO

OH OPO(OH)2

3.2 Nucleoside Pyrophosphates. – The reaction of ADP (disodium salt) with amino acid methyl esters mediated by trimethylsilyl chloride in pyridine produced adenosine 5 0 -phosphoramidates. This reaction was regiospecific, with the nucleophilic attack of the amino acid methyl esters only occurring on the aphosphorus of ADP after silylation of all oxyanions.104 Scott reported the onepot synthesis of the isoprenoid conjugates (223a–c). These were obtained by nucleophilic displacement reactions of either isoprenyl chlorides or isopentenyl tosylate with nucleoside diphosphates.105 Bertozzi described the synthesis of a bisubstrate analogue (224), targeting estrogen sulfotransferase.106 This synthesis required the use of an orthogonally-protected 3 0 -phosphoradenosine 5 0 phosphate derivative, allowing for the selective functionalisation of the 5 0 -phosphate with the sulfate acceptor mimic. The 2 0 - and 3 0 -deuteriocytidine 5 0 -diphosphates (225a,b) were synthesized from 5 0 -MMT-3 0 -OTBDMS and 2 0 ,5 0 -O-diTBDMS cytidine derivatives, respectively, by oxidation followed by acidic removal of the 5 0 -protecting group, reduction with NaBD(OAc)3 and ﬁnally displacement of a tosyl group by pyrophosphate.107

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Organophosphorus Chem., 2006, 35, 304–354

O

O

R O P O P O OH

O

B

OH OH OH

(223a) B= Gua, R= (223b) B= Ade, R= (223c) B= Gua, R=

NH2 H

N O

H H

O P O P O

O

OH

N

O O

N

N

OH O OH

(224)

HO P O OH

NH2 O

O

N

HO P O P OH

NH2

O

OH

O

N

O O

O

HO P O P OH

OH

N O O

D

O

N D

OH OH (225a)

OH OH (225b)

Based on his study of hydrolytic reactions of diadenosine 5 0 ,5 0 -triphosphate, Mikkola reported that Ap3A was very resistant towards nucleophilic attack and that efﬁcient hydrolysis was only observed under acidic conditions.108 Stec described the synthesis of novel diadenosine polyphosphate analogues (226a–d) as putative inhibitors of ADP-triggered blood platelet aggregation. The most active compounds incorporated a sulfur atom replacing one or both nonbridging oxygens of the phosphorus bound to the adenosyl residues or with hydroxymethyl groups on the bis(hydroxymethyl)phosphinic acid moiety.109 Pyrophosphonate analogues, the diaryl dinucleoside phosphonate-phosphate derivatives (227a–c), were synthesised by reacting arylnucleoside H-phosphonates and aryl nucleoside P-acylphosphonates generated in situ from

338

Organophosphorus Chem., 2006, 35, 304–354

appropriate H-phosphonate and acylphosphonate monoester precursors, in the presence of a tertiary amine.110 The syntheses of the polyphosphates (228a–h), linked by a 5 0 -5 0 phosphate bridge and composed of modiﬁed 7-methylguanosine and guanosine, have been reported. These compounds were designed as tools for studying the mechanism of protein translation.111 Franchetti reported the synthesis of two dinucleoside polyphosphate NAD analogues (229a–b), as putative NMN adenylyltransferase inhibitors. These were synthesised by coupling ATP (as a sodium salt) with nicotinamide riboside monophosphate imidazolide.112 The synthesis of mycophenolic adenine biphosphonates, (230a,b), analogues of mycophenolic adenine dinucleotide, has been described by Pankiewicz.113 These were prepared by diisopropylcarbodiimide coupling of 2 0 ,3 0 -O-isopropylideneadenosine 5 0 -methylenebisphosphonate with mycophenolic alcohols. OH OH

NH2 N S

N N

N

O

N

N

S

O

O P O C P C O H2 H X OH 2

P O

O

N

N

X

H2N OH OH (226a) X= SH (226b) X= OH

OH OH

NH2 N S

N N

N

O

N

OH

O P O C C O H2 H SH

N

S C P O H2 SH

O

N

N

H2N (226c)

OH OH

OH OH

NH2 N S

N N

N N

O

O P O C C N H2 H2 H OH

C P O H2 OH

O

N

H2N (226d)

N

S

OH OH

N

339

Organophosphorus Chem., 2006, 35, 304–354 X

O

O O

T

O

P

O

P

CH

T

O O

O-

O-

R

X

(227a) X= OH, R= tBu (227b) X= N3, R= tBu (227c) X= N3, R= Ph X Y

O N

H2N

O

N

N

O

N

+

OH

N O

CH3

NH

O

O

O P O

P O

n

P O

O

N

N

OH

OH

OH OH (228a) X= OH; Y= OMe; n=1 (228b) X= OH; Y= H; n=1 (228c) X= H; Y= OMe; n=1 (228d) X= OMe; Y= OH; n=1 (228e) X= OH; Y= OMe; n=2 (228f) X= OMe; Y= OH; n=1 (228g) X= H; Y= OH; n=2 (228h) X= OH; Y= OMe; n=3

X Y

O N O

N

+

O

NH2

O P O OH

P O OH

N

O

O n

P O

O

N

N

OH

CONH2

OH OH (229a) n=1 (229b) n=2 NH2 N

O

O P OH

O

C H2

P O

O

N

OH

N (230a)

OMe CH3

N

O

O

OH

OH OH

340

Organophosphorus Chem., 2006, 35, 304–354

Klaﬀke developed a scaleable three step synthetic method to prepare uridine diphospho-D-xylose and UDP-L-arabinose from D-xylal and L-arabinal respectively and UDP.114 The synthesis of ADP- L-glycero- and D-glyceroD-manno-heptopyranoses (231a,b) and of GDP- D-glycero-D-mannoheptopyranose (231c) has been reported by Kosma.115,116 The a-anomers of the heptosyl phosphates were obtained using the phosphoramidite procedure, whereas the b-phosphates were formed by reacting diphenyl phosphorochloridate with the reducing heptoses. Schmidt reported the UDP-glycal derivatives (232a–d) as transition state analogues, inhibitors of UDP-GlcNAc 2-epimerase.117 He also described the synthesis of UDP-C-glycosidic derivatives of 2-acetamidoglucal (232e) and of ketosides (232f–g). Three O-methylated UDPGalNAc analogues (233a–c) have been synthesised from appropriate 3,6-dipivaloyl GlcNAc derivatives.118 N-acylated UDP-GalNAc derivatives (234a–c) have been synthesised using Khorona’s morpholidate coupling method, starting from D-galactosaminyl-1-phosphate after selective N-acylation of its amino group with appropriate N-acetyloxysuccinimides.119 Rice reported the synthesis of 5 0 -(2,3,4-tri-O-acetyl-6-S-acetyl-6-thio-a-D-galactopyranosyl-uridine diphosphates (235)120 while Palcic described the synthesis of GDP-5-thiosugars (236a–b) and their use as substrates for glycosyltransferases.121 NH2 N O P OH

O

N

O

O

OH

O

C H2

P O

O

N

N

OH

(230b)

OMe OH OH

CH3

NH2 N

OH O

HO

O P

N

O

O O

P O

O

N

N

OH

OH

(231a)

OH

HO

OH OH

OH

NH2 OH HO

O

N O P OH

O

P O

O

N

OH

OH

HO OH

N

O

O

OH OH

N

(231b)

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Organophosphorus Chem., 2006, 35, 304–354

OH N

OH HO

O P

O

N

O

O O

P O

O

N

N

NH2

OH

OH OH

HO

OH OH

OH

O

HO

P

O

O

z OH

(232a) (232b) (232c) (232d)

W

P O

O

N

O

OH

OH

Y

NH

O

O

X OH OH

W=Y= OH, X=Z= H X=Y= OH; W=Z= H W=Z= OH; X=Y= H W=NHAc, Y=OH; X=Z= H

O

HO

O

P

NH

O

O O

P O

O

N

O

OH

OH NHAc

HO

OH OH

OH (232e)

O

HO

O

P OH OMe NHAc

HO

NH

O

O O

P O

O

N

OH OH OH

OH (232f)

O

(231c)

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Organophosphorus Chem., 2006, 35, 304–354

O OH HO

O

P

O

OH

P O

O

N

O

OH

OH OMe NHAc

HO

NH

O

O

(232g)

OH OH

O

R"O

O

O P

NH

O

O O

P O

O

O

N

OH

OH NHAc

R'O

OH OH

OR (233a) R=CH3, R'=R"= H (233b) R=R"= H; R'=CH3 (233c) R=R'= H; R"= CH3

O

HO

O

O P

NH

O

O O

P O

O

N

O

OH

OH NHR

HO

OH OH

OH (234a) R=COCH2CH3 (234b) R=COCH2CH2CH3 (234c) R=COCH2Br

O

AcS

O

O P OH

NH

O

O O

P O

O

N

OH

OAc

AcO

OH OH

OAc (235)

O

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Organophosphorus Chem., 2006, 35, 304–354 O

S

HO

NH

O

O O P

O

P O

O

O

N

OH

OH OH

HO

OH OH

OH (236a)

Inhibition properties and the syntheses of a conformationally restricted probe for the mutase-catalysed UDP-galactose/furanose interconversion (237a) and of a C-glycoside derivative of UDP-Galf (237b) have been reported by Sinay.122,123 O

O P

S

NH

O

O O

P O

O

O

N

OH

OH OH

HO

OH OH

OH (236b)

O

HO

P

O

O

HO

P O

O

O

N

OH

OH

HO

NH

O

O

OH

OH OH

(237a)

To establish the SAR analysis of adenosine diphosphates (hydroxymethyl)pyrrolidinediol inhibition of poly(ADP-ribose) glycohydrolase, Jacobson has synthesised a series of guanosine- and adenosine-modiﬁed pyrrolidinediol pyrophosphates (238a–j).124 O

O O

P OH

NH

O

O

OH

O

P O

O

N

OH

OH OH OH

OH (237b)

O

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Organophosphorus Chem., 2006, 35, 304–354

Much synthetic work has been reported by various groups on cyclic adenosine diphosphate ribose. Potter described the synthesis and biological evaluation of a series of 8-substituted analogues (239a–d) of cyclic ADP-carbocyclic ribose,125 a stable mimic of cADPR, and also the ﬁrst enzymatic synthesis of the N1-cyclic cADPR analogue (240) incorporating a hypoxanthine partial structure.126 Another type of cADPR mimic, (241), incorporating a pyranose and a pyrimidine residue, was reported by Piccialli and was synthesized by a chemical strategy employing a Mitsunobu reaction for the condensation of the glucosyl moiety on the protected uridine and a Matsuda procedure for the cyclisation.127 A similar cyclisation procedure was used by the same laboratory to prepare the N1-pentyl analogue of cyclic inosine diphosphate ribose, (242).128 R'

R

Y N O

N H

O

O P O P O OH

N

z O

N

N

X

OH OH OH

(238a) X=Z=H; Y= NH2; R=R'= OH (238b) X=Z=H; Y= NH2; R= OH; R'= H (238c) X=Z= H; Y= NH2; R=R'= H (238d) X= H; Y= NH2; Z=N3; R=R'= OH (238e) X= N3; Y= NH2; Z=H; R=R'= OH (238f) X= H; Y= NH2; Z=NH(CH2)6NH2; R=R'= OH (238g) X= H; Y= NH2; Z=NH(CH2)6NHCOCF3; R=R'= OH (238h) X= H; Y= NH2; Z=S-C6H5-pCl; R=R'= OH (238i) X= H; Y= NHCH2C6H5; Z=H; R=R'= OH (238j) X= H; Y= NH(CH2)5-CH3; Z=H; R=R'= OH

HO

HO

OH O

O O P O O P O HO

OH

O

N

+

N O

NH2

O P O O P O

N

HO

N

O

O N N O

N N Br

X OH OH

OH OH (239a) (239b) (239c) (239d)

O

X=Cl X= N3 X= NH2 X= SPh

(240)

345

Organophosphorus Chem., 2006, 35, 304–354

A synthetic method for the synthesis of 8-vinyl adenosine 5 0 -di and triphosphate (243a–b) has been developed. This procedure eliminates unwanted depurination side-reactions under acidic conditions by introduction of acetyl protecting groups at the 2 0 and 3 0 positions of adenosine. The di- and triphosphate esters were obtained by treatment of the adenylic acid with phosphate and pyrophosphate anions.129 6,6-Bicyclic pyrimidopyridazin-7-one nucleoside triphosphate (244) was synthesized by nucleophilic ring-opening and rearrangement of a furanopyridine nucleoside in the presence of anhydrous hydrazine.130 HO

OH

O

O

OH O

O P O O P O HO

N

O

O

O

O P O O P O HO

N

O

N

O

N

O N

N

O

OH OH

OH OH

(242)

(241)

Borowski reported the synthesis of so called ‘‘fat’’ or ring expanded nucleoside triphosphates (245a,b) and evaluated these compounds and others previously synthesized in his laboratory against Flaviviridae NTPases and helicases.131 2Deoxycytidine nucleoside triphosphates, (246a–c), bearing amino and thiol groups appended to the 5-position of the nucleobase have been chemically synthesized and enzymatically incorporated into oligodeoxynucleotides.132 Kulikowski reported the synthesis of thiated analogues of 2 0 ,3 0 -dideoxy-3 0 ﬂuorothimidine triphosphate, (247a–c). O HO P OH O P O HO

O

N N n

O

OH OH (243a) n=1 (243b) n=2

NH2 N

N

HO P O HO

O

H N

O n

O

N

OH OH (244) n=3

N N

346

Organophosphorus Chem., 2006, 35, 304–354 O

H2N

HO P OH O P O

O N

N

NH2 N

HN

HO

O

n

N

O

O

H N

HO P OH O P O

HN

NH N

O

HO

O

OH OH

n

N

O

OH OH

(245a) n=2

(245b) n=2

The nucleoside 5 0 -monophosphate was prepared by regioselective enzymatic phosphorylation of a nucleoside employing wheat shoot phosphotransferase while the triphosphates were obtained by a modiﬁcation of the Ludwig procedure employing direct phosphorylation with POCl3 and a tri-N-butylamine/bis-tri-Nbutylammonium pyrophosphate mixture.133 Shaw used the synthetic procedure well-established in her laboratory to achieve the synthesis of the Rp-stereoisomers of 5 0 -(a-P-borano)triphosphates of 2 0 -deoxycytidine and 2 0 ,3 0 -dideoxycytidine, (248a) and (248b) respectively, and examined their incorporation into oligonucleotides by MMLV reverse transcriptase and Taq DNA polymerase.134 She also reported the synthesis of an acyclonucleoside-(a-P-borano)triphosphate, (249), achieved via a phosphoramidite approach in a one-pot reaction. This compound was effectively incorporated by the MMLV retroviral reverse transcriptase.135 Mikhailopulo used an enzymatic procedure to synthesize adenosine-5 0 -O-(1thiotriphosphate), (250),136 while Huang used the chemical approach based on the chemical synthesis of 5 0 -(a-P-thio)triphosphates to prepare nucleoside triphosphate analogues containing a-non-bridging selenium, (251).137 Non-natural azole carboxamide nucleoside triphosphates (252a–c) have been synthesized as alternative substrates for DNA and RNA polymerases. Tosylate intermediates were employed to introduce the diphosphate ester which was subsequently enzymatically converted to the triphosphate ester as the conventional nucleoside triphosphate synthetic methods failed for non-purine and non-pyrimidine nucleosides.138 A series of non-natural b-C-nucleoside triphosphates, (253a–e), bearing an aromatic nucleobase with phenolic hydroxy groups, has been synthesized by Shionoya and evaluated as inhibitors against DNA polymerase.139 NH2

R

N

O HO

P O

X

n

O

N

NH

O

O

OH

HO

P O

n

O

N

Y

OH

OH (246a) n=3; R= NHCOCF3 (246b) n=3; R= SSC(CH3)3 (246c) n=3; R= NH2

F (247a) n=3; X=S; Y=O (247b) n=3; X=S; Y=S (247c) n=3; X=O; Y=S

347

Organophosphorus Chem., 2006, 35, 304–354

OH HO P O O O -H3B P

NH2

n

N

O

N

O

O

OH HO P O O O -H3B P

O

n

NH

O

N

O

O

R (248a) n= 2; R= OH (248b) n= 2; R= H

(249) n = 2

OH

O HO P OH O P S HO

N

NH2

n

N

O

HO P O O O P -Se

N

O

NH

O

N

O

n

N

O

O OH

OH OH (250) n=2

(251) n= 2

O

O

HO P OH O P O

HO P OH O P O

HO

O

CONH2

n

N O

OH OH (252a) n=2

N N

HO

O

n

N O

CONH2

N N

OH OH (252b) n=2

Burgess reported the synthesis of a set of energy transfer dye-labeled nucleoside triphosphates (254a–f). To achieve this synthesis, the coupling of the dye to the nucleosidic moiety had to be performed after formation of the triphosphate esters.140

348

Organophosphorus Chem., 2006, 35, 304–354 OH

O HO P OH O P O HO

HO P O O O HO P

n

CONH2

N

O

O

N N

O

n

Ar

O

OH

OH OH (252c) n=2

(253a) n= 2; Ar= (253b) n= 2; Ar=

OH HO OH

(253c) n= 2; Ar= OH

(253d) n= 2; Ar=

OH

(253e) n= 2; Ar=

O

O

O

O COOH

HO

COOH

HO

OH HO P O O O HO P

O

n

OH NH

O

O

N O

X

HO P O O O P HO

O

n

NH

O

O

N O

(254a) X= H (254b) X= OH X

(254c) X= H (254d) X= OH

349

Organophosphorus Chem., 2006, 35, 304–354 O O COOH

HO

OH HO P O O O HO P

O

n

NH

O

O

N O

(254e) X= H (254f) X= OH

X

References 1. 2. 3. 4. 5. 6. 7. 8.

9. 10. 11. 12. 13. 14. 15. 16. 17.

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6 Ylides and Related Species BY NEIL BRICKLEBANK

1

Introduction

The Wittig reaction and its derivatives continue to find application in the synthesis of a diverse range of molecules. However, the aim of this chapter is to provide an overview of the literature published between July 2001 and June 2002 that concentrates on the chemistry of the organophosphorus reagents themselves, and so coverage of their synthetic applications is limited to a number of pertinent, illustrative examples. Selected highlights from this period include the first structurally authenticated oxaphosphetane that does not contain fluorine-bearing or bicyclic groups at either the phosphorus atom or at the 4-position of the oxaphosphetane ring. So-called ‘green synthesis’ remains a topical area for the chemical community at large and a recent paper reports the solid-state synthesis of ylides, and their use in Wittig reactions, achieved through a ball-milling process. Also, salt-free Wittig olefinations have been achieved using that ubiquitous species Wilkinson’s catalyst [Rh(PPh3)3C1].These developments are discussed in greater detail below.

2

Phosphonium Ylides

2.1 Mechanistic and Theoretical Studies of Phosphonium Ylides and the Wittig Reaction. - The physico-chemical nature of the P-C bond in phosphonium ylides is complex and, despite intensive research over many years, remains the subject of dispute! Numerous theoretical studies of this problem have appeared in the scientific literature. A recent contribution to this area by Mitrasinovic uses sharing indices and sharing amplitudes to study P-C bonds in a number of triand penta-valent phosphorus species. Sharing indices and amplitudes are quantitative, orbital dependent, measurements of the degree to which an electron, as a wave, is shared between two spatial points in a many electron system. Ylides studied using this method include (l),(2) and (3).’t2 Phosphorus-3 1and 13CNMR, together with X-ray crystallography, have been utilised by Naya and Nitta to study the structural nature of ylides (4a-d). Previous crystallographic studies had concluded that (4c) and (4d) do not contain formal P-0 bonds but that appreciable coordinative interaction exists Organophosphorus Chemistry, Volume 34

0The Royal Society of Chemistry, 2005 316

6: Hides and Related Species H\ H-P H

317

/H

=C,

H (1)

F\ F-P=C I F

/H

H, H-P H

\

H

(2)

/H

=C,

F

(3)

between the phosphorus and oxygen atoms, and that three canonical forms (5), (6) and (7) contribute to the overall resonance hybrid (8).These results show that in the solid state, the contribution to the resonance hybrid from the oxaphosphole structure (5) decreases in the order (4b) > (4c) > (4a) > (4d).The presence of the electron-donating methyl group in (4b) results in a greater contribution from resonance structure (5) in this derivative. In contrast, the electron-withdrawing nitrile group helps to stabilise ylides and so canonical form (7) predominates in (4d). As the P - 0 bonding character increases, so there is a shift in the geometry around the phosphorus atom from tetrahedral to trigonal bipyramidal coordination. Moreover, a linear correlation between 31Pchemical shifts and P-0 bond lengths was ~ b s e r v e d . ~

R (8)

The presence of 2-fury1 substituents on the ylide-phosphorus atom can improve the (2)-selectivity of Wittig reactions. This is a major conclusion of a study by Berger and coworkers who followed the Wittig reactions of 2-fury1substituted ethylphosphonium ylides (9) by NMR. The results showed that the fury1 groups help to stabilise the observed 1,2h5-oxaphosphetane intermediates. Indeed, tris(2-furyl) derivative (9c) was so stable that these workers were able to grow single crystals of the intermediate and determine its structure crystallographically, this representing the first example of an oxaphosphetane structure that does not contain fluorine-bearing or bicyclic groups at either the phosphorus atom or at the 4-position of the oxaphosphetane ring. The phosphorus atom of (9c) has a slightly distorted trigonal bipyramidal geometry with a P - 0 bond length of 1.78A, which is amongst the shortest oxaphosphetane P-0 bonds." Other reports of substituent effects upon the outcome of Wittig olefinations include an experimental study on the stereoselectivity of the reaction between ortho-halo-substituted benzaldehydes and benzylidenetriphenylphosphoranes (10);the results show that one ortho-halogen on each of the reactants increases the (2)-selectivity, whereas two ortho-halogens on the same reactant gave high (E)-selectivity. The observed stereoselectivity was rationalised in terms of the relative stabilities of the oxaphosphetane intermediates.' An ab initio investiga-

318

Organophosphorus Chemistry

tion (at HF 6-31G* and MP2/6-31G* levels) of the Wittig reaction between a series of phosphoranes (1la-d) and formaldehyde shows the calculated energy barrier for the fluoro-substituted ylide (1la) to be much higher than those for (llb-d), and for ( l l b ) a large energy difference between the two proposed transition states is predicted. The authors conclude that the only simple ylide that can be used to model the Wittig reaction effectively is ( l l ~ )Nevertheless, .~ other workers clearly believe that simple species such as ( l l a ) and ( l l b ) are valuable models, and a recent theoretical treatise of the aza-Wittig reaction (MP2/6-31G** level) employed iminophosphoranes (12a-b) as model^.^ Density functional theory (B3LYP/6-311+ G**), ab initio (HF/3-21G*) and semiempircal (PM3) methods have been utilised in a comprehensive study of the intrinsic basicities, protonation energies and protonation enthalpies of a wide range of organic phosphorus imines (iminophosphoranes) and ylides.' The crystal structure of (2-fluorophenylimino)tri(1-pyrroly1)phosphorane(1 3) has been reported. The phosphorus atom has a distorted tetrahedral geometry, with P-N bond lengths in the range 1.671(1)- 1.680(3)Aand a P = N bond length of 1.517(3)A. The pyrrolyl groups adopt a chiral propeller-like arrangement about the phosphorus atom.9

(9)a n = 1 b n=2 c n=3

(10) R = H, R' = F, CI or Br R = R1 = F, CI or Br

(11) a R = F b R=H c R=Me

(12) a R = H

b R=CI

d R=Ph

(13)

Toshimitsu et al. have reported a mechanistic study of the reaction between phosphonium sila-ylides (14) and acetylene, and compared their reactivity to that of the corresponding ammonium sila-ylides. The reaction pathway of the phosphonium sila-ylide is different to that of the ammonium sila-ylide. This was attributed to the differences in the cationic character of the ylides." Borisova and coworkers continue to publish the results of their structural and theoretical investigations into heteroorganic phosphonium betaines containing silicon and germanium, e.g., (15), which are obtained by treating group 14 organometallics with ylides."*12 Keglevich et al. have reported a series of papers on the mechanistic aspects of what they term 'inverse Wittig reactions', i.e. the preparation of phosphoranes from the [2 + 21 cycloadditions of phosphine oxides and acetylenedicarboxylates, an example of which is given in Scheme 1. A raft of spectroscopic and structural evidence, coupled with theoretical calaculations, indicate that these reactions proceed via oxaphosphetane intermediates (1 6).i33143i5

319

6: Ylides and Related Species Me

H Me (14) R = Et or Ph

(15) R'.

x

i2)P" 0

R'

C02Me C02Me

Scheme 1

2.2 The Synthesis and Characterisation of Phosphonium Ylides. Mechanochemistry, the use of mechanical alloying techniques such as highenergy ball-milling, has been widely applied in inorganic synthesis but its application in organic synthesis is an underdeveloped area, despite the obvious 'green' credentials of such solvent-free methods. However, a recent paper by Balema et al. describes the novel synthesis of phosphoranes using a ball-milling process (Scheme 2). The method involves mixing precursor phosphonium salts with an excess of anhydrous potassium carbonate in a ball-mill that operates under a helium atmosphere. Although stabilised ylides (17) could be isolated in pure form, non- and semi-stabilised ylides (18) were generated in situ in the presence of carbonyl compounds, generating alkenes through a solvent-free Wittig reaction.16 For several years, Streubel and coworkers have been exploring the chemistry of nitrilium phosphine ylides that contain low-valent organophosphorus fragments, such as complex (19) (Scheme 3). In their latest contributions to this area, they have investigated the reactions of complex (19) with phosphoranes and iminophosphoranes which have led to a number of new species containing ylidic moieties, such as the tricyclic complex (20),17and 2H- 1,2-azaphosphole complexes (21) and (22).'*Similarly, treatment of other low-valent organophosphorus complexes such as phosphinidine species (23) with stabilised phosphoranes produces new ylidic-aducts (24) and (25) (Scheme 4).19 A series of mixed phosphonium-iodonium ylides (26) and (27), compounds that contain both phosphoranyl and hypervalent iodine (A3-iodanes),have been prepared and characterised (Scheme 5). These compounds might prove to be synthetically valuable reagents.20 Aitken et al. have prepared a series of a-aminoacyl stabilised ylides (28) - (30) by the condensation of N-alkoxycarbonyl-protected amino acids and

320

Organophosphorus Chemistry

P i (17) R = PhorOEt [Ph3P-CH2R1] X

R2

R = C(O)Ph, C(O)(OEt) or H, X R=Ph, X=CI R3 (18)

R1=Ph, R 2 = H , R 3 = 0 o

r

w

Br

Scheme 2

'"'..: Me02CC=CC02Me

ph3p=/

toluene, 75 "C

Me3Si

toluene, 75 "C

Me0,CC

+C ,C ; =",'

,w(co)~

ph2p&~(~~CH(SiMe3)2

CC0,Me

(oc)5wk ,CH(SiMe3)*

H

Ph,P=C,

Me02C.C/

CN toluene, 75 "C

\\

p ,

lI

F\+ N-PPh3

/

Me02C

Me02C.

c/ p\ \\

/I

/

\

C-C

Me02C

C=C

I

C02Me

d

)e-bPh3 Me02C

(21)

Scheme 3

(ethoxycarbon ylmethy1ene)t riphenylphosp horane, using the peptide coupling reagent l-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride. The thermal decomposition of ylides (28) - (30) using flash vacuum pyrolysis techniques was investigated; under these conditions the compounds generally decompose to give a$-acetylenic y-amino esters and triphenylphosphine oxide.21

6: Hides and Related Species

321

toluene, 110 "C, 2 hours

CN toluene, 2 hours

/ J

\

CN Ph,P=C H \ / P-W(CO)5 (24)

Ph3P=< OTf - I'Ph

(25)

Scheme 4

Phl(OTf),.2Py CH,CI, r.t., 3 h 4

(26)

PhP ,

-

PhI (0)OTs CH,CI, r t., 12 h

=C, H

R Ph3P=< 0 ~ I'Ph ~ (27)

Scheme 5

Rl*J$k

C02Et

W

Et02C PPh3 (28) R' = PhCH , R2 = Me, P$ or Bu' R' = Et, R = H, Me, Pr', Bu' or Bus R' = But, R2 = Me

H

P

P

h

3

oAOR: (29) R' = PhCH2or Et

EtoLN+PPh3 H C02Et

(30)

The reactions between triphenylphosphine and acetylenic esters have been used to produce a number of different ylidic species including (31),22dialkyl 2-(imido-N-yl)-3-(triphenylphosphoranylidene)butanedioates(32),23 the sterically congested ylide (33)24and heterocyclic phosphonium ylides (34).25Thiazolyl derivatives, such as (35) and (36) have also been prepared and utilised in the synthesis of heterocylic corn pound^.^^^^' 2.3 Reactions of Phosphonium Ylides. - 2.3.1 Reactions with Carbonyl Compounds. This year we are able to report several variations of the traditional Wittig olefination which employ the addition of catalysts to effect the reaction. For example, Lebel et al. have reported a new 'salt-free' process for the methylenation of aldehydes, in which the phosphorane is generated in situ from triphenylphosphine and a diazo precursor with either a rhodium- or rheniumbased catalyst (Scheme 6). It was found that the most effective combination of catalyst and diazo-compound were Wilkinson's catalyst [RhCl(PPh3)3] and

322

Organophosphorus Chemistry R02C " Y X P h 3 P h0 " CO*R (32) R = Me or But, X = -CH2CH2R = Me, X = 1,2-C6H4

(31) R = Me, Et or But, R' = H or Me

P h , P S - $S C02Me (33)

(34) R = Me, Et ot But

Ph3P

+

catalyst

(35)

+

R

+

alcohol

H catalyst = [RuC12(PPh&], RuCI(NO)(PP~~)~], [ R U ( N O ) ~ ( P P ~or~[RhCI(PPh3)3] )~] R = H, SiMe3 or C02Et alcohol = MeOH, EtOH, Pr'OH or Bu'OH Scheme 6

trimethysilyldiazomethane, respectively, which facilitated the quantitative conversion of cinnamaldehyde into the corresponding diene within 30 minutes at 25°C. Furthermore, these reagents were able to convert a wide range of aldehyde substrates, (37), including those containing amides, enolisable ketones or epoxides and different protecting groups, as illustrated in Scheme 7.28 Tang and coworkers have reported a series of papers in which they disclose the use of an efficient triphenylphosphite/PEG-supportedtelluride (PEG = polyethylene glycol) catalyst for the Wittig olefination reaction. In this instance, however, the ylidic species is centred on the tellurium and the triphenylphosphite simply re-generates the ylidic site in the catalytic process.29,30-31 Shi and Xu have reported a route to both symmetrical and unsymmetrical alkenes that involves the oxidative coupling of phosphonium ylides (scheme 8). The reaction, which is carried out under phase-transfer conditions, is catalysed by vanadyl acetylacetonate. Other transition metal acetylacetonate complexes were also investigated as potential catalysts for this process, though none were as effective as the vanadium Taylor and Runcie have disclosed more of their results regarding the manganese dioxide-mediated oxidation-Wittig reaction in which alcohols are converted into alkenes in a one-pot process which involves trapping the intermediate aldehydes in situ with stabilised phosphoranes. This methodology has now been applied to a-hydroxyketones (38) giving high yields of y-ketocrotonates (39) (Scheme 9).33Furthermore, the utility of this reaction has

6: Hides and Related Species

323 R-0

-R+

(37) Reagents and conditions: [RhCI(PPh3)3],(2.5 mot Yo),THF, 25 "C, Pr'OH (1.1 equiv.), PPh3 (1.1 equiv.), 1 5 hours

+

OBn

(37) =

Ph-0,

L

o

A

, TBSO-

'0, Ph

'0,

Scheme 7

RG+pph3 VO(acac)2, (1 mol YO),K2C03 (2.5 equiv.)

Br- 18-crown-6 (0.01 equiv.), PhMe, 02,60-70°C,

R = MeO, F or NO2

4 h).

Scheme 8

MnO,, CH,CI,

r.t.

R'

* R

R

(38)

R'

(39)

Ph,P=<

R2

R = Ph, R' = C02Et, R2 = Me R = pMeOC6H4, R1 = C02Et, R2 = H R =& 0 R = Me, R=Me, R = Me, R = Me,

, R' = COZEt, R2 = H

R' = C02Et, R2 = H

R'=COMe, R 2 = H R' = CON(Me)OMe, R2 = H R' = CN, R2 = H R = c~H~ R' I=-CO~BU', , R~ = H R = C-C~HS-, R' = C02Et, R2 = H

Scheme 9

now been widened to include non-stabilised phosphoranes (40) (Scheme 10)and phosphonates (41) (Scheme 1l), the latter in a pseudo 'oxidation-Horner-Wadsworth-Emmons-reaction'. This modified route requires conditions that are somewhat more rigorous than the analogous process using stabilised ylides, including pre-drying of the manganese dioxide and the use of a nitrogen atmosphere, but it has nevertheless been used to convert benzylic, allylic and propargylic alcohols into the corresponding a l k e n e ~ . ~ ~ A detailed mechanistic study of the reaction between stabilised ylides (42) and 1,2-dioxineshas been reported by Taylor and coworkers. This reaction provides a facile route to functionalised cyclopropanes (Scheme 12).35The same group has also discovered that addition of chiral P-ketoiminato (43) or cobalt salen (44) complexes, leads to a catalytic asymmetric ring-opening of meso 1,2-dioxines, affording enantio-enriched cis y-hydroxy enones that react with the stabilised ylides to give enantio-enriched c y c l ~ p r o p a n e s . ~ ~

324

Organophosphorus Chemistry

:

(EtO),PCH,CO,Et,

THF

ci>

(411

R”OH

MnO,, LiOH or

L R

m C 0 2 E t

\

Me R = pN02C6H4-, pMeo@-i4-,

Ph, Ph%

F

, Pr

, Me-

or C6H,3+

Scheme 11

R = Me, Et, Bu‘,l-Adamantyl or Bn, R’ = H, alkyl or aryl Scheme 12

One of the main drawbacks of the Wittig reaction is the formation of unwanted triphenylphosphine oxide. A new route, which makes use of polymersupported triphenylphosphine and microwave dielectric heating has been developed (Scheme 13), which yields the required alkene without the triphenylphosphine An alternative strategy for separation of the product alkene from unwanted phosphine oxide by-product is to carry out the Wittig reaction in a fluorous solvent using a perfluorinated ylide such as (45). One drawback of this

6: Hides and Related Species

325

Scheme 13

approach is the need for specialist equipment for handling the fluorous solvent~.~* The use of the Wittig reaction and its modifications for the synthesis of vinylchalcogenides, ketene chalcogenoacetals and related species has been reNew developments on this topic include the synthesis of a series of polymer-supported alkyltriphenylphosphoranes (46) which have been utilised in the preparation of vinylic ~elenides.~' The synthesis of vinylic selenides, such as 1-chloro-1-phenylselenoalkenes, has also been accomplished in a one-pot reaction which proceeds through the formation of selenoylphosphorane (47) intermediates?l

(46) R = H, Me, Et or Ph

(45) R = C02Et or CN

Wittig reactions of a-alkoxy aldehydes and sugar lactols, such as pentose ketal (48), with stabilised ylides usually proceed with low (E)-selectivity. However, Harcken and Martin have discovered that treatment of these aldehydes with (methoxycarbonylmethy1ene)tributylphosphorane (49) and a catalytic quantity of benzoic acid produces the heptenonate (50) with a E:Z ratio of 95:5.42The stereoselectivityof the reactions between aldehydes and spirophosphoranes (51) has been examined and the phosphoranes found to favour the formation of (2)-a,P-unsaturated aldehydes and amide~!~

R

(51) R = CN, CONMe2or CONH2

Wittig methodology has been used to prepare a variety of heterocyclic species, including cyclopentenones and cyclohexenones through the intramolecular Wittig reaction of 2-oxoalkylidenetriphenylphosphoranes (52) (Scheme 14),44fluorinated butanolides and buten~lides:~ 2,5-disubstituted-pyrroles and -pyrrolidenes, which utilised the phosphorane 4-[ { 4-methylphenyl)sulfonyl]- 1-

326

Organophosphorus Chemistry COPh

Ph3p+,i(,R

+ PhOC-

/

COPh

(ii) ACOH, (i) sBuLi, THF, 48 h.,-78 30 "C "C

*

PhP*COPh d

Scheme 14

(52) R = H, Me, Et or M e 0

(triphenylphosphoranylidene)butan-2-one (53),46pyrazole~,4~ pyrimidines:* and isoquin~lines$~ together with more exotic species such as (54)." Treatment of the silyl esters of S-acyl or aroyl thiosalicylic acids with (trimethylsily1)methylenetriphenylphosphorane produces ylides (55) which undergo an intramolecular Wittig cyclization to give 4H-1-benzothiopyran-4-ones (56) (Scheme 19, which are useful intermediates for the synthesis of biologically active compounds, in good yields."

(55) R = Me, Et, Ph, PN02C6H4-, pCIC6H,--, pMeOC6H4--, (FCIC6H,--, @N02CeH4-, m-( Meo)&H3Scheme 15

(56)

m-N02&H4--,

Several macrocyclic compounds have been prepared using Wittig reactions including tetraepoxyannulenes, which utilized the ylide derived from phosphonium salt (57),52and rotaxanes, molecules in which one or more macrocyclic components are trapped around a rod section of a dumbbell-shaped molecule, obtained by treating terephthaldehyde derivatives with dibenzylic bis(tripheny1phosphonium)-stoppered [2]rotaxane (58).'3 Aromatic triesters have been obtained by the (ethoxycarbonylmethylene)triphenylphosphorane-catalysed cyclotrimerisation of ethyl p r o ~ y n o a t e . ~ ~ Standard Wittig procedures have found application in the synthesis of new biologically active molecules including fused 1,3-dioxolocoumarins, which were evaluated as antioxidant and antiinflammatory alkylidenedimethylpetylpyranones (59) (Scheme 16), which also possess antiinflammatory properties,'6 and (62,92,1 lE)-octadecatrienoic and (82,11Z,13E)-eicosatrienoicacids and their [l-'4C]-radiolabeled analogues. Conjugated linoleic acids such as these occur naturally in ruminant animal tissues and milk fat. The synthesis of the linoleic acids required phosphonium salts (60) and (61).57 The use of ketenylidenetriphenylphosphoranein the synthesis of natural products and their analogues has been reviewed.58 2.3.2 Miscellaneous Reactions. Intramolecular Wittig reactions of vinyl phos-

327

6: Ylides and Related Species

H v,CHR

C09H

Y

(59) R = heptyl, octyl, nonyl, decyl, dodecyl or Et02C(CH2)4Scheme 16

+

I- Ph3P

OTHP

I- Phsb-OTHP

(60)

(61)

phonium salts generated in situ from triphenylphosphine and acetylene dicarboxylates continue to attract the attention of a number of groups. Thus, Murphy and coworkers have found that a-hydroxy and protected a-aminoesters can be converted into 2,5-dihydrofurans and 2,5-dihydropyrroles, respectively (Schemes 17 and 18). However, ethyl thioglycolate does not react under the same conditions to give substituted t h i ~ p h e n e sSimilarly, .~~ Yavari et al. have prepared a series of highly substituted furans, starting from enols such as acetylacetone (Scheme 19).60Functionalised carboxylates, such as (62) (Scheme 20) have also been prepared using this methodology.61,62 A regio- and diastereo-selective synthesis of functionalised cyclopentenones has been achieved by treating maleic (63) diesters with (3-alkoxycarbonyl-2-oxopropylidene)triphenylphosphoranes (Scheme 21).63Microwave radiation has been used to stimulate the reaction between a-keto phosphoranes and aryl azides which affords 1-aryl-1,2,3triazoles in moderate ~ields.6~ Further studies have been reported into the use of phosphorane-borane adducts (64), which dissociate into the corresponding phosphonium ylides in situ, as latent catalysts for the addition polymerisation of bisphenol A diglycidyl ether and bisphenol A.65Protonation of nonstabilised

328

Organophosphorus Chemistry C02Me I

+ PPh3 +

'I'

EtO

C02Me

Dioxane, 10 "C, 1 h.. reflux, 16 h.

*

Scheme 17 E

x

M

e

Dioxane, 10°C, 1 h., reflux, 16 h.

* R

OH

8 EtEt2Me

"CO2Me

,

"C02Me

I

P

P

Scheme 18

C02Ph

0 PPh3+

-+

C02Me+ I

C02Me R = H, R' = Et, P = BOC R = M e , R ' = Et, P=Boc R = P h , R ' = Me, P=Boc R = H, R' = Et, P = C02CH2Ph R = Me, R' = Et, P = C02CH2Ph R = Ph, R' = Me, P = C02CH2Ph

C02Me

R

C02Me

R = H, Me or Ph

EtO

111

r.t., 12 h.

