Enzyme Catalysis in Organic Synthesis: A Comprehensive Handbook

Organic Synthesis Highlights V Edited by Hans-Cunther Schmalz and Thomas Wirth

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Organic Synthesis Highlights V

Edited by Hans-Cunther Schmalz and Thomas Wirth

Prof: Dr. Hans-Gunther Schmolz Institute of Organic Chemistry University of Cologne Greinstrage 4 50939 Koln Germany

This book was carefully produced. Nevertheless, editors, authors and publisher do not warrant the information contained therein to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

Prof: Dr. Thomas Wirth Cardiff University Department of Chemistry PO Box 912 Cardiff CFlO 3TB United Kingdom

Library of Congress Card No.: applied for A catalogue record for this book is available from the

British Library. Bibliographic information published by Die Deutsche Bibliothek

Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data is available in the Internet at http:/dnb.ddb.de. 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim All rights reserved (including those of translation in other languages). No part of this book may be reproduced in any form - by photoprinting, microfilm, or any other means - nor transmitted or translated into machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Printed in the Federal Republic of Germany. Printed on acid-free paper. Typesetting Asco Typesetters, Hongkong Printing betz-druck gmbh, Darmstadt Bookbinding j. Schaffer GmbH & Co. KG

Griinstadt ISBN 3-527-30611-0

Iv

Contents

Preface xiii List o f Contributors

xu

Part I. Synthetic Methods Direct Conversion o f Sugar Glycosides into Carbocycles Peter 1. Dalko and Pierre Sinai;

1

Synthesis o f Diary1 Ethers: A Long-standing Problem Has Been Solved Fritz Theil

15

Take The Right Catalyst: Palladium-Catalyzed CC-, CN- and CO-Bond Formation on Chloro-Arenes 22 Rainer Stiirmer Alkyne Metathesis i n Natural Product Synthesis Thomas Lindel

27

Transition Metal-Catalyzed Functionalization o f Alkanes Oliver Seitz An Eldorado for Homogeneous Catalysis? Gerald Dyker

36

48

New and Selective Transition Metal Catalyzed Reactions o f Allenes A. Stephen K. Hashmi

56

Controlling Stereoselectivity with the Aid o f a Reagent-Directing Group Bernhard Breit Solvent-Free Organic Syntheses Jiirgen 0. Metzger

82

68

vi

I

Contents

Fluorous Techniques: Progress i n Reaction-Processing and Purification U/f Diederichsen

93

Recent Developments i n Using Ionic Liquids as Solvents and Catalysts for Organic 105 Synthesis Peter Wassencheid Recent Advances on the Sharpless Asymmetric Aminohydroxylation Dmitry Nilov and Oliver Reiser Asymmetric Phase Transfer Catalysis Christabel Carter and Adam Nelson

118

125

Asymmetric Catalytic Aminoalkylations: New Powerful Methods for the Enantioselective 134 Synthesis o f Amino Acid Derivatives, Mannich Bases, and Homoallylic Amines Michael Arend and Xiaojing Wang IBX - New Reactions with an Old Reagent Thomas Wirth Parallel Kinetic Resolutions Jason Eames

144

151

The Asymmetric Baylis-Hillman-Reaction Peter Langer

165

Simple Amino Acids and Short-Chain Peptides as Efficient Metal-free Catalysts in Asymmetric 178 Synthesis Harald Groger, Jorg Wilken, and Albrecht Berkessel Recent Developments i n Catalytic Asymmetric Strecker-Type Reactions

187

Larry Yet Highly Enantioselective or Not? - Chiral Monodentate Monophosphorus Ligands i n the Asymmetric Hydrogenation 193 lgor V. Komarou and Armin Borner Improving Enantioselective Fluorination Reactions: Chiral N-Fluoro Ammonium Salts and Transition Metal Catalysts 201 Kilian Mufiiz Catalytic Asymmetric Olefin Metathesis Amir H . Hoveyda and Richard R. Schrock

210

Contents

Activating Protecting Groups for the Solid Phase Synthesis and Modification o f Peptides, 230 Oligonucleotides and Oligosaccharides Oliver Seitz Traceless Linkers for Solid-Phase Organic Synthesis florencio Zaragoza Donuald

251

Merging Solid-Phase and Solution-Phase Synthesis: The “Resin-Capture-Release” Hybrid Technique 265 Andreas Kinchning and Riidiger Wittenberg Polymeric Scavenger Reagents in Organic Synthesis Jason Eames and Michael Watkinson

280

Part II. Applications Total Syntheses o f Vancomycin 297 Lars H. Thoresen and Kevin Burgess Bryostatin and Their Analogues Uf Diederichsen

307

Eleutherobin: Synthesis, Structure/Activity Relationship, and Pharmacophore Uf Diederichsen Total Synthesis o f the Natural Products CP-263,114 and CP-225,917 Ulf Diederichsen and Katrin B. Lorenz Polyene Cyclization t o Adociasulfate 1 Thomas Lindel and Cordula Hopmann

326

342

Sanglifehrin A An Immunosuppressant Natural Product from Malawi Thomas Lindel Short Syntheses o f the Spirotryprostatins Thomas Lindel

360

The Chemical Total Synthesis o f Proteins Oliver Seitz

368

Solid-Phase Synthesis o f Oligosaccharides Ulf Diederichsen and Thomas Wagner

350

384

Polymer-Supported Synthesis o f Non-Oligomeric Natural Products Stefan Sommer, Rolf Breinbauer, and Herbert Waldmann

395

317

I

vii

viii

I

Contents

Explosions as a Synthetic Tool? Cycloalkynes as Precursors to Fullerenes, Buckytubes and Buckyonions 409 Rudiger Faust

Dendralenes: From a Neglected Class o f Polyenes to Versatile Starting Materials in Organic Synthesis 419 Henning Hopf Fascinating Natural and Artificial Cyclopropane Architectures Riidiger Faust

index

435

428

Development in chemical sciences in general and in organic synthesis in particular has a strong impact on our life. Synthesis as a central position within the field of organic chemistry is contributing to a large variety of different applications. Men’s ability to synthesize complex biologically active or functional molecules has dramatically improved during the past years. However, the art and technology of organic synthesis is still far from being fully developed. Intense research is performed worldwide, and it is important and fascinating to follow the steady development of increasingly powerful methods and tools for organic synthesis. The fifth volume of Organic Synthesis Highlights is divided in two parts. In the first part, recent developments in synthetic methodologies are described and new and improved techniques are highlighted including some general applications of those strategies. The second part of the book is devoted to the total synthesis of natural and non-natural compounds. The complexity and the efficiency of multi-step sequences is still highly challenging and success in this field often has to go hand in hand with the development of new methods. In continuing the tradition of Organic Synthesis Highlights, about 40 articles have been selected from the “Highlights” section of Angewandte Chemie (1998-2001),from the “Concepts” section of Chemistry - A EuropeanJournal(2000-2001), and from the review section of Nachrichten aus der Chemie (1999-2001),the members journal of the GDCh. The articles from the “Synthese im Blickpunkt” have all been carefully translated and updated by the authors ( U . Diederichsen, T. Lindel, 0. Seitz) and we would like to express special thanks to these colleagues and their co-authors. We are also grateful to all the other authors for their excellent contributions and for the good cooperation. We also like to thank the team at Wiley-VCH, especially Dr. E. Westermann, for the excellent and professional support and for the prompt help in all questions. We hope that this volume will stimulate interest in the field of synthesis across a broad range of chemists, from undergraduate students to research group leaders in industry and academia. Cologne and Cardiz September 2002 Hans-Giinther Schmalz and Thomas Wirth

List of Contributors

Dr. Michael Arend Fibrogen 225 Gateway Boulevard South San Francisco, CA 94080 USA Professor Dr. Armin Borner Institut fur Organische Katalyseforschung an der Universitat Rostock e. V. Buchbinderstrasse 5/6 18055 Rostock Germany Professor Dr. Bernhard Breit Albert-Ludwigs-Universitat Freiburg Institut fur Organische Chemie und Biochemie Albertstrasse 21 79104 Freiburg Germany Professor Kevin Burgess Department of Chemistry Texas A&M University Box 30012 College Station TX-77842.3012 USA Professor Dr. Ulf Diederichsen Institut fur Organische Chemie Universitat Gottingen Tammannstr. 2 37077 Gottingen Germany Professor Dr. Gerald Dyker Ruhr-Universitat Bochum Fahltat fur Chemie Universitatsstrasse 150 44780 Bochum Germany

Dr. lason Eames Department of Chemistry Queen Mary and Westfield College Mile End Road London E l 4NS U.K. Dr. Rudiger Faust Department of Chemistry Christopher Ingold Laboratories University College London 20 Gordon Street London WClH OAJ U.K. Dr. Harald Groger Project House Biotechnology Degussa AG Rodenbacher Chaussee 4 63457 Hanau Germany Professor Dr. A. Stephen K. Hashmi hstitut fur Organische Chemie Universitat Stuttgart Pfaffenwaldring 55 70569 Stuttgart Germany Professor Henning Hopf Institut fur Organische Chemie Technische Universitat Braunschweig Hagenring 30 38106 Braunschweig Germany Professor Amir H. Hoveyda Boston College Department of Chemistry Merkert Center Chestnut Hill

xii

I

List ofcontributors

Massachusetts 02467 USA Professor Dr. Andreas Kirschning Institut fur Organische Chemie Universitat Hannover Schneiderberg 1 B 30167 Hannover Germany Professor Dr. Peter Langer Institut fur Chemie und Biochemie Ernst-Moritz-Arndt Universitat Soldmannstrage 16 17487 Greifswald Germany Professor Dr. Thomas Lindel Department Chemie LudwigMaximilians-Universitat Munchen Butenandtstrasse 5-13 81377 Miinchen Germany Professor Dr. Jurgen 0. Metzger Carl-von-OssietzkyUniversitat Fachbereich Chemie der Universitat Carl-von-Ossietzky-Strasse 9-1 1 26111 Oldenburg Germany

Dr. Oliver Seitz MPI fur Molekulare Physiologie Abteilung Chemische Biologie Otto-Hahn-Strasse 11 44227 Dortmund Germany Dr. Rainer Stiirmer BASF AG Hauptlaboratorium GHF/D, A30 67056 Ludwigshafen Germany Dr. Fritz Theil ASCA Angewandte Synthesesysteme Adlershof GmbH Richard-Willstatter-Strasse 12 12489 Berlin Germany Dr. Peter Wasserscheid Institut fur Technische Chemie und Makromolekulare Chemie Bereich Technische Chemie Worringer Weg 1 52074 Aachen Germany

Dr. Kilian Mufiiz KekulC-Institut fur Organische Chemie und Biochemie Gerhard-Domagk-Strage 1 53121 Bonn Germany

Professor Dr. Herbert Waldmann MPI fur Molekulare Physiologie Otto-Hahn-Strasse 11 44227 Dortmund Germany

Professor Dr. Adam Nelson School of Chemistry University of Leeds Leeds. LS2 9jT U.K.

Professor Thomas Wirth Department of Chemistry Cardiff University P.Q. Box 912 Cardiff CFlO 3TB United Kingdom

Professor Oliver Reiser Institut fur Organische Chemie der Universitat Regensburg Universitatsstrasse 31 93053 Regensburg Germany Prof. Pierre Sinay Ecole Normale Supkrieure DCpartement de Chimie UMR 8642 24, Rue Lhomond 75231 PARIS Cedex 05 France

Dr. Larry Yet Albany Molecular Research, Inc. 21 Corporate Circle P.O. Box 15098 Albany NY 12212-5098 USA Dr. Florencio Zaragoza Dorwald Novo Nordisk A/S Novo Nordisk Park 2760 Milm Denmark

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

I’

Direct Conversion of Sugar Clycosides into Carbocycles Peter 1. Dalko and Pierre S h y

Carbocyclic polyols are important constituents of many biologically active molecules. They exhibit far reaching biological effects ranging from cellular regulation, to the selective inhibition of enzymes, which play key roles in living organisms [ 1, 21. Some of the most prominent six membered representatives are cyclohexane hexitols such as inositol derivatives [ 11 or pseudo-sugars [2, 31, such as cyclophellitol [4],or valienamine [ 51. Structural analogues of the latter are constituents of compounds of key pharmacological interest such as acarbose [GI, adiposin [7], trestatin [8], and amylostatin [9]. Together with a growing number of structurally related alkaloids [lo] and purely synthetic compounds Ill], as well as five membered polyol-contain natural products [ 121, these small, but synthetically challenging molecules received growing interest in the last few years. The biological significance and the inherent structural challenge of these molecules have led to the development of a variety of different approaches in optically pure form [13]. To access this class of compounds both (1)a cyclization strategy of alicyclic, polyfunctionalized molecules and (2) transformations of conveniently substituted carbocycles into cyclitols were largely exploited. The former strategy includes Diels-Alder reactions [ 141, Wittigtype olefinations [ 151, radical cyclization approaches [ 161, ring-closing metathesis (RCM) [ 171, and a variety of anionic cyclization/organometallic coupling reactions of advanced polyhydroxylated compounds [ 181. Some of these allow the direct conversion of carbohydrate furanosides and pyranosides to carbocyclic polyols. The tandem fragmentation/Henry-type cyclization reaction provided the first examples in which cyclohexane [ 191 and cyclopentane [ 201 derivatives were obtained from carbohydrate derivatives. Likewise, the elegant application of the Fujimoto-Belleau reaction [21], and the anionic rearrangements of anhydrosugars [ 221 are examples of this transformation. The strategy which includes enantiopure carbocycles as starting materials features transformations of quinic acid 1231, inositols or conduritol derivatives [ 241, desymmetrization of meso cyclohexene derivatives using asymmetric palladium catalyzed hydroxycarboxylation [25], or other enantioselective reactions [ 261, transformation of homochiral carbocycles obtained either by microbial metabolites [ 27, 281, or by some other type of oxidation [29]. At this stage it is important to briefly examine the biosynthesis of carbocyclic polyols, concentrating on six membered rings. Myo-inositol derivatives, for example, are formed from D-glucose6-phosphate 1 by a stereospecific ring-closure under the catalytic influence of inositol cyclase (Scheme 1) [ Ib].

2

I

Direct Conversion of Sugar Clycosides into Carbocycles

@o H

o

b

o

H

-

OH

HO

o a H

o

~

HO

~

~

~

o

~

o

OH

2

1

4

3

myo-inositol 1-phosphate Scheme 1.

Other mechanisms bear strong resemblances to that by which D-glucose is converted into shikimic acid (Scheme 2). This is the biogenetic path in which nature produces the benzoid rings of the aromatic amino acids and an extensive range of other metabolites. At an early stage of this sequence the hemiacetal intermediate Ga undergoes rearrangement and forms the quinic acid derivative 7. As Bartlett and Satake demonstrated, however, the unstable Ga, generated in situ from the 0-nitrobenzyl protected cc-glycoside Gb is rearranged spontaneously to 3-dehydroquinic acid without any specific enzyme [ 301. Moreover, this uncatalyzed reaction gives rise to a single stereoisomer identical to that of the biosynthetic path. This fact suggests the possibility that a key step in cyclitol biosynthesis may also be nonenzymatic.

5

6aR=H 6b R = o-nitrobenzyl

0 H0m.u ~ HO

'OH

0

7 3-dehydroquinic acid Scheme 2.

-

2H

o 8 H ~o ~ ~ 0 2 H HO

8

shikimic acid

Direct Conversion of Sugar Clycosides into Carbocycles

13

Nature found a direct path to perform this tandem fragmentation cyclization reaction in a stereospecific manner and under neutral conditions. Human creativity and luck aimed to uncover synthetic variants, which can compete efficiently with it. With the advent of mild, metal mediated cyclization reactions, the early idea of Grosheinz and Fisher [19a], who converted 6-deoxy-6-nitrohexosesto nitroinositols in a single step, matured to a general strategy of broad interest. The direct conversion of sugar glycosides to a carbocycle can take place either by a domino sequence, or by a concerted reaction. In the former case the reaction combines two distinct steps: an opening step, liberating a highly reactive metal enolate (or equivalent) and electrophile functions (i.e. an aldehyde or oxycarbenium function), which undergo subsequent cyclization. The carbocyclization can proceed with ring contraction providing cyclopentanes and cyclobutanes [31], or alternatively may give rise cyclohexitols, or larger rings. Sugar enol-ethers, which inherently carry both the masked nucleophilic and electrophilic functions, were converted to carbocycles in different reactions. Among the carbocyclization methods the Ferrier (I I) cyclization of hex-5-enopyranosides affording six membered carbocycles in the presence of Hg(11) salts is perhaps the most popular one (Scheme 3) [ 321. This remarkable reaction has provided a practical route to a large variety of bioactive substances such as aminocyclitols [ 331, pseudosugars [34], inositols [35], and other complex hexitols [36].

Hg”

~ BnO ~ 0 %

[

B BnO n

O

OBn

9aR=H 9b R = OAc

-

q +B BnO n

OH OBn

OMe

L

~

OBn

h

O

]

OBn

OMe

10a R = H 10b R = OAc

BnO

O

lla R =H l l b R = OAc

J

Bno BnO

OBn OH

12a R = H (68%) 12b R = OAC(59-72%)

13a R = H (17%) 13b R = OAc (13 %)

Scheme 3.

According to the original protocol the six membered vinyl glycoside such as 9a undergo rearrangement under hydroxymercuration conditions providing cyclohexitols (Schema 3). Among the various conditions proposed for the Ferrier (11) reaction, both catalytic and stoichiometric methods were investigated, which afforded similar but not identical results [ 13, 371. Also, a “nontoxic alternative” consists of using a catalytic amount of palladium(I1) salt [38], instead of mercury(I1) [39]. This modification may alter the selectivity, which is not surprising given the different coordination pattern of the metal in the transition state. A

4

I

Direct Conversion of Sugar tlycosides into Carbocycles

basic feature of this transformation is the loss of the aglycon, for example methanol, and the fragmentation ring-closing aldol reaction. In this cyclization the carbanionic center (C6) attacks the electrophilic carbonyl center (Cl). The stereochemistry of the newly formed asymmetric center is determined by the conformational bias of the molecule, and by the chemical nature of the functions present. The stereoselectivity of the newly formed asymmetric center as well as isolated yields are highly dependent upon the experimental conditions used, however. This fact is mainly due to the preferred conformation of the given sugar derivative in the transition state and also to the formation of a sensitive 8-hydroxy ketone, which may undergo elimination and subsequent aromatization. The scope of the reaction was enlarged by showing that functionalized exocyclic olefins may be converted into carbocycles as well [40]. Accordingly, alkene-bearing oxygen substituents at C6, such as 9b, made from the corresponding aldehyde, were transformed to inosose derivative 121, with high stereoselectivity of each newly formed stereogenic center. Noteworthy, the geometry of the enol acetate of 91, does not affect the stereochemical outcome of the reaction, nor in the Hg(I1) neither in the Pd(I1) salt mediated cases [33c]. The Ferrier (11) reaction is quite efficient to form six membered carbocycles, but is unsuitable to prepare cyclopentitols. Five membered enollactone 14 was converted to the cyclopentanone derivative 16 as a single epimer upon treatment by LiAlH(OtBu)3 (Scheme 4) [41]. Spectroscopic studies established some mechanistic details. Accordingly, the hydride of the reducing agent rapidly added to the carbonyl and formed with the metal a stable aluminate complex. The carbocyclization occurred by protonation followed by fragmentation and aldol type cyclization process.

x-1 14

L

-

\/

1

15

16 (74%)

Scheme 4.

Under particularly mild conditions the triisobutylaluminium (TRIBAL) mediated rearrangement avoided the fragmentation of the “locked’ anomeric substituent in 9a, and even preserved its original configuration with high selectivity (Scheme 5) [42,43]. Lewis acid assisted endo activation, followed by a ring-opening step, generated the zwitterionic enolate intermediate 17 as the hypothesized intermediate of the reaction. The ring closure occurs via an intramolecular 6-em-trig aldol condensation. The “bonus” of the reaction is the stereoselective formation of a hydroxyl, resulting from the final reduction of the keto group probably by an intramolecular hydrogen delivery from the less hindered P-side. The reaction is fairly general and high yielding using a wide array of sugar starting materials. It is worthy to note the good selectivity in conserving the anomeric stereochemical information by retention

Direct Convenion of Sugar Clycosides into Carbocycles

15

18

OMe

OMe

19 (79%)

Scheme 5.

The fact that both the stereochemistry and the substitution pattern of the sugar anomeric center is conserved allowed to realize a direct transformation of a hex-5-enopyranosides of sucrose 20 into a carba-disaccharide analogue 21 (Scheme G), and to achieve cascade rearrangements [45].

OBn

PhMe, 50°C

BnO""

Brio'“‘ OBn

20

21 (34%)

Scheme 6.

No synthetically useful rearrangement occurs, however, by replacing the TRIBAL by DIBAL-H, or by using stronger Lewis acids such as TiC14, Ti(OiPr), or BF3, SnC14, AlC13 under similar conditions [4G].In contrast, slightly modified conditions, by using Ti(OiPr)C13, prepared from TiC14 and Ti(OiPr),, the reaction afforded the rearranged cyclohexanone derivative with retention of the stereochemical information and substitution pattern on the anomeric center [47]. The a-D-glycoside 9a in the presence of Ti(OiPr)C13 provides the expected endo-cleavage of the glycosidic bond and forms the carbocyclic glycoside 23 (Scheme 7). Although the a-glycoside starting material affords nearly quantitative yield, the corresponding I(-glycoside gives rise to a mixture of different products. This Ti'" version

6

I

Direct Conversion of Sugar Glycosides into Carbocycles

Ti(OiPr)C13(1.5 equiv.), BnO

CH2C12, -78"C, 15 min. OMe

9a

OMe

23 (98%) Scheme 7.

involves milder reaction conditions than the triisobutylaluminium mediated rearrangement and does not result in the reduction of the keto function. Vinyl carbohydrate derivatives such as 24 or 27 can be converted to carbocycles 26 and 28 respectively by sequential treatment with "CpzZr" and BF3.0Et, (Scheme 8) [48]. The reaction offers complete cis-selectivitybetween the vinyl groups and the newly formed hydroxyl.

24

"1 * BnO

OBn

26 (65%)

>98% de.

OMe

"Cpzzr"

WoH +

BF3.OEt2 * OBn

27 Scheme 8.

(60%)

"'OBn

OH

*,'

OBn

Direct Conversion ofsugar Clycosides into Carbocycles

Although the major stereoisomer was expected to be trans to the adjacent cc-substituent, the overall selectivity of the reaction depends intimately on the stereochemistry and nature of the substituents present. Despite the difficulty encountered with different derivatives in controlling stereochemistry, the easy access and the seemingly unhindered choice of the vinyl carbohydrate starting materials renders this methodology appealing. Like the in situ generated propargyl-zirconium species, generated from vinyl-carbohydrate derivatives the intramolecular propargylation promoted by SmIz in the presence of a catalytic amount of Pd(0) complexes affords the ring-contracted carbocycle (Scheme 9). The reaction products are usually cyclopentanols and cyclobutanols. The transformation is characterized by high trans selectivity with regard the two newly created stereogenic centers. This procedure represents an extension of the “CpzZr” mediated ring-contraction reaction of vinylfuranosides or pyranosides in a sense that allows also the transformation of alkynylpyranosides [ 491. Like the earlier discussed zirconium mediated ring-contraction reaction the reaction is thought to proceed through the corresponding ally1 or allenylsamarium complexes that undergo cyclization in the presence of the carbonyl of the liberated aldehyde function [SO].

SmI2 (2eq),

OBn

P ~ ( O A C ) ~ . ~(5%) BU~P OBn

OBn

rt

29

30 (82%)

Scheme 9.

Samarium(11) iodide promotes comparable transformations of aldehydo sugar 31 to ring contracted product 34 (Scheme 10) [ 511. The presences of HMPA and tea-butyl alcohol as a proton source are necessary to obtain good conversion to cyclopentane derivatives. The reac-

rBuOH (2 equiv.)

BnO

31

32

OMe

BnO

&

BnO BnO

33 Scheme 10.

H

34 (63%)

8

I

Direct Conversion of Sugar Clycosides into Carbocycles

tion is considered to proceed via the samarium ketyl intermediate, which is reduced to the disamarium species 32 under the reaction conditions. After fragmentation the system is ideally suited for a subsequent aldol cyclization, involving intramolecular nucleophilic attack of the samarium enolate onto the aldehyde through a 5-enol exo-trig process. As expected from the metal linked chelate, the major stereoisomer of the two newly created stereocenters is cis, and trans with regard to the adjacent substituents. A limited number of Sm12-mediated reductive rearrangements affording six membered carbocycles have been reported (Scheme 11) [52a]. The transformation occurs often with high stereoselectivity, and can be explained by assuming a chelation control model. The outcome of the reaction may depend, however, on the stereochemistry of the substitution pattern of the molecule, and the nature of the intramolecular trap. Six membered carbocycles are formed from the ally1 sulfides such as 35, in sharp contrast with a,p-unsaturated methyl esters of sugar pyranosides such as 37, which afford the corresponding five membered carbocycles (38) through a similar SmI2-induced cyclization [ 521. SPh I

b

o

H

Sm12

HOt,/(@H

THF / MeOH

BnO\\\\

'"OBn OBn

5: 1 (83 %)

BnO'"'

""OBn OBn

dr=3: 1

35

36

37

THF / MeOH 15: 1 (91 %)

OBn 38

Scheme 11.

Sugar spiroisoxazolines intermediates such as 40 undergo rearrangement under reductive conditions (Scheme 12) [53]. The starting material can be prepared by an intermolecular [ 3+2] cycloaddition by using pent-4-enofuranosides such as 39 and nitrile oxides. Although this reaction proceeds often in a high facial selectivity, the diastereoselectivity of this transformation is of no importance since the spiro-carbon loses the stereochemical integrity in the following step. The reduction of this intermediate by using Raney Nickel hydrogenation in MeOH-AcOH yield in high diastereoselectivity the corresponding cyclic enaminone 42. The reaction is a result of a selective N - 0 cleavage and a spontaneous aldol-like condensation of the resulted enamine or enone of type 41.This reaction allows the formation of both five and six membered carbocycles respectively. The efficiency of the transformation depends on the substitution pattern of the spiro-isoxazoline moiety.

Direct Conversion of Sugar Clycosides into Carbocycles

eoMe Low,, 2,6-ClzC6H&NO (1.1 equiv.),

-

-:

:

i

-

2,6-C12C~H3

-.-~ --

Y

c

k 0

CH2C12, reflux, 4 h

39

40 (66%)

Raney Ni, MgS04, H2 (1 atm.)

.

MeOWCH&OOH, (6: 1) 20 "C, 90 min. 41 Scheme 12.

Let's now consider concerted skeletal rearrangements which allow the direct transformation of a sugar structure into a carbocycle. The Claisen rearrangement has been used for the direct conversion of sugar C-glycosides to eight membered carbocycles, respectively. The to reaction has precedents in the transformation of 2-methylene-6-vinyl-tetrahydropyrans cyclooctenone derivatives, a transformation that has been applied in the synthesis of several natural products [ 541. The rearrangement can be promoted by heat [55] or by using TRIBAL [%I. For example, simple heating of a solution of 43 in boiling xylene leads to the eight membered carbocycle 44 in 60% (Scheme 13).

43

44 (60%)

Scheme 13.

The rearrangement of methyl vinylketoside 45 can be accelerated by using TRIBAL. In this case the reaction affords at room temperature the corresponding cyclooctanol derivative 46 with a high preference for a syn-hydrogen delivery compared to the adjacent benzyloxy function (Scheme 14)[57]. An elegant method was devised in preparing pseudo-sugars using thermal [3, 31 sigmatropic rearrangement (Scheme 15) [58]. This methodology is based on the earlier works of Buchi [ 591. Although the generality of this approach using different sugar series remains to be demonstrated, the simplicity is attracting: the vinyl glucal derivative 47 affords the cyclohexene aldehyde 48 by heating. One of the advantages of this transformation is that

19

10

I

Direct Conversion of Sugar Clycosides into Carbocycles

TRIBAL OMe

toluene OBn 45

46 (83%)

Scheme 14.

the formed pseudosugar retains the original configuration of the starting sugar: the D-glucal derivative gives entry to the pseudo-o-glucal series.

240°C

o-dichlorobenzene sealed tube, l h

BnO"" OBn

47

B n ~ " OBn

48 (84%)

Scheme 15.

The intramolecular nitrone cycloaddition (INC) has been used particularly for the synthesis of amino carbasugars [GO, 611. The following scheme illustrates this strategy (Scheme 16) [GO]. The cycloaddition of nitrone derived from lactol 49 and an excess of Nmethylhydroxylamine occurs from the least hindered face affording the isoxazolidine 51 (85% yield). The amino carbasugar 52 was obtained after the cleavage of the N - 0 bond.

F4

O

)"

MeNHOH-HCl, t

>

5

k 0

pyridine, rt, 12h,

49

50

.OH I

Me"\/

\ Scheme 16.

51(85%)

\

52

References and Notes

I

l1

Conclusion

The easy access to enantiomerically pure carbocyclic polyols from carbohydrate furanosides and pyranosides is an appealing transformation in organic synthesis. New methods made possible to carry out this transformation under mild conditions with high yield and with predictable and high stereoselectivity. Beyond elegance, the compatibility towards a large variety of substituents gives to the discussed rearrangements strategic importance.

References and Notes a) Y. CHAPLEUR (Ed.) Carbohydrate Mimics, Wiley-VCH, Weinheim, 1997; b) D. C. BILLINGTON,The Inositol Phosphates Chemical Syntheses and Biological Sign$cance, VCH, New York, 1993; c) L. C. HUANG,J. LARNER, Adv. Prot. Phosphatases 1993, 7, 373; d) G. ROMERO, Cell. Biol. Int. Rep. 1991, 15, 827; e ) M. J. MCCONVILLE, M. A. J. FERGUSON, Biochem.]. 1993, 294, 305; f ) R. H. MITCHELL, A. H. DRUMMOND, C. P. DOWNES, Inositol Lipids in Cell Signaling, Academic Press, New York, 1989; g) R. KAPELLER,L. C. CANTLEY, BioEssays 1994, 16, 565; h) K. HINTERDING, D. ALONSO-DIAZ, H. WALDMANN, Angew. Chem. Int. Ed. 1998, 37, 668; i) R. I. G . J. WANG,Chem. Rev. HOLLINGSWORTH, 2000, 100, 4267; j) D. C. BILLINGTON, Chem. SOC. Rev. 1989, 18, 83; k) T. HUDLICKY, D. GONZALEZ, D. T. GIBSON, Aldrichim. Acta 1999, 32; 1) B. FRASERREID,Acc. Chem. Res. 1996, 29, 57; m ) B. FRASER-REID, K. TATSUTA, J. T H I E M(Eds) , Glycoscience: Chemistry and Chemical Biology, Vol. 1-111, Springer, Berlin, 2001. 2 a) T. SUAMI,S. OGAWA, Adv. Carbohydr. Chem. Biochem. 1990, 28, 41; b) A. BERCIBAR, C. GRANDJEAN, A. SIRIWARDENA, Chem. Rev. 1999, 99, 779. 3 Pseudosugars are carbohydrate derivatives in which the ring oxygen has been replaced by a methylene group. 4 S. ATSUMI, K. UMEZAWA, H. IINUMA,H. NAGANAWA, H. NAKAMURA, Y. IITAKA, T. Antibiot. 1990, 43, 49. TAKEUCHI,]. 5 T. K. M. SHING,L. H. WAN,Angew. Chem. Int. Ed. Engl. 1995, 34, 1643. 6 D. SCHMIDT, W. FROMMER, B. J U N G E , K. MULLER, W. WINGENDER, E. TRUTSCHEIT, Natunvissenschaften 1977, 64, 536. 1

a) S. OGAWA,Yuki. Gosei Kagaku Kyokai Shi 1985, 43, 26; b) Y. KAMEDA, N. ASANO, M. YOSHIKAWA, K. MABUI,S. HORII, H. FUKAWASE, ]. Antibiot. 1983, 36, 1157. 8 J. ITOH, S. OMOYO, T. SHOMURA, H. OGINO,K. IWAMATSU, S. INOUYE, J . Antibiot. 1981, 34, 1424 and 1429. 9 N. SAKAIRI, H. KUZUHARA, Tetrahedron Lett. 1982, 23, 5327. 10 a) R. L. POLTin Amaryllidaceae Alkaloids with Antitumor Activity, Series Organic Synthesis: 7'heory and Application, Vol. 3 (Ed. T. HUDLTCKY), JAI Press, Greenwich, 1996, pp 109-148; b) P. MAGNUS, I. K. SEBHAT,].Am. Chem. SOC.1998, 120, 5341. 11 S. VORWERK, A. VASELLA, Angew. Chem. Int. Ed. 1998, 37, 1732. 12 M. ISHIBASHI, C. M. ZENG,J. KABAYASHI, ]. Nat. Prod. 1993, 58, 186. 13 a) R. J. FERRIER, S. MIDDLETON, Chem. Rev. 1993, 93, 2779; b) G. D. PRESTWICH, Acc. Chern. Res. 1996, 29, 503; c) P. 1. DALKO, P. SINAY,Angew. Chem. Int. Ed. 1999, 38, 773; d) P. SINAY,Pure Appl. Chem. 1998, 70, 1495. 14 a) S. ALLEMAN, P. VOGEL,Helv. Chim. Acta 1994, 77, 1; b) R. LEUNG-TOUNG, Y. LIU, J. M. MUCHOWSKI, Y.-L. Wu, ]. Org. Chem. 1998, 63, 3235; c) 0. ARJONA, C. BORRALLO,F. IRADIER, R. MEDEL, J. PLUMET, Tetrahedron Lett. 1998, 39, 1977; d) E. ROMAN, M. BANOS,I. I. GUTIERREZ, J . A. SERRANO,].Carbohydrate Chem. 1995, 14, 703; e) S. C. PELLEGRINET, M. T. A. B. BAUMGARTNER, R. A. SPANEVELLO, PIERINI,Tetrahedron 2000, 56, 5311; f ) C. TAILLEFUMIER, Y. CHAPLEUR, Can.]. Chem. 2000, 78, 708; For a general review on the preparation of carbocycles by Diels7

12

I

Direct Conversion of Sugar Clycosides into Carbocycles Alder chemistry see: g) K. GOTHELF,K. A. )0RGENSEN, Chem. Rev. 1998, 98,863. 15 a) H. PAULSEN, W. VON DEYN,Liebigs Ann. Chem. 1987, 125; b) H. J. M. GITSEN,C. H . WONG,Tetrahedron Lett. 1995, 36, 7057. 16 a) T. V. RAJANBABU, Acc. Chem. Res. 1991, 24, 139. b) A. MARTINEZ-GRAU, 1. MARCOChem. SOC. Rev. 1998, 27, 155; CONTELLES, c) I. MARCO-CONTELLES, C. ALHAMBRA,A. Synlett 1998, 693; d) M. MARTINEZ-GRAU, ADINOLFI, G . BARONE,A. IADONISI,L. MANGONI,Tetrahedon Lett. 1998, 39, 2021; e) J. MARCO-CONTELLES, P. GALLEGO, M. RODRIGUEZ-FERNANDEZ, N. KHIAR,C. DESTABEL, M. BERNABE, A. MARTINEZGRAU,J. L. CHIARA,J . Org. Chem. 1997, 62, 7397; f ) A. M. H O R N E M A N I. ,LUNDT, Synthesis 1999, 317; g) A. M. HORNEMAN, 1. LUNDT,J . Org. Chem. 1998, 63, 1919; h) A. M. HORNEMAN, I. LUNDT,Tetrahedron 1997, 53,6879; i) A. M. HORNEMAN, I. LUNDT,I. SOTOFTE,Synlett 1995, 918; j) A. M. GOMEZ,G. 0. DANELON, E. J. C. LOPEZ,Chem. MORENO,S. VALVERDE, Commun. 1999, 175; k) E. MAUDRU, G. SINGH,R. H. WIGHTMAN,Chem. Commun. 1998,1505; 1) A. M. GOMEZ,G. 0. DANELON, S. VALVERDE, J. C. LOPEZ,J . Org. Chem. 1998, 63, 9626; m) J. C. LOPEZ,A. M. GOMEZ, B. FRASER-REID,Aust.]. Chem. 1995, 48, 333; n) A. M. GOMEZ,S. MANTECON, S. VALVERDE, J. C. LOPEZ,J.Org. Chem. 1997, 62, 6612; 0) K. Y. HSIA, P. WARD,R. B. LAMONT,P. M. D. LILLEY,D. J. WATKIN, G . W. J. FLEET,Tetrahedron Lett. 1994, 35, 4823. 17 a) F. E. ZIEGLER, Y. WANG,J . Org. Chem. 1998, 63, 426; b) D. J. HOLT,W. D.

BARKER, P. R. JENKINS, D. L. DAVIES,S. G A R R A J.~ ,F A W C E D. ~ , R. RUSSELL, S. GHOSH,Angew. Chem. Int. Ed. 1998, 37, P. VAN D E WEGHE!D. 3298; c) 0. SELLIER, LE NOUEN,C. STREHLER, J. EUSTACHE, Tetrahedron Lett. 1999, 40, 853; d) R. N. CONRAD,M. J. GROGAN,C. R. BERTOZZI, Org. Lett. 2002, 4, 1359; e) L. HYLDTOFT,R. MADSEN, J . Am. Chem. SOC.2000, 122, 8444; f ) I. HANNA,L. RICARD,Org. Lett. 2000, 2, 2651; g) P. KAPFERER, F. SARABIA, A. VASELLA, Helu. Chim. Acta 1999, 82, 645; h ) F. D. BOYER,I. HANNA,S. P. NOLAN, J . Org. Chem. 2001, 66, 4094; i) A. KORNIENKO, M. D’ALARCAO, Tetrahedron: AsymmeQ 1999, 10,827.

18 For aldol-type cyclization see: a) D. HAAG,

X. T. C H E N ,B. FRASER-REID, Chem. Commun. 1998, 2577; b) A. J. WOOD,D. J . HOLT,M. C. DOMINGUEZ, P. R. J E N K I N S , J . Org. Chem. 1998, 63, 8522; c) A. J. WOOD,P. R. JENKINS, J. F A W C E D. ~ , R. I. Chem. Soc. Chem. Commun. RUSSELL, 1995, 1567; d) A. H U I , A. J. FAIRBANKS, R. J. NASH,P. M. D E Q. LILLEY,R. STORER,D. J. WATKIN,G. W. J . FLEET, Tetrahedron Lett. 1994, 35, 8895; e) F. CHRETIEN,F. KHALDI,Y. CHAPLEUR, Tetrahedron Lett. 1997, 38, 5977; f ) V. C E R E ,F. PERI,S. POLLICINO,Tetrahedron Lett. 1997, 38, 7797. For related anionic cyclization see: g) A. J. FAIRBANKS, A. HUI,B. M. SKEAD,P. M. DE Q. LILLEY,R. B. LAMONT, R. STORER,J. SAUNDERS, D. J. WATKIN, G. W. J. FLEET,Tetrahedron Lett. 1994, 35, 8891. For Cr/Ni mediated carbocyclization see: h) A. LUBINEAU,I. BILIAUT,J . Org. Chem. 1998, 63, 5668. 19 a) J.M. GROSHEINZ, H. 0. L. F I S C H E R , ~ . Am. Chem. Soc. 1948, 70, 1479; b) for a n intermolecular tandem, ring opening cyclization variant of this reaction see: I . KITAGAWA, A. KADOTA,M. YOSHIKAWA, Chem. Pharm. Bull. 1978, 26, 3825. 20 S. 1. ANGYAL,S. D. GERO,Aust. J . Chem. 1965, 18, 1973. 21 S. MIZRA,L.-P. MOLLEYERES, A. VASELLA, Helu. Chim. Acta 1985, 68, 988. 22 a ) A. KLEMER, M. KOHLA,Liebigs Ann. Chem. 1986,967; b) A. KLEMER, M. KOHLA,Liebigs Ann. Chem. 1987, 683. 23 a) T. K. M. SHING,Y. CUI, Y. TANG,J . Chem. Soc. Chem. Commun. 1991, 754;

b) T. K. M. SHING,Y. TANG,Tetrahedron 1991, 47, 4571.

M. BALCI,Pure Appl. Chem. 1997, G9, 97. B. M. TROST, L. S. CHUPAK,T. LUBBERS, J. Am. Chem. SOC. 1998, 120, 1732. 26 a) Y. LANDAIS, Chimia 1998, 52, 104; b) R. ANGELAUD, Y. LANDAIS,Tetrahedron Lett.

24 25

1997, 51, 8841. 27 For a reviev, see: T. HUDLICKY, D. A.

ENTWISTLE, K. K. PITZER,A. J. THORPE, Chem. Rev. 1996, 96, 1195. 28 a) M. BANWELL, C. DE SAW, K. WATSON, Chem. Commun. 1998, 1189; b) F. YAN, B. V. NGUYEN,C. YORK,T. HUDLICKY, Tetrahedron, 1997, 53, 11541; c) T. HUDLICKY, A. J. THORPE,Chem. Commun. 1996, 1993; d) T . HUDLICKY, K. A.

References and Notes ABBOUD,D. A. ENTWISTLE, R. FAN, R. B. MAURYA,A. J. THORPE,J. BOLONICK, MYERS.Synthesis 1996, 897. 29 A. MARAS,H.SEFEN,Y. SUTBEYAZ, M. BALCI,J . Org. Chem. 1998, 63, 2039. 30 P.A. BARTLETT,K. SATAKE, J . Am. Chem. SOC.1988, 110, 1628. 31 For a highlight on carbohydrate ring contraction reactions see: H . REDLICH, Angew. Chem. Int. Ed. Engl. 1994, 33, 1345. 32 R. J. FERRIER,]. Chem. SOC.Perkin Trans. 1 1979, 1455. 33 a) D.H. R. BARTON,J. CAMARA,P.DALKO, S. D. GERO,B. QUICLET-SIRE, P. STUTZ,J . Org. Chem. 1989, 54, 3764; b) D. J. CLEOPHAX, M. V. DE DUBREUIL, ALMEIDA,C. VERRE-SEBRIE, J. LIAIGRE,G. VASS,S. D. GERO,Tetrahedron 1997, 53, 16747; c) H. TAKAHASHI,H. KITAKA, S. IKEGAMI, J . Org. Chem. 2001, 66, 2705. 34 a) D. H. R. BARTON,S. AUGY-DOREY, J. CAMARA, P. DALKO,J. M. DELAUMENY, S. D. GERO,B. QUICLET-SIRE, P. STUTZ, Tetrahedron 1990, 46, 215; b) S. AUGYDOREY,P. DALKO,S. D. GERO,B. QUICLETSIRE,J. EUSTACHE,P. STUTZ, Tetrahedron 1993, 49, 7997. 35 a) D. J. JENKINS, D. DUBREUIL, B. V. L. POTTER,J . Chern. SOC., Perkin Trans. 1 1996, 1365; b) S. K. CHUNG,S. H . Yu, Y. T. CHANG,J. Carbohydrate Chem. 1998, 17, 385; c) S. K. C H U N G ,S. H. Yu, Bioorg. Med. Chem. Lett. 1996, 6, 1461. 36 a) S. AMANO,N. OGAWA,M. OHTSUKA,S. OGAWA,N. CHIDA,Chem. Commun. 1998. 1263; b) T. MOMOSE,M. SETOGUCHI, T. FUJITA,H. TAMURA,N. CHIDA,Chem. Commun. 2000, 2237; c) S. AMANO,N. TAKEMURA, M. OHTSUKA,S. OGAWA,N. CHIDA,Tetrahedron 1999, 55, 3855; d) S. AMANO,N. OGAWA,M. OHTSUKA,N. CHIDA,Tetrahedron 1999, 55, 2205; e) S. AMANO,N. OGAWA,M. OHTSUKA,S. OGAWA,N. CHIDA,Chem. Commun. 1998, 1263; f ) N. CHIDA,M. JITSUOKA, Y. YAMAMOTO, M. OHTSUKA,S. OGAWA, Heterocycles 1996, 43, 1385; g) N. CHIDA, S. OGAWA,J. Chem. SOC. K. SUGIHARA, Chem. Commun. 1994, 901. 37 C. TAILLEFUMIER, Y. CHAPLEUR, D. BAYEUL,A. AUBRY,J. Chem. SOC.Chem. Commun. 1995,937. 38 a) H. TAKAHASHI, H. KITTAKA,S. IKEGAMI, J. Synth. Org. Chem. Jpn. 2000, 58, 120;

b) H . TAKAHASHI, T. IIMORI,S. IKEGAMI, Tetrahedron Lett. 1998, 39, 6939; c) H. OHTAKE,X. L. LI, M. SHIRO,S. IKEGAMI, Tetrahedron 2000, 56, 7109; d) H . OHTAKE, S. IKEGAMI,Org. Lett. 2000, 2, 457; e) H . TAKAHASHI, H. KITTAKA,S. IKEGAMI, Tetrahedron Lett. 1998, 39, 9703; f ) T. IIMORI,H. TAKAHASHI,S. IKEGAMI, Tetrahedron Lett. 1996, 37, 649. 39 a) S. ADAM,Tetrahedron Lett. 1988, 29, 6589; b) P. LASZLO,A. DUDON,J. Carbohydr. Chem. 1992, 11, 587. 40 a) S. L. BENDER, R. J. BUDHU,J. Am. Chem. SOC.1991, 113, 9883; b) V. A. ESTEVEZ,G. D. PRESTWICH,].Am. Chem. SOC.1991, 113, 9885; c) J. CHEN,L. FENG, Org. Chem. 1998, 63, G. D. PRESTWICH,~. 6511; d) J. CHEN,G . D. PRESTWICH, J . Org. Chem. 1998, 63,430; e) Q. M. Gu, G. D. J. Org. Chem. 1996, 61, 8642; PRESTWICH, f ) A. CHAUDHARY, G. D. PRESTWICH, Bioconjugate Chem. 1997, 8, 680; g) 0. THUM,J. CHEN,G. D. PRESTWICH, Tetrahedron Lett. 1996, 37, 9017; h) J. R. PENG,G. D. PRESTWICH,Tetrahedron Lett. 1998, 39, 3965; i) J. C H E N ,A. A. PROFIT, G. D. PRESTWICH, J . Org. Chem. 1996, 61, 6305; j) J. CHEN,G. DORMAN,G. D. J . Org. Chem. 1996, 61, 393; PRESTWICH, k) G. DORMAN,J. C H E N ,G. D. PRESTWICH, Tetrahedron Lett. 1995, 36, 8719. 41 P. BEIANGER,P. PRASIT,Tetrahedron Lett. 1988, 29, 5521. 42 S. K. DAS, J.-M. MALLET,P.SINAY,Angew. Chem. Int. Ed. Engl. 1997, 36, 493. 43 see also: P. A. V. VAN HOOFT,R. E. J. N. LITJENS,G. A. VAN D E R MAREL,C. A. A. VAN BOECKEL, J. H. VAN BOOM,Org. Lett. 2001, 3, 731. 44 a) M. SOLLOGOUB, A. J. PEARCE, A. HERAULT,P. SINAY, Tetrahedron:Asymmetry 2000, 11, 283; b) M. SOLLOGOUB, J. M. MALLET, P. SINAY.Angew. Chem. Int. Ed. 2000, 39, 362. 45 a) B. D u ROIZEL,A. M. P. HENRIQUES, A. J. PEARCE,P. SINAY,IsraelJ. Chem. 2000, 40, 317; b) A. J. PEARCE,J. M. MALLET,P. SINAY,Heterocycles 2000, 52, 819; c) A. J. PEARCE,R. CHEVALIER, J.-M. MALLET,P. SINAY,Eur. J. Org. Chem. 2000, 2203; d) J. PEARCE,M. SOLLOGOUB, J.-M. MALLET,P. SINAY,Eur.J. Org. Chem. 1999, 3105. 46 For related Lewis acid mediated rearrangements of cyclic vinyl acetals affording

14

I

Direct Conversion of Sugar Clycosides into Carbocycles

47 48

49 50

51

52

53

tetrahydrofuranes o r tetrahydropyranes see: a) N. A. PETASIS,S:P. Lu, /. Am. Chem. SOC. 1995, 117, 6394; b) N. A. PETASIS,S.-P. Lu, Tetrahedron Lett. 1996, 36, 141; c) H.-D. SCHARF,H. FRAUENRATH,Chem. Ber. 1982, 115, 2728; d) R. MENICAGLI, C. MALANGA, M. G U I D I ,L. LARDICCI,Tetrahedron, 1987, 43, 171; e) D. J. DIXON,S. V. LEY,E. W. TATE,/. Chem. SOC., Perkin Trans. I 2000, 2385; f ) R. MENICAGLI, C. MALANGA, L. LARDICCI,J. Org. Chem. 1982, 47. 2288; g) R. MENICAGLI, C. MALANGA, M. DELL’INNOCENTI, L. ~ R D I C C/.I Org. , Chem. 1987, 52, 5700; h) A. B. SMITH, I l l , K. P. MINBIOLE, P. R. VERHOEST,M. /. Am. Chem. SOC.2001, 123, SCHELHAAS, 10942; i) A. B. SMITH,P. R. VERHOEST, K. P. MINBIOLE, J. J. LIM, Org. Lett. 1999, I, 909; j) A. B. SMITH,K. P. MINBIOLE, P. R. VERHOEST, T. J. BEAUCHAMP, Org. Lett. 1999, I, 913 a n d references cited. M. SOLLOGOUB, J.-M. MALLET,P. SINAY, Tetrahedron Lett. 1998, 39, 3471. H. ITO,Y. MOTOKI,T. TAGUCHI,Y. HANZAWA, /. Am. Chem. SOC. 1993, 115, 8835. Y. YOSHIDA, T. NAKAGAWA, F. SATO,Synlett 1996.437. a) J. M. AURRECOECHEA, B. LOPEZ,M. ARRATE,/. Org. Chem. 2000, 65, 6493; b) J. M. AURRECOECHEA, M. ARRATE,B. LOPEZ,Synlett 2001, 872. A. CHENEDB,P. POTHIER,M. SOLLOGOUB, A. J. FAIRBANKS, P. SINAY,J. Chem. SOC. Chem. Commun. 1995, 1373. a) T. KAN,S. NARA,T. OZAWA,H. F. MATSUDA,Angew. Chem. SHIRAHAMA, Int. Ed. 2000, 39, 355; b) F. MATSUDA, /. Synth. Org. Chem. Jpn. 1995, 53, 987; c) J. J. C. GROVE,C. W. HOLZAPFEL, D. B. G. WILLIAMS,Tetrahedron Lett. 1996, 37, 5817; d) 2. H . ZHOU,S. M. BENNETT, Tetrahedron Lett. 1997, 38, 1153; e) J. L. CHIARA,J. MARCO-CONTELLES, N. KHIAR, P. GALLEGO, C. DESTABEL, M. BERNABE,/. Org. Chem. 1995, 60, 6010. a) J. K. GALLOS, T . V. K O F T I S , ~Chem. . SOC. Perkin Trans. 12001, 415; b) J. K. GALLOS,

T. V. KOFTIS,A. E. KOUMBIS,V. I. MOUTSOS,Synlett 1999, 1289; c) J. K. E. E. SPATA,Eur. GALLOS,C. C. DELLIOS, /. Org. Chem. 2001, 1, 79; d) J. K. GALLOS, V. P. XIRAPHAKI,C. C. A. E. KOUMBIS, DELLIOS,E. COUTOULI-ARGYROPOULOU, Tetrahedron 1999, 55, 15167; e) J. K. GALLOS,A. E. KOUMBIS, N. E. APOSTO-

54

55 56

57

58 59 60

61

LAKIS, J. Chem. SOC., Perkin Trans. I 1997, 2457. a ) L. A. PAQUETTE, C. M. G. PHILIPPO, N. H. Vo; Can.J. Chem. 1992. 70, 1356; b) C. M. G. PHILIPPO,N. H. Vo, L. A. J . Am. Chem. 1991, 113, 2762; PAQUETTE, c) L. A. PAQUETTE,D. FRIERICH,R. D. ROGERS, J. Org. Chem. 1991, 56, 3841: M. A. M. FUHRY,A. B. HOLMES,D. R. MARSHALL, /. Chem. SOL., Perkin Trans. I 1993, 2743 a n d references. B. WERSCHKUN, J. THIEM,Angew. Chem. Int. Ed. Engl. 1997, 36, 2793. a ) W. WANG,Y. ZHANG,M. SOLLOGOUB, P. SINAY,Angew. Chem. Int. Ed. 2000, 39, 2466; b) W. WANG,Y. ZHANG,H . Z H O U , Y. BLERIOT,P. SINAY,Eur. J. Org. Chem. 2001, 1053. P. A. V. VAN HOOFT,G. A. VAN D E R MAREL,C. A. A. VAN BOECKEL, J. H. VAN BOOM,Tetrahedron Lett. 2001, 42. 1769. A. V. R. L. SUDHA,M. NAGARAJAN,/. Chem. SOC. Chem. Commun. 1998, 925. G . BUCHI, J. E. POWELL JR.,/. Am. Chem. SOC.1967, 89, 4559. For selected examples see: a) T. K. M. SHING,D. A. ELSLEY, J. G. GILLHOULEY, J. Chem. SOC. Chem. Commun. 1989, 1280; b) S. JIANG,K. J. MCCULLOUGH, B. MEKKI, G. SINGH,R. H . WIGHTMAN,]. Chem. SOC., Perkin Trans. 11997, 1805; c) S. D. JIANG,B. MEKKI,G. SINGH,R. H. WIGHTMAN,Tetrahedron Lett. 1994, 35, 5505; d) R. A. FARR,N. P. PEET,M. S. KANG,Tetrahedron Lett. 1990, 31, 7109; N. P. PEET,E. W. HUBER,R. A. FARR, Tetrahedron 1991, 47, 7537; e) K. VANHESSCHE, C. G. BELLO,M. VANDEWALLE, Synlett 1991, 921. S. JIANG,G. SINGH,A. S. BATSANOV, Tetrahedron:Asymmetty 2000, 1 I, 3873.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Synthesis o f Diary1 Ethers: A Long-standing Problem Has Been Solved Fritz Theil

Until quite recently the synthesis of diaryl ethers has not been an easy task unless the target molecule was not sensitive towards the very harsh reaction conditions employed. The diaryl ether structural unit (Figure 1) is found in natural products such as perrottetines (1) [l],their cyclic analogues [lb], riccardin B (2) 121, and a variety of more complex molecules containing sensitive functional groups and stereogenic centres [ 31 to which for example the cyclic peptides K 13 (3) [ 3 ] and vancomycin [4,51 belong. The diaryl ether formation in cyclic peptides was reviewed by Rama Rao et al. [6] in 1995. Furthermore, poly (aryl ethers) such as 4 are important commercial polymers used as engineering thermoplastics [ 71. Both the synthesis of highly functionalized molecules and the large-scale preparation of polymers are challenging tasks for synthetic organic chemists. However, the classical arylation procedure of phenols with aryl halides under Ullmann conditions [S] using copper powder or copper salts requires harsh reaction conditions as a result of the poor nucleophilicity of the phenoxide and the low reactivity of the aryl halides involved. The reactions have to be carried out in a temperature range of 120-250 "C by using high boiling solvents or neat reagents over an extended period of time. These conditions have been applied to the synthesis of relatively simple diaryl ethers such as riccardin B (2), which lacks sensitive functional groups, by using a copper phenoxide and an aryl bromide in refluxing pyridine for twenty hours. For the preparation of poly (aryl ethers), the most reactive electrophiles towards sodium phenoxides are aryl fluorides and triflates. In a model reaction complete conversion has been achieved at 150 "C in N-methyl-2-pyrrolidinone (NMP) within four hours if both the haloarene and the phenol are activated by a paracarbonyl group (Scheme 1)191. The structural relevance of diaryl ethers and the lack of a convenient, mild and general method for their preparation has resulted in increased efforts towards filling this gap in the synthetic methodology during the past decade. Yamamura et al. [lo] developed a method that encompasses the oxidative coupling of 2,6-dihalophenols with T1(N03)3to afford a 2-substituted quinone, which subsequently is reduced to the corresponding diaryl ether. This procedure has been applied by the Evans group [ 111 for the synthesis of the orienticin C aglycone. Despite the fact that this reaction is conducted under mild conditions, it is nevertheless a two step procedure that requires a

16

I

Synthesis of Diaryl Ethers: A Long-standingProblem Has Been Solved

R'

HO

OH

HO

2

1

HO

Y = S(=O),,

3

c=o 4

Fig. 1. Examples for the diaryl ether function in natural products and synthetic polymers. R', RZ in 1 = H,OH,OMe.

ONa

I

NMP, 150 "C

X = F, OSO,CF, Scheme 1.

Diaryl ether formation from para-carbonyl activated phenolates and arylfluorides or triflates

specific type of substituted phenol and a highly toxic thallium salt. These requirements preclude it from being a general user-friendly method. The recent development directed towards the synthesis of diaryl ethers in a milder and more efficient manner was mainly driven by the synthesis of complex natural products. Eicher and Walter [ 11 introduced an activating ortho-nitro group in their synthesis of diaryl ethers (Scheme 2a), thus increasing the reactivity of aryl halides towards phenoxides s i g nificantly so that a reaction temperature of 125 "C for less than one hour was required. By using this coupling procedure perrottetines (1) [la], and very recently their cyclic analogues

Synthesis ofDiaty/ Ethers: A Long-Standing Problem Has Been Sobed 117

X = CI. F

0 rlJ

0 N I

KN

kN CuBr-SMe,, K,CO,

xR'J (

+

HoQ R2

MeCNIpyridine, 80 "C*

R'

bOQ R'

X = Br, I Diary1 ether formation by orthoactivation. a) Methods of Eicher et al. and Zhu et al., (R' = 4-CHO, 4-C02Me, 4CH2CH(NHBoc)C02Me; R2 = 2-OMe-4-CH0, 2.3(OMe)2-4-C02Me, 4-CH2CH(NH B0c)COzMe), Scheme 2.

b) Method of Nicolaou et al. (R' = 3-Me, 5-Me, 3,5-Me2; R2 = 2-CI, 4 4 , 2-CI-4-Me).1) NaH, DMF, 125 "C (X = CI); 2) NaZCO3 or CsF, DMF, 25 "C (X = F).

[Ib] under even milder conditions, have been synthesized. As reported by Zhu [3], phenoxides react smoothly at room temperature when ortho-nitro fluoro arenes are used as electrophiles. This approach has been applied to the synthesis of a variety of macrocyclic diaryl ethers [ 31 including vancomycin [4a, b] and its subunits [ 12a] or related compounds [ 12b]. However, this method requires subsequent reduction and deamination steps in order to remove the nitro group unless the target molecule bears this functional group. The approach from Nicolaou [ 131 is similarly based on the activation of an aryl halide. Aryl bromides and iodides substituted with ortho-triazene react smoothly with phenols at 80 "C in the presence of KZC03 and CuBr.MezS to afford diaryl ethers in good yields (Scheme 2b). The use of this procedure requires the preformation of the requisite triazenes and the subsequent removal or transformation of this functional group. Alternatively, chloroarenes can be activated via the formation of manganese, chromium, iron or ruthenium n-complexes that react at low temperature with phenoxides to yield diaryl ethers [14]. Higher temperatures (DMF, 90 "C) require the formation of diaryl ethers from iodonium salts and phenoxides [ 151 and the coupling of bromo benzoquinones with phenoxides (DMF, 100-110 "C) followed by a subsequent reduction with dithionite [lG]. Palladium catalyzed couplings between sodium phenoxides and electron deficient aryl bromides have been reported by Hartwig et al. [I71 based on an in-situ-ligand exchange of dibenzylideneacetone (dba) with 1,l'-diphenylphosphinoferrocene(dppf) [ 17a] (Scheme 3a). Further improvements of this methodology have been achieved for unactivated aryl halides by the Hartwig group by using ferrocenyldi-tert-butylphosphine instead of dppf [17b] or the as the palladium ligand [ 17~1. Buchwald group by using 2-(di-tert-butylphosphino)biphenyl The reactions still need relatively high temperatures and long reaction times.

18

I

Synthesis ofDiary1 Ethers: A Long-Standing Problem Has Been Solved

a)

(CuOTf),PhH, EtOAc R2

R'

Cs,CO,,

toluene, 110 "C

X = Br, I Palladium- a n d copper triflate-catalyzed diarylether synthe. sis. a) R' = CN, CHO, COCFj, COPh; R2 = Me, O M e ; b) R' = 4-CI, 4-C02Et. 4-Me, 4431.1, 4-OMe, 4-NMe2, 4-CN, 4-COMe, 2,5-Me2, 3,sMe2; R2 = 2-Me. 4-Me, Z-iPr, 4-CI, 3,4-Me?. Scheme 3.

Another phenoxide activating approach published by Buchwald et al. [ 181 is based on the reaction of cesium phenoxides with aryl bromides or iodides in the presence of catalytic amounts of copper(1) triflate and ethyl acetate in refluxing toluene (Scheme 3b). In certain cases equimolar amounts of 1-naphthoic acid have been added in order to increase the reactivity of the phenoxide. The authors assume the formation of a cuprate-like intermediate of the structure [(Ar0)2Cu]-Csf as the reactive species. In addition, diaryl ether formation between phenols and aryl halides has been achieved using a phosphazene base forming naked phenoxide in the presence of copper bromide in refluxing toluene or 1,4-dioxane [19]. Besides, an enzymatic approach has been developed by Sih and his group by using an oxidative coupling of tyrosine or hydroxyphenylglycine units by hydrogen peroxide in the presence of peroxidases followed by a subsequent reduction step (Scheme 4). Yields in general are moderate and sometimes low. Dependent on the pH of the medium, diaryl ether formation is accompanied by more or less C-C-coupling reactions.

x+x

H,O,.

&:ex pH 4-6

R

CrCI, or NaHSO,

OH

R

R Enzymatic diaryl ether formation. X = F, CI, Br; X' = CI, Br, H; R = C H * C H ( N H A c ) C 0 2 H , (CH?)?NHAc, CH(NHAc)CO2Me.

Scheme 4.

Synthesis o f D i a v / Ethers: A Long-standing Problem Has Been Solved

Finally, the remarkably simple solution came from Evans et al. [2la] and researchers of DuPont [2lb] simultaneously. Their method allows the coupling of structurally and electronically diverse phenols and aryl boronic acids in the presence of copper(11) acetate, triethylamine or pyridine, and molecular sieves at ambient temperature (Scheme 5). Even phenolic amino acid derivatives react smoothly without racemization. The only limitation has been observed when using ortho-heteroatom substituted boronic acids which resulted in lower product yields. The initial step in the proposed pathway (Scheme G) is the transmetallation of the boronic acid residue with the copper salt.

RIW

$2

Copper(l1)-promoted coupling of boronic acids with phenols. R' = 4-Me, 2-CI, 2-1, 2-OMe, ~ - C H ~ C H ( N H B O C ) C O3,s. ~M~, tBu2; R2 = 4-Me, 4-F, 4-OMe, 3-OMe, 3-NO2, 2-Me, 2-OMe, 3-CI-4-F.

Scheme 5.

L

reductive

At-0-

/ Ar'

'OAr'

L Ar/\c$k \OAr' d elimination v e Scheme 6.

Proposed mechanism for the copper(l1)-promoted coupling o f boronic acids with phenols.

The solution of this long-standing problem has been achieved by application of this general method that allows for the coupling of diverse phenols with a variety of aryl boronic acids, many of which are commercially available. It overcomes problems associated with procedures used before and offers significant advantages such as a broad substrate variety, mildness and avoids the use of highly toxic materials. In addition, under the reaction conditions employed N-arylation of different types of Nnucleophiles has been achieved [ 21b]. By using this mild and versatile methodology, symmetrical diaryl ethers have been synthesized in a one-pot, two-step procedure starting from arylboronic acids and their partial conversion to the corresponding phenols by oxidation with hydrogen peroxide and a subsequent coupling of the formed phenols with the remaining arylboronic acids upon addition of copper(I1) acetate, molecular sieves and triethyl amine (Scheme 7) [22]. A much more detailed discussion of the most recent developments in inter- and intramolecular diaryl ether formation can be found in the literature [23].

20

I

Synthesis of Diary/ Ethers; A Long-Standing Problem Has Been Solved 1. HO ,,

CH,CI,

(30%)

-

2.Cu(OAc),, NEt, MS (4A). 25 "C

R

One-pot conversion of arylboronic acids into diary1 ethers. R = 3-NO2, 4-Me, 4-OMe, 4-Ac, 4-F, 4 4 , 4-Br.

Scheme 7.

References 1 a) T. EICHER,M. WALTER,Synthesis 1991,

W. LABADIE, J. L. HEDRICK,M. UEDA, Am. Chem. SOC.Symp. Ser. 1996, 624, 210-

7 J.

469-473; b) T. EICHER,S . FEY,W. PUHL,

2 3

4

5

6

E. BUCHEL,A. SPEICHER, Eur. ]. Org. Chem. 1998, 877-888. M. IYODA,M. SAKAITANI, H. OTSUKA,M. ODA,Tetrahedron Lett. 1985, 26, 4777-4780. a) J. ZHU, Synlett 1997, 133-144, b) A. BIGOT,M. BOIS-CHOUSSY, J. ZHU, Tetrahedron Lett. 2000, 41, 4573-4577. Vancomycin syntheses: a) D. A. EVANS, M. R. WOOD,B. W. T R O ~ E T. R , I. RICHARDSON, J. C. BARROW,J. L. KATZ, Angew. Chem. 1998, 110, 2864-2868; Angew. Chem. Int. Ed. 1998, 37, 27002704; b) D. A. EVANS,C. J. DINSMORE, P. S. WATSON,M. R. WOOD,T. I. RICHARDSON, B. W. TROTTER,J. L. KATZ, Angew. Chem. 1998, 110, 2868-2872, Angew. Chem. Int. Ed. 1998, 37, 2704S. NATARAJAN, 2708; c) K. C. NICOLAOU, H. LI, N. F. JAIN,R. HUGHES,M. E. SOLOMON, J. M. RAMANJULU, C. N. C. BODDY,M. TAKAYANAGI, Angew. Chem. 1998, 110, 2872-2878 Angew. Chem. Int. Ed. 1998, 37, 2708-2714; d) K. C. NICOIAOU,N. F. JAIN,S. NATARAJAN, R. HUGHES,M. E. SOLOMON, H. LI, J. M. RAMANJULU, M. TAKAYANAGI, A. E. KOUMBIS,T. BANDO,Angew. Chem. 1998, 110, 2879-2881, Angew. Chem. Int. Ed. 1998, 37, 2714-2716; e) K. C. NICOLAOU, M. TAKAYANAGI, N. F. JAIN,S. NATARAJAN, A. E. KOUMBIS, T. BANDO,J. M. RAMANJULU, Angew. Chem. 1998, 110, 2881-2883, Angew. Chem. Int. Ed. 1998, 37, 2717-2719. Highlight on the vacomycin syntheses: A. J. ZHANG,K. BURGESS, Angew. Chem. 1999, 11 1, 666-669, Angew. Chem. Int. Ed. 1999, 38, 634-636. A. V. RAMA RAo, M. K. GURJAR,K. L. REDDY,A. S. RAO, Chem. Rev. 1995, 95, 2135-2167.

225. 8 J. LINDLEY, Tetrahedron 1984, 40, 1433-

1456. 9 H. JONSSON, J. L. HEDRICK,J. W. LABADIE,

Polymer Prepnnts 1992, 33, 394-395. H. NODA,M. NIWA,S. YAMAMURA, Tetrahedron Lett. 1981, 22, 3247-3248. For further applications of this methodology by Yamamura's group and others see [ 61. 11 D. E. EVANS,C. J. DINSMORE, A. M. RATZ, D. A. EVRARD,J. C. BARROW,].Am. Chem. SOC.1997, 119,4317-3418. 12 a) D. L. BOGER,R. M. BORZILLERI, S. NUKUI,R. T. BERESIS, /. Org. Chem. 1997, 62, 4721-4736, b) L. NEUVILLE, M. BoisCHOUSSY,J. ZHU, Tetrahedron Lett. 2000, 10

41, 1747-1751. 13

14

15 16

17

K. C. NICOLAOU, C. N. C. BODDY,S. NATARAJAN, T.-Y. YUE, H. LI, S. B R ~ S E , J. M. RAMANJULU, J . Am. Chem. SOC. 1997, 119, 3421-3422. a ) A . J. PEARSON, J. G. PARK,P. Y. ZHU,]. Org. Chem. 1992, 57, 3583-3589; b) A. J. PEARSON, K. LEE,]. Org. Chem. 1994, 59, 2304-2313; c) A. J. PEARSON,P. 0. BELMONT,Tetrahedron Lett. 2000, 41, 1671-1675; d) M. F. SEMMELHACK in Comprehensive Organometallic Chemistry II? Vol. 12 (Ed.: E. W. ABEL,F. G. A. STONE, G. WILKINSON), Pergamon, NY, 1995, p. 979. M. J. CRIMMIN,A. G. BROWN,Tetrahedron Lett. 1990, 31, 2017-2020. B. SIMONEAU, P. BRASSARD,].Chem. SOC. Perkin Trans. 1, 1984, 1507-1510. For further applications of this method see (61. a) G. MANN,J. F. HARTWIG,Tetrahedron Lett. 1997, 38, 8005-8008; b) G . MANN, C. INCARVITO, A. L. RHEINGOLD, J. F. HARTWIG,]. Am. Chem. SOC. 1999, 121, 3224-3225; c) A. ARANYOS, D. W. OLD,

References 121

A. KIYOMORI,1. P. WOLFE,I. P. SADIGHI; S. L. BUCHWALD,]. Am. Chem. SOC.1999, 121, 4369-4378. 18 J.-F. MARCOUX, S. DOYE,S. L. BUCHWALD, I.Am. Chem. SOC. 1997, 119,10539-10540. 19 C. PALOMO, M. OIARBIDE, R. LOPEZ, E. GOMEZ-BENGOA, Chem. Commun. 1998, 2091-2092. 20 a) 2. Guo, G. M. SAIAMONCZYK, K. HAN, K. MACHIYA, C. J. SIH,]. Org. Chem. 1997, 62, 6700-6701; b) 2. G u o , G. M. SAJAMONCZYK, K. HAN,K. MACHIYA, C. J . SIH,J. Org. Chem. 1998,63, 4269-4276;

21

c) I. MALNAR, C. J. SIH, Tetrahedron Lett. 2000, 41, 1907-1911 and references cited therein. a) D. E. EVANS,I. L. KATZ,T. R. WEST, Tetrahedron Lett. 1998,39, 2937-2940; b) D. M. T. CHAN,K. L. MONACO,R.-P.

WANG,M. P. WINTERS,Tetrahedron Lett. 1998,39, 2933-2936. 22 J. SIMON,S. SALZBRUNN, G. K. S. PRAKASH, N. A. PETASIS,G. A. OIAH,]. Org. Chem. 2001, 66, 633-634. 23 J. S. SAWYER, Tetrahedron, 2000, 56, 50455065.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

** I

Take The Right Catalyst: Palladium-catalyzed CC, CN and CO-Bond Formation on Chloro-Arenes Rainer Sturmer

Chlorinated arenes are cheap to manufacture and therefore play a vital role as intermediates in chemical industry. However, in contrast to their - much more expensive - brominated and iodinated counterparts chloroarenes are quite unreactive in subsequent reactions. Classical functionalizations of the C-CI- bond in non-activated arenes usually require harsh conditions and side reactions may produce environmentally hazardous oxygenated chloroarenes. This leads to considerable problems in using these compounds as intermediates in the synthesis of higher functionalized biologically active molecules, e.g. agrochemicals and pharmaceuticals. Due to recent developments in catalysis former problems might be overcome: The groups of S. L. Buchwald, G. C. Fu and J. F. Hartwig among others reported significant improvements on the CC, CN and CO-Bond formation on chloroarenes. For all of these bond formations the right choice of catalyst is crucial for success. In other words: by ligand tuning all three bond forming reactions can be realized by palladium catalysis. The following account focuses on recent work, since the subject has been already reviewed [ 11. Heck and Suzuki type couplings have been described by Fu [2] et al. The reaction of chlorobenzene and styrene in refluxing dioxane in the presence of [Pd2(dba)3]and the electron rich tri-tert.-butyl-phosphane [eq. (a)] gives rise to trans-stilbene in 83% yield. Besides the choice of the ligand - aryl phosphanes, tri-n-butyl-phosphane or tri-cyclohexyl-phosphane show no conversion - the base is also crucial for success. Cesium carbonate gives the best results, although the cheaper potassium phosphate gives comparable yields.

\

*#

1.5 rnol-% [Pd2(dba)3]

(JQ-

/

(a)

6 mol-% P(Wu),

Cs2CO3 Scheme 1.

83 %

Take The Right Catalyst: Palladium-catalyzedCC, CN and CO-Bond Formation on Chloro-Arenes

Under the same conditions the sterically more demanding 2-chlorotoluene is coupled in 70% yield. However longer reaction times are necessary. Acceptor- as well as donorsubstituents are tolerated under these conditions. Tri-tea.-butyl-phosphane is the ligand of choice in Suzuki-couplings [ 31 as well: 2-chlorotoluene reacts with 2-methyl-phenylboronic acid to 2,2'-disubstituted biphenyl in 87% yield [eq. (b)].

B(oH)2

o("'+ 0:

1.5 r n o l - O h [Pd2(dba)3]

* 3.6 rnol-% P ( ~ B u ) ~

f l

(b)

87 Yo Scheme 2.

Another contribution from Fu [4]et al. describes the Stille-coupling of chloroarenes, in which vinyl-, allyl-, phenyl-, and even alkyl groups can be transferred in the presence of cesium fluoride. An improved procedure of Suzuki-couplings was recently described by Buchwald [ 51 et al. By using 0-(di-tert.buty1-phosphin0)-biphenylas ligand, palladium acetate and potassium carbonate couplings are facilitated at room temperature [eq. (c)].

B(OH)z OMe

1 mol-% Pd(OAc)2 >

(c)

2 mol-%

95 Yo

RT Scheme 3.

Catalyst concentrations may be kept quite low in the range of 0.02-0.05 mol%. In a similar context Hartwig [GI et al. published a screening method aiming at the rapid identification of efficient ligands in Heck-type couplings based on a fluorescence assay. Arylations of ketones and malonates with aryl chlorides have been recently published [eq. (d)] by the same research group [7]. Electron rich phosphanes are used to secure good conversions.

( ~ c +l /

6

2 mol-% Pd(0Ac)p

50'C, 12 h Scheme 4.

(a

2 mob% P ( C Y ) ~

93 %

I

23

24

I

Take The Right Catalyst: Palladium-catalyzed CC,

CN and CO-Bond Formation on Chloro-Arenes

0-(Di-tert.-buty1phosphino)biphenyl has been used by Buchwald IS] et al. as the most efficient ligand in the Pd-catalyzed amination of aryl chlorides. 2-Chloro-4-methyl-toluene can be aminated with pyrrolidine in 98% yield using sodium-tert.-butoxide [eq. (e)].

98 %

RT Scheme 5.

These reactions went to completion at room temperature within 15-20 hours; donor- and acceptor-substituents are tolerated. Pd-catalyzed CO- bond forming reactions were performed by Buchwald [ 8 ] et al. with 2-dimethylamino-2’-di-(tert.-butyl)-biphenyl as ligand. 3,4-Dimethylphenol can be arylated smoothly with 2-chloro-4-methyl-toluenein the presence of sodium hydride [eq. (f)].

1 mob% Pd(OAc),

*

2 mol-% P(m2

&p

(f)

78 %

Me2N Scheme 6.

Hartwig [91 et al. developed a novel ferrocene-based dialkyl-phosphine-ligand for this arylation: 2-methoxy-4-methyl-phenolis arylated with 2-chloro-pxylene in 81% yield [eq. (g)].

a:+ *no& (9)

OMe 2 mob% [Pd2(dba)s] 4 mol-% FcP(tBu)2

81 % Scheme 7.

Recent work from Lipshutz [lo] et al. even shows at least in CC-bond formations the replacement of the rather expensive palladium with nickel. Chloroarenes are coupled with organo zink compounds under nickel(0) catalysis.

References 125

After the original publication of this highlight in 1999 more than 300 related papers have appeared in the field. A complete coverage is well beyond the scope of this book. Therefore only an update on some selected developments is given. Carbonylations [ 111 and Cyanations [ 121 of chloroarenes have been described by Beller et al. Several new catalysts have been introduced during the past two years; especially noteworthy are nucleophilic carbene-ligand based catalysts developed [ 131 by Herrmann’s group among others. A saturated variant has been established by Hartwig et al. Related work with donor-substituted carbenes has been published [ 151 by McGuiness and Cavell. Several detailed mechanistic papers have been published by Hartwig [ 161 et al. Palladacycles [ 171 have been established as important class of catalysts, an unusual phosphine-free sulfur containing catalyst was introduced by Zim [ 181 et al. A phosphinite based palladacycle [ 191 proved to be very efficient in Suzuki coupling reactions. An N,P-Ligand type was synthesized by Kocovsky [20] et al. Tridentate pincer ligands [21] have been proved useful in the Heck reaction. Recent developments regarding Heck 1221 and Suzuki [23] reactions have been reviewed by Fu and Littke. A new catalyst especially suitable for Heck couplings has been introduced by Beller [24] et al. Carbene [25] - as well as phosphine [26] ligands have been attached to polymer supports and proved to be recyclable catalysts in the Heck reaction. With special regard to CO-bond formation including intra-molecular examples two papers by Buchwald [27] have been published. Recent advances in amination chemistry was highlighted by Buchwald [28] and Hartwig [29]. Besides palladium nickel [ 301 evolved as a suitable metal for several coupling reactions. For quite a long time chloroarenes were considered as too unreative for catalysis. However the significant improvements in various coupling reactions of chloroarenes by the use of electron rich phosphanes have rendered this statement as no longer valid. The use of these cheap intermediates as coupling partners in the synthesis of higher functionalized molecules of industrial relevance is now within reach. Since some of these ligands are already commercially available it’s probably only a question of time when we will see the first industrial applications of these improved procedures.

References a) M. BELLER, T. H. RIERMEIERin Transition Metals for Organic Synthesis, Vol. 1 (Hrsg.: M. BELLER, C. BOLM): Wiley-VCH, Weinheim, 1998, S. 184-193; M. BELLER, T. H. RIERMEIER, G. STARKibid. S. 208Angew. Chem. 1998, 236; b) J. F. HARTWIG, 110, 2154-2177, Angew. Chem. Int. Ed. 1998, 37, 2046-2067; c) B. H. YANG, S. L. BUCHWALD, 1. Organomet. Chem. 1999, 576, 125-146. z A. F. LITTKE,G. C. Fu,J. Org. Chem. 1999, 64, 10-11. 3 A. F. LITTKE,G. C. Fu, Angew. Chem. 1998,

1

110, 3586-3587, Angew. Chem. Int. Ed. 1998, 37, 3387-3388. 4 A. F. LIITKE,G. C. Fu, Angew. Chem. 1999, 111, 2568-2570; Angew. Chem. Int. Ed. 1999, 38, 2411-2413. 5 a) J. P. WOLFE, S. L. BUCHWALD,Angew. Chem. 1999, 111, 2570-2573; Angew. Chem. Int. Ed. 1999, 38, 2413-2416; b) R. A. SINGER, S. L. BUCHWALD,Tetrahedron Lett. 1999, 40, 1095-1098. 6 K. H. SHAUGNESSY, P. KIM, J. F. HARTWIG, J . Am. Chem. Soc. 1999, 121, 2123-2132.

26

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Take The Right Catalyst: Palladium-catalyzedCC, CN and CO-Bond Formation on Chloro-Arenes 7

8

9

10

11 12

13

14

15 16

17 18

M. KAWATSURA, J. F. HARTWIG,/. Am. Chem. SOC.1999, 121, 1473-1478. A. ARANYOS, D. W. OLD,A. KIYOMORI, J. P. WOLFE,J . P. SADIGHI,S. L. BUCHWALD,/.Am. Chem. SOC.1999, 121, 43694378. G. MANN,C. INCARVITO, A. L. RHEINGOLD, J. F. HARTWIG,/.Am. Chem. SOC.1999, 121, 3224-3225. a) B. H. LIPSHUTZ, P. A. BLOMGREN, /. Am. Chem. SOC.1999, 121, 5819-5820; b) B. H. LIPSHUTZ, T. TOMIOKA, P. A. J. A. SCLAFANI, Inorg. Chim. BLOMGREN, Acta 1999, 296, 164-169. M. BELLER, A. F. INDOLESE, Chimiu 2001, 55, 684-687. M. SUNDERMEIER, A. ZAPF,M. BELLER,J. SANS,Tetrahedron Lett. 2001, 42, 67076710. a) W. A. HERRMANN, V. P. W. BOHM, C. W. K. GSTOITMAYR, M. GROSCHE, C. P. REISINGER,T. WESKAMP, /. Orgunomet. Chem. 2001, 617, 616-628; b) T. WESKAMP,V. P. W. BOHM,W. A. HERRMANN, J . Organomet. Chem. 1999, 585, 348-352; c) C. ZHANG,J. HUANG, M. L. TRUDELL, S. P. NOLAN,/.Org. Chem. 1999, 64, 3804-3805. S. R. STAUFFER,S. W. LEE, J. P. STAMBULI, S. I. HAUCK,J. F. HARTWIG, Org. Lett. 2000, 2, 1423-1426. D. S. MCGUINNESS, K. J. CAVELL, Orgunometallics 2000, 19, 741-748. a) L. M. ALCAZAR-ROMAN, J. F. HARTWIG, A. L. RHEINGOLD,L. M. LIABLE-SANDS, I. A. GUZEI,/. Am. Chem. SOC.2000, 122, 4618-4630; b) A. H. ROY, J. F. HARTWIG, /. Am. Chem. SOC. 2001, 123, 12321233. V. P. W. BOHM, W. A. HERRMANN, Chem. Eur. /. 2001, 7,4191-4197. D. ZIM,A. S. GRUBER, G . EBELING, J.

19 20

21 22 23 24 25

26 27

28

29

30

DUPONT,A. L. MONTEIRO, Org. Lett. 2000, 2, 2881-2884. R. B. BEDFORD,S. L. WELCH,Chem. Commun. 2001, 129-130. P. KOCOVSKY, S. VYSKOCIL, I. CISAROVA, J. SEJBAL, 1. TISLEROVA, M. SMRCINA, G . C. LLOYD-JONES,S. C. STEPHEN, C. P. Burrs, M. MURRAY,V. LANGER,]. Am. Chem. SOC. 1999, 121, 7714-7715. D. E. BERGBREITER, P. L. OSBURN, Y.-S. LIU. J. Am. Chem. SOC.1999, 121,9531-9538. A. F. LITTKE, G. C. Fu,/. Am. Chem. SOC. 2001, 123, 6989-7000. A. F. LITTKE, G. C. Fu,]. Am. Chem. SOC. 2001, 123, 2719-2724. A. EHRENTRAUT,A. ZAPF,M. BELLER, Synlett 2000, 1589-1592. J. SCHWARZ, V. P. W. BOHM, M. G. GARDINER, M. GROSCHE, W. A. H E R R M A N W. N , HIERINGER, G. RAUDASCHL-SIEBER, Chem. Eur. /. 2000, 6, 1773-1780. C. A. PARRISH, S. L. BUCHWALD,/. Org. Chem. 2001, 66, 3820-3827. a) S. KUWABE, K. E. TORRACA, S. L. BUCHWALD, /. Am. Chem. Soc. 2001, 123, X. H . 12202-12206; b) K. E. TORRACA, H U A N GC. , A. PARRISH, S. L. BUCHWALD, /. Am. Chem. SOC.2001, 123, 10770-10771. J. P. WOLFE,H. TOMORI;J. P. SADIGHI; J. J. Y I N , S. L. BUCHWALD, 1. Org. Chem. 2000, 65, 1158-1174. J. F. HARTWIG,M. KAWATSURA, S. I. HAUCK,K. H. SHAUGHNESSY, L. M. ALCAZAR-ROMAN, /. Org. Chem. 1999, 64, 5575-5580. a) D. ZIM,V. R. LANDO, J. DUPONT,A. L. MONTEIRO, Org. Lett. 2001, 3, 3049-3051; b) V. P. W. BOHM,T. WESKAMP, C. W. K. GSTOTTMAYR, W. A. HERRMANN, Angew. Chem. 2000, 112, 1672-1674; Angew. Chem. h t . Ed. 2000, 39, 1602.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Alkyne Metathesis in Natural Product Synthesis Thomas Lindel

The application of alkene [ 11 - and, more recently, enyne [ 21 and alkyne - metathesis to the synthesis of natural products has been triggered by the development of powerful catalysts that allow metathesis reactions to be carried out under mild conditions. Scheme 1 outlines two important cases of alkene and alkyne metathesis of particular interest to the synthesis of natural products (together with the general scheme of enyne metathesis, not discussed in this review). The metathesis products can be obtained in high yields, since ethene/2-butyne are formed as volatile products. After the alkene/alkyne metathesis, the substituents (R) of the alkenes/alkynes are located on the same multiple bond. Enyne metathesis can be considered as the more general case of alkene metathesis, because two new double bonds are again formed, albeit now connected by a single bond.

p== f+ II cat.

alkene metathesis

R

+

R

enyne metathesis

alkyne metathesis

Scheme 1 .

1

+

,(I k

cat.

R

111

+

111

R

Alkene, enyne, and alkyne metathesis.

This short review focuses on the application of alkyne metathesis in the field of natural product synthesis, which is central for the evaluation and ranking of synthetic methods. Natural products are often complex, with the simultaneous presence of different functional groups and novel molecular architecture. If a method works for chemicals bought from the

28

I

Alkyne Metathesis in Natural Product Synthesis

catalog, this does not necessarily mean that it works for important cases of application. After about four years of alkyne metathesis in total synthesis, the problems tackled have already become quite demanding and relevant. Alkyne metathesis reactions have considerable potential for the synthesis of novel polymers, not covered in this article. For a leading reference, see Bunz [ 31. Scheme 2 shows two pioneering experiments. The first homogeneously catalyzed alkyne metathesis was achieved in 1974, by Mortreux and Blanchard. In a sealed flask, 4-methyland resorcin, resulting in the tolane (1)was heated in the presence of 10 mol% of MO(CO)~ formation of the metathesis products tolane (2) and 4,4'-dimethyltolane (3) [4]. After three hours the statistical equilibrium was reached. The mechanism of the molybdenum-catalyzed alkyne metathesis is still unknown. In 1981, Schrock et al. reported the capability of tungsten alkylidyne complexes to catalyze alkyne metathesis [ Sa]. With the complex 4, the equilibrium of 1, 2, and 3 was reached under milder reaction conditions and with shorter reaction times than had been obtained with the Mortreux catalyst. As early as 1975, Katz and McGinnis had proposed metallacyclobutadienes as intermediates of alkyne metathesis [ 61. In 1984, Schrock et al. were successful in obtaining a crystal structure of the catalytically active triaryloxytungstate complex 5, and thereby proved the earlier hypothesis [ Sb]. The geometry of the planar four-ring, with an approximately trigonal bipyramidal-coordinated tungsten, is shown in Scheme 2. It should be mentioned that the metathesis of terminal alkynes, unlike the analogous reaction of terminal alkenes, is inhibited, due to the formation of catalytically inactive, deprotonated tungsten cyclobutadiene complexes [ Sc]. Hence, alkyne metathesis liberating acetylene instead of 2-butyne has no use in synthesis.

Mortreux and Blanchard, 1974 10 mol-% [MO(CO)~]/ resorcin (1:6), 160'C, 3 h

2 or 4 - t ~ ~ 4 mol-% [ ( t ~ ~ ~ ) 3] ~ toluene, rt, 1 h Schrock et al., 1981 1

2

3

5

Pioneering experiments by Mortreux et al. (1974) and Schrock et al. (1981). Geometry o f the tungstacyclobutadiene 5 in the crystal (OAr = 0-2,6-diisopropyIphenyl; bond lengths in pm).

Scheme 2.

A major drawback of alkene metathesis is lack of control over the stereochemistry of the newly formed double bond. For unstrained systems, E/Z ratios are virtually unpredictable. Alkyne metathesis, on the other hand, can always be combined with subsequent Lindlar hydrogenation, thereby giving access to stereochemically pure Z-olefins. In 1998, Fiirstner and Seidel were the first to report a ring-closing alkyne metathesis [7]. Under high-dilution conditions (0.02 M) and reduced pressure (20 mbar, removal of 2-butyne, solvent 1,2,4trichlorobenzene (b.p. 214 "C)) the Schrock catalyst was applied to assemble macrocyclic

Alkyne Metathesis in Natural Product Synthesis

lactones, lactams, and cyclic silyl ethers. Soon, various olfactory macrolides, such as the mint-scented yuzu lactone (7) or the strongly musk-scented ambrettolide (9), became synthetic targets, pioneered by Furstner et al. Scheme 3 gives the syntheses, both starting with 9-undecyn-1-01,using the "instant" Mortreux catalyst for ring-closing alkyne metathesis of 6 and 8 under high-dilution conditions, and finishing with Lindlar hydrogenation. The sim(civetone) has been obtained in a similar ple macrocyclic musk (Z)-cycloheptadec-9-en-1-one manner [8]by use either of the Schrock catalyst or of the quite harsh Mortreux conditions (5 mol% Mo(CO)~,p-trifluoromethylphenol, chlorobenzene, 140 "C, 7 h), as optimized by Bunz et al. [9].

68 Yo

6

1. 5 mol% MO(CO)~, 1 eq. pchlorophenol chlorobenzene. 14O'C 2. HP, Lindlar cat.

-~

8

c: 7 : yuzu lactone

-

-

9: ambrettolide

Scheme 3. Simple examples of natural products synthesis by alkyne metathesis with the Mortreux catalyst.

The Mortreux and Schrock catalysts have a somewhat different scope. In particular, secondary amides and silyl ether groups are not compatible with the Mortreux conditions. The high temperatures (140-150 "C) are also not desirable for complex, multifunctional natural products. Scheme 4 gives the key steps of the syntheses of several nitrogen-containing macrocycles, of which motuporamine (13) from the marine sponge Xestospongia exigua [ 101, and epilachnene (16) and homoepilachnene (17), defense secretions of the pupae of the Mexican beetle Epilachnar uariuestis [ 111, are natural products [ 121. In all cases the amino functions had to be protected as carbamates (Boc or Fmoc) prior to alkyne metathesis. The secondary amide present in the metathesis product 18, however, did not have to be protected for use of the Schrock catalyst at 80 "C. In the key reaction of the eight-step synthesis of motuporamine C (13), the open-chain, Nprotected bisalkyne 10 was exposed to Mortreux and to Schrock conditions [13]. The yields (67% vs. 71%) of the macrocycle 11 were comparable, but the reaction temperature (140 "C vs. 80 "C) and the reaction times (30 h vs. 1 h) clearly favor the Schrock conditions. Epi-

30

I

Alkyne Metathesis in Natural Product Synthesis

5 rnol% MO(CO)~, 1 eq. pchlorophenol chlorobenzene, 140aC,30 h, 67 Yo or: 10 rnol% (‘BuO)~WCCM~~, chlorobenzene 80‘C, 1 h, 65 Yo

e F;J

Frnoc

10

-~

Z 3 steps

H2 Lindlar cat., quinoline

Frnoc

Frnoc 11

-

Q L

12

N H

w NH,

13: rnotuporarnine C

1 . Mortreux cond., 67 %

or: 1. Schrock cond., 71 % 14: n=l; 15: n=2

-~

*

-

G

H

16: epilachnene (n=l) 17: hornoepilachnene (n=2)

2. H2, Lindlar cat., 94 % 3. TBAF, H20, 62 %

- O Z s S :I: 0 : a\ 18

cry;H

19: nakadornarin A

1. ‘BuC(NH)CCI3, BF3.Et20, CH2CI2, rt, 8 h, 83 % 2. Schrock cond., 66 % 3. Hz, Pd/C, MeOH, rt, 12 h 4. Frnoc-OSu, dioxane, O‘C, 76 %

*

h N H 0 20 Scheme 4.

BocHN

I l F r n o c ‘BuO~C 21

Alkyne metathesis affording nitrogen-containing natural products or synthetic intermediates.

Alkyne Metathesis in Natural Product Synthesis

I

31

lachnene (16) and its homologue 17 were obtained by starting from the homologous precursors 14 and 15 ( 6 2 4 9 % macrocyclization yields) [12]. For the structurally more complex molecule 18, only the Schrock conditions worked. Compound 18 has been synthesized as a synthetic precursor of the marine alkaloid nakadomarin A (19 [14]) from the marine sponge Amphimedon sp. Nakadomarin A (19) belongs to the manzamine alkaloids, which are also targets of biomimetic syntheses [15]. For both strategies, there is still some distance to go. Diaminosuberic acid (21, protected form) is used as a dicarba isostere of cystine in peptides to provide stable analogues of disulfide bridges. Occasionally, the conformational flexibility of diaminosuberic acid is a disadvantage and conformationally restricted cystine isosteres are desired. Rutjes, van Boom, et al. report the application of alkyne metathesis to the synthesis of analogues containing Z-alkene or alkyne functionalities [ 161. Moreover, orthogonal protection is frequently needed. Scheme 4 gives the synthesis of N’-Boc-N-Fmocdiaminosuberic acid mono-tert-butyl ester (21) (see also [ 171) starting from the open-chain bisalkyne 20. The established tungsten catalyst 4 ( G mol%) in chlorobenzene was used, affording macrocyclization in 66% yield. Alkyne metathesis can also be employed to synthesize open-chain natural products through intermolecular reactions. Fiirstner and Dierkes reported the total synthesis of the natural product (S,S)-(+)-dehydrohomoancepsenolide (24) from the gorgonian Pterogorgia citrina, to which it contributes to chemical defense (Scheme 5) [18]. The synthesis features both alkene and alkyne metatheses. The butenolide unit 23 was assembled first, by alkene metathesis starting from the open-chain precursor 22, in the presence of Grubbs’ catalyst [ 191. Interestingly, competing enyne metathesis was not observed. Subsequent alkyne metathesis with the Schrock catalyst and Lindlar hydrogenation successfully provided 24 from 23.

16 mob% (PCy&ClzRu=CHPh,

c

CH2C12, A, 24 h, 70 % 22

1. l o mol-% [(‘Bu0)3W-‘Bu] toluene, 100 ‘C, 10 h, 75 %

23

.

2. H P , Lindlar cat., quinoline, hexane/EtOH, rt, 30 min, 96 YO

0

24: (S,S)-(+)-dehydrohomoancepsenolide Scheme 5. Combined application of alkene and alkyne metathesis, affording the open-chain natural product 24.

32

I

Alkyne Metathesis in Natural Product Synthesis

It is of key importance for the success of a synthetic method that it be compatible with the greatest possible variety of functional groups. The tungstacyclobutadiene 5, for example, is ring-opened by pyridine and looses its catalytic activity [20]. In 1999, Fiirstner et al. found a new molybdenum catalyst with wider scope (Scheme 6) [21]. Dissolution of the trisamidomolybdenum complex 25 12.21 in dichloromethane results in the endothermic formation of the chloride 26, The catalytic activity of 26 was demonstrated with the alkyne metathesis of the pyridine-2,3-dicarboxylatediester 27 in toluene, affording the macrocyclic alkyne 28 in the very good yield of 88%. The new catalyst 26 has several advantages, including the tolerance of basic nitrogen functional groups, thioethers, and polyether chains. The probable reason for this is the steric hindrance of the Lewis acidic molybdenum center. Complex 26 is not compatible with substrates containing acidic protons, such as secondary amides, which are tolerated by the Schrock system. Despite intensive studies, no X-ray structures of reactive intermediates composed of both molybdenum and alkyne components have so far been obtained, and the mechanism of catalysis is still unknown. Fiirstner et al. give a detailed account of their work on trisamidomolybdenum complexes of the general type [Mo(('Bu)(Ar)N}3]in ref. [23].

10 mol% of 26 toluene, 80'C

88 % 27 Scheme 6.

28 Furstner's new molybdenum catalyst 26.

There are already advanced applications of the new catalyst to the synthesis of natural products. Scheme 7 gives the metathesis steps towards, and the structures of, the target molecules prostaglandin Ez methyl ester (31), its lactone 33 from the nudibranch Trtetys Jimbria [24], and the structures of the glycolipid sophorolipid lactone (34) from the yeast Candida bombicola [25] and of the microtubule-stabilizing epothilone C (35)from the myxobacterium Sorangium cellulosum 1261. To obtain the open-chain prostaglandin Ez methyl ester (31), the symmetrical Cl0 alkyne 30 was employed as the source of the Cs unit to be introduced into the starting material 29 (Scheme 7). The yield of this less symmetrical alkyne metathesis was 51% [27]. The macro-

Alkyne Metathesis in Natural Product Synthesis

I

33

1. 10 mol% [MO(N(~BU)(A~)}~], CH2C12,toluene, 80'C, 51 % 2. Hz, Lindlar cat. quinoline, hexane, rt, 87 %

3. aq. HF, THF, rt, 1 h , 88 %

HO 31 : PGE2 methyl ester

Ar = 3,5-dimethylphenyl

1:

1. 7.5 mol% [Mo(N('Bu)(Ar)J3],

CH2C12,toluene, 80'C, 16 h, 70 % 2. HP,Lindlar cat. quinoline, hexane, rt, 2 h, 86 % 3. aq. HF, MeCN, rt, 1 h , 88 %

HO 33: PGE2 lactone

'*m 13

U 34: sophorolipid lactone Scheme 7.

35: epothilone C

The most complex natural products so far obtained by alkyne metathesis.

cyclization of the bisalkyne 32 to the analogous lactone 33 proceeded in the higher yield of 70% [28]. The molybdenum catalyst 26 is compatible with esters, ethers, silyl ethers, tertiary amides, thioethers, pyridines, and ketones. Sophorolipid lactone (34) was obtained from an open-chain bisalkyne precursor (concomitant formation of 2-butyne) in a macrocyclization yield of 78% [29]. The epothilones have been obtained through non-stereoselective alkene metathesis [ 2Gd], making them worthwhile targets for the combination alkyne metathesis/Lindlar hydrogenation to assemble the C12-Cl3 Z double bond. Furthermore, epothilone C (35) shows the most complex array of functional groups among the substrates of alkyne metathesis. The macrocyclization yield, starting from the expected OTBS-protected precursor (not shown) was 81% 123, 301. Neither

34

I

Alkyne Metathesis in Natural Product Synthesis

the basic nitrogen not the sulfur of the thiazole ring interfered with the catalyst. The labile aldol and the already present alkene double bond stayed intact. Only the OH group had to be protected, as a TBS ether. Epothilone C (35)can be epoxidized stereoselectivelyto epothilone A by dimethyldioxirane [ 311. In summary, alkyne metathesis seems about to become one of the key reactions frequently employed in the synthesis of increasingly complex natural products. Recently, Trost et al. and Furstner et al. reported new hydrosilylation protocols for the convenient, chemoselective transformation of alkynes to E alkenes which will extend the value of alkyne metathesis for natural product synthesis [32].

References A. FURSTNER, Angew. Chem. 2000, 112, 3140-3172; Angew. Chem. Int. Ed. 2000, 39, 3012-3043; b) R. H. GRUBBS,S. CHANG,Tetrahedron 1998, 54, 4413-4450; c) M. SCHUSTER, S. BLECHERT, Angew. Chem. 1997, 109, 2124-2145; Angew. Chem. Int. Ed. 1997. 36, 2037-2056.

1 Reviews o n alkene metathesis: a)

2 Examples o f enyne metathesis in natural products synthesis: a) S. C. SCHURER,

S. BLECHERT, Synlett 1999, 1879-1882; b) B. M. TROST,G. A. DOHERTY,J. Am. Chem. SOC. 2000, 122, 3801-3810; c) D. BANTI,M. NORTH,Tetrahedron Lett. 2002, 43, 1561-1564 d) J. S. CLARK,F.

3

4

5

6

ELUSTONDO, G. P. TREVITT,et al., Tetrahedron 2002, 58, 1973-1982. e) M. MORI,K. TONOGAKI, N. NISHIGUCHI, J. Org. Chem. 2002, 67, 224-226. a) U. H. F. BUNZ,ACC.Chem. Res. 2001, 34, 998-1010.17) U. H. F. BUNZ,L. KLOPPENBURG, Angew. Chem. 1999, 111, 503-505; Angew. Chem. Int. Ed. Engl. 1999, 38, 478-481. A. MORTREUX, M. BLANCHARD, J . Chem. SOC.Chem. Commun. 1974, 786-787. a) J. H. WENGROVIUS, J. SANCHO,R. R. SCHROCK,].Am. Chem. SOC.1981, 103, 3932-3934; b) M. R. CHURCHILL, J. W. ZILLER,J. H. FREUDENBERGER, et al., Organometallics 1984. 3, 1554-1562; c) L. G . MCCULLOUGH, M. L. LISTERMANN, R. R. SCHROCK, et al., /. Am. Chem. SOC. 1983, 105, 6729-6730; d) Summary: R. R. SCHROCK,Polyhedron 1995, 14, 31773195. T. J. KATz, J. MCGINNIS,J.Am. Chem. SOC. 1975, 97, 1592-1594.

7 A. FURSTNER,G. SEIDEL,Angew. Chem.

8 9

10

11

12

13 14 15

16

17 18 19

20

1998, 110, 1758-1760; Angew. Chem. Int. Ed. Engl. 1998, 37, 1734-1736. A. FURSTNER,G. SEIDEL, J . Organomet. Chem. 2000, 606,75-78. L. KLOPPENBURG, D. SONG,U. H. F. BUNZ,I. Am. Chem. SOC.1998, 120,79737974. D. E. WILLIAMS, P. LASSOTA,R. J. ANDERSEN,J. Org. Chem. 1998, 63,48384841. A. B. ATIYGALLE, K. D. MCCORMICK, C. L. BLANKESPOOR, et al., Proc. Natl. Acad. Sci. USA 1993, 90, 5204. A. FURSTNER, 0. GUTH,A. RUMBO,et al., / . A m . Chem. SOC.1999, 121, 11,10811,113. A. FURSTNER, A. RUMBO,J . Org. Chem. 2000, 65, 2608-2611. J. KOBAYASHI, D. WATANABE, N.KAWASAKI, et al., /. Org. Chem. 1997, 62, 9236-9239. a) J. E. BALDWIN, R. C. WHITEHEAD, Tetrahedron Lett. 1992, 33, 2059-2062; b) J. E. BALDWIN, T. D. W. CIARIDGE,A. J. CULSHAW, et al., Angew. Chem. 1998, 110, 2806-2808; Angew. Chem. Int. Ed. Engl. 1998, 37, 2661-2663. B. AGUILERA, L. B. WOLF,P. NIECZYPOR. et al., /. Org. Chem. 2001, 66, 35843589. R. M. WILLIAMS? J. LIU,J. Org. Chem. 1998, 63, 2130-2132. A. FURSTNER, T. DIERKES, Org. Lett. 2000, 2, 2463-2465. P. SCHWAB,R. H. GRUBBS,J. W. ZILLER,/. Am. Chem. SOC.1996, 118, 100-110. M. L. LISTERMANN, R. R. SCHROCK, Organometallics 1985, 4, 74-83.

References I 3 5 21

22 23

24 25 26

A. FURSTNER,C. MATHES, C. W. LEHMANN,].Am. Chem. Soc. 1999, 121, 9453-9454. C. C. CUMMINS, Chem. Commun. 1998, 1777-1 786. A. FURSTNER, C. MATHES, C. W. Chem. Eur.]. 2001, 7, 5299LEHMANN, 5317. G. CIMINO, A. SPINELLA, G. SODANO, Tetrahedron Lett. 1989, 30, 3589-3592. A. P. TULLOCH, A. HILL,J. F. T. SPENCER, Can.]. Chem. 1968, 46, 3337. (a) G . HOFLE,N. BEDORF, K. GERTH,et al. (GBF Braunschweig), Ger. Offen. DE 4138042 A1 19930527,1993 [ Chem. Abstr. 1994, 120, P526411; (b) D. M. BOLLAG, P. A. MCQUEENEY, J. ZHU, et al., Cancer Res. 1995, 55, 2325-2333; (c) G . HOFLE, N. BEDORF, H. STEINMETZ, et al., Angew. Chem. 1996, 108,1671-1673; Angew. Chem. Int. Ed. Engl. 1996, 35, 1567-1569; (d) see also L. A. WESSJOHANN, G. SCHEIDin

Organic Synthesis Highlights Iy H.-G. (Ed.), Wiley-VCH, 2000, p. 251SCHMALZ 267. 27 A. FURSTNER, C. MATHES,Org. Lett. 2001, 3, 221-223. 28 a) A. FURSTNER, K. GRELA, Angew. Chem. 2000, 112, 1292-1294; Angew. Chem. Int. Ed. Engl. 2000, 39, 1234-1236; b) A. FURSTNER, K. GRELA, C. MATHES, et af., /. Am. Chem. SOC.2000, 122, 11,799-11,805. 29 A. FURSTNER, K. ~ D K O W S K J. I , GRABOWSKI, et al.,]. Org. Chem. 2000, GS, 8758-8762. 30 A. FURSTNER, C. MATHES,K. GRELA, Chem. Commun. 2001, 1057-1059. 31 D. MENG,P. BERTINATO,A. BALOG, et al.,j. Am. Chem. SOC.1997, 119, 10,073-10,092. 32 (a) B. M. TROST,2. T. BALL, T. JOGE, I. Am. Chem. SOC.2002, 124, 7922-7923; b) A. FURSTNER, K. RADKOWSKI,Chem. Commun. 2002, 2182-2183.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Transition Metal-catalyzed Functionalization o f Alkanes Oliver Seitz Introduction

Alkanes, which are the principal components of natural gas and crude oil, are still the preferred energy source of our society. In regard to the prime importance of alkanes as feedstock for the chemical industry, it appears a waste of resources “simply” to burn these precious raw materials. Unfortunately, attempts to transform alkanes into more valuable products are hampered by their low reactivity, as best illustrated by the use of alkanes as inert solvents. For example, the cracking process requires temperatures of about 1000 “C in order to convert long-chain alkanes into short-chain alkanes. Controlled conversion of hydrocarbons is difficult to achieve and limited to partial oxidations, such as the conversion of butane into acetic acid. It is obvious that processes that would enable efficient functionalization to occur at low temperature would have enormous potential application. Achievements towards this goal will almost certainly rely on the use of catalysts, which will have to activate the stable C-H bond (375-440 kJ mol-’) in order to induce its scission. C-H activation reactions can be induced by one-electron or two-electron transfer processes. Radical chain reactions, which operate in many alkane oxidations, belong to the first category (Scheme 1). In a “conventional” oxidation reaction, molecular oxygen effects the initiation and the propagation of the radical chain. Metals, transition metals in particular, are able to accelerate the cleavage of the formed hydroperoxides, thereby catalyzing the ratelimiting radical chain initiation. With a few exceptions, radical reactions of alkanes proceed relatively unselectively, but with tertiary C-H bonds being preferred [l].This is due to the high reactivity of radicals such as the hydroxyl radical and the differences in the C-H bond strengths (tea CH < sec CH < primary CH < CH3-H). In contrast, homogenous transition metal systems, which proceed by - for example - oxidative addition, show higher reactivity for primary C---Hbonds than for secondary and tertiary C-~Hbonds. The latter process is much more attractive when aiming for functionalization of linear alkanes. For this reason, this “account” focuses on transition metal-catalyzed two-electron processes. It is not intended to present a comprehensive overview, but to highlight some instructive examples for the generally interested reader, with a strong emphasis on newly developed catalysts. For a more detailed coverage the reader is referred to the review literature [ 2-51.

Alkane Functionalization with Homogenous Transition Metal Catalysts

I

37

One-electron transfer

Contribution of the metal: ROzH + M"

+

M"+'

+ RO- + OH.

Two-electron transfer M+RH

1

[M-RH]

2

Scheme 1.

-

A

0R

(%

M+RX+H2

H 3

4

C-H activation reactions proceed by transfer of one or two electrons

Alkane Functionalization with Homogenous Transition Metal Catalysts

To unlock its full potential, C-H activation has to be coupled with a functionalization event (e.g., 3-4). For instance, a hydride elimination occurring after the formation of metal complexes such as 3 furnishes olefins, versatile intermediates for further modification reactions. Transition metal-catalyzed atom- or atom group-transfer reactions that permit the introduction of oxygen-, carbon-, and boron-containing groups are also presented. The development of catalytic C-H activation reactions is one of the most challenging enterprises in organic chemistry. The only complexes able to activate C-H bonds by oxidative addition are coordinatively unsaturated at the metal center. The lifetimes of these highly reactive metal species, however, are usually very short. A key issue is therefore the development of stabilizing metal ligands. In addition, it is desirable that the ligands should confer a selectivity to the functionalization reaction, such that repeated functionalization can be prevented. Oxygenation

The most widespread efforts made towards the achievement of selective oxidation of alkanes are targeted on methane, a principal constituent of natural gas 16-81. Activation of the very stable C-H bond of methane is a particularly demanding problem. One example in which this has been achieved on industrial scales is the Degussa process "91. Methane is coupled to ammonia by heterogeneous catalysis in order to produce HCN, an important fundamental material for industrial chemistry. An unsolved problem is the selective oxidation of methane to methanol: a reaction that would convert the methane gas into a transportable liquid. In nature, monooxygenases have evolved. These are able to activate molecular oxygen and to

38

I

Transition Metal-catalyzed Functionalization of Alkanes

insert one oxygen atom into a C-H bond of an alkane. This process has inspired many efforts devoted to the development of biomimetic chemical model systems [ l o , 111. The most important catalysts for achieving selective hydroxylation of methane by two-electron transfer are based on the so-called Shilov system. Shilov and Shteinman reported a Pt(1v)mediated C-H activation as early as 1972 [12, 131. Typically, these reactions are performed under oxidative and highly acidic conditions, which results in the separation of a metal precipitate. This precipitation promotes the decomposition of the formed methanol and reduces the lifetime of the catalytically active species. Complexation with stabilizing ligands can substantially increase the lifetime of the catalyst. Periana and co-workers identified 2,2'bispyrimidine as a suitable ligand [14]. A solution of the bispyrimidine-Pt(I1) complex 5 in 20% oleum remained homogeneous even after 50 h at 200 "C, and no formation of insoluble platinum complexes such as (PtC12),or metal precipitates was observed (Scheme 2). The fact that metallic platinum dissolves upon treatment with a solution of bispyrimidine in 96% sulfuric acid is testimony to the remarkable affinity of the bispyrimidine ligand for platinum. It is this astonishing stability that renders the Pt(I1) complex functional under the drastic conditions of methane hydroxylation. At a temperature of 220 "C in concentrated sulfuric acid, complex 5 catalyzed more than 500 conversion cycles of methane to sulfuric acid methyl ester 6. The only liquid products detectable were sulfuric acid methyl ester 6 and methanol, which were formed in 73% yield and with 81% selectivity (based on methane). A mechanism similar to the Shilov process has been suggested [15]. According to this, acid treatment of the bispyrimidine-Pt(Ir) complex 5 results in the formation of the coordinatively unsaturated 14-electron complex 7. Subsequently, C-H activation proceeds by oxidative addition of methane to furnish complex 8. Periana and co-workers recognized the oxidation to the Pt(~ vcomplex ) 9 as the rate-limiting step. Finally, reductive elimination ejects methyl sulfate 6 and regenerates the active species 7. Recently, Sames and co-workers showed an interesting application, in which it was demonstrated that the Shilov chemistry permits heteroatom-directed functionalization of polyfunctional molecules [ 161. The amino acid valine (10) was allowed to react in an aqueous solution of the oxidation catalyst K2PtC14 and CU(11) chloride as stoichiometric oxidant (Scheme 3). At temperatures >130 "C a catalytic reaction was observed, and a regioselective C-H functionalization delivered the hydroxyvaline lactone 11 as a 3:l mixture of antilsyn isomers. It was noted that the hydroxylation of amino acid substrates occurred with a regioselectivity different from those for simple aliphatic amines and carboxylic acids. The authors therefore proposed that the amino acid functionalization proceeded through a chelate-directed C-H activation. Dehydrogenation

Specific dehydrogenation at the terminal positions of alkanes is a reaction that would be of high utility. The 1-alkenes obtained by such a reaction are the basis of a variety of additional products. Felkin and co-workers discovered that metal complexes are able to mediate the transfer of hydrogen from alkanes 13 to olefins 14 (Scheme 4) [ 171. The specific advantages of a transition metal catalyst can be applied to the benefit of the chemoselectivity of this reaction. In a kinetically controlled process, it is predominantly primary C-H bonds that add to the metal complex. A subsequent /?-hydride elimination affords the terminal alkenes

Alkane Functionalization with Homogenous Transition Metal Catalysts

I

39

5

CH4

+

2H2S04

+

CHBOSO~H

2H20

+

SO2

220’C,73%

6

+ X

N

X

ld

7

X = CI, HS04

-

\

HX

X

S o p + HpO

Scheme 2.

SO3 + 2 HX

Efficient Pt-catalyzed oxidation of methane

1 5 (R’ = R 2 = H). Successive isomerization reactions, which begin to dominate after a very short period of time, complicate the preparative usefulness of this reaction. A remarkable selectivity for the formation of cc-olefins has been reported by Jensen, Goldman, and co-workers [18].The iridium “pincer” complexes 20a and 20b were compared in the dehydrogenation of octane 17 (Scheme 5). When norbornene (Ma) was used as acceptor

40

I

Transition Metal-catalyzed Functionalization of Alkanes

5 mol% KpPtC14, 7 eq. CuCIp, 160’C, H20

1) BOQO 2) AcOH

NH2

NH-BOC

NH2

12

11

10

27 % (isolated yield)

56 % (crude in mixture with starting material) Scheme 3.

H

Pt-catalyzed oxidation o f amino acids.

R1#R3 R2 R4

13 Scheme 4.

metalcatalyst

R5

H

+ R6

Ra

-

14

H

R’

+ R2

R4

15

H

R5*R7 R6 Ra 16

Metal-catalyzed transfer (de) hydrogenation.

olefin, the highest cc-selectivities were obtained with the iPr complex 20a. After 5 minutes (12 turnovers) the 1-octene 21 had been formed with 91% selectivity. At prolonged reaction times and increased turnover the isomerization reaction began to dominate, and after 30 minutes (132 turnovers) 1-octene constituted only 30% of the product mixture. The use of a more reactive hydrogen acceptor such as 1-decene (18b) in combination with the sterically demanding tBu complex 201, enhanced the r-selectivity, particularly at prolonged reaction time. For instance, 1-octene was formed with 95% selectivity after 15 minutes (13 turnovers). After 90 minutes (111 turnovers) the product mixture still contained 84% of 1-octene and only 16% of the isomerization product 2-octene 22. The proposed mechanism involves a hydrogen transfer from the hydrido-iridium complex 20 to the alkene 18 as the first step. The formed complex 23 undergoes /3-hydride elimination. The coordinatively unsaturated iridium species 24 causes the oxidative oxidation of octane (24125). This C-H activation step is then followed by a reductive elimination, which gives rise to the formation of the dehydrogenation product 21. Recently, a new type of “pincer” complex has been introduced [19]. The “anthraphos” ligand confers a thermal stabilization on the iridium complex 26 (Figure 1). Hence, dehydrogenation reactions can be performed at temperatures (>200 “C) that would normally result in complete decomposition of the pincer complexes 20. Reluctant reactions, the kinetics and/or the thermodynamics of which require high temperatures, can therefore succeed. In spite of the remarkable improvement upon previously existing methodology, there is one disadvantage that remains. For the synthesis of an olefin, a second olefin has to be sacrificed. It is obvious that a process that would enable dehydrogenation to occur in the absence of sacrificial reagents would be highly desirable. Moreover, the selectivities that can be obtained at high turnovers are still too low for practical applications. Neither turnover frequencies nor turnover numbers of the catalysis are sufficient to be useful for industrial processes. These limitations are less of an issue in total synthesis, provided that the “quality” of the metal-mediated reaction justifies the use of stoichiometric processes.

Alkane Functionalization with Homogenous Transition Metal Catalysts

b

18a

catalyst 20a

5 rnin (TON = 12): 91% 21, 9% 22 30 min (TON = 132): 30% 21,67% 22

18b

catalyst 20b

15 min (TON = 13): >95% 21, 0% 22 90 min (TON = 1 11): 84% 21, 16% 22

mC8H1,

k

A

r( H

(PCP)lr,

23

H

mC6H13 CHz 17

- CH3

(PCP)lr 24

H

H

19

I Scheme 5.

A dehydrogenation with high a-selectivity (PCP = C G H ~ ( C H ~ P R ~ ) ~ ) .

I

41

42

I

Transition Metal-catalyzed Functionalization of Alkanes

H H Fig. 1.

A thermally stable pincer complex.

Such an example has been demonstrated by Johnson and Sames, who chose a platinummediated dehydrogenation as a key step in the synthesis of the antimitotic rhazinilam 33 (Scheme 6) [20]. The key intermediate 27 was converted into the imine 28, which was allowed to react with [ MezPt(,u-SMez)]z to afford the platinum complex 29. Subsequent treatment with triflic acid resulted in elimination of methane and furnished the cationic complex 30. Upon thermolysis in trifluoroethanol, the complex lost a second methane molecule, which resulted in the activation of the ethyl group. A subsequent P-hydride elimination gave the hydrido-Pt(I1) complex 31. Treatment with aqueous KCN followed by hydroxylamine removed the platinum and yielded the liberated amine 32. Johnson and Sames added a homologization and a macrolactamization and completed the total synthesis of rhazinilam (33) by removal of the carboxyl group.

c- C-Coupling Reactions that combine C-H activation with a C-C bond-forming event are invaluable synthetic tools, allowing concise construction of carbon frameworks. Rhodium( I ) catalysts have been shown to catalyze alkane carbonylation [ 211. Recently, Sakakura and co-workers succeeded in subjecting methane to a catalytic acetaldehyde synthesis [22]. They found that, in dense carbon dioxide, the complex [ RhC1(PMe3)3]catalyzed the carbonylation of methane with 77 turnovers. One problem that occurs when this class of catalysts is used is a concomitant dehydrogenation. To achieve a selective carbonylation, Murai and co-workers used substrates in which the metal complex was coordinated by a directing group, thereby placing the active metal center in close proximity to the C-H bond to be cleaved. This tactic was applied to the carbonylation of alkylamines (Scheme 7) [ 231. In the presence of ethylene, the rhodiumcyclooctadienyl complex 35 catalyzed the conversion of the pyrrolidines 34 into the saturated ketones 36. Different pyridine substituents were examined in terms of their suitability to support the rhodium-catalyzed carbonylation reaction. Electron-donating groups at the 5position (34, R = 5-Me) increased product formation. In the absence of the pyridine ring the reaction failed to take place. The introduction of electron-withdrawing (34, R = 5-CF3) or sterically demanding groups (34, R = 6-Me), reducing the basicity or accessibility of the pyridine nitrogen, gave decreased product yields. Murai and co-workers also explored the use of acyclic amines such as 36. Carbonylation to 37 and 38 proceeded, albeit in low yields. It is noteworthy that a preference for the sterically less demanding primary C-H bond (-37) as

Alkane Functionalization with Homogenous Transition Metal Catalysts

I

43

0

COOMe

27

phx 30

0

J

CF3CH20H, 70'C, 60h, 90%

& -

/

a) KCN, H20, 60% from 29 ~)%~OH,MeOH, ___)

/

phw N-Pt'H

II

NH2

\

/

32

31

33

Scheme 6.

