Heterocyclic Scaffolds I: ß-Lactams (Topics in Heterocyclic Chemistry)

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22 Topics in Heterocyclic Chemistry Series Editor: Bert U. W. Maes

Editorial Board: D. Enders S.V. Ley G. Mehta K.C. Nicolaou R. Noyori L.E. Overman A. Padwa S. Polanc l

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Heterocyclic Scaffolds I b-Lactams

Volume Editor: Bimal K. Banik

With contributions by B. Alcaide P. Almendros A. Arrieta B.K. Banik I. Banik S.S. Bari B. Basu F.F. Becker A. Bhalla F.P. Cossı´o P. Ghosh C. Granito B. Lecea B. Mandal M. Oiarbide C. Palomo E. Pindinelli L. Troisi

The series Topics in Heterocyclic Chemistry presents critical reviews on “Heterocyclic Compounds” within topic-related volumes dealing with all aspects such as synthesis, reaction mechanisms, structure complexity, properties, reactivity, stability, fundamental and theoretical studies, biology, biomedical studies, pharmacological aspects, applications in material sciences, etc. Metabolism will also be included which will provide information useful in designing pharmacologically active agents. Pathways involving destruction of heterocyclic rings will also be dealt with so that synthesis of specifically functionalized non-heterocyclic molecules can be designed. The overall scope is to cover topics dealing with most of the areas of current trends in heterocyclic chemistry which will suit to a larger heterocyclic community. As a rule, contributions are specially commissioned. The editors and publishers will, however, always be pleased to receive suggestions and supplementary information. Papers are accepted for Topics in Heterocyclic Chemistry in English. In references, Topics in Heterocyclic Chemistry is abbreviated Top Heterocycl Chem and is cited as a journal. Springer www home page: springer.com Visit the THC content at springerlink.com

Topics in Heterocyclic Chemistry ISSN 1861-9282 ISBN 978-3-642-12844-8 e-ISBN 978-3-642-12845-5 DOI 10.1007/978-3-642-12845-5 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2010927759 # Springer-Verlag Berlin Heidelberg 2010 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Cover design: WMXDesign GmbH, Heidelberg, Germany Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Series Editor Prof. Dr. Bert U.W. Maes Organic Synthesis Department of Chemistry University of Antwerp Groenenborgerlaan 171 B-2020 Antwerp Belgium

Volume Editor Prof. Bimal K. Banik University of Texas-Pan American Department of Chemistry W. University Drive 1201 78539 Edinburg Texas USA [email protected]

Editorial Board Prof. D. Enders

Prof. K.C. Nicolaou

RWTH Aachen Institut fu¨r Organische Chemie 52074, Aachen, Germany [email protected]

Chairman Department of Chemistry The Scripps Research Institute 10550 N. Torrey Pines Rd. La Jolla, CA 92037, USA [email protected] and Professor of Chemistry Department of Chemistry and Biochemistry University of CA San Diego, 9500 Gilman Drive La Jolla, CA 92093, USA

Prof. Steven V. Ley FRS BP 1702 Professor and Head of Organic Chemistry University of Cambridge Department of Chemistry Lensfield Road Cambridge, CB2 1EW, UK [email protected] Prof. G. Mehta FRS Director Department of Organic Chemistry Indian Institute of Science Bangalore 560 012, India [email protected]

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Editorial Board

Prof. Ryoji Noyori NL

Prof. Albert Padwa

President RIKEN (The Institute of Physical and Chemical Research) 2-1 Hirosawa, Wako Saitama 351-0198, Japan and University Professor Department of Chemistry Nagoya University Chikusa, Nagoya 464-8602, Japan [email protected]

William P. Timmie Professor of Chemistry Department of Chemistry Emory University Atlanta, GA 30322, USA [email protected]

Prof. Larry E. Overman Distinguished Professor Department of Chemistry 516 Rowland Hall University of California, Irvine Irvine, CA 92697-2025 [email protected]

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Aims and Scope The series Topics in Heterocyclic Chemistry presents critical reviews on “Heterocyclic Compounds” within topic related volumes dealing with all aspects such as synthesis, reaction mechanisms, structure complexity, properties, reactivity, stability, fundamental and theoretical studies, biology, biomedical studies, pharmacological aspects, applications in material sciences etc. Metabolism is also included which provides information useful in designing pharmacologically active agents. Pathways involving destruction of heterocyclic ring are also dealt with so that synthesis of specifically functionalized non-heterocyclic molecules can be designed. Overall scope is to cover topics dealing with most of the areas of current trends in heterocyclic chemistry which suits a larger heterocyclic community. The individual volumes of Topics in Heterocyclic Chemistry are thematic. Review articles are generally invited by the volume editors. In references Topics in Heterocyclic Chemistry is abbreviated Top Heterocycl Chem and is cited as a journal. vii

.

Preface

The significance of the stereocontrolled synthesis of chiral and achiral b-lactams with their mechanism of formation has gained attention in connection with the structure–activity relationship study and the development of b-lactam antibiotics, b-lactam anticancer agents, cholesterol-lowering drugs, nitrogen-containing heterocycles and inhibitors of b-lactamases. However, b-lactam antibiotics have still occupied a major role in the treatment against pathogenic bacteria and thus improve in quality of human life. But, the extensive use of common b-lactam antibiotics (e.g., penicillins and cephalosporins) in medicine has created severe obstacles because of an increasing number of resistant strains of bacteria through mutation and b-lactamase gene transfer. Due to the increased bacterial as well as tumor cell resistance, there has been enormous effort devoted to prepare new structural types of compounds having the 2-azetidinone ring as a common feature. The diversity of this book by Springer “Heterocyclic Scaffolds I: b-Lactams” in “Topics in Heterocyclic Chemistry” is confirmed in the wide range of significant topics written by experts in this field. Each one of the seven chapters presented in this book has focused on the very recent aspects in the b-lactam research. Alcaide and Almendros as well as Bari and Bhalla have described very powerful strategies for the preparation of unusual spirocyclic b-lactams. Troisi et al. and Palomo and Oiarbide have described the synthesis and application of b-lactams for the preparation of nitrogen-containing molecules. Basu et al. describe the preparation of b-lactams using solid-supported reagents. Cossio’s group has studied computational approach to identify the mechanistic routes on the synthesis of a variety of b-lactams. Development of novel anticancer b-lactams along with their mechanisms of action has been provided by our group. I take this opportunity to sincerely thank and congratulate the authors for their very significant and useful contribution. This book provides a deeper understanding of the art of b-lactam research to the chemists, biologists, pharmacologists, and clinicians at industrial and/or academic research institutions throughout the world. Edinburg, Texas TX, USA April 2010

Bimal K. Banik

ix

.

Contents

Novel Aspects on the Preparation of Spirocyclic and Fused Unsual b-Lactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Benito Alcaide and Pedro Almendros Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Shamsher S. Bari and Aman Bhalla Novel and Recent Synthesis and Applications of b-Lactams . . . . . . . . . . . . . 101 Luigino Troisi, Catia Granito, and Emanuela Pindinelli b-Lactam Ring Opening: A Useful Entry to Amino Acids and Relevant Nitrogen-Containing Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 C. Palomo and M. Oiarbide Recent Approaches Toward Solid Phase Synthesis of b-Lactams . . . . . . . 261 Bablee Mandal, Pranab Ghosh, and Basudeb Basu Computational Studies on the Synthesis of b-Lactams via [2þ2] Thermal Cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 Ana Arrieta, Begon˜a Lecea, and Fernando P. Cossı´o Novel Anticancer b-Lactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349 Bimal K. Banik, Indrani Banik, and Frederick F. Becker Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375

xi

Top Heterocycl Chem (2010) 22: 1–48 DOI 10.1007/7081_2009_7 # Springer‐Verlag Berlin Heidelberg 2010 Published online: 22 January 2010

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams Benito Alcaide and Pedro Almendros

Abstract b-Lactam antibiotics have occupied a central role in the fight against pathogenic bacteria and the subsequent rise in quality of life for the world population as a whole. However, the extensive use of common b-lactam antibiotics such as penicillins and cephalosporins in medicine has resulted in an increasing number of resistant strains of bacteria through mutation and b-lactamase gene transfer. The resistance of bacteria to the classical b-lactam antibiotics can be overcome, e.g., by using novel b-lactam moieties in drugs, which show much higher stability towards these resistance bacteria. In addition, there are many important nonantibiotic uses of 2-azetidinones in fields ranging from enzyme inhibition to gene activation. These biological activities, combined with the use of these products as starting materials to prepare a- and b-amino acids, alkaloids, heterocycles, taxoids, and other types of compounds of biological and medicinal interest, provide the motivation to explore new methodologies for the synthesis of substances based on the b-lactam core. The aim of this chapter is to provide a survey of the types of reactions used to prepare nonconventional spirocyclic and fused b-lactams, concentrating on the advances that have been made in the last decade, particularly in the last 5 years. We will draw special attention to radical cyclizations, cycloaddition reactions, and transition metal-catalyzed reactions. Keywords b-Lactams Cycloadditions Fused-rings Metals Spirocycles

B. Alcaide (*) Departamento de Quı´mica Orga´nica I, Facultad de Quı´mica, Universidad Complutense de Madrid, 28040 Madrid, Spain e-mail: [email protected] P. Almendros (*) Instituto de Quı´mica Orga´nica General, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain e-mail: [email protected]

2

B. Alcaide and P. Almendros

Contents 1 2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Preparation of Spirocyclic-b-Lactams with Nonclassical Structure . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.1 Using Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.2 Using Cyclization and Rearrangement Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2.3 Using Metal-Mediated Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 3 Preparation of Fused b-Lactams with Nonclassical Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3.1 Using Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3.2 Using Radical Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 3.3 Using Metal-Mediated Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 3.4 Using Cyclization Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

1 Introduction Since the advent of penicillin, the b-lactam antibiotics have been the subject of much discussion and investigation, within the scientific as well as the public sectors [1–7]. b-Lactam antibiotics have occupied a central role in the fight against pathogenic bacteria and the subsequent rise in quality of life for the world population as a whole. However, the extensive use of common b-lactam antibiotics such as penicillins and cephalosporins (Fig. 1) in medicine has resulted in an increasing number of resistant strains of bacteria through mutation and b-lactamase gene transfer. It is well known that bacterial resistance to b-lactam antibiotics stems from the expression of a b-lactamase that catalyzes the hydrolytic cleavage of the substrate amide bond. b-Lactamases can be classified into four different classes (A–D) according to structure. Class A, C, and D b-lactamases are serine enzymes, the serine residue acting as the nucleophile in the hydrolysis reaction. Class A b-lactamases are also known as “penicillinases” on account of the ease with which they can hydrolyse penicillins, and class C b-lactamases as “cephalosporinases” by virtue of their increased activity against cephalosporins. Of the four structural classes of this enzyme, metallo-b-lactamases (class B) contain zinc and other divalent cations as cofactors. Two main therapeutic strategies have been adopted to counteract bacterial resistance to b-lactam antibiotics. One strategy consists of modifying the structure H N

R O

S N

O

Me

Me H CO2H

penicillins

Fig. 1 Common b-lactam antibiotics

H N

R O

S N

CH2OAc CO2H cephalosporins O

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams

3

of the b-lactam antibiotic, aiming to render it insensitive to the b-lactamase attack. Recently, trinems antibiotics (depicted in Fig. 2) have been the subject of considerable study owing to their broad spectrum of antibacterial activity, resistance to b-lactamases, and stability to renal dehydropeptidases [8–13]. As a result of their impressive biological activity, tricyclic b-lactams have become interesting targets for synthesis. A second approach uses a reagent, typically a b-lactam derivative, that incapacitates the b-lactamase, in synergy with the b-lactam antibiotic. Clavulanic acid (depicted in Fig. 2) is the archetype of b-lactamase inhibitors [14]: in synergistic mixture with amoxicillin (depicted in Fig. 2), under the name “augmentin”, it arrived in the field some years ago. Both approaches have produced results and a new generation of antibiotics has been developed. In addition, there are many important nonantibiotic uses of 2-azetidinones in fields ranging from enzyme inhibition [15–21] to gene activation [22]. Systems containing one carbon atom common to two rings, spirocyclic compounds, represent an important structural organization. Spirocyclic b-lactams (Fig. 3) behave as b-turn mimetics [23–26] as well as enzyme inhibitors [27, 28], they are precursors of a,a-disubstituted b-amino acids [29–32], and the spiranic b-lactam moiety is present in chartellines and chartelamides [33–38], a family of marine natural products. Synthetic studies and biosynthetic speculation inspired by an unexpected reaction on the marine alkaloid chartelline C have been described [38]. These biological activities, combined with the use of these products as starting materials to prepare a- and b-amino acids, alkaloids, heterocycles, taxoids, and other types of compounds of biological and medicinal interest [39–47], provide the motivation to explore new methodologies for the synthesis of substances based on the b-lactam core. The cyclic 2-azetidinone skeleton has been extensively used as a template on which to build the carbo(hetero)cyclic structure joined to the four-membered ring, using the chirality and functionalization of the b-lactam ring as a stereocontrolling element. This review embraces the gamut of unusual b-lactams, including spiranic and fused 2-azetidinones. Without a doubt, this contribution does not include every report of unusual b-lactams, nor does it fully summarize all aspects of the cited references. Instead, examples have been chosen based on their demonstrated and potential usefulness, in the opinion of the authors. The aim of this review is to provide practicing and aspirant b-lactam chemists with a survey and flavor of the types of reactions used to prepare nonconventional b-lactams, and an insight into why certain methodologies are advantageous under particular circumstances, HO H H N O

NH2 H N OMe CO2H

trinems

HO

O

S N

O

amoxicillin

Fig. 2 b-Lactam antibiotics and b-lactamase inhibitor

O

Me N

Me CO2H

O

CO2H clavulanic acid

OH

4

B. Alcaide and P. Almendros R1 N

R2

R2

N

O

Cl

N

N N H R1 b-turn mimetics

O

O

R3 inhibitors of cholesterol absortion R1 = OH, R2 = F, R3 = OH (Sch 58053) R1 = OMe, R2 = H, R3 = H (Sch 54016)

O Br

Br

O

N

R N

Br

N

N

R Br

H3C Br

N

R'

O

R = H (chartelamide A) R = Br (chartelamide B)

N

Cl N Br N H

R = R' = Br (chartelline A) R = Br, R' = H (chartelline B) R = R' = H (chartelline C)

Fig. 3 Biologically relevant spirocyclic b-lactams

concentrating on the advances that have been made in the last decade, particularly in the last 5 years. We will draw special attention to radical cyclizations, cycloaddition reactions, and transition metal-catalyzed reactions.

2 Preparation of Spirocyclic-b-Lactams with Nonclassical Structure 2.1

Using Cycloaddition Reactions

The synthesis of pyrrolidine and tetrahydrofuran spiro-b-lactams by a Staudingertype process [48] has been reported. The b-lactams 4 and 5 were prepared by reaction of either 2-tetrahydrofuroyl chloride 2 or 3-tetrahydrofuroyl chloride 3 with imines 1 (Scheme 1). The acid chloride was added to a stirred, refluxing solution of the imine and triethylamine in toluene. After refluxing of the solution overnight and aqueous work-up, a mixture of cis- and trans-spiro-b-lactams 4 or 5 was obtained in good to moderate yields. When other solvents such as dichloromethane and lower temperatures were used, the starting materials were always recovered. The b-lactams 4 and 5 are the expected products of the [2þ2] cycloaddition reaction of imines with the corresponding cyclic ketenes. In all cases, the

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams

5

R2 1

R

1 COCl

N

X

R1

R3

X

Et3N, toluene, D 49–77%

2X=O 3 X = NCbz

(d.r. = up to 85:15)

R2 N

O

X

R1 +

R2 N

R3

O

4

R3

5

Scheme 1 Preparation of spirocyclic b-lactams through Staudinger reaction

X

Me N

Me O N COCl

X = NCbz, O

Et3N, toluene

+

N Ar 6

RT or D 77–91%

O

N Ar X

O

7

Scheme 2 Preparation of spirocyclic diazepan-b-lactam hybrid 7 through Staudinger reaction

diastereomeric mixtures of spiro-b-lactams 4 and 5 were separated by column chromatography. The relative configuration in the stereogenic centres of the azetidinone ring was established by nuclear overhauser effect (NOE) difference NMR experiments. This protocol was also applied to diazepam derivatives 6 [49]. When these compounds were treated with N-benzyloxycarbonyl-L-proline acid chloride and tetrahydrofuroyl chloride, the expected spirocyclic systems 7 (Scheme 2) were obtained in good yields. In the case of the N-benzyloxycarbonyl-L-proline acid chloride, the reaction was carried out at room temperature, while the process involving the tetrahydrofuroyl chloride needed to be performed in refluxing toluene. This higher temperature was the likely cause of the loss of selectivity observed in the latter case, in which a 10:1 mixture of diastereoisomers was obtained. Staudinger reaction of imine 8 derived from 7-oxanorbornenone with 2-alkoxyacetyl chlorides in the presence of Et3N (toluene, RT), afforded b-lactams 9 (Scheme 3). These were obtained as single diastereomers, and no traces of the corresponding isomeric exo-b-lactams were detected in the crude reaction products [50]. It is worth mentioning that this stereochemical outcome of b-lactam formation with acid chlorides under Staudinger reaction conditions was opposite to the one expected from a simple [2þ2]-cycloaddition reaction, which should have taken place from the exo face of compound 8. Optically active a-methylene-b-lactam 10 was synthesized and submitted to 1,3-dipolar cycloadditions with diazomethane, 4-methoxybenzonitrile oxide, and diphenylnitrone [51]. All cycloadditions proceed with complete regioselectivity giving products 11–13 in an antifashion with respect to the substituent at the

6

B. Alcaide and P. Almendros O

O RO

Et3N

Cl

toluene, RT 70–80%

+ N

O

N RO

O

8

9

Scheme 3 Preparation of spirocyclic 7-oxanorbornene-b-lactam 9 through Staudinger reaction

OTBS

CH2N2, Et2O

N O

6h, 0oC (d.r. = 87:13)

TBS

N N

OTBS

+

N O

TBS

TBS 11b

11a

PMP

PMP N OH

PMP OTBS

Cl

N O

TBS 10

NEt3, Et2O 95% (d.r. = 87:13) – O N+ Ph

OTBS N TBS 10

OTBS

N O

10

O

N N

Ph toluene 3h, reflux (d.r. = 86:14)

N O

OTBS +

N O

N O

OTBS N

O

TBS

TBS 12b

12a

Ph

Ph Ph N O

OTBS

+

Ph N O

OTBS N

N O

TBS 13a

O

TBS

13b

Scheme 4 Preparation of spirocyclic b-lactams using cycloadditions

C4-position of the starting b-lactam in diastereomeric ratios of about 85:15 (Scheme 4). Pure optically active compounds could be obtained in almost all cases after chromatography. Unambiguous structure elucidation could be achieved by X-ray crystal analysis and NOE investigations.

2.2

Using Cyclization and Rearrangement Reactions

A model compound 15 containing an indole b-lactam moiety in chartellines was synthesized from the Mannich reaction of isatin imine with ketene silyl acetal, followed by b-lactam formation through cyclization of the resulting b-amino acid 14 (Scheme 5) [52]. L-Proline-catalyzed direct asymmetric Mannich reactions of

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams Scheme 5 Preparation of spirocyclic oxindole-blactam 15

7 O

COOH NH2 O N Me

NH

Et3N

O

CH3CN, reflux

N Me

70%

14

Scheme 6 Preparation of spirocyclic dihydropyridine b-lactam 17 (i) LDA, –40 C; (ii) E–Cl

15

X

E

O X

N N

N

But Ph

Y 16

i

Y

Ph

ii

N O

But

17 (39–91%)

N-PMP protected a-imino ethyl glyoxylate with various a, a-disubstituted aldehydes affords quaternary b-formyl a-amino acid derivatives with excellent yields and enantioselectivities. The Mannich products are further converted to the corresponding spiranic b-lactams [53]. The synthesis of spiro-linked b-lactam-dihydropyridines 17 through the cyclization of lithiated pyridine carboxamides 16 has been achieved (Scheme 6) [54]. Thus, treatment of 16 with LDA at 40 C and addition of methyl chloroformate led to the formation of the corresponding dearomatized product in 91% yield. Other acylating agents, namely, benzyl chloroformate and benzoyl chloride, were equally effective at promoting this new type of cyclization as was methyl triflate. Methyl iodide gave significantly lower yields, and no dearomatized product was obtained on quenching with ammonium chloride – a good indication that electrophilic attack at the pyridine nitrogen is needed to promote the cyclization. It is presumed that the electrophile attacks the lithiated amide at the pyridine nitrogen rather than the considerably more basic organolithium center, presumably for steric reasons. The resulting pyridinium system is activated towards attack at C4, and the spirocyclic b-lactam results. 1,3-Dipolar cycloaddition of nitrones 18 to bicyclopropylidene 19 gave the corresponding cycloadducts 20. Treatment of these bis-spirocyclopropanated isoxazolidines with trifluoroacetic acid in acetonitrile furnished the corresponding 3-spirocyclopropanated b-lactams 21 in good yields. The structure of the b-lactam derived from N-benzyl-C-(methoxycarbonyl)nitrone was proved by X-ray crystal structure analysis. Thus, this new method furnishes compounds with a 5-azaspiro [2.3]hexan-4-one skeleton in 68–94% overall yield in two simple steps (Scheme 7) [55]. The one-pot three-component reaction for the direct conversion of certain alkylhydroxylamine hydrochlorides (alkyl = benzyl, p-methoxybenzyl, benzhydryl, tert-butyl), formaldehyde or an alkyl glyoxylate and bicyclopropylidene 19

8

B. Alcaide and P. Almendros R1 R2

+ N

+ – O

71–100%

18 R1

R1

C6H6, 20–60oC

R2 N O

19

R1

CH3CN, TFA 70oC 75–96%

R2

N

20

= CO2Me, Ph, CN, 2-Py;

R2

O 21

= Bn, PMB, Me

Scheme 7 Preparation of spirocyclic cyclopropane b-lactam 21

O2N

HO H

Br

O O

N O

PMP

O K2CO3, MeOH

H

O O

O 2N N

RT, 5h

O

22

PMP

23 (60%)

Scheme 8 Preparation of spirocyclic oxirane b-lactam 23

Scheme 9 Preparation of spirocyclic 1,3-dioxolane b-lactam 25 (i) BnNH2, 1,4-dioxane, RT; (ii) K2CO3, THF, RT, 8 days

O

N3CH2

O CH2OTf

O

O

O

i ii

N3CH2 HO O

24

O N Bn

25 (89%)

to furnish the 3-spirocyclopropanated 2-azetidinones related to 21 has also been developed. Microwave heating of mixtures of the three components in the presence of sodium acetate in ethanol for 15–120 min furnished the spirocyclic b-lactams in 49–78% yield (seven examples) [56]. Oxaciclopropane formation has been observed to give the highly strained oxiranyl-b-lactam 23, possessing a spirocyclic structure by treatment of a 3-[bromo(nitro)methyl] 3-hydroxy-b-lactam 22 with bases (Scheme 8) [57]. The structure of the spirocycle 23 was proved by X-ray crystal structure analysis. Treatment of bicyclic lactone 24 with benzylamine in dioxane afforded an open chain triflate amide, which was stirred in THF in the presence of potassium carbonate to cyclizate to the spirocyclic b-lactam 25 (Scheme 9) [58].

2.3

Using Metal-Mediated Reactions

The synthesis of oxaspiro-b-lactam structures containing five- and six-membered rings was explored through RCM reaction. Unfortunately, dienes 26–29 having a

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams

O H

O

O

O H

O

9

O

i N

N O

O

PMP

MeO2C

PMP

30 (91%)

26

O H

O

O

O H

O

O

i N

N O

O

PMP

PMP

31 (60%)

27

O

O O H

O

O

O H

O

O

i N

N O

O

PMP

O

O

O

PMP 34

O

O H

O

O

OH

O

O

i

X

N

PMP

32 (100%)

28

N

N O

PMP 29

O

PMP

33 (53%)

Scheme 10 Preparation of spirocyclic b-lactams using alkene methatesis (i) [Cl2(PCy3)2Ru = CHPh], toluene, reflux

quaternary center proved to be resistant to ring closure mediated by Ru-based first generation Grubbs’ carbene under smooth reaction conditions (5 mol%, CH2Cl2, 25 C). The majority of the reaction mixture was composed of unreacted dienes. It was found that dienic substrates 26–29 require more vigorous conditions for ring closure. Spiro ring-closing metathesis was achieved upon heating at reflux temperature in a toluene solution. Under optimized conditions (5 mol% Grubbs’ carbene, toluene 0.03M, 110 C), good yields of unusual b-lactams 30–32 containing dihydrofuran, dyhydropyran, and dyhydropyranone spiranic rings were obtained (Scheme 10). The six-membered spiro compound 33 which bears an exocyclic methylene was achieved when the spirocyclization took place on triene 29. No traces of the five-membered regioisomer 34 could be detected, because only the least substituted double bond of the 1,3-diene system reacted (Scheme 10) [59]. Treatment of enynes 35 and 36 with first generation Grubbs’ carbene under the above diene ring-closing metathesis conditions did not furnish the desired spirocycles. Next, trials of cyclization were attempted by using its imidazolidinylidene

10

B. Alcaide and P. Almendros

Scheme 11 Preparation of spirocyclic b-lactams using alkyne methatesis (i) [Cl2(Im) (Cy3P)Ru = CHPh], toluene, reflux

O H

O

O

O H

O

O

i N O

N PMP

O

35

PMP

37 (35%)

O H

O

O

O H

O

O

i N O

N O

Bn 36

Bn

38 (44%)

CO2Me MeO2C

O

O H

O

O H

O

O

i Br

N

N O

R

39a R = PMP 39b R = Bn

O

R

40a R = PMP (47%) 40b R = Bn (50%)

Scheme 12 Preparation of spirocyclic b-lactams 40 using Heck reaction (i) Pd(OAc)2, PPh3, K2CO3, DMF, 105 C

analog, the more active second generation Grubbs’ carbene. In this way, the spirocyclization was effective on enyne-b-lactams 35 and 36 to afford the innerouter-ring dienes (cyclic dienes in which one of the double bonds is endo-cyclic) 37 and 38 (Scheme 11) [60]. Palladium-catalyzed reaction of bromo dienes 39 was complete after a few hours, and afforded spirocycles 40a and 40b as single regio- and stereoisomers (Scheme 12). The Heck spirocyclization reaction is regioselective, giving fivemembered heterocycles. In addition, it is stereoselective because the Heck adducts were obtained as single geometric isomers [60]. The AgNO3-induced reaction of b-lactam-tethered a-allenic alcohols 41 gave, with concomitant acetonide cleavage, the spirocyclic dihydrofurans 42 in quantitative yields (Scheme 13) [59]. The palladium-catalyzed cyclizative coupling reaction of a-allenols 41 with alkenyl halides was also explored. The transformation of allenols 41 into spirocyclic disubstituted dihydrofuran b-lactams 43 was readily achieved in high yields, by treatment with allyl bromide or 2,3-dibromopropene in the presence of palladium (II) chloride (5 mol%) (Scheme 14) [60]. The formation of spirocyclic azetidinones 43 could be explained following a Pd (II)-catalyzed mechanism. Initial Pd(II)-coordination gave an allenepalladium

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams

O

R2 OH

O H

O

OH

11

OH

i N O

R1

42a (100%)

41a R1 = PMP, R2 = Me 1=

N

R2 O

R1

42b (100%) 42c (100%) 42d (100%)

R2 =

Ph 41b R PMP, 41c R1 = Bn, R2 = Me 41d R1 = Bn, R2 = Ph

Scheme 13 Ag-promoted preparation of spirocyclic b-lactams 42 (i) AgNO3 (1 equiv), acetone– H2O (1:1), reflux X

O

R2 OH

O H

O

O

O

i N O

R1

41a R1 = PMP, R2 = Me 41b R1 = PMP, R2 = Ph 41c R1 = Bn, R2 = Me 41d R1 = Bn, R2 = Ph 41d R1 = Bn, R2 = Ph

X Br

R2 O

N

R1

43a X = H (85%) 43b X = H (100%) 43c X = H (65%) 43d X = H (93%) 43e X = Br (95%)

Scheme 14 Pd-catalyzed preparation of spirocyclic b-lactams 43 (i) 5 mol% PdCl2, DMF, RT

complex 44. Species 44 suffered an intramolecular cycloetherification reaction to give the palladadihydrofuran 45. Intermediate 45 reacted with the appropriate allyl bromide to form intermediates 46, which after dehalopalladation generated spirob-lactams 43 with concomitant regeneration of the Pd(II) species (Scheme 15) [60]. Using a single catalytic system a domino cyclization of a-allenols-cross coupling (Heck, Sonogashira, and Suzuki) reaction sequence for the synthesis of spirob-lactams [61] has been successfully accomplished. Treatment of enantiopure a-allenols 41 with the appropriate coupling partner under optimized conditions, led to the formation of the desired products 47–49 as single isomers (Scheme 16). Similarly, the heterocyclizative cross-coupling between 2-azetidinone-tethered allenols and a-allenic acetates has resulted in the achievement of b-lactam-dihydrofuran hybrids in good yields [62]. The formation of spirolactams 47–49 could be rationalized in terms of a sequence domino cyclization of a-allenols-cross coupling reactions. A palladium (II)-catalyzed mechanism for the domino sequence leading to spiranic adducts 47–49 is proposed in Scheme 17. It could be presumed that the initially formed allenepalladium complex 50 undergoes an intramolecular attack by the hydroxyl group (oxypalladation), giving rise to the spirocyclic vinylic palladium species 51.

12

B. Alcaide and P. Almendros

X O H N

R2 O

O

O N

O

R1 PdII Cl2

43

Br

O

R2 OH

O

41

X O H

O

R1

LnCI2Pd

O

O

R2 OH

O N

L2ClPd

N

R2 O

R1

O

R1

44

46

O H

L2ClPd

O

O X

R2 O

N 45

Br R1

Scheme 15 Mechanistic explanation for the formation of spirocyclic b-lactam 43

O

Me OH

TMS

+ N O

PMP

Cu(OAc)2, K2CO3, O2

Me

MeCN, RT

B(OH) 2 O

Bn

O

Me

Me

MeCN, RT

41c

O N

O

Bn

48 (47%)

O

Bn

O

CO 2 Me Pd(OAc)2, LiBr, PPh3 +

N

O

MeO2 C

O

41c 41d

PMP

O

Me Cu(OAc)2, K2CO3, O2

N

O

N O

Pd(OAc)2, LiBr, PPh3 +

R OH

O

47 (43%)

O

O

O

Pd(OAc)2, LiBr, PPh3

41a

Me OH

O

TMS

O

Cu(OAc)2, K2CO3, O2

R O

MeCN, RT

O N Bn

49a R = Me (58%) 49b R = Ph (56%)

Scheme 16 Pd-catalyzed preparation of spirocyclic b-lactams 47–49

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams

R3 HO R

N

O

CO2Me

PdLn(OAc)2

R3 HO Pd(II)

2

O

2

R

coordination

R

N

N

R1 49a, 49b

R1 50

b-hydride –HPdLn(OAc) elimination

oxypalladation

FG O R2 N

R3 O

R1 47–49

PdLn(OAc) O cross-coupling reaction

R3 O

R2

R3 O

2

O

R1 41

13

N

CO2Me O O OMe

insertion

R1 51

R3 O

R2

PdLn(OAc)

N R1 52

n = 0, 1; FG = aryl, heteroaryl, alkenyl, alkynyl Pd(0)

oxidizing agent

Pd(II)

Scheme 17 Mechanistic explanation for the formation of spirocyclic b-lactams 47–49

Next, palladadihydrofuran intermediate 51 is trapped by the cross-coupling reagents leading to compounds 47–49. For example, the palladium species 51 can then form the intermediate 52 in a subsequent Heck reaction with acrylate, which leads to the final spirocycles 49a and 49b and Pd(0) in a b-hydride elimination [61]. It is necessary for the catalytic cycle that Pd(0) is reoxidized to Pd(II); this is achieved by the addition of Cu(OAc)2, which does not interfere with the course of the reaction.

3 Preparation of Fused b-Lactams with Nonclassical Structure 3.1

Using Cycloaddition Reactions

Enantiopure carbacepham derivatives 54 have been prepared in good yields via Lewis acid promoted carbonyl-ene cyclization of the corresponding 2-azetidinonetethered alkenylaldehydes 53 (Scheme 18) [63]. Starting from some of the above 1-hydroxycarbacephams 54, the synthesis of inner-outer-ring 2-[tert-butyldimethylsilyloxy]dienes 55 with a carbacepham structure and their totally p-facial endo selective Diels–Alder reactions to structurally novel polycyclic b-lactams 56 have been reported (Scheme 19) [64]. It has been shown that the combination of ring-closing metathesis and Diels– Alder reaction sequences is a useful synthetic tool for the asymmetric synthesis of

14

B. Alcaide and P. Almendros

R1O

CHO Me N

Me

O

BF3 OEt2 0oC, 2h 64–88%

R2

H

R1O

OH Me

N O R2

53

54

R1 = Ph, Bn, Me R2 = H, CO2Me

Scheme 18 Preparation of bicyclic b-lactam 54 using ene-reaction

Me

O N

O MeO

H

OH

N O

2 R1 R

54

i, MsCl, Et3N Me ii, RuCl3, NaIO4, Cl2C2H4

MeO

H OP NMM, toluene N

iii, DBU, C6H6 iv,TBSTf, Et3N, CH2Cl2, 0 oC

O

55

H N

sealed tube 145 oC 63–91%

2 R1 R

48–64%

MeO

O

OP

H 2

R1 R 56

Scheme 19 Preparation of tetracyclic b-lactam 56 using Diels-Alder reaction

CO2Me OTBS

OTBS RuCl2(=CHPh)(PCy3)2

Me N O 57

CH2Cl2, 50oC, 22h 87%

OTBS CO2Me

Me N O

CO2Me CO2Me

Me N

92% O

58

59

Scheme 20 Preparation of tricyclic b-lactam 59 using Diels-Alder reaction

novel polycyclic carbacephem derivatives [65–67]. Thus, enyne metathesis of monocyclic 2-azetidinone 57 afforded the bicyclic compound 58. This diene was then engaged in a Diels–Alder reaction with dimethyl acetylenedicarboxylate as dienophile to obtain tricyclic b-lactam 59 in high yield (Scheme 20). It has been demonstrated that the intramolecular Diels–Alder reaction is a simple and efficient entry to different tricyclic 2-azetidinones, with a six-membered ring fused to the b-lactam nucleus. Homoallylic mesylate 60 was used for the stereoselective preparation of fused tricyclic 2-azetidinone 61 through a tandem one-pot elimination-intramolecular Diels–Alder reaction (Scheme 21) [68, 69]. In a similar way, starting from mesylate 62, elimination and intramolecular Diels–Alder reaction have allowed the preparation of enantiopure fused tetracyclic b-lactam 63 (Scheme 22) [70]. 1,4-Cyclohexadiene 63 is prone to undergo aromatization to afford the tetracyclic b-lactam 64 containing a benzene ring, as illustrated in Scheme 22.

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams

MeO

H

OMs DBU, toluene

N

190 oC, 68h 51%

O 60

MeO

15

H N

H

O 61

Scheme 21 Preparation of tricyclic b-lactam 61 using tandem elimination-intramolecular DielsAlder (IMDA) reaction

MeO

H

OMs DBU, benzene

N O

190 oC 68%

62

MeO

H N

O

63

H

CDCl3, RT, 24h quantitative yield

MeO

H N

O

64

Scheme 22 Preparation of tetracyclic b-lactam 64 using tandem elimination-IMDA reaction

Reaction of enallenes 65 or allenynes 66 in the presence of methanesulfonyl chloride at 190 C provided tricyclic azetidinones 67 or 68. These tricycles have been obtained from monocyclic allenols, masked functionalized dienes, via a domino allenol transposition/intramolecular Diels–Alder reaction process (Scheme 23) [71, 72]. The mechanism of the one-pot allenol-diene transformation is depicted in Scheme 24. The extremely high selectivity observed in the formation of dienes may point to a pericyclic reaction pathway. Accordingly, the allenol component reacts with methanesulfonyl chloride resulting in a methanesulfonate intermediate. Next, the in situ generated a-allenic methanesulfonate 69 suffers a [3,3]-sigmatropic rearrangement, involving the six-membered cyclic transition structure 70, to give the corresponding mesyloxy-diene counterpart 71. A convenient metal-free methodology for the preparation of structurally novel strained tricyclic b-lactams containing a cyclobutane ring has been developed. The first examples accounting for the intramolecular [2þ2] cycloaddition reaction in blactams have been achieved via the thermolysis of 2-azetidinone-tethered enallenols 72 and 74 [73]. As shown in Scheme 25, enallenes 72 and 74 efficiently undergo [2þ2] thermal cyclization to afford the corresponding strained tricycles 73 and 75. The tricyclic ring structures 73 and 75 arise from a formal [2þ2] cycloaddition of the alkene with the distal bond of the allene, most likely via a diradical intermediate. Exposure of N-methallyl allenols 76 to the above thermal treatment afforded methylenecyclobutane 2-azetidinones 77 as the only products (Scheme 26). Notably, the presence of an internal substituent on the alkene moiety switched the regioselectivity. The successful reversal of regioselectivity in the allene component by just a subtle variation in the substitution at the alkene moiety is an important development. In the current case, it allowed the preparation of a diverse array of structurally novel strained tricyclic b-lactams. For example,

16

B. Alcaide and P. Almendros

H H

i

Me

43%

N O

OMs

H

OH

H Me H

H

N PMP

O

PMP 65a

67a (100:0) H

H H

O

OMs

OH Me

54%

N

O

i

H

Bn

O

N

H Me H Bn

O

67b (95:5)

65b

OMs H H

MeO

OH i

Me

MeO

47%

N O

Me H H N

H H

O 65c

67c (100:0) OMs OH

H H

Me

H

N O

45% PMP

N O

H H

OH

OMs Me i

N O

PMP

68a (100:0)

66a

O

H Me H

i

58%

Bn

O H

N

H Me H Bn

O

68b (85:15)

66b

OMs H H

MeO

N O 66c

OH Me

i

MeO

52%

Me H H N

H

O 68c (100:0)

Scheme 23 Preparation of tricyclic b-lactams 67–68 using allenol transposition-IMDA reaction (i) CH3SO2Cl, Et3N, toluene, sealed tube, 190 C

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams

CH3SO2Cl

O

R1

EtN3

65, 66

69

R2

Me

MsO 67, 68

S

O

R2

R1

O

R1

IMDA

O

Me

OH

17

O S

O

R1

R2 71

R2 70

R1 = 2-azetidin one-tethered alkene(alKyne); R2 = Me or Ph

Scheme 24 Mechanistic explanation for the allenol-1,3-diene transformation

MeO

H H

OH

R

MeO X

N

H H

OH R

MeO

i

H H

N

O

OH

R

N

O

O H

H H

MeO

72d R = Me

73a, 56%, dr = 100 : 0

72e R = Ph

73b, 58%, dr = 100 : 0

72f R = H

73c, 40%, dr = 100 : 0

OH R i

MeO

OH

R

N

N O

H H

O H

74a R = Me 74b R = Ph

75a, 45%, dr = 100 : 0 75b, 57%, dr = 100 : 0

Scheme 25 Preparation of tricyclic b-lactams 73 and 75 using [2+2] cycloaddition (i) Toluene, sealed tube, 220 C

enantiopure compounds 77 are remarkable since they bear two quaternary stereogenic centers. The formation of fused strained tricycles 73 and 75 can be rationalized by a mechanism which includes an exocyclic diradical intermediate 78 through an initial carbon–carbon bond formation, involving the central allene carbon and the proximal alkene carbon atom (path A, Scheme 27). An alternative mechanism for the

18

B. Alcaide and P. Almendros

Scheme 26 Preparation of tricyclic b-lactams 77 using [2+2] cycloaddition (i) Toluene, sealed tube, 220 C

OH

H H

R1O

R2

R1O

i N

H H

76a R1 = Me, R2 = Ph

77a, 56%, dr = 100 : 0

76b R1 = Ph, R2 = Me

77b, 52%, dr = 100 : 0

76c R1 = Ph, R2 = Ph

77c, 57%, dr = 100 : 0

R2 path A

R1

N

R

OH

R2

R1

N

R2 path B

R1

N R3

H

R1 R3 R3

H H

OH

R3

R3

R2

N O H

R3 79

R2

73, 75

H H

O

OH

O

R2

N

O 72, 74

H R3 OH

OH

H H N

R3

78

72, 74 H H

H H

O

R3 R3

1

R2

O

OH

O

OH

N

O

R1

H H

R3

R3

73, 75

Scheme 27 Mechanistic explanation for the formation of tricyclic b-lactams 73 and 75

thermal reaction leading to tricyclic 2-azetidinones 73 and 75 is proposed in path B (Scheme 27). This pathway involves an endocyclic diradical intermediate 79 arising from the initial attack of the terminal olefinic carbon onto the distal allene carbon. For both pathways, the final step must be a rapid ring-closure of the diradical intermediates which takes place before bond rotation can occur. Analogously, the thermal formation of fused strained tricycles 77 can be rationalized by a mechanism which includes an exocyclic diradical intermediate 80 through an initial carbon–carbon bond formation, involving the proximal allene carbon and the internal alkene carbon atom (path C, Scheme 28). The alternative pathway leading to tricyclic 2-azetidinones 77 is proposed in path D (Scheme 28). This proposal involves an endocyclic diradical intermediate 81 arising from the initial attack of the terminal olefinic carbon onto the central allene carbon. The final ring-closure step of the diradical intermediates account for the cyclobutane formation. It seems that the regioselectivity in this type of [2þ2] cycloaddition reactions is determined by the presence or absence of an alkyl substituent at the internal alkene carbon atom, as the enallenes 72 and 74 lacking a methyl group exclusively gave addition at the b,g-double bond, while the enallenes 76 bearing a methyl group at

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams

R1

H H

OH

R2 path C

R1

H H

R2

80 R2 path D

R1

N O

H H

R2

77

OH R2 R1

N

H H

OH

R2

N

O 76

OH

O

76 OH

H H N

O

O

H H

R1

N

N

R1

OH

19

O 81

77

Scheme 28 Mechanistic explanation for the formation of tricyclic b-lactams 77

the internal olefinic carbon underwent a formal [2þ2] cycloaddition reaction at the a,b-double bond. The pathway A proposed in Scheme 27 looks valid for the formation of products 73 and 75, where when R3 = Me makes the exocyclic diradical most stable and the presence of the double bond makes the allylic radical 78 favored over the alternate endocyclic vinylic radical 79 in path B. However, it could be presumed that for the formation of compounds 77 the pathway D proposed in Scheme 28 is more reasonable. The simultaneous stabilization of the endocyclic diradical 81 in the presence of the methyl substituent as well as the allylic stabilization makes this radical favored over the exocyclic diradical 80. The intramolecular nitrone-alkene cycloaddition reaction using 2-azetidinonetethered alkenyl(alkynyl)aldehydes 82–85 as starting materials has been introduced as an efficient route to prepare fused tricyclic aziridine-, isoxazoline-, and isoxazolidine-b-lactams 86–89 [74–76]. The regioselectivity of this cycloaddition deserves special mention, because depending on the alkene(alkyne) substituent position at the tethered alkenyl(alkynyl)aldehyde, the regioselectivity was tuned from bridged (86) to fused (87–89) tricyclic compounds (Scheme 29). When the alkene substituent was moved from C3 to N1 in the 1,4-tethered alkenylaldehyde, the bridged N,O-heterocycles 86 were formed as the exclusive products. Formation of the bridged-ring products 86 is worthy of note because only fused-ring products have been found in the intramolecular nitrone-alkene cycloaddition reactions of related N-alkenyl-2-prolinaldehyde and related cyclic-bridged alkenylaldehydes. It is possible that, because of the rigid angular disposition imparted by the planar lactam group, the fused-ring transition state increases in energy thereby becoming uncompetitive with the usually unfavored bridged-ring transition state. The aziridine carbaldehyde 88 may arise by thermal sigmatropic rearrangement. The reactivity of 2H-azirines 91 and 93 as 1,3-dipolarophiles towards b-lactam based azomethine ylides derived from oxazolidinones 90 has been investigated [77]. The reaction of 3-(4-methoxyphenyl)-2H-azirine 91 with oxazolidinone 90 did not afford the expected cycloadduct. However, compound 92 was isolated as the

20

B. Alcaide and P. Almendros

PhO H H CHO N ( )n

O

MeNHOH.HCl

86

N PMP

( )n

O

H

O

O

N

Et3N, 70–80%

82

O H H CHO

Me N

PhO H H

MeNHOH.HCl

O H

Et3N, 75%

O

n = 1–3 O H N

Me

H N

PMP

83

87

PhO H H CHO

PhO H H

Me N CHO

H

MeNHOH.HCl N O

Et3N, 55%

84

N O

88 Me PhO H H

PhO H H CHO MeNHOH.HCl N

N

Et3N,15%

O

N

O

H

O 89

85

Scheme 29 Preparation of tricyclic b-lactams 86–89 using nitrone-alkene(alkyne) cycloadditions

Ar

N 91 N

O

H

Ar

O

MeCN, 100 oC sealed tube CO2PNB 90a (Ar = 4-MeOC6H4) 41%

N

NH

N O

H

Ar CO2PNB 92

Scheme 30 Preparation of tricyclic b-lactam 92 using azirine-azomethine cycloaddition

major product in 41% yield (Scheme 30). In contrast, by using a nitroaryl moiety at the 3-position of the azirine ring, the initial cycloadducts 94 were prevented from further fragmentation (Scheme 31). Subsequent release (by nitro group reduction and protection) of the corresponding anilide then triggers the desired C–N bond cleavage. It has also been demonstrated that depending on the nature of the esterprotecting group (94a vs. 94b) these conditions lead to either 95 or 96, both of which are novel azacepham derivatives.