C02Ph Scheme 19 Me Me CCH2Ph Me Me

C02Me Ph' Scheme 20

'C02Me (62)

R'02C

I

III + Ph3p-rf--K0R 0 0

R'02C

R'd (63) R = Et or Me, R' = Me, Et, CH2=CHCH2 or Me(CH2)3 Scheme 21

Ph36-CH-ER3

A'

(64) R = F, R' = H, CHO or COMe; R = H, R' = H or COMe; R = Ph, R' = H or COMe

ylides by 4,4'-methylenebis(2,6-di-tert-butylphenol) yields phosphonium bis(ary1oxide)salts in which the ion pairs are linked through a series of hydrogen bonds.66 Treatment of ketenylidenetriphenylphosphoranewith an excess of water in THF produces the hydrated phosphonium salt, methyltriphenylphosphonium hydrogen carbonate, which decomposes upon heating to give carbon dioxide, water, benzene and diphenylmethylphosphine oxide.67

6: Hides and Related Species

329

2.4 Aza-Wittig Reagents. - A review of the synthetic applications of lithium phosphonium azadiylides, e.g., (65),and the coordination chemistry of the corresponding anions, has appeared.68An experimental 13Cand 31PNMR study of iminophosphorane (66), which acts as a ‘proton sponge’, has been reported. A 4hJppcoupling constant of 1.6 Hz involving the H-bond was determined together with a 2A31P(13C) isotope shift of 9 ~ p bThe . ~structure ~ and bonding in donoracceptor adducts of cyanogen halides (XCN, X = C1, Br, I) with trimethylsilyl phosphoranimine (67) have been investigated using Raman spectroscopy and X-ray diffraction. Overall, the interaction between the imine and the acceptor is weak; the crystal structure of the ICN complex revealed two distinct, but long, N . . . I bonds with lengths of 2.634(1) and 2.739(14)A.70

The majority of published work on aza-ylides concerns their applications in synthesis, and here we report a selection of contributions from this area. The Staudinger reaction is a popular route to aza-ylides and has been used to prepare a series of perfluoroalkyl-tagged aza-Wittig reagents, e.g., (68), which were generated in situ (Scheme 22), and utilised in the synthesis of 3H-quinazolidine4-ones in a fluorous biphasic system.71A method for the preparation of azapolycyclic compounds derived from pyrrolidine, indolizidine and indole has

R5

ll? R2

\ PhMe, o

C

F

3

R3

Scheme 22 OMe

N

N AC02Et R (69) R = 2-fuVl, R1 = Ph (€) R = 2-thieny1, R1 = Ph (€) R = 3-pyridy1, R1 = Ph (Q R = H, R’ = Ph R = H R’ = Me R = R \ = H (,q

(€,a (€,a

PPh3 (70)

3 30

Organophosphorus Chemistry

been developed. The sequence involves tandem aza-Wittig reactions, employing N-vinylic aza-ylides (69), and intramolecular aza-Diels-Alder reactions.72Multistep synthesis of the marine alkaloid, variolin B, a potent antitumoral, was accomplished starting from ylide (70).73The reactions of cyclic aza-ylides, e.g., (7l), with t h i ~ e s t e r sand ~ ~ P-di~arbonyls~~ have been investigated, the latter furnishing enamino phosphine oxides, e.g., (72), which can be stereoselectively converted into 1,6- and 1,7-dienes. 0

5

P h 2 1 v b 4 \

R2

(71) n = 1 , 2

(72) n = 1, R' = Me, R2 = Me, Ph, 4-MeC6H4- or OEt R' = CF3, R2= OEt n = 2, R' = Me, R2 = Me, Ph or 4-MeC6H4-

2.5 Ylides Coordinated to Metals. - Complexes of iminophosphoranes have attracted attention due to their potential application as catalysts for the polymerisation of olefins. A recent contribution to this field reports the coordination of sterically hindered iminophosphorane (73) towards titanium and zirconium tetrachlorides. Treatment of TIC4 with (73) led to the phosphoranato complex (74) whereas ZrCb was unreactive. However, treatment of Zr(NMe2)4with (73) led to complexes (75) and (76) (Scheme 23). The structures of ligand (73) and

+

Q PPh2

(75) Reagents and conditions: i, Zr(NMe2)4,toluene, 110 "C, 24 h.; ii, excess Me3SiCI, toluene, reflux Scheme 23

complex (75) were determined ~rystallographically.~~ Bidentate iminophosphorane-phosphine ligands, e.g., (77), have attracted attention recently. Molybdenum and tungsten complexes of (77a) have been characterised spectroscopially.^^ Treatment of ruthenium arene or ally1 species with ligands (77a-c)has led

6: Ylides and Related Species

331 N=Pn Ph2

PPh2

(77)a, R = SiMe3, b, R = F

F

F

F

\

NaPF,, MeOH, r.t.

(80) R = pCNceF4- or -CSF~N L = pyridine or PR3

(79) R = H, pcNc6F4- or +F4N

//I

NaX, MeOH, r.t.

(81) X = Br, I, N3, CN or NCO

NaX, MeOH, r.t.

(82) R = pCNC6F4- or 4 5 F 4 N X = Br, I, N3, CN or NCO

Scheme 24

to the synthesis of an extensive series of neutral and cationic complexes (78)- (84) (Scheme 24 and Scheme 25). The results demonstrate that iminophosphoranephosphine ligands are hemilabile, and when coordinated in a chelating mode, as in (79), the Ru-N bond is readily cleaved by addition of neutral donors such as pyridines and tertiary phosphines, giving (80), or a variety of anionic species, resulting in compounds (81) and (82). Attempts to generate cationic complexes structurally related to (79) by treating the dimeric ruthenium(1V) complex [(RU(~~:~~-C~~H~~)(~-CI)C~}~] with (77a-c) and sodium hexafluorophosphate or silver tetrafluoroborate failed (Scheme 25). Instead, neutral complex (83a) reacts cleanly with silver tetrafluoroborate to yield (84) after cleavage of the N-SiMe3 bond. This difference in behaviour was attributed to steric hindrance between the octadienyl group and the iminophosphorane ligand and replacement of the

332

Organophosphorus Chemistry

fkfu-$ I I

$1:

ARu-P-PPh, w

I

AgBF,, R =CH2C12, SiMe, r.t.

Ph2

II

l+

BF4-

trace H 2 0

N, R

N=P H'

(83) a R = SiMe3 b R=pCNCeF4c R=CSF~N

Ph2

(84)

Scheme 25

fluoroaromatic moieties in (77b,c)by hydrogen allows the iminophosphorane to adopt a chelating mode.78The coordination chemistry of a-acetyl-a-benzoylmethylenetriphenylphosphorane (85) towards mercury (11) halides has been investigated. The chloro-complex (86), is a square-planar monomer, whereas the bromo- and iodo-complexes (87),which are isostructural, form halogen-bridged dimers with tetrahedral geometry about the mercury centres. These complexes represent the first structurally authenticated examples of keto-ylides that are bonded to mercury through their oxygen atoms.79 Ph

Ph3P

0

I

CI-Hg-CI Ph

I

Ph C

Me O & F OPPh3

(85)

Me

(E

Although boron is more accurately described as a metalloid rather than a metal, this section is concluded by two papers that describe the structures and bonding in several organoboron/organophosphorus compounds that display ylidic character. The X-ray structure of 9-borylanthracene (88) shows that only one of the diisopropylphosphine moieties is bonded to the boron in the solid state. However, 'H NMR evidence shows that an intramolecular bond-switching process takes place very rapidly in The structures of a series of borabenzene adducts of phosphorus ylides, iminophosphoranes and tertiary phosphines have also been determined. Treatment of 1-chloro-3,5-dimethyl-2(trimethylsilyl)-1,2-dihydroborinine (89) with methylenetriphenylphosphorane (90) produces (triphenylphosphonio)methanide-3,5-dimethylborabenzene(91). However, if the reaction sequence is reversed and (90) is treated with (89), then (trimethylsilyl)(triphenylphosphonio)methanide-3,5-dimethylborabenzene (92) is obtained (Scheme 26). Treatment of an isomeric mixture of 1-chloro(trimethy1sily1)dihydroborinines (93) with N-(triphenylphosphorany1idene)aniline (94) produces N-(tripheny1phosphonio)anilide-borabenzene (95) (Scheme 27). Crystal structures of (91), (92) and (95) show that the P-C or P-N bonds are

333

6: Hides and Related Species

.

.

Et20, r.t., 2 h.

Et20, r.t., 2 h.

+ Ph3P=CH2

‘

n

s Ii

CI (89)

(91) 6Ph3

M

e

3

(90)

+A SiMe3

Ph3P

(92)

Scheme 26

SiMe3

SiMe3

2

2

Cl (93)

Scheme 27

longer than those in the parent ylides. Similarly, the B-C or B-N bonds are also elongated, indicating that there is no conjugation between the oppositely charged centres within the adducts.81 2.6 Wittig-Horner Reactions of Metallated Phosphine Oxide Anions. - Significant contributions to this area continue to emanate from the laboratory of Warren and co-workers, including the synthesis of protected P-aminophosphine oxides e.g. (96), (97) and (98), together with an investigation into their WittigHorner addition reactions, which generally proceeded with poor stereoselectivity.82The same workers have also reported the Horner-Wittig elimination of hydroxyphosphine oxides as a route to allene~.’~ The majority of papers concerning the Wittig-Horner reaction relate to its application in synthesis. Recent examples include the tetrabutylammonium fluoride-mediated reaction of 2,2,2trifluoroethyldiphenylphosphine oxide with aldehydes (Scheme 2QS4and the synthesis of a-hydroxymethyl esters using lithiated dimethoxymethyl diphenylphosphine

,l, 0 II

-k

TBAF. THF, r.t.

Ph2P\/CF3

Scheme 28

t

R W c F 3

334

Organophosphorus Chemistry

2.7 Homer-Wadsworth-Emmons Reactions of Phosphonate Anions. - As with the Horner modification of the Wittig reaction, the principal focus of papers that mention the Homer-Wadsworth-Emmons reaction relate to synthetic applications. The use of pressure to induce the synthesis of p-amino esters, P-thioesters and P-thionitriles via tandem Horner-Wadsworth-Emmons and Michael reactions has been reported.86The reagent (1-tritylimidazol-4-y1)methylphosphonate (99) has been prepared and, when treated with aldehydes and ketones, affords (E)-vinylimidazolesin high yields.87

0 II

-P(OEt)P

Ph3C-N

/=c N

U

(101)

0 (100)

(99)

1

Me

Me

(102) R = Me, Et or Ps

A series of chiral phosphonates, (loo), (101) and (102), has been prepared. These compounds undergo base-catalysed cyclisations to give non-racemic dihydronaphthalene derivatives with moderate enantiomeric excess.88Similarly, intramolecular Horner-Wadsworth-Emmons reactions of chiral phosphonates, (103) have been used to prepare novel perhydro-indanones and -naphthalen0nes.8~Alkenyl phosphonates, e.g., (104), obtained from methylenebisphosphonate esters and carbonyl compounds, undergo a further HornerWadsworth-Emmons reaction to afford allenes (Scheme 29).90 Taylor and coworkers have previously reported the diastereomeric synthesis of substituted cyclopropanes through the Wittig reaction of stabilised ylides with 1,2-dioxines, as illustrated earlier in Scheme 12.35The scope of this reaction has been extended to include stabilised phosphonates, e.g, (105) (Scheme 30), in place of phosphonium ylides. The phosphonate precursors give similar yields of cyclopropanes to their ylide counterparts, but with shorter reaction times and improved diastereoselectivity.9' The reaction between (dipheny1phosphono)acetamides and aldehydes affords (2)-a,P-unsaturated amides with high stereoselect i ~ i t y Enantioselective .~~ Horner-Wadsworth-Emmons reactions of fluoro-substituted phosphonates, e.g., (106),with a variety of carbonyl substrates have been

6: Hides and Related Species

335

Scheme 29

0

:

0

H

Ph

R' = C02Me, C02But, CN, ,C.

Scheme 30

0 II

( E t o ) 2 P v C02R FI

o'p(oEt)2

(106) R = Et, Pr', dicyclohexylmethylor But

(107)

R

a

x NH2

1

5 rnol %, Rh,(OAc), 20 mol O h phenol

R=H, X=IorBr R = M e. X = B r Scheme 31

336

Organophosphorus Chemistry

accomplished using tin(I1) triflate and N-ethyl piperidine.93~94Bis-sulfinyl phosphonate (107) has been prepared and utilised in a diastereoselective nitrone cycloaddition reaction for the asymmetric synthesis of the antifungal antibiotic cispentacin."A polymer-supported a-diazaphosphonate has been prepared (Scheme 31) and used to prepare indoles via a Horner-Wadsworth-Emmons reaction followed by a palladium-catalysed intramolecular c y ~ l i s a t i o n . ~ ~ Horner-Wadsworth-Emmons reactions have been widely deployed as steps in the total synthesis of range of biologically active compounds including laulimalide, a metabolite from marine sponges, using phosphonate ( 108),97non-calcemic sulfones, analogues of the hormone la,25-dihydroxyvitarnin D3 (calcitrioE),98 analogues of 2-arachidonoylglycerol, a endogenous cannabinoid the macrolactones epithiolone A and epithiolone B, which required phosphonate (109),andwhich display taxol-like antitumor mechanisms and antifungal properties,'OO.'O1the fungal metabolites, ( + )-ampullicin and ( + )-isoampullicin which display growth regulatory activity and which were obtained from (R)-(-)-carvone in an eighteen step synthesis using phosphonate (110),'O2and the preparation of justicidin B and retrojusticidin B, inhibitors of HIV-1 reverse transcriptase. A key feature of this synthesis is sequential Horner-Wadsworth Emmons and Claisen condensations, the former employing phosphonate (1 1l).'03

0 II

CH,P(OEt)2

I

(113)

(EtO)zP-CH,

(114)

@

0

CH2-F(OEt)2

RO (115) R = Me(CH2)17,Me(CH2),, or Me(CH2)7

6: nides and Related Species

337

Homer-Wadsworth-Emmons procedures are also commonplace in synthetic materials chemistry, recent examples including donor-acceptor substituted molecules with bicyclo-spacers, which require napthalene-, anthracene-, and pyrenesubstituted phosphonates, (112), (113) and (114) respectively,lM well-defined, electroactive PPE/PPV copolymers through the condensation of dialdehydes and bisphosphonate (115),lo5 and triphenylamine-substituted PPV.lo6

I

.

Ti(OPr')3

Scheme 32

Finally, Muller and coworkers have reported the synthesis and X-ray crystal structure of a novel heterobimetallic lithium titanium phosphonate (116) (Scheme 32) which, although not strictly a Horner-Wadsworth-Emmons reagent, represents a new class of closely-related organometallic reagent. Moreover, the structure of this interesting species, which crystallises as a complex aggregate containing titanium phosphonate, lithium chloride, lithium oxide, lithium dimethylphosphonate and lithiated dimethylphosphate, may give insight into the structural nature of similar metallated phosphonates and their mode of reactivity.lo7

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12. 13. 14.

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47. 48. 49. 50. 51. 52.

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78.

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79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95.

96. 97. 98.

99. 100. 101. 102. 103. 104. 105. 106. 107.

7 Phosphazenes BY J. C.VAN DE GRAMPEL

1

Introduction

This review covers phosphazene literature over the period June 2001 to December 2002 (Chemical Abstracts Vols. 135, 136 and 137), and discusses linear phosphazenes including compounds derived thereof (Section 2), cyclophosphazenes (Section 3) and polyphosphazenes (Section 4). Structural data have been summarized in Section 5. References have been given in Section 6. 2

Linear Phosphazenes

One of the common synthetic routes to prepare the phosphoranimine (RN = P) moiety consists of the reaction of an azido (-N3)and a phosphine (-PR3) group, the so-called Staudinger reaction. The phosphazide intermediate can be isolated when dealing with sterically-demanding reagents. This has been demonstrated by the reaction of N3CH2SPhwith But3Pyielding the phosphazide (l),whereas Pri3P gives the phosphoranimine (2).' Complex formation of (1) with NiC12(DME)(DME = 1,2-dimethoxyethane)or FeC12leads to the paramagnetic compounds (3a) and (3b). The reaction of (2) with FeC12 affords the bimetallic complex (4).l

71

PhS-CH2 HS-SPh ,,N-M--N' BJ~P=N--N

\\N--N=PB~~~

(3a) M = Ni (3b) M = Fe

Organophosphorus Chemistry, Volume 34 0The Royal Society of Chemistry, 2005

341

342

Organophosphorus Chemistry

The isolation of phosphazides has also been reported for Staudinger reactions of R3P (R = Me, Et, Ph) with azido-p-benzoquinonedibenzenesulfonimines? Enantioseparations have been carried by application of the Staudinger proto~ 0 1 . An ~7~ interesting tripodal ligand system (5) has been prepared by the reaction .~ of equimoof bis-2,6-diphenylphosphanylpyridine with a ~ i d e sComplexation lar amounts of [MCl,(thf),] (M = Co, Fe) with (5b) in thf leads to the formation of the complex (6) and (7), respectively.

(5a)

R = Ph

R = Mes (mesityl) R = Ad (adamantyl) (5d) R=SiMe3

(5b) (5c)

Me

Me CI, CI,

C ,l

Fe\ CI Fe'

Me

Me

343

7: Phosphazenes

The cationic complex (8) has been obtained in addition to (6)for the reaction of (5b) and [ C ~ C l ~ ( t h fin ) ~MeCN ] as solvent.'

Another multidentate ligand (9) has been prepared in an almost quantitative yield by the reaction of the diphosphine Ph2P-N(Me)CH2CH2N(Me)-PPh2 and a phosphorylazide! Me Me I I PhzP-N-CH$HZ-N-PPhz

2 N3P(0)(0Ph)2

z

Ph0,II

Ph Me Me Ph I I I I P-N=P-N-CH2CHZ-N-P=N-P<

0

Phd

I

Ph

I

Ph

0

I I OPh

OPh

Decomplexation of the P(II1) moiety of the boronhydride complex (10) by the base 1,4-diazabicyclo[2.2.2]octane (DABCO) followed by an internal Staudinger reaction has been reported to yield the linear polymer (12). Hyperbranched polymers are obtained by using the same procedure but starting from the diphosphine (13). Treatment of (11) with NaN3 leads to an intramolecular Staudinger polycondensation affording polymer (12) as well.7 Compound (13) has proven to be a useful starting material for the synthesis of dendrimers with phosphine end group^.^^* A tri-h5-phosphazene system has been isolated from the reaction mixture of a-methyl substituted triazides and MeC(CH2PPh2)3.9 When the Staudinger reaction is carried out in the presence of an excess of C 0 2 or CS2, a subsequent aza-Wittig reaction can lead to an in situ formation of i s o ~ y a n a t e s 'or ~ ~iso~ thiocyanate~,'~?'~ respectively. Several papers deal with the use of phosphoranimines as reagents in organic syntheses, i.e. the preparation of glycosyl phosphoramidates,'5 preparation of neoglycolipid analogues of glycosyl ceramides,16 modification of protein^,'^ coupling of peptides,'* preparation of amines19.2021 and preparation of indan derivatives 22. Peracetylated azidodeoxyP-cyclodextrin can be easily transformed into a amide derivative by a reaction with a carboxylic acid in the presence of PPh3,according to a combined Staudinger/aza-Wittig p r o t o ~ o l ?Carbodiimides ~ ( 16)24and ( 17)25are formed by the reaction of phosphoranimines (14) and (15) with isocyanates. In the latter case, (17) undergoes cyclization to give the tricyclic pyrimidopyrrolopyridine derivative ( 18).25

Organophosphorus Chemistry

344 OPh N3--i-O_Q_gh-

BH3 Ph

S

OMe

\ DABCO

OMe

I

OMe

I

II

PPh3

RN=C

RNH’

R = PhCHMe

N-vinylic phosphazenes react with isocyanates to yield N-vinylic carbodiimides.26The reaction of isothiocyanates and an N = P moiety has been used to prepare oxazole deri~atives.2~ The reactivity of the -N = P moiety in synthetic procedures has also been demonstrated by the aza-Wittig reaction with aldehyde~?*-~ l Mono-and disubstituted ketenes react with N-imidoyl phosphoranimines (19) to give pyrimidinone (20) and quinazoline (21) derivative^.^^ Quinazolines have also been prepared by the reaction of a polystyrene-bound phosphoranimine and isocyanates, followed by an intramolecular cyclization of the carbodiimide intermediate.334-Ferrocenylidene-1-aminoimidazolone derivatives have been obtained from P-ferrocenyl-a-azidoacrylates and isocyanates followed by condensation of the resulting carbodiimidoester with h y d r a ~ i n e s . ~ ~ In a Staudinger/ aza-Wittig process and in the presence of PPh3, bimetallic ferrocenyl oxazole derivatives (23) - (26) have been formed by the reaction of a-

7: Phosphazenes

345

azidoacetyl ferrocene (22) with corresponding dicarboxylic acid chlorides. Formation of a second oxazole ring failed in the case of phthaloylchloride and only compound (27) could be isolated. Electrochemical studies show that the metallic centres in (23) - (26) do not interact with each On the contrary, electrochemical interaction has been observed for the trimetallic compounds (31) and (32), prepared from (22) and 1,l'-bis(chlorocarbony1ferrocene(28), and the ferrocenes (29) and (30).36 Decarbonylation of the osmium complex [os3(co)~(~3-r)2:~2:r)2-c6~)] by

I)

R

0

R

i

A

1

R

NZPPh3

R=H,Me

i ring closure

I

(20a) R = H, R

= CI

(20b) R = Me, R = Me

R' = R" = Ph

ii [1,7lH shifl

(20c) R = H, R = Me

1

(2Od) R = H , R = P h (2Oe) R = Me, R' = Ph R

CHPh,

(21) 0

PPhS CIOC- A- CoCl

(22)

(23-26)

Organophosphorus Chemistry

346 PPh3

( -N O PPha

F

Fe 3

-6N O-)-

PhCH2NPPh3 affords the isocyanide derivative [Os3(CO)g(CNCH2Ph)(p3q2:q2:q2-C60)].37 The Staudinger reaction in combination with an intramolecular aza-Wittig ring closure reaction has been applied in the synthesis of quinazolin4-0nes.~'Other examples of intramolecular aza-Wittig reactions are reported as parts in multi-step synthetic A theoretical study of the aza-Wittig reaction of HN = PX3(X = H and C1) with formaldehyde in the gas phase and in solution has been reported.44 Phosphoraniminato complexes are presented not only because of their synthetic and structural aspects but also because of their potential application as catalysts, in particular the complexes with transition and rare earth An interesting and extended review covers the coordination chemistry of imino -P(V), aza-P(V) and imino-aza- P(V) ligands.46A new one-pot synthesis has been reported for the preparation of Me3SiNPC13starting with the reaction of PC13 and LiN(SiMe3)2and followed by oxidation with S02C12.47 The ferrocenyl-substituted phosphoraniminato boron complex (33) has been obtained from ferrocenylboron dibromide and Me3SiNPMe3.The cation of this complex consists of a planar four-membered BN ring with one boron in a planar trigonal, the other in tetrahedral coordination.4'

+

-

Br

(33)

The chlorine atoms in the titanium complexes (34) and (35) can be stepwise replaced by cyclopentadienyl [via (dme)NaCp] or indenyl groups [via Li(in-

7: Phosphazenes

347

denyl)], resulting in the compounds (36) - (41). Both q1and q5bonding modes have been observed for the organic ligands towards the metal at0m.4~ Metal nitrogen heterocubane structures have been found for the potassium, and cesium phosphoraniminato complexes [KNPCy3I4 (Cy = cyclohexyl),sO [CsNPCy3I4 and for the nickel phosphoraniminato complexes (42);' and (44).52A N&N3Brheterocubane structure has been found for complex (43)." The catalytic activity of [NiBr(NPMe3)I4in the ring opening polymerization of norbornene has been patented.53Tetrahedral coordination of nickel occurs in the complexes [NiBr2{HNP(NMe2)3}2],S1 [INi{ Me2Si(NPMe3)2)(HNPMe3)]152 and [Ni(HNPEt3)4]12.S4The structure of zinc-containing anion (45) is characterized by a heterocubane unit consisting of three zinc, one lithium and four nitrogen atoms.55The structure of [Me3SiNPEt2CHMeLiI4,formed by the reaction of Me3SiNPEt3 and BunLi, can be described as a highly distorted LiC heterocubane. In addition, each Li atom is coordinated to a nitrogen atom, forming four CPNLi-ring~.~~ An even more extended structure has been found for [NaNPPh& (46), oiz. six sodium and six nitrogen atoms form a slightly distorted hexagonal prism.57

Liondenyl)

I

(37)

I

*(38)

I

BU~~P=N--TCI,

(35)

Li(indeny1)

Li(indeny1)

BU:P=

N-T

Organophosphorus Chemistry

348

Br

(43)

PPh3 (45)

(46)

The aminophosphoranimine (Me3Si)2NP(C12)NSiMe3reacts in an equimolar ratio with TIC4or NbCl5 to form the perhalogenated phosphazene metallacycles (47) and (48),respectively. The use of ZrC14.2thf or HfC14.2thf leads to the formation of (50a) and (50b), in which the coordination around the central metal consists of one thf molecule and three chlorines. Treatment of (47) with thf results in the analogous complex (49).58Two interesting bimetallic niobium complexes ( 5 1)and (52)could be isolated in small amounts from a complex reaction mixture of NbC15and 2.5 equivalents of (Me3Si)*NP(C12)NSiMe3. Complex (51)exhibits a distorted octahedral geometry around one of the metal atoms, whereas the second metal lies in the centre of a trigonal bipyramid. An unusual planar six-membered ClNbNPNNb-ring has been observed in complex (52).58 Deprotonation of iminophosphorano(pyridy1)methane (53) by Bu"Li yields the difunctional ligand (54). Compound (54) reacts with 0.5 equivalents of MC12 (M = Ge, Sn, Pb) to form the 1,3-dimetallacyclobutanes (55), (%a) and (56b), respectively. A mixed 1,3-stanna-plumbacyclobutane(58) can be prepared via the chlorotin (11)complex (57). In these complexes sidearm donation takes place via the imino nitrogen.59 Analogous metal complexes (60) and (61) have been obtained from reactions of the ortho-metalated species (59) and the metal chlorides FeC12 and InC13,respectively. Elimination of LiCl leads to the formation of 0-metal carbon bonds, whereas additional metal coordination is provided by imino nitrogens. For complex (62) only 0-metal carbon bonds are operative. The lengthening of the N(M)P bond lengths in (60) and (61) in comparison to the others in (61) and (62) (see Section 5 ) can be ascribed to the imino N-metal bonding.60 The mode of coordination of Me3SiNP(Ph2)CH(SiMe3)(C6H4Me-4) (63) towards Bu"Li depends on the reaction medium used. When carried out in hexane/toluene and recrystallization of the reaction product from benzene, the reaction of (63) with Bu"Li affords a dimeric product (64) in which the aromatic moieties are $-bonded to the lithium atoms. Recrystallization of the reaction product from thf, however, leads to coordination of solvent molecules to lithium in combination with C-N chelate formation (65). An ql-bonding mode via an

349

7: Phosphazenes CI (Me,Si),N-P=NSiMe,

I

CI

TiCI,

-

,Ti-

-CI

CI <Ti'

SiMe,

Me3Si-N<6>N-

c12

thf

*

Me.,Si-N<

->N-SiMe3

P CI2

CI

CI. Nb

(Me+)2N-P=NSMe3

I

CI c

NKI,

Me&i-N<-

->N-SiMe, D

CI @le3Si)2N-

MCIJTHF

P=NSiMe3

I

CI

*

M = Zr.Hi

@so-carbon atom has been observed for complex (67) formed by the reaction of (66) and Bu"Li in benzene.61 C-N chelation has also been observed for the titanium and zirconium complexes (68), (69), and (70). These compounds belong to the class of the sterically hindered phosphoraniminato complexes, and exhibit modest catalytic activity in ethene polymerization. The complex formation is reflected by the elongation of the N P bond length, 163.1(3) pm in (70) versus 156.2(1)pm in the free ligand (C6H&k3- 1,3,5)NP(Ph2)CH2(C6H4B~t-4).62 The reaction of the P-alkynyl silylated phosphoranimine (71) with KP(H)Ph yields a cyclic product which adopts a polymeric structure (72) after careful recrystallization from diethyl ether. The formation of the cyclic structure probably arises from addition of [P(H)Ph]- to the phosphoranimine, followed by a 1,3-H shift from phosphorus to carbon. In the structure of (72) each potassium atom is coordinated to one N atom and two P(II1) atoms from different ligands with a mean K-P distance equal to 327.3(6) pm.63Attack at the carbon atom adjacent to P(V) has been observed for the reaction of (73)with LiP(R)Ph (R = H or SiMe3But),affording the products (74a) and (74b).The tin analogues (75a) and (75b) can be prepared in low yield by the reaction of SnC12with (74a) and (74b), re~pectively.~~ Difunctional phosphoranimine- phosphine ligands [(76a), R = Me&; (76b),C6F4CN-4;(76c),CsF4N-4]have been converted into Ru (11)(77a - 77c) and

Organophosphorus Chemistry

350

(53)

(57)

(54)

\\

/ 0.5 GeCI,

0.5 Pb[N(SiMe&

(56a) M

Sn

(56b) M = P b

@,

P=NSiMe,

/

Me3Si\

/

1

Me3Si,

N InCI,

ph28i L

(61)

\

Ph3GeCI

Me3Si, N Ph,P//

GePh,

b (62)

7: Phosphazenes

351

Me3Si-N

MenH ?;

C'

'N-SiMe3

SiMe3

(: BunLi

N-SiMe,

Ru(1V) (81a - 81c) complexes when allowed to react with [{Ru(q 6-p-cymene)(pCl)Cl},] and [{ Ru(q3:~3-CloH16)(~-C1)Cl}*], re~pectively.~~ Treatment of (77a 77c) with NaPF6 in methanol solution shows coordination of the metal atom by the imino nitrogen with the formation of the cationic complexes (78a - 78c). It has been found that the Ru-N bond in the complexes (78b - 78c) can be cleaved under very mild conditions by a large variety of anionic and neutral ligands. An example is given for the reaction of (78b) with NaNCO yielding (80). When treated under the same reaction conditions, complex (78a) does not exhibit this Ru-N bond instability, but the metathesis of the chloro ligand by an NCO group (79).64

Organophosphorus Chemistry

352 H

Ph Buk'

i KP(H)Ph iii CBu'

,NSiMe3 '

-P-K-P-K-P-

D

ii recrystall. from Etfl

Phz

/F?\ ,

Bu'C,

/

\ Ph ,,NSiMq

$-Fh2

Me2

Me3SiN=P,

C

Ill

LiP(R)Ph

Me P-C'

thf

MesSiN, ,PPh

3,

Me P

3,-

SnCI,

Me,SiN,

\

Li (thfln

CPh

(73)

R I ,C-Ph

R I /C-Ph

(74a)

R = H, n = 1.5

(74b)

R = SiMe,Bu', n = 2

d\

/PPh

Sn,

Ph?

/NSiMe3

/~-pICle2 Ph-C' I R

(75a)

R=H

(7%)

R = SMe2But

Depending on the metal involved, different reaction products have been observed for the reaction of equimolar amounts of phosphoranimine (76a) and [M(C0)312(MeCN)2] (M = Mo, W). An octahedral complex [MO(CO)J(NP(P~)~CH~PP~~-P,N}] has been formed for M = Mo, whereas for M = W the reaction product appears to be a seven-coordinated complex with formula [W(C0)312(NP(Ph)2CH2PPh2-P,N)],which hydrolyses to give an amide complex.65 One report deals with an elegant method that seems to be generally applicable to synthesize P-metalated phosphoranimine derivatives. Treatment of the cationic phosphite complexes (82) and (83) with NaNH2 affords the P-metalated phosphoranimines (84) and (85),respectively. The short N P bond lengths in (84) and (85) [mean value 157.4(1)] are in complete agreement with this bonding mode. The stability of the complexes has been discussed.66 Preparation and structural data of the labile complex [Me3SiNPPh3.1CN] have been d e ~ c r i b e d .The ~ ~ electrochemical and spectroscopic properties of p-phenylene phosphine imides, monomeric and polymeric, have been studied.68 Bis(iminophosphorano)methanes are versatile ligands in complexation reactions as the acidic methylene groups can be deprotonated, thus allowing complexation not only at nitrogen but also at the methylene carbon. The preparation and structure of the chromium complex [HC((PPh2)NSiMe3)2Cr(y-C1)21 (88) via (86) and (87) has been described. Preliminary results of ethylene polymerization in the presence of (88) have been mentioned.69Also the reaction product of CrC13.thf and the methane derivative CH2[P(Ph2)NC6H2(Me3-2,4,6)I2 has been claimed to be an active component in catalysts for ethylene p~lymerization.~' Complete deprotonation has been observed for the reaction of (86) with M[N(SiMe3)2]2(M = Pb, Sn), affording the products (89a - 89b).The reaction of

3 53

7: Phosphazenes

1+ Ph2 L

(7k) R=SiMe, (76b) R CeFhCN-4 (76c) R=CSF,N-4

(77a) (77b) (770)

(78a) R = H (78b) R = C,F,CN4 (7&) R=CsFdN4

R = SMe, R = CeFdCN4 R = C,F,N-4

(79)

(80) R

R=H

Me

I

(76a) (76b) (76c)

R=SMe, R = CBF,CN-4 R = C$,N4

@la) R = SiMe, (81b) R = CeF,CN-4 (8lc) R C5F4N4

MeMT Me

m, \

OC‘

,OMe Fe-T‘OMe HNPh

-

pF6

NaNH2 P

NaNH,

\

OC,,,

,OMe oc/Fe-F-OMe NPh

m/,,\

,OMe ,Ru-F--OMe oc NPh

CnF4CN-4

354

Organophosphorus Chemistry

(87) with GeC12 or PbC12, yielding (90) and (89a), respectively, also shows a complete d e p r ~ t o n a t i o n . ~ ~

?Me3

(89a) (89b)

M =Pb M =Sn

The formation of the biscarbene complex of zirconium (92) from silylated phosphoranimine (91a) and [Zr(CH2C6H&] also proceeds with complete dep r ~ t o n a t i o n .It ~ ~is remarkable that the complexation of Cp*TiC13 with H2C[P(R2)NSiMe3I2 [(gla), R = Me; (91b),R = Cy; (91c),R = Ph] and leading to compounds (93a - 93c)and (94a - 94c) does not involve the methylene group. Steric factors are supposed to be responsible for this behavior.73 An interesting study concerns the preparation of phosphoranediiminato complexes of NiC12 (95 - 98) and their application as precatalysts for ethylene oligomerization. The selectivity in oligomerization can be tuned by the nature of the carbon backbone of the ligand.74 The bidentate ligands R2P(E)NHP(E’)R’,(R, R’ = any organic group; E, E’ = 0, S, Se) still attract considerable attention, due to their ability to form chelate rings with a large degree of conformational freedom. Unsymmetrical ligands R2P(E)NHP(E’)R’,(R, R‘ = Ph, OPh, Pr’; E, E’ = 0, S, Se) have been prepared from the condensation reaction of R2P(E)NH2(R = Ph, OPh; E = 0,S, Se) with R’,P(E’)Cl (R’= Pri, Ph, OPh; E’ = 0,S, Se). Generally, the crystal structures of these compounds consist of hydrogen bonded P(E)-NH dimers with a preference for 0 . . . NH, rather than S . . . NH or Se . . . NH. This is exemplified for (Ph0)2P(0)NHP(S)Ph2(99). A chain or polymer-like structure has been found ( Deprotonated ligands form six- or fourfor (PhO)2P(0)NHP(S)(OPh)2 membered chelate rings with Pd(OAc),. Six-membered chelate rings have been observed for palladium complex (101). It has been argued that the ability of oxygen to act as donor atom depends on the substituents at phosphorus.