@ -

fl 0

Pt-mediated dehydrogenation in the total synthesis of rhazinilam.

opposed to the energetically favored benzylic C-H bonds ( 1 3 8 ) was observed. Interestingly, the use of the ruthenium catalyst 39 allowed the introduction of ethyl groups [24]. Cyclic amines were more reactive than acyclic ones. For example, double alkylation occurred with the pyrrolidine 34, whereas monoalkylation was possible when the acyclic alkylamine 41 was

44

I

Transition Metal-catalyzed functionalization of Alkanes

d R=

R

34

H

36

40h

3-Me 60h

4-Me 60h

5-Me 40h

6-Me 60h

5-CF3 60h

68%

73%

73%

84%

12%

15%

Ph

CO, H2C=CHp

iPrOH, 160’C 36

37

18% (9:l)

34

Ph

41 Scheme 7.

38

40

Ph

42 (8%)

Ph

43 (20%)

Directed C-H activation for the carbonylation and alkylation of alkylamines.

Ph

44 (12%)

Alkane Functionalization with Homogenous Transition Metal Catalysts

employed as substrate. It is also interesting to note that the use of the ruthenium catalyst 39 changed the selectivity. The complex predominantly activated the benzylic C-H bond (+43) rather than the primary C-H bond ( 1 4 2 ) preferred when the C-H activation was catalyzed by the rhodium complex 35. At first glance, the requirement for the use of already functionalized alkanes seems to limit the applicability of the directed C-H activation approach. However, the utility of such a method is obvious for chemists familiar with the use of auxiliary groups during stereoselective synthesis (neighboring group participation was also applied in the total synthesis shown in Scheme 6). Borylation

The formation of carbon-boron bonds is one of the most versatile tools for the functionalization of hydrocarbons. The repertoire of functional group conversions in which organoboranes are transformed into alcohols, amines, ketones, alkenes, etc. is rich and characterized by broad applicability. Hartwig and co-workers recognized that the combination of a C-H activation with an alkane borylation can afford an exothermic process. Hence, the development of a catalytic alkane borylation seemed attainable. Hartwig's group first elaborated a photochemical means of alkane borylation [25]. Another impressive example of this hypothesis was also reported by Hartwig and co-workers, who described a thermal process for transition metal-catalyzed functionalization of alkanes [2G]. As an example, 5 mol% of the rhodium-bisethylene complex 46 catalyzed the reaction between n-octane (17) and the dioxaborolane 45 (Scheme 8). Complete conversion of the diborane 45 was achieved after 1 h at 150 "C. The n-octylborane 47 was formed in 84% yield after an additional 4 h reaction time. It has to be emphasized that both boron atoms of dioxoborolane 45 were transferred by the rhodium complex. Hartwig and co-workers showed that the pinacolborane 48 formed upon conversion of 45 is also a substrate and supports the catalytic octane borylation. The C-H activation was highly selective towards the primary position, GC-MS analysis attesting that n-octylborane was the only octylborane formed. Nevertheless, various ethylborane products were detected. Ethylborane formation seemed to be associated with a dissociation of ethylene ligands from rhodium complex 46a. Indeed, the use of the hexamethylbenzene complex 46b, which would dissociate by liberation of unreactive hexamethylbenzene, led to increased product yields. The driving force for this remarkably efficient alkane functionalization seems to be provided by the unusual thermodynamic properties of boron reagents. In the initial stage of the reaction, one octane C-H (412 kJ mol-') and one B-B bond (437 kJ mol-') are broken, while one B-C (470 kJ mol-') and one B-H bond (466kJ mol-') are formed. In total, an energy of 87 kJ mol-' is released. Analogously, conversion of the borane 48 gives rise to the formation of Hz (H-H bond: 437 kJ mol-') thereby releasing an overall bond energy of 29 kJ mol-'. This thermodynamic peculiarity enables C-H activation to occur even in absence of a catalyst. For instance, Knochel and co-workers showed that a thermal reaction can induce the activation of remote C-H bonds of acyclic tertiary alkylboranes to afford cyclic organoboranes [ 271. A theoretical study has suggested that even intermolecular C-H activation reactions such as direct methane borylation could succeed [28].

I

45

46

I

Transition Metal-catalyzed functionalization of Alkanes

46a =

46b =

Scheme 8.

* Rh

5 mol% Cat, 84% (5h); 1 mol% Cat, 64% (1 10h)

5 mol% Cat, 88% (25h); 1 mol% Cat, 72% (80h)

Thermal, catalyzed functionalization of alkanes t o organoboranes.

Conclusion

The first activation of an alkane C-H bond was described in 1969 [29]. Three decades were to pass until the development of the current catalytic procedures for dehydrogenation and G O , C-C, and C-B bond-forming reactions. Progress has been slow. Nevertheless, significant advances in catalyst research were achieved in the 1990s, aided by the development of improved metal ligands and the increased understanding of the mechanism of transition metal-catalyzed C-H activation reactions. Further improvements of catalytic cycles are nec-

Literature 1 4 7

essary, especially for the goal of application in economically useful industrial processes. As far as chemoselectivity is concerned, modern alkane functionalization reactions seem to suit the needs of laboratory practice, with the promise of a concise means of carbon framework synthesis. The examples presented here suggest that the goal of achieving both high catalytic efficiency and high chemoselectivity might be within reach. In particular, the thermally catalyzed alkane borylation indicates that C-H activation reactions present new opportunities and increase the repertoire of organic synthesis. It thus seems conceivable that alkanes will find a place not only as a source of energy but also as valuable building blocks in chemical synthesis. Literature

J. M. THOMAS,R. RAJA, G. SANKAR, et al., Acc. Chem. Res. 2001, 34, 191-200. 2 A. E. SHILOV, G. B. SHULPIN, Chem. Reti 1997, 97, 2879-2932. 3 G. DYKER, Angew. Chem. 1999, 111, 18081822; Angew. Chem. Int. Ed. 1999, 38, 1699-1712. 4 C. G . JIA, T. KITAMURA,Y. FUTIWARA, ACC. Chew. Res. 2001, 34, 633-639. 5 R. H. CRABTREE,J. Chem. SOC.,Dalton Trans. 2001, 2437-2450. 6 R. H. CRABTREE, Chem. Rev. 1995, 95, 987-1007. 7 S. S. STAHL,J. A. LABINGER, J. E. BERCAW, Angew. Chem. 1998, 110, 2298-2311; Angew. Chem. Int. Ed. 1998,37,2181-2192. 8 J. H. LUNSFORD,Catal. Today 2000, 63, 165-174. 9 For a mechanistic investigation: M. DIEFENBACH, M. BRONSTRUP, M. ASCHI,et al., J. Am. Chem. SOC.1999, 121, 10,61410,625. 10 An overview of mechanistic aspects: A. E. SHILOV,A. A. SHTEINMAN, Acc. Chem. Res. 1999, 32, 763-771. I 1 For an overview of the scope of enzymatic alkane hydroxylation: H. L. HOLLAND, Curr. Opin. Chem. Biol. 1999, 3, 22-27. 12 N. F. GOL’DSHLEGER, V. V. ES’KOVA,A. E. SHILOV, et al., Zh. Fiz. Khim. 1972, 46, 1353. 13 A. E. SHILOV, A. A. SHTEINMAN, Coord. Chem. Reu. 1977, 24, 97-143. 14 R. A. PERIANA, D. J. TAUBE,S. GAMBLE, et al., Science 1998, 280, 560-564. 15 M. W. HOLTCAMP, J. A. LABINGER,J. E. BERCAW,J . Am. Chem. SOC.1997, 119, 848-849. 1

16 17

18 19

20 21

22

23

24

25 26

27

28

29

B. D. DANGEL, J. A. JOHNSON, D. SAMES, J . Am. Chem. SOC.2001, 123, 8149-8150. D. BAUDRY,M. EPHRITIKINE, H. FELKIN, et al., J . Chem. SOC.,Chem. Commun. 1983, 788-789. F. C. LIU, E. B. PAK,B. SINGH,etal., J. Am. Chem. SOC.1999, 121,4086-4087. M. W. HAENEL, S. OEVERS, K. ANGERMUND, et al., Angew. Chem. 2001, 113, 3708-3712; Angew. Chem. Int. Ed. 2001, 40, 3596-3600. J. A. J O H N S O N , D. SAMES, J . Am. Chem. SOC. 2000, 122, 6321-6322. T. SAKAKURA, T. SODEYAMA, K. SASAKI,et al., J. Am. Chm. SOC.1990, 112, 72217229. J. C. CHOI,Y. KOBAYASHI,T. SAKAKURA, J. Org. Chem. 2001, 66, 5262-5263. N. CHATANI, T. ASAUMI,T. IKEDA, et al., J . Am. Chem. SOC.2000, 122, 12,88212,883. N. CHATANI,T. ASAUMI,S. YORIMITSU,et al., J. Am. Chem. SOC.2001, 123, 10,93510,941. K. M. WALTZ,J. F. HARTWIG,Science 1997, 277, 211-213. H. Y. C H E N ,S. SCHLECHT, T. C. SEMPLE, et al., Science 2000, 287, 1995-1997. H. LAAZIRI, L. 0. BROMM, F. LHERMIITE, et al., J . Am. Chem. SOC.1999, 121, 69406941. B. GOLDFUSS, P. KNOCHEL, L. 0. BROMM, et al., Angew. Chem. 2000, 112, 4299-4302; Angew. Chem. Int. Ed. 2000, 39, 41364139. N. F. GOL’DSHLEGER, M. B. TYABIN, A. E. SHILOV, et al., Zh. Fiz. Khim. 1969, 43, 2174.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

An Eldorado for Homogeneous Catalysis? Gerald Dyker

Gold has always been the embodiment of something extremely valuable and evidently holds a fascination deeply rooted in the cultural history of mankind. As is generally known, the endeavour to produce gold synthetically played a significant role in the development of chemistry over a long period [2]. Concerning the search for catalysts gold has until recently lived in the shadows, which perhaps has its reason in the preconceived opinion that gold is expensive and inert. Indeed, gold is the most precious metal and was considered for a long time to be extremely chemically inert particularly in reactions with nonmetals such as hydrogen, carbon, and oxygen [3]. Through successes in heterogeneous catalysis, which are also of economic significance, this assessment has fundamentally changed [4a]: tetrachloroauric acid on active charcoal is currently the best catalyst for the hydrochlorination of ethyne, and gold clusters (diameter 2-5 nm) on iron oxide are particularly active for the oxidation of carbon monoxide [4b]. Other possible applications in environmentally relevant fields are the oxidative decomposition of halogenated hydrocarbons and the reduction of nitrogen monoxide with carbon monoxide and hydrogen to give nitrogen, carbon dioxide, and water [4c, 4d, 51. Surprisingly, gold can also catalyze skeletal rearrangements of hydrocarbons: for instance, the isomerization of 2,2-dimethylbutane to n-hexane has been achieved by Schmid with the aid of Auss clusters on titanium dioxide [4c, 61 and the aromatization of the dispirocycle 1 to tetrahydronaphthalene 2 was achieved by de Meijere et al. in a reactor with gold surface at 100 "C in a few seconds (Scheme 1) [ 7 ] .

Au-surface helium 100 O C . 10 s 1 Scheme 1.

2 (> 90%) Gold-catalyzed skeletal rearrangement of a strained hydrocarbon.

An Eldorado for Homogeneous Catalysis?

In the field of homogeneous catalysis only a few gold-catalyzed processes are known to date, which, however, are characterized by the need for extremely small amounts of gold salts. In view of the high catalytic activity of gold salts the higher price for gold is relativized in comparison to that for the corresponding palladium and ruthenium compounds. Recent developments in gold chloride catalyzed C-C and C-0 coupling reactions provide a fitting opportunity to highlight the current status [8] of homogeneous catalysis with gold salts and to show the potential for further developments. A first landmark in gold catalysis was made by Ito and Hayashi when they carried out an asymmetric aldol reaction in 1986 [9]: aldehydes 3 were treated with isocyanoacetate 4 to give oxazolines 5 (Scheme 2). The active catalyst is a ferrocenylphosphane-gold(I) complex (structure G sketches the complex with coordinatively bound reactants). In general, nearly quantitative yields and diastereo- and enantioselectivities of greater than 90% in favor of the 4S,SR-configurated trans-product 5 are achieved in this reaction. For instance, this method facilitates a two-step synthesis of the naturally occurring amino acid threo-3-hydroxylysine from 4-phthalimidylbutanal as the aldehyde component 3 [ 9d].

. cat. 6

R-CHO

(1 mol-%)

+

CHZC12 25 O C , 20 h

yo C

O v N

5

4

3

r

Me Me Me. Ph?

1

/

6 Scheme 2.

Synthesis o f oxazolines by a gold-catalyzed asymmetric aldol reaction.

Also in the activation of alkynes for nucleophilic attack, gold salts prove to be soft, exceptionally carbophilic Lewis acids, as confirmed by the examples shown in Scheme 3 [lo]. According to Utimoto and Fukuda both the addition of water as well as of amines to alkynes are catalyzed by gold(111) salts, in particular by sodium tetrachloroaurate; ketones such as 8 and imines such as the ant toxin 10 are obtained as products in excellent yields [loa-el. In the cyclization reaction giving the 1,4-dioxane 12 developed by Teles et al.,

I

49

50

I

An Eldoradofor Homogeneous Catalysis?

Au"'-cat. (2 mol-%)

MeOHiHzO reflux, 1 h

7

8 (929'0)

Ill

Au -cat.

(5 mol-%,)

MeCN

reflux, I h

10 (900/)

H', Au'-cat. (0.001 mol-%)

cfL

MeOjt,,

McOH

Me

55 O C , 20 h

\ L 13 Scheme 3.

12 (93%)

-3T.r Au 111-cat. ( 5 mol-%)

MeN02, H N 0 3 , N a N 0 2 , 50 'C

Gold-catalyzed additions t o alkynes; Ac

'0

14 (35%) =

acetyl.

the short reaction time and use of extremely small amounts of catalyst, in this case methyl(triphenylphosphane)gold(I), are particularly impressive [ 1Od-el. In the isoxazole synthesis according to Gasparrini et al., gold salts catalyze the addition of H N 0 3 to alkynes; under the oxidative reaction conditions nitrile oxides are formed, which undergo a cycloaddition to give final products such as 14 [ 1Of 1. In the gold-catalyzed carbonylation of olefins according to Xu et al., gold(I) carbonyl complexes are considered as active catalysts; this reaction proceeds already at room temperature in concentrated sulfuric acid at a CO pressure of 1 atm and leads after acid-catalyzedskeletal rearrangement to tertiary carboxylic acids such as 16, 18, and 19 (Scheme 4) [ll]. In a more recent publication Hashmi et al. reported that propargyl ketones such as 20 and allenyl ketones such as 21 can be cyclized to furans such as 22 in reactions catalyzed by gold(II1) chloride (Scheme 5) [12]. This type of reaction had already been described as a

An Eldorado for Homogeneous Catalysis?

I

51

Ab.03 (10 mol%) H2S04, 1 atm CO A,2h 15

16 (56%)

AU203 (10 mol%) H2SO4, 1 atm CO A.2h

18 (53%)

17 Scheme 4.

19 (25%)

Cold-catalyzed carbonylation of alkenes.

silver(I)-catalyzed process by Marshall et al. (typical reaction conditions: 20% catalyst and a reaction time of several hours) [13]; obviously. gold salts are the significantly more active catalysts, which is confirmed by the fact that quantitative yields are obtained after a few minutes at room temperature using only 1 mol% of the catalyst.

'0

20

or

AuC13 (1 mol-%) MeCN

E t q E t

20 T

22 (quant.)

Et 0

21

-

R

AuC13 (1 mol-%)

MeCN 2 0 OC R = CHZ-~-(TBDMSO)C~H~

23 Scheme 5.

R

24 (42%)

New gold-catalyzed C-C and C - 0 coupling reactions; TBDMS = tea-butyldimethylsilyl.

52

I

An Eldorado for Homogeneous Catalysis?

Of particular interest is the observation that in certain cases products such as 24 resulting from domino processes are obtained: After the formation of the furan, evidently a double Michael-type addition of these intermediates to the remaining starting material 23 can take place at the unsubstituted 5-position. Preliminary experiments to investigate scope and limitations of such addition reactions in the presence of gold salts also confirm the applicability to the functionalization of other electron-rich arenes (Scheme 6 ) : Besides furans, azulene 28 and di- and trialkoxybenzene are suitable as nucleophiles for the reaction with unsaturated carbonyl compounds [ 141. For instance, 2-methylfuran (25) reacts at the reactive 5-position with methyl vinyl ketone 26 to give the addition product 27, and with azulene 28 a twofold

20 OC, 40 min 25

26

27 (91%)

aAuC13 (1 mol-%)

+ 26 (3 equiv.)

\ \

MeCN, 20 OC 28

29 (49%)

Pd"-cat.

PhCOgBu 25

31 (67%)

30

Pd"-cat.

~

p C 0 2 E t

(1 mol-%)

OCH3 32

H 33

CF3C02H 25 'C, 45 h

OCH3 34 (78%)

Gold and palladium-catalyzed Michael-type additions o f electron-rich arenes to *,,&unsaturated carbonyl compounds.

Scheme 6.

An Eldorado for Homogeneous Catalysis?

alkylation occurs to give 29. In contrast to the catalysis of these reactions with hydrochloric acid and other protic and Lewis acids [15], gold(II1) chloride in acetonitrile guarantees sufficiently mild reaction conditions; the otherwise typical decomposition and polymerization reactions, particularly in the case of furans, are suppressed. On the basis of the results obtained so far, the acidic hydrate of gold(II1) chloride or tetrachloroauric acid works as a protic catalyst [14]. It is important to note that similar products are obtained from palladium-catalyzed reactions, but presumably through a different mechanism. In this case the reaction sequence clearly starts with an electrophilic metalation of the electron-rich arene, followed by intermolecular carbornetalation of the olefinic coupling component, a reaction sequence that by far is a domain of palladium and ruthenium catalysis [16, 171. As shown by the coupling reaction of 2-methylfuran (25) with the acrylate 30 developed by Tsuji and Nagashima [18], owing to the pronounced tendency of alkylpalladium intermediates for /I-H elimination the unsaturated product 31 is obtained; the generally associated reduction of the active palladium(11) catalyst necessitates the addition of an oxidizing agent such as a peroxy acid ester. Very recently Fujiwara et al. [ 191 reported that correponding coupling reactions with alkynes such as 33 in trifluoroacetic acid as solvent proceed already at room temperature with reaction times of several hours. Whether gold salts can also directly metalate electron-rich arenes under C-H activation in analogy to palladium and ruthenium catalysts will require detailed reactivity studies.

35

36 (95%)

Ar

AuCI~ (3 mol-%)

37

+

CH3CN

80 OC, 1 h

AAr

r

W

Ar

Ar

Ar = 4-anisyl 39 (43%)

38 Scheme 7.

Additional examples of protic catalysis provided by gold(ll1) chloride.

I

53

54

I

An Eldorado for Homogeneous Catalysis?

However, the ability of gold(111) chloride to provide protic catalysis under exceptionally mild conditions is further demonstated by two recent examples: the hydroxyallene 35 bearing a silyl protecting group is efficiently cyclyzed to give the 2,s-dihydrofuran 36 without deprotection [20]; other acidic catalysts which in principle sufficiently promote this type of cyclization - such as HCI gas or Amberlyst 15 resin - are of course much less compatible with acid sensitive functionalities. Also for the formation of macrocycle 39 gold(111) chloride turned out to be the catalyst of choice [21]. A new chapter for gold catalysis was opened up by Hashmi et al. when they found a highly selective gold catalyzed arene synthesis [ 221: the efficient formation of the annulated phenol 41 from furan 40 with a terminal alkyne in the side chain is certainly not a simple intramolecular cycloaddition reaction followed by rearomatization, since the oxygen atom obviously migrates during the transformation. According to a recent mechanistic suggestion even gold carbene complexes have to be taken into account as reactive intermediates [ 231. Clearly, it has been shown that gold salts display considerable catalytic activity under moderate conditions and gold catalysis will likely provide for some more surprises. Thus, an extensive development of gold catalysis with numerous new applications is anticipated.

AuC13 (2 mol%)

"3C

/

~

CH3CN 20 OC

40

H3C

OH 41 (94%)

Scheme 8.

References 1

2

An appeal to catalyst research from Faust 11: Man grefe nun nach.. . . Gold, dem Greijeenden ist meist Fortuna hold. a) 0. K R ~ T Z ,7000Jahre Chemie, Nikol Verlagsgesellschaft, Hamburg 1999; b) H. SCHMIDBAUR, Natunv. Rdsch. 1995, 48, 443-451; c) A. GROHMANN, H. SCHMIDBAUR, Organogold Chemistry in: Comprehensive Organometallic Chemistry rr, E. w. ABEL,F. G. A. STONE; G. WILKINSON (Edts.), Pergamon Press Ltd., Oxford, UK, 1994, 1-56; d) H. SCHMIDBAUR, Gold: Organometallic Chemistry in: Encyclopedia of Inorganic Chemistry, John Wiley & Sons, Ltd., Chichester, 1994, 1226-1234; e) H. SCHMIDBAUR, Chem. SOC.Rev. 1995, 24, 391-401; f ) H. SCHMIDBAUR (Ed.), Gold -

Progress in Chemistry, Biochemistry and Technology, John Wiley & Sons, Inc., New York, 1999. 3 L. JAENICKE, Chemie in unserer Zeit 1995. 29, 272-273. 4 a) J. SCHWANK, Gold Bulletin 1985, 18, 210; b) D. THOMPSON, Gold Bulletin 1998, 31, 111-118; c) D. THOMPSON, Gold Bulletin 1999, 32, 12-19; d) G. C. BOND, D. THOMPSON, Catal. Rev.-Sci. Eng. 1999, 41, 319-388. 5 a) T. AIDA,R. HIGUCHI, H. NIIYAMA, Chem. Lett. 1990, 2247-2250; b) T. M. SALAMA, T. SHIDO,R. OHNISHI,M. ICHIKAWA, J. Chem. Soc., Chem. Commun. 1994, 2749-2750. 6 G. SCHMID,Progress in the Science and Technology of Gold, Hanau, June 1996, see Gold Bulletin 1996, 29, 105.

References I 5 5

7 L.-U. MEYER, A. D E MEIJERE,Tetrahedron

Lett. 1976, 497-500. 8 For some special gold( I)-catalyzed processes, see: a) boration of vinylarenes: R. T. BAKER; P. NGUYEN, T. B. MARDER, S. A. WESTCOTT, Angew. Chem. 1995, 107, 1451-1452; Angav. Chem. Int. Ed. Engl. 1995, 34, 1336-1338; b) dehydrogenative dimerization of trialkyltin compounds: H. ITO, T. YAJIMA, J. TATEIWA, A. HOSOMI,Tetrahedron Lett. 1999, 40, 78077810. 9 a) Y. ITO, M. SAWAMURA, T. HAYASHI,]. Am. Chem. SOC. 1986, 108, 6405-6406; b) T. HAYASHI, M. SAWAMURA, Y. ITO, Tetrahedron 1992, 48, 1999-2012; c) A. TOGNI,S. D. PASTOR, J . Org. Chem. 1990, 55, 1649-1664; d) P. F. HUGHES,S. H. SMITH,J. T. OLSON, J. Org. Chem. 1994, 59, 5799-5802. 10 a) Y. FUKUDA, K. UTIMOTO, J. Org. Chem. 1991, 56, 3729-3713; b) Y. FUKUDA, K. UTIMOTO,Bull. Chem. SOC.Jpn. 1991, 64, 2013-2015; c) Y. FUKUDA, K. UTIMOTO, Synthesis 1991, 975-978; d) J. H. TELES,S. BRODE,M. CHABANAS, Angav. Chem. 1998, 110, 1475-1478; Angew. Chem. lnt. Ed. Engl. 1998; 37, 1415-1418; e) J. H. TELES, M. SCHULZ(BASF AG), WO 97/21648 (CA 127:121499u); f ) F. GASPARRINI, M. GIOVANNOLI, D. MISITI,G. NATILE,G. PALMIERI, L. MARESCA,J. Org. Chem. 1993, 115,4401-4402. 11 Q. Xu, Y. IMAMURA, M. FUJIWARA, Y. SOUMA, J. Org. Chem. 1997, 62, 15941598. 12 A. S. K. HASHMI,L. SCHWARZ; J.-H. CHOI, T. M. FROST,Angew. Chem. 2000, 112, 2382-2385; Angew. Chem. Int. Ed. Engl. 2000, 39, 2285-2288.

J. A. MARSHALL, G. S. BARTLEY, J. Org. Chem. 1994, 59, 7169-7171. 14 A. S. K. HASHMI,G. DYKER, E. MUTH, unpublished results. 15 a) K. ALDER, C.-H. SCHMIDT,Chem. Ber. 1943, 76, 183-205; b) M. CATTALINI, S. Cossu, F. FABRIS,0. DE LUCCHI, Synth. Commun. 1996, 26, 637-647; c) M. YAMAGUCHI,M. SHIROTA, T. WATANABE, Heterocycles 1990, 31, 1699-1704; d) C. ROGERS,B. A. KEAY, Can.J. Chem. 1993, 71, 611-622. 16 G. DYKER, Angav. Chem. 1999, 111, 18081822; Angew. Chem. Int. Ed. Engl. 1999, 38, 1698-1 7 12. 17 The addition of carbonyl-functionalized arenes to electron-rich alkenes and alkenes is achieved under ruthenium catalysis (Murai reaction): S. MURAI,F. KAKIUCHI, S. SEKINE,Y. TANAKA, A. KAMATANI, M. SONODA, N. CHATANI,Nature 1993, 366, 529-531. 18 J . TSKJJI, H . NAGASHIMA, Tetrahedron 1984, 40, 2699-2702. 19 C . J I A , D.PIAO,J. OYAMADA, W. Lu, T. KITAMURA, Y. FUJIWARA, Science 2000, 287, 1992-1995. 20 A. HOFFMANN-RODER, N. KRAUSE,Organic Lett. 2001, 3, 2537-2538. 21 G. DYKER, J. LIKJ,unpublished results. 22 a) A. S. K. HASHMI,T. M. FROST,J. W. BATS,]. Am. Chem. SOC.2000, 122, 1155311554; b) A. S. K. HASHMI,T. M. FROST, J. W. BATS,Org. Letters 2001, 3, 3769-3771; c) A. S. K. HASHMI,T. M. FROST,J. W. BATS, Catalysis Today 2002, 72, 19-27. 23 B. MARTIN-MATUTE, D. J. CARDENAS, A. M. ECHAVARREN, Angew. Chem. 2001, 113, 4890-4893; Angew. Chem. Int. Ed. Engl. 2001, 40,4754-4757.

13

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

New and Selective Transition Metal Catalyzed Reactions of Allenes A. Stephen K. Hashmi

Among the most popular organic substrates for transition metal catalyzed reactions are alkenes A and alkynes B. Allenes C have received much less attention. This is easily explained by increasing selectivity problems when we proceed from A to C. While in A we face the question of regioselectivity (Markovnikov versus anti-Markovnikov orientation leading to constitutional isomers, Scheme 1)and stereoselectivity of an addition reaction (cis- or trans-addition at possibly enantiotopic or diastereotopic faces of the double-bond leading to stereoisomers), in B we have to cope with the problem of chemoselectivity (single or double addition leading to different products) and for each addition the regio- and stereoselectivity problems apply as discussed for A. In C the situation is even more complicated: as with the alkynes chemo-, regio- and stereoselectivity are significant, but furthermore we face the question of positional selectivity (which of the two orthogonal double bonds will react in the case of a single addition, thus again leading to constitutional isomers).

R’

dR2 R’ = R2

regioselectivity

regioselectivity

regioselectivity

regioselectivity

stereoselectivity

stereoselectivity

stereoselectivity

stereoselectivity

chemoselectivity

chemoselectivity positional selectivity

A Scheme 1.

B

C

Selectivity problems in different types of unsaturated substrates A-C.

In early investigation of the reactions of allenes with transition metals, the conversions proceeded quite unselectively due to the enhanced reactiuity of the allenes [ 11. This observation led to the neglect of allenes as substrates in such reactions for a long time. In the past

Cyclopropyl Allenes

decade allenes have reemerged as interesting compounds for scientist working in the field of transition metal catalysis. Three major principles were used to overcome the selectivity problem: (1) In intermolecular reactions, the positional selectivity was often controlled by steric hindrance, that is, by substituents on only one of the double-bonds. (2) Intramolecularization of the reactions, usually by placing the reacting groups in such a distance that five- or six-membered rings are formed, automatically solved the positional selectivity problem. (3) Allenes bearing functional groups on the carbon atom next to the allene allowed to control the selectivity by both geometrical restrictions and electronic differentiation of the two cumulated double bonds of the allene, not only in intramolecular but also in intermolecular reactions. While approach ( 1) has allowed some very interesting transformations and numerous mechanistic details could be investigated [ 21, the substituents used to provide steric hindrance also limited the synthetic potential. Principle (2) seems to have a higher potential for organic synthesis [ 31. Principle (3), in paticular, seems to provide some interesting and truly new transformations, which shall be summarized here. The following section is organized along the different types of substrates that all belong to principle (3). If nothing else is mentioned, the reactions proceed with 0.5-5 mol% of catalyst. Vinyl Allenes

As mentioned in the introduction [Ic], no selectivity was observed in early dimerization experiments of 1. But when other partners were offered, the corresponding crossdimerizations were quite selective. Probably methylene metallacyclopentenes 2 [4], which could be isolated, are intermediates that then react with the other partners. Generally, the related 1,3-dienes are less reactive than 1 with its reactive allenic double-bond and do not react in a similar manner [4a]. Rh-catalyzed [4+1] cycloadditions with CO as a second reaction partner led to alkylidene cyclopentenones 3 and 4 [4, 51, while in Pd-catalyzed reactions where 1 was generated in situ and a base was present, only 4 [GI was formed. When Pt(0) was used instead of Rh(I) in the carbonylation reaction, both in the presence of the (R,R)DuPHOS-ligand, opposite enantiomers of 3 were obtained [ Sb]. This observation still needs a precise explanation. [ Fe(CO)5]-mediated reactions of diallenes form dialkylidene cyclopentenones 7 (Scheme 2, here 10 mol-% of catalyst are needed) [7]. Other partners like alkynes in Rh- or 1,3-dienes in Pd-catalyzed reaction led to arenes 5 [8] or vinyl alkylidene cyclohexenes 6 [9]. Since these [4+2] cycloadditions take place between two electronically quite similar partners, a direct Diels-Alder reaction is not feasible. With a certain substitution pattern even [4+4+1] cycloadditions that deliver ninemembered rings 8 [ 101 could be achieved (Scheme 3). With Rh' the very same substrate delivers 3. Cyclopropyl Allenes

Substrates 9 can be regarded as homoolefinic derivatives of 1. Here also the analogous vinyl cyclopropanes don't react similarly to 9, the allenic unit makes 9 more reactive [ll].In Ir'catalyzed reactions with CO the sixmembered analoges of 3, the cyclohexenones 11 [ll], were formed in a [ 5+1] cycloaddition (Scheme 4).

I

57

58

I

New and Selective Transition Metal Catalyzed Reactions of Allenes

R3

R'

R

R3

M"Lm

1

R4

-

y

i

M"+~L,,, R4

2

M"orPto = Rh'

co

Z 68-99%

+ HC=CR5

R3@Ri

* R4

R3

64-82%

3

R3xR R4

4

R'

4

8596%

5 (regioselective! for R4 = H) 15-94%

Scheme 2.

Reactions of vinyl allenes 1.

-@ R

2

R q o 4

Pdo

co R R = Ph, CH=CHZ Scheme 3.

61-8770

Formation of nine-membered rings from vinyl allenes and CO

On the other hand, Rh' in the absence of CO leads to 12 [12] formed via a vinyl cyclopropane/cyclopentene rearrangement. Such a rearrangement without a catalyst would require temperatures between 300 and 400 "C! Again one suspects metallacycles 10 as intermediates that either insert CO or undergo a reductive elimination immediately. With [ CozCOe] 1-hydroxycyclopropyl allenes 13 can be transformed into hydroquinones 14 and the corresponding diacetates 15, respectively, under mild conditions [ 131. This methodology can be used in the synthesis of vitamine E and K analogues (Scheme 5).

Allenes with Neighbouring OH- or NH-groups

I

59

co

9 10

I Scheme 4.

11 28~83% M" = Rhl

Reactions of cyclopropyl allenes 9.

R'

14

13

15 51-90% over two steps

Scheme 5.

Formation of dihydroquinones from cyclopropyl allenes 13

Allenes with Neighbouring OH- or NH-groups

The addition of hydroxy groups to the distal double bond of the allene, mediated by Hg" or Ag' and leading to dihydrofurans, has been known for quite a while [14]. Quite recently Krause et al. could show that Au"' is also able to catalyze such a reaction with complete axis to center chirality transfer, even with substrates that possess additional alcohol groups or silyl ethers therefore were notoriously difficult [ 151. Marshall et al. very successfully applied this principle to the synthesis of natural products and extended it to allenyl carboxylic acids like 16 [16], which can lead to lactones like 17 (Scheme 6).

HOAO

16 (-)-Kallolide B 68%

Scheme 6.

Silver-catalyzed lactonization i n Marshall's synthesis of (-)-Kallolide B (17)

60

I

New and Selective Transition Metal Catalyzed Reactions of Allenes

Further targets were analogues of pseudopteranes [ 171 and of (-)-deoxypukalide [ 181. comparable lactones 19 can be synthesized from allenyl alcohols 18 by a rutheniumcatalyzed carbonylative cyclization [ 191 and an extension of this procedure to the synthesis of lactames 21 has also been reported [ 20). In these examples with one more carbon atom between the allene and the OH or NH group, the corresponding sixmembered compounds could be obtained. With substrates 22 additional C-C bonds can be formed in Pd-catalyzed reactions with aryl halides as reaction partners (Scheme 7) [ 211. With enantiomerically pure bis(oxazoline) ligands ee-values up to 53% could be observed in such reactions [22].

RU3(CO)I2

p,4>**R2

R'

OH

R5

NEt,, dioxane 10 atm. CO,100°C

18

R4 R5

19

RU3(CO)12

R1<*=

NEt,, dioxane 20 atm. CO,100°C

NHR~

20 Scheme 7.

Carbonylative cyclization o f hydroxymethyl allenes 18 and aminomethyl allenes 20.

In the case of Pd-catalyzed reactions of aryl halides with allenyl carbinols 24, enones 27 [23] were obtained (Scheme 8). R

+

Ar-X

OH

22 Scheme 8.

X=Br, I

K2C03

59-79%

23

Combination o f C-C-bond formation and lactonization.

Interestingly, in DMF as solvent and with C032-, for 24 a cyclization leading to the corresponding vinyl epoxides 26 [24] could be achieved! Simple treatment of 24 with Ag' delivers 25. The silver(1)-catalystsshow significant lower reactivity, thus usually 20 mol% or even more are applied. Similar developments were possible for the amines 28, which either formed dihydropyrroles 29 or vinyl aziridines 30 (Scheme 8) [ 251. Here also the reaction heavily depends on the solvent, but no explanation has been provided so far. On the other hand, in the presence of a Pd-catalyst and CO, tertiary amines 31, which cannot form another C-N bond, gave a-vinyl acrylamides 32 (Scheme 9) [26].

Allenes with Neighbouring OH- or NH-groups

I

61

24

25 T R

l PPhl d oor Ph,l+BF;

i

h

l

DMF/CO:-

'

R-S

R d p h

0 27 (HZ-mixtures)

::-65?!0

54~88%

I

1

Mts

28 29

50%

!Zxane

a

30 [cis:trans = 82:18)

,ph

77-83%

1

Mts

Reactions of allenyl carbinols 24 and related amines 28. Mts = 2,4,6-trimethylbenzenesulfonyl.

Scheme 9.

R' R

p

R2

N-R3

R

R3'

Pdo

* R2

'

1 mol% pTsOH

31

At?:

co

R'

R~ R'

32 59-84 Yo

Scheme 10.

Formation of vinylacrylamides 32. p-TsOH = para-toluenesulphonic acid

An alkylative version of the dihydrofuran-synthesis, leading to 35, was developed by Ma et al. [27]. Recently Trost et al. reported that in vanadium-catalyzed additions of allenic alcohols 36 and aldehydes 37 aldol-type products 38 can be obtained in an atom economic manner [28]. Backvall et al. utilized a stereoconvergent palladium-catalyzed S N ~ reaction ' of cc-allenic acetates 39 for the synthesis of (Z,E)-2-bromo-l,3-dienes40 [29]. With different allenylcarbinols 41 a nickel-catalyzedliving polymerization was possible, but no regioselectivity of the C-C bond formation was observed (40% reaction of the @-double bond, 60% reaction at the P-double bond in 42) [ 301.

62

I

wR4

New and Selective Transition Metal Catalyzed Reactions of Allenes

+

R2>*=

R'

" c , R4 r

PdCI,

R2

DMA rt

R'

P

OH

33

34

35 57-86%

Scheme 11. Alkylative cyclization o f hydroxymethyl allenes 33.

R

+

Ph--(F*& OH

VO(OSiPh,),

LRI

-

CH2CI2, rt

36 Scheme 12.

0

37

0

OH

Ph+R' R 6O-88% usually syn preferred

38

Aldol-like products 38 from hydroxymethyl allenes 36.

R2

Pd(0AC)p R'-(=*&

R

'

b

OAc

39 Scheme 13.

2.5 eqs LiBr AcOH/acetone, 40°C

v

R Br

2

40 77-94%, de 86-99%

(E,Z)-Configurated 2-bromo-l,3-dienes 40 from 39.

1.. N!

WCF3 PPh3

/=*=

R

41 R = CH20H, CHMeOH, CMe,OH

Scheme 14.

42

M, = 9.6.103 M,/M,=1.13

Polymerization of hydroxymethyl allenes 41.

Allenyl Ketones

Here also a diversity of reactions was developed. With y,y-disubstituted derivatives 43 and [ Fe(C0)5] (again 10 mol-%), the lactones 44 were formed (Scheme 10) [ 311. Rh' or Ag' cause the cycloisomerization of 45 to the corresponding furan 46 [32]. Again this principle was used in the synthesis of natural products like the enantiomer of the furanocembrane rubifolide [ 331. Even greater is the diversity of substrates 47. Pd" leads to the formation of dimer 48 [ 341, Au"' to a constitutional isomer of 48, the dimer 50.When the latter reaction was performed in the presence of Michael acceptors, the addition products 49 were formed [35]. Finally, in the case of alkoxy-substituted allenyl benzyl ketones 51, the spirocycles 52 are obtained (Scheme 11) [ 361.

Allenyl Carboxylic Esters and Related Substrates R’

43

44 54-89%

45

46 72-99%

21-91Yo

50 24-51% 49 46-7470 Scheme 15.

Transition metal-catalyzed reactions o f allenyl ketones 43, 45 and 47

RO

Q

a=

+

ROH

0

51

80~84%

Scheme 16.

Hg(ll)-catalyzed formation o f spiro[4,5]decanes 52 from p-alkoxy allenyl ketones 51.

Allenyl Carboxylic Esters and Related Substrates

In Nickel(0)-catalyzed reactions these substrates 53 selectively delivered the head-to-head [ 2+2] dimers 54 [ 371.

2

=* dEWG 10 mol% Ni(PPh,), 53

toluene

EWG = COpR, CONRp, SOpPh, COR Scheme 17.

[2+2] Cycloaddition o f 53.

f EWG

54 33-81Yo

I

63

64

I

New and Selective Transition Metal Catalyzed Reactions of Allenes

Transition Metal Catalysis for the Synthesis o f Allenes with Neighboring Functional Groups

The last chapters might have led to the conclusion that transition metals will always react with allenes bearing functional groups in the direct neighborhood. But this is not automatically the case, such substrates can often be prepared by transition metal catalysis without reacting to another product in situ. For example, the copper catalyzed addition of Grignard compounds to alkynyl substituted p-lactones 55 delivers p-allenic acids 56 in high yields [ 381, During these reactions, the central chirality of one of the stereogenic centers of the p-lactone is transferred to the axial chirality of the allene. R3-MgBr

C02H

* 10 mol% CuBr or CuCN.2 LiBr " THF, -78°C

55

56 79-94?0 '

Copper-mediated ring-opening of 55.

Scheme 18.

Amino allenes of type 58 can be prepared by palladium-catalyzed reduction 57 [ 391.

N PG

Br 2 eqs EtJn THF, rt

57

80 - 90%

PG = MTS or Boc Palladium-catalyzed reduction o f amino allenes 58. Mts = 2,4,6-trimethylbenzenesulfonyl.

Scheme 19.

Ma et al. demonstrated that the palladium-catalyzed coupling of vinyl halides GO and allenyl/propargyl metal species 59 can deliver vinyl allenes 61 [40]. R'

Ph

+JR1

Ph+(

59

M

M

R' Pd(O)

b

R2?Od

R4

4-

R2

60 Scheme 20.

R3

xR4

x

X=Br, I

R3

61

5 - 77%

Vinyl allenes 61 by palladium-catalyzed cross-coupling.

2-Bromo-l,3-butadienes 62 can be coupled with nucleophiles to deliver allenylcarbinols and the related amines and phosphanes 63 [41]. In some cases even chloroprene can be used [421.

Conclusion I 6 5

T:

M-NU

R

62

-

[rr-allylPdCI],

R3 Nu

THF

63

M-NU= NaOPh, KN(Boc),, LiPPh,

Scheme 21.

Palladium-catalyzed allylic substitution at 62.

Palladium catalysts rearrange chiral 2-alkynyl sulfinates 64 into chiral allenyl sulfones 65

WI.

65

(Ss,S)-64 Scheme 22.

39-89% 60-89% ee

Palladium-catalyzed isornerization of 64.

The iron-catalyzed reaction of propargyl sulfides 66 and trimethylsilyldiazomethane 67 delivers allenyl cc-silyl sulfides 68 [44].

DCE, 83°C

66 Scheme 23.

67

d’ 68 48-90%

Iron-catalyzed synthesis o f 68.

The Latest Highlight: Selective Reactions between Two Allenes

As mentioned in the introduction, the reactivity of the allenes is high. Therefore the oxidative and cyclizative cross dimerization of two different allenic substrates just recently reported by Ma et al. can be considered to be a milestone in this field! They discovered that one equivalent of 2,3-dienoic acids 69 and five equivalents of allenyl ketones 70 with the simple PdC12(MeCN)2catalyst can deliver up to 92% of the cross dimerization product 71

PSI. Conclusion

The recent investigation in many groups made selective and synthetically interesting transformations of allenes available, one important motive for this achievement is the presence

66

I

New and Selective Transition Metal Catalyzed Reactions ofAllenes

.=

69

R.<

PdCI,(MeCN),

+ MeCN, rt * ''-H*"

R*

R'

+{ HO

ko

R4

0

70

71

61-92°/o

Scheme 24. Cyclizative cross-dimerization of two different allenic substrates 69 and 70

on fuctional groups in the direct proximity of the allene. Still, often the unique chemoselectivity still lacks explanation. A deeper mechanistic understanding of these selectivities might be the key for future developments of even more exciting and synthetically fruitful reactions. References a) B. L. SHAW,A. J. STRINGER, Inorg. Chem. Acta Rev. 1973, 7, 1-10; b) F. L. BOWDEN,R. GILES,Coord. Chem. Rev. 1976, 20, 81-106; for further efforts, see: c) H . SIEGEL,H. HOPF,A. GERMER,P. BINGER,Chem. Ber. 1978, 111, 3112-3118; d) G. ERKER,Methoden Org. Chem. (Houben-Weyl)4th ed, 1952-, Vol. E18, 1986, pp. 870-873 and 882-883. 2 For selected examples and additional references, see: L. BESSON,I. G o R ~B. , CAZES,Tetrahedron Lett. 1995, 36, 3853H . ALPER, 3856; W.-J. XIAO,G. VASAPOLLO, J . Org. Chem. 1998, 63, 2609-2612; R. C. LAROCK, Y. H E , W. W. LEONG,X. HAN, M. D. REFVIK,J. M. Z E N N E RJ,. Org. Chem. 1998, 63, 2154-2160; T. SUDO,N. ASAO,V. GEVORGYAN, Y. YAMAMOTO, J . Org. Chem. 1999; 64, 2494-2499; S. KACKER, A. S E N ,J. Am. Chem. SOC.1997, 119, 10028-10033; B. M. TROST,A. B. PINKERTON, J . Am. Chem. SOC.1999, 121, 10842-10843; D. HIDEURA,H. URABE,F. SATO,J . Chem. SOC.,Chem. Commun. 1998, 271-272. 3 For selected examples and additional references, see: V. M. ARREDONDO, S. TIAN,F. E. MCDONALD, T. J. MARKS,J . Am. Chem. SOC.1999, 121, 3633-3639; R. D. WALKUP,G. PARK,J . Am. Chem. SOC. 1990, 112, 1597-1603; R. GRIGG,J.M. SANSANO, Tetrahedron 1996, 52, 1344113454; C. JONASSON, J.-E. BACKVALL, Tetrahedron Lett. 1998, 39, 3601-3604; 1

4

5

6

7 8

9

D. N. A. Fox, D. LATHBURY, M. F. MAHON, K. C. MOLLOY,G. GALLAGHER, J . Am. Chem. SOC.1991, 113, 2652-2656; M. LAUTENS,C. MEYER, A. V A N OEVEREN, Tetrahedron Lett. 1997, 38, 3833-3836; J. S. PRASAD,L. S. LIEBESKIND, Tetrahedron Lett. 1988, 29, 4253-4256; F. P. J. T. RUTJES,K. C. M. F. T J E N ,L. B. WOLF,W. F. J. KARSTENS, H. E. SCHOEMAKER, H. HIEMSTRA,Org. Lett. 1999, 1, 717-720; K. M. BRUMMOND, J. Lu,J. Am. Chem. SOC.1999, 121, 50875088; for an example of a diastereoselec, FUJI, tive reaction, see: P. A. W E N D E RM. C. 0. HUSFELD, J. A. LOVE,Org. Lett. 1999, 1, 137-139. a) M. MURAKAMI, K. ITAMI,Y. ITO, Angew. Chem. 1995, 107, 2943-2946; Angew. Chem Int. Ed. Engl. 1995, 34, 2691; b) M. MURAKAMI, K. ITAMI,Y. ITO,]. Am. Chem. SOC.1996, 118, 11672-11673. a) M. MURAKAMI, K. ITAMI,Y. ITO,J . Am. Chem. SOC.1993, 115, 5865-5866. b) M. MURAKAMI, K. ITAMI,Y. ITO,J . Am. Chem. SOC.1999, 121,4130-4135. T. MANDAI,J. TSUJI,Y. TSUJIGUCHI, S. SAITO,J. Am. Chem. SOC.1993, 115, 58655866. M. S. SIGMAN,B. E. EATON,J . Am. Chem. SOC.1996, 118, 11783-11788. M. MURAKAMI, M. UBUKATA,K. ITAMI,Y. ITO, Angew. Chem. 1998, 110, 2362-2364. M. MURAKAMI, K. ITAMI,Y. ITO, J . Am. Chem. SOC.1997, 119, 7163-7164.

References I 6 7 10 M. MURAKAMI, K. ITAMI,Y. ITO, Angav.

Chem. 1998, 110, 3616-3619; Angew. Chem. Int. Ed. 1998, 37, 3418-3420. 11 M. MURAKAMI, K. ITAMI,M. UBUKATA,I. TSUJI,Y. ITO,J. Org. Chem. 1998, 63, 4-5. 12 M. HAYASHI, T. OHMATSU,Y.-P. MENG,K. SAIGO,Angav. Chem. 1998, 110, 877-879. 13 Y. OWADA,T. MATSUO,N. IWASAWA, Tetrahedron 1997, 53, 11069-11086. 14 L.-I. OLSSON, A. CLAESSON, Synthesis 1979, 743-745. 15 A. HOFFMANN-RODER, N. KRAUSE,Org. Lett. 2001, 3, 2537-2538. 16 J. A. MARSHALL, K. G. PINNEY,J. Org. Chem. 1993, 58, 7180-7184; J. A. G. S. BARTLEY, E. M. WALLACE, MARSHALL, J. Org. Chem. 1996, Gl, 5729-5735. 17 J. A. MARSHALL, L. M. MCNULTY, D. Zou, J. Org. Chem. 1999, 64, 5193-5200. 18 j. A. MARSHALL, E. A. VAN D E V E N D E R , ~ . Org. Chem. 2001, 66, 8037-8041. 19 E. YONEDA,T. KANEKO,S.-W. ZHANG,K. ONITSUKA,S. TAKAHASHI,Org. Lett. 2000, 2,441-443. 20 S.-K. KANG, K.-J. KIM, C.-M. Yu, J.-W. HWANG,Y.-K. Do, Org. Lett. 2001, 3, 2851-2853. 21 S. MA, Z. S H I ,J. Org. Chem. 1998, 63, 6387-6389. 22 S. MA, Z. SHI, S. W u , Tetrahedron: Asymmetry 2001, 12, 193-195. 23 I. SHIMIZU,T. SUGIURA, J. TsurI, J. Org. Chem. 1985, 50, 537-539. 24 S.-K. KANG,T. YAMAGUCHI, S:J. PYUN, Y.-T. LEE,T.-G. BAIK,Tetrahedron Lett. 1998, 39, 2127-2130; S. MA, S. ZHAO,J. Am. Chem. Sac. 1999, 121, 7943-7944. 25 H. OHNO,M. ANZAI,A. TODA,s. O H I S H I , N. FUJII,T. TANAKA, Y. TAKEMOTO, T. IBUKA,]. Org. Chem. 2001, 66,4904-4914. H. OHNO,A. TODA,Y. MIWA,T. TAGA,E. N. FUJII,T. IBUKA,]. OSAWA,Y. YAMAOKA, Org. Chem. 1999, 64, 2992-2993; See also A. CLAESSON, C. SAHLBERG, K. LUTHMAN, Acta Chem. Scand. B 1979, 33, 309-310. 26 Y. IMADA,G . VASAPOLLO, H . ALPER,J. Org. Chem. 1996, 61, 7982-7983. 27 S. MA, W. GAO, Tetrahedron Lett. 2001, 41, 8933-8936. 28 B. M. TROST,C. JONASSON, M. WUCHRER, J. Am. Chern. Soc. 2001, 123, 1273612737. 29 A. H O R V ~ T H j.-E. , BACKVALL, J. Org. Chem. 2001, 66,8120-8126. 30 M. TAGUCHI,I. TOMITA,T. ENDO,Angav.

Chem. 2000, 112, 3813-3815; Angau. Chem. Int. Ed. 2000, 39, 3667-3669. 31 M. S. SIGMAN,C. E. KERR,B. E. EATON,]. Am. Chem. Soc. 1993, 115, 7545-7546; M. S. SIGMAN,B. E. EATON,J. D. HEISE, C. P. KUBIAK,Organometallics 1996, 15, 2829-2832; For the analogous allenyl imines, see: M. S. SIGMAN,B. E. EATON,J. Org. Chem. 1994, 59, 7488-7491. 32 J. A. MARSHALL, E. D. ROBINSON, J. Org. Chem. 1990, 55, 3450-3451; J. A. X. WANG,J. Org. Chem. 1991, MARSHALL, 56, 960; j. A. MARSHALL, X. WANG,J. Org. Chem. 1992, 57, 3387; J. A. MARSHALL, G . S. BARTLEY, J. Org. Chem. 1994, 59, E. M. WALLACE, 7169-7171; j. A. MARSHALL, P. S. COAN,J. Org. Chem. 1995, GO, 796; J. A. MARSHALL, C. A. SEHON,J.Org. Chem. 1995, 60, 5966; J. A. MARSHALL, j. LIAO,J. Org. Chem. 1998, 63, 5962. 33 j. A. MARSHALL, C. A. SEHON,]. Org. Chem. 1997, 62,4313-4320. 34 A. S. K. HASHMI,Angew. Chem. 1995, 107, 1749-1751; Angew. Chem. Int. Ed. Engl. 1995, 34, 1581-1583; A. S. K. HASHMI, T. L. RUPPERT,T. KNOFEL,J. W. BATS,J. Org. Chem. 1997, 62, 7295-7304. 35 A. S. K. HASHMI,L. SCHWARZ,j.-H. CHOI, T. M. FROST,Angew. Chem. 2000, 112, 2382-2385; Angew. Chem. Int. Ed. Engl. 2000, 39, 2285-2288. 36 A. S. K. HASHMI,L. SCHWARZ, M. BOLTE, Tetrahedron Lett. 1998, 39, 8969-8972. 37 S. SAITO,K. HIRAYAMA, C . KABUTO,Y. YAMAMOTO, J. Am. Chem. Soc. 2000, 122, 10776-10780. 38 Z. WAN, S. G. NELSON,J.Am. Chem. SOL. 2000, 122, 10470-10471. 39 H . O H N O ,A. TODA,S. OISHI,T. TANAKA, Y. TAKEMOTO, N. FUJII, T. IBUKA,Tetrahedron Lett. 2000, 41, 5131-5134. 40 S.-M. MA, A,-B. ZHANG,Pure Appl. Chem. 2001, 73, 337-341. 41 M. OGASAWARA, H . IKEDA,T. HAYASHI, Angew. Chem. 2000, 112, 1084-1086; Angew. Chem. Int. Ed. 2000,39,1042-1044. 42 M. OGASAWARA, H. IKEDA,T. NAGANO,T. HAYASHI,Org. Lett. 2001, 3, 2615-2617. 43 K. HIROI, F. KATO,Tetrahedron 2001, 57, 1543-1550. 44 R. PRABHARASUTH, D. L. VANVRANKEN,]. Org. Chem. 2001, 66, 5256-5258. 45 S. MA, Z. Yu, Angew. Chem. 2002, 114, 1853-1856; Angew. Chem. Int. Ed. 2002, 41, 177551778,

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

I

Controlling Stereoselectivity with the Aid o f a Reagent-Dir e dng Croup Bernhard Breit

Introduction

Substrate control can be a useful tool to allow for high levels of selectivity in organic reactions. This is particularly valid for reactions in which the reacting substrate is equipped with a functionality suitable to allow for a precoordination of the reagent followed by an intramolecular reagent delivery. This type of reactions, named according to Evans et al. as substrate directable reactions, is of great synthetic value as proven in numerous total syntheses [ 11. However, known substrate directable reactions rely on the nature of the coordinating functionality present in a particular substrate. This clearly defines limitations to the set of reagents potentially directable by a specific functional group. A way to overcome such an intrinsic limitation may provide a specifically introduced reagent-directing group into an organic substrate (see Scheme 1).

Reagent Directing Group via precoordination

Concept of a specifically introduced reagent-directing group into an organic substrate as a selectivity control instrument.

Scheme 1.

Such a specifically introduced functionality should have the ability to precoordinate the desired reagent which would result in an intramolecular pathway for the desired chemical reaction with a corresponding reactive functional group within the substrate. By choosing the appropriate point of attachment of the directing functionality, as well as by choosing the appropriate geometry of this group, one should have complete control of the trajectory of a particular reagent, which of course should be the ideal basis to control any type of selectivity for a given chemical reaction.

Discussion I 6 9

Such an approach necessitates two additional synthetic operations: introduction as well as removal of the reagent-directing group. However, such a disadvantage at first sight should be acceptable if one could solve a selectivity problem for a synthetically valuable reaction which is otherwise not susceptible to stereocontrol. In this context transition metal catalyzed addition reactions have gained importance as a consequence of their intrinsic atom economy and efficiency which may be beneficial for enviromental and economic grounds [ 21. An example is the rhodium catalyzed hydroformylation reaction, which is an industrially important homogenous catalytic process [ 3 ] . In contrast, it is amazing that such an important transition-metal catalyzed CjC bond-forming process has been employed only rarely in organic synthesis [4]. Part of the reason stems from the difficulty in controlling stereoselectivity. Even though some recently developed chiral rhodium catalysts allow for enantio- and diastereoselective hydroformylation of certain specific classes of alkenes [ 5, 61, only little is known about the diastereoselective hydroformylation of acyclic olefins [ 7, 81. Discussion

The difficulty of this task became obvious in an attempt to achieve a diastereoselective hydroformylation of a simple methallylic alcohol system. It was expected that in analogy to the known substrate-directed rhodium-catalyzed hydrogenation reaction, substrate direction via the hydroxyl substituent would control diastereoselectivity in the course of the hydroformylation reaction [91. However, a completely stereorandom hydroformylation product formation was observed (1+3) [lo, 111.

1

2

3 syn : anti 50 : 50

Reagents and conditions (a) 0.35 mol% [Rh(CO)~acac], 7 mol% PPh,, 20 bar H 2 / C 0 (l:l),toluene, 90 "C, 6-24 h (83-95%); (b) PCC on A1203, CH2C12, 25 "C, 16 h (95%).

Scheme 2.

In contrast to the rhodium-catalyzed hydrogenation reactions, the hydroxyl group does not operate as an efficient catalyst-directing group in the rhodium catalyzed hydroformylation. This may be primarilly due to the carbon monoxide, itself an excellent ligand for rhodium(I), which is present in large excess under hydroformylation conditions. Hence, the hydroformylation reaction is an ideal first-test case for the concept of a specifically introduced catalyst-directing functionality with respect to its potential to control diastereoselectivity in the course of the hydroformylation reaction. Therefore, a specific catalyst-directing group needed to be designed, which itself had to (a) function as a good ligand for rhodium under hydroformylation conditions, (b) provide reversible coordination of the catalytically active rhodium

70

I

Controlling Stereoselectivity with the Aid ofa Reagent-Directing Group

species to allow for turnover, (c) enable facile introduction into the substrate as well as removal from the product and (d) allow for a highly ordered cyclic transition state for the stereochemistry defining step of the hydroformylation reaction.

(c-DPPBA) 4

Scheme 3. Design o f a catalyst-directing group for the control of diastereoselectivity upon hydroformylation of acyclic methallylic alcohols.

As an ideal catalyst-directing group for that particular problem the ortho-diphenylphosphino benzoate system (0-DPPB) was introduced [lo]. With the aid of the o-DPPB functionality a substrate-directed diastereoselective hydroformylation of methallylic alcohol derivatives could be achieved with high levels of acyclic stereocontrol to provide the syn-aldehydes6 as the major diastereomers [ 101.

5

syn-6

up to

96

anti-6 4

Scheme 4. o-DPPB-directed stereoselective hydroformylation o f methallylic alcohol derivates. Reagents and conditions (a) 0.7 mol% [Rh(CO)zacac], 2.8 mol% [P(OPh)3], 20 bar Hz/CO ( l : l ) , toluene, 90 "C, 24 h (63-99%).

Support for the role of the o-DPPB substituent as a catalyst-directing group was provided in a control experiment with the benzoate 7. Thus, exchanging the phosphorus of the oDPPB group with a CH moiety, itself not able to coordinate to the catalytically active rhodium center, caused a complete loss of stereoselectivity in the hydroformylation reaction [lo].

Discussion

F X P . 2

P

h

Rh-Cat. H&O

q

0 p X P h 2

P

h

h

0 2 X P ~ 2

+

Ph% CH3 0

CH3 0

CH3

TOF [h-'1 X = P:

5a

21

syn-6a

92

:

a

anti-6a

X=CH:

7

1.4

syn-8

50

:

50

anti-8

Reagents and conditions (a) 0.7 mol% (Rh(CO)lacac], 2.8 mol% [P(OPh),], 20 bar H?/CO ( l : l ) , toluene (0.1 M), 90 "C, 2 h Scheme 5.

The o-DPPB-directedhydroformylation of methallylic alcohol derivatives could be applied for the construction of stereotriads - central building blocks of the polyketide class of natural products. Thus, starting from the methallylic o-DPPB esters 9, 11 the anti-syn and all-syn stereotriad building blocks 10 and 12 could be obtained in good yields and diastereoselectivities [ 121.

+

OTr

O(o-DPPB)

Rh-Cat. H$CO (a)

+

OTr

*

O(o-DPPB)

anti-syn

CH3 CH3 0

CH3 CH3

dr b 96 : 4 9

OPiv O(eDPPB)

YY

CH3 CH3

* 10

Rh-Cat. H$CO (b)

OPiv O(eDPPB) t

all-syn

CH3 CH3 0

dr 95 : 5

11

12

Scheme 6. Reagents and conditions (a) 0.7 mol% [Rh(CO)zacac], 2.8 mol% [P(OPh),], 20 bar H 2 / C 0 ( l : l ) , toluene, 90 "C, 24 h (91%), (b) same as (a) (70%).

Interestingly, the same concept involving a catalyst-directing group allowed also to make efficient use of 1,3 asymmetric induction. This, of course, is a much more difficult situation, since additional degrees of freedom have to be controlled in the course of the stereo-

I

71

72

I

Controlling Stereoselectivity with the Aid ofa Reagent-Directing Group

chemistry defining step of the hydroformylation reaction. However, homomethallylic oDPPB esters 13 were reacted to give the anti-aldehydes 14 as the major diastereomer in selectivities of ca. 91:s) [13]. Rh-Cat.

13

anti-14

syn-14

o-DPPB-directed stereoselective hydroformylation of homomethallylic alcohol derivates. Reagents and conditions (a) 0.7 mol% [Rh(CO)~acac],2.8 mol% [P(OPh),], 20 bar H2/CO ( l : l ) , toluene, 3O-5O0C, 24 h (72-90%).

Scheme 7.

In these cases, the interplay of a preferred substrate conformation as well as catalyst delivery via the catalyst-directing group form the basis for the diastereoselectivity observed ~31. Removal of the Reagent Directing Group

After successful hydroformylation one may decide to remove the catalyst-directing o-DPPB group, which may be achieved by simple alkaline hydrolysis (syn-Gaisyn-3) [lo] or via hydride reduction after transferring the aldehyde e.g. to an alkene via Wittig olefination (syn-6b+syn-23) [14]. OH

0

syn-2

syn-3 (92 : 8)

4

0

(*)-syn-sa (92 : 8)

O(eDPPB)

O(eDPPB) i-Pr

CH3 0

(+)-sy1~6b (96 : 4)

CH3

syn-15 (96 : 4)

Reagents and conditions (a) KOH, T H F / M e O H / H 2 0 (2:2:1), 50 "C,2.5 h (99%); (b) 2 equiv. PCC on A1203,25 "C, 16 h (95%); (c) Ph3P = CH2, THF, -78"+0 "C (89%); (d) LiAIH4, ether, 0 "C (95%). Scheme 8.

CH3

syn-16 (96 : 4)

Multiple Use of One Reagent-Directing Croup: Towards a RDC-Controlled Organic Synthesis

I

73

Multiple Use of One Reagent-Directing Group: Towards a RDC-Controlled Organic Synthesis

To increase the efficiency of a specifically introduced directing functionality one should make use of that functionality as often as possible to control selectivity in further skeletonconstructing processes (see Scheme 9). In an ideal scenario each reaction would generate the functionality required for a subsequent transformation. Hence, at the end an organic synthesis could be the result in which one reagent-directing group (RDG) would control the selectivity of each single reaction step.

8-9 Reagenta

R

reaction i

@ Scheme 9.

R-A

Reagentb

Reagent c

____)

reaction ii

R-A-B

reaction iii

8

R-A-B-C

Reagent-Directing Group: Controls selectivity of reaction i-iii

R

Organic Substrate

A

Via reaction 1 and reagent a introduced modification

Multiple use of a reagent-directing group - towards an RDC-controlled organic synthesis.

Towards this goal, the potential of the o-DPPB group to control diastereoselectivity in a carbon carbon bond forming reaction, following the hydroformylation step was explored [15]. Enoates 17, were chosen as the test substrates since the stereoselective 1,4-addition of a methyl would provide a structural building block found in biologically important natural products of the polyketide class (e.g. antitumor agent dictyostatin 1 and the ionophore calcimycin).

conjugate addition

Scheme 10. Working hypothesis for the o-DPPB group t o act as an organometallic reagent directing group for the conjugate addition of Cilman cuprates t o acyclic enoates.

The enoates 17 were obtained in good yield and diastereoselectivity by subjecting the crude hydroformylation products 6 to Horner-Wadsworth-Emmons olefination conditions (HWE). Reaction of enoates 17 with dialkyl Gilman cuprates gave the anti 1,4-addition

74

I

Controlling Stereoselectivity with the Aid ofa Reagent-Directing Group

product 18 in good yield as the major diastereomer (dr 2 95:s with respect to the newly formed stereogenic center) [ 151. Rh-Cat. H&O

O(o-DPPB)

O(o-DPPB)

HWEolefination

(b)

(a)

R?

R +

CH3 5

*

CH3 0 6

17

18 dr 595:5

dr294:6 E:Z > 95:5 Sequential use o f t h e reagent directing o-DPPB group t o control stereoselectivity in the course o f hydroformylation and subsequent conjugate addition with organocuprates. Reagents and conditions (a) 0.7 mol% [Rh(CO)zacac], 2.8 Scheme 11.

mol% [P(OPh)j], 20 bar H2/CO ( l : l ) ,toluene, 90 "C;(b) (EtO)z(O)PCH2CO,Et, n-BuLi, DME, 20 "C (71-83% both steps); (c) 1.5 equiv. R'ZCuLi, ether, -78"+0 "C (61-93%).

Thus, combining o-DPPB-directed hydroformylation with the o-DPPB-directed cuprate addition afforded building blocks with up to four stereogenic centers (19-21). (?(o-DPPB)

OPiv O(o-DPPB) *OE' CH3 CH3 CH3 0 19

20

dr 8 5 : 15

dr 95 : 5

/--7

O(o-DPPB)

'UN

I 2o

-i-Pr

CH3 CH3 CH3 0 21 dr 95 : 5

lonophore A-23187 (Calcimycin)

Interestingly 1,4-addition product 21 is equipped with the same relative and absolute configuration of the four stereogenic centers found in the ionophore calcimycin.

o-DPPB-directed Hydroformylation as Part of Sequential Transformations

I

75

o-DPPB-directed Hydroformylation as Part o f Sequential Transformations

One may improve efficiency of an o-DPPB directed hydroformylation by incorporating this reaction into sequential transformations (domino reactions) [ 161. The hydroformylation itself should be ideally suited for such a purpose, since this reaction provides under fairly mild reaction conditions access to the synthetically valuable aldehyde functionality. The aldehyde itself should be ideally suited to allow for further skeleton-constructing reactions. One type of sequential transformations employing the hydroformylation reaction as a key step is the hydroaminomethylation of olefins originally discovered by Reppe [ 171. However, efficient control of diastereoselectivity in the course of this hydroaminomethylation reaction was unknown [18, 191. Employing the same concept and catalyst-directing o-DPPB group enabled the development of a substrate-directed diastereoselective hydroaminomethylation of acyclic methallylic alcohol derivatives 5 to give in diastereoselectivities of greater 94% the corresponding amines 22 [20]. This process allows, in one step, the formation of a C~-Cbond, a C-heteroatom bond, introduction of the ubiquitous amine functionality, and, additionally, generates a new stereogenic center with high levels of acyclic stereocontrol. The mechanism of this sequential transformation involves presumably three steps. First o-DPPB directed stereoselective hydroformylation of the methallylic o-DPPB esters 5 provides the aldehyde 6 . Enamine formation ( 1 2 3 ) with the secondary amine present and subsequent rhodium catalyzed hydrogenation finishes the sequence of reactions, and affords the saturated amines 22.

+

O(eDPPB)

Q(eDPPB)

HNR'z Rh-cat; CO/Hp t

CH3

syn/anti> 94 : 6 22

5

I

enamine hydrogenation

hydroformylation

I

'

6

2

3

Scheme 12. o-DPPB-directed hydroaminomethylation with secondary arnines. Reagents and conditions: 1.5 Equiv. HNR'?, 0.7 mol% [Rh(CO)?acac], 2.8 mol% [P(OPh)3], 20-80 bar H 2 / C 0 ( l : l ) , toluene, 90"-120 "C (40-65%).

In addition to secondary amines, primary amines could be employed furnishing the corresponding secondary amine derivatives as the final products in equally high diastereoselectivity.

76

I

Controlling Stereoselectivity with the Aid ofa Reagent-Directing Group HzNR'

Rh-cat; CO/H2D

O(c-DPPB) R+NHR 1

CH3 syn/anfi 2 94 : 6 24

5

I

imine

hydroformylation

2

6

5

Scheme 13. o-DPPB-directed hydroaminomethylation with primary arnines. Reagents and conditions: 1.5 Equiv. HINR', 0.7 mol% [Rh(CO)2acac], 2.8 mol% [P(OPh)3], 20+80 bar H2/CO ( l : l ) , toluene, 90"-120 "C (40-46%).

In these cases, the reaction sequence must have proceeded through an imine intermediate 25 followed by a rhodium catalyzed imine reduction. This appeared surprising, since known hydroaminomethylation attempts starting from primary amines and alkenes, employing similar rhodium-catalysts, under similar reaction conditions were found to stop generally at the stage of the imine [21]. Hence, a special situation may be given for o-DPPB derivatives 5. A plausible explanation for the increased reactivity towards imine hydrogenation may take into account the presence of the catalyst-directing o-DPPB group.

Catalyst-Directing Group (CDG)

[mine-Hydrogenation Scheme 14.

Possible role of the o-DPPB group in the course of the imine hydrogenatlon step.

Thus, it is likely, that after imine formation a second catalyst precoordination occurs and an intramolecular imine hydrogenation takes place. Such an intramolecular process should be kinetically favored compared to a corresponding intermolecular reaction pathway. Hence, the catalyst-directing o-DPPB group may be acting within one sequential transformation in

o-DPPB-directed Hydroformylation as Part of5equential Transformations

two different ways. Firstly, the CDG controls diastereoselectivity in the hydroformylation step and secondly controls chemoselectivity in the course of the imine reduction. Other sequential transformations employing the hydroformylation as the key step may be realized if other nucleophiles such as e.g. carbon nucleophiles are offered in the course of the hydroformylation reaction. A resulting domino reaction would approach an ideal synthetic method as defined by Hendrickson [21]. Thus, according to his definition, only skeleton-constructing reactions are inevitable and consequently an efficient synthesis should consist only of framework elaborating steps. Furthermore, if a particular target contains stereogenic centers the most efficient synthetic steps are according to Corey those which in addition to carbon skeleton construction allow for the generation of new stereogenic centers selectively [22]. A reaction in agreement with these efficiency criteria would be a domino stereoselectivehydroformylation-Wittig olefination process. This would require that the hydroformylation reaction be compatible with the presence of a Wittig ylid throughout the course of the reaction. Reacting both methallylic and homomethallylic alkenic substrates under hydroformylation conditions in the presence of stabilized Wittig ylids gave the corresponding domino hydroformylation products 26 in good yields and diastereoselectivities [24]. Whereas in the case of the disubstituted stabilized Wittig ylids the reaction stopped at the stage of the trisubstituted olefin 26, in the case of monosubstituted ylids a further hydrogenation reaction of the @'unsaturated carbonyl functionalities occurred and provided the corresponding saturated derivatives 27. Control of diastereoselectivity was provided via the catalyst-directing o-DPPB group making use of both 1,2- and 1,3-asymmetric induction.

O(PDPPB)

Ph3P=CMeCOR' Rh-Cat.; H2/C0 *

R+

CH3

O(@DPPB) CH3 ++R

0

CH3

synhnfi 5

up to 96 : 4 26

Scheme IS. Domino hydroformylation-Wittig olefination. Reagents and conditions: 1.1 Equiv. Ph,P = CMeCOR'. 0.7 mol% [Rh(CO)zacac],2.8 mol% [P(OPh)p], 20 bar H2/C0 ( l : l ) , toluene, 90 "C (60-78%). R' = Me, OEt.

This domino reaction enables in one step the construction of two carbon carbon single bonds and additionally, generates a new stereogenic center with high levels of acyclic stereocontrol. Through the substituents R and R' this domino reaction may potentially be used as a fragment coupling step in the course of a convergent synthetic strategy. However, although synthetically useful, in terms of atom economy the Wittig olefination suffers from the stoichiometric loss of phosphane oxide as the byproduct. This deficiency of the above Domino protocol could be overcome employing the Knoevenagel condensation as the key olefination step. Thus, when methallylic o-DPPB esters were subjected to hydroformylation conditions

I

77

78

I

Controlling Stereoselectivity with the Aid ofa Reagent-Directing

O(oDPPB)

Ph3P=CHCOR', Rh-Cat.; H$CO R' = Alkyl, OEt

R+

Group O(oDPPB)

*

R R +8

0 CH3 syn/anfi 2 90 : 10 27

CH3 5

+

hydroforrnylation

hydrogenation

1 I

[

wittig olefination

.D

[

R*Rt]

CH3 6

28

Domino hydroformylation-Wittig olefination-hydrogenation Reagents and conditions: 1.5 Equiv. PhlP = CMeCOR', 0.7 mol% [Rh(CO)2acac],2.8 mol% [P(OPh),], 20 bar Hz/CO (l:l), toluene, 90 "C (60-82%). R' = Me, OEt.

Scheme 16.

O(oDPPB)

JY

.EWG ( EWG

O(oDPPB) EWG R

Rh-Cat.; H$CO D EWG = COR', C02R'

CH3

W

W

G

CH3 syn/ani 2 92 : 8 29

5

hydroforrnylation

hydrogenation

t

[ 4-31

E

1 I

Knoevenagel

D

[

R%R\]

6

CH3

30

Domino hydroformylation-Knoevenagel condensationhydrogenation. Reagents and conditions: 1.1 Equiv. CH2EWC2, 1.2 equiv. piperidinium acetate, 0.7 mol% [Rh(CO)2acac], 2.8 mol% [P(OPh)3], 20 bar H*/CO (1:1), toluene, 90 "C (51-71%). Scheme 17.

in the presence of catalytic amounts of piperidinium acetate and 1.1 equivalent of a CHacidic compound (e.g. malonates, 8-ketoesters, 1,3-diketones) a Domino hydroformylationKnoevenagel condensation-hydrogenation reaction occured to furnish the saturated derivatives 29 in good yields and with excellent diastereoselectivities [ 2 5 ] .

Conclusion 179

o-DPPB-directed Allylic Substitution with Organocopper Reagents

When looking for a process to remove the reagent-directing o-DPPB group with concomitant formation of a new carbon skeleton bond, allylic substitution with organocopper reagents appeared to be a synthetically appealing candidate.

O(eDPPB) H

3

C

e

p

h

symaddition mol% CuBr.SMe2/ 1.1 equiv. MeMgl

CH3

*

H

3

(-)-31

C

d

P

h

(+)-32

€:Z>99:1 ee > 99 %

mol% CuBr.SMe2 €:Z

yield

2 98:2

95:5 > 9 9 % >99% 92 Yo 85 %

t Scheme 18.

o-DPPB-directed allylic substitution with organocopper reagents.

Interestingly, the o-DPPB group was found to serve as an efficient reagent-directing leaving group for copper mediated and catalyzed allylic substitution with Grignard reagents [ 261. The o-DPPB group provided almost perfect control over regioselectivity, alkene geometry and 1,3 chirality transfer, and could be recovered as the corresponding o-DPPB acid almost quantitatively. Conclusion

The introduction of an appropriately designed reagent-directing group allowed the development of a substrate-directed, stereoselective hydroformylation reaction of acyclic methallylic and homomethallylic alcohol derivatives. The potentially multifunctional character of the introduced reagent-directing o-DPPB group was explored in the course of a stereoselective addition of Gilman cuprates to acyclic enoates. Thus, by combining both o-DPPB-directed hydroformylation and o-DPPB-directedcuprate addition a short and efficient synthesis of the building blocks for polyketide synthesis were devised. Incorporating the o-DPPB-directed hydroformylation as part of sequential transformations allowed a further increase of synthetic efficiency. An efficient way to remove the o-DPPB group from the organic substrate, with concomitant extension of the carbon skeleton, was found to be its use as a reagentdirecting leaving group for allylic substitution. Thus, complete control over all issues of selectivity in the course of allylic substitution with organocopper reagents was obtained.

80

I

Controlling Stereoselectivity with the Aid o f a Reagent-Directing Group References 1

2

3

4

5

6

A. H. HOVEYDA, D. A. EVANS, G. C. Fu, Chem. Rev. 1993, 93, 1307-1370. a) B. M. TROST,Angew. Chem. 1995, 107, 285-307; Angew. Chem. Int. Ed. Engl. 1995, 34. 259: b) B. M. TROST,Science 1991, 254, 1471-1477. For recent reviews see: a) J. A. MOULIJN, P. W. N. M. VAN LEEUWEN,R. A. VAN SAUTEN, Catalysis - A n Integrated Approach to Homogenous, Heterogenous and Industrial Catalysis, Elsevier, Amsterdam 1995, S. 199-248; b) C. D. FROHNING,C. W. KOHLPAINTNER in Applied Homogeneous Catalysis with Organometallic Compounds, (Eds.: B. CORNILS, W. A. HERRMANN), VCH, Weinheim 1996, Kap. 2.1.1, S. 29104; c) M. BELLER,B. CORNILS, C. D. FROHNING,C. W. K O H L P A I N T N EMol. R,~. Cat. A 1995, 104, 17-85; d) J. K. STILLEin Comprehensiue Organic Synthesis, (Eds.: B. M. TROST,I. FLEMING),Pergamon, Oxford 1991, Vol. 4, pp 913-959; e) F. AGBOSSOU,J.-F. CARPENTIER, A. MORTREUX, Chem. Rev. 1995, 95, J. C. BAYON, 2485-2506; f ) S. GLADIALI, C. CIAVER,Tetrahedron Asymrn. 1995, 6, 1453-1474. For exceptions see: S . D. BURK, J. E. COBB, K. TAKEUCHI, /. Org. Chem. 1990, 55, 2138-2151; T. TAKAHASHI, K. MACHIDA, Y. KIDO,K. NAGASHIMA, S. EBATA, T. DOI, Chem. Lett. 1997, 1291-1292; B. BREIT, S. K. ZAHN,Tetrahedron Lett. 1998, 39, 1901-1904; I. OTIMA, E. s. V I D A L ,Am. ~. Chem. SOC.1998, 63, 7999-8003. N. SAKAI, S. MANO,K. NOZAKI,H. TAKAYA, 1.Am. Chew SOC.1993, 115, 7033-7034: N. SAKAI, K. NOZAKI,H. TAKAYA,].Chem. SOC.,Chem. Commun. 1994, 395-396; K. NOZAKI,N. SAKAI, T. NANNO,T. HIGASHIJIMA, S. MANO,T. HORIUCHI, H. TAKAYA, /. Am. Chem. SOC.1997, 119, 4413-4423; T. HORIUCHI, T. OHTA,E. SHIRAKAWA, K. NOZAKI,H. TAKAYA, Tetrahedron 1997, 5, 7795-7804; K. NOZAKI, W. LI, T. HORIUCHI, H. TAKAYA, Tetrahedron Lett. 1997, 38, 4611-4614; T. HORIUCHI, T. OHTA,E. SHIRAKAWA, K. NOZAKI,H. TAKAYA, 1.Org. Chem. 1997, 62,4285-4292. J. E. BABIN, G. T. TODD(Union Carbide) IPN: W093/03839.

7 For a review on stereoselective hydrofor-

8

9

10

11 12 13

14

15

16

17

18

mylations see P. EILBRACHTin HoubenWeyl, Methods of Organic Synthesis, E 21, Stereoselective Synthesis, (Eds.:G. HELMCHEN, R. W. HOFFMANN, J. MULZER, E. SCHAUM A N N ) , Thieme, Stuttgart, 1995, p. 24882557. For substrate-directed diastereoselective hydroformylation of cyclic systems see S. D. BURKE,J. E. COBB,Tetrahedron Lett. 1986, 27, 4237-4240; W. R. JACKSON, P. PERLMUTTER, E. E. TASDELEN, J. Chem. SOC.Chem. Commun. 1990, 763-764. For a review see J. M. BROWN, Angew. Chem. 1987, 99, 169-182; Angew. Chem. Int. ed. engl. 1987, 26, 190-203. - See also ref. [l]pp 1331-1340. a) B. BREIT,Angew. Chem. 1996, 108, 3021-3023; Angew. Chem. Int. Ed. Engl. 1996, 35, 2835-2837; b) B. BREIT, Liebigs Ann. 1997, 1841-1851. T. DOI,H. KOMATSU, K. YAMAMOTO, Tetrahedron Lett. 1996, 37, 6877-6880. B. BREIT, M. DAUBER, K. HARMS,Chem. Eur. /. 1999, 5, in press. B. BREIT,/. Chem. SOC.,Chem. Commun. 1997, 591-592; B. BREIT, Eur. 1.Org. Chem. 1998, 1123-1134. B. BREIT, unpublished results. B. BREIT, Angew. Chem. 1998, 110, 535538; Angew. Chem. Int. Ed. Engl. 1998, 37, 525-527. For the concept of domino reactions in organic synthesis see a) L. F. TIETZE, Chem. Rev. 1996, 96, 115-136; b) L. F. TIETZE,U. BEIFUSS, Angew. Chem. 1993, 105, 137-170; Angew. Chem. Int. Ed. Engl. 1993, 32, 131-163; c) T. L. Ho, Tandem Organic Reactions, Wiley, New York 1992 d) H. M. R. HOFFMANN, Angew. Chem. 1992, 104, 1361-1363; Angew. Chem. Int. Ed. Engl. 1992, 31, 1332-1334. a) W. REPPE,Experientia, 1949, 5, 93; b) W. REPPE, H. KINDLER,Liebigs Ann. Chem. 1953, 582, 133. a) A. F. M. IQBAL, Helv. Chim. Acta 1971, 45, 1440; b) R. M. LINE, J. Org. Chem. 1980, 45, 3370; c) K. MURATA, A. MATSUDA, T. MATSUDA, 1.Mol. Cat. 1984, 23, 121; d) F. JACHIMOWICZ (W. R. Grace and Co.) Belgian Patent 887630 (1980); Chem. Abstr. 1981, 95, 152491; e) F.

References I 8 1 JACHIMOWICZ, P. MANSON (W. R. Grace and Co.) Canadian Patent 1231199 (1984); Chem. Abstr. 1988, 109, 38485; f ) F. JACHIMOWICZ, J. W. RAKSIS, /. Org. Chem. 1982, 47, 445; g) E. E. MACENTIRE, J. F. KNIFTON (Texaco Development Corp.) European Patent 240193 (1987); Chem. Abstr. 1989, 110, 134785; h) S. TOROS,I. GEMES-PESCI, B. HEIL,S. MAHo, Z. /. Chem. SOC., Chem. Commun. TUBER, 1992, 858; i) E. DRENT,A. J. M. BREED (Shell Int. Res. M) European Patent 457386 (1992); Chem Abstr. 1992, 11 6, 83212; j) M. D. J O N E S , J . Organomet. Chem. 1989, 366, 403; k) T. IMAI (Uop Inc) US Patent 4220764 (1978); Chem. Abstr. 1980, 93, 239429; 1) G. DIEKHAUS, D. KAMPMANN.C. KNIEP, T. MULLER,I. WALTER, J. WEBER(Hoechst AG) German Patent DE 4334809 (1993); Chem. Abstr.

1995, 122, 314160. 19

For recent results on efficient hydroaminomethylation of functionalized derivatives see T. RISCHE, P. EILBRACHT, Synthesis 1997, 1331-1337; C. L. KRANEMANN, P. EILBRACHT,Synthesis 1998. 71-77.

20

B. BREIT,Tetrahedron Lett. 1998, 39, 51635166.

21

a) T. BAIG,P. KALCK,/. Chem. SOC.,Chem. Commun. 1992, 1373; b) T. BAIG,J. P. KALCK, /. Organomet. Chem. MOLINIER, 1993, 455, 219; c) A. L. JAPIDUS, A. P. RODIN, L. Y . BREZHNEV, I . G. PRUIDZE, B. I. UGRAK,Izv. Akad. Nauk SSSR, Ser. Khim. 1990, 1448; Chem. Abstr. 1990, 113,

22

a) J.B. HENDRICKSON,/. Am. Chem. SOC. 1975, 97, 5784-5800; b) ibid. 1977, 99, 5439-5450; c) J. B. HENDRICKSON, Angew. Chem. 1990, 102, 1328-1338; Angew. Chem. Int. Ed. Engl. 1990, 29,

171812.

1286-1295. 23 E. J. COREY, X.-M. CHENG,The Logic of Chemical Synthesis,Wiley, New York 1989, Chapter 4, pp 47-57. 24 B. BREIT, S. K. ZAHN,Angew. Chem. 1999, 1 1 1 , 1022-1024; Angew. Chem. Int. Ed. Engl. 1999, 38,969-971. 25 B. BREIT,S. K. ZAHN,Angew. Chem. 2001, 113, 1964-1967; Angew. Chem. Int. Ed. Engl. 2001,40, 1910-1973. 26 B. BREIT,P. DEMEL, Ado. Synth. Cat. 2001, 343,429-432.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

82

I

Solvent-Free Organic Syntheses Jiirgen 0. Metzger

A consequence of the necessity to minimize the amount of toxic waste and by-products from

chemical processes is a need for the development of new, more environmentally friendly and resource-saving synthetic methods in which fewer toxic substances are used. Nowadays in the development of new syntheses, ecological points of view must also be taken into consideration and apportioned due importance in the assessment of viability [l,21. In this process the solvents are especially important, as they are generally used in large quantities. Many organic solvents are ecologically harmful, and their use should therefore be minimized as far as possible or even avoided altogether [ 2 ] . In industry they are of course recycled wherever possible. However, in practice this is only rarely accomplished with complete efficiency, which means that some organic solvent from chemical production will inevitably escape and severely pollute the environment. Alternatives under investigation as solvents for organic reactions are water [ 31 and supercritical gases, in particular COz [ 41. The best solvent from an ecological point of view is without doubt no solvent. There are many great reactions that can already be carried out in the absence of a solvent, for example numerous industrially important gas-phase reactions and many polymerizations. Diels-Alder and other pericyclic reactions are also often carried out without solvents. Reports on solventfree reactions have, however, become increasingly frequent and specialized over the past few years. Areas of growth include reactions between solids [S], between gases and solids [GI, and on supported inorganic materials [ 71, which in many cases are accelerated or even made possible through microwave irradiation [ 81. Some most important solvent-free routes for selective oxidations of hydrocarbons and aromatics [ 91, hydrogenations [ 101, and for a one step production of ecaprolactam from cyclohexanone with a mixture of air and ammonia using porous heterogeneous catalysts have been reported, in which the active sites have been atomically engineered [ 111.There are also reactions in which at least one reactant is liquid under the conditions employed, which means the solvent normally used can simply be left out. To begin with, two industrially important examples are discussed, which confirm that a reaction process that is more environmentally friendly can also be economically very acceptable. This is followed by some recent examples of solvent-free reactions covering a remarkably broad range of reaction types in which the term “solvent-free” refers solely to the reaction itself. On the other hand, workup processes, except for a few examples, invariably involve the use of solvent. The

Polymer Syntheses

examples show that these reactions proceed with similar and in many cases even higher yield and/or selectivity and, because of the higher concentration of the reactants, with a larger rate of reaction. Polymer Syntheses

The method for the manufacture of polypropylene by the Ziegler-Natta process, which has been in widespread use for several decades, involved some years ago a polymerization in a relatively volatile solvent, for example a light petroleum fraction. That was the drawback of this process, since in the separation and subsequent drying of the polymer formed the solvent could not be completely recovered. Problems are thus experienced in fulfilling environmental protection requirements. An additional obstacle was the large volume of aqueous waste that is generated during workup of the polymer suspension. The new polypropylene processes do not require solvents because of a new and highly efficient catalyst [12].Therefore, there are also no solvent emissions in the exhaust gases. Small amounts of gaseous hydrocarbons that are formed are incinerated. In the manufacture of the polymer the amount of aqueous wastewater accumulated is much smaller, since the amount of catalyst used can be reduced to such low levels that it no longer needs to be washed after the reaction. Comparable results have also been achieved in the manufacture of high-density polyethylene. Polycarbonates are amorphous polymers with excellent handling properties. Their spectrum of applications ranges from baby bottles to compact discs. Most of the polycarbonate produced is generated by the polycondensation of bisphenol A with phosgene in a biphasic system (sodium hydroxide/dichloromethane). The solution of the polycarbonate product in dichloromethane is washed with water to remove the by-product NaC1. However, in this washing process some 20 g . L-' of the dichloromethane ends up dissolved in the aqueous phase. The dichloromethane must also be removed from the polycarbonate, which is not easy. This means that the polycarbonate will invariably contain some chlorinated impurities, which adversely affects the properties of the polymer. Komiya et al. [ 131 recently introduced the novel, environmentally friendly process from Asahi Chemical Industry Co. for the production of polycarbonates, which requires neither phosgene nor solvent (Scheme 1). In this process bisphenol A undergoes a prepolymerization with diphenyl carbonate in the melt. A simple crystallization of the prepolymer is fol-

1

Scheme 1.

Solvent-free synthesis of polycarbonate from bisphenol A and diphenyl carbonate [lo].

I

83

84

I

Solvent-Free Organic Syntheses

lowed by a solid-state polymerization to a polycarbonate of high molecular weight. Its quality is superior to the product of the phosgene process, and the production costs appear to be similar. A variety of strategies for reducing or eliminating the use of traditional organic solvents in polymer synthesis and processing have been discussed recently [ 141. Radical Additions

For some time, intermolecular radical additions have been an integral part of the methodological arsenal of preparative organic chemistry. However, from an ecological point of view the methods that have been used to date suffer from a number of drawbacks that present obstacles to their broad-based industrial application. This applies particularly to the commonly used organotin compounds. Transition metal complexes and salts which initiate radical reactions through electron transfer processes are a highly promising alternative, and some recent examples even do not require the use of solvents [ 15, lG]. Thus, cc-iodo esters undergo addition to alkenes through an electron transfer initiated by metallic copper [15]. The reaction procedure is very simple: The alkene, iodo compound, and commercial copper powder are mixed together without any pretreatment and heated to 130 "C under an inert atmosphere (Scheme 2). After a simple workup the products were obtained in good yield; the entire reaction was carried out in the complete absence of solvent, as the product was distilled off directly from the reaction mixture. The iodo compound could be replaced by the corresponding, more easily accessible bromo compound; in this case an equimolar quantity of sodium iodide is added. The iodo compound is formed initially as an intermediate by a solvent-free Finkelstein reaction.

Scheme 2.

Copper-initiated radical addition of methyl 2-iodopropionate to methyl 10-undecenoate [15].

cc-Iodonitrile [ 151 and perfluoroalkyl iodides [ 161 underwent addition to alkenes in a completely analogous solvent-free reaction. Additional points in favor of these solvent-free radical additions are that the yields are generally better than with the conventional methodology and that they also permit additions to 1,2-disubstituted alkenes. Enzyme-Catalyzed Reactions

The selective enzyme-catalyzed acylation of carbohydrates is of great interest, as of carbohydrates fatty acid esters of carbohydrates have important applications in detergents, cosmetics, foodstuff, and pharmaceuticals because of their surface-active properties. Monoacylated sugars have been synthesized by lipase-catalyzed transesterifications of activated esters in pyridine and by protease-catalyzed esterifications in DMF. A most remarkable new development

Enzyme-Catalyzed Reactions

is the use of immobilized lipases for the selective acylation of I-0-ethyl glucopyranoside with free carboxylic acids in the absence of solvent. This afforded G-0-acyl glucopyranosides in 8 5 9 0 % yield [ 171, with small amounts of the 2,G-O,O-diacylglucopyranosides being formed as by-products. This reaction can also be carried out without problems on a large scale. Thus, 8 kg of glucose was allowed to react with ethanol in the presence of an ion-exchange resin to form 1-0-ethyl glucopyranoside. After removal of the ion exchange resin and the residual ethanol 12.7 kg of coconut oil fatty acids were added to the crude 1-0-ethylglucopyranoside, and the mixture was heated to 70 "C. Then 400 g of immobilized lipase from Candida antarctica was added, and the water of reaction that formed was removed under vacuum. After 28 h a conversion of greater than 90% was achieved. After the enzyme was filtered off, a crude product was obtained which contained 70% of the 6-0-monoester.After removal of the excess fatty acid (21%) by distillation, the final product had a 6-0-monoester content of greater than 85% (Scheme 3). HO

RC02H

RCO2

Lipase, 70"C, 24h .OEt

H

O

85 - 90%

O

E

t

H OH

OH

Lipase-catalyzed acylation o f 1-0-ethyl glucopyranoside with carboxylic acids t o 6-0-acyl glucopyranosides (R = n-C7H15, n-CgH19, nCII H23, n-C13H27, n-C15H31, n-Cl7H35) [171. Scheme 3.

In another solvent-free process with the same lipase as above, trimethylene carbonate underwent an almost quantitative ring-opening polymerization in 120 h at 70 "C to form poly(trimethy1ene carbonate) [ 181. No decarboxylation was detected (Scheme 4). wPentadecalactone was likewise polymerized with lipases in the absence of a solvent to form polyesters of high molecular weight [ 191. 0

II

0

O A O

70°C,48h Scheme 4. Lipase-catalyzed ring-opening polymerization of trimethylene carbonate t o linear poly(trimethy1ene carbonate) [18]

The latter two successful processes were combined in the solvent-free lipase-catalyzed reaction of 1-0-ethyl glucoside with trimethylene carbonate or c-caprolactone to form amphiphilic oligomers and polymers [ 201. The products are biodegradable polycarbonates and polyesters that are formed regioselectively by reaction with the primary hydroxyl group of the sugar moiety. Lipase catalyzed esterifications were performed favorably solvent-free [21] and were applied also to bulk polymerization for polyester synthesis [ 221.

86

I

Solvent-Free Organic Syntheses

Homogeneous Catalysis

Oxidations are of great importance, and it would be highly desirable to carry them out with environmentally friendly oxidants such as atmospheric oxygen and hydrogen peroxide -30% H202 if possible. Ideally such reactions should also be carried out without the need for any additional organic solvent. Noyori et al. [23] recently reported an efficient oxidation of secondary alcohols to ketones with sodium tungstate as catalyst and methyltrioctylammonium hydrogen sulfate as phase-transfer catalyst (Scheme 5). The yield in the case of 2-octanol was approximately 95%. Primary alcohols are four to five times less reactive and were generally oxidized to carboxylic acids. More remarkably, unsaturated secondary alcohols, including even allylic alcohols, were oxidized with high selectivity to the corresponding ketones. Moreover, using the same catalyst, cyclohexene was efficiently oxidized to give adipic acid [ 241. However, if a catalytic quantity of arninomethylphosphonic acid was added, an efficient epoxidation catalyst was obtained, and terminal alkenes could be oxidized to the epoxides in greater than 90% yield using 30% H 2 0 2(Scheme 6) [25].

Scheme 5.

Oxidation of secondary alcohols to ketones with 30%

H202

[23]

Scheme 6. Epoxidation of 1-alkenes with 30% H 2 0 2by addition o f aminomethylphosphonic acid t o the catalytic oxidation system shown i n Scheme 5 [25].

The chiral Cr"' - salen complex 1 is a highly efficient catalyst for the enantioselective ring opening of epoxides with Me3SiN3 [26]. For example, cyclohexene oxide underwent ring opening with 2% of 1 and MejSiNj in the complete absence of solvent - the product was removed by short-path distillations under reduced pressure from the reaction mixture - in 90% yield and with 84-88% ee (Scheme 7). The catalyst was easily recovered and could be reused without any loss of activity. The yield and enantioselectivity were similarly high as for the corresponding reaction in diethyl ether. Palladium complexes with phosphinooxazoline ligands such as 2 have been proven to be very efficient catalysts for the coupling of alkynes to enynes in solvent-free reactions (Scheme 8) and provided an efficient tool for regiocontrolled cross-coupling reactions between mono- and disubstituted alkynes [ 271. The neat Ru-catalyzed hydroesterification of 3,3-dimethyl-l-propene with 2-pyridylmethyl formates afforded exclusively a linear ester in 89% isolated yield using only 0.2 mol%

Homogeneous Catalysis

187

2% (R,R)-l, 20h D 91%,88% ee

+ Me3SiN3

(RR1-1 Catalytic enantioselective ring opening of cyclohexene oxide with trimethylsilyl azide using the chiral Cr(lll) - salen complex 1 1261. Scheme 7.

2

H13C6

Pd(0Ac)zi 2

2

*

C6H1 3

H13C6

'tBu

2 Scheme 8.

Pd-catalyzed coupling of 1-octyne 1271

Ru3( C0)12 [ 281. Furthermore, the Pd-catalyzed solvent free arsination of aryl triflates (Scheme 9) [ 291, and the hydroamination of phenylacetylene with aniline in the presence of [ Ru3(C0)12]/NH4PF6 proceeds with high regioselectivity giving the product by simple distillation with greater than 99% purity in 92% yield (Scheme 10) [ 301. Pd(OAc)Z P ~ ~ A115°C s,

40 - 50%

Fn

0

AsPh;!

Fn

-

Fn = COOMe, COMe, CHO, CN, NOz, OMe Scheme 9.

Pd-catalyzed arsination of aryltriflates with triphenylarsine (291.

88

I

Solvent-Free Organic Syntheses

Scheme 10.

Catalytic hydroamination of phenylacetylene with aniline [30]

Lewis Acid and Base Catalyzed Reactions

Several examples have been described on Lewis acid and base catalyzed Michael addiacid ethylester was added at room temperature to methyl tions. Cyclopentanone-2-carboxylic vinyl ketone using 2 mol% FeC13.G HzO as catalyst yielding > 90% of the addition product (Scheme 11) [31]. Cerium(II1) chloride in the presence of sodium iodide [32] and trifluoromethanesulfonic acid have been used as catalysts as well [ 331.

d

M0

e

2 mol% >FeC13 90%

- 6 H20*

W

C02Et M

e

I

Scheme 11. FeCI3-catalyzed Michael-addition of cyclopentanone-2carboxylic acid ethyl ester with methylvinylketone [31].

Modified guanidines 3 efficiently catalyzed the asymmetric Michael addition of a prochiral glycine derivatives with acrylate, acrylonitrile and methyl vinyl ketone under simple and mild conditions. Remarkably, both product formation and enantioselectivity were dramatically improved using solvent-free conditions (Scheme 12) [34]. The addition of alcohols to methyl propiolate was performed using fluorous phosphines such as P[(CH2)2(CFZ),CF3I3 and again better yields of 99% have been obtained under solvent-free conditions. Toluene was added to efficiently separate the product from the solid catalyst, which was then reused without loss of activity [ 351. Ph2C=NCH2COOtBu

+ //'\cooE~

+ 3(0.2 eq)

*

20"C, 3d, 87%, 97% ee

MeN

K

NMe

Ph

Ph 3

Scheme 12. Cuanidine-catalyzed asymmetric Michael-addition of tert-butyl diphenyliminoacetate with ethyl acrylate [34].

Ph2C=N Y O t B u COOEt

Reactions Using Organometallic Reagents

The indium trichloride-catalyzed Mukaiyama aldol reaction of 3-aminoketoesters with various silylenolethers gave under solvent-free conditions 1,3-amino alcohols with high stereoselectivity [ 361. Several Robinson annelation reactions have been carried out enantioselectively using (S)-proline as a chiral catalyst [ 371. Remarkably, the enantioselectivity was distinctly higher in the absence of solvent than in DMSO. The ytterbium triflate catalyzed Biginelli reaction of aldehydes, ethyl acetoacetate and urea to give in a one-pot synthesis dihydropyrimidones was performed again in higher yields without any solvent (Scheme 13) [ 381.

OEt

5mol% Yb(OTf)3 w

IOO'C, 20 tnin., 98%

Me H

Scheme 13.

Ytterbium triflate catalyzed Biginelli reaction [38].

The same Lewis acid has been applied also as a catalyst for the syntheses of 2J-dihydro1H-1,s-benzodiazepines in very good yields from o-phenylenendiamine and ketones [ 391.

Solvent-free coumarin [40] and porphyrin syntheses have also been reported [41]. The Baylis-Hillman reaction of aldehydes with methyl methacrylate can be catalyzed with tetramethylguanidine (TMG) whereby the activity of the catalyst is decreased when solvents are used in the reaction (Scheme 14) [42].

1,

Ph

+

5%TMG

fiCOOMe 20"C, 6h, 58%

Scheme 14. Tetramethylguanidine ( T M C ) is an efficient catalyst for the solvent-free Baylis-Hillman reaction [42].

A catalytic amount of aluminum chloride hexahydrate enables solvent-free tetrahydropyranylation of alcohols and phenols at moderate temperatures and a simple addition of methanol helps to regenerate the corresponding alcohols and phenols [43]. Reactions Using Organornetallic Reagents

Solvent-free enantioselective additions of diethylzinc to aldehydes and to N-diphenylphosphinoylimines using p-amino alcohols as chiral catalysts afforded chiral sec-alcohols and N-

90

I

Solvent-Free Organic Syntheses

diphenylphosphinoylamines, respectively, with high enantiomeric excess, and is faster than using organic solvents in these reactions (Scheme 15) [44]. Ph

EtZZn, 4 (1 eq.) phv,N, ,Ph O'C, 76%, 84% ee

;lPh

0

*

0

phMMe

HO

4

c-

Scheme 15.

Catalytic enantioselective addition of diethylzinc to N-diphenylphosphinoylimines [44b].

Indium mediated Barbier-type cross coupling between carbonyl compounds and allyl halides proceed efficiently under solvent-free conditions. No apparent competing pinacolcoupling or homo-coupling of the allyl halide was observed. The reactions were found to be mediated also by zinc, tin, bismut and copper [45]. Cycloadditions

The solvent-free asymmetric Hetero-Diels-Alder reaction of 14 different aldehydes with Danishefsky's diene was carried out with 0.1-0.005 mol% of chiral titanium complexes to afford dihydropyrones with up to quantitative yields and 99.8% ee. A library of chiral metal complexes was generated by combining one or two different chiral diol ligands e.g. 5 (13 different diols were applied) with titanium isopropylate (Scheme 16) [46]. OMe Ti-2.5 99%E

Me3Si-0

5 Scheme 16.

Asymmetric Hetero-Diels-Alder reaction of benzaldehyde w i t h Danishefsky's d i m e [46].

References I 9 1

+

[2 2lCycloadditions of cyclic ketene trimethylsilyl acetals with ethyl propynoate and other electrophilic alkines were run at room temperature, without a catalyst and solvent-free (47). Nucleophilic Substitutions and /I-eliminations

As has already been pointed out, the Finkelstein reaction can be conducted in situ in the absence of solvents. For example, alkylations of purine and pyrimidine bases with alkyl halides and dimethyl sulfate have been carried out by solid/liquid phase-transfer catalysis in the absence of any additional solvent [48], as have cyanation of haloalkanes [49] and peliminations [SO]. Noteworthy is the synthesis of glycosyl isothiocyanates by the reaction of potassium thiocyanate with molten glycosyl bromide at 190 "C [Sl]. To summarize, solvent-free reactions are not only of increasing interest from an ecological viewpoint, but in many cases also offer considerable synthetic advantages in terms of yield, selectivity, and simplicity of the reaction procedure. References 1

2

3 4

5

6

7

8

P. T. ANASTAS, T. C. WILLIAMSON in Green Chemistry, Designing Chemistry for the T. C. Environments (Eds.: P. T. ANASTAS, WrLLrAMsoN), American Chemical Society, Washington DC, 1996, pp. 1-17. M. EISSEN,J. 0. METZGER, E. SCHMIDT, U. SCHNEIDEWIND, Angew. Chem. 2002, 114, 402-425, Angew. Chem. Int. Ed. 2002, 41, 414-436. C.-J. LI, T.-H. CHAN,Organic Reactions in Aqueous Media, Wiley, Chichester, 1997. P. G. JESSOP, W. LEITNER (eds.), Chemical Synthesis Using Supercritical Fluids, WileyVCH, Weinheim, 1999. a) F. TODA,Acc. Chem. Res. 1995, 28, 480A N D F. TODA,Chem. 486; b) K. TANAKA Rev. 2000, 100, 1025-1074; c) G. W. V. J. L. SCOTT,Chew. CAVE,C. L. RASTON, Commun. 2001, 2159-2169. a) G. KAUPP, J. SCHMEYERS, Angew. Chem. 1993, 105, 1656-1658; Angew. Chem. Int. Ed. Engl. 1993, 32, 1587-1589; b) G. KAUPP, J. S C H M E Y E R Org. S , ~ .Chem. 199.5, 60, 5494-5503; c) G. KAUPP,Andreas Herrmann, lens Schmeyers, Chem. Eur. I. 2002, 8, 1395-1406, and references therein. J. H. CLARK, Catalysis oforganic Reactions by Supported Inorganic Reagents, VCH, New York, 1994. a) R. S. VARMA,Clean Prod. Proc. 1999, 1, 132-147; b) R. S. VARMA, Green Chew. 1999, 1, 43-55; c) A. LOUPY, Top. Curr. Chem. 1999. 206, 153-208.

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J. M. THOMAS, R. RAJA,G. SANKAR, B. F. G. J O H N S O N , D. W. LEWIS, Chem. Eur. /. 2001, 7, 2973-2978. S. HERMANS, R. RAJA,J. M. THOMAS, B. F. G. J O H N S O N , G . SANKAR, D. GLEESON, Angew. Chem. 2001, 113, 12511255; Angew. Chem. Int. Ed. 2001, 40, 1211-1215. R. RAJAQ, G. SANKAR, J. M. THOMAS,J. Am. Chem. Soc. 2001, 123, 8153-8154. a) J. HORNKE; R. LIPPHARDT, R. MELDTin Produktionsintegrierter Umweltschutz in der chemischen Industrie (Ed.: J. WIESNER) DECHEMA, Frankfurt/Main, 1990, pp. 17-18; b) A. N. THAYER, Chew. Eng. News 1995, 73(37), 15-20. K. KOMIYA,S. FUKUOKA,M. AMINAKA, K. HASEGAWA, H. HACHIYA, H. OKAMOTO, T. WATANABE, H. YONEDA, J. FUKAWA,T. DOZONO in Green Chemistry, Designing Chemistryfor the Environment (Eds.: P. T. ANASTAS, T. C. WILLIAMSON), American Chemical Society, Washington DC, 1996, p. 20-32. T. E. LONG, M. 0. HUNT,Solvent-Free Polymerizations and Processes, ACS Symposium Series 1999, 713. a) J. 0. METZGER, R. MAHLER, Angew. Chem. 1995, 107, 1013-1015; Angew. Chem. Int. Ed. Engl. 1995, 34, 902-904; b) J. 0. METZGER, R. MAHLER, G. FRANCKE, Liebigs Ann. 1997; 2303-2313. a) 2.-Y. YANG,B. V. NGUYEN,D. J.

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SON,R. A. GROSS,D. L. KAPLAN,G. SWIFT, Macromolecules 1997, 30, 7735-7742. 19 K. S. BISHT,L. A. HENDERSON, R. A. GROSS,D. L. KAPLAN,G. SWIFT,Macromolecules 1997, 30, 2705-2711. 20 K. S. BISHT, F. DENG,R. A. GROSS,D. L. KAPLAN,G. SWIFT,]. Am. Chem. Soc. 1999, 119, 1363-1367.

35 36 31

38 39

2001, 42, 3193-3195. 40

21 a) J. M. S. ROCHA,M. H. GIL, F. A. P.

GARCIA,1.Chem. Techn. Biotechnol. 1999, 74, 607-612; b) N. WEBER,P. WEITKAMP, K. D. MUKHERJEE, J . Agnc. Food Chem.

110-111.

2. GRVSS,N. GALILI,1. SALTSMAN, Angew. Chem. 1999, 111, 1530-1533; Angew. Chem. Int. Ed. 1999, 38, 14271429; b) 2. GROSS,N. GALILI,L. SIMKHVVICH, I. SALTSMAN, M. BVTOSHANSKY, D. B L ~ S E RR., BOESE,I. GOLDBERG, Org. Lett. 1999, 1, 599-602; c) M. G. WARNER, G. L. SUCCAW, J. E. HUTCHISVN,Green Chem. 2001, 3, 267-

A. K. CHAUDHARY, J. LOPEZ,E. J. BECKMAN, A. J. RUSSELL, Biotechnol. Prog. 1997, 13, 318-325.

K. SATO,M. AOKI,J. TAKAGI,R. NVYVRI,]. Am. Chem. SOC.1997, 119, 12386-12387. 24 K. SATV,M . AVKI,R. NOYORI,Science 23

25

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1998, 281, 1646-1647.

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a) K. SATO,M. AOKI,M. OGAWA,T. HASHIMOTO,R. NVYVRI,]. Org. Chem. 1996, 61, 8310-8311; b) K. SATV,M. AOKI, M. OGAWA,T. HASHIMOTO, D. PANYELLA, R. NOYORI,Bull. Chem. Soc.]pn. 1997, 70,

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1261-1 264. 28 S.

Ko, Y. NA, S. CHANG,]. Am. Chem. SOC.

2002, 124, 750-751. 29 30

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F. Y. KWVNG,c . w. h I , K. s. CHAN,]. Am. Chem. SOC.2001, 123, 886443865, M. TOKUNAGA, M . ECKERT,Y. WAKATSUKI, Angew. Chem. 1999, 111, 3416-3419; Angew, Chem. lnt. Ed. 1999,38,3222-3225. a) J. CHRISTOFFERS, Org. Synth. 2000, 78, 249-253; b) I. CHRISTVFFERS, J . Chem. Soc., Perkin Trans. 11997, 3141-3149. G. BARTOLI,M. Bosco, M. C. BELUCCI, E. MARCANTONI, L. SAMBRI,E. TVRREGIANI, Eur.]. Org. Chem. 1999, 617-620. H. KVTSUKI,K. ARIMURA, T. OHISHI,R. MARUZASA, I. Org. Chem. 1999, 64, 37703773.

34

T. ISHIKAWA, Y. ARAKI,T. KUMAMOTO, H.

N. E. LEADBEATER, c . VAN DER PVL,]. Chem. Soc., Perkin Trans. 12001, 28312835.

905-9 15.

L. E. MARTINEZ, J. L. LEIGHTVN,D. H . CARSTEN, E. N. JACOBSEN,].Am. Chem. SOC.1995, 117, 5897-5898. 27 U. LUCKING,A. PFALTZ,Synlett 2000,

T. SUGINO,I. TANAKA, Chem. Lett. 2001,

41 a)

2001, 49, 5210-5216. 22

SEKI,K. FUKUDA,T. ISOBE,Chem. Commun. 2001, 245-246. M. WENDE,R. MEIER,J. A. GLADYSZ,]. Am. Chem. SOC.2001, 123, 11490-11491. T.-P. LOH, J.-M. HUANG,S.-H. GVH, J. J. VITTAL, Org. Lett. 2000, 2, 1291-1294. D. RAJAGOPAL, K. RAJAGOPALAN, S. SWAMINATHAN,Tetrahedron:Asymmetry 1996, 7, 2189-2190. Y. MA, C. QIAN, L. WANG,M. YANG,]. Org. Chem. 2000, 65, 3864-3868. M. CURINI,F. EPIFANV,M. C. MARCVTULLIV, 0. ROSATI,Tetrahedron Lett.

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V. V. NAMBVVDIRI, R. S. VARMA, Tetrahedron Lett. 2002, 43, 1143-1146. a) I. SATV,T. SAITO,K. SOAI, Chem. Commun. 2000, 2471-2472; b) I. SATO,R. KVDAKA,K. SOAI,J . Chem. Soc., Perkin Trans. 12001, 2912-2914. a) X.-H. YI, J. X. HABERMAN, C.-J. LI, Synth. Commun. 1998, 28, 2999-3009; b) P. C. ANDREWS, A. C. PEATT,C. L. RASTON, Green Chem. 2001, 3, 313-315. J. LONG,J. H u , X. SHEN,B. J I , K. D I N G , J . Am. Chem. Soc. 2002, 124, 10-11. M. MIESCH,F. WENDLING, Eur.]. Org. Chem. 2000, 3381-3392. G. BRAM,G . DECODTS,Synthesis 1985, 543-545.

Y.-Q. CAO,B.-H. C H E M ,B.-G. PEI, Synth. Commun. 2001, 31, 2203-2207. 50 a) J. BARRY,G . BUM, G. DECODTS, A. LVUPY,P. PIGEON,J. SANSONLET,].Org. Chem. 1984, 49, 1138-1140; b) P. VINCZER,S. SZTRUHAR, L. NOVAK,C. SZANTAY, Org. Prep. Proced. lnt. 1992, 24,

49

540-543. 51

T. K. LINDHVRST,C. KIEBURG, Synthesis 1995, 1128-1130.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

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93

Fluorous Techniques: Progress in ReactionProcessing and Purification Ulf Diederichsen

Fluorous solvents contain perfluorinated or very highly fluorinated alkanes. They have been developed within the last decade as an interesting alternative to classical organic solvents [I31. They are inert, thermally stable, non-polar, immiscible with water and most organic solvents, and non-toxic. The ecological reservations against fluorine hydrocarbons can be met by using higher perfluorinated alkanes with lower vapor pressure. Perfluorinated solvents provide a third liquid phase next to water and organic solvents; this can be advantageous both during reaction-processing and for purification procedures. As is known from phasetransfer catalysis, the distribution of starting materials, products, and reagents in triphasic systems extends the possibilities for planning of syntheses and separation strategies. Provided that they are not modified with fluorous tags, neither salts nor organic compounds are found in the fluorous phase. The heavier fluorous phase can easily be separated from the organic phase or water solution by simple phase-separation techniques. The biphasic system of fluorous phase and organic solvent is especially interesting, since the partition coefficient is temperature-dependent: while phase separation is suitable for successful extraction at room temperature, at temperatures higher than GO "C the phases form a homogeneous solution. Hence, reaction processes in homogeneous solution at higher temperatures can be combined advantageously with workup by extraction at room temperature. There are two main applications for fluorous-phase chemistry in organic synthesis. First of all, catalytic reactions can take advantage of thermoregulation of the two-phase systems, especially when the catalyst is soluble in the fluorous phase. On the other hand, the fluorous phase gives an additional dimension to traditional organic chemistry and parallel synthesis. For reactions, partially fluorinated solvents are usually preferred over perfluorinated solvents. Perfluorinated solvents are often not polar enough for many organic reagents, and this phase is therefore applied only for the workup procedure. Fluorous Biphasic Catalysis

Catalysts immobilized on resins are quite often used for catalytic reactions. Phase-transfer conditions, guaranteeing separation and recovery of the catalysts by use of water/organic solvent biphasic systems, are another possibility. Unlike homogeneous processes, these kind of catalytic processes take account of product loss and substrate selectivity. Furthermore,

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Fluorous Techniques: Progress in Reaction-Processing and Purification

catalysts that are sensitive to hydrolysis cannot be used. In this respect, solvation of the catalyst in the fluorous phase offers an interesting alternative. The catalyst can be separated from the organic phase at room temperature, whereas at higher temperatures a homogeneous reaction mixture is provided. In order for the catalyst to be soluble in the fluorous phase, it needs to be modified at the ligands with perfluoroalkyl chains, the length of which (C6F13-C8F17)is decisive for the distribution between the fluorous phase and the organic solvent. The option of tailoring the partition coefficient provides conditions similar to those created by slow addition of reaction partners [4]. The fluoroalkyl groups are electronwithdrawing because of the high electronegativity of fluorine. In order to avoid influencing the catalytic activity, the fluorous tags are usually linked to the catalyst ligands through an ethylene, propylene, or CHzCHzSiMe spacer. To date, the following catalytic processes have been carried out within biphasic systems, taking advantage of the fluorous phase: hydroformylation of olefins [ 51, hydroboration [GI, hydrogenation of alkenes [ 71, hydrosilylation of ketones [8], oligomerization of ethylene [O],cyclopropanation [ 101, transesterification [ 111, various oxidations [ 12-18], asymmetric reduction of ketones [ 191, cross-coupling of organozinc bromides with aryl iodides [ 201, palladium allylic alkylation [ 211, the Heck reaction [22], Suzuki coupling [23], and asymmetric alkylation of aromatic aldehydes [24], as well as Friedel-Crafts acylation and Diels-Alder reactions (Figures 1 and 2) [ 25, 261. An application of the fluorous two-phase system to catalytic reactions is the hydroformylation of terminal olefins with CO and H2 [S]. Aldehydes 1 can be isolated, together with the branched side products 2. In the C6FI1CF3/toluene solvent mixture, the catalyst [HRh(CO){P[CH2CHz(CF2)5cF,]3}3]is obtained in situ. It acts in the hydroformylation reaction at 100 "C and can be separated afterwards in the fluorous phase. In this process, however, approximately 0.5% of the catalyst remains in the organic phase. Furthermore, the lower solubility of CO and Hz in the fluorous phase produces a lower catalyst activity. Accordingly, the hydroformylation of ethene can be conducted in a continuous process in an autoclave. The use of the fluorous analogue of the Wilkinson catalyst [RhCl{P[ CHzCH2(CF2)5CF3]3}3](3) is advantageous for hydroboration, because cleaning of the often inflammable organoborane is facilitated and destruction of the catalyst by the commonly used oxidative workup (H202/NaOH) is avoided [GI. In this case, the heterogeF ~ catecholborane 5 has even proven neous hydroboration of norbornene (4) in C ~ F I I C with to be better than the fluorous two-phase system. The organoborane can be extracted with THF, and the C6FllCF3 mother liquor containing the catalyst can be used for further synthesis cycles. Turnover numbers (TONS)higher than 10,000 are reached. For a practical transesterification reaction, next to high yields, an equimolar ratio of the reactants is desirable. The catalyst should be neutral and easily separable, and no special technology for alcohol removal should be needed [ 111.These requirements are fulfilled by the fluorous tagged distannoxane catalyst 6 . Transesterification yields are quantitative and the FC-72 solution (FC-72 and FC-75 are commercially available mixtures of perfluoroalkanes) of the catalyst can be reused. Asymmetric alkylation of benzaldehyde can be performed in a toluene/FC-72 biphasic system with Ti(O-iPr)4and the fluorous BINOL ligand 7 (Figure 2) with reasonable yield and enantioselectivity [241. The asymmetric hydrogen-transfer reduction of ketones works fairly

Fluomus Biphasic Catalysis

I

95

Hydroformylation

+

H

R

CH3

2 Hydroboration

5

Transesterification

-

MeOH I FC 72

+

*

CI C2H4-C6F13 C H -C6F13 .**' C6Fl,-C,H4,,, -c HjSn-O-Sn-CI 6 13 2 4 I I I I gCzH4-C6F~3

I

\

6 Fig. 1. Fluorous biphasic catalysis part I: hydroformylation, hydroboration, and transesterification with fluorous tagged catalysts.

similarly [ 191, hydrogen transfer taking place in a mixture of perfluoroalkane and isopropanol with iridium complexes in association with the chiral perfluorosalen ligand 8. Oxidation of aldehyde 9 can be accomplished at 64 "C with oxygen and a catalytic amount of nickel derivative 10 in a homogeneous phase consisting of the toluene/perfluorodecalin solvent mixture [12]. After phase separation at room temperature, the catalyst is kept in the fluorous phase by its fluoroalkyl chains and can easily be separated from the product, which remains in the organic phase. The catalyst can be used again, still yielding 70% of the oxidation product after six reaction cycles. No leaching of the catalyst was observed. Esters, chlorides, and silyl ethers are functional groups that are tolerated in this reaction. The high solubility of Oz in fluorinated solvents is of special advantage for this oxidation reaction. In analogous systems, sulfides can be oxidized to sulfoxides or sulfones in the presence of isobutyraldehyde, while epoxides are selectively obtained from substituted olefins [ 121. Further catalysts that take advantage of the fluorous phase and are used for alkene epoxidation are

EtOH

96

I

Fluorous Techniques: Progress i n Reaction-Processing and Purification Asymmetric alkylation

+

&H

Ti(0i-Pr), FC-72IToluene

Et,Zn

*

0""

3::

(C,F,,CH,CH,)3Si

\

/

(C,F,3CHzCH,)3Si 7 Reduction [Ir(COD)CI], i-PrOH/C,F,8/KOH

ph+dph F17c8

+OH tBu

a

tBu

Oxidation

10 (3 Mol.%)

AcO J y H

9

0, (1 atm) Toluene / Perfluorodecalin

AcO &OH

Cross coupling

Fig. 2. Fluorous biphasic catalysis part II: asymmetric alkylation, reduction, oxidation, and cross-coupling reactions with fluorous tagged catalysts.