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams Ts N

N O N

93

O

N

Ar

MeCN, 80 oC O CO2R sealed tube,18h 90a R = PNB (Ar = 4-NO2C6H4) 40–66% 90b R = Me

H2, Pd/C, EtOAc, 18h

N

O

CO2R

NO2 then TsCl, py, CH2Cl2 R = PNB, 29%

21

N O NH Ts

96

94 R = Me H2, Pd/C, EtOAc, 8h 34% thenTsCl, py, CH2Cl2 Ts N N

NHTs

O CO2Me

95

Scheme 31 Preparation of bicyclic b-lactams 95 and 96 using azirine-azomethine cycloaddition

O

MeO N

Ph O

Cp2TiCl2, Zn O

O O

O

97

THF, RT 57%

MeO O

H N H O

OH Ph H O

O

O

98

Scheme 32 Titanocene-promoted preparation of tricyclic b-lactam 98

3.2

Using Radical Reactions

The reductive opening of epoxy-b-lactam 97 with titanocene(III) chloride gives rise to a benzyl radical that can be trapped by intramolecular p systems to give the tricyclic 2-azetidinone 98 (Scheme 32) [78]. An approach (racemic and asymmetric) to benzofused tricyclic b-lactams including benzocarbapenems as well as benzocarbacephems, through intramolecular aryl radical cyclization of 2-azetidinone-tethered haloarenes has been reported [79]. Haloaryl b-lactams 99–103 were reacted with tributyltin hydride and AIBN in benzene at reflux to give the expected benzocarbapenems 104 and 106 and benzocarbacephems 105, 107, and 108 in good yields as single diastereomers after chromatographic purification (Scheme 33, Table 1). These intramolecular radical reactions were carried out under standard dilution conditions, and did not require the use of high dilution techniques. Removal of the organotin halides by a solution of KF in water is essential for an appropriate chromatographic purification of compounds 104–108. With the exception of the reaction of 101b, neither cyclization products different from 104–108 nor reduction products were detected in the 1 H-NMR spectra of the crude reaction mixtures. The full stereoselectivity of the radical cyclization is particularly attractive, being independent of the substitution at

22

B. Alcaide and P. Almendros

R1

R3

R3

R2 H

i, ii N

O

R2 H

R1

N

( )n

O X

104 n = 0 105 n = 1

99 n = 0 100 n = 1 O N

O H H N

O

H H

R3

H H

N Ph

( )n

101 n = 0 102 n = 1

PhO

O

O

R3 i, ii

Ph

( )n

N O

Br

( )n

106 n = 0 107 n = 1 R3

R3 i, ii

PhO

N

H H N

O

O 103

Br

108

Scheme 33 Preparation of benzocarbacephems 104–108 using radical cyclization (i) Bu3SnH (1.2 equiv), AIBN (0.1 equiv), benzene, reflux, 1–2 h; (ii) 10% aqueous KF, 30 min Table 1 Preparation of fused tricyclic b-lactams 104–108 R1 R2 R3 X n Producta Substratea 99a Me Me Ph Br 0 104a 99b PhO H Ph Br 0 104b cis-99c BnO H Ph I 0 cis-104c trans-99c BnO H Ph I 0 trans-104c 100a PhO H Ph Br 1 105a 100b BnO H Ph Br 1 105b 101a Ph 0 106a 101b Me 0 106b 102 Ph 1 107 108a 103a CO2Me 103b Me 108b a Compounds 99, 100, 104 and 105 are racemic b Yield of pure, isolated product with correct analytical and spectral data

Yield (%)b 65 66 60 65 50 61 70 30 57 64 47

C3 or N1 on the b-lactam ring. In addition, 2-azetidinones bearing styryl or carboxymethyl substituents at C4 underwent 5(or 6)-exo-trig radical cyclization to benzocarbapenems and benzocarbacephems 104–108 in a totally regioselective fashion, as expected when the radical acceptor has a radical-stabilizing moiety at the b-position. The radical reaction of the crotonaldehyde-imine derived b-lactam 101b, lacking a radical-stabilizing moiety, deserves special mention. Haloalkenyl

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams

23

b-lactam 101b formed, along with benzocarbapenem 106b benzocarbacephem 106c (Scheme 34). A mechanistic explanation for tricyclic b-lactams 104 and 106 is depicted in Scheme 35. The complete selectivity observed in the formation of benzocarbapenems 104 and 106 and benzocarbacephems 105, 107, and 108 must be due to the preference of the radical intermediates for the conformation depicted in Scheme 36 for these cyclizations. The extension of the above radical intramolecular cyclization of N-haloaryl-blactams to 2-azetidinones bearing the proradical center at C3 was also explored. The treatment of haloarenes 109a–c under similar conditions for the preparation of benzocarbapenems and benzocarbacephems 104–108 gave the fused tricyclic b-lactams 110a–c (Scheme 37, Table 2). Compounds 110a and 110b were obtained as mixtures of diastereomers, which are epimers at the newly formed C5 stereocenter, while the amino derivative 110c could be prepared as a single isomer. Me

(S)-Ox H H N

i, ii

Br

Me

(S)-Ox H H

(S)-Ox H H N

N

O

O

O

106c

106b

101b

Me

(S)-Ox = (S)-4-phenyl-2-oxo-1,3-oxazolidin-3-yl

Scheme 34 Preparation of benzocarbapenem 106b using radical cyclization (i) Bu3SnH (1.2 equiv), AIBN (0.1 equiv), benzene, reflux, 1.5 h; (ii) 10% aqueous KF, 30 min

Bu3Sn

R1

99, 101 (–Bu3SnX)

5-exo-trig

R1

R3

R2

R3

R2 N

O

6-endo-trig

R1

R2

R3 N

N

O

O

104, 106

106c

Scheme 35 Mechanistic explanation for the formation of compounds 104 and 106

24

B. Alcaide and P. Almendros

Scheme 36 Preferred conformations for the radical intermediates leading to compounds 104–108

R3

R2 R1

R1 H R2 N O

R3

H N

O 104, 106 R3

R3 R1 R2 N O

R2 H R1

H

N O 105, 107, 108

Br

H OH H

XR

O H

N O

i, ii

PMP

N

O

109

XHR H PMP

110

Scheme 37 Preparation of tricyclic b-lactams 110 using radical cyclization (i) Bu3SnH (1.2 equiv), AIBN (0.1 equiv), benzene, reflux, 1 h; (ii) 10% aqueous KF, 30 min

Table 2 Preparation of fused tricyclic b-lactams 110 R X d.r.c Substratea 109a Ph CH 85:15 CH 70:30 109b CO2Me 109c Bn N >95:5 a PMP = 4-MeOC6H4 b Compounds 109 and 110 are racemic c The ratio was determined by integration of well-resolved signals crude reaction mixtures before purification d Yield of pure product (mixture of isomers)

Producta 110a 110b 110c

Yield (%)b 69 56 60

in the 1H NMR spectra of the

The formation of rings with more than seven atoms has unfavorable rates because the addition step is often too slow to allow it to compete successfully with other pathways open to the radical intermediate. In stannane based chemistry for example, premature hydrogen abstraction from the organotin hydride is difficult to avoid. However, Baylis-Hillman adducts 111 derived from enantiopure 1-alkenyl (or alkynyl)-4-azetidinone-2-carbaldehydes are used for the stereoselective and divergent preparation of highly functionalized bicycles 112 and 113 fused to medium-sized heterocycles (Scheme 38) [80, 81]. The Baylis-Hillman reaction using nonracemic protected a-amino aldehydes has been attempted with limited success due to partial racemization of the chiral aldehyde by DABCO after

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams

R1O O

H H

O

N ( )n

(n = 1, 2, 3)

MeCO DABCO

1O

R

O

H H

OH

N ( )n 111

ArCH2R2 210 oC

R1O

COMe

PH AIBN (P = PhS, Ph3Sn)

H H

25 OH

COMe Ar

N

O

R2 ( )n 112 d. r. 10:0 20–60%

H H R1O

OH

COMe

N O 113

( )n

P

Z:E. 6:4 –10:0 65–90%

Scheme 38 Radical divergent preparation of bicyclic b-lactams 112 and 113

prolongate exposure times. However, this is not the case of 4-oxoazetidine2-carbaldehydes, because on reacting with various activated vinyl systems the corresponding adducts can be prepared almost as single diastereoisomers. The diastereofacial preference of this addition reaction for syn-addition to the aldehyde moiety was interpreted by the Felkin–Anh model. Formation of N-fused bicyclic b-lactams 112 and 113 can be explained in terms of a competition between a tandem radical Michael addition/endo-cyclization and a tandem radical addition/ Michael addition, depending on the electronic nature of the radical promoter (Scheme 39). It is known that nucleophilic radicals react more rapidly with electron poor alkenes than with electron rich alkenes or alkynes, and conversely, electrophilic radicals react more rapidly with electron rich alkenes than electron poor alkenes. In the above case, Baylis-Hillman adducts may react through two different pathways to give the bicyclic systems. The more nucleophilic benzylic radical would favor formation of compounds 112, while the more electrophilic radicals, such as PhS. and Ph3Sn., should promote formation of compounds 113. Alternatively, the differences in reactivity between the benzylic and the thiyl and stannyl radicals, respectively, could be explained by other considerations. Thus, for the thiyl and stannyl radicals the initial addition to the double bond is fast but reversible. Since the cyclization is a slow reaction, it cannot compete with fragmentation. However, the addition to the triple bond is irreversible and therefore only products deriving from addition to the triple bond are isolated. Addition of the benzylic radical to the double bond of course is not reversible. The synthesis of N-fused tricyclic b-lactams involving a radical cascade sequence in enyne 2-azetidinones 114 and 115 bearing a methylenecyclopropane unit has been reported [82]. Slow addition of Bu3SnH/AIBN to a refluxing solution of 114 gave tricyclic vinylstannane 116 as a single stereoisomer in 42% yield, whereas cyclization of 115 under identical conditions gave fused heterocycles 117 and 118 in 73 and 11% yield, respectively, in all three cases via a 7-endo cyclization. Treatment of vinyl stannanes 117 and 118 with PPTS in dichloromethane yielded a common tricyclic product 119 (Scheme 40).

26

B. Alcaide and P. Almendros

Scheme 39 Mechanistic explanation for the radical divergent formation of bicyclic b-lactams 112 and 113

H H

R1O O Ar

R1O

H H

OH

EWG

N () 111 n

R

OH

P

EWG

OH

H H

1O

R

N ( )n

O

R2

N ( )n

O

pathway A

R1O

H H

OH

EWG

N

R1O O

N

2 eq. Bu3SnH 1 eq. AIBN

TBSO

113

H H N

O 115

TBSO

H H

2 eq. Bu3SnH 1 eq. AIBN toluene reflux

TBSO

TBSO

H H

H

H H

N O 117 (73%) Bu3Sn

+

H

O Bu3Sn

TBSO

H

H

N

O Bu3Sn

H

H

N

O

114

TBSO

H

N

toluene reflux

O

H H

P

H

112

H

EWG

( )n

H

H H

OH

H H N

R2

( )n

P

pathway B

Ar

O

TBSO

EWG

Ar

H H

H

116 (42%) Bu3Sn

TBSO

H

N

SnBu3

O

H H

H

H

N O 119

118 (11%)

PPTS, CH2Cl2

Scheme 40 Preparation of tricyclic b-lactams 116 and 119 using cascade radical cyclization

A different report provided the access to a highly strained tetracyclic [3.6.6.4] ring system containing a fused tetrahydropyran-b-lactam moiety [83]. The radical precursors 120 were easily accessible via cycloaddition reaction of the appropriate imines with a chiral chloride derived from enantiomerically pure (+)-3-carene.

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams H

O

H

O N

H

Br

H

R2 120

R1

H

O

Bu3SnH, AIBN

27

H

O N

benzene, reflux H

H

H

R1

R2 121 (60–96%)

Scheme 41 Preparation of tetracyclic b-lactams 121 using radical cyclization

When compounds 120 were subjected to radical cyclization conditions, fused tetracyclic b-lactams 121 were achieved as a single diastereomer (Scheme 41). The high stereoselectivity in this 6-exo-trig cyclization was rationalized by invoking a six-membered transition state mode. The conformational constraint within the rigid bicyclic system and b-lactam framework with a flexible oxygen tether does not allow the system to go through the generally favored 6-exo-chair transition state, and now an energetically favored six-membered boat-like transition state seems to be involved. Six-, seven-, or eight-membered bicyclic 2-azetidinones have been prepared through triphenyltin hydride-promoted intramolecular free radical cyclization reaction of b-lactam-tethered bromodienes (Scheme 42) [84]. The tin-promoted radical reaction of bromodienic alcohol 122a gave the eight-membered ring fused-blactam 123 together with the homoallylic alcohol 124. The free radical cyclization proceeded elegantly in bromodiene 122b to provide the desired nonconventional bicyclic b-lactam 125 as single isomer. The 1-vinyl-3-hydroxy-6-hexenyl radical (radical numbering) derived from bromide 122c afforded the seven-membered ring fused bicycle 126 prevailing over the isomeric product 127 containing a sixmembered ring. Triphenyltin hydride-promoted cyclization of bromodiene 122d afforded the expected fused 2-azetidinone 128 as a single isomer in fair yield. The synthesis of eight- and nine-membered rings fused to 2-azetidinones has been investigated using radical chemistry in b-lactam ene adducts bearing an extra alkyne tether [70]. The tin-promoted radical cyclization proceeded in enynes 129a and 129b to provide the desired nonconventional bicyclic b-lactams as single isomers in moderate yields (Scheme 43). Treatment of vinylic stannane 130a with PTSA in CH2Cl2 yielded the destannilated eight-membered fused adduct 131. A novel approach to racemic and enantiopure nonconventional fused bi-and tricyclic b-lactams has been developed by using regio- and stereocontrolled intramolecular free radical reactions in monocyclic 2-azetidinone-tethered allenynes and haloallenes [85, 86]. In an initial study, we found that allenynol 132a when heated in the presence of triphenyltin hydride and AIBN in benzene solution gave the bicyclic b-lactam 133a in 64% yield as a single regio- and Z-isomer. Tinpromoted cyclization of allenynol 132b afforded the expected 2-azetidinone 133b containing a medium-sized ring. Allenynol anti-132c having the alkynyl side chain at C3 instead of N1 underwent cyclization to afford the C3–C4 fused b-lactam 133c. Similar behavior was observed for the free radical cyclization of allenynone 132d, which afforded the heterobicyclic ketone 133d. Interestingly, only bicycles

28

B. Alcaide and P. Almendros

H H

MeO

OH

OH

Br a)

MeO

H H

N

MeO +

N

O

OH

N

O 122a

H H

O 123 (57%)

124 (17%)

CO2Me H H

O

OH

MeO2C

Br

O H

a)

OH H

N O

N PMP

O

122b

H H

125 (46%)

OH

Br a)

H

O

122c

+

N PMP

O

126 (37%)

OH

PMP

127 (29%)

Br a)

Me

OH H

H N

N O

OH H

H

N PMP

H H

Me

OH H

N O

PMP

PMP

O

PMP

128 (40%)

122d

Scheme 42 Preparation of bicyclic b-lactams 123 and 125–128 using radical cyclization (a) Ph3SnH (1.2 equiv), AIBN (0.1 equiv), benzene, reflux

MeO O

H H

OH

OH Ph

N ( )n

MeO

Ph3SnH, AIBN C6H6, 80 oC, 1h

H H

Ph

N O

( )n P

129a n = 1 129b n = 2

PTSA CH2Cl2

130a n = 1, P = SnPh3, 46% 130b n = 2, P = SnPh3, 36% 131 n = 1, P = H, 100%

Scheme 43 Tin-promoted radical preparation of bicyclic b-lactams 130

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams

MeO

H H

OH

R

i

MeO

H H

OH

R CH3

N

N

29

O

O

Ph3Sn 132a R = Me

133a R = Me (64%, Z:E = 100:0)

132b R = Ph

133b R = Ph (49%, Z:E = 100:0) CH3

H H

OH

CH3

Ph3Sn H H

CH3

OH

i N O

N PMP

O

anti-132c

MeO

H H

133c (47%, Z:E = 0:100)

O

MeO i

N

PMP

H H

O

N

CH 3

O

O 132d

Ph 3Sn 133d (44%, Z:E = 100:0)

Scheme 44 Tin-promoted radical preparation of bicyclic b-lactams 133 (i) Ph3SnH (1.2 equiv), AIBN (0.1 equiv), benzene, reflux

133 were found as a consequence of a totally regioselective radical cyclization onto the central carbon (Scheme 44). Neither the endo-cyclized product nor the exocyclized product was detected. The extension of the above radical cyclization of 2-azetidinone-tethered allenynes to bromovinyl and haloaryl allenes bearing the proradical center at N1 was explored. The tin-promoted radical reaction was also useful in the conversion of the b-lactam allenes 134a and 134b with a bromopropenyl group substituted at the nitrogen atom, into the corresponding bicyclic systems 135a and 135b with similar efficiency and selectivity (Scheme 45). The treatment of b-lactam allenes 136a–d having a bromo- or iodophenyl group (N-tethered) under similar conditions for the preparation of bicycles 133 and 135 gave the fused tricyclic b-lactams 137a–c containing a central seven-membered ring (Scheme 46). Benzofused b-lactams 137 can be considered as superior cyclohomologous of benzocarbapenems and benzocarbacephems, which have been designed as suicide inactivators of b-lactamases. It is presumed that the stannyl radical, by addition to the terminal position of the triple bond in allenynes 132, or through bromine abstraction in bromovinyl and haloaryl allenes 134 and 136 gives the vinylic radical intermediates 138 and 142 in the propagation step, followed by cyclization toward the central carbon bond of the

30

B. Alcaide and P. Almendros

H H

MeO

OH

R MeO

i N

H H

Br

OH

R CH3

N

O

O

134a R = Me

135a R = Me (67%)

134b R = Ph

135b R = Ph (61%)

Scheme 45 Preparation of bicyclic b-lactams 135 (1.2 equiv), AIBN (0.1 equiv), benzene, reflux

R1O

H H

OH

R2

R1O

i N

using radical cyclization (i) Ph3SnH

X

R2 CH3

O

136a R1= Me, R2 = Me,X = Br R1=

Me,

R2 =

137a (52%) 137b (46%)

Ph,X = Br

136c R1= Me, R2 = Me,X = I 1=

136d R

MeO

OH

N

O

136b

H H

Ph,

H H

R2 =

OH

137a (50%) 137c (41%)

Me,X = I

Me i

N

MeO

Br

O

anti -136a

Scheme 46 Preparation of tricyclic b-lactams 137 (1.2 equiv), AIBN (0.1 equiv), benzene, reflux

H H

OH

CH3

N

CH3

O

anti -137a (42%)

using radical cyclization (i) Ph3SnH

allene moiety to give in a total regio- and stereoselective fashion fused cycles 133, 135, and 136 via allylic radical intermediates 139 and 143. While both endo- and exo-cyclizations of radical intermediates 138 and 142 would give vinylic radicals 140, 144 and 141, 145, respectively, central-cyclization would lead to the energetically more favored allylic radicals 139 and 143 (Schemes 47 and 48). Aryl-2-azetidinone-tethered haloarenes were used for the regiocontrolled preparation of fused tetracyclic biaryl-2-azetidinones which can be considered as b-lactam-biaryl hybrids via aryl-aryl radical cyclization [87]. Treatment of transb-lactams 146 with tributyltin hydride and AIBN in benzene at reflux under high dilution conditions (215 mL per mmol of starting 2-azetidinone) smoothly formed the corresponding condensed tetracyclic biaryl-2-azetidinones 147 in good yields as single trans-diastereomers after chromatographic purification (Scheme 49) together with small amounts of reduced starting material.

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams OH 1 ROH H

R

OH

2

N

2

R

1 ROH H

Ph3Sn

1

RO

O

Ph3SnH

OH

R

OH

2

CH3

N

1 RO H H

Ph3SnH

140

2

R

1

RO O

Ph3Sn

OH

H H

CH2

N

–Ph3Sn

O

SnPh3

R

2

Ph3SnH

N O

Ph3Sn

exo adduct

–Ph3Sn

Ph3Sn

Ph3Sn

133

endo adduct

–Ph3Sn

O 138

132

OH R2

N

N

O

1 ROH H

H H

31

141

139

central adduct

Scheme 47 Mechanistic explanation for the formation of bicyclic b-lactams 133

R1O

H H

OH

R2

R1O

Ph3Sn X

N

H H

OH

OH

R2

R1O H H

OH

142

R2 CH3

N O

Ph3SnH

R1O H H

OH

R2

R1O CH2

O

H H

OH

R2 Ph3SnH

N O

143

135, 137

endo adduct

144

N

–Ph3Sn

Ph3SnH –Ph3Sn

O

O

134, 136

R2

N

N

O

H H

R1O

exo adduct

–Ph3Sn 145

central adduct

Scheme 48 Mechanistic explanation for the formation of tricyclic b-lactams 135 and 137

X AcO

X HSnBu3 / AIBN C6H6 / D

N O Br

AcO N O

Y 146

Y 147 (60–72%)

X = MeO, H; Y = H, Me

Scheme 49 Preparation of tetracyclic b-lactams 147 using radical cyclization

32

3.3

B. Alcaide and P. Almendros

Using Metal-Mediated Reactions

It has been reported that the ring-closing metathesis (RCM) of 1,4-bis(ene)-substituted 2-azetidinones 148, allowed synthetically rapid access to a wealth of novel, potentially biologically active, bicyclic b-lactam arrays, 149 (Scheme 50) [88–90]. The ring-closing metathesis runs were performed using either a molybdenum catalyst (Schrock catalyst) or a ruthenium catalyst (Grubbs’ carbene), depending on the requirements of the reaction. Seven-membered ring closure to a homooxacephem derivative was achieved in an excellent isolated yield of 84%, clearly demonstrating the synthetic utility of this method in these systems. Closure of bicyclic b-lactams with increasing ring sizes was possible, albeit progressively less successful. The eight-membered ring system was produced in 52% yield using 5% mol of Schrock catalyst and in an improved 76% yield using 10% mol of the molybdenum catalyst. The nine-membered fused system was isolated in only 12% yield under the same conditions but could be optimized to 23% using 20% mol of Schrock catalyst. The ten-membered ring was produced in 3% yield using 5 mol % of the molybdenum catalyst and in 10% yield under high dilution and a higher catalyst loading. While these results clearly established that polyfunctional b-lactam dienes were excellent substrates for metathesis, the reactions were not appropriate for the synthesis of bioactive b-lactam carboxylic acids. In order to find utility for this metathetic approach in the generation of novel drug candidates, a carboxylic acid motif adjacent to the lactam nitrogen was installed. The requisite framework was incorporated via Ireland–Claisen rearrangement of silyl ketene acetals derived from allyl ethers 150. The silyl ketene acetals underwent smooth rearrangement affording the corresponding carboxylic acids in excellent yields, but as inseparable 1:1 mixtures of diastereoisomers. The above carboxylic acids had only limited solubility in the normal solvents for metathesis, and were directly converted into the corresponding ethyl or p-nitrobenzyl esters 151. Treatment of monocyclic dienes 151 with Schrock or Grubbs carbenes resulted in cyclization to provide bicyclic b-lactams 152 (Scheme 51) [91]. The synthesis of bicyclic 2-azetidinones 154 has been accomplished by ringclosing metathesis reaction of monocyclic diene- and enyne-b-lactams. The enyne metathesis of compounds 153 afforded bicycles 154 in good yields (Scheme 52) [92]. It has been reported that conveniently substituted bis-b-lactams, pyrrolidinylb-lactams, and piperidinyl-b-lactams undergo ring-closing methatesis using

X N O

Scheme 50 Preparation of bicyclic b-lactams 149 using alkene-methatesis

( )n

X () n

catalyst CH2Cl2 RT

N O

148 n = 1–4 149 (10–92%) X = O, NTs, S, CH2

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams X

( )n

X

i–iii

( )n

X ( )n

iv

N

N O

N O

O CO2R

O 150

33

CO2R

O

152 (50–98%)

151

X = O, NTs, S, CH2 R = PNB, Et n = 0–1

Scheme 51 Preparation of bicyclic b-lactams 152 using alkene-methatesis (i) LiHMDS, THF; (ii) TMSCl, D; (iii) RBr, K2CO3, DMF; (iv) catalyst, CH2Cl2, RT

R1

i N

R1

R2

O

R2 N

O 153

R1 = H,

154 (72–100%) OTBS ; R2 = H, OTBS

Scheme 52 Preparation of bicyclic b-lactams 154 using alkyne-methatesis (i) [Cl2(PCy3)2Ru = CHPh], CH2Cl2, RT

Grubbs’ carbene, Cl2(Cy3P)2Ru = CHPh, to give medium-sized rings fused to bis2-azetidinone, pyrrolidinyl-2-azetidinone, or piperidinyl-2-azetidinone systems [93]. The diolefinic cyclization precursors were obtained from optically pure 4-oxoazetidine-2-carbaldehydes bearing an extra alkene tether at position 1 or 3 of the b-lactam ring via [2þ2] cycloaddition of imino 2-azetidinones, N-metalated azometine ylide [3þ2] cycloaddition, and subsequent N-acylation of the pyrrolidinyl nitrogen atom, or through aza Diels–Alder of 2-azetidinone-tethered imines. Under standard reaction conditions, the combination of cycloaddition reactions of 2-azetidinone-tethered imines with ring-closing methatesis offers an asymmetric entry to a variety of unusual fused tricyclic 2-azetidinones bearing two bridgehead nitrogen atoms. Treatment of dienes 155, 157, and 159 with Grubbs’ catalyst under smooth ringclosing metathesis conditions (5 mol%, CH2Cl2, 25 C), analogous to those described for bicyclic b-lactams, did not furnish the desired tricycles. The majority of the reaction mixture was composed of unreacted dienes. It was found that dienic substrates 155, 157, and 159 require more vigorous conditions for ring closure. Among the various solvents and conditions tested, it was found that toluene at reflux temperature gave the best yields of tricyclic-b-lactams containing mediumsized central rings. Exposure of dienes 155, 157, and 159 to the ruthenium catalyst Cl2(Cy3P)2Ru = CHPh under optimized cyclization conditions (5 mol% catalyst,

34

B. Alcaide and P. Almendros

Scheme 53 Preparation of tricyclic b-lactams 156 using alkene-methatesis (i) [Cl2(PCy3)2Ru = CHPh], toluene, reflux

PhO H H

MeO

N

PhO

O N

MeO ( )n

H

i

MeO

N

H N O

156a n = 1(69%) 156b n = 2(54%)

H

MeO

i

N

H

H H H N

O

( )n

158a R1 = H, R2 = H, n = 1 (62%) 158b R1 = H, R2 = Me, n = 1 (67%) 158c R1 = CO2Me, R2 = Me, n = 1 (57%) 158d R1 = H, R2 = H, n = 2 (58%) 158e R1 = H, R2 = Me, n = 2 (58%) 158f R1 = H, R2 = Me, n = 3 (35%)

157a 157b 157c 157d 157e 157f

O

R2 CO2Me

N H

O

O

R1

MeO2C

( )n

MeO2C

( )n

O

R1 R2 CO2Me

O

N

N

155a n = 1 155b n = 2

H H

H H H

O

MeO2C

O

N

Me CO2Me

H O H

i

N

O PMP

O

O Me CO2Me N H H

CO2Me

PMP

158g (35%)

157g

Scheme 54 Preparation of tricyclic b-lactams 158 using alkene-methatesis (i) [Cl2(PCy3)2Ru = CHPh], toluene, reflux O

MeO

H H H N

O

Scheme 55 Preparation of tricyclic b-lactams 160 using alkene-methatesis (i) [Cl2(PCy3)2Ru = CHPh], toluene, reflux

O

159a 159b 159c

( )n

N

i

MeO

H H

N H

N O

( )n

160a n = 1 (53%) 160b n = 2 (31%) 160c n = 3 (33%)

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams

35

0.03M, toluene, 110 C) resulted in clean formation of tricycles 156, 158, and 160 in moderate to good yields (31–69%) (Schemes 53–55). It should be mentioned that for a successful RCM, a structural condition must be satisfied in the starting dienes, namely, a relative antistereochemistry at the single bond connecting the two heterocyclic rings. Interestingly, in the Grubbs’ carbene promoted reaction of compounds 159b and 159c together with the RCM products 160b and 160c N-deallylation products were also isolated. The synthesis of tricyclic b-lactams via palladium-catalyzed cyclization of iodoaryl b-lactams using a catalyst system comprising 10 mol% Pd(AcO)2, 20 mol% PPh3, and Tl2CO3 (2 mol) has been afforded [94]. The methallyl b-lactam 161 underwent 7-endo-trig cyclization to give an 8:1 mixture of double bonds isomers 162 and 163 (Scheme 56). It has been shown that combination of bromoallylation reaction and Heck cyclization is a useful methodology for the preparation of a variety of fused bicyclic b-lactams of nonconventional structure [95]. Starting from acetates 164 and using palladium acetate as the palladium source, DMF as solvent, potassium carbonate as base, and triphenylphosphine, the reaction occurred. The reaction conditions were further optimized and typical results for the preparation of bicyclic b-lactams 165–168 are summarized in Schemes 57. The Heck reaction of acetate 164d deserves special mention. Substitution pattern on bromodiene 164d should direct the regiochemical outcome of the cyclization to the six-membered or seven-membered ring formation. Interestingly, we found that the reaction produced the five-membered fused bicycle 169a as the only isomer. As a result of steric congestion, the stereocontrolled construction of carbon atoms having four carbon ligands is a formidable challenge for chemical synthesis. Compound 169a is remarkable since it bears a quaternary stereocenter. Adduct 169a presumably arises from the Pd-catalyzed 5-exo cyclization of the initially formed a,b-unsaturated carbonyl compound 170a. A similar reaction pattern was observed on reacting bromodienes syn-164e and anti-164e. Thus, bicyclic b-lactams 169b and 169c were also prepared through essentially the same procedure (Scheme 58). The above hypothesis was probed showing that the intermediate 170 could be obtained from 164 and that this new bromodiene does give the corresponding fused b-lactam 169 under Heck conditions. This mechanistically informative result was provided by the treatment of the bromohomoallylic acetate 164d with potassium carbonate in acetonitrile to give a separable mixture of isomeric bromodienes

N O

O

O

H H

H H

N

Pd(0) N

O 161

I

62%

O

O

N O

N +

O

H H N

O 162

Scheme 56 Preparation of tricyclic b-lactams 162 and 163 using Heck reaction

163

36

B. Alcaide and P. Almendros

O

H H

OAc Br Pd(OAc)2 PPh3, K2CO3

N PMP

O

164a

DMF 95 oC, 26h

OAc

O H

H

+

N

H N

PMP

O

OAc

O H

PMP

O

166 (27%)

165 (21%)

CO2Me

O

H H N

O

PMP

164b

H H N O

MeO2C

OAc Br Pd(OAc)2

O H

PPh3, K2CO3 DMF 105 oC, 4h

O

OAc H N

PMP

167 (47%)

OAc Br Pd(OAc)2 PMP

164c

PPh3, K2CO3 DMF 105 oC, 3h

OAc H

H N

O

PMP

168 (60%)

Scheme 57 Preparation of bicyclic b-lactams 165–168 and 163 using Heck reaction

E-170a and Z-170a, which under palladium catalysis afforded the expected bicycle 169a. The two-step synthesis of compound 169a from diene 164d is depicted in Scheme 59. The allene moiety represents a versatile and useful building block in organic synthesis. However, selectivity problems are significant. Intramolecularization of the reactions, usually by placing the group at a distance suitable for five- or sixmembered rings to be formed, should automatically solve the positional selectivity problems because larger rings are unfavored. The less exploited allenic variant of the Pauson–Khand type cycloaddition was explored in allenynes 171 [96]. Substitution patterns on allenynes 171 were selected to direct the regiochemical outcome of the cycloaddition to the six-membered central ring formation because the intramolecular variant of the Pauson–Khand reaction has been largely restricted to the construction of bicyclo[3.3.0]octenones and bicyclo[4.3.0]nonenones. However, it was found that the [2þ2þ1] cycloaddition produced tricycles 173 bearing a central seven-membered ring as the only isomer. Cycloadducts 173 presumably arises from the isomerization of the initially formed adducts 172 (Scheme 60). Conjugation of the dienone moiety with the lone pair of the nitrogen atom is believed to promote the formation of compounds 173.

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams

OAc Br

H H

Heck

R

reaction

N O

OAc R H or H

H

OAc H

N

PMP

37

N

O

PMP

O

PMP

164d R = H syn-164e R = Me Pd(OAc)2, PPh3 K2CO3, DMF H

OAc Br

OAc H

R

R N O

N PMP

O

PMP

169a (60%; 150 oC, 1 h) 169b (65%; 105 oC, 0.5 h)

170a,170b

OAc Br

H H

OAc H

Me Pd(OAc)2, PPh3

Me N O

PMP

K2CO3, DMF 105

anti-164e

oC,

0.5 h

N O

PMP

169c (60%)

Scheme 58 Preparation of bicyclic b-lactams 169 using Heck reaction

H H

OAc Br

H

OAc Br

N O

PMP 164d

MeCN 105 oC,18h

OAc H

Pd(OAc)2

K2CO3 N O

PMP E-170a (38%) + Z-170a (24%)

PPh3, K2CO3 DMF 95 oC,1h

N O

PMP

169a (99%)

Scheme 59 Preparation of bicyclic b-lactam 169a using Heck reaction

The 1,2-functionalization of the allene moiety in 2-azetidinone-tethered allenynol derivatives has also been explored [96]. Carbamate 174 was selected as the starting material for the palladium(II)-catalyzed reaction. The above carbamate was prepared from the a-allenic alcohol 171a by treatment with tosyl isocyanate. Reaction of compound 174 was carried out at room temperature in acetonitrile in the presence of 10 mol% of Pd(OAc)2, 5 equiv of LiBr, 2 equiv of Cu(OAc)2 and 1.2 equiv of K2CO3 under an atmospheric pressure of oxygen. The 1H-NMR spectrum of the crude material displayed neither signal corresponding to the allene

38

B. Alcaide and P. Almendros

H H

MeO

OR

N

MeO

H H

i

O

OR MeO

OR

N

N

O

O 172

171a R = H

H H

O

O

173a R = H, 40% 173b R = Ac, 42%

171b R = Ac

Scheme 60 Preparation of tricyclic b-lactams 173 using Pauson-Khand reaction (i) Co2(CO)8, Me3NO, CH2Cl2, RT

Scheme 61 Preparation of tricyclic b-lactam 175 using amino-allene cyclization (i) TsNCO, THF, RT; (ii) Pd (OAc)2 10 mol%, LiBr, Cu (OAc)2, K2CO3, O2, acetonitrile, RT

O

MeO

H H

OR MeO

H H

O

NTs

ii N

41%

O 171a , R = H

i

N O 175

Br

94%

174, R = OCONHTs

or alkyne moieties. To our delight, the resulting product was identified after purification as the tricycle 175 (Scheme 61). Compound 175 was isolated in moderate yield as the only isomer, indicating that both the regio- and stereoselectivity are extremely high. The formation of compound 175 could be rationalized in terms of an unprecedented domino allene amidation/intramolecular Heck-type reaction. Compound 176 must be the nonisolable intermediate. A likely mechanism for 176 should involve a (p-allyl)palladium intermediate. The allene–palladium complex 177 is formed initially and suffers a nucleophilic attack by the bromide to produce a s-allylpalladium intermediate, which rapidly equilibrates to the corresponding (p-allyl)palladium intermediate 178. Then, an intramolecular amidation reaction on the (p-allyl)palladium complex must account for intermediate 176 formation. Compound 176 evolves to tricycle 175 via a Heck-type-coupling reaction. The alkenylpalladium intermediate 179, generated in the 7-exo-dig cyclization of bromoenyne 176, was trapped by the bromide anion to yield the fused tricycle 175 (Scheme 62). Thus, the same catalytic system is able to promote two different, but sequential catalytic cycles. The reactivity of the allenynol moiety itself under these cascade conditions was also explored [96]. Interestingly, treatment of allenynols 171a, 180, and 181 under the above palladium-catalyzed domino reaction conditions afforded the bridged medium-sized ring tricycles 182 as single isomers albeit in moderate yields (Scheme 63). Although complete conversion was observed by TLC and 1H NMR

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams O

CH3O

O

H H

39

O NHTs

H H

CH3O

Pd(II)

O

NHTs Br–

N

N

O

O 174

Pd

177 O NHTs Br

O CH3O

O

H H

NTs

N

CH3O

H H

O

N

Br

Pd

O

O 176

178 Pd

L O

CH3O

H H

O

O

NTs Br–

CH3O

N

H H

O

NTs

N

O

O 179

PdBrLn

Br

175

Scheme 62 Mechanistic explanation for the formation of tricyclic b-lactam 175

MeO

H H

OH MeO i

N O

N

( )n

O

H H N O 181

Br

OH ii PMP

( )n

182a (48%) 182b (26%)

171a n = 1 180 n = 2

Scheme 63 Preparation of bridged tricyclic b-lactams 182 using oxy-allene cyclization (i) Pd(OAc)2 10 mol%, LiBr, Cu(OAc)2, K2CO3, O2, acetonitrile, RT; (ii) Pd(OAc)2 10 mol%, LiBr, Cu(OAc)2, K2CO3, O2, acetonitrile, reflux

O

H H

Br

O H

H N

O

PMP

182c (52%)

40

B. Alcaide and P. Almendros

MeO

H H

OH Pd(II)

N O

MeO

H H

Br– N

( )n

OH

O

( )n

P d

171, 180

MeO

H H

O MeO

Br N

O

H H N

( )n

O

Pd

( )n

P d

H H

L

O Br–

MeO

O

H H N

N O

Br

183

184

MeO

OH

( )n

O PdBrLn

( )n

182

Br

Scheme 64 Mechanistic explanation for the formation of tricyclic b-lactams 182

analysis of the crude reaction mixtures, the high polarity of adducts 182 may be responsible for the modest isolated yields. Compounds 182 are remarkable since they possess an unusual pyramidalized bridgehead structure. An analogous cascade process to compound 175 formation seems to be taking part in this transformation. However, a dramatic change in the regioselectivity of the nucleophilic insertion into the (p-allyl)palladium intermediate 183 was observed when the bridged dihydrofurans were formed as the exclusive products. The thermochemically more stable five-membered intermediate 184 must be involved in the reaction rather than the corresponding regioisomeric oxirane. Taking into account the precedent explanation for fused compound 175 formation, Scheme 64 outlines a mechanistic hypothesis for the achievement of bridged compounds 182. g-Allenol 185a was used as initial substrate in a screen to identify regioselective hydroalkoxylation catalysts for the preparation of bicyclic b-lactams [97]. Thus, [PtCl2(CH2=CH2)]2 and AgNO3 afforded rather low yield or disappointing diastereomeric mixture of bicycle 186a. Although AgNO3 was less diastereoselective than [PtCl2(CH2=CH2)]2 (60:40 vs. 100:0), it was a more efficient catalyst affording adduct 186a in reasonable yield (54% vs. 12%). Gratifyingly, it was found that AuI or AuIII salts were effective as 5-exo selective hydroalkoxylation catalysts. AuCl3 was selected as catalyst of choice because of its superior performance.

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams

OTBS

H H

HO

N O

5 mol % AuCl3, CH2Cl2, RT

O

OTBS H

H N

R1

41

O

R1

186a R1 = Bn (57%) 186b R1 = allyl (58%)

185a R1 = Bn 185b R1 = allyl

Scheme 65 Preparation of bicyclic b-lactams 186 using Au-catalyzed oxy-allene cyclization

Y Y HO

OTBS

H H

O H

i)

N O

Br

N

1

O

R

185a R1 = Bn 185a R1 = Bn 185a R1 = Bn 185b R1 = allyl

OTBS H R1

187a R1 = Bn, Y = H (83%) 187b R1 = Bn, Y = Me (67%) 187c R1 = Bn, Y = Br (63%) 187d R1 = allyl, Y = H (94%)

Scheme 66 Preparation of bicyclic b-lactams 187 using Pd-catalyzed oxy-allene cyclization (i) 5 mol% PdCl2, DMF, RT

MOMO

H H

OP

5 mol % AuCl3, CH2Cl2, RT

O H N

N O

OP H

Bn

188a P = 4-BrC6H4CO 188b P = PMPCO

O

Bn

189a P = 4-BrC6H4CO (58%) 189b P = PMPCO (45%)

Scheme 67 Preparation of bicyclic b-lactams 189 using Au-catalyzed oxy-allene cyclization

No diastereo- or regioisomeric products were detected, giving exclusively the fused five-membered oxacycles 186 (Scheme 65). Tetrahydrofuran-fused 2-azetidinones 186 are remarkable since they bear a quaternary stereocenter. A solution for the 5-exo selective hydroalkoxylation having been found, the more intricate heterocyclizative problem associated with tuning the regioselectivity of g-allenols was next examined. Worthy of note, the PdII-catalyzed cyclizative coupling reaction of g-allenols 185a and 185b with allyl halides gave impressive yields (up to 94%) of the desired seven-membered adducts 187a–d (Scheme 66), resulting from a 7-endo oxycyclization [98]. When MOM protected g-allenol derivatives 188a and 188b were used as starting materials for the AuIII-catalyzed cycloisomerization, the 5-exo mode was

42

B. Alcaide and P. Almendros

O H

OP H N

O

189

MOMO

H H

R1

OP

N

AuCl3

O

188

Bn

+H+ -CH3OCH2OH MOMO

H H

AuCl3

AuCl3

N O

MOM O H

190

OP N Bn 192

Bn

X

5-exo oxyauration

H

O

OP

7-endo oxyauration

Cl3Au MOM O H

OP H N

O

191

Bn

Scheme 68 Mechanistic explanation for the formation of bicyclic b-lactams 189

completely reverted to a 7-endo cyclization to afford bicycles 189 in fair yields (Scheme 67). It seems that the reactivity in this type of AuIII-catalyzed reactions is determined by the presence or absence of a methoxymethyl protecting group at the g-allenol oxygen atom, as the free g-allenols 185a and 185b gave 5-exo hydroalkoxylation, while MOM protected g-allenol derivatives 188a and 188b exclusively underwent a 7-endo oxycyclization [98]. No other isomers or side products were detected. The pathway proposed in Scheme 68 looks valid for the formation of products 189. It could be presumed that the initially formed allenegold complex 190 undergoes an intramolecular attack (7-endo vs. 5-exo oxyauration) by the (methoxymethyl)oxy group, giving rise not to species 191 but to the tetrahydrooxepine intermediate 192. Protonolysis of the carbon–gold bond linked to an elimination of methoxymethanol would then liberate the bicycle 189 with concomitant regeneration of the AuIII species. Probably, the proton in the last step of the catalysis cycle comes from the trace amount of water present in the solvent or in the catalyst. In order to confirm the mechanistic proposal of Scheme 68, labeling studies with deuterium oxide were performed. Thus, the addition of two equivalents of D2O to the solution of MOM protected g-allenol 188b and AuCl3 in dichloromethane caused the disappearance of the peak at 6.35 ppm, which is a signal of the proton H4, on the 2-oxa-8-azabicyclo[5.2.0]non-4-en-9-one 189b. The fact that the AuCl3catalyzed conversion of allenol 188b into bicycle 189b in the presence of 2 equiv of D2O afforded 4-[D]-189b as judge by 1H NMR spectroscopy, suggests that a deuterolysis of the carbon–gold in species 192 has occurred. It may be inferred

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams HO

43

OH O

O N

H

CuI, Et3N

Ph

H +

MeCN 65% N

N

Ph

193

Ph

4

O

:

1

Scheme 69 Preparation of tricyclic b-lactams 193 using Kinugasa reaction

Cl N

N

O R

H

+

Ar1

SO2Ar Ar2

Mes N N Ar1

O 10 mol %

R H

Ar2 N

15 mol % DBU 0.1 M EtOAc, RT

O

SO2Ar

194 (62–80%) dr>10:1; up to 99%ee

Scheme 70 Preparation of bicyclic b-lactams 194 catalyzed by NHC

that different steric effects in the organometallic species 191 and 192 may be responsible for the different reactivity preference, stabilizing one of the intermediates rather than the other. In the presence of MOM group, 5-exo cyclization falters. Probably, 5-exo oxyauration via 191 is restricted by the steric hindrance between the (methoxymethyl)oxy group and the substituents at the quaternary stereocenter [99]. A synthetic route to b-lactam-fused enediynes by intramolecular Kinugasa reaction has been successfully developed. The method has widened the scope of the Kinugasa reaction in the synthesis of sensitive systems like tricycle 193 (Scheme 69) [100].

3.4

Using Cyclization Reactions

A wide range of a,b-unsaturated aldehydes, including 3-alkyl derivatives, undergo N-heterocyclic carbene (NHC)-catalyzed annulations with N-sulfonyl ketimines under mild conditions to provide bicyclo[3.2.0]lactams 194 with outstanding diastereo- and enantioselectivity (Scheme 70) [101]. This concise route to b-lactams

44

B. Alcaide and P. Almendros

N3

H H

OH Ac2O, Et3N

N O

PMP 195

DMAP, CH2Cl2 RT

N3

H H

OAc Ph3SnH

H H

C6H6, RT

N O

H2N

PMP

OAc

N PMP

O

196 (77%) 6-exo-dig cyclization 1,3-H shift

HN H

OH H N

O

PMP

acetate cleavage

HN H

OAc H N

O

PMP

197 (53%)

Scheme 71 Preparation of bicyclic b-lactam 197 using azido-allene cyclization

established four new chiral centers in a single operation. Although this process could occur via the intermediacy of a catalytically generated homoenolate equivalent, the stereochemical outcome supports a tandem or concerted aza-benzoin/ oxy-Cope reaction as the key bond-forming step. Two different stereocontrolled accesses to new 4-hydroxypipecolic acid analogs with a bicyclic b-lactam structure have been developed by using intramolecular reductive amination or allenic hydroamination reactions in 2-azetidinone-tethered azides [102]. When attempts were made to reduce azide 195 using the triphenylphosphine method, a complex reaction mixture was observed. Fortunately, it was found that 2-azetidinone-tethered azidoallenic acetate 196 when treated at room temperature with triphenyltin hydride in benzene solution, gave in a totally regioselective fashion, the bicyclic 4-hydroxypipecolic acid analog 197 through a 6-exo-dig aminocyclization with concomitant acetate cleavage (Scheme 71). Exposure of aldol adduct 198 to the Ph3P–H2O reductive system did afford a mixture of highly polar compounds, which could not be characterized. The hydrogenation reaction of azidoaldol 198 performed in the presence of Boc2O revealed through 1H NMR monitoring the formation of little cyclization product, while the major components in the mixture were side-products. Then, it was decided to carry out reduction of the azide and in situ cyclization and protection of the resultant secondary amine as the benzylcarbamate. Interestingly, exposure of compound 198 to H2 (1 atm) in ethyl acetate at room temperature in the presence of a catalytic amount of Pd (10% on C) followed by the addition of benzyl chloroformate, provided the 4-hydroxypipecolic acid analog 199 with a bicyclic b-lactam structure (Scheme 72). A convenient approach to synthesize novel selenium-b-lactams, namely 3-selena-1-dethiacephems 200, was accomplished via the regioselective iodocyclization reaction (Scheme 73) [103]. The key starting materials, alkyne-selenoureas 201, for this approach were readily prepared by the N-alkylation reaction of the corresponding previously known propargyl-azetidinones with a wide variety of isoselenocyanates under basic conditions. First, the reaction of b-alkyne-selenourea

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams

N3

H H

OH O H2N

H2, Pd–C N

O

PMP 198

H H

OH

O N H

OH H N

N

AcOEt, RT

O

CbzN H

OH H

PMP

O

PMP

HN BnOCOCl, Na2CO3 H

N O

45

CH2Cl2, RT

PMP

OH H N

O

PMP

199 (49%)

Scheme 72 Preparation of bicyclic b-lactam 199 using azido-ketone cyclization TBSO

R2-N=C=Se NaH

H H

Me N O

H

R1 THF, –10oC

TBSO

TBSO H H

I2

Me N O Se

NH R2

R1 CH2Cl2, RT

201 (85–99%)

I

H H Me

R1 N

Se

O N

R2

200 (82–95%)

Scheme 73 Preparation of bicyclic b-lactam 200 using selenacyclization

201a (R2 = 4-ClC6H4) with 1.05 equiv of iodine or NIS in THF at room temperature was examined. It was found that the reaction was highly dependent on the type of electrophile used. With NIS, the desired 3-selena-1-dethiacephem 200a (R1 = H, R2 = 4-ClC6H) along with 3-aza-4-selenoxo-1-dethiacephem and 3-aza-4-oxo-1dethiacephem was obtained. The 3-aza-4-oxo-1-dethiacephem was probably formed by the decomposition of 3-aza-4-selenoxo-1-dethiacephem. However, when the reaction was carried out using 1.05 equiv of iodine, the desired product 200a was exclusively produced in good isolated yield (84%) with only trace amount of byproducts (as indicated by TLC). To improve the yield of cyclization, different reaction conditions were then screened. CH2Cl2 was found to be the best solvent for the cyclization reaction. Furthermore, the reaction was heavily influenced by the amount of iodine added, and the best result was obtained when 1.25 equiv of iodine was used (92% yield). On the basis of the above results, the iodocyclization of other alkyne-selenoureas 201 with 1.25 equiv of iodine was conducted in CH2Cl2 at room temperature. A variety of 3-selena-1-dethiacephems 200 were obtained in good to excellent yields. The nature of the R2 group on the selenourea had very little effect on the reaction rate or product yields. Aryl-substituted selenoureas gave slightly higher yield than alkyl-substituted selenoureas. The aryl substitution at alkynes was also well accommodated and afforded the cyclized products in excellent yields. The reaction shows high regioselectivity for six-membered ring selenacephems 200. Seven-membered ring products were never detected under these reaction conditions.