355

7: Phosphazenes SiMe, I Me2

P=N’

SiMe3 [Zr(CH2C6Hdd

H2C,

11

b

P=N, Me2

SiMe3

\

\

N=PMe2 I SiMe3

Me2P=N I SiMe,

R2 ,SiMe3 P=N f

H2C, P=N, R2

SiMe,

(91a) (91b) (91c)

FPh3

R = Me R=Cy R=Ph

(93a) (93b) (93c)

(94a) (94b) (94c)

R=Me R=Cy R=Ph

a

iPh3

EPh3 \ NiCI2

H?N H2GN/ N\NiC12 II

PPh3

a N > NN iC12 I1

PPh3

N/ II PPh3

R=Me R = Cy R=Ph FIPh3

N PhHC’

\NiC,2

Phd,

/

! PPh3

Electron-withdrawing groups such as phenoxy render the oxygen too ‘hard’, thus preventing coordination to the metal centre. This leads (102a) and (102b) to form four-membered chelate rings with general formula [Pd{PR2P(S)NP(0)( OPh)2-N,S}2] .75 Oxidation of palladium powder by Ph2P(S)NHP(S)Ph2.12has been shown to yield the complex [Pd{ Ph2P(S)N(H)P(S)Ph2}]12. Recrystallization of the reaction product from MeCN gives [Pd{ Ph2P(S)NP(S)Ph2-S,S’)2], which possesses a similar structure to ( 101).76 Spectral and structural evidence point to a reversible isomerism that occurs between a tetrahedral and square planar NiS4 core in the homoleptic complex [Ni{ Ph2P(S)NP(S)Ph2-S,S’}2].77Promising non-linear optical properties have Instead of a mononuclear been reported for [BU~~S~(P~~P(S)NP(S)P~~-S,S’}~].~~ complex an unusual binuclear complex (103) has been formed by the reaction of K[Me2P(S)NP(S)Ph2] and BrMn(CO)s. In this complex the manganese atoms are coordinated to three sulfur atoms, resulting in the coupling of two sixmembered chelate rings by Mn-S bridges.79 Six-membered chelate rings are also present in the tellurium complexes cis- and ~~U~S-[T~{P~~P(S)NP(S)(OP~)~-S,S’}~.~~ An interesting complex (104) has been synthesized by the reaction of K[Ph2P(S)NP(S)Ph2] and the dimer [Et4N]2[Mo2Cu6Br2I40~S6]. Preliminary non-linear optical (NLO) data of (104)

Organophosphorus Chemistry

356

(99)

(102a) (102b)

R=Pr' R=Ph

I oc

(103)

in D M F (DMF = dimethylformamide) solution have been reported.81 In addition to the synthesis of the metal bis chelate complexes [M{Ph2P(S)NP(Se)Ph&T,Se]2](M = Co, Zn, Sn) and the tris chelate complex [Bi{ Ph2P(S)NP(Se)Ph2-S,Se}3],a new method has been described for the preparation of Ph2P(S)NHP(Se)Ph2,which involves the reaction Ph2P(S)NH2and Ph2P(Se)Cl in the presence of NaH in thf.82Organotellurium(1V) compounds with general formula (105a - 105c)and (106) have been obtained by the reaction of RTe12(R = C4H8, C8H8)and K(Ph2P(E)NP(E)Ph2}.Two different sets of Te-E lengths have been observed, one ranging from 262 - 272 pm, the other from 328 346 pm. The latter set represents a weak coordination between Te and E. The compounds C4H8Te12 and Na{ Ph,P(0)NP(O)Ph2}react to form the unexpected ionic compound (107)in a low yield.83 It has been shown that complex formation of Ph2P(Se)NHP(E)Ph2(E = Se, S, 0)with AgBr does not lead to deprotonation of the NH-moiety. Instead complexes (108a), (108b)and (109) have been isolated.84The mode of coordination in

7: Phosphazenes

357 4-

(10%) (105b)

E = Se, R = CH ,, E m s , R=CdHB

(10%)

E = S , R=CsH8

(106)

E

S, R = C,HB

(107)

R = CH ,,

(109), involving only Se centres, follows the same reasoning as given before.75 Complex (108a) appears to convert into (110)upon standing in pentane-acetonitrile. The preparation of bicyclic bromide (111)was in~luded.’~ Computational studies concerning theoretical approaches to the intrinsic basicity of neutral nitrogen bases have been reported, including those of phosph0ranimines.8~~~~ The non-ionic phosphazene bases BEMP (112p7BTPPs7(113) and (114, R = Ph)” appear to be excellent catalysts for the Michael addition reactions. Thus the yield of the coupling reaction of ethyl isocyanoacetate with 1,2-bis(4-bromornethylphenyl)ethaneis increased by the addition of the phosphazene base BEMP.89Polymer-supported BEMP (P-BEMP) has been applied for the allylation of 2H-benzo[d]1,3-dioxolan-5-ol by ally1 bromide.” Cyclodehydration of 1,2 diacylhydrazines by tosyl chloride in the presence of PBEMP leads to excellent yields of 1,3,4,-0xadiazoles?~Addition of P-BEMP also improves the yield of the Hofmann elimination step in the synthesis of tertiary mines using REM resin (polymer-bound acrylate Corresponding a-sulfonyl carbanions are generated from o-halobenzyl and p-halobenzyl sulfones by means of the base Et-P2 [(Me2N)3P=NP(NMe2)2=NEt]?3 The phosphazene base But-P4 [{(Me2N)3P= N}3P = NBu’]

Organophosphorus Chemistry

358 r

l +

(108a) E = S (108b) E = S e

But

I

BEMP

BlPP

or its conjugate acid [But-P4H]+ have been widely applied in organic syntheses9498and in anionic ring opening polymerization of e p o ~ i d e sand ~ ~cyclo~'~ silo~anes.'~'-'~~ Phosphazene bases with 1, 2 and 4 phosphorus atoms, among which is But-P4, have been used as catalysts for isomerization of non-conjugated unsaturated glyceride mixtures to conjugated g1y~erides.l~~ Nucleophilic substitution of chlorine in chlorinated aromatics (e.g. chlorobenzene) by X (X = F, OMe, Sbu', OPh, etc.) can be achieved in high yields by {[(Me2N)3P= N]4P} +Xas nucleophilic agent.lo6Cations of {[(Me2N)39P= NI4P}+X- (X = OH, OMe) are active catalysts in ring opening polymerization of propylene ~ x i d e . ' ~ ~ ~ ' ~ ~ Improved methods of preparati~n'~' of [(Me2N)3P= N]3P = 0 and its applicationl'0, 111, 112 in ring opening polymerization have been covered by patents. Catalytic properties have been described for [{ Ph2P(NCHzPh)2}zZrJC12113 (polymerization of olefins) and (Ph3P= N-PPh3)X (X = C1, Br) (phase transfer cata-

7: Phosphazenes

3 59

l y ~ t ) . ' ' ~The ~ ' ~interaction ~ of C13P=N-P(0)C12with Me3Si(OSiMe2),0SiMe3(n = 0, 1,2) has been studied by 31Pand 28SiNMR methods."6 X-ray structure determinations of some miscellaneous linear compounds containing a N = P entity are summarized in Section 5."7-'33

3

Cyclophosphazenes

Review papers on cyclic compounds with a phosphazene moiety have covered several areas, viz. metal complexes derived from organo-s~bstituted,'~~ polymers with cyclotriphosphazene en ti tie^'^^*'^^, and chemistry of perfluorinated cyclopho~phazenes.'~~ Azaphosphinines have been reviewed in the scope of the phosphorus-carbon heterocyclic chemistry.138 Quantum mechanical calculations on a number of homogeneously substituted cyclotriphosphazenes clearly support the absence of aromaticity in the phosphazene ring. The N P bond is highly polarized with an electron transfer from phosphorus to nitrogen. The charge density on phosphorus varies with the substituents, whereas the charge on the ring nitrogens remains almost con~ t a n t . 'This ~ ~ finding agrees with the results from an ab initio and density calculations on (NPC12)3and (NPF2)3,showing a greater positive charge on the phosphorus atoms for the fluorine deri~ative.'~' The preferential attack on a PF2 rather than on a PC4 centre for the reaction of a mixture of (NPF2)3and (NPC12)3 with NaOPh also reflects the differencein charge density.'40It has been shown by theoretical calculations and UV-photoelectron spectroscopy that the substituent effect of the phosphazene ring in compounds N3P3F5R with R = Et, CH = CH2 and C=CH is similar to that of a CF3group and occurs via a a-bond polarization mechanism. The same mechanism also applies for the charge distribution in compounds N3P3F5ECH= CH2 (E = 0, CH2). No mesomeric effects were observed for styryloxy substituted cyclophosphazenes.'41Interesting results have been obtained from a structural investigation of (NPF2)4. Below the phase transition temperature (- 74 "C), the eight-membered ring appears to be nonplanar with a saddle form, resembling the K form of (NPC12)4.Above the phase transition temperature, disordering of the nitrogen atoms leads to two superimposed puckered rings, chair and saddle shaped.'42Studies on the mesogenicity of cyclophosphazenes with different hard groups and long alkyl or alkyloxy end groups have been ~ 0 n t i n u e d . The I ~ ~ thermal stability of the mesophase of phosphazene derivatives (114a - 114c) and (115a - 115b) decreases in the order phenylazophenyl > phenyliminomethylphenyl > bi~heny1.l~'NMR studies of smectic A phase of the liquid crystals of (114a, R' = C12H25) show the side groups being parallel to the magnetic field with the average ring plane perpendicular to the magnetic field direction.14 Dielectric properties of the smectic C* phase of (114d)have been in~estigated.'~~ Splitting patterns in the 31PMAS spectra for the PCl and PC12 groups in trans-(NPClNMez)3 and (NPC12)3can be ascribed to P-Cl spin-spin interaction~.'~~ The structure of amorphous tris-(2,2'-dioxy- 1,l'-binaphthy1)cyclotriphosphazene (116) has been studied by theoretical methods in combination with

Organophosphorus Chemistry

360

(115a) R =

(1 16)

OR

OR

I

I

- A ~ -O C l , H ,

(1 17)

energy dispersive X-ray diffra~ti0n.l~~ Investigations into the uptake of guest molecules in the channels in the crystal structure of tris(o-pheny1enedioxy)cyclotriphosphazene (117) have been continued. Selective clathrate formation of (117) with polymers or small molecules offers the possibility to separate these compounds based on their microstructure, molecular weight and end-group functionality. Both for linear alkanes and polymers, the higher molecular weight species are absorbed ~referentia1ly.l~~ Interaction of thf clathrate [( 117)][thf]0.58 crystals with dipolar molecules such as 4-N,N-dimethylamino-4'-nitrostilbene at about 120 "C in vucuo leads to a partial exchange of thf by these molecules. The exchange process, which starts from the end-capped crystal faces, has been discussed in terms of counter d i f f ~ s i 0 n .Similar l~~ results have been obtained using iodine as guest molecule. Thf-free iodine complexes could be obtained by dissolving (117) and iodine in mesitylene at 80 - 100 "C and subsequent slow cooling of the solution. Conductivity measurements on [(117)][12], (y = 0.7) show a preferred conductivity along the iodine chains in the channels of the crystal structure of (117).''O The molecular behavior of the deuterated guest molecules viz. n-alkane~'~'and six-membered organic ring^'^^,'^^ in (117) has been studied by dynamic *HNMR

7: Phosp hazenes

361

techniques. In order to study the segmental mobility in dendrimers, solutions of compound (118) with twelve pyrene labels have been investigated by Fluorescent Spectroscopy and compared to the model molecule (119) having two labels. It turned out that that the interior of the dendrimer contains solvent molecules adjacent to the pyrene-labeled side chains. The movement of the pyrene groups is influenced by the solvent molecules but not by the dendrimer core.154

6

I

L

(120a)

R = H, X = CI

(120b) R = Me, X = I, (120c) R = Me, X = MeCOO

Preparation and possible applications of polycationic dendrimers (120a 120c)have been patented.'55 The kinetics of the reaction of [NP(OPh)(OC6H4(CH2CH= CH2-2)}I3with bismaleimides has been investigated by DSC ana1y~is.l~~ Conformation polymorphism has been observed for a chiral spiro-cis-ansabridged spermidine derivative of NPPh2(NPC12)2(121).15' by dibenzylamino groups Chlorine substitution in (NPC12)3or (NPC12)2NPPh2 is governed by steric rather than by electronic effects with a preference for trans-

362

Organophosphorus Chemistry H2C'b'FH2 I

H2

HN, ,N-C-CH2 N/p\ 'N It

I

\ CH2 I

isomers in the case of bis(dibenzy1amino)d e r i v a t i ~ e s .Compounds '~~ with general (R = NMe2, morpholinyl) and formula NPR2[NPRNH(CH2)3Si(OEt)3]2 [NP{ NH(CH2)3Si(OEt)3)2]3 have been synthesized to be applied in sol-gel type reaction^.'^^ Isomer ratio of the bis-substituted products formed by the reaction of (NPC12)3and FcCH2NH2(Fc = ferrocenyl) appears to depend on the polarity of the solvent used. A surprising preferentially gerninal substitution pathway has been observed for the reaction of (NPC12)2NPCl[O(CH2)40C(0)CHMe = CH2] and FcCH2NHMe. Electrochemical studies of the ferrocenyl derivatives show one-electron reversible oxidation-reduction processes.lm The reaction of ferrocenylcarboxaldehyde FcCHO and methylhydrazine substituted cyclophosphazenes constitutes another procedure to link ferrocenyl groups to the cyclophosphazene system. In these compounds the ferrocenyl group is coupled to the phosphazene ring via a -N(Me)-N(H)= C- bridge.16' Decomposition of the arylbis(azid0)phosphanes (122a) and (122b) in hexane solution has been shown to yield, among other products, the azidocyclophosphazenes (123) and (124), respectively.'62 Another four-membered phosphazene ring (126) has been prepared by pyrolysis of azide (125) (Cp* = C5Me5,Mes* = C6H2But3-2,4,6). Metallation of (126), followed by protonation with ButOH gives the tautomeric cyclodiphosphazane ( 127).'63 Nickel dichloride complexes of cyclotriphosphazenes (NPR2)3(R = NHEt, NHCH2C6H5, OEt) have been prepared and characterized. These complexes have been investigated for their antifungal activity. In all cases, lower activities are found in comparison to a current industrial product Dithiane M-45.164The dimethylpyrazolyl (Dmpz) derivative (128), and pyrazolyl (Pz) derivatives (131) and (132) have been proven to be excellent starting materials for the preparation of Re@)carbonyl complexes. The cyclophosphazenes (131) and (132) have been prepared by the reaction of their respective dichlorocyclophosphazene precursors (129) and (130) with molten pyrazole. Compound (128) reacts with ReC1(C0)5to form a complex cation (133). A cationic complex (134) has also been formed from the reaction of (131) with Re(MeCN)3(C0)3fSbF6-in thf, whereas (132) forms a neutral complex (135) in CH3Cl. It is noteworthy that the rhenium center interacts with two gerninal pyrazolyl groups in (135), whereas no interaction with nitrogen of the phosphazene ring takes place.'65 Deprotonation of [NP(NHC6H40Me-2)2]3with twelve equivalents of Bu"Li in thf has been reported to yield the dodecanuclear lithium complex [Li12{NP(NC6H40Me-2)2)3(CH2 = CH0)6(thf)6].In the crystal structure of this complex six lithium atoms are located on each side of the phosphazene ring.'66

7: Phosphazenes

363

/

(124) R = C6Hfle3-2,4,6 Cp*, N3

AT m.

Cp*-P( N(H)Mes*

N(H)Mes*

P' I\\ N+ /N IP\

Mes*(H)N

i MeLi

ii B ~ O H

Cp*

Cp*,

+NMes*

,p\ HN, ,NH P M=*N+ %p*

The cyclophosphazenes [NP(OPh)2l2NP(0Ph)(OC6H4CH2CN-4) and [NP(OC6H4CH2CN-4)2]3have been used for complexation reactions with a number of 3d-transition metal chlorides. The complexes have been characterized by physical methods and elemental analysis.'67 A new synthetic method describes the synthesis of aryloxy-substituted cyclotriphosphazenes [NP(OC6H4R-4)2]3(R = H, Me, OMe, But, CHO, F, C02Me, C02Et, C02Bun,Ph, NOz) from (NPC12)3and the corresponding substituted phenols in refluxing MeCN with an excess of anhydrous potassium phosphate.16* A study of the coordination behavior of the crown ether substituted cyclophosphazene (137) showed that, for complexation of Na+ and K + ions, only crown ether oxygen atoms and water molecules participate in the complex f ~ r m a t i o n , ' ~whereas ~ ' ~ ' complexation of Ag takes place via crown ether oxygens and a ring nitrogen.'71It has been shown that chlorine substitution of (136) by sodium phenolate or sodium 2-naphtholate in thf is controlled by supramolecular assistance involving the transition state (138), thus following the sterically unfavored geminal pathway and ultimately yielding (139) as major product. It has been stated that the same transition state, however, hampers a geminal pathway at the second stage of substitution, unless the co-substituent +

364

Organophosphorus Chemistry

can act as an electron-withdrawing entity. This is the case for reactions with the sodium enolates of acetylacetone or ethyl acetylacetate with the formation of the bis(gemina1)compound ( 140).'72Substitution reactions with MOC6H4N02-4(M = Li, Na, K) reveal the role of the cation in the substitution process. The smaller ions Li+ and Na+ show a better affinity to the crown ether moiety than the larger K + and are associated with a predominately geminal substitution pattern [formation of (141)]. The reaction with KOC6H4N02-4affords (142) as major p r 0 d ~ c t . IInterestingly, ~~ when incorporated in solvent polymeric membrane electrodes, aryloxy or mixed aryloxy and alkylamino derivatives of (136) and (143) show a pronounced selectivity for the larger cations Rb+ and Cs+ over the smaller Li+ and Na+ ions.'74 31PNMR study of the chiral configuration of the unsymmetrical substituted cyclophosphazenes (146) and (147), prepared from (136) via (144) and (149, has shown these compounds to be diastereoisomeric each consisting of two different racemic mixtures.'75The spermine-bridged cyclophosphazenes (148) appear to exist in meso and racemic forms, which for the gem-diphenyl derivative were separated by column chromatography and investigated by 31PNMR spectroscopy and X-ray structure determination^.'^^ Cyclotriphosphazenes with one (149) or two radical centers (150) have been prepared by a simple substitution reaction involving tris(2,2'-dioxybipheny1)cyclotriphosphazene and (4-hydroxy-2,3-dichlorophenyl)-bis(2,4,6trichloropheny1)methyl radical and Cs2C03as HCl ~ c a v e n g e r . ' ~ ~

365

7: Phosphazenes CI,

C ,I I

CI,

co F'yr = pyrmdinyl

CI

2:

oJ .,

ArONa

O.1

C

O

J

CI, CI N'P
Me R=

M6 I

C=C-C-Me H I1

or

C-C-C-OEt

n

II

M = Li, Na

/ CI, N";"

CI,

,CI

,CI

H N-"N

H

n=2-12

The introduction of the reactive oxazoline group into the triphosphazene ring has been achieved by the reaction of (NPCl& and 2-(4-hydroxyphenyl)-2-oxazoline, giving a hexasubstituted product (lSl).The reactivity of the oxazoline entities in (151) could be demonstrated by reaction with 4-benzoylbenzoic acid [formation of the photosensitive cyclophosphazene (152)]17' by the reactive blending with poly(ethy1ene tere~hthalate),'~'and the compatibilizing activity for polycarbonate - polyamide blends.'79 Mono- and bis(ferroceny1ethoxy) derivatives (153, 154) and a mono(ferrocenylisoproxy)derivative (155) have been prepared by the reaction of (NPC12)3 and the appropriate lithium alcoholates. Introduction of a second ferro-

366

Organophosphorus Chemistry

Nd' -9

HN, ,NN*'>N

(CH& -N,p,NH N' >N

(148a) R = P h

(14%)

R = BdNH

CI

CI

CI

q6

CI

bCI

C CI I

'CI

(1 49)

(1 50)

cenylethoxy group provides a non-separable mixture of disubstituted isomers with the cis-isomer being the major compound. Electrochemical experiments show the ferrocene centers in the disubstituted isomers to be independent.180 Metal ion (Cr3+,Fe3+, Ce3+ and Eu3+)complexes with the new cyclophosphazene derivative (156)have been described.181 Interaction of hexakis(4-pyridylmethoxy)cyclotriphosphazene with silver alkylsulfonates AgS03C,H2,+1(n = 12, 14,16,18)has been reported to lead to a

367

7: Phosphazenes

CI,

,CI

CI,

CI

N,p
CI ...I

,AN:P< CICI

-CH,~HO

& HO,

I

Me

,OH

c=c

Ho\ R=

c=c

/

0

I I ./"-C+o

0

supramolecular self-assembly, forming rod-like polymers with three silver sulfonate groups per cyclophosphazene ring. Each silver ion is coordinated to two pyridyl nitrogens belonging to different cyclophosphazene rings. Additionally, the polymer rods arrange into lamellar structures for complexes with alkyl chains with n > 12.'82A similar self-assembly mechanism has been found for hexakis(4-carboxyphenoxy)cyclotriphosphazeneand p-xylenediamine, resulting in the formation of a 1:3 ionic complex (157). A polyamide (158) has been formed by heating (157) in a sealed tube at 240 "C in the presence of an excess of p-~ylenediamine."~ The preparation of a number of fluoroaryloxy (OCsH4F-4,0C6F5,OC6H4CF34) derivatives of (NPC12)4has been described.ls4 Cyclic P-C organo-substituted phosphazenes have been obtained from the reaction of N-silylphosphoranimines Me3SiN = PMe(R)OR' (R = Me, Ph; R' = OCH2CF3,Ph) with trifluoroethanol. The reactions proceed at room temperature and give the cyclophosphazenes (NPMe2)3(R = Me) and cis- and trans(NPMePh)3 (R = Ph) in high yields.lg5Another method to prepare organosubstituted cyclophosphazenes has been reported and consists of thermolysis of

368

Organophosphorus Chemistry

w t

240 O C

Q co2C0,-

Me3SiN= PPr"(R)OPh under dynamic vacuum conditions (removal of MesSiOPh). The trimers (NPPr"R)3(R = Pr', Hex", Ph, OPh, OCH2CF3)formed in these reactions appear in a cis and trans onf figuration.^^^ A valuable extension has been given to the chemistry of the mixed ring system (NPC12)2NSOCl(159). Friedel-Crafts reaction of (159) with C6H5Buffollowed by a fluorination reaction with KS02Fgives the S-aryl derivative (160).The fluorine atoms in (160) can be easily substituted by a reaction with LiO(CH2)30Li providing the ansa derivative (161) as major product. The dispiro compound (162) has been obtained by the reaction of (160) with Me3SiOCH2(CF2)2CH20siMe3 in the presence of C S F . ' ~Reactions ~ with the S-phenyl derivative (163) show a geminal substitution pattern with FCCHRP(S)(OCH~OL~)~ (R = H, Me) affording the monospiro compounds (164a) and (164b). Dispiro derivatives (166a) and (166b) have been obtained in good yields by the reactions of (165a) and (165b). An analogous substitution reaction affords compound (168) using (167) as starting material.187Isomer formation has been observed for compound (168), comparable to isomers of the analogous compound ( 169).'87

369

7: Phosphazenes

N/xN

0, CI,I

,d,N,

c1

CI

I CI

. PC''CI

i C,H,B~IAICI,

1 KSqF

(CF&HflSMe&

I CsF

(164a) R = H

(164b) R - M e

(I=) X=H

(166s) X = H

(165b) X = CI

(166b) X = C I

370

Organophosphorus Chemistry

A reversible ring skeletal substitution has been observed for the reaction of the boratophosphazene (170) with one equivalent of AlMe3, which results in the formation of the aluminatophosphazene (171). This (171) reacts with AgBF4 quantitatively to give the fluoroboratophosphazene (172), now replacing aluminum by boron.18*

(1 71)

(1 70)

(172)

Cyclophosphazenes with polymerizable substituents form the basis for the preparation of organic polymers with pendant phosphazene groups. Vinyloxy derivatives (NPC12)2NPCl(OCH= CHZ) and (NPC12)3NPC1(OCH= CH2) have been described to undergo radical homopolymerization and copolymerization, exhibiting a 'vinyl acetate' polymerization behavior. Thermolysis of the homopolymer [CH(OP3N3C15)CH2In (173) appeared to lead to cross-linking processes and yields polymer (174) accompanied by elimination of HCl and the 0x0-bridged dimer (175).189 The pyrazolyl derivative (177a) has been prepared in high yield from the chloro precursor (176) and 3,5-dimethylpyrazole. Polarization of the vinyl group in the pyrazolyl substituted trimer (177a) is prevented by the presence of the biphenyloxy spacer between the double bond and the phosphazene ring. Interesting cross-linked copolymers (178) exhibiting a high loading of pendant cyclo-

HCI

NGr'CI

+

-

phosphazene groups have been synthesized from (177a) and divinylbenzene. Copolymer (178) reacts easily with CuC12 to give a hydrolytically stable phosphazene-Cu complex (179), that has been applied successfully as heterogeneous catalyst in phosphate ester hydrolysis. Application of the complexes (180a) and (180b) failed as these compounds decomposed during the hydrolysis experiment~.~~* In a related study, preparation of the Pd(0) complex of the cross-linked copolymer (183) [prepared via (181) and (182)] and its catalytic activity have been investigated and compared with the small molecule model (184). The polymeric Pd complex appeared to be effective in heterogeneous catalysis of the Heck arylation reaction. Recycling of the catalyst is possible without significant loss of activity.191 Another approach for the preparation of organic polymers with cyclophosphazene side groups involves the Staudinger reaction of an azido- substituted cyclophosphazene with a phosphine residue in an organic copolymer. Freeradical copolymerization of styrene with diphenyl-p-styrylphosphine yields

371

7: Phosphazenes

CI. a,d\N-'P:c Il

AIW

I CI

R = C,H,C,H,(CH=CH24)

(177a) R = C$iH,C6H,(CH=CH2-4)

(18Oa)

(177b) R = C&I,CHO4

(18Ob) R=C&14CH04

copolymer (185), which can react with the azidophosphazenes (186a) and (186b) to give the polymeric structures (187a)and (187b). An analogous procedure with methyl methacrylate results in formation of copolymers (189a) and (189b) via copolymer (188). It has been demonstrated that the incorporation of cyclophosphazene groups improves the thermal stability and fire resistance of the organic

copolymer^.'^^ Considerable interest still exists in the application of fluorine-containing cyclophosphazenes in lubricant technology. Recent advances in the use of N3P,(OC6H4F-4),(OCsH4CF3-3)6-n (n z 2; code name X-1 P) as lubricant either by itself or as an additive to perfluoropolyethers (PFPE) have been reviewed.'93 Addition of X-1P to PFPE films reduces the critical dewetting thickness on amorphous nitrogenated carbon compared to that of neat PFPE.'94 The influence of x-1P on the stabilization of the PFPE lubricant for the slider/disk interface in hard disk drives has been studied.19' Micro-phase separation of X-1P

372

Organophosphorus Chemistry

I

cross-linked polymer

AlBN

RO, N",:

0

OR

i PdClz(PhCN)*

8 CH=CH,

ii N2H,.H@,

PPh3

in PFPE film on hard disk media has been ~ t u d i e d . ' ~ ~Cyclophosphazenes *'~' N3P3(0CsH4R)2(0C6HSCF3'3)4168 have been compared with respect to the influence of substituent R on their tribological properties in a steel-steel or steelaluminum system. It turned out that compounds with a polar substituent R give a much lower wear than compounds with nonpolar s ~ b s t i t ~ e n t sThe . ' ~ prepara~ tion and application of cyclotriphosphazenes as lubricants with perfluorooxyalkylene groups bonded to the phosphazene ring have been covered by patent s.199,200 The compound {NP[O(CH,),OC(O)C(Me) =CH2]2}3has been used as UVcuring agent for a polyurethane coating system.201Numerous patents cover the

7: Phosphazenes

373

I

PPh,

I

PPh,

(1 86a)

R = CsH5

I RPh2

(1 85)

OR

(187a)

R = C~HS

(187b) R = CH,CF,

(189,)

R=C,H,

(189b) R = CH,CF,

application of cyclophosphazenes with phenoxy or substituted-phenoxy groups as flame retardant additives in various formulations.202 The methoxy derivative [NP(OMe)2]3203 and the mixed amino phenoxy derivative2Mhave also been applied as flame retardant materials. The mixed cyclophosphazene NSO(OPh)[NP(OPh)& also appears to be an excellent flame retardant.205Other patents concern, amongst others, the use of (NPC12)3as cross-linking c a t a l y ~ t ~ ~ ' azido cyclophosphazenes as cros~-linkers,2~~ a cyclotriphosphazene-platinum complex as anticancer agent,208 water soluble cyclophosphazenes as photoinitiators:w polynorbornenes with cyclophosphazene side-groups as pH dependent membranes2I0and (NPF2)3,4as an additive for non-aqueous liquid secondary cells.211 X-ray structure determinations of some miscellaneous cyclophosphazenes are summarized in Section 5.212-220

4

Polyphosphazenes

Recent developments in the polyphosphazene chemistry have been re~ i e w e d . ' The ~ ~ *role ~ ~of~ polyphosphazenes as biodegradable polymer^^^^,^^^, as hydrogels for tissue enginee~-in&~~ and as induced helical polymers225has been discussed. Preparation and application of poly(thiony1 phosphazenes) are discussed in two review chapter^.^^^,^^^

374

Organophosphorus Chemistry

In a theoretical study, linear and non-linear properties of (NP), have been compared with those of (C = C), by using the Pariser-Parr-Pople approach.228 X-ray diffraction data from unorientated bulk samples have been used to determine the structure of the a-form of [NPPh2]229and of the ordered and disordered phase of [NPEt2]n.230The rheological properties of poly(2,2'-dioxybiphenylphosphazene) (190) have been studied.231.Its thermal degradation in the temperature range 100-200 "C only shows a decrease of molecular weight without change of chemical composition. Molecular dynamics simulations point to a preferred trans-conformation of the skeleton bonds. The polymer backbone adopts a distorted helical structure.232

0

0

(1 90)

Hydrodynamic and optical properties of polymers [NP(OR)2], [R = CH2CF3,CH2(CFJ2H, CH2(CF2)4H]have been a n a l y ~ e dMechanical .~~~ properties of polyphosphazene-silicate nanocomposites, prepared from { NP[(OCH2CH2)20Me]2}, (MEEP) and tetraethoxysilane, have been investigated as function of the catalyst Poly(methylpheny1phosphazene)((NPMePh),, PMPP) has been shown to stabilize gold nanoparticles. This stabilization has been tentatively ascribed to the interaction of gold with lone pair electrons of the nitrogen in the polymer backbone. The P M P P - Au composites are relatively stable at room temperature. During the preparation of the composites the size of the nanoparticles can be controlled by the amount of PMPP, the larger the concentration of PMPP the smaller the particle size.235In the preceeding Section the preparation of trimers (NPPr"R)3 from Me3Si = PPr"R(0Ph) and trifluoroethanol has been mentioned.Ig5The synthesis of polymers [NPPr"R], (R = Pr", Pr', Hex", Ph, OPh,OCH2CF3) (192) could be achieved by heating the corresponding phosphoranimines (191)in sealed ampoules without removal of any reaction product. Depending on the reaction temperature, polymers (193) can be synthesized.236 Several blends of organic polymers and polyphosphazenes have been investigated with respect to their c ~ m p a t i b i l i t y ?thermal ~~ degradation238and flame r e t a r d a n ~ y ~A~morphological ~. and thermal study of CNP(OCH2CH20Ph)zln shows the existence of two crystal forms.240 The conductivity of the system MEEP -LiC104 can be improved by the addition of a-A1203, which has been explained by an additional hopping of Li+-ions over the dispersed a-A1203particles.241From a NMR study of the N'' labeled MEEP-Li CF3SO3 system, it has been concluded that beside oxygen, nitrogen is also involved in the complexation of lithium It has been demonstrated by Raman spectroscopy for { NP[(OCH2CH2),0Me]2).LiCF3S03(x = 1, 2, 5), that association of triflate ions depends on the salt concentration and chain length of the organic side

7: Phosphazenes

375

PP I Me3SiN=P-OPh

sealed ampoule

I

AT 3-7days

R (191a) R = PI"

(191d) R = Ph

(192a) R = P P

(191d) R = P h

(191b) R =Pr'

(1918) R = OPh

(192b) R =Pr'

(191e) R = OPh

(192c) R = Hex" (1910 R = OCH2CF3

(191c) R = Hex" (1910 R = OCH2CF3

Me3SiN= P Pr" I-OPh

I

OCH2CF3 (1919

sealed ampoule AT 3-7days

-

+N=r+N=r+ OCHZCF3

OPh (1 93)

Polymers { NP(OCH2CF3)x[(OCH2CH2)20Me]2-x}n with x varying from 0.4 to 1.6 have been synthesized to prepare polymer gel electrolytes in combination with LiCF3S03 and propylene carbonate. All systems exhibit a larger mechanical stability than (MEEP).244Poly(phosphazene-ethylene oxide) copolymers with (OCH2CH2),0Meside groups have been prepared to be applied as solid polymer electrolytes. Their synthesis proceeds along a living polymerization of C13P= NSiMe3 with (194) and (195) as macroinitiators, and leads to the formation of poly(ethy1eneoxide)-block-polyphosphazenediblock (196) and polyphosphazene-block-poly(ethy1eneoxide)-block-polyphosphazene triblock (197) polymers, respectively. In an analogous way poly(ethy1ene oxide)-blockpolyphosphazene-block-ply(ethy1eneoxide) triblock polymers have been synthesized by using the living polymer [Cl(C12P= N),PC13]+PC16- and a poly(ethy1ene oxide) substituted trimethylsilyl phosphoranimine. Complexation with LiCF3S03shows conductivities at room temperature comparable with those of high-molecular weight MEEP h o r n ~ p o l y m e r s . ~ ~ ~ Based on the presence of carbazole substituents, the blue-light emitting polymers (198) and (199) appear to be attractive materials for electroluminescence application^?^^,^^^ Related polyphosphazenes (200)have been prepared aiming at photoreactive mate~ials.2~~ Poly[bis(4-methoxyphenoxy)phosphazenes bearing poly(pheny1ene vinylene) (201a, b) grafts have been reported to exhibit fluorescence in the blue region of the spectrum.249 Polymers with 4-hydroxyphenylamino groups have been prepared by the reaction of (NPC12)n with p-aminophenol. Chlorine substitution in the presence of K2C03takes place exclusively through the amino group via a non-geminal substitution pattern with a maximum degree of substitution of about 25 % (202). No chlorine substitution has been observed for the reaction of the 2,2' dioxybiphenyl derivative (203) with p-aminophenol at room temperature in the presence of K2C03. Using Cs2C03 as HCl scavenger, chlorine substitution takes

376

Organophosphorus Chemistry

place in refluxing thf, however, via the OH group, affording (204).250 Two methods have been presented for the phosphonation of poly(bromoaryloxyphosphazenes), viz. via sodium dialkyl phosphite as reagent or via a treatment with Bu"Li in combination with dialkyl chlorophosphate. The reactions are visualized by the product formation of (206) and (208) from (205) and (207),re~pectively.2~~ Polyphosphazenes with diphenyl phosphonate groups (209) have been synthesized by the reaction of the bromophenoxy substituted polymer (207)with Bu'Li followed by a rapid addition of diphenyl chlorophosphate in thf. Only 50% of the available bromophenoxy groups are converted to diphenyl phosphonate esters groups.252

i x Me3SiN=PC13 ii NaR b

OCH2CF3 MeOf

CI-P-

CI I+

CFSCHg N=i-

I

it

CH,CHflt

CF3CH20

Cl

P

i x Me3SiN=PC13

ii NaR

R I

R = O(CH2CH20)2Me

CF3CH2O 1

I

H r

x

OCH2CF3 CI H I I+ CH2CH2N- P=NP- CI (Pcl6)2 2I I OCH2CF3 CI

(1 95)

r

R

C H 2 C H 2 0 tCH2CH2NH P= II N-----f-$=N+PR, P OCH2CF3 R

7: Phosphazenes

377

In addition to the termination of living poly(dich1orophosphazene)with phosphoranimine-terminated poly(dimethylsiloxane), another method has been presented to synthesize poly(phosphazene-siloxane)block copolymers. Hydrosilylation reactions of hydride-terminated poly(dimethylsi1oxane) and allylterminated polyphosphazenes (210a, 210b) have been shown to yield polyphosphazene-block-polysiloxane-block-polyphosphazene polymers (211a, 2 11b).253

N

+-

‘ T ,

‘i;;

N= P(OCH2CH,),(OEt),

N= P(OCH2)x(OEt),

x +y =2, x

’y

N

‘N=N

0

0

Me

Me

(201a) R = H

(201b) R = OMe

378

Organophosphorus Chemistry

Phosphoranimine-functionalizedpolynorbornenes (2 13) have been prepared by ring opening polymerization of a mixture of norbornene and (212) using C12Ru(Pcy3)2(CHPh) (Grubbs catalyst) as initiator. In an analogous way, polynorbornene-graft-polyphosphazenes (215) have been synthesized by using a mixture of norbornene and (214).254 The reaction Of { [NP(O~CI~&)]~.~[NP( OC6H4CH2CN-4)2]o,is} (O2C12H8 = 2,2'-dioxybiphenyl) with Cr(C0)6 yields the green chromium complex ( [ N P ( 0 ~ C ~ ~ H ~ ) ] o . ~ [ N P ( ~ ~ ~ H ~ ~ ~ ~ Thermal ~ N - 4 )behavior ~]~.~~[~~(~ of this copolymer and its organometallic derivative appears to be almost identica1.255 (NPC1Snreacts with 1-hexanethiol to give the fully substituted thio polymer utilizing 4-picoline as base in thf solutions. Only degradation products are obtained when the reaction is carried out with sodium hexanethiolate as

CI I

tN=Fi--f; CI

I NH2 b

K2C03

Q OH

w

OH

0 0

*

""t; 0.8

NH2

nucleoplilic agent.256Also the introduction of thiophenoxy groups to (NPC12)n is accompanied by appreciable decomposition. Polymers (216) and (217a, b) have been obtained in low yields at room temperature in thf. The nucleophiles p-bromophenol or 2,2' dioxybiphenyl have been used to replace the remaining chloro l i g a n d ~ . ~ ~ ~ The poly(p-phenylene phosphoranimine) (218) has been prepared by a Staudinger reaction of 1,4-bis(diphenylphosphino)-2,5-bis(n-hexoxy)benzene

379

7: Phosphazenes CHzBr

Ye

QQ Me

Me

Me

he

005)

QQ i Bu”Li

ii OP(CI)(OEt)2

* 0

QQ Me

i Bu‘Li

ii OP(Cl)(OPh),

Me

Me

Me

n

Organophosphorus Chemistry

380

(2lOa) R = R = OCHSF,

(211a) R = R = OCH,CF,

(2lOb) R = OCH,CF,. R = (OCH&HJ,OMe

(211b) R = OCH2CF,. R = (OCH2CHJ20Me

Me+N=P-O-CH,

I

R = OCH,CF,

Q Br

Br

(21 6 )

R

(217a) R = H

(217b) R = Br

and 1,4-dia~idobenzene.~~* Coupling of an amine-functionalized Ru(I1) phenanthroline complex to a poly(thiony1phosphazene) backbone has been reported to yield polymer (219) with excellent oxygen-sensing Cyclolinear phosphazene polymers (221) have been prepared by polymerization of (220)2607261 with Grubbs catalysts as initiators. No polymerization has been observed using NP(NH2),{NPNH2[O(CH2)9CH= CH2]}2 as precursor, probably caused by metal-nitrogen interactions.260Polymerization of (220a, x =

7: Phosphazenes

38 1

9) with 1,9-decadieneaffords the copolymer (222).261 New cyclolinear phosphazene poly(ether ketones) (224a, b) have been synthesized by the condensation of the new spiro-substituted cyclophosphazene (223)with 4,4'-difluorobenzophenoneand a bispheno1.262 Nucleophilic substitution of the chlorine atoms in (NPC12)3by 3-t-butylhydroquinone leads to the formation of the corresponding hexa-substituted product, while the reaction with 3-methylhydroquinone affords an oligomer with a molecular weight about six times larger than that calculated for the monomer. The ratio 3-methyl / 2-methyl substitution, estimated from 'H and I3C NMR data, in combination with analytical data, points to a structure with one to two bridging methylhydroquinone units per phosphazene ring. The difference in reaction products has been ascribed to the smaller steric hindrance of the methyl group resulting in a limited protection of the OH groups group, thus allowing crosslinking.263The preparation of cyclomatrix polyesters from { [NP[OC6H3(Bu'OHex"

OHexn

R = NHBu"

//

phen = 1,I 0-phenantroline

Ru(phen)&I2

3)(OH-4)]2}3 and diacid chlorides has been ~ a t e n t e d . 2 ~ ~ Cross-linked phenoxycyclophosphazenes appear to be excellent flame retardant additives.265 Organo-substituted polyphosphazenes are widely applied in membrane technology. Membranes of [NP(OC6H4CF3-3)l.s(Oc6H4c02Li)~.2]~ doped with lithium triflate have been applied as protective coatings to lithium electrodes in lithium-water systems. These polymers have also been used in multilayer systems in combination with membranes of MEEP.266Dewatering of metal-ion containing solutions, using a cross-linked 1:l polymer mixture of [NP(OPh)2], and

382

Organophosphorus Chemistry

7% PCY3 Clg?=CHPh

CC,Ru=CHPh

or MesNANMes

pcY3

L/

(220a) R = 0Ph:x = 2 - 4 . 8 9

(221% R = OPh; x

(220b) R = ( O C H ~ H z ) @ e ; x = 2 4 9

(221b) R = (OCHFHJpMe; x = 2 J . 9

+

H,C=CH(CHJ,CH=CH,

(220a), x = 9

1

lM1-165'C

K 2 C q , iduene, dimethylaceiamide

(224) R = H (224b) R = F

= 24, &9

7: Phosphazenes

383

[NP(OC8H17)2]n as membrane, has shown permeation of water while retaining the metal ions.267Proton conductivity, methanol crossover and swelling of membranes consisting of sulfonated CNP(OC6H4Me-31, and poly(viny1idene fluoride-co-hexafluoropropylene) have been shown to depend on the composition and the degree of cross-linking.268 Blends of sulfonated [NP(OC6H4Me-3], and polyacrylonitrile have been cross-linked by UV radiation with benzophenone as initiat0r.2~~ They have been applied as polymer electrolyte membranes for direct methanol fuel cells, showing a low methanol crossover.269Low permeability for methanol has also been observed for membranes fabricated from polyphosphazenes bearing phenyl phosphonic acid side groups (225).27s272 These proton-conducting polymers have been prepared from (209)by hydrolysis with an aqueous NaOH solution followed by acidification with an aqueous HCl s01ution.~~~ P(O)(OPh)OH

Me

I

I

89 0 \

\

Me

\

Me

n

Me

Preliminary results with membranes based on sulfonimide-substituted polyphosphazenes (226) show a good proton conductivity and moderate swelling in water, depending on the degree of ~ross-linking.~~~

'

n

Me

Me

(226)

Thermally

cross-linked

membranes

of

polyphosphazenes

with

384

Organophosphorus Chemistry

(OCH2CH2)20Me,OC6H4(0Me-4) and OC6H4(CH2CH= CH2-3) side groups have been used in pervaporation experiments (a combination of permeation and evaporation) involving H20-dye, MeOH-dye, MeC(0H)Me-dye, H20-MeOH and H20-MeC(0H)Me mixtures.274The same polymers form a basis to the development of C02 selective Several organo-substituted polyphosphazene membranes have been involved in gas transport experiments.276279 It has been demonstrated that molecularly imprinted phosphazene films of (227) can act as coatings for the detection of the antibiotic rifamycin SV in water.280

Q

x=y
NH*

Block copolymers (228),consisting of a hydrophilic poly(ethy1eneglycol) and a hydrophobic polyphosphazene residue, have been investigated with respect to their micelle formation in aqueous Micelle formation in water has also been observed for polymers (229) with ethyl glycinato substituents. Hydrolytic degradation of these polymers has been studied in aqueous thf.282

It has been shown that the rate of hydrolytic degradation of a 1:l blend of poly(1actide-co-glycolide)and [NP(OC6H4Me-4)(NHCH2c(0)OEt}],,lies in between the rates of the separate polymers. It is important to note that the phosphazene degradation products neutralize the acidic degradation products of poly(lactide-co-glycolide)~83 Degradation studies of blends of [NP{NHCH2C(0)OEt),{NHCH2C(O)[NP(NHCH2C(0)0Et)2]284 or NHOC(0)Ph),],28S with poly(1actide-co-glycolide),poly[sebacic anhydride-cot rimellitylimidoglycine-block-poly(ethylene glycol)], respectively, have shown the rate of degradation to be dependent on the blend composition. A watersoluble polyphosphazene bearing methylamino and 4-acetamidophenoxy groups has been prepared as a possible drug-release system?86

385

7 : Phosphazenes

The polymer [NP(OCH2CF3)2],has been applied as an antithrombogenic polymer film in medical devices.287 Thermosensitive polyphosphazenes with o-methoxy poly(ethy1ene glycol) in combination with glycine ethyl ester and depsipeptide ethyl esterZp8oralk y l a m i n e ~as~substituents ~~ have been synthesized and characterized. All polymers exhibit LCST properties. Thermosensitive polymers have also been prepared by the introduction of a-amino-o-methoxy- poly(ethy1ene glycol) and L-isoleucine ethyl ester substituents to the phosphazene backbone. Polymer (230) shows reversible sol-gel transitions in aqueous solution depending on the temperature of the solution.290

5

Crystal Structures of Phosphazenes and Related Compounds

The following compounds have been examined by diffraction methods. Distances are given in picometers and angles in degrees. Standard deviations are given in parentheses. Endo (exo) means endo (exo) cyclic. Compound

Comments

Re$

3a 3b 4 8 9

N P 165.2(6),167.5(6) N P 165.0(3), 166.0(3) N P 161.9(3) mean N P 160.1(5) mean N P 157.6(4) N(Me)P 165.1(2) LNPN 118.9(1) LPNP 133.9(1) mean N P 162.2(9) N P 158.5(2) two independent mols. in unit cell mean N P 159.0(1) N P 160.4(4) two independent mols. in unit cell mean N P 162(1) N P 160.9(3) two independent mols. in unit cell mean N P 162.0(7)