Fluorous-Phase Strategy for lmprouing Separation Eficiency

I

97

a cobalt complex of a tetraarylporphyrin, an optically active (sa1en)Mn"' complex, and a catalyst generated in situ from a bipyridine, RuC13, and NaI04 [13]. In addition, M ~ ( O A C ) ~ . ~ H2O in a heterogeneous mixture with pivalaldehyde catalyzes aerobic epoxidation in FC-75 as a solvent [27]. Olefins are epoxidized with 5 mol-% perfluoroheptadecan-9-one and H z 0 2 in boiling CH2C12, in which the catalyst is not wholly soluble. Up to 92% of the catalyst can be recycled by crystallization at 0 "C. In addition, the Wacker oxidation of an olefin to the respective ketone can be successfully performed in the two-phase system of benzene and bromoperfluorooctane with tert-BuOOH and a catalyst similar to 10, with palladium as the metal [28]. The palladium-catalyzed cross-coupling of an aryl, alkenyl, or benzylzinc bromide 11 with aryl iodide 12 succeeds with 0.15 mol-% [ Pd{ P ( C G H ~ C ~ F in ~ ~toluene/l-bromo)~}~] perfluorooctane, taking advantage of variable miscibility through thermoregulation [20]. In this case the electron-deficiencyof the phosphanes, due to the perfluorinated side chains, appears to influence the reductive elimination step in the cross-coupling reactions. Finally, 10 mol-% of the lanthanide perfluoroalkylsulfone amide complex in CGH~CF3 catalyzes both Friedel-Crafts acylation and the Diels-Alder Yb(N( S02C4F9)2)3 reaction [ 261. The high Lewis acidity of the metal complexes seems to be crucial. Fluorous-Phase Strategy for Improving Separation Efficiency

Apart from its use for solvation and separation of catalysts, the fluorous phase can also be used advantageously for separation processes during workup. Strategic synthesis planning is facilitated by tagging with fluorous residues to overcome the frequently limiting recovery and purification difficulties [ 11. As in solid-phase syntheses, an excess of components can be used to drive the reactions to completion. Side products can easily be separated if, for example. only the product is tagged with fluorous alkyl residues and therefore precipitates from the reaction mixture or is extracted with the fluorous phase. Isoxazoline 13 is obtained by 1,3-dipolar cycloaddition of nitrile oxide tBuCNO to olefin 14, labeled with a fluorous alkyl residue, with CH2C12 or C6H5CF3 as the solvent (Figure 3) [29]. Since these solvents are partially halogenated, all substrates appear to dissolve fully. After extraction with benzene, the fluorous-labeled product 13 remains. Cleavage of the fluorous alkyl tag from the product allows extraction into the organic phase by a three-phase extraction procedure (water, CH2C12,FC-72).The problem with this 'one-phase' reaction procedure is that phase separation does not distinguish between substrate 14 and product 13. An excess of reagents and reactants is required to overcome this problem and to drive the reaction to completion. Another way of avoiding the one-phase problem is to conduct a phase switch, as illustrated for Grignard addition to aldehyde 15. Acetaldehyde is soluble in the organic phase and is transferred into the fluorous phase during the course of the reaction, as the generated hydroxyl group is immediately silylated with a fluorous tag. Separation of derivative 16 from remaining starting material is therefore facilitated. Subsequent cleavage of the fluorous label lets alcohol 17 switch into the organic phase and thus facilitates efficient separation from both reactants and side products. In a fluorous variant of the Ugi and Biginelli multicomponent reactions, it has been

98

I

Fhorous Techniques: Progress in Reaction-Processing and Purification

One-phase reaction process 1. t-BUCNO. c6H5cF3

N

OSi(CHzCHzC6F13)3

-

2. extraction

14

OSi(CH2CH,C6Fl3), t-Bu 13

Reaction with phase change 1. PhMgBr 2. BrSi(CH2CH,C6F13)3

Si(CH2CH2C6F13)3 1. CsF

*

H3C 15 Fig. 3.

3. extraction in the fluorous phase

16

'h H3CP

2. extraction in the organic phase

"7

I I

Fluorous-phase reactions: single-phase reaction versus reaction with phase changes.

shown that larger molecules, with molecular weights of about 450, can also be synthesized through the advantages of fluorous-phase separation. The desired condensation products are obtained in good yields, even though only 6 weight-% of the reaction mixture belongs to the products [30]. At this point, atom economy [31] becomes an obvious problem of fluorousphase chemistry, with regard both to the starting material/product relationship and to fluorous labeling ((CloF21-C2H4)3-Sitags). This is particularly the case with rising polarity and size of the substrates, since an even higher degree of fluorination is needed. If protecting groups are required for synthetic transformations, fluorous tagging reagents can be introduced directly for the protection of functional groups, thereby meeting two needs without additional steps [ 321. After application of the fluorous benzyl protecting group Bnf, glucal 18 is converted by an excess of diacetone galactose 19 into the disaccharide 20, which, despite its relatively high polarity, is extracted into the FC-72 fluorous phase (Figure 4). Fluorous tags are also interesting as scavengers for an excess of starting material or of one of the reagents. Compounds that are not entirely converted after the reaction can be quenched with molecules bearing an alkyl fluorous group and can then be removed by fluorous-phase extraction [ 331. This principle has been applied, for example, to an excess of ~CH~CH~]~N isocyanate, which was quenched with the amine [ ( C ~ F ~ S C H ~ C H ~ ) ~ S ~ C H and then extracted into the fluorous phase. Although tin hydride is widely used as a reagent in ionic and radical reactions, it is prone to problems regarding its complete removal and its toxicity. The fluorous reagent tris[2(perfluorohexyl)ethyl]tin hydride ( ( C ~ F I ~ C H ~ C H ~21) ) ~has S ~normal H; tin hydride reactivity and can be completely extracted with perfluoromethylcyclohexane [34]. It can be used

Fluorous-Phase Strategy for lmproving Separation Eficiency

I

99

OH

p

OBnf I

I

'""0 (10 equiv.)

BnfO"' OH Br

9BnfBr

OBnf 18

OBnf

+

extraction in the FC-72 phase Fig. 4.

excess in the MeOH phase

Fluorous protecting group (Bnf): simultaneous function as protecting group and as fluorous tag.

advantageously in reactions carried out in a partially fluorinated solvent such as C ~ H S C F ~ , which provides a homogeneous reaction mixture. The rate constants for radical trapping by the fluorous tin hydride reagent 21 are about twice those of the reaction between Bu3SnH and the primary radical 22 [35]. This implies a convenient application of fluorous tin hydride reagents that can closely mimic tributyltin hydride in preparative chemistry (Figure 5). Another application of fluorous chemistry is offered by palladium-catalyzed Stille crosscoupling between fluorous aryltin reactants and organic halides or triflates [ 361. This reaction is catalyzed by [PdC12(PPh3)2] and carried out in a DMF/THF/C~FSCF~ solvent mixture, with LiCl as an additive. Workup is by extraction from the three-phase system of water, CH2C12,and FC-72. As an example, coupling of the heteroaryl tin derivative 23 with aryl triflate 24 (Figure 5) indicates the broad applicability of the fluorous Stille reaction. This fluorous variant of Stille coupling can be achieved in only two minutes (as opposed to 24 hours) by use of microwave irradiation in DMF. The fluorous allyltin reagent 25 is also valuable in the radical allylation of alkyl or aryl halides [ 371 and in a radical four-component carbonylation reaction (Figure 5) [ 381. Fluorous allyltin reagent 25 reacts with the acrylic ester 26 and the alkyl iodide 27 in the presence of CO (90 atm) in the partially fluorinated solvent C6HSCF3.The product 28 resulting from a radical tandem sequence is extracted from the two-phase mixture CH3CN/FC-72.The chainpropagating abilities of fluorous allyltin reagents have been found to be slightly weaker than those of conventional allyltin reagents.

100

I

Fluorous Techniques: Progress in Reaction-Processing and Pur$cation

Trapping of a primary radical (c6F1 3CH2CH2)3SnH u

p

h

d

I

P

21

h

kT

*

dPh @Ph

Stille cross coupling

eTfo& mo A

U

M~ PdC12(PPh& *

(C6F13CH2CH2)3Sn

\ I +I

23

/ \

LiCI, DMF

OMe

Radical allylation

+

&Br

(C6F13CH2CH2CH2)3Sn 25 (C6F1,CH2CH2CH2),Sn Br

Fluoroallylation in a four-component coupling

+

25

EtO

+

&COOMe 26

Ll

+

co

-

EtO*

0

COOMe

27

28 Fig. 5.

Reactions that have been performed with the aid o f the fluorous-phase approach.

Fluorous Reversed-Phase Silica Gel I 1 0 1

+

-

FH3

coz

(~FI3CH,CH,),SnH

I

21

Cbz

+

(C6Fl,CH,CH,)3Snl

\

Cbz

0

Fig. 6.

Radical cyclization in supercritical COz.

Reactions in Supercritical C 0 2

Although supercritical C02 is interesting as a reaction medium from the toxicological and environmental points of view, its use is limited because of the poor solubility of polar molecules. Organofluorine compounds are well known to be highly soluble in supercritical C02; this greatly extends synthetic possibilities in this medium [ 391. This is particularly the case for radical reactions, which require neither nucleophiles nor electrophiles and do not involve charged intermediates during the course of the reaction. Indeed, the fluorous alkyltin hydride 22 can be used for radical cyclizations in supercritical CO2 at moderate pressure. The formation of tin formate 29 (a side product often encountered in tributyltin hydride reactions in COz) is completely suppressed (Figure 6). The use of highly COz-soluble fluorous reagents, catalysts, and protecting groups should prove to be a valuable strategy for transportation of other reactions into supercritical CO2. In the long run, COZ should thereby serve as both the reaction and the separation solvent. Fluorous Reversed-Phase Silica Gel

A silica gel with a fluorocarbon bonded phase was first introduced in 1978 [40].It is ~C~FI~ commercially available with either of two residues, - S ~ ( M ~ ) ~ C H ~ C Hor -Si(Me)2CH2CH2CH2C(CF3)zCFzCFzCF3, attached to silica gel. These solid-phase materials retain fluorinated molecules with an affinity defined primarily by fluorine content [41-431. Fluorous solid-phase extractions are a first application of this material. As an alternative to liquid-liquid extractions, it is possible to extract fluorous products, catalysts, or reagents into the solid phase. Organic products are eluted with CH3CN, whereas various mobile phases of differing eluting power (hexanes, THF, partially fluorinated solvents, fluorocarbon solvents) are used afterwards to elute the fluorinated compounds from the silica gel. Another application is in fluorous chromatography: separation of fluorous compounds from other fluorous compounds on the basis of their respective fluorine content is possible. This chromatographic separation is quite sensitive, as shown by the following example of a small library synthesis of 100 mappicine analogues [44]. Starting with a mixture of pyridines 30, in which each residue R1 corresponds to a defined fluorous tag Rf, a series of cascade transformations and radical annulations is performed as indicated in Figure 7. Finally, a mixture

102

I

Fluorous Techniques: Progress in Reaction-Processing and Purijication OMe

A

-

,Me

2. BBr,

*a* TMS 30

I

0-Si(iPr),CH,CH,-

I

Rf

0-Si(iPr),CH,CH,-

Rf Five propargyl halides

Four pyridine derivatives

31 I 0-Si(iPr),CH,CH;

Rf- CH,CH,Si(iPr),-0

Rf

100 tagged mappicines R1

R2

H TBS Et H tBu H Bn H Ph Et

R3 Me iPr iPr iPr iPr

Rf (tag)

retention time (min)

C,H,, C,F, C,F,, C,F,, C,,F,,

2 11 16 24 30

Fig. 7. Synthesis of a library containing 100 rnappicine derivatives with fluorous tags (Rf): efficient separation on fluorous reversed-phase silica gel is possible on the basis of the fluorine content of the tag [44].

of tagged mappicines 31 is obtained, and these can be separated and deconvoluted on the basis of their fluorous tags. Separation is very efficient, as shown by the retention times of five derivatives. In fluorous synthesis, the possibility for separation on a fluorous solid phase allows for reduction of the fluorine content in the tags. Fluorous resins offer a way to confront the high molecular weight problem resulting from fluorous tagging and therefore the problem of atom economy in fluorous-phase chemistry.

References 1 a) B. CORNILS, Angew. Chem. Int.

Ed. Engl.

1997, 36, 2057-2059; b) D. P. CURRAN, Angew. Chem. Int. Ed. 1998, 37, 11751196; c) E. D E WOLF,G. VAN KOTEN,B.-J. DEELMAN, Chem. SOC.Rev. 1999, 28, 37-41. 2 M. VOGT; Ph.D. thesis, RWTH Aachen, 1991.

of fluorous phase chemistry see the following internet pages: http://www.fluorous.com and

3 For commercial use

http://www.ict-inter.net. TAKEUCHI, Y. NAKAMURA, Y. OHGO, et al., Tetrahedron Lett. 1998, 39, 86918694.

4 S.

References I103

I. T. H O R V ~ T HJ. , R ~ B A IScience , 1994, 266,72-75;b) I. T.H O R V ~ T G. H , Kiss, R. A. COOK,et a]., J . Am. Chem. SOL.1998, 120.3133-3143;c) S. KAINZ. D. KOCH. W. BAUMANN,et al., Angew. Chem. Int. Ed. Engl. 1997, 36,1628-1630. 6 a) J. J. J. JULIETTE, I. T. H O R V ~ T H J. ,A. GLADYSZ, Angew. Chem. Int. Ed. Engl. 1997, 36.1610-1612;b) J. J. J. JULIETTE, D. RUTHERFORD,I. T. H O R V ~ T Het H ,al., /. Am. Chem. SOC.1999, 121,2696-2704. 7 a) D.RUTHERFORD,J. J. J. JULIETTE, C. ROCABOY, et al., Catal. Today 1998, 42, 381-388;b) C. M. HAAR,J. HUANG,S. P. NOLAN, et al.. Organometallics 1998, 17, 5018-5024;c) B. RICHTER,A. L. SPEK,G. VAN KOTEN,et al., /. Am. Chem. SOC.2000, 122,3945-3951. 8 L. V. DINH,J. A. GLADYSZ, Tetrahedron Lett. 1999, 40,8995-8998. 9 W. KEIM,M. VOGT,P. WASSERSCHEID, et al., /. Mol. Catal. A : Chem. 1999, 139,1715 a)

175. 10 A. ENDRES,G. MAAS,Tetrahedron Lett.

1999, 40,6365-6368. 1 1 J.XIANG,S. TOYOSHIMA, A. ORITA,et al.,

Angew. Chem. Int. Ed. 2001, 40,3670-3672. I. KLEMENT, H. LUTJENS, P. KNOCHEL, Angew. Chem. Int. Ed. Engl. 1997, 36, 1454-1456. a) G. POZZI,F. MONTANARI, S. QUICI. Chem. Commun. 1997, 69-70;b) G. POZZI, F. CINATO,F. MONTANARI, et al., Chem. Commun. 1998, 877-878;c) G. POZZI,M. CAVAZZINI, F. CINATO,et al., Eur. /. Org. Chem. 1999, 8,1947-1955;d) S.QUICI,M. CAVAZZINI, S. CERAGIOLI, et al., Tetrahedron Lett. 1999, 40,3647-3650;e) G. POZZI,M. CAVAZZINI, S. QUICI,et al., Tetrahedron Lett. 1997, 38.7605-7608. K. S. RAVIKUMAR, F. BARBIER,J:P. BBcuB, et al., Tetrahedron 1998, 54,7447-7464. T. NISHIMURA, Y. MAEDA,N. KAKIUCHI. et al., J . Chem. Soc., Perkin Trans. 1 2000, 4301-4305. B. BETZEMEIER, M. CACAZZINI, S. QUICI, et al., Tetrahedron Lett. 2000,41,43434346. B. BETZEMEIER,P. KNOCHEL,in ‘Peroxide Chemistry’ (Ed. W. ADAM),Wiley-VCH 2000,454-468. J.-M. VINCENT, A. RABION,V. K. YACHANDRA, et al., Angew. Chem. lnt. Ed. Engl. 1997, 36,2346-2349.

12 a)

13

14 15

16

17

18

19 D. MAILLARD, C. NGUEFACK, G. POZZI,S.

QUICI,B. VALADE, D. S I N O UTetrahedron , Asymmetry 2000, 1 I , 2881-2884. 20 B. BETZEMEIER, P. KNOCHEL,Angew. Chem. Int. Ed. Engl. 1997, 36,26232624. 21 R. KLING, D. SINOU,G. P o z z ~ et , al., Tetrahedron Lett. 1998, 39,9439-9442. 22 J. MOINEAU, G. POZZI,S. QUICI,eta].: Tetrahedron Lett. 1999, 40,7683-7686. 23 S. SCHNEIDER, W. BANNWARTH,Hela Chim. Acta 2001, 84,735-742. 24 Y. NAKAMURA, S. TAKEUCHI, Y. OHGO,et al., Tetrahedron Lett. 2000,41, 57-GO. 25 K. MIKAMI,Y. MIKAMI, Y. MATSUMOTO, et al., Tetrahedron Lett. 2001, 42,289-292. 26 J. NISHIKIDO, H. NAKAJIMA, T. SAEKI,et al., Synlett 1998, 1347-1348. 27 M. c. A. VAN VLIET, I. w. c. E. ARENDS, R. A. SHELDON, Chem. Commun. 1999, 263-264. 28 B. BETZEMEIER,F. LHERMITE, P. KNOCHEL, Tetrahedron Lett. 1998, 39, 6667-6670. 29 a) A. STUDER,S. HADIDA, R. FERRITTO, et al., Science 1997, 275,823-826;b) A. STUDER,D. P. CURRAN,Tetrahedron 1997, 53,6681-6696. 30 A. STUDER. P. J E G E R , P. WIPF. et a]., /. Org. Chem. 1997, 62,2917-2924. 31 B. M.TROST,Angew. Chem. Int. Ed. Engl. 1995, 34,259-281. 32 a) D.P. CURRAN, R. FERRITTO,Y. HUA, Tetrahedron Lett. 1998, 39,4937-4940;b) T. MIURA,Y. HIROSE,M. OHMAE,eta]., Org. Lett. 2001, 3,3947-3950. 33 B. LINCLAU,A. K. SING,D. P. CURRAN,]. Org. Chem. 1999, 64,2835-2842. 34 D. P.CURRAN, S. HADIDA, /. Am. Chem. SOC.1996, 118,2531-2532. 35 J. H. HORNER, F. N. MARTINEZ, M. NEWCOMB, et al., Tetrahedron Lett. 1997, 38,2783-2786. 36 a) D.P. CURRAN, M. HOSHINO,J.Org. Chem. 1996, 61,6480-6481;b) M. LARHED, M. HOSHINO,S. HADIDA, et al., /. Org. Chem. 1997, 62,5583-5587;c) M. HOSHINO,P. DEGENKOLB, D. P.CURRAN, J . Org. Chem. 1997, 62,8341-8349. 37 D.P. CURRAN, Z. Luo, P. DEGENKOLB, Bioorg. Med. Chem. Lett. 1998, 8,24032408. 38 I. RYU, T. NIGUMA,S. MINAKATA, et al., Tetrahedron Lett. 1999, 40,2367-2370.

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Fluorous Techniques: Progress in Reaction-Processing and Purification 39 a) S. KAINZ, D. KOCH, W. BAUMANN,

et al., Angew. Chem. Int. Ed. Engl. 1997, 36, 1628-1630; b) S. HADIDA,M. S. SUPER,E. J. BECKMAN,et a!.,]. Am. Chem. SOC.1997, 119, 7406-7407; c) J. S. KEIPER, R. SIMHAN, J. M. DESIMONE, et al., J . Am. Chem. SOC.2002, 124, 18341835. 40 G. E. BERENDSEN, L. D. GALAN,].Liquid Chromatop. 1978, I , 403. 41 D. E. BERGBREITER,J. G. FRANCHINA, Chem. Commurz. 1997, 1531-1532.

a) D. P. CURRAN, S . HADIDA, M. HE,]. Org. Chem. 1997, 62, 6714-6715; b) S . KAINZ, 2. Luo, D. P. CURRAN, et al., Synthesis 1998, 1425-1427; c) D. P. CURRAN, Z. Y. Luo,]. Am. Chem. SOC. 1999, 121, 9069-9072; d) D. P. CURRAN, Synlett 2001, 1488-1496. 43 W. ZHANG,D. P. CURRAN, C. H.-T. CHEN, Tetrahedron 2002, 58, 3871-3875. Issue 20 is a special issue on fluorous chemistry. 44 Z. Luo, Q. ZHANG,Y. ODERAOTOSHI, et a!., Science 2001, 291, 1766-1769. 42

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

I105

Recent Developments in Using lonic Liquids as Solvents and Catalysts for Organic Synthesis Peter Wasserscheid Introduction

An ionic liquid is a liquid that consists only of ions and has a melting point below 100 “C. The apparently somewhat arbitrary line drawn between molten salts and ionic liquids at a melting temperature of 100 “C is justified by the possibility to replace water and organic solvents in synthetic applications with salts melting below this temperature. Research in ionic liquids and in organic synthesis using ionic liquids as solvents and/or as catalysts is attracting a lot of interest today. More than 300 citations in the SciFinder database looking for the keyword “ionic liquid(s)” in 2001 clearly indicate this. However, the big interest in ionic liquid methodology has only developed quite recently. In the years before 1997, less than 10 publications per year referred to the progress in this research field. What are the reasons for this rapidly growing interest? As far as I can see, there are three main contributions which will be briefly summarised in the following sub-chapters. Availability of Hydrolysis Stable lonic Liquids

So far the historical development of ionic liquids has mainly been driven by combining imidazolium, pyridinium, ammonium and phosphonium cations with different classes of anions. Chloroaluminate ionic liquids were the first more detailed studied ionic liquids. As early as 1948 they were synthesized by Hurley and Wier at the Rice Institute in Texas as bath solutions for electroplating aluminum [ 11. Later in the seventies and eighties, these systems were further developed by the groups of Osteryoung [2], Wilkes [3], Hussey [4] and Seddon [4c, 51. Due to their chemical nature, chloroaluminate ionic liquids must be classified as extremely hygroscopic and labile towards hydrolysis. In 1992, Wilkes and Zaworotko described the synthesis of the first imidazolium tetrafluoroborate ionic liquids [GI. These systems together with the slightly later published [7] hexafluorophosphate analogues are the “working horses” of the actual research with ionic liquid. However, their use in many technical applications is still limited by their relatively high sensitivity versus hydrolysis. The tendency of anion hydrolysis is of course much less pronounced than for the chloroaluminate melts but still existent. The [PF,j- anion of 1butyl-3-methylimidazolium ([ BMIM]) hexafluorophosphate - for example - has been found in our laboratories to completely hydrolyse after addition of excess water when the sample

106

I

Recent Developments in Using Ionic Liquids as Solvents and Catalystsfor Organic Synthesis

Tab. 1. Comparison of some properties of well-established ionic liquid systems with the l-ethyl-3methyimidazolium ([EMIM]) ion

ionic liquid

phasetransition

viscosity‘ fCPl

density‘ fgWl

tendencyfor hydrolysis

ref:

7 (mp)

18

1.240

very high

10

[EMIM] [ B F4] [EMIM][CF3SO,]

6 kP) -3 (mp)

34

1.240

relatively low

11

45

1.390

very low

9

[EMIM][(CF~SWZNI

-9 (mp)

31

1.518

very low

12

“Cl ~

[ EMIM][ AIC14]

4 a t 25 ” C ; mp = melting point: gp = glass point

was kept for 8 h at 100 “C. HF (toxic and highly corrosive) and phosphoric acid was formed. Under the same conditions hydrolysis of the tetrafluoroborate ion of [BMIM][BF4] was observed as well, however to a much smaller extend [8]. Consequently, the application of tetrafluoroborate and hexafluorophosphate ionic liquids is effectively restricted - at least under a technical scenario - to those applications where water-free conditions can be realised at acceptable costs. In 1996, Gratzel, BonhBte and coworkers published synthesis and properties of ionic liquids with anions containing CF3-groupsand other fluorinated alkyl groups [9].These do not show the same sensitivity towards hydrolysis than [BF4]- and [PF6]- containing systems. In fact, heating [BMIM][CF3S02),N] with excess of water to 100 “C for 24 h did not reveal any hint for anion hydrolysis [8]. In addition to their hydrolysis stability, a number of other very suitable properties of imidazolium salts with [ CF3S02)2N]-anion should be mentioned here. In comparison to other well established ionic liquids they combine low melting points and low viscosity with high thermal stability (for a comparison of some physico-chemical data see Table 1). Moreover, they can be easily prepared in high quality due to their miscibility gap with water. Commercial Availability

Historically, the know-how to synthesise and handle ionic liquids has been treated somehow like a “holy grail”. Indeed, only a small number of specialised industrial and academic research groups were able to prepare and handle the highly hygroscopic chloroaluminate ionic liquids which were the only ionic liquid systems available in larger amounts up to the mid-nineties. The first publication describing the synthesis of tetrafluoroborate and hexafluorophosphate ionic liquids by metathesis reaction from the corresponding alkali salts [ 131 opened up the way towards a commercial ionic liquid production. Nowadays, a number of commercial suppliers offer ionic liquids even in large quantities [14]. Moreover, the availability of many ionic liquids on a rapid delivery basis has been established through internationally operating distributors [ 151. Without any doubt the improved commercial availability of ionic liquids is a key factor for the strongly increasing interest in this new class of liquid materials. In fact, a synthetic

Progress in lonic Liquid Design and Synthesis

chemist searching for the ideal solvent for his specific application usually takes solvents which are ready for use on the shelf of his laboratory. The additional effort of synthesising a new special solvent can be rarely justified especially in industrial research. Green Chemistry

For good reasons, ionic liquids are often discussed as solvents for a “Greener Chemistry” [lG]. In contrast to volatile organic solvents and extraction media, they have no measurable vapour pressure. Therefore there is no loss of solvent through evaporation. Environmental and safety problems arising through the use of volatile organic solvents can be avoided. For catalytic application where a transition metal catalyst is dissolved in the ionic liquid or the ionic liquid itself acts as the catalyst two additional aspects are of interest. Firstly, the special solubility properties of the ionic liquid enables a biphasic reaction mode in many cases. Exploitation of the miscibility gap between the ionic catalyst phase and the products allows, in this case, the catalyst to be isolated effectively from the product and reused many times. Secondly, the non-volatile nature of ionic liquids enables a more effective product isolation by distillation. Again, the possibility arises to reuse the isolated ionic catalyst phase. In both cases, the total reactivity of the applied catalysts is increased and catalyst consumption relative to the generated product is reduced. For example, all these advantages have been convincingly demonstrated for the transition metal catalysed hydroformylation [ 171. Therefore, the general trend towards a “greener” and more sustainable chemistry has contributed substantially to the growing interest in using ionic liquids for synthetic applications. Following the large number of original publications describing the use of ionic liquids in synthetic applications an extensive reviewing practise about this topic has developed over the last three years. Olivier-Bourbigouand Magna [18], Sheldon [19] and Gordon [20] published three excellent reviews presenting a comprehensive overview of the actual work carried out on catalysis involving ionic liquids with slightly different emphasis. All three up-date earlier published reviews by the author and Keim [21], Welton [22] and Seddon and Holbrey [23] on the same topic. Moreover, a whole book has been dedicated to the application of ionic liquids in synthetic applications [ 241. Obviously, it can not be the aim of this contribution to repeat or summarise the above mentioned reviews again. In contrast, a few selected recent developments in different areas of ionic liquid research should be highlighted which are believed to be of some general relevance for the future development of ionic liquids and their application in synthetic chemistry. Progress in Ionic Liquid Design and Synthesis

In the last two years, an interesting process could be observed in the research aiming for the development of new ionic liquids. Depending on the complexity of the combination of properties required and on the amount of ionic liquid consumed for a given application, the recently developed ionic liquids can be divided in two groups: The first group falls under the definition of “bulk ionic liquids”. This means a class of ionic liquids that is designed to be produced, used and somehow consumed in larger quan-

I

107

108

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Recent Developments in Using Ionic Liquids as Solvents and Catalystsfor Organic Synthesis

r-

Fig. 1.

1

Examples for “bulk ionic liquids” developed in the last three years.

tities. Applications for these ionic liquids are expected to be solvents for organic reactions, homogeneous catalysis, biocatalysis and other synthetic applications with some ionic liquid consumption as well as non synthetic applications such as the application as heat carriers, lubricants, additives, surfactants, phase transfer catalysts, extraction solvents, solvents for extractive distillation, antistatics etc. Cation and anion of these “bulk ionic liquids” are chosen to make a relatively cheap (expected price on a multi-hundred litre scale: ca 30 (€/litre), halogen-free (e.g. for easy disposal of spent ionic liquid by thermal treatment) and toxologically well-characterized liquid (a preliminary study about the acute toxicity of a nonchloroaluminate ionic liquid has been recently published [25]). It can be expected that from all ionic liquids meeting these requirements only a very limited number of candidates will be selected for an industrial use on larger scale. However, these candidates will become well characterised and - due to their larger production quantities - readily available. Promising examples for this type of “bulk ionic liquids” include benzenesulfonate [ 261, toluenesulfonate [ 271, octylsulfate [ 281 and hydrogensulfate [ 291 ionic liquids. Some examples are given in Figure 1. On the other hand several research groups are active in developing highly specialised, task-specific ionic liquids that - of course - will be used in much smaller quantities. Fields of applications for the latter are expected to be special solvents for organic synthesis, homogeneous catalysis, biocatalysis and all other synthetic applications with very low ionic liquid consumption (e.g. due to very efficient multiphasic operation). Non-synthetic applications for these materials are analytic applications (stationary or mobile phases for chromatography, matrixes for MS etc.), sensors, batteries etc. These ionic liquids are designed and optimised for the best performance in high-value-adding applications. Consequently, in future research only the scientist’s fantasy will limit the number of used ionic liquids in this group. Interesting recently published examples include ionic liquids with fluorinated [ 301. functionalized [31] and chiral cations [32] and anions (331. Advanced Acidic Ionic Liquids

Acidic chloroaluminate ionic liquids were used as reaction media for Friedel-Craftsreactions as early as 1976 [ 341. Systematic investigations into Friedel-Crafts alkylations of benzene with the same acidic systems followed in 1986 by Wilkes et al. [35]. The alkylation of benzene with alkenes in acidic imidazolium chloroaluminate melts was disclosed in a patent by BP Chemicals in 1994 [36]. Here, as advantages over the reaction with aluminum trichloride in organic solvents, claims are made regarding the easy isolation of the product, the practically total reusability of the liquid catalyst and the better selectivity to the desired products.

Advanced Acidic fonic Liquids

Fig. 2.

Examples for task specific ionic liquids developed in the last three years.

Following up this initial work a large number of reactions have been published by academic and industrial groups wherein a Lewis-acidic chloroaluminate ionic liquid is used as the acidic catalyst. A comprehensive overview on these research activities can be found in several reviews on this topic and the literature cited therein [18, 22, 371. However, acidic systems based on chloroaluminate ionic liquids have some serious limitations. They are extremely oxophilic thus forming adducts with C-0 functionalities. This makes their catalytic use difficult if the substrate or product of the reaction under investigation contains such a functional group. Often, it is necessary in these cases to hydrolyse the ionic liquid prior to product isolation including complete loss of the acidic ionic liquid catalyst. Moreover, chloroaluminate ionic liquids are difficult to handle since they react irreversibly with traces of water to form HC1 and Al-oxides. In this chapter alternative acidic ionic liquids systems will be briefly presented that have been recently developed as alternatives to chloroaluminate ionic liquids. In spite of this selection, it should be noted that chloroaluminate ionic liquids may still be attractive catalyst phases in reactions where their tuneable acidity and solubility properties offer advantage over AlC13 in organic solvents. Non-chloroalurninate Lewis Acidic Ionic Liquids

Seddon and co-workers described the Friedel-Crafts acylation reaction of benzene with acetylchloride using acidic chloroferrate ionic liquids as catalysts [38]. In contrast to the same reaction in presence of acidic chloroaluminate systems the ketone product could be separated from the ionic liquid by solvent extraction, provided that the molar ratio of FeC13 is in the range 0.51-0.55 in the applied ionic liquid catalyst (Scheme 1).

Scheme 1.

Friedel-Crafts acetylation using an acidic chloroferrate ionic liquid

I

109

110

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Recent Developments in Using Ionic Liquids as Solvents and Catalystsfor Organic Synthesis Examples for non-chloroaluminate ionic liquids formed by the reaction of a halide salt with a Lewis acid.

Tab. 2.

ionic liquid

anion species

references

[cation] Cl/FeClj [cation] CI/AlEtC12 [cation] CI/BCl, [cation] Cl/CuCI [cation] Cl/SnC12 [cation] X/SbF, [cation] CI/ZnC12

C1-, [FeC14][AlEtCl,] , [A12Et2Cls]-, [AlzEtC16]Cl-, [BC14][CuC12]-, [Cu2C1,]-, [Cu3C14][SnCI,]-, [Sn,Cl,]e.g. [SbFSXIe.g. [ZnC13]

38 39

cation

= pyridinium,

40 41

42 43 44

imidazolium, ammonium.

This simple example may illustrate that in general the reaction of an organic halide salt [cation]X with an excess of a Lewis-acid MX, can result in new catalytic materials even if other Lewis-acidsare applied than AlC13. In contrast, the use of other Lewis-acidsto form the ionic liquid of type [cation][MX,+l] + excess MX, (the excess of MX, may be dissolved in the neutral ionic liquid or may form acidic anionic species such as e.g. [M2X2y+l]-)gives access to new combinations of properties (e.g. a liquid, less oxophilic, Lewis-acidic catalyst with defined solubility and acidity properties). In Table 2 other examples of ionic liquids are presented which are formed by the reaction of an organic halide salt with different Lewis-acids. All these systems should be in principle useful acidic catalysts for synthetic organic chemistry even if not all displayed examples have been already discribed in the literature for this application. However, the formation of Lewis-acidic ionic liquids is not restricted to those systems obtained by reaction of an organic halide salt with an excess of Lewis-acid. For example, Kitazume and Zulfiqar have investigated the scandium(111) trifluoromethanesulfonate catalyzed Claisen rearrangement of several aromatic ally1 ethers in a neutral trifluoromethanesulfonate ionic liquids [45]. The reaction initially gave the 2-allylphenol but this reacted further to give 2-methyl-2,3-dihydrobenzo[b]furan (Scheme 2). The yields in this reaction were highly dependant on the ionic liquid chosen, with [EDBU][OTf] giving the best yields (e.g. 91% for R = G-CH3).

6 Sc(OTf)3 "JL"

R

Scheme 2.

PH

'J - \

\

R

R

Claisen rearrangement catalysed by Sc(OTf)3 in .a trifluoromethansulfonate ionic liquid

Conceptsfor Transition Metal Catalysis Using lonic Liquids

Brmsted-acidic lonic Liquids

The easiest way to create a Brensted acidic ionic liquid is to dissolve a strong Brernsted acid in an ionic liquid. Already in 1989, Smith and coworkers described that mixtures of HC1 and acidic chloroaluminate ionic liquids result in the formation of superacidic Brensted acids (more acidic than 100% sulfuric acid). This is due to the reaction of HC1 with the acidic anions (e.g. [AlzC17]-) of the melt forming a proton with extremely low solvation and therefore very high acidity [46]. A more recent - but much less acidic example - was presented by Raston et al. who converted 3,4-dimethoxyphenylmethanolto cyclotriveratrylene using mixtures of tributylhex] [ ( C F ~and phosylammonium bis(trifluoromethanesulfony1)amide [ N B u ~ ( C ~ H ~ ~ )S02)2N] phoric or ptoluenesulfonic acid (Scheme 3) [47]. H3C0

OCH3

L4

OCH3 I

H3c0&0H H3COH3CO

OCH3

The cyclisation of 3,4-dimethoxyphenylmethanol catalyzed by phosphoric acid dissolved in a neutral ionic liquid.

Scheme 3.

The synthesis of several hydrogensulphate and tetrakis(hydrogensu1phato)borate ionic liquids has been described by our group [29]. Mixtures of these ionic liquids with sulphuric acid were used as non-volatile acidic phases with tuneable solubility properties for catalytic applications such as e.g. the alkylation of benzene with 1-decene. The results demonstrate that hydrogensulfate and tetrakis(hydrogensu1fato)borate ionic liquids are highly interesting additives to mineral acids to form new, highly Brensted-acidic catalysts. For example, it was found that a mixtures of sulphuric acid with only 2.2 mol% of [ OMIM][B( HS04)4] ionic liquid yielded 90% more monoalkylbenzene product than the neat sulphuric acid catalyst under identical reaction conditions. This and related results are explained by an interplay of solubility and acidity effects caused by the ionic liquid additive. Concepts for Transition Metal Catalysis Using Ionic Liquids

In the following sub-chapters two selected examples will be presented to illustrate general concepts for transition metal catalysis in ionic liquids. In both examples the role of the ionic liquid is different being alternatively used mainly in its function as ligand precursor or selective extraction solvent respectively.

I

111

112

I

Recent Developments in Using Ionic Liquids as Solvents and Catalystsfor Organic Synthesis lonic Liquid as Reactive Catalyst Phase Forming in-situ Transition Metal Carbene Complexes Exempl8ed for the Pd-catalysed Heck Reaction in Ionic Liquids

The Heck reaction and other related transformations for selective C-C-couplings are receiving a great deal of attention among synthetic chemists due to their versatility for fine chemical synthesis. However, these reactions suffer in many cases from the instability of the Pdcatalysts used, leading to high catalyst consumption and difficult processing. Starting from the early work by Kaufmann and al. in 1996 [48], many groups have investigated Heck-reactions in ionic liquids (for detailed reviews see [49, 20, 211). However, as has been demonstrated by Xiao et al. [SO] and Welton et al. [51],the use of imidazolium based ionic liquids in Pd-catalysed Heck reaction always bears the possibility of an in-situ formation of Pd-carbene complexes. The reason for this originates from the well-known relatively high acidity of the H atom in the 2-position of the imidazolium ion [ 521. Xiao and coworkers demonstrated that a Pd imidazolylidene complex is formed when Pd(OAc)2 was heated in presence of [BMIMIBr. The isolated Pd carbene complex was found to be active and stable in Heck coupling reactions. Welton et al. were later able to characterize an isolated Pd-carbene complex obtained in this way by X-ray spectroscopy. The reaction pathway to form the Pd-carbene in presence of a base is displayed in Scheme 4.

w Formation of a Pd-carbene complex by deprotonation o f the imidazolium cation.

Scheme 4.

It should be noted here that the abstraction of the acidic proton in 2-position of the imidazolium ring by a base is not the only possibility to form a metal carbene complex. Cave11 and co-worker have observed the in-situ metal carbene complex formation in an ionic liquid by direct oxidative addition of the imidazolium cation on a metal centre in a low oxidation state (Scheme 5) [53]. However, the Pt-carbene complex formed can decompose by reductive elimination.

[

N

~

1

/ v \

Scheme 5.

N[BF,I-

Pt(PPh314

Formation of a Pt-carbene complex by oxidative addition o f 1,3-dimethylimidazolium ion,

Conclusions and Outlook I 1 1 3

In the light of these results, it is very important to check catalytic results obtained from imidazolium ionic liquid for a possible influence of in-situ formed carbene species. This can be done especially by testing a given reaction as well in ionic liquids which do not form carbene complexes e.g. in pyridinium based ionic liquids. lonic Liquid as lnert Catalyst Phase Preventing Product lnhibition by Selective Extraction Exernplifiedfor the Pd-catalyzed Dirnerisation of Methylacrylate in lonic Liquids

-

Recently, our group described in collaboration with Tkatchenko et al. the Pd-catalyzed dimerisation of methylacrylate(MA) using a tetrafluoroborate ionic liquid as catalyst solvent (Scheme 6) [ 541.

2 / T O

OMe

-

Pd(acac)2/ [HOEt2][BF4] ligand, H[BF4]

-

PMIM"F41

'0

OMe selectivity > 92 % Scheme 6. Pd-catalyzed dirnerisation of methylacrylate u s i n g a tetrafluoroborate ionic liquid as catalyst solvent.

However, in batch mode all dimerisation reaction (with and without added IL) were found to stop at a maximum MA conversion of about 80%. By adding fresh feedstock (and by some other experiments) we could reveal that the reaction suffers at this conversion from a product inhibition effect. To overcome this limitation we decided to carry out the reaction in a continuous biphasic mode using [BMIM][BF4]/tolueneas the solvent mixture. For the continuous experiment, a mixture of substrate and toluene was pumped into a glass tube containing the ionic liquid catalyst phase [Pd(acac)2,H[BF4] and an ionic phosphine ligand]. Driven by its lower density the feed rose in the tube and the organic phase - a mixture of product/substrate and organic solvent - was removed at the top of the reactor. Using this method a continuous experiment over 50 h could be carried out obtaining an overall TON of 4000 mol MA converted per rnol of Pd. Our results clearly demonstrated that the product inhibition problem could be efficiently solved by the continuous extraction of the MA dimer from the ionic catalyst solution. In general, this type of highly specialised liquid-liquid biphasic operations can be regarded as an ideal field for the application of ionic liquids. Due to their tuneable solubility properties (by proper cation/anion choice) an efficient optimisation of those combined reaction/ in-situ extraction systems becomes possible. Conclusions and Outlook

Obviously, there are many good reasons to study ionic liquids as alternative solvents in synthetic organic chemistry and particularly in catalytic reactions. Besides the engineering

114

I

Recent Developments in Using Ionic Liquids as Solvents and Catalystsfor Organic Synthesis

advantage of their non-volatile nature, the investigation of new biphasic reactions with an ionic catalyst phase is of special interest. The possibility to adjust solubility properties by different cation/anion Combinations has already been mentioned. Moreover, the application of an ionic liquid catalyst layer often enables a biphasic operation even in those cases where this is not possible using water or polar organic solvents (e.g. due to incompatibility with the catalyst or due to problems with substrate solubility). In this context, recent developments to apply ionic liquids in combination with biocatalysts should be mentioned here. After pioneering studies by Magnuson et al. [55] this new research area was developed by Kragl et al. [56] and others [57]. The first promising results, namely the fact that the use of ionic liquid in biocatalysis can help to overcome common problems observed in aqueous media (such as e.g. product and substrate hydrolysis or low substrate solubility) led to a busy research activity in this field (comprehensive reviews describing these activities have been published by Kragl et al. [ 581 and Sheldon [ 191). However, research on catalytic reactions in ionic liquids should not focus only on the question how to make some specific products more economical or ecological by using a new solvent and presumably a new multiphasic process. By bridging in a novel and highly attractive manner the gap between homogeneous and heterogeneous catalysis, the application of ionic liquids in catalysis gives rise to more fundamental questions. In fact, in many respects catalysis in ionic liquids is better regarded as heterogeneous catalysis with a liquid catalyst support than as conventional homogeneous catalysis in an organic solvent. As for heterogeneous catalysis, support-catalyst interactions are known in ionic liquids and can lead to catalyst activation. Product separation from an ionic catalyst layer is often easy (at least if the products are relatively unpolar and have low boiling points) like in classical heterogeneous catalysis. However, mass transfer limitation problems (when the chemical kinetics are fast) and some uncertainty concerning the exact microenvironment around the catalytically active centre represent common limitations for transition metal catalysis in ionic liquids and in heterogeneous catalysis. Of course, the use of a liquid catalyst immobilisation phase still makes some very important differences in comparison to classical heterogeneous supports. Obviously, by using a liquid ionic catalyst support it is possible to integrate some classical features of traditional homogenous catalysis into this type of “heterogeneous” catalysis. For example, a defined transition metal complex can be introduced and immobilised in an ionic liquid giving access to the chance to optimise the selectivity of a transition metal catalyzed reaction by ligand variation, which is a typical approach in homogeneous catalysis. Catalytic reactions in ionic liquids proceed under similar mild conditions as are typical for homogenous catalysis. Analysis of the active catalyst in an ionic liquid immobilisation phase is in principle possible by using the same methods developed for homogeneous catalysis which should enable a more rational catalyst design in the future. In comparison to traditional biphasic catalysis using water, fluorous phases or polar organic solvents, catalysis in ionic liquids represents a new and advanced way to combine the specific advantages of homogeneous and heterogeneous catalysis. In many applications the use of a defined transition metal complex immobilised on a liquid ionic “support” has already shown its unique potential. To identify new exciting examples for the use of ionic liquids in synthetic and catalytic reactions, it is probably the most promising way to start from a detailed understanding of

References

I

115

the special properties of the ionic liquid material and to identify from this point attractive targets for this methodology. Two successful examples from the past should illustrate this approach in more detail. The fact that ionic liquids with weakly-coordinating anions can combine in a unique manner relatively high polarity with low nucleophilicity allows for the first time biphasic catalysis with highly electrophilic, cationic Ni-complexes [ 591. The wide electrochemical window of ionic liquids in combination with their ability to serve as solvents for transition metal catalysts opens up new fascinating ways for a combination of electrochemistry and transition metal catalysis. A first very exiting example has been recently published by Bedioui et al. [GO]. Without any doubt, a lot of exciting chemistry is still to be done in ionic liquids! References 1

2

3 4

5

6 7

8 9

10

a) F. H. HURLEY, U.S. Patent 2,446,331, 1948 [Chem. Abstr. 1949,43, P7645bl; b) F. H. HURLEY, T. P. WIER,JR.,]. Electrochem. SOC.1951, 98, 207. a) H. L. CHUM,V. R. KOCH,L. L. MILLER, R. A. OSTERYOUNG, 1.Am. Chem. SOC. 1975, 97, 3264; b) J. ROBINSON, R. A. OSTERYOUNG,]. Am. Chem. SOC. 1979, 101, 323. J. S. WILKES, J. A. LEVISKY; R. A. WILSON, Inorg. Chem. 1982, 21, 1263. C. L. HUSSEY, a) T. M. LAHER, C. L. HUSSEY, lnorg. Chem. 1983, 22, 3247; b) T. B. SCHEFFLER, Znorg. Chem. 1984, 23, 1926; C. L. HUSSEY, c) D. APPLEBY,C. L. HUSSEY, K. R. SEDDON, J. E. TURP,Nature 1986, 323, 614. a) P. B. HITCHCOCK, T. J. MOHAMMED, K. R. SEDDON, j. A. ZORA,C. L. HUSSEY, E. H. WARD,Znorg. Chim. Acta 1986, 113, L25. J. S. WILKES, M. J. ZAWOROTKO,]. Chem. SOC.Chem. Commun. 1992, 965. J. FULLER,R. T. CARLIN, H. C. D E LONG, D. HAWORTH,].Chem. SOC. Chem. Commun. 1994,299. A. BOSMANN, P. WASSERSCHEID, unpublished results. P. BONHBTE, A,-P. DIAS,N. K. KALYANASUNDARAM, PAPAGEORGIOU, M. GFL~TZEL, h r g . Chem. 1996, 35, 1168. a) J. S. WILKES, j. A. LEVISKY,R. A. WILSON, C. L. HUSSEY, Znorg. Chem. 1982, 21, 1263; b) A. A. FANNIN J R . , D. A. FLOREANI, L. A. KING, J. S. LANDERS,B. J. PIERSMA, D. J. STECH,R. J. VAUGHN, J. S. WILKES, J. L. WILLIAMS,]. Phys. Chem. 1984, 88, 2614.

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J. FULLER, R. T. CARLIN, R. A. 1.Electrochem. SOC.1997, OSTERYOUNG,

144, 3881. A. NODA, K. HAYAMIZU, M. WATANABE,]. Phys. Chem. B 2001, 105,4603. 13 P. A. 2. SUAREZ, J. E. L. DULLIUS, S. EINLOFT, R. F. DE SOUZA,J. DUPONT, Polyhedron 1996, 15(7), 1217. 14 a) Solvent Innovation GmbH, Cologne/ Germany (wwwsolvent-innovation.com); b) Covalent Associates (www.covalentassociates.corn); c) Sachem Inc. (www.sacherninc.corn); d) Cytec Inc. (www.cytec.com). 15 a) Fluka (www.fluka.com); b) Merck (www.merck.de); c) Acros Organics (www.acros.corn); d) Wako (www.wakochem.co.jp). 16 a) M. FREEMANTLE, Chem. Eng. News 1999, 77(1), 23; b) D. BRADLEY, Chem. lnd. 1999, 86; c) M. FREEMANTLE, Chem. Eng. News 2000, 78/20), 37. 17 a) Y. CHAUVIN, L. MUSSMANN, H. OLIVIER, European Patent, E P 776880, 1997; b) Y. CHAUVIN, L. MURMANN, H. Angew. Chem. 1995, 107, 2941; OLIVIER, Angew. Chem., Int. Ed. Engl. 1995, 34, 2698; c) W. K E I M , D. VOGT,H. P. WASSERSCHEID,]. of WAFFENSCHMIDT, Cat. 1999, 186, 481; d) C. C. BRASSE, U. ENGLERT,A. SALZER, H. WAFFENSCHMIDT, P. WASSERSCHEID, Organometallics 2000, 19, 3818; e) P. WASSERSCHEID, H. WAFFENSCHMIDT, P. MACHNITZKI, K. W. KOTTSIEPER, 0. STELZER, Chem. Comm. 2001, 451; f ) F. FAVRE, H. OLIVIERBOURBIGOU,D. COMMEREUC, L. SAUSSINE, 12

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Recent Developments in Using Ionic Liquids as Solvents and Catalystsfor Organic Synthesis Chem. Commun. 2001, 1360; g) D. J. BRAUER, K. W. KOTTSIEPER,C. LIEK, 0. STELZER, H. WAFFENSCHMIDT, P. WASSERSCHEID, ]. Organomet. Chem. 2001, 630, 177. 18 H. OLIVIER-BOURBIGOU, L. MAGNA, 1.Mol. Cutal. A: Chemical 2002, 182-183, 419. 19 R. SHELDON, Chem. Commun. 2001, 2399. 20 C. M. GORDON, Applied Catalysis A: General 2001, 222, 101. 21 P. WASSERSCHEID, W. K E I M ,Angew. Chem. 2000, 112, 3926; Angew. Chem. Int. Ed. Engl2000, 39, 3772. 22 T.WELTON, Chem. Rev. 1999, 99, 2071. 23 J. D. HOLBREY, K. R. SEDDON, Clean Products and Processes 1999, 1, 223. 24 P. WASSERSCHEID, T.WELTON[eds.), “Ionic liquids in Synthesis”, Wiley-VCH, Weinheim 2002. 25 J. PERNAK, A. CZEPUKOWICZ, R. POZNIAK, Ind. Eng. Chem. Res. 2001, 40, 2379. 26 H. WAFFENSCIIMIDT, PhD-thesis, RWTH Aachen. 2000. 27 N. KARODIA, S. GUISE,C. NEWLANDS,J.-A. ANDERSEN, Chem. Commun. 1998, 2341. 28 P. WASSERSCHEID, R. VAN HAL,A. BOSMANN, Green Chem., 2002, 4, 400. 29 a) P.WASSERSCHEID, M. SESING,W. KORTH, Green Chem. 2002, 4, 134; b) W. WO KEIM.W. KORTH. P. WASSERSCHEID. 0016902 [to BP Chemicals Limited, UK; Akzo Nobel NV; Elementis UK Limited) 2000 [Chem.Abstr. 2000, 132, 2386911. 30 T.L. MERRIGAN, E. D. BATES, S. C. DORMAN, J. H. DAVISJR., Chem. Commun. 2000, 2051. 31 a) A. E. VISSER,R. P. SWATLOSKI, W. M. REICHERT,R. MAYTON, S. SHEFF,A. WIERZBICKI, J. H. DAVISJ R . , R. D. ROGERS,Chem. Commun. 2001, 135; b) A. E. VISSER,R. P. SWATLOSKI, W. M. REICHERT, R. MAYTON,Rebecca; S. SHEFF, A. WIERZBICKI, J. H. DAVISJ R . , R. D. ROGERS,Environmental Science and Technology 2002, 36(1 I ) , 2523. 32 P. WASSERSCHEID, A. BOSMANN,C. BOLM, Chem. Commun. 2002.200. 33 M. J. EARLE,P. B. MCCORMAC A N D K. R. SEDDON, Green Chemistry 1999, 1, 23. 34 V. R. KOCH, L. L. MILLER, R. A. OSTERYOUNG, J. Am. Chem. SOC.1976, 98, 5277. 35 J. A. BOON, J. A. LEVISKY,J. L. PFLUG,J. S. WILKES, 1.Org. Chem. 1986, 51, 480.

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M. L. M. ELLIS,P. K. G. HODGSON, MORGAN,K. R. SEDDON, WO 9521806 (to BP Chemicals Ltd, UK) 1995 [ Chem. Abstr. 1995, 124, 83811. 37 M. EARLEi n P. WASSERSCHEID, T. WELTON (Eds.) “Ionic Liquids in Synthesis”, WileyVCH, Weinheim, 2002, pp. 174-213. 38 P. N. DAVEY, M. J. EARLE,C. P. NEWMAN, K. R. SEDDON, WO 9919288 [to Quest International B.V., Neth.), 1999 [Chem. Abstr. 1999, 130, 2818711. 39 a) Y. CHAUVIN, S. EINLOFY,H. OLIVIER, Ind. Eng. Chem. Res. 1995, 34, 1149; b) B. GILBERT, Y. CHAUVIN, H. OLIVIER, F. DI MARCO-VAN TIGGELEN,].Chem. SOC. Dalton Trans. 1995, 3867. 40 S . D. WILLIAMS, J. P. SCHOEBRECHTS, J. C. G. MAMANTOV,]. Am. Chem. SOC. SELKIRK, 1987, 109, 2218. 41 Y. CHAUVIN, H. OLIVIER-BOURBIGOU, CHEMTECH 1995, 25, 26. 42 a) G . LING, N. KOURA, Denki Kagaku Oyobi Kogyo Butsuri Kagaku 1997, 65, H. WAFFEN149; b) P. WASSERSCHEID, SCHMIDT,].Mol. Cataf. A: Chem. 2000, 164( 1-2), 61. 43 P. BONNET, E. LACROIX, J.-P. SCHIRMANN, WO 0181353 (to Atofina, France) 2001 [Chem. Abstr. 2001. 135, 3384831. 44 A. P. ABBOTT,D. L. DAVIES, WO 0056700 (to University of Leicester, UK) 2000 [ Chem. Abstr. 2000, 133, 2690581. 45 F. ZULFIQAR, T.KITAZUME, Green Chem. 2000, 2, 296. 46 a) G . P. SMITH,A. S. DWORKIN, R. M. PAGNI,S. P. ZINGG,]. A m . Chem. SOC. 1989, 111, 525; b) M. MA, K. E. JOHNSON, J. Am. Chem. Soc. 1995, 117, 1508. 47 J. L. SCOTT,D. R. MACFARUN, C. L. RASTON, C. M. TEOH,Green Chem. 2000, 2, 123. 48 D. E. KAUFMANN.M. NOUROOZIAN, H. HENZE,Synlett 1996, 1091. 49 a) P. WASSERSCHEID in P. WASSERSCHEID, T. WELTON(Eds.) “Ionic liquids in synthesis”, Wiley-VCH, Weinheim, 2002, pp. 213-257 50 L. Xu. W. CHEN,J. XIAO,Organometallics 2000, 19, 1123. 51 C. J. MATHEWS, P. J. SMITH,T. WELTON, A. J. P. WHITE,Organometallics, 2001, 20( 18), 3848. 52 a) A. J. ARDUENGO, R. L. HARLOW, M.

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HARLOW, J . Am. Chem. SOC.1992, 114, 9th 5530; c) G. T. CHEEK,J. A. SPENCER, Int. Symp. on Molten salts, (Hrsg.: C. L. HUSSEY, D. S. NEWMAN, G. MAMANTOV, Y. ITO),The Electrochem. Soc., Inc., New York, 1994,426; d) W. A. HERRMANN, M. ELISON, J. FISCHER, C. KOECHER, G. R. J. ARTUS,Angew. Chem., Int. Ed. Engl. 1995, 34, 2371; e) D. BOURISSOU, 0. GUERRET, Chem. Rev. F. P. GABBAI,G. BERTRAND, 2000, zoo, 39. D. S. MCGUINNESS, K. J. CAVELL, B. F. YATES,Chem. Commun. 2001, 355. P. WASSERSCHEID, J. ZIMMERMANN, I. TKATCHENKO, S. STUTZMANN, Chem. Commun. 2002, 760. D. K. MAGNUSON, J. W. BODLEY,D. F. J . Solution Chem. 1984, 13, 583 EVANS, S. SCHOFER, N. KAFTZIK,P.

WASSERSCHEID, U. KRAGL, Chem. Commun. 2001,425. 57 a) S. G. CULL,1. D. HOLBREY, V. VARGASMORA,K. R. SEDDON, G. J . LYE, Biotechnol. Bioeng. 2000, 69, 227; b) M. ERBELDINGER, A. J. MESIANO, A. j. RUSSEL, Biotechnol. Prog. 2000, 16, 1131; c) R. MADEIRA JAW, F. VAN RANTWIJK,K. R. SEDDON, R. A. SHELDON, Org. Lett. 2000, 2, 4189. 58 U. KRAGL, N. KAFTZIK, S. H. SCHOFER,M. ECKSTEIN, P. WASSERSCHEID, C. HILGERS, C H I M I C A OGGI/Chemistry Today 2001, 7/8, 22; b) U. KRAGL, M. ECKSTEIN, N. KAFTZIK in P. WASSERSCHEID, T. WELTON (Eds.) “Ionic liquids in Synthesis”, Weinheim, Wiley-VCH, pp. 336-347. 59 P. WASSERSCHEID, C. M. GORDON,C. HILGERS: M. J. MALDOON; I. R. DUNKIN; Chem. Commun. 2001, 1186. 60 L. GAILLON, F. BEDIOUI, Chem. Commun. 2001, 1458.

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Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Recent Advances on the Sharpless Asymmetric Am inohyd roxyIation Drnitry Nilov and Oliver Reiser

Introduction

The asymmetric aminohydroxylation (AA), although only discovered [ 11 by B. Sharpless et al. in 1996, has rapidly become an invaluable synthetic tool in organic chemistry. Its great value is given in the possibility of enantioselectively introducing a 1,2-amino alcohol functionality, being most important for the construction of biologically active compounds and chiral ligands, from readily available alkenes. Although initially only a N-tosyl protected amino group could be transferred, quite rapidly other nitrogen sources transferring the amino group with standard protecting groups such as BOC [2] (tert-butoxycarbonyl) or Cbz [3] (benzyloxycarbonyl)were discovered, broadening greatly the utility of the AA. Moreover, by appropriate choice of the ligands or substrates, the regioselectivity of the reaction can be XNClNa or AcNBrLi K ~ O S O ~ ( O(1 H-4mol%) )~ DHQ2PHAL (1.25-5 mol%)

Rl/\\/R2

*

NHX Rl+R2

+

OH R 1 k R 2

OH

ROH I H20 O'C or room temp

NHX

X = Ts, Ms, Cbz. Boc, TeoC, Ac

OAlk'

OAlk* PHAL

OAlk*

0 AQN OAlk*

0

IND Scheme 1.

OAlk'

I

.

WoMe DHQD

OAlk* PY D

Overview of the Sharpless asymmetric aminohydroxylation (AA)

New Substrates and Applications

I

119

controlled either way quite efficiently (41, a strategy that has been further improved during the last three years [S]. There have been already a number of reviews [GI about the AA, but nevertheless, rapid progress in this area is still being made, so that a comprehensive compilation of all contributions towards the AA is beyond the scope of this article. New Substrates and Applications

The most amenable substrates for the AA have been so far cc,p-unsaturated carboxylic esters and styrenes, and quite a number of publications have been reported that further demonstrate this trend [7]. Especially useful appears the possibility to use Baylis-Hillman adducts 1 as starting materials, giving syn-2 with good preference over the diastereomer anti-2 without the need of adding the chiral ligands of the AA [8].The amino group is exclusively introduced at the terminal end of the alkene, however, it is interesting to note that the ligands of the AA does not seem to influence the course of the reaction at all: In the presence of (DHQ)zPHAL the products were obtained racemically, i.e. no kinetic resolution seems to have taken place, with the hydroxy group in 1 obviously acting as a directing group. OH

0

OH

0

R ’HO Y O / R 2 no AA ligand * R’ . y U ‘ . OOH NR2+ 65-88% 1

NHTs

HNTs

syn-2

R’= H, Me, Et, i-Pr, cyclohexyl, Ph &Me, Et, i-Pr, cyclohexyl, t-Bu

anfi-2

syn/anfi: 86:14 up to 99:l

Asymmetric arninohydroxylation o f Baylis-Hillrnan adducts.

Scheme 2.

The excellent results being usually obtained with cinnamates can be also used to arrive at acyclic saturated compounds as demonstrated in the synthesis of a precursor 5 of Ramoplanin A2 [9]. The para-methoxy phenyl group in 4 can be readily degraded to an ester group by oxidation with RuC13/NaI04. NHCbz

rcooM -

Me0

(DHQD)2PHAL AA

MeO

64%

299% ee

4

3

-

Fmoc , NH 0 BnO#N,Ttl

0

OH 5

Scheme 3.

Application of the AA toward the synthesis o f Rarnoplanin A2.

120

I

Recent Advances on the Sharpless Asymmetric Aminohydroxylation

Changing the ester to a related phosphonate group allows the synthesis of biologically important [ 101 2-amino-1-hydroxyphosphonic esters 7. However, the selectivities and especially the yields are significantly lower compared to the corresponding acrylates [ 111. NHR'O

O

Ar-?-OR

AA

OR

P-OR \OR OH

* Ar? (DHQ)2PHAL

21-53% 42-98% ee

R = Me, Et, 'Pr R' = Ts, COOEt

6 Scheme 4.

7 Synthesis of 2-amino-1-hydroxy phosphonic esters via the AA.

In the synthesis of manzamine alkaloids, the AA of 8 proceeded with remarkable selectivity, given the fact that the double bond is electronically not differentiated [12]. The formation of 9 as the exclusive product can be understood by a transfer of the nitrogen group via the least hindered trajectory to the alkene, i.e. the less-substituted position of the double and equatorial approach.

mBnmBn H

U

AA * N (DHQD)zPHAL BOC'

N

Boc'

H

76%

a Scheme 5.

H

>99% de

OH NHTS

9

Application of the AA toward the synthesis of manzarnine alkaloids,

Heteroaromatic alkenes have been found to be especially useful substrates for the AA, since they offer a considerable potential for further synthetic transformations. Thus, in a most elegant application the product 12 obtained from vinylfurane (10) via the AA was used for the synthesis of azasugars like 13 as precursors toward deoxymannojirimycin [ 131.

21 % (86% ee)

10

11

(1:2)

12

13 Scheme 6.

Application o f the AA toward the synthesis of deoxyrnannojirimycin.

N e w Nitrogen Sources I 1 2 1

While acrylates being substituted with a furan, thiophene, or indole moiety serve as excellent substrates in the AA [ 141, pyrrole and pyridine substituted acrylates fail in the title reaction [ 14al. However, the corresponding pyridine-N-oxides 16 can be used alternatively in the AA and subsequently reduced, thus providing an indirect solution to access aminohydroxylated products 14 or 15 of pyridine substituted acrylates [14a]. It was interesting to note that the major regioisomer 17 was formed with good enantioselectivity,while the minor 18 was obtained virtually racemic. This approach was used for the synthesis of the pyridyl analog of the side chain of taxol, which had been demonstrated to yield a considerable more potent taxol derivative than the natural product itself [ 151.

14

15

i 0-

0-

63-79% ee

17

16 Scheme 7.

(2.3-2.8: 1)

18

Indirect AA of pyridinyl acrylates via the corresponding N-oxides.

A quite remarkable desymmetrization of 19 was achieved using the AA: 20 was obtained with complete regioselectivity, indicating a strong directing effect of the silyl group due to its p-effect [ 161. SiMepOH AA

75% >98% ds, 68% ee

20

19 Scheme 8.

Desyrnmetrization of cyclohexa-l,4-dienes via the AA.

New Nitrogen Sources

There were a number of new nitrogen sources for the AA introduced, such as tertbutylsulphonamide [ 171, primary amides [ 181 and N-bromobenzamide [ 191. The combination of urethanes as the nitrogen and 1,3-dichloro-5,5-dimethyl hydantoin as a co-oxidant/

122

I

Recent Advances on the Sharpless Asymmetric Aminohydroxylation

chlorine source could be utilized in a one-pot procedure of chiral oxazolidin-2-ones 24 and 25, being most valuable chiral auxiliaries 1201. AA / Urethane 1,3-dichlor0-5,5-dimethyl hydantoin

Ar\=\

"kR ArxoH

HN

(DHQ)zPHAL 28-81Yo

b-OEt L

21

OH+HO

22

NH

Et0-d '0 23

0

0 81-98% ee 24

4-5:l

25

Ar = Ph, 4-MeO-C&l6,4-02NC6H4 R =Me, Ph, COOEt Scheme 9.

A one pot synthesis o f oxazolidones via the AA.

Similarly, an intramolecular variant utilizing carbamates 26 derived from allylic alcohols has been developed using an amine like Hunigs base (ethyl diisopropylamine) as additive 1211. The products were obtained with complete regio- and diastereocontrol, but surprisingly, only in racemic form when chiral ligands like (DHQ)zPHAL, being established for the AA, were employed. 0

(DHQ)2PHAL orkPr2NEt 41 -61Yo

R

R--(

OH

R = H, Ph, Pr, CH,CH=C-

(rac)-27

26 Scheme 10.

An intramolecular variant of the AA

New Ligands and Catalysts

Based on the established alkaloid ligands, a number of modifications have been reported which have led to alternative ligands and catalysts for the AA [7c, 221. Conceptually interesting is the discovery that products obtained by the aminohydroxylation itself can serve as ligands 1231. Thus, the AA of styrenes 28 proceeds in high yields to the regioisomeric amino alcohols 29 and 30 in the presence of catalytic amounts of 31, being the AA product of cinnamic acid, with moderate, nevertheless significant enantioselectivity.

References NHTs

AA

7

PhWR

Ph-R

4-

OH

29 (30-59% ee)

28

NHTs

1 . 2

30 (24-55%ee)

NHTs ph*CooH

OH 31 Scheme 11.

AA adducts o f cinnamic acid serve as ligands for the AA

Related to the previous example is the report that the AA of carboxylic acids [24] - as well as of carboxylic amides [25] or pinenes and camphenes [2G] - proceeds well in the absence of any ligand. It can be assumed that the reaction is autocatalytic, however, no definite experimental evidence has been provided to prove this speculation. While osmium is the metal of choice for the AA, there has been a recent report of the copper(1)-catalyzed intramolecular aminohydroxylation starting from hydroxylamines [ 271. The mechanism of this reaction is distinctively different, involving radicals as intermediates. Conclusion

There remain still quite a few conceptual advances to be discovered in the asymmetric aminohydroxylation, broadening further the scope and limitations of this process. On the other hand, the utility of the AA is demonstrated in many applications now, giving ample proof that this reaction has become an indispensable tool in organic synthesis. References G. LI, H.-T. CHANG,K. B. SHARPLESS, Angew. Chem. Int. Ed. 1996, 35, 451-454. 2 (a) K. L. REDDY,K. B. SHARPLESS,]. Am. Chem. SOC.1998, 120, 1207-1217. (b) P. O’BRIEN,S. A. OSBORNE, D. D. PARKER, Tetrahedron Lett. 1998; 39, 4099-4102. (c) P. O’BRIEN, S. A. OSBORNE, D. D. ]. Chem. Soc., Perkin Trans. 1 1998, PARKER, 1

2519-2526. 3 G . LI, H. H. ANGERT, K. B. SHARPLESS, 4

Angew. Chem. Int. Ed. 1996,35,2813-2817. (a) B. TAO,G . SCHLINGHOFF, K. B. SHARPLESS, Tetrahedron Lett. 1998, 39, C. E. 2507-2510. (b) A. I. MORGAN, MASSE,J. S. PANEK, Org. Lett. 1999, I, 783-786.

5 (a) C.-Y. CHUANG, V. C. VASSAR, 2 . MA, R.

GENEY, I. OJIMA,Chirality 2002, 14, 151162. (b) R. M. DAVEY, M. A. BRIMBLE, M. D. MCLEOD,Tetrahedron Lett. 2000, 41, 5141-5145. (c) H. HAN,C.-W. CHO, K. D. JANDA: Chem. Eur. 1999, 5; 1565-1569. (d) C. E. MASSE,A. J. MORGAN, J. S. PANEK, Org. Lett. 2000, 2, 2571-2573. 6 (a) G. SCHLINGLOFF, K. B. SHARPLESS in Asymmetric Oxidations Reactions: A Practical Approach (Ed.: T. KATSUKI), Oxford University Press, Oxford 2001. (b) H. C. KOLB, K. B. SHARPLESS in Transition Metals for Fine Chemicals and Organic Synthesis, Vol. 2 (Eds.: M. BELLER, C. BOLM),WileyVCH, Weinheim, 1998, pp. 243-260.

I.

I

123

124

I

Recent Advances on the Sharpless Asymmetric Arninohydroxylation

7

8 9

10 11 12

13

14

(c) P. O’BRIEN,Angew. Chem. Int. Ed. 1999, 38, 326-329. (d) 0. REISER,Angew. Chem. Int. Ed. Engl. 1996, 35, 1308-1309. (a) C. E. SONG,C. R. OH, E. J. ROH, S. LEE,J. H . CHOI, Tetrahedron: Asymmetry 1999, 10, 671-674. (b) S. H. K. REDDY,S. LEE,A. DATTA,G. I. GEORG;]. Org. Chem. 2001, 66, 8211-8214. (c) A. MANDOLI,D. PINI, A. AGOSTINI,P. SALVADORI, Tetrahedron: Asymmetry 2000, 11, 4039-4042. (d) S.-H. LEE,J. YOON,S.-H. CHUNG, Y . 4 . LEE,Tetrahedron 2001, 57, 2139-2145. (e) H. PARK,B. CAO,M. M. JOULLIE,]. Org. Chem. 2001, 66, 7223-7226. ( f ) I. H. KIM, K. L. KIRK, Tetrahedron Lett. 2001, 42, 8401-8403. (8) R. N. ATKINSON, L. MOORE,J. TOBIN,S. B. KING,1.Org. Chem. 1999, 64, 3467-3475. W. PRINGLE,K. B. SHARPLESS, Tetrahedron Lett. 1999, 40, 5151-5154. D. L. BOGER,R. J. LEE,P.-Y. BOUNAUD, P. MEIER,J . Org. Chem. 2000, 65, 6770-6772. Review: H . GROGER,B. HAMMER,Chem. Eur. 1.2000, 6, 943-948. A. A. THOMAS,K. B. SHARPLESS,].Org. Chem. 1999, 64,8379-8385. J. S. CLARK,R. J. TOWNSEND, A. J. BLAKE, S. J. TEAT,A. JOHNS,Tetrahedron Lett. 2001, 42, 3235-3238. (a) M. L. BUSHEY,M. H. HAUKAAS,G . A. O’DOHERTY, ]. Org. Chem. 1999, 64, 2984-2985. (b) M. H. HAUKAAS,G. A. O’DOHERTI, Org. Lett. 2001, 3,401-404. See also (c) N. XI, M. A. CIUFOLINI, Tetrahedron Lett. 1995, 36, 6595-6598. (d) C. F. YANG,Y. M. Xu, L. X. LIAO, W.4. ZHOU, Tetrahedron Lett. 1998, 39, 9227-9228. (a) D. RAATZ,C. INNERTSBERGER, 0. REISER,Synktt 1999, 1907-1910. (b) H.

15

16

17 18 19

20

21

22

23

24 25

26

27

ZHANG,P. XIA, W. ZHOU,Tetrahedron: Asymmetry 2000, 11, 3439-3447. See: G . I. GEORG,G . C. B. HARRIMAN, M. HEPPERLE, J. S. CLOWERS, D. G. V. VELDE, R. H. HIMES,]. Org. Chem. 1996, 61, 2664-2676. R. ANGELAUD; 0. BABOT,T. CHARVAT, Y. LANDAIS,].Org. Chem. 1999, 64, 9613-9624. A. V. GONTCHAROV, H. LIU, K. B. Org. Lett. 1999, I , 1949-1952. SHARPLESS, 2. P. DEMKO,M. BARTSCH,K. B. SHARPLESS, Org. Lett. 2000. 2, 2221-2223. C. E. SONG,C. R. O H , E. J. ROH, S. LEE, J. H. C H O I ,Tetrahedron: Asymmetry 1999. 10, 671-674. N. S. BARTA,D. R. SIDLER,K. B. SOMMERVILLE, S. A. WEISSMAN, R. D. LARSEN,P. J. RIEDER,Org. Lett. 2000, 2, 2821-2824. T. J. DONOHOE,P. D. J O H N S O N , M. HELLIWELL, M. KEENAN,Chem. Commun. 2001, 2078-2079. R. M. DAVEY,M. A. BRIMBLE,M. D. MCLEOD,Tetrahedron Lett. 2000, 41, 5141-5 145. M. A. ANDERSON,R. EPPLE,V. V. FOKIN, K. B. SHARPLESS, Angew. Chem. Int. Ed. 2002, 41, 472-475. V. V. FOKIN,K. B. SHARPLESS, Angew. Chem. Int. Ed. 2001, 40, 3455-3457. A. V. GONTCHAROV, H. LIU, K. B. SHARPLESS, Org. Lett. 1999, I , 19491952. S. PINHEIRO,S. F. PEDRAZA,F. M. C. FARIAS,A. S. GONCALVES, P. R. R. COSTA, Tetrahedron: Asymmetry 2000, 11, 3845-3848. M. NOACK,R. G O ~ L I C HChem. , Commun. 2002, 536-537.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co I125

Asymmetric Phase Transfer Catalysis Christabel Carter and Adam Nelson Introduction

Phase transfer catalysis is a powerful method for the acceleration and control of the selectivity of chemical reactions. An important development has been the use of chiral phase transfer catalysts to induce asymmetry in reactions involving anionic intermediates [ 11. The efficient transfer of stereochemical information between contacting ions is a challenging goal; nonetheless, some isolated examples of highly enantioselective phase-transfer catalysed reactions have been known for many years [ 2 ] . Recently, however, the structural features of cinchonidinium (1) and cinchoninium (2) salts which are necessary for effective asymmetric phase transfer catalysis have been unravelled [ 31. These salts have proved to be extremely versatile reagents for controlling the enantioselectivity of a wide range of synthetically important transformations.

1

2

a; R’ = Ph, R2 = H; X = CI b; R’ = 9-anthracenyl; R2 = allyl; X = Br c; R’ = 9-anthracenyl, R2 = H; X = CI d; R’ = 9-anthracenyl; R2 = Ph; X = Br e; R’ = 9-anthracenyl, R2 = H; X = Br f; R’ = p-CF3C&-, R2 = H; X = Br

Asymmetric Alkylation of Clycine Derivatives

Asymmetric alkylations of the glycine derivative 3 have become the standard by which chiral phase transfer catalysts are judged, and enable the preparation of a wide range of unnatural

126

I

Asymmetric Phase Transfer Catalysk 0

0

conditions BnBr

Ph

4

3 Scheme 1.

a-amino acids. A key discovery has been the realisation that the size of the R1 substituent of salts 1 and 2 has a profound effect on the enantioselectivity of alkylation of the glycine derivative 3 (Scheme 1, Table 1). The benzyl cinchoninium salt 2a induces a modest level of enantioselectivity in the reaction of 3 with benzyl bromide (entry 2, Table 1) [4]. Corey [3] and Lygo [5] have found that by changing the quaternary ammonium substituent to the bulkier 9-anthracenylmethyl group, good to excellent levels of enantioselectivity can be obtained, using either solid-organic or aqueous-organic biphasic systems (entries 3-5, Table 1). An important feature of this methodology is that the cinchonidinium salts 1 and the cinchoninium salts 2 induce almost equal levels and opposite senses of enantioselectivity (compare entries 1-2 and 4-5, Table 1). The symmetrical quaternary ammonium salts 5-6 have also been shown to be effective reagents for the enantioselective alkylation of the Schiff base 3 under mild phase-transfer conditions [6]. Although results with the Cz-symmetrical quaternary ammonium salt 5 were disappointing (entry 6, Table l),the more rigid spiro ammonium salts G were much more effective catalysts. The rate and enantioselectivity of the benzylation of 3 was found to depend critically on the substituent R. With the ammonium salt Gc (R = P-Np), the reaction was complete within 30 min at 0 "C (entry 9, Table 1) and gave the amino acid derivative 4 with 95% ee, whereas the unsubstituted catalyst Ga ( R = H) required a longer reaction time and gave 4 in only 79% ee (entry 7, Table 1).

Tab. 1. Asymmetric PTC alkylation of 3 with benzyl bromide

Entry

catalyst

mol%

1

la

10

2

2a

3

Temp, Time

Reagents

Solvent

Product

ee@)

Yield(%)

Ref:

25 "C, 9 hr

NaOH

CHzCl2H2O

(R)-2

66

75

4

10

25 "C, 9 hr

NaOH

CHzCl2~H20

(S)-2

64

85

4

lb

10

-78 "C, 23 hr

CH2C12

(R)-2

94

87

3

4

lc

10

25 "C, 18 h r

CsOH. H20 KOH

HzO-PhMe

(R)-2

89

63

5

5

2c

10

25"C, 1 8 h r

KOH

HzO-PhMe

(S)-2

91

68

5

6

5a

1

O0C,6hr

KOH

H2O-PhMe

(R)-2

21

34

6

7

Ga

1

O0C,6hr

KOH

HZO-PhMe

(R)-2

79

73

6

8

6b

1

0"C,0.5 hr

KOH

H2O-PhMe

(R)-2

89

81

6

9

Gc

1

0 " C , 0 . 5 hr

KOH

H20-PhMe

(R)-2

96

95

6

Introduction I 1 2 7

a&@% \

\

\

\

5a; R = Ph 5b; R = a-Np

/

R

B

r

\

/

\

6a; R = H 6b; R = Ph 6 ~R ;= P-Np 6d; R = 3,4,5-F~-Ph

Synthesis of Unnatural Amino Acid Derivatives by Asymmetric Alkylation

The power of this methodology lies in the ability to prepare unnatural amino acid derivatives by asymmetric alkylation of prochiral enolates. Several asymmetric alkylations of the alanine derivative 7, catalysed by the Cz-symmetrical quaternary ammonium salt 6d, have been reported: these reactions yield unnatural amino acids such as 8 in high enantiomeric excess (Scheme 2) [7]. The chiral salen complex 9 has also been shown to be an effective catalyst for the preparation of u,a-dialkyl a-amino acids [8, 91. For example, benzylation of the Schiff base 10 gave the r-methyl phenylalanine derivative 11 in 92% ee (Scheme 3 ) [8]. Similar reactions have been catalysed by the TADDOL 12, and also give u,cc-dialkyl a-amino acids in good enantiomeric excess [ 101.

1 mol% 6d CsOH.H20 ____)

toluene, -1 0 "C Me

8, 91% ee

7 BOC 70% Scheme 2.

Lygo has extended his asymmetric alkylation methodology to the synthesis of bis-cc-amino acids (Scheme 4) [ 111. Bis-amino acids, such as rneso-diaminopimelic acid, dityrosine and isodityrosine, are found in nature and are thought to act as cross-linking agents which stabilise structural proteins in plants and bacteria. For example, asymmetric alkylation of the Schiff base 3 with the dibromide 13, catalysed by the quaternary ammonium salt le, gave the bis-amino acid derivative 14 in >95% ee. Asymmetric Alkylation of Other Enolates

The asymmetric alkylation of other prochiral enolates has also been studied, and good results have been obtained provided that the intermediate enolate is stabilised by conjugation. For example, the extended enolate derived from 15 has been trapped with a range of alkylating agents to give cc-alkylated esters such as 16 in 98% ee (Scheme 5) [ 121.

128

I

Asymmetric Phase Transfer Catalysis

1 mol% 9

0

CsOH.Hz0

Ph+N

OiPr

BnBr

Me

71Yo

Ph 11, 92% ee

10 Scheme 3.

KOH, 10 mol% l e

0

H20-PhMe ______)

Ph r"31,,,u Ph

tBuO

Br

0

3

Ph

14, >95% ee diast. ratio: 86:14

55%

Scheme 4.

10 mol% 3d M

e

2

N

v

O

t

B

u

P CsOH.Hz0 c

/

~

e

2

N

-~

$

/

\

NMep

15

81o/o

Ph \ I Me2N 16; 98% ee

Scheme 5.

Phh,,/OH

9

12

HO-Ph

17

u

Application Asymmetric Phase Transfer Catalysis t o Other important Reactions

Manabe has prepared the chiral quaternary phosphonium salt 17 with a multiple hydrogen bonding site; this salt accelerates the alkylation of the ketoester 18, giving products such as 19 with ca. 40% ee at room temperature (Scheme 6) [ 131.

-

0.2 mol% 17, BnBr

n

19; 40% ee

18 Scheme 6.

Application Asymmetric Phase Transfer Catalysis to Other Important Reactions

Chiral phase transfer catalysts have been exploited in a wide range of reactions which involve anionic intermediates. Remarkably, quaternary ammonium salts of 1 and 2 have been shown to induce asymmetry in many different synthetic reactions, and the cinchona alkaloids appear to be a “charmed’ template for the design of effective phase transfer catalysts [ 141. Asymmetric Michael Reactions

The enolate derived from the Schiff base 3 has been added to a$-unsaturated esters and ketones with a high level of enantioselectivity. For example, in the presence of 10 mol% lb, the enolate of the glycine derivative 3 was added to cyclohexenone with excellent diastereoselectivity to give the ketoester 20 with >99% ee (Scheme 7) [ 151. Promising results have also been obtained in the Michael additions of malonates to chalcone deriviatives [16]. The novel cinchonidinium bromide Ig was found to be the most effective catalyst for this transformation, yielding the Michael adduct 21 with 70% ee (Scheme 8).

CsOH.H20,3 10 mol% l b

b

O

tBu

CH2C12, -78 “C 88% Ph

20; 99% ee, 25:l d.r. Scheme 7.

P

h

d

P

h

21; 70% ee

Scheme 8.

I

129

130

I

Asymmetric Phase Transfer Catalysis

Asymmetric Epoxidation Reactions

Two different epoxidation reactions have been studied using chiral phase transfer catalysts. The salts 22 and 23 have been used to catalyse the nucleophilic epoxidation of enones (e.g. 24) to give either enantiomer of epoxides such as 25 (Scheme 9) [ 171. Once again, the large 9-anthracenylmethyl substituent is thought to have a profound effect on the enantio selectivity of the process. A similar process has been exploited by Taylor in his approach to the Manumycin antibiotics (e.g. Manumycin C, 26) [IS]. Nucleophilic epoxidation of the quinone derivative 27 with tert-butyl hydroperoxide anion, mediated by the cinchonidinium salt la, gave the cc,p-epoxyketone 28 in >99.5% ee (Scheme 10).

22

23

R = 9-Anthracenyl

24

(+)-25: 95%, 89% ee (cat. 22) (-)-25: 93%, 86% ee (cat. 23)

Scheme 9.

NHBOC

‘BuOOH, NaOH 25% 0

27

28, >99.5% ee

0 HO

Manumycin C, 26 Scheme 10.

A complementary approach to similar products involved the asymmetric Darzens reaction of cc-chloro ketones such as 29 with aldehydes. The cinchoninium salt 2f allowed the epoxide 30 to be prepared with reasonably high enantiomeric excess (Scheme 11) [ 191.

Application Asymmetric Phase Transfer Catalysis to Other lmportant Reactions

'BuCHO, LiOH.HzO " d p h

10 mol% 2f

29

BuzO, 4 "C 73%

-Ph

30,69% ee

Scheme 11.

Asymmetric Cyclopropanation Reactions

The enantio-determining step of nucleophilic additions to cc-bromo-cc,p-unsaturated ketones is mechanistically similar to those of nucleophilic epoxidations of enones, and asymmetry has also been induced in these processes using chiral phase-transfer catalysts [ 2 0 ] . The addition of the enolate of benzyl a-cyanoacetate to the enone 31, catalysed by the chiral ammonium salt 32, was highly diastereoselective and gave the cyclopropane 33 in 83% ee (Scheme 12). Good enantiomeric excesses have also been observed in reactions involving the anions of nitromethane and an cc-cyanosulfone [ 201.

32 Scheme 12.

Asymmetric Oxidative Cyclisation of 7,5-dienes

An exciting addition to the armoury of asymmetric phase transfer catalysed reactions has been the oxidative cyclisation of 1,s-dienes (Scheme 13) [21]. This tandem reaction process leads to the formation of tetrahydrofurans such as 35 in a single step from the open chain dienes 34. The step which determines the sense of asymmetry is the initial attack of permanganate anion, and this chiral information is efficiently relayed in the cyclisation to give products with three new stereogenic centres. For example, oxidation of the dienone 34 with potassium permanganate, catalysed by the salt 36, gave the tetrahydrofuran 35 in 72% ee.

KMn04, AcOH 10 mol% 36 F - H CHPCIZ,-30 "C 34

50%

35, 72% ee 36

Scheme 13.

I

131

132

I

Asymmetric Phase Transfer Catalysis

/-

alkvla tion

37

-lb

Fig. 1.

Rationalisation o f the Mechanism of Transfer of Stereochemical Information

Corey studied the X-ray crystal structures of cinchonidinium salts and has formulated a model which explains the highly enantioselective alkylation of the enolate of 3 [ 3 ] . This model accounts for the sense of asymmetric induction in this process and the importance of the size of the R' substituent in the salts 1 and 2; the model can be used to rationalise other phase transfer catalysed processes involving similar catalysts. The enolate 37 is thought to be in close contact with the least hindered face of the tetrahedron formed by the four atoms surrounding the quaternary nitrogen atom (the rear face of this tetrahedron is blocked by the bulky 9-anthracenylmethyl group). Alkylation of the less hindered face of 37 leads to the observed enantiomer of the product (see Figure 1). Summary

Several families of efficient chiral phase transfer catalysts are now available for use in asymmetric synthesis. To date, the highest enantiomeric excesses (>95% ee) are obtained using salts derived from cinchona alkaloids with a 9-anthracenylmethyl substituent on the bridgehead nitrogen (e.g. lb, 2b). These catalysts will be used to improve the enantioselectivity of existing asymmetric PTC reactions and will be exploited in other anion-mediated processes both in the laboratory and industrially. References A. NELSON, Angew. Chemie., Int. Ed. Engl. 1999, 38, 1583-1585. 2 E. V. DEHMLOW, P. SINGH,J. HEIDER,]. Chem. Res. Synop. 1981, 292-293, and 1

3 4

references therein. E. J. COREY,F. Xu, M. C. NoE,]. Am. Chem. SOC.1997, 119, 12414-12415. M. J. O'DONNELL, W. D. BENNETT, S. Wu, ]. Am. Chem. SOC.1989, I 1I, 23532355.

B. LYGO, P. G. WAINWRIGHT, Tetrahedron Lett. 1997, 38, 8595-8598. 6 T. 001,M. KAMEDA, K. MARUOKA,]. Am. Chem. SOC.1999, 121, 65196520. 7 T. 001,M. TAKEUCHI, M. KAMEDA, K. MARUOKA,].Am. Chem. SOC.2000, 122, 5228-5229. a Y. N. BELOKON, M. NORTH,v. s. KUBLITSKI,N. S. IKONNIKOV, P. E. KRASIK, 5

References I133 V. I. MALEEV,Tetrahedron Lett. 1999,40, 6105-6108. 9 Y. N. BELOKON, R. G. DAVIES,M. NORTH, Tetrahedron Lett. 2000,41, 7245-7248. 10 Y. N. BELOKON, K. A. KOCHETKOV, T. D. A. A. CHURKINA, N. S. IKONNIKOV, 0. V. LARIONOV, V. S. CHESNOKOV, PARMAR,R. KUMAR,H. B. KAGAN, Tetrahedron: Asymmetry 1998,9, 851-857. 1 1 B. LYGO,J. CROSBY, J. A. PETERSON, Tetrahedron, 2001,57, 6447-6453. 12 E. J. COREY, Y. Bo, J. BUSCH-PETER SEN,^. Am. Chem. SOC.1998,120, 13000-13001. 13 K. MANABE,Tetrahedron Lett. 1998,39, 5807-5810. 14 K. KACPRZAK, J.GAWRONSKI. Synthesis, 2001,961-998.

15

16 17 18

19 20

21

E. J. COREY,M. C. NOE, F. Xu. Tetrahedron Lett. 1998,39, 5347-5350. D. Y. KIM, S. C. H U H , S. M. KIM, Tetrahedron Lett. 2001,42, 6299-6301. B. LYGO,P. G. WAINWRIGHT, Tetrahedron Lett. 1998,39, 1599-1602. L. ALCARAZ, G . MACDONALD, J. RAGOT, N. J. LEWIS,R. J. K. TAYLOR,Tetrahedron 1999, 55, 3707-3716. S . ARAI, T. SHIOIRI,Tetrahedron Lett. 1998, 39, 2145-2148. S. ARAI,K. NAKAYAMA, T. ISHIDA,T. SHIOIRI,Tetrahedron Lett. 1999,40, 4215-4218. R. C. D. BROWN,I. F. KELLY,Angew. Chem., Int. Ed. Engl. 2001,40, 44964498.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Asymmetric Catalytic Aminoalkylations: New Powerful Methods for the Enantioselective Synthesis o f Amino Acid Derivatives, Mannich Bases, and Homoall y k Am ines Michael Arend and Xiaojing Wang

The economical importance of enantiomerically pure compounds has grown considerably during the last years and will increase even further [ 11. Therefore, the development of efficient asymmetric syntheses using chiral catalysts is a main focus of modern industrial and basic research. As a result, there are meanwhile powerful asymmetric catalytic variants for many essential reactions [2]. However, until recently this did not include the important class of aminoalkylation reactions [ 31, if one leaves aside aminoalkylations of organometallic compounds such as Grignard, organolithium, or organozinc reagents catalyzed by chiral ligands (Lewis bases) [3c-d, 4, 51. Analogous attempts to activate and to chirally modify other nucleophiles such as ester enolates with chiral ligands (e.g., diether or aminodiether) [ 61, and to aminoalkylate them enantioselectively were only partly successful. These methods either require stoichiometric amounts of the chiral ligand or provide good enantioselectivities solely in special cases. However, the potential of chiral organocatalysts (i.e., metal-free catalysts) [ 71, for asymmetric aminoalkylation reactions is definitely not exhausted yet. Impressive examples are asymmetric variants of the Mannich reaction [S, 91 employing the cheap and readily available (S)-proline or related compounds as chiral catalysts [ 101. This approach provides among other things an easy and convenient access to the enantioselective synthesis of b-amino ketones 2 (Scheme 1) from acetone (large excess), various aldehydes 1 ( R = alkyl, aryl), and p-anisidine (1.1eq) [Sa]. The methodology also proved to be suitable for the regio-, diastereoand enantioselective aminoalkylation of ketones other than acetone furnishing Mannich bases such as 3 which can serve as valuable synthetic building blocks (Scheme 1) [Sa]. It is assumed that an (E)-enamine from (S)-prolineand the ketone and an (E)-imine from the aldehyde and p-anisidine are formed in situ. The enamine then selectively attacks the si-face of the imine (access to the corresponding re-face is limited by unfavorable steric interactions between the pyrrolidine and the aromatic ring) to allow protonation of its lone pair as shown in the transition state 4 depicted in Scheme 1 (i.e., proline activates both, the nucleophile and the electrophile: it hence acts as a bifunctional catalyst) [10a, l l a ] . Despite the fact that the method requires 35 mol% of the catalyst and a large excess of the ketone [Ilb], these results are quite remarkable. A modification of this methodology using the preformed, highly electrophilic imine 5 as the aminoalkylating agent [9] casts additional light on the scope and limitations of this approach. On the one hand, various aldehydes (1.5 eq)

Asymmetric Catalytic Aminoalkylations n

12-48 h, rt

I

1

2 R = alkyl, aryl 35-SO%, 70-96% ee n

Ty

OH

3 57%, dr = 17:1, 65% ee

4

5

Diastereo- and/or enantioselective aminoalkylation of ketones catalyzed by a chiral bifunctional organocatalyst [gal.

Scheme 1.

could be successfully aminoalkylated with imine 5 in the presence of 5 mol% proline (rt, dioxane, 2-24 h) furnishing the corresponding [{-amino aldehydes in good yields, excellent syn-diastereoselectivities (mostly 219:l) and enantioselectivities (mostly 299% ee) [ 9b]. However, on the other hand, in order to achieve similar results in the aminoalkylation of the less reactive ketones with imine 5 (rt, 2-24 h) [gal, a large excess of the ketone (the reactions were performed in DMSO/ketone = 4:l) and 20 mol% of the proline catalyst were used. Chiral organocatalysts also proved to be highly useful for the development of various asymmetric catalytic variants of the Strecker reaction [12, 131. An especially efficient and broadly applicable methodology is the aminoalkylation of HCN with N-ally1 or N-benzyl imines G in the presence of the imino peptide catalyst 7a [ 12d] developed by combinatorial methods (Scheme 2; for a closely related earlier publication, see: [12b]). The resulting aamino nitriles 8 were formed quantitatively with no detectable byproducts. However, losses occurred upon product isolation as a result of the need to separate the catalyst chromatographically. In order to avoid product losses the reaction was also performed using the polymer-supported imino peptide catalyst 7b, which could easily be removed by filtration and was recycled nine times without any significant loss of reactivity or product enantioselectivity. However, the ee values obtained with the polymer-supported catalyst 71, were about 2-4% lower compared to the use of the soluble catalyst 7a. Catalyst 7a was, among other

I

135

136

I

Asymmetric Catalytic Aminoalkylations

1) 2 mol% catalyst 7 , toluene, -70 "C, 20 h 2) ( c F 3 c O ) ~ o

N. R'

)I

+

R

6

0 F3

HCN

R = alkyl, aryl; R' = allyl, benzyl

cJy' R

CN

8

65-99%, 77-97% ee

Scheme 2.

Enantioselective variant of the Strecker reaction catalyzed by chiral organocatalysts [I Zd].

uses, also applied successfully in the aminoalkylation of N-benzyl ketimines (ArCOMe and tert-BuCOMe derivatives) employing similar reaction conditions ( 2 mol% catalyst, toluene, -75 "C, 15-90 h) to give the corresponding N-benzyl-a-amino nitriles in excellent yields (generally 297%) and good enantioselectivities (in most cases 290% ee, examples are given for enantioselectivities 299.9% ee after recrystallization) [ 12el. These are really noteworthy findings taking into account all the difficulties that usually occur in the construction of N-substituted quaternary carbon atoms by 1,2-addition of nucleophiles to ketimines [ 141. Attempts to aminoalkylate Me3SiCN or HCN with an imine derived from acetophenone and benzylamine employing chirally modified Lewis acids (10 mol%) as the catalyst generally gave lower ee values [ 151. Nevertheless, the use of chirally modified Lewis acids as catalysts for enantioselective aminoalkylation reactions proved to be an extraordinary fertile research area [ 3b-d, 161. Meanwhile, numerous publications demonstrate their exceptional potential for the activation and chiral modification of Mannich reagents (generally imino compounds). In this way, not only HCN or its synthetic equivalents but also various other nucleophiles could be aminoalkylated asymmetrically (e.g., trimethylsilyl enol ethers derived from esters or ketones, alkenes, allyltributylstannane, allyltrimethylsilanes, and ketones). This way efficient routes for the enantioselective synthesis of a variety of valuable synthetic building blocks were created (e.g., x-amino nitriles, a- or b-amino acid derivatives, homoallylic amines or p-amino ketones) [ 3b-d]. 9 (R = alkyl, aryl) together with chiral zirconium For example, N-(2-hydroxyphenyl)imines catalysts generated in situ from binaphthol derived ligands were used for the asymmetric synthesis of a-amino nitriles [ 171, the diastereo- and/or enantioselective synthesis of homoallylic amines [ 181, the enantioselective synthesis of simple p-amino acid derivatives [ 191, the diastereo- and enantioselective preparation of a-hydroxy-b-aminoacid derivatives [ 201 or aminoalkyl butenolides (aminoalkylation of triisopropylsilyloxyfurans,a vinylogous variant of the Mannich reaction) [21]. A good example for the potential of the general approach is the diastereo- and enantioselective synthesis of (2R,3S)-3-phenylisoserinehydrochloride (10)

Asymmetric Catalytic Aminoalkylations

10 mol%

R’

OTB:S

9

-78 “C, 20 h, PhCH3

OTBS R = Ph

10

loo%, 95% ds, 94% ee

88%

Asymmetric catalytic aminoalkylation a s key step in the diastereo- and enantioselective synthesis of (2R,3S)-3-phenylisoserine hydrochloride (10) [20]. TBS = tea-butyldimethylsilyl, L = 1,2dimethylimidazole, CAN = cerium ammonium nitrate. Scheme 3.

depicted in Scheme 3 [20]. The advantages of the methodology include good yields and stereoselectivities, a broad scope, and also the fact that the N-(2-methoxyphenyl)-moiety is easily removed by oxidation with cerium ammonium nitrate (CAN). It should be noted however, that generally low reaction temperatures and/or relatively large amounts of the catalyst (often up to 10 mol%, in some cases up to 20 mol%) were required to achieve the aforementioned results [ 17-21]. Nevertheless, it has been shown impressively that these problems can be solved in principle by the design of improved chiral ligands and N-aryl moieties. An interesting example is the asymmetric synthesis of /I-amino esters 11 (Scheme 4) [22] with the key step performed highly enantioselectively at 100 “C in the presence of 2 mol% of a chiral (R)-VAPOL zirconium catalyst (the catalyst was generated from = (R)-VAPOL, and N-methyl Zr(OiPr).+, (R)-2,2’-Diphenyl-[3,3/]biphenanthrenyl-4,4’-diol imidazole = NMI). Additional related methods are direct asymmetric Strecker reactions employing aliphatic or aromatic aldehydes and 2-amino-3-methyl-phenol instead of the preformed imines 9 [ 17b-c], and enantioselective aminoalkylations of ketene acetals with N-4-trifluoromethylbenzoyl hydrazones [ 231. The imines 12 (X = 4-CH3-C6H4-S02(Ts), Ar, C 0 2 R , COR, etc.) preformed or generated in situ from N,O- or N,N-acetals or hemiacetals are another important class of Mannich reagents frequently used for diastereo- and/or enantioselective aminoalkylation reactions catalyzed by chiral Lewis acids (usually copper or palladium BINAP complexes such as 13). Among other things excellent results were obtained in the aminoalkylation of silyl enol ethers or ketene acetals [24]. A typical example is the synthesis of Mannich bases 14 depicted in Scheme 5 [24b]. Because of their comparatively high electrophilicity imines 12 could even be used successfully for the asymmetric aminoalkylation of unactivated alkenes 15 (ene reactions, see Scheme 5) [ 24h, 251, and the diastereo- and/or enantioselective aminoalkyla-

I

137

138

I

Asymmetric Catalytic Aminoalkylations

OSiMe3

2 mol% Zr-catalyst

toluene, 100 "C, 5-24 h

HN

Ar 83-95%, 93.0-99.8% ee

lc

Ph Ph

AN

NH2

(4-VAPOL

11 59-79%0

Asymmetric catalytic aminoalkylation as key step i n t h e enantioselective synthesis of the p - a m i n o esters 11 [22]. CAN = cerium a m m o n i u m nitrate. Scheme 4.

"&(i X.

Ar

re3+ N

5 mol%, ML = CuC104

k.CO2Et

R

0

NHTs

RU C 0 2 E t 14

THF, 0 "C, 24 h

12

65-93%, 90-98% e e

Rk +

R'

15

R 2 C T s

13 0.1-1 mol%, ML = CuPF,

12

I

b

CH2CI2,0 "C, 22-60 h

r

R'

C02Et

62-82%, 78-98% ee

Enantioselective catalytic aminoalkylation of silyl enol ethers [24b] and alkenes [24h, 251 w i t h imines 12 (X = Ts) a n d BINAP catalysts 13 (Ar = 4-MeC6H4). Scheme 5.

tion of numerous other nucleophiles such as allyl silanes [24c, 24h, 261, allyl stannanes [26], ketones [ 271, electron-rich aromatic compounds [ 281, trimethylsilyl nitronates [2Gb-c, 29a], nitroalkanes [ 2Gb, 29b], and alkyl radicals [ 301. The aforementioned aminoalkylations catalyzed by chirally modified Lewis acids employ special imino compounds such as 9 and 12 that can act as bidentate ligands and form

Asymmetric Catalytic Aminoalkylations

chelate complexes with the chiral Lewis acid catalysts. On the other hand, simple Mannich reagents usually furnish significantly lower enantioselectivities [ 24a, 311. One can easily explain this by the restriction of the configurational diversity in chelate complexes favoring a stereochemically uniform course of the reaction. However, it could be shown that in principle simple imines can be used successfully as well for asymmetric aminoalkylation reactions catalyzed by chiral Lewis acids. The asymmetric allylation of simple imines 16 with allyltributylstannane (Scheme 6) catalyzed by the /I-pinene derivative 17 [32a], for example furnished comparatively good results (for related asymmetric catalytic allylations of simple imines, see: [ 32b-d]). Moreover, it was demonstrated on the basis of several Strecker-typesyntheses [33-351 that catalysts such as the chiral aluminum complex 18 (Scheme 6) [ 33a-b] are also well suited for enantioselective aminoalkylations with simple imines. The mechanism indicated in Scheme 6 shows that the

DMF, 0 "C, 62-173 h

Ar

*

ArM

\

R = Pr, CH2Ar'

16

30-74%, 61-81% ee

CI

HN 20 mol% PhOH CH2CI2, -40 "C, 24-68 h 66-97%, 70-96% ee

8 Ph

19 Asymmetric catalytic arninoalkylation of allyltributylstannane [32a] and M e s S i C N [33a-b] with simple irnines.

Scheme 6.

I

139

140

I

Asymmetric Catalytic Aminoalkylotions

catalyst 18 acts in a bifunctional way (i.e., catalyst 18 activates both, the imine and the nucleophile) has been proposed to explain the selectivity and the broad scope of this method (the imines used in this study were derivatives of aromatic, heteroaromatic, aliphatic or qBunsaturated aldehydes). Additional interesting examples are the diastereo- and/or enantioselective aminoalkylation of nitroalkanes with N-phosphinoylimines catalyzed by chiral heterobimetallic complexes [ 361 and the asymmetric arylation of aromatic [ 37a], or qpunsaturated N-sulfonylimines [ 371 with arylstannanes catalyzed by chiral rhodium complexes. During the past few years impressive progress has been made in the field of catalytic asymmetric aminoalkylation. For example, the development of powerful bifunctional catalysts mimicking enzymes by activating both, nucleophile and electrophile and in addition controlling their orientation (e.g., see: 4 and 19; see also: [ 10, 12c, 33d, 34~1).Nevertheless, this chemistry is still in its infancy. An important reason for this is that the common techniques (even if they have been applied successfully to formally closely related reactions such as aldol additions) in many cases are only imperfectly or not at all applicable to aminoalkylations (e.g., see: [31]). Hence, the hitherto known methods for asymmetric aminoalkylation are mostly limited to special cases. Furthermore, they often require low reaction temperatures, relatively large amounts of the catalyst or long reaction times to give good yields or ee values. However, it can be assumed that in future both scope and efficiency of enantioselective aminoalkylations can be enhanced considerably by the development of more advanced tailor-made catalysts. There is no doubt that modern methodologies such as the design of chiral catalysts using combinatorial and evolution-based techniques will play a key role in this process [ 381. References and Notes For reviews, see: a) Chirality in Industry: The Commercial Manufacture and Applications of Optically Active Compounds (Eds.: A. N. COLLINS, G. N. SHELDRAKE, J. CROSBY), Wiley, Chichester, 1992; b) Chirality in Industry 11: Developments in the Commercial Manufacture and Applications of Optically Active Compounds (Eds.: A. N. COLLINS, G . N. SHELDRAKE, J. CROSBY), Wiley, Chichester, 1997; c) S. C. STINSON, Chem. Eng. News 2001, 79(40), 79. 2 For reviews, see: a) Comprehensive Asymmetric Catalysis (Eds.: E. N. J A C O B S E N , A. PFALTZ,H. YAMAMOTO), Springer, Berlin, 1999; b) Catalytic Asymmetric Synthesis (Ed.: I. OTmA), 2nd ed., Wiley-VCH, New York, 2000; c) H. TYE,J . Chem. Soc., Perkin Trans. 1 2000, 275; d) H. TYE,P. J. COMINA, J . Chem. Soc., Perkin Trans. 1 2001, 1729. 3 For reviews, see: a) M. AREND, B. WESTERMANN, N. RISCH, Angew. Chem. 1

1998, 110, 1097; Angew. Chem. Int. Ed. Engl. 1998, 37, 1045; b) M. AREND, Angew. Chem. 1999, 11 I, 3047; Angew. Chem. Int. Ed. Engl. 1999, 38, 2873; c) S. KOBAYASHI, H. ISHITANI, Chem. Rev. 1999, 99, 1069; d) S. E. DENMARK, 0. I.-C. NICAISEin Comprehensive Asymmetric Catalysis (Eds.: E. N. JACOBSEN, A. PFALTZ, H. YAMAMOTO),Springer, Heidelberg, 1999, p. 923. 4 For reviews, see: a) N. RISCH, M. AREND, Methoden Org. Chem. (Houben- Weyl) 4th ed. 1952-, Vol. E21b 1995, p. 1833; b) S . E. DENMARK, 0. J.-C. NICAISE, Chem. Commun. 1996, 999; c) D. ENDERS,U. REINHOLD,Tetrahedron: Asymmetry 1997, 8, 1895; d) R. BLOCH,Chem. Rev. 1998, 98, 1407. 5 For two recent examples of asymmetric catalytic aminoalkylations of Reformatskytype reagents, see: a) Y. UKAJI,Y. YOSHIDA, K. INOMATA, Tetrahedron:

References and Notes

6

7

8

9

10

11

12

Asymmetry 2000, 11, 733; b) Y. UKAJI,S. TAKENAKA, Y. HORITA,K. INOMATA, Chem. Lett. 2001, 254. a) H. FUJIEDA, M. KANAI,T.KAMBARA, A. IIDA,K. TOMIOKA,].Am. Chem. SOC.1997, 119, 2060 b) T. KAMBARA, M. A. HUSSEIN, A. IIDA,K. TOMIOKA, TetraH. FUJIEDA, hedron Lett. 1998, 39, 9055; c) T. KAMBARA, K. TOMIOKA,).Org. Chem. 1999, 64, 9282; d) K. TOMIOKA, H. FUTIEDA, S. HAYASHI, M. A. HUSSEIN, T. KAMBARA, Y. NOMURA,M. KANAI,K. KOGA, Chem. Commun. 1999, 715; e) T. KAMBARA, K. TOMIOKA, Chem. Pharm. Bull. 1999,47,720; f ) M. A. HUSSEIN,A. IIDA,K. TOMIOKA, Tetrahedron 1999, 55,11219; g) T. KAMBARA, K. TOMIOKA, Chem. Pharm. Bull. 2000, 48, 1577. For a general review on asymmetric organocatalysis, see: P. I. DALKO,L. MOISAN,Angew. Chem. 2001, 113, 3840; Angew. Chem. Int. Ed. Engl. 2001, 40, 372G. a) B. LIST,]. Am. Chem. SOC.2000, 122, 9336; for a closely related method using among other things the penicillamine derivative 5,5-dirnethylthiazolidine-4carboxylic acid as a chiral catalyst, see: b) W. NOTZ,K. SAKTHIVEL, T. BUI, C. ZHONG,C. F. BARBAS111, Tetrahedron Lett. 2001, 42, 199. a) A. CORDOVA, W. NOTZ,G. ZHONG,J. M. C. F. BARBAS 111,). Am. Chem. BETANCORT, SOC.2002, 124, 1842; b) A. CORDOVA, S. WATANABE, F. TANAKA, W. NOTZ, C. F. BARBAS111, J. Am. Chem. SOC.2002, 124, 1866. For reviews on the use of proline and related compounds as chiral catalysts for asymmetric syntheses, see: a) B. LIST, Synlett 2001, 1675; b) H. GROGER,J . WILKEN, Angew. Chem. 2001, 113, 545; Angew. Chem. Int. Ed. 2001, 40, 529. a) The transition state 4 depicted in Scheme 1 [ lOa] differs from the transition states postulating (2)-imineintermediates [8al proposed in the original publication; b) The reactions were performed in DMSO/ketone or CHC13/ketone = 4:l or the ketone was used as the solvent. a) M. S. IYER, K. M. GIGSTAD, N. D. NAMDEV, M. LIPTON,]. Am. Chem. SOC. 1996, 118,4910; b) M. S. SIGMAN,E. N. JACOBSEN,]. Am. Chem. SOC.1998, 120,

13

14

15

16

17

18

19

20 zi

4901; c) E. J. COREY,M. J. CROGAN, Org. P. Lett. 1999, 1, 157; d) M. S. SIGMAN, VACHAL, E. N. JACOBSEN, Angew. Chem. 2000, 112, 1336; Angew. Chem. In#. Ed. 2000, 39, 1279; e) P. VACHAL, E. N. Org. Lett. 2000, 2, 867; f ) B. JACOBSEN, LIU, X. FENG,F. C H E N G. , ZHANG,X. CUI, Y. JIANG,Synlett 2001, 1551. For recent reviews on modern variants of the Strecker reaction, see: a) D. ENDERS,J. P. SHIVLOCK, Chem. SOC. Rev. 2000, 29, 359; b) L. YET, Angew. Chem. 2001, 113, 900; Angew. Chem. Int. Ed. 2001, 40, 875. For a review, see: A. G. STEINIG, D. M. SPERO,Org. Prep. Proced. In#.2000, 32, 205. a) J. J. BYRNE, M. CHAVAROT, P.-Y. CHAVANT, Y. V A L L ~Tetrahedron E, Lett. 2000, 41,873; b) M. CHAVAROT, J. J. BYRNE,P. Y. CHAVANT, Y. V A L L ~ E , Tetrahedron:Asymmetry 2001, 12, 1147. For early publications on enantioselective aminoalkylations mediated by stoichiometric amounts of chiral Lewis acids, C. P. DECICCO,R. C. see: a) E. J. COREY, Tetrahedron Lett. 1991, 32, 5287; NEWBOLD, b) K. ISHIHARA, M. MIYATA,K. HATTORI, Am. Chem. SOC. T. TADA,H . YAMAMOTO,]. 1994, 116, 10520. a) H. ISHITANI,S. KOMIYAMA, S. KOBAYASHI, Angew. Chem. 1998, 110, 3369; Angew. Chem. In#. Ed. Engl. 1998, 37, 3186; b) H. ISHITANI,S. KOMIYAMA,Y. HASEGAWA, S. KOBAYASHI,]. Am. Chem. SOC.2000, 122, 762; c) S. KOBAYASHI, H. ISHITANI,Chirality 2000, 12, 540. T. GASTNER, H. ISHITANI, R. AKIYAMA, S. KOBAYASHI, Angew. Chem. 2001, 113, 1949; Angew. Chem. Int. Ed. 2001, 40, 1896. a) H. ISHITANI, M. UENO,S. KOBAYASHI,J. Am. Chem. SOC.1997, 119, 7153; b) H. ISHITANI, T. KITAZAWA, S. KOBAYASHI, Tetrahedron Lett. 1999, 40, 2161; c) S. KOBAYASHI,K. KUSAKABE,J . Org. Chem. 1999, 64, 4220; d) H . ISHITANI, M. UENO, S. KOBAYASHI.J. Am. Chem. SOC.2000, 122, 8180; e) S. KOBAYASHI, H. ISHITANI, Y. YAMASHITA,M. UENO,H. SHIMIZU, Tetrahedron 2001, 57, 861. S. KOBAYASHI, H. ISHITANI,M. UENO,]. Am. Chem. SOC. 1998, 120,431. S. F. MARTIN,0. D. LOPEZ,Tetrahedron Lett. 1999, 40, 8949.

I

141

142

I

Asymmetric Catalytic Aminoalkylations XUE,S. Yu, Y. DENG,W. D. WULFF, Angew. Chem. 2001, 113, 2331; Angau. Chem. Int. Ed. 2001, 40, 2271. S. KOBAYASHI, Y. HASEGAWA, H. ISHITANI, Chem. Lett. 1998, 1131. a) E. HAGIWARA, A. FUJII,M. SODEOKA,]. Am. Chem. SOC.1998, 120, 2474; b) D. FERRARIS, B. YOUNG, T. DUDDING,T. LECTKA,]. Am. Chem. SOC.1998, 120, 4548; c) D. FERRARIS, T. DUDDING, B. YOUNG, W. J. DRURY111, T. LECTKA,].Org. Chem. 1999, 64, 2168; d) D. FERRARIS, B. YOUNG, C. Cox, W. J. DRURY111, T. DUDDING, T. LECTKA,]. Org. Chem. 1998, 63, 6090; e) A. FUJII,E. HAGIWARA, M. SODEOKA,]. Am. Chem. SOC.1999, 121, 5450; for an example using polymer supported BINAP derived palladium catalysts, see: f ) A. FUJII,M. SODEOKA, Tetrahedron Lett. 1999, 40, 8011; g) D. FERRARIS. B. YOUNG,T. DUDDING, W. J. DRURY,T. LECTKA, Tetrahedron 1999, 55, 8869; h) D. FERRARIS, B. W. J. YOUNG, C. Cox, T. DUDDING, DRURY111, L. RYZHKOV, A. E. TAGGI,T. LECTKA,]. Am. Chem. SOC.2002, 124, 67; for an example using chiral copper complexes derived either from xylyl-BINAP or chiral diamines, see: i) S. KOBAYASHI, R. MATSUBARA, H. KITAGAWA,Org. Lett. 2002, 4, 143. a) W. J. DRURY111, D. FERRARIS, C. Cox, B. YOUNG, T. LECTKA,]. Am. Chem. SOC. 1998, 120, 11006; b) S . YAO, X. FANG, K. A. J B R G E N S E N , Chem. b n m U n . 1998, 2547. a) X. M. FANG,M. J O H A N N S E N , S. L. YAO, N. GATHERGOOD, R. G. HAZELL, K. A. JBRGENSEN, /. erg. Chem. 1999, 64, 4844; 17) Cl-symmetric bisoxazoline copper catalysts were used; c) a BINAP derived catalyst proved to be less suitable. K. JUHL, N. GATHERGOOD, K. A. J B R G E N S E N , Angew. Chem. 2001, 113, 3083; Angew. Chem. Int. Ed. 2001, 40, 2995. a) M. J O H A N N S E N , Chem. Commun. 1999, 2233; b) S. SAABY, X. FANG,N. GATHERGOOD, K. A. J B R G E N S E N , Angew. Chem. 2000, 112, 4280; Angew. Chem. Int. Ed. 2000, 39, 4114. a) K. R. KNUDSEN, T. RISGAARD, N. NISHIWAKI, K. V. GOTHELF, K. A. JBRGENSEN,]. Am. Chem. SOC. 2001, 123, K. R. K N U D S E N , 5843; b) N. NISHIWAKI,

22 S.

23 24

25

26

27

28

29

30 31

32

33

34

35

K. v. GOTHELF,K. A. JBRGENSEN, Angew. Chem. 2001, 113, 3080, Angew. Chem. rnt. Ed. 2001, 40, 2992. N. HALLAND, K. A. J B R G E N S E N , I. Chem. SOC.,Perkin Trans. 12001, 1290. a) S. YAMASAKI,T. IIDA,M. SHIBASAKI, Tetrahedron Lett. 1999, 40, 307; b) S . YAMASAKI, T. IIDA,M. SHIBASAKI, Tetrahedron 1999, 55, 8857. a) H. NAKAMURA, K. NAKAMURA, Y. YAMAMOTO,J. Am. Chem. SOC. 1998, 120. 4242; for a closely related method using H. allylsilanes, see: b) K. NAKAMURA, NAKAMURA, Y. YAMAMOTO,J . Org. Chem. 1999, 64, 2614; for intramolecular diastereo- and enantioselective asymmetric catalytic allylations of imines, see: c) J. Y. PARK,I. KADOTA, Y. YAMAMOTO,]. Org. Chem. 1999, 64, 4901; for the application of a polymer-supported chiral n-allylpalladium catalyst for the allylation of imines. Y. see: d) M. BAO, H. NAKAMURA, YAMAMOTO,Tetrahedron Lett. 2000, 41, 131. a) M. TAKAMURA, Y. HAMASHIMA, H. USUDA,M. KANAI,M. SHIBASAKI, Angew. Chem. 2000, 112, 1716; Angew. Chem. Int. Ed. Engl. 2000, 39, 1650; b) M. TAKAMURA, Y. HAMASHIMA, H. USUDA,M. KANAI, M. SHIBASAKI, Chem. Pham. Bull. 2000, 48, 1586; for enantioselective Strecker-type reactions promoted by related polymer supported bifunctional catalysts, see: M. KANAI, c) H. NOGAMI,S. MATSUNAGA, M. SHIBASAKI, Tetrahedron Lett. 2001, 42, 279; for a review on multifunctional asymmetric catalysis covering related M. examples, see: d) M. SHIBASAKI, KANAI, Chem. Pharm. Bull. 2001, 49, 511. For the use of bifunctional chiral imino peptide titanium catalysts identified by screening of parallel libraries, see: a) C. A. KRUEGER,K. W. KUNTZ,C. D. DZIERBA, W. G. WIRSCHUN, J. D. GLEASON, M. L. SNAPPER, A. H. HOVEYDA,].Am. Chem. SOC.1999, 121,4284; b) J. R. PORTER, W. K. W. KUNTZ, M. L. G. WIRSCHUN, SNAPPER, A. H. HOVEYDA, J . Am. Chem. SOC.2000, 122, 2657; c) N. S. J O S E P H S O H N , K. W. KUNTZ, M. L. SNAPPER, A. H. HOVEYDAJ.Am. Chem. SOC. 2001, 123, 11594. For the use of a chiral aluminum salen complex, see: M. S. SIGMAN,E. N.