46

B. Alcaide and P. Almendros

4 Conclusion The synthesis of spirocyclic and fused unusual b-lactam derivatives has been discussed. The 2-azetidinone skeleton has been extensively used as a template on which to build the carbo(hetero)cyclic structure joined to the four-membered ring, using the chirality and functionalization of the b-lactam ring as a stereocontrolling element. In many cases the compounds described in this chapter were included because of an interesting synthesis or structure, although limited biological data were found.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

13. 14. 15.

16. 17. 18. 19. 20. 21. 22.

23.

Singh GS (2004) Mini-Rev Med Chem 4:69 Singh GS (2004) Mini-Rev Med Chem 4:93 Niccolai D, Tarsi L, Thomas RJ (1997) Chem Commun 2333 Southgate R (1994) Contemp Org Synth 1:417 Southgate R, Branch C, Coulton S, Hunt E (1993) Recent progress in the chemical synthesis of antibiotics and related microbial products. In: Lukacs G (ed) Springer, Berlin, 2:621 Page I (ed) (1992) The Chemistry of b-Lactams. Chapman and Hall, London Morin RB, Gorman M (eds) (1982) Chemistry and biology of b-lactam antibiotics. Academic, New York Cabri W, Di Fabio R (2000) Sanfetrinems from bench to market: the evolution of chemical synthesis. Oxford University Press, Oxford, 72 Kanno O, Kawamoto I (2000) Tetrahedron 56:5639 Hanessian S, Reddy B (1999) Tetrahedron 55:3427 Biondi S, Pecunioso A, Busi F, Contini SA, Donati D, Maffeis M, Pizzi DA, Rossi L, Rossi T, Sabbatine FM (2000) Tetrahedron 56:5649 Ghiron C, Rossi T (1997) The chemistry of Trinems in targets in heterocyclic systemschemistry and properties. In: Attanasi OA, Spinelli D (eds) Societa Chimica Italiana, Rome, 1:161 Ngo J, Castan˜er J (1996) Drugs of the future 21:1238 Brown AG, Butterworth D, Cole M, Hanscomb G, Hood JD, Reading C (1976) J Antibiot 29:668 Veinberg G, Vorona M, Shestakova I, Kanepe I, Lukevics E (2003) Some of the more notable advances concern the development of mechanism-based serine protease inhibitors of elastase, cytomegalovirus protease, thrombin, prostate specific antigen, and cell metastasis and as inhibitors of acyl-CoA cholesterol acyl transferase. Curr Med Chem 10:1741 Hogan PC, Corey EJ (2005) J Am Chem Soc 127:15386 Clader JW (2004) J Med Chem 47:1 Kvaerno L, Ritter T, Werder M, Hauser H, Carreira EM (2004) Ang Chem Int Ed 43:4653 Burnett DA (2004) Curr Med Chem 11:1873 Page MI, Laws AP (2000) Tetrahedron 56:5631 Haley TM, Angier SJ, Borthwick AD, Singh R, Micetich RG (2000) Drugs 3:512 Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Hoberg MD, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su Zz, Gupta P, Fisher PB (2005) Nature 433:73 It has been reported that b-lactams act to modulate the expression of glutamate neurotransmitter transporters via gene activation Macı´as A, Mora´n Ramallal A, Alonso E, del Pozo C, Gonza´lez J. (2006) J Org Chem 71:7721

Novel Aspects on the Preparation of Spirocyclic and Fused Unusual b-Lactams

47

24. Bittermann H, Gmeiner P (2006) J Org Chem 71:97 25. Bittermann H, Bo¨ckler F, Einsiedel J, Gmeiner P (2006) Chem Eur J 12:6315 26. Alonso E, Lo´pez-Ortiz F, del Pozo C, Peralta E, Macı´as A, Gonza´lez J. (2001) J Org Chem 66:6333 27. Kambara T, Tomioka K (1999) J Org Chem 64:9282 For their evaluation as cholesterol absorption inhibitors, see 28. Skiles JW, McNeil D (1990) Tetrahedron Lett 31:7277 For their evaluation as inhibitors of poliovirus and rhinovirus 3C-proteinases, see 29. Macı´as A, Alonso E, del Pozo C, Venturini A, Gonza´lez J (2004) J Org Chem 69:7004 30. Macı´as A, Alonso E, del Pozo C, Gonza´lez J (2004) Tetrahedron Lett 45:4657 31. Alonso E, del Pozo C, Gonza´lez J (2002) Synlett 69 32. Dolle RE, Li CS, Novelli R, Kruse LI, Eggleston D (1992) J Org Chem 57:128 33. Baran PS, Shenvi RA (2006) J Am Chem Soc 128:14028 34. Sun C, Lin X, Weinreb SM (2006) J Org Chem 71:3159 35. Baran PS, Shenvi RA, Mitsos CA (2005) Ang Chem Int Ed 44:3714 36. Nishikawa T, Kajii S, Isobe M (2004) Synlett 2025 37. Pinder JL, Weinreb SM (2003) Tetrahedron Lett 44:4141 38. Kajii S, Nishikawa T, Isobe M (2008) Chem Commun 3121, Synthetic studies and biosynthetic speculation inspired by an unexpected reaction on the marine alkaloid chartelline C have been described 39. Alcaide B, Almendros P, Aragoncillo C (2007) Chem Rev 107:4437 40. Alcaide B, Almendros P (2004) Curr Med Chem 11:1921 41. Deshmukh ARAS, Bhawal BM, Krishnaswamy D, Govande VV, Shinkre BA, Jayanthi A (2004) Curr Med Chem 11:1889 42. Alcaide B, Almendros P (2002) Synlett 381 43. Palomo C, Aizpurua JM, Ganboa I, Oiarbide M (2001) Synlett 1813 44. Alcaide B, Almendros P (2001) Chem Soc Rev 30:226 45. Palomo C, Aizpurua JM, Ganboa I, Oiarbide M (1999) Amino-acids 16:321 46. Ojima I, Delaloge F (1997) Chem Soc Rev 26:377 47. Wagle MMS, DR CJ, Bose AK (1988) Heterocycles 27:1755 48. Alonso E, del Pozo C, Gonza´lez J (2002) J Chem Soc Perkin Trans 1:571 49. del Pozo C, Macı´as A, Lo´pez-Ortiz F, Maestro MA, Alonso E, Gonza´lez J (2004) Eur J Org Chem 535 50. Arjona O, Murcia MC, Plumet J (2002) Tetrahedron Lett 34:6405 51. Anklam S, Liebscher J (1998) Tetrahedron 54:6369 52. Nishikawa T, Kajii S, Isobe M (2004) Chemistry Lett 33:440 53. Chowdari NS, Suri JT, Barbas CF III (2004) Org Lett 6:2507 54. Clayden J, Hamilton SD, Mohammed RT (2005) Org Lett 7:3673 55. Zanobini A, Gensini M, Magull J, Vidovic´ D, Kozhushkov SI, Brandi A, de Meijere A (2004) Eur J Org Chem 4158 56. Zanobini A, Brandi A, de Meijere A (2006) Eur J Org Chem 1251 57. Alcaide B, Almendros P, Luna A, Torres MR (2008) Org Biomol Chem 6:1635 58. Simone MI, Edwards AA, Tranter GE, Fleet GWJ (2008) Tetrahedron: Asymmetry 19:2887 59. Alcaide B, Almendros P, Martı´nez del Campo T, Rodrı´guez-Acebes R (2004) Tetrahedron Lett 45:6429 60. Alcaide B, Almendros P, Martı´nez del Campo T, Rodrı´guez-Acebes R (2007) Adv. Synth Catal 349:749 61. Alcaide B, Almendros P, Rodrı´guez-Acebes R (2005) Chem Eur J 11:5708 62. Alcaide B, Almendros P, Martı´nez del Campo T, Carrascosa R (2008) Chem Asian J 3:1140 63. Alcaide B, Pardo C, Rodrı´guez-Ranera C, Rodrı´guez-Vicente A (2001) Org Lett 3:4205 64. Alcaide B, de Murga RM, Pardo C, Rodrı´guez-Ranera C (2004) Tetrahedron Lett 45:7255 65. Desroy N, Robert-Peillard F, Toueg J, Duboc R, He´naut C, Rager MN, Savignac M, Geneˆt JP (2004) Eur J Org Chem 4840

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66. Desroy N, Robert-Peillard F, Toueg J, He´naut C, Duboc R, Rager MN, Savignac M, Geneˆt JP (2004) Synthesis 2665 67. Duboc R, He´naut C, Savignac M, Geneˆt JP, Bhatnagar N (2001) Tetrahedron Lett 42:2461 68. Alcaide B, Almendros P (1999) Tetrahedron Lett 40:1015 69. Alcaide B, Almendros P, Salgado NR (2000) J Org Chem 65:3310 70. Alcaide B, Almendros P, Pardo C, Rodrı´guez-Ranera C, Rodrı´guez-Vicente A (2003) J Org Chem 68:3106 71. Alcaide B, Almendros P, Aragoncillo C, Redondo MC (2005) Eur J Org Chem 98 72. Alcaide B, Almendros P, Aragoncillo C, Redondo MC (2002) Chem Commun 1472 73. Alcaide B, Almendros P, Aragoncillo C, Redondo MC, Torres MR (2006) Chem Eur J 12:1539 74. Alcaide B, Sa´ez E (2005) Eur J Org Chem 1680 75. Alcaide B, Alonso JM, Aly MF, Sa´ez E, Martı´nez-Alca´zar MP, Herna´ndez-Cano F (1999) Tetrahedron Lett 40:5391 76. Alcaide B, Sa´ez E (2000) Tetrahedron Lett 41:1647 77. Brown D, Brown GA, Andrews M, Large JM, Urban D, Butts CP, Hales NJ, Gallagher T (2002) J Chem Soc Perkin Trans 1:2014 78. Ruano G, Grande M, Anaya J (2002) J Org Chem 67:8243 79. Alcaide B, Almendros P, Rodrı´guez-Vicente A, Ruiz MP (2005) Tetrahedron 61:2767 80. Alcaide B, Almendros P, Aragoncillo C (2001) J Org Chem 66:1612 81. Alcaide B, Almendros P, Aragoncillo C (1999) Chem Commun 1913 82. Penfold DJ, Pike K, Genge A, Anson M, Kitteringham J, Kilburn JD (2000) Tetrahedron Lett 41:10347 83. Joshi SN, Puranik VG, Deshmukh ARAS, Bhawal BM (2001) Tetrahedron: Asymmetry 12:3073 84. Alcaide B, Almendros P, Rodrı´guez-Acebes R (2005) Synthesis 2335 85. Alcaide B, Almendros P, Aragoncillo C (2003) Org Lett 5:3795 86. Alcaide B, Almendros P, Aragoncillo C, Redondo MC (2007) J Org Chem 72:1604 87. Alcaide B, Almendros P, Pardo C, Rodrı´guez-Vicente A, Ruiz MP (2005) Tetrahedron 61:7894 88. Barrett AGM, Baugh SPD, Braddock DC, Flack K, Gibson VC, Procopiou PA (1997) Chem Commun 1375 89. Barrett AGM, Baugh SPD, Gibson VC, Giles MR, Marshall EL, Procopiou PA (1997) Chem Commun 155 90. Barrett AGM, Baugh SPD, Braddock DC, Flack K, Gibson VC, Giles MR, Marshall EL, Procopiou PA, White AJP, Willians DJ (1998) J Org Chem 63:7893 91. Barrett AGM, Ahmed M, Baker SP, Baugh SPD, Braddock DC, Procopiou PA, White AJP, Willians DJ (2000) J Org Chem 65:3716 92. Tarling CA, Holmes AB, Markwell RE, Pearson ND (1999) J Chem Soc Perkin Trans 1:1695 93. Alcaide B, Almendros P, Alonso JM, Redondo MC (2003) J Org Chem 68:1426 94. Burwood M, Davies B, Dı´az I, Grigg R, Molina P, Sridharan V, Hughes M (1995) Tetrahedron Lett 36:9053 95. Alcaide B, Almendros P, Rodrı´guez-Acebes R (2005) J Org Chem 70:2713 96. Alcaide B, Almendros P, Aragoncillo C (2002) Chem Eur J 8:1719 97. Alcaide B, Almendros P, Martı´nez del Campo T (2007) Angew Chem Int Ed 46:6684 98. Alcaide B, Almendros P, Martı´nez del Campo T, Soriano E, Marco-Contelles, JL (2009) Chem Eur J 15:1901 99. Alcaide B, Almendros P, Martı´nez del Campo T, Soriano E, Marco-Contelles, JL (2009) Chem Eur J 15:1909 100. Pal R, Basak A (2006) Chem Commun 2992 101. He M, Bode JW (2008) J Am Chem Soc 130:418 102. Alcaide B, Almendros P, Luna A, Martı´nez del Campo T (2008) J Org Chem 73:1635 103. Garud DR, Koketsu M (2008) Org Lett 10:3319

Top Heterocycl Chem (2010) 22: 49–99 DOI 10.1007/7081_2009_8 # Springer‐Verlag Berlin Heidelberg 2010 Published online: 22 January 2010

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles Shamsher S. Bari and Aman Bhalla

Abstract b-Lactam rings containing compounds are a group of antibiotics of unparalleled importance in chemotherapy. Considerable effort has been reported in the development of novel, more effective b-lactam compounds as well as their biological evaluation. This article reviews the progress made in the stereoselective synthesis of spiro-b-lactams, a unique class of heterocycles, their biological evaluation, and their applications in various related fields. The introductory paragraph highlights the significance of the b-lactam chemistry and is followed by an overview of monocyclic-, bicyclic-, and tricyclic-b-lactams. The other sections of the article deal with the stereoselective synthesis and biological evaluation of spiro-b-lactams, including their use as synthetic intermediates for b-turn mimics and b-turn nucleators. The potential of spiro-b-lactams as cholesterol absorption inhibitors, b-lactamase inhibitors, and antiviral, antibacterial, and antimicrobial agents has also been described. Keywords Biological activity Cholesterol absorption inhibitors Ketene-imine cycloaddition Spiroazetidin-2-ones Spiro-b-lactams Synthetic intermediates b-Lactamase inhibitors

Contents 1 2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Monocyclic, Bicyclic and Tricyclic b-Lactams: An Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Monocyclic b-Lactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Bicyclic b-Lactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Tricyclic b-Lactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

51 53 53 56 57

S.S. Bari ð*Þ and A. Bhalla Department of Chemistry, Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh 160 014, India e‐mail: [email protected]; [email protected]

50

S.S. Bari and A. Bhalla

Spirocyclic b-Lactams: Synthesis and Biological Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 3.1 Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 3.2 Biological Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 4 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 3

Abbreviations Ac AIBN Ar Bn Boc BSA Bu t-Bu Cbz d DCC de DEAD DIBALH DIPEA DMAP DMF DMSO ee Et h HATU IR KHMDS LDA LHMDS MCPBA Me MIC min mL Ms NCS

Acetyl 2,20 -Azobisisobutyronitrile Aryl Benzyl tert-Butoxycarbonyl N,O-Bis(trimethylsilyl)acetamide Butyl tert-Butyl Benzyloxycarbonyl Day(s) N,N-Dicyclohexylcarbodiimide Diastereomeric excess Diethyl azodicarboxylate Diisobutylaluminum hydride N,N-Diisopropylethylamine 4-(Dimethylamino)pyridine N,N-Dimethylformamide Dimethyl sulfoxide Enantiomeric excess Ethyl Hour(s) O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluranium tetrafluroborate Infrared Potassium hexamethyldisilazide Lithium diisopropylamide Lithium hexamethyldisilazide m-Chloroperoxybenzoic acid Methyl Minimal inhibitory concentration Minute(s) Milliliter(s) Mesityl N-Chlorosuccinimide

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles

NMP NMR NOE Nu PCC Ph i-Pr PTC p-TSA f TBAF TBAI TCNE TEA THF TMS Ts

51

N-Methylpyrrolidone Nuclear magnetic resonance Nuclear overhauser effect Nucleophile Pyridinium chlorochromate Phenyl Isopropyl Phase transfer catalyst p-Toluenesulfonic acid Room temperature Tetrabutylammonium fluoride Tetrabutylammonium iodide Tetracyanoethylene Triethylamine Tetrahydrofuran Tetramethylsilane Tosyl

1 Introduction b-Lactam antibiotics have proved to be chemotherapeutics of incomparable effectiveness, possessing a broad spectrum of biological activities with low host toxicity [1]. First synthesized in 1907 by Staudinger, [2] the four membered cyclic amide derivatives of 3-aminopropionic acids known as b-lactams, did not come to the forefront in organic chemistry until Fleming’s landmark discovery of penicillin in 1929 [3]. The resulting recognition of the b-lactam moiety as the key pharmacophoric component of the penam antibiotics initiated a flurry of synthetic activity. Today, thousands of compounds containing b-lactam rings are known. Whether isolated from natural sources or synthesized chemically, penicillins and cephalosporins are marked by high efficacy and safe toxicological profiles and are still the most commonly used antibiotics the world over [4]. Further, the discovery of 7-a-methoxycephalosporins [5] from “Streptomyces” in 1971, carbapenems [6], thienamycin [7], clavulanic acid [8], sulbactum [9] as well as the totally synthetic oxapenems [10], oxacephams [11], and other bicyclic b-lactams stimulated the search for novel antibiotics. More recent dedicated efforts to find new active molecules and modify the penicillin and cephalosporin structure have resulted in the discovery of simple monocyclic b-lactams such as norcardicins and monobactams [12, 13]. Yet another dimension has been added to the b-lactam research with the recent discovery of tricyclic b-lactam antibiotics called trinems [14]. Thus, b-lactam antibiotics in general can be classified into several groups based on their structures (Fig. 1).

52

S.S. Bari and A. Bhalla H

R

S

N O

R

CH3 CH3

N

O

HO

H

H H

H H

N

H3C

S R

O

H COOH Penicillins

H R

S

NH2

N

H H

N

H

O

COOH Thienamycin H S N O Sulbactam

CH3 CH3 CO2H

N

R1

O

COOH Oxacephems

R

N

R N

O O

H

OH

H

H COOH Norcardicins

CH2OH

O

O

O

O COOH Carbapenems

N

O

O

O

R3 N

1

COOH Cephalosporins

H H

H

R2

N

O

R1

N

COOH

Clavulanic acid HO

H N

O O

H H N

SO3H

Monobactams

O

OMe COOR

Trinems

Fig. 1 b-Lactam antibiotics

Very recently, b-lactam antibiotics have been shown to offer neuroprotection by increasing glutamate transporters expression via gene activation [15]; in addition, the discoveries of new biologically active b-lactams such as cholesterol acyl transferase inhibitors [16–18], thrombin inhibitors [19], human cytomegalovirus protease inhibitors [20], matrix-metallo protease inhibitors [21], inhibitors of human leukocyte elastase (HLE) [22, 23] and cysteine protease [24, 25], and apoptosis inductors [26, 27] have provided much needed motivation for continuous development of new b-lactam systems. Besides this, the utility of b-lactams as intermediates for a- and b-amino acids, alkaloids, other heterocycles, taxoids, and other important compounds of biological and medicinal interest [28–34] has given impetus to research leading to the synthesis of novel bioactive b-lactam compounds. Enthused by their pharmacological applications besides the limitation associated with their biosynthesis, organic chemists were challenged with the task of synthesizing the strained four-membered ring (azetidin-2-one), with a variety of appendages like side chains, unsaturations, heteroatoms, and, in many cases, another ring system. The vast work reported on the chemistry of b-lactams has demonstrated that b-lactam systems are quite readily accessible through a number of different approaches, with newer versions still being reported. These molecules possess enough stability as to be suitable for the standard isolation, separation, and purification processes at both the laboratory and the industrial scales [35–37]. Recently, several review articles have highlighted the different methodologies for the steroselective syntheses of mono-, bi-, tri-, and polycyclic b-lactams with associated biological activities [38–43].

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles

53

The Alcaide and Almendros group [38] have reviewed the synthesis of fused and nonfused bi-, tri-, and polycyclic b-lactams of biological interest, while Singh [39] has reviewed recent developments in synthetic and biological studies of monobactams and carbapenems. In addition to this, Palomo and coworkers [40] have described the recent progress made in the asymmetric synthesis of b-lactams and their use as building blocks of natural and non-natural products. Besides this, Deshmukh et al. [41] have made efforts to explore new aspects of azetidin-2-ones as synthons for biologically important compounds in their latest review on b-lactams. Chmielewaski et al. [42] have focused attention on explaining strategies for the stereocontrolled formation of oxygen analogs of penicillins and cephalosporins, while Buynak has reviewed the detailed research directed toward the development of useful broad-spectrum b-lactamase inhibitors [43]. The resistance of pathogenic bacteria to b-lactam antibiotics has an important incidence in human infections. As a consequence, in the last few years many research groups have been actively involved in improving the microbiological activity of antibacterial agents, as well as finding b-lactamase inhibitors [44], and exploring new b-lactam containing ring systems. In particular, spirocyclic b-lactams have, at present, become the center of attraction as they exhibit cholesterol absorption inhibiting (CAI) activity [45, 46], antiviral [47] and antibacterial properties [48], serve as efficient b-turn nucleators [49], behave as b-turn mimetics [50] and precursors of a,a-disubstituted b-amino acids [51]. This article aims to review the development in stereoselective synthesis of spirob-lactams and their biological evaluation as well as applications in various fields.

2 Monocyclic, Bicyclic and Tricyclic b-Lactams: An Overview 2.1

Monocyclic b-Lactams

Synthesis of unusual amino acids, peptidomimetics, synthetic enzymes, and new drugs containing b-lactam rings as an integral part of their structure, has currently renewed interest worldwide in this four-membered heterocycle [52–54]. Furthermore, the appropriately substituted and configuredb-lactam frameworks now constitute effective tools for the incorporation of a wide variety of both b- and a-amino acids in short peptide segments of various biologically active molecules. The discovery of the norcardicins and monobactams demonstrated for the first time that a conformationally constrained bicyclic structure was not necessary for antibacterial activity of b-lactams [12, 13]. In recent years, various natural and unnatural monocyclic-b-lactams have been shown to exhibit high biological activity, suggesting that the biological activity of the particular ring is influenced by the type of substitution attached to the azetidin-2-one ring (Fig. 2). Burnett et al. [16] have reported monocyclic b-lactam I as a potent cholesterol absorption inhibitor in vivo, and this can inhibit the absorption of dietary

54

S.S. Bari and A. Bhalla Cl OMe H3CO

H

N

H N

Antiviral b-lactam

Cholesterol absorption inhibitor R1

O H S

R2

N

N

R2

N

CO2H b-Lactamase inhibitors

CH3

R

N O

O R1 b-Turn mimics

O

O O

N

O

O O S O

O

O

N H

O

H N CH3

b-Turn nucleators

Fig. 2 Biologically active spirocyclic b-lactams

cholesterol by inhibiting the enzyme acyl-CoA: cholesterol acyl transferase (ACAT), which is associated with cholesterol esterification. The potential use of monocyclic b-lactam II as thrombin inhibitor [19] and III as prostate specific antigen inhibitor [55] has been documented well. Many of the anticancer drugs in current use are toxic and thus, limited in their efficacy. Recently, Smith et al. [26, 27] have discovered and characterized the apoptosis inducing properties of a family of novel monocyclic cis-3-methoxy-b-lactam IV antibiotics against leukemia, breast, prostate, and head-and-neck cancer cells. The clinical demand for newer, more specific and potent inhibitors of proteases is growing continuously, especially for enzymes such as HLE whose activity has proven to be instrumental in a number of cases of severe, acute, and chronic pathology. Garbisa et al. [21] have reported that monocyclic b-lactam V exhibits activity against HLE at micromolar concentrations. Monocyclic azetidin-2-ones have been assessed for enzyme inhibiting and antitubercular activity as well. Georg and Schloss [56] revealed that 3-amino b-lactam VI is a time-independent inhibitor of a-chymotrypsin, carboxypeptidase Y, and cathepsin G. N-Substituted azetidin-2one VII, which was screened in vitro and has been found to exhibit antitubercular activity against Mycobacterium tuberculosis H37Rn strain [57]. The discovery of b-lactams likes VIII, IX, X, which find use as hypocholesterolemic, anti-inflammatory, antidegenerative, and antileukemic, respectively, has added another distinct dimension in the search for biologically active novel monocyclic b-lactams [58–60]. Recently, Banik et al. [61, 62] have explored the anticancer activity of monocyclic b-lactam XI against leukemia and colon carcinoma cell lines and very recently, Imbach et al. [63] reported the monocyclic b-lactam XII as the selective inhibitor of the chymotrypsin-like activity of the human 20 S proteasome (Fig. 3).

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles OCH3 H

NH

H

H H

N H

H 2N N

O

N

O

55

CO2CH3 O S O

OCH3 Cholesterol acyl transferase inhibitor (I) O

CO2H

OH H

HO

H H

CH3

Thrombin inhibitor (II)

O

O

HO

OH

O

H H

O HO

N

O

F

N

O

O

R

Cl H3CO

OTBS

H H

F

Hypocholesterolemic (VIII)

CO2Bn Prostate specific antigen inhibitor (III)

Et

Et

COOEt

O N

O

Me

O N S CH3 O Antitumor (IV)

Cl N

S

O

CH3

O

Pr Anti-inflammatory & antidegenerative (X)

O

O

O N H

OAc

Anticancer (XI)

Fig. 3 Biologically active monocyclic b-lactams

CO2H O

N

CH3

Antituberculic (VII)

N Ph

O O

O

O

O

O

N

Enzymatic inhibitor (VI)

Et

Et

N

CO2H

Pr Antileukemic (IX)

R

O N

HN

OCH2Ph

Human leukocyte elastase inhibitor (V)

Ph PhCONH

N

O

O N H

N H

NH O Inhibitor of chymotrypsin-like activity of human 20S proteasome (XII)

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S.S. Bari and A. Bhalla

Bicyclic b-Lactams

2.2

The development of antibacterial chemotherapy during the past 75 years has spearheaded the successful use of today’s drugs to combat bacterial infections. Studies in b-lactam chemistry were stimulated when b-lactam ring, the four membered heterocycle, was recognized as a key structural feature as well as a key therapeutic feature of the bicyclic b-lactam antibiotics such as penicillins, cephalosporins, and other classical antibiotics. The last two decades have registered the discovery of several nonclassical bicyclic b-lactam antibiotics, e.g., thienamycin and carbapenems of natural origin like olivanic acids, carpetimycin, pluracidomycin, and aspareomycins. Currently, bicyclic b-lactams such as, imipenem (XIII), panipenem (XIV), and meropenem (XV) have been shown to exhibit broad antimicrobial spectrum and potent bactericidal activity [64–66]. Recently, Kang et al. [67] have found that the bicyclic b-lactams (XVI) exhibit potent antibacterial activities against a wide range of Gram-(þ) and Gram-() bacteria and high stability to the renal dehydropeptidase-I (DHP-I). Mikamo et al. [68] have reported in vitro and in vivo antibacterial activity of bicyclic b-lactam S-4661 (XVII) against S. agalactiae, E. coli, P. magnus, B. fragilis, and P. bivia, the major pathogens in the fields of obstetrics and gynecology [69] (Fig. 4).

HO

HO

H H N

O

H N

S

N

H H

S

NH

COOH Panipenem (XIV) HO

Me2NOC

H H SH

NH N

N

O

COOH

Imipenem (XIII) HO

H H

NH

N

S

S

O

O

R

COOH 1b-Methylcarbapenems (XVI)

COOH Meropenem (XV) HO

H H O N

S

O

S N NH2 H O

N H 1b-Methylcarbapenem S-4661 (XVII) COOH

Bicyclic-b-lactams: Antibacterial and highly stable to porcine renal dehydropeptidase-I (DHP-I)

Fig. 4 Biologically active bicyclic b-lactams

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles HO

HO

H H

COOH

Trinem (XVIII) HO

H H

H H

NH2

N O

S

N O

COOH N H

Trinem (XIX) H

N R

N O

COOH R = (p)-CS-NH-3-pyrrolidinyl, C(NH)=NH Azatrinems (XX)

57

X

N O

COONa X = CH2, S

Trinems (XXI)

Tricyclic-b-lactams: Antibacterial and b-lactamase inhibitors

Fig. 5 Biologically active tricyclic b-lactams

2.3

Tricyclic b-Lactams

Trinems are a class of fused tricyclic totally synthetic antibiotics. These are potent antibacterial agents with broad spectrum of activity against both aerobic and anaerobic Gram-(þ) and Gram-() bacteria. Kanno et al. [70] have reported that tricyclic b-lactam XVIII showed antibacterial activity against both Gram-(þ) and Gram-() bacteria (MIC ¼ 0.01–6.2 mg mL1). However, tricyclic b-lactam XIX having pyrrolidinylthiomethyl moiety exhibit the most potent anti-MRSA activity (MIC ¼ 1.5 mg mL1) against Gram-(þ) bacteria S. aureus 209P [71]. Recently, Mori et al. [72] have reported the stereoselective synthesis and antibacterial activity of tricyclic b-lactams with azacyclohexane ring (XX). These 5-azatrinems (XX) showed high potency and well-balanced spectrum against Gram-(þ) and Gram-() bacteria. In continuation to this study, Copar et al. [73] have designed biologically active tricyclic b-lactams XXI using theoretical computation and molecular modeling. These trinems have been shown to possess inhibitory activity against Class C b-lactamase (Fig. 5).

3 Spirocyclic b-Lactams: Synthesis and Biological Evaluation Although, considerable synthetic progress has been made in the area of mono and bicyclic b-lactam antibiotics in recent years, the discovery and development of new antibacterial agents with enhanced bioactivity and greater stability toward b-lactamases still remains an important endeavor for medicinal chemists. Also, the widespread incidence of antibacterial resistance to b-lactam antibiotics caused by

58

S.S. Bari and A. Bhalla

b-lactamase formation has provoked a growing interest in the development of effective b-lactamase inhibitors. In addition, the search for novel candidates with different biological activities still remains a field of much interest. The synthesis of b-lactams having a small fused ring is of interest since the large strain of the ring should substantially alter the reactivity of b-lactams. Several approaches for the synthesis of spiro-b-lactams have been described in literature.

3.1

Synthesis

Bose et al. [74] have investigated the novel synthetic route for the preparation of spirobarbiturates–a class of compounds known for their interesting physiological activity. The synthesis of spiro-b-lactams 3 (Scheme 1) was achieved by the reaction of 4,4-dicarboxy-N-phenylazetidin-2-one 1 with carbodiimides 2 in tetrahydrofuran. Moricini and Kelly [75] have reported the synthesis of spiro-b-lactams 6 containing an exocyclic double bond (Scheme 2) by the 1,2-dipolar cycloaddition of symmetrically/unsymmetrically substituted allene 4 with chlorosulfonyl isocyanate 5 in ether. In the course of their studies on the synthesis of a-amido-spiro-b-lactams as analogs of penicillin and cephalosporin, Manhas et al. [76] have prepared 1-phenyl3-phenoxy-4,4-spirocyclohexylazetidin-2-ones by the reaction of phenoxyacetyl chloride 7 and cyclohexylidenephenylamine 8 in the presence of triethylamine and dichloromethane. Azidoacetyl chloride was found to be even more reactive

N O

R=

N

CO2H + R N C N R C6H5

THF O

2

1 CH3 ,

,

R

O

CO2H

CH

3

N N O R C6H5

O

CH3 CH3

Scheme 1 Preparation of spirobarbiturates using 4,4-dicarboxy-N-phenylazetidin-2-one and carbodiimides

H2C C CH2 4

+

R N C O

Et2O

5

R = SO2Cl2 , H

Scheme 2 Synthesis of spiro-b-lactams by 1,2-dipolar cycloaddition

N O 6

R

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles Scheme 3 Preparation of spiro-b-lactams using of phenoxyacetyl chloride and cyclohexylidenephenylamine

R

R

CH

Et3N CH2Cl2

+ H5C6N

C

59

O

N O

7

8

C6H5

9

R = OC6H5, –N3, –NH2, –NHCOCH2OC6H5

O

O

Scheme 4 Photochemical synthesis of spirocyclic-b-lactams

H N

CH3

N

hn

H N N

H3C

O

O X

X 10 X = CH2, S

11 O

O H N N

CH3

hn

H3C

H N N

O

O 12

13

than phenoxyacetyl chloride in the cycloaddition reaction, giving azido b-lactam in 54% yield. The azide group was easily reduced by catalytic hydrogenation in the presence of Adam’s catalyst. Acylation with phenoxyacetyl chloride of the amine group readily transformed it into a-amido-spiro-b-lactam 9 (Scheme 3) in a quantitative yield. Johnson et al. [77] have prepared spiro-1-acylaminoazetidin-2-ones 11, 13 (Scheme 4) by photolysis of spiro-2-acylpyrazolidin-3-ones 10, 12, respectively. The N-acylaminoazetidin-2-one moiety has been found to be the dominant feature of 6-azapenicillins and 7-azacephalosporins. Novel spiropenicillins (Scheme 5) have also been prepared by Sheehan et al. [78]. b,b,b-Trichloroethyl-6-diazopenicillanate 14 reacts with acrylonitrile, ethyl acrylate, and t-butyl acrylate to give isomeric compounds 16 and 17. The preferred mode of addition is from the sterically less hindered a-side. This study has further been extended by carrying out the reaction of dipolarophile penicillin molecule 18 with diphenyldiazomethane 19 and this reaction resulted in the formation of single isolable spiro-b-lactams 20. Further pyrolysis of 20 gave spiro-b-lactams 21 (Scheme 6). Addition is expected to occur from the a-side. Singh and Mehrotra [79] have published the synthesis of spiro-b-lactams 24 (Scheme 7) by the reaction of 2-diazo-1,2-diphenylethanone 22 with 2-phenyliminoacenaphthenone 23 in refluxing benzene. These compounds were further subjected to reduction with sodium borohydride which afforded spiro-b-lactams 25. This study has also revealed that the carbonyl group in the spiro-b-lactams 24 have

60

S.S. Bari and A. Bhalla H N N

H

N2

S N

O 14

R

+

H

C

CH2

CH2Cl2

S N O

CO2CH2CCl3

H

H

R

15

R = CN, CO2CH2CH3, CO2tBu, CO2Ph

R

CO2CH2CCl3

H 16 Major + H S

N N H O

N CO2CH2CCl3

H 17 Minor

Scheme 5 Divergent synthesis of spiropenicillians

R1

R1 H

Ph

S

R2

+

N O 18

H

Ph Ph

C N2

CH2Cl2

Ph

H

N N R2

CO2CH2CCl3

S N

O

19

20

R1 = H, CO2CH2Ph

CO2CH2CCl3

H

N2

R2 = CO2CH2Ph, H R1

Ph

Ph H S

R2

N O

H

CO2CH2CCl3

21

Scheme 6 Use of diphenyldiazomethane in preparation of spiropenicillians

been found to be unaffected either by hydrolysis or treatment with sodium borohydride and could be used as precursors for the introduction of other desired functionalities. Ikeda et al. [80] have reported a photochemical entry to spiro-b-lactams 27 (Scheme 8) by the irradiation of a solution of 2-(N-acyl-N-alkylamino)cyclohex2-enone 26 in acetone with a 300 W high pressure mercury lamp in a pyrex vessel under nitrogen. The reaction occurred with the intervention of the 1,4-diradical intermediate formed via abstraction of a hydrogen on the N-acyl group by the b-carbon atom of the a,b-enone system. Joshi et al. [81] have incorporated azetidin-2-one moiety into indole nucleus and synthesized several fluorine containing spiro-b-lactams (Scheme 9). The synthesis involved the condensation of primary amines with an appropriate indole-2,3-dione

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles

61

Ph N

O

R1

O

O

Ph

N R1

+

Ph C N N

C6H6

+

Reflux

Ph C O 22

23

24 NaBH4

R1= Ph, C6H4 – CH3(p)

Ph HO

Ph

O N R1

25

Scheme 7 Preparation of spiro-b-lactams using 2-diazo-1,2-diphenylethanone and 2-phenyliminoacenaphthenone

O

R1 N R2

O O

hn

R3

R1 N R2

26 R1 = CH3, R2 = CH3, R3 = CH3,

O O R3

R1 N

R3

O R2

27 iPr, CH2Ph

SCH3, Ph, [CH2]5 H, [CH2]5

Scheme 8 Photochemical entry to spiro-b-lactams

28 resulting in the formation of the intermediate Schiff’s bases 29 which on cycloaddition with chloroacetyl chloride gave the spiro-b-lactams 30. Georgiev et al. [82] have described the preparation of novel adamantine-spiroheterocyclic b-lactams 34, 35, and 40. Grignard reaction of 2-adamantanone 31 with benzylmagnesium halide provided the compound 32, which on further dehydration afforded corresponding analogs 33. Condensation reaction of compound 33 with chlorosulfonyl isocyanate in ether afforded spiro-b-lactams 34 and cycloaddition with chlorosulfonyl isocyanate resulted in the formation of spiro product 35 (Scheme 10). In another synthetic approach for the preparation of spiro-b-lactams, treatment of N-methyladamantanyl nitrone 36 with methyl crotonate 37 gave rise to the spiro esters 38, which on further catalytic hydrogenation resulted in the ring opening to

62

S.S. Bari and A. Bhalla H O X N R1 28

RNH2

NR X

O

N R1 29

O

O

Cl N R

ClCH2COCl X (C2H5)3N

N O R1 30

X = H, 5 F, 6 F R = C6H5, 3 FC6H4, 4 FC6H4, 3 CF3C6H5 R1 = H, CH2N

O

Scheme 9 Synthesis of fluorine substituted spiro-b-lactams

R1CH2C1 Mg, Et2O

p TSA

R1 O 31

HO 32

33

R1

R2 N C O Et2O

R1 = H, C6H5, C6H4 CH2Br(p), C6H4 OCH3(p), C6H4 CH3(p) R2 = SO2Cl R3 = H, C6H4 CH2Br(p) O

R2 N

N

R2

O R3

CH3O

34

35

Scheme 10 Preparation of adamantine-spiroheterocyclic b-lactams

provide the aminoalcohol ester 39. Subsequent treatment of compound 39 with ethyl magnesium bromide furnished spiro-b-lactam 40 (Scheme 11). Bycroft et al. [83] have prepared a series of novel 6-spiro-epoxypenicillins 43, 44 (Scheme 12) by the reaction of diazopenicillanate 41 with oxalyl chloride followed by reactions with various nucleophiles. These compounds notably exhibit b-lactam inhibitory and antibacterial properties [84] depending on substituents and stereochemistry of epoxides. These inhibitors possess side-chains, which are highly conformationally restricted but structurally similar to those of some active penicillins. The reaction sequence proposed in Scheme 12 is consistent with the approach of the reagent from the least hindered a-face of the penicillanate and interaction of the diazo-group predominantly with the re-face of one of the carbonyl groups of the oxalyl chloride thus, resulting in the formation of spiro product 43, 44 by displacement of nitrogen.

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles

H

CH3 C

+ +

N

CH3N

CH3

36

H

Reflux

CO2CH3

H

O

C6H6

C

63

CO2CH3 CH3 O

H

38

37

Pd / C Glacial acetic acid

HO

N

H

H

CH3

CO2CH3 CH3

C2H5MgBr, Et2O THF

CH3NH HO H

O H CH3 40

39

Scheme 11 Parallel synthesis of spiro-b-lactams using N-methyladamantanyl nitrone O Cl

Cl

O

O N

H

N2

S

Cl

H

N

Cl O N2

S

H S

(COCl)2 N O 41

H

Cl

N

N O

CO2R

H

CO2R

O 42

H

CO2R

O O H

Cl

S

Cl

+

N O

H Minor 44

CO2R

Cl

O H S N

O O

H Major 43

CO2R

R = H, CH2Ph, CH2CCl3

Scheme 12 Synthesis of series of 6-spiro-epoxypenicillins by use of diazopenicillanate and oxalyl chloride

In the year 1990, Skiles and McNeil [47] synthesized novel spiro-b-lactam 51, making it a successful entry into the class of antiviral b-lactams. This b-lactam has been found to be a good inhibitor of both poliovirus and human rhinovirus 3C-proteniases (IC50 ¼ 20 mg mL1). All picornaviruses studied produced a 3C-proteinase, which is required for the virus to undergo maturation.

64

S.S. Bari and A. Bhalla

O

O

N H

O

2. C6H5CH2Cl, Toluene

45

N

OCH3

H2NC6H4OCH3

1. Na, C2H5OH N

Toluene

O

N

46

O

47 CH3OCH2COCl, Et3N, CH2ClCH2Cl

H3CO

H3CO

O

H

O

H

N

N +

N

O

(NH4)2Ce(NO3)6 CH3CN, H2O

N

OCH3

49 H3CO

NH N

50

O

O

H N

ClO2S C6H4 CH3(p) KOH, Bu4NBr, THF

OCH3

48 H3CO

O

H

O

N

O S

CH3

O O

51

Scheme 13 Synthesis of antiviral spiroindolinone-b-lactams

The synthesis of antiviral spiro-b-lactam 51 begins with the benzylation of isatin 45 to give 1-benzylisatin 46, which affords Schiff’s base 47 on reaction with anisidine in ethanol. The Schiff’s base 47 on treatment with methoxyacetyl chloride by the chloride–imidate cycloaddition [85] route afforded a mixture of spiro E- and Z-azetidin-2-ones 48 and 49, which were separated by chromatography. The (Z)-Narylazetidin-2-one 49 was further converted to desired 4-spiro-b-lactam 51 by treatment with ceric ammonium nitrate and subsequently with tetrabutylammonium bromide in THF in the presence of pulverized KOH (Scheme 13). Durst and Sharma [86] have reported the stereospecific synthesis of 3-spiroepoxyazetidin-2-ones 55 (Scheme 14). The oxidation of the diastereoisomers of compound 52 with PCC provided a single acetyl compound 3-acetyl-3-benzyloxyazetidin-2-one 53. Nonchelation controlled L-Selectride reduction of 53 gave the isomerically pure 3-hydroxyethylazetidin-2-one as the sole reduced product, which was further converted to tosylate 54 using NaH/tosylimidazole. The debenzylationoxirane formation sequence was conveniently performed as a single pot operation with ammonium formate, 5% Pd/C in refluxing methanol as the hydrogen transfer reagent combination. This study shows that by combining the diastereospecific reduction of acylazetidin-2-ones and the suitable functional group manipulations, it has been possible to synthesize the 3-spiro-epoxyazetidin-2-ones in a diastereospecific manner.

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles O BnO

OTBDMS 1.LDA, THF, 2.PCC, NaOAc

N

O

78ºC,

OBn OTBDMS

CH3CHO O

OCH3

52

65

N OCH3

53 1. L Selectride, TMEDA, THF, 78ºC 2. NaH, DMF, Tosylimidazole

H

OR OBn

O H OTBDMS

H3C N

O

HCOONH4, CH3OH 5% Pd / C

OTBDMS O

OCH3

55

N OCH3

54 R = H, Ts

Scheme 14 Stereospecific synthesis of 3-spiro-epoxyazetidin-2-ones

O R3R2HC C

N Cl

+

N

N R1

55

O 56

N

R2 Et3N CH2Cl2

R3 O

N 57

N O R1

R1 = Ph, CH3, CH2Ph, CH2CH2OSi(CH3)2C(CH3)3, CH2CH2OH, C6H4 OCH3(p) R2 = R3 = Ph, Me, Cl, OPh

Scheme 15 General strategy for the synthesis of spiro-b-lactam oxadiazolines

Warkentin and Zoghbi [87] have demonstrated the synthesis of novel spirob-lactam oxadiazolines 57 (Scheme 15) by the reaction of differently substituted acid chloride 55 and 2-amino-D3-1,3,4 oxadiazolines 56 using triethylamine in dichloromethane. Ishibashi et al. [88] have studied the radical cyclization of N-vinylic-a-chloroacetamide. They found that n-Bu3SnH mediated cyclization of a-chloroacetamide 58 gives spiro-b-lactams 59 (Scheme 16). The difference in the mode of cyclization among various substrates 58 may be explained in terms of the electronic stability and/or the steric conjestion between radical intermediates generated by ring closure of 58. The exclusive formation of the b-lactam 59 when R ¼ H suggests that the benzylic radical generated by 4-exo-ring closure is more stable than the acylamino radical, led to the formation of 60. However, substitutents like Me and Ph undergo steric repulsion with the neighboring gem-dialkyl groups, which leads to the predominant formation of a-acylamino radical thus, resulting in an increase in the amount of the g-lactam 60.

66

S.S. Bari and A. Bhalla

H

R N Me

Cl n-Bu3SnH AlBN O

R

O

R = H, Me, Ph

H

+

R +

N H Me

NMe

58

R

59

O

N Me

60

50 % (R = H) 42 % (R = Me) 0 % (R = Ph)

O

61

0 % (R = H) 35 % (R = Me) 76 % (R = Ph)

32 % (R = H) 19 % (R = Me) 0 % (R = Ph)

Scheme 16 Preparation of spiroazetidin-2-ones through n-Bu3SnH mediated cyclization of a-chloroacetamide OM OEt + 62 Me

R +

H

R=

R

Ar N

63 O

O Ar = C6H4 OCH3(p)

N

R O

64

Ar

N O

Ar

65

OMe OMe

M = Li, Ti(OiPr)3

Scheme 17 Stereodivergent synthesis of spiro-b-lactams using ester enolates and chiral imines

Fujisawa et al. [89] have reported the stereodivergent synthesis of spirob-lactams 64, 65 (Scheme 17) by reaction of lithium or titanium ester enolates 62 with single chiral imines 63 by taking advantage of different coordination states of the enolate metals. Almost complete reversal of the diastereofacial-discrimination with respect to the C-4 of the b-lactam skeleton has been attained in this reaction coupled with flexibility in the selection of the enolates and ready removal of the chiral auxiliary. Pavia et al. [90] have developed a new, efficient, and diastereoselective method to synthesize spiro-b-lactams (Scheme 18). The strategy involves the direct conversion of unsaturated N-benzyl-a,b-unsaturated cyclic oxomides 67 to spiranic b-lactams 68, 69 by intramolecular hydrogen abstraction under photochemical activation. Starting oxomides 67 were synthesized from the corresponding known unsaturated oxoacids or commercially available oxoacid 66 and primary or secondary benzylamines. Aoyama et al. in relation to their studies on photochemical synthesis of b-lactams [91] reported the synthesis of 4-spirocyclopropylazetidin-2-one [92] via photocycloaddition of 4-thioxoazetidin-2-one to alkenes followed by subsequent desulfurization. A solution of 1-isopropyl-3-phenyl-4-thioxoazetidin2-one 70 and 1,1-diphenylethylene in benzene on irradiation with a high pressure mercury lamp afforded a [2 þ 2] adduct 72 (R ¼ Ph), in 67% yield which, on desulfurization with Raney-nickel [93] in anhydrous ethanol gave two isomeric

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles O

O

R2

Ph

R2 n

R R

R1

OH

X

O R2

X O

H

N

Ph

+

R R

R1

n

N

X

R

67

N

O

69

R1

O

hn 313 nm Solvent, r.t.