1 1 1 5 6

33 [(indenyl)TiMe2(N= PBut3)] 37 38 39 40 41

48 49 49 49 49 49 49

386 Compound

CKNPCY314 [KNPCy3]+20PCy3 [C~NPCy3]4.40PCy3

Organophosphorus Chemistry Comments

mean N P 153.6(2) meanNP 153.7(5) mean N P 151(1) [Li4(NPPh3)(0SiMe2NPPh3)3(DME).0.5N P 153.1(4), 155.5(2) DME] mean N P 159.3(2) 42 mean N P 159.1(4) 43.3CH2C12 mean N(Me)P 164.1(3) N P 158.1(3) mean N(Me)P 163.5(4) mean N P 159(1) 44.C4HgO.C,H8 [INi{ Me2Si(NPMe3)2}(HNPMe3)]I mean N P 158(2) mean N P 159.0(2) [Ni(HNPEt3)4]I2 mean N P 156.0(8) 45 [Me3SiNPEt2CHMeLi14 N P 158.8(1) mean N P 153.0(2) 46.C7H8 N P 156.5(3) [NaI(HNPPh,),].OSthf N P 157.1(3),158.7(3) [Sr12(HNPPh3)2( t hf),] .2t hf mean N P 159.5(6) 48 LNPN 102.1(3) mean N P 158.1(2) 49 LNPN 103.8(8) N P 158.0(1), 158.5(1) 50a LNPN 105.3(1) N P 156.5(4)- 159.4(4) 51 LNPN 101.7(2)- 103.8(2) N P (ClNbNPNNb ring) 158.5(3) 52 N(Si)P 155.8(3), 159.5(3) LNPN (ClNbNPNNb ring) 115.9(2) LN(Si)PN(Si) 103.6(1) mean N P 163.1(1) 55 N P 158.0(7), 160.1(6) 58 N(Fe)P 159.1(2) 60 N(1n)P 157.0(2),158.2(2) 61 N P 155.0(2) 62 N P 153.8(4) N P 159.5(3) 64 N P 158.9(1) 65 N P 159.9(2) 67 = P(Ph2)CH2(C6H4- N P 156.2(1) (C6H2Me3-1,3,5)N Bu'-~) N P 163.1(3) 70 N P 156.6(7) 72 N P 156.7(5) 74a mean N P 159(1) 75a N P 156.9(4) 80 82 N P 165.8(2), 167.2(2) 84 N P 157.4(1)

Re$

50 50 50 50 51 51 51 52 52 54 55 56 57 57 57 58 58

58 58 58

59 59 60 60 60 61 61 61 62 62 63 63 63 64 66 66

387

7: Phosphazenes

Compound

Comments

Ref:

85 [Me3SiN= P(PPh,).ICN]

N P 157.5(2) two independent mols. in unit cell mean N P 156.5(5) two independent mols. in unit cell N P 157.5(3)- 160.8(3) N P 157.3(6)- 160.4(5) meanNP 154.4(9) N(Ge)P 162.3(7),165.5(7) N P 163.0(1) E t 2 0mean N P 158.2(2) two independent mols. in unit cell meanNP 157.5(3) meanNP 158.7(4) mean N P 161.5(3) N P 163.4(3), 168.9(3) LPNP 130.7(2) N P 165.4(6), 167.1(2) L P N P 131.8(4) two independent mols. in unit cell N P 162.0(2)- 169.4(2) L P N P 129.3(1),132.4(1) N P 162.7(3), 170.2(3) L P N P 131.3(2) N P 164.0(2), 170.2(2) LPNP 130.2(21) N P 163.6(5), 168.6(5) LPNP 136.5(4) two independent mols. in unit cell N P 167.0(2)- 168.3(2) LPNP 132.3(2), 134.9(2) N P 164.0(3),165.0(3) L P N P 127.4(2) N P 167.4(2), 168.1(2) N P 155.3(4),159.6(4) LPNP 132.9(2) two independent mols. in unit cell N P 160.8(4),- 163.3(4) mean LPNP 129.2(2) mean N P 162.4(3) LPNP 129.4(2) mean N P 159.6(2) mean N P 160.2(2) LPNP 119.8(1) two independent mols. in unit cell N P 155.8(9)- 159.2(8) LPNP 131.0(6), 133.0(6) N P 156.7(2) - 158.0(2) L P N P 133.8(1),140.8(2)

66 67

88 89a 90 92 93c. 94a

95 96 99

R2P(E)NHP(E’)R’z R = OPh, R’ = Ph, E = 0,E’ = Se R,P(E)NH P(E’)R’2 R = OPh, R’ = Pr’, E = 0,E’ = Se R2P(E)NHP(E’)R’2 R = OPh, R’ = Ph, E = S, E’ = Se RzP(E)NHP(E’)R’2 R = OPh, R’ = Ph, E = S, E’ = S R2P(E)NHP(E’)R’2 R = OPh,R = Pf,E = S,E‘= S R2P(E)NHP(E’)R’Z R = Ph, R’ = Pr’, E = S, E’ = S 100 P hC(O)N(H)P(S)(OPh)2 101 102a

102b [Pd{ Ph2P(S)NP(S)Ph2-S,S}2] .2thf [Ni( Ph2P(S)NP(S)Ph2-S,S’}2]

103 cis-[Te { Ph2P(S)NP(S)(OPh)2-S,S’}2]

69 71 71 72 73 73 74 74 75 75 75 75 75 75 75

75 75 75 75 75 76 77 79

80

Organophosphorus Chemistry

388 Compound

Comments

Ref.

trans- [Te{Ph2P(S)NP(S)(OPh)2-S,S’}2]

N P 155.4(3),158.5(4) L P N P 141.4(2) mean N P 158.3(4) LPNP 138.7(3) N P 168.1(2), 169.4(2) 82 LPNP 132.0(1) mean N P 158.7(4) LPNP 129.7(4),134.3(4) mean N P 159.1(1) LPNP 129.9(l), 133.6(1) mean N P 158.7(4) mean LPNP 132.1(2) N P 158.0(5)- 160.5(4) L P N P 129.9(3)- 142.5(3) N P 157.2(7), 161.4(7) LPNP 132.1(5) N P 157.1(8), 160.4(8) L P N P 138.9(5) N P 157.0(6),160.7(6) LPNP 140.1(4) N P 157.4(5)- 161.4(5) LPNP 129.9(3), 132.5(3) mean N P 156(2)- 161(2) LPNP 129(1),131(1) mean N P 168.2(3) L P N P 125.3(3),127.9(3) mean N P 168.2(3) L P N P 128.3(1) N P 165.3(3)- 171.0(3) LPNP 118.4(2), 120.3(2) N P 157.8(8) N P 158.9(6) mean N P 159.7(4) N P 163.3(2) N P 162.0(2) N P 165.3(6) N(S)P 161.6(2) mean N(Morph)P 164.0(2) N(C)P 151.7(3) mean N(Pyrro)P 167.6(3) N P 154.6(1) LPNP 143.1(3) N P 154.6(2) LPNP 143.3(4) N P 151.9(3),153.0(3) L P N P 154.3(3) N P 155.5(2) LPNP 136.8(3)

80

104

{ Ph2P(S)NHP(Se)Ph2} [Co{ Ph2P(S)NP(Se)Ph2-S,Se}2] [Zn{ Ph2P(S)NP(Se)Ph2-S,Se}2] [Sn( Ph2P(S)NP(Se)Ph2-S,Se}2] [Bi{ Ph2P(S)NP(Se)Ph2-S,Se}3] 105a 105b 10% 106 107 lOSb 110.2Me2C0 111.1.5EtOH [Et3PNAsPh312CAg*Br41 [Et3PNAsPh3I2[Pd2Br6] trans-[TcNC12{N(H)PPh3}J CSHSB.N(Ph)= PPh3 Ph3P = NC(O)CC13 Ph3PNBr.Br2 (MorphhP = N-S3N3 Morph = morpholinyl (Pyrro),P = N(C6H4F-2) Pyrro = pyrrolyl [C13PNPC13] + [NbCl,] -

[C13PNPC13]+ [Ti2C1,] [C13PNPC13]+ [Zr2Cllo]-

81

82 82 82 82 83 83 83 83 83 84 84 84 117 117 119 119 118 121 122 123 124 124 124 124

389

7: Phosphazenes

Compound

Comments

[Ph3PNPPh3] [S04H] -.CHCl3

mean N P 158.9(2) LPNP 134.4(2) [Ph3PNPPh3]+ [CPMOCO~Imean NP 158.2(3) LPNP 142.6(1) [Ph3PNPPh3]+[MeCH(CO,Et)CrCO,]- mean NP 158.2(2) LPNP 138.1(2) NP 158.3(3),159.4(3) [Ph3PNPPh3]+ [CuC13]LPNP 134.0(2) NP 156.8(4) [Ph3PNPPh3] [CuBr3]LPNP 140.5(6) mean NP 158.1(3) [Mn( Ph2P(O)NP(S)Ph,-O,S) 21 LPNP 134.5(4),137.0(3) NP 157.6(3) [ZrC13(NPPh3)(HNPPh3)2] mean N(H)P 159.8(4) two independent mols. in unit cell [ZrC12(NPPh3)2(HNPPh3)2] NP 153.9(3)- 155.9(3) N(H)P 156.7(3)- 158.2(3) two independent mols. in unit cell mean NP 154.1(3) two independent mols. in unit cell NP 153.8(3)- 156.2(3) mean N(H)P 158.7(2) NP 155.0(3)- 162.0(3) [OC(N=PPh,)C(I)=C(N= PPh,)C(N =PPh3)Jf +

+

Me3SiN= P(But2)NHSiMe3

[P(But2)(NSiMe3),Li].2thf (NPF2)4(at 172 K)

121

121

N P 153.1(2),N(H)P 166.6(2) LNPN 109.9(1) mean NP 158.1(1) LNPN 109.0(1) NP 153.6(2)- 154.9(2) LNPN 123.0(1)- 123.4(1) LPNP 139.1(1)- 143.5(1) monoclinic, P i three independent mols. in unit cell NP(endo) 156.5(2)- 161.7(2) NP(exo) 161.8(2) - 167.4(2) LNPN(endo) 112.5(1)- 118.9(1) LPNP 117.7(1)- 124.1(1) monoclinic, C2/c NP(endo) 157.1(2)- 160.7(2) NP(exo) 163.8(3)- 167.0(2) LNPN(endo)115.8(1)- 116.5(1) LPNP 119.8(2)- 123.4(1) NP(endo) 156.3(2)- 159.7(2) NP(exo) 161.8(1) LNPN(endo) 117.6(1)- 119.2(1) mean LPNP 120.2(1) - 120.9(1) NP(endo) 156.3(2) - 160.0(2) mean NP(exo) 162.3(1)

Ref. 125 126 127 128 128 129 130 130

131 131

132 133 133 142

157

157

158

158

390 Compound

[NPClN(CH2Ph)2]2NPPhz

(NPC12)2NCPN(Me)(CH2),N(Me)l

126

127

133

134

[NP(NHC6H40Me-2)2]3.0.5thf

NaLI(H20)

Organophosphorus Chemistry Comments

LNPN(endo) 118.2(1)- 119.5(1) LPNP 120.0(1)- 121.4(1) NP(endo) 155.5(4)- 161.8(4) NP(exo) 163.0(4) LNPN(endo) 115.8(2)- 120.4(2) LPNP 119.3(2)- 122.2(2) NP(endo) 157.8(1) - 160.4(1) mean NP(exo) 162.8(1) LNPN(endo) 116.7(1)- 119.4(1) LPNP 119.9(1)- 122.1(1) NP(endo) 155.9(2) - 163.0(2) NP(exo) 163.0(2)- 164.2(2) LNPN(endo) 112.1(1)- 120.5(1) LPNP 118.3(1)- 124.2(1) mean NP(endo) 158.8(1) mean NP(exo) 170.0(2)- 171.2(2) LNPN(endo) 116.2(1)- 118.0(1) LPNP 118.4(1)- 122.6(1) mean NP(endo) 163.5(4) NP(exo) 168.7(3) LNPN(endo) 95.5(1) LPNP 84.5(1) mean NP(endo) 165.9(1) NP(exo) 162.6(1) LNPN(endo) 91.5(1) LPNP 88.5(1) mean NP(endo) 166.9(3) NP(exo) 156.5(2) LNPN(endo) 85.0(2) LPNP 95.0(2) NP(endo) 156(1)- 160(1) NP(exo) 165(1)- 170(1) mean LNPN 117.2(5) LPN(Re)P 120.0(7) mean remaining L P N P 123.2(7) NP(endo) 154.2(7)- 166.0(7) NP(exo) 161.8(8)- 171.5(7) LNPN(endo) 108.9(4)- 124.8(4) LPNP 119.2(4)- 134.0(4) mean NP(endo) 159.2(2) NP(exo) 164.6(2)- 166.5(2) LNPN(endo) 116.1(1)- 117.8(1) LPNP 120.8(1)- 121.5(1) NP(endo) 163.8(2) NP(exo) 163.7(3) LNPN(endo)ll3.4(3) LPNP 126.6(3) NP(endo) 157.4(4)- 160.3(4)

Ref.

158

158

158

162

162

163

163

165

165

166

166

169

7: Phosphazenes

Compound

39 1 Comments

NP(exo) 162.5(4) - 165.2(4) LNPN(endo) 115.4(2) - 117.0(2) LPNP 118.6(2)- 123.5(2) KLI(H20),.H20,space group P2,/c mean NP(endo) 158.5(5) mean NP(exo) 163.2(6) L = 137 LNPN(endo) 115.4(3)- 117.7(3) LPNP 121.0(3)- 124.1(3) 137 NP(endo) 153.1(5)- 158.9(4) NP(exo) 161.9(6)- 165.6(6) LNPN(endo) 115.3(3)- 118.9(3) mean LPNP 122.3(3) NP(endo) 156.0(5)- 159.6(5) KLI(H,O), space group Pi mean NP(exo) 163.2(4) L = 137 LNPN(endo) 114.9(2)- 116.8(3) LPNP 120.3(3)- 122.8(3) NP(endo) 155.9(4)- 161.8(4) 148 (meso) NP(exo) 164.0(5) - 165.5(4) LNPN(endo) 114.8(2)- 121.7(2) LPNP 120.3(3)- 124.7(3) NP(endo) 155.7(3) - 162.4(3) 148 (racemate) NP(exo) 161.8(3) - 167.6(3) LNPN(endo) 114.8(2)- 121.0(2) LPNP 118.4(2)- 124.7(2) N P 158.5(5) 153 mean mean LNP(C1,)N 119.5(3) LNP(0, C1)N 118.2(4) mean LPNP 120.8(2) NP 154.2(6)- 157.2(6) LNPN 120.7(3)- 123.8(3) LPNP 133.1(4)- 136.4(4) mean NP 160.0(1) mean LNPN 116.9(1) mean LPNP 121.3(2) two independent mols. in unit cell N P 157.5(8)- 161.8(7) LNPN 115.9(4) - 118.0(4) LPNP 120.9(5)- 124.7(5) NP 153.4(5) - 156.1(5) 160 mean NS 155.4(4) LNPN 118.8(3), 119.2(3) LNSN 113.0(2) LPNP 119.6(3) mean LPNS 124.7(2) NP 151.8(4) - 157.2(4) 161 mean NS 154.6(4) LNPN 115.7(2), 117.0(2) LNSN 112.3(2) LPNP 117.7(2)

L

=

Re$

137

170

171

171

176

176

180

184

185 185

186

186

Organophosphorus Chemistry

392 Compound

Comments

164a

166a

171

176

177a

180b.2CH2C12 (R

=

C6H4CHO-4)

NPPh,{NP[NC(Me)

= CHC(Me) = N]

mean LPNS 122.1(3) mean N P 156.4(3) mean NS 156.8(6) LNPN 118.1(3),119.1(3) LNSN 113.3(3) LPNP 119.5(4) mean LPNS 124.8(4) N P 157(1)- 162(1) mean NS 154.6(7) mean NP(exo) 162.1(8) LNPN(endo) 112.2(6),118.5(6) LNSN 116.4(6) LPNP 123.8(7) LPNS 121.6(6), 127.0(7) mean NP(C12)156.3(1) mean N(Me)P 157.5(1) mean NA1 188.9(1) mean LNPN 115.0(1) LPNP 130.2(2) LNalN 103.3(1) mean LPNAl121.4(2) mean N P 157.5(2) mean LNPN 11831) mean L P N P 121.2(2) (R = C6H4C6H4(CH = CH2)mean NP(endo) 157.2(6) mean NP(exo) 167.5(7) mean endo LNPN 117.3(4) mean LPNP 122.5(4) mean N(Cu)P 159.6(2) remaining N P 156.9(3)- 159.0(3) NP(exo) 167.8(3)- 169.3(3) mean endo LNPN 118.2(2) LPN(Cu)P 117.8(2) remaining LPNP 120.7, 122.0(2) N(Co)P(endo) 161.2(3), 162.2(3)

NP(endo) 155.7(3)- 162.4(3) mean NP(exo) 167.9(4) mean endo LNPN(Co) 117.7(1) endo LNPN 115.)(2) LPN(Co)P 113.7(2) LPNP 120.8(2), 122.6(2)

Re$

187

187

188

190

190

190

212

7: Phosphazenes

393 Comments

Re$

mean NP(endo) 157.1(2) mean NP(exo) 163.9(4) endo LNPN 117.3(2)- 118.7(2) L P N P 119.8(3)- 121.2(3) N P 156.8(3)- 161.7(3) LNPN 115.6(1)- 118.7(2) LPNP 118.8(2), 123.1(2)

213

mean N P 157.7(3) LNPN 117.4(2)- 118.7(2) LPNP 118.6(2)- 121.8(2)

215

N P 155.9(2) - 159.6(2) LNPN 116.3(1)- 119.2(1) LPNP 119.4(1)- 121.9(1) mean (NPMO~~~,)~[NP(NHP~") M O NP(endo) ~ ~ ~ ] ~ 157.9(3) NP(exo) 164.2(4)- 168.4(4) Morph = morpholinyl endo LNPN 117.5(2), 122.5(2) LPNP 130.4(2), 136.9(2) NP(endo) 157.5(3)- 158.9(3) NP(exo) 162.6(4)- 165.5(4) endo LNPN 117.7(2), 121.6(2) LPNP 130.0(2),133.2(2) two independent mols in unit cell NP(endo) 158.2(2)- 161.1(2) NP(bridge) 170.7(2)- 172.4(2) NP(exo) 161.0(2)- 165.5(2) endo LNPN 115.7(1) - 120.5(1) LPNP 117.8(1) - 124.9(1) mean LPNP(bridge) 107.9(1) mean NP(endo) 158.8(2) mean NP(exo) 166.6(3) LNPN 115.9(2)- 117.9(2) LPNP 120.5(2)- 122.7(2) I

(NPCl,),N[POCH,C( Me2)CH20]

214

216

217

218

219

220

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47,2495. 267. E. S. Peterson, M. L. Stone and D. W. Marshall, U.S., US 2002144947. 268. R. Wycisk, R. Carter, P. N. Pintauro and C. Byrne, Polym. Muter. Sci. Eng., 2001, 85,519. 269. R. Carter, R. Wycisk, H. Yo0 and P. N. Pintauro, Electrochem. Solid-State Lett., 2002,5, A 195. 270. X. Zhou, M. A. Hofmann, J. A. Weston, E. Chalkova, H. R. Allcock and S. N. Lvov, in ‘direct Methanol Fuel Cells’, Eds. S. Narayanan, S. Zowodzinski and S. Gottesfield, The Electrochemical Society Proceedings Series, Pennington, NJ,2001, 34. 271. M. V. Fedkin, X. Zhou, M. A. Hofmann, E. Chalkova, J. A. Weston, H. R. Allcock and S. N. Lvov, Mater. Lett. ,2002,52, 192. 272. H. R. Allcock, M. A. Hofmann, C. M. Ambler, S. N. Lvov, X. Y. Zhou, E. Chalkova and J. Weston, J. Membr. Sc., 2002,201,47. 273. M. A. Hofmann, C. M. Ambler, A. E. Maher, E. Chalkova, X. Y. Zhou, S. N. Lvov and H. R. Allcock, MacromoEecules,2002,35,6490. 274. F. F. Stewart, C. J. Orme, M. K. Harrup, R. P. Lash, D. H. Weinkauf and J. D. McCoy, Polym. Muter. Sci. Eng. ,2001, 85, 577; C. J. Orme, M. K. Harrup, J. D. McCoy, D. H. Weinkauf and F. F. Stewart, J. Membr. Sci., 2002,197,89. 275. C. J. Orme, M. K. Harrup, T. A. Luther, R. P. Lash, K. S. Houston, D. H. Weinkauf and F. F. Stewart, J. Membr. Sci., 2001,186,249. 276. K. S. Houston, D. H.Weinkauf and F. F. Stewart, J. Membr. Sci., 2002,205,103. 277. M. L. Stone, F. J. White, F. F. Stewart, M. N. Tsang, C. J. Orme and E. S. Peterson, Sep. Sci. Technol., 2001,36, 1067. 278. M. L. Stone, C. J. Orme, F. F. Stewart, M. T. Benson and E. S. Peterson, Polym. Prep. (Am. Chem. Soc.),2002,43(2), 1374. 279. D. Roizard, E. Favre, L. Perrin, C. Vallieres, D. Sacco, V. Teplyakov, L. Starannikova, D. Tur, N. Laguntosov, A. Shumeiko, N. Kanellopoulos, and A. Brovko, Rdcents Progr2s en Gdnie des Procddds, 2000,14,257. 280. S. Gutierrez-Fernandez, M. J. Lobo-Castahon, A. J. Miranda-Ordieres, P. TufionBlanco, G. A. Carriedo, F. J. Garcia-Alonso and J. I. Fidalgo, Electroanalysis,2001, 13, 1399. 281. Y. Chang, R. Prange, H. R. Allcock, S. C. Lee and C. Kim, Macromolecules, 2002, 35,8556. 282. Y. Chang, J. D. Bender, M. V. B. Phelps and H. R. Allcock, Biomacromolecules,2002,3, 1364. 283. A. M. A. Ambrosio, H. R. Allcock, D. S. Katti and C. T. Laurencin, Biomaterials, 2002,23, 1667. 284. L. Y. Qiu, Polym. Int., 2002,51,481. 285. L. Y. Qiu and K. J. Zhu, Int. J. Pharm., 2001,219, 151. 286. S.-K. Kwon, Bull. Korean Chem. SOC.,2001,22, 1243. 287. S. Nagel and M. Boxberger, Eur. Pat. Appl., E P 1179353; M. Grunze, PCT Int. Appl., WO 2001070296; M. Grunze and C. Gries, Ger. Oflen., DE 10019982; M. Grunze and C. Gries, PCTInt. Appl., WO 2001080919; A. Pertsin, M. Grunze and D. Tur, PCTInt. Appl., WO 2002077073. 288. B. H. Lee, Y. M. Lee, Y. S. Sohn and S. C. Song, Polym. Int., 2002,51,658. 289. B. H. Lee, Y. M. Lee, Y. S. Sohn and S. C. Song, Bull. Korean Chem. SOC.,2002,23, 549. 290. B. H. Lee, Y. M. Lee, Y. S. Sohn and S. C. Song, MacrornolecuEes,2002,35,3876.

Nucleotides and Nucleic Acids; Oligo- and Poly-Nucleotides BY DAVID LOAKES Medical Research Council, Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, U.K.

1

Introduction

Nucleic acid chemistry and biology has significantly advanced since the structure of DNA was solved just over 50 years ago. It is a constantly expanding area of research, and the applications of nucleic acids have become incredibly diverse. This review covers a two-year period (2002–2004) and is focussed on oligonucleotide modiﬁcations. The largest group of modiﬁcations involves novel nucleobases that are used not only for duplex stabilisation and tertiary structures, but ﬁnd application in understanding the mode of action of other biological molecules, conjugation with small molecules as well as macromolecules and in nanotechnology devices. A number of advances have also been achieved with sugar and backbone modiﬁcations, especially LNA and PNA, and as in previous years, there have been a large number of structures solved for nucleic acids. There are also some noteworthy emerging areas of research, which includes templated organic synthesis, single molecule detection and, as noted above, nanodevices.

1.1 Oligonucleotide Synthesis. – 1.1.1 DNA Synthesis. Whilst DNA synthesis has been routinely carried out for many years, there are still many reports on methods for improving synthesis. These range from new protecting group strategies and new solid support methodologies (which make up the majority of new reports), to new reagents for oligonucleotide synthesis. Possibly the most important paper in this ﬁeld during this review period is a new synthesis strategy developed by Caruthers and co-workers. The method makes use of a 5 0 -aryloxycarbonyl group, the usual 5 0 -dimethoxytrityl protecting group being used instead to protect exocyclic amino groups. The internucleotide phosphite group is then oxidised by a buﬀered (pH 9.6) peroxy anion solution, which additionally removes the 5 0 -protecting group thus reducing the number of steps involved in the synthesis cycle.1 Organophosphorus Chemistry, Volume 35 r The Royal Society of Chemistry, 2006 355

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A synthesiser has been developed which allows for the synthesis of 1536 oligonucleotides in parallel. Reactions are carried out in microwells, and oligonucleotides up to 119 nucleotides have been synthesised.2 Various miscellaneous methods are reported for DNA synthesis. These include photosensitive nitrobenzyl esters which yield a-chloro-substituted acetic acid derivatives which may be used for 5 0 -deprotection with reduced depurination;3 synthesis of 3 0 -modiﬁed oligonucleotides using reverse synthesis (i.e. in the 5 0 -3 0 direction);4 a method for the synthesis of H-phosphonate oligonucleotides using N,N-diisopropylamino-p-methoxybenzylphosphoramidites;5 synthesis of phosphonoacetate and thiophosphonoacetate oligonucleotides using 3 0 -Ophosphinoamidite monomers6 and a non-enzymatic chemical template synthesis of RNA using imidazole-activated 5 0 -monophosphates.7 Non-enzymatic templated transcription of DNA may be carried out using monophosphates activated by 2-aminoimidazole. Using such transcription reactions, it has been shown that diaminopurine is a much better cognate base for 5-propynyluracil than adenine.8 For large-scale oligonucleotide synthesis, solution phase is the preferred method. Two reports deal with solution phase synthesis, one using phosphotriester chemistry to synthesise a G-rich iso-oligonucleotide9 the other H-phosphonate chemistry to synthesise a phosphorothioate oligonucleotide.10 A few new protecting group strategies have been reported. Methyl-SATE (2S-AcetylThioEthyl) pro-oligonucleotides can be prepared using ﬂuoridelabile protecting groups.11,12 SATE oligonucleotides have the advantage that their phosphate groups are fully protected and are therefore more readily taken up into cells where they may be hydrolysed. 6-(Levulinyloxymethyl)-3methoxy-2-nitrobenzoyl has been introduced as a base-labile 5 0 -hydroxyl protecting group,13,14 and 5 0 -hydroxyl protection has also been carried out using modiﬁed pixyl groups that are more acid-labile than dimethoxytrityl.15 Dimethylacetamidine can be used as a selective protecting group for exocyclic amines in conjunction with other ultra-mild deprotection groups. It is stable to potassium carbonate in methanol, and is removed by methanolic ammonia.16 Two alternative phosphate-protecting groups, 3-(N-tert-butylcarboxamido)1-propyl17 and 2-[N-methyl-N-(2-pyridyl)]aminoethyl-phosphates,18 have been described, both protecting groups being removed thermolytically. Terminal phosphate groups have been introduced via an oxime-derived solid support19 and a phosphoramidite building block,20 as well as for the introduction of phosphorothiolates.21 New sulfurising agents have also been described such as dimethylthiuram disulﬁde22 and diethyldithiodicarbonate23 for introducing phosphorothioate linkages, and a novel solid support to allow the synthesis of 3 0 -phosphorothioate oligonucleotides.24 Stereocontrolled synthesis of Rp or Sp phosphorothioates may be carried out using new oxazaphospholidine derivatives.25 A method for desulfurisation of phosphorothioates has also been described.26 Sekine et al. have described the synthesis of oligonucleotides which does not require all protecting groups. Synthesis without exocyclic amino protecting groups involves protonation with 5-nitrobenzimidazolium triflate27 whilst a novel HOBt-mediated coupling strategy reduces the phosphitylation at

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exocyclic amino positions28 and allows for no internucleotide phosphate protecting groups.29 New reagents useful during DNA synthesis include NBS in DMSO as a nonbasic reagent for the oxidation of phosphite to phosphate triesters,30 and a solution of CCl4 and N-methylmorpholine in pyridine for the oxidation of Hphosphonate diesters to phosphates.31 Removal of dimethoxytrityl protecting groups can be accompanied by depurination side-reactions, but the latter may be reduced by use of buﬀered (pH 3.0-3.2) sodium acetate solution.32 2-Methyl5-tert-butylthiophenol and triethylamine in acetonitrile can be used to remove phosphate methyl protecting groups.33 An on-column method for cross coupling of alkynylated nucleobases via a copper-catalysed oxidation reaction has also been described.34 Various new solid supports have been used for oligonucleotide synthesis. Two cis-diol universal supports have been developed, one which is conformationally preorganised for more efﬁcient oligonucleotide synthesis,35 and one which is compatible with polyamine-assisted oligonucleotide deprotection,36,37 as well as a photocleavable universal support which uses long wavelength UV light to avoid photolytic damage to the oligonucleotide.38 A polymeric solid support has been described which has a 10-12 fold higher loading of functional groups for increased oligonucleotide loading.39 It is reported that attachment of the dA to a solid support via its exocyclic amino group leads to reduction of (n-1)-mer formation.40 Solid supports for 3 0 -modiﬁed oligonucleotides include a support that allows synthesis of 3 0 -amino-modiﬁed oligonucleotides41 and a method for attachment of ligands via a 2 0 -succinyl linker.42 Linker phosphoramidites, such as (1) are described which are suitable for attachment of the ﬁrst nucleoside to underivatised solid supports.43 DMTO

B

O

OCH2CH2CN O

X

O O

P O

NiPr2

O

X = CH2CH2 CH2OCH2 OH2C

OCH2

1

1.1.2 DNA Microarrays. The synthesis of DNA on microarrays is now an established procedure, but there are further developments in this ﬁeld. There are methods for light-directed synthesis, one dealing with 5 0 -3 0 synthesis,44 and another with the effects of stray light on the ﬁdelity of oligonucleotide

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synthesis.45 Methods for removal of contaminating ﬂuorescence from DNA microarrays have also been described.46 Triplet-sensitised deprotection of oligonucleotides bearing the photolabile 2-(2-nitrophenyl)propyl-protecting group has also been reported.47 DNA sequencing on a chip has been demonstrated using photocleavable ﬂuorescent nucleotides such as (2).48 After incorporation of the ﬂuorescent dNTP, the ﬂuorescence signal was detected and then the ﬂuorophore cleaved by 340 nm irradiation. The labelling of probes for microarray studies usually requires about 20 mg of total RNA. A method has been described which allows the synthesis of ﬂuorescent probes using as little as 1 mg of RNA.49 The method uses random DNA hexamers that have a free amino group at the 5 0 -terminus, which are then incorporated into cDNA using aminoallyl-dNTPs and ﬂuorescent dyes are then attached to the free 5 0 -amino groups. Fluorescently-labelled cRNA libraries have also been produced by using Cy-modiﬁed aminoallyl-UTP.50 Microarray-bound oligonucleotides can also be biotinylated using the aryldiazomethane reagent (3).51–53 O

O HN O

N H

Me O O2N

N

Me

O N H

O O-Dye

N HN H

NH2

NH H NH

dRTP

S O

2

3

Analysis of microarrays is important for quality control of data obtained from hybridisation experiments. An analysis of probe density demonstrated its correlation to the efﬁciency of hybridisation and kinetics of capture.54 The manufacture of microarrays from unpuriﬁed PCR products to aminated glass slides has been described which reports a signal intensity of 94% compared to that for puriﬁed PCR products.55 The effects of linkage to solid support have been studied using C5-thymidine and N4-dC as the linkage point.56 A threecolour cDNA array has been developed to allow for assay of the microarray, by using ﬂuorescein-labelled probes which are compatible with Cy3 and Cy5 target labelling dyes,57,58 whilst scanning electrochemical microscopy may be used as a label-free method for examining electrostatic interactions of DNA probes binding on a microarray.59 A thin-ﬁlm amorphous silicon photodetector has been used to quantify the density of both immobilised and hybridised oligonucleotides labelled with a ﬂuorophore.60 There are a number of novel methods for the attachment of oligonucleotides to various solid surfaces. Oligonucleotides have been attached to glass surfaces coated with polycarbodiimide, and un-modiﬁed oligonucleotides may be attached by UV-irradiation, which increases coupling efﬁciency, and hence signal intensity.61 A bifunctional reagent (NTMTA, 4) has been reported that reacts with the glass surface whilst the triﬂuoromethansulfonyl group reacts with aminoalkyl- or mercaptoalkyl-modiﬁed oligonucleotides.62,63 Amino-modiﬁed glass surfaces can be functionalised with dendrimers bearing aldehyde groups

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for the attachment of 5 0 -amino-oligonucleotides.64 Commercial aldehyde-modiﬁed glass has also been used to attach oligonucleotides containing oxyamino groups by oxime bond formation.65 High uniform loading of oligonucleotides to glass surfaces can be attained by functionalisation of the glass with gaminopropyltriethoxysilane or 3-glycidoxypropyltrimethoxysilane followed by a poly-L-lysine or polyacrylic acid polymer coating.66,67 Following activation, amino-modiﬁed oligonucleotides may be attached. Zirconium phosphonatederivatised glass surfaces allow for oligonucleotides with terminal phosphate groups to bind tightly to the organophosphonate groups.68 Attachment of oligonucleotides has also been achieved using polylysine and other polyaminemodiﬁed oligonucleotides.69 OEt

Me

Si

N

O

F

EtO EtO

S O

F O

F

4

The functionalisation of poly(methyl methacrylate) (PMMA) using hexamethylene diamine generates an aminated surface suitable for the attachment of oligonucleotides.70 A comparison of the oligonucleotide hybridisation signal with other PMMA-modiﬁed surfaces and silanised glass demonstrated that the new surface is highly robust. The impact of surface chemistry and blocking strategies on DNA microarrays has been studied in detail.71,72 Advances in applications of microarrays are varied and include SNP detection,73,74 gene analysis,75–78 DNA cleavage,79 ﬁngerprinting,80 combinatorial decoding of nucleic acids,81 nucleic acid quantiﬁcation,82 nucleic acid ampliﬁcation83 and puriﬁcation.84 Methods for the synthesis of PNA microarrays have also been reported.85 1.2 RNA Synthesis. – There are few reports concerning modiﬁcations to RNA synthesis. A new base-labile 5 0 -OH protecting group has been introduced, the (2-cyano-1-phenylethoxy)carbonyl group, which is removed 0.1M DBU.86 15 N-labelled uridine and cytidine {[(triisopropylsilyl)oxy]methyl} (tom)-protected phosphoramidites have been prepared for use in NMR studies,87 and 2 0 -Se-methyl pyrimidines for X-ray crystallography.88 The thermolabile 4-methylthio-1-butyl group has been introduced for protection of phosphate/ thiophosphate groups during RNA synthesis,89 and can be removed under neutral aqueous conditions. A pivaloyloxymethyl (POM)-protected C-linked imidazole ribonucleoside has been prepared to study its role as a general acid and base catalyst in ribozymes.90 RNA oligomers (35–40 mers) were formed within one day in a reaction catalysed by montmorillonite clay at 251C in aqueous solution.91,92 The reactions used imidazole-activated monophosphates (5), and gave ladders, which increased with increased reaction time. 5–17 Mers could be formed in ice

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eutectic phases when dilute solutions of activated monomers (5) and Mg(II) and Pb(II) catalysts are maintained at 181C for periods of up to 38 days.93 O N N

P

O O

OH HO

Base

OH

5

1.3 Synthesis of Modiﬁed Oligodeoxyribonucleotides and Modiﬁed Oligoribonucleotides. – 1.3.1 Oligonucleotides Containing Modiﬁed Phosphodiester Linkages. A number of different internucleotide linkages have been examined for their effects in oligonucleotides. Of these, most reports are concerned with PNA or PNA analogues. Amongst oligonucleotide modiﬁcations, some reports are concerned with mixed DNA/RNA backbones but these are excluded from this review as this is such a common modiﬁcation. Oligonucleotides containing 2-5 linkages are discussed in section 1.3.2. Since introduced by Eckstein, probably the most widely studied modiﬁed phosphodiester linkage is the phosphorothioate.94 Phosphorothioate-linked oligonucleotides are of significant interest because they have enhanced resistance to nuclease degradation, and have therefore been used in antisense,95,96 siRNA97 and enzyme studies.98,99 A study of the effect of duplex stability of stereodeﬁned phosphorothioate oligonucleotides100 demonstrated that oligonucleotide stability is sequence-dependent, but Rp linked DNA showed generally higher stability than Sp with complementary RNA. Most phosphorothioate oligonucleotides involve substitution by sulfur of a non-bridging oxygen. However, replacement of the 3 0 -bridging oxygen has been shown to increase duplex stability, and induces a conformational shift as demonstrated by NMR studies.101,102 Phosphorothioate oligonucleotides bearing an additional 3 0 -terminal phosphorothioate ester have been investigated for the effect of the additional negative charge, and has been shown that there was no effect for the recruitment of RNase H.103 Other phosphorothioate analogues that have been examined include methylthiophosphonate oligonucleotides,104 and the biochemical properties of N3 0 -P5 0 thiophosphoramidates105 and thiophosphonoacetates.106 Phosphoroselenoates have been used for heavy atom replacement for phase determination in X-ray crystallography.107,108 A few other reports describe oligonucleotides containing minor modiﬁcations to the internucleotide linkage. Oligonucleotides containing boranophosphate in place of a non-bridging oxygen are still able to induce RNase H activity.109 DNA containing a single ethyl phosphotriester linkage was found to be a substrate for T4 DNA polymerase and E. coli DNA polymerase I.110 The

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replacement of a phosphate non-bridging oxygen by an alkyl group leads to neutralisation of charge on the phosphate backbone. Methyl phosphonates have previously been widely studied, but are used less frequently now. The effect of charge neutralisation in a DNA duplex has been studied using methylphosphonates where it was shown that the minor groove became narrower, particularly in GC rich regions.111 The thermal stability of ODN duplexes containing various alkarylphosphonates has been measured. Short alkyl linkers gave higher stability with Rp isomers, whilst this trend was reversed with longer linkers.112 a-Hydroxyphosphonate linkages between thymidine dimers have similarly been examined for thermal and nuclease stability.113 A phosphoramidite derivative of the dinucleotide (6) was incorporated into a TFO where one of the diastereoisomers strongly enhanced the triplex stability.114 A

HO

O

O

(CH2)6 O

HN

O

P

O

O

O

C

OH

O 6

A popular strategy for triple helix formation is the use of an oligonucleotide that will hybridise to adjacent purine tracts by switching strands at the junction between an oligopurine-oligopyrimidine domain. In order to maintain the direction of hydrogen bonding (parallel or antiparallel) a 3 0 -3 0 linkage is introduced. A number of examples of these alternate-strand TFOs have been examined,115–117 including those in which an intercalating agent is introduced to aid thermal stability.118–120 The immunostimulatory effect of oligonucleotides containing 3 0 -3 0 - or 5 0 -5 0 -linked CpG domains was found to enhance or suppress immunostimulation, respectively.121,122 Cyclic and lariat oligonucleotides have attracted much attention since they were shown to be unusually good substrates for polymerases and as splicing intermediates, respectively, and a number of reports have dealt with their synthesis. A variety of methods have been used to cyclise oligonucleotides, the most common being a ligation method using linear templates.123–125 Ligation methods have also been used for the synthesis of branched oligonucleotides.126,127 Other methods of cyclisation use chemical ligation, for example ligation of a 5 0 -iodo-modiﬁed oligonucleotide to a 3 0 -phosphorothioate128 and ligation of a 5 0 -oxyamino group to a 3 0 -aldehyde.129 Branched RNA oligonucleotides have also been synthesised using the 2 0 -O- and 3 0 -O-positions as branching sites.130

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Applications of cyclised oligonucleotides are varied. They have been used to produce artiﬁcial human telomeres by rolling circle DNA synthesis,131 as inhibitors of viral replication in inﬂuenza virus132 and as structural motifs for quadruplex formation.133,134 A further form of ‘cyclic’ oligonucleotide ﬁgures in a recently described method in which a self-complementary oligonucleotide, e.g., a hairpin structure, is denatured and allowed to re-anneal in the presence of circular DNA such as a plasmid (7). The effect is that the short oligonucleotide traps the plasmid in what has been termed a padlock.135 Such structures have been successfully used to inhibit transcription elongation reactions based on triple helix formation of the padlock structure.136

7

Phosphoramidates have received much attention, and a number of reports have dealt with this modiﬁcation. The most widely studied modiﬁcation has been the N3 0 -P5 0 amidate linkage. This has recently been demonstrated to be effective in an antisense therapy as an inhibitor of human telomerase.137 Substitution by nitrogen at the 5 0 -end, P3 0 -N5 0 linkages, are less well studied, but oligonucleotides containing P3 0 -N5 0 modiﬁed 2 0 -ﬂuoroarabinonucleosides have been prepared and shown to be substrates for certain RNases.138 A P3 0 -N5 0 linkage has also been used to investigate cleavage reactions by an adjacent ribonucleotide (8). Upon protonation, the phosphoramidate linkage is attacked by the 2 0 -hydroxyl group to generate a 2 0 ,3 0 -cyclic phosphate with cleavage of the amidate linkage.139 Further substitution of phosphoramidate linkages by aminooxyethyl groups convey enhanced protection against exo- and endonucleases.140

Base

O

Base

O

O

O +

O O

P O

OH

O P

Base

N H2

O

O

O

O

Base

H2 N

O

O

O 8

The above phosphoramidates involve substitution of a bridging oxygen of the phosphate linkage. Examples have been reported in which the amino group replaces a non-bridging oxygen. Compound (9), in which the amidate contains