References and Notes I 1 4 3 JACOBSEN, J .

Am. Chem. Soc. 1998, 120,

5315. 36 a) K. YAMADA,S. J. HARWOOD, H. GROGER,

M. SHIBASAKI, Angew. Chem. 1999, 111, 3713; Angew. Chem. Int. Ed. 1999,38, 3504; b) K. YAMADA,M. SHIBASAKI, Synlett 2001,980.

37

a) T. HAYASHI, M. ISHIGEDANI, J . Am. Chem. SOC.2000, 122, 976; b) T. HAYASHI, M. ISHIGEDANI, Tetrahedron 2001, 57,

2589. 38 For a general review, see: M. T. REETZ, Angew. Chem. 2001, 113, 292; Angew. Chem. Int. Ed. Engl. 2001,40, 284.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

IBX - New Reactions with an Old Reagent Thomas Wirth

Hypervalent iodine reagents have attracted increasing interest during the last decade because of their selective, mild, and environmentally friendly properties as oxidizing agents in organic synthesis [ 11. 2-Iodoxybenzoic acid (IBX, l-hydroxy-1,2-benziodoxol-3( lH)-one 1-oxide 1)was first reported in 1893 [2] but has been rarely used in reactions, probably due to its insolubility in most organic solvents [3]. Dess and Martin transformed IBX (1) into the much more soluble Dess - Martin periodinane (DMP, l,l,l-triacetoxy-l,l-dihydro-1,2benziodoxol-3(lH)-one 2) [ 3, 41, which has received much attention. Improved procedures for the synthesis of reagents 1 and 2 have been disclosed recently [ 51.

1 (IBX)

2 (DMP)

Fig. 1.

The broad functional group tolerance of these reagents and high-yielding reactions without over-oxidation have made DMP (2) very prominent for the oxidation of alcohols to the corresponding carbonyl compounds. But IBX (1)in DMSO was also found to be a highly efficient reagent for the clean oxidation of alcohols 3 to carbonyl compounds 4 even in the presence of thioethers or amines [6, 71 (the number of reported examples are given below the arrows here and in the following). It is also possible to selectively oxidize 1,2-diols to 1,2diketo derivatives without oxidative cleavage of the glycol C-C bond [ 6, 81. The selective oxidation of 1,4-diols 5 to the corresponding y-lactols 6 can also be realized [9]. Recently, the research groups of Giannis and Rademacher have published independently polymer-supported IBX-reagents of type 7 [lo, 11).These reagents on solid support can be used with similar efficiencies to IBX for the oxidations of alcohols, but other functionaliza-

ISX

1 (IBX)

OH

A-

DMSO

A

R k 0 I - l

78-98% 15 examples

DMSO 1 (IBX)

60-93%

5

5 examples

7

Reactions with an Old Reagent

.

.

6

8

Scheme 1.

tions highlighted later in this article can be achieved only with much lower yields. The synthesis of a water soluble IBX derivative 8 has been reported as well [ 121. This reagent is able to perform the alcohol to carbonyl conversion in pure water or in aqueous solvent mixtures with very good yields. The first step in these oxidation reactions is a fast pre-equilibrium, which can be formally considered as ligand exchange (hydroxy - alkyloxy) on the iodine atom. The product 9 then disproportionates to the carbonyl derivative 4 and the iodosoarene 10 (IBA) [ 8).

3

1 (IBX)

9

A 4

I

-.RoH

- New

+ 10 (IBA)

Scheme 2.

The known paths for the oxidation of alcohols have been extended by recent reports utilizing IBX (1)and DMP (2) [13] in other transformations. The introduction of an cc,jl-double bond into carbonyl compounds is sometimes a challenging transformation, which is pre-

145

146

I

IBX

- New Reactions with an Old Reagent

dominantly performed by using selenium or palladium reagents. A ligand exchange on IBX with the ketone-enolate might be involved as a key step and a subsequent SET is postulated in the mechanism of this new and general procedure. Although the reaction proceeds only at elevated temperatures (65-85 "C, conditions l), even acid-labile carbonyl compounds can be employed in the process, from which derivatives 11are obtained in good yields [14]. Recently it was found that the reactivity profile of IBX can be modulated by ligand complexation. Various IBX ligand adducts are known and used for different transformations. The IBX. NMO (NMO: N-methylmorpholine-N-oxide) adduct can be used for the dehydrogenation of aldehydes and ketones to the a$-unsaturated carbonyl compounds 11 at room temperature (conditions 2) [ 151. A reaction employing the corresponding trimethylsilylenol ethers as substrates has been published recently [ 161.

0

0

;? .--. '\.

*

+

[q '.--.' ,

<

11

'\

'---*'

*

,

'---*'

*

conditions 11141 1 (IBX), to1uene:DMSO 2:l 65-85"C, 3-72 h 40-89%, 29 examples conditions 2 [15]: IBX . NMO, DMSO 25"C, 15-48 h 43-96%, 17 examples

conditions I1 61: IBX . NMO, DMSO 25"C, 0.3-6 h 43-96%, 13 examples

11 Scheme 3.

Even alcohols can be converted to a$-unsaturated carbonyl compounds directly by using an excess of IBX (l),as shown in the oxidation of the phenylalanine derivative 12 to 13. The involvement of an aldehyde-enolate as a ligand on IBX has also been postulated in a first oxidative C-C bond cleavage reaction using IBX. N-Protected amino alcohols 14 have been oxidized with IBX in DMSO to the corresponding imides 15 [17]. Although hypervalent iodine compounds are often used as oxidants and sometimes as electrophilic reagents, the cyclization of aryl-substituted unsaturated amines to heterocycles 19 is started by a single-electron transfer (SET) reaction. Either 1 or an IBX THF adduct serves as the oxidant to initiate the heterocyclization by a SET process. The subsequently generated N-centered radical will then cyclize in a 5-exo-trig manner to yield, after hydrogen abstraction from the solvent, heterocycles of type 19. The cyclization of amides to y-lactams offers the possibility to synthesize even a variety of annelated heterocyclic compounds. The IBX-mediated cyclization of (thio)carbamates and ureas to (thio)oxazolidinones and cyclic ureas can be followed by hydrolysis to synthesize, for example, 1,2-aminoalcohols of type 20 [MI.The fast access to the carbamate starting materials by adding allylic alcohols to isocyanates allows the rapid generation of compound libraries [ 191.

ISX

PhyC02Me

2.5 eq. 1 (IBX)

- New Reactions with an Old Reagent

phyCoPMe

65 "C, 12 h 86%

12

%,\ ,

13

NHBoc

2 eq. 1 (IBX) DMSO

R

75 "C, 5 h 63-68%, 3 examples

14

15

Scheme 4.

The mechanism of this transformation has been investigated in detail. Although amide radicals have already been employed in cyclization reactions [20], their involvement in the IBX-mediated reaction has been proven by a detailed analysis [18b]. It was concluded that the irreversible SET from the aryl moiety to the IBX . THF adduct is the rate-determining step of the reaction and can only proceed with a free ortho-position in the substrate as shown in the mesomeric structures 17 and 18.

,: H N Ar'

1 (IBX) THF:DMSO

, .

,,--

< - -

,

%

I

hydrolysis

(1O:l)

H

9O"C, 24h

16

J

NH OH

X

y0

Scheme 5.

Ar/

(x=CHZ,0,NR~ Ar"y

0 70-95% 29 examples

1. l*THF (SET) 2. -H+

-

Y

19

t

1. cyclisation 2. Ha -abstraction

20

I

147

148

I

IBX - N e w Reactions with an Old Reagent

On the basis of this reaction mechanism, a process for the oxidation of the benzylic position has been developed. This reaction is quite general and proceeds with an excess of 1 at higher temperatures. Over-oxidation of compounds 21 with R' = H to the corresponding carboxylic acids was not observed, and the yields of ketones or aldehydes 22 even with labile substrates were generally quite high [ 211.

6 7.

R

21

1 (IBX) DMSO

52-95% 22 examples

R

22

(R' = H, alkyl)

Scheme 6.

To show the selectivity and controllability of these IBX-mediated reactions, substrate 23 was synthesized and converted in a series of steps to compound 27. The cyclization reaction 26 + 27 must not necessarily be the last step in the sequence.

HO

24

23

3 eq. 1

DMSO 90 "C,2 h 76%

0

OHC

2.2 eq. 1 THF:DMSO(10:1)

,j

OHC

26 Scheme 7.

25

27

References I 1 4 9

IBX can also be used to oxidize phenols to ortho-quinones at room temperature. A variety of phenols 28 has been converted to the corresponding ortho-quinones 29 in good yields [22].

1 eq. 1 (IBX) CDCl3 or d7-DMF X

Y

1.5-53 h, 16-99% 11 examples

--&. X

28

Y

29

Scheme 8.

AS shown recently in the hydrolysis of phosphonofluoridates, 1 can also be used as a catalyst with oxone being the stoichiometric oxidant [23]. IBX (1) is able to oxidize thiols selectively to the corresponding disulfides [24]. It can also be used as a versatile reagent for the cleavage of oximes and tosylhydrazones to the corresponding carbonyl compounds [ 251. The first attempts to synthesize chiral reagents derived from IBX have appeared, although the selectivities obtained in the sulfide oxidation are low (up to 16% ee) [26]. The further development of electronically modified IBX reagents [ 271 to tune electron transfer processes, their application to new reactions, and the synthesis of efficient polymer-bound IBX [28] for rapid combinatorial chemistry will undoubtedly be reported in literature in the near future.

References 1 a) A. VARVOGLIS, Hypervalent Iodine in

Organic Synthesis, Academic Press, London, 1997 b) T. WIRTH, U. H. HIRT, Synthesis 1999, 1271-1287. 2 C. HARTMANN, V. MEYER,Chem. Ber. 1893, 26, 1727-1732. 3 D. B. DESS,J. C. MARTIN,J. Am. Chem. SOC. 1991, 113, 7277-7278. 4 D. B. DESS,J. C. MARTIN,]. Org. Chem. 1983, 48,4155-4156. 5 IBX: a) M. FRIGERIO,M. SANTACOSTINO, S. SPUTORE, J. Org. Chem. 1999, 64,4537L. J. LIU, J . 4538;DMP: b) R. E. IRELAND, Org. Chem. 1993, 58,2899;c) S. D. MEYER, S. L. SCHREIBER, /. Org. Chem. 1994, 59, 7549-7552;Caution! IBX and DMP are explosive under impact or heating >200 "C: d) J. B. PLUMB,D. J. HARPER, Chem. Eng. News 1990, 68(29),3. 6 M. FRIGERIO, M. SANTAGOSTINO, Tetrahedron Lett. 1994, 35, 8019-8022. 7 M. FRIGERIO, M. SANTACOSTINO, S.

SPUTORE,G. PALMISANO, J. Org. Chem. 1995, 60, 7272-7276. 8 With DMP 1,2-diolsare cleaved at the C-C bond: S. DE MUNARI,M. FRIGERIO,M. SANTAGOSTINO, I. Org. Chem. 1996, 61,

9272-9279. a) E. J. COREY,A. PALANI,Tetrahedron Lett. 1995, 36, 3485-3488;b) E. J.COREY,A. PALANI,Tetrahedron Lett. 1995, 36, 79457948;1,5-Diols can also be converted to lactols: c) J. M. BUENO,J. M. COTERON, J. L. CHIARA,A. FERN~NDEZ-MAYORALAS, j. M. FIANDOR,N. VALLE,Tetrahedron Lett. 2000, 41,4379-4382;d) J. ROELS,P. METZ, Synlett 2001, 789-790. 10 M. MULBAIER, A. GIANNIS,Angew. Chem. 2001, 113,4530-4532;Angew. Chem. Int. Ed, 2001, 40,4393-4394. 11 G. SORG,A. MENGEL, G. JUNG,J. RADEMANN, Angew. Chem. 2001, 113, 4532-4535;Angew. Chem. Int. Ed. 2001, 40,4395-4397. 9

150

I

IBX - New Reactions with an Old Reagent 12 A. P. THOITUMKARA,T. K. VINOD, 13

14

15

16

17

18

19

Tetrahedron Lett. 2002, 43, 569-572. a) K. C. NICOLAOU, Y:L. ZHONG,P. S. BARAN, Angew. Chem. 2000, 112, 636-639; Angew. Chem. Int. Ed. 2000, 39, 622-625; b) K. C. NICOLAOU,K. SUGITA,P. S . BARAN,Y.-L. ZHONG,Angew. Chem. 2001, 113, 213-216; Angew. Chem. Int. Ed. 2001, 40, 207-210; c) K. C. NICOLAOU, Y.-L. ZHONG,P. S. BARAN.K. SUGITA,Angew. Chem. 2001, 113, 2203-2207; Angew. Chem. Int. Ed. 2001, 40. 2145-2149. K. C. NICOLAOU, Y.-L. ZHONG,P. S. BARAN, / . A m . Chem. SOC.2000, 122, 7596-7597. K. C. NICOLAOU, T. MONTAGNON, P. S. BARAN,Angew. Chem. 2002, 114, issue 6; Angew. Chem. Int. Ed. 2002, 41, issue 6. K. C. NICOLAOU,T. MONTAGNON, D. L. F. GRAY,S. T. HARRISON, Angew. Chem. 2002, 114, 1035-1038; Angew. Chem. Int. Ed. 2002, 41, 993-996. G. CABARROCAS, M. VENTURA, M. J. M A H ~ AI. , M. VILLALGORDO, MAESTRO, Tetrahedron:Asymmetry 2001, 12, 18511863. a) K. C. NICOLAOU, Y.-L. ZHONG,P. S . BARAN,Angew. Chem. 2000, 112, 639-642; Angew. Chem. Int. Ed. 2000, 39, 625-628; b) K. C. NICOLAOU, P. S . BARAN,R. KRANICH,Y.-L. ZHONG,K. SUGITA,N. Z o u , Angew. Chem. 2001, 113, 208-212; Angew. Chem. Int. Ed. 2001, 40, 202-206. K. C. NICOLAOU,P. S. BARAN,Y.-L. ZHONG,1. A. VEGA,Angew. Chem. 2000,

20

21

22

23

24

25 26

27

28

112, 2625-2629; Angew. Chem. lnt. Ed. 2000, 39, 2525-2529. a) J. L. ESKER,M. NEWCOMB,Tetrahedron Lett. 1993, 34, 6877-6880; b) B. GIESE,B. KOPPING,T. GOBEL,J. DICKHAUT,G . THOMA,K. 7. KULICKE, F. TRACH, Org. React. 1996, 48, 301-856. K. C. NICOLAOU, P. S. BARAN,Y.-L. Z H O N G , ~Am. . Chem. SOC. 2001, 123, 3183-3185. D. MAGDZIAK, A. A. RODRIGUEZ, R. W. VAN DE WATER,T. R. R. PEITUS, Org. Lett. 2002, 4, 285-288. C. A. BUNTON,H. 7. FOROUDIAN, N. D. GILLIIT,/. Phys. Org. Chem. 1999, 12, 758764. R. A. Moss, H . MORALES-ROJAS, H. ZHANG,B. PARK,Langmuir 1999, 15, 2738-2744. D. S. BOSE,P. SRINIVAS,Synktt 1998, 977-978. V. V. ZHDANKIN, I. T. SMART,P. ZHAO, P. KIPROF,Tetrahedron Lett. 2000, 41, 5299-5302. a) A. R. KATRITZKY, B. L. DUELL,H. D. DURST,B. L. KNIER,/. Org. Chem. 1988, 53, 3972-3978; b) V. V. ZHDANKIN,R. M. ARBIT,B. J. LYNCH,P. KIPROF,/. Org. Chem. 1998, 63, 6590-6596.

For the reduction and quantitative removal of iodine species after IBX oxidations by a thiosulfate resin, see: 1. I. PARLOW,B. L. CASE,M. S. SOUTH,Tetrahedron 1999, 55, 6785-6796.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co I151

Parallel Kinetic Resolutions Jason Eames

The continuing development of new resolution procedures within Organic Synthesis is still an important area [ 11. Traditionally, kinetic resolution involves separating a racemic mixture of two enantiomeric substrates (A and A’) using a single chiral reagent to give two enantiomerically enriched derivatives ( P or P’) (Scheme 1) [2]. For resolution to occur the reaction rates must be unequal ( k A # kA8) and for efficiency the reaction must be stopped at some stage before completion [2]. Theoretically, when only one enantiomer reacts (e.g., A) with a chiral reagent B, it can lead to a maximum of 50% product P (derived from A) and 50% recovered A’, both of which are enantiomerically pure. For such selectivity to occur, the selectivity factor s ( k A / k A I ) needs to be greater than 200 [2]. This required selectivity is generally above that of most chemical kinetic resolutions, and even for some enzyme-based processes [ 31. Due to this selectivity difference, further problems can arise due to the buildup of the less reactive enantiomer having a much greater concentration than the more reactive enantiomer A due to its preferential removal. As a result of this, as the resolution approaches completion, both enantiomers react equally due to a balance between this inherent rate and available concentration [ 21. One way of preventing the concentration effect of this less reactive enantiomer A’ being dominant near the end of the resolution is to remove it in parallel using a complementary

Kinetic Resolution

Parallel Kinetic Resolution chiral

-

reagent B kA#kA#

enantiomeric products are formed Scheme 1.

kA=kA!

different products are formed

152

I

Parallel Kinetic Resolutions

reagent C to form Q during the course of the resolution (Scheme 1).Ideally, the rate needs to be similar to that of the other enantiomer. This has lead to a new strategy termed Parallel Kinetic Resolution (PKR) [4].The theory of this concept has been around for sometime [ S ] , and it has been shown that the selectivity factor s can be significantly lower for a parallel resolution than that of a tradition kinetic resolution to achieve the same result; for example, an s factor of 49 corresponds to that of a kinetic resolution with an s factor of 200, where the products are isolated in 49% (out of a maximum 50%) in 96% ee. One of the first reports [GI using this PKR strategy involved the use of a stereorandom substitution reaction to remove the unwanted less reactive enantiomer (Scheme 2). Faber [ 61 has demonstrated that enantioselective hydrolysis of the racemic epoxide ( rac)-1 can occur using the Rhodococcus sp immobilized enzyme (SP 409) giving the diol (S)-2 in a modest 40%yield with a modest 72% enantiomeric excess (Scheme 2). They have further shown that conducting the reaction in the presence of an additional non-natural nucleophilic azide (N;) increased the enantiomeric excess of this diol (S)-2 to >90% ee. It appears that this additional nucleophile (Ny)removes the less reactive (Qenantiomer 1 by a non-catalyzed S N ~ reaction to give the azide alcohol (R)-3 in around 60% ee. The lower ee for this alcohol is not unusual due to the reaction being uncatalyzed and clearly the azide reacts equally with both enantiomers of epoxide 1 , but preferentially with ( R ) - l due to its higher concentration. A superb example illustrating this PKR strategy has been developed by Vedejs [4] using a chiral DMAP acyl transfer reaction involving two quasi-enantiomeric pyridines (R)-4and ( S ) 5 (Scheme 3). Activation of these pyridines (R)-4 and (S)-5 with a hindered chloroformate 6 and (+)-fenchyl chloroformate 7 gave the acyl transfer agents 8 and 9, both of which have previously been shown to have opposite and complementary stereocontrol. The alkyl substituent of these chloroformates is very important, since it is transferred to the resolved alcohol, and is obviously different to enable product separation. The fact that the fenchyl group in 9 is chiral it is assumed to be irrelevant to the selectivity. Addition of equimolar amounts (1.1 mol equivalent) of the separately formed pyridinium salts 8 and 9, combined with an excess of MgBr2 and EtsN to a solution of racemic 1-(1-naphthy1)ethanol(rac)-10 (1 mol equivalent) gave the mixed carbonates 11 in 46% yield (>88% ee) and 12 in 49% yield (95% de). Separation was made much simpler by treatment of the mixture with Zn in acetic acid (which chemoselectively removed the trichlorobutyl protecting group) to give the more separable resolved alcohol (S)-10 and the fenchyl carbonate 12. The stereoselectivity was excellent, both mixed carbonates were isolated in near perfect yield and enantiomeric excess. These quasi-enantiomeric chiral DMAP equivalents (R)-4 and (S)-5 have additionally been shown to be fully recyclable. Vedejs has extended this idea even further by using two unrelated complimentary reagents [7, 81; the chiral phosphine 14 and the purified crosslinked lipase (ChiroCLEC)16 to serve as the acyl transfer catalyst (Scheme 4). This catalytic adaptation [7] was achieved by ensuring both reagents 14 and 16 ignore their complimentary activating reagent 17 and 13 respectively. This was achieved using an insoluble polymeric mixed carbonate 13 (to activate the phosphine 14) and an organic soluble vinyl pivalate 17 (to activate the insoluble lipase ChiroCLEC 16). This use of a triphasic reaction is an elegant way of ensuring that the activated P-acylphosphonium carboxylate 15 does not come into contact with the other cornplementary reagent, lipase ChiroCLEC 16. Addition of racemic 1-(naphthy1)ethanol (rac)-lO to a solution of carbonate 13, phosphine 14, ChiroCLEC 16 and vinyl pivalate 17 gave the ( R ) -

Scheme 2.

less reactive enantiomer removed

(R)-3;60% ee

*

*

Tris-buffer N3-

SP 409

Tris-buffer

SP 409

(9-2;>90% ee

( S ) - 2 ;72% ee; 40%

154

I

Parallel Kinetic Resolutions

NMe2

NMez

I

I

1 Hco:, chloroformate (+)-fenchyl

NMe2

NMez

I

I

t-Bu

0

I

8

Np

A.

0 dBn

9

Et3N (3 eq.) MgBr2 (2.25 eq.)

Zn, AcOH Me

Np = 1-naphthyl

H

x

HO

+ NP

(S)-lO

Ax H0 0

H

0

Me NP

12

Scheme 3.

enantiomer in the form of an ester 19 (97% ee) and the (S)-enantiomer as a polymeric ester (S)-lO - simple filtration and cleavage with Bu4NOH in THF gave the required (S)-l(naphthy1)ethanol 10 in 92% ee. Both of these products, (S)-10 and (R)-19 were isolated within 2% of their theoretical enantiomeric excess [8]. Goti, Brandi, and co-workers have investigated this PKR strategy using two quasienantiomeric dihydropyrans 21 and 22 as complimentary reagents (Scheme 5) [ 91. They have shown that under a traditional kinetic resolution procedure the racemic syndihydroxypyrroline N-oxide 23 can be partially resolved using a 1,3-dipolar cycloaddition

Parallel Kinetic Resolutions

13

I

- MstlO’

15

mod( ChiroCLEC

18

16

(R)-10

(S)-10

16,17 0

II

I

13,14

OH

0

+&

(R)-19; 97% ee

THF (S)-20

(S)-lO; 92% ee

Scheme 4.

to give the recovered 23 enantiomer in either configuration with a modest enantiomeric excess (37-43%) depending on which dihydropyran used. In the parallel kinetic resolution experiment - racemic nitrone 23 was treated with a slight excess of the two dihydropyrans 21 and 22, both of which displayed complementary selectivity and thus afforded two distinct and separable adducts 24 and 26. Since the two competing reactions have similar rates, maintenance of the optimum S0:50 substrate ratio was achieved, and therefore the maximum inherent selectivity was preserved throughout. These exo-adducts 24 and 26 were formed exclusively derived from the ‘matched’ interactions in an expected 5050 ratio by a 1,3-dipolar cycloaddition on the more electon rich bottom-face of the dihydropyran. No minor diastereoisomeric adducts 25 and 27 were observed, indicating that a near perfect match in their relative rates were achieved. These adducts were further converted into quasienantiomeric imino-C-disaccharides [ 91. These reports into the use of a PKR strategy have relied on an additional complementary reagent C to remove the less reactiue enantiomer (Scheme 6). However, this need not be the

I

155

Scheme 5.

O x 0

(3S,4R)-23

(3R,4S)-23

00

O x 0

H e H +

?a

26; 29%

AcO

24; 34%

22(1.5equiv.)

21 (1.5 equiv.)and

AcO

..

24: 23%

I bottom face preferred I

..

27; 7%

25; 10%

AcO

e

H

26; 24%

O X 0 (3R,4S)-23 32%ee; 43%

H@H

00

O x 0 (3S,4R)-23 37% ee; 34%

H

?@

Parallel Kinetic Resolutions

I

157

case if a single chiral reagent B allows two distinct pathways; one for one enantiomer and one for the other enantiomer to give two distinct products P and Q [lo]. As long as their reaction rates are equal; all conditions for a PKR strategy are satisfied. This has lead to a new strategy termed Divergent Kinetic Resolution [ 11, 121 ( DvKR) (Scheme 6). Parallel Kinetic Resolution

Divergent Kinetic Resolution

chiral

chiral

pF* p

iQ chiral reagent B kA=kA’

different products are formed

different products are formed

Scheme 6.

One of the first examples to illustrate the usefulness of this strategy surfaced in the intramolecular cyclopropanation of racemic secondary allylic diazoacetates (Scheme 7) [13]. Treatment of (rac)-28 with the catalyst Rh2(4S-MEOX)429 gave the tricyclic ketone (lS,2R,GS)-30in 40% yield with an enantiomeric excess of 94%. Surprisingly, the byproduct which accounted for the fate of the other enantiomer (R)-28 gave the 2-cyclohexenone 31 which was formed via an intramolecular hydride abstraction with subsequent ketene loss. Furthermore, it has been shown that the chiral catalyst selectively removes just one enantiomer in the resolution by converting it into the ketone and consequently the concentration effect is removed. Both enantiomers of the catalyst are available, and thus either enantiomer of the tricyclic ketone 30 can be synthesized efficiently. It is also worthy of note that under a mutual kinetic resolution - by using (rac)-28 gives exclusively (lSR,2RS,GSR)-30in near perfect yield without formation of the byproduct cyclohexanone 31 which is due to the complementary recognition. Deng has recently reported [ 141 the use of a modified cinchona alkaloid (DHQD)zAQN 32 as a nucleophilic catalyst to resolve a series of succinic anhydrides (Scheme 8). This catalyst (DHQD)2AQN32 was used in a sub-stoichiometric quantity (10 mol%) and was shown to be particularly selective in controlling the reaction pathway for each enantiomer of substrate; for example the (S)-enantiomerof 2-methyl succinic anhydride 33 preferred to react at its more hindered carbonyl group [to give the monosubstituted succinic ester (S)-34],whereas the (Qenantiomer reacted preferentially at the less hindered carbonyl group to give complementary separable product, (R)-35. As long as each enantiomer of the racemate (rac)-33 react at an equal rate, but with opposite regiocontrol all conditions of the parent PKR strategy are satisfied. The overall selectivity was found to be influenced by the structural nature of the alcohol (ROH). Increasing the size of the primary alcohol from MeOH to both EtOH and PrOH moderately increased the enantiomeric excess up to 82% for 34 (Scheme 8, entries 1, 2, and 3). However, by using a slightly more sterically demanding secondary alcohol like

158

I

Parallel Kinetic Resolutions

0

+

v

0

6f +

m

(S)-34

0

Scheme 8.

HO

RO?Me

O (S)-33

0

0

I

+

+ (R)-35

0

M e t : :

ROH, Ether

Me0

/

"

\/

-25

25

25

(DHQD)2AQN 32

-

/ \

/

91

4456

o /

85

-

-

49:5 1

81

4555

82

4951

25

14

39:61

25 25

(S)-34; % ee

(S)-34:(R)-35

Temp./'C

12

67

61

(R)-35;% ee

OMe

80

12

-

xgog

CF3CH20H

i-PrOH

(DHQD)2AQN 32 (10 mol%) 6

4

n-PrOH

3

CF3CH20H

0

EtOH

2

5

(R)-33

Me$

MeOH

ROH

1

Entry

160

1

Parallel Kinetic Resolutions

i-PrOH completely prevented the reaction from occurring (Scheme 8, entry 4). By increasing the steric demand of the alcohol at the p-position (by using trifluoroethanol) allows the reaction to occur with good stereocontrol (Scheme 8, entry 5) and with near perfect regiocontrol. This stereocontrol can be further improved to 91% ee by conducting the reaction at a slightly lower temperature (Scheme 8, entry 6). Further improvements in the stereocontrol were achieved by changing the substitution pattern of the succinic anhydride; 2-phenyl succinic anhydride (rac)-36gave the best control giving the monosubstituted succinic ester (R)-37 and (S)-38in 95% ee and 85% ee respectively (Scheme 9). Simple chemoselective reduction gave the corresponding y-lactones ( R)-39 and (S)-40in similar enantiomeric purity. 0

0

(10 mol%)

*

FBCHPCO

CF3CHlOH 0

(rac)-36

Ether, -24OC

0

( 0 3 8 ; 85% ee

(R)-37;95% ee

1

LiHNEt3 then H30+

(R)-39 44%; 95% ee

(S)-40 32%; 82% ee

Scheme 9.

Pineschi and Feringa have also used this DvKR strategy to resolve a series of vinyl epoxides using their phosphoramidite (R,R,R)-41as the chiral pro-catalyst (Scheme 10) [11, 151. Treatment of racemic vinyl epoxide 42 with an excess of diethyl zinc (1.5 equiu.) in the presence of the catalyst [prepared in-situ from [Cu(OTf)2](1.5 mol%) and phosphoramidite (R,R,R)-41( 3 mol%)] gave the homoallylic alcohol 43a in 99% ee [by S N catalysed ~ epoxide ring opening of (3R,4S)-42]and the complementary allylic alcohol 44a in 80% ee (formed by S N ~addition ’ to the vinyl epoxide (3S,4R)-42)[ 111. Clearly, this catalyst (R,R,R)-41efficiently controls the reaction pathway for both enantiomers of the vinyl epoxide (rac)-42,thus giving the two positional products in near perfect ratio (SN2&2’ 45:55). The structural nature of the dialkyl zinc reagent was found to be important factor in improving the enantiomeric excess of the allylic alcohol 44. The use of a less sterically demanding dimethyl zinc appears to be slightly more stereoselective towards sN2‘ addition of the epoxide 42 than using diethyl zinc; e.g., 44b was formed in 96% ee, whereas, 44a was formed in 80% ee.

Parallel Kinetic Resolutions

+ N

I

161

162

I

Parallel Kinetic Resolutions

Cook has similarly reported a palladium-mediated regio-divergent kinetic resolution of a racemic 5-vinyloxazolidinone45 (Scheme 11) [ 121. This study was prompted by the discovery that the chiral ligand associated with the catalyst was responsible for the regiochemical outcome of a phthalimide addition to (S)-45. Potassium phthalimide displacement of the carbamate group (within the oxazolidinone ring) mediated by the palladium( O ) / ( R)-BINAP catalyst gave the allylic phthalimide (S,S)-46with a trace of the other regioisomeric phthalimide (S)-47[ratio 20:1]. However, using the (S)-enantiomerof BINAP, this regiocontrol was significantly lowered to 3:l (Scheme 11). This result suggested that (R)-enantiomer of the catalyst favoured formation of (S,S)-46 (under both substrate and reagent control), whereas the (S)-enantiomer favoured the alternative pathway to give the allylic phthalimide (S)-47. Interestingly, the control exerted by the substrate appears to be more dominant than that associated with the chirality of the ligand.

[ C ~ H S P ~ CLigand ~]~, Ph

*

phthalimide K-phthalimide (20 mol%) THF, rt

Bi (S)-45

Ph

+

Bi

ph

B i

(S, S)-46

(S)-47

(R)-BINAP 46:47 S N ~ : S N 20:1 ~' (S)-BINAP 46147& 2 : s ~ 2 '3: 1 Scheme 11.

By using this approach they have selectively resolved 5-vinyloxazolidinone ( 4 - 4 5 with a (R)-BINAP-palladium(0)based catalyst (Scheme 12). At best, the enantioselectivity was moderate; up to 62% ee for (R)-47. The choice of solvent was also very important; THF favoured the (S,S)-allylicphthalimide (S,S)-46 (kl),whereas acetonitrile favoured the complementary phthalimide (R)-47 (2.4:1)(Scheme 12: entry 1 versus 3). Ideally, the selective removal of both enantiomers need to occur at an equal rate to satisfy this PKR approach. This relative rate was achieved by changing the solvent to dichloromethane (Scheme 12: entry 2); but sadly the overall enantiocontrol was much lower. Whereas, by changing the chiral ligand to (S,S)-DIOP the relative rate of removal of both enantiomers were near perfect (1:1.2) and equally the enantiomeric control in both allylic phthalimides (S,S)-46 and (R)-47were very similar; 50% ee and 46% ee respectively (Scheme 12: entries 4 and 5). From these studies, they have clearly shown that by removing both enantiomers of substrate (A and A') at an equal rate during the course of a resolution significantly improves the overall efficiency with regard to a traditional kinetic resolution procedure (Scheme 1). However, a disadvantage for this strategy lies in the fact that these procedures can only a give maximum yield of 50% of a minimum of two possible products. Alternatively, the overall yield can be improved to 100% by conducting a dynamic kinetic resolution [16] (DKR), but only a single product can be formed. This strategy also relies on removal of the less reactive enantiomer - in this case by recycling through racemisation - rather than by direct derivatization with an additional complementary chiral reagent as in a parallel kinetic resolution.

References

BNA0

0

I

163

0

Ph

PhKNH

(S)-45

(S, S)-46

[C3H5PdC1]2, Ligand

+

phthalimide K-phthalimide (20mol%) THF, rt

Ph

(S)-47

+

w

0 PhKNH

0 NPhth

Ph

k

Bn

Bn

(R)-45

(R, R)-46

EntV

Ligand

Solvent

(S, S)-46:(R)-47

1

(R)-BINAP

THF

5:1

2

(R)-BINAP

CHzC12

1:l

3

(R)-BINAP

NH U Bn

P

(R)-47

Products

(S,S)-46; 73%; 14% ee (S,S)-46; 35%; 33% ee

(R)-47 11%; 62% ee (R)-47; 37%; 29% ee

CH3CN

12.4

(S,S)-46; 24%; 36% ee

(R)-47;47%; 17% ee

4 (S,S)-DIOP

THF

1:1.8

(R)-47;47%; 37% ee

5 (S,S)-DIOP

toluene

1:l.z

(S,S)-46; 23%; 44% ee (S,S)-46; 35%; 50% ee

(R)-47; 41%; 46% ee

Scheme 12.

From these studies it has been shown that for a successful and efficient parallel kinetic resolution the following guidelines need to be adhered to; a) derivatisation with two complementary chiral reagents have to occur without mutual interference [ 171; b) both reactions need to occur with similar but preferably equal rate and have complementary stereocontrol and c) afford distinct and easily separable products. Whereas, for a related divergent kinetic resolution ( DvKR) the following guidelines need to be taken into consideration; a) both regio-divergent reactions must occur with a single chiral reagent and give two distinct and different products and b) both these regio-divergent pathways must occur at an equal rate.

References M. KEITH,J. F. LARROW,E. N. JACOBSEN, Adu. Synth. Catal. 2001, 343, 5. 2 H . B. KAGAN, J . C. FIAUD,Topics Stereochem. 1988, 18, 249. 3 C. J . S I H , S.-H. Wu, Topics Stereochem. 1989,19,63. 4 E. VEDEJS, X. CHEN,J. Am. Chem. SOC. 1997, 119,2584. 1 J.

h

U G I , P. J O C H U M , Tetrahedron 1997, 33, 1353. K. FABER, Tetrahedron Lett. 6 M. MISCHITZ, 1994, 35, 81. 7 E. VEDEJS, E. ROZNERS, J. Am. Chem. SOC. 2001, 123, 2428. 8 E. VEDEJS, 0.DAUGULIS, J . A. MACKAY,E. ROZNERS,Synlett 2001, 1499. 5 J . BRANDT,C. J O C H U M , I.

t

h

164

I

Parallel Kinetic Resolutions

F. CARDONA, S. VALENZA, A. GOTI, A. BRANDI,Eur. J. Org. Chem. 1999, 1319. 10 H. KAGAN,Croat. Chem. Acta 1996, 69, 669. 11 F. BERTOZZI, P. CROTTI,F. MACCHIA,M. PINESCHI,B. L. FERINGA,Angew. Chem. Int. Ed. 2001, 40, 930. 12 G. R. COOK,S. SANKARANARAYANAN, Org. Lett. 2001, 3, 3531. 13 M. P.DOYLE, A. B. DYATKIN, A. V. KALININ,D. A. RUPPAR,S. F. MARTIN, S. L I R A S , Am. ~ . Chem. SOL. M. R. SPALLER, 1995, 117, 11021. 9

Y. C H E NA N D L. DENG,J. Am. Chem. SOC. 2001, 123, 11302. 15 F. BERTOZZI, P. CROTTI,F. D. MORO,B. L. FERINGA,F. MACCHIA,M. PINESCHI, Chem. Commun. 2001, 2606. 16 R. S. WARD,Tetrahedron: Asymmetry 1995, 6, 1475. 17 A n example where lower selectivity was reported using a combination of reagents than just a single reagent; see T. M. E. L. HANSEN,J. KANE,T. REIN, PEDERSEN, P. HELQUIST,P.-0. NORRBY, D. TANNER, J. Am. Chem. SOC. 2001, 123, 9738. 14

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

I165

The Asymmetric Baylis-Hillman-Reaction Peter Langer

Optimization o f the Chemical Yield o f the Baylis-Hillman-Reaction

The stereoselective formation of carbon-carbon bonds is an important problem in organic chemistry. The Baylis-Hillman-reaction allows the direct preparation of a-methylene-Phydroxycarbonyl compounds by base-catalyzed reaction of a,P-unsaturated carbonyl compounds with aldehydes [ 1-31. The first step of this reaction involves nucleophilic attack of the catalyst onto the Michael-acceptor 1 under formation of the zwitterionic intermediate 2. Subsequently, this intermediate reacts in the rate-determing step of the Baylis-Hillmanreaction with the aldehyde 3 under formation of the alcoholate 4 (Scheme 1).The product 5

1

2A

..

2B

-

R3N + A 0

DABCO

3-QDL

6

7

Scheme 1.

Mechanism of t h e Baylis-Hillman reaction.

OMe

166

I

The Asymmetric Baylis-Hillman-Reaction

is finally formed by a shift of a proton from the cc-carbon to the oxygen atom of the alcoholate and extrusion of the catalyst [4]. The densely functionalized Baylis-Hillman-products can be stereoselectively transformed for example into azirines [S], epoxides [6], trioles [7] and antialdol-products [ 81. In addition, cc-methylene-p-hydroxycarbonylcompounds represent versatile starting materials for the synthesis of a variety of natural and non-natural target molecules [9, 101. Unfortunately, the applicability of the Baylis-Hillman-reaction is very often limited by low rates and conversions and low, highly substrate-depending yields. It is particularly important for the development of an efficient asymmetric version of the Baylis-Hillman-reaction that these problems are adequately addressed. The use of high pressure or of the microwave technique resulted in significant increase of the rate of the reaction, but only for a few substrates [Ill. Increase of the reaction temperature above 20 "C resulted in polymerization of the sensitive acrylates. Recent work by Leahy and coworkers suggested that, counterintuitively, better yields and higher rates were observed at lower temperatures [12]. These results can be explained by the different rates of the formation of the diastereomeric baseacrylate-adducts ( 2 A and 2B). Product formation and yields in the Baylis-Hillman reaction also depend on a balance between the reactivities of the carbonyl and olefin partners as was shown, for example, for reactions of fluorine-containing carbonyl compounds [ 131. The rate and the conversion of the Baylis-Hillman-reaction was significantly improved when nucleophilic non-hindered bases, such as diaza[2.2.2]bicyclooctane (DABCO, G), rather than simple tertiary amines were used. Further improvements were observed when 3quinuclidinole (3-QDL,7)was employed, due to stabilization of the zwitterionic intermediate 2 by formation of intramolecular hydrogen bonds [ 14a-c]. Similar effects were observed by the addition of methanol [14d] or acetic acid [14e] to the reaction mixture (formation of intermolecular hydrogen bonds) or by the presence of a hydroxy group in the acrylate [ 14f 1. The rate of the reaction was decreased by the presence of substituents in the cc-position of tertiary amines. This was explained by the decrease of the rate of the addition of the catalyst onto the acrylate [ 151. Recent work by Agganval and coworkers has shown that very good rates and chemical yields could be obtained using the non-nucleophilic base DBU [16]. However, the use of enolizable ketones led to formation of aldol-products. The success of the use of DBU was explained by the assumption that the reaction of the zwitterionic intermediate with the acrylate rather than the attack of the catalyst onto the acrylate represents the rate-determing step of the reaction: although DBU represents a sterically hindered base, the zwitterionic intermediate is stabilized by conjugation of the positive charge. The concentration of the intermediate in the equilibrium is increased and, hence, the overall rate of the reaction is enhanced. A stabilization of the zwitterionic intermediate and a significant enhancement of the rate of the reaction was also induced by the use of metal salts, such as La(OTf)3and LiC104 [ 171. Shi and coworkers have reported that the rate and product distribution of Baylis-Hillman reactions of aldehydes with a,p-unsaturated ketones can be drastically affected by the reaction temperature and by the presence of Lewis bases [ 181. When the reaction was carried out at -78 "C using catalytic amounts of quaternary ammonium salts as Lewis bases, in the presence of titanium( IV) chloride, chlorinated syn-aldol adducts were obtained as the major products. Quaternary ammonium bromides and iodides showed higher catalytic activity than

Asymmetric Baylis-Hillman-Reactions of Chiral Substrates

I

167

the corresponding chlorides. When the reaction was carried out at room temperature, the elimination products were predominantly formed. A substantial acceleration of the Baylis-Hillman reaction has been observed when the reaction was conducted in water 119, 201. Several different amine catalysts were tested by Agganval and coworkers, and as with reactions conducted in the absence of solvent, 3hydroxyquinuclidine was found to be the optimum catalyst in terms of rate [19]. The reaction has been extended to other aldehyde electrophiles including pivaldehyde. Further studies on the use of polar solvents revealed that formamide also provided significant acceleration. Asymmetric Baylis-Hillman-Reaaions of Chiral Substrates Diastereoselective Baylis-Hillman-Reactions

of Chiral MichaeCAcceptors

During the course of the Baylis-Hillman-reaction two stereocenters are formed, one of which remains in the Baylis-Hillman-product.An obvious concept for the development of an asymmetric version of the reaction represents the use of an enantiomerically pure acrylic acid derivative. The use of enantiomerically pure menthyl acrylates resulted, but only in certain cases, to respectable diastereomeric excesses [ 211. A significant improvement was reported in 1997 by Leahy and coworkers who used the Oppolzer-sultame as a chiral auxiliary in DABCO-catalyzed Baylis-Hillman-reactions (Scheme 2) [ 221. In this reaction, the

IL-

MeoL 10

\

MeOH, CSA 85 %

M

e O HO

12 Scheme 2.

k

Rh', H2 85 %

HO

13

Diastereoselective Baylis-Hillrnan-reaction using Oppolzer sultarn (Leahy et a/.).

168

I

The Asymmetric Baylis-Hillman-Reaction

1,3-dioxan-4-one 11 was obtained, which was transformed by methanolysis into the c(methylene-p-hydroxyester 12 which was subsequently diastereoselectively hydrogenated to give the anti-aldol product 13. The esters 12 were isolated in good yields. However, 15 equivalents of the aldehyde had to be used. The stereoselectivity can be explained by the following: Michael-addition of the catalyst onto the acrylate 8 results in formation of a Zenolate which mainly resides in the anti-conformation 9-B, since in this case the dipolrepulsion between the sulfone- and the carbonyl group is minimized. Due to the steric interaction with the axial oxygen atom of the sulfone, the attack of the aldehyde proceeds diastereoselectively from the re-site of the acrylate to give the adduct 10, which subsequently reacts with a second aldehyde molecule to give a hemiacetale. Extrusion of the catalyst and cyclization with extrusion of the chiral auxiliary finally afforded the 1,3-dioxan-4-one11. Asymmetric Baylis-Hillman reactions using sugar acrylates have been reported to proceed with moderate diastereoselectivity (5-40% ee) [ 231. The reaction of camphor-based chiral acryloylhydrazides with aldehydes in the presence of DABCO afforded D-hydroxy-ccmethylene carbonyl derivatives in 68-92% yield with high diastereoselectivity (up to 98% de) [24]. Both diastereomers could be selectively obtained simply by changing the solvent.

PhSeLi 60 “C

py7&& \%

SePh

14

15 R-CHO - 60 “C

k

17

\

- 20

Scheme 3.

“C

\

Chirality transfer in a lithium phenylselenide induced domino-Michael-aldol-retro-Michaelreaction (Jauch et 01.).

R = Ph. iPr. tBu. CH=CHPh

Asymmetric Baylis-Hillman-Reactions of Achiral Michael-Acceptors a n d Aldehydes

R

R-(-)-I9

20 R = CN, C02Me

R,R-(+)-21

aa%, 295%

de

Diastereoselective Baylis-Hillman reaction o f planar chiral arylaldimine tricarbonylchrornium complexes (Kundig et a / , ) .

Scheme 4.

An interesting protocol for the diastereoselective Baylis-Hillman reaction under mild conditions has been reported by Jauch (Scheme 3) [25a]: The lithium phenylselenide induced domino Michael-aldol-retro-Michael reaction of aldehydes with (enantiomerically pure) Feringa's butenolide 24 afforded, after quenching with NH4C1/H20 at -GO "C, y-lactones 27 with very good diastereoselectivity. Treatment of 26, prior to aqueous work-up, with either PhCH2Br/n-Bu4NI at -GO "C or simply warming the reaction mixture to -20 "C gave the Baylis-Hillman adducts 28 in excellent yield and with high stereoselectivity. Formation of 28 can be explained by diastereoselective Michael addition of PhSeLi to butenolide 24 to give intermediate 25 and subsequent diastereoselective aldol-reaction (intermediate 26). The selectivity of the aldol-reaction can be rationalized through the Zimmermann-Trader model of the transition state. The methodology was applied to the total synthesis of the natural products Mniopetal F and kuehneromycin A [ 25b-c]. Diastereoselective Baylis-Hillman-Reactions of Chiral Carbonyl Derivatives

Aggarwal and coworkers have studied the electrophilic behavior of enantiomerically pure N-ptoluenesulfinimines and N-tea-butanesulfinimines in the asymmetric Baylis-Hillman reaction with methyl acrylate with and without Lewis acids [2G]. In the presence of In(0Tf)j good yields and high diastereoselectivities have been achieved providing an effective route to jl-amino-cc-methyleneesters. The Morita-Baylis-Hillman reaction of chiral glyoxylic acid derivatives with cyclic a$unsaturated ketones proceeded under the catalytic influence of dimethyl sulfide in the presence of titanium tetrachloride [27]. The adducts were obtained with high diastereomeric excess (>95% de) and typical yields around 80%. Kundig and coworkers have reported the Baylis-Hillman-reaction of methyl acrylate and acrylonitrile with planar chiral arylaldimine tricarbonylchromium complexes, such as 19 (Scheme 4)[ 2 8 ] . These reactions proceeded by attack of the acrylate from the sterically less encumbered site of the metal complex and afforded the products 21 with very good diastereoselectivity. Asymmetric Baylis-Hillman-Reactions of Achiral Michael-Acceptors and Aldehydes

Much work related to the development of a catalytic, enantioselective version of the BaylisHillman-Reaction by the use of chiral bases has been published. Only low enantiomeric excesses were obtained when brucin, N-methylprolinol, N-methyl-ephedrine and nicotine

I

169

170

I

The Asymmetric Baylis-Hillman-Reaction

were employed. The use of Cinchona alkaloids and of enantiopure 3-QDL 7 resulted in significant increase of the rate of the reaction, but only in low enantiomeric excesses which decreased when the reactions were carried out under pressure [29a-d]. Enantiomeric excesses of 9 4 4 % ee were obtained in the reaction of pyrimidine-5-carbaldehydeswith acrylates using (S)-BINAP as the catalyst [ 301. Baylis-Hillman reactions were promoted by mild cooperative catalysts of PBu3 with phenols, such as (*)-1,l'-bi-2-naphthol (BINOL), in THF to give cc-methylene [I-hydroxy alkanones in good yield and with good ee [31]. Besides the stereoselectivity, the reactions proceeded much faster in the presence of l,l'-bi-2naphthol than in its absence. Enantioselectivities of 21-7056 ee were observed in the reaction of ethyl- and methylvinylketone with aromatic aldehydes 22 using the chiral hydroxy-pyrrolizidine-catalyst24 which was prepared in four steps starting from BOC-L-prolinol (Scheme 5) [32]. The enantioselectivity was explained by the predominant formation of intermediate 2G-A, which is less sterically hindered than the isomeric intermediate 26-B. The employment of a reaction temperature of -40 "C, the use of NaBF4 as a co-catalyst,and the presence of a hydroxy group in the base (which allows the formation of intramolecular hydrogen bonds) resulted in good conversions and rates.

22

25

23

R

26-A

26-B

Scheme 5. Enantioselective Baylis-Hillrnan reaction using a chiral hydroxy-pyrrolizidine-catalyst (Barrett et a/.).

Very good enantioselectivities were recently reported by Hatakeyama and coworkers [ 331. The reaction of a variety of aldehydes 28 with the highly reactive 1,1,1,3,3,3-hexafluoroisopropylacrylate 27 using modified Cinchona-alkaloids as the catalyst resulted, at a temperature of -55 "C, in formation of the Baylis-Hillman-products 30 in 31-58% yields with 91-99% ee (Scheme 6). The use of the tricyclic derivative 29, which was prepared from quinidine in one step [34], proved crucial in order to obtain high enantioselectivities. The success of catalyst 29 can be explained by the [compared with quinidine) increased nucleophilicity, by the

Syntheses of Non-Racernic Bay/is-Hi//rnan-Productsby Other Methods

29 -55 "C

27 CF3

28

OH 0

CF3

R V O h C F 3

R-30

0-0

+Rye S-31

-

29

32

Scheme 6. Enantioselective Baylis-Hillman reaction using modified Cinchona-alkaloids (Hatakeyama et a/.).

presence of a free hydroxy group at the quinoline moiety, and by the anti-open-conformation [ 351 of the alkaloid which allow an optimal stabilization of the zwitterionic intermediate 32 by formation of intramolecular hydrogen bonds. Using the Oppolzer-auxiliary (vide supra) only low enantioselectivities could be obtained for aldehydes branched at the a-position. In contrast, the Baylis-Hillman-products derived from isobutyric aldehyde and cyclohexane carbaldehyde could be prepared in 31 and 36% yields with 99% ee when the catalyst 29 was used. A disadvantage of the method of Hatakeyama results from the decrease of the yields due to formation of the dioxanones 31, which were formed with opposite absolute configurations and with lower enantioselectivities compared to the products 30. However, the formation of these undesired side products was helpful for the elucidation of the mechanism of the reaction. The methodology was successfully used for an enantiocontrolled synthesis of the potent immunosuppressant (-)-mycestericin E [ 361. The conjugate addition of (R)-N-methyl-N-a-methylbenzylamide 33 to tert-butyl cinnamate 34, followed by an asymmetric aldol reaction and subsequent N-oxidation/Cope elimination afforded the p-substituted homochiral Baylis-Hillman product 39 in good yield (Scheme 7) [ 371. This chemistry requires the use of stoichiometric rather than catalytic amounts of the chiral base. Warren and coworkers have reported an interesting synthesis of nonracemic allenes by reaction of vinylphosphine oxides with aldehydes in the presence of chiral lithium [( R)-1phenylethyl](benzy1)amide to give hydroxyvinylphosphine oxides in 33-87% yields (051% ee) [38]. These products underwent a Horner-Wittig elimination reaction to produce nonracemic allenes. A mechanism similar to the Baylis-Hillman reaction was suggested. Syntheses of Non-Racemic Baylis-Hillman-Products by Other Methods

A number of alternative syntheses of non-racemic Baylis-Hillman-products by other

methods have been reported. Barrett and coworkers developed a two-step synthesis of Emethylene-D-hydroxyketones43 with 34-94% ee (Scheme 8) [ 391. From a preparative view-

I

171

172

I

The Asymmetric Baylis-Hillman-Reaction

Me

PhK N , M e Li

THF

A

(5)-33

A N - M e Ph PhL C O 2 t B u

-78 "C 94%, 88% de

&C02tBu

Ph

35

34

Me CWBu

H,&. '

1

1) 3 LDA, THF -78 "C 2) B(OMe13

3) R-CHO

2 mCPBA

Ph

CHC13,20 "C

H

H

38, R = Ph, 74%, >99% ee Scheme 7.

36, R = Me, 76%, 93:7 dr 37, R = Ph, 62%, 9218 dr

Stepwise Baylis-Hillman reaction using (R)-N-rnethyl-N-a-methylbenzylarnide (Davies et 01.).

39

40

OiPr 0

C02H

X=S,Se

4 2 ~

I

42 B CHzC12 H202

OH 0

41 Scheme 8.

43

Stepwise synthesis of nonracernic Baylis-Hillrnan adducts (Barrett et a/.)

point, this sequence was equivalent to an asymmetric Baylis-Hillman-reaction. The overall yields were in the range of 18% (X = S, R' = Me, R2 = Et) to 52% (X = Se, R' = Me, R2 = Me). In the first step, the enantioselective condensation of the cc,fi-unsaturatedketone 39 with the aldehyde 40 and trimethylsilylphenyl sulfide or - selenide afforded the diaster-

Syntheses of Non-Racemic Baylis-Hillman-Products by Other Methods

eomeric 8-hydroxyketones 42A and 42B with 63-97% ee. This reaction was catalyzed by the chiral acyloxyborane 41. The Baylis-Hillman-products 43 were subsequently prepared by oxidative elimination using mCPBA or H202. The enantioselectivities of this step were in the range of 50 to 96% ee. The copper-catalyzed S N ~addition ’ of organozinc reagents ZnR2 to allylic substrates ( Z ) ArHC=C(CH2X)(COzEt)(X = Br, C1, OSOzMe) yielded Baylis-Hillman products ArH( R)C-C(=CH2)(CO2Et)[40]. The use of chiral ligands gave up to 64% ee. Sat0 and coworkers have reported an asymmetric synthesis of Baylis-Hillman-type allylic alcohols 48,49via a chiral acetylenic ester titanium alkoxide complex (Scheme 9) [41]. These reactions rely on the use of the novel acetylenic ester titanium alkoxide complex 44 with a camphor-derived chiral auxiliary. Optically active, stereodefined hydroxy acrylates 46,47 were obtained in high yields and with excellent regio- and diastereoselectivities. The chiral auxiliary was subsequently cleaved off by alcoholysis.

0

44

45

C02H I

MesSi\//\/R

-

1

R-CHO

KOH. EtOH

OH

0

48, R = Et, 92% ee 49, R = Ph, 98% ee

SiMe3

46, R = Et, 94% de 47,R = Ph, 98% de

Scheme 9. Asymmetric synthesis of Baylis-Hillman-type adducts via a chiral acetylenic ester titanium alkoxide complex (Sato et a/.).

Unusual P-branched Baylis-Hillman adducts have been prepared by Li and coworkers by a novel Et2A1C1 promoted domino Michael-aldol reaction of propynoates 50 with organocuprates and chiral p-toluenesulfinimines 52 (Scheme 10) [42]. These condensations proceeded with very good diastereoselectivity to give allylic amines 53. The selectivity can be explained through the chairlike transition state 54.The anion intermediate approaches the sulfinimine from the sterically less hindered side of the lone pair of electrons. The nucleo-

I

173

174

I

The Asymmetric Baylis-Hillman-Reaction

Et2AICI

R' = H, Me, Ph R2 = Me, nBu, Ph

To1

H

52

R3 = Ph, 2-Fut~4 54 - 81%

complete diastereo-

and EIZ-selectivity

53

54 Domino Michael-aldol reaction of propynoates with organocuprates and chiral p-toluenesulfinimines (Li et a / . ) .

Scheme 10.

philic attack is controlled by the size of the substituents (RL, Rs, S = small, L = Large) of the vinylic organocopper intermediate which coexists with the respective allenoate species in equilibrium. In contrast to the work of Agganval (vide supra), propynoates rather than acrylates were used as starting materials. In addition, stoichiometric rather than catalytic amounts of a vinylic carbanion were formed. The asymmetric catalytic aldol reaction of silyl allenolates ICH=C=CR20SiMe3with aldehydes R'CHO has been achieved by Li et al. by using N-C3F,CO oxazaborolidine as the catalyst [43]. The fluoroacyl group of the catalyst was found to be crucial for control of enantioselectivity.The reaction provides the first enantioselective approach to j'-halo BaylisHillman-type adducts. Trost and coworkers have shown that Baylis-Hillman adducts can be efficiently deracemized by Pd2dba3,CHCl3catalyzed reaction of the corresponding carbonates 55 with phenols 56 in the presence of chiral Cz-symmetric P,N-ligands (Scheme 11) [44].The strategy follows a dynamic kinetic asymmetric transformation process via n-ally1 palladium chemis-

Acknowledgment

OC02Me

Pd2(dba)3.CHCl3 (1 mol-Yo) ligand (3 mol-%)

55

CH2Cl2, 20 "C

+ Ar-OH

57

0.05- 0.1 M

56

ligand

*

=d

R' = Alkyl R2 = C02Et, CN Ar =Aryl

ys

NH

'

PPh2

HN

Ph2P

72 - 77% 85 - 99% ee

/

58 Scheme 11.

Palladium-catalyzed deracemization of Baylis-Hillman adducts (Trost et a/.).

try. Using the chiral ligand 58, the reactions proceeded with excellent enantioselectivity. Depending on the substrate, ligand and reaction conditions, moderate to high regioselectivities were observed. Conclusions

The development of efficient, asymmetric versions of the Baylis-Hillman-reaction for the synthesis of enantiomerically pure cc-methylene-jl-hydroxycarbonyland related compounds is still a rewarding issue. Interesting recent approaches for the solution of this problem include the use of chiral Michael acceptors or aldehyde/aldimine components. The use of stoichiometric or catalytic amounts of chiral base is also of great current importance. Besides the development of an asymmetric version of the Baylis-Hillman-reaction, alternative reaction sequences giving nonracemic Baylis-Hillman-adducts have attracted considerable attention. Likewise, the recently reported Palladium-catalyzed deracemization of Baylis-Hillmanadducts appears to be promising. Besides stereoselectivity, the low rate and chemical yields often observed in Baylis-Hillman reactions remain important issues to be carefully addressed in all future studies. Acknowledgment

This work was supported by the Fonds der Chemischen Industrie (Liebig-scholarship and funds for P. L.) and by the Deutsche Forschungsgemeinschaft (Heisenberg-scholarship for P.L.). P. L. thanks Prof. Dr. A. de Meijere for his support.

I

175

176

I

The Asymmetric Baylis-Hillman-Reaction References

1 Reviews: a)

P. LANGER,Angew. Chem. 2000, 112, 3177-3180; Angew. Chem. Int. Ed. 2000, 39, 3049-3052; b) E. CIGANEK, Org. React. 1997, 51, 201-350; C) D. BASAVAIAH, P. D. RAo, R. S. HYMA, Tetrahedron 1996, 52, 8001-8062; d) S. E. DREWES, G. H. P. Roos, Tetrahedron 1988, 44, 4653-4670; e) K. MORITA,2. S u z u ~ r , H. HIROSE,Bull. Chem. SOC.]pn. 1968, 41, 2815. 2 A. B. BAYLIS, M. E. D. HILLMAN, German Patent 2155113, 1972 [Chem.Abstr. 1972, 77, 34174q1. 3 a) H. M. R. HOFFMANN, J. RABE,Angew. Chem. 1983, 95, 795-796; Angew. Chem., Int. Ed. Engl. 1983, 22, 795-796; b) J. RABE,H. M. R. HOFFMANN, Angew. Chem. 1983, 95, 796-797; Angew. Chem., Int. Ed. Engl. 1983, 22, 796-797; c) H. M. R. J. RABE,Angew. Chem. 1985, HOFFMANN, 97, 96-112; Angew. Chem., Int. Ed. Engl. 1985, 24, 94-109. 4 Mechanistic studies: a) J. S. HILL,N. S. ISAACS,]. Phys. Org. Chem., 1990, 3, 285293; b) M. L. BODE, P. T. KAYE,Tetrahedron Lett. 1991, 32, 5611-5614; c) Y. FORT,M. C. BERTHE,P. CAUBERE, Tetrahedron 1992, 48,6371-6384; d) E. M. L. ROSENDAAL, B. M. W. Voss, H. W. SCHEEREN, Tetrahedron 1993, 31, 6931-6936. 5 a) R. S. ATKINSON, J. FAWCETI,D. R. RUSSEL,P. J. WILLIAMS, ]. Chem. SOC., Chem. Commun. 1994, 2031-2032. 6 M. BAILEY,I. E. MARKO,W. D. OLLIS, Tetrahedron Lett. 1991, 32, 2687-2690. 7 I. E. MARKO,P. R. GILES,2. J A N O U S E K , N. J. HINDLEY, J:P. DECLERCQ, B. TINANT,J. FENEAU-DUPONT, J. S. SVENDSEN, Red. Trav. Chim. Pays-Bas 1995, 114, 239-246. 8 J. M. BROWN, Angew. Chem. 1987, 99, 169182; Angew. Chem., Int. Ed. Engl. 1987, 26, 190-203. 9 a) A. H. HOVEYDA, D. A. EVANS,G . C. Fu, Chem. Rev. 1993, 93, 1307-1370; b) R. ANNUNZIATA, M. BENAGLIA, M. CINQUINI, F. COZZI,L. RAIMONDI,]. Org. Chem. 1995, 60,4697-4706; c) 0. B. FAMILONI, P. T. KAYE, P. J. KIAAS, Chem. Commun. 1998, 2563-2564. 10 W. R. ROUSH,B. B. BROWN,].Org. Chem. 1993, 58, 2151-2161.

1 1 a) J.AuGE, N. LUBIN,A. LUBINEAU, Tetra-

hedron Lett. 1994, 58, 7947-7948; b) M. K. KUNDU,S. B. MUKHERJEE, N. BALU, R. S. V. BHAT,Synlett 1994, PADMAKUMAR, 444. 12 S. RAPEL,J.W. LEAHY,]. Org. Chem. 1997, 62, 1521-1522. 13 P. RAMACHANDRAN, P.,R. VEERARAGHAVAN, M. REDDY,R. VENKAT,M. T. RUDD, H. C. BROWN,R. B. WETHERILL, Chem. Commun. 2001, 757-758. 14 a) S. E. DREWES, S. D. FREESE, N. D. G. H. P. Roos, Synth. Commun. EMSLIE, 1988, 18, 1565-1668; b) M. BAILEY,I. E. MARK^, W. D. OLLIS,P. R. RASMUSSEN, Tetrahedron Lett. 1990, 4509-4512; c) M. L. BODE,P. T. KAYE, Tetrahedron Lett. 1991, 5611-5614; d) F. AMEER,S. E. DREWES, S. FREESE, P. T. KAYE,Synth. Commun. 1988, 18,495-498; e ) H . M. R. HOFFMANN? ]. Org. Chem. 1988, 53, 3701-3712; f ) D. BASAVAIAH,P. K. S. SARMA,Synth. Commun. 1990, 20, 1611-1614. 15 R. J. W. SCHUURMAN, A. VANDERLINDEN, R. P. F. GRIMBERGEN, R. J. M. NOLTE, H. W. SCHEEREN, Tetrahedron 1996, 52, 8307-8314. 16 V. K. AGGARWAL, A. MEREU,Chem. Commun. 1999, 2311-2312. 17 V. K. AGGARWAL, A. MEREU,G. J. TARVER, R. J. MCCAGUE, ]. Org. Chem. 1998, 63, 7183-7189. 18 M. SHI, Y . 3 . FENG,]. Org. Chem. 2001, 66, 406-411. 19 V. K. AGGARWAL, D. K. DEAN,A. MEREU, R. WILLIAMS, ]. Org. Chem. 2002, 67, 510-514. 20 C. Yu, B. LIU, L. Hu,]. Org. Chem. 2001, 66, 5413-5418. 21 N. S. ISAACS, A. GILBERT, T. W. HERITAGE, Tetrahedron:Asymmetry 1991, 2, 969-972. 22 L. J. BRZEZINSKI,S. RAFEL, J. W. LEAHY,]. Am. Chem. SOC.1997, 119, 4317-4318. 23 K. P. RADHA V. KANNAN, A. ILANGOVAN, G. V. M. SHARMA, Tetrahedron:Asymmetry 2001,829-837. 24 K . 4 . YANG, K. CHEN,Org. Lett. 2000, 729731. 25 a) J. JAUCH,]. Org. Chem. 2001, 66, 609611 and references cited therein; b) J. JAUCH,Eur. I. Org. Chem. 2001,473-476;

References I 1 7 7

26

27 28 29

30

31 32

33

34

35

c) J. JAUCH,Angew. Chem. 2000, 112, 2874-2875; Angew. Chem. Int. Ed. 2000, 39, 2764-2765. V. K. AGGARWAL, A. M. M. CASTRO, A. MEREU,H. ADAMS,Tetrahedron Lett. 2002, 1577-1581. T. BAUER,J. TARASIUK, Tetrahedron: Asymmetry 2001, 1741-1745. E. P. KUNDIG, L. H. Xu, B. SCHNELL, Synlett 1994, 413-415. a) Ref. lb; b) Ref. 17; c) I. E. MARKO,P. R. GILES,N. J. HINDLEY, Tetrahedron 1997, 53, 1015-1024; d) D. BASAVAIAH,N. KUMARAGURUBARAN,D. S. SHARADA, R. M. REDDY, Tetrahedron 2001, 57, 8167-8172. a) T. HAYASE, T. SHIBATA, K. SOAI,Y. WAKATSUKI, Chem. Commun. 1998, 12711272; b) M. SHI, J.-K. JIANG, S.-H. Cur, Y . 4 . FENG,]. Chem. Soc., Perkin Trans. 1 2001, 390-393. Y. M. A. YAMADA,S. IKEGAMI,Tetrahedron Lett. 2000, 2165-2169. A. G. M. BARRETT, A. S . COOK,A. KAMIMURA,Chem. Commun. 1998, 2533-2534. Y. IWABUCHI, M. NAKATANI, N. YOKOYAMA, S. HATAKEYAMA, ]. Am. Chem. Soc. 1999, 121, 10219-10220. a) C. VON RIESEN,H. M. R. HOFFMANN, Chem. Eur. 1.1996, 2, 680-684; b) W. P. LANCER, BFAJE,1. FRACKENPOHL, H. M. R. HOFFMANN, Tetrahedron 1998, 54, 3495-3512. For the conformational analysis of Cinchona-alkaloids, see: a) G. D. H. DIJKSTRA, R. M. KELLOGG,H. J. WYNBERG, J . S. SVENDSEN, 1. MARKO,K. B.

36

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38

39

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41

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SHARPLESS,]. Am. Chem. SOC.1989, 111, 8069-8076; b) G. D. H. DITKSTRA, R. M. KELLOGG,H. J. WYNBERG, J. Org. Chem. 1990, 55, 6121-6131. Y. IWABUCHI, M. FURUKAWA, T. ESUMI, S. HATAKEYAMA, Chem. Commun. 2001, 2030-2031. S. G. DAVIES, C. A. P. SMETHURST, A. D. SMITH,G. D. SMYTH,Tetrahedron: Asymmetry 2000, 1 I , 2437-2441. D. J. Fox, J. A. MEDLOCK, R. VOSSER, S. WARREN,].Chem. Soc., Perkin Trans. 1 2001, 18, 2240-2249. A. G. M. BARRETT, A. KAMIMURA,]. Chem. SOC.,Chem. Commun. 1995, 17551756. C. BORNER, P. J. GOLDSMITH, S. WOODWARD, ].GIMENO,S. GIADIALI, D. RAMAZZOTTI, Chem. Commun. 2000, 2433-2434. D. SUZUKI, H. URABE, F. SATO,Angew. Chem. 2000, 112, 3428-3430; Angew. Chem. Int. Ed. 2000, 39, 3290-3292. a) G . LI, H.-X. WEI, B. R. WHITTLESEY, N. N. BATRICE,]. Org. Chem. 1999, 64, 1081-1064; see also: b) G. LI, H.-X. WEI, J. D. HOOK,Tetrahedron Lett. 1999, 46114614; c) H.-X. WEI, J. D. HOOK,K. A. FITZGERALD,G. LI, Tetrahedron: Asymmetry 1999, 661-665. G. LI, H.-X. WEI, B. S. PHELPS,D. W. PURKISS,S. H. KIM, H. SUN,Org. Lett. 2001,823-826. B. M. TROST,H.-C. Tsur, F. D. TOSTE,J . Am. Chem. SOC.2000, 122, 3534-3535. See also: S. V. LEY,F. RODRIGUEZ, Chemtracts 2000, 13, 596-601.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Simple Amino Acids and Short-chain Peptides as Efficient Metal-free Catalysts in Asymmetric Synthesis Harald Croger, Jorg Wilken, and Albrecht Berkessel Introduction

The development of suitable enzyme mimics as (0rgano)catalysts in asymmetric syntheses is highly attractive, not at least due to the fact that enzymes are regarded to be the most efficient catalysts. Since these efficient natural catalysts are based on a sequence of amino acids organic chemists became interested to investigate if peptide fragments thereof or simple amino acid monomers can act like an enzyme itself [ 11. It is noteworthy that such a reaction, namely the intramolecular aldol reaction with proline as a catalyst [2],was reported already in 1971. The question if a simple amino acid or a short-chain peptide thereof can act like an enzyme for a broad range of reactions was impressively answered recently by numerous important contributions showing that those small building blocks represent highly active and enantioselective organocatalysts [ 31. These asymmetric syntheses with organocatalysts possess a high synthetic value since they represent a remarkable alternative to many established asymmetric transformations. In the following a brief overview about advantages of amino acid and peptide catalysts, and selected recent synthetic highlights of amino acid-, and peptide-catalyzed reactions, including a comparison of mechanistic aspects of those reactions with enzymatic reacions, is given.

Advantages o f Amino Acid and Peptide Catalysts

In particular, such type of processes might allow a cost effective manufacture of chiral building blocks on an industrial scale in the future. Furthermore, the application of enantiomerically pure, “small” amino acid or oligopeptide molecules represents a promising alternative catalytic concept in addition to other frequently used syntheses based on metalcontaining catalysts [l].These organic catalysts not only function like an enzyme, but also with respect towards technical application - show the following interesting properties: (a) easy availability,(b) both enantiomers are often available with comparable price, (c) low price of amino acids since often directly accessible from the “chiral pool” or produced in large amount by fermentation, (d) low molecular weight, (e) easy separation from the product and ( f ) easy recovery after work-up.

Asymmetric Synthesis Using Amino Acid Catalysts

Asymmetric Synthesis Using Amino Acid Catalysts lntermolecular Amino Acid-catalyzed Asymmetric Aldol Reaction

The capability of L-proline - as a simple amino acid from the “chiral pool” - to act like an enzyme has been shown by List, Lerner und Barbas 111 [4] for one of the most important organic asymmetric transformations, namely the catalytic aldol reaction [ 51. In addition, all the above-mentioned requirements have been fulfilled. In the described experiments the conversion of acetone with an aldehyde resulted in the formation of the desired aldol products in satisfying to very good yields and with enantioselectivities of up to 96% ee (Scheme 1) [4]. It is noteworthy that, in a similar manner to enzymatic conversions with aldolases of type I or 11, a “direct” asymmetric aldol reaction was achieved when using L-proline as a catalyst. Accordingly the use of enol derivatives of the ketone component is not necessary, that is, ketones (acting as donors) can be used directly without previous modification [6]. So far, most of the asymmetric catalytic aldol reactions with synthetic catalysts require the utilization of enol derivatives [ 51. The first direct catalytic asymmetric aldol reaction in the presence of a chiral heterobimetallic catalyst has recently been reported by the Shibasaki group [ 7 ] .

1 + I

H3C

CH,

(20 vol-Yo)

(R)-2a 94% yield 69% ee

H L-proline (30 mol-Yo)

* DMSO /acetone (4:l)

1

H3C

(R)-2 up to 97% yield up to 96% ee

(R)-2b 54% yield 77% ee

(R)-2C 97% yield 96% ee

Scheme 1. The direct intermolecular asymmetric aldol reaction using L-proline

Promising prospects for synthetic applications in the future were opened up by List et al.’s experimental studies into the substrate range (Scheme 1).The proline-catalyzed reaction proceeds well when using aromatic aldehydes as a starting material with enantioselectivities of 60 to 77% ee and yields of up to 94%. The direct L-proline-catalyzed aldol reaction proceeds very efficiently when using isobutyraldehyde as a substrate. For this reaction the

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Simple Amino Acids and Short-chain Peptides as Eficient Metal-free Catalysts in Asymmetric Synthesis

product 2c has been obtained in a very good yield of 97% and with an excellent enantioselectivity of 96% ee. An enantioselective proline-catalyzed self-aldolization of acetaldehyde was found very recently by Barbas and co-workers (Scheme 2, reaction 1) [8]. As a product, the valuable building block 5-hydroxy-(2E)-hexenal3 was obtained with up to 90% ee, albeit yield did not exceed 13% independently from the reaction conditions. 0

L-proline (ca. 2.5 rnol-Yo)

THF / acetaldehyde (4:l); 5h; 0 . c

(20 vol-%)

*

H3CU

H3.4

OH

(20 vol-%)

Scheme 2.

+

3

(R=alkyl,aryl)

DMSO / hydroxyacetone * (4:l)

OH

0

(20 - 30 rnol-oh) H3C

HKR

(reaction 1)

10% yield 90% ee

L-proline

0

H

-

(reaction 2)

OH

4 up to 95% yield dr (sydanti) up to >20:1 up to >99% ee

Further L-proline-catalyzed intermolecular asymmetric aldol reactions.

The concept of the proline-catalyzed aldol reaction has been recently extended by List et al. towards the synthesis of aldol products with two stereogenic centers [9). The desired antidiols 4 have been obtained in a regio-, diastereo- and enantioselective step starting from achiral compounds. Impressive diastero- and enantioselectivities were observed, with a diastereomeric ratio up to dr > 20:l and ee-values of up to >99% ee (Scheme 2, reaction 2). In addition, the reaction leads to a high regioselectivity of >20:1. From an industrial point of view, the following characteristics of these aldol reactions are noteworthy in particular: The direct aldol reaction possess a high synthetic value since the use of modified starting materials is not necessary, and the ketones can be used directly instead of enol derivatives. Furthermore, the price of L-proline - which is available on technical scale in both enantiomeric forms - is only about 40 $/kg (referring to L-proline).This represents an economically highly attractive access to a chiral catalyst - in particular compared with other types of chiral catalysts. In addition, the possibility of easily separating the proline catalyst from the product and recovering it by aqueous work-up (due to its water solubility) is also of economical interest. At present, the increase of the enantioselectivity and the improvement of the substrate range indicate a challenge of the future. Such improvements could enable the realization of a technical applicability of the direct asymmetric aldol reaction using r-proline. Another disadvantage is the large excess of the ketone component. In addition, a further decrease of the required catalytic amount of 20-30 mol% would be desirable.

Asymmetric Synthesis Using Amino Acid Catalysts

The Mechanism: Similarities of Amino Acid-catalyzed and Enzymatic Reactions

In principle, L-proline acts as an enzyme mimic of the metal-free aldolase of type I. Similar to this enzyme L-proline catalyzes the direct aldol reaction according to an enamine mechanism. Thus, for the first time a mimic of the aldolase of type I was found. The dose relation of the reaction mechanisms of the aldolase of type I [Sb] and L-proline [4] is shown in a graphical comparison of both reaction cycles in Scheme 3. In both cases the formation of the enamines IIa and IIb, respectively, represents the initial step. These reactions are carried out starting from the corresponding ketone and the amino functionality of the enzyme or L-proline. The conversion of the enamine intermediates Ira and IIb, respectively, with an aldehyde, and the subsequent release of the catalytic system (aldolase of type I or r-proline) furnishes the aldol product. a) Catalytic cycle with the aldolase of type I

b) Catalytic cycle with L-proline

(Lys (aldolase)

la

8.

H3C

. *R OH OH

CH3

L-proline H3C

2

(R = OPO:o)

However, a difference between both catalytic cycles can be seen in the reaction sequence for the formation of the enamines which are key intermediates of these aldol reactions. In case of the aldolase of type I a primary amino function of the enzyme is used for the direct formation of a neutral imine (Ia), while the enamine synthesis proceeds through a positive iminium system (Ib) when starting from L-proline (Scheme 3). In this connection, inves-

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Simple Amino Acids and Short-chain Peptides as Eflcient Metal-free Catalysts in Asymmetric Synthesis

tigations by List et al. on the dependence of the catalytic potential from the type of amino acid are of particular interest. In these studies it has been shown that for the catalytic activity the pyrrolidine cycle (in L-proline) is required as well as the carboxylic acid group [4]. In conclusion, the aldol reaction with L-proline as an enzyme mimic is a successful example for the concept of using simple organic molecules as chiral catalysts. However, this concept is not limited to selected enzymatic reactions, but opens up a general perspective for the asymmetric design of a multitude of catalytic reactions in the presence of organocatalysts [ 1, 3). This has been also demonstrated by very recent publications in the field of asymmetric syntheses with amino acids and peptides as catalysts. In the following paragraphs this will be exemplified by selected excellent contributions. lntramolecular Amino Acid-catalyzed Asymmetric Aldol Reaction

For the Hajos-Eder-Sauer-Wiechert reaction [2a, b], which was found in the 7Oties, Barbas 111 et al. recently reported an optimized protocol [lo]. This reaction furnishes the chiral Wieland-Miescher ketone. It has now been shown, that this synthesis (which comprises three reactions) can be carried out as a one-pot synthesis (49% yield; 76% ee; Scheme 4) [lo]. Prolin functions as an efficient catalyst for all three reaction steps (Michael-addition, cyclization, dehydratization). A very interesting theoretical study of the mechanism of this reaction has been recently published by the Houk group [ 111.

XCH2

0

CH3

+

L-proline (35 mol-%)

DMS0;35 C

0

5 49% yield 76% ee Scheme 4.

The direct intramolecular asymmetric aldol reaction using L-proline.

Amino Acid-catalyzed Asymmetric Mannich-reaction

A further application of L-proline as a catalyst in asymmetric synthesis, which was found by List, is the three-component-Mannich reaction for the preparation of p-amino ketones [ 121. In the presence of L-proline as a catalyst the Mannich product 6 has been obtained in 50% yield and with 94% ee (Scheme 5, reaction 1). This method can be applied to a series of different aldehydes, whereby enantioselectivities of up to 96% ee are obtained. I t is noteworthy that - similiarly to the proline-catalyzed aldol reaction - the Mannich reaction can also be extended to an enantio- and diastereoselective process. For example, the uic-aminoalcohol 7 is formed with a diastereomeric ratio of 17:l and an enantioselectivity of 65% ee (Scheme 5; reaction 2). Amino Acid-catalyzed Asymmetric Michael Reaction Using C-donors

Recent contributions by several groups revealed that L-proline is also a suitable catalyst for the asymmetric Michael reaction using C-donors [l, 13-15]. In the first reports, in general

Asymmetric Synthesis Using Short-chain Peptide Catalysts

a

H3C

CH3

9

+

0 Htj,PMP

L-proline (35 mol-%); p-anisidine (1.1 eq.,)

(20 vol-%)

NO2

H3C'

DMSO I acetone (4:l)

1:-

n N o 2 ( r e a c t i o n 1)

6 50% yield

94% ee (PMP = pmethoxyphenyl) L-proline (35 mol-%); panisidine (1.1 eq.)

H 3 C 3 OH

-t

.

H CH3

0 HNSPMP (reaction 2)

H3C*cH3

DMSO / hydroxyacetone

OH CH3

(4:l)

7

(20 vol-%)

57% yield dr (sydanfi) 17:l 65% ee Scheme 5.

Asymmetric Mannich reactions using L-proline as a catalyst.

excellent yields and high diastereomeric ratio but low enantioselectivities were obtained [ 131. Using modified reaction conditions, however, Enders et al. found an improved enantio- and diastereoselective proline-catalyzed Michael addition of ketones to nitrostyrenes [ 151. The optically active y-nitro ketone products of type 8 were obtained with increased enantioselectivities of up to 76% ee. The yields remained in a medium to excellent range of up to 99%, and diastereomeric ratio of up to 98.5:l.S were observed. So far, however, the long reaction time of 2-8 d represents a limitation which has to be further improved. A representative example is shown in Scheme 6.

(1 0 equiv.)

Scheme 6.

8 74%yield dr (sydanti) 16:l 76% ee

Asymmetric L-proline-catalyzed Michael reactions with C-donors.

Asymmetric Synthesis Using Short-chain Peptide Catalysts feptide-catalyzed Asymmetric Michael Reaction with N-donors

An asymmetric version of a Michael addition with nitrogen nucleophiles can be also realized with simple short-chain peptides as catalysts. This has been demonstrated by Miller et al. for the addition of an azide to a,p-unsaturated carbonyl compounds [16]. In the presence of the tripeptide 9 as a catalyst (2.5 mol-%) the products 10 have been formed in excellent yields and with up to 85% ee (Scheme 7). In addition, this reaction represents an attractive access to p-amino acids.

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Simple Amino Acids and Short-chain Peptides as E$cient Metal-free Catalysts in Asymmetric Synthesis

0

0

Bn

9 (2.5 mol-Yo) A

N

L

R

TMSN3; HOAC toluene; 25 C

10 up to 97% yield up to 85% ee

Scheme 7.

Asymmetric tripeptide-catalyzed Michael reaction with an N-donor.

Short-chain Peptide-catalyzed Asymmetric Epoxidation

In addition, solid-phase bound short-chain peptides have been recently found by the Berkessel group to act as highly efficient catalysts in asymmetric epoxidation reactions [ 171. In the early 1980s, J u k and Colonna reported that chalcone 11 can be epoxidized asymmetrically by akaline hydrogen peroxide in the presence of poly-amino acids as catalysts [ 18, 191. The work by Berkessel et al. revealed that in fact as little as five L-Leu residues are sufficient for the epoxidation of the enone 11 with 96-98% ee (Scheme 8).

11 Scheme 8.

c a t a l y s t : (L-Leu), on TentaGel S NH2 Asymmetric enone epoxidation with solid-phase bound peptide catalysts.

Their results strongly suggest that one turn of a helical peptide is the minimal structural element required for catalysis. Based on structure-activity studies of the catalyst, and based on molecular modeling, it was concluded that the N-terminus of the peptide functions as the active site of these "mini-enzymes". Three N-H bonds (not involved in intrahelical Hbonding) protrude from the N-terminus of a-helices. Binding and activation of the enone is effected by H-bonding of the carbonyl oxygen atom to the terminal amino acid (n) and the one at position (n-2). The oxidant, i.e. a nucleophilic hydroperoxide anion, is delivered selectively to one enantiotopic face of the enone by the remaining NH-bond of the penultimate amino acid (n-1) (Figure 1). In other words, the sense of asymmetric induction is determined by the helicity of the peptide. A catalytic method for the preparation of enantiomerically pure cc,P-epoxy ketones as building blocks for organic synthesis is highly desirable. Unfortunately, the Julia-Colonna

References and Remarks

Fig. 1. Proposal for the mechanism o f asymmetric induction i n peptide-catalyzed enone epoxidations. Note that the enone carbonyl oxygen atom forms two H-bonds t o the N-terminal amino acid (n) and to the one at position (n-2); a hydroperoxide anion is delivered faceselectively by NH (n-1).

method is still limited to chalcones and closely related substrates [ 2 0 ] . It is hoped that the above mechanistic model will aid in the design of peptide catalysts for the asymmetric epoxidation of enones other than chalcones, e.g. cyclohexenones or quinones. Summary

In conclusion, the recent contributions by several groups in the field of asymmetric syntheses with amino acids and short-chain peptides as efficient chiral catalysts appear to be very interesting for chemists from academia as well as from industry. In addition, those new syntheses are promising alternatives to existing asymmetric technologies. Without any doubts it is surprising to observe that a simple amino acid molecule - as shown in case of proline - can in principle act like an enzymatic system, thus representing an efficient enzyme mimic. References and Remarks 1

For recent reviews in the field of organocatalytic reactions, see: a) H. GROGER,J. WILKEN,Angew. Chem. 2001, 113, 545; Angew. Chem. Int. Ed. 2001,40,529; b) B.

LIST,Synlett 2001, 1675; c) P. I. DALKO, L. MOISAN,Angew. Chem. 2001, 113, 3840; Angew. Chem. Int. Ed. 2001,40, 3726.

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3

4 5

a) U. EDER, G. SAUER, R. WIECHERT, Angew. Chem. 1971, 83, 492; Angew. Chem. Int. Ed. Engl. 1971, 10, 496; b) 2. G . HAJOS,D. R. PARRISH, J . Org. Chem. 1974, 39, 1615; c) C. AGAMI,N. PLATZER, H. SEVESTRE, Bull. SOC.Chim. Fr. 1987, 2, 358. For selected previous contributions about the application of further simple organic molecules as chiral catalysts in asymmetric synthesis, see: a) Hydrocyanation using cyclic dipeptides: K. TANAKA, A. MORI,S. INOUE, /. Org. Chem. 1990, 55, 181; b) Hydrocyanation using a chiral imine: M. S. SIGMAN, E. N. JACOBSEN, /, Am. Chem. SOC.1998, 120, 4901; c) Hydrocyanation using chiral bicyclic guanidine derivatives: E. J. COREY,M . J. GROGAN, Org. Lett. 1999, 1, 157; d) Baylis-Hillman reaction: Y. IWABUCHI, M. NAKATANI,N. YOKOYAMA,S. HATAKEYAMA, J . Am. Chem. SOC.1999, 121, 10219; e) Michael-Addition using alkali metal salts of proline: M. YAMAGUCHI,T. SHIRAISHI, M. HIRAMA, /. Org. Chem. 1996, 61, 3520, and cited references therein; f ) Diels-Alder reacC. J. BORTHS, tion: K. A. AHRENDT, J . Am. Chem. SOC. D. W. C. MACMILLAN, 2000, 122, 4243; g) /3-lactam formation: A. E. TAGGI, A. M. HAFEZ,H. WACK,B. YOUNG, W. J. DRURY, Ill, T. LECTKA,J . Am. Chem. SOC.2000, 122, 7831. B. LIST, R. A. LERNER,C. F. BARBAS 111, /. Am. Chem. SOC.2000, 122, 2395. For a review about the asymmetric catalytic aldol reaction, see: a) H. GROGER,E. M. VOGL,M. SHIBASAKI, Chem. Eur. J. 1998, 4, 1137; b) T. D. MACHAJEWSKI, C.-H. WONG,Angew. Chem. 2000, 112, 1406; Angew. Chem. Int. Ed. 2000, 39, 1352.

This also means that a further reaction step - deprotonation or silylation - in order to prepare the required enolates and enol ethers, respectively, can be avoided. 7 a) Y. M. A. YAMADA, N. YOSHIKAWA, H. SASAI, M. SHIBASAKI, Angew. Chem. 1997, 109, 1942; Angew. Chern. Int. Ed. Engl. 1997, 36, 1871; b) N. YOSHIKAWA, Y. M. A. YAMADA,J. DAS,H. SASAI,M. SHIBASAKI, J . Am. Chem. SOC.1999, 121; 4168. 8 A. CORDOVA, W. NOTZ,C. F. BARBASIl1,J. Org. Chem. 2002, 67, 301. 9 W. NOTZ,B. LIST, J . Am. Chem. SOC.2000, 122, 7386. 10 T. BUI, C. F. BARBAS, Ill, Tetrahedron Lett. 2000, 41, 6951. 11 S. BAHMANYAR, K. N. HOUK,J. Am. Chem. SOC.2001, 123, 12911. 12 B. LIST,/. Am. Chem. SOC.2000, 122, 9336. 13 B. LIST, P. POTARLIEV, H. 1. MARTIN, Org. Lett. 2001, 3, 2423. 14 J. BETANCORT, K. SAK-ITHIVEL, R. THAYUMANAVAN, C. F. BARBAS,111, Tetrahedron Lett. 2001, 3, 4441. 15 D. ENDERS,A. SEXI,Synlett 2002, 26. 16 T. E. HORSTMANN, D. J. GUERIN, S. J. Angew. Chem. 2000, 112, 3781; MILLER, Angew. Chem. Int. Ed. 2000, 39, 3635. 17 A. BERKESSEL, N. GASCH,K. GLAUBITZ, C. KOCH, Org. Lett. 2001, 3, 3839. 18 S. JULIA, J. MASANA, J. VEGA,Angew. Chem. 1980, 92, 968; Angew. Chem. Int. Ed. Engl. 1980, 19, 929. 19 S. JULIA, J. GUIXER, J. MASANA, J. ROCAS, S. COLONNA, R. ANNUZIATA, H. MOLINARI, J. Chem. SOC., Perkin Trans. 11982, 1317. 20 M. J. PORTER, J. SKIDMORE, Chem. Commun. 2000, 1215. 6

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

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Recent Developments in Catalytic Asymmetric Strecker-Type Reactions Larry Yet

The Strecker amino acid synthesis, which involves treatment of aldehydes with ammonia and hydrogen cyanide (or equivalents) followed by hydrolysis of the intermediate cc-amino nitriles to provide cc-amino acids (Scheme l),was first reported in 1850 [ 11. This method has been applied on an industrial scale toward the synthesis of racemic cc-amino acids, but more recently interest in nonproteinogenic a-amino acids in a variety of scientific disciplines has prompted intense activity in the asymmetric syntheses of cc-amino acids [ 21. The catalytic asymmetric Strecker-type reaction offers one of the most direct and viable methods for the asymmetric synthesis of cc-amino acid derivatives. It is the purpose of this Highlight to disclose recent developments in this emerging field of importance.

RCHO

+

Scheme 1.

NH,

+

HCN

-

Classical Strecker synthesis of r-amino acids.

Lipton and co-workers investigated the viability of the asymmetric Strecker amino acid synthesis in which they utilized cyclic guanidine dipeptide 2 in the reaction of N-benzhydrylimines 1 with hydrogen cyanide to give N-benzhydryl-cc-aminonitriles3 (Scheme 2) [3]. N-Benzhydrylimines 1, derived from aromatic aldehydes, gave products 3 in generally high enantiomeric excess. However, electron-deficient 3-nitro, 3-pyridyl, and aliphatic aldehyde derivatives afforded racemic products. H

2 (2 mol%)

0 MeOH, 75 "C 1 Scheme 2.

71-97%, 10-99% ee

H

3

Asymmetric Strecker synthesis with cyclic dipeptide 2 (Lipton and co-workers)

188

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Recent Developments in Catalytic Asymmetric Strecker-Type Reactions

Sigman and Jacobsen reported the first example of a metal-catalyzed enantioselective Strecker-type reaction using a chiral Al"'-salen complex (salen = N,N'-bis(salicy1idene)ethylenediamine dianion) [4]. A variety of N-allylimines 4 were evaluated in the reaction catalyzed by complex 5 to give products 6,which were isolated as trifluoroacetamides in good yields and moderate-to-excellent enantioselectivities (Scheme 3). Substituted arylimines 4 were the best substrates, while alkyl-substituted imines afforded products with considerably lower ee values. Jacobsen and co-workers also reported that non-metal Schiff base catalysts 8 and 9 proved to be effective in the Strecker reaction of imines 7 with hydrogen cyanide to afford trifluoroacetamides 10 after reaction with trifluoroacetic anhydride, since the free amines were not stable to chromatography (Scheme 4) [S].

0 N-

RAH 4

1. 5 (5 mol%), PhMe, -70 "C, 15 h +

HCN

!=,CANd

RACN

2,TFAA 91-99%, 37-95% ee

6

5 Asymmetric Strecker synthesis with chiral Al"'-salen catalyst 5 (Sigman and Jacobsen). TFAA = trifluoroacetic anhydride.

Scheme 3.

0

N,R2

+ R1JL

HCN

1 . 9 (2 mol%), PhMe, -70 "C, 20 h 9

2. TFAA

7

65-99%, 77-97% ee

R2 = Bn, ally1

CF3AN*R2 R'&N 10

8 R = polystyrene, X = S

9 R=Ph,X=O OC(0) tBu Asymmetric Strecker synthesis with salicylimine catalyst 9 (Vachal and Jacobsen). Bn = benzyl.

Scheme 4.

Catalyst 9 was very effective for the hydrocyanation of both aromatic and aliphatic imines 7 in high enantioselectivities and yields, and either N-benzyl- or N-allylimines could be used. The key elements responsible for the high enantioselectivity were the presence of bulky tea-

Recent Developments in Catalytic Asymmetric Strecker- Type Reactions

butyl substituents at both the amino acid position and at the 3-position of the salicylimine moiety. Resin-bound catalyst 8 allowed purification of the Strecker products by simple filtration and solvent removal, and the catalyst could be reused indefinitely without loss of either activity or enantioselectivity. Recently, Vachal and Jacobsen have applied catalyst 9 to ketoimines in the presence of hydrogen cyanide in the catalytic synthesis of quaternary a-carbon atoms [6]. Snapper, Hoveyda and co-workers employed a similar salicylimine Schiff base ligand 12 in the asymmetric titanium-catalyzed Strecker reaction of aromatic N-benzhydrylimines 11 to give addition products 13 (Scheme 5) [ 7 ] . It was found that catalyst turnover was facilitated significantly in the presence of 2-propanol as an additive. The aminonitriles 13 are stable and directly purified by chromatography (acylation is not needed) and can be readily converted into the corresponding amino acids with 6 N HCI by concomitant cyanide hydrolysis and amine deprotection. Schiff base-type ligands 12 were also usefully employed in the titanium-catalyzed regio- and enantioselective addition of cyanide to unsaturated imines to give P,X-unsaturated a-amino nitriles in good yield and enantiomeric excesses [ 8 ] . Both aromatic and aliphatic substrates presented no problems in these reactions. Cyanide hydrolysis and amine deprotection could be carried out to afford optically enriched cc-amino amides and acids. Hoveyda, Snapper and co-workers have also investigated in detail the mechanism of this enantioselective titanium-catalyzed Strecker reaction with the appropriate kinetic, structural, and stereochemical data [9]. A mechanistic model consistent with the kinetic and stereochemical data was presented in which the titanium center is coordinated to the Schiff base unit of the ligand and the AA2 moiety of the peptidic segment of the chiral ligand associates and delivers the hydrogen cyanide molecule to the activated bound substrate in a bifunctional fashion. tBU H

0

Ph RANAPh 11

12 (10 mol%)

Ti(OiPr)4 (10 mol%), TMSCN (2 equiv) iPrOH (1.5 equiv), PhMe, 4 "C, 20 h

H 13

80-97%, 85-99% ee Strecker synthesis with chiral Schiff base ligand 12 (Snapper, Hoveyda, and co-workers). TMS = trirnethylsilyl.

Scheme 5.

Shibasaki and co-workers disclosed a general asymmetric Strecker-type reaction that was controlled by bifunctional Lewis acid-Lewis base catalyst 14 [ 101. N-Fluorenylimines 15 underwent catalytic asymmetric Strecker-type reactions with binaphthol catalyst 14 to give a-aminonitriles 16 in good to excellent enantioselectivities and yields (Scheme 6). aAminonitrile 16 (R = Ph) could then be converted to cc-aminoamide 17 in several steps. Aromatic, aliphatic, heterocyclic and ccJ-unsaturated imines 15 were used as general substrates in these reactions. The origin of the highly enantioselective cataylsis by 14 is believed to be attributed to the simultaneous activation of imines and trimethylsilyl cyanide by the

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190

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Recent Developments in Catalytic Asymmetric Strecker-Jype Reactions

Ph, ,Ph

;p

Cl-Al<E

14

0

9'

Ph' \Ph

1. HCI (g), HCOpH

1. 14 (9 mol%), TMSCN (2 equiv), PhOH (20

3. 1N HCI

2.2N HCI 66-97%, 70-96% ee

15

16

17

4. Amberlyst A-211MeOH

91%, 98% ee (R = Ph) Asymmetric Strecker synthesis with bifunctional Lewis acidLewis base catalyst 14 (Shibasaki and co-workers). DDQ = 2,3-dichloro5,6-dicyano-l,4-benzoquinone.

Scheme 6.

Lewis acid and the oxygen atom of the phosphane oxide, respectively. With this catalyst system, N-allyl- and N-benzhydrylimines generally gave lower enantioselectivities. The addition of phenol was found to have a beneficial effect on the reaction rates. The JandaJELTMsupported bifunctional catalyst of 14 has also been shown by Shibasaki and co-workers to promote the Strecker-typereaction of aromatic and cc,p-unsaturatedimines in excellent yields with 83437% ee in the presence of tert-butanol (110%) [ l l ] .The reactivity of the JandaJELTM catalyst was comparable to the homogeneous analogue 14, and the catalyst could be recycled at least four times. Corey and Grogan recently developed a novel catalytic enantioselective Strecker reaction which utilized the readily available chiral Cz-symmetric guanidine 19 as a bifunctional catalyst [12]. The addition of hydrogen cyanide to achiral aromatic and aliphatic Nbenzhydrylimines 18 gave N-benzhydryl-cc-aminonitriles 20 (Scheme 7), which were readily converted to the corresponding amino acids with G N HC1. The use of N-benzyl- or Nfluorenylimines afforded products of poor enantiomeric purity.

Ph

R

~

A

N ph

+

HCN

H 19 (10 mol%) * PhMe. -40 "C. 20 h

18 Scheme 7.

CN

80-99%, 76-88% ee

Ph

RANAPh H 20

Asymmetric Strecker synthesis with chiral guanidine catalyst 19 (Corey and Crogan).

Kobayashi and co-workers employed the chiral zirconium binuclear catalyst 22 in the asymmetric Strecker-type synthesis of cc-aminonitriles 23 from aldimines 21 with tributyltin cyanide (Scheme 8) [ 131. Aldimines 21 were in turn derived from aliphatic, aromatic, and

Recent Developments in Catalytic Asymmetric Strecker-Type Reactions I 1 9 1

heterocyclic aldehydes. High levels of enantioselectivities were observed in these reactions. These u-aminonitriles could be converted to cc-amino acid derivatives by methylation of the phenolic hydroxyl group, followed by acid or base hydrolysis and oxidative cleavage with cerium ammonium nitrate. Furthermore, the catalytic asymmetric Strecker amino acid synthesis starting from achiral aldehydes, amines, and hydrogen cyanide using catalyst 22 has been achieved (Scheme 9). It is noted that 150 years after the first discovery of the Strecker reaction, a truly efficient three-component asymmetric version has been accomplished. While the use of tributyltin cyanide is suitable for laboratory-scale experiments, industrial applications are expected for a more benign three component catalytic asymmetric Strecker process using hydrogen cyanide.

22 (3 rnol%), Bu,SnCN, PhMelPhH (1:l)

-65"C + 0 "C, 12 h t

HN

55-98%,74-92% ee RXCN 21

23

L = N-rnethylirnidazole 22 Asymmetric Strecker synthesis with chiral zirconium binuclear catalyst 22 (Kobayashi and co-workers).

Scheme 8.

RCHO

+

Hop +

HZN

HCN

22 (1-5rnol%) CHZCIZ, -45"C

*

76-1OO%, 84-94% ee

Me

Hop HN

ACNMe

Three-component Strecker synthesis with chiral zirconium binuclear catalyst 22 (Kobayashi and co-workers).

Scheme 9.

Two other types of catalysts have been investigated for the enantioselective Strecker-type reactions. Chiral N-oxide catalyst 24 has been utilized in the trimethylsilyl cyanide promoted addition to aldimines to afford the corresponding aminonitriles with enantioselectivities up to 73% ee [14]. Electron-deficient aldimines were the best substrates, but unfortunately an equimolar amount of catalyst 24 was used in these reactions. The asymmetric Strecker addition of trimethylsilyl cyanide to a ketimine with titanium-based BINOL catalyst 25 gave fast conversions to quarternary aminonitriles with enantiomeric excesses to 59% 1151.

192

I

Recent Developments in Catalytic Asymmetric Strecker-Type Reactions

0

0

\ / MeMe 24

25

Several reports have employed a more traditional approach where the use of enantiopure chiral amino auxiliaries, that, after the successful Strecker reaction, can be chemically modified to yield the free amino acids. For example, Chakraborty and co-workers have reported the highly diastereoselective addition of trimethylsilyl cyanide to a variety of aphenylglycinol-derived benzaldimines [ 161. (S)-a-Methylbenzylamine has been used as a chiral auxiliary for the asymmetric Strecker reaction [ 171. (R)-Phenylglycinol has been utilized as a chiral auxiliary from the asymmetric Strecker reaction products of aldehydes in the synthesis of apdisubstituted amino acids [ 181. (R)- and (S)-2-Amino-2-phenylethanol were used as chiral auxiliaries in the synthesis of optically pure a-arylglycines [19]. Ohfune and co-workers have developed several methodologies involving an asymmetric version of the Strecker synthesis called asymmetric transferring Strecker synthesis (ATS) which has been successfully applied to the synthesis of optically active p-hydroxy-asubstituted wamino acids [20]. This technique was further applied toward the synthesis of the Corey intermediate of lactacystin [21]. This Highlight has shown that catalytic asymmetric Strecker-type reactions are possible but are still under active investigation for improvements and generalizations. Important areas for future study will include wider application of starting aldimine substrates, finer catalyst tuning, and of the simple conversion of a-aminonitriles to a-amino acid derivatives. More importantly, large-scale industrial applications of these methods to the production of optically active a-amino acids will be the ultimate goal of these investigations. References A. STRECKER, Ann. Chem. Pharm. 1850, 75, 27. a) R. M. WILLIAMS, Synthesis of Optically Active @-AminoAcids; Pergamon: Oxford, 1989; b) R. M. WILLIAMS, J. A. HENDRIX, Chem. Rev. 1992, 92, 889; c) R. 0. DUTHALER, Tetrahedron 1994, SO, 1539; d) M. AREND,Angew. Chem. Int. Ed. 1999, 38, 2873; Angew. Chem. 1999, I I I, 3047. a) M . S. IYER, K. M. GIGSTAD, N.D. M. LIPTON, ]. Am. Chem. SOC. NAMDEV, 1996, 118,4910; b) M. S. IYER,K. M. GIGSTAD,N. D. NAMDEV, M . LIPTON, Amino Acids 1996, I I, 259. M. S. SIGMAN, E. N. JACOBSEN, ]. Am. Chem. SOC.1998, 120, 5315.

M. S. SIGMAN, P.VACHAL,E. N. Chem. Int. Ed. 2000, 39, 1279; b) M. S. SIGMAN,E. N. JACOBSEN, J . Am. Chem. SOC.1998, 120, 4901. 6 P. VACHAL, E. N. J A C O B S E N , Org. Lett. 2000, 2, 867. 7 C. A. KRUEGER, K. W. KUNTZ, C. D. J . D. DZIERBA, W. G. WIRSCHUN, GLEASON, M. L. SNAPPER, A. H. HOVEYDA, I . Am. Chem. SOC.1999, 121, 4284. 8 J. R. PORTER, W. G. WIRSCHUN, K. W. KUNTZ,M. L. SNAPPER, A. H. HOVEYDA,]. Am. Chem. SOC.2000, 122, 2657. 9 N.S. JOSEPHSOHN, K. W. KUNTZ, M. L. SNAPPER, A. H . HOVEYDA,].Am. Chem. SOC.2001, 123, 11594. 5 a)

JACOBSEN, Angew.

References 10

11

12

13

14

15

a) M. TAKAMURA, Y. HAMASHIMA, H. USUDA,M. KANAI,M. SHIBASAKI, Angew. Chem. Int. Ed. 2000, 39, 1650 b) M. TAKAMURA,Y. HAMASHIMA, H.USUDA,M. KANAI,M. SHIBASAKI, Chem. Pharm. Bull. 2000. 48, 1586. H . NOGAMI,S. MATSUNAGA, M. KANAI, Tetrahedron Lett. 2001, 42, M. SHIBASAKI, 279. E. J. COREY,M. J. GROGAN,Org. Lett. 1999, I , 157. a) H. ISHITANI,S. KOMIYAMA, S. KOBAYASHI, Angew. Chem. lnt. Ed. 1998. 37, 3186; b) H. ISHITANI, S. KOMIYAMA, Y. HASEGAWA, S. KOBAYASHI, J . Am. Chem. SOC.2000, 122, 762; c) S. KOBAYASHI, H. ISHITANI,Chirality 2000, 12, 540. B. LIU, X. FENG,F. CHEN,G. ZHANG,X. CUI. Y. JIANG, Synlett 2001, 1551. J . J . BYRNE,M. CHAVAROT, P.-Y. CHAVANT, Y.V A L L ~ Tetrahedron E, Lett. 2000, 41, 873.

a) T. K. CHAKRABORIY, K. A. HUSSAIN, G. V. REDDY,Tetrahedron 1995, 51, 9179; b) T . K. CHAKRABORIY, G. V. REDDY,K. A. HUSSAIN,Tetrahedron Lett. 1991, 32, 7597. 17 R. WARMUTH, T . E. MUNSCH,R. A. STALKER, B. LI, A. B E A T ” , Tetrahedron 2001, 57, 6383. 18 a) D. MA, K. DING, Organic Lett. 2000, 2. 2515; b) K. DING,D. MA, Tetrahedron 2001, 57, 6361. 19 R. H.DAVE,B. D. HOSANGADI, Tetrahedron 1999, 55. 11295. 20 a) K. NAMBA,M. KAWASAKI, I. TAKADA,S. IWAMA,M. IZUMIDA,T. SHINADA, Y. OHFUNE,Tetrahedron Lett. 2001, 42, 3733; b) S.-H. MOON,Y. OHFUNE,J . Am. Chem. , SOC.1994, 116, 7405; c) Y. O H F U N EM. HORIKAWA, J . Syn. Org. Chem. Jpn. 1997, 55, 982. 21 S. IWAMA, W.-G. GAO,T. SHINADA, Y. OHFUNE,Synlett 2000, 1631. 16

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Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Highly Enantioselective or Not? - Chiral Monodentate Monophosphorus Ligands in the Asymmetric Hydrogenation lgor V. Kornarov and Armin Borner

The development was over before it had really begun - this was certainly true for the use of monodentate chiral monophosphorus ligands in rhodium( I) catalysts for enantioselective hydrogenation reactions. Initially everything seemed very promising. In 1965 Wilkinson and co-workers discovered that [ RhCl(PPh3)3] catalyzes the hydrogenation of olefins [ 11. Only a few months later Vaska and Rhodes reproted the use of trans-coordinated bis(monophosphane) iridium complexes in the reduction of alkenes [ 21.Monophosphane ligands were also prominent in other newly discovered metal catalysts, whereas cis-chelating diphosphanes, such as bis(diphenylphosphany1)-ethanegreatly reduced the rate of hydrogenation. Mechanistic studies showed that the dissociation of a phosphane from Wilkinson's complex is essential for the initiation of the catalytic cycle. For this reason bidentate diphosphane ligands were regarded as unsuitable since the chelate effect enhances their binding to the metal center [ 31. In 1968, the suggestion from Horner and co-workers to employ chiral monophosphanes for the enantioselective hydrogenation of prochiral olefins was both timely and logical [4].Two Monsanto chemists, Knowles and Sabacky, realized this idea only a few months later through the use of a rhodium complex with the P-chiral ligands PAMP (oanisylmethylphenyl-phosphane la) and CAMP (0-anisylcyclohexylmethyl-phosphane Ib) for the hydrogenation of atropic acid [S]. They generated hydratropic acid in a 15% optical yield. With this report itaconic acid (ItH2) began its career as a prochiral test substrate, it was reduced with a 3% optical yield. la: R' = o-MeO-C,H,,

R2 = Ph (PAMP)

b: R' = Ph, R2 = CpCeH11 (CAMP) c: R' = Ph, R2 = mCsH7

MeQ>R2 R

Still in the same year Horner et al., now showed that a prochiral styrene could be hydrogenated in up to 8% optical yield by using an in situ formed Rh' complex of rnetbylphenyln-propyl-phosphane (Ic) [ 61. Clearly the disappointingly low enantioselectivities were a deciding factor that greatly hindered the rapid adoption of the new hydrogenation method. In addition came the blinkered focus on P-chiral phosphane ligands, the synthesis of

Highly Enantioselective or Not?

which, at that time, was relatively complicated and did not always proceeded without racemization. AMe: R’ = Ph, R2 = NHAc, R3 = Me AH: R’ = Ph, R2 = NHAC, R3 = H aMe: R’ = H, R2 = NHAc, R3 = Me

aH: R’ = H, R2 = NHAc, R3 = H ItMe2:R1= H, R2 = CH2COOMe, R3 = Me

R

ItH2: R’ = H, R2 = CHpCOOH, R3 = H

The situation changed drastically in 1971 when Dang and Kagan reported the synthesis and use of (R,R)-DIOP, the first chiral diphosphane ligand (71. The corresponding Rh’ complex was used for the hydrogenation of (2)-N-acetylaminocinnamic acid (AH) and promptly gave an optical yield of 72% and almost quantitative conversion - all this with the rhodium complex of a diphosphane! Four requirements were central to the design of DIOP 1)maximum conformational rigidity of the ligand, 2) strong coordination to the metal center 3) use of a ligand with chemically equivalent phosphorus atoms (C2-symmetry) and 4) facile and short access [8].

PPh2

H (R,R)-DIOP

(S)-BINAP

(S,S)-DuPHOS

It remains for chemical historians to analyze the reasons in all their complexity for the change in the direction of research, from mono- to diphosphane ligands, that now followed. The simple preparation of enantiomerically pure (R,R)-DIOP from naturally occuring (+)tartaric acid, the typically short hydrogenation times with seven-membered ring chelates, and the, for that time, impressive enantioselectivities even for the reduction of other substrates no doubt played an important role and stimulated the search for similarly effective (diphosphane) ligands. In the following years huge numbers of this type of ligand were prepared and tested in particular in the normal-pressure hydrogenation of the substrates itaconic acid ( ItH2), N-acetylaminoacrylic acid (aH), and (2)-N-acetylaminocinnamic acid (AH), or their methylesters (ItMez, aMe, AMe)-substrates which are still the standards against which hydrogenation catalysts are measured [ 91. Milestones in the development of the diphosphane family include the establishment of BINAP [lo] and DuPHOS 1111. The potential offered by the chiral diphosphane complexes of ruthenium [ 121 and iridium [ 131 in hydrogenation was also recognized. In parallel inves-

I

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Highly Enantioselectiue or Not?

tigations into the mechanism of the enantioselective hydrogenation [ 141 and the influence of the ligand parameters on it were carried out [15]. Diphosphinites [lG] and more recently diphosphonites [ 171 and diphosphites [ 181 as well hybrid ligands [ 191 have also been shown to be similarly effective to diphosphanes. That in 1972 Knowles and co-workers achieved an optical yield of 90% in the hydrogenation of unsaturated N-acetylphenylalanine precursors with an Rh catalyst containing the monophosphane CAMP, was completely lost in the euphoria over the bidentate ligands [20]. In the subsequent 30 years as far as enantioselective hydrogenation is concerned monophosphorus ligands have been living in the shadows. Of course, every now and then chiral monophosphane ligands would be prepared, but usually only as intermediates on the road towards more efficient and hopefully unpatented diphosphoms ligands. Almost ironically it is Kagan, who with DIOP initiated the rapid development of the chelating diphosphane ligands and who has had such a lasting influence on this area, who recently in a retrospective over monophosphanes, with regard to enantioselective hydrogenation, came to the following conclusion: “We can expect that they [monophosphanes] will play a role of increasing importance in many aspects of organometallic catalysis. We hope that this review will encourage practitioners of asymmetric catalysis to consider the potential of chiral monodentate phosphines and to investigate this area which has been quite neglected till now” [21]. This impulse from such a respected source found an unexpectedly rapid response. In the last two years several groups have reported the use of monophosphorus ligands in highly enantioselective hydrogenation reactions, whereby different oxidation state of the trivalent phosphorus atom have received attention. Leading the way Guillen and Fiaud reported as early as 1999 a rhodium complex of 1,2,5-triphenylphospholane(2a), a monodentate species of the DuPHOS-type, that reduces AMe with 82% ee (Table 1) [22, 231. Incidentally this ligand is closely related to 2,s-dimethylphospholane 2b the compound that stands at the beginning of the development of the bidentate DuPHOS by Burk et al., but on ground of its

Tab. 1. Highly enantioselelective Rh-catalyzed hydrogenation with

monophosphorus ligands. Ligand

Substrate

ee [%]

Author(s), Ref:

2a

AMe aMe aMe ItMe2 ItMe2 AMe AH aMe aH ItH2 ItH2 ItH2 ItH2

82-92 (S)

Fiaud [22, 231 Orpen and Pringle [26] Reetz [ 271 Reetz [ 271 Reetz [28] de Vries and Feringa [ 301 de Vries and Feringa [ 301 de Vries and Feringa [ 301 de Vries and Feringa [ 301 de Vries and Feringa [ 301 Beller [ 311 Helmchen [ 321 Helmchen [ 321

(S)-3a (R)-3b (R)-3b (S)-3c (S)-3d (Sj-3d (S)-3d (S)-3d (S)-3d (574 5a

ent-5b

92 (4 94 ( S ) 90 ( R ) >99 ( S ) 98.4 ( R ) 97.1 (R) >99 ( R ) 98.7 (R) 96.6 (S) 90.0 (R) 92.6 (R) 96.0 (S)

Highly Enantioselective or Not?

poor enantioselectivity in hydrogenation reactions (maximum 60% ee) [24] has since only been used as a synthetic building block on the way to bidentate ligands [ 251. R

mo'

q P - P h

3a: R = ferf-Bu 3b: R = Et 3c: R = (R)-0-CH(Me)-Ph 3d: R = NMe2

R 2a: R = Ph b:R=Me

4

5a: R = iPr b: R = C y

In 2000 Orpen, Pringle, and co-workers attained the hydrogenation of aMe in 92% ee with the asymmetric monophosphonite 3a and thus a higher enantioselectivity than is possible with comparable Cz-symmetricdiphosphonite analogues [ 261. With this publication the widely accepted dominance of the bidentate diphosphorus ligands was questioned for the first time. Reetz and Sell showed in response that through the exchange to the tert-butyl group for an ethyl group (+3b) the enantioselectivity can be increased further [ 271. With the same catalyst ItMez was also hydrogenated with a respectable 90% ee. However, in spite of this a related diphosphonite ligand when tested delivered >99% ee. The old rule that chelating diphosphorus ligands are superior still appeared to hold. A clear tie in regard to performance, with enantioselectivities that could not be topped, was achieved with the use of monodentate binaphtholphosphites and phosphoramidites. Reetz and Mehler prepared the monophosphite 3c [28]. The corresponding catalyst induces >99% ee in the hydrogenation of ItMez. Particularly noteworthy is the high substrate:rhodium ratio of up to 5000:1, that still guarantees complete conversion in 20 h under normal pressure. Surprisingly the configuration of the chiral carbon atom of the benzyl ether does not play any kind of role. The enantioselectivity of this type of ligands is dominated by the chiral binaphthyl unit, in complete contrast to other P substituents, for example, sterically demanding aryloxy groups, that have a very significant influence on the enantioselectivity and conversion. Phosphoramidites, a ligand class that has only recently been introduced into asymmetric hydrogenation, in the form of hybrid chelate ligands [291, induce excellent enantioselectivity as monodentate ligands. Thus de Vries, Feringa, and co-workers could reduce standard substrates in >96% ee with a rhodium complex based upon the binaphtholphosphoramidite 3d, once the solvent and reaction temperature had been optimized [ 301.

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Highly Enantioselective or Not?

A

B

Fig. 1. Monodentate (A) and chelating (B) binaphthyl ligands on a metal center and their effect on the stereoselective occupation of the squares.

The high stereodiscriminating ability of the binaphthyl backbone was also shown by Beller et al. with the relevant phosphane (S)-4 in hand [31]. Thus, up to 90% ee were achived in the hydrogenation of AMe in toluene as solvent. A breakthrough in the design of a new class of ligands was achieved by Helmchen and co-workes in 2002 [32]. They found that oxaphosphinanes like Sa,b can provide up to 96% ee in the Rh-catalyzed hydrogenation of ItH2. Moreover, this paper describes the first example that even secondary phosphanes can be successfully employed as ligands in enantioselective catalysis. I t is noticeable that most monodentate ligands that induce a high enantioselectivity are phosphorus derivatives of binaphthol. Based on the crystal structure of a Pt” complex with monophosphonite ligands Orpen and Pringle have proposed a plausible explanation that could be helpful in the development of other selective monophosphorus ligands [26]. Through the cis coordination both the sterically demanding monophosphonite ligands take up an exceptionally stable configuration around the metal center, through which rotation about the P - 0 bond is reduced. In this conformation the two biaryl fragments point out of the plane of the projection in what is described as edge-on arrangement. In a virtual coordination system two diagonally opposing squares are occupied (Figure 1 A). The squares at the top left and bottom right are not effectively occupied, because of the planar arrangement of the two phenyl groups in the plane of the projection (face-on). From investigations with chelating bis(diary1)phosphorus ligand complexes it is known that such an alternating edge/ face arrangement [ 331 can support the diastereo-differentiating coordination of a prochiral substrate through the minimization of repulsive interactions [ 341. In contrast, by the cis coordination of the diphosphonite ligands the rotamer stabilized is that in which the biaryl units are in the face-on orientation; none of the squares is favored (Figure 1 B). Thus the chances of diastereomeric recognition of the prochiral substrate are greatly reduced. On the basic of the model by Pringle and Orpen [ 2 G ] and supported by first semiempirical calculations from de Vries and Feringa [30] it is clear that for the mechanism of chiral transfer in asymmetric hydrogenation, mono- and diphosphorus ligands do not necessarily fundamentally differ [ 35-37]. The requirement originally laid down by Kagan, that the catalyst must be conformationally rigid, is clearly also achievable with two appropriate monodentate monophosphorus ligands. As a consequence of these results the strategic decision as to whether one should favor mono- or diphosphorus ligands comes down to the principle question asked of every asymmetric catalyst: is it highly enantioselective or not?

References

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Clearly the potential that chiral monophosphorus ligands have in hydrogenation reactions is far from exhausted, a hypothesis that is supported by the well known and excellent results from other asymmetric catalytic reactions [21]. Naturally the demands for the design of monophosphorus ligands that effect high enantioselectivity are higher, something that stimulate the search for new principles for the selective stabilization of diastereomeric catalysis intermediates, for example, by secondary interactions between the ligand and the metal or substrate [38]. The synthesis of monophosphorus ligands is often simpler than that of diphosphorus compounds, which is justification enough to look closer at these types of ligands that in the past were often undervalued. References 1

J. F. YOUNG, J. A. OSBORNE, F. A. J A R D I N E , G. WILKINSON, ]. Chem. Soc.; Chem. Commun. 1965, 131-132.

2 L. VASKA, R. E. RHODES, ]. Am. Chem. SOC.

1965, 87,4970-4971. 3 A highly informative review over the

initial problems associated with the use of diphosphane ligands in homogeneous catalyst: P. W. N. M. VAN LEEUWEN,P. C. J. KRAMER,J. N. H. REEK,P. DIERKES, Chem Rev. 2000, 100, 2741. 4 L. HORNER, H. BUTHE, H. SIEGEL, Tetrahedron Lett. 1968, 4023-4026. 5 W. S. KNOWLES, M. J. SABACKY,]. Chem. Soc.; Chem. Commun. 1968, 1445-1446. 6 L. HORNER, H. SIEGEL, H. BUTHE, Angmv. Chem. 1968, 80, 1034-1035; Angew. Chem. Int. Ed. Engl. 1968, 7, 942-943. 7 T. P. DANG,H. B. KAGAN, ]. Chem. Soc.; Chem. Commun. 1971, 481. 8 H. B. KAGAN. T. P. DANG,]. Am. Chem. SOC.1972, 94, 6429-6433. 9 H. BRUNNER, W. ZETTLMEIER, Handbook of Enantioselectiue Catalysis with Transition Metal Compounds, Vol. 1, VCH, Weinheim, 1993; U. NAGEL, J. ALBRECHT, Top. Catal. 1998, 5, 3-23. 10 A. MIYASHITA, A. YASUDA.H. TAKAYA, K. TORIUMI, T. ITO,T. SOUCHI,R. NOYORI,/. Am. Chem. SOC.1980, 102, 7932-7934. 11 M. J. BuRK,J.Am. Chem. SOC.1991, 113, 8518-8519. 12 R. G. BALL, B. R. JAMES, J. TROTTER, D. K. DANG,]. Chem. SOC.;Chem. Commun. 1979, 460-461; J,-P. G E N ~inT Aduanced Asym-metric Synthesis (Ed.: G. R. STEPHENSON), Chapman & Hall, London, 1996, pp. 146-180.