Ph

X

Ph

n

O

n

R

R

DCC (1 eq.) / 3Å M. S. DMAP (cat.) / CH2Cl2

O 66 X=CH2, O

R

N

67

R2 R1

68

R = H, CH3 R1 = H, CH3, C6H5CH2, iPr R2 = H

Scheme 18 Photochemically induced diastereoselective route to spiro-b-lactams

H

Ph

S N

O

70

+ iPr

R

H

Ph

O

Ph R

H

iPr

N O

72 R = Ph, Me

R S

R +

N R

R 71 R = Ph or Me

S

iPr

73 R = Me

Raney-Ni Ethanol

H

H

R N

O

R Ph

R

Ph

74 R = Ph

+ iPr

N O

R

iPr

75 R = Ph, Me

Scheme 19 Synthesis of 4-spirocyclopropylazetidin-2-one via photocycloaddition

4-spirocyclopropylazetidin-2-ones 74, 75 (R ¼ Ph). However, photochemical reaction of 70 with 2-methylpropene yielded two isomeric thietanes 72 (R ¼ Me) and 73 both of which produced the spiro-b-lactam 75 (R ¼ Me) on desulfurization with Raney-nickel (Scheme 19). Otto et al. [94] have described the synthesis of spiro-b-lactam 78 (Scheme 20) by the addition reaction of nucleophile to the exocyclic double bond of dicarboxylates of 3-methylene b-lactams 76.

68

S.S. Bari and A. Bhalla PhHN

COOEt EtOOC

NH

Ph

C N

O

PhNHNH2

H

(EtOOC)2HC N

O OCH3

76

Ph H

OCH3

77 HCl CHCl3, Ph N NH

O EtOOC

Ph N

O

H

OCH3

78

Scheme 20 Preparation of spiro-b-lactams using addition reactions to exocyclic double bond

R H

O Me3SO+I

N

Ph

C 79

COOEt

THF

R H

O N COOEt

Ph

COOEt

COOEt

80

Toluene OCH3

Toluene R H

O N

COOEt

CH3SiO

CH2

COOEt

Ph

R H

O N

O

Ph EtO2C

82

CO2Et

OCH3

81

R = C6H4 OCH3(p), tBuPh2Si, 3,4-(MnO2)C6H3

Scheme 21 Use of Diels-Alder reaction in synthesis of spiro-b-lactams

The addition of the hydrazine derivative to 76 at room temperature resulted in the hydrazine adduct 77. When phenyl hydrazines adduct 77 was heated in CHCl3 solution with conc. HCl solution, the N-atom and one COOEt group underwent thermally reversible reaction to afford spiro-b-lactam 78. In continuation to this, they used a,b-unsaturated b-lactams 79 for the construction of spirocyclic compounds 80–82 (Scheme 21) by the addition of a methylene

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles R H R1OOC

C6H5

N Ph

C N

O

O

Ph

Oxidation

H

HO

R

69

N

H

R 84 R = C6H4 OCH3(p)

83 R = Ph, C6H4 OCH3(p) R1 = Ph, Me, Et

O

Scheme 22 Unusual rearrangement of monocarboxylates of 3-methylidene-b-lactams to spirob-lactams

R H

O N

R R1

H R2

Ph H

O N

Ph H

H (Z)-85

H

R1

R2

R TCNE THF Reflux

H Ph

N

OH R1 R2

NC

H

NC NC 86

CN

R = Ph, C6H4 OCH3(p) R1 = H, Me R2 = H, Me, Ph

Scheme 23 Incorporation of 3-(prop-2-enylidene)azetidin-2-one for the synthesis of spirob-lactams via Diels-Alder reactions

group forming cyclopropane derivatives and the use of the electron-poor double bond as a dienophile in Diels-Alder reactions. The spiro-b-lactams 80 were prepared by the addition of the ylide from trimethylsulfoxonium iodide and 79, whereas the use of Diels-Alder reactions in the synthesis of spiro-b-lactams 81–82 was demonstrated by carrying out the reactions of 79 with cyclopentadiene and Danishefsky’s diene in toluene, respectively. The structures of these compounds were supported by their NMR (NOE and 2DNOESY) spectra and it established that these isomers are not endo/exo-isomers but cis/trans isomers. They could not detect any other isomer but believed the main products formed are cis isomers, as reaction was believed to proceed by transaddition, meaning that the Diels-Alder reactions at the side opposite to the bulkier constituent at C-4 is favored. In their further studies [95], the synthesis of spiro-b-lactams 84 (Scheme 22) were carried out by unusual oxidative rearrangement of monocarboxylates of 3-methylidene-b-lactams 83 with different oxidizing reagents such as H2O2 in alkali, t-BuOOH, or KOCl. The reaction always resulted in the single isolated crystalline spiro-b-lactam 84 whose stereochemistry was established by single X-ray crystallography. Otto and Ruf [96] have incorporated the 3-(prop-2-enylidene)azetidin-2-one derivatives 85 for the synthesis of spiro-b-lactams 86 via Diels-Alder reactions (Scheme 23). The reaction of (Z)-85 with highly reactive tetracyanoethylene (TCNE) was performed in THF at refluxing temperature, which afforded spiro-b-lactams 86.

70

S.S. Bari and A. Bhalla 1

H

Ar

H

Ar

a, b HO2C

CO2Et

1

Ar

H

1

H

c, d

O

87

H g, h, i

OH EtO2C

1

e, f

O

88

Ar

1

O O

Xc SiPh2tBu

O MeO2C

89

Ar

90

91

SiPh2tBu

j Ar N

Ph

Ar l, m

N

Ph

k

O

H

1

1

Ar

Ar

O

O H

H

Ar1

H

Xc

O

Ar

H

SiPh2tBu

OH

94

93

Ar = C6H4 OCH3(p) Ar1= C6H4 Cl(p)

NHPh O

Xc =

O

92

N Ph

n

Reagents: a) LiBH4, b) PhCH3, H , c)DIBALH, d) BuLi, (EtO)2P(O)CH2CO2Et, e)Mg/MeOH, f)tBuPh2SiCl g) LiOH, h) (COCl)2, i) Xc-H, j) TiCl4, ArCH=NPh, k) BSA, TBAF, l) CBr4, Ph3P, m) LDA +

Scheme 24 Enantioselective synthetic route to cholesterol absorption inhibitor spiro-b-lactams

Out of (E, E)-, (Z, E)-, or (Z)-isomers, the (Z)-isomers are the favorable substrates for Diels-Alder reactions as calculated by preferred conformations and minimum energies, which is also in agreement with the performed experiments. Spiro-b-lactams (þ)-SCH 54016 94 have been found to exhibit CAI activity, therefore an efficient synthetic route for these spiro-b-lactams for continuing biological evaluation was of great interest. Chen et al. [45] have reported an efficient and highly enantioselective synthetic route to spiro-b-lactam (þ)-SCH 54016 (Scheme 24). (R)-3-(4-Chlorophenyl)glutarate monoethyl ester 87 was reduced to hydroxy acid and subsequently cyclized to afford lactone 88. This was further submitted to reduction with diisobutylaluminium hydride to provide lactol followed by Horner-Emmons reaction, which resulted in the formation of hydroxy ester product 89 in good yield. The alcohol was protected as silyl ether and the double bond in 89 was reduced with magnesium powder in methanol to provide methyl ester 90. The hydrolysis to the acid and condensation of the acid chloride with Evans’s chiral auxiliary provided product 91, which was further converted to titanium enolate on reaction with TiCl4. This was submitted to enolate-imine condensation in the presence of amine to afford 92. The silylation of the 92 with N, O-bis(trimethylsilyl) acetamide followed by treatment with tetrabutylammonium fluoride resulted in cyclization to form the azetidin-2-one ring and subsequently hydrolysis provided 93. This product was converted to bromide analog, which on treatment with LDA underwent intramolecular cyclization to afford the cholesterol absorption inhibitor spiro-b-lactam (þ)-SCH 54016 94. They have employed the strategy of intramolecular trans alkylation of azetidin2-ones since C–4 substituted azetidin-2-one enolates, predominantly yield the C–3, 4-trans-diastereomer upon reaction with electrophiles, [45] thus, providing control of stereochemistry of substituents at the cyclohexyl ring (Scheme 25).

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles

Ar N

Y X

Ar

Ar

Ar

71

Ar

N H

95

H

O

O Ar

trans alkylation

cis alkylation Ar

Ar

Ar

N

Y

96

Ar

N

O

O

H

Ar Ar

H

98 cis-Spiro

97 trans-Spiro

Scheme 25 Intramolecular alkylation of azetidin-2-ones to access spiro-b-lactams

H OTMS O O O

OEt a, b

HO

OEt O

c, d, e O

98

NHAr

O O O

99

HO

100 f, g

1

Ar

2

N

Ar

i, j

N

O

Ar3

103

Ar

H

2

h O

Ar1

HO OEt

O O

O OH

Ar1

O

102

101

Ar1 = C6H4 OBn(p) c) O Ar2 = C6H4 F(p) 3 Ar = C6H4 Cl(p) O N Reagents: a) LDA, b) TMSCl, d) Ar1CHO, e)nBu4NF, f) Ar2NH2/Me3A1, O2S B g) HCl, h) (EtO)2P(O)C1/CH2C12/NaOH/PTC (BnNEt3Cl), R H i) Ar3MgBr, j) Pd/C/H2, ZnBr2 R = 2-naphthyl

Scheme 26 Catalytic enantio- and diastereoselective synthesis of spiro-b-lactam (+)-SCH 58053

Similarly, Guangzhong Wu et al. [46] have published the catalytic enantio- and diastereoselective synthesis of another spiro-b-lactam (þ)-SCH 58053 103 (Scheme 26) which has been shown to exhibit CAI activity. Treatment of the starting ester 98 with LDA and subsequent trapping with TMSCl provided the silyl ester enol ether 99. The desired chiral center via an

72

S.S. Bari and A. Bhalla N

N

N

N +

O

NH2

R

S Na

CS2, NaOH DMF

N

O

+

R

S Na

104

105 ClCH2CH2Cl

N R

N O

N O

107

N

S S H

ClCH2COCl Et3N Dioxane

N S O

R

Cl

N S

106

R = H, OCH3(p), Cl(p), CH3(p), NO2(p)

Scheme 27 Efficient synthetic route to antimicrobial spiroazetidin-2-ones

aldol condensation was constructed and followed by n-Bu4NF deprotection to furnish the hydroxy ester 100 in 95% ee. The hydroxy ester 100 was reacted with amine in the presence of Me3Al to achieve aminated compound 101, which was further cyclized to generate the b-lactam ring 102 by using (EtO)2P(O)Cl and subsequently NaOH/PTC. Addition of Grignard reagent to this compound 102, followed by selective debenzylation produced spiro-b-lactam (+)-SCH 58053 103 in 99.5% chemical purity and 99.5% ee. Hussain and Nizamuddin have synthesized 1, 3-dithiolane substituted spirob-lactams (Scheme 27) since 1, 3-dithiolane derivatives exhibit various biological activities like fungicidal, bactericidal, and insecticidal [97]. The starting thiadiazoles 104 were treated with sodium hydroxide and carbon disulfide to get the corresponding disodium dithiocarbamate 105, which were stirred with 1,2-dichloroethane to obtain 106. Cyclocondensation of 106 with chloroacetyl chloride in dry dioxane in the presence of triethylamine gave the spiro-b-lactams 107. These spiro-b-lactams were found to exhibit antifungal activity 75–85% at 100-ppm concentration against P. oryzae and F. oxysporum. Basak et al. [98] have reported the synthesis of spiro-b-lactams 110 (Scheme 28), which serve as the synthetic intermediates for preparation of 3-hydroxyazetidin-2ones following Baldwin [99] strategy, which deals with regiospecific nitrone cycloaddition. Keeping this in mind, Basak et al. have carried an enatiospecific cycloaddition route keeping a substituent at C-4. The alkenyl b-lactams 108 were subjected to cycloaddition conditions along with various nitrones 109 to provide spiroazetidin-2-ones 110. Liebscher and Anklam [100] have introduced a facile access to novel optically active spiro-b-lactams 112–113, 115–116 through cycloaddition reaction of diazomethane to a-alkylidene-b-lactams (Scheme 29). Diazomethane gave a clean reaction to a-methylene-b-lactam 111 affording spiroazetidin-2-ones 112, 113 (d.r. 87:13, 93%) with preference of anti-addition with respect to the CH2OTBS substituent. The a-ethylene-b-lactam 114 reacted slowly with diazomethane and

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles

73

Ph N R

H2C N

O

H R1

Ph

O

R N

O

( +) 109

108

O

Benzene/Toluene Reflux

N

+

R = Ph,

+

R1

Ph

( +) 110

Ph

, O

S

R1 = Ph,C6H4 OCH3(p), O

Scheme 28 Preparation of spiro-b-lactams using regiospecific nitrone cycloaddition

H H2C N O

OTBS CH N , Et O 2 2 2 0 ºC TBS

111

H

N

OTBS

N N O N

Ph N 114

Ph

O

N O

Ph

115

+ Ph

OTBS

N

TBS N

N N

0 ºC

+

112

CH2N2, Et2O O

N

N

Ph N

O

TBS

113

Ph

116

Scheme 29 Synthesis of optically active spiro-b-lactams using a-alkylidene-b-lactams

resulted into spiro products 115, 116 (d.r. 82:18, 97%). The diastereomers were obtained in pure form by column chromatography. The CH2OTBS moiety found in the spiro-b-lactams 112, 113 offers the possibility of establishing tricyclic system related to the carbapenam series [6]. Al-Thebeiti and El-Zohary [101] have reported an efficient synthesis of a new series of spiroazetidin-2-one derivatives incorporated with quinazoline (Scheme 30). 3-Amino-2-methyl-3H-quinazolin-4-one 117 was treated with cyclic ketones 118 to afford the corresponding cycloalkylidene-3-aminoquinazolinone derivatives 119 in good yields. The reaction of the compounds 119 with chloroacetyl chloride in the presence of triethylamine as a catalyst yielded the spiroazetidin-2-ones 120. Santillian et al. [102] have investigated the synthesis of N-aryl substituted spirob-lactams 125 (Scheme 31) using [2 þ 2] cycloaddition of isomaleimides to acid chlorides. The arylamines 121 were treated with maleic anhydride 122 to afford arylmaleamic acids 123 in excellent yields, which on reaction with dicyclohexylcarbodiimide provided isomaleimides 124. Further these underwent [2 þ 2] cycloaddition reaction with acid chlorides in the presence of triethylamine and resulted in the regioselective formation of spiro-b-lactams 125. The trans stereochemistry of

74

S.S. Bari and A. Bhalla

O

R1 N NH2

+

O

CH3

N

n

R3

117

118

N N

Fusion

= R2 = H,

R3 = R4 =

O

n

3 R4 CH3 R 119 ClCH2COCl Et3N Benzene

N

R4

n = 0-1 R1

R2

R1

O

R2

O

Cl R1

R2

N N N

n R4

CH3 R3 120

Scheme 30 Competent synthetic route to quinazoline substituted spiro-b-lactams

R

R NH2

O +

R 121

R

O

N THF

DCC CH2Cl2 HN OH

O

O

O

R1CH2COCl Et3N CH2Cl2

O N R1 O

O 122

O

123

124

O

H

125

R = H, OCH3, OH, OAc 1 R = Cl, OC6H4 Cl(o)

Scheme 31 Preparation of N-aryl-substituted spiro-b-lactams via Studinger cycloaddition

these spiro-b-lactams 125 was established by NOE experiments and X-ray diffraction analysis. The molecular perspective of these compounds nearly show a planner arrangement for the b-lactam ring and the N-phenyl group. Kim et al. [103] have shown that spiro-b-lactams 128 (Scheme 32) obtained by a facile synthesis, serves as a precursor for the synthesis of hitherto unknown b-lactams undergoing cleavage of the bond between S-1 and S-2 with nucleophiles. Treatment of 5-substitutedimino-4-chloro-5H-1,2,3-dithiazoles 126 with 2-chloro2-phenylacetyl chloride 127 in the presence of triethylamine afforded spirob-lactams 128. Gonzalez et al. [104] have synthesized spiro-b-lactams directly by employing Staudinger reaction using unsymmetrical ketenes. The b-lactams 130–133 were prepared by reaction of either 2-tetrahydrofuroyl chloride or 3-tetrahydrofuroyl chloride with imines 129 resulting in the generation of a mixture of cis- and transspiro-b-lactams (Scheme 33).

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles

R

N S

+

N

Cl

Et3N CH2Cl2

Cl

S

Cl

O

O

Cl

Ph

126 127 R = C6H4 OCH3(p), C6H4 CH3(p), C6H4 Cl(p), C6H4

Ph Cl

N R

75

S

N S 128 NO2(p), C6H4 COCH3(p)

Scheme 32 Synthesis of spiro-b-lactams using 5-substitutedimino-4-chloro-5H-1,2,3-dithiazoles and 2-chloro-2-phenylacetyl chloride

R1

O

+ NEt3 N 2 R 129 Refluxing Toluene

O

O O

Cl

–Et3N.HCl

–Et3N.HCl O

O

O

R1 N

130-trans

R1

O

O

R1

R1

+

+ R2

Cl

N O 131-cis

R2

N O 132-cis

R2

N R2 O 133-trans

R1 = C6H5, C6H4 OCH3(p), C6H4 NO2(p), C6H5CH=CH, 2-Furyl, 3-Pyridyl R2 = CH3, C6H5, C6H4 OCH3(p), C6H4 NO2(p)

Scheme 33 Synthesis of cis- and trans-spiro-b-lactams using unsymmetrical ketenes

The ratio of cis/trans reported, is to be strongly influenced by two factors: the position of oxygen on acyl chloride precursor and the electronic nature of substituents R1 and R2 on the imine. Thus, the reaction of 2-tetrahydrofuroyl chloride with imine is more stereoselective than that of 3-tetrahydrofuroyl chloride. The presence of electron withdrawing group decreases the stereoselectivity of reaction while the presence of electron releasing group on imine increases stereoselectivity. Gonzalez et al. [105] have further investigated the diastereoselective [2þ2] cycloaddition reaction of unsymmetrical cyclic ketenes with imines for the synthesis of a variety of spiro-b-lactams (Scheme 34). The reaction of N-benzyloxycarbonyl L-proline acid chlorides 134 with imine 135 in the presence of triethylamine, at room temperature, gave the corresponding spiro-b-lactams 136, 137 as a 1:1 mixture of diastereoisomers, which were separated by column chromatography. The Staudinger reaction proceeds with complete stereoselectivity with a cis relative disposition of the pyrrolidine nitrogen and the phenyl group, but no asymmetric induction was observed. However, very

76

S.S. Bari and A. Bhalla

R

Ph COCl N

+

N

Cbz 134

R1

NEt3 CH2Cl2, r.t.

N

R

Cbz Ph N

O

135

N

R +

Cbz Ph N

R1

O

136

R1

137

R = H, tBuCH2SiO, tBuPh2SiO R1 = C6H4 OCH3(p)

O HO COCl N

N R1

Cbz 138 R1

+

HO H O

NEt3 CH2Cl2, r.t.

N Cbz

139

N O

H

O HO

N

+ Cbz

R1

140

N O

R1

141

= C6H4 OCH3(p)

Scheme 34 Preparation of spiro-b-lactams using unsymmetrical cyclic ketenes X O H

OH H R a, b

O H

R

N

N

N O

O 143

OCH3

R

a, c O 142

OCH3

144

OCH3

X = CH2, O R = [(S)-2,2-dimethyl-1,2-dioxalan-4-yl] Reagents: a) Cl2(Cy3P)2Ru=CHPh (5 mol%), Toluene, Reflux b) Methyl propiolate, NEt3, CH2Cl2, 0ºC c) CH2=CH–CH2Br, TBAI, NaOH (50%)–CH2Cl2 (1:1), r.t.

Scheme 35 Metal catalyzed intramolecular cyclization accessing enantiopure spirocyclic b-lactams

good levels of asymmetric induction were achieved in the Staudinger reaction of N-benzyloxycarbonyl L-proline acid chlorides 138 with optically active imine 139. The reaction afforded the diastereomeric spiro-b-lactams 140, 141 (d.r. 95:5), separable by column chromatography. A novel approach to enantiopure spirocyclic b-lactams has been developed by Alcaide et al. [106] using different intramolecular metal catalyzed cyclization reactions with monocyclic unsaturated alcohols 142 (Scheme 35). Ring-closing metathesis is one of the most powerful and reliable methods to construct a ring system. Transformation of alcohols in diolefin precursors followed by ring-closing

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles

N

X

COR

X

Ac2O, Toluene

COOH

COR O

N

X +

PhCH=NSO2Ph

N

H Ph

145

R

COR O

N

+

SO2Ph Ph

146

N H

77

N

X

SO2Ph

N

Ph

147

148

X = S, O, CH2, (CH2)2, CHCOR; R = H, CH3, C6H5

N

R

R

COPh

Ac2O, Toluene

COOH

COPh

N

H

PhCH=NSO2Ph O

N

Ph N

H SO2Ph

O

SO2Ph

150

COPh

H

+

Ph

N

149

R

H

151

R = CH3COO, PhCOO

N S

N

COR

Ac2O, Toluene

COOH

COR O

S

PhCH=NSO2Ph

N S

+ N

H Ph

152

SO2Ph Ph

R

COR O

N +

N H

S

SO2Ph

Ph

155

154

153

N

R = H, CH3, C6H5

Scheme 36 Stereoselective synthesis of N-phenylsulfonyl-spiro-b-lactams CH3OOC +

CH3OOC N S

N MeI

COOtBu COOH

–

N

Cl PhCH=NCH2Ph Et3N, CH2Cl2

COOtBu

156

N

Ph

S O

CH3OOC

N

H

+

S H

157

+

N S

COOtBu

PhCH=NCH2Ph Et3N, CH2Cl2

CH2Ph

158

–

Cl

COOH

159

N MeI

N

Ph

CH2Ph

COOtBu O

N

COOtBu O

S N

Ph H

CH2Ph

160

Scheme 37 Diastereoselective preparation of spiro-b-lactams using Mukaiyama’s reagent

metathesis proved to be a straightforward access to spirocyclic b-lactams containing five or six-membered oxacycles 143 and 144, respectively. Rosa et al. [107–111] have been actively engaged in developing new stereoselective routes to the spiro-b-lactams (Schemes 36 and 37). They have reported on the reactivity of bicyclic mesoionic compounds derived from cyclic N-acyl-a-amino

78

S.S. Bari and A. Bhalla

acids 145 [107, 108]. The method involves a convenient and simple synthesis of a mixture of two diastereoisomeric spiro-b-lactams 146, 147 (Scheme 36) by the reaction of N-acyl-a-amino acids 145 with N-(phenylmethylene)benzene sulfonamide in toluene using acetic anhydride as the dehydrating agent. These results prompted them to attempt the stereoselective synthesis of the N-phenylsulfonyl substituted spiro-b-lactams 150, 151 (Scheme 36) from the N-(phenylmethylene)benzenesulfonamide and the ketene valence tautomer of the bicyclic mesoionic compounds such as (2 S,4R)-4-acetyloxy or benzoyloxyN-acyl-prolines 149 in the presence of acetic anhydride [109]. The presence of the stereocenter in position 4 of the cyclic amino acid 149 was found to be sufficient to ensure complete stereoselectivity on the spiranic C-4. In connection with these results, and as an extension of their studies toward the reactivity of new bicyclic mesoionic compounds and their usefulness in the synthesis of condensed heterocycles, they further reported the stereoselective synthesis of spiro-b-lactams 153, 154 (Scheme 36) by reactions of imines with mesoionic compounds or ketenes generated from N-acyl-thiozolidine-2-carboxylic acids 152 [110]. Recently, they have synthesized enantiomerically pure 1,3-thiazolidine-derived spiro-b-lactams [111] (Scheme 37) using Staudinger ketene-imine reaction starting from optically active N-boc-1,3- thiazolidine-2-carboxylic acid derivatives and imines, thus confirming the generality of the earlier reported 1,3-thiazolidinederived spiro-b-lactams. Treatment of amino acid 156, imine and 2-chloro-1-methylpyridinium iodide (Mukaiyama’s reagent) in the presence of triethylamine in refluxing dichloromethane afforded spiro-b-lactams 157, 158. These were obtained as a 1.8:1 mixture of diastereoisomers and separated by column chromatography. The reaction of 159 and imine under the usual experimental conditions resulted in the formation of a single diastereoisomer 160. The absolute (3 S, 4 S, 7 S)-configuration was assigned on the basis of mechanistic considerations and 1H NMR spectra. The presence of the stereocenter affords complete diastereoselectivity (only trans diastereoisomers 157, 158) and enantioselectivity (160). Thiruvazhi et al. [112] have shown interest in the area of b-turn mimetics and the synthetic application of D- and L-proline for asymmetric synthesis of prolinederived spiro-b-lactams. It has been shown that the asymmetric Staudinger reaction of optically active acid chloride of D- and L-proline with achiral imines is impossible due to the loss of stereochemistry at C-2. The authors have developed a strategy in which a chiral group at C-4 of the acid chloride of proline directs the stereoselectivity of the reaction and is sacrificed later to obtain optically active spirob-lactams (Scheme 38). The Staudinger reaction between optically active acid chloride 161 and N-benzyl-N-[(1E)-phenylmethylene]amine in the presence of triethylamine in dichloromethane resulted in the formation of two diastereomerically pure spirob-lactams 162 (51%), 163 (20%) as single enantiomers in each case. The spirob-lactams 162, 163 were further transformed to proline-derived spiro-b-lactams 165, 167 via elimination of methanesulfonic acid using K2CO3/MeOH and

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles R3

R1O

R3 N

R1O O N Cbz 161

a

Cl

R1O

R2

b

R3 N

R2

c

N

N

N

Cbz O 162 + O

Cbz O 164

H

O N

R2

b

N

R2

N

R2

O 165 O

N

R2

c

N

N

79

N

Cbz R3 H Cbz R3 163 166 Reagents: a) E-R3 CH=NR2, Et3N, CH2 Cl2 b) K2CO3, MeOH, c) H2,10% Pd/C, EtOH R1 = Ms, Ts, Ns R2 = CH2C6H5, CH2C6H5 OCH3(p), C3H5

R3 167

R3 = C6H5, CH3, C3H5, C6H11, C6H5 OCH3(p), C6H5 F(p)

Scheme 38 Asymmetric synthesis of proline-derived spiro-b-lactams

O

EtO2C

H CO2H N H (30 mol%)

N

H

+ 168

169

OCH3

O

OCH3

HN

H

CO2Et

DMSO

170 1. NaClO2 2. NaOH 3. HCl CO2Et N O

OCH3

171

Scheme 39 Proline-catalyzed Mannich reaction furnishing spiro-b-lactams

deprotection along with hydrogenation. The proposed mechanism of Staudinger reaction on proline-derived ketenes demonstrated that for the achievement of excellent stereoselectivity in the synthesis of these types of spiro-b-lactams, R1 substitutent of proline should be aliphatic, R2 of the imine could be either aliphatic or aromatic and R3 should be aromatic. Barbas et al. [113] have published the asymmetric synthesis of spiro-b-lactams 171 (Scheme 39) using proline-catalyzed Mannich reaction with branched aldehyde donors. The Mannich reactions of a,a-disubstituted aldehydes 168 with

80

S.S. Bari and A. Bhalla Me

Me

O

NH

N O(p) Ns

X

NMe

Base THF

O Me N H 172 X = H, Br

X

O Me

+

Me N

N H 174

X

173

Scheme 40 Efficient synthesis of indolenine spiro-b-lactams in Chartelline

O

O X N E

N

X

tBu

1. LDA 2. E-Cl Ph

Y

175

E

N N

tBu

Ph Y

176

X = Y = H, Cl E = CO2Me, CO2Bn, Bz, MeOTf

Scheme 41 Synthesis of spiro-b-lactams via cyclization of lithiated pyridine and quinoline carboxamides

N-p-methoxyphenyl protected a-imino ethyl glyoxalate 169 in the presence of L-proline as catalyst resulted in the formation of enantioselective b-formyl a-aminoacid derivatives 170 in excellent yields. The authors have demonstrated for the first time the use of a,a-disubstituted aldehydes in the Mannich reaction to generate all-carbon quaternary stereocenters. The enantioselective b-formyl a-aminoacid derivatives 170 were further transformed to spiro-b-lactams 171 using oxidation followed by basic hydrolysis and acidification. Isobe et al. [114] have revealed the novel synthesis of indolenine spirob-lactams 173 (Scheme 40) in Chartelline, which belongs to the family of marine natural products. The starting precursors 172 were submitted to cyclization by employing a variety of bases such as EtMgBr, n-BuLi, t-BuOK, LDA, KHMDS, NaHMDS, and LiHMDS in THF at different reaction temperatures. Out of all these bases, LiHMDS at –78 C was found to be the best which provided the exclusive formation of spiro-b-lactams 173 without N-methylamide 174 as a side product. Clayden et al. [115] have reported the synthesis of spirocyclic b-lactams 176 (Scheme 41) by exo-cyclization of lithiated pyridine and quinoline carboxamides. The reaction of isonicotinamide or chlorinated isonicotinamide 175 with LDA at – 40 C with addition of methyl chloroformate led to the formation of spirocyclic b-lactams 176 in good yields. Benzyl chloroformate, benzoyl chloride, methyl triflate can also be used as the effective acylating agents. In these type of reactions, lithiation of N-benzyl pyridine and quinoline carboxamides to nitrogen provided

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles

81 O

O N3

1. PhOCOCl, C6H5N, CH2Cl2

BnO2C OH

HN 2. Ph3P, THF H2O BnO2C

177

O

1.Boc2O, Et3N DMAP, CH2Cl2 2.Pd/C, EtOAc, H2

BocN

O

RO2C

178 1. 1-Chloro-N,N,2-trimethyl1-propenylamine,CH2Cl2 2. Et3N, CH2Cl2 H

179 R = Bn, H Me PMP N

O O

O

O TMS

BocN N O

PMP

H TMS Me 180

Scheme 42 Preparation of spiro-b-lactams, synthons for proteasome inhibitors

anions, which underwent intramolecular attack on the pyridine or quinoline ring either directly or on activation of the ring by N-acylation. Corey et al. [116] have published the synthesis of spiro-b-lactam 180 (Scheme 42), which is a synthetic intermediate for other b-lactams, which are able to inhibit proteasome. Proteasome inhibition helps in the therapy of cancer and has been evaluated for multiple myeloma [104]. The alcohol 177 was converted to starting substrates oxazolidinone 178 by acylation followed by reduction of the azide function along with cyclization. Oxazolidinone 178 was protected with t-butylpyrocarbonate-4-(dimethylamino) pyridine (DMAP) and triethylamine, which was further subjected to reductive cleavage of the benzyl ester unit to afford carboxylic acid 179. The treatment of 179 with solution of 1-chloro-N,N,2-trimethyl-1-propenylamine resulted in the easy formation of the corresponding acid chloride which on reaction with imine in the presence of triethylamine provided the stereoselective formation of spirob-lactam 180. Meijere et al. [117] group have investigated the direct synthesis of 3-spirocyclopropanated b-lactams 184 (Scheme 43) using novel three-component cascade reaction. Earlier, Alberto Brandi and coworkers [118–120] have applied nitrones 181 and bicyclopropylidene 182 to obtain cylcoadducts 183, which were further fragmented under acidic conditions to afford spiro-b-lactams 184. However, this reaction required longer reaction time for the formation of cycloadducts 183. Taking this into account, Meijere and Brandi [117] together explored the effect of microwave heating during the 1,3-dipolar cycloaddition of nitrones, generated in situ and bicyclopropylidene 182 for the synthesis of these spiro-b-lactams 184 (Scheme 43). The reaction of N-substituted hydroxylamine hydrochlorides 185,

82

S.S. Bari and A. Bhalla

R2

H

R2

R2 +

R1

H,

+

N+ O 181

R1 N

O 183

182

H R1

+

N

OH

NaOAc, EtOH o 80-100 C (MW)

+

R2

184

R1

R2

O

.HX 185

N

O

H 186

N

O

182

184

R1

R1 = Bn, Me, CHPh2, tBu, CH2C6H4 OCH3(p) R2 = H, CO2Et, CO2Me X = Cl, (COOH)2

Scheme 43 Three-component cascade reaction to afford 3-spirocyclopropanated b-lactams

a N Boc

187

COOH

H N

N O

O

O

O

R

b, c

N O

O

188

OH H N O

O

O

189

R R O

N

d, e

N O

O O

O

R1

190

Cl O CH

2 R = H, DCCB DCCB: Cl R1= NHCH3, OH Reagents: a) HATU, DIPEA, NMP, GlyOMe.HCl (R = H)/O-(2,6-dichlorobenzyl)tyrosine methyl ester hydrochloride (R = DCCB), b) O3, CH2Cl2, c) Na[BH(OAc)3] d) DEAD, PPh3, THF, e) CH3NH2, EtOH / LiOH, THF, H2O

Scheme 44 Chirospecific synthesis of spiro-b-lactams serving as efficient b-turn nucleators

aldehydes 186, and bicyclopropylidene 182 in the presence of sodium acetate and ethanol under microwave irradiation furnished the desired spiro-b-lactams 184 after 30–120 min in single operation. The time required for the completion of this reaction was never more than 2 h, whereas, with traditional heating at 45 C reaction completed in 16 d and at higher temperatures, only the corresponding spirocyclopropanated piperidone derivative was formed. Recently, Bittermann and Gmeiner [49] have provided a novel protocol for the synthesis of enantiomerically pure spiro-b-lactams 190 and characterized them as efficient b-turn nucleators (Scheme 44). The starting substrate, protected a-vinylproline 187 was activated by HATU and coupled with glycine methyl ester hydrochloride to give protected peptide derivatives 188. Further, ozonolysis of these derivatives and subsequent reduction with excess of Na[BH(OAc)3] provided the hydroxymethyl-substituted derivative 189 in

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles

H H

PhCH2S O

R1 PhCH2S NCS, AIBN CCl4, Reflux N R2 O

191

Cl H

R1

N

O H

HC CH2OH ZnCl2 SiO2 CHCl3, Reflux Mol. Sieves (3-4)Å

R2

83

PhCH2S

N

O

192 _

_ .. ZnCl3 HOCH .. 2C CH H

..

PhCH2S

H

R1

O

193

S O

X2 = I2 or Br2

R2

H

O

X2, CH2Cl2 N

N

O

X

R1

1

R

PhCH2S

N 2 O R (Carbocation)

PhCH2S

R2

193 ZnCl3

O H

R1

N

194

R2

R1 R2

R1 = C6H5, C6H4 OCH3(p), C6H4 CH3(p) R2 = C6H5, C6H4 OCH3(p), C6H4 Cl(p)

Scheme 45 Novel synthetic approach to spiro-b-lactams via halogen-mediated intrasulfenyl cyclization

PhCH2S O

Cl H

O H

R1

H2C CHCH2OH ZnCl2 SiO2 CHCl3, Reflux N 2 R Mol. Sieves (3-4)Å 192

PhCH2S

N

O

R1 R2

195 X2 CH2Cl2

O

X S O X2 = I2 or Br2

H N 196

O

R1 X

+ 2

R

S O

H N 197

X

O H

R1

+ 2

R

S O

N 198

R1 R2

R1 = C6H5, C6H4 OCH3(p), R2 = C6H4 OCH3(p)

Scheme 46 Extended halogen-mediated intrasulfenyl cyclization using allyl alcohol

excellent yields. The derivatives 189 were introduced to intramolecular Mitsunobu reaction using DEAD with PPh3, which on subsequent aminolysis or LiOH-promoted hydrolysis afforded spiro-b-lactams 190. In connection with these studies, recently, we have reported from our laboratory a novel, operationally simple and efficient approach for the synthesis of spirob-lactams 194, 196–198 (Schemes 45 and 46) [121]. In our earlier publications, we have demonstrated well the synthetic potential of cationic b-lactam equivalents

84

S.S. Bari and A. Bhalla

192 for the synthesis of novel azetidin-2-ones and their C-3 functionalizations [122–127]. The trans-3-benzylthio-3-chloro-b-lactams 192, the appropriate b-lactam carbocation equivalents, were prepared by stereospecific chlorination of their corresponding trans-3-benzylthio-b-lactams 191 using N-chlorosuccinimide and catalytical amount of AIBN [125]. These b-lactam carbocation equivalents 192 on treatment with propargyl alcohol or allyl alcohol in the presence of ZnCl2/SiO2 were further transformed to suitable substrates, such as, cis-3-benzylthio-3-(prop2-ynyloxy/enyloxy)-b-lactams 193 and 195 respectively [126]. Initially, the substrates 193 were subjected to halogen-mediated intrasulfenyl cyclization reactions with iodine or bromine in the presence of dichloromethane. The reaction afforded the exclusive formation of the five membered ring spiro-blactams 194 (Scheme 45). To probe further into the underlying features governing the selectivity in 5-exo versus 6-endo additions, we set out to examine the halogen mediated cyclization reactions of 3-alkenyloxy-b-lactams 195 (Scheme 46). The treatment of 195 with iodine or bromine under similar reaction conditions resulted in the formation of a mixture of two diastereomeric five-membered ring spirob-lactams 196 and 197 as the major products along with a single isomer of sixmembered ring spiro-b-lactams 198 as the minor one. Further, the major isomeric cyclized 5-membered ring adducts 196 and 197 were formed in 1:1 ratio as evident from 1H NMR and one of the isomer 196 crystallized in pure form, whereas, the other isomer 197 remained an oily product. The exclusive formation of five membered ring cycloadducts and the stereochemistry at spiro-junction C-3 of 194, 196 was established through single crystal X-ray crystallographic analysis. These studies have revealed interesting features of the halocyclization of cis-3-alkoxy-b-lactams 193 and 195. The regio- and stereochemistries of the products, formed after the intramolecular addition of heteronucleophile depends on the type of unsaturation within the substrate. Further, the alkynyloxy sulfide ring closures led to the exclusive formation of five-membered ring spiro-b-lactams 194, whereas, alkenyloxy sulfide ring closures led to the formation of a mixture of five-membered ring spiro-b-lactams 196, 197 as the major products along with six-membered ring spiro-b-lactams 198 as the minor products. The regiospecificities of these ring closures may in part, be due to a kinetic preference for formation of the five-membered rings. Further, we have investigated [128] the synthesis of spiro-b-lactams 200, 201 (Scheme 47) using a similar strategy i.e. through halogen-mediated intrasulfenyl cyclization reactions of 3-allyl-3-benzylthio-b-lactams procured through a Lewis acid mediated C-3 alkylation of the trans-3-benzylthio-3-chloro-b-lactams 192 [112]. TiCl4 promoted allylation of b-lactams 192 with allylsilane provided the suitable substrates 199, which were further subjected to halogen-mediated intrasulfenyl cyclization reactions with iodine or bromine under similar reaction conditions. The reaction produced a mixture of two isomers of five membered ring spiro-b-lactams 200, 201, which were separable by column chromatography. However, a small amount of an additional product 202 was obtained, when bromine was used as a halogenating reagent.

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles

Cl H

PhCH2S

H

R1 SiMe3

O

N

PhCH2S

TiCl4

R2

R1

N

O

R2

199

192 X

X2 CH2Cl2

X H S O

N

H

R1

+

S O

R2

200

85

N

X R1

+ R2

PhCH2S * X

O

201

H

R1

N R2 X = Br 202

X H

H H

R1 n Bu3SnH N 2 (excess) R O 204 X2 = I2 or Br2

S O

H

1

Rn Bu3SnH (1-1.2 equiv.) AIBN, Benzene N R2 201

S O

N 203

R1 R2

R1 = C6H5, C6H4 OCH3(p), C6H4 CH3(p) R2 = C6H5,C6H4 OCH3(p), C6H4 Cl(p)

Scheme 47 Synthesis of spiro-b-lactams using 3-allyl-3-benzylthio-b-lactams

These halospiro-b-lactams 201 were further subjected to dehalogenation reactions using tri-n-butyltinhydride in the presence of catalytic amount of AIBN and gave the clean dehalogenated spiro-b-lactams 203. However, it was observed that increasing the amount of tri-n-butyltinhydride led to desulfurization also along with dehalogenation leading to ring opening and formation of cis-3-propylb-lactams 204. The construction of naturally occurring or unnatural b-lactams with attendant control of functional groups and stereochemistry has been the goal of the synthetic organic chemists for the past few decades. In addition, the ever-increasing bacterial resistance to b-lactam antibiotics presents a very serious concern and efforts have been made to meet this challenge by exploring new b-lactam chemistry by the skeletal modification of naturally occurring b-lactam antibiotics. The sulfur atom of penicillins and cephalosporins has been replaced by selenium and its chemophysical and microbiological effects have also been investigated. Very recently, in continuation to our studies directed toward the synthesis of spiro-b-lactams, we have reported the synthesis of a new class of spiro selenob-lactams [129] (Scheme 48). No report on the synthesis of spiro seleno-b-lactams has appeared in literature so far. The seleno-b-lactam 207, required for this study, was prepared from 2-benzylselenoethanoic acid [130] 205 and appropriate imine 206 in the presence of phosphorus oxychloride as the condensing reagent and triethylamine as the base. This was further transformed to appropriate b-lactam carbocation equivalent,

86

S.S. Bari and A. Bhalla

PhCH2Se

PhCH2Se + OH

O

POCl3, Et3N C6H6, Reflux

N

205

OCH3

206

O H PhCH2Se

N

O

209

O

HC CCH2OH ZnCl2 SiO2 CHCl3, Reflux Mol. Sieves (3-4)Å

H H N

207 NCS, AIBN CCl4, Reflux PhCH2Se

OCH3

O

OCH3

Cl H N

208

OCH3

X2 (X2 = I2 or Br2) CH2Cl2 O

X Se O

H N

210

OCH3

Scheme 48 Facile synthesis of new class of spiro seleno-b-lactams

cis-3-chloro-3-benzylseleno-b-lactam 208 using N-chlorosuccinimde and AIBN. The cis-3-chloroseleno-b-lactam 208 was successfully converted to cis-3-benzylseleno-3-(prop-2-ynyloxy)-b-lactam 209, which served as potential substrate for undergoing halogen-mediated intraselenyl cyclization reaction. Exposure of 3-alkoxyseleno-b-lactam 209 to iodine or bromine in dry dichloromethane at room temperature afforded the exclusive formation of five-membered ring spiro seleno-b-lactams 210 in quantitative yields. Tolomeli et al. [131, 132] have reported novel classes of four- and five-membered hydroxyl-spiro-b-lactams 213, 217 and 214, 218 via regioselective ring opening of hydroxyl-epoxides 212, 216, respectively (Scheme 49). Treatment of hydroxyl-alkenyl-b-lactams 211, 215 with meta-chloroperoxybenzoic acid in dichloromethane led to the formation of trans-epoxides 212, 216 in high diastereomeric ratio, which were further subjected to intramolecular ring opening using BF3Et2O in dichloromethane affording spiro-b-lactams 213–214, 217–218 in highly regio- and stereoselective fashion. These spiro-b-lactams have been found to exhibit CAI activity and confirmed through ACAT inhibition assays. Guarna et al. [133] have employed unsymmetrical bicyclic ketene in the Staudinger reaction for diastereoselective synthesis of highly constrained

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles

HO

O

Ph

Et

a

211

HO

Ph O

Ph

Et

a

215

R1

H + Ph

R1

H

b

Ph

N 216

R1

214 H

Ph N

O

217

R1

OH H Ph N

O

H

O

Ph

O

2 13

Ph

H

R1

N O

O

HO

HO H

Et

N O

Ph

N 212

Ph

H

b O

H

O

Ph

H

R1

H

Ph

Et

N O

HO

HO H

Ph

87

O H + Ph

R1

OH H Ph N

O

218

R1

Reagents: a) MCPBA, CH2Cl2, r.t., overnight, b) BF3.Et2O, CH2Cl2, r.t. R1 = CH2C6H5, CH2CH2COOEt, (S)-CH(CH3)Ph

Scheme 49 A synthetic route to four- and five-membered hydroxyl-spiro-b-lactams O Bn O Bn

N O

O H 219

O

R'

R' N O

Et3N + Toluene N Cl R 110 °C 220

R' = C6H5, C6H4 NO2(p), C6H4

Bn

N O

O O N O R O R cis-b-lactam +Bn O N N O H O 221 + H R' 223 O

N R O trans-b-lactam 222 OCH3(p), C6H4 Br(p)

R = CH2C6H4, C6H4 NO2(p), C6H4 OCH3(p), C6H4 CH3(p), CH(CH2C6H5)COOCH3

Scheme 50 Diastereoselective synthesis of spiro-b-lactams using unsymmetrical bicyclic ketene

spiro-b-lactams 221–222 (Scheme 50). The reaction of unsymmetrical bicyclic acyl chloride 219 with appropriate imines 220 in triethylamine and toluene proceeded with high stereoselectivity to produce the cis-spiro-b-lactams 221 as the major compounds accompanying with trans-spiro-b-lactams 222 as the minor compounds. The cis stereochemistry of spiro-b-lactams 221 was established by NOE experiments and X-ray diffraction analysis. These spiro-b-lactams would serve as important heterocyclic compounds possessing diverse scaffolds to which different functional groups could be fixed in a stereodefined 3D topological arrangement.

88

S.S. Bari and A. Bhalla Cl OBn O

O

Et3N R2 Dry CH Cl 2 2 N 40°C to r.t. R2

+ OO 224

H

R1

R1

N

R1 H

OBn O

+R

2

N

OO

O

225

OBn O OO

O 227

226

1

R = C6H5, C6H4 CH3(p), C6H4 OCH3(p), Styryl R2 = C6H5, C6H4 OCH3(p), C6H4 Cl(p), C6H4 CH3(p)

Scheme 51 Stereoselective synthesis of spiro-b-lactams using ketenes

O

N

R

N

O

228

O

H3CO

O Oa

D-(+)–glucose

b

OCH3

H3CO N

c

O

N H

derived chiral

O

N

OCH3

N

229 231

230

d X

X

O

O

R N

R

N c

O

O

N

N

N

N

232

O

O N

N

233

Reagents: a) Benzyl bromide, CaH2, DMF, 50° C, b) 2,4-Dimethoxyaniline, EtOH, Reflux c) RCH2COCl, Et3N, CH2Cl2, 10 °C to r.t. d) Diamine, EtOH, Reflux O R = OCH3. OC6H5, PhthN, X = CH2, O

N O

Scheme 52 Synthesis of mono- and bis-spiro-b-lactams from benzylisatin

Deshmukh et al. [134] have investigated the use of D-(+)–glucose derived chiral ketenes in the stereoselective synthesis of spiro-b-lactams 226–227. The D-(+)– glucose acid chloride 224, serving as a ketene precursor, in the Staudinger cycloaddition reaction with appropriate imines 225 afforded the diastereomeric mixture of spirocyclic-b-lactams 226–227 in 70:30 ratio, respectively. This reaction has cleanly produced only two diastereoisomers instead of theoretically possible four

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles

NC

NH2

NC EtOH Piperidine

+ HN R

ClCOCH2Cl R Et3N Dioxane

HN

235

S

HN N

N R

R = H, NO2(p), Cl(p) 234

NC

S

S

O

NH2

NH2

NH2

89

236

Cl

O 237

Scheme 53 Synthesis of spiro-b-lactams using chloroacetylchloride and Schiff bases

diastereomers and this outcome was in accordance with the remarkable influence of the toroquoelectronic effect (Scheme 51). Jarrahpour et al. [135] have described the synthesis of novel mono- and bis-spirob-lactams 231 and 233, respectively, from benzylisatin 229 (Scheme 52). The starting substrate, benzylisatin 229 was prepared by reaction of isatin 228 with benzyl bromide and calcium chloride in DMF. The benzylisatin substituted imines 230 and di-imines 232 were further subjected to Staudinger reaction with ketenes derived from methoxy, phenoxy, and phthaloglycyl chlorides to afford novel mono- and bis-spiro-b-lactams 231 and 233, respectively. The configuration of benzylisatin 229 and monocyclic spiro-b-lactams 231 was established by X-ray crystallographic studies. These spiro-b-lactams will be studied as precursors of modified b-amino acids, b-peptides and monobactam analogues. Recently, Soleiman et al. [136] have published the synthesis of novel class of spiro-b-lactams 237 using chloroacetylchloride and Schiff bases 236 in the presence of triethylamine and dioxane (Scheme 53). The new Schiff bases 236 were prepared by reaction of 234 with different aromatic amines using ethanol and piperidine as catalysts.