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pendant groups with either terminal hydroxyl or amino functions, has been used to stabilise TFOs.141 The Rp modiﬁcations were found to exert the greatest stability, particularly with multiple substitutions. A method for postsynthesis modiﬁcation to form cationic oligonucleotides has been described for the guanidine analogue (10).142 The presence of a pendant imidazole group on a phosphoramidate-linked oligonucleotide improved afﬁnity towards target nucleic acids.143 Oligonucleotides containing the cationic amidate (11) efﬁciently target ssDNA and ssRNA, and have been shown to inhibit translation by Hepatitis C virus.144

O

Base O

O RHN

P

O

O 9

R = (CH2)n(CH2CH2OH)2 or (CH2)n(CH2CH2NH2)2

10

R = (CH2)4NHC(NH2)=NH2+

11

R = (CH2)3N(CH3)3

Alkyl linkers have been incorporated into oligonucleotides for a variety of uses. Incorporation of alkane-diol and hexaethylene glycol linkers to investigate stability of DNA quadruplexes demonstrated that the quadruplex stability increased with chain length.145 The presence of an alkyl linker (C2-C12) within a CpG site neutralises the immunostimulatory effect of the CpG.146 Phosphoramidate linkages containing pendant alkyl thiol groups form disulﬁde crosslinked duplexes, which may have application in nanostructures.147–149 Likewise, calix[4]arene-linked nucleoside building blocks incorporated into oligonucleotides can be of use for the construction of oligonucleotide nanostructures.150 Linkers have been used for the synthesis of branched151,152 and dendritic153,154 oligonucleotide structures. Various other internucleotide linkages have been introduced into oligonucleotides. Bruice et al. examined oligonucleotides in which the internucleotide linkage is replaced by the guanidine linkage (12). The resulting oligonucleotide bound to complementary DNA with enhanced afﬁnity for homopolymers, but with reduced afﬁnity in mixed sequences,155,156 in both duplex and triplex structures.157 The replacement of the phosphate group by an amide linkage led to a slight increase in thermal stability towards an RNA target,158 but the use of a tetrazole group as internucleotide linkage led to considerable duplex destabilisation.159

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HN

Base O

NH H2N HN 12

The neutral bis(methylene) sulfone internucleotide linkage (13) was introduced into oligonucleotides by solution phase synthesis, but was found to be considerably destabilising in duplexes and triplexes.160,161 Replacement of the phosphate linkage by a squaryl diamide unit also caused duplex destabilisation, though NMR studies revealed that the overall structure of the duplex was largely unperturbed.162,163 The presence of a single vinylphosphonate linkage within an oligonucleotide does not affect templating by a DNA polymerase, but multiple consecutive substitutions inhibits DNA synthesis. The presence of the vinylphosphonate linkage does not infer nuclease stability.164 However, the incorporation of the disaccharide nucleoside linkage (14) into DNA does infer nuclease stability without loss of genetic information, whilst the modiﬁcation can be used for chemical cleavage following an oxidation step.165,166 O

Base

O

Base

O

O O

CH2 O

S

O

Base

CH2

O

O

13

P

O

O

O O

O

OH

OH

14

PNA, ﬁrst introduced by Nielsen et al.167, is able to form stable structures with either DNA or RNA, but has the unique property that it is able to strandinvade a DNA duplex, and is best accomplished with pyrimidine-rich PNA sequences. It has been reported that a pyrimidine hexamer of PNA combined with a mixed sequence decamer can strand-invade both duplex and triplex structures. Decreasing the pyrimidine region below six residues leads to a decrease in effectiveness of strand-invasion.168 Two PNA strands connected by

Organophosphorus Chem., 2006, 35, 355–478

365

a ﬂexible linker forming a clamp structure (triplex) with DNA is known as bis-PNA. A bis-PNA conjugated to a 40 nucleotide DNA strand homologous to an adjacent region of the PNA clamp underwent site-directed recombination with a plasmid substrate in cell-free extracts.169 Strand-invasion using PNA has also been used to initiate polymerase extension on dsDNA by opening the duplex structure to leave ssDNA primer binding sites.170 PNA-DNA chimeras have been used to form stable duplexes171 and TFOs172 with DNA, which also exhibit enhanced protection against exonucleases. Chimeras of 2 0 -O-methyl RNA and PNA have similarly been used for enhanced binding towards complementary RNA.173 PNA may be used for the detection of single-nucleotide polymorphisms (SNPs). When PNA binds to fully complementary ssDNA, the DNA is protected from restriction digestion, but in the presence of a DNA mismatch the DNA is digested.174 PNA is well known for stabilising duplex and triplex structures, and there are now reports of PNA involved in quadruplex structures. One report described the synthesis of four PNA-DNA chimeric quadruplexes, but concluded that the quadruplexes do not form well-deﬁned structures as determined by NMR.175 However, a second report describes a PNA-DNA chimeric structure studied by CD, UV and FRET in which the quadruplex adopts a parallel structure.176 A four-stranded PNA quadruplex has also been reported in which an antiparallel structure is adopted, and the quadruplex exhibits many of the properties of a DNA quadruplex.177 Cyclic PNA corresponding to the loop region of the TAR RNA of HIV-1 has been synthesised and examined as an inhibitor of the HIV-1 dimerisation process. The cyclic PNA was designed to form a kissing complex with the loop region of TAR RNA. In a preliminary report it was suggested that the cyclic RNA was able to inhibit HIV dimerisation,178 but a later report claimed that no interaction occurred between the cyclic PNA and the RNA, though some interaction was observed with the linear form of the PNA.179 The original PNA consisted of an aminoethylglycine backbone (15) to which the nucleobases were attached. PNA has attracted much attention, and as a result many novel backbones have been reported. The analogue (16) has been used as a mimic of 2 0 ,5 0 -RNA linkages.180 However, PNAs derived from (16) were destabilising against both DNA and RNA compared to (15), and it was suggested that the glycylalanine backbone is not of optimal length for hybridisation. Replacement of glycine with arginine introduces a guanidinium group into the PNA backbone (17), which was developed to facilitate cellular uptake of the resultant PNA. This PNA was shown to preferentially form duplexes rather than triplexes, but enhanced cellular uptake was observed.181 The use of ornithine in the PNA backbone has also been reported, and whilst there was no comparison with PNA it was reported that it formed more stable duplexes with DNA than DNA-DNA duplexes.182 PNA derived from serine, (18), forms ahelical PNA structures composed of a repeating tetrapeptide unit.183 These structures are able to hybridise to ssDNA, forming more stable parallel than antiparallel structures.

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Organophosphorus Chem., 2006, 35, 355–478 Base O

Base O

O

N H

N

N H

H N O

O

H2N

H2 N

+

H2N 15

16

CO2H

N H

isoPNA

PNA

O

N

N H

Base

Base

O

17

18

The previously described PNA analogue (19)184 pairs with thymidine when in a Hoogsteen strand of a bis-PNA. The conformationally constrained analogue of (19, 20), was evaluated in bis-PNA, but there was no improvement of stability compared to (19).185 The conformationally constrained PNA monomer (21, X¼F) targeted towards DNA, formed stable structures, but was sequence dependent.186,187 PNA containing (21, X¼H) preferentially forms stable parallel duplexes with DNA rather than antiparallel.188 PNA containing the peptide ribonucleic acid derivatives (22) are reported, but no additional data is provided.189 O

O NH

NH

N

N

O N H

19

N H

O O O

O

O N

Base

T X

NH O N

20

OH

NH

N H

OH X = H, F

21

N H

O 22

Various cyclic PNA analogues have been reported where a ring structure is incorporated to add conformational restraint. A number of pyrrolidine-based structures have been synthesised, but were found to be destabilising towards complementary DNA or RNA.190–194 However, the pyrrolidine derivative (23, cis-L-derivative shown) demonstrated sharper melting proﬁles than (15),195 whilst (24) exhibited unprecedented kinetic binding selectivity for ssRNA over DNA.196 In an attempt to mimic the negative charge of the DNA backbone, phosphono derivatives of PNA have been examined. The phosphono-PNA derivative (25) derived from trans-4-hydroxy-L-proline was found to form exceptionally strong duplexes with either DNA or RNA.197 The pyrrolidinylPNA (26) exhibits discrimination towards DNA in that when paired with a mismatch, the duplex is significantly destabilised compared to natural PNA.198 Cyclopentane or cyclohexane modiﬁed PNA (27) show enhanced binding towards DNA and RNA.199–202 Incorporation of pipecolyl (28) and piperidine units into the PNA backbone also enhance duplex stability with complementary DNA.203–205 The incorporation of an aromatic ring into the backbone of

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PNA (29), however, was destabilising towards complementary DNA, though inclusion of carboxyl groups improves the aqueous solubility of the PNA.206 O

A

O

Base

N

O

N

23

O

O

P

H

HN

N

N

O

O

O

Base

N O

HN

O 25

24

T

H Base 26

Base

O

T

O O

H N

NH

N

N

O

N H

(CH2)n

R X

O n = 1, 2 X = CH, N 27

28

R = H, CO2H

29

As well as backbone modiﬁcations, a number of nucleobase modiﬁcations have been reported for PNA. 5-Propynyl- and 5-hexynyluracil have been incorporated into PNA where surprisingly it was found to be destabilising.207 N7-substituted guanine (30) has been used as a mimic of protonated cytosine in a triplex with dsDNA.208 A Janus-Wedge triple helix is a motif in which the incoming base from the third strand forms hydrogen bonds with the WatsonCrick faces of the target duplex.209 6-Amino-pseudocytidine forms a JanusWedge between a thymidine and cytidine in a bulge-loop.210 A G-clamp PNA monomer (cf 106) has been incorporated into PNA and targeted towards both complementary DNA and RNA, where it was shown, as with the DNA/RNA G-clamp, to significantly enhanced duplex stability.211 H

H N

H N

H

H

N N

N9 N7

N

H N

O

O protonated Cytosine (C+)

N7-guanine 30 212–214

Demidov et al. have described a method of DNA duplex recognition by modiﬁed PNA. Using strand-invading PNA containing diaminopurine and

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2-thiouracil in place of adenine and thymine, respectively, it was shown the PNA recognises its A-T or G-C counterpart, forming unstable duplexes due to steric interference with the modiﬁed nucleobases. The concept, known as pseudocomplementary-PNA, induces DNA bending at the target site and modiﬁes protein activity of duplex DNA. A method for discriminating between dC and MedC in DNA has been described.215 The method involves using PNA to strand-invade the target sequence bearing dC or MedC such that the target sequence binds to a further strand of DNA bearing a ﬂuorophore. The complex is then digested and, if dC is in the target sequence, there is an enhancement of ﬂuorescence as the ﬂuorophore is released, but there is no increase in ﬂuorescence from the MedC containing complex. A similar system of using PNA to strand invade a DNA duplex was used to selectively cleave one strand of DNA at a designated site by a restriction enzyme.216 Various ﬂuorinated aromatic nucleobases have been synthesised for PNA.217 As is found with similar ﬂuorinated aromatic bases in DNA (section 1.3.3), they behave as universal bases with complementary DNA. PNA with a terminal 9aminoacridine has been prepared to examine binding of monovalent ions.218 A T10 PNA oligomer was found to be sensitive to increasing the concentration of K(I) ions, but the presence of the terminal acridine significantly reduced the sensitivity. The incorporation of naphthalene diimide at the N-terminus of PNA stabilises DNA-PNA duplexes,219,220 whilst the bis-functionalised PNA (31) not only stabilises the duplex with DNA but also can be used to photocrosslink to DNA.221 The presence of the phosphonium ion in (31) aids mitochondrial location of the PNA. O

O N PNA N H H

H2NOC N H

O N H

O N H

P Ph

Ph Ph

O 31

PNA has been synthesised using an azido-group as a masking group for the terminal amine; mild deprotection is carried out with phosphines.222 Various terminal-modiﬁcation groups (aromatic, metal-binding and aliphatic) have been incorporated onto PNA to assess the thermal stability with complementary DNA.223 PNA has also been synthesised bearing an N-terminal spin-label (cf 44) to investigate binding of PNA to DNA by EPR.224 A series of trifunctional PNA conjugates has been examined for cellular uptake and ribonuclease activity.225 The conjugates consist of PNA to target RNA, the ribonuclease unit diethylenetriamine (DETA) and a cell-penetrating peptide. Various length spacers were incorporated between the PNA and the peptide. The pharmacokinetic properties of PNA can be modulated by sugar residues. The galactose-modiﬁed PNA monomer (32) in PNA is slightly destabilising towards complementary DNA but was effectively targeted to the liver compared to the unmodiﬁed PNA.226

369

Organophosphorus Chem., 2006, 35, 355–478 T O CO2H

H2N

X R

O

R = H, Me X = tetra-O-acetyl-galactose-1-yl 32

PNA analogues have been designed for metal binding (see also section 3.3). The neocuproine-Zn PNA monomer (33) has been used to target the RNA component of human telomerase.227 Incorporation of the Zn(II) binding units (34) and (35) at the termini of PNA substantially increases binding afﬁnity towards DNA,228,229 while (36) has been used to deliver radiometals, in particular 111In.230 The dioxime modiﬁcation (37) was designed for chelation to metal ions. Synthesis was carried out using iron(II)-clathrochelates as protection for the dioxime unit, and the modiﬁed PNA was found to bind Cu(II) and Ni(II) at micromolar concentrations.231 O

OH

HO O N

R

O

FmocHN

NH N N Me

N

N

R

N

R

N

Me

N

NH

OH (CH2)5 NH

34

N Me

33

N

O

N

O

N

35 36

R=H

PNA

O

R = CH2CO2H 37

There are also reports in which PNA has been used in antisense. PNA has been targeted at the initiation codon of the p75 neutrophin receptor where it showed a dose-dependent inhibition,232 for inhibition of murine CD40 expression by redirecting constitutive splicing,233 and down-regulation of microsomal triglyceride transfer protein expression in hepatocytes.234 A 13-mer antisense PNA was used to inhibit expression of the bcr/abl oncogene by binding to the junction of bcr/abl mRNA,235,236 and, by targeting Ha-ras mRNA translation, elongation was arrested.237 A 14-mer PNA was used to inhibit inducible nitric oxide synthase (iNOS) in macrophages.238 PNA was used to inhibit the expression of human caveolin-1 and to discriminate between its a and b isoforms, selectively blocking the a isoform.239 The degradation of dsDNA by exonuclease III can be inhibited in speciﬁc and non-speciﬁc manners in the presence of PNA.240 A promoter targeted PNA acted as a strong inhibitor of basal transcription in HeLa cells, but when

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Organophosphorus Chem., 2006, 35, 355–478

conjugated with a Gal80-binding peptide it activated transcription.241 A Cy3labeled PNA was targeted to telomeric DNA in living cells to observe the dynamics of telomers, where it was observed that a majority of telomers undergo constrained diffusive movement.242 BisPNA has been used to target duplex DNA, where it was shown that it could inhibit transcription.243,244 1.3.2 Oligonucleotides Containing Modiﬁed Sugars. There are many new sugar derivatives, with modiﬁcations at each of the ribose carbon atoms, though 2 0 modiﬁcations are the largest group. There is one 1 0 -modiﬁed analogue, the homo-N-oligonucleotide (38).245 Oligonucleotides (38) can form duplexes with either (38) or natural oligomers. Duplex homo-N-oligonucleotides form lefthanded helices, whilst with RNA they form right-handed helices. Base HO

O

OH

38 0

The most common C2 -modiﬁcation is 2 0 -O-methyl, which has been widely used because 2 0 -O-methyl modiﬁed oligonucleotides are more thermally stable and nuclease resistant. For this reason they are widely used in oligonucleotides which need to be stable in cellular environments. This modiﬁcation is so well known that reports which describe 2 0 -O-Me oligonucleotides are only included for completeness.246–253 Polymerases have been evolved by directed evolution that can efﬁciently synthesise oligonucleotides using 2 0 -O-methyl 5 0 -triphosphates,254 and 2 0 -O-methyl oligonucleotides conjugated to a phenanthroline derivative can cleave target complementary RNA sequences.255 2 0 -O-Alkyl-2-thiouridine-modiﬁed RNA duplexes were studied to show that the addition of an alkyl substituent to O-2 0 of 2-thio-U gave higher Tms, though it was destabilising compared to 2-thio-U.256 2 0 -O-alkyl modiﬁcations in siRNA are generally tolerated at the 5 0 -end, especially 2 0 -O-allyl, but at the 3 0 -end low tolerance was exhibited.257 2 0 -O-(2-Methoxy)ethyl (2 0 -MOE) substituents in ODNs are known to give rise to higher duplex stability with complementary RNA.258 The 2-MOE derivative of 2-thiothymidine in ODNs was therefore found to exhibit very high duplex stability with complementary RNA as well as enhanced resistance to nuclease degradation.259 2 0 -O-(2methylthio)ethyl-modiﬁcations (39) also exhibited high binding to RNA targets, but are more susceptible to nuclease degradation.260 The synthesis of 2 0 -MOE phosphorothioates has been studied and it has been shown that diastereomeric control may be achieved by varying activators and phosphate protecting groups.261 2 0 -MOE gapmers targeted towards telomerase were able to diffuse across cell membranes and inhibit telomerase without the use of a cationic lipid carrier.262 A cytidine bearing a 2 0 -O-ribose sugar modiﬁcation

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Organophosphorus Chem., 2006, 35, 355–478

within an ODN has been oxidised to yield an aldehyde derivative that could then be used to crosslink to the methyltransferase Eco-RII.263 Many C2 0 -modiﬁcations have been examined for their potential use in antisense therapy. 2 0 -O-{2-[2-(N,N-Dimethylamino)ethoxy]ethyl} (2 0 -DMAOE) modiﬁed nucleosides (40), cationic analogues of 2 0 -MOE nucleosides, when incorporated into ODNs exhibit high binding to RNA but not DNA targets,264,265 and are exceptionally stable towards nuclease degradation. Gapmer oligonucleotides with one or two regions of 2 0 -DMAOE modiﬁed nucleotides and a phosphorothioate DNA region were able to inhibit mRNA expression in vitro and in vivo.266 A 2 0 -O-hydroxyethyl modiﬁed nucleoside also suppressed gene activity when incorporated into TFOs.267 2 0 -O-(2-Amino)-2-oxoethyl derivatives (41) considerably stabilise duplexes with RNA but not with DNA,268 particularly (41, R¼CH2CH2N(CH3)2). The guanidinium derivative (42), however, stabilises duplexes with both DNA and RNA, and has been used for triplex stabilisation.269 Psoralen-linked 2 0 -O-(2-aminoethyl) oligonucleotides have been used in TFOs in a gene knockout assay, and maximum activity was achieved when four such modiﬁcations are clustered within the TFO.270 ODNs have been prepared in which adenosine bearing a 2 0 -O-pyrrolepolyamide ligand was incorporated to aid duplex stability.271 S

39

Me O

Base

N

40

HO

O

Me

R= HO

OR

Me

O R'

41

N H

42

N H

R' = CH3

or

N Me

NH2+ NH2

There are a few reports detailing the use of 2 0 -5 0 linked oligonucleotides, the best well known being 2 0 ,5 0 -A which is associated with the antiviral effect of interferon. Antisense ODNs have been synthesised containing 2 0 -5 0 -A tetramers at the 5 0 -end and shown to have enhanced nuclease stability,272–274 and were able to activate RNase L activity.272,273 DNA containing 2-5 linked uridine can direct DNA synthesis with either Klenow fragment or HIV-RT polymerases.275 2-5 Linked xylose oligonucleotides shows a preference for base-pairing with RNA, and is unable to form a duplex with ssDNA.276 A 2 0 ,5 0 -oligoribonucleotide derived from 1-methyl-6-thioinosinic acid showed no organised secondary structure, but was found to be a potent inhibitor of HIV-1-RT.277

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Organophosphorus Chem., 2006, 35, 355–478

A method has been described which allows for post-synthesis modiﬁcation of the 2 0 -hydroxyl group within an oligodeoxynucleotide. The silyl-protected 2 0 hydroxyl group is deprotected prior to cleavage from the support, and then treated with carbonyl diimidazole followed by an amine.278 The O2 0 -position has been used to attach a number of reporter groups. Highly conjugated pyrene and anthracene derivatives (43) have been attached via O2-carbamate linkages which show strong dye emissions at 401 and 485 nm respectively, but are not ideally suited for FRET analysis.279 Pyrene, as its arabinoside, has been incorporated via a 2 0 -carbamate linkage and is a strong interstrand excimer in DNA duplexes.280 Pyrene has also been used as a probe in RNA for acceptor sites by antisense.281,282 A Dansyl ﬂuorophore at the 2 0 -position of cytidine shows some quenching when base paired with guanosine.283 O

U

R

HO HO

H N

O O

R=

or

43 0

2 -Selenium modiﬁcations have been prepared as an aid to crystallography by multiple anomalous dispersion (MAD). The synthesis and incorporation into DNA of 2 0 -methylseleno-dC for this purpose has been described,284,285 as have phosphoroselenates.286 The 5 0 -triphosphates of 2 0 -C-branched-uridine derivatives have been synthesised and examined as substrates for T7 RNA polymerase.287 2 0 -Hydroxymethyluridine-5 0 -triphosphate is a substrate and is specifically incorporated into short RNA transcripts, whilst the 2 0 -hydroxyethyl derivative is not. 2 0 -Aminonucleosides are often used as a route for post-synthesis modiﬁcation in oligonucleotides. Using this approach, RNA oligonucleotides were synthesised incorporating 2 0 -N-amido and 2 0 -N-ureido groups to assess them for thermal stability. All analogues were found to be destabilising in RNA duplexes, the 2 0 -N-ureido modiﬁcation being the most stable.288 A series of 2 0 N-amido and 2 0 -N-ureido modiﬁcations were introduced into the hammerhead ribozyme to assess the affect of bulky residues on ribozyme activity.289 A

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Organophosphorus Chem., 2006, 35, 355–478

number of such modiﬁcations were found that inhibited cleavage by preventing the formation of the active conformation. A method for the selective acylation of 2 0 -N-amino cytidine nucleotides at a nucleotide bulge site of an ODN was used to study the DNA ﬂexibility. It was shown that a bulged (non-hydrogen bonded) 2 0 -N-amino dC was acylated 20 times faster than one involved in a hydrogen-bonded pair.290 The synthesis of RNA with a 2 0 -cap at the 3 0 -end is reported,291 where the incorporation of uridine bearing a 2 0 -N-aminoacyl anthraquinone significantly increases the Tm of short RNA duplexes. Various reporter or reactive groups have been incorporated into oligonucleotides via 2 0 -N-amido or ureido linkages. The spin label (44) was incorporated into RNA duplexes to measure distances between labels by pulsed electron double resonance (PELDOR).292 Two 2 0 -N-acylaminopyrene modiﬁed nucleosides were substituted into DNA duplexes to measure the formation rate of the pyrene dimer radical cation on one-electron oxidation.293 Formation of the radical cation in less than 5 ms was observed. The synthesis of ODNs containing the naphthalimide nucleoside (45) as a ﬂuorescent probe in DNA duplexes has been described.294 The presence of the ﬂuorophore did not significantly destabilise the duplex, and it is suggested that (45) could be used as an energy acceptor in FRET analysis. Arylazide-mediated photocrosslinking has been examined using the internally tethered derivative (46) in an RNA duplex. Crosslinking occurs broadly with functional groups in RNA, and is independent of the RNA local environment.295 U

O

HO

O HO

H N

HN

Me

O

O

HO Me

HO

HN

N

N O

O Me

U

Me

O

45

44

O

U

HO

N3 HO

HN 46

O

OH

A 2 0 -deoxy-2 0 -ﬂuoro-b-D-ribofuranoside can be considered a substitute for the natural b-D-ribose in RNA as it favors a C3 0 -endo sugar pucker and A-type conformation when hybridised with RNA. However, 2 0 -ﬂuoro containing oligonucleotides are not substrates for RNase H,296 and are inhibitors of human RNase L.297 2 0 -Deoxy-2 0 -ﬂuoro-b-D-arabinonucleoside oligomers (2 0 -F-ANA) are substrates for RNase H, and oligonucleotides of alternating DNA and 2 0 -F-ANA nucleosides (altimers) have been shown to induce RNase H cleavage of complementary RNA.298 Oligonucleotide gapmers, in which the

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Organophosphorus Chem., 2006, 35, 355–478

central portion is comprised of acyclic nucleoside residues and the termini from 2 0 -F-ANA, also induce RNase H activity299 Oligonucleotides comprised of 2 0 deoxy-2 0 ,200 -diﬂuoro-b-D-ribofuranosyl thymine as well as the a-D-analogue are destabilising in duplexes with RNA or DNA.300 Various 2 0 -modiﬁcations, including amino, methylamino, thiol, O-methyl and ﬂuoro, have been used to probe for exposed 2 0 -hydroxyl groups involved in solvation during group II intron catalysis.301 The synthesis of pyrimidine 3 0 -phosphorothioamidites has been carried out to prepare ODNs containing 3 0 -S-phosphorothiolate linkages for mechanistic studies.302 The stereospecific synthesis of 3 0 -deuterated pyrimidine nucleosides for NMR studies of ODNs has also been reported.303,304 The incorporation into DNA of a thymidine analogue bearing a 3 0 -methyl group was shown to be destabilising with both complementary DNA and RNA, though less so with RNA.305 Marx et al. reported a number of C4 0 -substituted alkyl-, alkenyl- and alkynyl-modiﬁed thymidine derivatives to investigate their effect on hybridisation and in primer extension reactions. In hybridisation studies, C4 0 -modiﬁed substituents caused some duplex destabilisation, increasingly with increasing size/chain length.306,307 In a primer extension assay with various DNA polymerases, C4 0 -methyl TTP was found to be a slightly better substrate than TTP, but longer alkyl chains decreased incorporation efﬁciency.308 Probes containing C4 0 -modiﬁed thymidine derivatives were used to detect SNPs, and it was shown that the use of C4 0 -vinyl thymidine gave enhanced SNP discrimination.309,310 The C4 0 -piperazinomethyl derivative (47), and its N-pyrenylcarbonyl derivative have been incorporated into DNA duplexes.311 With complementary DNA, each stabilised the duplexes, particularly the pyrene derivative, but there was reduced stability towards RNA. Various C4 0 -alkylamino-modiﬁed 5-methyl-dC derivatives were used in TFOs to aid thermal and nuclease stability. Aminoethyl and aminopropyl linkers were found to stabilise triplexes, but other linkers were destabilising.312 A range of other C4 0 -modiﬁcations, including 4 0 -N3, 4 0 -MeO and 4 0 -CH3OCH2CH2O, have also been used to aid stabilisation in TFOs.313 The pyrrolidino nucleoside (48) was designed to introduce a positive charge within oligonucleotides for stabilisation in triplexes. Using pseudo-isocytosine as the nucleobase the analogue was stabilising in TFOs.314 HO

HN

O

T

HO H N

Base

N OH 47

OH 48

A few phosphoramidites have been used to prepare 5 0 -modiﬁed ODNs. The synthesis of a 5 0 -13C-labeled ODN has been described to enable NMR analysis by 2D 1H-13C HMQC NOESY experiments.315 A formamidine-protected

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Organophosphorus Chem., 2006, 35, 355–478

5 0 -amino-dG phosphoramidite was used to prepare 5 0 -acyl end-capped ODNs.316 5 0 -Iodo-dT-containing ODNs have been used in enzyme-less template-directed ligation reactions to a 3 0 -phosphorothioate-linked ODN.317 The ligation was considerably enhanced in the presence of the intercalator proﬂavine. A trimethoxymethyl group was used to protect a 5 0 -thiol group during the synthesis of ODNs bearing 5 0 -thiol or thiol-modiﬁed groups.318 The hexofuranosyl derivative (49) in ODNs causes a decrease in stability with complementary DNA or RNA, though a single substitution in a homopolymer showed a slight increase in stability against DNA.319,320 The (5 0 S)-5 0 -C-modiﬁed nucleosides (50, R¼H or CH3) were incorporated into ODNs to explore alkyl-zipper formation between opposing alkyl groups in the minor groove, though both were destabilising in DNA duplexes.321 The presence of 5 0 -chloro- and 5 0 amino-dG modiﬁcations in RNA hairpin ribozyme structures inhibited hairpin-catalysed RNA-RNA ligation reactions.322

OH

HO HO

O

T

Me

O

T

R

49

OH R = H or Me 50

There are two reports describing the use of nucleosides with other sugar conformations. A method for preparing internally 32P-labelled L-DNA has been described using T4 polynucleotide kinase.323 Chimeric DNA composed of tandem a- and b-anomeric strands have been used in TFOs and shown to have enhanced thermal stability compared to all a- or b-anomeric oligonucleotides.324 Locked Nucleic Acids (LNA) were ﬁrst reported by the groups of Imanishi325 and Wengel,326 the Imanishi group terming the analogues as bridged nucleic acid (BNA). LNA (51) contains a methylene bridge between the 2 0 -oxygen and the C4 0 -carbon, which results in a locked 3 0 -endo conformation, reduced conformational ﬂexibility of the ribose ring, and increasing the local organisation of the phosphate backbone. The entropic constraint in LNA leads to significantly enhanced binding of LNA to complementary DNA and RNA. LNA-modiﬁed oligonucleotides have enhanced resistance to nuclease degradation, and have proven to be effective in antisense strategies. The properties of LNA have been widely investigated, and in this review period, publications regarding LNA fall into three categories, new analogues of LNA, other locked nucleosides and the use of LNA oligonucleotides, including in antisense therapy.

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Organophosphorus Chem., 2006, 35, 355–478 HO Base O OH O β-D-LNA 51

Analogues of LNA contain a methylene bridge between O2 0 and C4 0 , but there have been modiﬁcations to the sugar, phosphate backbone and base modiﬁcations. The substitution of the phosphate group by a methylphosphonate still showed enhanced binding afﬁnity towards DNA, but less so than normal LNA.327 The 2 0 -amino analogue of LNA bearing an N-acyl group bound preferentially to RNA with higher afﬁnity than DNA, but again less efﬁciently than LNA.328 However, LNA bearing a P3 0 -N5 0 phosphoramidate linkage exhibited slightly higher binding afﬁnity towards DNA, RNA than LNA.329 The LNA derivatives of hypoxanthine, 2-aminopurine and diaminopurine have all been prepared and incorporated into oligonucleotides. As found with their DNA/RNA derivatives, each LNA analogue forms stable base pairs with their cognate nucleobase.330,331 A series of aryl C-nucleoside derivatives of LNA were assessed for binding afﬁnity towards both RNA and LNA. The analogues were generally destabilising, the pyrene analogue was the most stabilising where it behaved as a universal base.332,333 As with DNA analogues there are base-modiﬁed LNA analogues for stabilising triplexes. 2-Pyridones334,335 and 1-isoquinolone336,337 have been used to stabilise CG interruptions in TFOs. Each analogue was found to have high selective binding to their target sequence. The usual conﬁguration of LNA is b-D-ribose, but other conﬁgurations of LNA have been examined. a-D-LNA and b-L-LNA nucleosides have very high afﬁnity with complementary RNA in a parallel-stranded duplex.338,339 Aryl Cnucleosides in the a-L-conﬁguration (cf 52, base¼aromatic residue) demonstrate preferential binding to DNA, with a pyrene derivative showing highest afﬁnity and, as with the b-D-derivative332 it behaves as a universal base.340 Base OH O O HO α-D-LNA 52

A number of other locked nucleosides have been studied, and Imanishi and Obika have reviewed a series of bridged nucleic acid analogues.341 2 0 -O,4 0 -Cethylene (53) and propylene analogues also have C3 0 -endo conformations and

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Organophosphorus Chem., 2006, 35, 355–478

form duplexes and triplexes in the same way that LNA does. Oligonucleotides (53) have enhanced binding afﬁnities towards RNA, with stability similar to LNA. However, the propylene analogue has decreased afﬁnity towards RNA.342 Oligonucleotides (53) also form stable triplexes at physiological pH.343

HO

Base O OH O

53

The C1 0 -O2 0 locked pyrimidine analogues (54) also adopts a C3 0 -endo conformation. They have lower binding efﬁciency than their corresponding DNA analogues, but still elicit RNase H activity.344 2 0 -Spiro ribo- and arabinonucleotides (etheno and propano rings) are also destabilising compared to DNA, and it is suggested that this is due to steric constraints.345,346 The piperazine derivatives (55) and (56) were prepared to introduce basic functionality into the minor groove of DNA duplexes. Each analogue induced significant increase in thermal stability when in a DNA duplex.347 Oligonucleotides containing the modiﬁed backbone bicyclo[3.2.1]amide-DNA (57) will form duplexes with DNA and RNA, but exhibit considerable destabilisation.348–350 An anucleosidic analogue of (57) has also been used to study melting cooperativity in a helix-bulge-helix DNA model.351 Tricyclo-DNA (58) exhibits significantly enhanced stability with complementary RNA, but it does not elicit RNase H cleavage. However, in an antisense assay compared to 2 0 -Omethylphosphorothioate oligonucleotides, tricyclo-DNA exhibited an antisense activity in the absence of lipofectamine.352 The locked L-nucleoside derivatives, e.g., derived from thymine, (59), were destabilising in a duplex with DNA. However, the homo-uridine analogue showed enhanced binding with homo-rA compared to that formed with homo-dT.353

Me N HO Py O OH O 54

HO N

T

O

O

HO O OH 55

O

T

Me

N

N

OH

56

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Organophosphorus Chem., 2006, 35, 355–478 OH

O

OH

H N

O

Base

Base

O

HN

O

O OH

OH

N OH

O OH

57 58

59

LNA has been used in a number of applications. As probes, the effect of incorporation of a single LNA into an ODN has been studied by thermal denaturation experiments.354 LNA substitutions stabilise the duplex either by preorganisation or by improved stacking, but not both. The effects of mRNA target sequence and DNA-LNA chimera design have been examined,355 and a method for the capture of poly(A)1 RNA using oligo-LNA-thymidine has been reported.356 LNA oligonucleotides also bind to plasmid DNA by strand displacement without interfering with plasmid conformation or gene expression.357 LNA oligonucleotides are effective in the detection of SNPs358,359 and have been used for SNP genotype analysis by real-time PCR.360 The presence of LNA or a-L-LNA monomers stabilise duplexes towards endo- and exo-nucleases,361 including resistance to DNA polymerase exonuclease activity.362 DNA partially substituted by LNA has also been used to direct the repair of single base mutations in a yeast chromosomal gene.363 LNA has frequently been used to stabilise duplex structures, but in triplex structures the effect is mixed. Partial substitution of a DNA TFO by LNA increases triplex stability, whilst complete substitution leads to destabilisation.364 Optimal stabilisation was found with substitution every 2-3 nucleotides of the TFO. The incorporation of LNA into a G-quadruplex structure was shown to alter the orientation of the quadruplex from antiparallel to parallel.365 The primary application of LNA has been in antisense therapy due to the aforementioned properties. It has been used to knock down human protein kinase C-a (PKC-a) with greater efﬁciency than the corresponding phosphorothioate ODN,366 as an inhibitor of human telomerase,367 to block the synthesis of RNA polymerase II368 and to inhibit human vascular smooth muscle cell growth.369 LNA-modiﬁed oligonucleotides have also been used in RNA interference (RNAi).370,371 Other locked nucleic acid derivatives have also been used in an antisense strategy. a-L-LNA chimeras with b-D-LNA are shown to be effective with enhanced nuclease stability and to recruit RNase H activity,372 and are shown to be effective inhibitors of HIV-1 when targeted at TAR RNA.373 a-L-LNA has also been used as a decoy for the transcription factor kB.374 The tricyclo locked nucleic acid (58) has been used to target the splice sites of exon 4 of cyclophilin A (CyPA) pre-mRNA,375 whilst the ethylene-bridged nucleic acids (53) have been targeted at VEGF mRNA376 and rat organic anion-transporting polypeptide.377

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Organophosphorus Chem., 2006, 35, 355–478

Other sugar modiﬁcations include acyclic nucleoside analogues that have been incorporated into oligonucleotides. The analogues (60-62) were found to be destabilising towards DNA and RNA.378–380 The hydroxymethylphosphinic acid analogues (63-64) have also been reported, though no data concerning their effects in oligonucleotides were reported.381 An acyclic synthon for the introduction of a label or as a branching point for oligonucleotide synthesis382 and one bearing two nucleobase units383 have also been reported. U HO

O

HO

T

Pyrene

HO

HO 60

HO

OH 61

Base

HO O

62 HO

P

OH

O

P

OH

X

(CH2)n

OH X = O or NH n = 1 or 2 64

63

Various other sugars have also been incorporated into nucleosides. A method for the synthesis of arabinopyrimidine nucleosides has been described which are prepared from O2,2 0 -anhydronucleosides.384 The inclusion of arabinonucleosides into ODNs was shown to be slightly destabilising. Xylose-modiﬁed nucleosides (XNA), including a xylose locked nucleoside, when incorporated into DNA oligomers show a preference for pairing with complementary RNA rather than DNA. In homopolymers with either RNA or DNA, triplex structures are formed with two XNA strands385,386 in which one XNA strand is parallel and the other antiparallel.387 Phosphoramidate morpholino oligomers (65) have been used as antisense agents. Conjugation to arginine-rich peptides was found to significantly enhance cellular uptake.388 Hexitol nucleic acids based on 1,5-anhydrohexitol as the sugar component have previously been studied as an alternative backbone system, and it has now been shown that methylation of the free hydroxyl groups (66) gives rise to a system which is an exceptionally good binder with RNA.389 HO

O O

Base

N

OH Me

O

P

N Me

O 65

OMe Base

O

66

OMe

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Organophosphorus Chem., 2006, 35, 355–478

a-L-Threose nucleic acids, TNA, (67) is a nucleotide system built from sugar units with only four carbon atoms and therefore a shorter backbone. It efﬁciently forms Watson-Crick base pairs with TNA, RNA and DNA, and has been a topic of much investigation (for a review see Scho¨ning et al.390). Recent developments with TNA have been polymerase recognition; the incorporation of the thymine derivative as its 3 0 -triphosphate into DNA with either Vent (exo-) DNA polymerase or HIV-RT was found to be quite efﬁcient, comparing favourably with dTTP.391 Various DNA polymerases were used to try to synthesise DNA on a TNA template.392 Despite the differences in the sugar-phosphate backbone, several polymerases were able to copy limited stretches of a TNA template with good ﬁdelity. TNA synthesis on a DNA template was also found to be efﬁcient, with Deep Vent (exo-) DNA polymerase being the most efﬁcient polymerase.393 Base

O O O 67

1.3.3 Oligonucleotides Containing Modiﬁed Bases. Oligonucleotides containing modiﬁed nucleobases represent the largest group of analogues. Purine and pyrimidine analogues are reviewed ﬁrst, followed by a series of artiﬁcial nucleobases. There are then sections dealing with new base-pairs, universal base analogues, a number of aromatic nucleobases not dealt with within universal bases, and the ﬁnal group are abasic sites, which can be considered as a nucleobase modiﬁcation. In addition to the analogues discussed in this section there are also other nucleobase modiﬁcations covered in section 3, which deal with template-directed organic synthesis (3.2), metal-conjugates (3.3) charge transport analogues (3.4) and ﬂuorescent analogues (3.5). The synthesis and incorporation into RNA of three hypermodiﬁed tRNA nucleosides has been reported. The presence of the N6-isopentyl modiﬁed adenosine (68, i6A) in the anticodon stem-loop of E.coli tRNAPhe alters metal ion binding compared to the unmodiﬁed stem-loop sequence.394 The presence of the N6-lysine modiﬁed derivative (69), ms2t6A, found in tRNAlys,3 of the speciﬁc RNA primer for HIV-1 RT has been shown to increase the stability of the hairpin.395,396 1-Methyladenosine has also been incorporated into RNA.397 Me

OH

O OH

Me

HN

HN Me N

N N

N

N

N MeS

N

68

i A

N Rib

Rib 6

N H

69

ms2t6A

O

Organophosphorus Chem., 2006, 35, 355–478

381

A number of analogues have been investigated for their ability to stabilise duplex or triplex structures. 8-Chloroadenosine was found to be destabilising in RNA duplexes, though the chloro group did not perturb the helical structure.398 Various N6-alkyl adenosine derivatives were studied in RNA by a post-synthetic modiﬁcation of 6-methylthiopurine.399,400 For most of the modiﬁcations, it was found that the presence of alkyl groups was destabilising in duplexes and hairpins. However, the incorporation of various aromatic hydrocarbon groups via a urea linkage to C6, e.g., (70), lead to large stabilisation when in a duplex.401 O HN

N H N

N

N

N

dR 70

DNA polymerase incorporation of the mutagenic 2-hydroxy-dA has been examined and found to lead to GC-AT transition mutations.402 The synthesis, incorporation and repair of etheno-dA adducts have been reported.403–405 The use of a C2-alkaryl modiﬁed adenosine gave rise to enhanced stability towards a mutant U1A protein in which a conserved phenylalanine was substituted for alanine.406 2-Aminopurine (2-AP) has been widely used because of its ﬂuorescent properties. However, 2-AP dinucleotide also exhibits a distinct positive CD band at 326 nm, and this property has been used to probe changes in local conformation of ODNs containing (2-AP)2 by CD measurements.407 The effect of an 8-propynyl group on dA has been studied in quadruplex structures. The effect was to increase the stability of the quadruplex due to an increase in the syn glycosidic conformation.408 An 8-histaminyl-dA phosphoramidite has been incorporated into DNA, where it was suggested it might be useful to probe nucleic acid structures.409 8-Chloro-dA has been examined as a substrate both as its 5 0 -triphosphate and in a template by the polymerase Klenow (exo-) fragment. Although it behaved as dA, incorporation efﬁciency was reduced.410 A series of adenosine derivatives have been reported which deal with damaged or adducted analogues. 8-Oxo-7,8-dihydroadenosine has been incorporated into DNA and its templating properties with three reverse transcriptases examined. It was shown that as well as directing the incorporation of TTP, dGTP was incorporated.411 Another oxidative lesion of adenosine is formamidino-adenosine (Fapy-dA, 71). (71) and its C-nucleoside have been incorporated into DNA and its interaction with base excision repair enzymes assessed.412 (5 0 S)-8, 5 0 -cyclo-dA is another oxidative lesion, and an assay to determine levels of this lesion in DNA by nuclease digestion has been reported.413

382

Organophosphorus Chem., 2006, 35, 355–478 H

O NH2 HN N HN

N

dR

71

Polycyclic aromatic hydrocarbons (PAH) are a significant cause of tumorigenic lesions found in DNA, and purine analogues are particularly susceptible to adduction with PAHs. Two such analogues of dA have been reported, (þ)1R- or (-)-1S-trans-anti-[BPh]-N6-dA (72, (-)-1S- isomer shown) and the related 10S (þ)- and 10R (-)-trans-anti-[BP]-N6-dA, derived from benzo[c]phenanthrene diol and benzo[a]pyrene diol epoxides respectively. The presence of the lesion (72) in DNA was examined for its effect on transcription by human RNA Pol II, where it was found that the lesion caused polymerase stalling.414 It was also assayed with mismatch repair (MMR) enzymes, where it was found that effective MMR enzymes caused cell apoptosis.415 The translesion synthesis by human DNA polymerase i was examined with (72) and its dG analogue. The dG analogue causes a strong block to Pol i, but the dA analogue predominantly incorporated TTP opposite (72).416 With human DNA polymerase g, the dG analogue misincorporated dAMP and dGMP, whilst with the dA analogue, dTMP and dAMP was incorporated.417 The presence of the benzo[a]pyrene diol epoxide adduct during DNA synthesis by T7 DNA polymerase also caused stalling at the lesion, but some incorporation of dATP occurred.418 Interactions with nucleotide excision repair enzymes have also been reported.419

OH

OH

HN OH N

N N

N dR

72

A few deaza- and aza-dA analogues are reported. 3 0 -Deaza-dA has been used to probe minor groove recognition contacts,420,421 as well as its interactions in DNA curvature at A-tracts.421 1-Deaza-adenosine, tubercidin, purine and 4-methylindole deoxyribosides have all been used to probe for an essential

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Organophosphorus Chem., 2006, 35, 355–478

adenine in the U1A RNA complex.422 An analogue of tubercidin, (73), which has a naphthylmethyl group at C2 0 , was shown to be slightly destabilising in a DNA duplex except at the terminal nucleotide where a slight stabilisation was observed. However, against an RNA target opposite a 2-3nt bulge, (73) stabilised the heteroduplex.423,424 7-Deaza-7-nitro-dA (74) and dG with 5hydroxy-dU and dC have been used in a method for chemical cleavage of ODNs.425 The method involves the use of their triphosphates incorporated into DNA by PCR. Treatment with an oxidant followed by an organic base results in cleavage of the DNA at all sites where the 7-nitropurine or 5-hydroxypyrimidine was incorporated. The use of the 7-deaza-8-aza-diaminopurine analogue (75) in a DNA duplex stabilises the A : T base pair, and the 7-bromo-derivative harmonised the stability of A : T with C : G base pairs.426,427 Substitution of dA by 8-aza-dA accelerates the rate of adenosine deaminase reactions.428 7-Propynyl derivatives of 7-deaza-8-aza purines (dA, dG and diaminopurine) were all shown to give enhanced duplex stability.429 NH2 N N

N O HO HO

73

NH2

O2N

NH2

N

N N

N

N

H2 N

N

dR 74

N dR

75

8-Amino- dA and dG derivatives have been used to aid stabilisation of TFOs. G8AG : C and T8AA : T triplets are significantly more stable than corresponding native triplets.430,431 Other methods of stabilising duplex structures include the novel extended base pairs derived from imidazo[5 0 ,4 0 :4,5]pyrido[2,3d]pyrimidine nucleosides (76-79).432 In these structures, (76 : 77) and (78 : 79) are base pairing nucleosides each of which present four hydrogen bonds. A single substitution of one of these pairs in the middle of a duplex was found to be destabilising, but three consecutive substitutions led to significantly higher duplex Tms.