N. C. CHAN,J. A. OSBORNE!].Am. Chem. SOC.1990, 112, 9400-9401; F. SPINDLER, B. PUGIN,H.-U. BLASER, Angew. Chem. 1990, 102, 561-562; Angew. Chem. Int. Ed. Engl. 1990, 29, 558559. 14 A. S. C. CHAN,J. J. PLUTH,J. HALPERN, ]. Am. Chem. SOC.1980, 102, 5952-5954; J. M. BROWN,P. A. CHALONER,]. Chem. SOC.; Chem. Commun. 1980, 344-346; J. M. BROWNin Comprehensive Asymmetric Catalysis (Eds.: E. N. JACOBSEN, A. PFALTZ, H. YAMAMOTO), Springer, Berlin, 1999, pp. 121-182. 15 K. INOGUCHI, S. SAKURABA, K. ACHIWA, Synlett 1992, 169-178; T. V. RAJANBABU, T. A. AYERS,A. L. CASALNUOVO,]. Am. Chem. SOC.1994, 116,4101-4102. 16 R. SELKE, ]. Organomet. Chem. 1989, 370, 249-256. 17 M. T. REETZ, A. GOSBERG, R. GODDARD, S.-H. KYUNG, Chem. Commun. 1998, 2077-2078. 18 M. T. REETZ,T. NEUGEBAUER, Angew. Chm. 1999, 111, 134-136; Angew. Chem. Int. Ed. 1999, 38, 179-181. 19 A collection of ligands can be found in: H. BRUNNER, W. ZETTLMEIER, Handbook of Enantioselectiue Catalysis with Transition Metal Compounds, Vol. 11, VCH, Weinheim, 1993; J. HOLZ,M. QUIRMBACH, A. BO RN E R,Synthesis 1997, 983-1006; M. A. OHFF,J. HOLZ,M. QUIRMBACH, BORNER, Synthesis 1998, 1391-1415. 20 W. KNOWLES,M. J. SABACKY, B. D. VINEYARD,]. Chem. Soc.; Chem. Commun. 1972, 10-11. 21 F. LAGASSE, H. B. KAGAN, Chem. Pharm. Bull. 2000, 48, 315-324.

13 Y.

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24 25

26

27 28

29

30

31

32

33

F. GUILLEN, J.-C. FIAUD,Tetrahedron Lett. 1999, 40, 2939-2942. By optimizing the reaction conditions values of up 92% ee are possible: F. GUILLEN, Dissertation, Universitb ParisSud, 1999. M. J. BURK,J. E. FEASTER, R. L. HARLOW, Tetrahedron: Asymmetry 1991, 2, 569-592. M. J. BURK,A. PIZZANO,J. A. MARTIN, L. M. LIABLE-SANDS, A. L. RHEINGOLD, Organometallics 2000, 19, 250-260. C. CLAVER,E. FERNANDEZ, A. GILLON,K. HESLOP,D. J. HYEIT, A. MARTORELL, A. G. O R P E NP. , G. PRINGLE,Chem. Commun. 2000,961-962. M. T. REETZ,T. SELL,Tetrahedron Lett. 2000, 41, 6333-6336. M. T. REETZ,G. MEHLER,Angew. Chem. 2000, I1 2, 4047-4049; Angew. Chem. Int. Ed. 2000, 39, 3889-3890. G. FRANCIO,F. FARAONE, W. LEITNER, Angew. Chem. 2000, 112, 1486-1488; Angew. Chem. Int. Ed. 2000, 39, 14281430. M. VAN D E N BERG,A. I. MINNAARD, E. P. SCHUDDE, J. VAN ESCH,A. H . M. D E VRIES,J. G. D E VRIES;B. L. FERINGA, ]. Am. Chem. SOL.2000, 122, 11539-11540. K. JUNGE,G. OEHME,A. MONSEES, T. RIERMEIER, U. DINGERDISSEN, M. BELLER, unpublished results. M. OSTERMEIER. 1. PRIER, G . HELMCHEN, Angew. Chem. 2002, 114, 625-628; Angew. Chem. Int. Ed. 2002, 41, 612-614. B. D. VINEYARD, W. S. KNOWLES, M. J. SABACKY, G. L. BACHMANN, D. J.

34

35

36

37

38

WEINKAUFF, J . Am. Chem. SOC. 1977, 99, 5946-5952. H. BRUNNER, A. WINTER, I. BREU,]. Organomet. Chem. 1998, 553,285-306; C. R. LANDIS,S. FELDGUS, Angew. Chem. 2000, 112, 2985-2988; Angew. Chem. Int. Ed. 2000, 39, 2863-2866, and refs. therein. That n-stacking effects, such as those recently reported for a Pdbis(monophosphane) complex, contribute to the conformer stabilization cannot be ruled out ( H . BRUNNER, I. DEML,W. DIRNBERGER, B. NUBER,W. REIRER,Eur.]. Inorg. Chem. 1998, 43-54). Unfortunately, the square model does not hold for a [ PtC12(Sa)] complex, where significant distortion of the oxaphosphinane ringes were observed. Ref. [ 321. In contrast to the hydrogenation measurements reported in ref. [26, 27, 301, Reetz et al. in ref. [28] used predominantely an Rh:ligand ratio of 1:1, although with a 1:2 ratio no significantly different enantioselectivity was observed. Unpublished NMR spectroscopy experiments indicate that 1:2 precatalyst complexes are formed in the in situ reaction of [ Rh(cod)~]BF4(cod = 1,5-cyclooctadiene) with the monophosphites. In addition the hydrogenation reactions show a strong (positive) nonlinear effect, an indication that two monophosphite groups are also involved in the transition state. (M. T. REETZ,personal communication). Review see: A. BORNER,Eur. ]. Inorg. Chem. 2001, 327-337.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co I201

Improving Enantioselective Fluorination Reactions: Chiral N-Fluoro Ammonium Salts and Transition Metal Catalysts

Within the still growing area of enantiomerically pure compounds, chiral fluorinated molecules are gathering momentum due to the unique properties of the carbon-fluorine bond, and the importance of the fluorine moiety in molecules of pharmaceutical and biological interest is undisputed [ 11. Among all the asymmetric processes towards organofluoro compounds, the direct synthesis of fluorinated stereogenic centres, avoiding a resolution procedure [ 21, remains of special challenge. Basically, two different routes are conceivable for their asymmetric construction: 1) nucleophilic substitution reaction with a fluoride anion and 2) electrophilic addition of fluoronium cations to activated or masked carbanions. First attempts on enantioselective nucleophilic fluorination date back to the pioneering work of Hann and Sampson [3]. In an ambitious dehydroxylation/fluorination sequence the authors reacted a racemic atrimethylsiloxy ester with a half molar equivalent of an enantiomerically pure proline-derived aminofluorosulphurane in hope to achieve a kinetic resolution. Unfortunately, the fluorinated product was obtained without significant enantiomeric excess. Ever since, routes towards fluorinated stereogenic centres have relied on electrophilic fluorine sources for substitution reactions [4].This caused the development of a variety of suitable achiral N-F fluorinating reagents [ 51 and their exploitation in diastereoselective fluorinations which are characterised by efficient substrate control and reasonably high diastereoselectivities [6a]. Important contributions were made by Davis [ 61, Enders [ 71 and others [4,81. In an elegant approach, Enders has employed enantiopure a-silylketones that upon regioselective deprotonation and fluorination with N-fluorobenzosulfonimide 1 yield the corresponding mono-fluorinated compounds in good to high diastereomeric excesses. For example, acyclic ketone 2 can be converted into a-fluorinated 3 which was purified to 96% de. The geometry of the intermediary enolate could be controlled by the use of either LDA or LHMDS as base, and the removal of the TBDMS-group was achieved without racemization to yield 4 (96% ee). Most importantly, this protocol allows for the controlled synthesis of secondary stereogenic centers [ 7b]. At about the same time of the work on diastereoselective fluorination, chiral non-racemic N-fluoro compounds for direct enantioselective fluorination of C-H acidic substrates were developed. Initial work on reagent control by Differding and Lang, who introduced chiral N-fluoro

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aS-f7Q q,o o,,o 1

3

2

4

Scheme 1. Substrate mediated dia- and enantioselective fluorination with an achiral quaternary N-F ammonium salt.

sultam 5a [9], was followed by modified structures 5b,c [lo] as well as development of All these chiral reagents require a related compounds such as 6 [ 111 and 7 [ 121 [Fig. (l)]. sulfonamido group for activation of the N-F bond. In situ generated metallated enolates serve as substrates and the enantiomeric excesses generally reach satisfying values of up to 80%. However, preparation of these reagents is hampered by tiresome multi-step synthesis and use of hazardous fluorine sources such as FClO3 or F2 itself. Recently, two groups have now described the preparation and application of enantiopure N-fluoro ammonium salts from cinchona alkaloids [Fig. (2)]. In an elegant contribu-

5a:R=H b: R = CI c: R = OCH3 Fig. 1.

7 (R' = H, OAC; R" = CH3, pTol)

6

Achiral neutral N-fluoro reagents for electrophilic fluorination

BF4-

CH2CI OCH3 &OCH3 8

9

10

Fig. 2. Reagents for the stoichiometric enantioselective fluorination.

11

Improving Enantioselective Fluorination Reactions

tion, Takeuchi and Shibata used an in situ protocol to generate the active fluorinating species from neutral 9 and 10, respectively, and Selectfluor 8 [13, 141.Independently, Cahard described the synthesis of preformed cinchona alkaloid ammonium salts such as 11 [15]. While preliminary I9F nmr studies had revealed that the F+ transfer from Selectfluor onto the cinchona alkaloid is seemingly fast and irreversibe [ 13a], both groups have recently characterised some of these compounds in the solid state, thereby clearly establishing the existance of a N-F bond [13b, 16, 171. Using the conventional in situ generation of metallated enolates, 11 could be employed for enantioselective fluorination of a-methyl tetralone 12, however, two equivalents of base were necessary to deprotonate the acidic hydroxyl functionality of 11 in order to prevent competitive enolate protonation [Scheme 2, eq. (I)]. Unlike the case for unreactive neutral 5-7, preformed silylenolether 14 was now cleanly fluorinated by both the synthesised reagent 11 and the combination of 8 and 9 showing that the cationic nature of the new reagents results in higher fluorination power [eq. (2)]. However, since in the present systems both rate and enantioselectivity appear to be highly dependent on the reaction temperature, a precise comparison of the results is difficult. Under otherwise unchanged conditions, Takeuchi observed an increase in ee for five-membered substrates such as 16 [eq. (3)] and further successful examples include P-keto esters (up to 80% ee) and acyclic P-cyano esters such as 18 [eq. (4)].For the latter case, high enantioselectivity required preformation of the ammonium reagent from 10 and 8. Recent additional work by Shibata [13b] has shown that related compounds such as oxindoles 20 can also be employed as substrates. Fluorinated oxindole 22 could be obtained with up to 82% ee when the preformed N-F ammonium salt of the Sharpless ligand (DHQD)*PYR(21) was used. Based on their fluorination protocol, Cahard and co-workers have elaborated a convenient synthesis of a-fluoro-a-phenylglycinderivatives [ 181. For example, upon reaction with reagent 24 racemic nitrile 23 was converted into the fluorinated derivative 25 with 94% enantiomeric excess. The corresponding ester derivatives of 23 gave rise to somewhat lower ees. This difference was contributed to the fact that a-lithiated nitriles can be in equilibrium with axialchiral lithio ketene imines of low racemization barriers thus leading to a potential dynamic kinetic resolution. Obviously, the switch from neutral N-F compounds to N-F ammonium salts had not only a strong beneficial effect on reactivity but the commercial availability of both Selectfluor and cinchona alkaloids also ensures easy accessability of the chiral reagents. Still, from an economical point of view a catalytic version of the process would certainly be desirable and, based on recent catalytic variants by Lectka for bromination and chlorination [ 191, should be within reach. A first attempt to realize catalytic asymmetric fluorination under phase transfer conditions goes back to attempts by Cahard et al. [20] Quaternary ammonium salts of cinchona alkaloids were used as catalysts in the presence of TosNFtBu as F-source and 23 was employed as substrate. Unfortunately, enantioselectivities remained rather low. Very recently, Kim and Park have described a closely related system (Scheme 4) [21]. Here, the catalyst was ammonium compound 27, and 1 served as F-source. Under optimized conditions, methyl indanone carboxylate 26 was fluorinated with up to 68% ee. Within the context of asymmetric synthesis, it must be intriguing that no use of chiral

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13 80% cy, 56% ee

12

A: 11, NaOH, THF, -6OOC

14

B: 918, CH3CN, -2OOC

15 A: 93% cy, 61% ee

B: 93% cy, 54% ee

918, CHsCN,

-2OOC 16

17 99% cy, 89% ee F ,CN

d C O & H s

CH2C12, 1018, CHsCN, -6OOC

18

d C /O z C H 3

(4)

19 80% cy, 87% ee

21, CHaCN,

(5)

CH2C12, -6OOC H

H

20

22

H3C0

OCH3

21 Scheme 2. Representative enantioselective fluorinations with chiral quaternary N.F ammonium salts. The absolute configuration of product 22 is unknown.

Improving Enantioselective Fluorination Reactions

w

J C

BF4-H&?~~~3

0 2 LiHMDS, THF, 24, -78%

OCH3

-

$CNo

23

/

25

24

56% cy, 94% ee Scheme 3. Synthesis o f fluorinated amino acids via enantioselective fluorination. The absolute configuration of the product i s unknown.

27

27 (10 mol%)/ 1, COpCH3

&F

toluene, rt 26

CO2CH3 28

92% cy, 69% ee Scheme 4. Enantioselective fluorination via asymmetric phase-transfer reaction. The absolute configuration of the product is unknown.

non-racemic metal complexes for fluorination reactions had been reported. Given the extreme success of asymmetric metal-mediated and -catalysed processes [ 221, such an approach must appear highly attractive. Bmns and Haufe have described the first examples of a transition metal complex mediated asymmetric ring opening (ARO) of both rneso- and racemic epoxides via formal hydrofluorination [23]. Initial attempts with chiral Eu"' complexes led to very low asymmetric induction. Opening of cyclohexene oxide 30 with potassium hydrogendifluoride in the presence of 18-crown4 and a stoichiometric amount of Jacobsens chiral chromium salen complex 29 [ 24a] finally yielded two products 31 and 32 in a 89:11 ratio and 92% combined yield, the desired product 31 being formed with 55% ee. Limiting 29 to a catalytic amount of 10 mol% led to an increase in the ratio of 31, however, with the enantiomeric excess dropping to 11%(Scheme 5).

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29

29, KHFp,

30

*

18-crown-6, DMF A: 100 mol% 29 B: 10mo1°h29

31

32

55% ee 11% ee

First nucleophilic enantioselective epoxide opening with enantiopure transition metal Lewis acid 29. Scheme 5.

In the stoichiometric reaction the low extend to which chloride promoted ring opening occurs is noteworthy. In a stoichiometric ARO of cyclohexene oxide 30 with 29 and TMSN3, Jacobsen reported complete C1 incorporation [ 24a] indicating that under the reaction conditions no anion exchange takes place at the metal complex prior to ring opening. Since in the present case C1- displays a much higher nucleophilicity than FF, an identical product distribution should have been expected. The fact, however, that this is not the case, leads to the conclusion that the Cr complex acts as a conventional Lewis acid that activates the epoxide for ARO by fluoride. The amount of C1 incorporation is likely to be the consequence of competing ring opening by free chloride generated under the reaction conditions. One can almost assume that the present catalytic system cannot be operating by the cooperative mechanism [24a, b] that has been so successful in the related AROs described by Jacobsen [ 24~1.Furthermore, the dramatic drop in enantioselectivity in the catalytic reaction suggests that the fluoride source does not allow for rapid release of the catalyst after the ARO has occurred thus resulting in uncatalysed unselective ring opening. Final conclusions will have to await further detailed mechanistic investigation [ 251. A first real breakthrough in transition metal catalysed fluorination has recently been achieved by Hintermann and Togni [26]. In their work, monosubstituted 8-keto esters such as 34 were chosen as starting materials and focus was made on Lewis acid activation. It was anticipated that the necessary enolisation of the P-keto esters would be accelerated by catalytic amounts of metal complexes. From kinetic screening, complexes based on Ti emerged as the most suitable catalysts and TADDOL-modified [27] Ti complexes 33a and 331, as the best ones in terms of asymmetric induction. Isolation of these Ti complexes, which during course of this work [2G] was achieved for the first time, was necessary to guarantee reproducibility and enantioselectivity. In the presence of 5 mol% of catalyst and a slight

Improving Enadoselective Fluorination Reactions

excess of the fluorinating agent 8 conversion to the fluorinated products such as 35 occurred smoothly in acetonitrile at room temperature (Scheme 6). Not surprisingly, the sterically more elaborated complex 33b gave rise to higher enantioselectivities (62-90% ee for given examples vs. 28-59% ee with 33a) but it is interesting to see that it also represents the more reactive catalyst: for example, in the presence of 33b the reaction time for conversion of 34 is 20 min while it is 2 h with 33a!

33 a) R = Ph, L2 = ( C H Z O C H ~ ) ~ b) R = 1-Nph, L2 = 2 NCCH3

8 (1 16 mol%)

OCHPh2

34

33 CHSCN, b (5 mol%) RT, * 20 min

CzH5VOCHPh2

(6)

35 81 'Yo ee

Scheme 6. First enantioselective electrophilic fluorination reaction catalysed by enantiopure Ti-TADDOLates 33a,b. The absolute configuration o f the product is unknown.

Current understanding of the reaction suggests that an unprecedented mechanism is operating. Unlike in classical Lewis acid catalysed reactions [ 281, the metal complex does not activate the carbonyl moiety but is understood to enhance the degree of enolisation and thus create the necessary nucleophilic enol structure for reaction with the fluorinating agent [ 291. Regarding enantioselectivities, this new catalytic fluorination can readily compete with the results from stoichiometric reactions with chiral N-F compounds, and the fact that both the TADDOL ligands and the fluorine source Selectfluor are commercially available makes it the most convenient one presently at hand. Since the reaction is so far limited to B-keto esters, it will be interesting to see whether this catalyst system can be transferred successfully to other substrate classes. Clearly the enantioselective synthesis of fluorinated stereogenic centres other than quaternary remains a huge challenge. Future work could also aim to combine the two novel fluorination procedures. Especially where reaction rate is concerned, the combined use of (achiral) transition metal catalyst and substoichiometric amounts of cinchona alkaloids might give rise to successful complementary catalytic systems. An interesting complimentary approach has been devised by Togni and Mezzetti who reported on Ru-F complexes for a catalytic fluorination by exchanging existing halide groups for fluoride [30]. Use of a chiral nonracemic Ru" catalyst led to initially moderate asym-

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metric induction, however, at higher conversions the enantiomeric excess of the fluorinated product dropped significantly. This implies that a desired kinetic resolution might only be involved during the early stages of the reaction. To summarise, the development of novel enantioselective fluorination methods with the aid of either chiral N-fluoro ammonium salts or transition metal catalysts has established truely practical routes towards chiral fluorinated compounds. Despite the current mechanistic uncertaincies it appears that a door has been opened for exciting and promising further development of asymmetric (catalytic) fluorination reactions in the near future [ 31, 321. References

a) Enantiocontrolled Synthesis of FluoroOrganic Compounds (Ed.: V. A. SOLOSHONOK), Wiley, New York, 1999; b) Asymmetric Fluoroorganic Chemistry, Applications, and Future Directions, P. V. RAMACHANDRAN, ACS Symp. Ser. 746, Washington, 2000. 2 Myers has reported on interesting fluorinated HIV protease inhibitor analogues. However, their stereoselective synthesis as relying on the respective enantiopure fluorinated building blocks derived from resolution: A. G. MYERS,J. K. BARBAY, B. ZHONG,/. Am. Chem. SOC. 2001, 123, 7207-7219. 3 G . L. H A N N ,P. SAMPSON, /. Chem. SOC., Chem. Commun. 1989, 1650-1651. 4 S. D. TAYLOR, C. C. KOTORIS,G. H U M , Tetrahedron 1999, 55, 12431-12477. 5 G. S. LAL, G . P. PEZ. R. G. SYVRET, Chem. Rev. 199G, 96, 1737-1755. 6 a) F. A. DAVIS,P. V. N. KAsu, in Org. Prep. Proced. Int. 1999, 31, 125-143; see also: b) F. A. DAVIS,P. V. N. KAsu, Tetrahedron Lett. 1998, 39, 6135-6138; c) F. A. DAVIS, W. HAN, Tetrahedron Lett. 1992, 33, 11531156; d) F. A. DAVIS,R. E. REDDY,Tetrahedron Asymmetry 1994, 5,955-960. 7 a) D. ENDERS,M. POTTHOFF,G. RAABE,J. RUNSINK,Angew. Chem. 1997, 109, 24542456; Angew. Chem. Int. Ed. Engl. 1997, 36, 2362-2364; b) D. ENDERS,S. FAURE,M. POITHOFF,J . RUNSINK,Synthesis 2001, 2307-2319. 8 J. J. MCATEE,R. F. SCHINAZI, D. C. LIOTTA,/. Org. Chem. 1998, 63, 2161-2167. 9 E. DIFFERDING, R. W. LANG,Tetrahedron Lett. 1988, 29, 6087-6090. 10 a) F. A. DAVIS,P. ZHOU,C. K. MURPHY, Tetrahedron Lett. 1993, 34, 3971-3974; 1

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18

19

b) F. A. DAVIS,P. ZHOU,C. K. MURPHY, G. SUNDARABABU, H . QI, W. H A N ,R. M. PRZESLAWSKI, B.-C. CHEN,P. J. CAROLL, ]. Org. Chem. 1998, 63,2273-2280,9604. Y. TAKEUCHI, T. SUZUKI,A. SATOH,T. SHIRAGAMI, N. SHIBATA,].Org. Chem. 1999, 64, 5708-5711. a) Y. TAKEUCHI, A. SATOH,T. SUZUKI, A. KAMEDA, M. DOHRIN,T. SATOH,T. KOIZUMI? K. L. KIRK,Chem. Pharrn. Bull. 1997, 45, 1085-1088; b) See also: 2. LIU, N. SHIBATA,Y. T A K E U C H I ,Org. ~ . Chem. 2000, 65, 7583-7587 and cited literature. a) N. SHIBATA,E. SUZUKI,Y. TAKEUCHI,]. Am. Chem. SOC.2000, 122; 10728-10729. b) N. SHIBATA,E. SUZUKI,T. ASAHI, M. SHIRO,/. Am. Chem. SOC. 2001, 123, 70017009. a) Selectfluor is l-chloromethyl-4-fluoro-1,4diazoniabicyclo[ 2.2.2loctane bis{tetrafluoroborate} and is also known under the abbreviation F-TEDA; b) R. E. BANKS,/. Fluorine Chem. 1998, 87, 1-17. D. CAHARD,C. AUDOUARD, J.-C. PLAQUEVENT, N. ROQUES,Org. Lett. 2000, 2, 3699-3701. For a first isolation of the chiral ammonium salt of quinuclidine: M. ABDUL-GHANI, R. E. BANKS,M. K. BESHEESH, I. SHARIF,R. G . SYVRET, /. Fluorine Chem. 1995, 73, 255-257. D. CAHARD,C. AUDOUARD, J.-C. PLAQUEVENT, L. TOUPET,N. ROQUES, Tetrahedron Lett. 2001, 42, 1867-1869. B. MOHAR,J. BAUDOUX,J.-C. PIAQUEVENT, D. CAHARD,Angew. Chem. 2001, 113, 4339-4341; Angew. Chem. Int. Ed. Engl. 1997, 40, 4214-4216. Lectka has recently described an impressive asymmetric wchlorination

References I 2 0 9

20

21 22

23 24

25

reaction (up to 99% ee) in which the stereoselective step relies on only a catalytic amount of cinchona alkaloid: H. WACK,A. E. TAGGI,A. M. HAFEZ,W. J. DRURY 111, T. LECTKA,1.Am. Chem. Soc. 2001, 123, 1531-1532. D. CAHARD, C. AUDOUARD, J. BAUDOUX,B. MOHAR,J.-C. PIAQUEVENT, contribution A0081 at the ECSOC-4. See: http:// www.mdpi.org/ecsoc-4. htm D. Y. KIM, E. J. PARK,Organic Lett. 2002, 4, 545-547. a) R. NOYORI, Asymmetric Catalysis in Organic Synthesis, Wiley, New York, 1994; b) Transition Metalsfor Organic Synthesis (Eds.: M. BELLER,C. BOLM),Wiley-VCH. Weinheim, 1998; c) Catalytic Asymmetric Synthesis (Ed.: I. OJIMA), 2nd Edition, Wiley-VCH, New York, 2000; d) Comprehensive Asymmetric Catalysis (Eds.: E. N. JACOBSEN; A. PFALTZ; H. YAMAMOTO), Springer, Berlin, 1999. S. BRUNS,G. HAUFE, J . Fluorine Chem. 2000, 104, 247-254. a) E. N. JACOBSEN, Acc. Chem. Res. 2000, 33, 421-431; b) R. G. KONSLER,J. KARL, E. N. ]ACOBSEN,J. Am. Chem. SOC. 1998, 129, 10780-10781; c) Apparently, ARO with other halide sources does not proceed with high enantioselectivity neither (ref 24a). a) Formation of competing nucleophiles might be prevented by use offluorinated chiral Lewis acid catalysts; b) B. L.

PAGENKOPF, E. N. CARREIRA, Chem. Eur.1. 1999, 5, 3437-3442. 26 L. HINTERMANN, A. TOGNI,Angew. Chem. 2000, 112, 4530-4533. Angew. Chem. Int. Ed. 2000, 39,4359-4362. 27 TADDOL is 2,2-dimethyl-cc,cc.cc',cc'-tetraaryl28

29

30

31

32

1,3-dioxolane-4,5-dimethanol. a) S. SHAMBAYATI, S. L. SCHREIBER, J. A. RAGAU,R. F. STANDAERT in Strategies and Tactics in Organic Synthesis (Ed.: T. LINDBERG),Academic Press, San Diego, 1991, Vol. 3, 417-461; b) Lewis Acids in Organic Synthesis (Ed.: H. YAMAMOTO), Wiley-VCH, Weinheim, 2000. The related reactions regarding chlorination and bromination have also been A. TOGNI, described: L. HINTERMANN, Helu. China. Acta 2000, 83, 2425-2435. a) P. BARTHAZY, A. TOGNI,A. MEZZETTI, Organometallics 2001, 20, 3472-3477; b) P. BARTHAZY,R. M. STOOP,M. WOHRLE,A. TOGNI,A. MEZZETTI, Organometallics 2000, 19, 2844-2852. For a complementary approach of enantioselective enofisation by aid of chiral amide base and subsequent fluorination witch achiral8: A. ARMSTRONG, B. R. HAYTER,Chem. Commun. 1998, 621-622. For a complementary approach of asymmetric photodeconjugation to yield secondary stereogenic centers containing fluorine: F. BARGIGGIA,S. Dos SANTOS, 0. PIVA,Synthesis 2002, 427-437.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Catalytic Asymmetric Olefin Metathesis Amir H. Hoveyda and Richard R. Schrock Introduction

Rarely has a class of transformations so strongly influenced the field of organic synthesis as catalytic olefin metathesis has in the past decade [I]. Whether it is in the context of development of new methods or as part of total synthesis of a complex molecule, these catalytic reactions have been utilized to prepare a wide range of compounds, including small, medium and large rings [2]. Only a few years ago, an alkene metathesis step was viewed as a daring application of a relatively unknown technology in a multi-step synthesis. Today, metathesis-based approaches are employed with such regularity that their use is considered routine. With regard to the synthesis of optically pure materials, however, catalytic olefin metathesis has largely served a supporting role. In cases where ringclosing metathesis (RCM) is called for, an already optically pure diene is treated with an achiral metal catalyst to deliver a non-racemic cyclic unsaturated product [ 2a-c, 2e-f, 2h]. Alternatively, a racemic product obtained by metathesis may be catalytically resolved [2b]. Optically enriched cyclic alkenes are similarly employed in instances where ring-opening metathesis (ROM) is needed [Id, 2gl. Although such strategies have led to a number of notable and impressive accomplishments in asymmetric synthesis, some of the unique attributes of catalytic olefin metathesis can only be realized if chiral optically pure catalysts for olefin metathesis are available. This claim is tied directly to the fact that one of the most useful characteristics of metathetic processes is their ability to promote efficient skeletal rearrangements: simple achiral or racemic substrates may be transformed into complex non-racemic organic molecules by a single stroke. In numerous instances, products that are rendered readily available by a chiral metathesis catalyst would only be accessible, and often less selectively, by a longer route if alternative synthetic methods were to be used. The Catalyst Construct

From the outset, we judged that the makeup of Mo-based complexes, represented by 1 [3], offers the most attractive opportunity for the design, synthesis and development of effective chiral metathesis catalysts. This predilection was based on several factors: 1) Mo-based com-

Asymmetric Synthesis with Chiral Ma Catalysts

plexes such as 1 possess a modular structure involving imido and alkoxide moieties that do not disassociate from the metal center in the course of the catalytic cycle [4].Any structural alteration of these ligands may thus lead to a notable effect on the reaction outcome and employed to control both selectivity and reactivity. 2) Alkoxide moieties offer an excellent opportunity for incorporation of chirality within the catalyst structure through installment of non-racemic chiral bis(hydroxy) ligands. 3) Mo-based complexes provide appreciable levels of activity and may be utilized to prepare highly substituted olefins.

ligand

1

I N

i-Pr

Me s#t,ph

; “ . ; I . : ‘ F3C Me k M e Me

alkoxide ligands

1

With the above considerations in mind, in the past five years, we have prepared and examined numerous chiral Mo-based catalysts for both asymmetric RCM (ARCM) and ROM (AROM) transformations [51. In this article, we highlight several efficient and enantioselective reactions that are catalyzed by these chiral complexes [GI. The structural modularity inherent to the Mo-based systems allows screening of catalyst pools, so that optimal reactivity and selectivity levels are identified expeditiously. Initial advances towards the development of chiral Ru-based metathesis catalysts are also discussed. Mo-catalyzed Kinetic Resolution with Hexafluoro-Mo Catalysts [7]

The preparation and catalytic activity of chiral complex 2, based on the original Moalkylidene 1, has been disclosed by Grubbs and Fujimura [8].These workers report on the kinetic resolution of various dienes [9J. As the case regarding the resolution of 3 indicates however, levels of enantiodifferentiation were typically low ( krel < 3).

i-Pr

tPr

M6-s

Me

I

211

212

I

Catalytic Asymmetric Olefin Metathesis

Chiral Biphen-Mo Catalysts

To examine the possibility of a more selective catalytic olefin metathesis, we first prepared chiral Mo-based complexes, 4a and 4b [lo]. This approach was not without precedence: related chiral Mo complexes were initially synthesized in 1993 and used to promote polymer synthesis [6]. We judged that these biphen-based systems would initiate olefin metathesis with high asymmetric induction due to their rigidity and the steric differentiation imposed on the chiral complex's binding pocket. Mo complexes 4a and 41, are orange solids and indefinitely stable when kept under an inert atmosphere.

I 4a R = i P r 4b R = M e

X-ray structure of 4a

Catalytic Kinetic Resolution through Mo-Catalyzed ARCM

The catalytic kinetic resolution of various dienes through ARCM can be carried out efficiently at 22 "C in the presence of 5 mol% 4a [lo]. As the data in Scheme 1 illustrate, 1,6dienes 5-7 are resolved with excellent enantiocontrol (krel > 20) [ll].Chiral catalyst 4a promotes the resolution of allylic ethers 8-10 as well [ 121. The higher levels of enantioselectivity attained through the use of 4a (vs 2) is likely due to a strong preference for ARCM reactions to proceed via Mo-alkylidenes such as I (Scheme 1). The intermediacy (higher reactivity) of the anti Mo-alkylidene(alkylidene C-C anti to Mo=N) is based on extensive mechanistic studies [ 131. The stereochemistry of olefin-transition metal association is consistent with the position of the Mo-centered LUMO of the chiral complex [14],[13b]. The 1,l-disubstituted olefin interacts with Mo away from the protruding t-Bu group of the diolate and i-Pr groups of the imido ligands (see X-ray structure of 4a). Catalyst Modularity and Optimization of Mo-Catalyzed ARCM Eflciency and Selectivity

In spite of the high asymmetric induction observed in the Mo-catalyzed ARCM of 1,6-dienes, when 4a and 41, are used in reactions involving 1,7-dienes,inferior asymmetric induction is obtained. For example, as illustrated in Scheme 2, dienes 12 and 13 are not resolved with useful selectivity ( k , ? ~< 5) when 4a is employed as the catalyst. To address this shortcoming, we took advantage of the modular character of the Mo complexes and prepared a range of chiral complexes as potentially effective catalysts. Accordingly, as depicted in Scheme 2, we

Asymmetric Synthesis with Chiral Mo Catalysts I 2 1 3

Me?

OTES

Me?

OTES

Me?

OBn

Me

m-6

(R)-5

(R)-7

krel = 23

krel > 25

krel = 22

= OR or alkyl = CH2 or 0

I

krel = 10 Scheme 1.

enantiomer

krel = 23

krel = 17

Mo-catalyzed kinetic resolution of 1,6-dienes through ARCM.

l l a R=i-Pr l l b R=Me

(S)-12

\\

with 4a

krel = <5

with l l a

krel= 24

with 1 1 b

krel = <5

Me+

Mo-catalyzed kinetic resolution o f 1,7-dienes and the importance of subtle structural modification of the chiral catalysts.

Scheme 2.

discovered that binol-based complex l l a promotes the RCM of dienes 12 and 13 with outstanding levels of selectivity (kIel = 24 and >25, respectively) [15]. Binol-based complex l l b , bearing the (dimethy1)phenylimido ligand (vs (di(iso)-propy1)phenylimidoof l l a ) , is not an efficient catalyst for the kinetic resolution of the dienes 12 and 13.

214

I

Catalytic Asymmetric Olefin Metathesis

The data in Scheme 3 illustrate that various 1,7-dienes can be resolved with excellent levels of selectivity and efficiency. These findings provide further evidence regarding the importance of the availability of a diverse set of chiral catalysts: Although binol-based complexes (e.g., lla) typically promote ARCM of 1,7-dienes with higher selectivity than the biphenbased catalysts (e.g., 4a), such a generalization is not always true. As expected, lla catalyzes the kinetic resolution of 1,7-dienes 14 and 15 with krel > 25. Unlike biphen complex 4a, however, the closely related 41, also provides appreciable enantioselection, albeit less effectively than lla. With substrates 16 and 17, where two terminal alkenes are involved, the situation is completely reversed: now, it is the biphen-based complex 4a that is the only efficient catalyst. Although each catalyst is not optimal in every instance, efficient kinetic resolution of a wide range of chiral oxygenated 1,G- and 1,7-dienes can be achieved by different chiral Mo complexes.

with 4a

krel= <5

krel= <5

krel = 21

krel= >25

with 4b

krel= 10

krel= 14

krel= <5

krel= 15

with 11 a

krel= >25

krel = >25

krel= <5

krel= <5

Scheme 3. Small structural changes within the substrate structure can alter the identity of the optimum chiral metathesis catalyst.

Catalytic Asymmetric Synthesis through Mo-Catalyzed ARCM

The arena in which catalytic asymmetric olefin metathesis can have the largest impact on organic synthesis is the desymmetrization of readily accessible achiral molecules. Two examples are illustrated in Scheme 4.Treatment of achiral triene 18 with 5 mol% 4a leads to -0

. MefiMe 2 mol Yo4a

Me

Me

18

99% ee, 93%

no solvent, 22 "C, 5 min

Me2

Me2 e S i . 0

20

Si, 2 mol Yo l l a no solvent, 60 " C , 4 h

q.,,,,fle

>98%ee, 98%

Me (R)-21

Scheme 4. Mo-catalyzed ARCM of achiral trienes can be effected efficiently, enantioselectively and in the absence of solvent.

Asymmetric Synthesis with Chiral Mo Catalysts I 2 1 5

the formation of (R)-19in 99% ee and 93% yield [12]. The reaction is complete within five minutes at 22 “C and, importantly, does not require a solvent. Another example is illustrated in Scheme 4 as well; here, binol complex 1la is used to promote the formation of optically pure (R)-21 from doxy triene 20 in nearly quantitative yield. Once again, no solvents are needed [ 151. Readily accessible substrates are rapidly transformed to optically enriched molecules that are otherwise significantly more difficult to access without generating solvent waste. In connection with reactions where a solvent is required, it must be noted that all transformations promoted by chiral Mo catalysts may be carried out in toluene (in addition to benzene) or alkanes (e.g., n-pentane) with equal efficiency (see below for specific examples). Moreover, although 5 mol% catalyst is typically used in our studies, 1-2 mol% loading often delivers equally efficient and selective transformations. As the above studies predicate, reaction of 18 is significantly less efficient with 1la (<5% conv in 18 h) and that of 20 proceeds only to 50% conversion in 24 hours in the presence of 4a (65% ee). Remarkably, in the latter transformation, even in a 0.1 M solution, the major product is the product formed through homometathesis of the terminal alkenes. The absence of homodimer generation when l l a is used, particularly in the absence of any solvent, bears testimony to the high degree of catalyst-substrate specificity in these catalytic C-C bond forming reactions. The catalytic desymmetrization shown in Scheme 5 involves a meso-tetraene substrate: optically pure unsaturated siloxane 23 is obtained in >99% ee and 76% yield [IG]. The unreacted siloxy ether moiety is removed to deliver optically pure 24. Mo-alkylidenes derived from both enantiotopic terminal alkenes in 22 are likely formed. Since metal-alkylidene formation is reversible, the major product arises from the rapid RCM of the “matched’ segment of the tetraene. If any of the “mismatched’ RCM takes place, a subsequent and more facile matched RCM leads to the formation of the meso-bicyclized product. Such a byproduct is absent from the unpurified mixture containing 23, indicating the exceptionally high degree of stereodifferentiation induced by the chiral Mo complex. As before, catalyst 4a is not effective in promoting ARCM of 22.

5 mol% l l a b

C6H6, 60 “c

22

lhr

I

Me 24

I

Me

299% ee, 76%

70%

Mo-catalyzed desyrnrnetrization o f rneso tetraenes proceeds t o afford optically pure heterocycles. Scheme 5.

216

I

Catalytic Asymmetric Olefin Metathesis

Incorporation of electron-withdrawing groups within either the imido or diolate segments of Mo complexes might result in higher levels of catalytic activity, since the Lewis acidity of the transition metal center is enhanced. As the representative examples in Scheme 6 depict, such structural modifications can have a profound effect on the levels of enantioselectivity as well. In the desymmetrization of acetal 26, dichlorophenylimido complex 25 provides substantially higher levels of asymmetric induction than biphen- or binol-based catalysts that carry 2,6-dialkylphenylimido moieties (e.g., 4a). Acetals of the type represented by 27 in Scheme 7 retain their stereochemical integrity through various routine operations such as silica gel chromatography and can be readily functionalized to deliver a range of chiral nonracemic functionalized heterocycles [ 161.

T M l d >

C6H6,22"C 5 mot yo 25+

&P

CIQ

H 26

(S)-27

12 hr

with 4a

29% ee, >98% conv

with 4b

51YO ee, >98% conv

with 11a

13% ee, >98% conv

with 25

83% ee, >98% conv, 41%

C

I

I

Scheme 6. Chiral complex 25, bearing a 2,6-dichloro imido ligand is the catalyst o f choice for asymmetric synthesis o f acetals.

10 mol % 4a

Mee HP,Pd(C) M 87%

28 Scheme 7.

29 59% ee, 90%

e

S

H % 'Me 30 endo-brevicomin

Application of Mo-catalyzed ARCM to the synthesis o f brevicomin.

The emerging Mo-catalyzed ARCM technology summarized above has been utilized in a brief and enantioselective total synthesis of endo-brevicomin(30) by Burke. The key step, as illustrated in Scheme 7, is the desymmetrization of achiral triene 28 [17]. Mo-catalyzed ARCM may be used in the enantioselective synthesis of medium ring carboand heterocycles 1181. As shown in Scheme 8, medium ring tertiary siloxanes (e.g., 34), prepared with high levels of enantioselectivity. These processes can be effected efficiently in preparative scale and at low catalyst loading (e.g., 33134); such attributes render this catalytic enantioselective method attractive from a practical point of view. It should be noted that in this set of reactions, both 4a and the dichloroimido complex 25 provide high enantioselectivity; however, the more active 25 is preferable when lower catalyst loadings are required.

Asymmetric Synthesis with Chiral Mo Catalysts

Me2

A

31 Me

89% ee, 86% Br\

Br

13 rng 25 (1 rnol Yo) P

CsH6,22 "c

Me

34 94% ee, 98%

(0.659)

C&3,22 5 rnol Yo"4a c

- -%eM

35 Me

Me

90% ee, 50% Scheme 8. Mo-catalyzed tandem ARCM can be used t o synthesize seven-membered carbo- and heterocyclic structures efficiently and in optically enriched form.

The representative transformation in Scheme 9 illustrates that the optically enriched siloxanes obtained by Mo-catalyzed ARCM can be further functionalized to afford tertiary alcohols (e.g., 40) with excellent enantio- and diastereomeric purity. It should be noted that conversion of 37 to 38 in Scheme 9 is carried out without solvent, at 1 mol% catalyst loading and on one gram scale (only 30 mg of catalyst 4a needed) [MI.

-

30mg4a (1 rnol Yo)

1. m-CPBA

P

37

Me

(1 .o 9)

22 "C, 6 h, no solvent M~

2. n-Bu4NF

38 87% ee, 95%

Me

39 86% for two steps; 93% ee; >20:1 de

Mo-catalyzed tandem ARCM can be used to synthesize synthetically versatile intermedaites such as 1,3-tertiary diols in high enantio- and diastereopurity. Scheme 9.

Most recent studies indicate that ARCM can be used to synthesize small and medium ring N-containing unsaturated heterocycles in high yield and with excellent enantioselectivity through catalytic kinetic resolution and asymmetric synthesis [ 191. Levels of optical purity can vary depending on the nature of the arylamine (compare 44 to 46 in Scheme 10). As

I

217

218

I

Catalytic Asymmetric Olefin Metathesis

the synthesis of 48 indicates (cf. Scheme lo), particularly noteworthy is the facility and selectivity with which medium ring unsaturated amines are obtained by the Mo-catalyzed protocol. Cata/ytic Kinetic Resolution Me

krel=17 with 5 mol YO4a Me

Me I

I

Me0

41 krel=13 with 5 mol YO4a

42 krel>50 with 5 mol Yo 4a

Catalyric Asymmetric Synthesis 5 mol Yo 4a

Med

43 - PhG

M

e

d 44

R

Ph

98% ee, 78% Me

Me

d w

JLO

Me

Me

45 Ar

R

Ar

46 82% ee, 90%

&J

5mol%4b,

Me

Ph

47 Scheme 10.

C & j , 22 "C, Me 20 min

Ph

48 >98% ee, 93%

Enantioselective synthesis of amines through Mo-catalyzed ARCM.

Unlike carbocyclic and oxygen-containing heterocyclic systems, catalytic enantioselective synthesis of eight-membered ring amines not only proceeds efficiently and with excellent enantioselectivity, it can be carried out in the absence of solvent. Representative data regarding catalytic enantioselective synthesis of various N-containing heterocycles without the use of solvent is depicted in Scheme 11. This remarkably efficient and enantioselective

Asymmetric Synthesis with Chiral Mo Catalysts

95% ee, 95% (3 mol % 4a, 22 "C, 3.5h)

97% ee, >98% (4 mol % 25, 22 "C, 7 h)

Scheme 11. Catalytic enantioselective synthesis of amines in the absence of solvent through Mo-catalyzed ARCM

method again highlights the ability of asymmetric metathesis to deliver synthetically versatile materials that are otherwise difficult to prepare. Catalytic Asymmetric Synthesis through Tandem Mo-Catalyzed AROM/RCM

The appreciable levels of asymmetric induction observed in the catalytic ARCM reactions discussed above suggest a high degree of enantio-differentiation in the association of olefinic substrates to chiral Mo complexes. Such stereochemical induction may be exploited in asymmetric ring-opening metathesis (AROM). Catalytic ROM transformations [ 201 although less explored than the related RCM processes - offer unique and powerful methods for the preparation of complex molecules in a single step (2d, 2g]. The chiral Mo-alkylidenes that are products of AROM can be trapped either intramolecularly (RCM) or intermolecularly (cross metathesis, CM) to afford an assortment of optically enriched adducts. Transformations shown in Schemes 12-14 constitute the first examples of catalytic AROM reactions ever reported. Meso-triene 50 is converted to chiral heterocyclic triene 51 in 92% ee and 68% yield with 5 mol% 4a (Scheme 12) [21].Presumably, stereoselective approach of the more reactive cyclobutenyl alkene in the manner shown in Scheme 12 (11) leads to the enantioselective formation of Mo-alkylidene 111, which in turn reacts with an adjacent terminal olefin to deliver 51. Another example in Scheme 12 involves the net rearrangement of rneso-bicycle 52 to bicyclic structure 54 in 92% ee and 54% yield. The reaction is promoted by 5 mol% 4a and requires the presence of diallyl ether 53 [22]. Mechanistic studies suggest that initial reaction of 53 with 4a leads to the formation of the substantially more reactive chiral Mo=CHl complex (vs neophylidene 4a) which can react with the sterically hindered norbornyl alkene to initiate the catalytic cycle. In contrast to 52 (Scheme 12) diastereomer 55 (Scheme 13), because of its more exposed and highly reactive strained olefin, undergoes rapid polymerization in the presence of 4a. The less reactive Ru complex 56 [23] can however be used under an atmosphere of ethylene to effect a tandem ROMjCM to generate 57. The resulting triene can be subsequently

I

219

220

I

Catalytic Asymmetric Olefin Metathesis

Me

92% ee, 68%

R

J--

I

5 rnol % 4a

pMe

P /

pentane 52

\\// 53

c0)

54 92%ee,54%

10 mol % Mo-catalyzed tandem AROM/RCM allows access t o complex heterocyclic structures efficiently and i n optically enriched form.

Scheme 12.

induced to undergo Mo-catalyzed ARCM (5 mol% 4a) to afford optically pure 58, the AROM/ RCM product that would be directly obtained from 55. The Mo-catalyzed transformations shown in Scheme 14 may also viewed as AROMiRCM processes [24]. However, it is possible that initiation occurs at the terminal olefin, followed by an ARCM involving the cyclic alkene. Regardless of the attendant mechanistic possibilities, the enantioselective rearrangements shown in Scheme 14, catalyzed by binaphtholatebased catalyst l l a , deliver unsaturated pyrans bearing a tertiary ether site with excellent efficiency and enantioselectivity. It should be noted that this class of heterocycles would not be readily accessible by an enantioselective synthesis of the precursor diene, followed by RCM promoted by an achiral catalyst. The requisite optically enriched pure tertiary ether or alcohol cannot be easily accessed. It also merits mention that in this class of asymmetric reactions, biphenolate-based complexes provide significantly lower levels of enantioselectivity (e.g., 4a affords GO in 15% ee). The enantioselective synthesis of the pyran portion of the antiHIV agent tipranavir (Scheme 14) serves to demonstrate the significant potential of the method in asymmetric synthesis of biomedically important agents. The non-racemic pyrans shown in Scheme 14 can also be accessed by Mo-catalyzed ARCM

Asymmetric Synthesis with Chiral Mo Catalysts I 2 2 1

L

O

A

5 mol Yo 4a

*

pentane, 22 "C

POLYMERIZATION

55

ethylene

-

56

1

5 mol Yo 4a, pentane, 22 "C

57 >99%ee; 84%

58 Crubbs's Ru complex 56 (ROM) is used in conjunction with chiral catalyst 4a (ARCM) to obtain 58 in the optically pure form.

Scheme 13.

59

60 96% ee, 87%

61

62 96% ee, 73%

Mo-catalyzed enantioselective rearrangement o f mesocyclopentenes to chiral unsaturated pyrans. Scheme 14.

222

I

Catalytic Asymmetric Olefin Metathesis

of the corresponding trienes. The example shown in E q (1)is illustrative. Interestingly, elevated temperatures are required for high levels of enantioselectivity;under conditions shown in Scheme 14,trienes such as 65 afford the desired pyrans in significantly lower ee (e.g., 66 is obtained in 30% ee at 50 "C). Detailed mechanistic studies must be carried out before the origin of such variations in selectivity are understood.

I

5 mol Yol l a

*

toluene, 80 "C

Me

(1)

66 >98% ee, 90% Catalytic Asymmetric Synthesis through Tandem Mo-Catalyzed AROMICM

The chiral Mo-alkylidene complex derived from AROM of a cyclic olefin may also participate in an intermolecular cross metathesis reaction. As depicted in Scheme 15, treatment of meso-67a with a solution of 5 mol% 4a and 2 equivalents of styrene leads to the forma-

A0 . phg " OTBS

5 mol yo cat

67a

98% ee

with 4b

79% ee

with 11a

86% ee

"H

68

C6H6, 22 "c

with 4a

optimized (2 equiv styrene): >98% ee, >98% trans, 57% (Me0)3Si

67b

(MeO)3SiA C6H6, 22 "c

69 2.5 mol Yo

I >98% ee, >98% trans, 51% Scheme 15. Mo-catalyzed tandem AROM/CM proceeds with high enantioselectivity and olefin stereocontrol.

Asymmetric Synthesis with Chiral Mo Catalysts I 2 2 3

tion of optically pure 68 in 57% isolated yield and >98% trans olefin selectivity [25].The Mo-catalyzed AROM/CM reaction can be carried out in the presence of vinylsiloxanes: the derived optically pure 69 (Scheme 15) can subsequently be subjected to Pd-catalyzed crosscoupling reactions, allowing access to a wider range of optically pure cyclopentanes. The Mo-catalyzed AROM/CM may be performed on highly functionalized norbornyl substrates (e.g., 71 and 72 in Scheme 16) and those that bear tertiary ether sites (e.g., 73-75, Scheme 16). Although initial studies indicate that the relative orientation of the heteroatom substituent versus the reacting olefin can have a significant influence on reaction efficiency, the products shown in Scheme 16 represent versatile synthetic intermediates accessed in the optically pure form by Mo-catalyzed AROM/CM.

%

F h+ ’ i

71

:

Acd

72

6Ac

>90% ee, 94%

73

06% ee, 67%

74

>98% ee, 05%

76

>90% ee, 84%

>90% ee, 04%

(>98% trans in all cases) Scheme 16. Mo-catalyzed tandem AROM/CM delivers highly functionalized cyclopentanes in the optically pure form.

Towards User-Friendly and Practical C h i d Mo-Based Catalystsfor Olefin Metathesis

Although the main focus of our programs have so far been on issues of reactivity and enantioselectivity, we have recently begun to address the important issue of practicality in Mo-catalyzed asymmetric metathesis. Two key advances have been reported in this connection: (1)A general chiral Mo catalyst that can be prepared i n situ from commercially available compounds. (2) A recyclable polymer-supported chiral Mo catalyst. Chiral M o Catalyst Prepared in Situ from Commercially Available Materials

Up to this point, there have been two general classes of chiral Mo catalysts discussed: biphenolate-based complexes such as 4 and binaphtholate systems represented by 11 (Scheme 2). From a practical point of view, binaphthol-based systems have a significant advantage, as the synthesis of the optically pure diolate begins from the inexpensive and commercially available ( R ) -or (S)-binaphthol. Access to the optically pure biphenol ligand in 4 and its derivatives requires resolution of the racemic material by fractional crystallization of the derived phosphorus(V) mentholates [2].Accordingly, we prepared chiral Mo complex 77 [ 261, bearing a “biphenol-type” ligand, but synthesized from the readily available optically pure binaphthol. Complex 77 shares structural features with both the biphen-(4) and binol-

224

I

Catalytic Asymmetric Olefin Metathesis

based (11)systems and represents an intriguing possibility regarding the range of starting materials for which it may be a suitable catalyst. Two examples are depicted in Scheme 17. Catalyst 77 delivers compounds of high optical purity where either biphen- or binol-based complexes are ineffective. It is not in all instances that 77 operates as well as 4a and l l a . As an example, in the presence of 5 mol% 77, triene 18 (Scheme 4)is converted to furan 19 in 77% ee and 73% yield (vs 99% ee and 93% yield with 4a). It should be noted that catalyst 71 serves as an additional example, where modification of the chiral alkoxide ligand can lead to substantial variation in selectivity.

krel> 25 with 4 a krel<5 w i t h l l a ( 5 mol o/o loading)

Me2

vH.)rMe fSi-o

-70% ee with 4a

>99% ee with l l a

Me 21 96% ee, 56% Scheme 17. Chiral complex 77 represents a hybrid between biphenand binol-based catalysts and provides a unique selectivity profile that is often not seen with the latter two classes individually.

It is not only that catalyst 77 is more easily prepared than 4. As illustrated in Scheme 18, a solution of 77, obtained by the reaction of commercially available reagents bis(potassium salt) 78 (Strem) and Mo triflate 79 (Strem), can be directly used to promote enantioselective metathesis. Similar levels of reactivity and selectivity are obtained with in situ 77 as with isolated and purified 4a or 77 (cf. Scheme 18). Moreover, asymmetric olefin metatheses proceed with equal efficiency and selectivity with the same stock solutions of (R)-78and 79 after two weeks. The use of a glovebox, Schlenck equipment or vacuum lines is not necessary (even with the two-week old solutions). The First Polymer-Supported and Recyclable Chiral Catalyst for Olefin Metathesis

We have synthesized and studied the activity of 82, the first supported chiral catalyst for olefin metathesis (Scheme 19) [27]. Catalyst 82 efficiently promotes a range of ARCM and AROM processes; a representative example is shown in Scheme 19. Rates of reaction are lower than observed with the corresponding monomeric complex 4a, but similar levels of enantioselectivity are observed. Although 82 must be kept under dry and oxygen-free conditions, it can be recycled. Catalyst activity, however, is notably diminished by the third cycle. As the data and the figure in Scheme 19 show, the product solution obtained by filtra-

'

Practical and Recyclable Chiral Metathesis Catalysts

Me OTf

THF,

0,.I HNAr Me

-50+.22 "c ~ H ~ o ~ a , , , pinhood h ' O K Me OTf M~ \ .+oO K l h 79 / direct from (@-78 Strem bottle Strem

77 in THF

'

0

5 mol yo in situ

MeliYMe 78 & ; : : 22

88% ee, 80% with 5 mol Yo isolated 4a: 93% ee, 86% 5 mol Yo in situ

80

67c

>98% ee,>98% trans, 86% with 5 mol Yoisolated 4a: >98% ee, >98% trans, 87% Scheme 18.

In situ preparation and utility of chiral metathesis catalyst 77.

tion contains significantly lower levels of metal impurity than detected with the monomeric catalysts, where >90% of the Mo used is found in the unpurified product (by ICP-MS analysis). The supported chiral Mo catalyst is, as should perhaps be expected, less active than the parent system (4a).The lower levels of activity exhibited by 82 may be due to inefficient diffusion of substrate molecules into the polymer. The supported catalyst is expected to be less susceptible to bimolecular decomposition of highly reactive methylidene intermediates [28]. Synthesis of more rigid polymer supports or those that represent lower Mo loading should further minimize bimolecular decomposition and lead to a more robust class of catalysts. Towards Chiral Ru-Based Olefin Metathesis Catalysts

Grubbs and co-workers have recently reported a new class of Ru catalysts (83, Eq 2) [29] that bear a chiral monodentate N-heterocyclic carbene ligand [30]. The reactions illustrated in E q 2 include the highest ee reported (13-90% ee); asymmetric induction is clearly dependent on the degree of olefin substitution (6Schemes 18 and 4 for comparison with the Mo-catalyzed reactions of the same substrates). As is the case with nearly catalytic enantioselective reactions [4], the identity of the optimal catalyst depends on the substrate; a number of chiral

I

225

226

I

Catalytic Asymmetric Olefin Metathesis

OCH20Et

OCH20Et tBu

81 Ph

2 equiv styre; C6H6,22 "c

67c

80

Cycle 1: >98% conv, 30 min; 97% ee product contains 3% of total Mo initially used Cycle 2: 98% conv, 30 min; 98% ee product contains 10% of total Mo initially used Cycle 3: 55% conv, 16 h; 89% ee product contains 16% of total Mo initially used Scheme 19. The first recyclable and supported chiral catalyst for olefin metathesis, 82 delivers reaction products that contain significantly less metal impurity. The two dram vials show unpurified 80 from a reaction catalyzed by 4a (left) and 82 (right).

Ru catalysts were prepared and screened before 83 was identified as the most suitable. In addition, reactions were shown to be more selective in the presence of NaI. This important initial investigation is likely the harbinger of upcoming highly effective and practical chiral Ru-based metathesis catalysts.

0 -

MeAMe R

R

THF, 38 "C,1 equiv Nal R = H 78-+79 R =Me 18+19

39% ee, 22% conv 90% ee, 82% conv

References I 2 2 7

Conclusions and Outlook

The exciting results of the above investigations clearly indicate that the modular Mo-based construct initially reported for catalyst 1 can be exploited to generate a range of highly efficient and selective chiral catalysts for olefin metathesis. Both ARCM and AROM reactions can be promoted by these chiral catalysts to obtain optically enriched or pure products that are typically unavailable by other methods or can only be accessed by significantly longer routes. Substantial variations in reactivity and selectivity arising from subtle changes in catalyst structures, support the notion that synthetic generality is more likely if a range of catalysts are available [4]. The chiral Mo-based catalysts discussed herein are more senstive to moisture and air than the related Ru-based catalysts [l].However, these complexes, remain the most effective and general asymmetric metathesis catalysts and are significantly more robust than the original hexafluoro-Mo complex 1. It should be noted that chiral Mo-based catalysts 4,11,25, 34 and 77 can be easily handled on a large scale. In the majority of cases, reactions proceed readily to completion in the presence of only 1 mol% catalyst and, in certain cases, optically pure materials can be accessed within minutes or hours in the absence of solvents; little or no waste products need to be dealt with upon obtaining optically pure materials. Chiral catalyst 4a is commercially available from Strem, Inc. (both antipodes and racemic). The advent of the protocols for in situ preparation of chiral Mo catalyst 77, the supported and recyclable complex 82 and the debut of a chiral Ru catalyst (83) augur well for future development of practical chiral metathesis catalysts. The above attributes collectively render the chiral catalysts discussed above extremely attractive for future applications in efficient, catalytic, enantioselective and environmentally conscious protocols in organic synthesis. Acknowledgements

Financial support was provided from the National Institutes of Health (GM-59426 to A. H. H. and R. R. S.) and the National Science Foundation (CHE-9905806to A. H. H. and CHE9700736 to R. R. S.). We are grateful to all our workers whose names appear in the references for invaluable intellectual and experimental contributions. References select reviews on catalytic olefin S. metathesis, see: a) R. H. GRUBBS, CHANG,Tetrahedron 1998, 54, 4413-4450; b) A. FURSTNER, Angew. Chem. Int. Ed. 2000, 39, 3012-3043. For example, see: a) A. F. HOURI,2. Xu, D. A. COGAN, A. H. HOVEYDA,]. Am. Chem. SOC. 1995, 117, 2943-2944; b) 2 . Xu, C. W. J O H A N N E S , A. F. HOURI,D. S. LA, D. A. COGAN, G. E. HOFILENA, A. H. HOVEYDA, J . Am. Chem. SOC.1997, 119, 10302-10316; c) D. MENG,D-S. Su, A. BALOG, P. BERTINATO,E. J. SORENSEN, S. J.

1 For

2

DANISHEFSKY, Y-H. ZHENG,T-C. CHOW,L. HE, S. B. HORWITZ, J . Am. Chem. SOC. 1997, 119, 2733-2734; d) K. C. NICOIAOU, N. WINSSINGER, J. PASTOR, S. NINKOVIC, F. SARABIA, Y. HE, D. VOURLOUMIS, 2. YANG, T. LI, P. GIANNAKAKOU, E. HAMEL, Nature 1997, 387, 268-272; e) C. W. JOHANNES, M. S. VISSER,G. S. WEATHERHEAD, A. H. HOVEYDA, J . Am. Chem. SOC.1998, 120, 8340-8347; f ) M. DELGADO, J. D. MARTIN, J . Org. Chem. 1999, 64,4798-4816; g ) A. FURSTNER, 0. R. THIEL,]. Org. Chem. 2000, 65, 1738-1742;

fatalytic Asymmetric Olefin Metathesis

h) J. LIMANTO, M. L. SNAPPER,].Am. Chem. SOC.2000, 122,8071-8072; i) A. B. SMITH,S. A. KOZMIN,C. M. ADAMS,D. V. PAONE, ]. Am. Chem. SOC.2000, 122,49844985. 3 a) R. R. SCHROCK, J. S. MURDZEK, G. C. M. DIMARE,M. BAZAN,J. ROBBINS, O’REGAN,]. Am. Chem. SOC.1990, 112, 3875-3886; b) G. C. BAZAN,J. H . OSKAM, H.-N. CHO, L. Y. PARK,R. R. SCHROCK,]. Am. Chem. SOC. 1991, 113, 6899-6907. 4 a) K. W. KUNTZ,M. L. SNAPPER, A. H. HOVEYDA, CUT. Opin. Chem. Biol. 1999, 3, 313-319; b) K. D. SHIMIZU,M. L. SNAPPER, A. H. HOVEYDA In Comprehensive Asymmetric Catalysis I-IIk E. N. JACOBSEN, Eds.; Springer: A. PFALTZ,H. YAMAMOTO, Berlin, 1999; Vol. 3, 1389-1399; For a report regarding synthesis of various Mo complexes, see: c) J. H. OSKAM,H. H. Fox, K. B. YAP, D. H. MCCONVILLE, R. O’DELL, R. R. SCHROCK,]. B. J. LICHTENSTEIN, Organomet. Chem. 1993,459, 185-198. 5 For a previous brief overview of this Mocatalyzed asymmetric olefin metathesis, R. R. SCHROCK, see: A. H . HOVEYDA, Chem. Eur. ]. 2001, 7, 945-950. 6 For early reports regarding the preparation of chiral Mo-based catalysts used for ROMP, see: a) D. H. MCCONVILLE, J. R. WOLF,R. R. SCHROCK, J. Am. Chem. SOC. 1993, 115,4413-4414; b) K. M. TOTLAND, T. J. BOYD,G. G. LAVOIE,W. M. DAVIS, R. R. SCHROCK, Macromolecules 1996,29, 6114-6125. 7 Throughout this article, the identity of the recovered enantiomer shown is that which is obtained by the catalyst antipode illustrated. Moreover, transformations with binol-based complexes (e.g., 11) were carried out with the opposite antipode of the catalyst versus that illustrated. Because (S)-biphen and (R)-binolcomplexes were employed in our studies, this adjustment has been made to facilitate comparison between biphen- and binol-based catalysts. 8 a) 0. FUJIMURA, R. H. GRUBBS,]. Am. Chem. SOC.1996, 118: 2499-2500; b) 0. FUJIMURA, R. H. GRUBBS, ]. Org. Chem. 1998,63,824-832. 9 For a review on metal-catalyzed kinetic M. T. resolution, see: A. H. HOVEYDA, DIDIUK,CUT. Org. Chem. 1998,2,537574.

B. ALEXANDER, D. S. LA, D. R. CEFALO, A. H. HOVEYDA, R. R. SCHROCK, J . Am. Chem. SOC. 1998,120,4041-4042. 11 The value for k,l is calculated by the equation reported by Kagan: H. B. KAGAN, J. C. FIAUD,Top. Stereochem. 1988,53, 708-710. 12 D. S. LA, J. B. ALEXANDER, D. R. CEFALO, D. D. GRAF,A. H . HOVEYDA, R. R. SCHROCK,].Am. Chem. SOC. 1998, 120, 9720-9721. 13 a) J. H. OSKAM,R. R. SCHROCK,].Am. Chem. SOC. 1993, 115, 11831-11845; b) H. R. R. SCHROCK, H . Fox, M. H. SCHOFIELD, Organometallics 1994, 13, 2804-2816. 14 a) R. R. SCHROCK, Polyhedron 1995, 14, 3177-3195; b) Y.-D. W u , 2.-H. PENG,J. Am. Chem. SOC.1997, 119,8043-8049. 15 S. S. ZHU, D. R. CEFALO, D. S. LA, J. Y. JAMIESON, W. M. DAVIS,A. H. HOVEYDA, R. R. SCHROCK,].Am. Chem. SOC.1999, 121,8251-8259. 16 G. S. WEATHERHEAD, J. H. HOUSER,G . J. FORD,J. Y. JAMIESON, R. R. SCHROCK, A. H. HOVEYDA, Tetrahedron Lett. 2000, 41, 9553-9559. 17 S. D. BURKE,N. MULLER, C. M. BEUDRY, Org. Lett. 1999, 1, 1827-1829. 18 A. F. KIELY,J. A. JERNELIUS, R. R. SCHROCK, A. H. HOVEYDA,].Am. Chem. SOC.2002, 124, 2868-2869. 19 S. J. DOLMAN, E. S. SATTELY, A. H . HOVEYDA, R. R. SCHROCK,].Am. Chem. SOC.2002, 124, 6991-6997. 20 For representative studies regarding nonasymmetric ROM reactions, see: a) M. L. RANDALL, J. A. TALLARICO, M. L. SNAPPER, ]. Am. Chem. SOC.1995,117, 9610-9611; b) W. J. ZUERCHER, M. HASHIMOTO, R. H. GRUBBS,].Am. Chem. SOC. 1996, 118, 6634-6640; c) J. P. A. HARRITY,M. S. VISSER,J. D. GLEASON, A. H . HOVEYDA,J. Am. Chem. SOC.1997, 119, 1488-1489; d) M. F. SCHNEIDER, N. LUCAS,J. VELDER, S. BLECHERT, Angew. Chem. Int. Ed. 1997, 36, 257-259; e) F. D. CUNY,J. CAO,J. R. HAUSKE,Tetrahedron Lett. 1997,38, 5237-5240. 21 G. S. WEATHERHEAD, J. G. FORD,E. J. ALEXANIAN, R. R. SCHROCK, A. H. HOVEYDA, ]. Am. Chem. SOC.2000, 122,8071-8072. 22 J. P.A. HARRITY,D. S. LA,D. R. CEFALO, ]. Am. M. S. VISSER,A. H . HOVEYDA, Chem. SOC.1998, 120, 2343-2351.

10 J.

References I 2 2 9

M. B. FRANCE,J. W. ZILLER, 23 P. SCHWAB, R. H . GRUBBS, R. H. Angew. Chem. Int. Ed. 1995, 34, 2039-2041. 24 D. R. CEFALO, A. F. KIELY, M. WUCHRER, J. Y. JAMIESON, R. R. SCHROCK, A. H. HOVEYDA, J . Am. Chem. SOC.2001, 123, 3139-3140. 25 D. S. LA, G. J. FORD,E. S. SAITELY, P. J. BONITATBUS, R. R. SCHROCK, A. H. HOVEYDA,]. Am. Chem. SOC.1999, 121, 11603-11604. 26 S. L. AEILTS,D. R. CEFALO, P. J. BONITATEBUS, JR., J. H. HOUSER, A. H.

27

28

29

30

HOVEYDA, R. R. SCHROCK, Angew. Chem. Int. Ed. 2001, 40, 1452-1456. K. C. HULTSZCH, J. A. JERNELIUS, A. H. HOVEYDA, R. R. SCHROCK, Angav. Chem. Int. Ed. 2002, 41, 589-593. J. ROBBINS, G. C. BAZAN,J. S. MURDZEK, M. B. O’REGAN, R. R. SCHROCK, Orgunometullics 1991, 10, 2902-2907. T. J. SEIDERS, D. W. WARD,R. H. GRUBBS, Org. Lett. 2001, 3, 3225-3228. W. A. HERRMANN, L. J. GOOSSEN, C. KOCHER,G. R. J. ARTUS,Angew. Chem. Int. Ed. 1996, 35, 2806-2807.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Activating Protecting Groups for the Solid Phase Synthesis and Modification o f Peptides, Oligonucleotides and Oligosaccharides Oliver Seitz Introduction

Merrifields pioneering invention of solid phase peptide synthesis revolutionised the field of biological and medicinal chemistry [ 11. Quickly, the solid phase synthesis of peptides and oligonucleotides reached a high level of maturity. Ultimately, automation of the repetitive process gave non-chemists the opportunity to readily synthesise these complex biopolymers and allowed the first detailed investigations of the structure-affinity-relationships of peptides and oligonucleotides. The efficiency of the automated process led many to the assumption that all problems had been solved and that new developments would be unnecessary. However, the increasing pressure in pharmacological research to find more lead structures in even shorter periods of time has rejuvenated solid phase methods, demonstrated best by the developments in combinatorial chemistry. Not only has this effected the preparation of peptides and oligonucleotides, but also has encouraged research for the solid phase synthesis of the highly complex class of oligosaccharides. In the following, new strategies for the solid phase synthesis of these three classes of biopolymers will be presented. This article will focus on the use of activating protecting groups, which are capable of increasing the diversity in a given system. It is not intended to give a comprehensive overview of this field but to highlight some concepts [ 2, 31. Peptides

Peptides and proteins are characterised by a large structural and functional variability. A key feature of peptide synthesis is, thus, the need for numerous protecting groups. In the following the concept of activating protecting groups will be exemplified by discussing Cterminal and N-terminal as well as amide blocking groups. C-Terminal Modfication

During solid phase synthesis peptides are bound to the solid support by means of the Cterminal carboxyl group. The properties of the anchor group positioned between the growing oligomer and the solid support are crucial for the success of a solid phase synthesis. Usually, specialised linkers are used which provide either peptide carboxylic acids or peptide carboxylic amides upon cleavage [4]. A cleavage mechanism that proceeds by a nucleophilic attack

Peptides I 2 3 1

at the peptide carboxyl group offers access to a variety of C-terminal peptide modifications such as peptide esters, peptide thioesters, secondary and tertiary peptide amides and many more. One of the early examples of a linker that enables such a diversity-increasing peptide release is the Kaiser-oxime linker 1 (Scheme 1) [5]. A host of nucleophiles including alcohols, amines, thiols and even hydroxybenzotriazole has been shown to displace the oxime linkage. Aminolysis of the activated peptide ester has been performed in an intramolecular fashion to afford cyclic peptides [GI. Thioester resins have also been used for inter- and intramolecular aminolysis [4].However, these “permanently activated’ linkers are only compatible with the use of the Boc-strategy. The application of the popular Fmoc-strategy would lead to premature peptide losses due to the lability of the ester bond towards nucleophiles such as the piperidine used during Fmoc-removal. Both the Boc-strategy and the Fmoc-strategy can be applied with Kenners sulfonamide linker 2 [7]. The secondary sulfonamide 2 is stable against acids and bases but rendered labile against nucleophilic attack upon transformation to the tertiary sulfonamide 3. This safety-catch principle has been used for the preparation of peptide acids, peptide amides, peptide hydrazides and peptide thioesters. Recently, a more reactive linker has been developed by Ellman [8].Cyanomethylation instead of methylation (see Scheme 2 , 445),and the use of the alkane sulfonamide increase the cleavability with poor nucleophiles. One impressive application has been demonstrated by Bertozzi and co-workers (Scheme 2) [9]. The acid- and base-sensitive glycopeptide thioester G was synthesised by using Ellmans modification of Kenners sulfonamide linker and was subsequently employed in a fragment coupling with glycopeptide segment 8. The latter contained a N-terminal cysteine residue that according to the so-called Native Chemical Ligation [ 101 enabled the segment coupling to proceed in the absence of protecting groups. Acylated aryl hydrazides (10) can be cleaved upon oxidition to acyl diazenes 11 (Scheme 3).

= polystyrene

The Kaiser-oxim resin 1 is permanently activated and can be cleaved by nucleophiles. Kenners sulfonamide resin 2 is stable against acids and bases but rendered labile against nucleophilic attack after conversion t o the tertiary amide 3.

Scheme 1.

GalNAca

= polystyrene

8

6

Scheme 2.

T;rio

J.

-CHIEn

BnSH, THF

CICHzCN, DIPEA, NMP

GalNAca

AcsGalNAca

1OOmM NaH2P04, 4% PhSH, 55% b) 5% eq. HzNNH2, D l T . 53%

a) 6M GnHCI,

TFAPhOH/H20/PhSMe/EDT (82.5:5:5:5:2.5), 4h, 21% overall yield

Ac3GalNAca

I -+

Rl

(DIPEA, N-ethyl-N,N-diisopropylamine; DTT, dithiothreitol; EDT, ethanedithiol; GnHCI, guanidinium hydrochloride; NMP, N-methylpyrrolidone).

Boc-HN

Ellmans sulfonamide linker allowed the synthesis o f the acid- and base-labile glycopeptide thioester 6 , which was used for the Native Chemical Ligation with glycopeptide fragment 8

9

0

Ac-HN

Ac3GalNAca =

5, R =CHzCN

4,R=H

Ac3GalNAca

E.

z

Y

3

H

H

+

a) 50% TFNCH2C12 b) NBS, pyridine, CH2CI2,7 min

NuH

""0O

11

0

19% overall yield

Ala-Pro-Leu-Phe-Ala

The hydrazlde linker 10 can be activated by mild oxldatlon (NBS, N-bromosucctnlmide).

12

Boc-HN - Ala-Pro-Leu-Phe-Ala

Scheme 3.

10

H

Cu(OAc)p, NuH or NBS, pyridine, CH&, NuH

13

N w

-

234

I

Activating Protecting Groupsfor the Solid Phase Synthesis

This linker concept was originally introduced by Wieland and co-workers [ 111 but has been fashioned to suit practical applications by the groups of Semenov, Lowe and Waldmann [ 12141. The aminolysis has been achieved by treatment of the hydrazide 10 with copper (11) acetate in solutions of the amine in methanol. NBS in pyridine has been employed as an alternative oxidising agent that triggered a cyclative release of cyclopeptide 13 [ 151. The postsynthetic activation of a peptide ester was performed in the laboratories of Wells and Wong [lG,171. For the synthesis of a partial sequence of the C-terminal region of ribonuclease B, conjugate 14, consisting of N-Fmoc-protected alanine and the acid- and basestable PAM-Linker,was coupled to the Rink-Amide resin 15 (Scheme 4) [17]. The elongation of 1G followed standard Fmoc-protocols. Standard TFA-cleavageconditions removed all acidlabile side-chain protecting groups and also detached the N-Fmoc-protected peptide-PAM ester 17 from the solid support. Since a benzhydrylamine-type-linker was used, the peptidePAM conjugate 17 was liberated as a PAM-amide. Side-chain unprotected peptide esters of this type can serve as acyl donors in enzyme-catalyzed peptide couplings. Accordingly,

OMe

Fmoc-Ala-0 a

C

O

O

H

15

+

HZN Fmoc-Ala-PAM-OH

14

I

’

OCH2CO-N

a) HBTU, HOBt, NMM, DMF; b) Ac20, Pyr

16

Fmoc-Ala-PAM-Rink

Fmoc-solid-phase peptide synthesis, 89% TFNEt3SIHIHZO (95:25’2.5),

= polystyrene

Fmoc-Lys-Thr-Thr-Gln-Ala-Asn-Lys-His-lle-lle-Val-Ala-0 C O W

18 H-Gly-Gly-Ser-NH, I

AQGIcNAcP

Y

subtilisin (8397K256Y),

84%.

Fmoc-Lys-Thr-Thr-Gln-Ala-Asn-Lys-His-lle-lle-Val-Ala-G ly-Gly-Ser-NH,

19

I

AcaGlcNAcP Solid-phase synthesis of the peptidePAM ester 17 which served as an acyldonor in the subtilisin-catalysed segment condensation with glycopeptide fragment 18 (Ac~GIcNAc, 2-acetamido-3,4,6-tri-O-acetyl-2-deoxyglucose; Scheme 4.

HBTU, 2-(1 -H)-benzotriazole-1-yl)-1,1,3,3tetrarnethyluroniumhexafluorophosphate; HOBt, 1-hydroxy-1H-benzotriazole; NMM, Nmethylmorpholine).

Peptides I 2 3 5

the segment condensation of 17 with the N-terminally unprotected glycotripeptide 16 was achieved by catalysis of the protease subtilisin affording the glycopentadecapeptide 18 in 84% yield. Thus, the presented solid phase synthetic strategy is a viable alternative for the preparation of acid- and base-stable peptide esters. Since these esters are converted to active esters in the presence of subtilisin, they can be used in enzymic segment condensations, therefore serving as an useful alternative to the corresponding chemical process. N-Terminal Modification

Miller and co-workers utilised the acidifying effect of the ortho-nitrobenzenesulfonyl group (oNBS) to activate amide groups for a selective N-alkylation [18]. The incorporation of Nalkylated amino acids has often been used to probe the bioactive conformation of a peptide. In order to perform N-alkylations on the solid phase, N-oNBS protected amino acids were coupled to the unprotected amino group of a peptide 20 (Scheme 5). Subsequently, the NoNBS-peptidederivatives 21 were selectively alkylated at their acidic sulfonamide group. For example, reaction of the supported tetrapeptide 21a with methyl 4-nitrobenzenesulfonate and the base MTBD quantitatively yielded 22a. The Pdo-catalysed N-allylation of 21b succeeded with allylmethyl carbonate in a yield of 98%. For the cleavage of the oNBS-group the tertiary sulfonamides 22 were treated with mercaptoethanol/DBU. Under these conditions, the unalkylated secondary sulfonamides remained intact. The oNBS-group could also be used as a general temporary protecting group in the solid phase synthesis of unalkylated peptides [ 191. In the cleavage step, 21 was treated with 0.5 M potassium thiophenolate for 10 minutes, this liberated the amino group of 23 as well as a yellow chromophore. Thereby, the course of the cleavage reaction can be conveniently monitored photometrically. For comparison purposes, the synthesis of the thrombinereceptor-agonist 24 was carried out by both the oNBS- and the Fmoc-strategy. After HPLCpurification of the crude materials, which were obtained in 85% (oNBS) and 91% (Fmoc) purity, the pure peptide 24 was furnished in 50% (oNBS) and 62% (Fmoc) overall yield. Amide-backbone Substitution

Despite the great success of solid phase peptide synthesis there are a few sequences which are known as difficult. It is thought that the difficulties of achieving quantitative coupling and deprotection yields arise from intermolecular association of the resin-bound peptide chains [ 201. Sheppard and co-workers identified the amide-backbone as being responsible for maintaining an intermolecular hydrogen bonding network and introduced amide-backbone substitution with the 2-hydroxy-4-methoxybenzyl(Hmb) group as a means to prevent secondary structure formation [21]. However, the usefulness of the Hmb auxiliary is limited by the low reactivity of the secondary amino group of N-Hmb-modified peptides such as 25 (Scheme 6). The acylation of N-Hmb-amino acids proceeds through the 0-acyl intermediate 26 which undergoes a relatively slow 0 - N acyl transfer to form the peptide bond in 27. Miranda, Alewood and co-workers improved acyl transfer rates by attaching the electronwithdrawing nitro group in ortho-position [22]. For example, the difficult coupling of a valine to the valine peptide 25a proceeded with a N-acylation yield of only 23% 30a when the Hmb-auxiliary was employed. In contrast, the use of the Hnb-auxiliary greatly enhanced acyl

236

I

Activating Protecting Croupsfor the Solid Phase

d

2

6

Carbohydrates I 2 3 7

transfer efficiency affording coupling product 301, in 93% yield. The removal of the Hnbgroup was achieved by photolysis which liberated the unprotected peptide 31. Nucleic Acids

Protecting groups, which allow the introduction of additional functional groups after a solid phase assembly, are of particular interest for the construction of medicinally relevant DNAand RNA-conjugates. Contrary to proteins, only a few functional groups of nucleic acids can be used for the conjugation of reporter groups or crosslinkers without compromising their biological function. In 1990, Verdine reported a method, in which uridine derivatives were incorporated into oligonucleotides and subsequently modified [ 231. This concept has recently been extended to the synthesis of functionalised oligoribonucleotides [ 241. The inosine base 32 and the uridine base 34 carry para-chlorophenyl groups at the 06-or 04-position(Scheme 7). Simple substitution with primary amines (RNH2) resulted in the formation of the corresponding adenosine- and cytidine-derivatives. Thus, the R-group will be positioned in the major groove of a nucleic acid duplex. After substitution the fluoride and cleavage of the nitrophenylethyl(NPE)-protecting group the fluoroinosine 33 forms a guanosine system, positioning the R-group in the minor groove. For the synthesis of the RNA-oligomers 36a-c the phosphoamidites 35a-c were incorporated using a slightly modified RNA-synthesis-protocol(Scheme 8). The functionalisation of the oligomers 3Ga-c proceeded using the amines listed in Table 1. Subsequent treatment with either TBAF or NEt3.HF removed the NPE- and TBDMS-protecting groups. The relative yields were evaluated after purifying the products 37a-c by denaturing polyacrylamide gelelectrophoresis (PAGE) and enzymic hydrolysis. Finally, the composition of the nucleic acid was determined by HPLC. All conversions proceeded virtually quantitatively with exception of the reactions with benzylamine and of 36a with ammonia. Carbohydrates

The solid phase synthesis of complex oligosaccharides presents demanding challenges [ 25281. Each monomer embodies a multitude of functional groups of similar reactivity. A large number of protecting groups is available for the various needs of oligosaccharide synthesis. A few of them can be activated and converted to leaving groups such that subsequent functional group interconversions are facilitated. Anomeric Protection

The coupling of two building blocks involves a glycosylation reaction, which creates a new stereogenic centre (in contrast to peptides or nucleic acids). On solid phase the glycosidic linkage can be formed by two approaches. It is either the glycosyl donor that is attached to the solid support or the glycosyl acceptor. The former strategy requires an anomeric protecting group that can be selectively removed prior to activation of the anomeric centre. It is obvious that a protecting group amenable to a selective activation offers significant advantages as far as conciseness is concerned. Thioglycosides [ 291, n-pentenyl glycosides [ 301 and

238

I

Activating Protecting Croups for the Solid Phase Synthesis

(D

rb

a

N

K

8

E

U

N

0

29a (Hmb) 29b (Hnb)

Ala-Gly-Phe

+

1 Ala-Gly-Phe

CH2

30a (Hmb), 23% 30b (Hnb), 93%

""y

1) DMF,piperidme 2) mild TFA cleavage

Scheme 6. The Hnb-protecting group serves as an activated 0 - N transfer auxiliary for the efficient synthesis of difficult peptides.

R2

acyl

1

R*

Hmb: TFA Hnb: hv

HoeR1 HoeR

' CH2

HN

= trityl

240

I

Activating Protecting Groupsfor the Solid Phase Synthesis

A

I

34

RNH2, MeOH

Major Groove

N-H-

0

- -0

Minor Groove Scheme 7. Convertible nucleosides that allow for major-groove and minor-groove modifications.

glycosyl fluorides fulfil the demands and serve both anomeric protection and anomeric activation. Ito and co-workers were one of the first to attach a thioglycoside donor to a polymeric support [31]. In an approach that is known as orthogonal glycosylation they employed the polymer-bound thioglycoside 39 as glycosyl donor and the glycosyl fluoride 40 as glycosyl acceptor (Scheme 9). The formed dimannoside 41 was converted into a glycosyl donor by treatment with hafnocene, which promoted the glycosylation of the mannoside 42 to afford the trisaccharide resin 43.The following cleavage from the soluble support yielded the trimannoside 44 in 40% overall yield. There are some drawbacks of the donor-bound approach. Fraser-Reid and co-workers showed that the glycosylation with an immobilised n-pentenyl glycoside produced the desired glycoside but also the corresponding hemiacetal which resulted from hydrolysis of the resin-bound donor [ 321. Takahashi and co-workers compared several polymer-bound glycosyl donors and found that thioglycosides and glycosyl sulfoxides provided quantitative yields of disaccharide products [33]. The highest flexibility would be provided if the supported oligosaccharide were useful as both glycosyl donor and glycosyl acceptor. Such a bidirectional strategy has been reported by Zhu and Boons who demonstrated the elaboration of a growing oligosaccharide in both directions [ 341. For example, the polymer-bound thioglycoside 45 displayed one unprotected hydroxyl group, which was used as the glucosyl acceptor site in the glucosylation with the trichloroacetimidate donor 46 (Scheme 10). The formed 1,4-linked diglucoside 47 proved to be a good glycosyl donor when coupled with the acceptor 48 to give trisaccharide 49 in GO% overall yield.

Carbohydrates I 2 4 1

9;,\ -

RNA-solid-phase synthesis according to the phosphoamidite strategy

OTBDMS

-

DMT-0

TL

.,I OTBDMS

N(iPr)2

0 P ;

RNA OCH&H2CN

35 a: B=32, b: B = 33, c: B = 34

-0

-

0 RNA

36 a: 5'-GAC UU(32) GUA CC-3' b: 5'-AGU CC(33) GCU AG-3' C: 5'-GCU AA(34) CCU AU-3'

a) 2M RNH2 in MeOH b) a s : 1 M TBAF in THF; b: NEt3.3HF

J

KN.H

37 a: 5-GAC UUA'

GUA CC-3'

b: 5'-AGU CCGRGCU AG-3 C: 5'-GCU AACR CCU AU-3'

RNA Scheme 8.

- 0OH;$

0

- RNA

Postsynthetic modification of RNA by using the convertible nucleosides shown in Scheme 7.

Linkers

The feasibility of converting a protecting group into a leaving group is of high utility for the design of diversity-increasing linkers. Thioglycosides have been employed as solid-phase linkers and shown to withstand a wide range of reaction conditions [35]. Schmidt and Tab. 1. Relative yields of substitutions of 36a-c with RNH2 to give 37a-c (see Scheme 8).

R

aa

bb

Cb

H CH3 HzNCHzCHz HzN(CHz)4 HOCHzCHl PhCHz

0.24 1.0 1.0 1.04 1.1 0.67

1.0

0.85 0.9 0.88 1.0 0.65

1.0 1.0 0.96 1.0 1.04 0.79

"based on the reaction with methylamine; "based on the reaction with ammonia.

242

I

Activating Protecting Croups for the Solid Phase Synthesis

O(CH2)5CO

a

O(CHz)&O

Q B:;qQ

a

Bn:q B:iw Bntw Bn:q 1 40

BnO

F

BnO

39

MeOS02CF3, MeSSMe, 4A MS, CH2C12,89%

SMe

BnO

41

BnO

F

CpnHfCl2, AgOS02CF3, 4A MS, CH2C12,99%

BnO

O(CHz)&O

n = monomethyl-polyethyleneglycol

a

OSE

Bn:-i

%:H HO

40%

42

BnO

H-9 HO

overall

H O T

44

o

Bn:q BnO

43

%:nB BnO OSE

Scheme 9.

OSE Thioglycoside 39 and the fluoro disaccharide 41 as polymer-bound glycosyl donors.

co-workers used thioalkylated supports (see 50) and a NBS-mediated activation of the thioglycosidic linkage to prepare a pentamannoside or the branched pentasaccharide 51 as methyl glycosides (Scheme 11) [ 36, 371. The cleavage step can be fashioned into a diversityincreasing reaction which is of high interest in combinatorial synthesis [38]. Kunz and co-workers took advantage of a bromine-induced cleavage of the thioglycosides 52 and used the formed bromo sugar intermediate for the glycosylation of various alcohols (Scheme 12) [39]. Nicolaou and co-workers presented a seleno-based linker which allows for a stereocontrolled construction of 2-deoxy glycosides and orthoesters 1401. The carbohydrate was attached to the solid support by means of a glycosylation reaction using the trichloroacetimidate 54 as donor and the resin-bound selenol 55 as acceptor (Scheme 13). The C-2 ester of 56 was removed by basic methanolysis. Treatment of the 2-hydroxy compound with DAST induced a 1,2-selenophenyl migration affording the 2-seleno-1-fluoro sugar 57. The resin-

244

I

Activating Protecting Croupsfor the Solid Phase Synthesis

-

.-4

0

/

B:-4 BnO

NBS, DTBP, CH2CI2,MeOH

BnO

OBn

_____t

BnO&

= polystyrene

I BE=

0

Lco+:Troc

50

“O OAc

The thioglycoside linkage in 50 was activated to yield methyl glycoside 51 (DTBP, 2,6-di-tert-butyI-pyridine).

Scheme 11.

-

Br2, DTBP, cyclohexene

NH-~6

CH2C12, R’OH, Et4NBr

$’

H 0

R3-HN

52

&&,,vOR1 OR2

53

0

R’OH = MeOH, EtOH, iPrOH

= polystyrene

The activation of a thioglycoside linkage such as 52 enables the usage of galactose as a five-dimension diversity scaffold.

Scheme 12.

bound donor 57 was employed in a SnClz-promoted glycosylation of the glucoside 58 yielding the disaccharide resin 59. For release of the 2-deoxy glycoside 60, resin 59 was exposed to nBu3 SnH/AIBN, which afforded the radical cleavage of the Se-C bond. Alternatively, oxidation of 59 to a selenoxide intermediate and subsequent syn-elimination led to the formation of the orthoester 61. Schmidt and Seeberger developed linkers that can be cleaved by olefin metathesis. For example, ring-closing metathesis cleaved the diene linkage of 62 and released the ally1 glycosides 63 (Scheme 14) [41].Seeberger and co-workers used a cross-metathesis reaction to release oligosaccharides in form of n-pentenyl glycosides such as 65 [42]. These conjugates can be submitted to a variety of modification reactions or employed as donors in “postsynthetic” glycosylations [43].

n

54

BnO AGO

O

s

59

55

Bu3SnSe

b) A

1

Me0

CH2C12, -78°C

a) mCPBA,

Me0 OMe

Hoe* OMe

O Y N H cc13

~

58

Me0

B

BF3.Et20 ___)

Scheme 13. The seleno linkage in 56 and a 1 ,Z-seleno-migration (56-57) provided access to 2-deoxy-saccharldes such as 60 and orthoesters such as 61 (mCPBA, rneta-chloro perbenzoic acld; DAST, diethylamonium sulfur trifluoride).

BnO% BnO

nBu3SnH, AIBN, benzene

B

+ OMe B

BnO

56

= polystyrene

57

a) NaOMe, THF, MeOH b) DAST, CH2C12

OMe

c

AcO

246

I

Activating Protecting Croupsfor the Solid Phase Synthesis

63

BnO BnO

BnO

= polystyrene

0

PivO

HzC

= CHz

Clr.

I

65 PivO Ring-closing olefin metathesis o f 62 detached the ally1 glycoside 63.A cross-metathesis with 64 and ethylene liberated targetoligosaccharides such as 65 in form o f their n-pentenyl glycosides. Scheme 14.

Protecting Croupsfor Internal Aglycon De/;very

The stereoselective formation of a glycosidic bond is the key feature of oligosaccharide synthesis. Despite the many powerful glycosylation methods that have been developed, there are still a few glycosidic linkages that are difficult to synthesise. For example, the /I-mannosidic bond presents a synthetic challenge because the anomeric effect favours the formation of

Conclusion I 2 4 7

a-mannosides. Usually, P-glycoside formation can be accomplished by arming the glycosyl donor with a participating neighbouring acyl group at the 0-2 position. This approach is inappropriate when attempted with mannosides since participation of an axial 0-2-acyl substituent also leads to a-mannoside formation. With this difficult task in mind new types of protecting groups were developed which are able to stereospecifically direct the introduction of a reagent [44). The approach of attaching the aglycon to a bifunctional protecting group has been termed intramolecular aglycon delivery and has been frequently applied to the solution-phase synthesis of P-mannosides and a-glucosides. Ito and Ogawa demonstrated the utility of a polymer-bound protecting group for p-mannoside synthesis. According to a strategy published in 1991 by Barresi and Hindsgaul, the axial 2-OH-group can be utilised to present the aglycon in the glycosylation reaction to the b-face [45]. Similarly, Ito and Ogawa introduced a para-alkoxybenzyl group at this position [46]. For the attachment to a polymeric support, the alkoxybenzyl group of methyl thiomannoside 66 carried a carboxyl group (Scheme 15) [47]. Oxidation of the polymer bound mannoside 67 with DDQ in the presence of an alcohol yielded the acetal 68. Upon activation of the thioglycoside with methyl triflate, 68 reacted in an intramolecular transacetalisation to give b-mannoside 69. I t is necessary to emphasise that only the desired glycosylation products were liberated from the polymeric resin into the liquid phase. By-products such as the hydrolysis product 70 or the elimination product 71 remained on the solid phase. The polymeric resin hence serves as a molecular gatekeeper, which in the final synthetic step liberates only the desired products. Conclusion

The presented examples illustrate that protecting groups can be actively used in synthesis and achieve more than temporary blocking of a functional group. Permanently activated protecting groups such as the oxime- and thioester linkers, the oNBS- and the chlorophenylgroups allow for subsequent transformations that raise the diversity of a given system. In order to increase the orthogonality protecting groups were developed which can be converted to leaving groups. A prototype is the methylation-induced activation of sulfonamide linkers. Other groups such as the hydrazides, the thioglycosides, the n-pentenyl glycosides, the glycosy1 fluorides and the PAM-esters are activated in presence of certain reagents or (bio)catalysts. The products formed after such activation would normally have to be synthesised in a less efficient fashion. The example of the Hmb-peptide backbone protection and the polymer supported synthesis of P-mannosides demonstrated how protecting groups can facilitate peptide couplings and stereoselective glycosylation reactions, respectively, once a suitable orientation is obtained. The development and use of such multi-purpose protecting groups is certainly attractive for future research. One of the most difficult tasks of chemical biology is to match the different time scales of chemical and biological research. A combination of solid-phase techniques with “smart” protecting groups offers the prospect of significantly shortening the often time consuming synthesis of modified biopolymer probes, which are essential for the advancement of molecular life-sciences.

248

I

Activating Protecting Croups for the Solid Phase Synthesis

O(CH2)&+

R

I

phT+

66, R = Et

a) NaOH, tBuOH b) PEG-monomethylether, DEAD, PPh3, CH&, THF, 80%.

67, R = PEG

TBS)

SMe

J

liquid phase

4

R'-0 =

O a BnO

o

DDQ, MS4& CHzClp, 3h

polymeric phase

MeOTf, MeSSMe, DTBP, CICH&H2CI, MS4A, 21-120h

B

n

50%

9

1

O(CH2)5C-

I

OBn

R'-0 =

BnO -0

F NPhth

37%

; I I I

P

h TBS)

Scheme 15. The polymer-bound alkoxybenzyl protecting group in 67 serves as a directing group and enabled the intramolecular aglycon delivery t o afford a stereoselective formation of p-mannosides 69. By products such as 70 and 71 remained on the polymeric support

T

a o-R'

71

References

I249

References R. B. MERRIFIELD,]. Am. Chem. SOC.1963, 85, 2149. 2 K. JAROWICKI, P. KOCIENSKI,]. Chem. SOC. Perkin Trans. 1 2001, 2109-2135. 3 M. SCHELHAAS, H. WALDMANN, Angav. Chem. Znt. Ed. 1996, 35, 2056-2083. 4 For an excellent review about linker and cleavage strategies in solid-phase synthesis: F. GUILLIER, D. ORAIN,M. BRADLEY, Chem. Rev. 2000, 100, 2091-2157. 5 W. F. DEGRADO, E. T. KAISER,]. Org. Chem. 1980, 45, 1295-1300. 6 G. OSAPAY, A. PROFIT,J. W. TAYLOR, Tetrahedron Lett. 1990, 31, 6121-6124. 7 G. W. KENNER, MCDERMOT. J R , R. C. SHEPPARD,]. Chem. Soc., Chem. Commun. 1971, 636. 8 B. J. BACKES, A. A. VIRGILIO, J. A. ELLMAN,]. Am. Chem. SOC.1996, 118, 3055-3056. 9 Y. SHIN,K. A. WINANS, B. J. BACKES, S. B. H. KENT,J. A. ELLMAN,C. R. BERTOZZI,]. Am. Chem. SOC.1999, 121, 11684-11689. 10 P. E. DAWSON, T. W. MUIR,I. CLARKLEWIS,S. B. H. KENT,Science 1994, 266, 776-779. 11 T. WIELAND, J. LEWALTER, C. BIRR, Ann. Chem. 1970, 740, 31. 12 A. N. SEMENOV, K. Y. GORDEEV, Int. J . Pept. Protein Res. 1995, 45, 303-304. 13 C. R. MILLINGTON, R. QUARRELL, G. LOWE, Tetrahedron Lett. 1998, 39, 7201-7204. 14 F. STIEBER, U. GRETHER, H. WALDMANN, Angew. Chem. Int. Ed. 1999, 38, 10731077. 15 C. ROSENBAUM, H. WALDMANN, Tetrahedron Lett. 2001, 42, 5677-5680. 16 D. Y. JACKSON, J. BURNIER,C. QUAN,M. STANLEY, J. TOM,J. A. WELLS, Science 1994, 266, 243-247. 17 K. WITTE,0. SEITZ,C. H. WONG,]. Am. Chem. SOC.1998, 120, 1979-1989. 18 S. C . MILLER, T. S. SCANLAN,].Am. Chem. SOC.1997, 119, 2301-2302. 19 S . C . MILLER, T. S. SCANLAN,]. Am. Chem. SOC.1998, 120, 2690-2691. 20 A. G. LUDWICK, L. W. J E L I N S K I , D. LIVE, A. KINTANAR, J. J . DUMAIS,].Am. Chem. SOC.1986, 108, 6493-6496. 21 C. HYDE,T. J O H N S O N , D. OWEN,M. Int.]. Pept. QUIBELL, R. C. SHEPPARD, Protein Res. 1994: 43, 431-440. 1

P.MIRANDA, W. D. F. MEUTERMANS, /. Org. M. L. SMYTHE,P. F. ALEWOOD, Chem. 2000, 65, 5460-5468. 23 A. M. MACMILLAN, G. L. VERDINE,]. Org. Chem. 1990, 55,5931-5933. 24 C. R. ALLERSON, S. L. CHEN,G. L. VERDINE,].Am. Chem. SOC.1997, 119, 7423-7433. 25 P.SEARS, C. H. WONG,Science 2001, 291, 2344-2350. 26 P. H. SEEBERGER, W. C. HAASE,Chem. Rev. 2000, 100,4349-4393. 27 0. SEITZ,Chembiochem 2000, I, 215-246. 28 Solid Support Oligosaccharide Synthesis and Combinatorial Carbohydrate Libraries, SEEBERGER, P. H. ed., John Wiley & Sons, New York, 2001. 29 For a review: P. J. GAREGG, Adu. Carbohydr. Chem. Biochem. 1997, 52, 179-205. 30 B. FRASER-REID, U. E. UDODONG, 2. F. I. R. MERRITT,C. S. Wu, H. OTTOSSON, RAo, C. ROBERTS, R. MADSEN, Synlett 1992, 927-942. 31 Y. ITO, 0. KANIE, T. OGAWA, Angew. Chem. Int. Ed. 1996, 35, 2510-2512. 32 R. RODEBAUGH,S. JOSHI,B. FRASERREID, H. M. GEYSEN,].Org. Chem. 1997, 62, 5660-5661. 33 T. DOI, M. SUGIKI, H. YAMADA, T. TAKAHASHI, J. A. PORCO,Tetrahedron Lett. 1999, 40, 2141-2144. 34 T. ZHU, G. J. BOONS,Angew. Chem. Int. Ed. 1998, 37, 1898-1900. 35 S . H. L. CHIU,L. ANDERSON, Carbohydr. Res. 1976, 50, 227-238. 36 I. RADEMANN, R. R. SCHMIDT,].Org. Chem. 1997, 62, 3650-3653. 37 J. RADEMANN, A. GEYER, R. R. SCHMIDT, Angew. Chem. Int. Ed. 1998, 37, 1241-1245. 38 T. WUNBERG, C. KALLUS, T. OPATZ,S. HENKE, W. SCHMIDT, H. KUNZ, Angew. Chem. Int. Ed. 1998, 37, 2503-2505. 39 C. KALLUS, T. OPATZ,T. WUNBERG, W. S. H E N K EH. , KUNZ, Tetrahedron SCHMIDT, Lett. 1999, 40, 7783-7786. 40 K. C. NICOLAOU, H. J. MITCHELL, K. C. FYLAKTAKIDOU, H. SUZUKI,R. M. RODRIGUEZ, Angew. Chem. Int. Ed. 2000, 39,1089-1093. 41 L. KNERR, R. R. SCHMIDT, Synlett 1999, 1802-1804. 22 L.

250

I

Activating Protecting Groupsfor the Solid Phase Synthesis

R. B. ANDRADE, 0. 1. PIANTE,L. G. MELEAN, P. H. SEEBERGER, Org. Lett. 1999, 1, 1811-1814. 43 T. BUSKAS,E. SODERBERG, P. KONRADSSON, B. FRASER-REID,].Org. Chem. 2000, 65,958-963. 44 For a review about intramolecular 0glycoside bond formation: K. H. J U N G ,M.

MULLER, R. R. SCHMIDT,Chem. Rev. 2000,

42

100,4423-4442. 45 46

47

F. BARRESI,0. HINDSGAUL,].Am. Chem. SOC.1991,113, 9376-9377. Y. Iro, T. OGAWA,Angew. Chem. Int. Ed. 1994,33,1765-1767. Y. ITO, T. OGAWA,].Am. Chem. SOC.1997, 119,5562-5566.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

I251

Traceless Linkers for Solid-Phase Organic Synthesis Florencio Zaragoza Donodd Introduction

To expand the scope of products available by solid-phase synthesis, a series of strategies have been developed in recent years which enable the generation of C-H and C-C bonds upon cleavage from a support, and in this way enable the preparation of unfunctionalized hydrocarbons. These linkers are sometimes also called ‘traceless’ linkers, because in some types of product the attachment point to the support can no longer be located. Such traceless linkers can give access to compound libraries devoid of a common functional group that was required for covalent attachment of the intermediates to the support. The preparation of highly diverse compound arrays by solid-phase synthesis should, therefore, be possible with such linkers [ 1-31. The strategies described to date for the generation of C-H and C-C bonds during cleavage include decarboxylative cleavage, acidolysis of silanes, reductive cleavage of acetals, thioethers, selenides, sulfones, sulfonates, triazenes, sulfonylhydrazones, or organometallic compounds (Figure I ) , the nucleophilic cleavage of resin-bound alkylating agents by carbon nucleophiles, and the oxidative cleavage of hydrazides [ 31. Cleavage followed by decarboxylation has been used for the preparation of ketones [4-6], nitriles [5, 71, amides (81, quinazolines [9], amines [lo], and 3-methylindoles [ll].Because decarboxylation generally requires an additional functional group to promote decarboxylation, which reveals the original point of attachment, this cleavage strategy usually does not enable the preparation of unfunctionalized hydrocarbons, and does therefore not belong to the class of truely traceless linkers. Cleavage of Silanes, Organogermanium, and Organoboron Compounds

Polystyrene-bound silanes are usually prepared by reaction of organolithium compounds with resin-bound silyl chlorides [12,131. The C-Si bonds of aryl-, heteroaryl-, vinyl-, and allylsilanes are stable towards alcoholates or weak reducing agents, but can be cleaved under mild conditions by treatment with acids or fluoride to yield a hydrocarbon and a silyl ester or silyl fluoride. Several linkers of this type have been tested and have proven useful for the preparation of unfunctionalized arenes and alkenes upon cleavage from insoluble supports.

252

I

Traceless Linken for Solid-Phase Organic Synthesis

Z Nu(e.g. H-, Z,HC-)

Pd

R w O v P o l

i"

*

I

R -Nu

PdL,

RnxPol

homolytic or heterolytic, reductive cleavage

*

R"H

Fig. 1. Generation of C-C and C-H bonds upon cleavage from supports. Pol: polymeric support; Z: electron-withdrawing group; X: metal. NzNR, PR2+, 0, SO,, Se, etc.

The optimal conditions for cleavage of resin-bound arylsilanes depend on the substitution pattern of the arene (Table 1). Some donor-substituted arenes can already be cleaved from silyl linkers by treatment with trifluoroacetic acid (TFA) [ 141. Particularly acid-sensitive are resin-bound 3-(dialkylarylsilyl)propionamides(Entry 1, Table 1).Arylsilanes bearing electronwithdrawing groups on the arene are more difficult to desilylate with weak acids (compare, e.g., Entries 2 and 3, Table 1).When TFA fails to promote protodesilylation, hydrogen fluoride, cesium fluoride, or TBAF might bring about the cleavage (Table 1).Alternatively, resinbound arylsilanes can also be cleaved by treatment with 1,2-dihydroxybenzene (5 eq, MeCN, 50 "C, 20 h) or with glycolic acid, whereby bis(dio1ato)silicatesare formed [15]. Support-bound allylsilanes can be cleaved either by treatment with acids or by treatment with carbon electrophiles. The third reaction in Figure 2 is an example of a cleavage, in which the electrophile is an cc-alkoxy carbocation generated from an acetal and TiC14. Arylboronic acids esterified with support-bound 1,2-diols undergo Suzuki reaction with aryl iodides, whereby biaryls are released into solution (first reaction, Figure 3; see also [ 2 7 ] ) . This technique has also been used to prepare p-turn mimetics by simultaneous macrocyclization and cleavage from the support [ 281. The C-B bond of resin-bound boronates can also be converted to a C-H bond by treatment with aqueous silver ammonium nitrate (second reaction, Figure 3). Reductive Cleavage of Carbon-Oxygen Bonds

The direct homolytic, reductive cleavage of C-0 bonds has not been used to release products from polymeric supports. C-0 Bonds are too strong to undergo homolytic cleavage under acceptably mild reaction conditions, but acetals and allyl esters can smoothly be cleaved heterolytically. When resin-bound acetals are treated with Lewis acids in the presence of a reducing agent or a carbon nucleophile, reductive cleavage from the support can occur. Ethers and sulfonamides have been prepared using this cleavage strategy (Figure 4). Esters of allylic alcohols with resin-bound carboxylic acids can be converted into palladium allyl complexes by treatment with palladium(0). These allyl complexes react with carbon

Entry

Tab. 1.

CN

Loaded resin

TBAF, DMF, 65 "C, 1 h Ar: 4-(MeO)CaH4

TBAF (1mol/L), THF, 12 h

TFAIDCM 1:1, 20 "C, 24 h

CSF, DMF/H20 4x1, 110 "C (no cleavage b y neat TFA, 25 "C) Ar: 4-formylphenyl

TFA/DCM 1:1, 25 "C, 3 h

TFA/DCM 1:1, 20 "C, 2 h Ar: 1-naphthyl

Cleavage conditions

100%

Ph

58%

a

H

80%

93%

pho'o

Ar

Product, yield

see also 22

21

see also 19

18

17

13

16

Re$

Generation of arenes upon cleavage of support-bound aryl silanes and arylgerrnaniurn compounds. PS: cross-linked polystyrene; (PS): PS with spacer.

N W In

9

5

8

7

Entry

Tab. 1.

O

H


Ar

Loaded resin

(continued)

Ar: 4-(MeO)C6H4

TFA, GO "C, 24 h

Me2S/H20 85:lO:S) Ar: 4-(MeO)CbH4

HF, 12 h (nocleavage by TFAI

Cleavage conditions

-f$O

Product, yield

58%

68% 23 see also 24

23

Re$

sa

3.

4.

$

ul -c

3

P s

2a

%

2

fi

t

m,

-i

Reductive Cleavage of Carbon- Nitrogen Bonds

Fig. 2.

I

255

Cleavage of polystyrene-bound allysilanes by TFA or carbocations [25,261.

nucleophiles and with hydride sources to yield the products of allylic nucleophilic substitution (Entries 1 and 2, Table 2). Alkyl sulfonates have been reduced to alkanes with NaBH4 or cleaved from supports by treatment with Grignard reagents (Entries 3 and 4, Table 2). Aryl sulfonates (Entry 5 , Table 2) and aryl perfluoroalkylsulfonates [ 311 can be reduced to alkanes by treatment with catalytic amounts of palladium(I1) and formic acid as hydride source. Polymer-supported aryl perfluoroalkylsulfonates have been used to prepare biaryls from aryl boronic acids [ 321. Reductive Cleavage o f Carbon-Nitrogen Bonds

Support-bound triazenes, which can be prepared from resin-bound secondary, aliphatic amines and aromatic diazonium salts [37], undergo cleavage upon treatment with acids, whereby the aromatic diazonium salts are regenerated. In cross-linked polystyrene these diazonium salts decompose to yield nitrogen and, preferentially, aryl radicals. If the acidolysis of polystyrene-bound triazenes is conducted in the presence of hydrogen-atom donors

4-iodoanisole (5 eq), aq &PO, (2 mol/L, 3 eq) PdCI,BINAP (0.05 eq), DMF, 60 "C, 24 h

*

85%

Ag(NH,),NO,

Meon Ph

> 95% pure

(0.25 mol/L, 10 eq)

H,O/THF 1:1,67 "C, 8 h

57% SP, 0 Fig. 3.

Polystyrene-bound boronates as traceless linkers [28, 291

> 90% pure

256

I

Traceless Linkersfor Solid-Phase Organic Synthesis

TFA (5 eq), Et3SiH (10 eq), DCM 20 "C, 24 h

+ 41%

e S i M e 3

\

(2.5 eq), SnCI, (1.1 eq)

DCM, 20 " C , 24 h 47%

*

YNo \

\

Fig. 4.

Reductive cleavage of polystyrene-bound acetals and herniaminals [30].

(e.g. THF), unsubstituted arenes can be obtained (Entries 1 and 2, Table 3). In the presence of alkenes or alkynes and Pd(0Ac)Z the initially formed diazonium salts can undergo Heck reaction to yield vinylated or alkynylated arenes (Entry 3, Table 3). Similarly, unsubstituted arenes can be obtained by oxidative cleavage of support-bound N-aryl-N'-acylhydrazines (Entry 4, Table 3). Oxidation leads to the formation of N-aryl-N'-acyldiazenes,which in the presence of nucleophiles undergo deacylation to yield acid derivatives and aryldiazenes. The latter are unstable and decompose into arenes and nitrogen. Air in the presence of catalytic amounts of Cu(OAc)z,or NBS [38, 391 can be used as oxidants for hydrazides. Support-bound sulfonylhydrazones have been reduced to alkanes by sodium borohydride (Entry 5, Table 3). This reaction, which has not yet been fully optimized for solid-phase synthesis, should enable the support-aided conversion of ketones into alkanes under mild reaction conditions. Reductive Cleavage o f Carbon-Phosphorus and Carbon-Sulfur Bonds

Phosphonium salts can be dealkylated by treatment with alkoxides to yield alkanes. Although the hydrolytic cleavage of phosphonium salts in solution has been investigated extensively, the solid-phase variant of this reaction has not yet found broad application. One example, in which traceless linking was based on the alkoxide-induced dealkylation of a resin-bound phosphonium salt, is given in Table 4 (Entry 1). Hydrocarbons can be generated by nucleophilic cleavage of resin-bound ally1 sulfones with carbon nucleophiles (e.g. Entry 3, Table 4),whereby the resin-bound sulfinate acts as the leaving group. Thioethers, sulfoxides, and sulfones can also undergo C-S bond cleavage upon photolysis or upon treatment with reducing agents such as tin hydrides, sodium amalgam, or Raney nickel (Entries 4-6, Table 4). These reducing agents are, unfortunately, non-volatile, and further purification of the crude products will be necessary in most instances, making this cleavage strategy unsuitable for parallel synthesis. Resin-bound benzylic thioethers can be converted to sulfonium salts by S-alkylation with triethyloxonium tetrafluoroborate. These sulfonium salts react with palladium(0) complexes to yield benzylpalladium complexes, which undergo Suzuki coupling with arylboronic acids (Entry 7,Table 4).

5

4

2

1

Entry

,o& ,+ (s 0 PS

r/tkOSiMe'

HC02H (7.5 eq), NEt3 (8 eq), Pd(OAc)2 (0.2 eq), dppp, 110 "C, 12 h

(15 eq), Mg (15 eq), CuBr.SMez (1 eq), THF, 20 "C, 3 h, then CSA, MeOH, H20

B

NaBH4 (0.1 mol/L), DMSO, GO "C, 12 h

( M e 0 2 Q C H N a (3 eq), 7% Pd(PPhs).t, THF. SO "C, 8 h

THF, triethyl ammonium formate (5 eq), 7% Pd(PPh3)4,70 "C

PS

+
Cleavage conditions

Loaded resin

Tab. 2. Formation of C-H and C-C bonds upon reductive cleavage o f ally esters and sulfonates.

OR

(43-90%)

78%

35

34

33

33

Ref:

36-74%

k/J

47%

H i

36 see also 31

po

BnO"

OBn

69%

Product, yield (purity)

U

N

-

in

p

5

4

3

2

1

Entry

Tab. 3.

CPh

CPh

Ph

\

H

("NAPS

CO,tBu

cx2N-pS

\

OH

Loaded resin

NaBH4 (1.1 mol/L, 8 eq), THF, 67 "C, 8 h

Cu(0Ac)z (0.5 eq), pyridine (10 eq), air, MeOH, 20 "C, 2 h

Pd(0Ac)Z (5%), TFA, MeOH, 40 "C, 2-12 h

HCl/THF or H)P02/C12HCCOzH or HSiC13, DCM, 32 "C, 15 min

THF/conc HCI l O : l , 50 "C, ultrasound, 5 min

Cleavage conditions

Formation of C-H and C-C bonds upon reductive cleavage o f C-N bonds.

27%

93% (> 900/)

//

p

53% (85%)

81%

-co2tBu

Ph

OH

53%

0

7oKp;-o

Product, yield (purity)

44

39

40. 41 see also 42

Re$

d2.

0

B

s

2

8m

0) U

N

Reductive Cleavage of Carbon-Phosphorus and Carbon-Sufur Bonds

* 00

-P sE

YI

U 13 0

wl

s

I

V U m

LA

n I

V c W

2 -m U W

._ Y 3

3

x

n VI

U

x

0 5)

f-p

V V U S m

I V c 0 ._ 4-

\

oc

m

E LL

4 n

F

qR

0

S

N

m

t

I

259

260

I

Traceless Linkersfor Solid-Phase Organic Synthesis

-

Reductive Cleavage of Carbon-Selenium Bonds

R,Sn*

+

R/\*

I SnR, S Pe o,l

e S n R 3 -R,Sn*

R,SnH - R,Sn'

oxidant

H Rc/elP , ol

- R,SnHal

R- *

R/\/H

O

R,Sn*

-

/

R -

SeV' POI

-

H,

R-

+

R-

+

5)SPeo,l

S *eP ,ol

Fig. 5. Selenides as linkers for alkanes a n d alkenes.

Reductive Cleavage of Carbon-Selenium Bonds

Selenides are more readily cleaved by tin radicals than thioethers. Products bound to crosslinked polystyrene by a C-Se bond can be released from the support either by treatment with an oxidant to yield alkenes [ 1, 55-58], or by treatment with tin radicals to yield alkanes or alkenes (Figure 5). Various methods have been developed which enable the preparation of selenides bound to cross-linked polystyrene [ 31. As starting material either nucleophilic or electrophilic resinbound selenium derivatives are used. Alkali metal selenides, selenoborate complexes, or tin selenides are strong nucleophiles which react swiftly with organic halides or other alkylating agents to yield alkyl selenides [59]. Electrophilic selenium derivatives, such as the bromides BrSe-Pol, phthalimides PhtNSe-Pol [60], or sulfonates RSOzSe-Pol [61], undergo addition to alkenes under mild reaction conditions. The reaction of alkenes containing a nucleophilic functional group with polystyrene-bound selenenyl bromide can lead to the cyclization of the alkene by C-C, C-0, or C-N bond formation with simultaneous attachment to the support (see, e.g., first and third reaction, Figure 6; see also [57, 621). Enantiomerically pure, supportbound selenenyl bromides react with functionalized alkenes to yield resin-bound, enantiomerically enriched lactones, ethers, and acetals (e.g., first reaction, Figure 6 [63]). Examples of the tin radical mediated cleavage of selenides are sketched in Figure 6; more examples have been reported (59, 62, 641. The carbon-centered radicals initially formed by homolytic C-Se bond cleavage can be directly reduced to the alkane by treatment with a tin hydride, allylated by treatment with ally1 tin derivatives (Figure 5), or may add to multiple bonds before reduction. The fourth reaction in Figure 6 is an example of the formation of a polycyclic indoline through radical cyclization. Radical-mediated cleavage proceeds under mild, essentially neutral reaction conditions and is well suited for the release of sensitive organic compounds from insoluble supports. Because non-volatile, tin-derived byproducts are formed during these cleavage reactions, purification of the resulting products will, however, generally be required.

I

261

262

I

Traceless Linkersfor Solid-Phase Organic Synthesis

Bu,SnH (5 eq)

OMe

BrSe

58%

71% de

Bu,SnHPhMe, (3 eq), 110 AlBN "C, (0.005 6h eq)

B

n

O

aps

V Se

OBn

B n o T c p h

BnO'

OBn

SnC14 (3 eq), DCM 0 "C, 1 h BrSe

NH, 1 eq

H

3 eq 1. COCI,, DCM, 0 "C, 1 h 2. rnorpholine (10 eq), N,Et, DCM, 25 "C, 12 h 3. Bu,SnH (4 eq), AlBN (1.3 eq), PhMe, 90 "C, 2 h 17%

,,.Ph

0 Fig. 6.

0

Reductive cleavage of C-Se bonds (60, 63, 651.

Conclusion

Traceless linkers enable the solid-phase synthesis of products which were formerly only accessible by tedious, multistep solution-phase chemistry. Some of these linkers tolerate a broad range of reaction conditions, giving the chemist plenty of freedom in the design of new solid-phase synthetic sequences. Interestingly, polystyrene-bound selenium reagents can also mediate useful chemical transformations of substrates during their attachment to the support, and thereby function both as reagents and as linkers. Unfortunately, most traceless linkers described to date require non-volatile cleavage reagents. Future developments should focus on cleavage protocols that yield crude products devoid of non-volatile byproducts. Such cleavage strategies would enable the preparation of pure crude products, as required for the parallel synthesis of large arrays of compounds. New traceless linkers cleavable with volatile reagents would be a useful supplement to existing cleavage methodologies, and would have the potential of finding widespread application.