3.2

Biological Evaluation

For over 75 years, the b-lactam antibiotics have provided a powerful line of defence against a wide variety of bacterial infections. These potent antibacterial agents have helped in controlling not only the spread of life-threatening diseases, but also prevented the onset of opportunistic infections in immune-deficient patients. The agility with which these four-membered heterocycles can undergo ring scission and rearrangements has provided an easy access to get many other heterocycles and acyclic compounds of interest. The widespread incidence of antibacterial resistance to b-lactam antibiotics caused by b-lactamase formation and the use of b-lactams as important synthons for a variety of natural products has provoked renewed interest in the building of spiro-b-lactam systems. Recently, spiro-b-lactams have become centers of attraction due to their diverse biological applications.

90

S.S. Bari and A. Bhalla

3.2.1

Cholesterol Absorption Inhibitors

Atherosclerotic coronary heart disease (CHD) is a significant disease around the globe and is one of the major causes of death and cardiovascular morbidity in humans. Risk factors for CHD include hypertension, diabetes mellitus, male gender, cigarette smoking etc. but the most dominating risk factor is the serum cholesterol. The two significant sources of cholesterol in body are endogenously synthesized cholesterol and exogenous or dietary cholesterol. Efforts to inhibit the absorption of dietary cholesterol have primarily focused on the inhibition of ACAT, a major enzyme associated with cholesterol esterification. Inhibition of this enzyme blocks the absorption of intestinal cholesterol and may also inhibit cholesteryl ester deposition in the vascular wall in the form of fatty streaks associated with atherosclerotic plaque. Structure-activity relation studies have revealed that 3-spiro-b-lactams SCH 54016 A [45] and SCH 58053 B [46] (Fig. 6) exhibit CAI activity, making them potentially useful compounds for development of drugs for lowering the high level of cholesterol. Besides that, it has recently been shown that cholesterol regulation [137] is also coupled to the activity of an enzyme, which is responsible for the cleavage of the amyloid precursor protein, which is thought to be involved in the pathogenesis of Alzheimer’s disease. The dissymmetric spiroannulation at C-3 provided the trans relationship between lactam carbonyl and 4-chlorophenyl functionality, which imparts the

A

B Cl

Cl OH

OMe

H

HO

R

R

N

N O

O

SCH 54016

SCH 58053

Hamster ED50 = 0.50 mg/kg

Hamster ED50 = 0.66 mg/kg Rh monkey ED50 = 0.01 mg/kg

HO

HO

O Ph

H

N O

Ph (4R)-C % Inhibition = 45% (10 µM)

OH

H

O

Ph

Ph

Ph

O

Ph

Ph

N O

OH O

Ph

Ph

N O

N O

Ph

Ph (4S)-C 66%

F

(4R)-D 23%

Fig. 6 Potent cholesterol absorption inhibiting spiro-b-lactams

Ph (4S)-D 27%

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles

91

CAI activity with an ED50 ¼ 0.66 mg kg1 in cholesterol-fed hamster assay [138]. In addition, this spiro-b-lactam (A) has been found to be an active compound in inhibiting cholesterol absorption (ED50 ¼ 0.01 mg kg1) in rhesus monkeys, a primate species which shows similarity to the lipid profile of humans. The spirob-lactam B has also been found to show activity in the seven-day hamster cholesterol absorption assay with ED50 of 0.50 mg kg1. The axial benzylic hydroxyl group in the 4-position of cyclohexyl ring imparts about a favorable 10-fold shift in the potency as compared with similar analogs lacking this substitution. Recently, the enantiopure spiro-b-lactams C and D were reported to be ACAT inhibitors [131, 132]. These spiro-b-lactams were tested using Lovastatin as reference standard (IC50 ¼ 12 mM from the literature data, IC50 ¼ 16.8 mM when concurrently tested) with enzymatic assays performation and measured by quantitation of [14C]–Cholesterol esterification using palmitoyl-CoA. The biological evaluation displayed results that four membered ring spiro-b-lactams are more active than five-membered ones; further, the (4 S)- spiro derivatives are showing enhanced activity with respect to the (4R)- derivatives. Thus, ACAT inhibitor contains spiroazetidin-2-one ring system that provides sufficient ring scaffold upon which the substitution pattern and their orientation in three dimensions can be varied.

3.2.2

Antiviral Agents

The replication of many plant and animal viruses has been found to be entirely dependent on proteolytic processing [139]. The proteolytic enzymes are involved in a variety of functions, such as, separation of structural and nonstructural proteins, generation of specific enzymes (RNA polypeptides), coordinated assembly of the virion, and maturation. The evidence suggests that the processing of viral precursor polypeptide involves virus-encodea proteinases. All picornaviruses produce a polypeptide 3C-proteinase, which carried out the most cleavages of the polyprotein occurring between glutamine and glycine, thus, enabling the virus to undergo maturation. From the class of 4-spiro-b-lactams, b-lactam E (Fig. 7) has been found to be a good inhibitor of both poliovirus and human rhinovirus 3C-proteinases (IC50 ¼ 20 mg mL1) [47]. Besides this, it also inhibited HLE (IC50 ¼ 0.4 mg mL1) as well as Cathepsin G (IC50 ¼ 4.0 mg mL1).

E H H3CO

O

Fig. 7 Antiviral spirob-lactam

N N O O S O

CH3

92

3.2.3

S.S. Bari and A. Bhalla

b-Lactamase Inhibitors and Antibacterial Agents

Bycroft et al. [83] have reported a series of semisynthetic penicillin derivatives such as, 6-spiro-epoxypenicillins F, G (Fig. 8) possessing both b-lactamase inhibitory and antibacterial activity (Fig. 8). It has been found that novel chlorinated 6-spiroepoxypenicillins F are potent in vitro inhibitors of a range of chemically important b-lactamases [84], whereas, 6-spirocyclopropylpenems, G, show a reduced level of b-lactamase inhibitory activity. The significance of the five fold difference between the turnover numbers for F(a) and G(b) (differ only in their stereochemistry at one center) was found to be in close comparison with the turnover number of 20,000, reported for the established b-lactamase inhibitor, sulbactam [140]. Thus, the notable b-lactamase inhibitory and antibacterial properties of these spiro-b-lactams depend upon the substituents and the stereochemistry of the epoxide. A class of Fridricamycins having indoles with C-3 spiro atoms has shown pronounced biological activities such as antitumor and antibiotic. Taking a clue from this, Joshi et al. [81] have investigated the synthesis of spiro-b-lactams H (Fig. 9) by incorporation of fluorine substituted indole nucleus and screened them for antibacterial activity. The compounds were tested for antibacterial activity against gram-positive bacteria, such as, S. coagulase, S. viridaus, S. hemollyticus, and gram-negative bacteria such as, E. coli, P. pyocyneus, and C. frundii by disc method, in the presence of ethanol, at a concentration of 10 mg ml1. The study revealed that all the compounds are moderately active against gram-positive

F

G R1

R1

OH S

R2

H S

R2

N

N

O

O

CO2R3

CO2H

a)R1 = Fury1, R2 = H, R3 = Na b)R1 = H, R2 = Fury1, R3 = Na

a) R1 =PhNHCO ,R2 = Cl b) R1 =Cl, R2 = PhNHCO

Fig. 8 b-Lactamase inhibiting and antibacterial spiro-b-lactams

H

H

O

Cl N R

X N1 R

O

X = H, 5 F, 6 F R = C6H5, 3 FC6H4, 4 FC6H4, 3 CF3C6H5

Fig. 9 Antibacterial spirob-lactams

R1 = H, CH2N

O

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles Fig. 10 Antimicrobial spirob-lactams

I

N R

N

S N

O O

93

S H

Cl R = H, OCH3(p), Cl(p), CH3(p), NO2(p)

bacteria (zone of inhibition between 10–17 mm in diameter), maximum against S. hemollyticus. However, these spiro-b-lactams have been found to be inactive against gram-negative bacteria except against E. coli, where slight activity has been observed (zone of inhibition between 7–10 mm).

3.2.4

Antimicrobial Agents

Hussain and Nizamuddin [97] combined the 1,3-dithiolane moieties with azetidin2-ones for the study of different biological activities. The spiro-b-lactams I (Fig. 10) have been screened against A. niger, P. oryzae, F. oxysporum, and C. sacchari using agar growth technique at 100 and 10 ppm concentrations. The standard fungicide carbendazim was chosen to be the reference compound for studying the antifungal activities of these spiro-b-lactams I. The observed data reveals that these spiro-b-lactams are antifungal in nature and the introduction of chloro, methyl and methoxy group further enhances the antifungal activity whereas, nitro group reduces it. The spiro-b-lactams I were also found to exhibit strong antibacterial activity against E. coli, S. typhi, and B. aureus.

3.2.5

Precursors for Tabtoxinine-b-Lactams

Tabtoxin J is a dipeptide exotoxin produced by Pseudomonas tabaci, the organism responsible for the wildfire disease of tobacco plants [141]. When hydrolyzed by peptidase, in vivo, this exotoxin releases tabtoxinine-b-lactam K, which inhibits Glutamine synthetase of the photorespiratory nitrogen cycle, causing chlorosis and death of tobacco plants [142]. As the dipeptide J itself does not inhibit purified Glutamine synthetase in vitro [143], the amino acid K is considered to be the active form of J and hence, the actual toxin of wildfire disease. Since, the detailed mechanism of Glutamine synthetase inhibition by tabtoxinine-b-lactam attracts chemical interest, a synthetic approach to the toxin K and its analogs, is of increasing importance. Spiro-b-lactam L (Fig. 11) has been found to be an efficient precursor of toxin K.

94

S.S. Bari and A. Bhalla

J

K

OH

NH2

H N

NH2

OH

OH

HO2C

CO2 H O

L

NH

O

K

OMe

NH2

N

OH

O HO2C

O H

NH

OCH2Ph

N PhCH2O2C

NH

O

O

O

Fig. 11 Spiro-b-lactam: precursor for tabtoxin H N O

n O

O

n

N

N

N

O

N

R2

R1

R1 (i)

(ii)

O R2 N

N H O (iii)

R1

N O

O

1

O N H

R N H

M

Fig. 12 Spiro-b-lactams as b-turn mimics

3.2.6

b-Turn Mimics

Recently, much attention has been directed toward the synthesis of peptidomimetics. These compounds can replace native peptides in the interaction with receptors. They showed increased metabolic stability, better bioavailability, and longer duration of action than native peptides, thus displaying favorable pharmacological properties [52–54]. In this sense, the design and synthesis of conformationally restricted peptidomimetics is an important approach toward improving the potency, selectivity, and metabolic stability of peptide based drugs. Among the various strategies available for b-turn mimics, the Freidinger g-lactam structure (1), or a spiro system [144] (2),has been found suitable for the design of a variety of medicinally relevant targets. In addition, it has been recently reported that use of a,a-disubstituted b-lactam (3) could also be a good approach to promote a b-turn folding in a peptide chain [145] (Fig. 12).

Spirocyclic b-Lactams: Synthesis and Biological Evaluation of Novel Heterocycles Fig. 13 Spiro-b-lactams as b-turn nucleators

95

N

R N N O

O O

O

H N CH3

R = H, DCCB DCCB:

Cl O CH2 Cl

Molecular modeling calculations using ab initio methods (MP2/6-31þG*) predict that spiro-b-lactam of type M adopt a b-turn secondary structure [50] which is very close to the ideal type-III b-turns. Thus, these spiro-b-lactams are the important members of the core for the preparation of different types of peptidomimetics using well-established chemistry. They combine the structural features required for inducing b-turn motif.

3.2.7

b-Turn Nucleators

Bittermann and Gmenier [49] have reported the chirospecific synthesis of prolinederived spirocyclic b-lactams N (Fig. 13) and investigated their utilization as reverse turn nucleators. These spiro-b-lactams possess valuable conformational properties as established from NMR and IR spectroscopic studies. Interestingly, the combination of both the spirocyclic structure and further conformational constraints by a four-membered lactam, enables a more ideal calibration of the geometrical properties required for adoption of a canonical type-II b-turn leading to a coplanar spatial arrangement and thus, promising antiparallel pleated b-sheet nucleators.

4 Concluding Remarks In conclusion, the CAI activity of spiro-b-lactams, their antiviral and antibacterial properties, their potential as efficient b-turn nucleators and b-turn mimetics, and their application as synthons for a,a-disubstituted b-amino acids motivated synthetic and medicinal chemists to design novel spirocyclic b-lactams. Several approaches to the stereoselective synthesis of spiro-b-lactams have been described in this review. However, ketene-imine cycloaddition (Staudinger Reaction) shows much versatility for the access to diversely functionalized spiro-b-lactams. In addition, we have developed a facile route to novel spiro-b-lactams by using

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intramolecular halogen-mediated cyclization reactions of cis-3-prop-2-ynyloxy/ enyloxy- or 3-allyl-3-benzylthioazetidin-2-ones. We would like to apologize to those scientists whose work may not have appeared in this review either due to the limited scope of the review or oversight. We gratefully acknowledge the financial support for our spiro-b-lactam research programme from Council of Scientific and Industrial Research, New Delhi and Department of Science and Technology (DST), New Delhi, Government of India (Project No. SP/S1/G-50/99 and SR/FTP/CS-135/2006).

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Top Heterocycl Chem (2010) 22: 101–209 DOI 10.1007/7081_2009_12 # Springer‐Verlag Berlin Heidelberg 2010 Published online: 22 January 2010

Novel and Recent Synthesis and Applications of b-Lactams Luigino Troisi, Catia Granito, and Emanuela Pindinelli

Abstract In this chapter, a comprehensive overview of the most significant and interesting contributions published from 2000 until now, concerning the preparation of novel b-lactam structures is presented. Among the different synthetic strategies available, either novel or already known but efficient and versatile methodologies are covered. The simple modifications of one or more substituents linked to the nitrogen N-1, the C-3, and the C-4 carbon atoms of the b-lactam nucleus were considered as an alternative synthetic protocol of more complex and polyfunctionalized molecules. Indeed, it is well known and extensively reviewed that the biological activity of this strained four-membered heterocycle is strictly dependent on the nature of the substituent groups that affect the reactivity towards the molecular active sites, increasing or lowering the possibility of interaction with the substrates. Finally, a synthetic survey of the most significant biological and pharmacological applications of the 2-azetidinones is reported. Keywords Beta-lactam Cyclization reaction Enzyme inhibitor Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Biological Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Antibacterial Activity: Inhibitors of b-Lactamases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Inhibitors of Various Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Azetidin-2-Ones as Vasopressin V1a Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Hypocholesterolemic and Antihyperglycemic Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5 Anticancer Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6 Antiviral Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 General Synthetic Methodologies of b-Lactam’s Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

103 104 104 105 105 106 106 106 107

L. Troisi (*), C. Granito, E. Pindinelli Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, University of Salento, Via Prov. le Lecce-Monteroni, 73100 Lecce, Italy e-mail: [email protected]

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4 Literature Survey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Synthesis of Novel Substituted b-Lactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 Structural Modifications to the N-1, the C-3, and the C-4 Positions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4 Biological Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abbreviations ACAT Bn Boc bpy BQ BSA BTPP n-BuLi s-BuLi CAD CAI CAIBP Cbz CH3OTf CNS CSI DABCO DBU DCC DEAD DIPEA DME DMF DMSO ECM EDG EWG Fmoc GPCR HCMV HIU HLE HMDA LDA

Acyl coenzyme A cholesterol transferases Benzyl tert-butoxycarbonyl 2,20 -bipyridyl Benzoylquinine Bis-trimethylsilylacetamide tert-butylimino-tri(pyrrolidino)phosphorane normal-butyllithium sec-butyllithium Coronary artery disease Cholesterol absorption inhibitor Cholesterol absorption inhibitor binding protein Benzyloxycarbonyl Methyl triflate Central nervous system Chlorosulfonyl isocyanate 1,4-diazabicyclo[2.2.2]octane 1,8-diazabicyclo[5.4.0]undec-7-ene Dicyclohexylcarbodiimide Diethyl azodicarboxylate N,N-diisopropylethylamine 1,2-dimethoxyethane N,N-dimethylformamide Dimethyl sulfoxide Extracellular matrix Electron-donating group Electron-withdrawing group 9-fluorenylmethoxycarbonyl G protein-coupled receptor Human cytomegalovirus High intensity ultrasound Human leukocyte elastase Hexamethylendiamine Lithium diisopropylamide

109 109 153 160 175 198 198

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LE LHMDS MCBA MMP MMPP MRSA MW NMP NMR OMP PBP Pmb PMN PMP PPE PPY SAR SET TBAF TBDMSCl TBS TFA TIPS TMEDA TMSCl TPA TS Ts

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Leukocyte elastase Lithium bis(trimethylsilyl)amide meta-chloroperbenzoic acid Matrix metalloproteinase Magnesium monoperoxyphthalate Methicillin-resistant Staphylococcus aureus Microwave N-methylpyrrolidone Nuclear magnetic resonance ortho-methoxyphenyl Penicillin-binding proteins para-methoxybenzaldehyde Polymorphonuclear para-methoxyphenyl Porcine pancreatic elastase 4-(pyrrolidino)pyridine Structure-activity relationship Single-electron-transfer Tetrabutylammonium fluoride tert-butyl dimethylsilyl chloride tert-butyldimethylsilyl Trifluoroacetic acid Triisopropylsilyl N,N,N0 ,N0 -tetramethyl-1,2-ethylenediamine Trimethylsilyl chloride Tripyridylamine Transition state Tosyl, 4-toluenesulfonyl

1 Introduction b-Lactam nucleus is the core of the biological activity of a large class of antibiotics characterized by the presence of this four-membered ring and differentiated by side chains, unsaturations, heteroatoms, and, in many cases, by the presence of five-or six-membered rings. After the discovery of penicillins and cephalosporins as classical b-lactam antibiotics and clinically useful active agents, the past few decades have witnessed a remarkable growth in the field of b-lactam chemistry [1, 2]. The need for potentially effective b-lactam antibiotics as well as more effective b-lactamase inhibitors has motivated synthetic organic and medicinal chemists to design new functionalized 2-azetidinones. Besides their clinical use as antibacterial agents, these compounds have also been used as synthons in the preparation of various heterocyclic compounds of biological significance [3–7]. The potential use of some

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b-lactams as therapeutic agents for lowering plasma cholesterol levels has been documented as well [8, 9]. Extensive studies of the human leukocyte elastase (HLE) inhibitory mechanism and the biological activity of this class of compounds have also been published [10]. As a result, considerable attention is paid by the synthetic organic and medicinal chemists to continue updating their knowledge about novel b-lactam synthesis, based either on new or well established methodologies, or on the modification of preexisting groups linked to the four-membered ring. In this chapter, we present a comprehensive overview of the most significant and interesting contributions on the preparation of the b-lactam structures published in various journals since 2000. The synthetic methodologies covered are based either on new or well established methodologies. As an alternative protocol, the simple structural modification of preexisting groups linked to the nitrogen N-1, the C-3, or the C-4 carbon atoms was also examined. Moreover, a synthetic survey of the literature on the biological and pharmacological applications of the 2-azetidinone compounds is included, focusing attention on the structure-activity relationships (SARs) studies, which can be employed to design new and more efficient molecules.

2 Biological Activity In this paragraph, a synthetic survey of the most significant biological and pharmacological applications of b-lactam derivatives is reported. A more detailed survey of the current literature in this field is given in Sect. 4.3

2.1

Antibacterial Activity: Inhibitors of b-Lactamases

The emergence of pathogenic microorganisms resistant to multiple classes of antibiotics is a serious clinical challenge [11–16]. Among these classes of antibacterials, b-lactam antibiotics are still the most commonly used, over 50 years after their initial introduction. The most common mechanism for resistance to b-lactam antibiotics is the ability of bacteria to produce b-lactamases [17–21]. These enzymes hydrolyze the b-lactam moiety in the drugs, inactivating the antibiotics. Studies of amino acid sequence homology have identified four distinct classes of b-lactamase: A, B, C, and D [22]. Among these, classes A and C are currently the most important in human disease [21]. A successful approach to overcoming the adverse action of these enzymes has been the coadministration of b-lactamase inhibitors together with the typical b-lactam antibiotics, such as pennicillins [21–24]. Unfortunately, this approach has been compromised by the discovery of new variants of b-lactamases, resistant to the inhibition afforded by known inhibitors [25–30]. Therefore, the development of novel b-lactam inhibitors

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to withstand inactivation by the ever-increasing diversity of b-lactamases has thus been a continuous and still on-going battle. Several monocyclic b-lactams variously substituted have also been reported to have antibacterial activity against different strains of bacteria and with different mechanisms of action.

2.2

Inhibitors of Various Enzymes

Leukocyte elastase (LE) is a serine protease, expressed by polymorphonuclear (PMN) leukocytes, mainly neutrophils, which acts both intracellularly to kill engulfed pathogens and extracellularly to mediate coagulation, immune responses, and wound debridement [31]. Because LE has the potential to degrade some structural proteins of the extracellular matrix (ECM) such as elastin, fibronectin, and collagens, excess of LE activity has been involved in a number of pathological conditions that lead to the impairment of ECM organization, including rheumatoid arthritis, emphysema, cystic fibrosis, and tumor progression [32]. LE also activates the proenzymatic form of matrix metalloproteinase (MMP)-9 [31], massively released by the PMN leukocytes and instrumental to their extravasation [33, 34]. A number of b-lactams, compounds widely used as antimicrobial drugs, have been identified as inhibitors of these serine enzymes, in particular LE [35]. Inhibitors of LE, and in particular of HLE, have a core structure of a four-membered b-lactam ring. Most of them are based on the cephem nucleus or are bicyclic compounds, such as clavams and cephalosporins. More recently, monocyclic b-lactams variously substituted have also been studied. Among the inhibition of other types of enzymes, several representatives of the class of b-lactams have been found to effectively inhibit proteases. 2-Azetidinones tetrasubstituted have also been identified as powerful and selective inhibitors of thrombin, a serine protease involved in both venous and arterial thrombotic episodes. Analogous compounds have also been found to display inhibition towards tryptase.

2.3

Azetidin-2-Ones as Vasopressin V1a Antagonists

The neurohypophysical hormones vasopressin and oxytocin exert a wide range of physiological effects through binding to specific membrane receptors belonging to the G protein-coupled receptor superfamily [36]. To date, three vasopressin receptor subtypes and one oxytocin receptor have been pharmacologically and functionally described [36]. Although vasopressin is perhaps best-known for its role in the cardiovascular system, it also has actions in the central nervous system (CNS). Arginine vasopressin functions as a neurochemical signal in the brain to affect social behavior. There is an expanding literature from animal and human studies

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showing that vasopressin, through the vasopressin 1A receptor (V1a), can stimulate aggressive behavior. The b-lactam structure, prepared by different research groups, is the essential scaffold of several antagonists directed to the vasopressin V1a receptor.

2.4

Hypocholesterolemic and Antihyperglycemic Activity

Atherosclerotic coronary artery disease (CAD) is one of the major causes of death. Although reducing dietary fat and cholesterol is still considered the appropriate first-line therapy, the advent of more effective pharmacological agents has led to an increased use of drug therapy to control serum cholesterol [37, 38]. Serum cholesterol can be reduced by inhibiting endogenous cholesterol biosynthesis, promoting hepatic cholesterol clearance from the plasma, and inhibiting the absorption of dietary and biliary cholesterol from the intestines (for a review of pharmacological approaches to the treatment of atherosclerosis see [39]). 2-Azetidinones with various substituents have been studied as effective inhibitors of cholesterol absorption. Monocyclic b-lactams tetrasubstituted have been reported for antidiabetic activity, as they are able to control diabetic hypercholesterolemia. Induction of diabetes was confirmed by a significant rise in serum glucose and a depression in hepatic glycogen contents that control the cholesterol metabolism.

2.5

Anticancer Activity

Recently discovered antitumor monocyclic and bicyclic b-lactam systems [40–42] are, in general, in good agreement with the phenomenon of azetidin-2-one pharmacophore of inexhaustible pharmacological potential on account of the specific ability of its numerous derivatives to inhibit not only bacterial transpeptidase, but also mammalian serin and cystein proteases [43]. As a measure of cytotoxicity, some compounds have been assayed against nine human cancer cell lines. A family of novel b-lactam antibiotics based on N-methyltio substituted 2-azetidinones have also shown the apoptosis-inducing properties against human solid tumor cell lines such as breast, prostate, and head-and-neck [44].

2.6

Antiviral Activity

Human cytomegalovirus (HCMV) is a ubiquitous member of the herpes virus family. Although most infections are asymptomatic, severe manifestations of HCMV can be seen in individuals whose immune system has been weakened by

Novel and Recent Synthesis and Applications of b-Lactams

107

disease such as late-stage cancers and AIDS, or by immunosuppressive therapy following organ transplantation [45–47]. Due to its critical role in capsid assembly and viral maturation, HCMV serine protease has become an attractive target for the development of anti-HMCV drugs [48]. Among the latter, a series of monocyclic b-lactams have resulted in highly potent inhibitors.

3 General Synthetic Methodologies of b-Lactam’s Preparation Considering the large pharmacological potential and use of the b-lactam systems, intensive research has generated numerous methods for synthesizing this skeleton, and the topic has been amply documented and reviewed several times [49, 50]. Moreover, as documented in the subsequent Sect. 4, the chemical reactivity of the b-lactam ring depends strongly on the substitution at the N-1, the C-3, and the C-4 positions. The synthetic methodologies covered are either new or already known and they are classified, in this paragraph, by the kind of reaction. The most efficient and used class of synthetic reactions for preparing the b-lactam ring are reported as follows: Staudinger-reaction. The Staudinger reaction consists in the coupling of ketenes with imines. The ketene could be also prepared in situ in different ways (Scheme 1). Gilman–Speeter reaction. The Gilman–Speeter reaction is the coupling of anion enolates with imines (Scheme 2). Alper reaction. The Alper reaction corresponds to the ring expansion of aziridines by metal-catalyzed CO insertion (Scheme 3). Mitsunobu reaction. The Mitsunobu reaction is an intramolecular cyclization of suitable amides (Scheme 4). R1

H C

C

+

O

R

R1

O N R2

H

N R2

R

R1

O

N

R2

R

Scheme 1

R2 N R2 1

R CH2 COOR

B

H

O C

R

H

R3

R2 N

C OR1

1

R3

OR R

Scheme 2

O N

O R3

R

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L. Troisi et al.

Scheme 3

R1

N

CO [M]

3

R2

R

R3

H

OH

Scheme 4

O

R1

R N

DEAD

N

R

R1

R2

N

R1

PPh3

O

O

R R1

R1 R

CuI

+

N O

+

Et3N R2

R1 N

N R2

O

R2

O

Scheme 5

R1

R2 X

CO

+ N

Scheme 6

Pd R1

O N

R2

Kinugasa reaction. The Kinugasa reaction consists in the coupling of nitrones with propargyl moieties catalyzed by copper salts (Scheme 5). Torii Reaction. The Torii reaction is a metal-catalyzed cyclocarbonylation of allyl derivatives with imines (Scheme 6). Intramolecular cyclization. The intramolecular cyclization of suitable substrates can afford 2-azetidinones under the following conditions: (a) (b) (c) (d) (e)

Electrochemical induction Photo-irradiation Ultra-sound irradiation Lewis-acid catalysis Base catalysis

Heterocyclic rearrangement. Suitable heterocycles can rearrange to 2-azetidinones. Other reactions. In this paragraph, the reactions not included above are reported.

Novel and Recent Synthesis and Applications of b-Lactams

109

4 Literature Survey 4.1 4.1.1

Synthesis of Novel Substituted b-Lactams Staudinger Reaction

In 2000, the group of Banik et al. reported the enantiospecific synthesis of 3-hydroxy2-azetidinones by microwave assisted Staudinger reaction [51]. Chiral imines, derived from chiral aldehydes and achiral amines, reacted with methoxy- or acetoxy-acetyl chloride to afford a single, optically pure cis-b-lactam, (Scheme 7). 3-Unsubstituted b-lactams have instead been obtained, by the same authors, through indium-mediated reaction of imines with alkyl bromoacetates [52]. b-Lactams having a wide range of substituents linked to the nitrogen atom, such as aryl, aryl alkyl, or allyl groups, could be prepared by this pathway. Microwave-induced organic reaction enhancement chemistry techniques have been reported to allow highly accelerated synthesis of variously substituted vinylb-lactams, using limited amounts of solvents and with efficient stereocontrol [3]. Enantiopure tricyclic b-lactams have been prepared by a stereoselective synthesis. The [2+2] cycloaddition of imine, obtained from the corresponding tricarbonyl chromium(0) 2-fluoro benzaldehyde and para-methoxyaniline [53], with acetoxyacetyl chloride at 0 C and Et3N in CH2Cl2 afforded the cis b-lactam as a single diastereoisomer in 94% yield (de>98%). Subsequent treatment of the cis b-lactam with hydrazine in CH3OH gave, in 85% yield, the corresponding cis 3-hydroxy b-lactam. The intramolecular displacement of the fluorine atom, with an equimolar amount of NaH at room temperature, produced the tricyclic b-lactam. Finally, the uncomplexed compound was obtained quantitatively by exposure of the complex to air and sunlight in CH2Cl2 solution (Scheme 8), [54]. This latter product was also synthesized in racemic and enantiopure form starting from the enantiomerically pure tricarbonyl chromium(0) complex. The synthesis of penams has been reported to be conveniently prepared from Meldrum’s acid [55] and thiazoline [56]. The substrates were reacted in dry benzene containing dry HCl (gas) at reflux to afford a series of penam derivatives with aryl, n-hexyl, and cyclohexyl substituents (Scheme 9), [57].

R1

H

R2

2

R CH2COCl N

O

R = H

Scheme 7 Synthesis of optically pure cis-b-lactams

R

OMe

O

;

H

O O

R2 = OMe; OAc

R1

O O

O ;

H N

Et3N

R 1

H

O O

H O

O

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L. Troisi et al.

F F

AcO N PMP

Cr(CO)3

Et3N, CH2Cl2

+ AcOCH2COCl

N

0 °C

O

PMP

Cr(CO)3 N2H4, CH3OH

Cr(CO)3 O

CH2Cl2, hn

F HO

O

air

DME N

N O

O PMP (de > 98%)

Cr(CO)3

NaH N O

PMP

PMP

PMP = 4-MeO-Ph DME = 1,2-dimethoxyethane

Scheme 8 Stereoselective synthesis of tricyclic b-lactams

O O

R OH

O O

R

O

via

C R

S

Dry HCl (g)

+ H N

CO2Me

O

Dry benzene 5 °C - reflux

O

S N O

CO2Me (38-93%)

Scheme 9 Stereoselective synthesis of penam derivatives

The synthesis of enantiopure 4-unsubstituted 3-alkoxy- and 3-amino b-lactams has been reported to be performed in two steps: (a) and (b). (a) The [2+2] cycloaddition reaction of chiral formaldehyde N, N-dialkylhydrazones to alkoxy or aminoketenes. (b) The magnesium monoperoxyphthalate (MMPP)-promoted oxidative N–N bond cleavage of the resulting hydrazides (Scheme 10), [58]. A protocol has been reported based on a cyclization procedure followed by hydrolysis and oxidation, which allowed the preparation of a-keto-b-lactams (Scheme 11), [59]. The cyclization of imines with acetylglyoxylic acid, in the presence of POCl3 and Et3N, gave 3-acetoxy-b-lactams in good yields as cisisomers, prevalently. These latter were hydrolyzed to alcohols in excellent yields under very mild conditions. Subsequent oxidations were performed by treatment with dimethyl sulfoxide (DMSO) in the presence of phosphorous pentoxide to give a-keto-b-lactams. More 2-azetidinones were synthesized varying the substituent of the acetyl moiety.

Novel and Recent Synthesis and Applications of b-Lactams R1

O C

N

O N

BnO

N

BnO

A)

R2

H

N N

O R3

C R3

N

R2 Ph

N R4

= BnO

N

O

R2

NH R3

N

;

N

Ph ; O

N R4

Ph

= NMe2;

MeOH

R

R4

R1

MMPP

4

H

N

B)

R1 O

R3

NH

BnO

N

N

O

R2

H

R1

H

111

R

; O

O

O N

Ph

O

N O

O

Scheme 10 Synthesis of 4-unsubstituted 3-alkoxy- and 3-amino-b-lactams from formaldehyde N, N-dialkylhydrazones

Ar N + AcO PMP PMP = 4-MeO-Ph

O

Ar

AcO POlC3 N

HO Et3N O

HO THF/0°C

KOH PMP

(50-84%)

O

Ar

O P2O5 DMSO N O PMP

Ar N PMP

(76-90%)

Scheme 11 Synthesis of a-keto-b-lactams

4-acylamino and 4-sulphonamido-trans-b-lactams have been reported to be synthesized from trisubstituted amidines via cycloaddition reaction with ketenes (Scheme 12), [60]. Amidines bearing an electron-withdrawing substituent on enamine nitrogen could increase the b-lactam stability. The starting trisubstituted amidines were prepared by reacting N0 ,N0 -diarylamidines with aryloyl chloride in the presence of triethylamine. D-xylose derivative has been reported to be an excellent chiral auxiliary in the Staudinger reaction for the construction of b-lactams (Scheme 13), [61]. Cyclic imines furnished trans products whereas acyclic imines possessing trans geometry gave cis products.

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L. Troisi et al.

H N

H

R1 Ar

N

CH2Cl2

+ R1Cl

N

H

R2

Ar

N

CH2Cl2, Et3N, 0 °C - rt

N

1 H R N

H COCl

Ar

Et3N, 0 °C - rt

Ar

R2

O

Ar

Ar

Ar = Ph; 4-Cl-Ph; 3-Me-Ph; 4-MeO-Ph R1= PhCO; 4-NO2-PhCO; Ts R2 = PhO; Phthalimido

Scheme 12 Synthesis of 4-substituted amino-trans-b-lactams by cycloaddition reaction

MeO

MeO

O

O OMe

OH

Mukaiyama's reagent/Et3N

N

R

O

N O

O

O OMe

N

R1

N O

R1

O

R

(58-91%)

Scheme 13 Asymmetric synthesis of b-lactams by chiral auxiliary based on D-xylose derivative

N-Ts-imines have been reported to react with ketenes in the presence of suitable nucleophilic catalysts to give rac-b-lactams in good chemical yields at room temperature [62]. The diastereomeric ratios were highly influenced by the kind of nucleophile involved. For instance, using chiral nucleophiles such as benzoylquinine (BQ) the synthesis became highly diastereo- and enantioselective (dr, cis/ trans = 99:1; ee>95%). In 2001, b-lactams have been reported to be obtained via Staudinger reaction with complete cis-diastereoselection starting from prochiral imine chromium complexes (Scheme 14), [63]. Enantioselective synthesis of analogous b-lactams has been also reported [63]. If the starting imine complex was prepared from the corresponding chiral amine in enantiomerically pure form (Fig. 1), two separable diastereomers were obtained. Using, then, one of the two diastereomers, cis-b-lactams were isolated as single enantiomers. In 2002, the asymmetric synthesis of 3-substituted 3-hydroxy-b-lactams has been reported to be realized by metal-mediated 1,3-butadien-2-ylation reactions between 1,4-dibromo-2-butyne and optically pure azetidine-2,3-diones [64]. This latter starting material was prepared via Staudinger reaction followed by sequential transesterification and Swern oxidation (Scheme 15), [65]. An efficient synthesis of tetrahydrofuran-derived spiro-b-lactams has been reported to be performed by a Staudinger-type reaction of either 2- or 3-tetrahydrofuroyl chloride with imines [66]. The reaction was carried out by adding Et3N

Novel and Recent Synthesis and Applications of b-Lactams

Me2N

Me2N

O

113

Me2N

O

1) Et3N (CO)3Cr

O C

H

2) CH3CO2CH2COCl

O

(CO)3Cr RN

RN

O

O

CH3

RN

O

O

O

hn/O2

O

CH3 O

O

Scheme 14 cis-Diastereoselective synthesis of b-lactams using prochiral imine chromium complexes

Me2N

Me2N

O

(CO)3Cr

O ;

O R

N

N

Ph

O

1) Et3N, AcOCH2COCl 2) NaOCH3,CH3OH 3) Swern oxidation

O

H

O

Ph

O

OH

O Br

O

Br N

N O

O

(CO)3Cr

N

Fig. 1

O

R

O

R

Scheme 15 Asymmetric synthesis of 3-substituted 3-hydroxy-b-lactams

to the acyl chloride in refluxing toluene and adding then the imine. A mixture of cisand trans-spiro-b-lactams in good to moderate yield was obtained (Scheme 16). The Staudinger reaction of imines derived from 7-oxanorbornenone with 2-alkoxyacetyl chlorides has been reported to afford spiro-b-lactams with an unexpected exo stereochemistry [67]. The chiral glycine derivatives, having the oxazolidinone moiety as a chiral auxiliary [68], have been reported to give the asymmetric Staudinger reaction on solid support with different resin bound aldimines in the presence of triethylamine [69]. Optically active substituted b-lactams were obtained, after cleaving from the resin, in good to high overall yields with high diastereoselectivity (Scheme 17). Rink resin derived imines have been reported to give cycloaddition reactions with acetyl chlorides (or equivalent) using triethylamine as the base and dichloromethane as the solvent at temperature ranging from 0 C to room temperature [70]. The resin-bound b-lactam could be cleaved by using 50% trifluoroacetic acid (TFA) in dichloromethane, to afford the N-unsubstituted b-lactam.

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O O O

R1

O C O

Cl or

Et3N

N R2

O

R2

R2

O +

R1

O

O O

N

N

or

Toluene

O

R1

O

R1

O

C O

Cl

N

N R2

O

R2

O

cis

trans (49-77%)

Scheme 16 Synthesis of tetrahydrofuran-derived spiro-b-lactams

O O O O

NH2

O +

R1

Ph

O

O N

N COCl

R

1

N 1) TFA

Ph O

R

Ph

2) CH2N2

N

H

O

O 1

N O

O

O

COOMe

Scheme 17 Solid phase synyhesis of 3,4-substituted azetidinones

N,N-Dialkylhydrazones as the imine component in the Staudinger-like [2+2] cycloaddition to benzyloxyketene have been reported [71, 72]. The reaction led to the desired b-lactams in excellent yields (84–98%), moderate to good selectivities (3R,4S > 3S,4R), and only traces of trans isomers (3R, 4R) were detected in some cases. The coupling of ketenes and imines has been reported to be catalyzed by a bifunctional system in which a chiral nucleophile was paired with an achiral Lewis acid metal salt [73, 74]. Optically enriched b-lactam products were isolated in high yields, (Scheme 18). Among the various Lewis acids studied, such as Mg(OTf)2, Cu (MeCN)4ClO4, YbCl3, La(OTf)3, AgOTf, Al(OTf)3, Sc(OTf)3, Zn(OTf)2,and In (OTf)3, this latter was the best overall cocatalyst for promoting the reaction. The best chiral nucleophiles used are reported in Scheme 18. Planar-chiral derivatives of 4-(pyrrolidino)pyridine (PPY) have been reported as efficient catalysts for enantioselective Staudinger reactions [75]. These chiral derivatives catalyzed the reactions between a range of symmetrical and unsymmetrical disubstituted ketenes and a wide imine array leading to b-lactams with good stereoselections and yields. A methodology for the catalytic asymmetric synthesis of b-lactams has also been reported, resulting from the development of a catalyzed reaction of ketenes (or their derived zwitterionic enolates) and imines [76]. Despite the fact that simple tertiary

Novel and Recent Synthesis and Applications of b-Lactams O

O

Nu

R

H

115

Nu R

H L nM

X Lewis acid R1

X

1

R

H

O N

R1

N

MLn

N

X

R

H

OMe

OMe

N

OMe

N

Nu =

;

N

N

O

O

;

N

O

O

O

O

OH

Scheme 18 Bifunctional Lewis acid/nucleophile catalyzed synthesis of b-lactams

N

+ Ph

Ts

Ts

O

CH3

Ts = Tosyl

EtOOC

EtOOC

p-ClC6H4

O N CH3 Ph

: cis/trans = 55/45

Et3N O

catalyst =

catalyst

NEt2 NH

: cis/trans = 3/97

A i-Pr N : cis/trans = 98/2 N B

Scheme 19 Diastereoselectivity in the nucleophile-catalyzed reaction of methylphenylketene and imine

amines such as triethylamine usually catalyzed the reaction in a nonselective fashion, bifunctional catalyst, such as A and B (Scheme 19), may lead to a potentially rigid activated complex affording products in a cis/trans ratios of 3/97 and 98/2, respectively.

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L. Troisi et al.

The use of a chiral catalyst such as benzoylquinine in this reaction allowed the obtaining of a high enantioselectivity with ee > 95%. A multistep solid phase synthesis of b-lactams with imines of benzaldehyde coming out from commercially available fluorinated a-amino acids has been reported in 2003 [77]. Using the Merrifield resin-bound imine [78, 79] in dichloromethane, the cycloaddition was carried out between –78 C and rt by addition of benzyloxyacetyl chloride in the presence of triethylamine. The resin cleavage using sodium methylate resulted in the two cis b-lactam derivatives (Scheme 20). Alkylideneamido complex [Re(N=CPh2)(CO)3(bpy)] [80] has been reported to react with ketene to afford, via Staudinger reaction, a single b-lactam complex whose structure was determined by X-ray diffraction [75]. The b-lactam complex reacted with methyl triflate (CH3OTf), affording the free N-methyl-b-lactam and the complex used as precursor (Scheme 21), [81].

Ar M

Ar O

N O

Ph

Ph

O

ZCH2COCl

M O

Et3N,CH2Cl –78°C - rt

N O

CH3ONa CH3OH / THF, r t Ar = p -FC 6H4CH2-;p-FC6H4Z = PhO; PhCH2O

Z

or 1) TFA 2) SOCl2 / THF

Ar Ph

H3CO O

N O

Z

Scheme 20 Solid phase synthesis of cis b-lactams

O Ph [Re] OTf + KN

C Ph

[Re] N

R1RC C O C Ph

1

R Ph

Ph [Re] = [Re(CO3)(bpy)]

Ph CH3OTf

H3C [Re]OTf

N

O

+ Ph Ph

Scheme 21 Synthesis of b-lactams from N-rhenaimine

R

[Re] N

R R1

Novel and Recent Synthesis and Applications of b-Lactams R

117

R

ArO Et3N/CHCl3

ArO +

N

N O

COOH O

O

N Me

O

O

Cl I

1) 10% TFA 2) CH N 2 2 R

ArO N O

CO2CH3

Scheme 22 Stereoselective synthesis of b-lactams using Mukaiyama’s salt

Instead, complexes with chiral chelates of the 2,20 -bipyridine (bpy) ligand could lead to asymmetric induction in the synthesis of chiral b-lactams. The use of Mukaiyama’s salt for the Staudinger reaction in a solid-phase synthesis of b-lactams has been reported to produce the ring construction in a stereoselective manner [82, 83]. The cycloaddition reaction was carried out adding 2,5 equiv. of aryloxylacetic acid and 6 equiv. of triethylamine to a suspension of the resin-bound aldimine in chloroform, followed by 3 equiv. of Mukaiyama’s salt and stirring at reflux temperature for 2 h. After cleavage and esterification, b-lactam was obtained in good yield (50–85%), and fairly good stereoselectivity (cis > trans), (Scheme 22). The synthesis of an enantiopure b-lactam as advanced precursor of thrombin and tryptase inhibitor, has been centered on the condensation between S-2-pyridylthio 5-(4-methoxyphenoxy)pentanoate and the N-4-methoxyphenylimine derived from O,O-cyclohexylidene D-glyceraldehyde (Scheme 23), [84]. Chiral imines derived from D-(+)-glucose have allowed an asymmetric synthesis of b-lactams by the [2+2] cycloaddition with ketenes [85]. cis-b-Lactams were formed with very high diastereoselectivity and the stereochemistry at the C-3 and the C-4 was established as 3S and 4R from the known absolute configuration of the sugar moiety (Scheme 24). The stereochemistry of the Staudinger reaction was highlighted [86] using as substrates polyaromatic imines and acetoxy, phenoxy, or phthalimido acid chloride. The stereochemistry of the resulting b-lactams seemed to vary depending on the substituents present in the imines and the acid chlorides. For instance, if the polyaromatic moiety was linked to the iminic nitrogen, the reaction produced trans-b-lactams; if the same moiety was linked to the iminic carbon, cis-b-lactams were isolated.

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L. Troisi et al.

H

H

O O

PMPO N

O PMPO

O

SPy +

O

CH2Cl2 O

PMP

TiCl4 / Et3N

+

NPMP

H

H

O O

PMPO N O

PMP

diastereomeric mixture

Scheme 23 Synthesis of an enantiopure b-lactam as precursor of thrombin and tryptase inhibitor

O

R1 N D-(+)-glucose

H O OR

2 O + R OCH2COCl

O

Et3 N; CH2Cl2

R2 O

H

H

0 °C to rt N O

O

O

H OR R1

Scheme 24 Asymmetric synthesis of cis-b-lactams starting from chiral imines derived from D-(+)-glucose

In 2004, bis-(cyclophanyldiol)AlOTf complex has been reported to catalyze the enantio- and diastereoselective synthesis of b-lactams via Staudinger reaction (Scheme 25), [87]. The Staudinger [2+2] cycloaddition of chiral carbohydrate Schiff base with phthalimidoacetyl chloride has yielded the sugar-based monocyclic b-lactam as a single isomer [88]. This latter could be transformed in several b-lactams variously functionalized through ozonolysis, reduction, hydrolysis, and acetylation reactions, (Scheme 26). A chiral group at the C-4 of the acid chloride of proline directed the stereoselectivity of Staudinger reaction and later was sacrified to obtain optically active 5,4-spiro-b-lactams [89]. The Staudinger reaction between an in-situ generated ketene, derived from optically active acid chloride, and imines was conducted in CH2Cl2 using Et3N as base at rt (Scheme 27). The chromatography purification of the crude products afforded two diastereomerically pure b-lactams (single enantiomers in each case) in good yields. Proline-derived spiro-b-lactams were obtained eliminating the methansulfonic acid and the N-Cbz-group (with K2CO3/MeOH), and hydrogenating by Pd.