384

Organophosphorus Chem., 2006, 35, 355–478 H N N

H N

H

O

N

H

N

N

N N

N

dR

dR N

H

H

N

H

N

N N

N

H

N

O

H

N

N

N

O

H 76

O

dR

N N

H

dR

N

N

N

77

78

H 79

A set of six analogues (2-AP, 7-deaza-dG, pyrimidinone, 7-deaza-dA, 5methylpyrimidinone and purine) were used to probe DNA recognition by the Eco RV restriction endonuclease.433 Each of the analogues used has one or more hydrogen bonding functionality removed compared to native nucleosides, and hence gave useful information regarding hydrogen bond contacts between protein and DNA. Diaminopurine, purine, methylindole and an abasic site were each incorporated opposite dU in a DNA duplex to study their effects on base-ﬂipping by uracil DNA glycosylase.434 A number of guanosine analogues have been investigated for their ability to stabilise duplex or higher structures. 8-Methylguanosine and 8-methyl-dG stabilise Z-DNA helical structures,435,436 and the presence of 8-Me-G will convert a range of sequences from B- to Z-DNA.435 The incorporation of 436 L-nucleotides in a D-environment also leads to Z-form DNA duplexes. The incorporation of 8-Br-G into RNA, which is in equilibrium between a hairpin and a duplex, shifts the equilibrium towards the hairpin structure by destabilisation of the duplex due to the preferred syn-conformation of 8-Br-G.437 The use of N1-modiﬁed dI analogues (80) bearing pyrene or acridine were incorporated into ODNs where it was shown that the presence of the dangling aromatic group aided the stabilisation of both duplex and triplex structures.438 Rapid reversible G-quadruplex hairpin dimer formation was reported for bis(oligonucleotide) conjugates containing stilbene diether linkages connecting the two poly(G) sequences.439 O H N

N N

R

N O N

dR R = pyrenylmethyl or acridine

80

The genetic code only allows for two types of base-pair, A with T and G with C. There have been attempts to prepare nucleoside analogues to expand the

385

Organophosphorus Chem., 2006, 35, 355–478

number of base pairs and hence the genetic code (a number of such analogues will be discussed later). One particular analogue that has been examined in detail is isoguanosine (81), which forms a base pair with isocytidine (82). (81) has been incorporated into ODNs both as phosphoramidite and H-phosphonate derivatives.440 (81) and (82) have also been successfully used in PCR, conﬁrming that they act as a third base pair.441 Isoguanine adopts two tautomeric forms, and can form base pairs with isocytosine and thymine. These tautomeric properties have been examined theoretically,442 and the effect of adjacent nucleosides examined in primer extension reactions with Taq DNA polymerase where it was shown that the 3 0 -neighbour has an effect on the tautomeric state and hence the templating properties of iso-dG.443–445 The base pairing properties in parallel and antiparallel duplexes of ODNs containing 7-deaza-8-aza-iso-dG have also been examined.446 H N N dR

N

H

O

N

H

N

N

N O

H

N

dR H 82

81

The incorporation of 6-thio-dI447 and 6-thio-G448 phosphoramidites into oligonucleotides has been reported. 6-Thio-G has also been used to introduce 6-thio-modiﬁed oligonucleotides using on-column conjugation. The 6-thio group is selectively deprotected, which then reacts with various alkyl iodides, followed by cleavage and deprotection with ammonia.449 The incorporation of N2-benzyl-G into an Epstein-Barr virus encoded RNA sequence was shown to restrict the binding of protein kinase dependent on RNA (PKR).450 A series of N1 alkylated inosine and guanosine analogues was incorporated into RNA as potential inhibitors of HIV-RT and HCMV. Of the analogues selected, an oligomer containing 1-propyl-6-thioinosine was found to be highly active.451 An 8-ethylenediamine modiﬁed dG analogue (83) has been designed such that in the presence of a photosensitiser, such as riboﬂavin, a reporter group (e.g., TAMRA) is released on oxidation.452 R O

NH O

N

NH

HN N dR R = reporter group, e.g. TAMRA

83

N

NH2

386

Organophosphorus Chem., 2006, 35, 355–478

Guanosine is particularly susceptible to damage, either oxidatively as it has the lowest oxidation potential, or by external mutagens. The main oxidative lesion is 8-oxo-guanosine, a known mutagenic lesion. The role of the translesion polymerase k with a number of damaged bases has been examined, but opposite 8-oxo-dG, Pol k is able to efﬁciently insert adenosine and then extend beyond it.453 Ionising radiation leads to the formation of clustered DNA damage. When 8-oxo-dG is present within a clustered damaged site there is an enhanced mutagenic outcome with an increase in transversion mutations.454 Proof-reading studies using Klenow fragment with 8-oxo-dG and a further oxidation product, guanidinohydantoin, were carried out in different sequence contexts.455,456 It was shown that the presence of these lesions often led to primer slippage and therefore internal mismatches, but Klenow fragment was efﬁcient at repairing these internal mismatch sites. Klenow fragment (exo-) incorporates both dATP and dGTP opposite guanidinohydantoin.457 The synthesis of DNA containing the nitration product 5-guanidino-4-nitroimidazole has also been reported.458 The presence of 8-oxo-guanine residues within a recognition sequence has an effect on binding of proteins. Critical sites of the DNA sequence which binds to the p50 subunit of the NF-kB transcription factor were substituted with 8-oxodG, and the impact of these substitutions was assayed. Not every critical site was found to have an adverse affect on binding.459 The binding capacity of the human Y box-binding protein 1 (YB-1) to RNA is enhanced when 8-oxo-G residues are present.460 The interaction of the E.coli formamidopyrimidine DNA glycosylase with 8-oxo-G was examined using an oligonucleotide containing a photocrosslinking phenyl(triﬂuoromethyl)diazirine residue.461 The repair of oligonucleotides containing 8-oxo-dG has been studied using eurkaryotic 8-oxoguanine glycosylases, which repaired the lesion 1000-fold faster when it was base paired with cytosine than with adenosine.462,463 Repair was also studied using cellular extracts from human and rat testicular cells, though there was limited ability to repair the lesion.464 The mechanism of repair with human 8-oxoguanine glycosylases was examined at lesions where 8-oxo-dG was opposed to an abasic site.465 Further oxidation of 8-oxoguanine leads to the formamidopyrimidine derivative FapyG (84). (84) was incorporated into ODNs where its base pairing properties were compared with 8-oxo-dG. Whilst 8-oxo-dG pairs preferentially with dA and dC, (84) pairs with dT and dC.466 The repair of (84) by various repair enzymes showed little difference in efﬁciency compared to that of 8-oxo-dG.467 RNA containing the oxidised analogue 8-oxo-G may be cleaved at the 8-oxo-G site by ammonia in the presence of oxygen at 601C.468 O H N

H

NH O N

O HO HO 84

NH2

387

Organophosphorus Chem., 2006, 35, 355–478

Another form of guanine lesion arises from alkylation leading to O6alkylguanine derivatives. The enzyme that is involved in the repair of such lesions is O6-alkylguanine-DNA alkyltransferase (AGT), which also repairs O4alkylthymidine lesions. Using short ODN duplexes containing an O6-methyldG : T(U) mispair, it has been shown that AGT has two repair mechanisms, one of which is an ATP-dependent efﬁcient process. The other does not require ATP but is less efﬁcient.469 The repair of O6-methyl-dG by two thermophilic AGTs has been assessed and found to be efﬁcient, though less efﬁcient in the repair of O4-methyl thymidine lesions.470 The repair of O6-methyl-dG by human AGT has been shown to be 5-fold more efﬁcient when up to 0.1M Zn(II) is present.471 The mechanism by which AGTs work is not fully understood. Using alkylated nucleotides bearing an O-thiol tether, crosslinking between the ODN and protein occurs which demonstrates that the nucleotide is transiently extrahelical.472 O6-Benzyl guanine is an inhibitor of AGTs currently in clinical trials to enhance cancer chemotherapy. Short dG-rich ODNs containing one or more O6-benzyl guanine residues are even more effective inhibitors of AGTs than O6-benzyl guanine alone.473 The presence of the lesion (85), believed to be involved in the initiation of lung cancer in smokers has been studied in ODNs to investigate 3 0 -exonuclease resistance. It was found to be resistant to a number of exonucleases unlike O6-methyl-dG containing ODNs.474 DNA Polymerases Z and k are highly expressed in the reproductive organs where steroid hormones are produced. N2-dG and N6-dA estrogen adducts have been identiﬁed, and translesion synthesis past them using a truncated human Pol k has been examined. It was shown that translesion synthesis was efﬁcient with a high incorporation of the correct nucleotide inserted opposite them.475 Tamoxifen is used to treat breast cancer, but has been shown to cause liver cancer in rats. It forms adducts with N2 of dG, and the mutagenicity of the 4-hydroxytamoxifen adduct has been shown to lead to a high G-T transversion rate.476 N

O O

N N

N N

NH2

dR 85

Many other guanosine lesions have been investigated, the majority of which are those derived from polyaromatic hydrocarbons (PAHs), though adducts with smaller reactive species are also reported. Reaction with aldehydes, such as acrolein and crotonaldehyde leads to the formation of propano-dG adducts such as (86) and its a- and g-hydroxy derivatives as well as ring-opened derivatives like (87). Derivatives (87) can further react with other nucleobases, particularly guanine, leading to crosslinking. The reaction with aldehydes is

388

Organophosphorus Chem., 2006, 35, 355–478

accelerated by histones, and may therefore be linked to the mutagenic effects of these aldehydes.477 The formation of a dG-dG crosslink with acrolein is accelerated when the ring-closed propano-dG is opposite dC, which causes the ring system to transiently open to the linear chain.478,479 The a-hydroxy derivative of (86) acts as a strong block to DNA synthesis, and causes G-T transversions, whilst synthesis opposite the g-hydroxy derivative was efﬁcient and led to few mutagenic events.480 The malondialdehyde adduct is also a strong block to synthesis by T7 RNA polymerase and mammalian RNA Pol II.481 Propano-dG lesions derived from trans-4-hydroxynonenal have been shown to be repaired efﬁciently in human cell nuclear extracts by the nucleotide excision repair pathway.482,483 They are destabilising in a DNA duplex, depending on the absolute stereochemistry of the adduct, and only one of the stereoisomers is able to form dG-dG crosslinks.484 O N N

O N

N N

dR

N H

NH H

N

N H

N

dR

O

86

87

Translesion synthesis with DNA Pol z of the N-acetyl-2-aminoﬂuorene adduct of guanosine (88) is inefﬁcient with templates containing (88). In the presence of the Rev1 protein, translesion synthesis occurs and dCTP is the major nucleotide incorporated opposite it,485 and studies with a mutant DNA Pol I gave similar results.486 Benzo[a]pyrene is a potent environmental carcinogen, which when metabolised leads to anti-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (antiBPDE). With dG, the major lesion is (þ)-trans-anti-B[a]P-N2-dG, (89), and is usually repaired by the nucleotide excision repair (NER) pathway. The translesion synthesis past (89) has been examined with a number of polymerases. With human RNA Pol II, (89) is a block to synthesis,487 whilst DNA Pol k preferentially incorporated the correct nucleotide.488 In yeast cells, Pol z induced a large number of mutations involving Pol Z, whilst Pol Z alone contributed to 1-3 deletions or insertions.489 The NER of (89) with UvrB proteins was also studied.490 O N O N

N

N

NH

O

dR 88

N

N

NH

dR HO

N

Me

NH

NH2

HO OH 89

389

Organophosphorus Chem., 2006, 35, 355–478

Deaza- and aza-analogues of guanosine have been examined primarily in hybridisation and primer extension studies. 1-Deaza-dG incorporated into ODN duplexes exhibited no preference for pairing with the natural nucleotides, and was more destabilising than a mismatch. In primer extension reactions it preferentially formed pairs with dC.491 The importance of hydrogen bond recognition of the N3-nitrogen in guanosine was demonstrated by the incorporation of 3-deazaguanine into the hammerhead ribozyme. In most substitutions, catalytic activity was reduced except when a guanosine in the loop region was substituted when an increase in activity was observed.492 The anti-HIV activity of quadruplexes containing 8-aza-3-deaza-dG demonstrated only moderate activity.493 A series of 7-alkynylamino-7-deaza-dG analogues was examined for their ability to stabilise DNA duplexes. As the length of the alkynyl chain increases, duplex stability decreases.494,495 The incorporation of 7-deaza-8-aza-dG residues into guanine-rich sequences reduces the formation of guanine quartets due to the inability to form Hoogsteen base pairs.496 The N8-glycosylated 7-deaza8-aza-dG derivative (90) forms stable base pairs with iso-dC in antiparallel duplexes and with dC in parallel duplexes, but does not form guanine quartet structures.497 H2N NH O

N

N N dR 90

The deamination or action of nitric oxide on guanosine gives xanthine (X) (91), which is a mutagenic lesion. dX had been assumed to be an unstable lesion, but has been shown to be relatively stable when present in a duplex at pH 7,498 though depurination occurs at pH o 4.499 In a template, HIV-RT incorporated dCTP and dTTP opposite dX with equal efﬁciency, whilst Klenow fragment (exo-) preferentially incorporated dCTP.499 7-Deaza-dX has also been prepared and incorporated into ODNs.500 O N

NH

N

N H

dR 91

O

390

Organophosphorus Chem., 2006, 35, 355–478

The following section deals with the pyrimidine analogues that have been reported during this review period. There are a number of positions at which pyrimidines can be modiﬁed, though C5 is the most common position. There are two reports of N3 dU-modiﬁed ODNs; the introduction of N-nitrothymidine into ODNs allows for the generation of various N3-thymine modiﬁed ODNs.501 The base excision repair (BER) by E.coli GM31 extracts of ethenodU and etheno-dC identiﬁed a new repair mechanism termed very-long patch BER that is dependent on DNA Pol I.502 4-Thiouridine has been used in RNA for photo-crosslinking to identify the active site of the VS ribozyme.503 4-Thiouridine has also been modiﬁed to incorporate a C5 spin label that was used to study RNA structure and dynamics.504 As the C5 position of dU is the easiest to modify, there are many new C5-substituted analogues. Analogues have been prepared for SELEX reactions. 5-Aminoallyl UTP and 5-aminoallyl-2 0 -ﬂuoro-dUTP were both shown to be compatible with the enzymatic steps in SELEX.505 dUTP and dCTP analogues bearing ﬂexible and hydrophilic 7-amino-2,5-dioxaheptyl linker at C5 are also enzyme substrates.506 The imidazole modiﬁed dUTP analogue (92) has been used with 3-(aminopropynyl)-7-deaza-dATP in SELEX reactions to evolve DNAzymes capable of cleaving RNA in the absence of divalent metal ions.507

O O N H

HN O

N

N N H

dRTP 92

C5-Propynylated derivatives bearing terminal guanidinium groups have been prepared to examine duplex and triplex stability by introducing positive charges into the major groove.508 The introduction of guanidinium groups stabilised both duplex and triplex structures, but there was little difference between the use of guanidinium and amino groups. Introducing C5-(3-aminopropyl) groups into duplexes induces bending into the helical structure, and this has been examined thermodynamically,509 where the aminopropyl group induces a higher exposure of aromatic bases to the solvent. ODNs containing 5-(N-aminohexyl)carbamoyl dU derivatives (93) and (94) were prepared and the thermal and nuclease stability of duplexes containing them examined.510 Duplexes containing the 2 0 -O-methyl analogue (94) gave higher duplex stability particularly towards RNA targets, and were also more resistant to SVPD.

391

Organophosphorus Chem., 2006, 35, 355–478 O

O

HN O

NH2

N H N R

93 94

R = 2'-deoxyribose R = 2'-O-methylribose

5-(Methoxycarbonylmethyl)-dUTP (95) has been shown to be a good substrate for PCR, and, once incorporated, it can be reacted with a range of amine derivatives for post-synthetic modiﬁcation.511 The arabinoside derivative of (95) has also been incorporated into ODNs where it was post-synthetically modiﬁed,512 and ODNs containing the arabinoside derivative induce RNase H cleavage as well as being more resistant to nuclease digestion. A cyanomethyl ester of (95) has also been used for post-synthesis modiﬁcation by reaction with various amine nucleophiles.513 5-Carboxy-dU, a methyl oxidation product of thymidine, has been introduced into ODNs based on the hydrolysis of 5triﬂuoromethyl-dU.514 The mutagenic effect of the 5-formyl group has been examined. It was shown that it is sufﬁciently stable to allow for miscoding events to occur,515 and the NER of ODNs containing it have been studied.516 ODNs containing 5-formyl-dU are also able to form crosslinks to peptides by Schiﬀ base formation.517 O OMe HN O O

N dRTP

95

5-Hydroxymethyluracil (5 hmU) is another oxidative lesion, which is able to mispair with guanine. The excision repair of oligonucleotides containing 5 hmU has been examined.518 5 hmU is used in the synthesis of the naturally occurring glucopyranosylated nucleoside dJ, and improved synthetic yields have been reported.519 Galactose-modiﬁed uridine oligonucleotides linked via a propynyl group have also been prepared.520 In duplexes containing multiple substitutions it was shown that galactoside clusters were formed along the ODN. A series of hapten-labelled (e.g., adamantane, dansyl) phosphoramidites has been prepared and incorporated into ODNs suitable for use in immunodetection assays.521 EDTA has been conjugated to dU for the determination of protein binding by paramagnetic relaxation enhancement.522 A spin label has

392

Organophosphorus Chem., 2006, 35, 355–478

also been incorporated into TFOs for study by EPR spectroscopy.523 A disulﬁde-protected thiol linker has been attached to C5 as its 5 0 -triphosphate, and its incorporation by several DNA polymerases reported.524 A furan-linked phosphoramidite was used to prepare ODNs, which were then allowed to undergo Diels-Alder cycloaddition with ﬂuorescent maleimides for the incorporation of ﬂuorescent groups into DNA.525 5-Halo-dU derivatives have been used in DNA duplexes as they undergo photochemical crosslinking reactions. 5-Iodo-dU has been used in crosslinking reactions in Z-form DNA,526 and 4-thio-5-bromo-dU has also been prepared and incorporated into ODNs where it was demonstrated that cells containing it became sensitive to UVA light.527 The formation of a crosslink between Br-dC and dG has also been reported.528 5-Iodo pyrimidines as well as 7-iodotubercidin have been used for post-synthesis modiﬁcation whilst on solid support for Pd-catalysed substitution by an alkynylated spin label.529 DNA damage caused by g-radiolysis leads to the formation of lesions derived from the radical (97). The stable precursor (96), which leads to (97) on photolysis, has been introduced into ODNs and alkali-labile lesions generated on photolysis examined.530 The BER of the thymidine oxidative damage lesion thymine glycol has been examined using chromatographically pure stereoisomers531 opposite dA and as a mismatch with dG.532 Two other thymidine-derived lesions are the thymidine dimer T(6-4)T (98) and cis-syn thymidine dimer (99), both of which are formed by photolysis. A C5 thiolmodiﬁed derivative of (98) has been prepared as its phosphoramidite and incorporated into ODNs for MALDI mass spectrometer studies.533 The translesion synthesis past (98) by Pol Z showed a high level of mutagenic bypass.534 There are two reports of the cis-syn thymidine dimer phosphoramidite (99) and its incorporation into ODNs.535,536 Translesion synthesis past the dimer by Pol Z incorporated two adenylates,536,537 though a further report states that there are higher error rates opposite the 3 0 -thymine than at the 5 0 -thymine.538 The repair of thymine dimer (99) by DNA photylase539 and an NMR study of DNA containing (99) with human replication protein A (RPA)540 have also been described. O

O

HN

HN t

Bu

N

O O O O

N

O O

O O O

96

97

393

Organophosphorus Chem., 2006, 35, 355–478 O

O OH

HN O

O Me Me

Me HN O

N

N

NH N

O

N H

H dR

N Me

O

H

dR

dR

dR

T(6-4)T

Cis-Syn thymine dimer

98

99

3-Methylpseudouridine (m3c) has been synthesised and incorporated into RNA where it was found to be slightly destabilising compared to pseudouridine.541 Psuedouridine can be selectively cyanoethylated with acrylonitrile, aiding its detection in tRNA by MALDI mass spectrometry.542 The presence of pseudouridine in RNA has also been detected by NMR using chemical exchange spectroscopy as pseudouridine has an additional NH.543 Another naturally occurring tRNA analogue found in mitochondrial tRNA is 5-taurinomethyluridine (100), as well as its 2-thio analogue.544

O

O S

HN O

N H

OH

O

N Rib

100

Few cytidine analogues are described. The p-benzoquinone adduct of dC gives rise to the etheno-derivative (101).545 The introduction of a phosphate group to N4 of dC causes destabilisation when in a DNA duplex.546 Short duplexes have been prepared containing 1,3-N4C-alkyl-N4C interstrand linkages.547 The introduction of the crosslink leads to more stable duplexes, and ethyl and butyl linkers causes helix bending. 2 0 -Deoxycytidine bearing C5alkyne linked amino and thiol groups has been examined as 5 0 -triphosphates for incorporation by Vent (exo-) DNA polymerase.548 The amino-modiﬁed analogue was found to be a suitable substrate, replacing dCTP in PCR reactions. The analogue (102) has been introduced into ODNs to probe DNA-protein interactions by forming crosslinks with target protein residues.549 An N4-modiﬁed-dC nucleoside bearing a p-azidotetraﬂuorobenzamide group has been incorporated into ODNs for photocrosslinking studies,550 though the nature of the crosslink is unknown.

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Organophosphorus Chem., 2006, 35, 355–478 NH2

S HO

S N NH N N N

O

dR

N

O

dR 101

102

5-Aza-dC has been used to examine the role of methyltransferases,551 where it was shown to be an inhibitor of HhaI DNA methyltransferase. Isonucleosides, e.g., isocytidine, can be used for new base-pair motifs. However, iso-dC is unstable to acidic conditions making ODN synthesis problematic. The substitution of iso-dC by 6-aza-iso-dC leads to more stable ODNs, though some duplex instability is introduced.552 Various pyrimidine analogues, such as (103) and (104), have been used as substrates of modiﬁed HIV-RT polymerase in DNA containing non-standard base pairs with them.553 Such new base pairs are of interest for expansion of the genetic code (see later).

NH2 N

NH2

N

NH N NH2

O

dR

dR

103

104

The bicyclic pyrrolo-dC (105) has been used as a ﬂuorescent probe to study base-pair hybridisation in DNA/RNA duplexes and enzyme reactions using T7 RNA polymerase and HIV-RT.554 The tricyclic G-clamp cytidine analogue555 has been shown to endow ODNs with remarkably enhanced binding to RNA targets. The 2 0 -O-methyl analogue, (106), has been synthesised and shown that when in 2 0 -O-methyl oligonucleotides targeted towards TAR RNA there was significantly enhanced binding and a resultant marked decrease in in vitro transcription.556,557

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Organophosphorus Chem., 2006, 35, 355–478 O H2 N Me

HN

HN O N N O

N

O

N

O HO

dR

HO

105

OMe

106

The analogue (107) has been previously described558 and has been shown to behave as either a dC or a dU analogue as it exists as a mixture of amino and imino tautomers. The N1-methyl derivative was used to measure the tautomeric constant [imino:amino] that was found to be 11 : 1,559 which correlates with the incorporation of the 5 0 -triphosphate of (107) by Klenow (exo-) DNA polymerase.559,560 The 5 0 -triphosphate of (107) has also been used as a new method to sequence AT- and GC-rich sequences by introducing mutations into these intractable motifs.561 The hydrazine derivative of (107, 108) has also been synthesised562 and shown to exist as a dihydropyrimidopyridazine rather than as a pyrimidine, though biochemically it behaves as a thymidine analogue.563 Pyrimidinones have been used in the third strand of TFOs as analogues for the recognition of CG pairs,564–566 and as ﬂuorescent probes in duplex DNA.567 O

N

N HN O

Me

N HN

N dR 107

O

N dR 108

A variety of base analogues have been examined as new base pairs to expand the genetic code, including universal bases, aromatic analogues and abasic sites. Whilst certain analogues have been used to fulﬁl a speciﬁc task, most have been prepared primarily to see how they behave in oligonucleotides or to determine the range of an enzyme speciﬁcity, particularly of polymerases. The vinyl-dG derivative (109) has been incorporated into ODNs for post-synthetic modiﬁcation to expand the functional diversity of DNA. Derivative (109) reacts with a maleimide through a Diels-Alder reaction, and can be used to introduce reporter groups, such as spin labels, ﬂuorophores, biotin and active esters for further functionalisation.568 The 6-vinyl-dG derivative (110) has been used in

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TFOs where it has selectivity for recognition of dC of a G-C base pair.569 The pteridine nucleoside 3-methyl isoxanthopterin (3-MI) is highly ﬂuorescent and has been used as a probe for hybridisation. The probe is designed such that on hybridisation 3-MI forms a base-bulge whereupon ﬂuorescence intensity increases.570 The analogues (111), termed WNA, were designed with three parts, a benzene ring for stacking, a nucleobase for Hoogsteen base pairing and a bicyclo[3.3.0] skeleton to hold the structure in the correct conformation,. They were designed to form selective triplets in TFOs, including at TA or CG interruption sites.571 O N

NH N

N

NH2

N

dR

N

O HO

N

Base

NH2

dR 109

OH 111

110

O

New genetic base pairing systems are of considerable interest, and potentially may be used to expand the genetic code for the ultimate purpose of introducing different amino acids into peptides/proteins. Ring-expanded nucleosides have been considered as a method to diversify genetic pairing. The ring expanded derivatives of dA, (112), and dT, (113), when incorporated separately into ODNs cause some destabilisation, but a 10-mer duplex comprised of only (112) and (113) showed considerable stability (551C) compared to the natural AT duplex (211C), probably due to enhanced stacking interactions. The duplex formed a right-handed helix, and was also highly ﬂuorescent.572 O NH2 NH

N

N

N

N H

N

O

dR

dR dxA 112

dxT 113

The groups of Hirao and Yokoyama have examined various new base pairs. Base-pairing partners for 6-thienylpurine nucleoside (114) have been examined. This does not form stable base pairs with thymidine as there is a steric clash between the thienyl group and the thymidine C4-oxo group, but speciﬁc base pairs are obtained with the pyridinone analogues (115). The 5 0 -triphosphates of the ribonucleoside derivatives (115) were incorporated specifically opposite (114) with T7 RNA polymerase.573,574 In addition, (115, R¼phenylethynyl) was shown to stabilise an internal loop of a theophylline-binding RNA aptamer.574 Pyrrole-2-carbaldehyde derivatives (116) also form speciﬁc base pairs with the

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imidazopyridine analogue (117). 5 0 -Triphosphate derivatives of (116) are specifically incorporated opposite (117) by Klenow fragment, (116, R¼propynyl) being incorporated more efﬁciently.575,576 S

R NH

N N

O

N N dR

O

Rib

NH2

Me

H

R = H, I or

N N dR

R

N dR

R = H or propyne 114

116

115

N

117

The previous class of analogues was deﬁned as those that formed speciﬁc base pairing partners with nucleobases other than naturally occurring ones. Another class are those that are capable of forming base pairing partners with each of the naturally occurring nucleobases without discrimination, and are known as universal bases.577 They are generally non-hydrogen bonding, planar aromatic analogues that primarily stabilise base pairs by stacking interactions. The ﬁrst non-hydrogen-bonding analogue to be considered as a universal base was 3-nitropyrrole (118).578 This has been used in sequence-speciﬁc oligonucleotide hybridisation (SSOH) probes to enhance mismatch discrimination to increase allelic differentiation.579 The 5 0 -triphosphate of the ribosyl derivative of (118) was incorporated by polio-virus RNA polymerase opposite A and U only, and at a rate 100-fold lower than the structurally analogous ribavirin.580 Acyclic nitroimidazole (119, R-isomer shown) and nitropyrazole (120) also behave as universal bases in duplex DNA and considering that they are acyclic derivatives, surprisingly high Tms were observed.581 However, in TFOs each of these analogues is quite destabilising. NO2

NO2 NO2

N N N

N N dR 118

OH

OH OH 119

OH 120

The 5-nitroindole (121), benzimidazole and 5-nitro- and 6-nitro-benzimidazole as their 5 0 -triphosphates are all incorporated opposite each of the natural nucleotides by DNA Pol a and Klenow fragment with eﬃciencies up to 4000-fold better than a natural mismatch.582 Pol a preferentially incorporated each opposite pyrimidines, whilst Klenow preferentially incorporated them opposite purines. Both polymerases incorporated the triphosphates opposite an abasic site up to 140-fold more efﬁciently than dATP, whilst T4 DNA polymerase incorporated (121) 1000-fold more efﬁciently than dATP.583 Incorporation of the 5 0 -triphosphate derivative of the related indole nucleoside opposite

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Organophosphorus Chem., 2006, 35, 355–478

an abasic site is 3600-fold reduced compared to (121).584 Polymerases have been evolved to replicate oligonucleotides with very high speciﬁcity, and the introduction of modiﬁed nucleotides usually significantly reduces the polymerase efﬁciency and/or ﬁdelity. Polymerase evolution has been used to identify novel enzymes with expanded substrate speciﬁcity. A polymerase engineered to extend 3 0 -mismatches was found to additionally amplify a range of modiﬁed nucleotides, including an abasic site, thymine dimer and (121).585 4-Nitroindazole derivatives glycosylated at N7 or N8 also behave as universal bases, though with lower Tms than (121).586 Various ﬂuorinated aromatic nucleobases also behave as universal bases, but will be dealt with separately. NO2 N dR

121

Azole carboxamides were devised as analogues that could, in principle, behave as universal bases by presenting two alternative hydrogen-bonding faces, an inosine and an adenosine face. In practice, they exhibit more speciﬁc hydrogen-bonding preferences with, usually, two of the cognate bases. Ribavirin when incorporated as its 5 0 -triphosphate forms speciﬁc base pairs with the pyrimidines, though with reduced efﬁciency.587 A series of ﬁve nitroazoles (122) was compared in both hybridisation studies and for polymerase recognition to determine their unique properties,588 as was a set of imidazole4-hydrazide derivatives.589 O H2N

X X

X N dR

X = N or CH 122

One of the notable features of these aromatic nucleobases is a preference for forming self-pairs. Romesberg et al. have prepared a range of analogues possessing minor groove hydrogen bond donor and acceptor sites to stabilise duplexes and as polymerase substrates. The benzofuran, benzothiophene, indole (123) and benzotriazole artiﬁcial bases all destabilised DNA duplexes, but when the analogue is self-paired, duplexes are significantly stabilised compared to the natural nucleosides.590 Of these analogues, the benzothiophene analogue also behaved as a universal base. Klenow fragment was used to

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extend a primer-template with an analogue self-pair at the 3 0 -end. Of the analogues described, only the benzotriazole self-pair was extended with any efﬁciency. Similar results were found for the analogues (124), and the best analogue was Y¼S and X¼N, with the highest Tm for a self-pair. It was also most efﬁciently extended from a 3 0 -self pair by Klenow fragment, and behaved as a universal base.591 The analogues (125) and (126) were investigated in a similar manner, where again the self-pairing bases were the most stable.592 X

X X

X N dR X = O, S or NH 123

N

Y

dR

dR

X = CH or N, Y = O or S

Y

N

Y

dR

X = O or S, Y = O or S

124

125

126

Fluorinated aromatic bases are widely used as artiﬁcial bases, and many behave as universal bases. The effect on duplex stability and polymerase recognition of ﬂuorophenyl derivatives again demonstrated that self-pairs are more stable than those of the analogue with a cognate base, the best of which was 3-ﬂuorobenzene.593 Additionally, the stabilisation of a short duplex by a dangling ﬂuorobenzene derivative as probes of electrostatic effects in DNA base stacking has been examined.594,595 Dipole effects were shown to have a significant effect on DNA stabilisation due to base stacking as a result of dispersive induced-dipole attractions.596,597 Various ﬂuorinated phenyl and benzimidazole DNA analogues have been incorporated into RNA for structural investigations.598 The ﬂuorinated benzimidazole (127), incorporating a 2 0 O-ethylamine group was found to be a universal base, and duplexes containing (127) were as stable as an unmodiﬁed duplex. Incorporation of (127) into the hammerhead ribozyme resulted in cleavage rates significantly higher than for the normal mismatch ribozyme.599,600 F N

O

N

F

HO NH2 HO

O

127

The ﬁnal class of ﬂuorinated artiﬁcial nucleobases are non-hydrogen-bonding isosteres of the natural bases, ﬁrst described by Kool. The ﬁrst such

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Organophosphorus Chem., 2006, 35, 355–478

analogue described was diﬂuorotoluene (128), an isostere of thymidine. It was shown to have speciﬁc base pairing properties with adenosine, and the 5 0 triphosphate of (128) was specifically incorporated opposite A by various polymerases. This led to the conclusion that base-pair recognition in oligonucleotides and enzymes does not require hydrogen bonding, but that the geometry of the base pair is important. The HIV-1 polypurine tract contains base pairs that deviate from the normal Watson-Crick base pairs. To investigate this, the non-hydrogen-bonding isosteres (128) and the cytosine isostere 2-ﬂuoro-4methylbenzene were incorporated into DNA and hybridised to polypurine tract containing RNA primers to disrupt the hydrogen bonded structure. Cleavage of these hybrids was examined with HIV-RT, where it was shown that cleavage still occurred but 3-4bp from the site of insertion.601 A-tract containing duplexes exhibit curvature at the A-tract, and thymidines in an Atract were substituted by the isostere (128) to determine the effect on the bend angle. The effect was variable, depending upon the position of the substitution, but the results support the view that A-tract bending arises as a result of localised electrostatic interactions.602 F Me

F dR 128

The effect of incorporating the non-hydrogen-bonding isosteres of thymidine (128) and adenosine, (117), in bacteria has been investigated. They were introduced into E.coli by insertion into a phage genome and transfected into bacteria. The two base mimics were bypassed with moderate efﬁciency in the cells and with very high efﬁciency under SOS induction conditions. Isostere (128) encoded genetic information in the bacteria as if it were thymine with high ﬁdelity, whilst (117) directed incorporation of thymine opposite itself with high ﬁdelity. Thus hydrogen bonding is not necessary for replication of a base pair in vivo.603 The guanosine isostere (129) is shown to be more stabilising than the natural bases in a dangling end context, but is destabilising and non-selective when paired opposite itself. It forms a stable pair with (128) with stability approaching that of a GT mismatch.604 The ethynylﬂuorobenzene derivative (130), an analogue of (128), has been shown to be more stable in DNA duplexes than (128).605 A series of nonpolar adenine isosteres was examined to study the importance of hydrogen bonding functions in the repair of 8-oxo-dG by the E.coli repair enzymes Fpg and MutY. The absence of hydrogen bonding groups appeared to increase the rate of removal of analogue by the enzyme Fpg, but had a deleterious effect on repair by MutY.606

401

Organophosphorus Chem., 2006, 35, 355–478 F

F N N

Me dR

dR 129

130

In addition to the ﬂuorobenzene derivatives discussed above, a number of polycyclic aromatic nucleosides have been prepared to improve base stacking interactions. Perylene C-nucleoside was incorporated at either terminus of a DNA duplex where it stabilised the structure.607 Binding studies of the methyltransferase MTaqI with duplexes in which pyrene, naphthyl, acenaphthyl or biphenyl C-nucleosides were opposite the MTaqI target adenosine showed enhanced binding compared to dA paired with any of the natural nucleosides, in particular, a 400-fold enhanced binding with pyrene C-nucleoside.608 Uracil DNA glycosylase (UDG) is another enzyme that operates by ﬁrst ﬂipping a nucleobase out of the DNA duplex. The incorporation of pyrene C-nucleoside opposite the uracil in a DNA duplex increases the rate of recognition of the uracil by mutant UDGs, suggesting that the pyrene forces the uracil into an extrahelical position.609 A similar outcome was observed for a DNA glycosylase engineered to site specifically remove cytosine bases in a duplex with pyrene C-nucleoside opposite to the target cytosine. The effect is to have a pre-ﬂipped cytosine base that can then be recognised and excised by the modiﬁed glycosylase.610 Two other pyrene nucleosides have been prepared attached to modiﬁed sugar residues. Pyrene attached to a pyrrolidine as modiﬁed sugar (131) was investigated as an intercalating agent where it was found to be slightly destabilising as a bulged nucleoside in DNA, but strongly destabilising with RNA. However, stabilisation was achieved when it was incorporated as a bulge in a three-way junction.611 The acyclic pyrene derivative (132) aided stabilisation towards complementary DNA strands when present as a base bulge, and particularly when two residues are present. However, it is destabilising when partnered with RNA.612 Two consecutive substitutions of (132) in a matched DNA duplex results in quenching of the excimer band at 480 nm, but in a mismatch environment the excimer band is present, and therefore can be used as a method to detect SNPs.613 R