References I 2 6 3

References F. ZARAGOZA, Angew. Chem. Int. Ed. 2000, 39,2077-2079. 2 S . B ~ s E S. , DAHMEN, Chem. Eur./. 2000, 6, 1899-1905. 3 F. ZARAGOZA, Organic Synthesis on Solid Phase; Wiley-VCH: Weinheim, New York, 2000. 4 P. GARIBAY, J. NIELSEN, T. HBEG-JENSEN, Tetrahedron Lett. 1998, 39, 2207-2210. 5 M. M. SIM,C. L. LEE, A. GANESAN, Tetrahedron Lett. 1998, 39, 2195-2198. 6 M. M. SIM,C. L. LEE. A. GANESAN, Tetrahedron Lett. 1998, 39, 6399-6402. 7 F. ZARAGOZA, Tetrahedron Lett. 1997, 38, 7291-7294. 8 B. C. HAMPER, K. 2. GAN,T. J. OWEN, Tetrahedron Lett. 1999, 40, 4973-4976. 9 J. M. COBB,M. T. FIORINI,C. R. GODDARD, M. E. THEOCLITOU, C. ABELL, Tetrahedron Lett. 1999, 40, 1045-1048. 10 G. J. KUSTER,H. W. SCHEEREN, Tetrahedron Lett. 2000, 41, 515-519. 11 J. R. HORTON, L. M. STAMP,A. ROUTLEDGE,Tetrahedron Lett. 2000, 41, 9181-9184. 12 F. X. WOOLARD, J. PAETSCH, J. A. ELLMAN. /. Org. Chem. 1997, 62, 6102-6103. 13 Y. Hu, J. A. PORCO,J. W. LABADIE,0. W. GOODING, B. M. TROST,/.Org. Chem. 1998, 63,4518-4521. 14 S. CURTET, M. LANGLOIS, Tetrahedron Lett. 1999, 40, 8563-8566. 15 R. TACKE, B. ULMER,B. WAGNER, M. ARLT,Organometallics2000, 19, 5297-5309. 16 N. D. HONE,S. G. DAVIES, N. J. DEVEREUX, S. L. TAYLOR, A. D. BAXTER, Tetrahedron Lett. 1998, 39, 897-900. 17 B. CHENERA, J. A. FINKELSTEIN,D. F. VEBER, /. Am. Chem. SOC.1995, 117, 11999-12000. 18 Y. LEE, R. B. SILVERMAN,/. Am. Chem. SOC.1999, 121,8407-8408. 19 Y. LEE, R. B. SILVERMAN, Org. Lett. 2000, 2, 303-306. 20 C. A. BRIEHN,T. KIRSCHBAUM, P. BAUERLE,/. Org. Chem. 2000, 65, 352359. 21 T. L. BOEHM, H. D. H. SHOWALTER,]. Org. Chem. 1996, 61, 6498-6499. 22 L. S. HARIKRISHNAN, H. D. H. SHOWALTER, Tetrahedron 2000, 56, 515519. 1

M. J. PLUNKETT, J. A. ELLMAN,/. Org. Chem. 1997, 62, 2885-2893. 24 A. C. SPIVEY, C. M. DIAPER,H. ADAMS, A. J. RUDGE,/. Org. Chem. 2000, 65, 5253-5263. 25 M. SCHUSTER, S. BLECHERT, Tetrahedron Lett. 1998, 39, 2295-2298. 26 M. SCHUSTER, N. LUCAS,S. BLECHERT, Chem. Commun. 1997, 823-824. 27 M. GRAVEL, C. D. BERUBE,D. G. HALL,/. Comb. Chem. 2000, 2, 228-231. 28 W. LI, K. BURGESS,Tetrahedron Lett. 1999, 40, 6527-6530. 29 C. POURBAIX, F. CARREAUX, B. CARBONI, H. DELEUZE, Chem. Commun. 2000, 12751276. 30 D. CRAIG,M. J. ROBSON, S. J. SHAW, Synlett 1998, 1381-1383. 31 Y. PAN,C. P. HOLMES, Org. Lett. 2001, 3, 2769-2771. 32 Y. PAN,B. RUHLAND,C. P. HOLMES, Angew. Chem. Int. Ed. 2001, 40,44884491. 33 S. C. SCHURER, S. BLECHERT,Synlett 1998, 166-168. 34 T. TAKAHASHI, H. INOUE, Y. YAMAMURA, T. DOI,Angew. Chem. lnt. Ed. 2001, 40, 3230-3233. 35 I. HIJIKURO, T. DOI,T. TAKAHASHI, J . Am. Chem. SOC.2001, 123, 37163722. 36 S. J I N , D. P. HOLUB,D. J. WUSTROW, Tetrahedron Lett. 1998, 39, 3651-3654. 37 J . C. NELSON,J. K. YOUNG?J. S. MOORE,/. Org. Chem. 1996, 61, 8160-8168. 38 C. R. MILLINGTON, R. QUARRELL, G . LOWE, Tetrahedron Lett. 1998, 39, 7201-7204. 39 F. STIEBER, U. GRETHER, H. WALDMANN, Angew. Chem. Int. Ed. 1999, 38, 10731077. 40 S. BR~SE, D. ENDERS,J. K O BBE RL I N GF. , AVEMARIA, Angew. Chem. Int. Ed. 1998, 37, 3413-3415. 41 M. LORMANN, S. DAHMEN, S. B R ~ S E , Tetrahedron Lett. 2000, 41, 3813-3816. 42 S. SCHUNK, D. ENDERS, Org. Lett. 2000, 2, 907-910. 43 S. B ~ S EM., SCHROEN, Angew. Chem. Int. Ed. 1999, 38, 1071-1073. 44 H. KAMOGAWA, A. KANZAWA, M. KADOYA, T. NAITO,M. NANASAWA, Bull. Chem. SOC. Jpn. 1983, 56, 762-765. 23

264

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Traceless Linkersfor Solid-Phase Organic Synthesis

I. HUGHES,Tetrahedron Lett. 1996, 37, 7595-7598. 46 L. F. HENNEQUIN, S. PIVA-LEBLANC, Tetrahedron Lett. 1999, 40, 3881-3884. 47 C. HALM,J. EVARTS, M. J. KURTH, Tetrahedron Lett. 1997, 38, 77097712. 48 W.-C. CHENG, C. HALM,J. B. EVARTS,M. M. OLMSTEAD, M. J. KURTH,J. Org. Chem. 1999, 64, 8557-8562. 49 K. W. J U N G , X. Y. ZHAO,K. D. J A N D A , Tetrahedron Lett. 1996, 37, 6491-6494. 50 K. W. J U N G , X. Y. ZHAO,K. D. J A N D A , Tetrahedron 1997, 53, 6645-6652. 51 I. SUCHOLEIKI, Tetrahedron Lett. 1994, 35, 7307-7310. 52 F. W. FORMAN, I. SUCHOLEIKIJ. Org. Chem. 1995, 60, 523-528. 53 X. Y. ZHAO,K. W. J U N G , K. D. JANDA, Tetrahedron Lett. 1997, 38, 977-980. 54 C. VANIER, F. L O R C ~ A. , WAGNER, C. MIOSKOWSKI, Angew. Chem. Int. Ed. 2000, 39, 1679-1683. 55 K. C. NICOLAOU,J. A. PFEFFERKORN, G.-Q. CAO,Angew. Chem. Int. Ed. 2000, 39, 734739.

45

K. C. NICOLAOU, G.-Q. CAO,J. A. Angew. Chem. Int. Ed. 2000, PFEFFERKORN, 39,739-743. 57 K.-I. FUJITA, K. WATANABE, A. OISHI,Y. IKEDA, Y. TAGUCHI, Synlett 1999, 1760-1762. 58 R. MICHELS, M. KATO, W. HEITZ, Makromol. Chem. 1976, 177, 2311-2320. 59 T. RUHLAND, K. ANDERSEN, H. PEDERSEN, J. Org. Chem. 1998, 63, 9204-9211. 60 K. C. NICOLAOU,J. PASTOR, S. BARLUENGA, N. WINSSINGER,J. Chem. SOC.,Chem. Commun. 1998, 1947-1948. 61 H . QIAN,X. HUANG, Synlett 2001, 1913-1916. 62 K. C. NICOLAOU, J. A. PFEFFERKORN, G.-Q. CAO,S. KIM, J . KESSABI, Org. Lett. 1999, 1, 807-810. 63 L. UEHLIN, T. WIRTH,Org. Lett. 2001, 3, 2931-2933. 64 2. LI, B. A. KULKARNI,A. GANESAN, Biotechnol. Bioeng. (Comb. Chem.) 2000, 71, 104-106. 65 K. C. NICOIAOU, A. J. ROECKER, J. A. PFEFFERKORN, G:Q. CAO,J . Am. Chem. SOC. 2000, 122, 2966-2967.

56

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Merging Solid-Phase and Solution-Phase Synthesis: The “Resin-Capture-Release” Hybrid Technique Andreas Kirschning and Riidiger Wittenberg Introduction

R. B. Merrifield [ 11 and the solid phase synthesis based on his concepts revolutionized polypeptide and polynucleotide synthesis and more than ten years ago it set the stage for combinatorial chemistry. Todays driving force for this still rapidly growing technique is associated with the need to quickly generate libraries of compounds [ 2 ] . As an alternative, the utilization of functionalized polymers as reagents and catalysts has recently appeared on this scene after an incubation time of more than 25 years (31. Here, it is not the substrate which remains attached to the solid support during a multistep synthesis but instead, the polymerbound reagent or catalyst promotes a chemical transformation of a substrate which is present in solution. One advantage of this polymer-assisted solution phase synthesis is the possibility to monitor the reaction using known analytical techniques [4]. Besides the use of stoichiometric reagents another technique for polymer-assisted solution-phase purification has often been employed recently. Polymer-bound scavengers are resins which are added after a chemical reaction to remove excess reactants and byproducts [ 51. However, the true potential of polymers in organic synthesis will fully be exploited if the whole orchestra of techniques are combined. And in fact, a hybrid technique that combines the concept of solid-phase synthesis with the idea of polymer-supported scavenging reagents has seen increased interest in polymer-assisted synthesis. Often, this method, which is only one example among other polymer-assisted combinations, has been termed the “resincapture-release” methodology and we shall use this terminology throughout this report. The functionalized polymers which have been developed for this technique allow the trapping of a small molecule as an activated polymer intermediate. After washing to remove soluble byproducts, this intermediate is subjected to a second transformation by adding a new reaction partner in solution. This reactant not only chemically alters the polymer-bound intermediate but at the same time provokes release of the product from the resin back into solution (Scheme 1). Sometimes the second transformation is only used to modify the immobilized

B-A Scheme 1.

C

-+

A-C

The “resin-capture-release” methodology

+

D

266

I

Merging Solid-Phase and Solution-Phase Synthesis: The “Resin-Capture-Release” Hybrid Technique

intermediate and it is a third transformation which leads to release of the product from the resin. However, it needs to be pointed out that due to the fact that this methodology is located in between two distinct polymer-assisted techniques a clear cut is not always possible and therefore, some of the sequences given in this article could well be defined as examples for solid phase synthesis. Nevertheless, it is the intention of this report to familiarize the reader with methodologies that merge various polymer-assisted techniques. The “resincapture-release’’methodology even if the terminology will not prevail in the longrun is one important group of polymer-assisted techniques in organic synthesis, which clearly illustrates this development. The transformations given here though some of them showing reminiscence to solid phase synthesis are easily incorporated into a multistep polymerassisted synthesis in solution where polymer-supported reagents or catalysts are employed prior or after the “resin-capture-release” transformation. Functional Polymers for “Capture-Release” Techniques

Acyl and Sulfonyl Transfer Protocols

Probably the most widely employed applications of the “resin-capture-release” methodology are acylation and sulfonylation reactions using polymer-supported amines such as polyDMAP (polymer-bound dimethylamino pyridine) 1, poly(4-vinylpyridine) [G] and (poly-TBD) 2 (polymer-attached 1.5.7-triaza-bicyclo[4.4.0]dec-5-ene). Reagent 1 is well suited for trapping acyl chlorides as well as sulfonyl chlorides [7]which then react with amines to the corresponding amides and sulfonamides, respectively (Scheme 2) [8]. Furthermore, it should be noted that silylation of alcohols can be achieved in an analogous manner using Amberlyst A21 (poly-CHzNEtz)in the presence of silyl chloride. Again the reagent is trapped on the resin prior to reaction with the alcohol and release into solution [9].

RCOCl (2 equiv), CH2C12

RSO2Cl (2 equiv), ICH2C12 ~

Scheme 2.

0

R’NH2 (0.7 equiv), CHpC12 77 - 83%

+ R’\NKR

+1

H

R’NH2 (0.7 equiv), 0 CH2C12 R’\N,S \\‘R 1 0 66 - 88% H

+ 1

Capture-release resins in acylation reactions

Polystyrene-bound pyridineboronic acid 5 is another example of an acylation catalyst which is easily recovered and reusable. Based on work by Yamamoto and coworkers [lo] Wang et al. [ 111 developed an acylation protocol for amines, in which the carboxylic acid is

Functional Po/yrnenfor “Capture-Release” Techniques

6

5

7

8

activated as a mixed anhydride on the polymer 5 prior to release into solution as amide in up to 98% yield. Alternatively polymer-bound sodium selenide 6 served as the starting point for an acylating protocol (Scheme 3) [ 121. Transformation into selenol ester 9 afforded an active polymerbound intermediate which was cleaved in the presence of an alkinylcopper species to generate a$-alkinyl ketones 10 while the copper selenide can be reacylated using acyl chlorides. Weakly nucleophilic heterocyclic amines have efficiently been acylated utilizing solidsupported reagent 7 [ 131. Here, the electron-deficient phenol group allows for intermediate anchoring of an acyl chloride onto the resin which then is released upon treatment with various 2-aminopyridines and 2-aminothiazoles. Traces of unreacted starting material were then conveniently removed by addition of the acidic ion exchange resin Amberlite IRA-120. Likewise, polymer-anchored 1-hydroxybenzotriazole (HOBT) 3 was originally developed as a highly reactive N-acylating agent for the formation of peptide bonds in solution [ 141. Recently, it was shown that this functionalized polymer also performs coupling of acids and amines, including the transfer of protecting groups (Fmoc, Cbz, Boc) [ 151 and the synthesis of N-hydroxysuccinimideesters [ 161 in a “resin-capture-release” mode. In a similar fashion, an acylsulfonamide library was constructed by immobilizing and activating carboxylic acids on functionalized diimide resin 4 [ 171 which reacted further to acylsulfonamides with sulfonamides [ 181. Recently, polymer-bound diimide served as a coupling reagent in the synthesis and preparation of the bisquinone alkloid (-) saframycin A [19].

6 X= Na 9 X= COR Scheme 3.

2 RCOCl

SeCu

Acylation via selenol ester.

The use of basic poly-TBD 2, allows for the rapid synthesis of aryl triflates (Scheme 4) [20]. Phenols were immobilized on resin 2 to afford intermediate polymer 11. This resin was

I

267

268

I

Merging Solid-Phase and Solution-Phase Synthesis: The “Resin-Capture-Release” Hybrid Technique

Ar-OH

10 examples, 65 - ~ 9 9 %

11 Scheme 4.

Preparation of aryl triflates promoted by PTBD 2.

treated with 4-nitrophenyl triflate, which plays the role of a triflate transfer reagent thereby releasing the desired aryltriflate into solution. In an earlier example of the “resin-capture-release” methodology trifluoracetylation of amines was achieved using polymer-bound benzyl thiol 8. Trifluoroacetic anhydride was employed in the capturing process while addition of amines to the intermediate polymerbound thiolester released the desired trifluoroacetamide from the resin [ 211. Finally, polymer-supported oxime 12 has served as a reagent for trapping primary amines after treatment with phosgene [22] to furnish intermediate oxime carbamates 13 (Scheme 5) [ 231. Thermolysis in the presence of amines results in release of ureas into solution.

1. COC12, CHzCI2 2. R’NH2, CH2Cl2

12 R2R3NH, toluene, A

0 10 77examples, - 99% yield,

R’HNKNR2R3

76 - 98% purity Scheme 5.

Polymer-assisted preparation of substituted urethanes using polymer-anchored oxime 12.

Functional Polymers for “Capture-Release” Techniques

Alkylation Protocols

In an opposite manner to bases such as 1 and 2 in terms of reactivity, polymer-supported tosyl chloride equivalent 14 is able to capture alcohols as polymer-bound sulfonates 15, which are released as secondary amines, sulfides and alkylated imidazoles with primary amines, thiols and imidazoles as nucleophiles in a substitution process (Scheme 6 ) [ 241. This technique has further been extended for the preparation of tertiary amines [25] and esters [26]. Excess of amine was scavenged by polymer-supported isocyanate 16 [27, 281 while excess of carboxylic acid was removed by treatment with aminomethylated polystyrene 17. SO2CI

14

1

ROH (10 equiv.), CH2C12, PY

r

I

@s-OR

oo

1. R’R2NH (2 equiv.), DlEA (6 equiv.), CH3CN 2. W Y Y , T H F

1

66 - >99%

7 R’”,R2

1. R’COzH, CH2CI2

N-methylimidazole

Scheme 6. Polymer-supported sulfonyl chloride 14 as a capture-release resin

Recently, three research groups independently disclosed that benzotriazoles 18 attached through various linkers to a polymeric support react with aldehydes and amines to form polymer-anchored Mannich-type adducts 19 (Scheme 7) [ 291. These intermediates are cleaved under reducing conditions and in the presence of organomagnesium or organozinc reagents to provide libraries of secondary and tertiary amines in moderate yield (1145%) and with acceptable purity (13->99%) [29]. Cleavage Protocols with Srnultaneous Ring Closure

In various cases, the release step is accompanied by a cyclization leading to heterocycles. It should be noted that under these conditions parts of the linker can become part of the product which is released into solution. Thus, gel-type polystyrene-sulfonyl-hydrazideresin 20, which originally was developed for carbonyl scavenging applications [30] can also serve as a linker for carbonyl compounds in solid phase synthesis and gives access to support-bound sulfonyl hydrazones 21 (Scheme 8)

I

269

270

I

Merging Solid-Phase and Solution-Phase Synthesis: The "Resin-Capture-Release" Hybrid Technique

R'R2NH

+

N "N N 18 H t = various linkers

R3CH0

r

1 N "N N

R4MgHal or R4ZnHal or NaBH4 (R4= H) R3 t R4 Scheme 7.

R' N 'R2

Preparation o f tertiary amines assisted by polymer-bound benzotriazoles.

1. nBuMgCI, THF, 0 "C

Br

20 NHNH2 AcOHTTHF, 50 "C

3(

r

1

Q -

Scheme 8.

21

Br

Polymer-assisted preparation o f 1,2,3-thiadiazoles

J

Br

[ 511. Treatment with thionyl chloride initiated the Hurd-Mori reaction and cleavage from the resin afforded 1,2,3-thiadiazoles. In order to generalize this strategy non-commercially available ketones were first generated by reacting a set of Weinreb-amides with Grignard reagents followed by immobilized sulfonic acid-mediated decomposition of the tetrahedral intermediate. Additional diversifications of resin-bound sulfonylhydrazones 21 such as Stille coupling or Shapiro olefin synthesis are possible. Polymer-supported oxime 12 (see also Scheme 5) may also serve as a nucleophile in SNAr reactions (Scheme 9) [32]. This procedure afforded aryl oxime adducts 22 which were released as 3-aminobenzoisoxazoles by means of an acid-promoted cyclization.

Funct;onal Polymersfor “Capture-Release” Techniques

12 CN

R

Scheme 9.

8 examples, 55 - 86% yield, 79 - >99% purity

Polymer-assisted synthesis of 3-arninobenzoisoxazoles

In analogy to a related strategy by Jung et al. for the solid phase preparation of pyridines [ 33a,b], Katritzky and co-workers devised a very elegant polymer-assisted “cyclizationcleavage” approach which starts from functionalized polymer 23. It allows the synthesis of variously substituted phenols (Scheme 10) [ 33~1. Base-catalyzed reaction between polymer-bound acetonyl building block 24 and an cc,/i’-unsaturated ketone resulted in a tandem addition/annulation reaction to afford immobilized intermediate 25. This sequence was followed by elimination and rearrangement to the corresponding phenol. Selenium-Based Polymer-Assisted Synthesis

Another example of the “resin-capture-release” technique which should see widespread applications in the future is the selenium-mediated functionalization of organic compounds. Polymer-supported selenium-derived reagents [ 341 are very versatile because a rich chemistry around the carbon-selenium bond has been established in solution and the difficulties arising from the odor and the toxicity of low-molecular weight selenium compounds can be avoided. Thus, reagent 26 (X = C1) was first prepared by Michels, Kato and Heitz [35] and was employed in reactions with carbonyl compounds. This treatment yielded polymer-bound wseleno intermediates, which were set free back into solution as enones from hydrogen peroxide induced elimination. Recently, new selenium-based functionalized polymers 26 (X = Br)-28 were developed, which have been utilized in syntheses according to Scheme 11 (refer also to Scheme 3) [36].

I

271

272

I

1;:1-1--

Merging Solid-Phase and Solution-Phase Synthesis: The "Resin-Capture-Release" Hybrid Technique

\

0Q

N

/

\

EtOH, NaOEt

L

t

p

3.

24 11 examples; 52 - 85% yield, 72 - 299% LC-purity

Scheme 10.

Polymer-assisted preparation of complex phenols,

nBu3SnH AIBN (cat.) Me-R

92% 1. H20, CSA

2. nBu3SnH AlBN (cat.) 82%

26 X= Br

OH

MeAR

and regioisomer

-Np 0

27 X=

0

Scheme 11.

Applications of organoselenium reagents covalently bound t o polymers.

OH

0

Functional Polymersfor “Capture-Release” Techniques

The reactivity of functionalized polymer 26 was elegantly exploited for the cyclization of alkenyl-substituted 8-dicarbonyls by Nicolaou and co-workers which gave access to the core structure of garsubellin A [ 371. Recently, Wirth and Uehlin further extended the selenium-based solid-phase assisted chemistry by introducing a new polymer-bound chiral selenium electrophile 29. Regioand stereoselective 1,2-methoxyselenylation of propenylbenzene gave intermediate adduct 30 which was cleaved by oxidative elimination via the selenoxide to yield the corresponding allylmethyl ether (Scheme 12) [38].

1. MeOH,

O d L v l O M ?Me M e -J(

2.

H202

29 56% (48% ee)

*

r

Scheme 12.

Electrophilic addition o f polyrner-bound chiral organoselenium reagents to alkenes.

Miscellanous Applications

An extended application of the resin-capture-release technique is depicted in Scheme 13. With the help of reagent 31, a functionalized pyridine was captured as an acyl pyridinium cation 32 on a solid support which was followed by Grignard addition and hydrolysis under acidic conditions to afford polymer-supported N-acylated dehydropyridinones 33 [ 391. Advantageously, any unreacted acylium complex collapses to the parent resin upon workup. These heterocycles, which ideally can serve as scaffolds, are then released under basic conditions. A very interesting variant of the polymer-supported Mitsunobu reaction was recently disclosed by Gelb and Aronov (Scheme 14) [40]. Polymer-bound phthalimide 34 was designed which is able to trap alcohols such as nucleosides under Mitsunobu conditions. After purification by washing the loaded resin the corresponding amine was subsequently released into solution in high yield by hydrazinolysis. Polystyrene loaded with cyanoethoxy N,N-diisopropylamine phosphine 35 has turned out to be a versatile and mild phosphitylating agent (Scheme 15) [41].The intermediate phosphite triester 36 was oxidized and the cyanoethoxy group was removed using DBU followed

I

273

274

I

Merging Solid-Phase and Solution-Phase Synthesis: The “Resin-Capture-Release” Hybrid Technique

t

2. R’MgX, THF 3. 3N aq. HCI, THF

-

33

7 examples 31 - 67% yield, 92 - 98% purity

Preparation of dehydropyridinones utilizing the “capture-release” technique.

Scheme 13.

34

HN& J J 1.- (

0

n v

FN HO%NaN HO

N W

NHBn

PPh3, DEAD, THF 2. NzH4, EtOH, CHpClz

OH

Scheme 14.

N W

> 96%

HO

OH

A polymer-based Mitsunobu-reaction. 1. t-BUOOH 2. DBU, THF 3. NaOMe

AcO AcO 0-

37

CN

0 0

r-0

0

1Ktetrazole,

2 ROH=

35 X= N(iPr)z

36 X= OR

AcO

OH Scheme 15.

Phosphitylation of alcohols.

by basic cleavage of the p-hydroxybenzyl linker to yield monophosphates including the labile glycosyl phosphate 37 in remarkable 78% yield and high purity. Very recently, Ito and coworkers disclosed a a resin-aided capture-release strategy in conjunction with oligosaccharide synthesis on a polymer support (Scheme 16) [42]. Interest-

Functional Polymers for “Capture-Release” Techniques I 2 7 5

ingly, the strategy is based on two polymers of which the first one, the soluble PEG monomethyl ether (MPEG), serves as a support in a conventional sense. The second polymer is based on insoluble polystyrene and is employed for purification reasons. The immobilized disaccharide 40 which is obtained from thioglycoside 39 and glycosyl acceptor 38 is captured through the chloroacetyl protecting group with functionalized polymer 41 to yield insoluble disaccharide 42. The disaccharide is purified in this way and released as disaccharide 43 from the polystyrene resin back into solution where it can serve as a new glycosyl acceptor or can be cleaved from MPEG in an oxidative manner to yield disaccharide 44. This is an excellent example for mixing various polymer-assisted techniques in synthesis. An interesting polymer-assisted variant of the Suzuki-reaction was recently disclosed by Vaultier and coworkers (Scheme 17) 1431. Aryl boronic acids can be immobilized on an ion exchange resin. Under Suzuki-Miyaura coupling conditions bisaryl species are released into solution and isolated with minimum purification. The authors also demonstrated that this strategy can be employed for the synthesis of macroheterocycles.

0 Ho&OMP BnO

0

NPhth

0

Me2S-SMe OTf

,94%

40

38

3 equiv. NHFmoc

41 ____L

0

42 NHMe I

15 equiv.

6 .I

l.Zn/Cu then AQO, Et3N 2. DDQ

*copo NPhth

h

82%

86%

BnO

Release

OBn

44 = PEG monomethyl ether

= Wang resin Scheme 16. Solid-phase capture-release strategy applied t o oligosaccharlde synthesis.

276

I

Merging Solid-Phase and Solution-Phase Synthesis: The “Resin-Capture-Release” Hybrid Technique

45

cat. Pd(Ph&

I

46

Scheme 17. Polymer-assisted Suzuki reaction.

Other synthetic applications of this technique are the immobilization of vinylboronates by means of a Suzuki-coupling. Release from the resin by a second transformation afforded substituted styrenes including tamoxifen and analogues derived therefrom, a drug to be used clinically for treatment of estrogen dependent breast cancers [44]. In a related purely for purification designed version [45, 461 of the “resin-capture-release”technique p-amino alcohols were captured by PEG-supported dialkylborane [47]. Purification of the target molecules was achieved after precipitation, washing and release under mildly acidic conditions. In Scheme 18 Wang resin 47 is depicted, which is functionalized with N-hydroxy thiazole 2(3)-thione 1481. This supported reagent can be used as a radical source thus allowing a solid phase version of the Hunsdiecker reaction. Acylation using O-benzotriazol-yltetramethyluronium hexafluorophosphate (HBTU) yielded intermediate 48, which was subjected to a BrCC13 solution under irradiating conditions. This photochemical induced fragmentation released the corresponding bromide into solution.

Outlook

Here, we gave a brief description of a hybrid technique in the realm of polymer-assisted synthetic methodologies which merges scavenger protocols with solid-phase synthesis 1491. This singular strategy is part of a broader development in this field. Indeed, the true potential of polymers in organic synthesis will fully be exploited if the whole orchestra of techniques is combined 1501. Hybrid-techniques will play an increasingly important role that combine both solid phase organic synthesis followed by derivatization of functional groups with polymer-supported reagents after release and cleavage of the substrate from the polymer or vice versa. These developments will also enhance the utility of soluble polymers in automated parallel synthesis. Thus, soluble polymers may be loaded with substrates which are processed by polymer-anchored reagents or catalysts. In summary, the “resin-capture-release” hybrid methodology will become one important instrument in this orchestra of techniques.

References I 2 7 7

Ho*cL C02tBu

NHBoc N A s HO

HBTU, DIPEA, rt, 6h

48

47 BrCCI3, benzene, 200 W lamp, 2h

NHBoc

75%

kCoztBu + NHBoc

(4 examples; 62 - 75%) Scheme 18. Photochemically induced Hunsdiecker reaction.

References R. B. MERRIFIELD, J. Am. Chem. Soc. 1963, 85, 2149-2154. 2 a) F. 2. DORWALD, Organic Synthesis on Solid Phase, Wiley VCH, Weinheirn 2000; b) N. K. TERRETT, Combinatorial Chemistry, Oxford University Press 1998; c) D. OBRECHT, J. M. VILLALGORDO, Solidsupported combinatorial and parallel synthesis of small-molecular-weight compound libraries, Pergamon, Elsevier Science Ltd, Oxford, 1998; d) S. R. WILSON, A. W. Combinatorial Chemistry, CZARNIK, Synthesis, Application, Wiley, New York 1997; e) J. S. FRUCHTEL,G. J U N G , Angew. Chem. 1996, 108, 19-46; Int. Ed. Engl. 1996, 35, 17-42. 3 Recent reviews on polymer-supported reagents: a) A. KIRSCHNING, H. MONENSCHEIN, R. WITTENBERG, Angew. Chem. Int. Ed. Engl. 2001, 40, 650-679; b) S. V. LEY, I. R. BAXENDALE,R. N. BREAM, P. S. JACKSON, A. G. LEACH, D. A. LONGBOTTOM.M. NESI,J . S. SCOTT, R. I. STORER, S. J . TAYLOR, J. Chem. Soc.. Perkin. Trans. I , 2000, 3815-4195; A. KIRSCHNING,H. MONENSCHEIN. R. WITTENBERG, Chem. Eur. /. 2000, 6,44451

4

4450; d) D. H. DREWRY, D. M. COE,S. POON,Med. Res. Rev. 1999, 19, 97-148; S. M. ALLIN,P. K. e) S. J. SHUTTLEWORTH, SHARMA, Synthesis 1997, 1217-1239; f ) C. U. PIITMAN,JR., Polym. News 1998, 23, 416-418; g) S. W. KALDOR, M. G. SIEGEL, C u r . Opin.Chem. Bid. 1997, I, 101-106; h) P. h sz r o , Preparative Chemistry using Supported Reagents, Academic Press, San Diego, 1987. For reviews on polymer-supported catalysts D. J. refer to ref. [3] and a) B. JANDELEIT, SCHAEFER, T. S. POWERS, H. W. TURNER, W. H. WEINBERG, Angew. Chem. 1999, 11I , 2648-2689; Angew. Chem. Int. Ed. Engl. 1999, 38, 2476-2514; b) E. LINDNER, T. SCHNELLER, F. AUER,H. A. MAYER, Angew. Chem. 1999, 11 1, 2288-2309; Angew. Chem. Int. Ed. Engl. 1999, 38, 2154-2174; c) J. H. CAMERON in Solid state organometallic chemistry: Methods and applications, (Eds.: M . GIELEN, R. WILLEM, B. WRACKMEYER), Wiley, Chichester 1999, p. 473-519; d) J. H. CLARK, D. J. MACQUARRIE, Chem. SOC.Rev. 1996, 3033 1 0 e) D. C. BAILEY, S. H. LANGER,Chem. Ren 1981, 81, 109-148.

278

I

Merging Solid-Phase and Solution-Phase Synthesis: The “Resin-Capture-Release” Hybrid Technique

For reviews on scavenger techniques refer to: a) D. L. FLYNN, R. V. DEVRAJ, J. J. PARLOW, in Solid Phase Organic Synthesis (Eds.: K. BURGESS), Wiley, New York, 2000, p. 149-194; b) J. J , PARLOW, R. V. DEVRAI, M. S. SOUTH,Cum. Opin. Chem. Bid. 1999, 3, 320-336; c) J . C. HODGES, Synlett 1999, 152-158; d) D. L. FLYNN,R. V. J. J. PARLOW, Cum Opin. Drug DEVRAJ, Disc. Deu. 1998, I, 41-50; e) L. M. GAYO, Biotechnob Bioeng. 1998, 61, 95; f ) R. J. BOOTH, J. C. HODGES, ACC.Chem. Res. 1999, 32, 18-26; g) D. L. FLYNN, R. V. Med. DEVRAJ, N. NAING. J. J. PARLOW, Chem. Res. 1998, 8, 219-243. 6 J:G. R O D R ~ G U R. E ZMART~N-VILIAMIL, , S. RAMOS,New. I . Chem. 1998,865-868. 7 a) J. G. KEAY, E. F. V. SCRIVEN, Chem. Ind. 1994, 53, 339-350; b) C. GIRARD,I. TRANCHANT, P.-A. NOIRE,J. HERSCOVICI, Synlett 2000, 1577-1580. 8 L. L. TAMANAHA, J. A. P o ~ c oJR., , Synthesis @ Punjcation 1999, 2, 1-4 (Catalogue of Argonaut Technologies). 9 N. HOFFMANN, Diplomarbeit Universitat Hannover 2001. 10 K. ISHIHARA, S. OHARA,H. YAMAMOTO,]. Org. Chem. 1996, 61, 4196-4197. 1 1 R. LATTA, G. SPRINGSTEEN, B. WANG, Synthesis 2001, 1611-1613. 12 QIAN,L.-X. SHAO,X. HUANG, Synlett 2001,

STEPHENS STRAMIELLO, Tetrahedron Lett.

5

1571-1572. 13 K. KIM, K. LE, Synlett 1999, 1957-1959. 14 a) R. KALIR,A. WARSHAWSKY, M. FRIDKIN, Eu.]. Biochem. 1975, 59, A. PATCHORNIK, 55-61; b) M. STERN, R. KALIR,A.

PATCHORNIK, A. WARSHAWSKY, M. J. Solid-Phase Biochem. 1977, 2, FRIDKIN, 131-139; c) I. E. POP, B. P. DEPREZ,A. L. TARTAR,].Org. Chem. 1997, 62, 2594J. J E O N G , W. 2603; d) K. DENDRINOS, HUANG, A. G. KALIVRETENOS, Chem. Commun. 1998, 499-500. 15 K. G. DENDRINOS, A. G. KALIVRETENOS.]. Chem. Soc., Perkin Trans I , 1998, 14631464. A similar functionalized polymer, based on N-hydroxysuccinimide was disclosed by M. ADAMCZYK, J. R. P. G. MATTINGLY, Tetrahedron FISHPAUGH, Lett. 1999, 40, 463-466. 16 K. G. DENDRINOS, A. G. KALIVRETENOS, Tetrahedron Lett. 1998, 39, 1321-1324. 17 Other applications of reagent 4 include the preparation of amides: M. C. DESAI,L. M.

1993, 34, 7685-7688 and thiol esters: M.

Tetrahedron ADAMCZYK, J. R. FISHPAUGH, Lett. 1996, 37, 4305-4308. 18 C. F. STURINO, M. LABELLE,Tetrahedron Lett. 1998, 39, 5891-5894. 19 A. G . MYERS, A. T. PLOWRIGHT,]. Am. Chem. SOC.2001, 123, 5114-5115. 20 S. BOISNARD,J. CHASTANET, J. Zu, Tetrahedron Lett. 1999, 40, 7469-7472. 21 P. I. SVIRSKAYA, C. C. LEZNOFF,M. STEINMAN]. Org. Chem. 1987, 52, 1362-1364. 22

M. A. SCIALONE, S. W. SHUEY,P. SOPER, Y. HAMURO, D. M. BURNS,].Org. Chem.

1998, 63, 4802-4807. 23 S . KOBAYASHI,T. FURUTA, K. SUGITA,0.

OKITSU,H. OYAMADA, Tetrahedron Lett. 1999,40, 1341-1344. 24 a) J. K.

RUETER, S. 0. NORTEY, E. W. BAXTER,G. C. LEO, A. 8 . REITZ,Tetrahedron Lett. 1998, 39, 975-978. Polymerbound arylsulfonate esters can undergo various reactions at remote functionalities prior to cleavage from the resin with diethyl amine: E. W. BAXTER, J. K. RUETER, S. 0. NORTEY,A. B. REITZ, Tetrahedron Lett. 1998, 39, 979-982.

F. H u , J . A. PORCO,Synth. Pur. Lett. 1999, 1, 1-5. 26 a) A. PATCHORNIK, Nouu.]. Chim. 1982, 6, 639-643. b) N. ZANDER, R. FRANK,Tetrahedron Lett. 2001, 42, 7783-7785. 27 a) S. W. KALDOR, J. E. FRITZ,J. TANG,E. R. MCKINNEY, Bioorg. Med. Chem. Lett. 1996, 6, 3041-3044; b) M. W. CRESWELL, G. L. BOLTON, J. C. HODGES, M. MEPPEN, Tetrahedron 1998, 54, 3983-3998. 28 B. RAJU,J. M. KASSIR, T. P. KOGAN, Bioorg. Med. Chem. Lett. 1998, 8, 3043-3048. 29 a) K. SCHIEMANN, H. D. H. SHOWALTER,]. Org. Chem. 1999, 64, 4972-4975; b) A. R. KATRITZKY,S . A. BELYAKOV,D. 0. TYMOSHENKO,]. Comb. Chem. 1999, 1. 173-176; c) A. PAIO,A. ZARAMELLA, R. FERRITO,N. CONTI,C. MARCHIORO, P. SENECI,].Comb. Chem. 1999, I, 31725

325. 30 a) 0. GALIOGLU, A. AKAR,Eur. Polym. I. 1989, 25, 313-316. b) D. W. EMERSON, S. C. J O S H I , E. M. R. R. EMERSON,

J. M. TUREK,].Org. Chem. SORENSEN, 1979, 44,4634-4640; c) H. KAMOGAWA,

T. NAITO, M. A. KANZAWA, M. KADOYA,

References

31 32 33

34

35 36

37

38 39

NANASAWA, Bull. Chem. SOC.Jpn. 1983, 56, 762-765. Y. H u , S. BAUDART,J. A. PORCO,JR.,]. Org. Chem. 1999, 64, 1049-1051. S. D. LEPORE.M. R. WILEY,J . Org. Chem. 1999, 64,4547-4550. a) P. GROSCHE, A. HOLTZEL,T. B. WALK, A. W. TRAUTWEIN, G. J U N G , Synthesis 1999, 1961-1970; b) D. G. SCHMID,P. GROSCHE,G. J U N G , Rapid Commun. Mass Spectrom. 2001, 15, 341-347; c) A. R. KATRITZKY, S. A. BELYAKOV, Y. FANG, J. S. KIELY, Tetrahedron Lett. 1998, 39, 8051-8054. For various examples of immobilized selenium reagents see a) Y. OKAMOTO, K. L. CHELLEPPA, R. HORNSANG,].Org. Chem. 1973, 38, 3172-3175; b) E. J. GOETHALS, Eu. Polym. ]. 1974, 10, 847849; c) K. KONDO,J . Polym. Sci., Polym. Lett. Ed. 1974, 12, 679-683; d) M. KATO, R. MICHELS, W. HEITZ,]. Polym. Sci., Polym. Lett. Ed. 1976, 14, 413-415; e) K.-I. FUJITA, K. WATANABE, A. OISHI,Y. IKEDA,Y. TAGUCHI, Synlett 1999,1760-1762. R. MICHELS, M. KATo, W. HEITZ, Makromol. Chem. 1976, 177,2311-2320. K. C. NICOLAOU, J. PASTOR,S. BARLUENGA, N. WISSINGER, Chem. Commun. 1998, 1947-1948. K. C. NICOLAOU, J. A. PFEFFERKORN, G.-Q. CAO,S. KIM, J. KESSABI,Org. Lett. 1999, I , 807-810. L. UEHLIN,T. WIRTH,Org. Lett. 2001,3, 2931-2933. a) C. CHEN,I. A. MCDONALD, B. MUNOZ, Tetrahedron Lett. 1998, 39, 217-220; b) B. MUNOZ,C. CHEN,I. A. MCDONALD, Biotechn. Bioengin. (Comb. Chem.) 2000, 71, 78-84. For the preparation of a resin-

bound chloroformate; see J. R. HAUSKE, P. DORFF,Tetrahedron Lett. 1995, 36, 1589-1592. 40 A. M. ARONOV, M. H. GELB,Tetrahedron Lett. 1998, 39, 4947-4950. 41 K. PARANG,E. J.-L. FOURNIER, 0. HINDSGAUL, Org. Lett. 2001,3, 307-309. 42 H. ANDO,S. MANABE, Y. NAKAHARA, Y. ITO, Angew. Chem. Int. Ed. 2001, 40, 4725-4728; Angew. Chem. 2001, 113, 4861-4864. 43 V. LOBREGAT, G. ALCAREZ, H. BIENAYME, Chew Commun. 2001, M. VAULTIER, 817-818. 44 a) S. D. BROWN,R. W. ARMSTRONG,].Org. Chem. 1997, 62, 7076-7077; b) D. BROWN, R. W. ARMSTRONG,].Am. Chem. SOC. 1996, 118,6331-6332. 45 An early example of this concept, using polystyrylboronic acid for separating and purifying 1,2-cis diols from cisltransmixtures, was presented by E. SEYMOUR, J. M. J. FRECHET,Tetrahedron Lett. 1976, 3669-3672. 46 S. SUNAMI, T. SAGARA, M . OHKUBO,H. MORISHIMA, Tetrahedron Lett. 1999, 40, 1721-1724. 47 M. H. KIM, D. JANDA,]. Org. Chem. 1998, 63, 889-894. 48 L. DE LUCIA, G . GIACOMELLI, G . PORCU, M. TADDEI,Org. Lett. 2001, 3, 855-857. 49 Recently, the first alkylating functionalized polymer was described by J. RADEMANN,J. SMERDKA, G. J U N G , P. GROSCHE,D. SCHMID,Angew. Chem. 2001, 113, 390393; Angew. Chem. Int Ed. 2001, 40, 381-385. 50 X. OUYANG, R. W. ARMSTRONG, M. M. MURPHY,J. Org. Chem. 1998, 63, 1027-1032.

I279

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Polymeric Scavenger Reagents in Organic Synthesis Jason Eames and Michael Watkinson

Solid-phase organic synthesis (SPOS) has become a popular method for the preparation of low molecular weight organic molecules [l, 21. A great deal of this attention has been focused on the lead optimisation of biologically active molecules within the pharmaceutical industry [ 31. One clear advantage of this biphasic methodology over traditional synthetic methods is in the area of purification - simple filtration of the reaction mixture generally leads directly to the required product in high purity [4]. However, this methodology is not without its limitations; excess of at least one reagent is generally required to drive the reaction to completion 151, and in some cases up to two additional synthetic steps may be required to mount and remove the substrate from its solid support. Moreover, the required target invariably has to be re-synthesised on a larger scale using classical solution methodology to provide sufficient quantities for screening [GI. Due to the problems associated with solid phase organic synthesis such as scalability and characterisation, considerable effort has being devoted to the development of new methodologies to assist in the purification of solution phase reactions. In addition to the existing use of solid-supported reagents [7-101, this area has recently been expanded towards the use of solid-supported reagents as purification aids within solution phase synthesis. These solid-supported reagents have been used to remove an excess of reactants to give the product in high yield and in a single operation (Scheme 1).This technique offers many of the advantages of solid supported organic synthesis such as ease of work-up, and product purification with the additional advantages associated with traditional Reactants A (xs)

+

A-B

Scheme 1.

B

-

Product A-B

I

+

A

e

x

polymeric-supported scavenger

I

A-B

+

XA

Polymeric Scavenger Reagents in Organic Synthesis

solution phase synthesis (scalability and ease of characterisation). These polymeric reagents have been referred to as polymer scavengers$
Chemical reactivity

Scavenger Resins

acidic

basic

NMe2

electrophilic

NCO

nucleophihc

NH2

W

N

CHO

Scheme 2.

Kaldor and co-workers [ 111 have reported an application of both nucleophilic and electrophilic polymer supported reagents within the synthesis of substituted ureas like 4a (Scheme 3 ) . Benzylamine 1was added to an excess of pmethoxyphenylisocyanate 2 in chloroform-dl for 1 hour, after which an excess aminomethylpolystyrene 3 (0.8 equiv/gram) was added to scavenge the unreacted and remaining isocyanate 2. Filtration of the reaction mixture (to remove the polymeric urea 4b), followed by 'H NMR analysis revealed only the required urea 4a was present, with no trace of the original isocyanate 2. This procedure was shown to be quite general, and a moderate library containing approximately a thousand different ureas and thioureas has been synthesised using this methodology (for a representative account see Table 1, entry 1).This methodology was further extended towards the preparation of amides, sulfonamides and carbamates. In these reactions the polymeric aminomethylated styrene 3 behaved as a double scavenger by removing unreactive electrophilic and acidic species. This technique has been applied to a variety of synthetic procedures (see Table 1: entry 1). t

This strategy has previously been referred to as solid-supported scavengers (SSS), polymersupported quench (PSQ) and complementary molecular reactivity and molecular recognition ( CM R/ R) .

.r

A nucleophilic polymer is a scavenger of

electrophiles and vice versa.

I

281

282

I

Polymeric Scavenger Reagents in Organic Synthesis

Q

+

b-

Polymeric Scavenger Reagents in Organic Synthesis

I

Representative Product

Yield

Purity

67%

94%

94%

93%

73%

90%

62%

>95%

283

Table 1. Selective scavenging of excess reagents

Entry

Limiting Reagent

Excess Reagent

1

R'R~NH

R'NCO R3COClt R30COC1t R'SOzCIt

3

Scavenger

/IR3 R'NH2

R2

R'R~NH

o(,:ocl 12

t piperidinomethyl

H

O

C

N

D

polystyrene or other solid-supported bases were added as an acid scavenger.

Two complementary procedures have been developed for alkylation of secondary amines [ 111 - both of which involve the use an excess of amine to drive the reaction to completion. The remaining amine was removed from the required tertiary amine using a polymer supported isocyanate 5 as a nucleophilic scavenger (under thermodynamic control) (Table 1: entry 2). The use of this amine scavenger has subsequently been applied in the purification of urea-based libraries prepared by solid-phase organic synthesis [ 121. As an alternative, secondary amines (e.g., 8) have also been prepared by reductive amination of primary amine 6 and aldehyde 7, using a polymer supported borohydride reducing agent (Scheme 4) [ 111. The excess primary amine 6 was removed using a polymer supported polystyrene carboxaldehyde 11. The high yield of secondary amine 8 presumably indicates that addition of the primary amine to the polymeric aldehyde 11 was considerably faster than the corresponding reduction involving both polymeric reagents. This secondary amine 8 was further converted into a urea 10 by the addition of an excess of isocyanate 9. The remaining unreacted isocyanate 9 was captured by the addition of the polymeric scavenger, amine 3. This type of methodology has proved very popular and has given rise to the synthesis of a variety of amines (for a representative account see Table 1: entry 3). An analogous procedure has been adopted for the formation of tertiary amines, which utilised a polymer supported acid chloride 12 to scavenge the excess secondary amine, (Table

284

I

Polymeric Scavenger Reagents in Organic Synthesis

R'NHz(1.5 eq.) 6

+ R2CHO(1 eq.)

(i-iv) w

H R,, N-

R2

8

7

@CHO

()-cH,NH,

11

+ R3NC0 (1.25 eq.) 9

I

(v-vii)

3

10

MeOH, r.t., 1 h; (ii) Amberlite@IRA-400 borohydride resin, r.t; (iii) polystyrene carboxaldehyde 11, CH2C12, overnight; (vi) filter; (v) ethanol-free CHCI,, 1 h; (vii) 3, 1 h, filter.

Reagents and conditions: (i)

Scheme 4.

1, entry 4).By coupling such procedures together, a series of substituted ureas were synthesised in excellent yield (89-100%) and chemical purity (81-97%). More recently, Bradley has demonstrated the chemoselective capture of primary amines over secondary amines using a polymeric methacrylate (AAEM) 13 as a purification method for an in-situ reductive amination procedure (Scheme 5) [13]. Reduction of the imines 17a-c (formed by addition of benzaldehyde 15 to an excess of the primary amines 16a-c) gave the required secondary amines Ma-c. The remaining unwanted primary amines 1Ga-c was chemoselectively removed by the addition of the scavenger resin, acetoacetoxy ethyl methacrylate (AAEM) 13 to give the enamines 19a-c. Simple filtration of the reaction mixture gave the required secondary amine in good yield and excellent purity. Previously, within this area benzaldehyde-based resins (like 14)have been used, but were problematic, as they were particularly air sensitive. Booth and Hodges [14]have investigated the use of three separate polymer supported reagents 20, 21 and 22, all of which were derived from commercially available polymers (Scheme 6 ) . These have either been used individually or in multiple Combinations to aid quenching and further purification during the solution phase synthesis of ureas, thioureas, sulfonamides, amides and pyrazoles. The utility of the covalent isocyanate scavenger 22 was individually demonstrated in both reactions steps, whilst the polymeric triamine 20 and morpholine 21 were employed as polymeric supported bases. These scavengers were shown to be efficient and provided reliable methods for removing unwanted reaction impurities. This strategy was also tested within single and multi-step reactions. For example, the substituted pyrazole 25 was synthesised by modifying the traditional method by simply incorporating their covalent scavenger resin (Scheme 6 ) . Although the yield for the first step of this synthesis, involving the condensation of 1,3-diketone 23 with an excess of phenylhydrazine-4-carboxylicacid (in the presence of the two scavengers 21 and 22) was

19a-c

o

y HN-R’

y

15

+

+

18a-c

Ph

14

(iii) f-------

0

I 18a-c

Ph

18c

3

(ii)

17a-c

18b

2

18a

18

Benzyl

2-Fu~l

Phenyl

R1

16a-c

R1-NH2

16a-c

100%

100%

100%

Purity

Scheme 5.

Reagents and conditions: (i) MeOH, 2h; (ii) MeOH, 24h, Amberlite IRA 400 borohydride resin (2 equiv.); (iii) MeOWCH,CI, (1 :1. viv), 36h, 13 (2 equiv.).

O

Ph

A,

13

O 0 Y 0 Y

1

Entry

87%

88%

81%

Yield

N ul 00

1.

0

3

286

I

Polymeric Scavenger Reagents in Organic Synthesis

N/\I

H 20

NH2

W

N

C

O

22

21

i) i-BuOCOC1,21, CH2Cl2 ii)

H2N"o'p-ir

Scheme 6.

moderate (75%), the reaction appeared to be very clean and this yield was accepted in favour of high purity (97% measured by HPLC). The second step of the synthesis involved amide bond formation by activation of the carboxylic OH group in 24 (with a mixed anhydride), followed by displacement with i-propyloxyaminopropane to give the amide 25 - both basic 20 and 21 and the electrophilic 22 scavengers were used to ensure efficiency [ 141. The reaction proceeded in good yield (75%) with excellent chemical purity (97%) (Scheme 6). The synthetic utility of ion exchange resins in combinatorial chemistry has been demonstrated by the use of a basic polymeric base PTBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) 26 in a series of 0-and N-alkylation experiments (Scheme 7) [ 151. For example, deprotonation of the phenol 27 with this polymeric base PTBD 26 gave the ionic polymeric species 28 which contained the more nucleophilic phenolate. Addition of the 2-bromo aryl ketone 29 gave the aryl ether 30 in reasonable yield and in high purity (Scheme 7). The basic polymeric scavenger PTBD 26 removed all the unwanted HBr produced within the reaction mixture (in the form of 31) and advantageously eliminated the need for an aqueous extractive work-up procedure. In a related report [ 161 it has been further demonstrated that aryl triflates could be readily synthesised using 4-nitrophenyl triflate 33 as the transfer reagent (Scheme 8). Deprotonation of the phenol 32 with PTBD 26 in acetonitrile at an elevated temperature (80 "C), followed by the addition of 4-nitrophenyl triflate 33 gave the required aryl triflate 35 after simple filtration. Any unreacted phenolate still present was removed as the ionic polymer 34 through filtration (Scheme 8). It has also been shown that initial deprotonation of the phenol was not necessary for optimal reactivity and that epimerisation of base sensitive compounds is not a problem

Polymeric Scavenger Reagents in Organic Synthesis

a3 3:

+

\

+

..a

\

n

I

287

288

I

Polymeric Scavenger Reagents in Organic Synthesis

al

E,

+

0

z

+

..m I

u N

6 m.

Polymeric Scavenger Reagents in Organic Synthesis

I

289

[ 161. This procedure appears to be particularly mild; racemisation of the tryptophane derivative 32 does not occur (Scheme 8). The chemoselectivity of this reaction is remarkable when considering the nucleophilic behaviour of the neighbouring amide group. Cresswell and coworkers 1171 have used a combination of both covalent and ionic scavengers to achieve an efficient library synthesis of piperidinones 39 using a Lewis-acid catalysed hetero-Diels-Alder reaction (Scheme 9). The scavenger resin 20 was used to remove any unreacted imine 36 as well as any hydrolysed product resulting from Danishefsky's diene 37, following an acid work-up (1M HCl) which was required to remove the ytterbium catalyst. This procedure was particularly efficient and up to forty piperidinones such as 39 were prepared using a representative group of building blocks (made up of four aldehydes and ten amines) in good yields and excellent purity. Chemoselective reduction of the carboncarbon double bond in 38 using L-Selectride gave the required piperidinone 39.

20

'NH,

CH(OCH3)3 PhCHZNH2

+ ArCHO 36

L-Selectride 4

THF, -78'C

0

39

I

31

(i-iv)

a:2ph

0

38; 73%; 99% purity

Reagents and conditions; (i) Yb(OTf)3 (0.1 eq.), CH3CN; (ii) 20, CH2Clz; (iii) filter; (iv) EtOAdlN HCI Scheme 9.

As this area of polymer supported reagents continues to expand the complexity of the polymeric supported resins has increased [ 181. Although electrophilic supported reagents like the isocyanate 5 and acid chloride 12 have been shown to be efficient reagents for the covalent capture for primary and secondary amines (Table I), they are not without their difficulties. The isocyanate resin is particularly expensive and the loading is rather low (approximately 1 mmol NCO/gram).

290

1

Polymeric Scavenger Reagents in Organic Synthesis

In an attempt to solve this problem, Coppola has designed a novel electrophilic scavenger based on an isatoic anhydride motif (Scheme 10) [IS]. This reactive mixed anhydride was shown to be particularly effective towards primary and secondary amines. The loading for this polymer was also shown to be high (3.2 mmol/gram). A series of amides (e.g. 41) and ureas (e.g. 43) were synthesised by the addition of benzylamine to the isatoic anhydride 40 and thioisocyanate 42 respectively. The excess and unreacted benzyl amine was removed by the addition of the polymeric scavenger anhydride 44 - simple filtration of the resultant scavenged polymer 45 gave the amide 41 and urea 43 in high yield and purity (Scheme 10).

41 Purity = 99%

40

0'

NCS

91%

(i) PhCH2NH2

*

(ii) 44 42

43 Purity = 99%

PhCH2NHz b

44

45

Scheme 10.

Despite the use of boronic acids as intermediates in Suzuki cross-coupling reactions, and in the biological application to sugar recognition, there are limited scavengers available for this functional group. In an attempt to solve this problem, Hall has designed and developed [ 191 a novel polymer scavenger resin DEAM-PS (N,N'-diethanolaminomethyl polystyrene) 47 for the parallel synthesis of aryl boronic acids in solution phase (Scheme 11).This resin was used to purify the crude dienylboronic acid 49 which was known to be difficult. The use of resin 47, to capture boronic acid 49, eliminates excess reagents and cyclohexanol byproducts and greatly facilitates its purification through simple rinsing of the resin bound form 48.

Polymeric Scavenger Reagents in Organic Synthesis

Y

I

46

(iii)

48

49

\

95% based on 46 Reagents and conditions: (i) addition of (C6Hl1)2BH(1 .O equiv.), then Me3NO; (ii) DEAM-PS resin 47; (iii) H20, THF. Scheme 11.

Of particular interest to combinatorial chemistry is the use of immobilised functionalised boronic acid templates which are capable of further transformations [20]. For instance, an aryl carboxylic acid 50 can be converted into the corresponding amide 51 (Scheme 12), whilst still being attached to the resin. Benzyl amine and butylamine were coupled efficiently to afford (after cleavage) the corresponding amides 52 in high yield (Scheme 12).

51

50

52

Reagents and conditions: (i) RNH2 (2.5 equiv), N-hydroxbenzotriazole(2.5 equiv) N,N'-diisopropylcarbodiimide(2.5 equiv); (ii) DEAM-PS resin 47; (iii) H20, THF. Scheme 12.

Taddei has developed a soluble PEG supported scavenger 53 to capture a variety of nucleophilic functional groups (Scheme 13) [21]. This scavenger was based on an electrophilic dichlorotriazine core and relied on selective precipitation (by the addition of ether to acetonitrile) to remove it from the reaction mixture. This scavenger 53 is particularly versatile, and has been used to remove primary, secondary and tertiary alcohols, diols and thiols

I

291

292

I

Polymeric Scavenger Reagents in Organic Synthesis

+ a V

3:

2

2

+

+

m r

Polymeric Scavenger Reagents in Organic Synthesis

I

293

within a multitude of different reactions ranging from the formation of esters such as 55, silyl ethers 56, ketals 57 and thioacetals 58 by the selective removal of the scavenged polymer 54. The versatility of this methodology was further illustrated in the conversion of citronellol 59 into the corresponding chloride GO using triphenylphosphine in tetrachloromethane. The reaction mixture was efficiently purified by the addition of the scavenger triazine 53, which not only removed the unreacted citronellol 59, but also the unreacted triphenylphosphine (in the form of 61) and triphenylphosphine oxide byproduct (in the form of 62). After selective precipitation the chloride GO was isolated in 65% yield (Scheme 13). By far, the majority of these reports into the applications of polymeric scavengers have been within the pharmaceutical field. However, recently this methodology has been used to assist in the development of new catalysts. In particular, the ability of high throughput catalyst screening for improving efficiency has generated a lot of interest. The use of a polymeric amine 20 and pyridine G3 as scavengers in the synthesis of substituted sulfonamides 66 and 75, which were known to catalyse EtZZn addition to a variety of carbonyl derivatives (Scheme 14 and 15) [22, 231. The required sulfonamide ligands 66 were efficiently synthesised by addition of a 1,l-diamine 64 to an excess of substituted chloride 65 to ensure complete conversion [ 221. The use of a polymeric nucleophilic covalent catalyst, dimethylamino pyridine 63, not only accelerates the rate of addition but also scavenges the HCl by-product (Scheme 14). The excess sulfonyl chloride was removed using the polymeric bound tris(2-

i) 63, CH2C12

YXN

ii) 20,CHzC12 65

R.R'. X and Y can be varied 66

NH

N H -N-NH2 20

NHBOC

024&

63

Ph

67

R~CHO 68

+

Et&n

+

Ti(O-i-Pr)4

67

9H R2& (R)-69

R2 = Cy, Ph, Ph(CH2)2and p-ClCbH4 Scheme 14.

294

I

Polymeric Scavenger Reagents in Organic Synthesis

N

d 3:

z

-9 N

/

d

Iv)

3?

zi=

N

d

+

+ I

+

U v)

References I 2 9 5

aminoethy1)amine 20. Thirty of the possible thirty-six component library were screened against the enantioselective Ti(O-i-Pr)4-mediatedaddition of Et2Zn to a series of four aldehydes 68. This screening revealed a number of interesting points; the best ligand was shown to be 67 - using the (lS, 2S)-diaminocyclohexane scaffold and the sulfonyl chloride derived from L-phenylalanine giving in all cases studied the (R)-alcohol 69 in high selectivity (8696% ee). The effect of varying the R' substituent has revealed the selectivity to increase in the following order CHzPh > CH3 > i-Bu > i-Pr > -(CH2)3-,which may assist in the design of future catalysts. Related sulfonamide ligands 75 have been used in the Cu(OTf)2 catalysed enantioselective 1,4-addition of Et,Zn to a series of enones 76; n = 1 and 2 to give the ketone 77 (Scheme 15) [231. Similar scavenger methodology was used to synthesise the sulfonamide component 72. This was further functionalised by incorporation of a substituted salicylaldehyde 74 to generate a library of chiral Schiff base ligands, which contain three different metal binding sites (imine, phenol and secondary sulfonamide). The acid scavenger 63 was used to purify this library to remove the generated HC1 from the Boc deprotonation step. Screening this 100 or so library, revealed that the ligand 78 (R' = i-Pr; R2 = (S)-CH(Me)Cy;R' = 3,5-CI2)gave the best selectivity for 2-cyclohexenone (82% ee) and 2-cycloheptenone (81% ee). These results have shown the importance of combinatorial techniques for probing the efficiency of a particular reaction to allow further optimisation. The use of polymer supported reagents and scavengers has greatly improved the efficiency of classical solution phase chemistry [ 241. This development has allowed combinatorial solution phase chemistry to be further extended. The advantages being; 1. Use of excess reagents or reactants to drive the solution phase reaction to completion; 2. Removal of the need for substrate linkage to the polymer support; 3 . Removal of the need for a liquid phase extraction and chromatography.

References E. M. GORDON,M. A. GALLOP,D. V. PATEL,Acc. Chem. Res. 1996, 29, 144-154. 2 S. V. LEY,I. R. BAXENDALE, R. N. BREAM, P. S. JACKSON, A. G. LEACH,D. A. LONGBOROM,M. NESI,J. S. SCOOT,R. I. STORERA N D S. J. TAYLOR, J . Chem. SOC., Perkin Trans 12000, 3815-4195. 3 N. K. TERRET,M. GARDNER, D. W. GORDON,R. J. KOBYLECK A N D J. STEELE, Tetrahedron 1995, 51; 8135-8173. 4 F. BALKENHOHL, C. VON D E M BUSSCHEHUNNEFELD, A. LANSKYA N D C. ZECHEL, Angew. Chem., Int. Ed. 1996, 35, 22881

2337. 5 6

S. H. DEWIIT A N D A. W. CZARNIK,Acc. Chem. Res. 1996, 96, 114-122. J. A. ELLMAN, ACC.Chem. Res. 1996, 29, 132-143.

s. v. LEYA N D R. SMITS, J . Chem. SOC.,Perkin Trans. I 1999, 24212423. 8 J. S. FRUCHTEL A N D G. JUNC,Angew. Chem., Int. Ed. 1996, 35, 17-42. 9 R. B. MERRIFIELD, J . Am. Chem. SOC.1963, 85, 2149-2154. 10 (a) B. HINZEN A N D S. V. LEY,J . Chem. SOC.,Perkin Trans. 1 1998, 1-2; (b) F. HAUNERT,M. H . BOLLI,B. H I N Z E NA N D S. V. LEY,J. Chem. SOC., Perkin Trans. 11998, 2235-2237; and references therein. 11 S. W. KALDOR,M. G. SIEGEL,J. E. FRITZ, B. A. DRESSMAN A N D P. J. HAHN, Tetrahedron Lett. 1996, 37, 7193-7196. 12 B. A. DRESSMAN, U. SINGHA N D S. W. KALDOR, Tetrahedron Lett. 1998, 39, 3631-3634. 7 J. HABERMANN,

296

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Polymeric Scavenger Reagents in Organic Synthesis 13 2. Yu, S.

ALESSO, D. PEARS,P. A. WORTHINGTON, R. W. A. LUKE A N D M. BRADLEY,Tetrahedron Lett. 2000, 41, 8963-8967. 14 R. J. BOOTHA N D J. c. HODGES, /. Am. Chem. Soc. 1997, 119,4882-4886. 15 W. Xu, R. MOHANA N D M. MORRISSEY, Tetrahedron Lett. 1997, 38, 7337-7340. 16 S . BOISNARD,1. CHASTANET A N D J. Z H U , Tetrahedron Lett. 1999, 40, 7469-7472. 17 M. W. CRESSWELL, G. L. BOLTON,J. C. A N D M. MEPPEN, Tetrahedron HODGES 1998, 54,3983-3998. 18 G. M. COPPOIA,Tetrahedron Lett. 1998, 39, 8233-8236. 19 D. G. HALL,J. TAILOR A N D M. GRAVEL, Angew. Chem., Int. Ed. 1999, 38, 30643067. 20 S. RANA.P. WHITEA N D M. BRADLEY, Tetrahedron Lett. 1999, 40. 8137-8140. 21 A. FALCHI A N D M. TADDEI, Org. Lett. 2000, 2, 3429-3431. 22 C. GENNARI, S. CECCARELLI, U. PIARULLI, C. A. G. N. M O N T A L B EA ~N DI R. F. W. JACKSON, J. Org. Chem. 1998, 63, 5312-5313. 23 I. CHATAICNER, C. GENNARI, U. PIARULLI A N D S. CECCARELLI, Angew. Chem., Int. Ed. 2000, 39,916-918. 24 Other representative examples in which polymeric scavenger reagents are used, include; L. A. THOMPSON A N D J. A. ELLMAN,Chem. Rev. 1996, 96, 555-600; D. H. DREWRY, D. M. COEA N D S. POON, Med. Res. Rev. 1999, 19, 97-148; B. J. COHEN,M. A. KRAUSA N D A. PATCHORNIK, /.Am. Chem. SOC.1981, 103, 7620-7629; J.

I.

PARLOW, Tetrahedron Lett. 1995, 36, 1395-1396; T. A. KEATINGA N D R. w. ARMSTRONG, I. Am. Chem. SOC.1996, 118, 2574-2583; D. L. FLYNN,J. 2. CRICH, R. V. DEvRAT, S. L. HOCKERMAN, J. J. PARLOW, M. S. SOUTHA N D S. WOODWARD, J. Am. Chem. SOC. 1997, 119,4874-4881; S. W. KALDOR,J. E. FRITZ,J. TANGA N D E. R. MCKINNEY,Bio. Med. Chem. Lett. 1996, 6, 3041-3044; S. E. AULT-JUSTUS, J . C. HODGESA N D M. W. WILSON,Biotechnol. Bioeng. (Comb. Chem.) 1998, 61, AND 17-22; J. J. PARLOW,D. A. MESCHKE S. S. WOODARD, /. Org. Chem. 1997, 62, 5908-5919; L. M. GAYOA N D M. J. SUTO, Tetrahedron Lett. 1997, 38, 513-516; M. G. SIEGEL,P. J. HAHN,B. A. DRESSMAN, J. E. FRITZ,J. R. GRUNWELL A N D S. W. KALDOR, Tetrahedron Lett. 1997, 38, 3357-3360; K. IIJIMA, W. FUKUDA A N D M. TOMOI,Pure Appl. Chem. 1992, A29, 249-261; U. SCHUCHARDT, R. M. VARGAS A N D G. GELBARD, /. Mol. Cat. A: Chem. 1996, 109, 37-44; B. A. KULKARNI A N D A. GANESAN, Angav. Chem., Int. Ed. 1997, 36; 2454A N D M. LABELLE, 2455; C. F. STURINO Tetrahedron Lett. 1998, 39, 5891-5894; C. K. BIACKBURN, B. GUAN,P. FLEMING, SHIOSAKI A N D S. TSAI,Tetrahedron Lett. 1998, 39, 3635-3638; J. J. WEIDNER, J. J. PARLOW A N D D. L. FLYNN, Tetrahedron Lett. 1999, 40, 239-242; J. S. WARMUS, T. R. RYDER,J. C. HODGES,R. M. K E N N E D YA N D K. D. BRADY,Bio. Med. Chem. Lett. 1998, 8, 2309-2314; Review: J. EAMES A N D M . WATKINSON, Eur. 1.Org. Chem. 2001, 1213-1224.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Total Syntheses o f Vancomycin Lars H. Jhoresen and Kevin Burgess

Five consecutive papers in Angew. Chem. recently described syntheses of the vancomycin aglycon. D. A. Evans and co-workers developed one route at Harvard [ 1, 21, while the other comes from K. C. Nicolaou’s group at Scripps [3-51. They represent an amalgamation of synthetic methodologies in schemes that took some of the most skillful bench chemists in academia years to execute. CI

OR

R=H vancomycin aglycon

R=

I

\

F 0

O 0

H

vancomycin

Stereoselective syntheses of several unnatural amino acids were required to initiate this work. Evans’ group used asymmetric reactions of chiral enolates to generate these starting materials, as illustrated in the diagram shown below. In this particular example, an isothiocyanate functionality traps the alcohol of an aldol product giving a thiooxazolidinone that provides 0- and N-protection in subsequent steps.

298

I

Total Syntheses of Vancomycin

+ CI

'4

iCS aldol-

cox,

0

CI

The Scripps group initiated their project to prepare vancomycin after many routes to the requisite amino acids had been published. They could have made their building blocks by repeating and/or modifying published procedures, but instead chose to develop new approaches or rely on those of colleagues at Scripps. An example featuring Sharpless' methodology is illustrated below [ 61.

Sharpless'

~

C02Et

_& _

aminohydroxylation

Et0&

I..,

"'NHCbz

A major obstacle to synthesis of the vancomycin aglycon has been construction of the fused macrocyclic ring systems with generation of the correct atropisomers. The Harvard and Scripps groups overcame this in different ways (Schemes 1 and 2, respectively). Evans' group began by forming the macrocycle encapsulating the AB biaryl functionality; for this they used an oxidative coupling developed almost ten years ago [ 7 ] . A SNAr reaction was then used to form the biaryl ether linkage between rings C and D (ie the C - 0 - D ring) [S]. That cyclization reaction also set one of the amide bonds in the AB ring into its required cisorientation. Scheme 2 indicates that, unlike the Evans' approach, the Nicolaou group constructed the C - 0 - D ring before the AB system. They used their copper-mediated coupling methodology, involving a triazine ligating-group, to form the ether linkage in the first macrocyclization. Unfortunately, this step gave no significant selectivity with respect to the atropisomer formed, hence separation of epimeric products was necessary. The precursor to the AB ring contained an amino acid with a preformed (Suzuki) AB biaryl fragment. Cyclization to form the AB ring system was accomplished via a macrolactamization reaction. Another significant difference in the two syntheses relates to the C-terminus of the ABC0 - D entity, ie at the amino acid precursor fragment attached to aryl nucleus A. That chiral center is stereochemically delicate; it epimerized if the C-terminus was an ester, for instance. The Evans group found that the corresponding N-methylamide imparted resistance to epimerization at this center making it resilient to subsequent steps in the synthesis, while the Nicolaou group avoided the problem by using a corresponding 0-protected alcohol. These

Total Syntheses of Vancomycin

I

299

300

I

Total Syntheses of Vancornych

CZ-2

'z0

Total Syntheses ofvancornycin

strategies necessitated some interesting functional group manipulations towards the end of the synthesis, as described later. Our interpretation of the two synthetic strategies is that the nature of the C-terminus, and the order of construction of the AB and C-0-D rings, is relatively unimportant, but the latter factor did have significant indirect consequences. Specifically>the Harvard group was able to achieve atropisomeric stereoselectivity in their C-0-D ring construction process and this might not have possible if the AB ring was not already in place. Development of a stereoselective C-0-D macrocyclization reaction came about by evaluating a flawed approach to give the C-0-D ring, formulating a hypothesis concerning factors governing the stereoselectivity of that process, then adjusting the overall synthetic strategy to accommodate its intrinsic stereochemical bias. Thus the Harvard group originally focused their efforts on an analog of compound 1 (Scheme 1) without a chlorine atom on ring C. Their intent was to transform the C-ring nitro group into a chlorine atom. However, a 7:l atropisomeric selectivity in the undesired sense was achieved under several sets of reaction conditions. Consequently, they accepted the fact that the nitro group was somehow forced into that orientation during the cyclization, and added the chlorine substituent shown in compound 1. Their new, and ultimately successful, plan was to substitute the nitro group with a hydrogen after it had served to facilitate the SNAr process with the desired atropisomeric selectivity. In this way the C-0-D structure was formed with a 5:l bias in favor of the isomer required for the new approach. The macrocyclization process was also accelerated by the chlorine substituents (reaction time 1.5 h uersus 66 h previously) since it increased the electrophilicity of the aryl fluoride. In fact, the aryl fluoride was so reactive that the steps leading to formation of compound 1 had to be designed very carefully to avoid premature SNAr reactions. Both groups wisely elected to couple their ABC-0-D ring intermediates with preformed protected-tripepetides, thus making the synthesis more convergent. As a result, the East and West US-Coast teams entered the end-game with similar intermediates, ie compounds 2 and 3, respectively. Only the Harvard team could construct the D-0-E ring with selectivity for the desired atropisomer. Their SNAr macrocyclization approach gave a 5:1 ratio of diastereoisomers, whereas in California a disappointing 1:3 selectivity was obtained. The Nicolaou group was able to recycle the undesired isomer by exploiting observations made by Boger and co-workers [9, lo]. Thus the undesired atropisomer was heated to 140 "C in DMSO for 4 h; this gave a thermodynamic 1:l mixture of D-0-E ring isomers which was separated to give the desired one. However, this discovery must have been a small conciliation for the sour stereochemical twist of fate that afflicted them in this final macrocyclization. Having formed the ABC-0-D-0-E skeleton, both groups were left with the task of functional group manipulations and deprotection steps to form the final product. These seem routine to describe but can be exceedingly difficult in practice. Nicolaou's group formed the desired C-terminal acid via a deprotection/oxidation operation on their masked alcohol. Conversion of an N-methyl amide to the corresponding group in the Evans synthesis seems harder, but was in fact accomplished in 68% yield via nitrosation then treatment with basic peroxide. This transformation was possible since that particular amide functionality is the least hindered of the eight present in Harvards aglycon precursor.

I

301

302

I

Total Syntheses of Vancomycin

The Scripps approach to the C-0-D-0-Eframework required that they convert a triazine to a phenol on ring D. This was accomplished in several steps. The triazine was reduced to an amine, and diazotized in the presence of KI to give the corresponding aryl iodide. Unfortunately, 40% of the diazonium compound was reduced to the compound with the corresponding Ar-H bond, and the problem of converting the remaining aryl iodide into a phenol remained. In a very bold step, this iodide was reacted with excess MeMgBr and 'PrMgBr to effect transmetallation, then quenched with trimethylborate. Finally, the phenol was formed via oxidation with basic peroxide. The Nicolaou group entered this area relatively recently, hence it is truly remarkable that they were able to develop a synthesis of the vancomycin aglycon so quickly. However, their route stumbles over the sections that involve atropisomeric selectivity or removal of the triazine. Evans' group synthesis addresses or avoids these problems. It is a more polished effort that took many years and high levels of financial and human resources to develop. In 1999 a third synthesis of the vancomycin aglycon was reported, this time by Boger and co-workers, also at Scripps [11, 121. Boger's synthesis has similarities to the first two syntheses. Like the Nicolaou route, it constructs the rings in the order: C-0-D to ABC-0-D to ABC-0-D-0-E,and uses an amide bond construction to form the AB ring. However, SNAr displacements on fluoronitro aryl systems were used to construct the C-0-D and D-0-E rings, just as in the Evan's syntheses. The feature that distinguishes the Boger syntheses from the other two is a very detailed consideration of the thermodynamics of equilibration of the atropisomers [9, 10, 131. Some illustrative data are shown in Scheme 3. At equilibrium, the two atropisomers of the D-0-E fragment shown in Scheme 3a form in near equimolar amounts, but the nitro derivative is more easily equilibrated than the chloro-compound. Consequently, equilibration of the nitro compound was used to augment the supply of the natural atropisomer, then the nitro group was converted to a chloride to give enhanced stability to isomerization throughout the rest of the synthesis. Scheme 3b is intended to illustrate that the acyclic AB fragment shown is relatively easy to equilibrate, and the thermodynamic resting point favors the natural atropisomer. After the AB ring is closed to form a completely cyclized ABC-0-D fragment, however, both rings become more resistant to isomerization. However, in the complete ABC-0-D-0-Eshown in Scheme 3c, it is, conveniently, the D-0-E that is most amenable to isomerization, again allowing the unnatural atropisomer to be equilibrated and recycled. Full details of the Nicolaou syntheses have now been reported [ 6 , 141, along with successful transformation of the vancomycin aglycon into vancomycin itself [ 15-17]. Their procedure featured three protection steps, ie silylation of all six hydroxyl groups, formation of a methyl ester at the C-terminus, and N-terminal protection with a benzyloxycarbonyl group. The central phenolic-OH was then selectively unmasked (KF A1203), and sequentially coupled with two monosaccharide units. The glycosyl donors used were first a trichloroacetimidate, then a glycosyl fluoride. Finally, deprotection gave the desired product. Of course, it is not necessary to go through the whole synthesis to explore the glycosidation steps; experiments may be done using the vancomycin aglycon from a natural source. Consequently, Kahne et al. were also able to show that vancomycin aglycon can be converted into vancomycin itself. They used a different protection/deprotection scheme and their own glycosidic sulfoxide/

Total Syntheses of Vancornycin I 3 0 3

eiyi)c

a

OMe

TBSO..,,,,

Me02C""' N H

140°C

~

'

Br OMe

TBSO..,,,, Me02C'

NHBOC H

R = NO2 1.O:l .I E, = 26.6 kcal/mol R = CI 1.0:1.2 E, = 30.4 kcal/mol

b

'

Br OMe

OMe

T B S O , , , , , , F ' F o H Me02C'""'

L'

120 OC

NHBOC OMe

Q 0 /-\

MEMO

,OMe OMe

TBSO..,,,,

OMe natural NHCBZ

3:l E, = 25.1 kcal/mol

OMe

OMe '''-OMEM unnatural

Scheme 3.

304

I

Total Syntheses of Vancomycin C

A ~

L N M e B O C NC

natural

Me0 OH

no

unnatural

Me0

R = NO2 1:I E, = 24.8 kcal/mol R = CI 1:1 E, = 23.6 kcal/mol Scheme 3.

(continued)

TfiO glycosylating procedure [ 181. The Nicolaou group have used their understanding of the glycosylation process to prepare libraries of vancomycin analogs. Thus the protected aglycon was supported and glycosylated in different ways to prepare a diverse set of vancomycin analogs [ 191, including dimers linked via the sugar fragments [ 201. Dimeric analogs of vancomycin can have very special activities due to the mode of action of the compound. Since their syntheses, the Boger and Evans groups have taken a different tack, turning their attentions to the related compound, teicoplanin. This is an even more challenging target, having an additional biaryl ether ring and two more {easily epimerized} phenyl glycine units than vancomycin as well as two additional glycosylation sites. Nevertheless, both groups have reported total syntheses of the aglycon [21-241.

References

I305

CI

OR‘

/

teicoplanin aglycon

R’ = R2 = R3 = H

R’ = R2 = R3 = sugars

teicoplanin aglycon

teicoplanin

References D. A. EVANS,M. R. WOOD,B. W. TROTTER, T. I. RICHARDSON,J. C. BARROW,J. L. KATz, Angew. Chem. Int. Ed. 1998, 37, 2700. D. A. EVANS,C. I . DINSMORE, P. S. WATSON, M. R. WOOD,T. I. RICHARDSON, B. W. TROTTER, J. L. KATz, 1998, 37, 2704. K. C. NICOLAOU, S. NATARAJAN, H. LI, N. F. J A I N , R. HUGHES, M. E. SOLOMON, J. M. RAMANJULU, C. N. C. BODDY,M. TAKAYANAGI, Angew. Chem. lnt. Ed. 1998, 37, 2708. K. C. NICOLAOU, N. F. J A I N , W. NATARAJAN, R. HUGHES, M. E. SOLOMON, H. LI, J. M. RAMANJULU,M. TAKAYANAGI, A. E. KOUMBIS,T. BANDO,Angew. Chem. lnt. Ed. 1998, 37, 2714. K. C. NICOLAOU, M. TAKAYANAGI, N. F. J A I N , S . NATARAJAN,A. E. KOUMBIS,T. BANDO, J. M. RAMANJULU, Angew. Chem. lnt. Ed. 1998, 37, 2717. K. C. NICOLAOU, C. N. C. BODDY,H. Li, A. E. KOUMBIS, R. HUGHES, S. NATARAJAN, S. BRASE, N. F. JAIN,J. M. RAMANTULU, M. E. SOLOMAN, Chem. Eur.]. 1999, 5, 2602. D. A. EVANS,J. A. ELLMAN,K. M. DEVRIES, J. Am. Chem. SOC.1989, 11 I , 8912. J. ZHU, Synlett 1997, 133.

9 D. L. BOGER, 0. LOISELEUR,S. L. CASTLE,

R. T. BERESIS,J. H. Wu, Bioorg. Med. Chem. Lett. 1997, 7, 3199. 10 D. L. BOGER, S. MIYAZAKI, 0. LOISELEUR, R. T. BERESIS, S. L. CASTLE, J. H. Wu, Q. J I N , J . Am. Chem. SOC.1998, 120, 8920. 11 D. L. BOGER, M. S . , S . H. KIM, J. H. Wu, 0. LOISELEUR,S. L. CASTLE, J. Am. Chem. SOC. 1999, 121, 3226. 12 D. L. BOGER, S. MIYAZAKI, S. H. KIM, J. H. WU, S. L. CASTLE, 0. LOISELEUR,Q. JIN,J. Am. Chem. SOC.1999, 121, 10004. 13 D. L. BOGER, S. L. CASTLE, S. MIYAZAKI, J. H. Wu, R. T. BERESIS,0. LOISELEUR,I. Org. Chem. 1999, 64, 70. 14 K. C. Nicoraou, H. LI, C. N. C. BODDY, J. M. RAMANJULU,T.-Y. YUE, S. NATARAJAN, X.-J. CHU, S. BRASE, F. RUBSAM, Chem. Eur. J. 1999, 5, 2584. 15 K. C. NICOLAOU,H. J. MITCHELL, N. F. J A I N , N . WINSSINGER, R. HUGHES, T. BANDO,Angew. Chem. Int. Ed. Engl. 1998, 38, 240. 16 K. C. NICOLAOU, A. E. KOUMBIS,M. TAKAYANAGI, S. NATARAJAN, N. F. J A I N , T. BANDO, H. LI, R. HUGHES, Chem. Eur. J. 1999, 5, 2622. 17 K. C. NICOLAOU,H. J. MITCHELL, N. F. J A I N , T. BANDO, R. HUGHES, N.

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WINSSINGER, S. NATARAJAN, A. E. Chem. Eur. ]. 1999, 5, 2648. KOUMBIS, 18 C. THOMPSON, M. GE, D. KAHNE,J . Am. Chem. SOC.1999; 121, 1237. 19 K. C. NICOIAOU,S. Y. CHO, R. HUGHES, N. WINSSINGER, C. SMETHURST, H. Chem. Eur. LABISCHINSKI, R. ENDERMANN, J . 2001, 7, 3798. 20 K. C. NICOIAOU,H . R., S. Y. CHO, N. H. LABISCHINSKI, R. WINSSINGER, Chem. Eur.J. 2001, 7, 3824. ENDERMANN, 21 D. L. BOGER,J.-H. WENG,S. MIYAZAKI, J. J. MCATEE,S. L. CASTLE,S. H. KIM,Y.

MORI,0. ROGEL,H. STRITTMATTER, Q. J I N ,]. Am. Chem. SOC.2000, 122, 10047. 22 D. L. BOGER,S. H. KIM, S. MIYAZAKI, H. STRITTMATTER, J.-H. WENG,Y. MORI;0. ROGEL,S. L. CASTLE,J.J. MCATEE,J . Am. Chem. SOC.2000, 122, 7416. 23 D. L. BOGER,S. H. KIM, Y. MORI,J.-H. WENG,0. ROGEL,S. L. CASTLE,J. J. MCATEE,J . Am. Chem. SOC.2001, 123, 1862.

A. EVANS,J. L. KATZ,G. S. PETERSON, T. HINTERMANN,].Am. Chem. SOC.2001,

24 D.

123, 12411.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co I307

Bryostatin and Their Analogues Ulf Diederichsen

The bryostatins are a class of twenty natural macrolides that were isolated from Bugula neritina (Linneaus) and in minor amounts from other marine organisms [ 1, 21. They all have in common a highly oxygenated twenty membered macrocyclic lactone (Figure 1). Therefore, the polyketide biosynthesis is likely to be their biosynthetic origin [ 31. The macrocycles contain three pyranose rings A-C in the preferred chair conformation, which are linked with equatorial configuration over the 2,6-positions. Most bryostatins only differ in the substituents at positions C7 and C20 where mainly hydroxyl groups or esters are found [4]. The family of bryostatins is of importance as a potential therapeuticum in cancer therapy. Bryostatin 1 (1)presently is in clinical tests, phase 11, mainly for the treatment of melanoma, non-Hodgkin's lymphoma, chronic lyphocytic leukemia, and sarcomas !5]. The molecular mode of action of bryostatins is still not known but they are agonists for protein kinase C (PKC) in uitro and in uiuo. The family of PKC enzymes are serine and threonine kinases that function as regulators within the signal transduction of cell proliferation and cell differentiation. Furthermore, the recognition of phorbol esters by PKC is competitively inhibited by bryostatins. This also seems to explain the protection of cells against an usually deadly dose of ionizing irradiation and was made responsible for the stimulation of the immune system by interleukin and interferon 2 production [6]. Even bryostatins are available by cultivation of Bugula neritina [7] but their isolation from marine organisms is laborious and hardly provides sufficient quantities. Therefore, the synthetic access to these natural products became increasingly important. Furthermore, there is interest in modified as well as more easily accessible bryostatin analogues with favourable pharmacological characteristics compared to the natural products. The synthesis of analogues might also help in evaluating the molecular mechanisms of bryostatin activity. The First Total Synthesis of a Bryostatin

Bryostatin 7 (3) was the first member of the bryostatin family that was accessible by total synthesis. Its preparation was described by Masamune et al. already briefly after its isolation Their concept was based on a Combination of the four synthons 4-7 from Bugula neritina [8]. (Figure 2): The (R,R)-2,5-dimethylborolanyl triflate mediated aldol reaction of aldehyde 4 with the enolate derived from ketone 5 leads after a sequence of deprotection steps, cycliza-

308

I

Bryostatin and Their Analogues

-

Bryostatin 1 (1): R, = O,CCH,,

R,= 0,C

/

C3H7

Bryostatin 2 (2): R, = OH,

R,= 0,C

/

C3H7

Bryostatin 7 (3): R, Fig. 1.

= O,CCH,, R, = O,CCH,

Molecular structures of bryostatin natural products which are accessible by total synthesis.

tions, and oxidations to the A/B-ring fragment 8. The C-ring fragment 7 is coupled by JuliaLythgoe olefination using PhLi as base of choice for selective deprotonation. Boron enolate 6 serves as the fourth building block for the extension of the tricyclic intermediate 9 by two carbons at position C3. Finally, the carboxylic acid is generated and macrolactonization achieved by carbodiimide activation. Synthesis of Bryostatin 2 According to Evans [9]

The total synthesis of bryostatin 2 (2) requires only three synthons: The ring systems A, B, and C are synthesized separately and can be fused in a sequence of olefination, sulfone alkylation and macrolactonization. As the methoxycarbonylmethylidene residue in the Bring turned out not to be compatible with sulfone alkylation, a subsequent functionalization of the macrolactone was necessary. Therefore, the three fragments A-C (Figure 3) were synthesized. All of them have in common the anti-l,3-diole substructure (highlighted). An aldol addition is used as the key step for the preparation of the three monocycles. The respective aldol products are obtained with good stereoselectivity using alkoxytitanate TiC12(OiPr)2 for the A-ring, catalysis with the copper complex [Cu(S,S)-Ph-py-box](SbF6)2 (10)[ 101 in case of

Synthesis of BIyostatin 2 According to Evans

'i -

Me Me

+

RO

R = TBDPS O R-M e

CHO

a O

o x o 5

PhozS\

\OR

..'

PA

7 Me Me

RO

Et,CS 6

Bryostatin 7 (3)

Fig. 2.

*

Bryostatin 7: The first total synthesis.

the B-ring, and the chiral boron enolate (-)-DIPCI(b-chlorodiisopinocampheylborane) for the aldol reaction in ring C. A suitable starting point for the connection of the ring fragments is the modified Julia olefination for the fusion of building blocks B and C. Predominantly, the desired trans-olefin is isolated ( E Z > 955). The hydroxyl group at C10 is activated as a triflate before building block A gets deprotonated with two equivalents n-BuLi and acts as a nucleophile at C10. Sulfinic acid elimination generates the hemiacetal at C9. Before macrolactonisation at C1 the ester needs to be generated from the anilide by acylation with BOQO followed by treatment with LiOCH2Ph. Furthermore, the primary alcohol at C25 needs to be selectively deprotected. In addition, the C-ring is prepared for later functionalization. Macrolactonization is obtained in good yields following the mild cyclization conditions of Yamaguchi via the anhydride, that results from activation with 2,4,6-trichlorobenzoic acid chloride [ 111.

I

309

MeOOC

*

Total Synthesis ofBryostatin 3

10

Me0

16

*

+

OTBS 0

22

'i

Bryostatin 3 (16)

18

OTES M . 3 I..=

MexMe PR T'++

PhS.

I

OHC+p

'

BOMO 19 Fig. 4.

OTBDPS

20

"+

Bryostatin 3 i s special because o f the y-lactone unit at the C-ring.

propylcarbodiimide (DIC), 4-dimethylaminopyridine (DMAP)). Oxidative cleavage of the p-methoxybenzyl ether (PMB) terminates the synthesis of bryostatin 2 (2), which can be converted into bryostatin 1 (I) through a sequence of protecting group manipulations and acylation [ 141. Total Synthesis of Bryostatin 3 [15]

Recently, also the total synthesis of bryostatin 3 (16) was completed (Figure 4) [15]. Similar to the synthesis of bryostatin 2 (2) the A/B-ring fragment 17 needs to be coupled to the C-ring 18. Especially, the synthesis of the bryostatin 3 C-ring should be mentioned since its y-lactone moiety is quite special within the family of bryostatins [lG]. An additional hydroxyl group at C22 is needed for the ring closure to the y-lactone. It is obtained by addition of vinyliodide 19 to the aldehyde 20 with a 3:l selectivity in favour of the desired anti-diol. Protecting group manipulations and cyclization yield acetal 18 as a precursor of the C-ring fragment in bryostatin 3 . Julia-Lythgoeolefination is used for the ClG-Cl7 linkage forming the desired trans double bond [17]. Deprotection and oxidation steps provide the y-lactone before macrolactonization takes place following Yamaguchi conditions. At this stage the Horner-Wadsworth-Emmons reaction with the chiral Fuji-phosphonate 12 ( Z E= 89:11) [ 121 can be used for stereoselective attachment of the missing methoxycarbonylmethylidene residue in the B-ring.

I

311

312

I

Bryostatin and Their Analogues

Bryostatin Analogues

Obviously, the access to the A, B and C ring fragments is the key to a successful synthesis of bryostatins. Therefore, next to the total syntheses several partial syntheses [ 181 and preparations of ring fragments are reported [ 191. These partial structures are also valuable components regarding the synthesis and evaluation of bryostatin analogues. A high binding affinity of bryostatin 1 is observed for protein kinase C (PKC,Ki = 1.35 nM) for which 1,2-diacyl-sn-glycerol(21, DAG) is well known as an endogenous activator. Furthermore, the activity of phorbol ester 22 as one of the strongest tumor promotors is likely to be also based on the activation of PKC [20].The structural comparison of these PKC binders suggests that the C1-carbonyl,C19-hydroxy1, and the C2G-OH groups of bryostatin 1 (1)have analogues orientation compared to the functional groups of 1,2-diacyl-sn-glycerol and those of the phorbol ester [21]. Because of the similar pharmacophors (Figure 5, circled) a common binding site seems likely. Furthermore, these PKC binders have lipophilic regions in common (highlighted). This raises the question about the function of the A and B rings in bryostatin. Following the arguments of Wender et al. the A/B-fragment is only responsible for the conformational adjustment of the macrocycle and the geometrical arrangement of the functionalities. In this case the A/B-rings could be replaced by lipophilic analogues bridging the C-ring recognition unit. Aiming for simplified bryostatin analogues might improve the therapeutic characteristics as well as the synthetic availability [22]. The

Me Me M

e

0

2

C

m 1,2-Diacyl-sn-glycerol (21)

O*CR

I

Me

Bryostatin 1 (1) Phorbol ester (22) Fig. 5. Comparison o f the most likely chromophors of bryostatin, 1,2-diacyl-sn-glyceroI and the phorbol ester. The oxygen functionalities belonging t o the pharmacophor are circled. Furthermore, non polar regions are indicated.

Bryostatin Analogues I 3 1 3

,OTBS

24

25

OH

26

l5 CHO

L 1

1

.

-

OH

0

OTBS MMee ~ , , , . . ~ y O P M B

\ COOMe 23

Fig. 6.

Me 27

Synthesis o f C-ring synthons for modified bryostatins as reported by Wender et a/. [20].

introduction of A/B-ring analogues allows a new strategy for the macrocyclization: Whereas the formation of an ester is still used to link the ends C25 and C1, the introduction of an oxygen at position 14 permits, however, efficient cyclization by macrotransacetalization. For the design of new A/B-ring analogues it is important to keep the isosterical geometry compared to the natural bryostatins. However, the knowledge that the pharmacophor is mainly located on the C-ring without direct participation of the A/B-ring system, allows the synthesis of a highly variable spectrum of derivatives. For the synthesis of bryostatin analogs a completely functionalized C-ring fragment 23 is incorporated. Cyclization takes place bridging the aldehyde at C15 and the alcohol at C27 (Figure 6 ) . The C-ring is accessible by addition of diketone 24 to aldehyde 25 followed by dehydratation, separation of the /3-isomer and Luche-reduction to yield glycal 26. Oxidation of the C-C double bond to the epoxide, ring opening with methanol, selective benzoylation of the equatorial hydroxyl group at C21 followed by oxidation at C20, and desoxygenation at C21 with Sm12 results in ketone 27. In analogy to the functionalization of bryostatin 2 (2), the methoxycarbonylmethylidene residue and the acyl side chain are attached to the building block 27. The concluding homologization by two C-atoms at C17 starts with oxidation of the deprotected alcohol to the sterically strongly hindered aldehyde, which is allylated with diethylallylborane. The hydroxyl group at C15 is acetylated, before the terminal olefin is dihydroxylated, and a glycole-cleavage follows under basic conditions (elimination to the Michael system). Finally, the hydroxyl groups at C19 and C27 are deprotected to yield the Cring fragment 23 that can be cyclized with appropriate A/B-ring analogues. The bridging A/B-segment 28 is linked as a menthone acetal to the C-ring building block 23 by ester formation following Yamaguchi conditions [ 111. A remarkable macrotrans-

"OBn

314

I

Bryostatin and Their Analogues

H

macrotransacefalization

H

I5c~o

+

b

Yarnaguchi esterification

29

23

hR

O V 0

PKC Affinity

Growth Inhibition

O\

Bryostatin 1

Ki = 1,35 nM

Bryostatin 2

Ki = 5,86 nM

Analogue 29

Ki = 3,4 nM

GI,,=

Analogue 30

Ki = 47

GI5,= 8-3300 ng.mL-'

Analogue 31

Ki = 8,3 nM

Me

nM

GI,,=

1,8-170 ng.mL-'

8-3300 ng.mL-'

30R=H 31 R = fed-butyl Fig. 7.

Bryostatin analogues and their biological activities.

acetalization is achieved in highly diluted CH2C12with amberlyst-15 and 4 A molecular sieve (Figure 7). Thermodynamically controlled only the expected cyclization product with equatorial configuration at C15 is formed. Finally, the hydroxyl groups are deprotected to yield bryostatin analogue 29. In an analogous procedure the bryostatin derivatives 30 and 31 can be obtained. The bryostatin analogues provide quite interesting PKC affinities and inhibition of tumor cell growth (Figure 7): The outstanding values for the analogues in comparison with bryostatins 1 and 2 suggest that the geometrical assumptions the structural modifications were based on. are efficient regarding PKC recognition. The C-ring building block 23, that is

References

available in gram quantities, might be combined - even by combinatorial chemistry - with further bridging units. If the hydroxyl group at C3 is missing, the PKC affinity decreases (Ki = 297 nM). This confirms the important role of the hydrogen bond between the C3oxygen atom and the C19-hydroxyl group for the active conformation, as it was already proposed from the crystal structure by Pettit et al. [ l a ] This hydrogen bond probably could be strengthened by a better proton acceptor at C3. Summary

The total synthesis of bryostatins starts with the preparation of the required ring fragments, followed by the macrocyclization as a key step, and is finished by remaining functionalizations. Even synthetic modifications of the bryostatin natural products presented here would not essentially change the underlying concept. In contrast, simpler analogues allow new and more efficient strategies. For the isosteric A/B-ring substitutes, that control the C-ring conformation, further synthetic simplifications seem possible. Future bryostatin analogues might give further insight in structure activity relationship and therefore improved pharmacological activity. References a) G. R. PETTIT,C. L. HERALD, D. L. DOUBEK,D. L. HERALD,E. ARNOLD,J. CURDY,]. Am. Chem. SOC.1982, 104, 6846-6847;b) G. R. PETTIT,Y. KAMANO, R. AOYAGI,C. L. HERALD,D. L. DOUBEK, J. M. SCHMIDT,J. J. RUDLOE,Tetrahedron 1985, 41,985-994; c) G. R. PETTIT. F. GAO,P. M. BLUMBERG, C. L. HERALD,J. C. COLL;Y. KAMANO,N. E. LEWIN,J. M. SCHMIDT,7.-C. CHAPUIS,]. Nat. Prod. 1996, 59, 286-289. 2 A review article about bryostatins: R. MUTTER,M. WILLS,Bioorg. Med. Chem. 2000,8,1841-1860. 3 R. G. KERR,J. LAWRY, K. A. GUSH, Tetrahedron Lett. 199G, 37, 8305-8308. 4 a) R. D. NORCROSS, I. PATERSON, Chem. Rev. 1995, 95, 2041-2114;b) G. R. PETTIT, J . Nat. Prod. 1996, 59,812-821. 5 a) A. S. KRAFT.S. WOODLEY, G. R. PETTIT, F. GAO,J. C. COLL,F. WAGNERF. Cancer Chemother. Pharmacol. 1996, 37, 271-278; b) R. GONZALEZ, S. EBBINGHAUS, T. K. HENTHORN, D. MILLER,A. S. KRAFT, Melanoma Rex 1999, 9, 599-606; c) M.L. M. S. VARTERASIAN, R. M. MOHAMMAD, SHURAFA, K. HULBURD, P. A. PEMBERTON, V. SPADONI,D. S. D. H. RODRIGUEZ, EILENDER, A. MURGO,N. WALL,M. DAN, A. M. AL-KATIB,Clin. Cancer Res. 2000,6,

1

6

7 8

9

10

11

12

13

825-828;d) http://www.dtp.nci.nih.gov/ docs/static~pages/compounds/339555. html. a) A. S. KRAFT,S. WOODLEY, G. R. PETTIT, F. GAO,J. C. COLL,F. WAGNER,Cancer Chemother. Pharmacol. 1996, 37, 271-278; b) 2. SZALUSI,L. Du, R. LEVINE,N. E. LEWIN,P. N. NGUYEN,M. D. WILLIAMS, G. R. PETTIT,P. M. BLUMBERG, Cancer Res. 1996, 56, 2105-2111. S. PAIN.New Scientist 1996, 151,38. M. KAGEYAMA, T. TAMURA,M. H . NANTZ, J. C. ROBERTS, P. SOMFAI,D. C. S. MASAMUNE, I. Am. WHRITENOUR, Chem. SOC.1990, 112, 7407-7408. D. A. EVANS,P.H. CARTER,E. M. CARREIRA, A. B. CHARETTE,J. A. PRUNET, Angew. Chem. Int. Ed. 1998, M. LAUTENS, 37, 2354-2359. D. A. EVANS,M. C. KOZLOWSKI, J. A. MURRY,C. S. BURGEY,K. R. CAMPOS,B. T. CONNELL, R. J. STAPLES, I. Am. Chem. SOC. 1999, 121,669-685. J. INANAGA, K. HIRATA,H. SAEKI,T. KATSUKI,M. YAMAGUCIII,Bull. Chem. Soc. ]pa. 1979, 52,1989-1993. K. TANAKA,K. OTSUBO,K. FUJI, Tetrahedron Lett. 1996, 37, 3735-3738. E. J. COREY,C. J . HEIAL,Angew. Chem. Int. Ed. 1998, 37, 1986-2012.

I

315

316

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Bryostatin and Their Analogues 14

15

16

17

18

19

G. R. PETTIT,D. SENGUPTA, D. L. HERALD, N. A. SHARKEY, P. M. BLUMBERG,Can. J. Chem. 1991, 69,856-860. K. OHMORI,Y. OGAWA, T. OBITSU,Y. ISHIKAWA, S. NISHIYAMA, S. YAMAMURA, Angew. Chem. Znt. Ed. 2000, 39, 2290-2294. T. OBITSU,K. OHMORI,Y. OGAWA,H. S. HOSOMI,S. OHBA,S. NISHIYAMA, YAMAMURA, Tetrahedron Lett. 1998, 39, 7349-7352. a) M. JULIA, J. M. PARIS,Tetrahedron Lett. 1973, 34,4071-4074; b) P. J . KOCIENSKI, ]. Chem. SOC., B. LYTHGOE, S. RUSTON, Perkin Trans. 11978, 829-834. a) M. KALESSE, M. EH, Tetrahedron Lett. 1996, 37, 1767-1770; b) J. M. WEISS, Tetrahedron: AsymH. M. R. HOFFMANN, metry 1997, 8, 3913-3920; c) S.-I. KIYOOKA, H. MAEDA,Tetrahedron: Asymmetry 1997, 8, 3371-3374; d) J. GRACIA, E. J. THOMAS, ]. Chem. SOC.,Perkin Trans. 11998, 28652872. a) K. J. HALE,M. FRIGERIO, S. MANAVIAZAR, Org. Lett. 2001, 3, 37913794; b) A. VAKALOPOULOS, T. F. J. LAMPE, H. M. R. HOFFMANN, Org. Lett. 2001, 3, 929-932; c) K. J. HALE,M. G. HUMMERSONE, G. S. BHATIA, Org. Lett. 2000, 2, 2189-2192; d) J. A. LOPEZ-PELEGR~N, P. WENWORTH, JR., F. SIEBER, W. A. METZ, K. D. JANDA, J. Org. Chem. 2000, 65, A. RAE, E. 8527-8531; e) P. ALMENDROS, THOMAS, Tetrahedron Lett. 2000, 41, 9565-

9568; f ) J. DE BRABANDER, B. A. KULKARNI, R. GARCIA-LOPEZ. M. VANDERWALLE, Tetrahedron: Asymmetry 1997, 8, 17211724; g) J. DE BRABANDER, M. VANDERWALLE, Pure Appl. Chem. 1996, 68, 715718; h) J. DE BRABANDER,K. VANHESSCHE, M. VANDERWALLE, Synthesis 1994, 855-865. 20 P. A. WENDER, Y. MARTIN-CANTALEJO, A. J. CARPENTER, A. CHIU,J. DE P. G. HARRAN, J.-M. J I M E N E Z , BRABANDER, M. F. T. KOEHLER, B. LIPPA,J. A. S. G. MULLER, S. N. MULLER, MORRISON, C. SIEDENC.-M. PARK,M. SHIOZAKI, M. TANAKA, K. BIEDEL, D. J. SKALITZKY, IRIE, Pure Appl. Chem. 1998, 70, 539-546. 21 P. A. WENDER, J. DE BRABANDER,P. G . HARRAN, J.-M. JIMENEZ, M. F. T. KOEHLER, B. LIPPA, C.-M. PARK,C. SIEDENBIEDEL, G. R. PETTIT,Proc. Natl. Acad. Sci. USA 1998, 95, 6624-6629. 22 a) P. A. WENDER, J. DE BRABANDER, P. G. HARRAN, J.-M. J I M E N E Z , M. F. T. KOEHLER, B. LIPPA,C.-M. PARK,M. SHIOZAKI,].Am. Chem. SOC.1998, 120, J. DE 4534-4535; b) P. A. WENDER, BRABANDER,P. G . HARRAN, K. W. HINKLE, B. LIPPA, G. R. PETTIT,Tetrahedron Lett. 1998, 39,8625-8628; c) P. A. WENDER, K. W. HINKLE, M. F. T. KOEHLER, B. LIPPA, Med. Res. Rev. 1999, 19, 388-407; d) P. A. WENDER, B. LIPPA, Tetrahedron Lett. 2000, 41, 1007-1011; e) P. A. WENDER, K. W. HINKLE,Tetrahedron Lett. 2000, 41, 6725-6729.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co I317

Eleutherobin: Synthesis, Structure/Activity Relationship, and Pharmacophore Ulf Diederichsen

The natural product eleutherobin (1)was isolated in 1994 by Fenical et al. from a marine soft coral from an Eleutherobia species and its structure was elucidated shortly afterwards (Figure 1) [ 1).Eleutherobin is a diterpene glycoside that possesses remarkable cytotoxicity against a wide variety of cancer cells, which is likely to be based on binding to tubulin and stabilization of microtubules [2, 31. Mitosis is interrupted and the cell division cycle is terminated. The mechanism of action of eleutherobin is comparable to that of highly potent cytostatic agents such as paclitaxel (Taxol), nonataxel, epothilones, and discodermolide. The 4,7-oxaeunicellane skeleton of the eleutherobins is also found in the eleuthosides (2, 3), the sarcodictyins (4), and the valdivones (5) (Figure 1) [4-6]. While the arabinosyl residue is not required for an antitumor effect, the methylurocanic acid ester side chain bound to C8 is part of the pharmacophore. Recent progress in the total synthesis of eleutherobin is discussed together with the identification of a common pharmacophore for tubulin-binding natural products, and a combinatorial way to determine the structure/activity relationship and drug optimization. Total Syntheses of Eleutherobin

Two methods for the total synthesis of eleutherobin have been described, differing mainly in the formation of the tricyclic skeleton and in the introduction of the arabinosyl moiety [7]. Nicolaou et al. had previously developed a synthesis of the tricyclic core structure for the preparation of sarcodictyins, starting from the monoterpene (+)-carvone [8].This concept can be applied to the synthesis of eleutherobin (Figure 2) [ 91. Compared to the sarcodictyins, eleutherobin contains an additional 0-acetyl-D-arabinosylresidue linked as the p anomer. This is introduced early in the synthesis by glycosylation of the open-chain acetylenic aldehyde 6 . The stereospecificity of this coupling with the D-arabinosyl trichloroacetimidate 7 is not easy to control, since the ratio of the c( and j? anomers strongly depends on the reaction conditions. In dioxane/toluene the desired p-glycoside 8 is formed preferentially in an 8:l epimeric mixture. Afterwards, even at -30 "C the ten-membered ring is formed by an intramolecular acetylide-aldehyde condensation with LiHMDS, followed by immediate Dess-Martin oxidation of the arising secondary alcohol. The key step in the synthesis is the stereoselective catalytic hydrogenation of the acety-

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0 II

OH COOMe

H

.-,)

'le hn

Me Sarcodictyin A 4

Me

0

OR3

I

Me

R, = Me, R, = R, = H: Eleutherobin (1) R, = H, R, = Ac, 4 = H: Eleuthoside A (2) R, = H, R, = H, R, = Ac: Eleuthoside B (3)

Valdivone A 5 Fig. 1.

Molecular structures of eleutherobin, eleuthosides, sarcodictyins, and valdivone.

lene moiety by use of Hz with Lindlar catalyst in toluene at 25 "C. This spontaneously and selectively affords the expected lactol, which is subsequently converted into the methoxy ketal 9. In the total synthesis of Danishefsky et al. (Figure 3) the tricyclic skeleton is established before the arabinosyl unit is linked [lo]. The key steps of this synthesis are the Nozaki-Kishi cyclization to the furanophane, a sequence of rearrangements to the 4,7-oxaeunicellane framework [ 111, and the oxycarbaglycosidation of the tricyclic core structure. The ten-membered ring is established by addition of the nucleophile resulting from monometalation of 2,5-dibromofuran (11) to aldehyde 10, which is derived from the monoterpene (-)-cc-phellandrene (Figure 3). After chain-extension by one carbon atom, alcohol 12 is formed in a 1.3:l diastereomeric mixture at C8, from which the desired isomer can be isolated in 57% yield. Cyclization forms the highly strained 2,s-furanophane 13 with good stereoselectivity at C3, through reductive Nozaki-Kishi cyclization of the bromine aldehyde 12. Epoxidation of the allylic alcohol 13 initiates a rearrangement to the pyranosyl derivative 14, which after stereocontrolled 1,z-addition of methyl lithium further rearranges to the furanosyl ring system to provide the eleutheside core structure 15. The anomeric mixture that would result from classical glycosylation is avoided by the use of Stille coupling of the (arabinosy1)methyldonor 17 to the vinyl triflate 16. The respective (arabinosy1)methyldonor 17 can be obtained with tri-n-butylstannylmethanol from the thioethyl glycoside after separation of the anomeric mixture. Stille coupling does not affect the stereochemistry of the C2/C3-double bond. Nevertheless, even optimization of reaction conditions resulting in the

Cornbinatorial Sarcodictyin Libraries

OTES

I

319

OTES OTES

OTES c

CHO OH

6

OTBS

-

OTBS Fig. 2.

L

FoTB OTBS-

Total synthesis of eleutherobin by the procedure o f Nicolaou et al.

addition of LiCl did not provide yields higher than 50% for the formation of 18. This synthesis, however, does provide a suitable means for the attachment of the sugar side chain to the eleutherobin core structure. Both total syntheses of eleutherobin (1) are completed by the introduction of the methylurocanic acid moiety through acylation of the C8 hydroxyl group. Finally, the natural product is obtained by removal of protecting groups. Combinatorial Sarcodictyin Libraries

Pharmacological evidence regarding the eleutherobin side chains can be investigated preferentially by the synthesis of derivatives based on the eleutherobin/sarcodictyin core structure by combinatorial chemistry [ 1 2 ] . Modifications with varying side chains at C3, C4, and C8 are tested for tubulin polymerization and cytotoxicity (Figure 4). The C4 anomeric hydroxyl group is suitable for linkage to the Merrifield solid support, since a variety of alcohols can be introduced by trans-ketalization at the end of the synthesis simultaneously with cleavage from the resin. Twelve atoms turned out to be a good choice for the length of the linker. The sarcodictyin core structure is bound to the solid support by means of a Wittig reaction, forming a double bond in the central position of the spacer. The side chains at the C8-

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' c-

:

OPiv Me

Me

15

OH

c--

OH

OPiv

-

14

c

16 Fig. 3.

Total synthesis of eleutherobin by the procedure of Danishefsky et al.

hydroxyl group are attached as esters or carbamates. After deprotection of the primary hydroxyl group there are three possibilities for the linkage of C3 side chains to 19: direct conversion to esters or carbamates 21, oxidation to the carboxylic acid followed by ester or amide derivatisation derivatization (20), or nucleophilic substitution with an azide, subsequent reduction to the amine, and linkage of the side chains as amides (22). Therefore, activated carboxylic acids such as acetic anhydrides and acetyl chlorides, as well as isocyanates or alcohols, are applied for functionalization of the resin-bound core structure, whereas the third side chain is introduced in combinatorial fashion with various alcohols in the trans-ketalization cleavage reaction. Structure/activity relationship studies on the sarcodictyin library are performed by induction of tubulin polymerization and by cytotoxicity studies with three cancer cell lines, including Taxol-resistantlines. Derivatives that induce tubulin polymerization more strongly than the natural product sarcodictyin have been determined, and can show higher cytotoxicity even as far as Taxol-resistant tumor cells are concerned. The results of the structure/

Combiflatorial Sarcodictyin Libraries

Fig. 4. Attachment of the pharmacophoric side chains t o the sarcodictyin core structure by combinatorial synthesis.

activity relationship studies are summarized in Figure 5: the methylurocanic acid side chain is necessary for activity, and both nitrogen atoms of the imidazole ring are required. Recent studies also prove the stringent requirement for the 2’,3’-double bond [13], but ketal substitutions are tolerated well. Esters are more active than the corresponding amides in the C3 side chain. Finally, with the exception of eleutherobin, reduction of the ester to the alcohol and derivatives thereof (21) are not tolerated. From an additional study, modification or removal of the sugar moiety also has a substantial influence on the cytotoxic potency of eleutherobin and its cross-resistance in Taxolresistant cells [14].These structure/activity profiles should be usable for future design of more potent eleutherobin derivatives.

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C8 Side chain is crucial for activity 2’,3’-Double bond is required Both nitrogen atoms are important

Ketal substitutions are tolerated Esters are preferred over amides; reduction to the alcohol is not tolerated Fig. 5.

Summary of the structure/activity relationship results.

Common Pharmacophore: Prediction of New Drugs

The natural products eleutherobin (l),epothilone (23), paclitaxel (24), nonataxel (25), and discodermolide (26) (Figure 6) show a similar mode of action. Furthermore, competitive inhibition of paclitaxel binding to rnicrotubules by epothilone, eleutherobin, and discodermolide is observed, and so a common pharmacophore and the existence of a common tubulin binding site are therefore strongly suggested [ 151. The identification of comparable structural characteristics is complicated, since conformations established by NMR spectroscopy or X-ray structure analysis do not necessarily correspond to the binding conformations [161. Ojima et al. compared the preferred conformations of paclitaxel, nonataxel, epothilones A and B, eleutherobin, and discodermolide with the aid of NMR spectroscopy and molecular dynamics calculations [ 17, 181. Although these natural products are constitutionally quite different, an outstanding topological homology can be recognized. A common pharmacophore seems to exist [19], and is defined by the three regions A, B, and C (marked in Figure 6). These functional regions can be superimposed within the three-dimensional structures. By this definition of a common pharmacophore, the multicyclic baccatin core structure of Taxol seems only to be required for spatial orientation of the substituents. Furthermore, the good in vivo activities of the epothilone analogues in which the epoxide is replaced by a double bond also support the prediction that the epoxide does not belong to the pharmacophore [20]. The eleutherobin modifications obtained by total synthesis also fit with the model of a common pharmacophore: the arabinosyl residue can be substituted by its enantiomer or simply by an acetyl group without appreciable loss of activity [ 101, whereas the C8 side chain is indispensable for activity [ 91. Caribaeoside represents a recently studied eleutherobin analogue with an additional hydroxyl group at C11 [21]. The significant decrease in antimitotic activity supports the pharmacophore model regarding the proposed apolar Bregion. With this knowledge of the three-dimensional orientation of the common pharmacophore, it is possible to design new and structurally simplified analogues of therapeutic interest. As an example, the hybrid derivative SB-TE-1120 (27),based on the baccatin core structure (Figure 7), has been synthesized [17]. This analogue has a good structural homology with epothilone B and eleutherobin, which is also indicated by a remarkable activity.

Biological Activity

Fig. 6. The common pharmacophore o f the presented tubulin-binding cytostatic agents is defined by the residues A, B, and C, which are superimposed in the three-dimensional structures.

Biological Activity

The antiproliferative activity of eleutherobin is based on interaction with tubulin, as is known for epothilone and taxol. These natural products induce depolymerization of microtubules and thereby interrupt the division of cancer cells [ 2 ] . From experiments with highly purified tubulin, it was possible to show that some eleuthesides as well as epothilone A induce tubulin aggregation comparable to that of paclitaxel, and are also promoted by microtubule-associated proteins or GTP [221. Furthermore, kinetic measurements indicate

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SB-TE-1120 (27) Fig. 7.

Hybrid structure SB-TE-1120, the result of studies determining a common pharrnacophore.

the recognition of eleuthesides and epothilone at the paclitaxel binding site [23]. Eleutherobin (k, = 2.1 J ~ M )has a strength similar to epothilone A (ki = 2.6 p ~ as) an inhibitor of radiolabeled paclitaxel binding. The tubulin affinity of sarcodictyines is significantly lower. The influence on cell growth was examined quantitatively in six human cancer cell lines, including two paclitaxel-resistant lines [ 221.The results obtained for antiproliferative activity are largely in accordance with the tubulin interactions. Once again, lower activity was found for the sarcodictyines (ICso = 200-500 nM) than the similar values found for paclitaxel (I& < 10 nM), epothilone A (ICso = 10-40 nM), and eleutherobin (IC50 = 10-40 nM). Overall, quite similar antimitotic effects are observed for several constitutionally diverse natural products. There seems to be evidence for different core structures presenting a common pharmacophore. This knowledge of the spatial and functional needs of the pharmacophore should in future hopefully result in new and easy accessible derivatives with high potency, more limited side effects, and lower resistance than the natural products. References

T. LINDEL, P. R.

J E N S E N , W.

FENICAL, et al.,

M. D'AMBROSIO, A. GUERRIERO, F. PIETRA,Hefu. Chim. Acta 1987, 70, 2019A. GUERRIERO, 2027; b) M. D'AMBROSIO, F. PIETRA,Helu. Chim. Acta 1988, 71,

4 a)

1. Am. Chem. Soc. 1997, 119,8744-8745. B. H. LONG,J. M. CARBONI, A. J. WASSERMAN, et al., Cancer Res. 1998, 58,

964-976.

1111-1115.

Review articles: a) K. C. NICOIAOU, D. N. P. KING, et al., Pure Appf. HEPWORTH, Chem. 1999, 71, 989-997; b) K. C. NICOIAOU, J. PFEFFERKORN, J. Xu, eta]., Chern. Pharm. Bull. 1999, 47, 1199-1213; c) S. J. STACHEL, K. BISWAS,S. J. DANISHEFSKY, CUT. Pharm. Des. 2001, 7, 1277-1290; T. LINDEL:Organic Synthesis 2000, Highlights I V (ed. H.-G. SCHMALZ) 268-274.

BOWLEY,D. J. FAULKNER, Tetrahedron 1993, 49, 7977-7984. R. BRITTON,M. ROBERGE, H. BERISCH, et al., Tetrahedron Lett. 2001, 42,

5 Y. LIN, C. A. 6

2953-2956. 7

T. LINDEL, Angew. Chern. 1998, 110,806808.

NICOIAOU, F. L. VAN DELFT,T. OHSHIMA, et al., Angew. Chern. 1997, 109, 2630-2634; b) K. C. NICOIAOU,

8 a) K. C.

References I 3 2 5

T. OHSHIMA,S. HOSOKAWA, et al.,]. Am. Chem. Soc. 1998, 120, 867443680, 9 a) K. C. NICOLAOU, J. Y. Xu, S. KIM, et al., 1.Am. Chem. SOC.1997, 119, 11,35311,354; b) K. C. NICOIAOU,J. Y. Xu, S. KIM, et al., J . Am. Chem. Soc. 1998, 120, 8661-8673. 10 a) X.-T. CHEN,C. E. GUITERIDGE, S. K. BHATTACHARYA, et al., Angav. Chem. 1998, 110, 195-197; b) X.-T. CHEN,B. ZHOU,S. K. BHATTACHARYA, et al., Angew. Chem. 1998, 110, 835-838; c) X.-T. CHEN,S. K. BHATTACHARYA, B. ZHOU,et a].,]. Am. Chem. SOC.1999, 121, 6563-6579. 11 S. K. BHATTACHARYA, X.-T. CHEN,C. E. GUTTERIDGE, et al., Tetrahedron Lett. 1999, 40, 3313-3316. 12 K. C. NICOLAOU, N. WINSSINGER, D. VOURLOUMIS, et al.,]. Am. Chem. Soc. 1998, 120, 10,814-10,826, 13 R. BRITTON,E. DILIPD E SILVA, C. M. BIGG, et al., 1.Am. Chem. SOC.2001, 123, 8632-8633. 14 H. M. MCDAID,S. K. BHAITACHARYA,X.-T. CHEN,et al., Canc. Chem. Pharm. 1999, 44, 131-137. 15 For a microtubule structure see: P. MEURER-GROB, J. KASPARIAN, R. H. WADE, Biochemistry 2001, 40, 8000-8008.