Novel and Recent Synthesis and Applications of b-Lactams

O

Ts

Cl

10% mol. complex

N

+ Bn

EtOOC

119 Ts

O N

10% BQ Toluene, –78 °C EtOOC

H

Bn

ee: 99% dr > 99:1

BQ = benzoylquinine Ts = tosyl complex = bis-(cyclophanyldiol)AlOTf

Scheme 25 Catalytic synthesis of b-lactams by a dimeric cyclophane ligand

Ph

O

OAc CH2OH O AcO N AcO H

Ph N +

O Cl

O

N

O

N O

O

OAc CH2OAc O OAc OAc

O3 / Me2S CH3NHNH2

O CHO OAc CH2OAc N O OAc OAc

N O O

Ph H2N N

LiAlH(t-OBu)3

O

O N O O

RCOCl CH2OH OAc CH2OAc O N OAc OAc

Ph

O HN R N O

CH3NHNH2 H2N

O

OAc CH2OAc O OAc OAc

CH2OH OAc CH2OAc O N OAc OAc

OAc CH2OAc O OAc OAc

O HN

RCOCl R

O

CH2OH OAc CH2OAc N O OAc OAc

Scheme 26 Synthesis of sugar-based monocyclic b-lactams by Staudinger [2+2] cycloaddition reaction

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L. Troisi et al.

MeSO2O

R1 O +

N Cl

Cbz

R2

MeSO2O N

N 2

R

O

MeSO2O R1

+

N

N

Cbz O

Cbz R2

N

R1

N

R1

Cbz = benzyloxycarbonyl 1) K2CO3 / MeOH 2) H2 / Pd 2

R

O N

R1

+

N H

N O

R2

H

Scheme 27 Synthesis of 5,4-spiro-b-lactams by Staudinger reaction

R1 H O

CHO

BnO

BnO

OBn

O

BnO

H H OBn or

O

H CHO OBn

Bn = benzyl

2) R2OH C 2

OR2

OBn

1) R1NH2

or BnO

H

BnO

OBn

BnO

O

O N

1

R

Cl / Et3N O BnO BnO

H

O N H

H

OR2

OBn

Scheme 28 Synthesis of 4-(C-galactosyl)- and 4-(C-ribosyl)-b-lactams

A collection of 4-(C-galactosyl)- and 4-(C-ribosyl)-b-lactams featuring different substituents at C-3 and N-1 has been prepared by combining in a one-pot procedure a formyl C-glycoside, a primary amine, and a substituted acetyl chloride in the presence of a base (Scheme 28), [90]. The synthesis of 1,3-disubstituted-4-trichloromethyl azetidin-2-ones by the Staudinger cycloaddition of ketenes with imines derived from chloral has been described to occur with high stereoselectivity [91]. The cis-isomer was obtained almost always as the major or the single product. Reaction of D-phenylalanine ethyl ester with cinnamaldehyde has been reported to give a chiral Schiff base, that underwent an asymmetric Staudinger [2+2] cycloaddition reaction with phthalimidoacetyl chloride to give the monocyclic

Novel and Recent Synthesis and Applications of b-Lactams

121 Ph PhtN

Ph CH2 CH CO2Et

PhCH CHCHO

Ph CH2 CH CO2Et

NH2

PhtNCH2COCl Et3N, CH2Cl2

N

N O

CO2Et

Ph 1) O3 / Me2S

Ph

2) LiAlH(t-BuO)3

PhtN

PhtN Ph N

2) DBU

O

CH2OH

1) MeSO2Cl N O

CO2Et

CO2Et

Ph DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene

Scheme 29 Synthesis of mono- and bicyclic b-lactams starting from D-phenylalanine ethyl ester

b-lactam as a single stereoisomer. Ozonolysis of this latter followed by reduction with lithium aluminum tri(tert-butoxy)hydride has produced the hydroxymethyl-blactam, that was converted to the bicyclic b-lactam upon treatment with metansulfonyl chloride and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), (Scheme 29), [92]. a-Amino-b-lactams have been reported to be prepared via Staudinger-like [2+2] cycloaddition of N,N-dialkylhydrazones to a-aminoketenes [93]. The reaction was stereoselective leading to trans-3-amino-4-alkylazetidin-2-ones as single diastereomers (Scheme 30). A solid-phase strategy for the synthesis of trans 3-alkyl b-lactams has been reported to start from 9-fluorenylmethoxycarbonyl(Fmoc)-glycine thethered to Wang resin [94]. The amine group was deprotected by treatment with 30% piperidine in N,N-dimethylformamide (DMF) and condensed with p-anisaldehyde in 1% acetic acid in DMF to give the corresponding aldimine. The subsequent [2+2] cycloaddition between the in situ generated ketene and the imine has produced the b-lactamic product. The resin cleavage followed by the esterification afforded the b-lactam as a single product with excellent trans selectivity. Benzodiazepines [95, 96] and triethylamine in CH2Cl2 treated with acetoxyacetyl chloride or phthalimidoacetyl chloride at 0 C afforded exclusively the b-lactamfused 1,4-benzodiazepines [97]. In all the cases studied, the reaction provided the final tricyclic systems in very good yields. A high level of diastereoselectivity was achieved and the final products were isolated as single diastereomers, with a cis relationship between the aryl group from the benzodiazepine and the substituent of the ketene. In 2005, reactions of ketenes generated from a-diazoketones with acyclic and cyclic imines have been investigated under both microwave and photoirradiation conditions [98]. The reported results indicated that the zwitterionic

122

L. Troisi et al. O Bn BnO

Cl

O

N

C

N I Me

Bn

O

H

N

OH i-Pr2EtN, Toluene 80 °C

BnO

O

Me N N R

Me H Me N

O O BnO

Me

N N

R

Bn

Scheme 30 Stereoselective synthesis of trans 3-amino-4-alkylazetidin-2-ones

2 R1 R

O

R2

R1

N2 MW or hn

1H

conrotate

R

H

R2

N O

R3

R3

N

R1

O

N

H H

H

R3

C R2

O N

R3

R1 H O

N

2

R H

conrotate

R1

H

H

R2

N R3

O

R3

Scheme 31 Mechanism of the Staudinger reaction starting from ketenes generated from adiazoketones under microwave and photoirradiation conditions

azabutadiene-type intermediates yielded from imines and ketenes underwent a conrotatory ring closure to produce exclusively b-lactams (Scheme 31). b-Lactams with polyaromatic substituents at C-4 have been reported to be synthesized, via Staudinger reaction [99]. The reaction of polyaromatic imines with acetoxy, phenoxy and phthalimido acid chloride in the presence of triethylamine at

Novel and Recent Synthesis and Applications of b-Lactams

+ ZCH2COCl

N

Ar'

Z

H

Ar'

123

Et3N; CH2Cl2 –78 °C to rt

Ar

N O

Ar

Z = OAc; OPh; Phthalimido Ar = Ph; 2-Pyridyl Ar' = 1-naphthalenyl; 1-anthracenyl;1-pyrenyl; 6-chrysenyl; etc.

Scheme 32 Synthesis by microwave irradiation of b-lactams having polyaromatic substituents at the C-4 position

R O Ph-CH=N-R1

N

R1

O

N

C O

COR N

S Ph

COR

Et3N; CH2Cl2

S

R1 = CH2Ph; Ph; p-MeO-Ph trans >>cis R1 = PhSO2

cis >> trans

N S

COOH + Cl

N

I CH3

Scheme 33 Synthesis of spiro-b-lactams by [2+2] cycloaddition reaction

–78 C to rt produced exclusively trans-b-lactams in good yields, (Scheme 32). The domestic microwave irradiation on this type of substrates was utilized with good success. The effect of a peri hydrogen was found to be significant in controlling the stereochemistry of the resulting b-lactams. Spiro-b-lactams have been synthesized via [2+2] cycloaddition of cyclic ketenes with imines [100]. Opposite trans or cis diastereoselectivity was obtained using different imines with electron-donating or electron-withdrawing (R1) substituents at the N-atom, (Scheme 33). The cyclic ketenes were generated from N-acyl-1,3-thiazolidine-2-carboxylic acids by means of Mukaiyama’s reagent. The same reaction generated enantiomerically pure 1,3-thiazolidine-derived spiro-b-lactams, using optically active N-tert-butoxycarbonyl-1,3-thiazolidine-2-carboxylic acid derivatives as precursors of the asymmetrical chiral cyclic ketenes (tert-butoxycarbonyl: Boc) [101]. A comprehensive study on the solid-phase synthesis of b-lactam compounds has been reported [102]. In situ generated ketenes reacted with aldimines, immobilized on commercially available solid supports, under mild conditions to generate libraries of b-lactams in good to very good overall isolated yields. Different b-lactam derivatives with various substituents at the C-3 and the C-4 position

124

L. Troisi et al.

were obtained. The utility of this protocol was also demonstrated by highlighting efficient asymmetric versions when homochiral ketenes or homochiral aldimines were used. The Staudinger reaction, catalyzed by 4-(pyrrolidino)pyridine derivative, could be controlled through the appropriate choice of the N-protecting group of the imine [103]. Thus, ketenes coupled with N-tosyl imines predominantly generated cis-blactams, whereas reactions with N-triflyl imines preferentially furnished trans isomers. A combined theoretical and experimental study has been reported for the formation of silylated b-lactams, via Staudinger [2+2] cycloaddition reaction from silylketenes and imines, in the presence or in the absence of a Lewis acid [104]. The experimental study was carried out with two different imines: a standard one, n-hesanaldimine, and an electron-poor one, n-butyl glyoxylate imine. The Scheme 34 shows that the formation of the b-lactam occurred only when the glyoxylate imime and BF3-Et2O reacted with (trimethylsilyl)ketene. The b-lactam was formed in fair yield and in a 60:15:15:10 (cis:cis:trans:trans) mixture of four diastereoisomers. In order to investigate the mechanism of the Staudinger reactions studied experimentally, the energy profiles for the formation of the cis and trans b-lactams were calculated. Theoretical results suggested that the reaction would proceed most favorably with the BF3 catalyst coordinated to the ketene. Treatment of imines with ethyl bromodifluoroacetate and Et2Zn, in the presence of RhCl(PPh3)3 in anhydrous medium, has been reported to give via Reformaskytype reaction difluoro-b-lactams and 3-amino-2,2-difluorocarboxylic esters, [105]. Different product ratios were observed changing the reaction conditions (solvent, reaction time, addition of MgSO4). A benzothiazepine-fused b-lactam library has been reported to be obtained [106] via Staudinger cycloaddition of 2,3- dihydro-1,5-benzothiazepines and various acyl chlorides such as phthalimidoacetyl chloride (path a, Scheme 35), chloroacetyl chloride (path b, Scheme 35), dichloroacetyl chloride (path c, Scheme 35), and phenoxyacetyl chloride (path d, Scheme 35). The Schiff base obtained by (S)-()-tyrosine ethyl ester hydrochloride with 2-hydroxybenzaldehyde has been reported to be transformed, via Staudinger

No reaction

Ph

O

Et2O; –30 °C to rt

N n-BuO2C

N

no Lewis acid

Ph

n-BuO2C

C H

BF3-Et2O

N

O n-C5H11

Ph

no Lewis acid

No reaction

Et2O; –30 °C to rt

SiMe3

No reaction BF3-Et2O

SiMe3

Scheme 34 Synthesis of silylated-b-lactams via Staudinger [2+2] cycloaddition reaction

Novel and Recent Synthesis and Applications of b-Lactams

125 R1

S

N

R2

O

O

N

O

O

N CH2COCl

R1

S

O path a ClCH2COCl S N

R1

N

path b O

Cl2CHCOCl path c

S

2

R

R2 Cl R1

PhOCH2COCl N

path d S

N O

R1

O

R2 Cl Cl

R2 OPh

Scheme 35 Synthesis of benzodiazepine-fused b-lactam library

reaction, into the chiral monocyclic b-lactam by treatment with achiral ketene prepared in situ from phthaloylglycyl chloride and triethylamine [107]. Ketene-imine cycloaddition reactions of ethoxycarbonyl(phenylthio)ketene with various imines and subsequent desulfurization reactions have been reported in 2006 to synthesize 3-ethoxycarbonyl b-lactam derivatives [108]. The stereoselective synthesis of bis-b-lactams grafted macrocycles has been described [109]. Macrocyclic imine and phenoxy acetyl chloride in the presence of triethylamine produced a diastereomeric mixture of cis macrocyclic bis-b-lactams (Scheme 36) by the Staudinger reaction. trans-b-Lactams have been reported to be regioselectively synthesized by [2+2] Staudinger cycloaddition reactions of imine such as (3,4-dimethoxybenzylidene)(4-methoxyphenyl)-amine and ketenes derived from different acyl chlorides and triethylamine [110]. trans-b-Lactams have also been obtained by the Staudinger reaction carried out between divinylimine and N-acylimidazoles possessing an electron-withdrawing group (EWG) in a position [111]. This latter were prepared by treatment of a-EWG substituted carboxylic acids with 1,1-carbonyldiimidazole.

N

O

Et3N; CH2Cl2 O °C - rt

phenoxy acethyl chloride

Scheme 36 Stereoselective synthesis of cis macrocyclic bis-b-lactams

O

N

H O N

O

H

O N H

O

O H O

+

H O N

O

H

O N H

O

O H O

126 L. Troisi et al.

Novel and Recent Synthesis and Applications of b-Lactams

127 H

R

Ar

X

N PMP

H H H 0°C - reflux R

C

Ar PMP

N O

O TS-1 (exo) O

Et3N; HC2Cl2

X

Ar H

N PMP

H Ar

H H

N

H

XR

Cl

H

RX

R Ar

PMP

HH

H

H Ar

H N PMP O TS-2 (endo)

XR

N O

PMP

O XR = OPh; OCH3; N3; SR; NPhth PMP = 4-methoxyphenyl

Scheme 37 Plausible mechanism for the formation of trans-b-lactams

A stereocontrolled Staudinger cycloaddition reaction has been reported to be performed on vinylketenes, possessing a g-heteroatom, and imines to produce trans-vinyl-b-lactams [112]. The vinyl side chain adopted stereoselectively the (Z) configuration in the transition state, stabilizing the vinyl ketene and leading, exclusively, to the trans-3-vinyl-b-lactam (Scheme 37). The (Z) configuration, adopted by the RX-vinyl groups, was explained by the authors via participation of the g-heteroatom ion pair of electrons. Although, the (E)-imine is more stable compared to the corresponding (Z)-imine, it is less reactive due to the severe steric interaction between the RX group and the aryl group of the imine in the transition state TS-2. This steric interaction is absent in TS-1 that arose from the exo attack of the (Z)-imine on the vinylketene. Therefore, TS-1 was preferentially formed, which by conrotatory ring closure gave trans-b-lactams. Chiral imines have been prepared by reacting (R)-glyceraldehyde acetonide with different o-haloalkylammonium halides. Treatment of the latter with 1.3 equiv. of benzyloxy-, phenoxy- or methoxy acetyl chloride in dichloromethane, in the presence of triethylamine afforded the optically active corresponding b-lactams (Scheme 38) in high yield and high diastereomeric excess [113]. The Staudinger reaction between enantiopure 5,6-dihydropyrazin-2-(1H)-ones and an excess of 2-heterosubstituted acetylchloride in the presence of triethylamine in dichloromethane at room temperature has been reported to produce in excellent yield and high diastereoselectivity fused oxopiperazino-b-lactams (Scheme 39), [114]. 3-Spirocyclopropanated b-lactams have been prepared by a three-component cascade reaction [115]. A mixture of alkylhydroxylamine hydrochlorides, aldehydes, and bicyclopropylidene, under microwave heating in ethanol as solvent, furnished 3-spirocyclopropanated 2-azetidinones with good yields (Scheme 40).

128

L. Troisi et al.

O

O

H

O

X H3N

H

X

O

Cl

RO

H

RO

O

H

O

O

N

Et3N; CH2Cl2 0°C - rt

O n

N O

X

n

X

X = Cl, Br

Scheme 38 Preparation of optically active b-lactams by the Staudinger reaction

Scheme 39 Synthesis of fused oxopiperazino-blactams by the Staudinger reaction

O N R'

OP

R1

O + OH

HX

R2 C

+ H

NaOAc, EtOH 80-100 °C (MW)

O

Et3N

N Bn

N

O

R'

Cl

R2

H+/D N

36%-99%

R2 H R1

O

R2 R1

OP

O

X CH2 C

R1

Bn

N

P = tert-butyldimethylsilyl (TBDMS) X = PhthN ; AcO ; Cl ; Benzyloxy

H N

H

X

N

O

R2 N

O

49%-78%

N R1

O H

Scheme 40 Synthesis of 3-spirocyclopropanated 2-azetidinones by a cascade three-component reaction

cis/trans Mixture of b-lactams have been obtained in 2007, by a new protocol involving a catalytic, one-pot reaction carried out in the absence of solvent [115, 116]. The Scandium (III) triflate catalyzed, at room temperature the condensation between silyl ketene thioacetals, readily obtained from 2-pyridyl thioesters, and imines in fair to good yields (45–71%), (Scheme 41). This procedure could be applied also to the stereoselective synthesis of enantiomerically pure azetidinones. Disubstituted b-lactams have been obtained with high trans diastereoselection in the reaction between N-phenylsulfenylimines, as nucleophilic partners in the Staudinger reaction, and acetoxyacetyl chloride (Scheme 42), [117].

Novel and Recent Synthesis and Applications of b-Lactams

129

1

R + OTBS

1

R

R

R

Sc(OTf)3 N

SPy

N O

PMP

PMP

Yields: 45-71%

Py = 2-pyridyl TBS = t-BuMe2Si PMP = 4-OMePh

Scheme 41 Synthesis of b-lactams by catalytic one-pot reaction

O

AcO

Ph

S

H N

N

AcO + 3 equiv.

N

O 3.5 equiv. (i-Pr) NET 2 Cl

S Ph N

CH2Cl2; Ar 40 °C; 6h.

O OAc

Scheme 42 Reaction between N-sulfenylimine and acetoxyacetyl chloride affording disubstituted b-lactams

R2

R1

R2

C

N O

R1

SPh

cis-b-lactam

R1

H H isomerization

C

N

O

SPh A

H

R2 H

R1

SPh

O

N

O

R2 N

B

SPh

trans-b-lactam

Scheme 43 Model for the relative stereoselectivity in the Staudinger reaction

The comparison of these results with those observed for the cycloaddition of alkoxyketene [118] suggested an exo approach of the ketene for the formation of the zwitterionic intermediate A (Scheme 43), that might directly affect ring closing to afford cis products. Alternatively, A might undergo a C=N bond isomerization to B prior to ring closing thus affording trans products. The use of less electron-releasing acetoxy substituent reduced the direct ring closure rate sufficiently to allow a complete C=N isomerization, thus affording pure trans products. b-Lactams have been obtained in 2008, by treatment of methyleneaziridines in THF with BnMgCl and CuI inducing ring opening of the aziridine at the C-3 to generate the metalloenamine, which was alkylated with BnBr. Subsequent addition of glacial acetic acid and then (benzyloxy)ketene (generated from BnOCH2COCl and Et3N) yielded b-lactam (Scheme 44), [119].

130

L. Troisi et al.

Scheme 44 Synthesis of substituted b-lactams by fourcomponent reaction

Bn N R

BnO

1) BnMgCl 2) BnBr

Bn

3) BnOCH2COCl/Et3N

N O

R

OC6H5 C6H5O H3CO

N3

1) PPh3, ClCH2CH2Cl 2) C6H5OCH2COCl, Et3N

N O OCH3

Scheme 45 Synthesis of 4-phenoxymethylene-b-lactam from (4-methyloxyphenyl)azides and phenoxyacetyl chloride

1-nosyl 3,3-dichloro-b-lactams were reported to be prepared using the Staudinger reaction between N-nosyl imines and dichloroketene [120]. N-Heterocyclic carbenes were demonstrated to be efficient catalysts for the Staudinger reaction of ketenes with N-aryl-, N-alkylcarbonyl imines [121]. Chiral N-heterocyclic carbenes gave the corresponding cis-b-lactams in good yields with good diastereoselectivities and excellent enantioselectivities (ee>99%). A one-pot cascade approach to 4-alkylidene-b-lactams from aryl azides and aryloxyacetyl chlorides has been reported. (4-Methyloxyphenyl)azides reacted with triphenylphosphine in 1,2-dichloroethane to form triphenylphosphazene, which was treated with phenoxyacetyl chloride and Et3N to afford 4-phenoxymethylene-b-lactam (Scheme 45), [122]. The synthesis of 4-aryl-3-(3-chloropropyl)azetidin-2-ones was reported to be performed by means of a Staudinger reaction between arylmethylideneamines and 5-chloropentanoyl chloride in the presence of 2,6-lutidine [123]. The [2+2] cycloaddition of aliphatic hydrazones derived from (2R,5R)-1-amino2,5-dimethylpyrrolidine to N-benzyl-N-(benzyloxycarbonyl)aminoketene was reported to take place affording the corresponding b-lactams in good yields when iPr2EtN was used as the base (Scheme 46), [124]. The reaction proceeded in all cases with excellent stereocontrol to afford exclusively products having the (3R) configuration. Temperature was observed to exert a strong influence on the cis/trans selectivity, allowing the obtention of single trans or cis cycloadducts in most cases, simply by performing the reactions at 80 C or room temperature, respectively. A new and efficient one-pot approach towards chiral 2-azetidinones has been reported to start from (2S)-chloro-1-propanol. The treatment of this latter with 5 equivalents of pyridinium chlorochromate in dichloromethane at room temperature afforded the (2S)-chloropropanal which treated with 1 equivalent of amine and 1.5 equivalents of MgSO4 yielded the (S)-N-(2-chloropropylidene)amines. Finally,

Novel and Recent Synthesis and Applications of b-Lactams Me Me

N R

CbzBnN

O N

H

+ CbzBnN

131 R

Toluene

C

reflux H

Me

N O

N Me

trans-(3R,4R)

Scheme 46 Synthesis of 3-amino-4-alkyl-2-azetidinones by [2+2] cycloaddion of aliphatic hydrazones to N-benzyl-N-(benzyloxycarbonyl)aminoketene

Scheme 47 One-pot synthesis of chiral 4-(1chloroethyl)-b-lactams from (2 S)-chloro-1-propanol

Cl

OH

1) 5 equiv. PCC 2) 1 equiv. R-NH2

BnO

H

H

Cl

N

3) 1.3 equiv. BnOCOCl O

R

treating the chloropropylideneamines with 1.3 equivalents of benzyloxyacetyl chloride, under Staudinger conditions, gave the corresponding b-lactams (Scheme 47), [125]. Although many attempts have been made to explain the Staudinger reaction, the nature of the relative stereoselectivity remains obscure. Several investigators have suggested different models to predict the stereoselectivity, but their proposals were in conflict to some extent [126–131]. An interesting contribution to the interpretation of the stereoselectivity in the b-lactam formation was done by Xu and coworkers [118]. They proposed a model based on a kinetic analysis of the cis/trans ratios of reaction product. Based on their results the origin of the relative stereoselectivity can be described as follows: a) the stereoselectivity is generated as a result of the competition between the direct ring closure and the isomerization of the imine moiety in the zwitterionic intermediate; b) the ring closure step is most likely an intramolecular nucleophilic addition of the enolate to the imine moiety, that is obviously affected by the electronic effect of the ketene and the imine substituents; c) electron-donating ketene substituents and electron-withdrawing imine substituents accelerate the direct ring closure, leading to a preference for cis-b-lactam formation, while electron-withdrawing ketene substituents and electron-donating imine substituents (EDG) slow the direct ring closure, leading to a preference for trans-b-lactam formation; d) the electronic effects of the substituents on the isomerization is a minor factor influencing the stereoselectivity (Scheme 48 and Fig. 2).

4.1.2

Gilman–Speeter Reaction

In a micro-review the group of Benaglia [132] reported in 2000 that S-thioesters could be used as versatile reagents for the efficient preparation of a variety of

132

L. Troisi et al.

R1

2

H C O

direct ring-closure k1

2

H

R +

ka

N R3

kd

1

R

H

R

H

R1

H

R2

N O

R3 cis-b-lactam

H N

O

k2'

R3 k2

R1

isomerization

O

H

R2 H

k3

H

R1

N R3

H

R2

N O

R3 trans-b-lactam

Scheme 48 Suggested model for the relative stereoselectivity in the Staudinger reaction

Competition between the direct ring-closure and the isomerization controls the relative stereoselectivity

EDG can accelerate direct ring-closure (increase k1)

R1 O

R2

H H

EWG can accelerate both direct ring-closure and isomerization (increase both k1 and k2)

N R3

Bulky group can slow the isomerization (decrease k2)

Fig. 2

b-lactams by the enolate/imine condensation reaction. The stereocontrol was provided by the stereocenter on the S-thioester or by the one on the imine nitrogen. Notwithstanding the numerous attempts made, varying also the cyclization conditions, it appeared very difficult to predict the trans/cis stereoselectivity as many different factors could concur in determining the stereochemical results. The condensation reaction of immobilized ester enolates with imines has been reported to give b-lactam resins in good yields and high diastereomeric excess (Scheme 49), [133]. Traceless cleavage from the linker system yielded the desired b-lactams. The cycloaddition of the N-2-methoxyphenyl aldimines with lithium ynolates (for a review see [134]) has been reported to give b-lactams enolates, that

Novel and Recent Synthesis and Applications of b-Lactams

133

N N

N

N

N N

1) LHMDS, –78 °C

1) TFA/CH2 Cl2

2 ) R2CH=NPh

2) THF/DMF, 60 °C

NH

Ar N

R O

O R1

O

OCH3

N H

1

R

O

NH Ar

O

R =H, Me, Ph;

Ph

O

Ar = aromatic group

N Ph

LHMDS = lithium bis(trimethylsilyl)amide

Scheme 49 Solid-phase synthesis of b-lactams via ester enolate-imine condensation

R2 R N OCH3

1

– 78 °C

+ LiO

H N

R2

1

OLi

R

THF R2

N OMP

R1 R2

OMP O

N OMP

(52-97%) R1 = Me, Bu;

R2 = Ph, Naph;

OMP = o-OCH3-Ph

single or mixture of diastereomers

Scheme 50 Cycloaddition of ynolates with N-2-methoxyphenyl imines affording b-lactams

reacted with one more equivalent of the imine to give b-lactams in good yields (Scheme 50), [135]. For activating the cyclization reaction a strategic role was played by the 2-position of the methoxy group linked to the imine and the R2 substituent should not be bulky. For instance, when the methoxy moiety was in 4-position and R2 = tert-butyl, the reaction proceeded very slowly or did not afford the desired product. In 2001, Sierra and coworkers have reported that ethyl 3-ferrocenylpropanoate reacting with an excess of lithium diisopropylamide (LDA) afforded an enolate that condensed with imine: the resulting reaction mixture contained the expected 2-azetidinone as a cis/trans mixture (3:1), and the unexpected 3-hydroxy b-lactam [136]. The ferrocene moiety was linked to the b-lactam ring at the C-3 position, (Scheme 51). In 2002, the condensation of the titanium enolate derived from 2-pyridylthio acetoxyacetate with N-4-methoxyphenylimine of (S)-O,O-cyclohexylidene protected glyceraldehyde has been reported to give (3S,4R,40 R)-b-lactam as a single product in 65% isolated yield (Scheme 52), [137]. A reactions sequence at C-3 and C-4 led in good yield to the b-lactam inhibitor of the serine protease prostatespecific antigen. The condensation of chiral furaldimines with lithium esther enolates has been reported as an efficient route to chiral furyl b-lactams [138]. The (4R)-b-lactam was formed with high diastereoselectivity.

134

L. Troisi et al.

Fe

Fe COOEt

Ph

H

LDA, THF, –78°C

Ph

HO

H

H

+

Fe Ph

N

N

N

PMP

O

PMP PMP = 4-MeO-Ph

PMP

O

(cis:trans = 3:1)

Scheme 51 Synthesis of C-3 ferrocene-substituted 2-azetidinones

O

O AcO

N

TiCl4 /Et3 N

+ O

AcO

H H O

H

O

O

O

RO

H3 CO

COOBn

N

N

SPy

H

OCH3

OCH3

Scheme 52 Stereoselective synthesis of b-lactam inhibitor of the serine protease prostate-specific antigen

OAc OAc

p-FC6 H5

O

O

Ar N

p-FC6 H4

O

N

N NS TiCl4

N Ar

NH

Ph

O

Ar p-FC6 H4 1) BSA 2)TBAF

Ph Ar = p-MeOC6 H4 CH2 -O-C6 H4TBAF = tetrabutylammonium fluoride

OAc

O

O

N N S

N O N S N

Scheme 53 Synthesis of enantiomerically pure b-lactams

The synthesis of b-lactams enantiomerically pure, via a multistep GilmanSpeeter type reaction [139] has been reported to be carried out with chiral oxazolidinones [140]. Titanium tetrachloride mediated condensation with imine gave an intermediate b-amino acyloxazolidinone, the major diastereomer of which could readily be purified by SiO2 chromatography. Silylation and fluoride catalyzed cyclization gave the final b-lactam (Scheme 53). The synthesis of monocyclic b-lactams via the ester-enolate imine condensation route has been reported to be carried out utilizing triazene esters (Scheme 54), [141]. Esters were attached to benzylamine resin by a triazene linker employing the respective diazonium salts. Immobilized ester-enolates were reacted with various imines to give polymer-bound b-lactams in different substitution patterns. Traceless cleavage from the triazene linker yielded the desired b-lactams.

Novel and Recent Synthesis and Applications of b-Lactams

135 N

1) BF3 Et2 O t-BuONO THF,–10°C

NH2 N

Ph +

H

Ph

N N

2) pyridine/DMF rt COOH

COO HNEt3 R1 Cl

N

H2 N

I

OCH3 O

CH3 N Ph O

C

N

Ph

N

N NH R1 R2 N O

R3

N

N TFA 5%

1) LiHMDS

CH2 Cl2

2) R2HC NR3 O

Ph

C

NH R1 R2

R1 O

C

N H

OCH3 O

N O

R3

Scheme 54 Solid phase synthesis of monocyclic b-lactam derivatives

Iridium-catalyzed reductive coupling of acrilates and imines has been reported to provide trans b-lactams with high diastereoselection [142]. The use of electrondeficient aryl acrylates resulted in improved product yields. The mechanism, proposed by the authors, started from an in situ generated iridium hydride reacting with the acrilate to provide an iridium enolate that, then, reacted with the imine to give a b-amido ester. Subsequent cyclization furnished the b-lactam and an iridium alcoxide. In 2007, Boyer and coworkers developed a complete study of the parameters that can influence the selective synthesis of b-lactam or b-aminoester during Reformatsky reaction between ethyl bromodifluoroacetate and various imines. It clearly appeared that by modifying the nature of the amine or the reaction conditions, it was always possible to inverse the b-aminoester/b-lactam ratio (Scheme 55). Moreover, high levels of stereoselectivity were obtained for gem-difluorob-aminoesters and gem-difluoro-b-lactams using either (R)-phenylglycinol or (R)-methoxyphenylglycinol [143].

4.1.3

Alper Reaction

The ring expansion of aziridines has been reported in 2001 as a well established protocol [144] for preparing b-lactams in a regioselective manner [145]. A variety of aziridines with different substituents and stereochemistry was subjected to cobalt carbonyl-catalyzed carbonylation to give b-lactams. The ring expansion to

136

L. Troisi et al. Ph OR1 N

F CO2Et

Br

+

F

F

R

Zn, THF

Ph

R

F N

reflux

OH

+

R1O

COOEt

O

1

R

Ph

R = H, CH3

NH

F

F

Scheme 55 Synthesis of gem-difluoro-b-aminoesters and gem-difluoro-b-lactams from ethyl bromodifluoroacetate R1

R2 N

CO (500 psi) DME, Co(CO)8 100 °C, 14 h

Ph

R1

R2 N

R2 Ph

R1

+

O

N

Ph

O

Scheme 56 Regioselective synthesis of b-lactams by cobalt-catalyzed ring expansion of aziridines n-Bu

n-Bu

n-Bu CO (500 psi)

N SiMe3

DME, Co2(CO)8 95°C, 16 h

O N

n-Bu

SiMe3

Scheme 57 Conversion of cis aziridines to trans b-lactams

b-lactams took place in the absence of an electron-withdrawing substituent and higher yields were always obtained for cis-aziridines, (Scheme 56). The regioselectivity of the reaction and then the b-lactam ratios, were affected by the nature of the substituents at the ring carbon atoms. A complete regioselectivity has been observed in 2002 in the carbonylative ring expansion of aziridines trimethylsilylsubstituted, using Co2(CO)8 as catalyst to give b-lactams (Scheme 57), [146]. [Lewis acid]+[Co(CO)4] complexes have been reported as a versatile class of catalysts for carbonylative ring expansion of aziridines to b-lactams [147]. For instance, catalysts such as [C5H5Ti(thf)2][Co(CO)4] and [(salph)Al(thf)2][Co (CO)4]1 [148] have been shown to efficiently carbonylate a variety of aziridines under mild conditions. Further, the authors proposed a mechanism for the CO insertion into aziridines. A theoretical investigation has been also reported for the [Co(CO)4]-catalyzed carbonylative ring expansion of N-benzoyl-2-methylaziridine to b-lactams (Scheme 58), [149]. Rhodium-complexed dendrimers, supported on a resin, have been reported to show high activity for the carbonylative ring expansion of aziridines with carbon monoxide to give b-lactams (Scheme 59), [150].

1

Salph = N,N0 -bis(3,5-di-tert-butylsalicylidene)phenylenediamine.

Novel and Recent Synthesis and Applications of b-Lactams Scheme 58 Proposed catalytic cycle for aziridine carbonylation

Me H

137

H H

N

Me H N

COPh

H

Co(CO)4

H

COPh Me H N

[Co(CO)4] PhOC

H H C

Co(CO)3

O

Me H N PhOC

CO

H H C O

Ph

Ph

Scheme 59 Carbonylative ring expansion of aziridines with rhodium-complexed dendrimers

G + N t-Bu

CO

N O

t-Bu

G = rhodium-complexed dendrimers

Theoretical studies have also been reported on the catalytic activity of the rhodium (I) in the carbonylative ring expansion of aziridines to b-lactams [151]. 4.1.4

Mitsunobu Reaction

b-Lactams have been reported in 2001 to be prepared on solid phase starting from serine, threonine, or other b-hydroxyacids derived from naturally occurring amino acids and a resin bound hydroxylamine [152]. The ring closure was carried out under Mitsunobu conditions, (Scheme 60). In 2005, a-benzylserine derivative [153] was reported to be converted into the b-lactone using PPh3 and diethyl azodicarboxylate, giving an aza-peptide, which was then subjected to Mitsunobu conditions to afford the 3-benzyl-b-lactam azapeptidomimetic (Scheme 61), [154]. N-Benzyloxy-4-aryl-3-(S)-hydroxybutanamide gave ring closure to b-lactam, via Mitsunobu reaction [155].

4.1.5

Kinugasa Reaction

In 2002, the coupling of alkynes with nitrones catalyzed by Cu(I)/bis(aza-ferrocene) has been reported to produce b-lactams enantioselectively [156]. The generation of

138

L. Troisi et al. FmocNHOH Cl

Piperidine

DIPEA

O

NHFmoc

DMF

(L)-Cbz-Ser-OH

Fmoc = 9-fluorenylmethoxycarbonyl DIPEA = N,N-diisopropylethylamine NMP = N-methylpyrrolidone R

DIPEA, NMP HO H N

NHCbz DEAD, PPh3

b-lactam peptidomimetics

O

NH2

O

R

O

N

NHCbz

O

O

Cbz = benzyloxycarbonyl DEAD = diethyl azodicarboxylate

Scheme 60 Solid phase synthesis of b-lactams under Mitsunobu conditions O OH

Ph

OBn

N N

O

Me

Ph OH Boc = tert-butoxycarbonyl DEAD = diethyl azodicarboxylate

BocHN

AlMe3

Ph3P DEAD

Me

O

O

BocHN

BocHN

N

OBn

Ph OH

O

H

H2N

Ph3P

O

DEAD O

Me

BocHN N Ph

N

OBn O

Scheme 61 Synthesis of 3-benzyl-b-lactam azapeptidomimetic

the b-lactam proceeded with excellent cis diastereoselectivity irrespective of the nature of the substituents linked to the alkynes or the nitrones (Scheme 62). In 2005, the Kinugasa reaction performed on N-propargyl nucleobases, such as adenine, uracil, and thymine derivatives, with diphenyl nitrone has been reported to produce cis- and trans-b-lactam nucleosides (Scheme 63), [157]. The 3-exo-methylene b-lactam was isolated only using the di-Boc protected adenine as substrate. The ynamide-Kinugasa reaction has been used for the highly stereoselective synthesis of chiral a-amino-b-lactams. The application of this reaction consists in the preparation of chiral a-amino-2-azetidinones starting from chiral ynamide (Scheme 64), [158].

4.1.6

Torii Reaction

In 2004, Troisi and coworkers have reported the palladium-catalyzed [2+2] carbonylative cycloaddition of imines to allyl halides of different structures to give b-lactams (Scheme 65), [159].

Novel and Recent Synthesis and Applications of b-Lactams R2

R

139 R2

R

H CuCl/ (+)chiral compex 10%

+

N -

N R1

O

R1

O

Yields: 42-91% ee: 67-93 Fe (+) chiral complex: N Fe

N

Scheme 62 Enantioselective catalyzed synthesis of cis b-lactams

B Ph

Ph

Ph

CuI/Et3N

+

B

H N

+

N

O

O

Ph

N

HN

HN ; O

B= H2N

Ph

O

O N

N O

Ph

; O

N

N

N H3C

N

Scheme 63 Synthesis of b-lactam nucleosides via Kinugasa reaction

O

O O

R1

O R

N

CuI, CH3CN

+

N O

Boc R1

N

H

2

R

Cy2NMe

R

+

N O

c-hex

HN

R2

O

N H

Scheme 64 Synthesis of a-amino-b-lactams via ynamide-Kinugasa reaction

The carbonylative [2+2] cycloaddition was performed also on chiral imines with allyl halides affording b-lactams with good stereoselectivity [160]. These results were obtained by performing the reactions in slightly different conditions than those used by Torii and coworkers. For instance, they reported the palladium-catalyzed cyclocarbonylation of allyl phosphate with imines in a stereoselective manner, depending on the imine used for the coupling, (Scheme 66), but they could not obtain any reaction product starting from allyl halides [161]. In 2006, the palladium-catalyzed carbonylative [2+2] cycloaddition of allyl bromide with heteroaryliden anilines was reported to afford 2-azetidinones

140

L. Troisi et al. R

N

1

R

Ph

R

R3

X

+ R2

Ph

R1

R

O N

Et3N, Pd(OAc)2, PPh3

R3

R

R1 R 2

Ph

R3

+ R

O N

O N

R1

Ph

R = Ph; CH2Ph; CH(CH3)Ph; CH(Ph)CH2OCH3

H

R2

H

CO (400 psi), 100°C

O N

R3

H

R1

H Ph

R2

R2

R1, R2, R3 = H; CH3; Ph; (CH2)2CH3

R3

Scheme 65 Stereoselective synthesis of allyl b-lactams

Ph

H N

R O

P(O)(OEt) 2

+

Ph

H

N

O

R

CO H

H

Ph

Ph O

N R

O

N

O

R

Scheme 66 Palladium-catalyzed cyclocarbonylation of allyl phosphate with imines

Ar'

Ar'

O

O

N

Ar'

H N

H N

Ar'

O

O

N Ar

Ar

Ar' Br

+ Ar

Ar

CO(400psi), 100°C

N H

+

O

Et3 N, Pd(OAc)2 , PPh3 N

Ar, Ar' = Ph; thiazolyl; benzothiazolyl; 2-pyridinyl; 3-pyridinyl

S

Ar O N

N

Ar

N

Ar

Scheme 67 [2+2] Cyclocarbonylation of allyl bromide with N-a-aza-heteroaryl substituted imines

N-phenyl substituted, with a heteroaryl moiety linked to the C-4 carbon, and an alkenyl group at the C-3 carbon [162]. The reaction proceeded with high stereoselectivity. A similar reaction performed with allyl bromide and N-a-aza-heteroaryl substituted imines has been reported to give partially b-lactams. This latter, for instance, underwent isomerization to the more stable a,b-unsaturated carbonyl compounds, and variously substituted pyrimidinones were also isolated (Scheme 67), [163].

Novel and Recent Synthesis and Applications of b-Lactams

141

In 2008, the same authors reported the synthesis of polyfunctionalized N-alkylb-lactams with high stereoselectivity in an efficient manner performing the same reaction with allyl bromide and heteroarylidene N-alkyl-amines. Interestingly, by modulating the type of alkyl group linked to the nitrogen atom, it is possible to influence the reaction stereoselectivity [164].

4.1.7

Intramolecular Cyclization

Electrochemical Induction In 2005, a diastereoselective synthesis of cis-3-alkyl-1-benzyl-4-ethoxycarbonylb-lactams has been reported to be developed by galvanostatic electrolysis of a solution of acetonitrile containing a tetraalkylammonium salt, as supporting electrolyte and N-(ethoxycarbonyl)methyl-N-benzyl-2-bromoalkylcarboxamides [165]. The electrogenerated cyanomethyl anion, at room temperature and under a nitrogen atmosphere, caused the cyclization of the substituted carboxamides. High cis/trans ratios were observed with all the substrates exploited, (Scheme 68). In 2006, electrochemically induced synthesis of b-lactams, by cyclization of haloamides, has been achieved in suitable solvent-supporting electrolyte solutions previously electrolyzed under galvanostatic control [166, 167]. The yields and the stereochemistry of the process were influenced by the nature of the R1–R4 substituents, by the solvent-supporting electrolyte solutions, and by the electrolysis conditions (Scheme 69). O Ph

Br

N

Et4N

CH2CN

R

O

Ph

N R

EtOOC

EtOOC

R = CH3; CH2CH3; CH(CH3)2; (CH2)3CH3; c -C5H9; c -C6H11

Scheme 68 Synthesis of disubstituted b-lactams by galvanostatic electrolysis

R3

R1

1) e Solvent-supporting electrolyte

X R3 2) R1

N R4

O

R2

N R2 X = Cl; Br R1 = CH(CH3)2; (CH2)3CH3; o -C6H11; Ph; CH3; H R2 = CH2Ph; p-CH3O-Ph; p-NO2-Ph O

Scheme 69 Electrochemical synthesis of b-lactams

R3 = CO2Et; CN; COPh; Ph; H R4 = CO2Et; H

142

L. Troisi et al. R1 R1

Z

N H

2

H

R

hn / Et2O

N2 + O

3

R

–15°C

Z

N H

H

H

N O

R1 2

Z

R

+ 3

R

H

N H

H

N O

R2 R3

(dr = 65:35 to 90:10)

Scheme 70 Stereoselective synthesis of b-lactams by photochemical rearrangement

More recently, electrochemically induced cyclization of linear bromoamides to b-lactams has been reported to be achieved in room-temperature ionic liquids [168].

Photo-Irradiation In 2001, diazoketones [169, 170] derived from suitably protected amino acids have been reported to be photochemically rearranged in the presence of imines leading exclusively to trans-substituted b-lactams with up to 84% yield [171]. Selectivities were dependent on the steric demand of the amino acid side-chain with dr ranging from 65:35 to 90:10, (Scheme 70). The photochemical reaction of alkoxychromium(0)carbene complexes and ferrocene mono- and disubstituted imines have been reported to form 2-azetidinones having one or two ferrocene moieties in good yields [136]. The chromium(0) carbene complex reacted smoothly with ferrocene imines that allowed to place ferrocene substituents at the N-1, and the C-4, or simultaneously at the N-1 and the C-4 positions of the b-lactam ring, with cis stereoselectivity (Scheme 71). By reacting the imine with the aminochromium(0)carbene complex, having the ferrocene group attached to the amino moiety, the corresponding 2-azetidinone was isolated as a cis-trans mixture (10:1), (Scheme 72). In 2002, a-oxoamides have been reported to be transformed into b-lactams via photochemical rearrangement [172]. Good results were obtained via irradiation of ionic and covalent chiral auxiliary-containing reactants in the crystalline state and in the interior supercages of zeolites (Scheme 73). The group of Podlech has reported that trans-substituted b-lactams (dr 70:30) can be prepared treating an Fmoc-protected leucine-derived diazoketone with a benzylidene-protected glycine ester in a photochemically induced Staudinger-type reaction [173]. Separation of the isomers, deprotection, and attachment of Fmocproline using the pentafluorphenyl ester activation protocol yielded the protected peptidomimetic in 93% yield, (Scheme 74). Deprotection and amidation resulted in formation of the trans-substituted b-lactam. In 2003, irradiation of isoxazolium anhydrobase in acetonitrile has been reported to give a novel b-lactam system such as a 4,5-dihydrofuroazetidinone (yield 60%) [174]. The mechanistic interpretation of this result involved a photochemical N–O bond cleavage, followed by the formation of a cyclopropanone intermediate (Scheme 75).

Novel and Recent Synthesis and Applications of b-Lactams

143

OR (CO)5Cr

hv

Me Et2O, CO

PMP N N

Fe Fe

Fe

N PMP

Fe

RO

Fe

Me H

PMP

N

O

PMP

Fe

Me H

RO

N

N O

Me H

RO

O Fe

PMP = 4-MeO-Ph

Fe

(cis >>trans)

Scheme 71 Synthesis of N-1 and C-4 ferrocene-substituted 2-azetidinones

Me N (CO)5Cr

Fe

Et 2O, hν, CO

Me

Ph

Fe

Me

Me N

PMP

N

Ph H N

PMP = 4-MeO-Ph

PMP

O

(cis:trans = 10:1)

Scheme 72 Synthesis of C-3 ferrocene-substituted 2-azetidinones

Scheme 73 b-Lactams synthesis via photochemical rearrangement of a-oxoamides

X

O N X

O

HO

hν N O

In 2004, Podlech and coworkers have reported some further advances in the photochemical treatment of Fmoc-protected diazoketones A and B, (Scheme 76), derived from leucine and alanine, respectively, with N-(benzylidene)glycine and leucine methyl ester to produce a mixture of the corresponding diastereomeric trans-substituted b-lactams [175].

144

L. Troisi et al.

Ph

H Fmoc

N H

N2

hν, –30°C

+

N

O

CO2CH3

H Fmoc

Et 2O

N H

H

Ph

N

HH

Fmoc

N H

CO2CH3

O

Fmoc = 9-fluorenylmethoxycarbonyl

+

Ph N

O

CO2CH3

Fmoc-Pro-OPfp

O

H H

C

N H N Fmoc O

Ph O

N

C

NH2

Scheme 74 trans-Substituted b-lactams synthesis by photochemically induced Staudinger reaction

Ph Ph

Me hν

COOEt Me

N

OEt OEt

O

Me

Ph

N

COOEt

O

O

Me O Me

N O

Me

O

OEt COOEt

OEt COOEt

O

Me

Ph N Me

O

Scheme 75 Synthesis of b-lactam system by photorearrangement of isoxazolium anhydrobase

Ph

R1 Fmoc

N H

O N2 O

A: R1= i-Bu B: R1= CH3

+

N

hν OMe

R2 Glycine: R2 = H Leucine: R2 = i-Bu

Et2O, -30 °C

Fmoc

R1H H N H

Fmoc

Ph O

+

N O

OMe R2

R1H H N H O

Ph O

N OMe R2

Scheme 76 Synthesis of b-lactam-containing dipeptide analogs

The moderate selectivity was in accordance with the bulkiness of the diazo ketone’s side-chains. a-Silylketoamides and a-stannylketoamides, irradiated in MeOH or MeCN with pyrex glass filtered light (l > 290 nm), have been converted into b-lactams alongwith other products, including oxazolidinones and a-hydroxamides (Scheme 77), [176].