O

HO

HO

Py N

Py HO Py = pyrene

OH R = H or CH2OH Py = pyrene 131

132

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Organophosphorus Chem., 2006, 35, 355–478

The 4-benzylmercaptophenyl C-nucleoside was designed such that when selfpaired in a DNA duplex it could form a disulﬁde interstrand crosslink.614 The presence of the crosslink considerably stabilised the duplex, but addition of a reducing agent led to duplex destabilisation. N-Methyl phenothiazine C-nucleoside was prepared as the terminal nucleoside in a DNA duplex, where it aided duplex stabilisation.615 A free porphyrin C-nucleoside was substituted into DNA duplexes and was thermally and thermodynamically stabilising, particularly as a dangling nucleotide. Unlike other ﬂuorophores, such as pyrene, porphyrin is not significantly affected by other nucleobases in ss- or dsDNA.616 A 2 0 -deoxyribosyl- and an acyclic phenanthridium artiﬁcial nucleoside were synthesised and incorporated into DNA duplexes as an intercalating agent to compare with the known DNA intercalator ethidium.617 As expected the phenanthridium was shown to intercalate into DNA irrespective of the complementary nucleoside. Two diastereoisomers of a photoreactive trans-azobenzene derivative (133, R isomer shown) were incorporated into DNA via a diol linker. When in the trans conformation, the azobenzene intercalates into the duplex and stabilises it. However, irradiation at 300 nm caused the azobenzene to isomerise into the cis conformation, which destabilised the duplex. This was used as a ‘‘switching’’ mechanism to regulate transcription by T7 RNA polymerase by having (133) incorporated into the T7 primer.618 Naphthyl Red is an azo dye, and has similarly been used as a visual probe for DNA hybridisation.619

N OH

N

O N H

Me OH

133

The analogues (134) were designed as nucleosides for TFOs to bind by Hoogsteen base pairing to an AT or CG pair respectively. The base pairing to the duplex is quite speciﬁc and they stabilise triplexes even at mixed purine/ pyrimidine sequences.620,621 A ureido isoquinoline homo-N-nucleoside was incorporated into TFOs to aid stabilisation of the third strand opposite each of the four base pairs, but was found to be destabilising.622 The analogues (135) and (136) were also incorporated into TFOs targeted towards inverted AT duplex base pairs. Analogue (135) was found to be almost as stable as having a guanosine in the third strand,623 whilst (136) was found to be very stabilising.624,625 Other analogues were found to be destabilising.626 N

NH2 X

N dR N H

S

dR

Me

X = CH, N 134

NH

135

HO

H N

O O OH 136

S

H N Me

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Organophosphorus Chem., 2006, 35, 355–478

An acridine unit was incorporated either at the 5 0 -end or at internal sites of an ODN designed to affect cleavage of target RNA. The two phosphodiester linkages in front of the acridine are selectively cleaved in the presence of La(III).627–629 Anthraquinone has been used in a TFO attached via a bis(hydroxymethyl)propionic acid linker and shown to facilitate triplex formation with pyrimidine-gapped polypurine sequences.630 8-Mer 2 0 -O-methylribonucleotides conjugated with the aminooxyethyl-2-(ethylureido)quinoline (137) bound to either complementary RNA or 2 0 -O-methyl RNA 9- or 10-mers with high binding afﬁnity, whilst the absence of the conjugate (137) resulted in no duplex formation. The presence of the aminooxy group allowed for further conjugation with aldehydes or ketones and was used to attach short peptides via a terminal aldehyde group.631 A variety of 5 0 -tethered stilbene derivatives were used to affect duplex stability. In a perfectly matched 5 0 -end the tethered stilbene derivatives significantly and selectively enhanced the melting temperature of the duplex.632 ONH2

O

O

O O

N

N H

N H

P

O

DNA

OH

137

A three-carbon spacer group (C3) has the same framework as the backbone of a nucleoside, but does not contain a sugar or a base. The C3 spacer has been used to investigate the stability of tri- and tetra-loop hairpins in which there is a sheared GA base pair. The inclusion of the spacer at the various positions of the loop demonstrated that substitution at the ﬁrst position of the loop (substituting the guanosine of the sheared pair) caused a large destabilisation supporting the presence of the sheared pair.633 The R and S derivatives of a butane-1,3-diol spacer have been assayed in binding afﬁnity studies, but it was found that there was no discrimination between the two isomers.634 The photocleavable linker (138) has been incorporated into ODNs for allele-speciﬁc primer extension reactions and identiﬁcation by MALDI-TOF mass spectroscopy after photocleavage.635,636 A variety of different size linkers based on ethyleneglycol (e.g., TEG, HEG) have been shown to be destabilising when incorporated into a duplex.637 However, the presence of an intercalating group such as (139) within a linker unit has a stabilising effect.638 O O

O

P

O

O OH

NO2

X

HO (CH2)n 138

n = 1, 2 X = O, S 139

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Organophosphorus Chem., 2006, 35, 355–478

A series of 21 ODNs was prepared containing a core sequence comprising a CpG linkage, each ODN bearing a different modiﬁcation to test for their immunostimulatory effect on murine macrophages. Many of the modiﬁcations failed to enhance immunostimulatory effects, but the presence of hexaethylene glycol linkers favouring nicked duplexes was found to enhance immunostimulatory effects.639 Lesion bypass DNA polymerases of the Y superfamily are able to replicate across DNA containing C3 or C12 carbon spacers, even though it lacks all features of DNA. DNA Pol V is able to either completely bypass by ‘‘hopping’’ across the spacer or alternatively will insert one or two nucleotides opposite the bypass before synthesis continues on a nucleotide template beyond the spacer.640 Several methods for modifying the termini of oligonucleotides are described. Biotin phosphoramidites possessing exceptionally long and uncharged linkers are better polymerase substrates.641 A biotinylated dUTP possessing a photocleavable linker has been prepared such that biotinylated DNA can be captured on streptavidin beads or surfaces, then cleaved by near UV irradiation.642 A ﬂuoride/amine-cleavable phosphoramidite designed for biotinylation, phosphorylation and afﬁnity puriﬁcation of oligonucleotides has also been reported.643 A 5 0 -modiﬁer prepared from aleuritic acid (140) attached to DNA via the terminal hydroxyl group during solid phase synthesis, followed by treatment with periodate, generates an aldehyde group which can then be reacted with amines and reduced.644 OH HO

CO2H OH 140

Duplexes are held together by a series of hydrogen bonds, but the termini are susceptible to ‘‘breathing’’ particularly if they are comprised of weak base pairs. The termini of duplexes have been stabilised by synthesising ODNs bearing 5 0 amino groups (e.g., from 5 0 -amino-2 0 ,5 0 -dideoxyadenosine) which can then be selectively acylated. A series of acyl end-caps have been examined and (S)-N(pyren-1-ylmethyl)pyrrolidine-3-phosphate (141) was found to enhance the Tm of an 8-mer duplex by 111C.645 The synthesis of a 2,2,7-trimethylguanosine (142, TMG) capped DNA/RNA hybrid has been reported. The TMG-capped oligonucleotide is conveyed into the nucleus by the nuclear-transport protein snurportin 1.646 O Me

N

O HO

P

NH

N N

O

Rib

O DNA

Me N

141

N Me

142

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Organophosphorus Chem., 2006, 35, 355–478

Abasic sites are a common lesion in oligonucleotides, and can arise for a number of reasons, such as depurination, g-radiolysis and DNA damaging agents. There are four types of abasic sites that have been investigated, the most common abasic site, (143), often referred to as AP, and the chemically stable tetrahydrofuran abasic site analogous to (143), (144, or F). There are also oxidised abasic sites, namely the C1 0 -oxidised (145, L, or 2-deoxyribonolactone) and the C4 0 -oxidised abasic site caused by DNA damaging agents, (146, C4-AP). The difference between (143) and (144) abasic sites has been investigated in vivo for mutagenic response in yeast. Opposite (143), cytosine is most commonly incorporated, whilst for the stable abasic site (144) adenosine is most frequently incorporated.647 The presence of the abasic site (144) in a DNA duplex opposite a natural DNA base has been detected using the naphthyridine (147) which in solution forms base pairs with the nucleoside opposite (144). Naphthyridine (147) forms particularly stable duplexes when there is a pyrimidine opposite (144).648 The T4 DNA polymerase usually terminates replicative DNA synthesis at an abasic site, but deletion of the 3 0 -5 0 exonuclease domain allows for translesion synthesis.649 O HO

O OH

HO

OH

OH

ap

F

143

144 O

O HO

O

HO

OH HO

OH L 145 0

Me

N

N

NH2

OH C4-AP 146

147

2 -Deoxyribonolactone lesions (145) are generated by DNA damaging agents and g-radiolysis. To study (145) lesions in DNA, two modiﬁed nucleosides have been used which on photolysis generate the lesion. The incorporation of 5-iododU in telomeric DNA quartets led to speciﬁc formation of the lesion (145) on photolysis at 302nm.650 Similarly, irradiation at 360nm of DNA containing 7nitroindole nucleosides led to (145) lesions.651,652 Further studies with (145) lesions using the 7-nitroindole precursor in E.coli showed that (145) gave G-A mutations.652 The SOS response in E.coli to plasmids containing (145) gave rise primarily to incorporation of dA and dG, the ratio of which depended on the sequence context of the lesion.653 Lesion (145) may be further oxidised leading to strand cleavage and a terminal butenolide. The base excision repair of DNA containing (145) and the butenolide were studied by incorporation of a photolabile precursor (the uracil derivative of the analogue 164).654

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The oxidised abasic site (146) was generated in ODNs by incorporation of 4 0 azido-2 0 -dUTP. ssDNA containing 4 0 -azido-dU treated with uracil DNA glycosylase generates the lesion (146), and characterisation of DNA containing (146) has been carried out.655 It has also been generated in situ by incorporation of a bis-O-veratryl modiﬁed nucleoside, which is then converted to (146) on photolysis.656 The translesion synthesis of (146) by Klenow fragment demonstrated that, like the (145) lesion, dA and dG are principally incorporated opposite the C4 0 -oxidised lesion.657

2

Aptamers

Aptamers are single-stranded nucleic acid sequences isolated from randomsequence libraries by in vitro selection. The usual method of selection is SELEX (Systematic Evolution of Ligands by Exponential enrichment), and the method can be applied to DNA or RNA. There are essentially two types of aptamer, those that are designed for binding to a speciﬁc target, and those that bind and then carry out a pre-deﬁned chemical reaction in a catalytic manner (known as deoxyribozymes or DNAzymes and ribozymes or RNAzymes). Each type of aptamer may also be allosteric or trans-acting, in that they require binding of a ‘‘co-factor’’ in order to either bind to their target sequence or to carry out their catalytic action. In the past few years, aptamer design has become an area of significant interest, and there are many reports concerning the selection and application of aptamers. In this review, DNA and RNA aptamers are discussed separately, but emphasis is made on aptamers designed using nucleoside analogues and on their applications. Little detail will be given for the selection of other aptamers. DNA-‘binding’ aptamers have been designed to bind to mRNA,658 g-quadruplexes,659 Tenascin-C, a protein found in the tumor matrix,660 and to thrombin.661 Aptamers have been selected as inhibitors of HIV-1 integrase,662 human RNase H1,663 human pro-urokinase664 and for the design of molecular beacons.665 An allosteric aptamer has been designed for binding as a colorimetric probe for cocaine.666 A greater number of aptamers with catalytic activity (DNAzymes) have been reported. Reactions include cleavage of RNA667,668 including 2 0 -5 0 linkages and 669 L-RNA. One DNAzyme designed for DNA cleavage was found to possess 0 0 2 -5 RNA ligase activity.670,671 Various other DNAzymes have been reported with ligase activity, ligating DNA,672 RNA,673 forming 2 0 -5 0 linkages674 and synthesising branched RNA.675,676 Aptamers are often found to have a metaldependence for functionality, and the metal-dependence of some DNAzymes is reported.677–679 Phosphorothioate-modiﬁed DNA aptamers have been selected for binding to NF-kB,680–682 and phosphoramidate ODNs for binding to TAR to inhibit Tatmediated transcription.683 Deoxyribozymes that cleave RNA have been modiﬁed with 3 0 -3 0 inverted linkages, phosphorothioate linkages, 2 0 O-methyl sugars and LNA in an attempt to enhance stability and cleavage activity.684–687

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Aptamers incorporating 2 0 -ﬂuoro-nucleoside from L-arabinose have also been selected that bind to neuropeptides.688 Various nucleobase modiﬁcations have been used to enhance functional groups available for catalytic aptamers, and imidazole has often been used as a general acid-base catalyst. Deoxyribozymes with RNA cleaving ability have been evolved in the presence of M21 ions incorporating a C5-amino modiﬁed dT analogue and the imidazole-modiﬁed dA derivative (148). The aptamers showed activity in the presence of Pb(II) ions, and (148) is essential for activity.689,690 The effects of incorporating a variety of nucleobase analogues into a Ca(II) dependent RNA-cleaving deoxyribozyme demonstrated that substitution of dC by C5-propynyl-dC in the catalytic site gave the highest increase in catalytic activity.691 The effects of substituting a variety of purine nucleobase analogues into a thrombin-binding quadruplex aptamer have been examined by thermal denaturation experiments.692 The attachment of spermine to the 5 0 -end of an RNA-cleaving ODN enhanced the cleavage reaction 40-fold compared to the unmodiﬁed ODN.693 NH2 N

N

NH N

N

dR

NH N

148

Protein-nucleic acid cross-linking has been examined using a 5-bromo-dUcontaining photoaptamer,694 whilst a deoxyribozyme incorporating the thymine dimer (99) was evolved that was able to photo-repair the dimer in the presence of serotonin as a cofactor.695 Aptamers have been modiﬁed by ﬂuorescent dyes to study their mode of action. Fluorescent labelling was used to monitor switching from DNA-DNA duplex to DNA-target complexes696 and the mode of action of a triﬂuorophore-labelled three-armed aptamer.697 A hemin-binding aptamer has been hybridised to a gold surface-bound hemin in the presence of luminol which bioluminesces in the presence of hydrogen peroxide.698 The amino-modiﬁed pyrimidine nucleoside (149) was used to develop cationic aptamers binding to sialyllactose. The strongest binding aptamer bound at 4.9 mM.699 O H N HN

(CH2)6 O

O

N dR 149

NH2

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Previously, reports on aptamers have concentrated on evolution of structures for binding or catalytic activity. There are progressively more reports on methods for aptamer design and their applications. Murphy et al.700 describe a method for evolution of aptamers used in enzyme-linked assays in the same manner as antibodies currently are. They offer the advantage of being easily reproduced and are more stable than antibodies. Evolution of aptamers by nonhomologous recombination (NRR) has been compared with SELEX and error-prone PCR.701 NRR was shown to be able to generate aptamers binding to streptavidin with 15-20-fold higher binding than SELEX, and 27-46-fold better than error-prone PCR. In vitro selection of aptamers requires a separation of step-binding structures from non-binding ones. Capillary electrophoresis has been used to separate active from inactive aptamers as active sequences bind to a target and undergo a mobility shift allowing separation from unbound structures.702 Aptamers have been used for chiral HPLC separation. An aptamer binding to the D-enantiomer of arginine-vasopressin was immobilised on a solid support and the separation of D- and L-enantiomers of the target analysed under a variety of conditions. The L-enantiomer eluted in the void volume, whilst the Denantiomer was strongly retained on the column.703 Aptamers have also been applied to molecular-scale logic gates. Using three deoxyribozymes, a system that can add to single binary digits as measured by ﬂuorescent output following cleavage reactions, has been described. The system uses two inputs and two outputs and is described as a half-adder.704 A larger-scale system comprising 23 deoxyribozymes have been used to encode a version of the game tic-tac-toe.705 It is claimed the system cannot be defeated because it implements a perfect strategy. Aptamer-based technologies have also been used as sensors for a variety of applications. When an aptamer binds to its target it undergoes a conformational change, and this change may be detected using the cationic polythiophene (150). The resultant complex leads to the formation of a colorimetric signal, and has been used to detect human thrombin in the femtomole range.706 FRET-labelled aptamers have been used to detect protein with aptamers binding to platelet-derived growth factor in the picomole range,707 and lead-dependent aptamers for detecting Pb(II) in the nanomolar range.708 A bis-pyrene labelled aptamer acted as a ﬂuorescent detector for ATP in the millimolar range709 whilst in a second report ATP detection in the micromolar range was detected using a 2 0 -amino-modiﬁed aptamer.710 N Me

O

N Me

S

150

n

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409

Using a FRET-labelled DNAzyme that undergoes target-assisted self-cleavage a method for ampliﬁcation-sensing has been reported. The probes undergo multiple-turnover upon binding to its target oligonucleotide sequence and ﬂuorescence increase can be measured.711 A further method of ampliﬁcation uses circularised aptamers (deoxyribozymogens or pro-deoxyribozymes) which are inactive until linearised. When linearised they create a cascade in which the linear species accumulate, resulting in ampliﬁcation of both function and selection.712 Circular deoxyribozymes targeted towards b-lactamase mRNA have been cloned into bacteria where they were efﬁciently reproduced and exhibited high inhibition of b-lactamase and bacterial growth.713 Bacterial cell division has also been inhibited by an aptamer binding to the cell division gene ftsZ.714 A majority of RNA aptamers have been targeted towards protein binding. Aptamers have been selected that bind to human epidermal growth factor receptro-3 (HER3),715 TATA-binding protein,716 E. coli C5 protein,717 peptide-acridine conjugates,718 the antibacterial protein Colicin E3,719 and the HIV-1 proteins RT720 and TAR.721 Aptamers designed against coagulation factor IXa have been shown to be effective anticoagulants,722 and an allosteric aptamer targeted towards the repair enzyme formamidopyrimidine glycosylase (Fpg) could be regulated in the presence of neomycin.723 RNA aptamers have also been selected for binding to nucleic acid, such as mutations in rRNA724 and viral RNA.725 Other binding aptamers are targeted towards small molecules, such as spectinomycin,726 theophylline,727 GTP728,729 and the dye malachite green (151).730,731 Me Me

N

Me

N Me 151

There are fewer catalytic ribozymes compared to deoxyribozymes. Examples include a trans-splicing ribozyme,732 an alcohol dehydrogenase,733 a ligase capable of functioning at low temperature,734 a ribozyme that will ligate the 5 0 terminus of RNA to a polypeptide,735 a transcriptional activator736 and a tRNA aminoacylation catalyst.737 An RNA aptamer bearing 5 0 -CoA has been selected to catalyse thioester formation in the presence of biotin-AMP.738 In vitro selection has also been used to identify allosteric hairpin ribozymes, activated in the presence of short oligonucleotides,739 and a ribozyme that catalyses amide bond formation from a 2 0 -amino nucleotide.740

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A few nucleoside analogues have been incorporated into RNA aptamers to provide additional functionality. The C5-modiﬁed uridine analogue (152) was incorporated randomly into RNA transcripts that were assayed for their ability to catalyse metal-metal bond formation.741 After eight rounds of selection, aptamers were found that would mediate the growth of hexagonal palladium nanoparticles. Micrometer-sized particles were formed within minutes using 100 mM metal precursor and 1 mM ribozyme. The cationic 5-(3-aminopropyl)uridine was incorporated into a random RNA library to select an ATP-binding aptamer that operated under physiological conditions. The presence of the cationic analogue was shown to be essential for ATP binding as determined by mutagenesis studies.742 2 0 -Amino-modiﬁed RNA was used to select for a prion-protein speciﬁc aptamer.743 In in vitro experiments, the presence of the aptamer demonstrated a marked reduction in the de novo synthesis of cellular prion protein within 16 hours. O HN O HO

O

N N H

N

O

OH

OH

152

To test the hypothesis that early life could have been based on a simpler genetic system, ribozymes have been generated using only two nucleotides.744 Using only diaminopurine and uracil ribonucleotides, a ribozyme capable of ligating two RNA molecules was evolved. The catalytic efﬁciency of the ribozyme was 36 000 fold faster than the uncatalysed reaction. Using RNA incorporating various anthracene dienes and maleimide dienophiles a Diels-Alderase ribozyme was developed. The ribozyme was further immobilised on an agarose matrix, and could be regenerated up to 40 times. Activity was only minimally reduced compared to the solution-phase ribozyme.745 As with DNA aptamers, there is a trend towards applying RNA aptamers to a particular application. Allosteric ribozyme sensors have been developed which are speciﬁc for caffeine and aspartame.746 Using a ﬂuorescence-based assay, caffeine or aspartame may be detected in solution over a 0.5–5mM concentration range. Aptamers designed to malachite green (151) or other triphenylmethane dyes have been developed that enhance the ﬂuorescence of the dye up to 2300-fold.747 A further ﬂuorescence-based assay has been

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411

developed for the detection of microRNAs (miRNA). Hairpin ribozymes were selected that cleave short RNA substrates labelled with a 3 0 -ﬂuorophore and a 5 0 -quencher. In the presence of miRNA the hairpin is cleaved and the resultant ﬂuorescence activity may be measured in real-time.748 Aptamers have also been used in in vitro applications. A cis-acting aptamer targeting the HCV NS3 proteases and HDV ribozyme-G9-II was shown to efﬁciently inhibit the protease,749 and a method for the automated selection of aptamers binding to translated U1A protein has been described.750

3

Oligonucleotide Conjugates

There have been very many examples of chemical moieties being attached to oligonucleotides, and the purpose of these conjugates is just as varied. These range from the attachment of reporter groups to larger constructs, such as oligonucleotide-peptide conjugates. In this section the oligonucleotide conjugates are reviewed according to various speciﬁc applications. The ﬁrst section deals with oligonucleotide-peptide conjugates, and then an exciting recent development is reviewed in which oligonucleotides are used as a template to direct various organic reactions. There are a number of examples of oligonucleotides that are conjugated to various metal ions, and a large number of references that deal with charge transport. Fluorescent labelling of oligonucleotides has been used in a number of applications including FRET and molecular beacons. Finally, there are a number of other miscellaneous conjugates that are dealt with as a group. 3.1 Oligonucleotide-Peptide Conjugates. – A number of developments for the synthesis of oligonucleotide-peptide conjugates have been reported. A method for condensing partially protected peptide fragments with oligonucleotides on a CPG support uses diisocyanatoalkane as linker between the fragments.751,752 The novel phosphoramidite linker (153) and the O-2 0 -modiﬁed uridine (154) have been developed for solid phase synthesis of oligonucleotide conjugates;753,754 peptide fragments are coupled to the linker through amide bond formation. Oligonucleotide-peptide conjugates are also synthesised using 2,2-dimethyl-3-hydroxypropionic acid as a linker via amide bond formation.755 The uridine (154) may also be used to couple to hydroxylaminoand hydrazino-modiﬁed peptides through the intermediate 2 0 -O-aldehyde derivative.756 Terminal linkers (5 0 - and 3 0 -) bearing cis-diols have been used, which after periodate oxidation leave aldehyde functions that react with hydroxylamine derivatives.757,758 Miscellaneous other synthetic methods include synthesis on macroporous polystyrene,759 a solution-phase synthesis in which oligonucleotide and peptide are linked through high molecular weight PEG,760–762 and a method which uses conjugation of cysteine-modiﬁed oligonucleotides to the C-terminus of recombinant proteins.763 3 0 -Peptide conjugates have also been prepared by amide bond formation to the 2 0 modiﬁed derivative (155).764

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Organophosphorus Chem., 2006, 35, 355–478 O

R

O

Me

O O

O P NiPr2

CN

R = trityl or 2-chlorotrityl 153

U

O O

O

i) NaIO4 ii) NaClO2

O

O

U

O

O O

O

O

O O

HO

OH 154

A

O

H2 N

OH

Me 155

Hybridisation properties of oligonucleotides are improved by conjugation to peptides. Short oligonucleotides conjugated to hydrophobic or cationic peptides improved duplex binding765 whilst detection of hybridisation was observed by conjugation of oligonucleotides to the photoprotein aequorin.766 Oligonucleotide-peptide conjugates are frequently used to aid cellular uptake. One report claims intracellular delivery has been improved by conjugation to signal peptides,767 whilst another claims that conjugation to one or two NLS peptides had no effect on oligonucleotide uptake.768 An antisense ODN targeted towards the 5 0 -non-coding region of HepC virus conjugated to recombinant E.coli RNase H was efﬁciently taken into cells where inhibition of HCV gene expression was observed.769 Catalytically active oligonucleotidepeptide conjugates have been prepared targeted towards ssRNA where they induce RNase H activity.770 tRNAs have been synthesised incorporating various unnatural acyl groups, which were added to a translation system where they were successfully incorporated into the new peptide chain.771,772 In addition to oligonucleotide-peptide conjugates, there are a few examples of PNA-peptide conjugates, which are easier to prepare as the two chemistries are compatible. A new chemistry using Fmoc and (1-(4,4-dimethyl-2,6-dioxacyclohexylidene)ethyl) (Dde) has been developed for the direct synthesis of PNA-peptide conjugates.773 A native ligation method between a terminal cysteine peptide and a PNA thioester is reported which uses a cysteine-PEGA resin to capture excess peptide.774 Like oligonucleotide-peptide conjugates, PNA-peptide conjugates are developed for antisense therapies. The conjugation of a cationic peptide derived from staphylococcal nuclease to a bisPNA resulted in enhanced strand invasion with the target DNA sequence.775 The stable somatostatin-receptor octreotide has previously been used to internalise reagents for targeting tumor cells, and an octreotide-PNA conjugate has been reported for the delivery of PNA to target the bcl-2 gene.776 BisPNAs have been tethered through variable amino acid linkers to target two DNA sequences. It was found that, provided the DNA sequences were of the same or longer length as the bisPNA sequences, efﬁcient assembly occurred.777 3.2 DNA-Templated Organic Synthesis. – An exciting recent concept developed largely by Liu and co-workers is DNA-templated organic synthesis. DNA-templated synthesis generates products individually linked to ODNs that encode and direct their synthesis. DNA-templated synthesis is limited by the fact that DNA-linked reagents need to be prepared, reactions need to be

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413

carried out in aqueous media, DNA-compatible chemistries are required and the scale of reactions and limitations for characterisation of products. Nevertheless, the range of reactions is increasing, and the methodology is ideal for the synthesis of large libraries. The range of suitable chemistries has expanded to include amine- and thiol-conjugate addition and nitro-Michael addition reactions,778 synthesis of N-acyloxazolidines,779 synthesis of PNA aldehydes,780 assembly of metallosalen-DNA hairpin conjugates,781 dimerization of hairpin polyamides782 as well as multistep small molecule synthesis.783 Stereoselective reactions have been performed,784 as well as in vitro selections of small molecules with protein binding afﬁnity.785 DNA-templated reactions are mediated by particular architectures, and examples of such have been reported.786 Dieneor dienophile-modiﬁed ODNs have been used for post-synthesis labelling or immobilisation.787,788 PNA has also been used for DNA-templated synthesis to carry out metal catalysed DNA cleavage reactions.789,790 3.3 Oligonucleotide-Metal Conjugates. – There are a number of applications involving metal-oligonucleotide conjugates (see also section 1.3.1), the most common of which is attachment to a gold surface. The interactions of oligonucleotides on gold surfaces may be monitored by a number of physical methods, which makes Au-oligonucleotide interactions an attractive method of analysis. Scanning tunnelling microscopy has been widely used to study ssDNA,791 dsDNA,792 hybridisation,793 mismatched duplexes794 and to study the enzymatic formation of DNA nanoparticles.795 X-ray photoelectron spectroscopy (XPS) and FTIR have been used to study ssDNA on gold surfaces,796,797 whilst atomic force microscopy (AFM) has been used to study DNA nanoparticles798 and surface plasmon resonance to examine Au-nanocrystals modiﬁed with PNA.799 More common methods of analysis are UV/visible spectroscopy, which have been used to study hybridisation,800,801 triplexes802 and nanoparticles.803 Other methods include ﬂuorescence to detect SNPs804 and Raman to study dsDNA and DNA/RNA duplexes.805 The detection of hybridisation has also been measured using a quartz crystal microbalance,806 whilst a mixture of goldDNA nanoparticles and DNA bound to magnetic particles, and magnetic particles with streptavidin-bound DNA via biotinylated DNA have been used to detect speciﬁc DNA sequences with very high sensitivity.807,808 Oligonucleotide monolayers on gold surfaces have also been used as a method of nanolithography.809,810 A number of methods of ultrasensitive electrical biosensing have been examined by attaching oligonucleotides either to quantum dots,811–813 magnetic beads814–816 or to electrodes,817–820 including with PNA probes.821 Pyridine-based nucleobases have been used for silver(I) mediated base pairs. In one report822 it was shown that the pyridine self-pair (156) was significantly destabilising in a duplex, but in the presence of Ag(I) only slightly destabilising compared to an AT pair. In a second report823 the same pyridine self-pair was destabilising in the presence or absence of Ag(I), but the self-pair (157) was more stable than the corresponding CG duplex in the presence of Ag(I). A

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bipyridyl nucleobase self-pair was shown to stabilise a DNA duplex, particularly with multiple consecutive substitutions, the self-pairs acting as a zip to stabilise the duplex.824 However, the same bipyridyl self-pair was destabilising in the presence of metal ions (Mn(II), Cu(II), Zn(II) or Ni(II)).825 A bipyridyl PNA analogue was found to be a selective binder to Ni(II).826 Another self-pair derived from the hydroxypyridone nucleoside (158) is destabilising in the absence of metal ions compared to the corresponding AT duplex, but stabilising in the presence of Cu(II) ions.827,828 Two azacrown ethers (159) and (160) have been incorporated into oligonucleotides as a method for delivering metal ions.829–831 SMe

O OH

N

N SMe

dR

dR

156

N

Me

dR

157

158 Ph

Ph O

O DNA

O

P

H N O

N H

O

O NH

N

N

O

O

HN

N

159 O

O P

O

O

DNA

160

Two different terpyridine-modiﬁed dU nucleosides have been incorporated into a 2 0 -O-methyl modiﬁed oligonucleotide antisense to an RNA target.832 In the presence of Cu(II) ions the terpyridine modiﬁed oligonucleotide cleaved the target RNA in a site-speciﬁc manner. Copper(I)-adenylates have also been shown to cleave DNA,833 and a europium complex conjugated at the end of a uniformly modiﬁed 2 0 -O-methoxyethyl oligonucleotide cleaved an RNA target in a site-speciﬁc manner.834 Ruthenium has been incorporated into ODNs, via an oxime conjugate,835 or through an amide linker.836 In the latter case, the ruthenium conjugate was used to photo-crosslink with a G residue on a complementary strand. Ruthenium and osmium have been incorporated into ODNs via a C5-phenanthroline dU amidite837 to study photoinduced energy transfer, and metallocarboranes have been used as redox labels by attachment to O4 of dT.838 Ferrocene has

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similarly been used as a redox label for electrochemical detection by cyclic voltametry,839 incorporated as a C5-modiﬁed dUTP analogue,840,841 as a C5modiﬁed phosphoramidite,842 as a 5 0 -modiﬁer843 and as a tag via a 3 0 -thiol linkage.844 Metal ions have also been used to assist hybridisation. Using two 9-mer ODNs, which bind to adjacent sites on a complementary target, one with a 3 0 imidoacetic acid terminus, the other with a 5 0 -amino modiﬁed terminus,845 in the presence of Gd(III), significantly stronger binding of the two 9-mers to the target was observed compared to no metal ions. Similar results were observed with terpyridine-modiﬁed short ODNs in the presence of Zn(II).846 The multiarm metal-centred cyclam (161) has been used to prepare supramolecular DNA structures.847 The structure is stabilised in the presence of Ni(II). DNA-O(CH2)6NHOH2C N DNA-O(CH2)6NHCH2

N

Ni

N

CH2ONH(CH2)6O-DNA

N DNA-O(CH2)6NHCH2 161

The ﬁnal class of metal-oligonucleotide conjugates are those involving platinum. Platinum has been introduced into ODNs via a 2-(2-aminoethylamino)ethanol-phosphoramidite followed by complexation with Pt(II).848 Site-speciﬁc platination has also been carried out during DNA synthesis.849 Cis-platin is widely used for the treatment of various cancers, and its mode of action is widely understood. Cis-platin is involved in intrastrand crosslinking, primarily between two guanosine residues, but also between G and A. It has been shown that GG crosslinks causes DNA bending and unwinding independent of ﬂanking bases.850 When crosslinks are present in nucleosomes, the nucleosome significantly inhibits nucleoside excision repair.851 It has been shown that a highly conserved non-histone DNA-binding protein (HMGB1) and YB-1, a multifunctional protein, bind to cis-platin-modiﬁed DNA.852–854 The proteins that interact with cis-platin-modiﬁed DNA have been probed using a photoreactive cis-platin analogue.855 The effect of Mn(II) on the replication of cis-platin-modiﬁed DNA by the herpes simplex virus type-1 DNA polymerase has also been investigated.856 The crosslinking of purines in human telomere sequences by cis- and transplatin reagents have been examined857 and it was suggested that crosslinking of telomere sequences could be used to inhibit telomerase. Crosslinking by transplatin reagents has been studied with RNA oligomers858 and it was suggested that this might be a method of trapping naturally occurring RNA tertiary structures. Trans-platination has also been used to generate novel quartet structures.859 Crosslinking of DNA and PNA has been demonstrated with

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trans-Pt(II) PNA derivatives.860 The translesion synthesis by DNA polymerases b and m past cis-, trans- and oxaliplatin adducts has also been examined.861,862 3.4 Charge Transport. – As guanine has the lowest ionisation potential, one electron oxidation of DNA leads to a guanine radical cation (Gd1), which then migrates along the DNA duplex via hopping steps. The guanine radical cation can be detected using pulse radiolysis.863 There have been two principal areas in which electron transport in DNA has been studied, the use of base analogues and the charge donor/acceptor. A number of base analogues have been explored in electron transport where they can act as radical traps. The oxidation of 8-oxo-dG has been used to probe the interaction of MutY, the enzyme that repairs 8-oxo-G:A mismatches.864,865 Charge transfer to 8-oxo-dG has also been used to probe the effects of C5 cytidine substituents,866 where the direction of transfer may be controlled by the introduction of C5 methyl or bromo groups. By using 8-bromo-dG, electron transport through B- and Z-DNA was studied,867 where it was shown that the reactivity of 8-Br-dG is greater in Zthan in B-DNA. 8-Methyl-dG and 8-methoxy-dG have also been used to study electron transfer to a 5-bromo-dU residue in both B- and Z-DNA.868 Again, transport was more efﬁcient in Z-DNA. A number of adenine analogues have also been used to study charge transfer. 2-Aminopurine (2-AP) is widely used as a ﬂuorescent analogue, and it has been shown that, in its photoexcited state, it initiates hole transfer through duplex DNA.869 In this case the guanosine analogue (162) was used as a radical trap, but N6-cyclopropyl-dA may also be used.870 Photoexcited 2-AP has also been used to study the efﬁciency of charge transfer in terms of direction and near-neighbour base coupling,871 and the role of temperature.872 2-Amino-7-deazaadenine (163) has also been shown to be an efﬁcient radical trap during electron transfer.873 O N N

NH2 NH

N

dR

N NH

N

N

NH2

dR 162

163

The redox potential of adenosine lies between that of thymidine and guanosine, and electron transfer to adenosine does occur. The adenosine derivative (164) has been used as the radical that is formed results in strand cleavage.874,875 The purine analogue 4-methylindole, which has a lower redox potential than dG, has been shown to be particularly effective in studying charge transfer because the 4-methylindole radical cation has a strong absorption at 600 nm. It has therefore been monitored by transient absorption and by EPR.876,877 The dA analogue (165) has lower oxidation potential than dA and a wider stacking area, but is not decomposed during charge transport, and has been used as a DNA wire, as it is more stable to oxidative damage.878

417

Organophosphorus Chem., 2006, 35, 355–478 O O

But

NH2

A

N N

O O

N

dR

164

165

0

2 -Deoxyuridine analogues have also been studied in electron transfer, though usually as electron donor or acceptor. The dU analogue (166) acts as a radical donor upon photolysis.879 Excess electron transfer occurs on photolysis of duplexes containing 5-Br-dU which are internally conjugated to an aromatic amine.880,881 The effect of helical order in charge transport has been examined using duplexes containing the LNA-T.882 Here it was shown that charge transfer was more efﬁcient in duplexes containing the LNA-T derivative with complementary RNA whilst with complementary DNA, where there is helical perturbation, then charge transfer efﬁciency is reduced. Excess electron transfer has also been studied using a ﬂavin-capped hairpin with a thymine dimer that acts as the electron acceptor,883–885 including in DNA:PNA duplexes.886 O

O

Me

OH t

Bu

N H

HN

O O

N dR 166

A number of modiﬁcations have been introduced into duplexes as charge donors. A C5 pyrene-modiﬁed dU887–889 and a 2 0 -N pyrene-modiﬁed dU890,891 have both been used as photochemical electron donors, as has the ethidium derivative phenanthridinium,892 which acts as an artiﬁcial base as well as charge donor. The mechanism of charge hopping has been studied using anthraquinone,893–897 (including the effect of mismatches898) naphthaldiimide (NDI),899–901 stilbene dicarboxamide902–906 and ﬂavin.907,908 Electron transfer through DNA with ferrocene at either 5 0 - or 3 0 -terminus showed little difference in the rate of transfer.909 The incorporation of a ruthenium-phenanthrene crosslinking agent at the end of a duplex was used to demonstrate that the yield of crosslinking is higher when there are guanosine residues close to the 3 0 -end of the complementary strand.910 Electron transfer has primarily been studied with DNA duplexes, but there are higher order structures that have been examined. Triplexes have been studied911,912 where it was shown that transfer to the third strand occurs. In quadruplex structures more damage occurs at the external tetrads, and quadruplex guanines are more effective traps than when in a duplex.913 Charge transfer has also been examined with three-way914 and four-way junctions.915 DNA bound to electrode surfaces has been used to study the electrochemical

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reduction of methylene blue to probe base pair stacking in different DNA conformations. Both A- (as a DNA/RNA duplex) and B-form DNA support efﬁcient charge transport as measured by methylene blue reduction, but Z-form DNA supports charge transport much less efﬁciently.916 Electron transfer has also been studied in PNA oligonucleotides.917 3.5 Fluorescence. – There have been many publications regarding the use of ﬂuorescently-labelled nucleotides and oligonucleotides. The major use is to be able to detect an oligonucleotide, and a ﬂuorescent label has many advantages. There are more speciﬁc applications that will also be covered which include ﬂuorescence resonance energy transfer (FRET), molecular beacons (including TaqMan probes) and the emerging area of single molecule detection. Finally, there are some applications applied to nano-devices. Many different ﬂuorophores have been incorporated into oligonucleotides, covering applications such as sequencing, ﬂuorescence detection and FRET dyes. Several sets of dideoxynucleoside triphosphates have been reported for sequencing applications918–924 and FRET.925 A photocleavable linker for attachment of dyes to oligonucleotides has been reported.926,927 The linker (167) may be incorporated as a 5 0 -triphosphate (R2 is attachment to C5 of dUTP via a linker) or to the 5 0 -end of an oligonucleotide (R2 is attachment via phosphate). UV irradiation at 340 nm cleaves the linker, and releases the dye. A method for introducing the ﬂuorophore (168) onto an oligonucleotide using a synthetic cofactor for DNA methyltransferases has been examined.928 The ﬂuorophore is ‘‘alkylated’’ onto the N6-amino group of adenines according to the speciﬁcity of the methyltransferase. Me

Me

N

OR2 R1O

NH2

O

Me

H S N

NO2

O

NH O

H N

HN R1 = dye

N

R2 = nucleoside

N

O O

N

N N

O

N HO

O 167

N N H

OH

N

168

A number of reports describe the use of pyrene as a ﬂuorophore, and there are methods for attaching ﬂuorophores to nucleosides. It has been attached to C5 of pyrimidines,929–931 C8 of purines,931 N3 of thymidine,932 at the O2 0 position of the sugar,933 as a C-nucleoside933,934 and has been incorporated as a phosphoramidite without being attached to a nucleoside.935,936 Pyrene has also been attached via an azido group to the 5 0 -end of an oligonucleotide using a Staudinger ligation reaction.937 A number of other dyes have been attached directly to nucleosides for incorporation into oligonucleotides. Burgess et al.