B. CINEL,B. 0. PATRICK,M. ROBERGE, et al., Tetrahedron Lett. 2000, 41, 2811-2815. 17 I. OJIMA,S. CHAKRAVARTY, T. I N O U E , et al., Proc. Natl. Acad. Sci USA 1999, 9 6 4256-4261. 18 For further advances in the search for a common pharmacophore: L. HE, G. A. ORR,S. B. HORWITZ,Drug Discovery Today 2001, 6, 1153-1164. 19 For the determination of a common pharmacophore compare: a) J. D. WINKLER, P. H. AXELSEN, Bioorg. Med. Chem. Lett. 1996, 6, 2963-2966; b) M. WANG,X. XIA, Y. KIM, eta]., Organic Letters 1999, I , 43-46. 20 a) T. CHOW,X. ZHANG, A. BALOG,et al., Proc. Natl. Acad. Sci. USA 1998, 95, 96429647; b) T. CHOW,X. ZHANG,C. R. HARRIS,et al., Proc. Natl. h a d . Sci. USA 1998, 95, 15,798-15,802. 21 B. CINEL,M. ROBERGE,H. BEHRISCH, et al., Organic Letters 2000, 2, 257-260. 22 E. HAMMEL, D. L. SACKETT, D. VOURLOUMIS, et al., Biochemistry 1999, 38, 5490-5498. 23 For a cocrystal structure analysis of tubulin dimers with GTP, GDP, and taxol S. G. WOLF,K. H. compare: E. NOGALES, DOWNING,Nature 1998, 391, 199-203. 16

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Total Synthesis o f the Natural Products CP-263,114 and CP-225,917 Ulf Diederichsen and Katrin 6. Lorenz

Two structurally remarkable natural products were recently isolated from a Texas juniper fungus by the Pfizer research team. Today these compounds are well known as phomoidrides A and B or by their code numbers CP-263,114(1)and CP-225,917 (2), respectively [I, 21. Their overall structures and relative configurations were assigned shortly afterwards by Kaneko et al., on the basis of extensive NMR analysis, and their absolute configurations were recently determined by asymmetric synthesis (Figure 1) [3]. The interest in these compounds derives from their attractive biological properties: both show potent inhibitory activities towards squalene synthase and farnesyl transferase. Squalene synthase is widely recognized to be the enzyme responsible for the first step in the biosynthesis of cholesterol from farnesyl pyrophosphate. Inhibition of squalene synthase at the initial stage would provide a possible means of lowering cholesterol levels without interfering with the production of nonsterolic compounds based on farnesyl pyrophosphate. Against squalene synthase from rat liver, the phomoidrides exhibit ICso values of 43 pM (phomoidride A) and 160 pM (phomoidride B). Farnesyl transferase from rat brain is inhibited by CP-263,114 (1) and CP-225,917 (2) with IC50 values of G pM and 20 pM, respectively. Farnesylation of the Ras protein, which works as a molecular switch for cell growth, by farnesyl pyrophosphate as a substrate allows it to bind to the lipophilic plasma membrane. Interference with membrane binding would be a promising approach through which to affect uncontrolled cell growth caused by mutated Ras [4]. Even though CP compounds are relatively small, they represent an extremely challenging target for synthetic chemists, due to their unusual arrangement of functional groups [ 51. Based on a cage-likebicyclo[4.3.l]deca-l,G-dien-lO-one core, the CP molecules present a highly oxygenated tetra- or pentacyclic ring system with two additional alkenyl side chains (Figure 1). The bridgehead double bond (anti-Bredt), the y-hydroxy-y-lactonefunctionality, and the fused maleic anhydride moiety deserve special attention as complex structural features. Pericyclic Reactions for the Construction o f the Bicyclic Core Structure

Much of the published work dealing with the synthesis of the phomoidrides has centered on devising methods for assembling their unique bicyclic carbon skeleton. The construction of this bicyclic core with additional potential for subsequent functionalization is a central

Pericyclic Reactionsfor the Construction ofthe Bicyclic Core Structure

I" 0 /

0 d 0

hl

"'I 0

4

Y

Y

0

x

n

Y

P

F r Y 0 .

I

M .U

I

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Total Synthesis ofthe Natural Products CP-ZG3,114 and CP-225,917

task in the synthesis of the CP compounds. Most of these concepts use pericyclic reactions, offering the possibility to introduce the bridgehead double bond directly with the cyclization step [6-121. Clive et al. demonstrated in a simplified model system that the bicyclic core structure can be achieved by means of an anionic oxy-Cope rearrangement [ 7 ] , but this method unfortunately fails for more highly substituted scaffolds. A silyloxy-Cope variant has hence been established, affording the same target molecules but enabling milder conditions to be used [Sl. Leighton et al. also made use of this favorable rearrangement to synthesize the central core structure (Figure 2) [ 91. Treatment of hydroxy enol triflate 3 with Pd(PPh3)4, Et3N, and CO generates the lactone spiroketal 4,which undergoes silyloxy-Cope rearrangement to the silyl enol ether 5 in good yields. The Cope precursor 4 does not need to be isolated. The activation of the silyloxy-Coperearrangement, achieved only by the introduction of the lactone spiroketal group, is remarkable: the orientation of the Cope system and the loss of ring tension during the pericyclic reaction give rise to an acceleration such that the rate exceeds that of the anionic oxy-Cope rearrangement. A more advanced, direct route to the core structure of CP-263,114(rac-1) has recently been published by Wood et al., who used carbon-based fragmentation after a phenolic oxidation/ intramolecular Diels-Alder sequence [ 101. In addition, various cycloadditions for the synthesis of the central bicyclic skeleton have been established [ll]. Further methods to construct the bicyclic backbone by means of a Diels-Alder reaction [I21 and by an exciting multi-step domino reaction [13] are introduced in the next sections, in the context of the total syntheses of the phomoidrides by Nicolaou and Shair, respectively [ 141. Danishefsky 's Total Synthesis: Carbobicyclic Core by Aldol and Heck Reactions

A basic approach combining the introduction of the fused maleic anhydride moiety with the cyclization uses the trisubstituted furan derivative 6 as a coupling partner to the ring system 7 (Figure 3) [GI. The furan ring serves as precursor for the maleic anhydride moiety, easily accessible through subsequent oxidation [ba]. The initial aldol condensation between the aldehyde G and the cyclic enone 7 proceeds with high diastereoselectivity, positioning the hydroxyl group anti to the alkyl substituent. A silyl protecting group is attached to the hydroxyl functionality before the bicyclic 8 is generated by intramolecular syn Heck carbopalladation. The bridging keto group can be reduced with the desired diastereoselectivity with DIBAH, followed by introduction of the side chain precursors at C-4 and C-3 by Suzuki coupling and Sakurai addition, respectively [ 151. The bridgehead double bond is accomplished by SeOz-mediated allylic oxidation, with subsequent manipulations and dehydration to furnish the bicycle 9. The simultaneous introduction of the carboxy groups to install the quaternary center at C14 (Figure 4) is remarkable [IS]. The keto group of bicyclic compound 9 is first converted into an exocyclic double bond by Tebbe olefination. A dichlorocyclobutanone ring is then formed by [ 2 + 21 cycloaddition between dichloroketene and the exocyclic double bond of compound 10. This reaction proceeds regioselectively in favor of the conjugated allylic double bond to furnish spirocyclobutanone 11 after reductive cleavage of the geminal chloro groups. After base-induced diastereospecific sulfenylation to 1 2 and subsequent oxidation to the sulfoxide lactone, the terminal ally1 group can be selectively dihydroxylated. The second-

Total Synthesis by Nicolaou

Intramolecular Heck reaction

1. LDA, THF, -78"C, 2h 2. TBSOTf, 2,6-lutidine, /-CH,CI,, RT, 1. h .l oa7 3. [Pd(OAc)z(PPh3),], NEt,, THF, reflux, 4d

TBS

0

t

CHO

i

49% overall

6

/

Aldol condensation

TBSO

0

H

9

Fig. 3. Total synthesis by Danishefsky: construction o f the carbobicyclic core structure by aldol condensation and carbopalladation. TBS = tee-butyldirnethylsilyl, LDA = lithium diisopropylarnide, Bn = benzyl.

ary hydroxyl functionality induces a rearrangement to the ketal 13. Under basic conditions, this intermediate cyclizes, providing the central bicyclic core 14 of the CP molecules. The C-7 side chain is introduced by addition of a Grignard reagent to the aldehyde generated from the primary hydroxyl function by oxidation, and subsequent Dess-Martin oxidation. The total synthesis is completed by conversion of the silyl-substituted furan into the maleic anhydride. The masked anhydride is liberated by successive photooxidation and further oxidation of the intermediate lactol with PCC [Gal. Unfortunately, this synthetic route results in the isolation not of the natural compound CP-263,114 (l),but of the C-7 epimer 15, which proved to be the more stable stereoisomer. The formation of the unwanted C-7 epimer is a consequence of the Os04-catalyzed dihydroxylation of intermediate 12, which occurs from the face of the C=C double bond opposite to that desired. Epimerization at C-7 takes place under basic conditions, and on closer inspection it was possible to identify both isomers in the original sample extracted from the fungus [ 161. However, the isolation of both isomers could also be an 'artefact' of the extraction process, during which the configuration at C-7 could be partially flipped during treatment with acid and base [2]. Total Synthesis by Nicolaou

Nicolaou et al. synthesized both racemic CP-263,114 (rac-1) and racemic CP-225,917 (rac-2) by the same synthetic pathway, since the two natural products are reversibly interconver-

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Total Synthesis ofthe Natural Products CP-263, I14 and CP-225,977

Tebbe

9 -

TBS

+

1. Trichloroacetyl chloride, Zn, Et,O, DME, ultrasound 2. Zn, NH,CI, MeOH, ultrasound 3. TBAF, THF, 0°C *

(CH,)60Bn

90%

CHZ

48% overall

10

TBSO

TBSO \

\

PhSSPh, NaHIKH, THF

. 80%

T

B

s

9

1. Dess-Martin periodinane, CH,CI, 2. H,O,, MeOH 3. OsO,, NMO, acetonelwater

) 12 6

0

B

n

60%

O H = '

-

\

-

NaOMe, MeOH

44% over 3 steps

(CH,),OBn 14

2

0

0

TBS

H

iCOOCH,

Fig. 4. Danishefsky's total synthesis: formation o f cyclobutanone, sulfenylation, and successive oxidation reactions. DME = 1 Jdimethoxyethane, TBAF = tetra-n-butylammonium fluoride, NMO = N-rnethylmorpholine-N-oxide.

(7S)-CP-263,114

(15)

Total Synthesis by Nicolaou I 3 3 1

tible (Figure 1) [ 17-20]. The Pfizer group had already shown that 2 may be converted into 1 under anhydrous acidic conditions and that 1 is stable in acidic aqueous media, so CP225,917 (2) was targeted first. Because of its higher stability and to avoid the use of additional protecting groups, the pyranose substructure was chosen as template for the synthesis. This first ever published, 40-step total synthesis of the highly oxidized and functionalized tetra- or pentacyclical systems deserves closer consideration, thanks to its cascade reactions and elegant synthesis steps. The Bicyclic CP Backbone and Stereoselective Chain Extension

The prochiral triene 16 (Figure 5) is a suitable precursor for the bicyclic core structure 17, and can be obtained in ten steps starting from dimethyl malonate. The intramolecular Diels-Alder cyclization to 17 proceeds with MezAlCl catalysis in very good yield under mild conditions [ 12, 181. The side chain at C-7 is introduced with high selectivity: the aldehyde group, obtained by desilylation and Dess-Martin oxidation, reacts regioselectively with the lithiated dithiane 18, since attack at the keto group is sterically hindered. In addition, the CP skeleton shields one side of the aldehyde, so that the desired diastereomer 19 is obtained as major product in a ratio of 11:l. Cascade Reactionfor the Construction of the Maleic Acid Moiety

The carbonyl group is an easy means of entry to the fused maleic anhydride moiety [ 19, 211. For steric reasons, alkylation in the a-position to the keto group in 19 is a difficult task. The synthesis sequence starts with the transformation of ketone 19 into the vinyl triflate, followed by Pd(OAc)z-catalyzedcarboxymethylation (Figure 6). The dithiane protecting group can be replaced by a dimethyl ketal, generating 20 in good yield. Stereoselective vanadiumcatalyzed epoxidation of the allylic alcohol, obtained by reduction of the unsaturated ester, yields the /I- and the wepoxides in a 11:1 ratio. Ring-opening with Et2AICN (Nagata reagent) proceeds with exceptional stereoselectivity, which may be due to the arrangement of the epoxide in the bicyclic skeleton. In the following seven-step cascade reaction, the resulting cyanodiol is converted into the targeted maleic anhydride 21. First, the primary hydroxyl group is mesylated and substituted by the vicinal tertiary alcohol. In the presence of K2CO3, the epoxide undergoes a /I-elimination followed by a 5-exo-dig cyclization, building up an iminobutenolide. Autoxidation and subsequent imine hydrolysis complete the synthesis of the corresponding maleic anhydride in 56% overall yield. Protecting group manipulations at the C-7 side chain yield the key intermediate 21, the structure of which was confirmed by X-ray analysis. Oxidation to the y-Hydroxy Lactol

The synthesis of the y-hydroxy lactol ring starts with the cleavage of the PMB protecting group and the oxidation of the resulting hydroxy compound to the enone 22 (Figure 7) [20]. Acid-induced removal of the isopropylidene group results in the spontaneous formation of

16

Fig. 5. Total synthesis by Nicolaou: intramolecular Diels-Alder cyclization and introduction o f the C-7 side chain. TBDPS = tert-butyldiphenylsilyl, PMB = p-rnethoxybenzyl.

TBDPSO

0

PMBO

90%

c

Me,AICI, CH,CI, -lO"C, I h

0

Li

PMBO

18

17

CH3

a

fo

a

a

D

5

c"

s

m

2

G'

g

-=VI 2

2 D

w w N

I

Total Synthesis by ~ i c o l a o u 333

Stepwise formation of the maleic anhydride substructure:

73%

pelimination

.VR

*K,C03

MsCI, NEt,

Fig. 6. Nicolaou's total synthesis: construction o f the rnaleic anhydride moiety. KHMDS = potassium hexamethyldisilazide, DIBAL = diisobutyl. aluminium hydride, acac = acetylacetonate, Ms = rnethanesulfonyl.

a cyclic hemiketal. The remaining primary hydroxyl group is protected as a silyl ether, furnishing compound 23. In simplified model systems, oxidation to the y-hydroxy lactol was easily achievable at this stage as a cascade reaction on treatment with Dess-Martin periodinane [21]. However, the conversion starting from the diol turns out to be problematic in the presence of the fused maleic anhydride moiety. This may be due to the decrease in conformational freedom caused by the annellation, which influences the equilibrium of the

1

Et,AICN

334

I

Total Synthesis of the Natural Products CP-2G3,114 and CP-22597 7 0

0

21

1. DDQ 2. PDC

1. AcOH 2. TESOTf ___)

43%

75%

0

overall

$-OTES

23 Ring-chain tautornerization

0

c--

49%

I

0

""-OTES

'<-OTES

L

25

\

0 &C5Hg

'HO

\

C,H,,

0 26

=-

OTES

Fig. 7. Nicolaou's total synthesis: oxidation to the y-hydroxy lactol. PDC = pyridinium dichromate, DMP = Dess-Martin periodinane.

ring-chain tautomerization between 23 and 24 [ 20, 221. Ring-opening to 24 is essential to initiate the cyclization to the y-hydroxy lactol: the primary hydroxyl group of the open-chain tautomer 24 is oxidized to generate intermediate 25, and subsequent nucleophilic attack of water results in lactolization to give the y-hydroxy lactol 26. The equilibrium can be shifted to the open-chain compound by an increase in the reaction temperature and the choice of an appropriate solvent. Under these conditions, Dess-Martin periodinane can be used to prepare y-hydroxy lactol 26 from 23 in 49% yield and as a single stereoisomer.

Total Synthesis by Nicolaou

26

'' 2. MeS0,H TFA

0

335

n

DMP, benzene

&c5Hg

P &c5Hg

83%

.un .-

O

I

.+-

'

90%

0

'-OH

-7

LI

'

'SH15

66% overall

-C5H9

CEH,,

I._

nu

+ n , /

-

I

28 H 1. TBSOTf 2,6-lutidine 2. NaCIO,, NaHpO,

Arndt-Eistert homologation 4

'/TBSO d

C

-.. E

H

1

5

'-COOH 30

1. Indoline, EDC, DMAP 2. TFA 3. DMP, NaHCO, CH2CI,

\

1. MsCI, Et3N 2. CH,N, 3. Ag,O, DMFIH,O

TBSO COOH

35% overall

29

74% overall

1. pChloroaniI 2. LiOH; NaH,PO,

CP-225,917 50% overall 0

Fig. 8. Nicolaou's total synthesis: ketalization and homologation of the carboxylic acid side chain. TFA = trifluoroacetic acid, EDC = 1-[3-(dirnethylarnino)-propyl]-3-ethylcarbodiirnide hydrochloride, DMAP = 4-(N,N-dimethylamino)pyridine.

Ketulization and Homologution ofthe Curboxylic Acid Side Chain

Cleavage of the silyl protecting groups under acidic conditions, followed by exposure to MeS03H, results in ketalization of 26 to the pyran-lactol 27 (Figure 8) [ZO]. To complete the synthesis of the CP compounds, the primary alcohol has to be oxidized to the carboxylic acid and the carboxylic acid side chain has to be elongated by means of an Arndt-Eistert reaction.

(rac-2)

336

I

Total Synthesis of the Natural Products CP-2G3,7 74 and CP-225,917

Treatment of the diol27 with Dess-Martin periodinane in benzene predominantly yields the aldehyde lactol 28. Simultaneous oxidation of the secondary alcohol to the y-hydroxy lactone is only a side reaction. The resulting y-hydroxy lactol 28 is again silyl protected and the aldehyde group can be oxidized by NaClOz to the sterically hindered carboxylic acid 29. Despite its concave skeleton, the carboxylic acid can easily be activated as an acyl mesylate and transformed into the corresponding diazo ketone, followed by a Wolff rearrangement to generate the homologated carboxylic acid 30. Before the lactol functionality is revealed and oxidized, a indoline amide is formed to decrease the reactivity of the carboxylic acid. Lactone 31 is once more prepared by Dess-Martin periodinane oxidation. The final step in the synthesis is the release of the carboxylic acid functionality. The indoline amide protecting group can be removed by oxidation to the indole amide and subsequent hydrolysis under mild basic conditions. In this step, the pyran ring is also opened, so CP-225,917(ruc-2) is initially formed. An easy procedure for conversion of CP-263,114 (1)into CP-225,917 (2) has already been presented in Figure 1. Asymmetric Total Synthesis by Nicolaou

After the completion of their racemic total synthesis of the phomoidrides, Nicolaou et al. developed an asymmetric version of this synthesis to determine the absolute configuration of these compounds through chemical synthesis [3, 181. A strategy based on chiral reagents was originally designed for the synthesis of enantiomerically enriched building blocks. As the key reaction, the Diels-Alder cyclization can be asymmetrically induced by use of chiral catalysts. Attempts to utilize this asymmetric induction, though, yielded only poor diastereoselectivities, despite the use of numerous chiral Lewis acid catalysts [ 181. A second approach employing substrate-based control was undertaken, a bulky chiral moiety being introduced into the enone precursor to influence the facial selectivity of the Diels-Alder reaction. The bis(TBS) ketone 32 cyclizes at -80 "C in the presence of catalyst 33, to furnish a 5.7:l mixture of diastereomeric Diels-Alder products (Figure 9). The major isomer 34 is desilylated with TBAF, and oxidative cleavage of the diol with sodium periodate generates the corresponding aldehyde 35, the racemic form of which is a known intermediate in the total synthesis of racemic CP compounds. The conversion to the indoline derivative ent-31 therefore follows the strategy of the racemic route. Circular dihroism (CD) spectroscopy verified the identity of the synthetic ent-31 as the enantiomer of the naturally derived indoline (-)-31. Synthetic ent-31 was also processed to give ent-1 and ent-2. Shair's Asymmetric Total Synthesis o f (+)-CP-263,114 (ent-1) and (-)-CP-225,917 (ent-2)

The asymmetric synthesis developed by Shair et al. employs a fragment coupling/cyclization reaction to establish the correct connectivity of the bicyclic backbone (Figure 10) [13]. The enantiomerically pure cyclopentanone 36, with appropriate side chain functionalization, is alkylated with a vinyl Grignard reagent 37. The bromomagnesium alkoxide 38 immediately undergoes an anion-accelerated oxy-Cope rearrangement to 39, followed by a sponta-

Fukuyama’s Asymmetric Total Synthesis of (-)-CP-ZG3,714 (1)

.CH3

Fig. 9.

Nicolaou’s asymmetric total synthesis: stereoselective intramolecular Diels-Alder reaction.

neous transannular Dieckmann-like cyclization to afford the carbocyclic core structure in a single stereospecific reaction. After the introduction of the jl-keto ester and the enol carbonate functionalities in six steps, a multitask one-pot reaction is initiated by addition of TMSOTf and (MeO)3CHto 40, directly affording compound 41. As mechanism, a Fries-like rearrangement is postulated, followed by subsequent ionization and cyclization to form the pseudoester cage ring system. After TMSOTf-mediated deprotection, the further transformations used to furnish (+)-CP263,114 (ent-1) and (-)-cP-225,917 (ent-2) employ common homologation steps, for the most part already used in Nicolaou’s asymmetric total synthesis. Fukuyama’s Asymmetric Total Synthesis o f (-)-CP-263,114 (1)

Although the asymmetric total syntheses developed by Nicolaou and by Shair provide easy routes to enantiomerically pure CP compounds, the target molecules (+)-CP-263,114 (ent-1) and (-)-CP-225,917 (ent-2)are only the enantiomers of the natural occurring phomoidrides. After the establishment of the absolute configuration of the CP molecules by chemical synthesis, the focus of synthetic interest is the asymmetric total syntheses of (-)-CP-263,114 (1) and (+)-CP-225,917 (2). The first total synthesis furnishing (-)-CP-263,114 (1) as the correct enantiomer has recently been reported by Fukuyama et al. [231. As the stereoselectivitydetermining step, an intramolecular Diels-Alder reaction was chosen, similar to that in Nicolaou’s synthesis (Figure 11). The Diels-Alder precursor 42 is prepared in four easy

I

337

338

I

Total Synthesis ofthe Natural Products CP-263,I14 and CP-225,917

(-3//cH3 1

0 0 ’,. +

toluene -78°C A

/

-g MrB

CH,

OMOM

COOCH,

53%

37

36

‘OPMB

A

‘CH, oxyCope rearrangement

c

I

39

BrMgO LOPMB I

Dieckmann-like cyclization

l

’

n

0

0

(+)-CP-263,114 (ent-I)

Fig. 10. Shair’s asymmetric synthesis: electrocyclic ring-closure and introduction of the carboxylic acid side chain. MOM = methoxymethyl.

steps by fragment condensation between an (E,E)-diene, an acryloyl derivative, and an u,Punsaturated aldehyde. Upon treatment with zinc chloride, 42 undergoes a smooth intramolecular cyclization to give predominantly the desired bicyclic core structure 43.The stereoselectivity, confirmed by NOE studies, seems to be dictated by the stereochemistry at the C-12 position, bearing Evans’ chiral auxiliary as substituent. The construction of the maleic anhydride moiety 44 in only five steps starts with the conversion of the amide into an appropriate thioester. Upon treatment with DBU, an aldoltype cyclization occurs to provide the B-hydroxy thiolactone as a single diastereomer. After removal of the allylic protecting group, dehydration and decarboxylation are carried out simultaneously by simple heating. The thiobutenolide is oxidized to the corresponding thio-

*, I

Fukuyama's Asymmetric Total Synthesis of (-)-CP-263,774 (7)

ZnCI,.OEt,, pyridine

-

____)

H3C

H,COOC

'COOCH,

339

\

.;:::-e:s

0

H,COOC"

42

43

0 :

H,COOC

O V N v B n

-k \

H3C

(-)-CP-263,114

44

HOOC'"' H,COOC

Stepwise formation of the maleic anhydride substructure: Ally1 thioglycolate, LHMDS, 0°C

*

53% over 2 steps

R

R

93%

/I

1. Pd(OAc),, PPh,, rt 2. pyridine, AqO, 100°C

1. TBSCI, DBU

LiOH.H,O, MeOH;

>54%

R

0

40

R

0 O Y N Y B n OJ

I

87% overall

9.2. AgNO,, NIS,rt DMSO 'R h s

58% overall

0

R

Fukugama's asymmetric synthesis o f (-)-CP-263,114: intramolecular Diels-Alder reaction and formation of the rnaleic acid anhydride moiety. DBU = 1,8-diazabicyclo[5.4.O]undec-7-ene, NIS = N-iodosuccinimide.

Fig. 11.

maleic anhydride and afterwards subjected to basic hydrolysis. During the hydrolysis, the less hindered methyl ester is also saponified, and can be converted into the homologated carboxylic acid by means of the Arndt-Eistert reaction. Oxidation of the sulfide with mCPBA followed by subsequent cleavage of the acetonide induces the cyclization to afford the ylactone acetal. Finally, Jones oxidation of the secondary alcohol furnished (-)-CP-263,114 (l), identical in all respects with natural CP-263,114 (1).

0

340

I

Total Synthesis of the Natural Products CP-2G3,714 and CP-225,977

With the asymmetric synthesis of the CP compounds completed and the synthetic route to various simpler variants now established, chemists have obtained extensive knowledge about the reactivity of these small but complex natural products. This knowledge may be extremely useful for the development of therapeutically valuable analogues with increased biological activities. Whether or not this search results in the discovery of efficient drugs, the phomoidrides have already provided a platform for some outstanding, highly inventive science.

References

a) T. T. DABRAH, T. KANEKO,W. MASSEFSKI, J R . , et al., J. Am. Chem. soc. 1997, 119, 1594-1598; b) T. T. DABRAH, L. H. HUANG,et al., J. H. J. HARWOOD, Antibiot. 1997, 50, 1-7. 2 The name is derived from the producing organism (a ‘Phomaoid fungus) and the proposed relationship of these molecules to the nonadrides, see D. HEPWOKTH, Chem. Ind. 2000, 2, 59-65. 3 K. C. NICOLAOU, J.-K. J U N G , W. H . YOON, et al., Angew. Chem. Int. Ed. 2000, 39, 1829-1832. 4 For biosynthetic studies and a biomimetic synthesis approach see: a) J. L. BLOOMER, C. E. MOPPETI,J. K. SUTHERIAND,J. Chem. SOC.C. 1968, 588-591; b) M. 0. Moss, Microbial Toxins (Ed.: A. CIEGLER), Academic Press, New York, London 1971, 6, 381-407; c) P. SPENCER, F. AGNELLI, et al., J. Am. Chem. SOC. H. J. WILLIAMS. 2000, 122,420-421; d) G. A. SULIKOWSKI, F. AGNELLI, R. M. CORBETT,].Org. Chem. 2000, 65,337-342; e) G. A. SULIKOWSKI, F. AGNELLI, P. SPENCER, et al., Org. Lett. 2002, 4, 1447-1450; f ) G. A. SULIKOWSKI, et al., Org. Lett. 2002, W. LIU, F. AGNELLI, 4, 1451-1454; g) J. E. BALDWIN, R. M. ADLINGTON, F. R o u s s ~ et , al., Tetrahedron 2001, 57, 7409-7416. 5 a) S. BOKMAN,Chem. Eng. News 1999, June 7, 8-9; b) J. T. STARK,E. M. CARREIRA, Angew. Chem. Int. Ed. 2000,39, 1415-1421. 6 a) 0. KWON,D.4. Su, D. MENG,et al., Angew. Chem. Int. Ed. 1998, 37, 18771880; b) 0. KWON, D . 4 . Su, D. MENG, et al., Angew. Chem. Int. Ed. 1998, 37, 1880-1882. 7 a) P. W. M. SGARBI, D. L. J. CLIVE,Chem. Commun. 1997, 2157-2158; b) D. L. J. CLIVE,J. ZHANG,Tetrahedron 1999, 55, 12059-12068. 1

8 9

10

11

12

13

14

15 16

17

D. L. J. CLIVE,S. SUN,X. H E , et al., Tetrahedron Lett. 1999, 40, 4605-4609. a) M. M. BIO, J. L. LEIGHTON,J. Am. Chem. SOC.1999, 121, 890-891; b) M. M. BIO, J. L. LEIGHTON, Org. Lett. 2000, 2, 2905-2907. a) J. T. NJARDARSON, 1. M. MCDONALD, et al., Org. Lett. 2001, 3, D. A. SPIEGEL, 2435-2438; b) J. T. NJARDARSON, J. L. WOOD,Org. Lett. 2001, 3, 2431-2434. a) N. OHMORI,Chem. Commun. 2001, 1552-1553; b) N . OHMORI,J.Chem. SOC., Perkin Trans. 2002, 1, 755-767; c) L. ISAKOVIC, J. A. ASHENHURST, J. L. GLEASON, Org. Lett. 2001, 3, 4189-4192. K. C. NICOLAOU, M. W. HARTER,L. BOULTON, et al., Angew. Chem. Int. Ed. Engl. 1997, 3G, 1194-1196. c. CHEN,M. E. LAYTON,S. M. SHEEHAN, et a]., J. Am. Chem. SOC.2000, 122, 7424-7425. For additional synthetic approaches see: S . J. DANISHEFSKY, a) A. J. FRONTIER, C. A. KOPPEL,et al., Tetrahedron 1998, 54, 12,721-12,736; b) A. ARMSTRONG, T. J . CRITCHLEY, A. A. MORTLOCK, Synlett 1998, 552-553; c) H. M. L. DAVIES,R. CALVO,G. AHMED,Tetrahedron Lett. 1997, 38, 1737T. ITOH, T. 1740; d) N. WAIZUMI, FUKUYAMA, Tetrahedron Lett. 1998, 39, 6015-6018; e) K. C. NICOIAOU, M. H. D. et al., Angew. POSTEMA, N. D. MILLER, Chem. Int. Ed. Engl. 1997, 36, 28212823. D. MENG,S. J. DANISHEFSKY, Angew. Chem. h t . Ed. 1999, 38, 1485-1488. D. MENG,Q. TAN,S. J. DANISHEFSKY, Angew. Chem. Int. Ed. 1999, 38, 31973201. a) K. C. NICOLAOU, P. S. BARAN, Y.-L. ZHONG,et al., Angew. Chem. Int. Ed. 1999, 38, 1669-1675; b) K. C. NICOIAOU,P. S.

References I 3 4 1

18

19

BARAN,Y.-L. ZHONG,eta]., Angew. Chem. Int. Ed. 1999, 38, 1676-1678; c) D. SPENCER, F. AGNELLI, G. A. SULIKOWSKI, Org. Lett. 2001, 3, 1443-1445. K. C. NICOLAOU, J. J U N G , W. H. YOON, et al., /. Am. Chem. SOC.2002, 124, 2183-2189. K. C. NICOLAOU, P. S. BARAN,Y.-L. ZHONG,et al.,]. Am. Chem. SOC.2002, 124,2190-2201.

20

K. C. NICOIAOU,Y.-L. ZHONG,P. S. BARAN,et al., 1.Am. Chem. SOC.2002, 124, 2202-2211.

21

22 23

K. C. NICOLAOU, P. S. BARAN, R. JAUTELAT, et al., Angew. Chem. Int. Ed. 1999, 38, 549-552. K. C. NICOLAOU, Y. HE,K. C. FONG,et a]., Org. Lett. 1999, 1, 63-66.

N. WAIZUMI,T. ITOH,T. FUKUYAMA,]. Am. Chem. SOC.2000, 122, 7825-7826.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Polyene Cyclization to Adociasulfate 1 Thomas Lindel and Cordula Hopmann

Polyene cyclizations belong to the most exciting reactions in organic synthesis. Every example of such cascade reactions [I] is an encouragement to search for biomimetic synthetic pathways to natural products, not only for reasons of elegance, but also of economy. In the tradition of pioneering studies by Johnson et al. [2], Overman et al. reported the enantioselective total synthesis of adociasulfate 1 (1,Figure 1) by cationic polyene cyclization [ 31. The hexaprenoid bissulfates adociasulfate 1 (I),2 (2, main metabolite), and its congeners are marine natural products, isolated from the sponge Haliclona (aka Adocia) sp. in 1998 by Faulkner et al. [4,51. Interest in the adociasulfates results from their unique biological activity as the first specific, non-nucleotide kinesin inhibitors. A short description of this particular biological activity is given here. There are over 100 kinesin superfamily members, playing roles in cell division, and in vesicle and organelle transport [6]. Kinesin motor proteins use the free energy of ATP hydrolysis to drive intracellular movements along the microtubules [4).Kinesins are highly elongated proteins, all sharing a conserved motor domain of approximately 340 amino acids, containing ATP- and microtubule-binding sites. This motor domain is attached to a unique tail domain, which carries the cargo to be transported by binding to receptor proteins on the cargo surface [6b, 71. The transport process can be observed in elegantly designed experiments, by binding kinesins on glass slides and viewing the movement of the microtubule by microscopy. For the isolation of the active principle [S], the wet sponge Haliclona (aka Adocia) was extracted with methanol and dichloromethane, followed by concentration to an aqueous suspension and bioassay-guided partitioning between water and dichloromethane. The water fraction was separated on Fractogels TSK HW 40 to yield the active components adociasulfate 1 (1) and 2 (2). The first enantioselective polyene tetracyclization starting with a chiral epoxide was reported by Corey et al. in 1997 [Sa]. The silylated enol ether 3 (Scheme 1) was converted into the tetracycle 4 by treatment with the Lewis acid MeAIClz at -90 " C .The synthetic route is modeled on the biosynthesis of lanosterol from (3s)-squalene 2,3-epoxide and has also been applied to the biomimetic synthesis of tetracyclic polyprenoids from sediment bacteria [8bI. Adociasulfate 1 (1,Figure 1) contains nine stereogenic centers, of which eight are contig-

Polyene Cyclhation to Adociasuyafate I

I

343

Na03S0,

1: adociasulfate 1

2: adociasulfate 2

7%

Fig. 1. Marine natural products adociasulfate 1 (1) and 2 (2) from the sponge Adocia sp.

SiMe2Ph 1) 1.2 eq. MeAICI2, CH2CI2 -90% 30 min; Et3N 2) HF, MeCN, rt, 90 min 3) 10% KOH/MeOH, A, 3 h 30 Yo

HO 4

3

fi Me0

3C ;;hH ;C ;e ,p 1 ;g 2 ';.'

-@ h : HO

0 BnO

15 %

5

'necessary

/ BnO

' 6

Epoxide-initiated, enantiospecific polyene cyclizations of the substrates 3 and 5 t o the synthetic precursors (4 and 6) o f the marine natural products scalarenedial and adociasulfate 1.

Scheme 1.

uous and four are quaternary. It was not clear whether Corey's example would be transferable to the synthesis of adociasulfate 1 (1).The nucleophilic reactivity of the enoxysilane terminating the precursor 5 towards carbenium ions should be much higher than that of the hydroquinone which would have to be employed for 1 [9]. Indeed, Overman et al. found that an allyloxy substituent in the 3'-position of the 0-methylated hydroquinone ring of 5 (Scheme 1) was necessary to induce a complete, scandium triflate-induced polyene cascade to the pentacycle 6. In the absence of the allyloxy substituent, only bi-, tri-, and tetracyclic

344

I

Polyene Cyclization to Adociasulfate I

products were observed. This is a remarkable example of the beneficial effect of a higher electron density at donor termini in substrates of cationic polyene cascades. The first rare earth triflate used for such polyene cyclizations, Sc(OTf)3 was the most effective Lewis acid investigated, affording the pentacycle 6 in a yield of 15% (62% per ring). If MeAlClz was used (as for 3),a yield of below 5% was achieved. The stereochemical outcome of the cascade reaction was established by X-ray analysis of a later synthetic intermediate. It should be mentioned that the efficiencyof an overall synthetic approach is governed not only by the elegance of the key step, but also by the accessibility of starting material. In the case of Overman’s synthesis, the diterpenoid cyclization substrate 5 is available in a facile manner, starting from the aryl bromide 7 (Scheme 2). The two monoterpenoid building blocks 8 and 10 are successively attached to the substituted hydroquinone derivative 7 by standard procedures. The product 11 already contains the full carbon skeleton of the cyclization substrate and was converted into 5 in five more steps. Desulfonation of 11 was achieved by a method of Inomata et al. [lo],by treatment with LiEt3BH and Pd(dppp) (dppp: 1,3-bis(diphenylphosphino)propane)at 0 “C without double bond isomerization or desilylation. As a slight drawback, the ally1 protection group already in place at 3’-0 was removed simultaneously and had to be reintroduced in the next step. Sharpless asymmetric epoxidation (95% ee) of the allylic alcohol obtained after desilylation is the source of enantioselectivity in the total synthesis of adociasulfate 1 (1). Following the cyclization step from 5 to the pentacycle 6 (see Scheme I), the 3’-allyloxy group had done its duty and was completely removed by deallylation, triflation, and Pdcatalyzed reduction of the resulting aryl triflate (Scheme 3) [ I l l . At this stage, ten carbon atoms needed for adociasulfate 1 (1)were still missing. After Dess-Martin oxidation of the primary alcohol 12, (S)-cyclogeranyllithium(13,obtained in two steps from (S)-cyclogeraniol [ 121) was introduced by addition to the aldehyde, affording 14. It is a characteristic of natural product synthesis that specific properties of substrates prevent the use of established conversions. In this case, the steric environment surrounding C8 caused several deoxygenation reactions to fail. Overman et al. were finally successful with the Barton procedure [13], by conversion of 14 to the xanthate, which was then reduced to 15 with 100 equivalents of tributyltin hydride and 10 mol% AIBN. The change of the 0-protecting group from TBDMS to acetyl has its logic in a facilitated workup of the bis-sulfate natural product. The sulfate groups were introduced after oxidative demethylation of the methoxy groups, followed by sulfation with excess SO3/pyridine. The final step was an alkaline deacetylation. Adociasulfate 1 (1)was obtained in 28 steps and a very high total yield of 5.7%. The total synthesis also allowed the determination of the absolute configuration of the natural product. Remarkably, the adociasulfates retain their kinesin-inhibiting property even after substantial structural modification. The removal of a sulfate unit is tolerated, which makes the synthesis of less polar and hence membrane-permeating analogues promising. Even the opening of rings A, B, and E is possible, with only 50% loss of activity. The ten adociasulfates so far known have in common the central decalin system and the hydroquinone component. Adociasulfate 4 (16) is partially open-chain (Figure 2). The structure of the hydroquinone bissulfate toxicol A (17) from the marine sponge Toxiclonu toxicus [ 141 indicates the possibility of incomplete cyclization of the hexaprenoid precursors. Adociasulfate 2 (2)showed the most potent kinesin inhibition, specifically interfering with both microtubule and kinesin

OMe 7

0 -

Scheme 2.

TBDMSOT

M

\

S

-

O Br ~

10

So2Ph

74 Yo

11

Short synthesis o f the geranylgeranyl hydroquinone 5.

3) 10, 'BUOK, THF/DMF (9:1), -2O"C, 4 h; -> rt

D

~ ~ ~ F ~ ~ ? ~ , 3 h ;

1) TBAF, THF, rt, 12 h 2) MsCI, Et3N,THF, LiBr, -3O"C, 2 h

Br

-6-

B

'BuLi, Li2CuC14,THF,

T

0 -

35 %from 9

5) BnBr, NaH, THF, "Bu4NI

m. S. 4 A, CH2CI2, -2O"C, 3 h

1) Pd(dppp), LiEt3BH,THF, 5 h, 0°C 2) allylbromide, K2C03,DMF, rt, 8 h 3) pTsOH, MeOH, rt, 8 h - 5 4) (+)-DET, TBHP, Ti(OiPr)4,

9

OMe

T

ei

w

-

2

2.

3

b

E;

3

2

i 7

2 -9 %

-=."

346

6

I

Polyene Cyclization to Adociasulfate 1

1) TBDMSOTf, lutidine, CH2C12, rt, 10 min 2) Pd(PPh3)4,pyrrolidine, MeCN, CHZCI2,40"C, 2 h; CSZCO~, o"C, 6 h 80"C, 6 h 3) PhNTfz, Pd(dppp), "Bu~N, HCOzH, *

4) Hz, Pd/C, THF, rt, 12 h 55 Yo .Li

&OMe TBDMSO

H

?-

HOi

12

MeO>

1) Dess-Martin periodinane, CHpCIz, O'C, 2 h

1) "BuLi, CSz; Mel, THF, -78% 10 h 14

67 YOfrom 12

1) "Bu~NF,THF, 35 C, 32 h

&

H

&

H

l5

.

2) AIBN, "Bu3SnH, toluene, 80°C 20 min

2) 13, hexane/EtzO,-78"C, 90 min

TBDMSO&OMe?,

H

-

2) AcpO, DMAP, CHzCIz, rt, 12 h 3) (NH4)zCe(N03)6,THF, O"C, 1 h: Na~S204,HzO, rt 4) SO3 Py, pyridine, rt, 12 h 5) NaOH, MeOH, 60°C, 12 h 40 Yo

1: adociasulfate 1

Scheme 3. Completion o f the enantioselective total synthesis of adociasulfate 1 (1) by Bogenstatter, Overman, et al., with incorporation o f the (5)-cyclogeranyl unit 13.

binding. However, the natural product did not display in vivo activity, presumably due to the two charged sulfate moieties. The adociasulfates are nevertheless considered to be valuable tools for obtaining further information about kinesin motor functions. Recently, abnormal nuclear displacement caused by adociasulfate 2 (2) provided the first evidence for the occurrence of kinesin like proteins in the unicellular green alga Micrasterias denticulata and suggested their function as force generating motor in postmitotic nuclear migration [Gc]. The synthesis of cell-permeable derivatives would be of particular interest. Scheme 4 gives the endgame from Corey's cyclization product 4 (Scheme 1)to the marine natural product scalarenedial (20, [15]), which is a strong fish feeding deterrent. The Barton-McCombie process [16] was employed to deoxygenate at C3, followed by conversion of the ketone to the vinyl triflate 18 with PhNTfz (McMurry's method [17]). After hydroxydesilylation of 18, the carbonylation to 19 was catalyzed by Pd(dppp) (see above). The vicinal

\F

Polyene Cyclization to Adociasu@te I

oH

I

347

NaO3S0<

OS03Na

16:adociasulfate 5

17: toxicol A

Fig. 2. Hexaprenoid hydroquinones adociasulfate 5 (19) and toxicol A (20). The hexaprenoid skeleton is shown in bold.

4

1.2 eq. CGF~OCSCI, 3 eq. DMAP CH2C12, O'C, 10,95Yo 2. 3 eq. Bu3SnH,0.1 eq. AIBN, benzene, 80"C, 3 h, 94 Yo 3. 2.5 eq. PhNTf2, 1.2 eq. KHMDS, THF, -78"C, 20 min, 90 %

SiMe2Ph

3p 18

0

1.3eq. DIBAL-H,CH2CI2, -78 to -2O"C, 1 h, 95 Yo

* 2.20 eq. DMSO, 10 eq. (COC1)2, 15 eq. EtsN, CH2C12, -5O"C, 1 h, 90 %

19 Scheme 4.

1. 10 eq. BF3 2 HOAc, CHCI3, 5 h; KF, KHC03, THFlMeOH (l:l), H202, O"C, 12 h, 94 Yo 2. 0.1 eq. Pd(OAc)2, 0.1 eq. dppp, CO, 'Pr2NEt, DMF, 65"C, 5 h, 100%

pc H

20

Endgame o f Corey's synthesis o f scalarenedial (20).

aldehyde groups of scalarenedial (20) were generated in two standard steps. Corey et al. synthesized other cyclized terpenoids in a similar manner [ 181. Unlike adociasulfate 1 ( I ) ,which is derived from a C30 building block assembled by headto-tail connection of two CIS sesquiterpenoid units, the key biosynthetic metabolite squalene, precursor of lanosterol and hence the steroids, is based on a head-to-head connection of those building blocks. Every double bond in squalene may be epoxidized (Scheme 5). Several natural products derived not from monoepoxides, but from oligoepoxides of squalene have been isolated from red algae, in particular from Laurencia obtusa. Among them are magireol A (21) and the meso compound teurilene (22), both of which originate from a central tetraepoxide of squalene (Scheme 5). The record is held by glabrescol, from the Caribbean plant Spathelia glabrescens 1191, the precursor of which should be a squalene hexaepoxide. (23) into the squalene Xiong and Corey successfully converted (3R)-2,3-dihydroxysqualene pentaepoxide 25, which was cyclized in the second step to the squalenoid 26, consisting of five contiguous tetrahydrofuran rings, in a yield of 31% (Scheme 5) [20].The epoxidation

348

I

Polyene Cyclization t o Adociasuljafate 7

21: magireol A

22: teurilene

oxone, pH 10.5

xo'::(-&Ox 0'

24

0

0

25

1

CSA !

OH

26

Natural products derived from oligoepoxides o f the key building block squalene (as highlighted). Elegant total synthesis o f the pentakis tetrahydrofuran system 26 by Xiong and Corey.

Scheme 5.

was formally diastereoselective, but in view of the distance of the terminal double bond from the single stereogenic center of 23 it may be regarded as enantioselective. Shi's chiral dioxirane [21], which did the job, was generated in situ from 24 (treatment with oxone) which in turn is derived from fructose. Comparison of 26 with the data for glabrescol indicated that the stereochemistry of the natural product had been incorrectly assigned. Further work revealed that glabrescol should be derived from a squalene with at least one Z double bond. Structure elucidation by total synthesis continues.

References I 349 References 1

Reviews: a) J. K. SUTHERIAND in Comprehensive Organic Synthesis, Vol. 3 (Eds.: B. M. TROST,I. FLEMING), Pergamon Press, Oxford, 1991, 341-377; b) L. F. TIETZE,U. BEIFUSS, Angew. Chem. 1993, 105, 137-170; Angew. Chern. Int. Ed. Engl.

8

9

1993, 32, 131-63.

a) W. S. J O H N S O N , M. B. GRAVESTOCK, B. E. MCCARRY,].Am. Chem. SOC.1971, 93, 4332-4334; b) W. S. JOHNSON, Angew. Chem. 1976, 88, 33-41; Angew. Chem. Int. Ed. Engl. 1976, 15, 9-17. 3 M. BOGENSTAITER, A. LIMBERG, L. E. OVERMAN, et aI.,J. Am. Chem. Soc. 1999, 2

10

11 12

1993, 49, 1871-1878.

BARTON,J. DORCHAK, J. JASZBERENYI, Tetrahedron 1992, 48,

13 D. H. R.

121, 12,206-12,207,

R. SAKOWICZ, M. S. BERDELIS, K. RAY,et al., Science 1998, 280, 292-295. 5 a) C. L. BIACKBURN,C. HOPMANN, R. SAKOWICZ, et al.,]. Org. Chem. 1999, 64, 5565-5570; b) J. A. KALAITZIS, P. D E ALMEIDA LEONE, L. HARRIS,et al., J. Org. Chem. 1999, 53, 5571-5574; c) J. A. KAIAITZIS, R. J. QUINN,J. Nat. Prod. 1999, 62, 1682-1684; d) C. L. BIACKBURN, D. J. FAULKNER, Tetrahedron 2000, 56,

7435-7446.

4

8429-8432. 6 a) L. S.

B. GOLDSTEIN, Trends Cell Biol.

14 S. ISAACS, A. HIZI, Y. KASHMAN,

Tetrahedron 1993, 49, 4275-4282. 15 A. RUEDA,E. Z U B ~ A M., ORTEGA,et

al.,

J. Org. Chem. 1997, 62, 1481-1485. 16 D. H. R. BARTON, S. W. MCCOMBIE,]. Chem. SOC.,Perkin Trans. 11975, 1574. 17 J. E. MCMURRY, W. J. SCOTT, Tetrahedron Lett. 1983, 24, 979. 18 P. SCHAEFFER, J. POINSOT,V. HAUKE, et al., Angew. Chem. 1994, 106, 1235-1238; Angew. Chem. Int. Ed. Engl. 1994, 33, 1166-1169.

2001, 1 I, 477-482; b) R. L. KARCHER,

7

a) E. J. COREY,G. Luo, L. S. LIN,J. Am. Chem. SOC.1997, 119,9927-9928; b) E. J. COREY,G. Luo, L. S. LIN, Angew. Chem. 1998, 110, 1147-1148; Angew. Chern. Int. Ed. Engl. 1998, 37, 1126-1128. J. BURFEINDT, M. PA=, M. MULLER,et al., 1.Am. Chem. SOC.1998, 120, 3629-3634. M. MOHRI,H. KINOSHITA, K. INOMATA, et al., Chem. Lett. 1985, 451-454. J. M. SAA, M. DOPICO,G. MARTORELL, et al.,]. Org. Chern. 1998, 55, 991-995. K. MORI,M. AMAIKE, M. ITOU,Tetrahedron

S. W. DEACON, V. I. GELFAND, Trends Cell Biol. 2002, 12, 21-27; c) A. HOLZINGER, U. LUTZMEINDL, Cell. Biol. Intern. 2002, 26,

19 W. W. HARDING, P. A. LEWIS,H. JACOBS,

689-697.

20

R. J. STEWART, J. P. THALER, L. S. B. GOLDSTEIN, Proc. Natl. Acad. Sci. USA

21

1993, 99, 5209-5213.

et al., Tetrahedron Lett. 1995, 36, 9137-9140.

Z. XIONG,E. J. COREY,].Am. Chem. SOC. 2000, 122,4831-4832.

2.-X. WANG,Y. T u , M. FROHN,et al.,]. Am. Chem. SOC.1997, 119, 11,224-11,235.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Sanglifehrin A an Immunosuppressant Natural Product from Malawi Thomas Lindel

About 20 years ago, the natural product cyclosporin A was discovered. It has revolutionized the practice of organ transplantation, because it prevents rejection of solid organs and bone marrow. In addition, cyclosporin A is frequently used for the treatment of autoimmune diseases. The major problems encountered with the clinical use of cyclosporin A include its toxicity, while it would also be desirable to improve its efficacy against chronic rejection and its immunosuppressive selectivity [l].Cyclosporin A is not only an important drug, but at the same time it allows the exploration of the molecular mechanisms resulting in suppression of immune response. From this perspective, it is extremely important to identify other molecules showing similar, but not identical biological activity. Besides cyclosporin A, the natural products FK50G (tacrolimus) and rapamycin (sirolimus) show comparable effects [I,21. In 1997, scientists at Novartis characterized a novel immunosuppressive natural product from the bacterium Streptomyces Jlaveolus, isolated from soil collected in the East African state of Malawi [3]. The compound, sanglifehrin A (1,Scheme l),was named after its discoverers Sanglier and Fehr. Sanglifehrin A (1)binds strongly (ICso = 2-4 nM) to the intracellular protein cyclophilin, which also mediates the effects of cyclosporin A ( ICso = 82 nM), but not to calcineurin. Despite its greater affinity for cyclophilin, the immunosuppressive effect of sanglifehrin A (1)is about 10 times lower than that of cyclosporin A. Unlike cyclosporin A, sanglifehrin A (1)inhibits the proliferation not only of T cells, but also of B cells (ICso = 90 nM). The structure of sanglifehrin A (1) is characterized by a novel, highly substituted [ 5.51spiro-lactam moiety and a 22-membered, partially peptoid macrocycle, connected by a nine-membered chain. The natural product 1 contains 17 stereogenic centers. There are two complete total syntheses of sanglifehrin A (1):by Nicolaou et al. (1999, [4]) and by Paquette et al. (2001, [S]). They follow very similar overall strategies, as outlined in Scheme 1. The same spirolactam subunit 2, representing C2G to C41 of the natural product 1, is coupled with exactly the same protected macrocyclic moiety 3 in a Stille reaction, forming the bond between C26 and C27. The preceding macrocyclization to the 22-membered ring is achieved either by another Stille coupling between C19 and C20 (Nicolaou et al.) or by lactonization (at C1, Duan and Paquette). Scheme 1 gives the experimental conditions used for the last two synthetic steps. It is apparent that both groups observed low yields in the differently

Sanglifehrin A: an Immunosuppressant Natural Product from Malawi Stille coupling (Nicolaou, Paquette)

1: sanglifehrin A

Nicolaou: 1. Pd,(dba),,

AsPh3, Pr2NEt, DMF, 40"C, 45 %

2.2N H2S04, THF/H,O, rt, 33 %

'I

Paquette: 1. PdC12(MeCN)2, DMF, rt, 40 % 2. ~ T s O H HsBO,, , THF, rt, 30 Yo

Stille macrocyclization (Nicolaou)

2: anti aldol

4:(3:) N,Oketalization rearrangement (Nicolaou) 2

3

Endgame to the immunosuppressive natural product sanglifehrin A (1) from Streptomycespaveolus. Nicolaou et al. and Paquette et al. connect the same building blocks 2 and 3 by Stile coupling reactions, followed by ketal hydrolysis. Strategic connections for the synthesis of 2 and 3 are given (see following Schemes). Scheme 1.

performed Stille couplings (40-45%) and subsequent hydrolyses (30-33%) of the ketal portion originating from 3. The last step was originally performed at Novartis [3a] and was apparently not optimized further. The syntheses of the spirolactam part (C2GC41) of sanglifehrin A (l),outlined in Schemes 2 and 3, is discussed first. Both groups start with a stereoselective syn aldol addition to form the bond between C36 and C37. Nicolaou et al. continue with the connection of C33 and C34 by stereoselective anti aldol addition and stereoselective formation of the C39-C40 bond by an Ireland-Claisen rearrangement. Unlike Nicolaou et al., Duan and Paquette chose the formation of the bond between C32 and C33 as their second key step. The starting materials used by Nicolaou et al. (Scheme 2, above) include 3-pentanone (4), methacrolein, 3-benzyloxypropanal, and propionic acid anhydride, which together account

I

351

I

352

Sanglifehrin A: an Immunosuppressant Natural Productfrom Malawi 1, (+)-lpc2BOTf,iPr2NEt,THF, -78°C;

methacrolein; 30% H202,pH 7, MeOH, 0°C 3

34 0v

2. TESCI, imidazole, CH2C12,0°C

cypBCI, Et3N, Et20 0°C; BnO(CH2)2CH0, -78 to -10°C; *

*

39

74 Yo

w 3 4 TESO 0

LiBH4 72 Yo

5

4

\

1 . (MeOWMe2, CSA, acetone . .2. ('PrC0)20, Et3N, CHpClp ~

B n36

39

TESO

,

+

34 OH OH

3. LDA, TBSCI, THF, -78°C; HMPPJTHF, -78 to 0°C

A 7

6

-

1, toluene, 70°C

2. BHyTHF, THF, -20°C; NaB03, THF/HpO 3. TPAP, NMO, CH2CIp 39 % from 6,ds 60:lO

40

0

Bn Me2AINH2 CHpCI2

0x0

OBn

0

90 Yo 9

8

( + ) - l P c z B ~

1. Hp, Pd(OH)p/C, EtOH 2. D.-M. periodinane, pyr, CHZCIZ * 3. HF/MeCN/H20 (120:i)

11 THF, -78"C, 3 h; NaB03, THF/H20

t

67 Yo, dS 70:30

52 %, single diastereorner

TB -

1. LOA, THF, -78°C;

1 . TBSOTf, 2,6-lutidine, CHpC12, -10 to -25°C 2. 03,Me2S, CH2C12,-78 to 25°C

56 %

H2N

TMSl&N'Bu

yo

13

-78°C to 0°C 2. Hr, Lindlar, MeOH 63 %

1

1

OTBS

NH

"'8)

yh

15

1. TBAF, THF, 45°C 2. NBS, AgN03, acetone 2

3. [Pd2(dba)3]-CHC13.Ph3P, "Bu3SnH 42 %

98 Yo

17 Scheme 2. Synthesis of the spirolactam part (2) of sanglifehrin A (1) by Nicolaou et al,

Sangl3ehrin A: an Immunosuppressant Natural Productfrom Malawi Sn(OTf),, Et3N, CH,CI, then

\

I

353

-78'C;

:

TBDPSO&O 73 %,41dS 9 2 8 37

36

TBDPSOW

19

O

"

36 P

M

B

OH 0 20

18

1. Me4NBH(OAc),, HOAc, MeCN, -25 to 0°C 2. DDQ, rnol. sieves (4 A), CH,CI, 0°C

TBDPSO

1. TESCI, irnidazole, DMF, 50°C 33

*

c

OH 0-0

70 Yo

Q

21

2. DIBAL-H, THF, O'C 3. DMSO, (COCI),, -78"C, Et3N 81 %

OCH,

30% HO ,,

pH 7, MeOH, 0°C 48 %

1. (MeO),CMe,, acetone, PPTS, rt 2. TBAF, THF, rt 3. PivCI, pyr, DMAP, rt 4. TESCI; hnidazole, DMF, 50°C 5. DIBAL-H, CH,CI, -78°C

Me4NBH(OAc)3,HOAc, MeCN, -25 to 0°C

* TMS 6. Dess-Martin periodinane, CH,CI, O'C 7. NaCIO,, NaH,PO,, Me,C=CHMe, tBuOH, HO , 8. CHZN,, EtOAc 67 yo

91 %

PMB' 25

26

1. TBAF, THF

-

D.-M. periodinane, 2. CHpCI, 3. CSA, CH,CI,

26

"1'1

MeOH

74 70,dS 8O:lO Scheme 3.

pMBo 27

1. DDQ, CHzCI,, H20 2. 3. NBS, [Pd2(dba),]-CHC13, AgN03, acetone t

37 NH

2

Ph3P, "Bu,SnH, THF

41

64 Yo

Synthesis of the spirolactam part (2) o f sanglifehrin A (1) by Duan and Paquette.

354

I

Sanglgehrin A: an lmmunosuppressant Natural Product from M a h i

for the C31-C41 fragment. Chain-elongation (C26-C30) is achieved by asymmetric crotyl boration from 4 to 5 [6], by Peterson olefination of the aldehyde 13 [7] with trimethylsilyl aldimine 14, and by Ohira-Bestmann homologation [8] of 15 to 17 with the diazophosphonate 16. The enantioselective aldol addition of the chiral boroenolate of 3-pentanone (4) to methacrolein generates the stereogenic centers C36 and C37. All subsequent steps up to the synthetic intermediate 10 are performed with achiral reagents. Compound 6, with its five contiguous stereogenic centers, is obtained after treatment of 5 with dicyclohexylboron chloride/triethylamine and then with 3-benzyloxypropanal,with subsequent diastereoselective in s i b reduction with lithium borohydride, by a procedure of Paterson and Perkins [9]. The stereogenic center C40 of the synthetic intermediate 8 is generated by Ireland-Claisen rearrangement of the silyl ketene acetal 7, obtained from 6 by a desilylation/acylation/ silylation sequence. The 1,3-diolmoiety of 6 is simultaneously protected as its dioxolane. The Ireland-Claisen rearrangement results in the loss of the stereogenic centers C37 and C38, which are reintroduced by means of a moderately diastereoselective (ds 60:10), substratecontrolled hydroboration of the double bond. Ley oxidation (TPAP/NMO) of the intermediate lactol to the lactone 8 and subsequent amidation (MelAlNHZ, Weinreb method [lo]) afford the amide 9, which is converted into the C37-ketone by debenzylation and Dess-Martin oxidation. A crucial step in the sequence is the spiroketalization to 10, which was obtained in a nearly quantitative yield as a single isomer (favored, not unexpectedly, by about 20 kj.mol-' over its diastereomer). The crotylboration of the spirolactam 10 with Brown's ( Z ) crotylborane 11 generates the two stereogenic centers C31 and C30, but is of limited diastereoselectivity (ds 70:30). After ozonolysis (reductive workup) the aldehyde 13 is obtained, and is treated with the lithio derivative of the silyl aldimine 14 [7], resulting in vinylogization. Five more synthetic steps yield the vinyl stannane 2. Duan and Paquette (Scheme 3, above) assemble 2 from three larger building blocks (18 [ 111, 19 [Sa], and 23 [Sc]),stereoselectively synthesized by the Evans oxazolidinone methodology. Duan and Paquette start with the substrate-controlled aldol addition of the chiral tin(I1) enolate of the ketone 18 to the aldehyde 19, which produces the syn aldol 20 with moderate diastereoselectivity (ds 92%). The configuration at C35 is conveniently induced by the C37-hydroxy-directedreduction of 20 with Me.+NBH(OAc)3, first reported by Evans et al. [12]. Treatment with DDQ does not cleave the PMB protecting group, but gives rise to the intramolecular formation of the acetal 21, which upon reduction does not revert to the starting material, but affords compound 22, with the PMB group on the secondary alcohol function (35-0). Following Paterson et al. [13], the boron enolate of the ketone 23 was added to the aldehyde 22 in an asymmetric aldol addition, generating the stereogenic center at C33. After substrate-controlled, stereoselective ketone reduction at C31 in 24 and several protection and deprotection steps, the ester 26 is obtained and converted into the amide 27 by treatment with MeZAlNH2. One OH group of 27 (at C37) is deprotected, and is conveniently oxidized to the ketone (Dess-Martin). Now, as in Nicolaou's synthesis, the stage is set for the double, intramolecular N,O-ketalization, stereoselectively regenerating the stereogenic information at C37. In contrast to the work of Nicolaou et al., no diastereoselectivity is reported. Conversion of 28 to 2 takes three more standard steps. Schemes 4 and 5 summarize the syntheses of the macrocyclic fragment (3) of sanglifehrin A (1). At the current state of development, Nicolaou's yield for the macrocyclizing Stille reaction (62%) is superior to that of Paquette's macrolactonization (21%). At this point,

Sanglifehrh A: an Immunosuppressant Natural Product from Malawi

25

TES

OTBS 1. CrCl2,CHI,, dioxane/ THF (9:1), 0 to 25°C 2. TBAF, THF, 0 to 25'C

11

3. EDCI, 4-PPy, 'Pr NEt, CHZCIZ, 32Y;0

34

l f l

29

-

'yo'

(+)-lPCzB 1.

I

''Zc

4. (EtO),P(=O)CH,CO,Et, NaH, THF, -78°C to fl 5. DIBAL, THF, -78'C NaBO,, THF/HzO -30°C 2. TBSOTf, 2,6-lutidine, CHzCI, 6. mCPBA,CH& ds 79:21 3. 0,. Sudan 78, CHpClp; PPh3 28 %

cNSBoc !'BOC

MgBr

\

$3

Et,O/THF ( l : l ) ,-40°C

36

TBSO 1. TFA, CHPCIP(111) 2. EDCI, HOAt, 'Pr,NEt, CHzCIz,

66 %

1. PivCI, pyr 5. TPAP, NMO, 2. HF/MeCN/H,O (1:lO:l) mol. sieves (4 A), CHzCIz 3. K,C03, MeOH 6. NaCIO,, NaH2P04,Me,C=CHMe, 4. "Bu3SnH, 'BuOH, HzO [PdCIz(PhCN)z], P(@tOl),, 'Pr,NEt, CH2CIZ, from -2O"Ci 44%

3. TFA, CH,CIz (1:l)

&L./.+KI

I /

OyO "~u,Sn3

33

17 5

15 1 3 14 40 H

30

1. HATU, 'PrzNEt, DMF, rt, 51 % (three steps) 2. Pdz(dba)3,AsPh,, 'Pr,NEt, DMF, rt, 62 %

5 .

Scheme 4.

Synthesis o f t h e rnacrocyclic part (3) of sanglifehrin A (1) by Nicolaou et al.

it should be mentioned that any total synthesis plan must be treated as a hypothesis. The experiments have to be performed. Both groups use the iodovinyl aldehyde 29 [14] as precursor, accounting for the C21LC25 fragment. While Nicolaou et al. assemble the macrocycle starting from 29 "counter-clockwise'' (with reference to the representation of sanglifehrin A as in I), Paquette et al. build it up "clockwise". The Takai olefination [15] of 29 belongs to the lower-yielding steps in the synthesis by Nicolaou et al. (57%). Coupling with the Boc-protected piperazic acid derivative 30 gives the bis-iodovinyl compound 31, which is further elongated to 33 at the less hindered P-NH

355

356

I

Sanglfehrin A: an Immunosuppressant Natural Product from Malawi

0 0 k k ' ( 0 E t ) z Me0

'' 29

LiHMDS, THF, -45°C 2. DIBAL, THF, -78°C 3. MnO,, CHzCIp

'

L 25

C OTBS

H

O

Et20, -78 to -20°C 2. Me4NBH(OAc)3,MeCN,

17

HOAC,-25 to 0°C

39

54 %

50 %

-

1. Phl(OCOCF3)p, CH2CIp 2. NaBH,, THF, HO ,

1

3. D.-M. periodinane, CH,CI,

'us 4. NaCIO,,

NaHZP04, Me2C=CHMe, 'BuOH, HO , 5. TBAF, THF, 0°C 48 %

41

HO& 42

13

1. LiOH, THF,

43

HpO, 0% 2. EDCI, 4-PPy, 10-3 M CH,CI,

&0Boc

c

HATU, 'Pr,NEt, MeCN

3

3. TMSOTf, 2,6-lutidine,

CH,CI,

15 %

67 % b O B , Scheme 5.

44

Synthesis of the macrocyclic part (3) of sanglifehrin A (1) by Paquette et al

group with the dipeptide fragment 32, composed of L-rn-tyrosineand L-valine. In the C13C19 fragment, the stereochemical information is induced by treatment of the TES-protected propargylic aldehyde 34 with Brown's (E)-crotylborane, with no comment as to the stereoselectivity. Two of the newly introduced carbon atoms are retained after ozonolysis. After bishomologation and reduction, the resulting allylic alcohol is epoxidized to 35 with rnCPBA, with only moderate diastereoselectivity (ds 79:21). In the following step, the C51-C54 side chain (see Scheme 1) is introduced by Grignard opening of the epoxide 35. Pivaloyl protection of the primary hydroxy group in 37 and desilylation of the masked secondary hydroxy group (17-OH) allows the favored 1,3-dioxolane to be produced by transketalization. The carboxyl group (C13) of 38 is obtained by a two-step oxidation, first with the Ley reagent and

Sanglifehrin A: an Immunosuppressant Natural Productfrom Malawi

Tab. 1. Strategic data relating to the total syntheses of sanglifehrin A (1). Diastereoselectivities have not been taken into account in calculation of the overall yields. Nicolaou et a/.

Paquette et a/.

Longest Linear Sequence

24 steps, starting from 4

Overall Yield Selected Diastereoselectivities

0.14%, starting from 4 to 8: 60:lO to 12: 70:30 to 35: 79:21 deprotection to 1: 33% Stille coupling (2 and 3): 45% Takai olefination of 29: 57%

25 steps, starting from 18 0.16%, starting from 18 to 20: 92:8 to 28: 80:lO

Worst Yields (Single Steps)

macrolactonization: 21% deprotection to 1: 30% Stille coupling (2 and 3): 40%

then with sodium chlorite. Of the two bonds still missing for the macrocycle, the amide bond is formed first from 33 and 38. Regioselective (!) Stille macrocyclization (DMF, 1 mM) gives 3 in a yield of 62%. Paquette et al. start with the bis-vinylogation of the same compound 29 [14], by WittigHorner reaction, reduction, and oxidation (Scheme 5). For the formation of the C17-ClG bond, the anti-aldol41 (ds not reported) is obtained by treatment of the aldehyde 39 with the (Z)-boronenolate 40, bearing a dithioketal moiety that is later to be the C51-C54 side chain. 3-Hydroxy-assisted,diastereoselective reduction of the keto group at C15 gives 41, which is converted into intermediate 42 in five more steps. The dethioketalization of 41 is achieved with phenyliodine(11 I ) bis(trifluor0acetate) [ 161, As in Nicolaou’s synthesis, the N12-Cl3 amide bond is formed first, followed by a low-yielding (21%, even at a concentration of 1 mM) macrolactonization to 3. Table 1 summarizes the benchmark data of the two total syntheses of sanglifehrin A (1). An alternative, but premature, approach to the C13-Cl9 fragment of sanglifehrin A (1) uses stereocontrolled radical reactions starting from the monosaccharide chiral pool [ 171. The synthesis of structural analogues of the 22-membered, macrocyclic partial structure of sanglifehrin A (1) lacking all stereogenic centers of the C13-Cl9 fragment employs ringclosing metathesis reactions [ 181. Selective chemical transformations can also be performed on the natural product sanglifehrin A (1) itself 1191. It is surprising that C2G-C27 of 1 can be chemoselectively cisdihydroxylated (Sharpless conditions) in a yield of 70%. The natural product can afterwards be reassembled by Julia-Kocienski olefination. The success of this operation indicates that total syntheses of sanglifehrin A (1) alternative to those by Nicolaou et al. and Paquette should be worth pursuing. From the crystal structure of the cyclophilin-sanglifehrin A complex it can be concluded that the peptide portion of the macrocycle is essential for binding. If the spirolactam part (C2G-C27) is cleaved off, the binding affinity of 1 to cyclophilin is only slightly changed. Figure 1 shows the recognition and spacer domains. The structurally simplified compound 45 has been synthesized by Wagner et al. [20]. The C53-deoxo analogue of 1 shows activity similar to that of 1, while deoxygenation at the phenyl position CGl results in a tenfold decrease in activity in the mixed lymphocyte reaction (MLR) and a tenfold decrease in bind-

I

357

358

I

SanglifehrinA: an Immunosuppressant Natural Product from Malawi

spacer domain

OH

45

1: sanglifehrin A Fig. 1. Model macrolide 45 displays an affinity for the intracellular binding protein cyclophilin a thousand times smaller than that of the immunosuppressive natural product sanglifehrin A.

ing affinity to cell-free cyclophilin. The biological activity of the natural product 1 has yet to be surpassed. Studies on the exact mode of action of the unmodified sanglifehrin A (1)by Liu et al. found that 1 inhibits the T cell cycle (G1 phase), mediated by activation of the tumor suppressor gene p53 [21]. Sanglifehrin A (1)is a novel immunosuppressant, which, in addition to CsA, FKSOG, and rapamycin, represents a fourth class of immunophilin-binding metabolites with a new, as yet undefined mechanism of action [22].The structural variation now accessible through total and partial synthesis should contribute to understanding of its biological action on the molecular level.

References 1

F. J. DUMONT,Curr. Opin. Invest. Drugs

2001, 2, 357-363. 2 Reviews: a) J. MANN,Nat. Prod. Rep. 2001, 18, 417-430; b) S. L. SCHREIBER, M. W. ALBERS,E. J. BROWN,Acc. Chem. Res. 1993, 26, 412-420. 3 a) T. FEHR,L. OBERER, V. QUESNIAUX RYITEL,et al., Novartis AG, PCT Int. Appl.

1997, PIXXD2 WO 9702285 A1 19970123. 1998, PIXXDZ WO 9807743 A1 19980226;

b) 7.-J. SANCLIER, V. QUESNIAUX, T. FEHR, et al., J . Antibiot. 1999, 52, 466-473; c) T . FEHR,J. KALLEN, L. OBERER, et al., J. Antibiot. 1999, 52, 474-479; S. J. CLARKE, G. P. MCSTAY,A. P. HALESTRAP,].Bid. Chem. 2002, 277, 34793-34799.

4 a)

K. C. NICOLAOU, J. Xu, F. MURPHY,et

al., Angew. Chem. 1999, I 1 I, 2599-2604; Angew. Chem. Int. Ed. 1999, 38, 2447F. MURPHY,S. 2451; b) K. C. NICOLAOU, BARLUENGA, et al., 1.Am. Chem. SOL 2000, 122, 3830-3838. 5 a) L. A. PAQUETTE, I. KONETZKI,M. DUAN, Tetrahedron Lett. 1999, 40, 7441-7444;

b) M. DUAN,L. A. PAQUEITE,Tetrahedron Lett. 2000, 41, 3789-3792; c) M. DUAN, L. A. P A Q U E ~Angew. E, Chem. 2001, 113, 3744-3748; Angew. Chem. Int. Ed. 2001, 40, 3632-3636; L. A. PAQUETTE, M. DUAN,I. KONETZKI,C. KEMPMANN, J. Am. Chem. SOC.2002, 124, 42574270.

References I 3 5 9 6

7 8

9 10 11

12

13 14

15

a) H. C. BROWN,R. K. DHAR,R. K. BAKSHI,et a]., /. Am. Chem. SOL. 1989, 1 1 1 , 3441-3442; b) I. PATERSON, A. N. HULME, 1.Org. Chem. 1995, 60, 3288-3300. E. J. COREY, D. ENDERS,M. G. BOCK, Tetrahedron Lett. 1976, 17, 7-10. a) S. OHIFS, Synth. Commun. 1989, 19, 561-564; b) S. MULLER, B. LIEPOLD,G. J. ROTH, et al., Synlett 1996, 521-522. I. PATERSON, M. V. PERKINS, Tetrahedron Lett. 1992, 33, 801-804. A. BASHA,M. LIPTON, W. M. WEINREB, Tetrahedron Lett. 1977, 18, 4171-4174. I. PATERSON, M. DONGHI,K. GERLACH, Angew. Chem. 2000, 112,34533457; Angew. Chem. Int. Ed. 2000,39, 3315-3319. D. A. EVANS,K. T. CHAPMAN, E. M. CARREIRA,]. Am. Chem. SOC.1988, 110, 3560. I. PATERSON, J. M. GOODMAN, M. A. LISTER,et al., Tetrahedron 1990, 46, 4663. K. C. NICOIAOU,N. P. KING, M. R. V. FINLAY, et al., Bioorg. Med. Chem. 1999, 7, 665-697. a) K. TAKAI,K. NIITA,K. UTIMOTO,J.Am. Chem. SOC.1986, 108, 7401-7408; b) D. A.

16 17 18

19

20

21

22

EVANS,W. C. BLACK,].Am. Chem. SOL. 1993, 115, 4497-4513. G. STORK,K. ZHAO,Tetrahedron Lett. 1989, 30, 287-290. M. K. CURTAR, S. R. CHAUDHURI, Etrahedron Lett. 2002, 43, 2435-2438. J. WAGNER, L. M. M. CABREJAS, C. E. GROSSMITH, et al., J. Org. Chem. 2000, 65, 9255-9260. a) R. BANTELI,I. BRUN,P. HALL,et al., Tetrahedron Lett. 1999, 40, 2109-2112; b) R. MEITERNICH, D. DENNI,B. THAI, et al., /. Org. Chem. 1999, 64, 9632-9639; c) P. HALL,I. BRUN,D. DENNI,et al., Synlett 2000. 315-318; d) R. BANTELI, J. WAGNER, G. ZENKE,Bioorg. Med. Chem. Lett. 2001, 11, 1609-1612. L. M. M. CABREJAS, S. ROHRBACH, D. WAGNER, et al., Angew. Chem. 1999, 111, 2595-2599; Angew. Chem. Int. Ed. 1999, 38, 2443-2446. a) L.-H. ZHANG,J. 0. LIU,/. Immunol. 2001, 166, 5611-5618; b) L.-H. ZHANG, H.-D. YOUN,J. 0. LIU,]. B i d . Chem. 2001, 276, 43534-43540. G. ZENKE, U. STRITTMATTER, S . FUCHS, et al., J. Immunol. 2001, 166, 71657171.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Short Syntheses o f the Spirotryprostatins

Heterocyclic natural products represent particular challenges to organic synthesis, because a “building block system” of standard reactions often fails. The five so far completed total syntheses of spirotryprostatin €3 (2, Figure 1)described below have been developed by leading groups in the field and outline the difficulties involved when dealing with heterocycles. In 198G, Osada et al. reported the isolation and structure elucidation of the natural products spirotryprostatin A (1)and B (2) from the fermentation broth of the fungus Aspergillus furntgatus [l]. Both alkaloids are derived from the amino acids tryptophan and proline, and each possesses a prenyl side chain (Figure 1). Unlike the diketopiperazine demethoxyfumitremorgen C (3) from the same source organism, 1 and 2 possess a challenging spirooxindole moiety. Compounds 1 and 2 inhibit the cell cycle (G2/M block), with spirotryprostatin B (2) being more potent by about one order of magnitude (ICso 14 pM). Small molecules such as the spirotryprostatins appear especially suitable as lead structures for industrial drug design. They hold the promise that structural variation by synthesis will remain more facile than by genetic engineering. Spirotryprostatin A (1)was synthesized earlier by Edmondson and Danishefsky [ 21. The difference between spirotryprostatins B (2) and A (1)is the absence of the G-methoxy group on the indole ring and - more importantly - the presence of the C8-C9 double bond in spirotryprostatin B. Scheme 1 presents the two approaches used by Wang and Ganesan [ 3 ] and by von Nussbaum and Danishefsky [4], which employ an essentially common intermediate (9/14), with the exception of the different protecting groups. The total synthesis by Wang and Ganesan can hardly be considered complete, because only marginal yields are achieved in the last steps introducing the double bond (Scheme 1).Both syntheses start from L-tryptophan methyl ester (4) and include steps with very low diastereoselectivity,and hence the separation of diastereomers. In two steps, Wang and Ganesan convert 4 first into the aJ-unsaturated imine G and then, by an acyliminium Pictet-Spengler condensation, into the p-carboline 8 (Scheme 1) [ 51. The trans diastereomer was formed as a side product, and had to be separated. Treatment of 8 with NBS in aqueous acetic acid by a procedure described in 1969 by van Tamelen [GI results in the formation of the oxindoline 9 through a spiro ring-contraction. The intermediate bromoniurn ion is generated on the less hindered a-face, in the position opposite to the

Short Syntheses ofthe Spirotryprostatins

1: spirotryprostatin A

2: spirotryprostatin B

3:demethoxyfumitremorgin C

Fig. 1. Secondary metabolites from the fungus Aspergillusfumigatus.

unreactive prenyl side chain. A pinacol-like rearrangement follows, with inversion of the stereogenic center C3 and retention of the rearranging center C18. It should be mentioned that the spiro ring-contraction cannot be applied to every starting material: if the NBS oxidation is applied to the complete diketopiperazine frame of demethoxyfumitremorgen C (3), oxidative cleavage of the CIS-NIO bond predominates and stereochemically undefined spirooxindoles are formed in only small amounts. In the alternative Mannich route to the spiro intermediate 14, the indole ring of 4 is oxidized first. The resulting oxoindoline 11 is then converted by treatment with senecialdehyde (5, “prenal”) into a mixture of four diastereomers of compound 12, which are acetylated, as a mixture, to 14. The two total syntheses differ with respect to the formation of the diketopiperazine structure and the introduction of the C8-C9 double bond of spirotryprostatin B (2), with quite divergent overall yields. Ganesan et al. first cyclize 9 to the spirotryprostatin A analogue 10. After selenylation of 10, the natural product spirotryprostatin B (2) is formed in the marginal yield of only 2%. As the dominant reaction, the hydroxylation of the second diketopiperazine cc-carbon (C12) is observed (20% relative yield). Von Nussbaum and Danishefsky perform the steps in the opposite order. On treatment of 14 with phenylselenyl chloride, the other cc-carbon (C9) is chemoselectively attacked. Oxidation with dimethyldioxirane gives the C8-C9 double bond. Unfortunately, the undesired 3-ent diastereomer of 15 is obtained as the major product and has to be separated chromatographically. As an additional isomer, the product with opposite configurations at C3 and C18 is formed. The ring-closure of 15 to the diketopiperazine is the last step of the total synthesis of spirotryprostatin B (2). It may be of practical importance for further biological studies that 500 mg of the natural product can be obtained in one batch starting from 5.5 g of tryptophan methyl ester (4). Sebahar and Williams published a non-biomimetic approach to spirotryprostatin B (2) [7] (Scheme 2). The key reaction of their sequence is an asymmetric [1,3] dipolar cycloaddition [S] between the oxindolidene acetate 16 and the intermediate azomethine ylide 19. The intermediate 19 is itself generated from the aldehyde 17 and the chiral diphenylmorpholinone 18. The stereochemistry of the spiro compound 20 (82% yield) was confirmed by X-ray analysis. Four contiguous stereogenic centers (C9, C8, C3, C18) are generated simultaneously. After removal of the bibenzyl moiety by hydrogenation it was found that condensation with the benzyl ester of D-proline (21) gave a higher yield than with the L-isomer. It was hoped that the thermodynamically favored, correct stereochemistry of the natural product 2 could be achieved later on by epimerization. After ringclosure to the diketopiperazine

I

361

362

I

Short Syntheses ofthe Spirotryprostatins

Lo

5

1.05 eq. DMSO, 12N HCI, AcOH, 0.05 eq. PhOH, rt, 4h

HCWH/

J

6

'$ 5, NEt3,3 8, sieves, pyridine, rt, 9 h

730 ' from

separation of diastereomers

, pyridine

CH2C12, rt, 8 h 32

from 4

/"

/ 8

'

@$

12

1.2 eq. BOP-CI, CH2CI2, 2.5 eq. NEt3, rt, 2 d 90 %

CO2CH3

9: PG = Fmoc

PG

414: diastereomers PG = B ~ c ,

/ \ 1) 2.2 eq. LiHMDS, THF, O'C, 30 min; 2.2 eq. PhSeCI,

piperidine/CH2CI2, rt, 15 min quant.

diastereomers

J

38 %

&$ 2) 4 eq. DMDO, THF, O'C, 4 h

0

3.8 eq. LDA, -75"C, 40 min;

..............

3.9 eq. PhSeBr, -75'C, 1 h

2

1) TFNCH2Ch rt, 30 min * 2) NEt3, CH2C12, rt, 4 h

2 Yo

\

Boc

/ \

86 %

10 Scheme 1. Biomimetic syntheses o f spirotryprostatin

C02CH3

15

B (2), by Wang

and Canesan (2000) and by von Nussbaum and Danishefsky (2000).

Short Syntheses ofthe Spirotryprostatins

I

363

C02Et 0 H

Et

16

'Lo OCH3

b

p

h

i?"::b,f?_

*

82 %

Ph

OCH3

18

19

17

1) HP,PdC12, THFIEtOH, 60 psi, 36 h

Ph Ph

0 MeCN 3) HP,Pd-C, EtOH 4) BOP, Et3N, MeCN

1 eq. p-TsOH toluene, A

*

/r OCH3

-

85 Y' o

70 % 20

22

1 ) Lil, pyridine, A

NaOMe, MeOH

2) DCC, DMAP, BrCC13, A,

separation of diastereomers

H o - N ~

s 23 Scheme 2.

65 %

25% 24

Total synthesis of spirotryprostatin B (2) by Sebahar and Williams (2000).

22, the prenyl group was formed by elimination of methanol on treatment of 22 with one equivalent of p-TsOH in boiling toluene. The initial [ 1,3] dipolar cycloaddition had resulted in the introduction of the ethoxycarbonyl group at C8, which now had to be removed. It was found that the ethyl ester of 23 could be hydrolyzed by LiI in boiling pyridine, but not by, for example, LiOH in THF/water. Among the possible conditions for the decarboxylation, the Barton version of the Hunsdiecker reaction proved to be optimal [9]. The C12 epimer 24 of spirotryprostatin B (2) was formed in a yield of 40% and was converted into the natural product in a yield of 65%, again making the separation of diastereomers necessary. A domino total synthesis of spirotryprostatin B (2) and three of its isomers has been published by Overman and Rosen, who apply two sequential palladium-catalyzed reactions (one-pot) to assemble the two spiro-fused rings [lo] (Scheme 3). This work again makes it clear that complex heterocyclic systems may represent a harder challenge to synthetic

*

2

364

I

Short Syntheses of the Spirotryprostatins

'1 r-OTBDPS

25

Meozc\

1. LiOH 2. TBDPSCI 78 % 3. 2-iodoaniline, 1-Me9-CCpyridinium iodide

1. CO, [Pd(dppf)Clz], MeOH 2. 2-iodoaniline, AIMe3 3. SEMCI. NaH

74 %

32

SEM I . N V o T B D p s 33

1. SEMCI, NaH

1. TBAF 2. DMSO, (COC1)2, NEt3 3. 27, KOtBu, [18]crown-6

71 %

3. DMP

(MeO)zOP

1

27

SEM\ N

O

18

&IF

20

34

I

0.2 eq [Pd2(dba)3]-CHC13, R-BINAP, PMP. DMA, IOO'C

0.1 eq [Pd2(dba)3]-CHC13, 72 % P(o-tol)3, KOAc, THF, 66'C

29

/ 30 Scheme 3.

\

o

6: 1

1 31

:1 36

Total synthesis of spirotryprostatin 8 (2) by Overman and Rosen (2000). The products 30, 31, 36,and 37 are deprotected with MezAlCIl'Pr2NEt in 90-95% yields.

37

Short Syntheses ofthe Spirotryprostatins

methodology - Pd chemistry in this case - than large acetogenins. Scheme 3 gives the last steps of two approaches that were carried out to gain access to all stereoisomers with the common 12s absolute configuration and also to establish the then unknown stereochemistry of the natural product. Two precursors 28 and 34, differing in the geometry of the C3-Cl8 internal double bond, were synthesized by independent routes. From the beginning, it was not clear which stereochemistry would be obtained in the spiro-fused products 30, 31, 36, and 37, because in the second reaction step the nitrogen nucleophile might attack v n or anti to the metal center of the q3-allylpalladium complexes 29 and 35. The experiments had to be performed. The first Heck cyclizations, forming the oxindole systems, proceeded in a 5-exo manner, regioselectively generating the assumed intermediates 29 and 35. In the case of 29, diastereoselectivity (G:l, total yield only 28%) a preference for 30 over 31 could be achieved, since it was possible to use (R)-BINAPas a chiral ligand. The synthesis of the intermediate 35 was only successful when the achiral P(o-tol)3 and KOAc as base were used, providing a 1:l mixture of SEM-protected spirotryprostatin B (36) and its 3,lS-bis-epi isomer 37 in the satisfying yield of 72%. Apparently, the C3-Cl8 double bond isomerizes on heating in dimethylacetamide, because the identical product 30 is formed on exposure of 34 to the same reaction conditions as used for its double bond isomer 28. Overman's strategy for the stereoselective build-up of the quaternary spiro center and its neighboring stereogenic centers is novel. For the first time it was demonstrated that Heck insertions of conjugated trienes can be regioselective and that the reaction between diketopiperazine nitrogen atoms and q3-allylpalladium intermediates occurs with anti selectivity. Spirotryprostatin B (2) was obtained in a total yield of 976, over ten isolated intermediates starting from methyl acrylate and 3-methyl-2-butenal (not shown), again including separation of diastereomers. The worst step, until conditions are found to carry it out enantioselectively, is the final cascade reaction (3G% per diastereomer). A key advantage of the Overman/Rosen approach is that the difficult introduction of the C8-C9 double bond by functionalization of C9, as employed by the other groups, is circumvented. The most recent synthesis of spirotryprostatin B (2) has been developed by Fuji et al. (Scheme 4) and starts from the chiral oxindole 38, obtained by asymmetric nitroolefination [I11 of the indole 3-position [12]. After conversion to the aldehyde 39 by treatment with TiC13, in situ hydrolysis, and further Strecker synthesis, the protected amino acid 40 is obtained. Double N-deprotection and attachment of the proline unit yields 41. The three-step introduction of the hydroxy group into the prenyl side chain, affording 42, follows a procedure developed by Sharpless [13]. An allylic carbocation is formed on exposure to p-TsOH and undergoes nucleophilic attack by the neighboring amide nitrogen atom. Since the earlier Strecker reaction was not carried out in an enantioselective manner, two spirocyclic diastereomers are now formed, of which only 43 has the correct spirotryprostatin B (2) stereochemistry. Compound 43 is obtained in a yield of only 24%, because the reaction was stopped after 50% conversion due to increasing loss of the Boc group. Compound 43 is identical to the intermediate used by von Nussbaum and Danishefsky. Fuji et al. also reproduce the endgame to 2 (21%). Of the five completed total syntheses of spirotryprostatin B (2), four struggle with the introduction of the C8-C9 double bond and all of them include steps of very low diastereoselectivity. It is unusual for the biological activity of natural products to be surpassed by synthetic

I

365

KNoZ 4 366

I

Short Syntheses ofthe Spirotryprostatins

MeOH/H20 TiCh aq, NH40Ac, (4:1), rt, 3 h r 55 Yo

/

\

/

\ 39

30

i:~

~

~rt* ~

c

3. CbZCI, Et3N, CHpCIp, rt, 12 h 4. K2C03, MeOH, rt, 6 h 5. HCI (1N), rt, 30 min

~

$

40

38 Yo

1. Pd black, 5 O h HCOpH

COPMe

0

-

2. in CHzCIp, KBoc-L-proline, MeOH,1220h minEDCI,

1. mCPBA, CHpCIp, O'C, 6h 2. PhSeSePh, NaBH4, MeOH, 65-C, 10 h

&3
/

\

I

69 %

3. Hp02 (30%), THF, O'C, 6 h

O

85 Yo

41

1. LiHMDS, THF, O'C, 30 min; PhSeCI, THF, O'C, 2 h 2. DMDO, THF, OaC4 h

pTsOH, MeCN, lOO'C, 25 rnin

- 2 3. HCI (4N) in dioxan, O'C, 30 rnin 4. Et3N, CH2C12, 4 h

t

24 Yo SeDaration of diastereomers

42 Scheme 4.

43

21 %

Total synthesis of spirotryprostatin B (2) by Fuji et al. (2002).

analogues (Figure 2). Danishefsky et al. were fortunate in finding a few synthetic intermediates with higher biological activity than the natural products themselves [ 2b]. Replacement of the prenyl group by a benzyloxymethyl group gives compounds 44,45, and 46, with a 5000-fold higher cytotoxicity than spirotryprostatins A (1)and B (2). The IC50 of compound 46, which additionally lacks the proline part of the diketopiperazine unit and possesses only the spirooxindole moiety, is surprisingly low (2.lo-' M against the MDA MB-4G8 breast cancer cell line). The relative stereochemistry at the C 3 and C18 centers of compounds 44 and 45 has hardly any influence on their cytotoxicity.

44

45

Analogues o f the spirotryprostatins from Danishefsky's synthetic program, with cytotoxicities 5000 times higher than those of the natural products. Fig. 2.

46

~

v

References I 3 6 7

References 1 a) C.-B. CUI, H. KAKEYA, H. OSADA, ].

Antibiot. 1996, 49, 832-835; b) C.-B. CUI, H. KAKEYA,H. OSADA,Tetrahedron 1996, 52, 12,651-12,666. 2 a) S. D. EDMONDSON,S. J. DANISHEFSKY, Angew. Chem. 1998, 110, 1190-1193; b) S. EDMONDSON, S . J. DANISHEFSKY, L. SEPPLORENZINO, et al.,]. Am. Chem. Soc. 1999, 121, 2147-2155; Angew. Chem. Znt. Ed. Engl. 1998, 37, 1138-1140. 3 H. WANG,A. GANESAN,].Org. Chem. 2000, 65, 4685-4693. 4 F. V O N NUSSBAUM, S. J. DANISHEFSKY, Angew. Chem. 2000, 112, 2259-2262; Angew. Chem. Int. Ed. 2000, 39, 21752178. 5 See the synthesis of demethoxyfumitremorgen C: H. WANG, A. GANESAN, Tetrahedron Lett. 1997, 38, 4327-4328.

6

7 8 9

10

11

12 13

E. E. VAN TAMELEN, J. P. YARDLEY,M. MIYANO,et al., ]. Am. Chem. SOC.1969, 91, 7333-7341. P. R. SEBAHAR, R. M. WILLIAMS,].Am. Chem. SOC.2000, 122, 5666-5667. For a review, see: K. V. GOTHELF.K. A. J O R G E N S E N , Chem. Rev. 1998, 98, 863-909. D. H. R. BARTON,D. CRICH,W. B. MOTHERWELL, Tetrahedron 1985, 41, 3901. L. E. OVERMAN, M. D. ROSEN,Angew. Chem. 2000, 112,4768-4771; Angew. Chem. Znt. Ed. 2000, 39,4596-4599. a) K. FUJI,T. KAWABATA, T. OHMORI, et al., Synlett 1995, 367; b) K. FUJI, T. KAWABATA. T. OHMORI,et al., Heterocycles 1998, 47, 951. T. D. BAGUL,G. LAKSHMAIAH, T. KAWABATA, et al., Org. Lett. 2002, 4, 249-251. K. B. SHARPLESS, R. F. L A U E R ,Am. ~. Chem. SOC.1973, 95, 2697-2699.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

The Chemical Total Synthesis o f Proteins Oliver Seitz Introduction

The incredible amount of sequence data being produced by the different genome projects is revealing the primary structures of thousands of new proteins. It is one of the foremost challenges of the “post genome era” to unravel the functions of these newly discovered protein molecules. Understanding of the molecular details of protein function is particularly important for the development of diagnostically or therapeutically active agents. In the acquisition of knowledge about the “active residues”, the most useful approaches have proven to be systematic variation of the target protein at defined positions and protein crystallography. In the last two decades, modified proteins were predominantly produced by making use of recombinant DNA techniques, which enabled molecular biologists to modify cells genetically. The variability of a protein generated by biosynthesis is limited, however, and, with a few exceptions, restricted to the exchange of the 21 proteinogenic amino acids. In contrast, chemical synthesis allows for the introduction of almost any kind of modification, both in the protein backbone and in the protein side chains. The chemical total synthesis of proteins, even of small proteins, is a tedious and by no means trivial enterprise. The following consideration might give some idea of the difficulties associated with the synthesis of a protein molecule. At present, solid-phase synthesis, introduced by the pioneering work of Merrifield, is the most powerful method for the synthesis of small to medium-sized peptides (5-50 amino acids). The solid-phase approach relies on iterative steps involving coupling of a N-protected amino acid building block with a polymer-bound amino acid- or peptidenucleophile and subsequent removal of the amino-protecting group. In order to obtain a theoretical overall yield of 90%, each coupling step of a linear synthesis of a 100-mer peptide must proceed with 99.9% yield. With a coupling/deprotection yield of 97%, a yield that would honor any preparative chemist, a 100-mer would be obtained in only 5% overall yield. It is not only the low yields that complicate the solid-phase synthesis of large peptides but also the need for an intricate purification procedure. The desired protein, produced in 5% yield, requires to be separated from 95% of formed by-products, a task difficult to accomplish even by modern separation techniques. Convergent methods avoid the “cumulative disaster” of linear synthesis. Access to large peptides can be provided by use of medium-sized peptide segments, easily available by solidphase synthesis. There are two distinct approaches. One involves the synthesis and puri-

Chemoselective Ligation of Unprotected Peptide Fragments

fication of protected peptide fragments to be joined in a fragment condensation strategy. Collected data indicate that protected peptides often show poor solubility in commonly used solvents, thereby complicating both purification and usage in peptide couplings. It adds to the difficulties that fragment couplings of the relatively unreactive segments suffer from undesired racemization of the activated amino acid. As a solution to these problems, protein chemists have developed new techniques based on the ligation of water-soluble unprotected peptide segments. In view of the multitude of functional groups present in an unprotected peptide (see Scheme l),it seems hopeless that a selective peptide bond formation could be feasible. Over the last 10 years, however, dramatic progress has been achieved in this field and it is now possible to obtain proteins made up of up to 200 amino acids by chemical protein synthesis. The current state of the chemical synthesis of proteins is presented here. It should be emphasized that this article focuses on fragment ligation techniques. The examples presented in the following sections have been selected with the aim of outlining some principles of current synthetic methodology and serving for instructive purposes rather than comprehensiveness. For more detailed information the reader is referred to some excellent review articles [ 1-71.

N-terminal fragment

H

C-terminal fragment

OH

J

chemo- and regioselective ligation

COOH

H

OH

Scheme 1. Fragment ligation o f two unprotected peptide segments.

Chemoselective Ligation of Unprotected Peptide Fragments

The ligation of two unprotected peptides is a challenging problem to the synthetic chemist (Scheme 1). The solubility of unprotected segments decreases with increasing molecular weight, and productive encounters between the reactive ends become less likely to occur. In order to compensate, the rate constant of the bimolecular reaction must be high. Despite

I

369

370

I

The Chemical Total Synthesis of Proteins

such high reactivity, though, the presence of the many potentially reactive functional groups must be tolerated. Reactions that meet these demands of chemoselectivity are classified into two categories, involving the formation of peptidic and non-peptidic bonds. Formation of Non-peptidic Bonds

Selective conjugation can be achieved by the introduction of functional groups not normally present in biopolymers 181. Figure 1 shows a selection of reactions for which the required chemoselectivity has been demonstrated. For example, the reaction between a thiocarboxylate and a bromoacetyl group proceeds at pH 5-6 without concomitant alkylation of the thiol groups of the cysteine side chains (Figure 1, entry A). As a trade-off for the high chemoselectivity, an alteration of the natural peptide backbone has to be accepted. Given that the ligation site has been carefully selected, proteins normally tolerate small structural alterations, particularly when introduced within flexible loop regions. As early as 1992 Schnolzer and Kent demonstrated that a synthetic HIV-1 protease, produced by the thioester-forming ligation of a 51-mer peptide-thiocarboxylate with a 48-mer bromoacetyl peptide, exhibited a proteolytic activity equal to that of the natural protein [ 91. The formed thioesters are sensitive to hydrolysis at pH values over 7, but alkylation of thiol groups furnishes ligation products of high stability. Under aqueous conditions, thiol groups selectively react with bromoacetyl or maleoylimido groups by forming thioethers (Figure 1, entries B and C). Rau and Hahnel made use of this reaction for the synthesis of a de novo designed cytochrome b model made up of 122 amino acids 110, 111. Following Mutter’s TASP (template-assembled synthetic protein) concept [ 121, four N-terminally bromoacetylated peptide helices were attached to a structured cyclopeptide template that contained four cysteine thiol groups. An illustrative example showing how biotechnology and chemical synthesis can be combined is shown in Scheme 2. An E. Coli-based expression system was used to produce a truncated version of the oncogenic H-Ras G12V protein 1, which serves as a central switch in the signal transduction cascade [13]. The omission of the C-terminal octapeptide segment, which normally anchors two lipid moieties and governs the insertion into the cell membrane, rendered the truncated protein biologically inactive. Restoration of H-Ras activity was achieved by appending the synthetic maleoylimide-modified lipoheptapeptide 2, which selectively reacted with the C-terminal cysteine side chain of the H-Ras protein 1. A highly chemoselective ligation of unprotected peptide segments can be accomplished by use of aldehyde and keto groups, which react with hydroxylamines, hydrazides, and phenylhydrazides to form oximes, semicarbazones, and hydrazones (Figure 1, entries D, E, and F) [ 14-16]. The reaction with 1,2-aminothiols, as present in N-terminal cysteine, furnishes thiazolidines (Figure 1, entry G, see also Scheme G). Particularly attractive is the orchestrated use of orthogonal conjugation techniques, as illustrated in Scheme 3. For the total synthesis of a 20 kDa transcription factor, Canne and co-workers combined thioester ligation with an oxime-forming ligation [ 171. The goal was to link the transcription factors cMyc and Max covalently and to study the DNA-binding of the resulting conjugate. Firstly, the N-terminal segments of the cMyc- (4) and Max-proteins (5) were synthesized in the forms of the thiocarboxylates. In preparation for the oxime-ligation, the C-terminus of the C-terminal cMycsegment was fitted with a hydroxylamino group (6-7). A keto group was introduced at the

Chemoselective Ligation of Unprotected Peptide Fragments

N-terminal fragment

C-terminal fragment

I

371

ligation product

0

0 R A S 7 w

0

B

RH S ,

C

RS ,H

0

D

R

R

1

R"

RA , . O . R

0

E

R

KR.

R

H

y R'

H

RAN.NyR

HzN"

0

0

"""q.. '9r H

F

R

iH

R-

R

N=N

0

0

G

Fig. 1.

R

1,

H2N

R"

H

Examples of chemoselective ligation partners.

C-terminal Max-segment by attaching a levolinic acid group at a lysine side chain (6+9), and segments 7 and 9 were equipped with N-terminal bromoacetyl groups required for the thioester ligation. Upon thioester ligation, the cMyc-segments 4 and 8 were joined together (Scheme 4),as were the Max-segments 5 and 10. The final condensation of the formed cMyc- and Maxproteins 11 and 12 proceeded chemoselectively under weakly acidic conditions (pH 4.7), providing the desired oxime 13 in 21% overall yield (based on 10).

Chemoselective Ligation of Unprotected Peptide Fragments

0 Solid phase synthesis 4

I

H N

BOC

CIZ-HN . 0 2 0 S ~ J

--

----)

CO-MBHA

5

6

HzN (CH~COCH~CHZCO)~~

BOC

0

CIZ-HN ‘

>&I4

iY Co-MBHA 4

a) TFA

Solid-phase synthesis o f brornoacetylated peptide fragments containing either an oxirne group (8, 10% overall yield) or a levulyl group (10, 14% overall yield). Scheme 3.

strategy (Scheme 5, 16+17) [19].The process commenced with the synthesis of a templated peptide ester such as the dibenzofuran ester 16. This template contains a mercapto group, which captures the N-terminal cysteine of the segment to be coupled. After formation of the disulfide, it is possible to induce an O+N-acyl transfer, which effects the coupling of the two unprotected segments. An elegant means of pursuing a chemoselective peptide bond-forming reaction can be achieved by taking advantage of integral structural elements of the peptide. In this approach it is the peptide itself that aligns the reactive ends, thereby avoiding the need for specially designed template molecules. The thiol group of an N-terminal cysteine offers a suitable combination of functional groups. An additional advantage is that the 1,2-aminothiol structure is not normally present in proteins, which facilitates specific “targeting” of this entity. Liu and Tam developed a ligation method that produces a pseudoproline structure (Scheme 6 ) [20]. The carboxylic acid ester of glycolaldehyde 18 reacts with the 1,2-aminothiol com-

I

373

374

I

The Chemical Total Synthesis of Proteins

8

S-

+ 4

+

Br

Br

O

1

I

0.1 M NaH2P04, 8M urea, pH 4.7, 4"C, 24h

0

5

0.1M NaH2P04, 8M urea, pH 4.7, 4"C, 24h

0.1 M NaH2P04,

12

peptide 4) S

21%

0

0

0

0 13

= N-terminal fragment of the cMyc protein

(peptide)

= C-terminal fragment of the Max protein

= Gterminal fragment of the cMyc protein

(peptide)

= Kterminal fragment of the Max protein

Scheme 4. Convergent chemical ligation for the chemical synthesis o f the transcription factor-related protein conjugate cMyc-Max 13.

pound 19 to form the thiazolidinyl ester 20. This sets the stage for a subsequent O+N-acyl shift, which transfers the acyl group to the secondary amino group of the thiazolidine ring. As the net result, the amide-linked conjugate 21 is formed. The application of this method allowed the synthesis of a modified HIV-1 protease through the joining of an unprotected 38-mer with a deblocked GO-mer. At present, it appears that the most powerful method for the coupling of two unprotected peptide segments is the "Native Chemical Ligation (NCL)" developed by Dawson and Kent [21]. As indicated by its name, NCL gives rise to the formation of a natural peptide bond. This reaction was described in principle as early as 1953, by Wieland, who reported that the reaction between the (S)-valinethiophenyl ester 22 and cysteine 23 proceeded by transfer of

Chemoselective Ligation of Unprotected Peptide Fragments

DMSO d

16

I

HO

17

Brenner’s “Acyleinlagerung” ( 1 4 i l 5 ) and Kemp’s thiolcapture strategy (16-17) as examples of template-assisted fragment condensations.

Scheme 5.

0

0

18 0

HS

20

0

Scheme 6.

0

The thiaproline ligation.

the valyl group to the thiol side chain (Scheme 7, Ar-Ph) [22].This thiol exchange is the rate-limiting step. The formed (S)-valyl-cysteine24 underwent a spontaneous S-N-acyl shift, thereby forming the dipeptide 25. Dawson and Kent perfected this methodology and developed a highly efficient technique for the ligation of large, unprotected peptide seg-

I

375

376

I

The Chemical Total Synthesis of Proteins

1

thiol exchange

intramolecular acyI transfer

Wieland: R = Val; R' = OH

0

Kent: R = 30mer-peptide; R' = 18mer-peptide

SH

25 Scheme 7.

Native Chemical Ligation.

ments. Since their landmark paper in 1994, the NCL has allowed the synthesis of numerous proteins. Several recent reviews give an idea of the tremendous impact the development of the NCL has had on protein chemistry [2, 4, 61. The application of solid-phase synthesis techniques enables rapid and efficient total synthesis of a desired protein molecule. In analogy to convergent solid-phase peptide synthesis, in which protected peptide fragments are coupled to polymer-bound peptides, fragment condensation can be accomplished by employing the NCL coupling strategy, with the advantage that unprotected peptides of higher solubility can be used [ 231. The choice of solid support is a key issue for the success of NCL-mediated solid-phase fragment condensations. Conventional polystyrene-based resins were optimized for the linear Merrifield synthesis in organic solvents and show limited swelling properties in aqueous media. It is therefore advantageous to attach the unprotected peptides to a water-swellable polymer such as agarose. Dawson and co-workers have presented a powerful approach [ 241. The synthesis of a 71-mer peptide was begun by using the resin-bound mercaptopropionic acid amide 26, known as the TAMPAL (trityl-associated mercaptopropionic acid leucine) support, for the assembly of the peptide thioester 27 and segments 30 and 32 (Scheme 8). During the subsequent attachment of thioester 27 to the cysteine-functionalized agarose resin it was essential to block the N-terminal cysteine with an acetamidomethyl (Acm) protecting group in order to avoid undesired oligomerization reactions. The C-terminal end of peptide thioester 28 was anchored through the SCAL (safety-catch acid-labile) linker [25]. This safety-catch anchor is stable during all protecting group manipulations performed during a protein synthesis, but is rendered acid-labile upon SiCl4-mediated reduction of the sulfonyl groups (see inset in Scheme 8). Treatment with Hg(r1) salts removed the Acm protecting group, thereby

Chemoselective Ligation of Unprotected Peptide Fragments

I

377

a) Boc-SPPS b) HF .--.t

Ttt-S H

H2N

SCAL-Gly2-S H

26

0

HzN

Hg(0Ac)2, pH

SCAL-Glyz-Cys

H2N

29

SCAL-Gly,-Cys

SCH2NHCOCH3

28

E - SR

H-CyS I

30

Acm

pH 7, 2% BnSH

Acm

J.

31

pH 7,2% BnSH

33

\S

0

RCO-SCAL

0

1 M TiCI4 TFA, 0°C

SiCl.,

1

TFA

0

= polystyrene resin

R-CONH2

Scheme 8. Solid-phase synthesis of a 71-mer vMIP-1 protein segment 3 4 (Acrn, acetamidomethyl; BnSH, benzyl mercaptan; Boc-SPPS, solidphase peptide synthesis by t h e Boc strategy).

= agarose resin

-0

378

I

The Chemical

Total Synthesis of Proteins

preparing resin-bound segment 29 for the NCL with peptide 30. This procedure was repeated for the introduction of fragment 32. The final detachment of the 71-mer peptide 34 was accomplished by reduction of the SCAL-sulfonyl groups in 33 and subsequent TFA treatment. By using the convergent strategy elaborated by Dawson and co-workers, the total synthesis of a protein can be accomplished within a few days, with the additional advantage of being automatable. The concept of NCL has recently been applied in the synthesis of selenocysteinecontaining proteins [26-28]. The rate-limiting step in NCL is the thiol exchange, which is induced by the attack of a cysteine thiolate. The pK, value of selenols is lower than that of thiols. Since selenolates are also more nucleophilic than thiolates, it was expected that selenocysteine should provide more rapid NCL than cysteine, especially at low pH. Indeed, kinetic analysis of the model reaction shown in Scheme 9 revealed that at pH 5 the reaction with the selenocysteine 36 is lo3 times faster than with cysteine [26]. It might therefore prove possible to combine cysteine- and selenocysteine-mediated NCL in the ligation of three segments, omitting the need for the employment of protecting groups.

yk,,

0

s. Ar

+

0

35

HzNYoo-

H-Se

36

J

coo0

37

intramolecular acyl transfer

38 Scheme 9.

Native Chemical Ligation with selenocysteine 36

Extending the Applicability of Native Chemical Ligation

The high chemoselectivity of NCL relies upon the distinct reactivity of an N-terminal cysteine. The requirement for cysteine at the ligation, however, restricts the applicability of NCL. It is possible to subject the ligation product to desulfurization, resulting in the net formation of a more commonly found X-Ala bond [ 291. The presence of cysteines other than that needed for ligation is not tolerated, however, since desulfurization would occur at both protected and unprotected cysteine thiols.

Chemoselective Ligation of Unprotected Peptide Fragments

In order to extend the principles of NCL to allow connection of any peptide fragment at ligation sites other than X-Cys, it is necessary to introduce an auxiliary containing a thiol group (Scheme 10). Canne and co-workers appended N-oxyethanethiol groups at the amino groups of glycine and alanine (43in Scheme 10)[30].In these cases NCL proceeded through a six-membered transition state and the rate of product formation was low. As a result, only the sterically less demanding Gly-Ala- or X-Gly-bonds were formed in significant yields. The N-oxyethanethiolgroups were reductively removed by treatment with Zn dust, furnishing an auxiliary-freepeptide. Canne and co-workers also investigated the use of N-(2-mercaptoethyl) groups 44 [301.This auxiliary showed useful rates of amide bond formation, but its subsequent removal was not possible. Offer and Dawson suggested the use of N-mercaptobenzylpeptides such as 45 [ 311. The mercaptobenzyl auxiliary allowed chemoselective ligations at Gly-Gly, Gly-Ala, and Ala-Gly sites, although cleavage of the benzyl amide was not demonstrated. The authors proposed to induce cleavability by attaching electron-donating substituents to the phenyl ring. Indeed, the 4,5-dimethoxy-2-mercaptobenzyl amide 46 can be cleaved with strong acids such as TFMSA in TFA, as shown by Aimoto and co-workers [32]. The groups of Botti and Kent [33] and of Dawson [34]drew on a similar principle and 2-mercapto-l-phenylethyl)-group 47 as a removable auxiliary. The effecintroduced the N-( 0

H

0

SH

39

40

HS

L i

auxiliary-mediated coupling

HS.X

removal

HS-X

43

Zn, AcOH

44

none

45

none

46

TFMSA. TFA

0

O

R

41

J

auxiliary removal

Me0

Jy OMe

O

R

42 Scheme 10. Auxiliaries for Native Chemical Ligation without cysteine (TFMSA, trifluorornethane sulfonic acid).

47

I

379

380

I

The Chemical Total Synthesis of Proteins

tiveness of this moiety was demonstrated in the total synthesis of cytochrome b562 (54),a 106-mer metalloprotein (Scheme 11) 1351. To arm a peptide segment with the 2-mercapto-lphenylethyl group, a resin-bound bromoacetyl peptide 48 is allowed to react with phenylethylamine 49, with subsequent acid cleavage. The 1-phenyl substitution in 50 gives a benzyl amine that is stable under the acidic conditions required for detaching peptide 51 from the solid phase. In the ligation event, the secondary amino group is converted into a tertiary amide group (51+53), which renders the benzyl protecting group acid-labile. The degree of acid-lability can be fine-tuned by altering the substitution pattern on the phenyl ring. For example, the presence of an additional methoxy group in the 2’,4’-dimethoxy-substituted auxiliary 47 induced lability towards weaker acids such as TFA.

PG

H

Br

0

s OMe

PG

~

I

50

48

2

-

R

HN

2% PhSH, pH 7, 5mM peptide

53

Scheme 11.

S

OMe

51

The phenylethyl auxiliary in the total synthesis of cytochrome b562 (54)

New Peptide Bondforming Reactions

So far, the methods that have been shown to enable chemoselective peptide bond formation have relied upon the particular reactivity between thioesters and aminothiols. Almost simultaneously, Raines [36] and Bertozzi [ 3 7 ] reported a new method for the formation of a peptide bond with high chemoselectivity: the so-called Staudinger ligation. This reaction had

Chemoselective Ligation of Unprotected Peptide Fragments

already been used by Bertozzi (381 in order to modify cell surfaces and represents a strategy applied by Goff and Zuckermann [39] in a benzodiazepinedione synthesis. The key feature is a Staudinger reaction between the phosphine 55 and the azide 56 (Scheme 12). An azaylide intermediate 57 is formed, and normally is subjected to hydrolysis in order to obtain the amine, together with the phosphine oxide as by-product. In the Staudinger ligation, the aza-ylide structure in 57 is located in a position y or 6 to the activated carboxyl group, thereby aligning the functional groups so that an intramolecular 0 - N - or S-iN-acyl transfer is facilitated. As a result, the ligation product 58 can form by ejecting the phosphine oxide 59. Various phosphinoesters 55 have been evaluated. When examining the acetylation of azidoadenine, Saxon, Armstrong, and Bertozzi noted that the use of the phenol 55b gave higher product yields than the use of thiophenol 55a [37]. Recently, Raines demonstrated an efficient variation in which the phosphinomethanethiol 55c mediated a high-yielding Staudinger ligation [40]. It should be emphasized that azido-amino acids are easy to prepare. The Staudinger ligation could therefore become a viable alternative to Native Chemical Ligation, provided that its general utility is demonstrated.

55

Ac-Phe-S

56

PPh2

+

35%

N3CH2CONHBn NH2 I

8

Ac-0

55b

PPh2 N

95%

+ OH

Ac-Phe-S

PPh2

+

N3CH2CONHBn

55c Scheme 12.

The Staudinger ligation.

92%

I

381

382

I

The Chemical Total Synthesis of Proteins

Conclusion

The examples presented illustrate that the chemical total synthesis of proteins is not only possible, but also workable. Large unprotected peptide fragments can be joined with high chemoselectivity by forming oximes, hydrazones, thioesters, or thioethers. As long as the ligation site has been carefully selected, proteins can tolerate small structural alterations, particularly when introduced within flexible loop regions. The need to select suitable loop regions can be circumvented by employing ligation strategies that allow the chemoselective formation of natural peptide bonds, thereby widening the scope of protein synthesis. At present it appears that the “Native Chemical Ligation” (NCL) developed by Dawson and Kent is the most powerful method for such a fragment condensation of two unprotected peptide segments. The requirement for cysteine at the ligation site, however, restricts the applicability of this technique. It is in this field that the development of new peptide bond-forming reactions is rapidly progressing. One promising example has been demonstrated with the use of a phenylethylamine auxiliary in the synthesis of cytochrome b562. The Staudinger ligation is an interesting reaction with the potential to be applicable to any kind of ligation site. However, neither its scope nor its limitations have been described yet, and Native Chemical Ligation therefore remains the most versatile and reliable means for synthesizing proteins by fragment ligation. Numerous proteins have already been synthesized, and it is no exaggeration to state that chemical synthesis has the potential to give a new impetus to the study of protein function and protein modification. References

J. P. TAM,Q. T. Yu, 2.W. MIAO, Biopolymers 1999, 51, 311-332. 2 G. G. KOCHENDOERFER, S . B. H. KENT, C u r . Opin. Chem. Biol. 1999, 3, 665671. 3 G. J. COITON,T. W. MUIR,Chem. Biol. 1999, 6, R247-R256. 4 J. A. BORGIA, G. B. FIELDS, Trends BiotechnoL 2000, 18, 243-251. 5 D. M. COLTART, Tetrahedron 2000, 56, 3449-3491. 6 P. E. DAWSON, S. B. H. KENT,Annu. Rev. Biochem. 2000, 69, 923-960. 7 S. AIMOTO,Cur. Org. Chem. 2001, 5, 45-87. 8 G. A. LEMIEUX,C. R. BERTOZZI, Trends Biotechnol. 1998, 16, 506-513. 9 M. SCHNOLZER, S. B. H. KENT,Science 1992, 256, 221-225. 10 H. K. RAU,W. HAEHNEL, J . Am. Chem. SOC.1998, 120,468-476. 11 H. K. RAU, H. SNIGUIA,A. STRUCK, et a1 Eur. J . Biochem. 2001, 268, 3284-3295. 12 M. MUTTER,S. VUILLEUMIER, Angew. Chem. Int. Ed. 1989, 28, 535-554. 1

B. BADER, K. KUHN, D. J. OWEN,et al., Nature 2000, 403, 223-226. 14 H. F. GAERTNER, K. ROSE,R. COTTON,et al., Bioconjugate Chem. 1992, 3, 262-268. 15 K. ROSE,J . Am. Chem. SOC. 1994, 116, 30-33. 16 H. F. GAERTNER, R. E. OFFORD, R. COTTON,et al., J . Biol. Chem. 1994, 269, 7224-7230. 17 L. E. CANNE, A. R. FERR~-D’AMARB, S. K. BURLEY, et al., J . Am. Chem. SOC.1995, 11 7, 2998-3007. 18 M. BRENNER,J. P. ZIMMERMANN, J. WEHRMULLER, et al., Experientia 1955, 11, 397-399. 19 D. S. KEMP,R. I. CAREY,].Org. Chem. 1993, 58, 2216-2222. 20 C. F. LIU, C. RAO,J. P. TAM,]. Am. Chem. SOC. 1996, 118, 307-312. 21 P. E. DAWSON, T. W. MUIR,I. CIARKLEWIS, et al., Science 1994, 266, 776-779. 22 T. WIELAND, E. BOKELMANN, L. BAUER,et al., Ann. Chem. 1953, 583, 129-149. 23 L. E. CANNE, P. B O T ~ IR. , J. S I M O Net , al., ]. Am. Chem. SOC.1999, 121,8720-8727. 13

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27 28 29 30 31 32

A. BRIK,E. KEINAN,P. E. DAWSON, J. Org. Chem. 2000, 65, 3829-3835. M. PATEK,M. LEBL,Tetrahedron Lett. 1991, 32, 3891-3894. R. J. HONDAL,B. L. NILSSON,R. T. RAINES,J. Am. Chem. SOC.2001, 123, 5140-5 141. M. D. GIESELMAN, L. L. XIE, W. A. VAN D E R DONK,Org. Lett. 2001, 3, 1331-1334. R. QUADERER, A. SEWING,D. HILVERT, Hela. Chim. Acta 2001. 84, 1197-1206. L. 2. YAN, P. E. DAWSON,].Am. Chem. SOC.2001, 123, 526-533. L. E. CANNE,S. J. BARK,S. B. H. KENT,]. Am. Chem. Soc. 1996, 118, 5891-5896. J , OFFER,P. E. DAWSON,Org. Lett. 2000, 2, 23-26. T. KAWAKAMI, K. AKAJI,S. AIMOTO,Org. Lett. 2001, 3, 1403-1405.