Novel and Recent Synthesis and Applications of b-Lactams

145

M M

H

R

O

C

C

N

C O

H

H-atom

R

OH

C

C

N

C

hν

O

CH3OH or CH3CN

H

H 1

R

HO R

R

H+ R

M = SiMe3; SnBu3

OH

C

C

N

C

+

N

M O

1

R

N O

R1

OH

O

R

1

N

+ R R1

OCH3

O

R1

O

Scheme 77 b-Lactam-forming photochemical reaction starting from a-silyl- and a-stannylketoamides

Me Ph

Me

H S

O

N

hν Ar

Ph

Ph

Me Ph

SH

SH Ar *

O

N

O Ph

* N

Ar

Ph

Scheme 78 Photochemical b-lactam synthesis by g-hydrogen abstraction by a thiocarbonyl group

Two mechanisms were proposed for the b-lactam-forming photoreactions, one radical involving excited-state H-atom abstraction while the other following a sequential single-electron-transfer (SET)-proton-transfer route. In 2008, Sakamoto and coworkers have reported the synthesis of optically active b-lactams via photochemical intramolecular g-hydrogen abstraction reaction of thioimides [177]. This reaction provides the first example of a chiral-memory effect for the photochemical g-hydrogen abstraction reaction of thiocarbonyl or carbonyl compounds, and a useful synthetic methodology for preparing optically active b-lactams (Scheme 78). Ultra-Sound Irradiation In 2004, the Reformatsky reactions of imine, a-bromoester, zinc dust, and a catalytic amount of iodine in dioxane under high intensity ultrasound (HIU) irradiation have been reported to afford b-lactam and the corresponding b-aminoester [178]. The reactions were performed in short reaction times and high yields of both products or a mixture of the two products were obtained, depending on the starting imine and on the a-bromoester (Scheme 79). Lewis-Acid Catalysis A Lewis acid-catalyzed cyclization of 2-aza-3-trimethylsilyloxybuta-1,3-diene has been reported in 2003 and the stereochemical differences with the uncatalyzed

146

L. Troisi et al. R2 N +

R1

H

R2

R4

HIU

N

O

R3

R4

and/or

CO 2 Et

BrZn

N

R4

H

R3

R1

R3

OEt

R1

O

R2

Scheme 79 Reformatsky reaction of imines and a-bromoesters affording b-lactams and b-aminoesters

O

O

R

N Ph

O

O

N

N Si

Si

H

O

Ph

O

N

R

N

BF3 Et2O

Ph

O

O

N BF3

Si

BF3

O R

O

O

O

O

N

N

R

Ph

+

Ph N

N O

R

H

O

H

Scheme 80 Lewis acid-catalyzed synthesis of trans-b-lactams

cyclization have been discussed [179]. The data reported showed that in analogy to the uncatalyzed reaction, diastereomeric trans-azetidinones were obtained (Scheme 80).

Base Catalysis In 2001, 3-unsubstituted 4-alkyl-4-carboxy-2-azetidinones have been reported to be prepared by base-assisted intramolecular alkylation of N-benzyl-N-chloroacetyl amino acid derivatives [180]. N-benzyl or N-(p-methoxybenzyl) amino acid derivatives in THF, treated with propylene oxide and chloroacetyl chloride afforded the N-chloroacetyl amino acid derivatives. The treatment of the latter in CH3CN with Cs2CO3 (or NaH) produced the intramolecular cyclization of 4,4-disubstituted b-lactams, (Scheme 81). An asymmetric synthesis of a,b-disubstituted b-amino esters and b-lactams has been reported [181]. Chiral b-amino esters were prepared by a stereocontrolled Mannich reaction with enolizable imines using an enolate derived from

Novel and Recent Synthesis and Applications of b-Lactams CO2R2

R1

ClCH2COCl

HN R3

CO2R2

R1

Propylene oxide/THF

N Cl

R

3

147 R1 Cs2CO3 (or NaH) CH3CN, rtN

CO2R2 R

O

3

O

Scheme 81 Synthesis of 4,4-disubstituted b-lactams by base-assisted intramolecular alkylation

OH OCH3

OH N Ph

N Ph

1) LDA/THF –78 °C NH

+ R

O

R O

2) ZnCl2

N

LHMDS

H3CO

O N R OCH3

Scheme 82 Asymmetric synthesis of b-lactams by base-promoted cyclization of b-amino esters

30%mol CuBr 30%mol TPA

Br O

N R

CH2Cl2, rt

Br

DBU/CH2Cl2

N O

N R

O

R

Scheme 83 Synthesis of b-lactams by bromo-enamides radical cyclization

(S,S)-(+)-pseudoephedrine propionamide as chiral auxiliary. The obtained b-amino esters were subjected to a reported base-promoted cyclization [182, 183] affording the b-lactams in good yields and as unique detectable stereoisomer (Scheme 82). Bromo-enamides have been reported to give radical cyclization in excellent yields (82–99%) to b-lactams using catalytic amounts (30%) of tripyridylamine (TPA) copper(I) halide complex [184]. The b-lactam developed under mild conditions via 4-exo bromine atom transfer and subsequent elimination of the tertiary bromide that could be readily achieved by reaction with DBU (Scheme 83). In 2002, 3,5-trans-(+)-(3R,5R)-3-carbomethoxycarbapenam has been reported to be prepared via a known cyclization reaction [185] starting from enantiopure carboxy pyrrolidine with di(2-pyridyl)disulfide, triphenylphosphine, and triethylamine in refluxing acetonitrile for 8 h (Scheme 84), [186].

148

L. Troisi et al.

O OMe HO

N H

O

H

(2-PyS)2, PPh3 Et3N

CH3CN, reflux, 8h

N O MeO2C

H

Scheme 84 Synthesis of 3,5-trans-(+)-(3R,5R)-3-carbomethoxycarbapenam starting from an enantiopure amino acid

The starting enantiopure pyrrolidine was prepared from 3-hydroxypyridine following the five-step sequence of the established route [187–189] and the piperidine-pyrrolidine ring-contraction reaction [190, 191]. A general approach towards the asymmetric synthesis of amino acid derived 4-alkyl-4-carboxy-2-azetidinones has been described [192]. The (+)- or ()-10-(N, N-dicyclohexylsulfamoyl)isoborneol was used as chiral auxiliary in the intramolecular cyclization of N-(p-methoxybenzyl)-N-chloroacetyl Phe and Ala derivatives for the stereocontrolled base-catalyzed construction of the b-lactam ring (Scheme 85). In 2003, dicarboxamides E and Z derived from fumaric and maleic acids, respectively, were reported to yield the same product, a single syn diastereomer of the b-lactam, when treated with LDA at 0 C (Scheme 86), [193]. The N-alkyl-N-chloroacetyl amino acid derivatives [180] have been reported to undergo the base-promoted cyclization to b-lactams [194]. The stereoselectivity, due to memory of chirality, was highly dependent on the substituents of the starting amino acids. The amino acid side-chain (R3) appeared to be the principal stereodirecting element, offering additional support for the explanation that the memory of chirality was caused by a hindered rotation around the C–N bond (Scheme 87). Treatment of isonicotinamide with LDA at 40 C and addition of an acylating or alkylating agent were reported in 2005 to form in good yield, a dearomatized product with spirocyclic b-lactam structure (Scheme 88), [195] In 2007, the desulfinylation and deprotonation of chiral 10 -aminodioxolanones followed by the based-induced cyclization was reported to afford the corresponding chiral tetrasubstituted 3-hydroxy-2-azetidinones (Scheme 89), [196, 197]. In 2008 Yang and coworkers have reported an efficient synthesis of substituted a-alkilidene-b-lactams via a NaOH- promoted intramolecular aza-Michael addition of a-carbamoyl, a-(1-chlorovinyl) ketene-S,S-acetals and subsequent nucleophilic vinylic substitution reaction in alcoholic media (Scheme 90), [198].

4.1.8

Heterocyclic Rearrangement

In 2002, alicyclic cis-b-amino acids have been reported to react with cyclohexyl isocyanide and substituted benzaldehyde via a liquid-phase Ugi four-center

Novel and Recent Synthesis and Applications of b-Lactams

149 O

O R1

R1

COF

R1

C

R*OH

OR* NH2

NH

NH Z

Z

1) Pmb

O R1

C

H 2/Pd-C

OR*

C

ClCH2COCl

OR* N

2) NaBH4

O R1

C OR* NH

CH2Cl

Pmb

Pmb O

Base

COOR*

COOR*

R1

R1

ee = 40-80

+ N

a>b if R* = (+)

N O

Pmb

O

Pmb

a

a
b

Pmb = p-methoxybenzaldehyde R* = (+)- or (-)-10-(N,N-dicyclohexylsulfamoyl)isoborneol

Scheme 85 Stereocontrolled construction of the b-lactam ring O H

O

N

O

Ph N

1) LDA, 0°C Ph

N O

2) NH4Cl Ph

N

Ph

Scheme 86 Selective synthesis of syn b-lactams from E and Z dicarboxamides

three-component reaction to afford b-lactams derivatives [199]. The products were isolated after 24 h at room temperature from the mixture in methanol, in moderate to good yields. Plausible reaction intermediates have been proposed (Scheme 91).

150

L. Troisi et al. R3

CO2R1 N

Cl

Cl

R2

R3

R1O

Base Solvent

O

O

R3

R1 O

R2

O

N

O

N R2

O Cl Base = Cs2CO3, BTPP, NaOH Solvent = MeCN, DMF, CH2Cl2 R3

>

N O

R3

CO2R1

N O

R2

CO2R1

R2

Scheme 87 Stereoselective synthesis of b-lactams from amino acid derivatives

O

O

O t-Bu

LDA (3 eq)

N N

Ph

t-Bu

–40 °C, 30'

N

Li

t-Bu

E-Cl

N

N N

E

Ph

E = CO2Me, CO2Bn, Me, Bz

Li

Ph

O E

N

N Ph

Scheme 88 Synthesis of spirocyclic b-lactams by dearomatizing cyclization reaction

O S HN R R3

O

R2 O

O

R

O HCl 2N MeOH/Et2O

R2 O

O 1

1

R

Bu

NH2 R3

R

LHMDS THF, HMDA

Bu

R3 R2

HO R N O

H

LHMDS = lithium bis(trimethylsilyl)amide HMDA = hexamethylendiamine

Scheme 89 Deprotection of 10 -aminodioxolanones to give the corresponding b-lactam

t-Bu

Novel and Recent Synthesis and Applications of b-Lactams Cl

O R1 N H R2S

Cl

OH-

Me

SR2 SR2

151 OR3 HOR3

Me

N

N

SR2

O

SR2 SR2

O

R1

R1

Scheme 90 Synthesis of a-alkilidene-b-lactams from a-acyl, a-carbamoyl ketene-S,S-acetals O

CHO

NC

COOH + NH2

O N

CH3OH

+

N H

rt X X

NC

COO

O O

NH

N N H X X

Scheme 91 Liquid-phase synthesis of alicyclic b-lactams via Ugi three-component reaction

A b-lactam ring substituted by a thiazole moiety has been reported to be formed simultaneously and under mild condition during the course of a multicomponent reaction [200]. When the 3-dimethylamino-2-isocyanoacrylate was reacted with the aldehyde in the presence of a b-aminothiocarboxylic acid, substituted 1-thiazole-2yl-methyl-azetidin-2-one was smoothly formed (Scheme 92). Plausible reaction intermediates have been proposed. In 2003, the thermolysis of 3,4-cis ring-fused 5-spirocyclopropane isoxazolidines, in the presence of a protic acid (TFA) at 70–110 C, has been reported to yield 3,4-cis ring-fused azetidin-2-ones with concomitant extrusion of ethylene, in good yields (Scheme 93), [201]. Analogously, in 2004, it has been reported that the treatment of bis-spirocyclopropanated isoxazolidines [202–207] with TFA in acetonitrile furnished the 3-spirocyclopropanated b-lactams in 75–96% yields [208]. The b-lactamic ring was also formed by the acidic thermal rearrangement of spiro[cyclopropane-1,50 -isoxazolidines], [209]. The rearrangement was almost instantaneous at 90 C, as the starting material was completely converted after 2 min. In 2008, a very mild reductive N–O bond cleavage of fluorinated isoxazolidines was reported to provide a novel and general entry to b-lactams and ester of b-amino acids containing a trifluoromethyl group (Scheme 94), [210].

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L. Troisi et al.

N

O +

H3COOC

CN

N

+ O

H

O

SH

H2N

S

N COOCH3

O

N HS

N O S

N

N COOCH3

N CN

H3COOC

O

HN S

N N

O

COOCH3

NH

S N

(H3C)2N

COOCH3

Scheme 92 Simultaneous assembly of b-lactam and thiazole moiety by a multicomponent reaction

N

H

O

N

H TFA

H

H

110°C 40 min

N

O

N

Z

Z

Scheme 93 Selective ring contraction of 5-spirocyclopropane isoxazolidines mediated by acids

R3

Scheme 94 Synthesis of a-trifluoromethyl-b-lactams via reductive cleavage of isoxazolidines

R1 R2 F3C

N

O

H2, Pd/C

F3 C X

R2

R1

NHR3

+

ROH X F F

R2 R1 N

O

R3

F3 C

X

CO2R

Novel and Recent Synthesis and Applications of b-Lactams

4.2

153

Other Reactions

In 2000, the metal-mediated carbonyl propargylation or allenylation of enantiomerically pure azetidine-2,3-diones [211] has been reported to afford stereoselectively functionalized 3-substituted 3-hydroxy-b-lactams (Scheme 95), [212]. A new protocol for the stereoselective synthesis of b-lactams [213] has been reported to be performed by a conrotatory ring closure of 1-halo-3-aza-4-alkyl-1, 3-dienes, previously prepared by Staudinger methodology, (for the synthesis and chemistry of N-silyl imines see [214]; for [2+2] cycloaddition of N-silyl imines and ketenes see [215]) in refluxing toluene (Scheme 96). When R was a stereogenic center, of the four possible stereoisomers only the two trans-3-halo-isomers were obtained. A modification of the so-obtained b-lactams [216] has been also reported consisting in a dehalogenation procedure giving rise to 3-unsubstituted b-lactams, (Scheme 96). The Mn(III)-mediated 4-exo-trig cyclization of enamides to b-lactams has been reported to be carried out with good diastereoselection by placing suitable chiral substituents on the nitrogen atom (Scheme 97), [217].

O

O

O

Br N O

R1

O

OH

R2 M THF/H2O/NH4Cl

R2

R2 OH

O +

N O

O

O

N O

R1

R1

M = Zn, Sn, In R1 = p -MeOPh; allyl; propargyl R2 = Me; Ph

Scheme 95 Metal-mediated carbonyl propargylation or allenylation of pure azetidine-2,3-diones

SiMe3 X

R N

TMSO

X

R

Me3Si

Si H

R

SiMe3

Toluene reflux

NH O

X = Cl, Br R = Ph; p-NO2Ph; p-ClPh; p-MeOPh;

Toluene, 100 °C OTIPS

NH O

OTBDMS

; TIPS = triisopropylsilyl TBDMS = tert-butyl dimethylsilyl

Scheme 96 Stereoselective synthesis of 3-unsubstituted b-lactams by conrotatory ring closure of 1,3-diene derivatives

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L. Troisi et al. O

Ph

MeO N

Mn(III)

Ph

MeO N

R2 R1

O

Ph

O

Ph

R2 R1

O

H

H 4-exo-trig Ph

O

O

Ph

MeO N

R2 R1

O

Ph Ph

MeO +

N

R2 R1

O

H

H Mn(OAc)3

Ph OAc Ph

O MeO N

R2 R1

O

Ph

O

OAc Ph

MeO +

N

R2 R1

O H

H

Scheme 97 Mn(III)-mediated cyclization of enamides to b-lactams H

H H HO O

COOMe NH2 OH

DCC, 2 equiv.

H

HO

MeCN, reflux 1.30h

CH2COOMe

NH O (49%)

DCC = dicyclohexylcarbodiimide

Scheme 98 Synthesis of b-lactams from substituted b-amino acids

b-Lactam structures have been reported to be constructed by treatment of substituted b-amino acids with dicyclohexylcarbodiimide (DCC) in refluxing acetonitrile (Scheme 98), [218]. The substrates were prepared by a multistep synthetic protocol previously reported [219]. In 2001, 3-(benzylamino)-3-phenylpropanoic acid [220] has been reported to give b-lactam in good yield, by cyclization reaction in the presence of phenylphosphonic dichloride and triethylamine in refluxing benzene (Scheme 99), [221]. b-Enaminoketoesters [222] have been reported to be used for preparing ()2-azetidinones by a simple route (Scheme 100), [223]. b-Enaminoketoesters were reacted with benzyl chloroformiate in the presence of sodium hydride to furnish the N-protected enaminoketoesters. The reduction of the carbonyl group with NaBH4 in methanol was followed by transformation of the derived hydroxyl group into the corresponding tert-butyl dimethylsilyl ether by

Novel and Recent Synthesis and Applications of b-Lactams Scheme 99 Synthesis of b-lactam by b-amino acid cyclization

R

NH O

155 R

PhP(O)Cl2, Et3N

Ph

O N

Benzene

OH

Ph

( )

( )

R = Ph; p-Ph-Ph; o-CH3O-Ph-; CH3(CH2)3-

O

O Me

NH2

MeO2C

CO2R

Me

1) ClCO2CH2Ph 2) NaH/THF 0°C

MeO2C

H

O Bn N

O CO2R

1) NaBH4/CH3OH 2) TBDMSCl, imidazole rt

H

TBDMSO Me

O CO2R

MeO2C

H2, Ni Raney EtOH, rt

TBDMSCl = tert-butyl dimethylsilyl chloride TMSCl = trimethylsilyl chloride TBDMSO

H H

TBDMSO CO2R

NH

H

H

CO2R

+ NH

O

O (75%)

(70%)

1) TMSCl, Et3N 2) t-BuMgCl CH2Cl2, 0°C

TBDMSO Me H MeO2C

H

O Bn N

TBDMSO Me N H + H H

CO2R (63%)

H N H H

MeO2C

CO2R (7%)

Scheme 100 Synthesis of ()-2-azetidinones starting from b-enaminoketoesters

N2

Rh2(OAc)4

N COOEt O

CH2Cl2 rt

N O COOEt

Scheme 101 Catalytic synthesis of b-lactam fused enediynes

reaction with tert-butyl dimethylsilyl chloride (TBDMSCl) in the presence of imidazole. The reduction of the carbon-carbon double bond was easily achieved by catalytic hydrogenation in the presence of Raney Nickel W-2. Finally, treatment with trimethylsilyl chloride (TMSCl) and triethylamine involved the formation in situ of the N-trimethylsilyl derivatives which, treated with tert-butyl magnesium chloride, gave the expected ()-2-azetidinones. A methodology was reported in 2002 for the synthesis of b-lactam fused enediynes [224]. When a solution of a diazo enediyne [225] was treated with a catalytic amount of rhodium acetate for 30 min, the b-lactam fused enediyne was obtained as the only product, (Scheme 101). The yield in the carbene insertion step was about 50%, the rest being decomposition products. Chiral vinyl ethers attached to a Wang resin through the p-oxyphenylsulfonyl linker, have been reported to give the [2+2] cycloaddition reaction with chlorosulfonyl isocyanates (CSI) [226]. The intramolecular alkylation of the b-lactam nitrogen atom gave mixtures of the corresponding diastereomeric clavams or oxacephams, (Scheme 102).

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L. Troisi et al.

R SO2O

R

1) CSI/Na2SO3

R

2) Red-Al

O

SO2O

CSI = chlorosulfonyl isocyanate

O

H

O

B

N

H N

O

O

H

R

SO3

H

H

H

O

N O

Scheme 102 Solid-phase synthesis of clavams and oxacephams trough b-lactam intermediate

OAc OAc O Ar

1) AgClO4/CH3I NHOBn

N

2) K2CO3

O

SPh

OAc OAc SPh Ar

CH3 O

NHOBn

1) AgClO4/CH3I 2) K2CO3

H

Ar OBn H

H

Ar

CH3

N O

OBn

Bn = benzyl

Scheme 103 Synthesis of b-lactams by intramolecular SN2 reaction

In 2003, b-hydroxyacetyl-a-thioalkylamides have been reported to give a cyclization reaction to b-lactams through an intramolecular SN2 mechanism (Scheme 103), [227]. The b-lactams were obtained in a diastereomerically pure form. Starting from the commercially available (+)-3-carene, the cycloaddition of chlorosulfonyl isocyanate [228] has been reported to furnish the enantiomeric b-lactam in a regio- and stereoselective manner [229]. Treatment of the b-lactam with di-tert-butyl dicarbonate resulted in N-Boc b-lactam, that could be readily opened under mild conditions (Scheme 104). The reactions of 1,3-thiazolium-4-olates with aliphatic aldehydes carried out in refluxing benzene or dichloromethane, have been reported to produce a series of highly functionalized b-lactams and thiiranes at the same time [230]. The critical issue of the stereoselection was discussed in terms of the endo and exo approaches (respective to the aldehyde substituent) to any enantiotopic face of the heterocyclic dipole. Such orientations involved either the Re or the Si faces of the prochiral aldehydes (Scheme 105). In 2004, b-lactams were obtained by the cyclization of b-amino esters [231]. The treatment of the latter with 10% Pd-C in the presence of ammonium formiate for 3 h, followed by silylation of the resulting hydroxyl esters gave the silyloxy esters that were subjected to cyclization using the Breckpot reaction [232, 233] to give the b-lactams (Scheme 106).

Novel and Recent Synthesis and Applications of b-Lactams CH3 1) CSI/Et2O

157 CH3

H Boc2O

N

2) Na2SO3, KOH

Et3N

O

H

Boc

N O

H

CSI = chlorosulfonyl isocyanate LiOH/H2O CH3

Boc N H COOH

H

Scheme 104 Regio- and stereoselective synthesis of b-lactams by cycloaddition reaction

Bn Ar N O

N Me S Ph

Si face

endo approach

O R H

Bn

N

Ph O

endo cycloadduct

H R N Ar

O

exo approach

O H

Bn S N Me Ar N O R C Ph H O

Bn

N

R

Ar

N Me O S H Ph R

O R H N Ph Ar O

S

exo cycloadduct

N

Bn

Me

N Me S Ph

Re face

N Me O S R Ph H

O S

Bn Ar N O

Bn

Me Bn S N Me Ar N O H C Ph R O

O

N Ar

Bn = benzyl

Scheme 105 Mechanism suggested for the formation of highly functionalized b-lactams

Et O OMe

OTBDMS

Et NHOBn

1) 10% Pd-C/HCO2NH4

O

2) TBSCl/imidazole 3) EtMgBr

NHBn

N O

OBn

Bn = benzyl TBDMSCl = tert-butyl dimethylsilyl chloride

Scheme 106 Synthesis of b-lactams by cyclization of b-amino esters

Quaternary b-formyl a-amino acid derivatives have been converted into spiro b-lactams in excellent yield, using oxidation followed by simple base and acid treatment (Scheme 107), [234].

158

L. Troisi et al. Ar O HN H

CO2Et

1) NaClO2/NaH2PO4 2h

Ar

O N

2) NaOH (1 eq) 3) HCl (1 eq)

CO2Et 80%

Scheme 107 Synthesis of spiro b-lactams starting from formyl amino acid derivatives

HO

O

O

DABCO

+

N O

OH H O

EWG

O

N

MeCN, –20 °C O

R

R

EWG = COMe; CN; CO2Me; SO2Ph R = 4-MePh; 2-propenyl; 3-butenyl; etc. DABCO = 1,4-diazabicyclo[2.2.2]octane

Scheme 108 Baylis-Hillman reaction of enantiopure azetidine-2,3-diones

O

O +

N O

R1 OH H O

HO

R

In/NH4Cl

R1 Br

THF/H2O

O

N O

R

Scheme 109 Synthesis of a-allenols from enantiopure azetidine-2,3-diones

The Baylis-Hillman reaction of optically pure azetidine-2,3-diones [235, 236] with methyl vinyl ketone in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) in acetonitrile at –20 C for 1 h have been reported to give functionalized allylic alcohols, having the b-lactam scaffold, in good yields (80%) and complete diastereoselectivity [237]. In terms of achieving good yields with a reasonable rate of reaction, 50 mol% of DABCO seemed to be the catalyst amount of choice for this reaction. No significant solvent effect was observed in the overall yield (Scheme 108). a-Allenols, containing the 2-azetidinone ring, have been reported to be obtained by reacting the same azetidine-2,3-diones with propargyl bromides in the presence of Indium as catalyst (Scheme 109), [238]. In 2005, the group of Choi has reported a catalytic system based on [RuCl2 (p-cymene)2] that produced the stereoselective cyclization of a-diazoacetamides by intramolecular carbenoid C-H insertion and afforded b-lactams in excellent yield (>97%) with cis-stereoselectivity (>99%), (Scheme 110), [239].

Novel and Recent Synthesis and Applications of b-Lactams

O R1

OEt N2

R1

EtOOC

O

N R2

159

[RuCl2(p-Cymene)]2 N

Toluene, 70 °C

O

R2

Scheme 110 cis-Stereoselective synthesis of b-lactams by catalytic systems

Scheme 111 Synthesis of 1,3,4,4-tetrasubstituted b-lactams from different amino acids

HN Me

COOMe Me

Pmb

Cl (S) COOH

Cl (R) COOH

Me 1 R

Cl (S)

Cl (R)

N (S) COOMe

O

N (S) COOMe

O

Pmb

H Me (R) O

Me 1 R

Pmb

R1 COOMe (R) N Pmb

R1 COOMe (S) N Pmb

H Me (S) O

Pmb = para-methoxybenzaldehyde

Scheme 112 Synthesis of 4-alkylidene-2-azetidinones

Br Br

NHR(Ar) O

CuI THF, reflux

Br

N O

R(Ar)

The reaction became enantioselective in the presence of a chiral pyridine-bis(oxazoline) ligand yielding trans-b-lactam with ee of 50%. In 2007, 1,3,4,4-tetrasubstituted b-lactams have been synthesized with exceptional stereoselectivity from amino acids [240]. The stereochemical control of the cyclization to the four-membered ring was fully dictated by the configuration of the N-2-chloropropionyl group in the linear precursor (Scheme 111). In 2008, Zhao and coworkers have reported a general and highly efficient method for the synthesis of 4-alkyliden-2-azetidinones via copper-catalyzed intramolecular C–N coupling of 3-bromobut-3-enamides [241]. Under Cu(I) catalysis

160

L. Troisi et al. Ph

CHO

chiral-N-heterocyclic carbene 5% mol.

Ph

DBU, CH2Cl2, 25 °C 50% conv.

O

N O

Mes

Ph

CHO * *

* + O

N

N O

Mes

Mes

cis-(-); 34% yield 64% ee

Scheme 113 Chiral N-heterocyclic carbene-catalyzed kinetic resolution of cis-4-formylb-lactams

Ar N O

Ph

Ar 10 mol % CuBr Toluene, 100 °C p-anisyl

N O

Ar

Ph

+ p-anisyl

N O

p -anisyl

(2:1)

Scheme 114 Five-bond-cleavage rearrangement of O-propargyl oximes to b-lactams

the 4-exo ring closure was found to be fundamentally preferred over other modes of cyclization (Scheme 112). Li and coworkers have previously found that in the presence of an N-heterocyclic carbene catalyst cis-4-formyl-b-lactams underwent the ring expansion reaction to afford succinimide derivatives [242]. More recently, they reported the kinetic resolution version of this transformation attempted with a chiral N-heterocyclic carbene (Scheme 113), leading to cis-4-formyl-b-lactams with moderate ee of 64% [243]. An unprecedent skeletal rearrangement of O-propargyl oximes has been reported to go via copper complex catalysis, involving cleavage of five different covalent bonds (C=N, N–O, C–O, C–C, and CC) and leading to reorganization into b-lactams in good to excellent yields (Scheme 114), [244].

4.3

Structural Modifications to the N-1, the C-3, and the C-4 Positions

The modification of the substituents linked to the 2-azetidinone ring can afford a new family of b-lactams having, often, a stronger and more efficient biological and pharmacological activity. A brief list of the more significant modifications performed on the groups linked at the N-1, the C-3, and/or the C-4 positions are reported in this paragraph, with the figures related to the new structures obtained.

Novel and Recent Synthesis and Applications of b-Lactams Nu Nu

161

PhO2S X

R1

Ph N

N R2

O

O

Nu = C6H5OMe; C6H4(OMe)2 C6H5OH; C10H7OMe

X = Cl, Br, I

I

O C R

II O

H

O N

R

N O

COOEt III

Ph

N O IV

SiMe3 SiMe3

Fig. 3

In 2000, a route to novel C-3 substituted 2-azetidinones (I, Fig. 3) has been reported involving a reaction of a b-lactam carbocation equivalent with active aromatic nucleophiles in the presence of a Lewis acid [245]. 3-halo-3-(phenylsulfonyl)-4-phenylazetidinones (II, Fig. 3) have been obtained by N-halosuccinimides [246]. The radical cyclization of N-acrylate-4-(2-bromoethyl)azetidin-2-ones [247] has been reported to form a bicyclic b-lactam (III, Fig. 3). The synthesis of a-branched 3-amino-4-unsubstituted b-lactams (IV, Fig. 3) could be performed efficiently via an asymmetric alkylation of a single 3-oxazolidinyl azetidin-2-one [248]. The addition of lithium bis(methylenecyclopropyl)cuprates to acetoxy azetidinones has been reported to give methylenecyclopropyl azetidinones (Fig. 4) which could be further converted into various N-functionalized b-lactams [249]. 4-Alkenyl-2-azetidinone systems could be converted to bicyclic b-lactam carboxylic esters and hence carboxylic acids (Fig. 5) via tandem Ireland-Claisen rearrangement and subsequent alkene metathesis [250]. The addition of nucleophiles to azetidinones has been reported to afford penems, carbapenems, and aza analogs of cephem (I, II and III, respectively, Fig. 6), [251]. In 2001, tetracyclic 3.6.6.4 ring systems fused to a b-lactam (IV, Fig. 6) have been reported to form via 6-exo-trig radical cyclization [252]. Carbapenams (V, Fig. 6) have been produced by warming a solution of b-lactams having a propargyl carbonate moiety linked at the C-4 position [253]. Carbapenems (VI Fig. 6) have been, instead, obtained when a solution of b-lactams having an allyl carbonate substituent at the C-4 was warmed [254]. (R)-40 -Alkoxy-azetidin-2-one has been reported to be transformed into 5-oxacepham (VII, Fig. 6) by intramolecular alkylation of the b-lactam nitrogen atom [255].

162

L. Troisi et al.

TBSO

H

TBSO

H

H

N O

N H

TBSO

H

O

OH

H

H N

O

COOBn

Cl COOBn

Bn = benzyl TBS = tert-butyldimethylsilyl TBSO

H

TBSO

H N

O

H

H N

SPh

O

Fig. 4

N O

Fig. 5

COOH

b-Lactams like structures VIII and IX of Fig. 6 have been obtained from a-benzyloxy a-CF3-b-lactams by the enolate [1, 2]- and the ortho-[2, 3]-Wittig rearrangements, respectively [256]. Optically pure cis-2-azetidinone-tethered dienes have been reported to undergo intermolecular Diels-Alder reaction with a variety of symmetric and unsymmetric dienophiles [257] providing a synthetic entry to various types of racemic and homochiral 1,3,4-trisubstituted 2-azetidinones (I, Fig. 7). Starting from substituted 2-azetidinones, a family of tribactams (II, Fig. 7) has been reported to be prepared by using two main steps: an intramolecular metathesis reaction and a Diels-Alder cyclization [258]. The combination of Baylis-Hillman reaction and tandem radical addition/ cyclization sequences [259], has been reported as a useful synthetic tool for the asymmetric synthesis of functionalized monocyclic and bicyclic b-lactams (III and IV, Fig. 7). 1,3,3-Trisubstituted b-lactams have been reported to be obtained through oxidative removal of the N-alkyl group from more complex b-lactams by treatment with cerium ammonium nitrate [260]. Anologous methodology was employed for a general synthesis of cis- and trans-b-lactams bearing a quinone moiety at the N-1, the C-3, or the C-4 position (I, II and III, respectively, Fig. 8), [261].

Novel and Recent Synthesis and Applications of b-Lactams

163 OTBDMS CHO

OTBDMS

N

S OMe

N

O

N O

O

CO2t-Bu

HO

CO2Me

N O MeO2C

TBS = tert-butyldimethylsilyl II

I CH3 O

H

OSi

H

O N

H

H

H

H

III

OSi H

H

CH3

H

N

R2

OH

N

O

O CO2Et

R1 V

IV

H

H

O

H

OH

F3C O

N

O

O

VI H3C OH

F3C Ph N

N

H

O

R

H VII

O

R

VIII

IX

Fig. 6

R3 2

R R1

H

OH

H

H

R4 H N

N O

CO2R

PMP = para-methoxyphenyl II

I

R1O

H

H

OH

OH EWG

R1O

H

H

N

N O

O

Fig. 7

OMe

O

PMP

III

IV

EWG

Ar

164

L. Troisi et al.

R1

H

H

O

O R H

N O

H

R1

O O

O

H

1

R

H

N R

O

R

II

I

O

N

O

III

Fig. 8

H S

BnO

H

H

R1

Ar

N

N

O

O

CO2PNB

Bn

Bn = benzyl

PNB = 4-nitrobenzyl I

II H

R R1

H

3

R O N

N

Fig. 9

N

N Ph H

H H

H

O

H

R2 PMP

N

O PMP = para-methoxyphenyl III

O

O PhSe

H

O

4

PMP IV

2-Substituted penam (I, Fig. 9) has been reported to be obtained by coupling of thioaldehyde with azomethine ylide which was derived from the b-lactam based oxazolidinone [262]. The preparation of 4-alkenyl b-lactams (II, Fig. 9) has been reported through either Horner-type olefination of a common 4-formyl b-lactam or the Corey-Winter alkene synthesis applied to 4-dihydroxyalkyl b-lactams [263]. Alcaide and coworkers have reported in 2002 the synthesis of various types of racemic and homochiral 1,3,4-trisubstituted- or fused polycyclic b-lactams (III and IV, respectively, Fig. 9) via intermolecular 1,3-dipolar cycloaddition reaction of 2-azetidinone-tethered nitrones with a variety of alkenes or alkynes [264]. The same authors have also reported the direct preparation of b-chlorovinyl alcohols (I, Fig. 10) by the coupling reaction of enantiopure 4-oxoazetidine-2carbaldehydes with a variety of propynyl-, and allenylmetal reagents [265].

Novel and Recent Synthesis and Applications of b-Lactams Fig. 10 2

R

H

H

OH

OH

Cl

N

MeO

Ph N

SiMe3

1

O

165

O

R

R

O I

II Ar

SO2Tol

H

H

N N

O

Ar

N

N

H Co2Me

O

O

CO2PNB

CO2PNB

III

Tol = 4-MeC6H4 PNB = 4-nitrobenzyl

IV

The synthesis of tricyclic b-lactams (II, Fig. 10) has been reported to be promoted by titanoncene (III) chloride (Cp2TiCl) on the epoxymonobactams in the presence of intramolecular p systems (i.e., conjugated alkenes and lactones and amide carbonyls) [266, 267]. The reaction of the b-lactam-based oxazolidinone with N-sulfonylimines has been reported to provide the exo and endo azapenams (III, Fig. 10), whereas the reaction with azirines provided cycloadducts (IV, Fig. 10) that are precursors of azacephams [268]. The synthesis of new “selectively activated” enediyne prodrugs (I, Fig. 11) has been reported to start from suitably substituted b-lactams [269]. The group of Palomo has reported in 2003 the preparation of short pseudopeptides containing enantiopure a-substituted a-amino-b-lactam fragments (II, Fig. 11) by a-alkylation of suitable N-[bis(trimethylsilyl)methyl]-b-lactams through a totally stereocontrolled way [270]. 3-Alcoxycarbonyl-1b-methylcarbapenem and 3-alcoxycarbonyl-1a-methylcarbapenem (III and IV, respectively, Fig. 11) have been reported to be prepared by using a palladium-catalyzed C–N bond-forming coupling of vinyl halide and b-lactam nitrogen [271]. Using a similar methodology but starting from a b-lactam having a propargyl moiety, the synthesis of 1b-methylcarbapenem and 1a-methylcarbapenem (V and VI, respectively, Fig. 11) has also been reported [272]. Alcaide and coworkers have reported the thermolysis of b-lactam-tethered enallenyl alcohols to give tricyclic ring structures (Fig. 12) via a formal [2+2] cycloaddition of the alkene with the distal bond of the allene [273]. The same authors have also reported the preparation of tricyclic b-lactams containing eight, nine, and 10 medium-sized central rings and four-, five-, and six-membered distal rings (I, II and III, respectively, Fig. 13) starting from

166

L. Troisi et al.

R3

R

H2N

4

O

OH

MeO

R1

R2

N N

O

N H

O

R R = OSiMe2t-Bu; OH; NH2; N3

COOH

II

I OTBS H H

CH3

OTBS H H

N

N

O

CO2Et

O

III OTBS H H

CH3

CO2Et IV

CH3

OTBS H H

CH3

N

N O

O

TBS = tert-butyldimethylsilyl V

VI

Fig. 11

OH 1

R2

H H

R

N O

Fig. 12

H

conveniently substituted bis-b-lactams, pyrrolidinyl-b-lactams, and piperidinyl-blactams, which underwent ring-closing methatesis using Grubbs’carbene, Cl2(Cy3P)2Ru=CHPh [274]. Furthermore, they have reported the preparation of aza-Diels-Alder cycloadducts (I and II, Fig. 14) arising from a useful dual Diels-Alder behavior. Imines derived from 4-oxoazetidine-2-carbaldehydes have been found to behave as azadienophiles with the Danishefsky’s reagent, and as azadiene with alkenes [275].

Novel and Recent Synthesis and Applications of b-Lactams R1 PhO

O

H H

MeO

H

n

H

O

R2 CO2Me

MeO2C

N

MeO

167

H

N

O

H H

H

N

N

N

O

O n = 1,2

O

n n = 1,2,3

I

N

MeO

n n = 1,2,3

II

III

Fig. 13

Me O

Me OMe

H H

R2

R2

H

H

N N O

H R1

3

N

R

O

N

H

H R1

I

II 3

OH R1

R

OTBS

H H

O

R4

C NH

N O

R2

R

O TBS = tert-butyldimethylsilyl

III

IV

Fig. 14

Using enantiopure 4-oxoazetidine-2-carbaldehydes, the same authors have also reported the coupling reaction with various activated alkenes, in the presence of a Lewis acid, leading to homoallyl b-lactams (III, Fig. 14), [276]. Cainelli and coworkers have reported the synthesis of a class of 4-(2-oxoethylidene)azetidin-2-ones (IV, Fig. 14) that could be carried out by a novel Lewis acid mediated reactions of 4-acetoxyazetidin-2-ones with a-diazocarbonyl compounds [277]. The same authors have also reported that the (E)- and (Z)-4-alkylideneb-lactams have shown a different reactivity in the acylation reactions under basic conditions [278]. For instance, the E isomer formed readily the N-acyl-4alkylidene-b-lactam, while the Z isomer reacted sluggishly rearranging to the corresponding oxazin-6-one (I and II, respectively, Fig. 15).

168

L. Troisi et al. COOEt TBSO

OTBS

COOEt

H

N N

R

O

O

R

O

O I

II

CH3 OTBS H H

OTBS CH3 H H COOH

X NH

NH

O

O

O TBS = tert-butyldimethylsilyl III

IV

Fig. 15

R

Ph

R

COOt-Bu N O O

n

S

N

O

O

I

N

n

S

O

O

O

II

TBSO

X

O

O

* X = NHCH

III

Me

; Ot-Bu; Ph OCH2Ph; NHPh OTBS

OTBS

CH3

Se NH

N O

O IV

CHO

N O

COOt-Bu TBS = tert-butyldimethylsilyl V

N O

R

VI

Fig. 16

Lee and coworkers reported in 2004 the preparation of a key 1-b-methylcarbapenem intermediate (III, Fig. 15) by condensation of 4-acetoxy-b-lactam with a titanium enolate of 20 -hydroxypropiophenone [279]. The resulting ketone was converted into the corresponding carboxylic acid (IV, Fig. 15) by a dry ozonation method. A simple synthetic protocol for the production of b-lactams fused to a sultam moiety (I and II, Fig. 16) using a ring closure metathesis has been developed [280].

Novel and Recent Synthesis and Applications of b-Lactams

169

Using suitable acylating agents and under the right conditions, different 1-acylb-lactams (III, Fig. 16) have been reported to be prepared from phenyl-derived 2-azetidinones [281]. An efficient route to 4/5/6 polycyclic b-lactams (IV, Fig. 16) by enzyme metathesis and Diels-Alder reactions has been described starting from 4-acetoxy3-substituted-2-azetidinones [282]. Selenopenams (V, Fig. 16) have been reported to be prepared in good to moderate yields in processes that presumably involved intramolecular homolytic substitution at selenium, starting from 2-azetidinone derivatives [283, 284]. The asymmetric hydroformylation of N-substituted 4-vinyl b-lactams, catalyzed by rhodium(I) complexes, leading to 1-b-methylcarbapenem precursors (VI, Fig. 16) has been reported [285]. In 2005, the group of Alcaide has reported the regiocontrolled preparation of biaryl-2-azetidinones (I and II, Fig. 17), via aryl-aryl radical cyclization and/or rearrangement of b-lactam-tethered haloarenes [286]. Moreover, using the same starting materials, they have reported the regio- and stereoselective synthesis of enantiopure or racemic benzofused tricyclic b-lactams such as benzocarbapenems and benzocarbacephems (III and IV, Fig. 17) via intramolecular aryl radical cyclization [287]. The same authors have reported the conversion of 4-oxoazetidine-2-carbaldehydes into thiazolyl derivatives, firstly (I, Fig. 18), and subsequently into a-alcoxy b-lactam acetaldehydes (II, Fig 18), through a three-step reaction [288]. They have also reported a direct route to optically pure, fused, or bridged tricyclic b-lactams (III and IV, Fig. 18) as further advances in the intramolecular nitrone-alkene cycloaddition reactions of monocyclic 2-azetidinone-tethered alkenylaldehydes [289].

X

AcO N

O

O N

Y

O

I

II R3

3

2

1

R

H

R

2

R

H

1

R

R N

O

Fig. 17

R

N O

III

IV

170

L. Troisi et al.

Fig. 18

H

H

MeO

OR2 H

N

OR2 CHO

H

N

N

R1

O

H

H

MeO

S

R1

O II

I O N

R2

R R1O

H

N O

H N

N

n

O

O

PMP PMP = para-methoxyphenyl

n = 1,2,3

III

IV

OTBS

O Ar

H

H

COXR

COOR

O

NH O X = O; NH TBS = tert-butyldimethylsilyl

NH O

II

I

H

H Et

Ph N3

Fig. 19

N O III (E/Z)

Ph N

NH R

H

Et

CBz

O

R

IV

A series of 4-alkyliden-b-lactams (I and II, Fig. 19) has been reported to be prepared combining the b-lactam with a polyphenol scaffold [290]. A mixture of diastereomeric azides (E/Z) in fast equilibrium (III, Fig. 19) has been obtained by treatment of 3-alkenyl-3-bromoazetidin-2-ones with NaN3 [291]. The subsequent hydrogenation and the following protection with CBz derivatives afforded 3-(20 -amino)-b-lactams as single diastereomers (IV, Fig. 19). A procedure based on Ru-catalyzed metathesis sequences with oxanorbornene precursors (I, Fig. 20), obtained by the Staudinger [2+2] cycloaddition of related imines, has been reported to lead to spiro-b-lactams tethered to tetrahydrofuran rings (II, Fig. 20), [292].

Novel and Recent Synthesis and Applications of b-Lactams Fig. 20

171

O O

R

R N

N 1

1

O

R O

O

R O II

I OR R N

COOEt NH O

O R = glycosyl

III

IV

A method has been developed for obtaining the N-alkylation of bicyclic b-lactams (III, Fig. 20) using silica supported cesium carbonate under solvent free conditions [293]. Cainelli and coworkers have reported in 2006, some further advances in the preparation of 4-alkyliden-b-lactams starting from 4-acetoxy azetidinones and diazoesters [294]. A new class of glycoconjugated b-lactams (IV, Fig. 20) has been reported to be obtained by direct glycosidation of a suitable 4-alkylidenazetidin-2-one acceptor with several glycosyl donors activated by catalytic Yb(OTf3) [295]. Two classes of structures containing azido- and aziridino-hydroxyl-b-lactam (I and II, respectively, Fig. 21) have been prepared by means of a stereo- and regioselective epoxide ring opening reaction [296]. The treatment of cis-3-(prop-2-ynyloxy)- or cis-3-(enyloxy)-b-lactam with one equiv. of iodine in dichloromethane at room temperature has been reported to produce two types of spiro-b-lactam (III and IV, respectively, Fig. 21) [297]. The same authors have also investigated the stereoselective synthesis of unsymmetrically disubstituted azetidin-2-ones (V, Fig. 21) by using Lewis acid mediated functionalization of b-lactams with various active aromatic substrates [298]. The preparation of novel, strained tricyclic b-lactams (Fig. 22) containing a cyclobutane ring has been developed to be performed by intramolecular [2+2] cycloaddition reactions of 2-azetidinone-tethered enallenols [299]. The group of Cainelli has reported in 2007, the direct vinylic substitution of 4-alkylidenazetidin-2-ones to give the corresponding chloro, bromo, iodo, and nitro derivatives (I, Fig. 23), [300]. The reductive radical cyclization of d- and e-epoxynitrile has been reported to be achieved using titanocene monochloride affording fused bi- and tricyclic b-lactams (II and III, respectively, Fig. 23), [301]. As an advancement of previous work, the group of Alcaide has reported the preparation of fused bi- and tricyclic b-lactams by a two step reaction: the carbonyl allenylation of substituted 4-oxoazetidine-2-carbaldehydes, followed by

172

L. Troisi et al. OH Br

OH

Ph

H3C

H3C N3

N

O S

H

N

N

O

Ph

II

H R1

O

I S

R2

CH3

O

Ph

I I

N

CH3

O

Ph

H R1 N

O

III

R2

IV Nu

H

R1

PhS N O

R2

V

Fig. 21

Me OH H

R

H

MeO

OH

H H

H N

N O

O

PMP

H CH3 OH H3C H

H

Fig. 22

H

H

OH

R2

N O

N O

R1O

PMP

H

PMP=para-methoxyphenyl

the tin-promoted radical cyclization of the resulting allene-b-lactams (I and II, Fig. 24), [302]. Benfatti and coworkers have reported further advancements in the intramolecular ring-opening reaction of b-hydroxy epoxides affording spiro-oxetanes and tetrahydrofurans (III and IV, respectively, Fig. 24), [303].