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Organophosphorus Chem., 2006, 35, 355–478

examined dyes that are p-conjugated to the nucleobase.938,939 Coumarin has been attached via a linker to C5 of dU,940 and ﬂuorescein has been attached to the amino groups of nucleosides via carbamoyl linkers.941 Nile Red, a benzophenoxazine dye, has been attached to oligonucleotides via a 2 0 -carbamate linkage942 where the dye ﬂuorescence is quenched in oligonucleotide conjugates. DABCYL has also been attached to the 3 0 - or 5 0 -OH groups of dT.943 Another class of analogues are those which are inherently ﬂuorescent due to their extended ring structure, and which retain hydrogen-bonding group capability. These analogues are useful for detection of change in the microenvironment of DNA. Examples of such analogues are pyrrolo-dC (169)944 and a series of analogues from the group of Saito et al which include benzopyridopyrimidine,945 naphthopyridopyrimidine (170)946 and the purine derivatives methoxybenzodeaza-inosine (171) and adenosine.947 Me

O

HN

MeO HN

O

N N O

NH

N R

R = dR or ribose 169

O

N

N

dR

dR

170

N

171

Other dyes include Methyl Red, as a phosphoramidite, for incorporation into ODNs, where it was used to generate aggregates when multiple consecutive residues are incorporated into ssDNA.619,948 A benzotriazole azo dye has been used for immobilisation of oligonucleotides onto metal surfaces949 and the coenzyme ﬂavin has been used as a ﬂuorophore and for electron exchange in ODNs.950 A probe termed MagiProbe has been designed which incorporates a ﬂuorophore and an intercalator that on hybridisation emits enhanced ﬂuorescence.951 Water soluble phthalocyanine dyes have been used which are suitable for conjugation to 5 0 -amino-modiﬁed oligonucleotides952 and phthalocyanine-conjugated oligonucleotides have been used to aid duplex and triplex stabilisation.953 Finally, there have been reports that deal with other forms of spectral detection. A platinum (II)-coproporphyrin reagent has been evaluated for phosphorescent labelling of oligonucleotides.954 The presence of the label had little effect on conjugation, and labelled primers were effective in PCR reactions. A silicon nanoparticle conjugated to ODNs acted as a luminescent label,955 and a molecular beacon (see later) has been prepared which contains a photoluminescent dye (Ru(II)(bpy)3) and the luminescent quencher Black Hole Quencher-2TM.956 Although there are some speciﬁc applications of ﬂuorescent analogues (FRET, molecular beacons, single-molecule detection described below) there are many reports that use ﬂuorescence as a means of detection and monitoring

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of biomolecules. One of the most widely used analogues in this area is 2aminopurine (2-AP), which emits ﬂuorescence when excited between 310–320 nm and is most often used to replace adenine where there is little perturbation caused by the substitution. Its ﬂuorescent properties within oligonucleotides have been further examined957 and ﬂuorescence is strongly inﬂuenced by an electron transfer quenching process from guanine and 7-deazaguanine.958 2-AP has been used to examine conformational changes in telomeric sequences,959 in AT sequences960–962 and to monitor conformational changes during nucleotide incorporation by Klenow fragment963 and by DNA Pol b by monitoring ﬂuorescence of 2-AP in conjunction with tryptophan ﬂuorescence.964 Fluorescently-labelled dNTPs have similarly been used to monitor nucleotide incorporation by Klenow fragment.965 2-AP is an effective analogue to monitor methyltransferase reactions where its environment is disturbed by base ﬂipping.966,967 It has been used to monitor changes in rRNA binding to antibiotics,968 to monitor the formation of an intramolecular triplex969 and probing of RNA-protein interactions.970 Another common ﬂuorophore is ﬂuorescein, which has been used to monitor siRNA expression in cells,971 to visualise hybridisation on the surface of a liposome,972 interaction of UvrB protein with damaged DNA973 and as a sensor on 3-way junctions.974 A method for colorimetric gene detection involves using the aggregation of ODNs immobilized onto organic nanospheres impregnated with ﬂuorescent dyes. Addition of complementary ssDNA causes the spheres to produce aggregates by cross-linked networking. The colours of the aggregates, which depend on the added ﬂuorophore, were observed using an ordinary ﬂuorescence microscope. FRET between the particles also provided information about point mutations on added DNA.975 The effect of temperature on ﬂuorescence has been studied,976 as has the effect of salt concentration977 and water-soluble conjugated polymers.978 A method for the quantiﬁcation of ssDNA:dsDNA is described,979 as well as kinetics of mismatch hybridization980 and the kinetics of collision in short ssnucleic acids.981 Fluorescence quenching of Cy-5 labelled oligonucleotides by poly(phenylene ethynylene) particles has been shown to be a more sensitive method than excitation of the Cy-5 ﬂuorophore.982 An ultrasensitive method for the detection of DNA uses highly ﬂuorescent conjugated nanoparticles, and detection limits below 1fM were achieved.983 DNA transport through a carbon nanotube has also been observed using ﬂuorescence microscopy.984 Fluorescence resonance energy transfer (FRET) involves the non-radiative transfer of energy from a ﬂuorophore in an excited state to a nearby acceptor ﬂuorophore. FRET has proven to be a useful tool for measuring distances of 10–100 A˚, and for monitoring conformational changes as a consequence of oligonucleotide- or protein-induced bending. A series of dye-conjugated pyrimidine nucleosides with differing linkers between the nucleoside and dye were evaluated for FRET.985,986 Whilst no conclusions were drawn as to the nature of the linker, it was noted that N4-dC-modiﬁed nucleosides did not perform as well as C5-dU analogues. Multi-step FRET has been reported between eosin (donor), TexasRed (acceptor) and tetramethylrhodamine

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421

(mediator),987 and has been used for high-throughput screening of small molecule inhibitors of a ribosome assembly.988 FRET has found many applications including measuring distances between species,989 measuring DNA bending on binding to proteins,990,991 actions of enzymes such as helicase unwinding,992,993 RNA degradation,994 catalytic folding of a ribozyme,995 monitoring hybridisation,282,996–998 PNA hybridisation,999 quadruplexes,1000,1001 interactions with proteins,1002 and the interactions of FRET dyes with other intercalated agents.1003 Molecular beacons (MB) are stem-loop hairpin oligonucleotide structures that have a ﬂuorescent dye at one end and a ﬂuorescence quencher at the other. In the hairpin state, the quencher and ﬂuorophore are in close proximity and therefore there is no ﬂuorescence from the probe. However, when the MB binds to a complementary oligonucleotide as a duplex then the ﬂuorophore and quencher are separated and the ﬂuorophore can emit ﬂuorescence. They are particularly useful in monitoring reactions with time, e.g., in PCR,1004 rolling circle ampliﬁcation,1005 hybridisation,1006–1008 telomerase activity,1009 ligation reactions1010 and DNA-photolyase activity.1011 MBs may be used attached to solid supports, e.g., gold surfaces,1012 and have been used to deliver drugs (biotin) by a photocleavage reaction when the MB is in a duplex form.1013 They have been used in vitro to detect delivery of peptides into cells1014 and nuclear mRNA export.1015,1016 A number of ﬂuorophores and quenchers that have speciﬁc use in MBs, TaqMan probes and Scorpion primers have been examined.1017–1023 With the advent of the confocal ﬂuorescence microscope it became possible to detect single molecules containing ﬂuorophores, allowing the monitoring of individual events. There are now a growing number of studies of biochemical reactions on a single molecule level using ﬂuorescently labelled reagents or by FRET. Using a single-molecule manipulation procedure, the real-time decatenation of two mechanically braided DNA molecules by Drosophila melanogaster topoisomerase (Topo) II and E.coli Topo IV were monitored.1024,1025 The equilibrium folding of the catalytic domain of Bacillus subtilis RNase P RNA has been investigated by single-molecule FRET. Histogram analysis of the Mg(II)-dependent single-molecule FRET efﬁciency revealed two previously undetermined folding intermediates.1026 Using single-molecule FRET, an indepth characterisation of the transition-state of a model two-state folding reaction of the hairpin ribozyme, where two RNA helical domains dock to make speciﬁc tertiary contacts, was studied.1027,1028 Single-molecule FRET has been used to study the kinetics of unfolding of the human telomeric intramolecular G-quadruplex,1029,1030 the DNA-binding orientation of an E.coli REP monomer to a ss/ds DNA junction,1031 four-way junctions1032 and to study pre-mRNA splicing1033 and gene expression.1034 The synthesis and study of multicolor quenched autoligating (QUAL) probes for identiﬁcation and discrimination of closely related RNA and DNA sequences in solution and in bacteria has been reported. A dabsyl quencher doubles as an activator in the oligonucleotide-joining reaction. The ODNs remain dark until they bind at adjacent sites, and ﬂuoresce on nucleophilic displacement of the

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dabsyl quencher.1035,1036 Many areas of biomedical research depend on the analysis of uncommon variations in individual genes or transcripts. A method has been developed that can quantify such variation. Each DNA molecule in a collection is conjugated to a single magnetic particle to which many copies of DNA, identical in sequence to the original are bound. This population of beads corresponds to a one-to-one representation of the starting DNA molecules. Counting ﬂuorescently labelled particles via ﬂow cytometry can then assess variation within the population.1037 As a step towards single-molecule sequencing there have been attempts to prepare DNA that is ﬂuorescently labelled at every nucleobase. A total of 30 different dNTPs labelled with various reporter groups (ﬂuorescent or nonﬂuorescent) were evaluated in the synthesis of labelled DNA. Using Vent (exo-) DNA polymerase a 300bp product was prepared using dNTPs fully labelled with biotin.1038,1039 Another group has demonstrated that DNA fully labelled with tetramethylrhodamine and rhodamine-green could be digested using E.coli Exonuclease III.1040 Naturally occurring DNA polymerases do not readily accept dye-terminators, and mutant polymerases are being developed that will accept them more readily.1041 In another report,1042 several different propynyl modiﬁed (C5 for pyrimidines, C7-deaza-C7-propynylated for purines) were assessed for their ability to be used in PCR, both as 5 0 -triphosphates and in a template. A set of four such modiﬁed nucleosides was found to be effective, but synthesis of fully modiﬁed DNA using these analogues was unsuccessful. Nanotechnology has become an area of intense research, and oligonucleotides have various roles in this developing ﬁeld. A number of nanodevices have been reported (see section 3.6) and there are reports concerned with monitoring of such devices. A molecular thermometer based on the change in p-stacks on converting from B- to Z-DNA has been described where the equilibrium between the Z- and B-conformations can be controlled by temperature. At low temperature the proportion of the Z-conformation is high due to lower entropy. An increase in temperature increases the proportion of the B-conformation. 2-AP was incorporated into the duplex and the ﬂuorescence intensity was reported to be a measure of temperature.1043 A novel molecular machine based on a four-stranded DNA structure called the i-motif, is formed from sequences containing series of cytosine residues. Protonated C forms a noncanonical base pair with an unprotonated C (C : C1), and this structure can interconvert to form a quadruplex that is stable under slightly acidic conditions. Using FRET, in the i-motif form, the ﬂuorophore and quencher are in close proximity, and there is no ﬂuorescence. At high pH, the i-motif collapses, and the oligonucleotide can be captured by a complementary strand as a duplex whereupon the ﬂuorophore ﬂuoresces.1044 Fluorescent-labelled oligonucleotides have been applied to the development of photonic logic gates,1045 which may have application in molecular computation. A machine which undergoes extension-contraction motion is described, which is monitored by FRET, between a duplex and a quadruplex structure.1046 The motion is driven by the addition of single-stranded oligonucleotide that causes the quadruplex to collapse and leads to a duplex structure.

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3.6 Miscellaneous Conjugates. – A number of new conjugation chemistries have been described for the synthesis of oligonucleotide-peptide conjugates (section 3.1) and surprisingly few for other oligonucleotide conjugates. The phosphoramidites (172) and (173) have been developed for enhanced attachment of oligonucleotides to surfaces.1047 5 0 - and 3 0 -amino-modiﬁed TFOs bearing the alkylating agent (174) has been used as gene therapy agents targeting HER-2 expression.1048 On binding to its target sequence the mustard alkylated target N7-residues of guanine.

Me Me

Me

O

N O P Me O

N H

MMTr NH HN O

H N Tr

NC

Me

Cl

O

NH DNA

O

N

HN NH

Me 172

N

Cl

PO

Me

NC

O

173

MMTr

174

Biotin is a common reagent for labelling oligonucleotides, and a new amidite (175) has been prepared for biotinylated oligonucleotides, but the biotin group may be removed by ﬂuoride treatment.1049 Biotinylated ddNTPs have been used for single base extension for multiplex genotyping by mass spectroscopy.1050 The binding of biotin to streptavidin has also been used for the self-assembly of DNA-templated protein arrays,1051 and solid-support-bound biotinylated oligonucleotides have been used to detect motion and interactions with DNA-binding proteins.1052 O

Me

HN O S H H HN

N H

O

O

Me

H N

Me

O Si O O

NH

Me

Me

Me

Me

O

O

N

OH

175 O

Oligonucleotides have been used as a platform for generating carbohydrate clusters. Various carbohydrates were attached to aminoalkylated oligonucleotide quadruplex structures to afford DNA-assisted tetrasaccharide cluster motifs.1053 Similar clusters have been used as a delivery system for oligonucleotides into cells for antisense therapy.1054 Oligonucleotides have been modiﬁed at both termini by glucose residues also for antisense delivery, though only hybridisation data are supplied.1055 A phosphoramidite for the introduction of a 5 0 -N-acetyl glucosamine unit onto oligonucleotides is reported as a substrate for glycosyl transferase enzymes.1056 Various drugs have been conjugated to oligonucleotides to target the drug to a speciﬁc site. The ibuprofen modiﬁed nucleoside (176) has been incorporated into ODNs to aid binding to human serum albumin,1057 whilst the DNA

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cleaving agents camptothecin and bleomycin have been conjugated to ODNs to direct cleavage to a speciﬁc RNA sequence.1058,1059 The DNA-binding agent daunomycin has been conjugated to DNA in an attempt to aid stabilisation of triplexes by intercalation,1060 and distamycin-based peptides have been used to aid stabilisation of DNA in a DNA duplex at A/T rich sequences.1061 A reagent for 18F-labelling of oligonucleotides for use in radiopharmaceuticals has been described.1062 The reagent is introduced as a bromoacetamide derivative that reacts with a terminal phosphorothioate to yield (177). The synthesis of the labelled ODN, including preparation of the 18F-reagent, was carried out in less than three hours. The conjugation of minor groove binders to TFO oligonucleotides gave rise to much more stable triplex structures.1063,1064 O NH N DMTO H Me Me

Me

H N

O

O

O O

DNA O P S O

O

H N O

CPG

O

O 18

F

N

177

176

Conjugates containing stilbene diether linkages form the most stable DNA hairpin structures reported to date. Hairpins with as few as two A-T base pairs or four non-canonical G-C base pairs are stable with stilbene linkages.1065 Similar results were found when pyrene is used in the loop of the hairpin structure.1066 Stilbene diether and related analogues have also been used to construct linear and branched conjugated nanostructures, modiﬁed stilbene units being used to introduce further strands of oligonucleotides.1067 Aromatic residues have been conjugated to oligonucleotides to aid duplex stability using phenanthrene1068,1069 and triplex stability using benzopyridoindoles1070 and benzoquinoquinoxaline conjugates.1071 Oligonucleotides that contain multiple (non-consecutive) substitutions of perylene are able to fold into structured species in which the perylene units pair by hydrophobic effects or p-conjugation.1072 Various aromatic and aliphatic linkers have been used to bind two oligonucleotides into a hairpin structure; the aromatic units gave rise to particularly stable hairpin structures.1073 Oligonucleotides conjugated to psoralen via various length linkers, e.g., (178), were tested for their ability to form triplexdirected psoralen photoproducts with the Sickle cell b-globin gene.1074–1076 CPG O DNA

Me

N H Me

O

O

O Me

178

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Oligonucleotides have frequently been used in the construction of nanodevices where they are used as a means of detection, as electrical ‘wires’ or as a scaffold (see also section on nanodevices in section 3.5). A real-time DNA detection method using ssDNA-modiﬁed nanoparticles and micropatterned chemoresponsive diffraction gratings has been reported that allows hybridisation detection of 40-900 femtomoles of surface-bound DNA.1077 Carbon nanotubes are widely used for the construction of nanodevices, and DNAfunctionalised carbon surfaces and nanotubes have been reported as platforms for electrochemical detection of hybridisation.1078,1079 PNA-modiﬁed carbon nanotubes have similarly been used for the detection of hybridisation with DNA.1080 DNA conjugated to carbon and other solid surfaces may additionally be used as molecular wires,1081–1084 and carbon-modiﬁed nanotubes have been developed that act as a ﬁeld-effect transistor.1085 Oligonucleotides may be deposited onto solid surfaces in deﬁned patterns, and this has been utilised to use oligonucleotide conjugates for a variety of applications. A widely used application is lithography that takes advantage of the fact that DNA interacts with various metals, and various new lithographic methods have been reported.1086–1089 A method for templated replication of DNA nanoscaffolds has also been developed.1090,1091 Oligonucleotides have been conjugated to various polymeric reagents, for example polyethylene glycol (PEG)1092 and poly(N-isopropylacrylamide)1093 as a method for delivery of antisense reagents. Polyethylene glycol (PEG) is often used as a linking agent in oligonucleotides. It has been used to link an oligonucleotide and biotin to observe motion of the oligonucleotide through the a-HL transmembrane pore1094 and as a linker between two oligonucleotides.1095 A series of spacer/linker phosphoramidites derived from, e.g., (179), have been prepared using methoxyoxalamido (MOX) chemistry, with linker length of up to 56 atoms.1096,1097 Dendrimers have been used as a method for generating self-assembled structures,1098,1099 as has nylon.1100 O H N H2 N

N H

OH

O 179

4

Nucleic Acid Structures

As in previous years, there is a growing number of nucleic acid structures reported. Advances in X-ray and NMR methodologies means that more complex structures are now being studied. However, in addition to these more traditional methods of structure analysis there are also other techniques emerging, and these are discussed at the end of this section. There has been a number of complex crystal structures reported that are beyond the scope of this review, but are included for completeness. RNA

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structures include ribosomal RNA,1101–1107 tRNA,1108–1111 ribozymes,1112,1113 siRNA,1114–1116 the trp RNA-binding attenuation protein (TRAP) bound to RNA containing UAG triplets,1117 the Rho transcription terminator bound to mRNA,1118 a zinc-ﬁnger-RNA complex1119 and NF-kB bound to an RNA aptamer.1120 DNA structures are more diverse, and include glia cell missing (GCM) domain bound to DNA,1121 endonuclease-DNA covalent intermediate,1122,1123 nucleosome DNA,1124,1125 transcription factors bound to DNA,1126–1129 myc protein bound to DNA,1130 telomeric DNA1131 and TraR bound to DNA.1132 A number of crystal structures of DNA and RNA polymerases or repair enzymes have been reported. For RNA polymerases there are structures for T7 RNA polymerase,1133–1135 RNA polymerase II,1136,1137 reovirus polymerase l31138 and for HIV-1 RT.1139–1141 There are also structures for DNA polymerases1142–1146 and DNA repair enzymes.1147–1150 A crystal structure of the duplex r(GUAUACA) which forms six base pairs and 3 0 -dangling adenosine ends was determined at 2.0 A˚ where it was shown that the structure forms two types of duplex. The ﬁrst duplex stacks to form a pseudo-continuous column typical of RNA, whilst the second duplex is in an ADNA conformation with its termini in abutting interactions.1151 A study of the binding of 13 different metal ions to the HIV-1 RNA dimerisation initiation site showed that divalent metal ions bind almost exclusively at Hoogsteen sites of guanine residues. Cobalt hexamine was unable to displace magnesium hexahydrate, raising questions about the use of cobalt hexamine as a magnesium mimetic.1152 The 1.25 A˚ structure of the ribosomal frameshifting RNA pseudoknot from beet western yellow virus uses both H-p and lone-pair-p interactions between water and functionally important unstacked residues.1153,1154 Retroviral conversion of ssRNA to dsDNA requires priming for each strand, and the viral polypurine tract (PPT) is the primer for one of these strands. A crystal structure of a 10-mer RNA from the PPT sequence bound to DNA shows a region similar to domain swapping in proteins, denoted as base-pair swapping, involving a highly mobile CA step. All sugars are C2 0 -endo except one, which is C3 0 -endo as in B-DNA, and this A-B conversion affects the pattern of hydrogen bonding interactions.1155,1156 The mechanism by which the adenine DNA glycosylase MutY repairs 8-oxo-dG mispairs has been investigated by the determination of a crystal structure of MutY with a DNA duplex containing an 8-oxo-dG:dA base pair. It interacts with the strand containing the adenine residue, which is completely extruded from the DNA helix and is inserted into an extrahelical pocket in the catalytic domain. MutY directly contacts the backbone of the complementary 8-oxo-dG-containing strand, and bends the DNA substrate 551, which is localized to the lesion.1157 An aptamer that site-specifically cleaves RNA in the presence of Pb(II) has been determined at 1.8 A˚ using Sr(II), which mimics binding of Pb(II) but not cleavage. Binding of Sr(II) induces local structural changes that align the catalytic 2 0 -hydroxyl group with the scissile bond for cleavage.1158 An RNA aptamer for binding the antibiotic streptomycin has been solved at 2.9 A˚. The structure shows that streptomycin is encapsulated by a stacked array of bases from two asymmetric internal loops.1159

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Of the DNA crystal structures, only three duplexes have been reported with the majority of structures involving higher order structures or analogues. The structure of the self-complementary duplex d(CATGGGCCCATG) shows a conformation between A- and B-DNA, with different hydration patterns for the GC and AT pairs providing the basis for the A-B-form transition.1160 A DNA duplex region of the HIV-1 polypurine tract has been solved which contains three separate A-tract regions, with each A-tract region showing marked similarities.1161 The sequence d(GCGAAAGCT) forms a mini hairpin in solution, but the X-ray crystal structure showed a short parallel-stranded duplex with homo base pairs between the CGAA residues, with the remainder of the residues splitting away in separate directions.1162 The sequence d(GCGAGAGC) has been determined at differing salt concentrations. At low potassium concentrations it forms a G-quartet structure between two duplexes, but at higher potassium concentrations it exists as a duplex.1163 The sequence d(TGGGGT)4 forms thymine tetrads that are stabilised by either Na1 or Tl1 ions.1164 The sequence d(GCATGCT) also exists as a quadruplex structure through G-C intrastrand hydrogen bonding.1165 Two DNA four-way junctions are reported in which the distortion of the junctions perturbs the conformational features of the duplex regions, and hydration pattern consequences are discussed.1166 A 1.7 A˚ structure of the excisionase (Xis) protein from the bacteriophage l with its DNA-binding site has been reported.1167 A number of DNA crystal structures involving intercalating reagents have been reported. The bis-acridine derivative (180) has been reported to be a intercalating threading agent by solution studies, but in the duplex d(CGTACG) it undergoes terminal base exchange with a cytosine residue to yield a guanine quadruplex intercalation site.1168 In the G-quadruplex structure d(GGGGTTTTGGGG) a single modiﬁed acridine residue also binds at the end of a G-quartet within a thymine loop.1169 However, an acridine-tetraarginine intercalator stacks within an AA/TT step rather than a CG/CG step in the duplex sequence d(CGCGAATTCGCG).1170 The trioxatriangulenium ion (TOTA1, 181) intercalates in GC base pairs in DNA duplexes, and can be used to inject a radical cation into DNA. The structure of the duplex d(CGATCG) with bound TOTA reveals considerable distortion of the DNA at the intercalation site, and orientation of (181) is sensitive to hydrogen bonding interactions with the phosphate backbone.1171 O

O

NH

HN N

N

Me

NH

HN

(CH2)8

O

O

N Me

N Me

Me

O 180

181

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Various DNA-drug interactions have been examined by crystallography. The structure of actinomycin D binding to its GpC site revealed that it binds preferentially when there is a T:T mismatch ﬂanking the GpC site.1172 The structure of a DNA hexamer duplex with a disaccharide anthracycline antibiotic showed two different binding modes giving rise to two duplex structures. In one, the disaccharide lies in the minor groove, whereas in the other it protrudes out of the helix.1173 The binding of the anticancer drug chromomycin A3 shows a marked preference for binding at GGCC sites in the presence of Mg(II) ions.1174 The anticancer drug daunomycin interacts with telomeric DNA, and a crystal structure has been reported which shows daunomycin binding to telomeric G-quartets in parallel stranded DNA.1175 The remaining DNA crystal structures involve base or sugar analogues. The replacement of a thymine base by the C-nucleobase (182) demonstrated that the analogue was able to effectively base pair with adenine, but the spine of hydration was destabilised compared to a normal AT base pair.1176 Two crystal structures involving the cis-syn-thymine dimer (99) are reported. A duplex structure incorporating (99) is bent towards the major groove with a slight unwinding of the helix. At the lesion site there is considerable distortion from the usual B-form DNA.1177 The second structure involves DNA containing (99) within the active site of a DNA polymerase (Pol Z). The 3 0 -thymine forms normal Watson-Crick base pairs with the incoming ddATP, but the 5 0 -thymine forms Hoogsteen base pairs with ddATP in a syn conformation.1178 O Me NH

dR

182

The Dickerson dodecamer in which an internal dC is replaced by the adduct N4-etheno-dC opposed to dG has been reported.1179 Minor perturbations are found local to the lesion, but the structure shows very similar features to that found for a T:G wobble pair. The structure of a duplex containing the 2 0 -dC analogue of (106) bearing a guanidinium group in place of the amino group has been solved and shows additional hydrogen bonds to O6 and N7 of guanosine.1180 A 3.1 A˚ crystal structure of human topoisomerase I in complex with DNA containing 8-oxo-dG at the þ1 position in the scissile strand shows the enzyme active site to be rearranged into an inactive conformation.1181 A primertemplate duplex in complex with the lesion-bypass polymerase Dpo4 is studied in which there is a benzo[a]pyrene diol epoxide adduct of dA (183) base paired with thymidine in the enzyme active site. Two conformations of the adduct are observed, one in which it is intercalated between base pairs, and the other in

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which it is solvent exposed, appears to be a more favourable conformation for lesion bypass.1182 A benzo[a]pyrene adduct with dG in a duplex showed that the dG does not base pair with either the adduct or other nucleobases.1183 A DNA hairpin containing a stilbene diether linkage forming the hairpin loop has been determined at 1.5 A˚, and shows two structures in the crystal unit.1184 One shows a planar stilbene unit stacking on the adjacent G-C base pair. In the other the stilbene is rotated to give edge-to-face orientation of the stilbene and the base pair. OH OH

OH NH N

N N

N dR

183

A duplex containing the 2 0 -O-modiﬁed guanidinium nucleoside (42) has been studied by crystallography and shown that the guanidinium group forms hydrogen bonds with the phosphate group of the adjacent 3 0 -nucleotide.269 Crystal structures have been solved for DNA duplexes containing one1185 or two1186 TNA nucleoside (67) derivatives. With one TNA analogue it was found that there was very little disruption of the normal B-form DNA helix. With two TNA substitutions it was found that the intranucleotide phosphorus-phosphorus distance was shorter than in B-form DNA, and was more like that found in RNA, which may explain why TNA base pairs with RNA better than DNA. There is one crystal structure involving PNA.1187 A PNA decamer with its complementary DNA has been solved at 1.66 A˚, and the heteroduplex adopts a P-helix conformation. The conformational rigidity and the presence of chiral centres limit PNA from adopting other conformations. There is a larger number of solution structures reported. The self-complementary RNA duplex r(GGCAAGCCU) has been examined to determine the effect of A:A mismatch within the duplex. The duplex has sheared Aanti:Aanti base pairs, in which only the exocyclic amino group of one of the pair is involved in hydrogen bonding. Replacement of the other amino group by hydrogen stabilises the base pair.1188,1189 The structure of a branched oligonucleotide has been studied where the solution structure was determined using 13Cisotopically-labelled nucleotides.1190 A number of stem-loop structures have been examined. The Bacillus subtilis T-box antiterminator RNA containing a UUCG stem-loop,1191 UACG loop structure of SL1 RNA in HIV-11192 and the 3 0 -stem-loop from human U4

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snRNA1193 have each been determined. The CACG tetraloop that forms part of the cloverleaf structure of the 5 0 -UTR of coxsackievirus B3 is involved extensive stacking and hydrogen bonding interactions, with the loop closed by a U:G wobble base pair.1194 Another stable loop structure is GNRA, where R is a purine. The structures of the pyrimidine-rich internal loop in the poliovirus 3 0 -UTR1195 and c-RNA stem-loop SL1 of HIV-11196,1197 belonging to this GNRA family have been reported. Other stem-loop structures reported include an essential stem-loop of human telomerase RNA (UGG) closed oﬀ by a U:G wobble base pair,1198 the HIV-1 frameshift inducing stem-loop (ACAA),1199 stem-loop IV domain of the Enterovirus internal ribosome entry site (UCCC)1200 and a family of stem-loop RNAs which bind to the N-terminal RNA-binding domains of nucleolin (UCCC).1201 Larger loop structures (CAGUGC) and (GCAUA) have also been reported in the iron-responsive element from the non-coding regions of mRNAs of proteins involved in iron regulation1202 and U6 RNA,1203 respectively. Three ribozyme structures have been studied; domain 5 of a group II intron ribozyme,1204 a hammerhead ribozyme1205 and the cleavage site from the Varkud satellite ribozyme,1206 each with particular reference to their metal binding sites. The structure of the group II intron ribozyme also revealed a novel RNA motif. The oligonucleotide r(GGAGGUUUUGGAGG) forms a quadruplex structure even in the absence of potassium ions, and at low potassium concentrations an unusually stable dimeric quadruplex forms.1207,1208 Two complex RNA structures are reported; the 101-nucleotide core of the encapsidation signal of MMLV1209 and the luteoviral P1-P2 frameshifting mRNA pseudoknot.1210 Only a few RNA structures involving modiﬁcations have been reported. A study of the hammerhead ribozyme with phosphorothioate modiﬁcations has been carried out, the aim being to determine the metal-binding site. Cd(II) binds not at the scissile bond but at another known metal-binding site.1211 An RNA-DNA duplex in which the pyrimidines in the DNA strand are modiﬁed with C5-propynyl groups has been compared to C5-methyl modiﬁed DNA. The propynylated structure was much more stable, with the propynyl groups occupying the major groove, making van der Waals interactions with their nearest neighbours.1212 Stem-loop structures of the form UUCG are more stable with 2 0 ,5 0 -linkages in the loop structure compared to the usual 3 0 ,5 0 linked RNA. The NMR of such a 2 0 ,5 0 -linked stem-loop structure revealed a novel fold in the loop region involving a U:G wobble-pair in which the nucleobases adopt an anti-conformation.1213,1214 NMR has been used to study the binding of various phenothiazine analogues, which have been identiﬁed as promising ligands for binding to HIV-1 TAR RNA.1215 RNA interference (RNAi) is a rapidly developing ﬁeld of research for gene regulation. The mechanism by which RNAi works is complex, and involves a number of proteins leading to the eventual cleavage of target RNA. NMR has been used to study some of these protein-RNA interactions, in particular the binding of RNA to the complex Argonaut 2 PAZ.1216–1218 Other RNA-protein interactions that have been examined are the N-terminal domain

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431

of nucleolin binding to pre-rRNA1219 and Rnt1p RNase III binding to dsRNA.1220 NMR structures of DNA containing non-canonical base pairs are reported, including an I-motif structure of d(MeCCTCnTCC)4, where n¼1–3, in which the two parallel duplexes are associated by hemi-protonated C–C1 pairs. The structure is revealed as an interconversion of a symmetric and an asymmetric structure, where the asymmetric structure involves a T–T base pair.1221 A stable loop structure has been investigated at low salt concentration where a closing G-C pair in the loops adopts a rare sheared Ganti-Csyn base pair.1222 A study of the kinetics of imino proton exchange in 9-mer duplexes containing different mismatches revealed that different mismatches have different lifetimes,1223 for example, a T-T mismatch has a shorter lifetime than a G-G mismatch. The effect of the mismatch was observed up to two nucleotides away, indicating that the disruption to the duplex structure is localised. A Asyn-Tanti Hoogsteen base pair has been observed in an otherwise undistorted B-DNA duplex in the MATa2 homoeodomain.1224 d(ATATAT) has been studied by both X-ray and NMR where different structures were observed.1225 By X-ray the base pairing is of Hoogsteen form with the adenines ﬂipped over such that the features of both grooves are changed. In solution, the structure adopts a B-form duplex. DNA sequences containing short adenine tracts often cause bending in DNA duplexes. It is reported that ApT steps exhibit a large negative roll, and the curvature is a result of in-phase negative roll and positive roll at the 5 0 -end of the duplex.1226,1227 The binding of Mn(II) ions in A-tract duplexes demonstrated that Mn(II) binds in the minor groove, though the position of the ion is dependent upon both the duplex sequence and length.1228 The solution structure of three-way junctions has been reported in an attempt to establish empirical stacking interactions of the helical arms.1229 A variety of quadruplex structures have also been examined. Telomeric sequences from Tetrahymena and human sequences have been solved by NMR,1230,1231 as well as the structures d(G4T4G3)2 and d(G3T4G4)2, each of which consist of three G-quartets.1232,1233 The telomeric sequences d(TTAGGGT)4 and d(GGAGG)4 each form quadruplex structures involving both G- and Atetrads,1234,1235 whilst d(GCGGTGGAT)4 forms tetrads involving G : C : G : C as well as an A-A mismatch.1236 The largest number of solution structures reported involves modiﬁed DNA structures, including a number of duplexes binding to small molecules. A number of structures are reported complexed to various antibiotics, including actinomycin D,1237 distamycin,1238 phleomycin1239 and nogalamycin.1240–1242 Structures are solved for DNA-binding to the alkaloid berberine,1243 the telomerase inhibitor RHPS4,1244 a DNA binding cyclic polyamide1245 and a spirocylic agent that modulates DNA strand slippage by DNA polymerase I.1246,1247 There are also structures reported for DNA binding to DNA-binding proteins.1248–1250 Of the DNA solution structures, there is a small number involving modiﬁcations to the internucleotide linkage or sugar residues. The cyclic

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oligonucleotide d(pCGCTCATT) forms a symmetric dimer that involves two GCAT tetrads1251 that are stabilised by sodium ions. The solution structure of the self-pairing duplex a-L-arabinopyranosyl-(4 0 -2 0 )-(CGAATTCG) (184) revealed that the structure adopts an antiparallel duplex with a strong propensity for interstrand base stacking.1252 A DNA duplex containing a single aanomeric adenosine, which is a substrate for endonuclease IV, reveals that the a-A stacks intrahelically by reverse Watson-Crick base pairing.1253 O O Base

HO O

α-L-arabinopyranosyl (4'→2')

184

The majority of DNA solution structures involve a nucleobase modiﬁcation. 6-Thioguanosine (6SdG) opposite dT and dC adopts the usual B-form duplex, though 6SdG-dT is a wobble base pair.1254 The structures of quadruplexes in which individual guanine residues are replaced by 8-bromoguanosine (8BrG) reveal that the 8BrG adopts the anticipated syn conformation, thus affecting the quadruplex stability but retaining the parallel orientation of the unmodiﬁed quadruplex.1255 A duplex incorporating an 8-oxo-dG:G mismatch is reported where the 8-oxo-dG is inserted into the helix, forming a Hoogsteen base pair with the guanosine on the opposite strand.1256 A number of guanosine crosslinked structures are reported. A duplex containing the G-G crosslink (185) formed between adjacent CpG steps by the action of nitrous acid is reported.1257,1258 The crosslinked guanines form an almost planar G:G base pair, whilst the cytosine partners are ﬂipped out of the helix into the minor groove. Using the stabilised analogue (186), it was shown that malondialdehyde crosslinking forms a G:G base pair that is not planar, but skewed about the trimethylene linker.1259 The action of trans-platin reagents revealed that an interstrand crosslink is formed in preference to an intrastrand crosslink. The structure exhibits significant distortion at residues adjacent to the crosslink.1260

O N N dR

NH N

O

OH N

N N H

185

N H

N dR

N N dR

O NH

N

N

HN N H

N H 186

N

N dR

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The pyridyloxybutyl derivative (187), derived from tobacco-speciﬁc nitrosamines, forms O6-adducts of guanosine. A solution structure of a duplex containing (187) showed the adduct in the major groove of the duplex, and the modiﬁed G:C in a wobble base pair.1261 Benz[a]anthracene forms adducts with the exocyclic amino groups of nucleobases (cf 72) and a duplex containing a guanosine adduct of benz[a]anthracene showed the anthracene residue located in the minor groove.1262 The aﬂatoxin adduct (188) intercalates into duplexes,1263 without significant disruption of the overall duplex structure.1264 The adenine adduct of the (þ)-CPI-indole (189), related to the daunomycin antitumor agents, was examined to compare with other daunomycin agents. It was shown that the indole resides in the minor groove, and that there was a local perturbation of the duplex, which was restricted to the modiﬁed base pair.1265 A duplex consisting of the ring expanded adenine base (190) paired with thymidine showed that whilst the base pairs are 2.4 A˚ longer than a canonical A:T pair, the structure largely resembles that of a regular B-form duplex.1266 O

O

OMe O H

N O

Me O

O

N

O

N

N

N

H

O N

HN

NH2

dR H2 N

187

N

N dR

188

N3-Adenine

NH2

HN N HO

N O

N

N

N

dR HN

190

189

There are a few pyrimidine-modiﬁed DNA structures. 5-(2-Hydroxyethyl)dU was substituted for thymidines in a quadruplex structure.1267 The presence of the hydroxyethyl groups allows for additional hydrogen bonding within the expected tetrads. A study of the effect of introducing C5-propyne groups showed that the propyne groups stack on the aromatic ring of the

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5 0 -nucleobases, and extend into the major groove. The results suggest that propynylated oligonucleotides are more stable due to pre-organisation of the propynylated ssDNA strands.1268 The presence of a 5-(3-aminopropyl)modiﬁed dU has little effect on overall duplex structure, the aminopropyl unit extending towards the 3 0 -direction from the modiﬁcation site in the major groove.1269 A self-complementary duplex with an opposed N4C-ethylN4C crosslink was studied as a model for crosslinking agents in cancer therapy. The ethyl crosslink extends within the major groove, and there is a widening of the groove at the crosslink site, resulting from underwinding at that base pair step.1270 NMR structures of duplexes containing cis-syn cyclobutane pyrimidine dimers (99) and up to two T:G wobble base pairs have been examined. The overall structures were similar to the usual B-form duplex except when two T:G base pairs were present, where significant duplex distortion was observed.1271 Other modiﬁcations include a formamide residue (191), a ring fragmentation product of thymine, which exists as either a cis or a trans conformer. Both isomers are rotated out of the helix, and the bases on either side of (191) occupy the space vacated by it.1272 A pyrene:abasic site base pair in DNA duplexes adopts the usual B-form duplex, with the pyrene residue within the duplex stacking on adjacent nucleobases. The abasic site folds back over the opposite strand to shelter the hydrophobic base from exposure to water.1273,1274 The photoresponsive azobenzene analogues (133, R- and S-forms) have been incorporated into DNA for NMR analysis. Both isomers intercalate between neighbouring base pairs, and the S-isomer exhibits more disturbance in its duplex structure which is reﬂected in lower Tms compared to the R-isomer.1275

HO

O

H N

O H

OH 191

The self-complementary hexamer d(TGCGCA) modiﬁed to incorporate cholesterol attached via a 5 0 -amine modiﬁcation showed that the duplex was stabilised by the stacking of the steroid on the terminal A:T base pair through van der Waals interactions.1276 Bleomycins damage DNA by 4 0 -hydrogen abstraction resulting in the formation of base-propenal adducts and 3 0 phosphoglycolate (192) modiﬁcations. The NMR structure of a duplex containing (192) at the 3 0 -end with a 5 0 -phosphate revealed a regular B-form duplex, both terminal modiﬁcations being extrahelical.1277 DNA containing the intercalating nucleic acid modiﬁcation (139) has been studied by NMR, in a duplex with two (139) opposing modiﬁcations.1278 The two modiﬁcations caused significant unwinding of the overall duplex structure, leading to a ladder-like structure.

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Organophosphorus Chem., 2006, 35, 355–478 O O DNA O

P

O

O

O

192

The solution structure of the ﬁrst fully modiﬁed LNA oligonucleotide with its complementary RNA is described.1279 The duplex adopts a canonical Aform duplex, and the helix is almost straight. The LNA oligonucleotide TGGGT forms a parallel stranded quadruplex structure with right-handed helicity.1280 a-L-LNA has also been incorporated into a DNA oligonucleotide with complementary DNA and RNA.1281–1283 Opposite DNA, it adopts a Bform duplex, with the backbone rearranged in the vicinity of the substitutions to accommodate them. Opposite RNA, the structure is a hybrid between Aand B-form with the phosphate groups of the LNA nucleotide rotated into the minor groove. The locked nucleic acid [3.2.0]bcANA (193) with an arabino-conﬁguration is ﬁxed in an O4 0 -endo conformation. The solution structure of DNA containing a single substitution of (193) showed a B-form duplex with stacking of the nucleobases unperturbed.1284 The 2 0 -O,3 0 -C-methylene bridge is located in the major groove and is accommodated by the B-form duplex. The O4 0 -endo conformation of the sugar causes a local disruption in the backbone angle. A PNA-DNA chimera 50TGGG30-t forms a regular parallel duplex as determined by NMR,1285 whereas 50TGG30-gt does not form well-deﬁned species.

O O

O

Base

O 193

As well as investigating structures by crystallography and NMR, there are other techniques that have been used. Electron microscopy has been used to study nucleoprotein RNA structures of measles virus.1286 Cryoelectron microscopy has been used to visualise tmRNA (RNA that acts as both messenger and transfer RNA) entry into the ribosome and ribosomal motion,1287–1290 and visualisation of a 1.7 kb ssDNA structure.1291 Atomic force microscopy (AFM) was used to visualise a DNA hemiknot structure,1292 four-arm DNA structures1293 and DNA hybridisation in the absence of a DNA label.1294 A surface plasmon diffraction sensor has also been used to study oligonucleotide hybridisation.1295 Other more established methods have also been used, such as footprinting to determine the binding of T7 endonuclease I to a Holliday junction1296 and the investigation of Holliday junctions using gel electrophoresis.1297

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