33

34 35

36 37

38 39 40

P. BOTTI, M. R. CARRASCO, S. B. H. KENT,Tetrahedron Lett. 2001, 42, 18311833. C. MARINZI,S. J. BARK,J. OFFER,et al., Bioorg. Med. Chem. 2001, 9, 2323-2328. D. W. Low, M. G . HILL,M. R. CARRASCO, et al., Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 6554-6559. B. L. NILSSON,L. L. KIESSLING, R. T. RAINES,Org. Lett. 2000, 2, 1939-1941. E. SAXON,J. I. ARMSTRONG, C. R. BERTOZZI,Org. Lett. 2000, 2, 21412143. E. SAXON,C. R. BERTOZZI,Science 2000, 287, 2007-2010. D. A. GOFF,R. N. ZUCKERMANN, ]. Org. Chem. 1995, 60, 5744-5745. B. L. NILSSON,L. L. KIESSLING, R. T. RAINES,Org. Lett. 2001, 3, 9-12.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Solid-Phase Synthesis of Oligosaccharides Ulf Diederichsen and Thomas Wagner

While automated solid-phase synthesis of peptides and oligonucleotides is well established, the preparation of oligosaccharides on solid support still remains challenging. The first two biooligomer families are based on linear backbones and are composed of monomers that differ only in their side chains or nucleobases, and no formation of a stereogenic center is involved in the coupling step. Oligosaccharides, in contrast, are usually branched, since sugar units with varying functionalization are linked at different positions, in a linear or branched manner, and with alternating stereochemistry. The advantages of solid-phase chemistry, such as the improvement of yield made possible by the use of excess of reagents, or the separation of reactants and side products, should also be of interest in oligosaccharide synthesis. Important for a successful oligosaccharide solidphase synthesis are the choice of the appropriate resin and linker, a suitable protecting group strategy, and the provision of a high-yielding, stereospecific coupling reaction. The sugar donor or acceptor can be applied either as the resin-bound component, or in excess as the reagent. The detection of successful coupling on solid support is of particular importance for the development of a solid-phase synthesis. Coupling of oligosaccharides remains more difficult to analyze than chain-elongation of peptides or oligonucleotides, because the coupling yield can not be determined simply from the concentration of cleaved protecting groups. In addition, the newly established stereocenter has to be considered. The use of enzymes for coupling of sugar units on solid support is especially valuable for control of regioselectivity and stereochemistry. Some further examples of promising approaches towards the solid-phase synthesis of oligosaccharides are reported in [ 11. Trichloroacetimidatesas Sugar Donors

Trichloroacetimidates are widely used in oligosaccharide syntheses as anomeric leaving groups. They can also be applied under solid-phase conditions when the acceptor is attached to the resin. Glucose is bound to the solid support by functionalization of the anomeric center with a propanedithiol linker [ 2 ] . (l,G)-Glycosylationis achieved by selective deprotection of the primary hydroxyl group and coupling of the obtained polymer-bound acceptor 1

Tn'chloroacetirnidates as Sugar Donors

rp

S : & .Q + BnO

BnO

Donor (2)

+

BnO H 0 BnO

S

s

Y

S

BnO

O Y N H CCI,

Acceptor (1)

TMSOTf (0.2 eq.) CH2CI2,r.t.,1 h

- P

BnO Fig. 1. 1,6-Clycosylation with a glucose acceptor attached t o a polymer support (P = solid support) and a trichloroacetimidate donor.

with the trichloroacetimidate donor 2 (Figure 1). In the absence of neighboring group participation a 1:l mixture of anomers is obtained, which might be useful for combinatorial approaches. Linear oligosaccharides are produced by multiple repetition of the glycosylation step. Monitoring of the progressing solid-phase synthesis is achieved by partial cleavage of small samples from the resin and analysis by MALDI-TOF mass spectrometry. Controlledpore glass (CPG),well established in oligonucleotide chemistry, can be used as an inert solid support to avoid problems with different swelling behavior according to solvent and temperature [ 31. Trichloroacetimidates are similarly used for CI-( 1,2)-mannoside oligomerization, with an CIdiastereoselectivity arising from neighboring group participation [4]. The synthesis of mannosyl pentamer 3 with trichloroacetimidates was chosen to introduce a new alternative regarding the solid support (Figure 2) [S]. The anomeric center of the mannopyranosyl trichloroacetimidate donor 4 is attached to the polyethylene glycol-wmonomethyl ether (MPEG) through an cc,cc'-dioxyxylyl (DOX) diether linker and can be elongated by subsequent reaction cycles. With this resin, the advantages of coupling in homogeneous solution are thus combined with the separation of reagents by filtration, since the resin is soluble in CHzClz under glycosylation conditions and can be precipitated with ethanol [GI. Furthermore, analytical methods such as NMR spectroscopy and mass spectrometry can easily be applied [ 71. Solid-phase synthesis of branched oligosaccharides requires a specific protecting group strategy [8]. This is shown by the synthesis of branched lacto-N-neohexanose, occurring in human milk (Figure 3). The oligosaccharide is constructed by sequential glycosylation of trichloroacetimidates: starting with the resin-bound lactosyl donor 5, elongation of the saccharide with lactosamine G is followed by branching with glucosamine 7. Finally, attachment of galactose 8 provides the branched hexasaccharide [ 91.

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Hy* HO BnO

*oG : Donor (4)

O Y N H

I'

H HO F

q

CCI,

H k HO * t

*

HF*oH HO

0-DOX-MPEG

3 Fig. 2. Application of the polyethylene glycol-w-monomethyl ether (MPEC) solid support with an cc,cc'-dioxyxylyl (DOX) diether linker for oligosaccharide synthesis in solution.

At this point it may be mentioned that the use of different protecting group strategies has recently enabled numerous linkers to be synthesized [ 101, and automated syntheses of longer oligosaccharides performed [ 111. Oligosaccharide Synthesis with Clycosyl Phosphates

Together with trichloroacetimidates, glycosyl phosphates have proven to be easily availabie and effective glycosyl donors. The driving force in the phosphate activation is considered to be the stoichiometric release of silyl phosphate, initiated by addition of TMSOTf. The acceptor is generated by cleavage of the respective silyl protecting group with tetrabutylammonium fluoride (TBAF). As an example, the /?(l,G)-linked triglycoside 10 was synthesized on solid support with octenediol as a linker (Figure 4). This allows the release of the trisaccharide 11 simply by cross metathesis with Grubbs' catalyst [ 121. Glycosyl phosphates have also been applied in automated solid-phase synthesis, enabling the first automated synthesis of a branched oligosaccharide on a peptide synthesizer [ 131. As regards other anomeric leaving groups, further progress has been obtained with the recently published DISAL (methyl dinitrosalicylate) group, which allows Lewis acidpromoted glycosylations [ 141. Solid-phase oligosaccharide synthesis conditions have also been applied with analogues based on azasugars [15].

Solid-Phase Synthesis of Carbohydrate Libraries

AcO AcO OAc AcO

OAc OAc

OAc

Lacto-N-neohexanose

AcO

OAc

NDMM FmocO

AcO ~

o yOAcc c l .

+

+

OBn

NH

8

7

'n? /

6 Fig. 3.

OLev OBn

5

Retrosynthesis o f the branched lacto-N-neohexanose occurring in human milk.

Solid-Phase Synthesis of Carbohydrate Libraries

Glycosylation conditions are highly sensitive to structural differences in the glycosyl donors and acceptors, which is a particular problem in combinatorial chemistry; glycosylation methods with reliable yields and stereochemistry would be required. In this regard, glycosylation with anomeric sulfoxides is especially remarkable [ 161. Sulfoxide glycosyl donors are activated between -30 and -78 "C, to couple in nearly quantitative yield to sugar acceptors attached to a Merrifield resin. It is even possible to achieve stereochemical control, through participation by a neighboring C2 protecting group (Figure 5). The benzyl-protected glycosyl sulfoxide 12 is activated with trifluoromethanesulfonic acid and treated with a suspension of the polymer-bound sugar acceptor 13 in CHIC12 to yield disaccharide 14 with high Mselectivity. The yield can be increased by repeated coupling, an important advantage of solidphase syntheses. The high reactivity at low temperatures, even with a secondary alcohol, is remarkable and most probably due to the low polarity of reagents and resin. The completely protected pentapivaloyl galactosyl sulfoxide 15 yields the P-configured disaccharide 16 thanks to neighboring group participation in the coupling step. Overall, this approach allows access

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6,

p

I . TBAF 2. TMSOTf

TIPSOY

BnO 10

BnO

OPiv

TIPSO

V

11 Fig. 4. Synthesis o f a tetrasaccharide with glycosyl phosphates as sugar donors; cleavage of the oligomer from solid support by Crubbs' cross-metathesis.

both to the c( and to the p anomer, ensuring high yields even with less reactive acceptors in the heterogeneous environment of the solid support. New resins more suitable for the preparation of libraries have recently been reported [ 171. Polystyrylboronic acid can be prepared with high loading capacity; even more importantly, a solvent mixture of acetone and water can be used to reduced the amount of impurities after the cleavage step. Polystyrylboronic acid has proven to be especially useful for coupling of thioglycosides, for which trichloroacetimidates give only modest results. Orthogonal Clycosylation

In the oligosaccharide syntheses described so far, the glycosyl acceptors have been attached to the solid phase. In a second approach, the glycosyl donor is linked to the solid support

Orthogonal Clycosylation

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Bno@OBn OBn BnO

OBn

12

BnO

*

14

phT*s. p

N3

PivO

13

PivO

Ph

15 Fig. 5.

OPiv

N3

OPiv

s’

16

Clycosylation with anorneric sulfoxides as donors for an efficient and stereocontrolled synthesis.

[18]. The problems with this strategy are the accumulation of poorly separable side products on the resin and the need to activate the anomeric position before each coupling step. Orthogonal glycosylation and exclusively hydrophobic labeling of the desired sequence are used to overcome these problems (Figure 6). Orthogonal glycosylation is based on the alternating coupling of a thioglycoside 17 under Suzuki conditions ([ Cp2HfC12]-AgOS02CF3/ CH2C12) and a glycosyl fluoride 18 with MeOS02CF3and MeSSMe in CH2C12. The different reaction conditions ensure stepwise single glycoside coupling. Furthermore, there is no need for activation of the anomeric center by use of additional reagents. Hydrophobic labeling is provided by linkage of 2-(trimethylsily1)ethyl(SE) glycoside 19 in the final step, which facilitates the isolation of the desired oligomer 20. Subsequent conversion of the SE residue to a trichloroacetimidate is possible.

/ p

P

$;o q MeOSO,CF, MeSSMe

O ’

SMe

Fig. 6. Orthogonal glycosylation: the glycosyl donor is attached t o the solid support; alternating coupling with a thioglycoside and a glycosyl fluoride acceptor.

P

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Glycals in the Solid-Phase Synthesis of Oligosaccharides

In general, polymer-bound glycals are versatile building blocks that also offer interesting constitutional and configurational alternatives in oligosaccharide synthesis [ 191. This method provides the donor linked to the resin and needing to be activated for each coupling step. Side reactions are reduced by hydrolysis of the activated intermediates. Activation of the glycals, to generate appropriate donors, can be achieved either by epoxidation with 2,2dimethyldioxirane or by aminoglycosylation (Figure 7). Glycal 21, linked to a polystyrene support, is first oxidized to the epoxide 22, which then is opened in the presence of ZnClz by the glycal acceptor 23. This elongation step diastereoselectively yields the /3 anomer 24. Simultaneously, an oligosaccharide with a /I(1,6)-linkage and a new secondary hydroxyl group with further /I-galactosylacceptor reactivity is established. The glycal method therefore appears especially useful for the preparation of branched oligosaccharides. Donor activation by aminoglycosylation allows the simultaneous formation of /I(1,3)-, /I 1,4)-, ( or p( 1,6)-linked oligosaccharides and the introduction of a /I-amino functionality, OH

0’

0’

CHzCIz

21

24

Aminoglycosylation

P

P

P’ BnO& BnO

0’

0’ I(coll)zcIo, PhSOflH, I

-

LHDMS, EtSH, DMF

*

BnO 26

25

BnO

I

NHSOQh

NHSOPh

27 MeOTf,

Ten

0’

I

B 0n -0- BnO

BnO NHSOQh

Fig. 7.

BnO I

28

Activation o f resin-bound glycals by epoxidation followed by ring-opening or aminoglycosylation.

Enzyme-Catalyzed Solid-Phase Synthesis of Oligosaccharides

I

often found in oligonucleotides at position C2 [20]. The polymer-bound glycal 25 is treated with I( Coll)2C104 and PhSOzNHz to generate the diaxial iodosulfonamide 26, which rearranges after substitution with ethanethiolate to give the glycosyl donor 27. The b(1,4)linkage is selectively formed with glycal 28 in high yield. Furthermore, the glycal strategy is advantageous as the reductive end can easily be functionalized. N-Glycoproteins can be obtained if tetrabutylammonium azide is used instead of ethanethiolate in the aminoglycosylation. After reduction to the b-aminal, peptides can be attached via the side chain of the aspartic acid. Finally, the glycal strategy has been used to develop an analytical method for the characterization of reaction products and intermediates during oligosaccharide synthesis on solid support without the need to cleave small samples from the resin [21]. High-resolution magic-angle spinning (HR-MAS) N M R spectroscopy provides a line-width sufficient for the characterization of a trisaccharide glycal. The synthesis is performed on a polystyrene resin, which allows a high loading density. The constitution and configuration of the resin-bound oligosaccharide are confirmed by ‘H and 13C NMR and HMQC N M R correlation spectra. Enzyme-Catalyzed Solid-Phase Synthesis of Oligosaccharides

The combination of solid-phase synthesis and enzymatic catalysis still remains a challenge in the preparation of oligosaccharides [22]. The major advantages of enzymatic glycosylations are their high regio- and stereoselectivities, as well as the possibility of working without protecting groups. Possible problems arise from the limited availability of substrates and enzymes, the high substrate-specificity of enzymes, and compatibility with the solid support. The kind of polymer and its properties in aqueous solvents are as crucial as the linkage of the first saccharide unit and its enzyme accessibility. Furthermore, there seems to be an optimal loading density of the resin in order to obtain good yields from enzymatic conversions [22e]. As an example, the enzymatic elongation of glycopeptide 29 (tripeptide Boc-Asp-GlyPhe-OH with N-acetyl-D-glucosamine(GlcNAc) connected to the Asp-side chain) linked to a silica gel matrix is presented (Figure 8) [ 22al. A glycine heptapeptide functions as a linker, to which the glycopeptide is bound as an ester. Uridine 5’-diphosphogalactose (UDP-Gal) and ~-1,4-galactosyltransferase are applied for the elongation of the GlcNAc unit by one galactosyl monomer. In a second cycle, cytidine 5’-monophospho-N-acetylneuraminic acid (CMP-Neu-Ac)and a-2,3-sialyltransferase proved to be suitable to attach a neuraminic acid unit to disaccharide 30. Both enzymatic glycosylation steps are performed with satisfying yields and selectivities. Finally, glycopeptide 31 is released by cleavage of 32 with achymotrypsin. With a( 1,4)-galactosyltransferase (LgtC), an oligosaccharide with a &-a( 1-4) linkage, usually difficult to obtain, can be prepared chemoenzymatically on solid support (Figure 9) [ 231. A lactosyl derivative attached to a poly(ethy1ene glycol) support through a dioxyxylene linker (33) can be stereoselectivelylinked to a galactosyl donor to form the problematic cis linkage. The advantage of a stereoselective enzymatic reaction is combined with simple purification methods. This chemoenzymatic synthesis afford the resin-bound trisaccharide 34, which is of special interest because of its potential binding to verotoxin-1 [24]. Further progress has recently been reported in the fields of solid supports in chemoenzymatic synthesis [22, 251 and of the use of enzyme-labile linker groups for the prepara-

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,)i,

BocNH

~

HOHO

7iJo7

NH-(Gly),-NH-Silica

NH

O

NHAc

H

O

W

:

&

o

i

&

29

'0"

H

YO NH

AcNH

HO HO

bH

NHAc

OH

YO NH

AcNH OH

Fig. 8. Enzymatic glycosylation i n the solid-phase synthesis of oligosaccharides: elongation of the glycopeptide with /J'-1 ,4-galactosyltransferase and a-2,3-sialyltransferase. The glycopeptide i s finally released by cleavage with wchymotrypsin.

tion of oligosaccharides [ 261. However, it remains uncertain whether the availability and the applicability of enzymes can keep up with the large diversity of synthetic problems in oligosaccharide synthesis. The use of enzymes in solid-phase synthesis opens a viable and efficient alternative to well known classical procedures and adds to the arsenal of synthetic methods.

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Solid-Phase Synthesis of Oligosaccharides Synlett 1999, 1802-1804; d) SeleniumH. J. based linker: K. C. NICOLAOU, MITCHELL, K. C. FYLAKTAKIDOU, et al., Angew. Chem. 2000, 112, 1089-1093; e) Y. NAKAI, Ether-type linker: K. FUKASE, K. EGUSA,et al., Synlett 1999, 1074-1078. X. W u , M. GRATHWOHL, R. R. SCHMIDT, Org. Lett. 2001, 3, 747-750; f ) Wang-type Y. NAKAHARA, Y. ITO, linker: S. MANABE, Synlett 2000, 1241-1244. S . MANABE, Y. ITO, Chem. Pharm. Bull. 2001, 49, 1234-1235; g) Amine-type linker: N. DRINNAN,M. L. WEST,M. BROADHURST, et al., Tetrahedron Lett. 2001, 42, 11591162. 1 1 a) J. RADEMANN, R. R. S C H M I D T ,Org. ~.

12

13

14 15 16

17

18

Chem. 1997, 62, 3650-3653; b) L. G. MELEAN, W.-C. HAASE,P. SEEBERGER, Tetrahedron Lett. 2000, 41, 4329-4333; c) 0. J. PLANTE,E. R. PALMACCI, P. H . Science 2001, 291, 1523SEEBERGER, 1527. a) R. B. ANDRADE, 0. J. PLANTE,L. G. MELEAN, et al., Org. Lett. 1999, I , 18111814; b) for general review see: E. R. PALMACCI, 0. J. PLANTE,P. H. SEEBERGER, Eur. J. Org. Chem. 2002, 595-606. a) M. C. HEWITT,P. H. S E E B E R G E ROrg. ,~. Chem. 2001, 66,4233-4243; b) M. C. HEWITT,P. H . SEEBERGER, Org. Lett. 2001, M. C. 3, 3699-3702; c) E. R. PALMACCI, Angew. Chem. HEWITT,P. H . SEEBERGER, 2001, 113, 4565-4569. L. PETERSEN, K. J . JENSEN,J.Chem. Soc., Perkin Trans. 12001, 2175-2182. B. RUITENS,J.VAN D E R EYCKEN, Tetrahedron Lett. 2002, 43, 2215-2221. a) R. LIANG,L. YAN,J. LOEBACH, et al., Science 1996, 274, 1520-2522; b) L. YAN, C. M. TAYLOR, R. GOODNOW, JR., et al., J. Am. Chem. SOC.1994, 116, 6953-6954; c) D. KAHNE,Curr. Opin. Chem. Biol. 1997; 1, 130-135. a) G. BELOGI,T. ZHU, G.-J. BOONS,Tetrahedron Lett. 2000, 41, 6965-6968; b) G . BELOGI,7.ZHU, G.-J. BOONS,Tetrahedron Lett. 2000, 41, 6969-6972. a) Y. ITO, 0. KANIE,T. OGAWA,Angew. Chem. 1996, 108, 2510-2512; b) 0. KANIE, Y. ITO,T. OGAWA,].Am. Chem. SOC.1994, 116, 12,073-12,074.

19 a) S. J.DANISHEFSKY, K. F. MCCLURE, J. T.

RANDOLPH,et al., Science, 1993, 260, 1307-1309; b) J. T. RANDOLPH, K. F. MCCLURE,S. J. DANISHEFSKY, /. Am. Chem. SOC.1995, 117, 5712-5719; c) P. H. SEEBERGER, S. J. DANISHEFSKY, Acc. Chem. Res. 1998, 31, 685-695; d) S. J. DANISHEFSKY, M. T. BILODEAU, Angew. Chem. 1996, 108, 1380-1419; e ) P. H . SEEBERGER, M. T . BILODEAU, S. J. DANISHEFSKY, Aldrichimica Acta 1997, 30, 75-92; f ) C . Z H E N G ,P. H . SEEBERGER, S. J. DANISHEFSKY, /. Org. Chem. 1998, 63, 1126-1130. 20 C. ZHENG,P. H . SEEBERGER, S. J. DANISHEFSKY, Angew. Chem. 1998, 110, 786-789. 21 P. H . SEEBERGER, X. BEEBE,G. D. SUKENICK, et al., Angew. Chem. 1997, 109, 491-493. 22 a) M. SCHUSTER, P. WANG,J. C. PAULSON, et al.,J. A m . Chem. SOC.1994, 116, 1135H. HUANG,C.-H. 1136; b) R. L. HALCOMB, WONG,J. Am. Chem. SOC.1994, 116, 11,315-11,322; c) S.-I. NISHIMURA, K. MATSUOKA, Y. C. LEE, Tetrahedron Lett. 1994, 35, 5657-5660; d) S.-I. NISHIMURA, K. B. LEE, K. MATSUOKA, et a]., Biochem. Biophys. Res. Commun. 1994, 199, 249254; e) K. YAMADA,E. FUJITA,S.-I. NISHIMURA, Carbohydrate Res. 1998, 305, 443-461; f ) M. MELDAL,F.-I. AUZANNEAU, 0. HINDSGAUL, et al.,J. Chem. SOC.Chem. Commun. 1994, 1849-1850; g) N. BRINKM A N NM. , MALISSARD, M. RAMUZ,et al., Bioorg. Med. Chem. Lett. 2001, 11, 25032506; h) for a review of enzymes in glycoL. L. KIESSLING, biology, see C. R. BERTOZZI, Science 2001, 291, 2357-2364. 23 F. YAN,M.GILBERT, W. W. WAKARCHUK, et al., Org. Lett. 2001, 3, 3265-3268. 24 a) P. I. KITOV,J. M. SADOWSKA, G. MULVEY, et al., Nature 2000, 403, 669; b) E. FAN,E. A. MERRITT,C. L. M. J. VERLINDE, et al., J. Curr. Opin. Struct. Biol. 2000, 10, 680-686. 25 S. NISHIGUCHI, K. YAMADA, Y. FUJI,et al., Chem. Commun. 2001, 1944-1945. 26 For general review, see R. REENTS,D. A. JEYARAJ, H . WALDMANN, Advan. Synth. Catal. 2001, 343, 501-513.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co I395

Polymer-Supported Synthesis o f Non-Oligomeric Natural Products Stefan Sommer, Rolf Breinbauer, and Herbert Waldrnann

Introduction

The continued quest for new medicines to cure discomfort and diseases coupled with man’s intrinsic curiosity to reveal nature’s hidden secrets provide a powerful motivation for research in the life sciences. The last decades have produced a tremendous gain in understanding the cell at its molecular level, which has led to the identification of a great number of new biological targets (in most cases proteins), that are involved in numerous diseases, including cancer, Alzheimer’s disease, AIDS, and heart failure. In order to cure these diseases new drugs, preferentially small organic molecules, are needed which inhibit or promote the target’s biological function and, in the ideal case, avoid side effects with perfect selectivity [ 11. The chemists’ solution for these demands is combinatorial chemistry, which has become an invaluable tool to meet this challenge. Solid-phase synthesis techniques applied either in a parallel fashion in automated synthesis or in split-pool-synthesis enable the rapid production of compound libraries containing thousands of members. But the original expectation that new hits will be discovered solely by the creation of a large quantity of library members was not fulfilled. Some of the libraries contained hardly any hit, because the underlying structures therein were not biologically relevant. Thus an old question returned Where in the almost indefinite space of thinkable chemical compounds are the structures which are of biological relevance [2]? Natural products have been identified as the active principle of herbs and extracts used in folk medicine [ 11. The importance of natural products in the pharmaceutical industry has continued to the present day and is reflected by the fact that close to half of the best selling pharmaceuticals are either natural products (e.g. cyclosporine, Taxol, FK 50G) or derivatives thereof [ 31. In high throughput screening processes performed by the pharmaceutical industry natural product extracts exhibit a hit rate which is estimated to be substantially higher than the hit rate of random libraries from combinatorial chemistry. Natural products such as epothilones, discodermolide or ecteinascidin are promising clinical candidates for future cancer treatment. Despite this proven record of biological significance there had been some doubts if natural products are suitable and accessible lead structures for combinatorial libraries by solid-phase synthesis. In contrast to the diversity-oriented approach of library design, which is driven by the underlying chemistry of reliable reactions with broad substrate scope [4], natural product

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library synthesis requires multi-step sequences requiring careful optimisation, which ultimately lead to the chosen target structure (focused library). This extra-mile in synthetic effort should be rewarded by a higher hit rate in biological screens and what would be even more significant: biologically validated hits. Recent results of protein sequencing, structural biology and bioinformatics have revealed an interesting pattern. Proteins can be regarded as modularly built biomolecules assembled from individual building blocks. These building blocks are called ‘domains’, parts of the proteins that fold independently from the rest of the structure to a compact arrangement of secondary structures and that are connected via linker peptides [S]. Although the estimate for the number of different proteins in humans range between 100,000 and 450,000, there is a common agreement that the number of domains and - even more - of topologically distinct folds will be much smaller. At present approximately 600 folds are known [ 6 ] ,and it is estimated that the number of existing folds are between 600 and 8000 distinct folds, and 4000-GOO00 sequence families [7]. Up to the present day it is unknown if the limited number of folds is due to physico-chemical constraints on stable folds or a result of the evolutionary process which has not fully explored all possible sequence combinations. Natural products have been selected by evolution to bind to these distinct protein domains. Considering that the small molecule has been biosynthesized by enzymes and that it exerts its biological function by addressing a specific target protein, most natural products have interactions with at least two different proteins. Considering that nature uses these protein domains for different biological purposes over and over again, there is a significant probability that natural products are privileged structures [ 8 ] . This term has been coined by medicinal chemists for small molecule scaffolds which bind to several proteins but with different biological functions [ 91. Benzodiazepines are a foremost example for such structures. Based on these assumptions one can reason why one should not only synthesise the natural product itself but a library thereof: the fine-tuning of substituents and variation of the molecular framework will allow for the requirements of different binding pockets and the desired selectivity to distinguish between similar protein domains. Additionally, it should be taken into account that natural products which are descended from marine or tropical sources are not optimised by nature for human cells, i.e. the fine work for getting better selectivity and less side reactions is due to pharmacological and combinatorial chemistry. Paramount to the success of this approach is that efficient and reliable methods and multistep sequences for the total synthesis of natural products and analogues thereof on polymeric supports are available. The corresponding transformations must proceed with a degree of selectivity and robustness typical of related classical solution phase transformations, irrespective of the stringencies and differing demands imposed by the anchoring to the polymeric support. Only recently the progress in solid-phase synthesis has met the demands of the intrinsic complexity of natural product library synthesis on solid support [lo]. The aim of this chapter is to describe the different approaches followed in this science and to highlight these with notable examples demonstrating the current state of the art. Solid-Phase Synthesis o f Natural Products

Two strategies have emerged for the synthesis of natural-product-like libraries on solid. The first involves building the entire core structure on solid support, a very challenging proposi-

Solid-Phase Synthesis of Natural Products

tion, since it often requires a multi-step synthesis applying a large range of organic reactions and often leads to the demand for the development of new methods. However, it allows maximum diversity in the core structure (e.g. ring size, chain length), by both variation of stereochemistry as well as the introduction and derivatisation of functional groups. In the second approach, a natural product skeleton is immobilised onto a solid support to facilitate installation of diversity. While the scaffold remains unchanged, building blocks are attached to already existing functional groups. Therefore, the core structure must already be validated by the biological target and the precursor molecule should be easily accessible either from natural sources, degradation chemistry or solution phase total synthesis. Furthermore, an appropriate site on the scaffold for attachment onto solid support must be identified to facilitate reliable loading and release, as well as installation of the most possible structural diversity. While the second strategy provides the advantage that nearly each step on solid support leads to diversification, the first one often requires considerable effort just to build up the scaffold. Modification of Core Structures

For building up a library around a given core structure many examples have been given, e.g. an Indolactam library by Waldmann et al. [ll],a Sarcodictyin-basedlibrary by Nicoloau et al. [ 121 and a Taxoid library by Xiao et al. [ 131

R3

Sarcodictyin - library

Indolactam - library

OBz

OAc

Taxoid - library Fig. 1. Examples of natural product libraries by modification of core structures

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Polymer-Supported Synthesis of Non-Oligomeric Natural Products

A recent example for this strategy is the combinatorial synthesis of macrolide analogues based on Erythromycin A by Akritopoulou-Zanze et al. which is outlined below [ 141. Erythromycin A is an important antibiotic used for the treatment of gram-positive bacteria; however, it is partially deactivated in the stomach due to the strongly acidic conditions. As a result, efforts have been made to improve the acid stability and hence increase the bioavailability by means of combinatorial chemistry. The synthesis by Akritopoulou-Zanze et al. is the first synthesis of a macrolide library on solid support (Scheme 1). The precursor molecule 1 was made in solution employing a 6-step synthetic sequence starting from 6-0-Allyl-Erythromycin.Macrolide 1 was attached to solid support with reductive amination to a pre-bound aminoacid ( R l ) (2). The resulting amine was then condensed with a second aldehyde (R2) to afford an intermediate tertiary amine. Deprotection of the side chain primary amine off the oxazolidinone moiety and reductive amination with another aldehyde (R3) afforded compound 3. Acidic cleavage from the solid support delivered the macrolide analogues (4) in high purity with reasonable to good yields. This synthesis can be considered as classical for the core functionalization strategy since only a limited number of methods are applied several times affording a good ratio of number of synthetic steps compared to the number of building blocks brought in. Thus, high yields and high purity are achieved through well optimised reactions. Another classical aspect is the choice of building blocks, which are readily available in a large variety. Synthesis of Scaflolds

Epothilones are natural products isolated from myxobacteria, which have been found to exhibit cytotoxic activity against Paclitaxel-resistent tumor cell lines, by inducing tubulin polymerisation. The successful synthesis of epothilone A by the Nicolaou group, represents a landmark in the solid-phase synthesis of complex molecules on solid support [15]. A polymer-bound Wittig ylide 5 was further elaborated by reaction with building blocks 6 , 7, 8 via an olefination reaction, an aldol reaction, and an esterification (Scheme 2). In the next step the macrocyle 9 was formed from the acyclic precursor through a ring-closing olefin metathesis reaction mediated by Grubbs’ catalyst liberating the substrate from solid support. This cyclorelease strategy pioneered by Rapoport offers the additional advantage that only molecules which undergo the desired transformation will be found in the cleavage solution [ 161. After deprotection and epoxidation of the less substituted double bond in solution epothilone A (10) was isolated. It deserves special attention that this example demonstrated for the first time the principal feasibility of multi step natural product synthesis on solid support. In a subsequent paper Nicolaou et al. prepared a library of further analogues, which helped to establish structure-activity relationships of this compound class [15b]. Prostaglandines play a prominent role in a wide variety of physiological processes and exhibit a very subtle structure-activity relationship, which make them a target for combinatorial chemistry of highest interest and significance. The group of J. A. Ellman has disclosed the solid-phase synthesis of a 26-member library of prostaglandin E l analogues (11).After modification of the core structure 12 via Suzuki-coupling with building block 13, the relative stereochemistry of the two carbons bearing the side chains was set by a diastereoselective Michael addition of a higher order cuprate 14 across the enone 15 (Scheme 3) [ 171.

Solid-Phase Synthesis of Natural Products

E

5

I

399

400

I

Polymer-Supported Synthesis of Non-Oligomeric Natural Products

no '

TBSO

ow

6

pph3

- woT H

THF, 0 "C, 3 h 5

OTBS

1) HF*pyridine, RT, THF 0 OTBS

2) Swern-oxidation

0

OH *& ' OH

8

\\+'

DCC. DMAP. RT 0 OTBS

r T

0

0 OTBS

Hog,

0

\\\+

0

I H

O

\\\"

Grubbs catalyst CH2C12, RT

W

0

1) 20% TFNDCM

OH

0

0 OTk

10

epothilon A Scheme 2.

0

:

&

0

9

+ 3 Isomers

Total synthesis of epothilon A on solid-phase by Nicolaou et al.

Waldmann et al. have synthesised a library of analogues of the anti-tumor active phosphatase inhibitor dysidiolide (16) [18]. A notable feature of this 11-step reaction sequence on solid-phase is that a wide range of transformations with vastly differing requirements could successfully be developed. Key transformations of the synthesis include an asymmetric

Solid-Phase Synthesis of Natural Products

OTMT

OTMT Y

&

Et

Pd[PPh&

I

Na2C03,THF

Et

si - 0" Et

12

1) 1 M HCOOH, DCM 2) Dess-Martin-oxidation

0

1) HF*pyridine

2) TMSOMe

11

26 prostaglandin El analogs Scheme 3.

Synthesis o f a prostaglandine library by Ellman et al.

Diels-Alder reaction with chiral dienophile 17, and an oxidative elaboration of furan 18 with singlet oxygen on solid-phase, as well as the traceless cleavage of the products via olefin-metathesis from the support (Scheme 4).The sequence rapidly yielded access to eight analogues of the natural product and led to the identification of a potent inhibitor of the cell-cycle-controlling phosphatase cdc25c which displays a very promising selectivity pattern. Shair et al. have produced a 2527 membered libarary based on the alkaloid natural product galanthamine using an elegant biomimetic oxidative cyclisation reaction (Scheme 5) [ 191. Starting from a tyrosine-derivative (19) attached onto solid support via an acid labile silylether linkage, adduct 21 was synthesized after coupling of building block 20 via reductive amination. In the following key step a PhI(OAc)2 mediated oxidative cyclisation produced the spiroazepine. The newly generated dienone 22 was further elaborated via two Michaeladditions involving an internal phenolate- and external S-nucleophile. Further 0- and Nalkylation, and imine formation of the keto-group enabled the introduction of four different

I

401

402

I

Polymer-Supported Synthesis of Non-Oligomeric Natural Products

THF, RT

1) PTSA, acetone, DCE 2) (Ph3PCH20Me)CI

KOt-Bu. THF

17

3) n-BuLi

TMSOTf, DCM, -78 "C 0

c"

-; i 1) 02,DIPEA, bengal rose

O

-

7

2) Grubbs' hv, -78 "C catalyst

= H

HO

OH

0

0 16

6-epi-dysidiolide (9 analogs) Scheme 4.

Synthesis of a library of analogs of 6-epi-dysidiolide by Waldmann et al.

diversity elements. After cleavage from solid support and biological screening of library 23, a library member was identified that perturbs the secretory pathway in mammalian cells - a process unrelated to the acetylcholine esterase inhibitory activity of the lead structure galanthamine. By its clever combination of scaffold building and subsequent modification, in which each synthetic step contributes to the overall diversity of the library, the galanthaminelibrary by the Shair group has set a benchmark for future library design.

Solid-Phase Synthesis of Natural Products

I

OH

1 CH(OCH& then NaBH3CN, MeOHflHF 2) allylchloroformate, DIPEA 3) piperidine, THF

si

?

OH

I \

ip;

+

iPr

-0

19

CHO

IP

20

1

hl(O A C ) ~

k 1) R%H 2) R3CH0, AcOH then NaBH3CN or R3COCI, 2,6-lutidine

Br&y 0

22

N

P

R4

1) R4NH2,AcOH 2) HF*pyridine

0I

OH \

R'

R3

R3

23 Scheme 5.

Synthesis o f a library of galanthamine analogues by Shair et al.

403

404

I

Polymer-SupportedSynthesis of Non-Oligomeric Natural Products

Privileged Structures

The concept of privileged structures is based on common structural motifs that are capable of interacting with a variety of seemingly unrelated biomolecular targets. Many successful libraries based upon structural types such as these have been made, e.g. libraries of benzodiazepines, benzoazepines, benzamidines, biphenyltetrazoles, spiropiperidines, indoles and benzylpiperidines. This concept was applied in a recent work by Nicolaou et al. constructing a 10,000-membered natural-product-like library based on the 2,2-dimethylbenzopyran [ 201. The benzopyran motif can be found in more than 4000 compounds including many bioactive natural products and pharmaceutically designed compounds, and it is therefore an excellent choice for combinatorial derivatisation.

R4 R3

25

[6-endo-frig]

1

Elaboration

R4

J

26 H202

27 Scheme 6. Cycloloading and elaboration strategy for benzopyran synthesis according to Nicoloaou et al.

Solid-Phase Synthesis of Natural Products

For the synthesis of the 2,2-dimethylbenzopyran loading and cleavage steps were chosen in a way that they already contribute to the complexity of the target structure, i.e. operations which do not serve the complexity built up of the structure are reduced (usually loading and cleavage) and the efficiency of the combinatorial synthesis is increased (Scheme G).

R4

R4

I

R4

Glycosidation

Annulation

Addition

$-

R4

Scheme 7.

Functionalisation of a benzopyran scaffold.

I

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Polymer-Supported Synthesis of Non-Oligomeric Natural Products

Nicoloau used a polystyrene-based selenyl bromide resin (24), which can be used to load substrates by electrophilic cyclisation reactions. In this case ortho-prenylated phenol 25 reacted with the selenyl bromide (24) to form the benzopyrane scaffold (26) via a 6-endo-trig cyclisation. The high chemical stability of the pyran linked via the seleno ether bridge allowed further elaborations on all four possible positions on the aromatic ring such as annulations, condensations, aryl/vinyl couplings, glycosidations and organornetallic additions (Scheme 7). Finally, the benzopyran analogues were released by oxidation of the selenide followed by syn-elimination furnishing the benzopyrans 27. Since certain chalcones are known to interrupt mitochondria1 electron transport by inhibition of NADH:ubiquinone oxidoreductase (complex I) a chalcone-based library was synthesised by parallel synthesis (Scheme 7). Among the first round 39 library members there were already 4 natural products and several compounds with high potency in inhibition of NADH:ubiquinone oxidoreductase. Encouraged by this success a 10,000-membered natural product-like library was constructed by directed split-and-pool techniques employing the NanoKan optical encoding platform. Such an advanced encoding technique allowed the whole project to be automated. But still all applied reactions needed a high degree of optimisation and building blocks were especially chosen to couple to the attached scaffold in high yield and to reach the goal of high purity (often >go%). An automated cleavage protocol employing hydrogen peroxide furnished 2-3 mg quantities of each library member. Biological testings in 96-well microtiter plates led to the identification of a novel structural class of antibacterial agents and a series of potent inhibitors of the NADHxbiquinone oxidoreductase enzyme. It should be mentioned that the Nicolaou group applied the libraryfrom-library concept which implied the construction of a second library from cleaved 2,2dimethylbenzopyrans by solution phase combinatorial chemistry. Conclusion

The ongoing progress in the development of solid-phase techniques, including reaction design and automation, has enabled the multi-step synthesis of complex synthetic targets on solid-phase. The examples above illustrate the structural complexity of natural product molecules which is already accessible by current methods. It can be anticipated that in the future even more challenging and demanding synthetic goals will be successfully accomplished. Considering the proven biological relevance of natural products these structures should be paid more attention for the design of future combinatorial libraries. New genome and proteome sequence data combined with the tool of bioinformatics will assist the chemist in the selection of both the synthetic and biological target [21].Future libraries will also be measured by their design, in which as many steps as possible in the multi-step-sequence should contribute to the diversity of the library. References J. DREWS,Science 2000, 287, 1960-1964; b) G. WESS, M. U R M A N NB. , SICKENB E R G E R , Aagew. Chem. Int. Ed. 2001, 40, 3341-3350.

1 a)

2

R. S. BOHACEK,C. MCMARTIN,W. C. GUIDA,Med. Res. Ren 1996, 16, 3-50; b) H. C. KOLB,M. G. F I N N , K. B. SHARPLESS, Angew. Chem. Int. Ed. 2001, 40, 2004-

References I 4 0 7

2021. For a discussion about the problem of diversity in combinatorial libraries, see S. R. KLOPFENSTEIN, c) A. GOLEBIOWSKI, D. E. PORTLOCK,Curr. Opin. Chem. Biol. 2001, 5, 273-284; d) J. S. MASON,M. A. Cur. Opin. Chem. Biol. HERMSMEIER, 1999, 3, 342-349; e) J. M. BLANEY, E. J. MARTIN,Curr. Opin. Chem. Biol. 1997, 1, 54-59; f ) R. W. SPENCER,Biotechnol. Bioeng. 1998, 61, 61-67. 3 a) For an outstanding analysis of the role of natural products in pharamceuticals, see C. M. CRAGG,D. J. NEWMAN,K. M. SNADER, /. Nat. Prod. 1997, 60, 52-60; b) T. H E N K E LR., M. BRUNNE,H. MULLER, F. REICHEL,Angew. Chem. lnt. Ed. 1999, 38, 643-647; c) Y.-Z. SHU,/. Nat. Prod. 1998, 61, 1053-1071; d) D. G. I. KINGSTON in “The Practice of Medicinal Chemistry”, C. G . WERMUTH(Ed.), Academic Press: London, 1996. 4 For an excellent account of this concept and its conceptual difference to targetoriented synthesis, see a) s. L. SCHREIBER, Science 2000, 287, 1964-1969. For some notable examples of this approach, see b) D. S. TAN,M. A. FOLEY,B. R. STOCKWELL, M. D. SHAIR,S. L. SCHREIBER, /. Am. Chem. SOC.1999, 121,9073-9087; c) D. LEE,J. K. SELLO,S. L. SCHREIBER, /. Am. Chem. SOC. 1999, 121, 10648-10649; recent review article: d) R. ARYA,M.-C. BAEK, CUT. Opin. Chem. Biol. 2001, 5, 292-301. 5 a) M. WEIR,M. SWINDELLS, J. OVERINGTON, Trends Biotechnol. 2001, 19, S61-S66; b) C. P. PONTING,J . SCHULTZ, R. P. COPLEY,M. A. ANDRADE, P. BORK, Adu. Protein. Chem. 2000, 54, 185-244. 6 SCOP database: A. G . MURZIN,S. E. BRENNER, T. HUBBARD, C. CHOTHIA,/. Mol. Biol. 1995, 247, 536-540. 7 a) C. CHOTHIA,Nature 1992, 357, 543544; b) P. GREEN,D. LIPMAN,L. HILLIER, R. WATERSTON, D. STOBES,J. M. CLAVERIC, Science 1993, 259, 1711-1716; c) Y. I. WOLF,N. V. G R I S H I NE. , V. KOONIN,J . Mol. Biol. 2000, 299, 897-905. 8 R. BREINBAUER, I. R. VETTER,H. WALDMANN, Angew. Chem. Int. Ed. 2002, 41, 2878-2890 9 B. E. EVANS,K. E. RITTLE,M. G. BOCK, R. M. DIPRADO,R. M. FREIDINGER, W. L. WHITTER,G. F. LUNDELL, D. F. VEBER, P. S. ANDERSON, R. S. L. CHANG,V. J.

L o r n , D. J. CERINO,T. B. CHEN, P. J. KLING,K. A. KUNKEL,J. P. SPRINGER, J. HIRSHFIELD, /. Med. Chem. 1988, 31, 2235-2246. 10 For a recent and comprehensive review of solution-phase and solid-phase synthesis of natural product libraries, see a) D. G. HALL,S. MANKU,F. WANG,]. Comb. Chem. 2001, 3, 125-150; b) L. WESSIOHANN,Curr. Opin. Chem. Biol2000, 4, 303-309; c) L. J. WILSONin “Solid-Phase Organic Synthesis”, K. BURGESS (Ed.), Wiley-Interscience: New York, 2000 d) C. WATSON,Angew. Chem. Int. Ed. 1999, 38, 1903- 1908. 11 B. MESEGUER, D. ALONSO-DIAZ, N. GRIEBENOW, T. HERGET,H . WALDMANN, Angew. Chem. Int. Ed. 1999, 38, 29022906. 12 K. C. NICOLAOU, N. WINSSINGER, D. VOURLOUMIS, T. OHSHIMA,S. KIM, J. PFEFFERKORN, 1. Y. Xu, T. LI,J. Am. Chem. SOC.1998, 120, 10814-10826. 13 Y.-X. XIAO, Z. PARANDOOSH, M. P. NOVA, /. Org. Chem. 1997, 62, 6029-6033. 14 I. AKRITOPOULOU-ZANZE, T. J. SOWIN,/. Comb. Chem. 2001, 3, 301-311. 15 a) K. C. NICOLAOU, N. WINSSINGER, J. PASTOR,S. NINKOVIC,F. SARABIA, Y. H E , Z. YANG,T. LI, P. D. VOURLOUMIS, GIANNAKAKOU, E. HAMEL,Nature 1997, 387, 268-272; b) K. C. NICOIAOU,D. VOURLOUMIS, T. LI, J. PASTOR,N. WINSSINGER, Y. H E , S. NINKOVIC,F. SARABIA, H. VALLBERG, F. ROSCHANGAR, N. P. KING, M. R. V. FINLAY,P. GIANNAKAKOU, P. VERDIER-PANARD, E. HAMEL,Angew. Chem. lnt. Ed. 1997, 36, 2097-2103. 16 a) J. I. CROWLEY, H. RAPOPORTJ. Am. Chem. SOC.1970, 92, 6363-6365; notable applications: b) K. C. NICOLAOU,N. WINSSINGER, J. PASTOR,F. MURPHY, Angew. Chem. Int. Ed. 1998, 37, 25342537; c) S. C. SCHURER,S. BLECHERT, Synlett 1999, 879-1882; review: d) 0. SEITZ,Nachr. Chem. 2001, 49, 312-316. 17 a) L. A. THOMPSON, F. L. MOORE,Y.-C. MOON,1. A. ELIMAN,/. Org. Chem. 1998, 63, 2066-2067; b) D. R. DRAGOLI,L. A. THOMPSON, J. O’BRIEN,J. A. ELLMAN, /. Comb. Chem. 1999, 1, 534-539; for a soluble supported synthesis of a prostanoid library and the screening

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thereof for antiviral activity, see c) K. J. LEE,A. ANGULO,P. GHAZAL,K. D. JANDA, Org. Lett. 1999, 1, 1859-1862. 18 D. BROHM,S. METZGER, A. BHARGAVA, 0. MULLER,F. LIEB,H. WALDMANN, Angew. Chem. Int. Ed. 2002, 41, 307-311. 19 a) H. E. PELISH,N. J. WESTWOOD, Y. FENG,T. KIRCHHAUSEN, M. D. SHAIR, J . Am. Chem. SOC.2001, 123, 6740-6741; b) for an earlier beautiful example of a biomimetic heterodimerization in the synthesis of carpanone library; see C. W. LINDSLEY, L. K. CHAN,B. C. GOES, R. JOSEPH,M. D. SHAIR,J . Am. Chem. SOC. 20

2000, 122,422-423. A discussion to the concept of natural product-like combinatorial libraries based on privileged structures and an impressive experimental proof of concept has been disclosed by the Nicolaou group: a) K. C.

NICOLAOU, J . A. PFEFFERKORN, A. J. ROECKER, G.-Q. CAO, S. BARLUENGA, H. J. MITCHELL, J . Am. Chem. Soc. 2000, 122, 9939-9953; b) K. C. NICOLAOU, J. A. PFEFFERKORN, H. J. MITCHELL,A. J . ROECKER, S. BARLUENGA, G.-Q. CAO, R. L. AFFLECK, J. E. LILLIG,1.Am. Chem. SOC. 2000, 122, 9954-9967; c) K. C. NICOLAOU, J. A. PFEFFERKORN, S. BARLUENGA, H. J. MITCHELL,A. J. ROECKER, G.-Q. CAO,/. Am. Chem. SOC. 2000, 122, 9968-9976; for a review see: K. C. NICOLAOU. J. A. PFEFFERKORN, Biopolymers 2001, 60, 171-193. 21 For an excellent review of chemogenomic approaches to drug discovery, see P. R. CARON,M. D. MULLICAN,R. D. MASHAL, K. P. WILSON,M. S. Su, M. A. MURCKO, Curr. Opin. Chem. B i d . 2001, 5, 464470.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Explosions as a Synthetic Tool? Cycloalkynes as Precursors to Fullerenes, Buckytubes and Buckyonions Rijdiger Faust

Why would anyone attempt to synthesize fullerenes from elaborate precursors if all it takes is graphite and a suitable energy source like a strong electric field or laser power? One of the answers to this somewhat unfair question bears a certain philosophical charme reminiscent of the motto that the way is the goal. And indeed, only in 2002, twelve years after its initial isolation [ 11, Scott et al. reported on a rational chemical synthesis of buckminsterfullerene c 6 0 in twelve steps from commercially available 1-bromo-4-chlorobenzene [ 21. Of course, the benefit of the synthetic methodology developed to obtain carbon-rich materials in a rational fashion is multitudinous and undisputed [3-6]. But there is more. Firstly, research on endohedral fullerene complexes and metal-filled nanotubes [7, 81, in many ways the most exciting and the most unprecedented aspect of fullerene chemistry and physics, is severely limited due to the low yields encountered in their preparation. A promising approach to improve this situation lies in the development of synthetic strategies towards these molecules. Secondly, knowledge about crucial stages of the fullerene formation process and about the rules that govern the observed product distribution remains rather sketchy [9, lo]. The design of more sophisticated fullerene precursors may allow the investigation of this process under conditions that are more controllable than the chaotic plasma of carbon atoms at ca. 3000 K. Strained cycloalkynes are attractive starting materials for the energy-induced transformation of carbon-rich materials to fullerenes or related structured forms of carbon. In ideal cases, the high energy content of a given cycloalkyne can lead to the coalescence of the cyclic structure to a thermodynamically more stable carbon sphere. Furthermore, incorporation of benzenoid substructures into cycloalkynes offers the opportunity to coordinate metal fragments, thereby providing a synthetic entry to endohedral fullerene complexes. Significant progress towards these goals has been made and a selection of the (therm0)chemistry of new dehydrobenzoannulenes and alkyne-based cyclophanes is highlighted in the following. First evidence for the feasibility of a cycloalkyne-to-fullereneconversion has been produced by Diederich et al. [ 11-13] shortly before macroscopic quantities of buckminsterfullerene c60 1 were available [ 1, 141. In Fourier-transform laser-desorption mass spectrometric (FTLD-MS) experiments they observed that cations of cyclo-C30 2 undergo an efficient ionmolecule coalescence to give fullerene ions such as 1+ (Scheme 1).

410

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Explosions as a Synthetic Tool? Cycloalkynes as Precursors to Fullerenes, Buckytubes and Buckyonions

I

0

0

T

Explosions as a Synthetic Tool? Cycloalkynes as Precursors to Fullerenes, Buckytubes and Buckyonions

In a related series of experiments, cyclic cationic carbon structures like 3 (depicted in symmetry, Scheme 1)were also shown to rearrange to spherical C60 ions [15-171. However, the preparation of bulk quantities of the neutral cyclocarbons and hence that of the fullerenes from these precursors remains elusive [ 181. More recent developments exploit the energy content of readily accessible cycloalkynes based on phenyl-alkynyl structural motives, albeit not always with fullerene formation in mind. For example, the strained dehydrobenzoannulene 4 [ 191 could be converted by light, heat (145 “C), or pressure (20000 psi) in a topochemical polymerization reaction typical for butadiynes to a deeply coloured polymer. A similar thermochemical behaviour (strongly exothermic transformation around 200 “C) was observed for compounds 5 and 6 [20]. However, none of the systems 4-6 shows any tendency to produce spherical forms of carbon under the conditions investigated.

4

5

6

The situation is drastically different when the thermochemistry of cycloalkyne 7 [21] is considered (Figure 1).The high energy content of 7 becomes apparent when the compound is heated to 245 “C. At this temperature 7 “explodes violently with a flash of orange light” [ 211. An investigation of the black, carbonaceous residue by transmission electron microscopy (TEM) revealed the presence of not only amorphous carbon and graphite, but also of closed-shell carbon particles, namely buckytubes and buckyonions in yields between 1-2% (by TEM) [22]. It is not unlikely that the molecular structure of 7 as observed in the crystal (Figure 1) supports its explosive transformation to these fullerenoid carbon allotropes. While 7 is commonly and deceivingly depicted as a planar rectangle, the X-ray structural analysis

I

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Explosions as a Synthetic Tool? Cycloalkynes as Precursors t o Fullerenes, Buckytubes and Buckyonions

7 Fig. 1. The structure o f 7 in the crystal deviates considerably from that suggested by the graphical representation.

reveals that 7 adopts a non-planar, twisted D2-symmetric conformation in the crystal, in which two butadiynyl linkages are crossing on top of each other. Vollhardt and coworkers further advanced their concept of acetylenic starting materials for the synthesis of carbon nanostmctures by exploring a metal-mediated version of the thermolytic transformations of oligoalkynes into carbon nanostructures [ 231. Thus, separate pyrolyses of the cobalt complexes 8 and 9 at temperatures around 800 "C led to the formation of large amounts (up to GO% by TEM) of buckyonions and multi-walled carbon nanotubes. In addition, some graphitic and very little amorphous carbon was produced. Thermal analysis of this transformation reveals that exothermic CO extrusion 153 "C signals the onset of the reaction, and is followed by an endothermic polymerisation process at 188 "C, possibly induced by initial Co--Co bond breaking. Interestingly, pyrolysis of a mixture of 7 with 5% C02(C0)8 produceed only soot with little graphitised carbon. Again, there appears to be a clear structural predisposition in 8 and 9 that favours the thermal production of carbon nanostructures. Structural analysis of the starting materials by X-ray crystallography, however, were inconclusive in this respect. The fate of the metal during the pyrolysis of 8 and 9 is intriguing. Whereas most of the metal is deposited amorphously in discrete domaines, some of it is trapped during the thermolysis process in carbon-coated nanorods or even in crystalline form inside the carbon tubes and onions. The thermal decomposition of 7, 8 and 9 into fullerenic substructures is a milestone in fullerene formation and represents the first example of a macroscopic preparation of closedshell carbon particles from acetylenic precursors. However, molecular allotropes of carbon, such as C ~ or O higher fullerenes were not found among the decomposition products. It is interesting to note in this context that 10 [24], a structural isomer of 7 with a saddle-shaped solid state conformation, also shows thermal transformations, but in this case they occur at temperatures ca. 50 "C lower than those of 7 and are accompanied by a release of 50 kJ mol-' more energy. Although an insoluble carbonaceous material is formed during this process, further details of its nature are currently not known.

Explosions as a Synthetic Tool? Cycloalkynes as Precursors to fullerenes, Buckytubes and Buckyonions

H

H

8

9

10

Cyclophanes have previously been envisioned as precursors to the fullerenes [ 251 and alkynyl-based cyclophanes ("cyclophynes") are beginning to play an eminent role in this field. Two experimental results may serve to demonstrate the substantial energy content of these molecules. Firstly, belt-shaped [ blparaphenylacetylene 11 [2G] explodes when heated to 80 "C in the presence of oxygen. Under inert gas, temperatures of ca. 240 "C are needed to induce the decomposition. No attempts have been made to characterize the decomposition products that are described as a brown, polymeric mixture. Secondly, [8.8]paracyclophaneoctayne 12 [27] could only be prepared in a protected form in which four of the eight acetylenic units arc complexed by bridging ( p-acetylene dicobalt) moieties. Efforts to release the highly strained hydrocarbon from its octacobalt complex resulted in large amounts of insoluble material. In light of the constitutional similarities between 8, 9 and the octacobalt complex of 12 an investigation of the pyrolytic behaviour would be very informative. Major steps towards the transformation of acetylenic cyclophanes into fullerenes have recently been made by Rubin et al. At the center of their promising approach [28-301 lies a preformed sixty carbon cyclophyne cage which is meant to be brought by appropriate acti-

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Explosions as a Synthetic Tool? Cycloalkynes as Precursors t o Fullerenes, Buckytubes and Buckyonions

11

12

vation techniques to coalesce to buckminsterfullerene CGO.The prototypical cyclophyne 13 [ 311 (C60H18), skillfully assembled in only four steps from 1,3,5-triethynylbenzene,is stable for weeks in dilute solutions in the dark. The cyclophyne 13 adopts a chiral, helical D3conformation in the solid state, and, according to calculations, racemizes rapidly even at low temperatures. Disappointingly, 13 was shown to be very reluctant to loose hydrogen in matrix-assisted LD-MS experiments and does not collapse under dehydrogenation to fullerene c 6 0 . The most abundant ion (negative ion mode) corresponds to the parent ion of 13 and only partial dehydrogenation to C6OH14- is observed. The authors speculate that the reasons for the failure of 13 to produce fullerenes are the pronounced flexibility of the system, and, more importantly, the bad leaving group properties of the remaining hydrogens of the c60 H 18 hydrocarbon. 0

0

0

0 13

14

(C60H18)

[C60H6(C0)121

In a straightforward refinement of their concept Rubin et al. have turned to cyclophyne 14 [32] in which the vinylic hydrogens of 13 are replaced by 1,2-dioxocyclobutenogroups. This cyclic diketone moiety has been used previously [18, 33, 341 as a synthetic equivalent for alkynyl groups which can be generated from the dione by thermally or photochemically induced CO expulsion. Successive decarbonylation of 14 should ultimately lead to cyclophyne 15 with the composition C6&.

Explosions as a Synthetic Tool? Cycloalkynes as Precursors to Fullerenes, Buckytubes and Buckyonions

In contrast to the synthesis of cyclophyne 13, the preparation of 14 is a more tedious multistep (eight) procedure that furnished a sensitive material that is stable in CH2Clz solution for only two hours. The instability of 14 notwithstanding, the mass spectrometric behaviour of the compound under FT-ICR-LD (ICR = ion cyclotron resonance) conditions proved to be intriguing. The parent ion of 14, C ~ O H ~ ( C can O ) ~neither ~ , be observed in the positive nor in the negative ion mode, but fragments thereof resulting from loss of eight, nine, ten, and eleven CO groups are detectable. The most abundant ions observed in the negative ion mode are c60'- and C60H6'~-.The anion of the carbon cluster c 6 0 was unambiguously identified as a fullerene, since its fragmentation pattern shows the successive loss of Cz-units typical for spherical carbon particles. C6OH6'- on the other hand does not lose C2 fragments, suggesting that its structure is not fullerene-like. It may be speculated that C60H6'- is best represented by structure 15. It is noteworthy that the formation of fullerene ions from acetylenic 14 is observed in the negative ion mode, which is considered to be "milder" than the positive ion mode which was previously used to detect ionized carbon spheres. It thus appears that 14 is structurally predisposed for fullerene formation. However, attempts to perform the exhaustive decarbonylation on a macroscopic scale by irradiating dilute THF solutions of 14 with pulsed laser light did not lead to the formation of buckminsterfullerene c 6 0 . A n alternative strategy for fullerene production through the intermediacy of 15 was adopted (and pursued independently and simultaneously to the work described above) by Tobe et al. [35] Their attempt to overcome the difficulties encountered in the exhaustive dehydrogenation of 13 led to design of a similar cyclophyne 16, in which six alkynyl groups are masked by so-called [4.3.2]propellatrienes. Laser-induced [ 2+2]cycloreversion [ 36-38] will cleave the bicyclic substructures to generate six equivalents of indane and will furnish cyclophyne 15. Consequently, the LD-mass spectra (positive ion mode) of 16 feature an intense signal for c60 cations with a C2-fragmentation pattern. In the negative ion mode, c60 anions are formed only to a minor extent, and the spectrum is dominated by C6OH6'anions. Again, upon photolysing solutions of 16 no indication for the macroscopic formation of fullerenes was observed, despite the promising confirmation that indane had been produced.

I

415

416

I

Explosions as a Synthetic Tool? Cycloalkynes as Precursors to Fullerenes, Buckytubes and Buckyonions

16: X = Y = Z = CH 17: X = Y = N,Z = CH 18: X = Z = N. Y = CH

Tobe and coworkers have extended their work to the pyridine-based cyclophynes 17 and 18 in efforts to detect the incorporation of heteroatoms into the fullerene structure [ 391. Similar to the behaviour of the hydrocarbon 16, heterocyclic 17 and 18 show the successive loss of indane units and hydrogen under the conditions of LD mass spectrometry (negative ion mode) culminating in the observation in both cases of the formation of the anion CssNz-. The relative low intensity of the diazafullerene anion observed can be attributed to the kinetic and thermodynamic instability of the heterocage formed.

19:R=H 20: R = CI

Tobe’s group also succeeded in applying the [ 2+2]cycloreversion process to the formation of smaller carbon cages, notably c36 [40]. Macroscopic quantities of cj6 have been produced before [41,42]and were shown to contain carbon cages that are covalently connected to form polymeric clusters of overall D6h-symmetry. In their efforts to obtain c 3 6 from acetylenic precursors, Tobe et al. prepared cyclophynes 19 and 20 [40]. LD time-of-flight mass spectra of 19 depict a signal for the anion of cyclophyne C36H8, generated from 19 by four-fold

References

cycloreversion of its propellatriene units, can be clearly observed. However, anionic fragments arising from the subsequent dehydrogenation of C36H8- could not be detected. Replacement of the benzenoid C-H bonds in 19 with the weaker C-C1 bonds in 20 and investigation of the latter with LD-TOF MS methods not only allowed the observation of the corresponding c36cl8- anion, but also showed the stepwise loss of chlorine atoms to produce c36-, for which the authors also assume D6h-symmetry.

21

22

23

In light of the mass spectrometric results described above, a rational fullerene synthesis from cyclophyne precursors appears to be within reach. Since superphane 21 [43] and superferrocenophane 22 [ 441 are established structural precedences, it may well be that reports about a successful synthesis of “superphyne” 23, an acetylenic isomer of buckminsterfullerene, or even a corresponding “superrnetallophyne” are only a short time away.

References W. KFL~TSCHMER,L. D. LAMB,K. FOSTIROPOULOS, D. R. HUFFMANN, Nature (London) 1990, 347, 354-358. L. T. SCOTT,M. M. BOORUM,B. J. MCMAHON,S. HAGEN,J. MACK,J . BLANK, H. WEGNER, A. D E MEIJERE, Science 2002, 295, 1500-1503.

F. DIEDERICH, Y. RUBIN,Angew. Chem. 1992, 104, 1123-1146; Angew. Chem. Int. Ed. Engl. 1992, 31, 1101-1123. F. DIEDERICH, Nature (London) 1994, 369, 199-207.

U. H. F. BUNZ,Y. RUBIN,Y. TOBE,Chem. SOC.Rev. 1999, 28, 107-119. A. J. BERRESHEIM, M. MULLER,K. MULLEN,Chem. Rev. 1999, 99, 1747-1785. F. BANHART,N. GROBERT, M. TERRONES, I. C. CHARLIER, P. M. AJAYAN, Int. ]. Mod. Phys. B 2001, 15, 4037-4069. M. TERRONES, W. K. Hsu, H. W. KROTO, D. R. M. WALTON,Top. Cum. Chem. 1999, 199, 189-234.

9

H. SCHWARZ, Angew. Chem. 1993, 105, 1475-1477; Angew. Chem. Int. Ed. Engl. 1993, 32, 1412-1415.

10

P. M. AJAYAN, Chem. Rev. 1999, 99, 1787-1799.

11

Y. RUBIN,M. KAHR,C. B. KNOBLER,F.

DIEDERICH,C. L. WILKINS,]. Am. Chem. SOC.1991, 113, 495-500. 12 S. W. MCELVANY, M. M. Ross, N. S. GOROFF,F. DIEDERICH, Science 1993, 259, 1594-1596. 13 N. S. GOROFF,Acc. Chem. Res. 1996, 29, 77-83. 14

For an account of the developments leading to the isolation of CGO,see H. W. KROTO,Angew. Chem. 1992, 104,113-133; Angew. Chem. Int. Ed. Engl. 1992, 31, 111129. See also R. F. CURL,Angew. Chem. 1997, 109, 1636-1647; Angew. Chem. Int. Ed. Engl. 1997,36, 1566-1577; H. W. KROTO,Angm. Chem. 1997, 109,16481664; Angew. Chem. Int. Ed. Engl. 1997, 36,

I

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418

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Explosions as a Synthetic Tool? Cycloalkynes as Precursors to Fullerenes, Buckytubes and Buckyonions 1578-1593; R. E. SMALLEY, Angew. Chem. 1997, 109, 1666-1673; Angew. Chem. Int. Ed. Engl. 1997, 36, 1594-1603. 15 J. HUNTER,J.FYE,M. F. JARROLD, Science 1993, 260,784-786. 16 D. E. CLEMMER, M. F. JARROLD, J. Am. Chem. SOC.1995, 117,8841-8850. 17 G. VON H E L D E NN. , G. Gorrs, M . T . BOWERS,Nature (London) 1993, 363, 60-63. 18 F. DIEDERICH, Y. RUBIN,0. CHAPMAN, N. S. GOROFF,Helv. Chim. Acta 1994, 77, 1441-145 7. 19 K. P. BALDWIN, A. J. MATZGER,D. A. SCHEIMAN, C. A. TESSIER,K. P. VOLLHARDT, W. J. YOUNGS,Synlett 1995, 1215-1218. 20 M. M. HALEY,S. C. BRAND,J. J. PAK, Angew. Chem. 1997, 109, 864-866; Angew. Chem. Int. Ed. Engl. 1997, 36, 836-838. 21 R. BOESE,A. J. MATZGER, K. P. C. VOLLHARDT, J. Am. Chem. SOC.1997, 119, 2052-2053. 22 M. S. DRESSELHAUS, G. DRESSELHAUS, P. C. EKLUND,Science ofFullerenes and Carbon Nanotubes, Academic Press, San Diego, USA, 1996. 23 P. I. DOSA,C. ERBEN, V. S. IYER,K. P. C. VOLLHARDT, I. M. WASSER, J. Am. Chem. SOC.1999, 121, 10430-10431. 24 M. M. HALEY,M. L. BELL,J. J. ENGLISH, C. A. JOHNSON, T. J . R. WEAKLEY, ]. Am. Chem. SOC.1997, 119, 2956-2957. 25 R. FAUST,Angew. Chem. 1995, 107, 15591562; Angew. Chem. Int. Ed. Engl. 1995, 34, 1429-1432. 26 T. KAWASE, H.R. DARABI,M. ODA,Angew. Chem. 1996, 108, 2803-2805; Angew. Chem. Int. Ed. Engl. 1996, 35, 2664-2666. 27 M. M. HALEY,B. L. LANCSDORF, Chem. Commun. 1997, 1121-1122. 28 Y. RUBIN,Chem. Eur. J. 1997, 3, 1009-1016. 29 Y. RUBIN,Chimia 1998, 52, 118-126. 30 Y. RUBIN,Top. Curr.Chem. 1999, 199, 67-91.

31 Y. RUBIN,T . C. PARKER, S. I. KHAN,C.

L.

HOLLIMAN, S. W. MCELVANY, 1.Am. Chem. SOC.1996, 118, 5308-5309. 32 Y. RUBIN,T. C. PARKER, S. J. PASTOR,S. JALISATGI, C. BOULLE,C. L. WILKINS, Angew. Chem. 1998, 110, 1353-1356; Angew. Chem. Int. Ed. 1998, 39, 12261229. 33 Y. RUBIN,C.B. KNOBLER, F. DIEDERICH, J. Am. Chem. SOC.1990, 112, 1607-1617. 34 Y. RUBIN,S. S. LIN, C. B. KNOBLER, J. ANTHONY,A. M. BOLDI,F. DIEDERICH, J. Am. Chem. SOC.1991, 113, 6943-6949. 35 Y.TOBE,N. NAKAGAWA, K. NAEMURA, T. WAKABAYASHI, T. SHIDA,Y. ACHIBA,]. Am. Chem. SOC.1998, 120,4544-4545. 36 Y. TOBE,T. FUJII,H. MATSUMOTO, K. NAEMURA, Y. ACHIBA,T. WAKABAYASHI, J. Am. Chem. SOC.1996, 118, 2758-2759. 37 Y. TOBE,H . MATSUMOTO, K. NAEMURA, Y. ACHIBA,T. WAKABAYASHI, Angew. Chem. 1996, 108, 1924-1926; Angew. Chem. Int. Ed. Engl. 1996, 35, 1800-1802. 38 Y. TOBE,T. F U ~ I IH. , MATSUMOTO, K. TSUMURAYA, D. NOGUCHI,N. NAKAGAWA, M. SONODA,K. NAEMURA, Y. ACHIBA,T. WAKABAYASHI, J. Am. Chem. SOC.2000, 122, 1762-1775. 39 Y. TOBE,H . NAKANISHI, M. SONODA,T. WAKABAYASHI, Y. ACHIBA,Chem. Commun. 1999, 1625-1626. 40 Y.TOBE,R. FURUKAWA, M. SONODA, T. WAKABAYASHI, Angew. Chem. 2001, 113, 4196-4198; Angew. Chem. lnt. Ed. 2001, 40,4072-4074. 41 C. PISKOTI,J. YARGER, A. ZETTL,Nature (London) 1998, 393, 771-774. 42 P. G. COLLINS, J. C. GROSSMAN, M. COTE, M. ISHIGAMI, C. PISKOTI,S. G. LOUIE,M. L. COHEN,A. ZETTL,Phys. Rev. Lett. 1999, 82, 165-168. 43 Y. SEKINE,M. BROWN,V. B O E K E L H E I D E , ~ . Am. Chem. SOC.1979, 101, 3126-3127. 44 M. HISATOME, J. WATANABE, K. YAMAKAWA, Y. IITAKA, J. Am. Chem. SOC. 1986, 108, 1333-1334.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co I419

Dendralenes: From a Neglected Class of Polyenes to Versatile Starting Materials in Organic Synthesis Henning Hopf

By connecting double and single bonds, formally five classes of hydrocarbons can be constructed which differ considerably from one another not only chemically and physically but also in terms of their practical significance [l]:the linear polyenes 1, the annulenes 2, which consist exclusively of endocyclic “double bonds”, the radialenes 3, polyolefins which are characterized by semicyclic double bonds, the fulvenes 4, hybrids containing endoand semicyclic double bonds, and finally, the dendralenes 5 [2] which are acyclic crossconjugated polyenes

01. 1

2

[A1 3

4

5

Scheme 1.

Of these n-systems, the first two are by far the most thoroughly investigated and also play the greatest practical role, be it in the form of vital molecules such as 8-carotene or as key substances in organic syntheses, such as benzene and its numerous derivatives. Of the remaining three classes, which are all cross-conjugated, fulvenes and their derivatives have been studied most extensively; however, in the last few years radialenes have gradually come out of the shadows as well [3, 41. Although von Auwers had obtained the first dendralene derivatives at the beginning of the 20th century already, and this class of hydrocarbons was later studied by Staudinger, among others, who described them as “open fulvenes” [ 21, there

420

I

Dendralenes: From a Neglected Class of Polyenes to Versatile Starting Materials in Organic Synthesis

have practically been no in depth studies of the chemistry of the parent dendralene systems. The reason for this is simple: Except for compounds 5 with n = 1 ([3]dendralene 7, Scheme 2) and n = 2 ([4]dendralene 15, Scheme 3), higher vinylogs were not known until the recent investigations by Sherburn et al., details of which are given below. A considerable number of processes have been described for the preparation of the two simplest dendralenes; however, most of them are rather means of formation than efficient preparative methods. As Scheme 2 shows for [ 3ldendralene 7, thermal methods of preparation predominate (1,2-eliminations and periyclic processes); however, these methods do not always start from readily accessible precursors (51. The most effective procedure - which can hence be employed in subsequent reactivity studies (see below) - consists in the cheletropic decomposition of 11 carried out by Cadogan and Gosney et al. [GI although the preparation of the sulfolene derivative also requires several steps.

AcO

R

OAc 6

H,, Lindlar-cat.

100%

11

12

Scheme 2.

The situation was even more critical for [41] dendralene 15 [2, 71, especially since the thermal decompositions shown in the lower half of Scheme 3 have all been carried out in connection with mechanistic studies. Before the first general synthetic concept for the preparation of the dendralenes is presented, it will be shown that these n-systems are interesting not only preparatively but also from a structural point of view. The application of dendralenes in Diels-Alder additions holds particular promise in synthetic chemistry. This is demonstrated in general form in Scheme 4 for the two simplest dendralenes. The [2+4]cycloaddition of 7 with a dienophile 20, not only leads to the expected 1:l-adduct 21 but also generates a new conjugated diene system which

Dendralenes: From a Neglected Class ofPolyenes to Versatile Starting Materials in Organic Synthesis I 4 2 1

=*-c* 13

i

Mg, (MeOCH,O)&H,

0.1 450”c Tom,

AcO

> 23%

14

16

15

> 100 “C

110 “C

.-

-~

(I.= 17

18

19

Scheme 3.

is available for a second addition with 20 to give 22 (Scheme 4, a). In principle, dienophiles containing a triple bond (see below) and heteroorganic compounds are also suitable as dienophiles. Tsuge and co-workers - building on work by Bailey and Blomquist [5] - have already made extensive use of the preparative potential of these so-called “diene transmissive” DielsAlder additions (DTDA additions) [ 81. Clearly, the dienophile does not have to be identical in the two stages of the reaction, which increases the preparative potential of these double cycloadditions considerably. The adducts of type 22 can be further processed in various ways, naphthalene derivatives as for example by dehydrogenation to give 1,2,6,7-tetrasubstituted will be discussed below. Consecutive reactions of this type with their excellent atom economy are of considerable interest particularly in view of the current efforts to increase the efficiency of organic transformations. As expected, the possibilities for [4]dendralene 15, which until now has only been used occasionally in diene-transmissive additions [ 7c], to participate in [ 2+4]cycloadditions are much greater (Scheme 4, b). Two possibilities arise for the first addition step, depending on whether 20 adds to a terminal diene unit (formation of 23) or to the central diene unit (formation of 25). For 23, two further alternatives are possible, which could either lead via 24 to

422

I

Dendralenes: From a Neglected Class of Polyenes to Versatile Starting Materials in Organic Synthesis

7

21

15

23

I

+20

25

I

+2x20

26

22

I

+20

27

Scheme 4.

the 3:l-adduct 27 or - by consecutive additions of two equivalent dienophiles - to the trisadduct 26 (which displays a quaternary carbon atom). Depending on the type of substituents in the dienophile, the adducts 27 could also be used again for aromatization experiments. New types of products are also expected in many other reactions of the dendralenes. Practically nothing is known so far about the photochemistry, metal complexation, ionic additions etc. of these cross-conjugated hydrocarbons, to name but a few directions for further study. As far as the structure of the dendralenes is concerned the early work concentrated on the analysis of their UV spectra - not surprising if one considers that the cross-conjugation motif occurs in many dyes (triphenylmethane dyes, indigo ete.). The electronic spectra show, for instance, that the dendralenes cannot exist in coplanar form. Their absorption maxima are very similar to those of simple 1,3-dienes; they are not shifted to longer wavelengths as one would expect for extended n-electron systems. This is confirmed by detailed structural investigations accompanied by various computational methods. According to electron diffraction measurements, 7 has the anti-skew-conformation 28 shown in Scheme 5 with a dihedral angle of 40" between the planes of the anti-butadiene fragment and the remaining

Dendralenes: From a Neglected Class of Polyenes to Versatile Starting Materials in Organic Synthesis

x 28

I

29

Scheme 5.

vinyl group [9]. In 15 this dihedral angle is 72" and again the anti-butadiene halves are practically planar (see structure 29, Scheme 5) [lo]. The unsatisfactory situation that a promising class of compounds could not be studied in greater detail has recently been rectified by the groups of Fielder, Rowan, and Sherburn who have developed a general route to the dendralenes [ I l l . In planning the corresponding sequences, the well known instability and tendency of the dendralenes to polymerize - as demonstrated by 7 and 15 - were taken into consideration from the very beginning, in that a synthetic route was designed in which the dendralene n-system is not released until the very end. In particular the butadiene fragment was transported in capped form, as a sulfolene ring, to the end of the synthesis, following the approach of Cadogan and Gosney et al. [6] for the simplest dendralene 7 (see Scheme 1). AS Scheme 6 shows, the Sherburn route begins with the vinyl stannane 30, which is initially converted by iodolysis to the vinyl iodide 31. The actual building process then took place by Stille cross-couplings; the mild reaction conditions used prevented the premature release of sulfur dioxide from the masked dendralene intermediates. The sulfolenes 11, 33, and 34 were obtained readily in the presence of [PdC12(CH3CN)z]in DMF under argon at temperatures up to 40 "C. The coupling of 31 with the bis-stannane 32, not only gave the bissulfolene 35, but also the [8]dendralene precursor 38. The masked dendralenes 36 are crystalline compounds, stable at room temperature, from which, as hoped, the hydrocarbons 37 could be released on demand in good yields by hightemperature pyrolysis. No solvent is required in these cheletropic reactions which facilitates the work-up. The dendralenes 37 obtained, up to [ 8]dendralene, have been completely characterized by the usual spectroscopic and analytical methods and can, although they tend to polymerize, be handled under the usual laboratory conditions (see below). The sulfolene decomposition route has recently been applied to the synthesis of many other cross-conjugated compounds, among them the hydrocarbons 39-42 (Scheme 7) [ 121. Having sufficient amounts of these novel dienes in hand opens the field for further study. Cycloaddition of acetylenedicarboxylic acid dimethyl ester (ADDE) to [ 3ldendralene 7 in toluene first afforded the 1:l-adduct 43, which by a second addition of ADDE provided the expected 21-adduct 44. After this had been aromatized by treatment with DDQ to the naphthalene derivative 45, a double benzannulation could be carried out as described in Scheme 8 [ 131. By reduction of the ester groups with lithium aluminum hydride the corresponding tetraalcohol was obtained which was converted to the tetrabromide 46 by treatment with phosphorus tribromide. Debromination with zinc in the presence of maleic anhydride (MA) furnished the bis anhydride 47, which, after esterification and aromatization, provided the

I

423

424

I

Dendralenes: From a Neglected Class of Polyenes t o Versatile Starting Materials in Organic Synthesis

SnBu, I,, CH,C1,

Stille

80%

Bu,SnCH=CH,

30

31

I

Stille H,C=CBr,

Stille

M

0,s so2

I

11 (92%)

+ 30\+,

o

so2

2

# 502

33 (1 1%)

34 (95%)

35 (43%)

+

38 (30%) 52 Scheme 6.

39 (63%)

40 (32%)

41 (25%)

42 (12%)

Scheme 7.

-

Dendralenes: From a Neglected Class ofPolyenes t o Versatile Starting Materials in Organic Synthesis

+ ADDE

C02Me

toluene

C02Me

7

+ADDE toluene

43

C02Me Me02C

*

DDQ toluene

C02Me C02Me 44 \

Me02Cm

\

C 0 2 C02Me

M

1. LiA1H4

“ZMe

e

2. PBr3

BrH2C CH2Br

46

45

Zn

MA, dioxane

1. MeOH/H+

2. DDQ, toluene

47

C02Me Me02CP

C

O

2

M

e

C02Me 48 Scheme 8.

tetraester 48, set up for another cycle of the annulation process. The 4G-47 reduction step most likely involves o-xylylene intermediates, presumably generated in succession rather than in one step. A similar sequence was carried out with [4]dendralene 14 and via the expected cycloaddition products 49 and 50 the tetraester 51 was isolated after aromatization, again a compound which can be employed for further extension of its aromatic core (Scheme 9) [ 131.

I

425

426

I

Dendralenes: From a Neglected Class of Polyenes to Versatile Starting Materials in Organic Synthesis

Me0,C

C0,Me

15

49

+CHC1, ADDE

-

M

e

0

2

C

~

C

Me0,C

O

z

M

s

C02Me 50

toluene DDQ

Me02C&C02Me -

-

Me02C

C0,Me 51

Scheme 9.

In principle an [nldendralene can undergo [ n- 11 cycloaddition reactions. To test whether this potential is actually used by these multi dienes Sherburn and co-workers have treated various dendralenes with 4-phenyl-l,2,4-trizoline-3,5-dione (PTAD) [ 121. Since this is one of the most reactive dienophiles known, chances are high that indeed the full addition [5]-,and [bldendralene added PTAD 3, 4, potential of the dendralene is used. Indeed [4]-, and 5 times, as expected. With [8]dendralene the cycloaddition process stopped after fivefold PTAD-addition, very likely because the lower mass cycloadducts were too poorly soluble to engage in further cycloaddition steps. References

Overview: H. HOPF,Classics in Hydrocarbon Chemistry, Wiley-VCH, Weinheim, 2000, Chap. 2, pp. 5-18. 2 At present only one review article exists on dendralenes: H. HOPF,Angew. Chem. 1984, 96, 947-958; Angew. Chem. Int. Ed. Engl. 1984, 23, 947-959; see also ref. [ I ] , Chap. 11, pp. 251-300. 3 Review: H. HOPF,G. MAAS,Angew. Chem. 1992, 104,953-977; Angew. Chem. Int. Ed. Engl. 1992, 31,931-954. 1

H. HOPF,G. MAAS in The Chemistry of Dienes and Polyenes, Vol. I (Ed.: 2. RAPPOPORT), J. Wiley, Chichester, 1997, Chap. 21, pp. 927-977. 5 a) A. T. BLOMQUIST, J. A. VERDOL,].Am. Chem. Soc. 1955, 77,81-83; b) W. J. BAILEY, J. ECONOMY, J. Am. Chem. SOC. 1955, 77, 1133-1136; c) A. T. BLOMQUIST, J. A. VERDOL, ]. Am. Chem. Soc. 1955, 77, 1806-1809; d) W. J. BAILEY, C. H. CUNOV, L. NICHOLAS, /. Am. Chem. Soc. 1955, 77,

4

References I 4 2 7

2787-2790; e) H.PRIEBE, H. HOPF,Angew. Chem. 1982, 94, 299-300; Angew. Chem. Int. Ed. Engl. 1982, 21, 286-287. 6 J. I. G. CADOGAN, S. CRADOCK, S. GILIAM, I. GOSNEY, J . Chem. SOC.Chem. Commun. 1991, 114-115. 7 a) K. GREINER, Dissertation, Universitat Erlangen, 1960; b) C. A. AUFDERMARSH, US Patent 3264366, 19GG IChem. Abstr. 1966, 65, 20 003gl; c) W. J. BAILEY, N. A. NIELSEN,J. Org. Chem. 1962, 27, 30883091; d) L. K. BEE,J. W. EVERETT,P. J. GARRATT, Tetrahedron, 1977, 33, 21432150; e) L. SKATTEBaL, s. SOLOMON, /. Am. Chem. SOC.1965, 87,4506-4513; f ) W. Angew. Chem. GRIMME, H:]. ROTHER, 1973, 85, 512-514; Angew. Chem. rnt. Ed. Engl. 1973, 12, 505-507; g) W. R. ROTH, B. P. SCHOLZ, R. BREUCKMANN, K. JELICH, H.-W. LENNARTZ, Chem. Ber. 1982, 115, 1934-1946.

8

9

10

11

12 13

0. TSUGE, E. WADA,S. KANEMASA,Chem. Lett. 1983, 239-242; 0. TSUGE,E. WADA, S. KANEMASA, Chem. Lett. 1983, 15251528. A. ALMENNINGEN, A. GATAIL, D. S. B. GRACE,H.HOPF,P. KLAEBOE,F. LEHRICH, C. J. NIELSEN, D. L. POWELL, M. TRAETTEBERG, Acta Chem. Scand. Ser. A , 1988, 42, 634-650. P. T. BRAIN,B. A. SMART,H. E. ROBERTSON, M. J. DAVIS,D. W. RANKIN, W. J. HENRY, I. GOSNEY, I.Org. Chem. 1997, G2, 2767-2773. S. FIELDER, D. D. ROWAN,M. S. SHERBURN, Angew. Chem. 2000, 112, 4501-4503; Angew. Chem. Int. Ed. 2000, 39,4331-4333. M. S. SHERBURN, private communication to H. Hopf, March, 2002. H. HOPF,S. YILDIZHAN, unpublished work.

Fascinating Natural and Artificial Cyclopropane Architectures Rudiger Faust

The various facets of the chemistry of cyclopropane derivatives are amazingly diverse and continue to fascinate scientists from a broad range of backgrounds, among them theoreticians, synthetically or structurally inclined chemists, and researchers with interests in natural product and/or medicinal chemistry. The challenges posed by the intriguing cyclic arrangement of only three tetravalent carbons are multitudinous, ranging from fundamental aspects of bonding, over the synthesis of highly strained molecules to an understanding of the mode of action of biologically active cyclopropyl derivatives. Selected examples of cyclopropane architectures encountered in compounds either derived from natural sources or prepared for the first time in the laboratory are highlighted together with key steps of their syntheses in the following. The fact that nature has chosen to use a cyclopropane skeleton to design a defense mechanism for certain pyrethrum flowers against insect attack has been known since 1924, when Staudinger and Ruzicka isolated and characterised (+)-trans-chrysanthemic acid 1 from the petals of these plants [ 11. The active insecticidal ingredients in these plants are in fact esters of 1,which can be easily modified and which have been commercially exploited to give birth to one of the most successful classes of biomimetic insecticides, the pyrethroids. In 1997, the market value of this class of insecticides amounted to a staggering 1.5 billion US$ [ 2 ] .

H T C O O H H3C ‘CH3 1

IxcooH NH2 2

But chrysanthemic acid derivatives are by far not the only examples of cyclopropanecontaining structures in nature. In fact, the highly strained threemembered carbocycle is virtually ubiquitous. It occurs, for example, in every green plant in the form of 1aminocyclopropanecarboxylic acid (ACC) 2, a direct precursor to the plant hormone ethylene [ 3 ] . In addition, the cyclopropane unit is found in a variety of other natural products, inter alia in terpenes and in various cyclopropanated fatty acids [4]. The biochemical precursors of the latter are unsaturated fatty acids, and in view of the existence of polyunsaturated fatty

Fascinating Natural and Art$cial Cyclopropane Architectures

acids it is perhaps not too surprising that poly cyclopropanated analogues occur also in nature. And indeed, in 1990 Yoshida et al. were able to isolate the potent antifungal agent FR900848 (3) from the fermentation broth of Streptouerticillium feruens [ 51. The unusual architecture of 3, ultimately proven by total synthesis and X-ray crystallographic analysis [ G , 71, consists of four contiguous and one isolated cyclopropane unit, all of which are arranged on the same face of an all-trans-configurated carbon backbone. But the amazing array of five cyclopropane units in 3 is not unique. Shortly before the structure of 3 was unequivocally established, chemists at the chemical company Upjohn isolated U-1OG305 (4) from Streptomyces sp. [8]This latter compound had aroused the scientist's interest because it acts as an effective inhibitor of the cholesteryl ester transfer protein in the blood and can thus be envisioned to slow the progression of atherosclerosis. 0

3

1/

"

H

s

I

'

0 4

The remarkable structural similarity between compounds 3 and 4, the latter endowed with five contiguous out of a total of six cyclopropane units, suggests that they are synthesised along the same biochemical pathway. As with 3, the structure and the absolute configuration of 4 was established by a total synthesis [9, 101 that made use of an enantioselective cyclopropanation reaction of allylic alcohols developed by Charette et al. (Scheme 1) [ll].This method uses the preformed [Zn(CH212)].DMEcomplex 5 and capitalises on the asymmetric induction from the chiral dioxaborolane 6 which coordinates to the intermediate zinc alkoxide, formed by the reaction of 5 with the allylic alcohol [ 111. Following this protocol,

0

O H, , - / , - , HO

0 7

Scheme 1.

6

Zn(CH2I2)*DME 5 91% (89% ee)

*

H

O

T

o 8

Enantioselective cyclopropanation developed by Charette.

H

I

429

430

I

Fascinating Natural and Artificial Cyclopropane Architectures

2(E)-butene-1,4-diol7 , for example, is enantioselectively cyclopropanated to 8 in 91% yield (89% ee). The power of Charette's cyclopropanation method is aptly demonstrated by key steps in the synthesis of 4, during which the six cyclopropane units in its backbone were assembled by iterative cyclopropanations as outlined in Scheme 2 [lo]. Hence, periodinane oxidation of diol 8 to the corresponding dialdehyde, followed by Wittig olefination with Ph3 P=CHC02Et and DIBAL-H reduction to the bis-ally1 alcohol 9 sets the stage for a second, double Charette cycloprocyclopropanation to generate 10. The oxidation/olefination/reduction/two-fold panation cycle is then repeated to furnish the quinquecyclopropane 11. With five of the six cyclopropane units of 4 in place, the last one is implemented after oxidation of mono-silyl protected 11, extension of the carbon chain by a Wadsworth-Emmons-Horner homologation with (Me0)2P(0)CH2CH=CHC02Me,NaH and DBU, and reduction of the intermediate ester with DIBAL-H to give 12. The fourth Charette cyclopropanation, regioselective on the ally1 alcohol moiety then generates 13, from which U-106305 (4) is readily prepared in a few steps.

Me2NY:B-B~ 1. Dess-Martin periodinane 8

-

h"'" 0

Me2N HO

2. PhsPCH=C02Et 3. DIBAI-H

*

Zn(CH2I2)*DME 9

1. Oxidation

OH 2. Wittig olefination

* H

H O -

O

3. Reduction 4. Charette Cyclopropanation

10 1. Oxidation 2. Wadsworth-ErnrnonsHorner olefination

m

o

11 R=H R = TBSJ

HO

R

TBSCI, irnidazole

OTBS

3. Reduction 12

Charette Cyclopropanation

-

OTBS

HO 13

Scheme 2.

Synthesis of a quinquecyclopropane en route to U-106305.

Shortly after Barrett's publication of the successful approach to U-106305, Charette and Lebel reported the enantioselective synthesis of its non-natural enantiomer [ 121, and thereby further emphasised the power and the generality of their method. The same methodology was used to make the unnatural, all-trans septicyclopropane derivative 14 [ 101, the most highly cyclopropanated linear structure prepared to date.

Fascinating Natural and Artificial Cyclopropane Architectures

H

O

I

o

H

14

Multiple cyclopropyl groups can also be arranged in a spiro-fused fashion around a core carbocycle, giving rise to the structurally fascinating classes of the so-called rotanes and triangulanes [ 131. These hydrocarbons have been investigated extensively by the groups of Conia and de Meijere. In 1973, Fitjer and Conia prepared the smallest system in this series, the highly strained [3]rotane 15 [14]. More recently, de Meijere’s team presented a succession of highlights in this area, including the first synthesis of an enantiomerically pure [4]triangulane 16 [ 151, the stunning perspirocyclopropanated [ 3lrotane 17 [ 161, or even the [ 15ltriangulane 18 [ 171, a record-breaking arrangement of fifteen spiro-linked cyclopropane rings.

15

16

18

17

Compound 16, prepared to test the hypothesis that chiral, unfunctionalised and completely saturated hydrocarbons can show optical activity if sufficiently rigid, was found to have a remarkably high specific rotation = -648.2), which the authors attribute to the helical arrangement of the CT-CC bonds in 16. It was therefore suggested that 16 is a CTbond analogue of the aromatic [ nlhelicenes, a class of compounds with similarly large optical rotations due to a helical arrangement of their n-bond backbone [ 181. Most recently, de Meijere and coworkers have climbed yet another mountain in cyclopropane architecture and prepared tetracyclopropylmethane 19 (Scheme 3) [ 191. Many organoelement derivatives with the maximum number of cyclopropyl groups are known, and in fact the heavier (and larger) homologues of 19, namely tetracyclopropylsilane, -germane

S

O

H

MeC(OEt), * 3 C 0 2 E t ~

2. PBr3

3. f-BuOK

20

22

21

CH2N2 (10 equiv.) Pd(OAc)2 repeated 10 times 19 Scheme 3.

23

Synthesis of tetracyclopropylmethane and tetraisopropylrnethane.

I

431

432

I

Fascinating Natural and Artificial Cyclopropane Architectures

and -stannane had been made before [20]. However, the corresponding hydrocarbon has remained elusive, and earlier attempts to generate the compound using standard cyclopropanation methods failed. One of the key steps in the synthesis of 19 [19, 211 is the formation of its quaternary carbon centre, which is implemented by an orthoester Claisen rearrangement of the allyl-vinyl ether generated by heating a mixture or allylic alcohol 20 together with triethyl orthoacetate in diphenylether to 150 " C (Scheme 3). Manipulations of the ester group in 21, i.e. reduction, bromination of the intermediate alcohol and baseinduced dehydrobromination leads to the diolefin 22, which is then doubly cyclopropanated with diazomethane in the presence of palladium acetate to give 19. The difficulties encountered in the final step become apparent when one considers that 22 had to be subjected up to six times to the cyclopropanation conditions in order to maximise the yield. The large steric crowding around the methane carbon in 19 gives rise to dynamic conformational effects that have been investigated by variable temperature N M R spectroscopy [21].Furthermore, the accumulated ring strain in 19 makes this compound a suitable starting material for the preparation of one of the most sterically congested methane derivatives prepared to date: palladium-catalysed, regioselective hydrogenolysis of the least substituted cyclopropane bonds in 19 furnishes tetraisopropylmethane 23 in almost quantitative yield. The elegance of the synthetic route to a highly crowded molecule like 23 can be fully appreciated when one ponders the fact that the sterically even more fraught tetra-tertbutylmethane remains elusive. Further progress in the area of sterically congested cyclopropylmethanes has recently been made in the work of Ramana et al., who prepared a higher homologue of 19, namely tetrakis(cyclopropylmethy1)methane28 (Scheme 4) [ 221. Simmons-Smith cyclopropanation of the allylic alcohol 24 and transformation of the resulting alcohol 25 into its corresponding xanthate 26 generates an activated system, in which two allyl units can be introduced by a radical allyl transfer from allyltributyltin and AIBN to give 27. The target hydrocarbon 28 was then generated using a two-fold palladium-catalysed cyclopropanation with diazomethane and palladium acetate.

24

Scheme 4.

25

Synthesis of tetrakis(cyclopropylmethyl)rnethane.

26

References

This short excursion into the diverse field of natural and artificial cyclopropane architectures highlights the fact that cyclopropanes continue to provide stimuli for and challenges to current concepts of synthesis, structure and theory. It’s amazing what three carbons can do. References 1 H . STAUDINGER, L. RUZICKA,Helu. Chim. 2

3

4

5

6

7

8

9

10

11

12

Acta 1924, 7, 177-235. R. FAUST,G. KNAUS,U. SIEMELING, World Records in Chemistry, ( E d H.-J. QUADBECKSEEGER), Wiley-VCH, Weinheim, 1999, p. 95. S. F. YANG,N. E. HOFFMAN, Annu. Rev. Plant Physiol. 1984, 35, 155-189. J. MANN,Secondary Metabolism, Clarendon, Oxford, 1987, p. 42. M. YOSHIDA,M. EZAKI,M. HASHIMOTO, N. SHIGEMATSU, M. M. YAMASHITA, OKUHARA,M. KOHSAKA,K. HORIKOSHI, /. Antibiot. 1990, 18, 748-754. A. G. M. BARRETT,K. KASDORF,].Am. Chem. SOC.1996, 118, 11030-11037. J. R. FALCK,B. M E K O N N E N J.,Yu, J:Y. LAI,/. Am. Chem. SOC.1996, 118, 60966097. M. S. Kuo, R. J. ZIELINSKI, J. I. CIALDELLA, C. K. MARSCHKE, M. J. DUPUIS,G . P. LI, D. A. KLOOSTERMAN, V. P. MARSHALL, /. Am. C. H. SPILMAN, Chem. SOC.1995, 117, 10629-10634. A. G. M. BARRETT,D. HAMPRECHT, A. J. P. WHITE,D. J. WILLIAMS, /. Am. Chem. SOC. 1996, 118, 7863-7864. A. G.M. B A R R E D. ~ , HAMPRECHT, A. J. P. WHITE,D. J. WILLIAMS, /. Am. Chem. SOC. 1997, 119, 8608-8615. See also: A. G. M. BARRETT,D. HAMPRECHT, R. A. JAMES,M. M. A. TOLEDO, OHKUBO,P. A. PROCOPIOU, A. J. P. WHITE, D. J. WILLIAMS, /. Org. Chem. 2001, 66, 2187-2196. A. B. CHARETTE,H . JUTEAU, H. LEBEL,C. MOLINARO,/. Am. Chem. SOC.1998, 120, 11943-11952. A. B. C H A R E ~HE., L E B E L ,Am. ~ . Chem. SOC.1996, 118, 10327-10328.

13 A.

D E MEIJERE, S. I. KOZHUSHKOV, Chem. Rev. 2000, 100, 93-142. 14 L. FITTER,J. M. CONIA,Angew. Chem. 1973, 85, 349-3501; Angew. Chem. In&.Ed. Engl. 1973, 12, 334-335. 15 A. D E MEIJERE, A. F. KHLEBNIKOV, R. R. P. R. KOSTIKOV,S. 1. KOZHUSHKOV, A. WITTKOPP,D. S . YUFIT, SCHREINER, Angew. Chem. 1999, 111, 3682-3685; Angew. Chem. Int. Ed. 1999, 38, 34743477. 16 S. J. KOZHUSHKOV; T. H A U M A N NR.. BOESE,A. D E MEIJERE, Angew. Chem. 1993, 105,426-429; Angew. Chem. Int. Ed. 1993, 32, 401-403. 17 M. VON SEEBACH, s. I. KOZHUSHKOV, R. BOESE,J. BENET-BUCHHOLZ, D. S . YUFIT,J. A. K. HOWARD,A. D E MEIJERE, Angew. Chem. 2000, 112, 2617-2620; Angew. Chem. Int. Ed. 2000, 39, 24952498. 18 R. H. MARTIN,Angew. Chem. 1974, 86, 727-738; Angew. Chem. Int. Ed. 1974, 13, 649-660. 19 S. I. KOZHUSHKOV, R. R. KOSTIKOV, A. P. MOLCHANOV, R. BOESE,J. BENETBUCHHOLZ, P. R. SCHREINER, C. RINDERSPACHER, I. GHIVIRIGA, A. DE MEIJERE,Angew. Chem. 2001, 113, 179182; Angew. Chem. In&.Ed. 2001, 40, 180-183. 20 B. BUSCH,K. DEHNICKE, /. Organomet. Chem. 1974, 67, 237-242. 21 J. E. ANDERSON, A. D E MEIJERE,S. I. KOZHUSHKOV, L. LUNAZZI,A. MAZZANI, /. Am. Chem. SOC. 2002, 124, 6706-6713. 22 C. V. RAMANA, S. M. BAQUER,R. G. GONNADE, M. K. GURJAR,Chem. Commun. 2002,614-615.

I433

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

I435

Index

a acetals 252 N-acetylaminoacrylicacid 195 acetylenedicarboxylicacid dimethyl ester 423 acyclic stereocontrol 75 acyloxyborane 173 - chiral 173 1,4-addition 73 - Gilman cuprates 73 adociasulfate 342ff - synthesis 342ff aldol condensation 4 aldol reaction 8, 49, 168, 174, 179, 180, 307, 328ff, 351 - asymmetric 49, 179 - catalytic 174, 179 - diastereoselective 168 aldolase type I 181 alkane 36ff alkene 210ff alkene formation 40 alkene metathesis 31 alkylation 283 - of secondary amines 283 alkyne metathesis 27ff allenes 56ff, 59, 63, 64 - carboxylic esters 63 - cyclopropyl 57 - neighbouring functional groups 64 - neighbouring OH- or NH 59 -vinyl 57 allenyl ketones 62 allenyl sulfones 65 allyl silanes 138 allyl stannanes 138 allyl transfer 432 - radical 432

allylic substitution 79 - organocopper reagents 79 amines 134, 218 - homoallylic 134 - medium ring size 218 amino acids and derivatives 126, 134, 178ff - r-amino nitriles 136 - p-amino acids and derivatives 136, 183 - 8-amino esters 137 - unnatural 126 - synthesis 187 1,2-aminoalcohol 118 aminoalkylations 134ff, 138 aminocyclopropanecarboxylic acid 428 aminoglycosylation 390 aminohydroxylation 118ff, 298 p-amino ketones 182 1,2-aminothiols 370 annulation 425 annulenes 419 anomeric center 5 anti-skew-conformation 422 arene synthesis 54 Arndt-Eistert reaction 336, 339 aryl triflate 344 - Pd-catalyzed reduction 344 arylation 15 -phenols 15 asymmetric 127, 130 - alkylation 94, 125ff - - glycine derivatives 125 - - of benzaldehyde 94 - aminohydroxylation (AA) 118 - catalysis 187 - - Strecker-type reactions 187

cyclopropanation 130 epoxidation 127 - induction 71 - - directed hydroformylation 71 - Michael reactions 127 atropisomers 298ff AUC13 5Off - as catalyst 5Off azasugars 120, 386 aziridines 60 azomethine ylide 361 -

-

b Barbier-type cross coupling 90 Barton deoxygenation 344 Baylis-Hillman reaction 89, 119, 165ff - asymmetric 165ff benzopyran 404 Biginelli reaction 89 BINOL 94, 170, 189ff - fluorous 94 BINOL complex 213 Biphen-Mo catalysts 212 BMIM 105ff boron enolate 309, 354 - chiral 309, 354 boronic acids 19 - aryl ether formation 19 borylation 45 - of alkanes 45 brucin 169 bryostatin 307ff - analogues 312 buckyonions 409 buckytubes 409 Burgess-reagent 310

436

I

Index cyclophanes 409 cyclophilin 350, 358 organogermanium 251 cyclophynes 413ff - radical-mediated 261 cyclopropanation 130, 429, 432 - silanes 251 - asymmetric 130 [COZCO,] 58 - diazomethane 432 combinatorial chemistry 286, - enantioselective 429 319 - [Zn(CH212)].DME 429 combinatorial synthesis 242 cyclopropanes 428ff n-complexes 17 cyclotriveratrylene 111 -chromium 17 cytochrome b562 380 -iron 17 cytostatic agents 317 - manganese 17 - ruthenium 17 d compound libraries 319, 395, DABCO 166 387, 397 - Baylis-Hillman-reaction 1G6 condensation 8 Danishefsky’s diene 90, 289 copper(I ) triflate 18 decarbonylation 414 copper(I1) acetate 19 decarboxylation 363 - aryl ether formation 19 Degussa process 37 Corey-Bakshi-Shibata dehydrogenation 38, 146 reagent 310 - of alkanes 38 coupling 17, 22ff, 42, 64 - of aldehydes and - C-C-bonds 42 ketones 146 - Heck 22 dehydrohomoancepsenolide 31 - palladium 17 dendralene 419ff, 423 - - - catalyzed 64 deoxymannojirimycin 120 - Stille 23 deracemization 174 - Suzuki 22 - palladium 174 CP-225,917 326ff Dess-Martin oxidation 317, CP-263,114 32Gff [CP~H~CI~I-A~OSO 389 ~ C F ~ 344 Dess-Martin periodinane 144, - glycosylation 389 310, 329ff, 354 cross metathesis 222 - intermolecular 222 desymmetrization 214 1,2-diamine 293 cross-coupling 97 - palladium 97 (1S,2S)-diaminocyclohexane 295 cross-metathesis 244 diaminosuberic acid 31 Cu(0Tf)z 295 - as isostere of cystine 31 cyclic peptides K 15 diary1 ethers 15ff cyclisation 406 diazomethane 432 - electrophilic 406 - cyclopropanation 432 cyclitols 1 Dieckmann cyclization 337 cycloadditions 90 [2+2] cycloadditions 63, 91, 328 Diels-Alder reaction 328, 331, 336,401,420f [ 3+2] cycloadditions 8, 10 - diene transmissive 421 [4+1] cycloadditions 57 1,G-dienes 212 [4+2] cycloadditions 57, 420 1,7-dienes 214 [4+4+1] cycloadditions 57 1,x-dienes 210ff [5+1] cycloadditions 57 diethyl zinc 89, 160, 293, 295 cycloalkynes 409 dihydrofuran 61 - strained 409 dihydropyrroles GO cyclogeranyllithium 344 diketopiperazine 361 cyclohexa-l,4-dienes 121 dimethyldioxirane 390 cyclopentanes 223

C

- organoboron 251

Cao 409 calcimycin 74 carbene complex 112 carbocycles 3, 7, 216 - medium ring size 216 - ring-contracted 7 carbocyclic polyols 1 - biosynthesis 1 carbocyclization 3 carbohydrates 237, 387 - solid phase synthesis 237, 387 carbonylation 42, 100 - ofolefins 50 - - gold-catalyzed 50 - radical 100 carbonylative cyclization 60 - ruthenium-catalyzed GO (+)-carvone 317 catalyst immobilisation 114 catalyst-directing group 69ff catalysts - amino acid 178ff - immobilization 93 - metal-free 178 - peptide 178 C-H activation 36, 53 chalcones 406 Charette cyclopropanation 430 chiral DMAP 152 chiral N-oxide 191 chirality 64 chirality transfer 59 - axial-to-central 59 - central-to-axial 64 chloroarenes 22 chromium 17 - n-complexes 17 chrysanthemic acid 428 cinchona alkaloids 170, 202 cinchonidinium and cinchoninium salts 125 - phase transfer catalysis 125 citronellol 293 civetone 29 Claisen rearrangement 9, 110, 432 - orthoester 432 cleavage 251, 255, 256, 261 - carbon-nitrogen bonds 255 - carbon-selenium bonds 261 - carbon-sulfur bonds 256 - of carbon-phosphorus 256

-

lndex I 4 3 7

anti-diols 180 dioxirane 348 [ 1,3]-dipolar cycloaddition 154, 363 discodermolide 322 dithiane 331 DMAP 266 - polymer-bound 266 domino reactions 52, 77, 168, 173, 328 - hydroformylation-Wittig olefination 77 - Michael-aldol 173 - Michael-aldol-retroMichael 168 dysidiolide 400

e electron-rich arenes 52 - functionalization 52 a$-unsaturated carboxylic esters 119 electrophilic selenium 261 eleutherobin 317ff -total syntheses 317 eleuthosides 317 elimination 38 - /I-hydride 38 1,2-eliminations 420 EMIM 106ff enamine 181 enantioselective alkylation 131 enantioselective synthesis 210ff endo-brevicomin 216 enol-ethers 3 enzymatic catalysis 391ff - glycosylations 391ff enzymatic glycosylation 392 enzyme 152 - rhodococcus 152 enzyme-catalyzed reactions 84, 391ff epilachnene 29 epothilone 322 epothilone C 32 epoxidation 86, 127, 184 - asymmetric 127, 184 epoxide opening 86, 206 - nucleophilic enantioselective 206 a$’-epoxy ketones 184 erythromycin A 398 EtzZn 89, 160, 293, 295 Evans oxazolidinone 338, 354

explosions 409 - as synthetic tool 409

f

farnesyl transferase 326 inhibition 326 FeC13.6 H20 88 Ferrier (11) cyclization 3 Finkelstein reaction 91 fluorination 201ff, 206 - enantioselective 201 - transition metal catalysed 206 N-fluorobenzosulfonimide 201 fluoronium cations 201 fluorous solvents 93ff fluorous-phase 93ff Fmoc-strategy 231 FR-900848 429 Friedel-Crafts acylation 109 fullerenes 409 fulvenes 419 functional polymers 266 furans 50 - from allenyl ketones 50 - from propargyl ketones 50 -

g galactosyltransferase 393 galanthamine-library 402 garsubellin A 273 Gilman cuprates 73 - 1,4-addition 73 glycals 390 glycine derivatives 125 - asymmetric alkylation 125 glycosidation 302ff glycosides Iff glycosyl phosphates 386ff - oligosaccharide synthesis 386ff glycosylation 237ff, 317ff, 384ff, 388 - orthogonal 388 gold 48ff - catalysis 48ff green chemistry 107 Gmbbs’ catalyst 31, 211, 398 guanidines 190

h hafnium 389 Hajos-Eder-Sauer-Wiechert reaction 182

Heck reaction 22, 112, 328ff, 365 heterocycles 146, 216, 273 - as scaffolds 273 hetero-Diels-Alder reaction 90, 289 HOBT 267 homoepilachnene 29 homogeneous catalysis 86 homometathesis 215 Horner-Wadsworth-Emmons olefination 73 Hunsdiecker reaction 276 hydride elimination 37 hydroaminomethylation 75 hydroboration 94 - Rh catalyzed 94 hydrocarbons 256 - synthesis 256 hydrocyanation of 188ff hydroformylation 69ff - diastereoselective 69 hydrogenation 76, 194ff, 196 - enantioselective 194, 196 - imine 76 hydrogenolysis 432 - palladium 432 y-hydroxy lactol 331 hydroxymercuration 3 hypervalent iodine reagents 144ff

i IBX 144ff immobilization 93 - of catalysts 93 indium trichloride 89 indolactam library 397 In(0Tf)j 168 ionic liquids 105ff Ireland-Claisen rearrangement 351, 354 iridium complexes 39 iron 17 - n-complexes 17 isatoic anhydride 290 itaconic acid 195

j Jones oxidation 339 Julia olefination 309 Julia-Kocienski olefination 357 Julia-Lythgoeolefination 311

438

I

Index

k

-

(-)-kallolide B 59 ketimines 136 kinetic resolution 151ff, 157, 162,217 - divergent 157 -dynamic 162 - parallel 151ff

-

(R,R)-DIOP 195 (S,S)-DIOP 162 - sulfonamide 293 - tri-teit-butyl-phosphane 22 linkers 251ff lipase 85, 152 - Candida antarctica 85 - crosslinked 152 Luche-reduction 313

motuporamine 29 (-)-mycestericin E 171

n Nagata reagent 331 nakadomarin A 31 nanostructures 412 native chemical ligation (NCL) 374ff natural products 396 I - solid-phase synthesis 396 m lactams 29 nickel 24 macrocycles 29, 307, 350 - macrocyclic, by alkyne macrocyclization 33, 298ff, 313 - catalysis 24, 63 metathesis 29 nicotine 169 - macrotransacetalization 313 lactones 29 macrolactonization 42, 308, 354 y-nitro ketone 183 - macrocyclic, by alkyne nitroolefination 365 macrolides 307 metathesis 29 nonataxel 322 magireol 347 y-lactones 160 Nozaki-Kishi cyclization 318 MALDI-TOF mass spectroLa(OTf)3 166 nucleic acids 237 - Baylis-Hillman-reaction 166 metry 385 - solid phase synthesis 237 Lewis acids 110, 136, 166, 168, manganese 17 - n-complexes 17 295, 342, 343 nucleophilic substitution 201 Mannich bases 134, 137 Ley reagent 356 - fluoride anion 201 LiA1H(OtBu)3 3 Mannich reaction 182 - three-component 182 LiEtjBH 344 0 ligands 22, 23, 24, 38, 40, 60, manumycin C 130 (o-DPPB) 70 86, 90, 122, 135, 137, 157, 160, manzamine alkaloids 120 - as a catalyst-directing 162, 194ff, 213, 293, 295 mCPBA 339 group 70 - alkaloid 122 Ohira-Bestmann MeAlClz 342 - alkaloid (DHQD)zAQN 157 N-mercaptobenzyl-peptides homologation 354 - anthraphos 40 379 olefin-metathesis ZlOff, 401 - BINAP 162, 195 Merrifield resin 319, 387 - asymmetric 210 - bis(diary1)phosphoms 198 Merrifield peptide oligonucleotides 230ff - bis(oxazoline) 60 synthesis 230, 376 - solid phase synthesis 230ff - 2,2’-bispyrimidine 38 metathesis 27ff, 210ff, 219 oligosaccharides 230ff, 384ff - chiral Schiff base 295 - alkynes 27ff - solid phase synthesis 230ff, 384ff - (DHQ)zPHAL 122 - asymmetric 210 - 2-dimethylamino-2’-di-(tee.- ring-closing 210 Oppolzer-sultame 167 buty1)-biphenyl 24 - ring-opening 210 organocopper reagents 79 - (dimethy1)phenylimido 213 - tandem reaction 219 - allylic substitution 79 - diol 90 metathesis catalysts 211ff, 225 organozinc reagents 173 - diphosphanes 196 - Mo-based 211ff - copper-catalyzed 173 - diphosphites 196 - Ru-based 211, 225 ortho-quinones 149 - diphosphonites 196 methyl-ephedrine 169 osmium 118ff methylprolinol 169 -DuPHOS 195 oxazolidinone 398 - imino peptide 135 Michael acceptors 167 oxidations 82, 144ff, 148, 149 - monodentate - chiral 167 - aromatics 82 monophosphoms 194 Michael addition 88, 127, 182f, - benzylic position 148 - 0-(di-teitbutyl-phosphino). 398,401 - hydrocarbons 82 biphenyl 23 - asymmetric 127, 182f - of alcohols 144ff - phosphinooxazoline 86 - diastereoselective 398 -phenols 149 - phosphoramidites 160, 197 Mitsunobu reaction 273 oxy-Cope rearrangement 328, - (R)-2,2‘-DiphenylMo-alkylidenes 212 336 [ 3,3’]biphenanthrenyl-4,4’- Mo(CO), 28 - silyloxy-Cope variant 328 diol = (R)-VAPOL 137 - alkyne metathesis 28 oxygenation 37

-methane 37 ozonolysis 356

pincer complexes 40 platinum 38 - catalysis 38 P,N-ligands 174 P paditaxel 322 - C2-symmetric 174 palladacycles 25 poly-amino acids as 184 palladium 17, 22ff, 97, 99, 112, polycarbonates 83 113, 174, 365,432 polyene cyclization 342ff - catalysis 22ff, 64 polyenes 419ff - - amination 24 polyketide 73, 307 - - reduction 64 polymeric scavenger - cross-coupling 17, 64, 97 reagents 280ff - cyclopropanation 432 polymerization 411 - deracemization 174 - topochemical 411 - dimerisation of polymer-supported catalyst methylacrylate 113 224 - Heck reaction 112, 365 polymer-supported - Stille cross-coupling 99 reagents 144, 265ff - IBX 144 [PdClz(CH3CN)2] 423 polymer-supported WdPPP) 344 Pd(0Ac)z-catalyzed synthesis 395ff carboxymethylation 331 polypropylene processes 83 pentadecalactone 85 L-proline 134, 179 peptides 178ff, 230ff, 369, 372 prostaglandin EZ 32 protecting groups 230ff - chemoselective bond - activating 230ff formation 372 - chemoselective ligation 369 proteins 368ff - solid phase synthesis 230ff - chemical total synthesis - - Merrifield synthesis 230 368ff - template-mediated 372 - solid-phase synthesis 368 pericyclic reactions 420 pyrans 222 perrottetines 15 pyridine-N-oxides 121 Peterson olefination 354 pharmacophore 322 9 phase transfer catalysis 125ff quaternary carbon atoms 136 - asymmetric 125ff r (-)-a-phellandrene 318 racemization 414 phenols 15, 149 radialenes 419 - arylation 15 radical reactions 36, 84, 99ff - oxidation 149 - fluorous phase 99ff phenyliodine(II1) bis(trifluor0acetate) 357 R-BINAP 36df 4-phenyl-l,2,4-trizoline-3,5- reactions in supercritical dione 426 coz 101 reagent-directing group 68ff PhI(0Ac)z 401 - substrate control 68ff phomoidrides 326 phosphitylation of alcohols 274 rearrangements 8, 48, 58 phosphonium salts 256 - of hydrocarbons 48 - vinyl cyclopropane/ PhSeLi 168 Pictet-Spengler cyclopentenc 58 reduction 64 condensation 360 - palladium-ca:alyzed 64 pinacolborane 45 reductive amination 283 pinacol-like rearrangement - primary amine 283 361

resin-capture-release 265 Rh2(4S-MEOX)4 157 [ RhCl(PPh3)3] 194 rhazinilam 42 rhodium - catalysis 42, 69ff, 194, 198 - hydroformylation 69ff rhodium-complex 45 riccardin B 15 ring-closing alkyne metathesis 28 rotanes 431 Rw(CO)IZ 87 ruthenium 17,43,60, 86, 87 - catalysis 43, 60, 86 - x-complexes 17 - carbonylative cyclization 60 S

safety-catch linker 376 saframycin A 267 Sakurai addition 328 salen complex 188 sanglifehrin A 350ff sarcodictyin 319, 317 - libraries 319, 397 Sc(OTf), 110, 343 scalarenedial 346 scavenger resins ZSlff, 265 Schiff base catalysts 188 Schrock-catalyst 210ff selectfluor 203 L-selectride 289 selenium-derived reagents 271ff, 328 - polymer-supported 271ff selenocysteine 378 SeO2 oxidation 328 sequential transformations 75, 363 Shapiro olefin synthesis 270 Sharpless asymmetric dihydroxylation 118, 357 [ 3, 31 sigmatropic rearrangement 9 silver ammonium nitrate 252 silver(I)-catalysts 60 Simmons-Smith 432 single-electron transfer [SET) 146 Srnlz 8 SN2’reaction 61, 173 - copper-catalyzed 173 - palladium-catalyzed 61

440

I

Index

SNAr 301 macrocyclization 301 - reactions 270 sodium periodate 336 solid phase synthesis 230ff, 251, 280, 265ff, 384ff - oligonucleotides 230ff - oligosaccharides 230ff, 384ff - peptides 230ff - traceless linkers 251 solvent-free organic syntheses 82 sophorolipid lactone 33 spiroisoxazolines 8 [ 5.51 spiro-lactam 350 spirotryprostatins 360ff - total synthesis 360ff squalene hexaepoxide 347 squalene synthase 326 - inhibition 326 squalene 2,3-epoxide 342 Staudinger ligation 380 Staudinger reaction 381 Stille coupling 23, 99, 270, 318. 350, 354,423 Strecker reaction 135, 137, 365 Strecker-typereactions 187ff - catalytic asymmetric 187ff structure/activity relationship 320 - sarcodictyin IibraDj 320 substrate control 68ff - reagent-directing group 68ff sulfoxide glycosyl donors 387 superferrocenophane 417 superphane 417 -

Suzuki coupling 22, 252, 256, 275ff, 290, 328. 398 t

TADDOL 206ff Takai olefination 355 tamoxifen 276 tandem Mo-catalyzed metathesis 219 taxoid library 397 teicoplanin 304 tertiary alcohols 217 tetramethylguanidine 89 teurilene 347 thiazolidines 370 thiazolidinyl ester 374 thioethers 256 thioglycosides 241, 275 TiClZ(0iPr)z 308 Tic13 365 Ti(OiPr)C13 5 tipranavir 220 titanium 189 - Strecker reaction 189 Tl(NO,)3 15 TMSOTf 386 toxicol A 344 traceless linkers 251 transesterification 94 transition metal catalysis 111 - in ionic liquids 111 triangulanes 431 triazenes 255 tricarbonylchromiurn complexes 168 trichloroacetimidates 240, 384ff triene 214 triisobutylaluminium 4

triphenylarsine 87 L-tryptophan methyl ester 360 tubulin 323 tubulin polymerization 320 U

U-106305 429 Ullmann reaction

15

vw valdivones 317 vanadium-catalyzed 61 vancomycin 15, 297ff - total syntheses 297 vinyl epoxides 60, 160 Wadsworth-Emmons-Horner homologation 430 Weinreb amides 270, 354 Wieland-Miescher ketone 182 Wilkinson catalyst 94 - fluorous analogue 94 Wittig olefination 72, 319, 430 Wittig ylide 398 - polymer-bound 398 Wittig-Horner reaction 357 Wolff rearrangement 336

Y Yamaguchi macrolactonization 309, 311 ytterbium triflate 89 Z

(2)-N-acetylaminocinnamic acid 195 - esters 195 Ziegler-Natta process 83 zirconium catalysts 136