Novel and Recent Synthesis and Applications of b-Lactams COOEt R

HO

Ph MeO

X

O

N H

Ph

MeO

N O

173

O

O

n

X = Cl, Br, I, NO2

O

N

n = 0,1

I

II

III

Fig. 23

HO

HO

R2

R1

CH3

N

CH3

N

O

O I

II H

HO H

O

Ph

H Ph

O

OH H Ph

H Ph

N

N O

O

Ph

Ph

Fig. 24

R2

R1

III

IV

The reaction of chlorosulfonyl isocyanate with 1,4-cycloesadiene [304] was previously reported to provide b-lactams in quantity. More recently, these CSIderived building blocks have been reported to be modified in various b-lactams bearing at C-3 and C-4 protected polar substituents (I, II and III, Fig. 25), [305]. Moreover, the C-3 and the C-4 positions of the azetidinone ring have been reported to be stereoselectively functionalized inserting various groups through the generation of a stable azetidinyl carbanion which can be captured by various electrophiles [164]. The Diels-Alder cycloaddition reaction of both cis- and trans-dienyl-2-azetidinones with unsymmetrical dienophiles in the presence of Lewis acid catalysts has been reported to give in regio-, stereo-, and remarkably high p-facial selectivity novel 1,3,4-trisubstituted-2-azetidinone derivatives in good yields (I and II, Fig. 26), [306]. Cu(OAc)2 in combination with a solid base such as K2CO3 has been reported to be an extremely efficient system in promoting the homocoupling of 2-azetidinonestethered alkynes, whereas the cross-coupling of bromoalkynyl-b-lactams with

174

L. Troisi et al.

Fig. 25

O

NH

O

NH t-BocHN

O

O

I

II NH t-BocHN

O III

R2

R2

Ar 3

Ar 3

R OC

R OC

N R

O

N

II

I

Fig. 26

MeO

H

H

O

O O

H

O

N

H OMe

N

O

R

O

R

O

R1 I

N O O O

H

H

OMe

Boc III

OH MeO

H

H

N O

N O

PMP II

Fig. 27

terminal alkynyl-b-lactams could be easily achieved by a copper-catalyzed CadiotChodkiewicz reaction. These methodologies offered a convenient method for the preparation of both racemic and enantiopure C2-symmetrical and unsymmetrical bis(-b-lactam)-1,3-diyne hybrids (I and II, Fig. 27), [307].

Novel and Recent Synthesis and Applications of b-Lactams

175

Electron-poor a-methylene-b-lactams were reported to undergo cross-metathesis more rapidly and efficiently than more electron-rich analogs. Significantly, tetrasubstituted alkenes have for the first time been accessed by cross-metathesis reactions (III, Fig. 27), [308].

4.4

Biological Activity

The most significant biological and pharmacological applications of the 2-azetidinones are reported in this paragraph, highlighting the SAR studies applied for the design of new and more efficient molecules.

4.4.1

Antibacterial Activity: Inhibitors of b-Lactamases

Three of the four classes of b-lactamases, A, C, and D are serine nucleophile-based enzymes, while the fourth, class B, contains zinc metallo-b-lactamases. Among the serine b-lactamases, classes A and C are currently the most intensely studied. However, extended spectrum class D enzymes have, of late, been growing in clinical importance [309–314]. The action mechanism of a novel class of monobactams, inhibitors for the class A b-lactamases has been reported in 1999 and is showed in Scheme 103 [310–313]. As exemplified by structure I, the inhibitor acylated rapidly the active site serine of b-lactamase and the tosylate was released from species II. The acyl-enzyme underwent fragmentation, resulting in enzyme inhibition by formation of three distinct products, depending on the type of functionality linked to the inhibitor (III, IV, or V, Scheme 115). The presence of a phenyl group at the C-4 position of the azetidinone ring favored a specific hydrophobic interaction with the active site of class A b-lactamases. Instead, the stereochemistry of the C-4 position appeared to be not important for the inhibition [310]. Studies recently reported for the structure-function analyses of the sulfonate moiety have argued for the requirement of a hydrophobic functionality, but its size did not appear to be restrictive. The absence of any hydrophobic functionality at this position lowered the ability of the molecules to inhibit b-lactamases [314]. Many serine-based b-lactamases are susceptible to inhibition by compounds containing a b-lactam nucleus such as clavulanic acid and sulbactam. Moreover, b-lactams that contain large substituents at the C-6 position, such as imipenem, moxalactam, and cefoxitin, inhibit both class A and class C b-lactamases. Previous studies have shown that conformational changes induced by large C-6 substituents destabilized these enzymes upon binding [315, 316]. The group of Beadle, in 2002, has reported crystallographic data of these inhibitors suggesting a different mechanism of action towards class A and class C enzymes, respectively [317].

176

L. Troisi et al. R1 R2

O O

NH2

Ser R1

III

R2

R1

O

O S

N O

O

O

Ser

R1

R2 O

O

O

O

O

H

Ser

CH3 I

R2

O

S

N

NH2 IV

CH3

II

R1 R2

O O Ser

O V

Scheme 115 The action mechanism of a novel class of monobactams, inhibitors for the class A b-lactamases

O O

S

OH N

N

O

O CH3 CH3

O

O CO2H Clavulanic acid

O S

N

N CH2

N

N

CH3

O CO2H Sulbactam

CO2H Tazobactam

Fig. 28

Known inhibitors of the class A, C, and D serine b-lactamases acylate the active site serine. The commercial inhibitors showed in Fig. 28 are selective for class A enzymes, since they structurally resemble penicillins more closely than they resemble cephalosporins. As in penicillin, the carboxylates of these commercial inhibitors are bonded to an sp3-hybridized carbon. Therefore, Buynak and coworkers in 2005 have hypothesized that a C-3-homologated penam-derived b-lactamase inhibitor might have broader specificity for both the A and C classes of b-lactamase than that performed by current commercial inhibitors [318]. The enhanced conformational flexibility of the carboxylate of the homologated penam derivative could enable the molecule to fulfill the geometric requirements of both A and C classes of serine b-lactamase. The longer chain might also enable the carboxylate to penetrate deeper into the positively charged pocket. In the second instance, they have hypothesized that placing a double bond in direct conjugation with the nitrogen, but exocyclic to the five membered ring, might also enhance acylation efficacy. The same group has

Novel and Recent Synthesis and Applications of b-Lactams O

O

O S

N O

O

O S

CH3 CH3

177

CH3 CH3

N O

O S

CH3 CH3

N O

CH2CO2H

CO2Na NaO2C

I

II

III

Fig. 29

reported the synthesis of these prospective inhibitors (Fig. 29) together with a preliminary investigation of their ability to inactivate serine b-lactamases. The inhibitory data obtained indicated that the homologated sulbactam analog I (Fig. 29), had a 10-fold improved inhibitory activity against the class C b-lactamase enzyme, as compared with sulbactam itself. The additional carbon could allow greater conformational flexibility, thus allowing the carboxylate of structure I to occupy a space similar to that occupied in a typical cephalosporin substrate. It may be noted, however, that the compounds having the exocyclic unsaturation (II and III, Fig. 29) did not display a significant ability to inactivate either class A or class C serine b-lactamases. This could be due to the conformational rigidity imposed by the exocyclic unsaturation. These compounds were slowly hydrolyzed in buffered aqueous media and this hydrolysis was accelerated in the presence of the class A serine b-lactamase, thus indicating that they were good substrates. As in the penems and carbapenems, the unsaturation present on the five-membered ring (endocyclic or exocyclic) presumably further activated the b-lactam moiety towards hydrolysis. This could explain the reduced hydrolytic stability of structures II and III (Fig. 29). As far as the metallo-b-lactamases (class B) are concerned, their emergence posed a new challenge as they are not susceptible to known inhibitors, and the newer generation of these enzymes acts on a broad variety of b-lactam structurespenicillins, cephalosporins, and carbapenems. Further, the 2-azetidinone nucleus has been employed in 2004 by Ruddle and Smyth to prepare b-lactamase-dependent prodrugs which have hidden or latent reactivity that is triggered by scission of the b-lactam ring [319]. Thus, the penam nucleus could be modified to behave as a b-lactamase-dependent “prodrug” by incorporation of a vinyl ester side chain at the C-6 position. b-Lactamase-catalyzed hydrolysis of the b-lactam ring uncovered the thiazolidine-ring nitrogen as a nucleophile that drove a rapid intramolecular displacement on the side chain (Scheme 116). Attachment of 7-hydroxy-4-methylcoumarin as the releasable group of this side chain generated a penicillin structure that can function as a fluorescence-based reporter substance/diagnostic for the presence of low levels of b-lactamase enzyme in solution (Scheme 117), [320]. Clavulanic acid, a naturally occurring powerful inhibitor of bacterial b-lactamases is a major b-lactam antibiotic produced by organism Streptomyces

178

L. Troisi et al. H+

O H3CO

O H3CO

H S

S

b-lactamase O

N O

O CH3OH

H

H CO2 Na

H

O

S

N O

H

N H CO2 Na

O

H CO2 Na

Scheme 116 Suggested mechanism of action ofa b-lactamase-dependent prodrug

Non-Fluorescent O ArO

Fluorescent

H

O

S

S

b-lactamase

N O

O

ArOH

H

H CO2

N O

H CO2

ArOH = 7-hydroxy-4-methylcoumarin

Scheme 117 Fluorescence-based penicillin structure having a 7-hydroxy-4-methylcoumarin as releasable group

clavuligerus and is active against a wide spectrum of Gram-pos. and Gram-neg. bacteria. The biosynthetic pathway, the fermentative production, the downstream processing, and applications of clavulanic acid has been reviewed in 2008 [321]. Another interesting review has been reported on Meropenem which is a broadspectrum antibacterial agent of the carbapenem family. It is indicated as empirical therapy prior to the identification of causative organisms, or for disease caused by single or multiple susceptible bacteria in both adults and children with a broad range of serious infections. Meropenem has a broad spectrum of in vitro activity against Gram-pos. and Gram-neg. pathogens, including extended-spectrum b-lactamase- and AmpC-producing Enterobacteriaceae [322].

4.4.2

Antibacterial Activity: Inhibitors for Pilus Formation

Bacteria need to adhere to host tissue in order to cause disease. Many pathogenic bacteria assemble pili, i.e., extracellular protein organelles, to mediate attachment to host epithelial cells. Pilus assembly is performed by periplasmic chaperones, which bring subunits to the outer cell membrane where they are incorporated in the growing pilus [323]. A drug inhibiting pilus formation, termed a pilicide, would therefore have the potential of being an effective antibiotic. It has been shown, both by nuclear magnetic resonance (NMR) spectroscopy [324] and by X-ray

Novel and Recent Synthesis and Applications of b-Lactams

179

Important hydrophobic interactions Anchoring to Arg8 and Lys112

N

MET-VAL-VAL-SER N H

CO2H O

R O

S

Mimicing the hydrophobic interactions

N O CHO Anchoring with possibility of forming an imine with Lys112

Fig. 30

crystallography [325, 326], that synthetic peptides from the conserved C-termini of the pilus proteins are bound by the PapD chaperone (found in uropathogenic Escherichia Coli, which is the main cause of urinary tract infections). Thus, it has been found that PapD binds polypeptides by anchoring the peptide carboxyl terminus to the side chains of Arg8 and Lys112 (Fig. 30), two residues that are invariant in all periplasmic chaperones and are required for pilus assembly. On the basis of the crystal structures of peptide-PapD complexes [325, 326], b-lactams have been selected as potential chaperone inhibitors with the requirement of having different stereochemistry than the original penicillin’s, thus having a chance to withstand enzymatic degradation by penicillin-resistant bacteria. The overall strategy consisted in creating small organic molecules with a rigid framework, which would locate the pharmacophores in the right position in the space [57]. In addition, this class of compounds allowed hydrophobic substituents (indicated by R) to interact with the chaperone while maintaining the important anchoring to Arg8 and Lys112. Moreover, the crystal structures showed that the C-terminal carboxyl group was within such a distance from Lys112 that replacing it with an aldehyde would allow an imine to be formed with Lys112.

4.4.3

Antibacterial Activity: Various Inhibitors

In 2000, a new family of N-methylthio-substituted b-lactams having promising antibacterial properties has been identified by Turos and coworkers. Curiously, most of this activity is directed towards Staphylococcus bacteria, including methicillin-resistant strains of Staphylococcus aureus (MRSA). These b-lactams showed

180

L. Troisi et al.

R = CH3; O

R2

Et N

R1 = H; CH3; H R3

O S

;

SR N

R1

S

;

;

SO3NBu4

H N

Ph Et R2 = H; OCH3; OAc; O(CH2)3; OCH2CHCH2; SO3Ph; SO3CH3

R3 =

; Ph X

Fig. 31

a different behavior compared to all other b-lactam antibiotics [327]. Rather than interfering directly with cell wall biosynthesis, through irreversible acylation of penicillin binding transpeptidases, these compounds seemed to affect cellular processes through transfer of the N-organothio group to a bacterial thiol. It has been also noted that these lactams exert antiproliferative properties against only a narrow range of bacterial genera, most significantly, Staphylococcus (including MRSA), Micrococcus, and Neisseria. This selectivity seems to be related to the levels and types of cellular thiols present in each microbe that is sensitive to the lactams, not to whether the microbes are Gram positive or Gram negative classes. The anti-Bacillus properties of a selected number of differentially substituted b-lactams based on the structure of Fig. 31 were also investigated by the same authors in 2006 [328]. The b-lactams have been individually tested for antibacterial activity against Bacillus anthracis and six other species of Bacillus by the well known Kirby-Bauer method on agar plates [329]. In general, lipophilic acyloxy or alkoxy groups at the C-3 carbon of the lactam ring led to the strongest growth inhibition properties against each of the seven Bacillus microbes examined. The most important substituent influencing the anti-Bacillus activity, as in the case of MRSA, was found to be the N-organothio moiety, with the sec-butylthio group having the best overall bioactivity. The mechanism of action of these lactams in Bacillus most likely paralleled that in Staphylococcus, with transfer of the N-organothio substituent from the lactam to a cellular thiol occurring within the cytoplasm of the bacterium [328]. Recent findings in 2007 indicated that N-thiolated-b-lactams react rapidly within the bacterial cell with CoA through in vivo transfer of the N-thio group to produce an alkyl-CoA mixed disulfide species, which then interferes with fatty acid biosynthesis. The studies on CoA disulfide reductase showed that the CoA thiolredox buffer was not perturbed by these compounds; however, the lactams appeared to act as prodrugs. The evidence that these b-lactams inhibit fatty acid biosynthesis in bacteria, and the elucidation of CoA as a primary cellular target, offers opportunities for the discovery of other small organic compounds that can be developed as therapeutics for MRSA and anthrax infections [330]. The same authors have found in 2008 that these lactams also possess antifungal activity against Candida

Novel and Recent Synthesis and Applications of b-Lactams

181

Ph

O

H N

R

AcOH2C O N

O O

N

OAc OAc

OAc

AcOH2C O N

O

OAc

O

OAc I a) R = Ph b) R = CH2OPh c) R = CH2Ph d) R = CH=CHPh

Ph

OAc

II H N

R

CH2OH AcOH2C O N

O O

OAc OAc

OAc III a) R = Ph b) R = CH2OPh c) R = CH2Ph d) R = CH=CHPh

Fig. 32

and other fungi by exerting powerful cytostatic effects that disrupt the structural integrity of cytoplasmic membranes. The mode of action and structure-activity trends of these lactams as antifungals parallel that previously seen in their antibacterial studies [331]. Jarrahpour and coworkers in 2004 have prepared and tested some new sugarbased monocyclic b-lactams possessing several other functionalities, in addition to the carbohydrate moiety [88]. The presence of a carbohydrate moiety side chain in a drug may also overcome the frequently observed water insolubility problem [332]. Moreover, the bacteria may utilize a carbohydrate uptake mechanism, which allows for a better transport of the monocyclic b-lactams across the membrane. The antibacterial activities of compounds depicted in Fig. 32 have been tested against one strain each of a Gram positive bacteria (Staphylococcus citrus), a Gram negative bacteria (Escherichia coli), a Gram negative containing capsule (Klebsiella), and a Gram positive spore (Bacillus subtilis). The antimicrobial activity tests have been performed according to the disk diffusion method [333], using Ampicillin and Gentamycin as reference compounds. The inhibition zones caused by the various compounds on the microorganisms have been measured and the activity rated on the basis of the size of the inhibition zone. The data obtained have shown that compound II (Fig. 32) was highly active against Staphylococcus citrus, Klebsiella pneumoniae, Escherichia coli, and Bacillus subtilis while b-lactams Ib and Ic were moderately active against these four microorganisms. Compound IIIb was highly active against Bacillus subtilis, while compound IIId was moderately active against Bacillus subtilis. Compounds IIIa–d were slightly active against Staphylococcus citrus [88].

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Fig. 33

Ph R

R

Ph N O

CO2Et

N O CO2Et

Ph R = PhtN; PhCH2COHN; PhOCH2COHN; CH2OH; CHO; PhCOHN; PhCH=CHCOHN

The same group of Jarrahpour has also synthesized a few mono and bicyclic b-lactams (Fig. 33) and tested their antimicrobial activity [92]. These compounds have been tested against one strain each of Gram positive bacteria (Staphylococcus citrus), Gram negative bacteria (Escherichia coli), a Gram negative containing capsule (Klebsiella), and a Gram positive spore (Bacillus subtilis). Monocyclic b-lactams with R = PhtN, PhCH2COHN, PhOCH2COHN were highly active against Bacillus subtilis and moderately active against Staphylococcus citrus. Other compounds were all inactive against these four pathogenic microorganisms [92]. Broccolo and coworkers in 2006 have reported the synthesis and antibacterial activity of a new class of monocyclic b-lactams substituted at the C-4 position with an alkyliden carboxy side chain [294]. Preliminary results of the antibacterial activity of some of these 4-alkyliden-b-lactams have disclosed the opportunity for the application of molecular modeling to relate chemical structures to antibiotic activity and to point out structural modifications that might increase antibiotic potency. Despite significant advances in the elucidation of the structures of penicillin-binding proteins (PBPs), the overall structural basis for multidrug bacterial resistance has not been clarified. PBPs are a heterogeneous family of enzymes with transpeptidase and transcarboxylase activities involved in the synthesis and crosslinking of the peptidoglycan component of bacterial cell walls, which is fundamental for the maintenance of bacterial cell morphology and integrity. On the basis of these considerations, the authors adopted a molecular modeling approach to identify attractive drug candidates and to contribute to the rationalization of functional group effects on the SARs. Thus, a series of b-lactams have been synthesized such as compounds of Fig. 34, that exhibited an inhibitory effect, generally more marked against Gram positive pathogens, although the spectrum of activity varied. Interestingly, the undifferentiated antibacterial activity against both methicillinsusceptible and -resistant strains of Staphylococcus aureus was suggestive of an alternative mechanism of action compared to that of typical b-lactams. The molecular modeling approach allowed the identification of interactions through oxygenated functions such as phenolic OH, which are valuable for the antibacterial activity [294]. Bactericidal effects have been reported for two b-lactams: amoxicillin and its combination with clavulanic acid. They showed in vitro effects on the oxidative

Novel and Recent Synthesis and Applications of b-Lactams Fig. 34 OEt

Cl NH

183

CH3 (R) TBSO

O

O

O

OBn

NH O

Z

E TBS = tert-butyldimethylsilyl

metabolism of PMN neutrophils. These cells play the major role in the “respiratory burst” as they produce superoxide anion to kill the infectious agent. An activation of this process by the injected antibiotics could enhance the bactericidal action or explain some of the adverse effects. Amoxicillin could either activate PMN neutrophils NADPH-oxidase or cause its activation by a membrane effect, or interfere with the zymosan activation way [334]. Amoxicillin has been reported among the amino-b-lactams like cefadroxil, and ampicillin as aminating agent of catechols to obtain novel cephalosporins, penicillins, and carbacephems using fungal laccase. All isolated monoaminated products inhibited the growth of several Gram pos. bacterial strains in the agar diffusion assay, among them methicillin-resistant Staphylococcus aureus strains and vancomycin-resistant Enterococci [335]. Antifungal and antibacterial activity have also been reported for bile acid dimers linked through 1,2,3-triazole and bis-b-lactam [336]. Investigations towards novel glycopeptide/b-lactam heterodimers were reported in 2008. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons were chemically linked to yield heterodimer antibiotics. These novel compounds were designed to inhibit Gram-pos. bacterial cell wall biosynthesis by simultaneously targeting the principal cellular targets of both glycopeptides and b-lactams. The positional attachment of both the vancomycin and the cephalosporin central cores has been explored and the SAR was reported. This novel class of bifunctional antibiotics all displayed remarkable potency against a wide range of Gram-pos. organisms, including methicillin-resistant Staphylococcus aureus [337].

4.4.4

Inhibitors of Human Leukocyte Elastase

The first b-lactams LE inhibitors were naturally occurring bicyclic compounds, such as clavams and cephalosporins [338], but more recently, synthetic monocyclic b-lactams have been developed. Time-dependent inhibitors of enzyme HLE, based on the cephem nucleus, have been reported. A series of cephalosporin tert-butyl esters have been examined, and the activity of these compounds has been found to be very sensitive to the C-7 substituents, the greatest activity being showed by small, a-oriented, and electron-withdrawing groups. Additionally, the oxidation

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Cl

O

O H

O

Cl

S

OAc Ser-O

N

HO

O

O

OAc

Ser-O

CO2-t-Bu

CO2-t-Bu

II

I

O

HO

O

MeO H

S N

OAc Ser-O

O

N

O

O

Ser-O

S

O

N

His

N

N

CO2-t-Bu IV

OAc CO2-t-Bu

O

MeO

Ser-OH

O S

O CO2-t-Bu

N

N

HN O

MeO MeO

His

S

N

CO2-t-Bu

Ser-OH

O

O S

III Ser-O O

N

O S HN

His NH

OH(Ac) CO2-t-Bu V

Scheme 118 Action mechanism of inhibitors for the HLE

state of the sulphur atom has been found to play a strategic role in strengthening molecular activity. For instance, sulfones showed considerably greater activity than the corresponding sulfides or b-sulfoxides, resulting the latter inactives [339]. The mechanisms thought to be at work when molecules of this type inhibit HLE have been studied (Scheme 118), [339]. Two types of inhibited complexes can be formed, at least, with HLE. The starting step, in all cases, is considered to be the b-lactam ring-opening performed by the OH of the Ser-195 belonging to the enzyme catalytic triad (Ser-195, His-57, Asp-102), to form the complex I. If the C-7 substituent is a chlorine atom, the expulsion of the 30 -acetate, followed by loss of HCl and Michael addition of His-57 imidazole ring to the N-1 nitrogen, led to the inhibited complex II. However, when the C-7 substituent is a poorer leaving group, such as methoxide (III, Scheme 118), crystallographic data suggested that this group is not lost but the thiazoline ringopening reaction generated an inhibited species. At this point, it is not possible to discern if there is a second covalent linkage between the inhibitor and the enzyme (IV, Scheme 118) or, alternatively, if a critical salt bridge between the released sulfinate and the His-57 imidazole is formed. In this latter case, the hydrolysis of the intermediate V is presumably slowed as the imidazole moiety is not properly aligned to deliver water to the serine carbonyl ester. In 2003, Cainelli and coworkers have shown that monocyclic b-lactams substituted at the C-3, the C-4, and the N-1 positions are the most active in inhibiting LE and gelatinases MMP-2 and MMP-9 [340]. They have also reported that C-4 unsaturation on the b-lactam ring raised the inhibitory activity towards these proteases, with selectivity over LE by 3-[1-(tert-butyldimethylsilyloxy)ethyl] derivatives, and over the gelatinase MMP-2 by C-3-unsubstituted 4-[1-ethoxycarbonyl]

Novel and Recent Synthesis and Applications of b-Lactams

185

OH OH COOEt

OTBS O

HO

OH

OBn

O OH

OBn

N OH

O

O

OBn O

OH OH I (–) epigallocatechin-3-gallate (EGCG) with encircled galloxyl moiety

II (N-galloxyl-4-alkyliden-b-lactam) TBS = tert-butyldimethylsilyl

Fig. 35

ethylidene-b-lactams. Some catechins (vegetable secondary metabolites of the flavonoid family), and in particular those with a galloyl group (I, Fig. 35), have been shown previously by the same authors, to exert a very powerful inhibition of LE activity [341–343], but their absorption, bioavailability, and metabolic fate awaited full clarification. Thus, in 2005 a number of monocyclic b-lactam derivatives with a galloyl moiety-like group in different positions were synthesized and tested [290]. Some of these, such as the N-galloxy-4-alkyliden-b-lactam (II, Fig. 35) appeared to exert an improved anti-LE activity. In 2002 Ge´rard and coworkers have studied two series of compounds, namely, 3-halide- [344, 345] and 4-alkoxycarbonyl-1-alkoxycarbonyl-2-azetidinones [346], (Scheme 119). These b-lactams behaved as reversible inhibitors of porcine pancreatic elastase (PPE) [347–350], which are considered good models of HLE and more readily available than HLE. The action mechanism of these 2-azetidinone derivatives was different, depending on the C-3/C-4 substitution. Indeed, after a transient inhibition of PPE, enzyme hydrolysis of structure I (Scheme 119) led to the b-lactam bond cleavage without expulsion of OR leaving group, while PPE processing of structure II led to the OR1 ester cleavage, without the b-lactam ring opening. Thus, the group of Gerard has designed structural modifications of the b-lactams II in two directions: a) decreasing the reactivity of the C-4 carbonyl substituent, b) increasing the b-lactam carbonyl reactivity and the consequent N-1 substituent expulsion, after C2–N1 bond cleavage. A series of 4-alkylaminocarbonyl-1-alkoxycarbonyl-2-azetidinones and 4-(alkoxycarbonyl)-2-azetidinones, bearing various carbonyl and thiocarbonyl functionalities at the N-1 position, have been prepared [351]. The results showed the potential interest towards N-thiocarbonyl-2-azetidinones as reactive structures for the design of novel elastase inhibitors. However, an electron-withdrawing substituent (activating group) placed at the C-4 position (or the C-3) was systematically required to reach a good level of enzyme inhibition. For

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Scheme 119 Different action mechanism of 2-azetidinone derivatives depending on the C-3/C-4 substitution

X

X N

O

O

O

R

O

CO2R

HN

OH X = Cl, Br, I

I CO2R1 N

CO2H

O

O

+

N

O

O R

O

O R1 = Me, n-Bu, i -Pr

II

R1OH

R

O C

CH2Ph

CO2n-Bu

N CH2Ph

N

O

O

N O

O

Fig. 36

I

S

O

C2H5

II

instance, compound I of Fig. 36 was a good reversible inhibitor of PPE and HLE, acting most probably like 3-halide-1-alkoxycarbonyl-2-azetidinones (I, Scheme 119). Compound II (Fig. 36) was more active against PPE and HLE, but behaved in the same way as 1,4-bis(alkoxycarbonyl)-2-azetidinones (II, Scheme 119) [351].

4.4.5

Inhibitors of Cysteine Protease

The cysteine proteases cathepsin B, L, K, and S are involved in diseases such as osteoporosis, cancer metastasis, rheumatoid arthritis, and infectious diseases [352– 357]. Thus, the proteases became an important target for developing inhibitors as therapeutic agents [358–363]. Recently, a series of 4-substituted-3-Cbz-phenyl-b-lactams (Fig. 37) has been identified as a novel class of cysteine protease inhibitors [364]. Several studies have suggested the importance of the (3S) stereoconfiguration of the C-3 carbon atom on the enzyme interactions, which is equivalent to the natural L-amino acids configuration. The different substitution at the C-4 position has shown significant effect on the inhibitory power: substituents such as

Novel and Recent Synthesis and Applications of b-Lactams Fig. 37

187

Ph H N

Cbz-NH

O

R Cbz =

O

NH

Ph

O

O

NH

NR COOMe

COOR H2N

N H

RHN N O

R1

I, II

N O

H

III

I: R = Me, R1 = H, COMe, Tos II: R = H, R1 = O

N H

N

III: R = Cbz or Boc

NCONHt-Bu

Fig. 38

–OR0 , –OCOR0 (R0 = generic aliphatic group), –OPh, –SPh and –S(O)2Ph appeared to be necessary for a good inhibitory activity. However, the C-4 substituents might not behave only as a leaving group, but they were involved also in the interactions with the enzyme S0 subsite. The C-4 stereo-configuration requirements depended, then, on the nature of the substituents [364]. In 2005 highly potent and selective inhibitors of cathepsin K were reported based on the 3,4-disubstituted azetidin-2-one which seemed to transiently acylate the sulfhydrile of cathepsin K [365].

4.4.6

Inhibitors of Thrombin and Tryptase

Several representatives of the class of the b-lactams can effectively inhibit proteases [366, 367]. For instance, the 2-azetidinone I of Fig. 38 has been identified [368] as a powerful and selective inhibitor of thrombin, a serine protease involved in both venous and arterial thrombotic episodes [369]. More recently, b-lactam II (Fig. 38) has been found to display inhibition of tryptase at the subnanomolar level and suppress induced inflammation in animal lungs [370]. These compounds featured an o-guanidyl-substituted n-propyl side chain at the C-3 position and a carboxylic residue at the C-4, both essential for biological activity. In 2003, Annunziata and coworkers [84] have reported an efficient synthesis of the stereoisomerically pure trans compound III (Fig. 38) which represented a convenient, advanced precursor of structures I and II and differently N-substituted

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derivatives thereof. The new synthesis of compound III (R = Boc) started from readily available and inexpensive D-glyceraldehyde and opened access to both enantiomers of the target molecules in enantiopure form. Since the thrombin inhibitor I has been described so far only in the racemic form, and no stereochemistry/activity relationship has been reported, the possibility of obtaining both enantiomers of compound III was worth investigating. b-Lactam compounds variously substituted at C-3, C-4, and N-1 were reported, more recently, as useful inhibitors of tryptase, and thrombin [371, 372].

4.4.7

Azetidinones as Vasopressin V1a Antagonists

Several research groups have prepared antagonists directed to the vasopressin V1a receptor [373–378]. Vasopressin, through the vasopressin 1a receptor (V1a), can stimulate aggressive behavior. Using a novel monocyclic beta lactam platform, a series of orally active vasopressin V1a antagonists was developed, by the group of Guillon, showing high affinity for the human receptor. SRX251 was chosen from this series of V1a antagonists to screen for effects on serenic activity in a residentintruder model of offensive aggression. The data obtained from this investigation corroborate previous studies showing a role for vasopressin neurotransmission in aggression and suggest that V1a receptor antagonists may be used to treat interpersonal violence co-occurring with such illness as autism, bipolar disorder, and substance abuse [379]. While V1a antagonists have been synthesized, none of these have been reported to penetrate the central nervous system efficiently. In 2007, the same authors have identified the azetidinone LY307174 (I, Fig. 39), for a screening based on 59% molecular similarity to ketoconazole (II, Fig. 39), a marketed antifungal agent O O

O

N N

N

N O

N

N O O

I LY307174

Fig. 39

O O

O O

O

II Ketoconazole

Novel and Recent Synthesis and Applications of b-Lactams Fig. 40

189

Zone A

Zone B R

R1

N

R2

O

R3

O

Zone C

Zone D

known to cause reproductive side-effects due to antagonism of the luteinizing hormone releasing hormone receptor [380]. Some features of structure II, such as the dioxolane ring and the terminal phenyl moiety were conserved in structure I, while others group were totally replaced. Beyond the simple issue of affinity, compound I has been considered an attractive lead for several reasons. First of all, LY307174 is a monocyclic b-lactam (monobactam). Unlike fused-ring b-lactams, such as penicillins and cephalosporins, simple monobactams such as structure I are highly stable to chemical or enzymatic hydrolysis of the azetidinone. The cis geometry of the rigid fourmembered ring forces the three side-chains together into a fixed geometric configuration, enabling, presumably, the complementarity with subpockets of the receptor. Although the molecular weight of compound I is relatively high, its compactness provided some hope that the series might show significant oral absorption [381]. Thus, SAR studies have been performed, based on the modification of the four zones A–D of the azetidinone molecule, as depicted in Fig. 40. Further, a novel series of vasopressin V1a antagonists has been synthesized, and subnanomolar affinities at the human V1a receptor have been achieved. On oral dosing, two members of the series, structures I and II of Fig. 41, reached brain levels ~100 times their in vitro receptor affinities. These molecules have been further developed for human clinical evaluation [381].

4.4.8

Hypocholesterolemic Activity

Burnett and coworkers have described the synthesis of a very potent class of cholesterol absorption inhibitors (CAI) typified by the original lead compound in this series: the compound I showed in Fig. 42 (SCH 48461). This 2-azetidinone has resulted as an effective inhibitor of cholesterol absorption in a cholesterol-fed hamster model [9]. Subsequently, the same molecule has been shown to reduce serum cholesterol in human clinical trials [382]. Although this class of compounds has been initially designed as acyl coenzyme A cholesterol transferases (ACAT) inhibitors, early structure-activity studies demonstrated a striking divergence of in vitro ACAT inhibition and in vivo activity in the cholesterol-fed hamster. A detailed examination of this molecule indicated that the hypocholesterolemic

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O

O

O

O N

N N

N

O

O HN O

O

O N

N

N O

F 3C

N

N

I

II

Fig. 41

OCH3

OH

OCH3

Ph

Ph

OCH3

OH

H Ph N

N O

O

N O

OCH3

SCH 48461

I

II

III

Fig. 42

activity was exerted at the intestinal wall by inhibiting the cholesterol absorption [383]. Reported studies on the structure I of Fig. 42 and analogs of this class have shown that the azetidinone nucleus is a critical element for in vivo activity [384]. On the basis of these findings, an investigation on SAR around the 2-azetidinone nucleus has been performed. The results have revealed a clear SAR for cholesterol absorption inhibition which is different from the modest ACAT inhibitory activity shown by these compounds. Thus, these molecules appeared to be acting via a mechanism which might be fundamentally important in the intestinal absorption of cholesterol [8]. Moreover, structurally related 2-azetidinones (II and III Fig. 42) containing hydroxyl groups on the phenylalkyl substituent at the C-3, have been reported as CAIs more active than their deshydroxy analogs [9, 385]. b-Lactams having a substituent containing a ketonic moiety at the C-3 have also been reported as good inhibitors for cholesterol absorption [386].

Novel and Recent Synthesis and Applications of b-Lactams

191

Stereochemistry important Chain Length important OCH3 Alkoxy group required

N O Stereochemistry not important Mono >> Di

Alkoxy group not required OCH3

Azetidinone ring required

Scheme 120 Summary of the basic SARs in the 2-azetidinone compounds

A summary of the basic SARs in the 2-azetidinone compounds is shown in Scheme 120. The presence of a 4-methoxyphenyl or similar hydrogen bonding moiety and a proper absolute stereochemistry at the C-4 carbon atom, are both critical in producing the activity. The phenylalkyl group at the C-3 and the monosubstitution at the C-3 and the C-4 positions seem to be less critical. A N-aryl group seems to be required, but there is considerable tolerance for the substitution at the phenyl ring. The azetidinone ring is required, but there is no evidence that it acts as anything more than a scaffold to correctly position the pharmacophore groups [384]. More development on the SAR studies have revealed the importance of sidechain metabolic hydroxylation to activity and led to the synthesis of compound I of Fig. 43 (SCH 58235), [387, 388]. While this 2-azetidinone together with compound I of Fig. 42 (SCH 48461) are extremely potent inhibitors of cholesterol absorption in vivo, the precise biological mechanism by which this inhibition takes place has yet to be discovered [383]. Data presented previously have suggested that there was a molecular target for these compounds, which has been designated as the CAI binding protein (CAIBP). The initial approach of Burnett and coworkers has been to use radiolabeled binding compounds for the identification of subcellular localization sites in intestinal cells [140, 389]. Having some knowledge of where the compounds were binding, they hoped to identify any specific proteins that had high affinity for this class of CAIs using other techniques. Based on their extensive SAR developments of the azetidinone CAI series, in 2002 the same authors have found that the two best structural sites for elaboration, while maintaining in vivo activity, were the N-aryl ring and the pendant aryl ring. For sensitivity reasons, their initial binding studies required radioiodinated analogs and thus, targets II and III (Fig. 43) came to the fore [140]. In the cholesterol fed hamster assay, these compounds were both active in vivo, with the N-iodophenyl analog III having slightly better potency. The derivatives bearing a benzylic hydroxyl moiety displayed a significant potency advantage over

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L. Troisi et al. OH O

OH

OH

R

R

O OH CO2H N

X

I-V

N

F

O

O

Y

VI

I

SCH58235(–) I : R = OH, R' = H, X = Y = F II: R = H, X = I, Y = OMe III: R = H, X = H, Y = I IV: R = OH, X = I, Y = F V: R = OH, X = F, Y = I

Fig. 43

compounds II and III while the N-iodophenyl analog V was slightly more potent than the pendent iodophenyl derivative IV. Since it has been discovered that compound I (SCH 58235) in vivo exists predominantly as its glucuronide [388], in the absence of a clear understanding of the mechanism of action, neither the free phenol nor the glucuronide could be precluded as the bioactive species. Therefore, the corresponding iodinated glucuronide of derivative V was required. This compound, depicted as VI in Fig. 43, has shown significant reduction of hepatic cholesterol esters. Thus, the same group of researchers has designed and prepared a number of potent CAIs with fluorescent absorption and emission properties making them suitable for use as biological tools in the investigation of the mechanism of action of this important class of new pharmacological agents [139].

4.4.9

Antihyperglycemic Activity

Goel and coworkers in 2004 have examined the effect of some monocyclic b-lactams for antihyperglycemic activity against alloxan-induced diabetes in rats (Fig. 44), as these 2-azetidinones have been shown to control disturbances in cholesterol metabolism induced by diabetes. The antihyperglycemic effect of test compounds was evaluated by monitoring their effect on blood glucose and liver glycogen contents [390]. In the diabetic rats, high glucose levels and depression in hepatic glycogen contents could be attributed to less availability of the active form of enzyme glycogen synthetase, which in turn has been reported to be responsible for incorporation of glucose moieties in pre-existing glycogen chain [391, 392].

Novel and Recent Synthesis and Applications of b-Lactams

193

CH3 R2

R3

O

R1

N

OCH3

CH3

O R2=

N

;

;

;

R1 =

;

O

;

;

O R3 =

;

OCH3;

Fig. 44

Test compounds significantly lowered the serum glucose levels indicating their antihyperglycemic activity. This activity may be due to increased utilization of glucose, as indicated by decreased serum glucose levels, and increase in the activity of glycogen synthetase enzyme, as evidenced by augmented liver glycogen contents in test groups. Concerning the antidiabetic activity of test compounds the following structure activity relationships were observed: l

l

l

At the C-3 position, the phthalimido substitution showed the best activity followed by phenyl and phenoxy substitution, while 1,3-butadienyl substitution resulted in total loss of activity At the N-1 position, cyclohexyl and isopropyl group favored activity more than the phenyl and the 4-methoxyphenyl substitution At the C-4 position, styryl and 4-methoxy-phenyl substitution were more favorable than the phenyl group

This study has revealed that 2-azetidinones are effective as antihyperglycemic agents and might act either through increased utilization of glucose or through increased insulin activity or induction of glycogen synthetase enzyme.

4.4.10

Anticancer Activity

In 2002, Turos and coworkers have discovered and characterized the apoptosisinducing properties of a family of novel b-lactam antibiotics against human solid tumor cell lines such as breast, prostate, and head-and-neck [44]. They have found a lead compound (structure I, Fig. 45), with an N-methylthio group, which was able to induce DNA damage, inhibit DNA replication, and activate the apoptotic death program in human leukemic Jurkat T cells within a 2 h treatment. Several important SARs have been observed. First and most significantly, the N-methylthio group was required for the apoptosis-inducing activity of b-lactam I, (Fig. 45). In the second instance, an increase in the number of carbons on the N-alkylthio group was inversely proportional to the apoptosis-inducing ability of these b-lactams. Moreover, replacement of the N-methylthio moiety with an N-benzylthio group (IV, Fig. 45) also decreased the apoptosis inducing activity by ~70%. Another SAR was found for the chlorophenyl group in b-lactam I. Among the isomers I, II, and III, having a chlorine group in ortho-, meta-, and para-positions, respectively, on the

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L. Troisi et al. Cl Cl Cl

Cl H3CO

H3CO

H3CO N

O

O

SCH3 II

N

N

N SCH3

I

H3CO

O

SCH3 III

O

S

IV

Fig. 45

phenyl ring, b-lactams II and III were less potent than b-lactam I (by ~20%). Because of their simple synthesis and their easy structurally manipulation for selective studies, these b-lactams may have great potential to be developed into anticancer drugs [44]. In 2008 the same authors reported two N-thiolated-b-lactam analogs, both containing a branched-chain moiety at C3 of the lactam ring exhibiting potent apoptosis-inducing activity. Furthermore, the branched b-lactams were able to inhibit growth of mice bearing breast cancer xenografts, associated with induction of DNA damage and apoptosis in tumor tissues [393, 394]. In 2003, the group of Banik has assayed some 2-azetidinones against nine human cancer cell lines as a measure of cytotoxicity [86]. Structure-activity studies have revealed that N-chrysenyl- and N-phenantrenyl-3-acetoxy-4-aryl-2-azetidinones (Fig. 46), respectively, have potent anticancer activity. The comparable N-anthracenyl, N-pyrenyl, and N-naphthalenyl derivatives became inactive. It is evident that the minimal structural requirement of the aromatic moiety for cytotoxicity is at least three aromatic rings in an angular configuration. The presence of the acetoxy group at the C-3 position of the b-lactams has proved to be obligatory for their antitumor activity [86]. Moreover, potent inhibiting properties exhibited by 7-alkylidene substituted cephalosporanate sulfones against tumor strains, both in vitro and in vivo [42], motivated researchers to subject penicillanate sulfones, together with 4-heteroaryldithio- and 4-methylsulfonylazetidin-2-ones, containing alkylidene side-chain, respectively, at the C-6 and the C-3 positions, to similar biological investigations. Veinberg and coworkers in 2004 have tested in vitro the cytotoxic properties of these compounds [395]. Their analysis has evidenced that the incorporation of tert-butoxycarbonylmethylene, benzylidene, and 4-nitrobenzylidene structures at the C-6 position of penicillanate sulfoxides and sulfones and at the C-3 position of 4-heteroaryldithio- and 4-methylsulfonylazetidin-2-ones, in many cases provided antitumor effect. Salinosporamide A and omuralide (I and II, respectively, Fig. 47), are potent naturally derived substances that inhibit proteasome function with very high selectivity [396–402].

Novel and Recent Synthesis and Applications of b-Lactams

195

O H3CCO R=

;

N O

R

Fig. 46

H

O

H N

OH O O Me

O

H N

O

H N

O

Me

Cl

I

OH O

II

OH O NH

Cl

III

O

H N

OH CO2CH3 H NH

H

IV

Fig. 47

Proteasome inhibition offers considerable promise in the therapy of a number of types of cancer and is already used for multiple myeloma [403–405]. A potential problem with the use of compounds I or II as therapeutic agents, is their short halflife in solution at pH 7 or in serum (estimated as 5–10 min). Because of this potential shortcoming, in 2005 Hogan and coworkers have developed a synthesis of the b-lactam III of Fig. 47, which is expected to be much more stable than the corresponding b-lactone (I or II, Fig. 47), [406]. The pathway of proteasome inhibition by the b-lactam III followed that of omuralide and salinosporamide A, that consisted in the acylation of a catalytically active threonine of a proteolytic b-subunit. This acylation was made irreversible by ring closure involving the chloroethyl group as an electrophile, as in the case of salinosporamide A [407], since treatment of III with methanolic base afforded the bicyclic pyrrolidine IV (Fig. 47). These results, together with the observation of proteasome inhibition in vitro, and the indefinite stability in neutral aqueous solution suggested that compound III was a worthy candidate for further biological evaluations. In 2006 the preparation of simplified analogs of natural occurring enediynes, e.g. antitumor antibiotic dynemicin, was reported by Banfi and coworkers. They succeeded in synthesizing two different classes of such compounds where the embedded 10-membered enediyne system is fused either with a b-lactam ring (lactenediynes) or with an epoxide. Biological tests on these molecules have demonstrated that some representatives are able to cleave the double strand of DNA even at very low concentrations [408].

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In 2007 a series of b-lactam derivatives was designed and synthesized to inhibit the chymotrypsin-like activity of the human 20S proteasome. The most potent compounds of this new structural class of b-subunit exhibit good selectivity over the trypsin-like and post-glutamyl-peptide hydrolytic activities of the enzyme [409]. In 2008 a series of novel b-lactam containing compounds were described as antiproliferative agents and potential selective modulators of the estrogen receptor. The compounds were designed to contain three aryl ring substituents arranged on the heterocyclic azetidin-2-one (b-lactam), thus providing conformationally restrained analogs of the triarylethylene arrangement exemplified in the tamoxifen type structure. These molecules showed high antiproliferative effects on human breast cancer cell line at low micromolar to nanomolar concentrations with low cytotoxicity and moderate binding affinity to the estrogen receptor. The effect of a number of aryl and amine functional group substitutions on the antiproliferative activity of the b-lactam products was reported and a brief computational SAR with molecular simulation was investigated [410].

4.4.11

Antiviral Activity

HCMV, a b-herpesvirus, is an opportunistic pathogen in immunocompromised individuals such as AIDS patients and organ transplant recipients [411]. Thus HCMV protease has become a viable target for antiviral chemotherapy [412, 413]. Several monobactams incorporating a benzyl side-chain at the C-4 carbon atom, such as compounds of Fig. 48, have been reported to be selective inhibitors of HCMV protease [367]. Substitution at the C-3 position was tolerated and gave small increases in stability and enzymatic activity. These compounds were much less selective however, than the corresponding inhibitors that were unsubstituted at the C-3 position. Substitution of the urea moiety suggested that benzyl groups were the best choice at this position. Both tri- and tetra-substituted ureas were effective, with tetra substitution giving a slight stability advantage. Modification of the benzyl function indicated that strong electron-withdrawing groups at the para position had the best activity. Moreover, mechanistic investigations indicated that these compounds are reversible and competitive inhibitors of HCMV protease and that inhibition involved the formation of an acyl-enzyme species [367]. R1 2

R

N

O

O

5

R

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Fig. 48

3

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CO2R1 H N

N

N

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X

O O

R2

O

R

II: X = NH, O; R1= t-Bu, H R2 = Ph, CH(CH3)Ph, t-Bu, CH2Ph

Ia: R = H Ib: R = (R)-Me Ic: R = (S)-Me

Fig. 49

CO2t-Bu N

R

O

a: R =

O H N

f: R =

O

Ph Ph

g: R =

O

t-Bu

O

(4S) CO2R H N N *

Ph 1'

O

(4R ) CO2R H N N *

Ph 1'

O

O

(4S, 1'S)-b: R = t-Bu (4S, 1'R)-c: R = t-Bu

(4R, 1'S)-d: R = t-Bu (4R, 1'R)-e: R =t-Bu

Fig. 50

Among these latter inhibitors, a series of monocyclic b-lactams I (compound Ia being the prototype, Fig. 49), has resulted in highly potent derivatives in the isolated enzyme assay, but their efficacy in cell culture was quite limited, as described for all inhibitors of this enzyme [367, 414–416]. Gerona-Navarro and coworkers in 2004 have reported the synthesis and the evaluation of a series of new 2-azetidinones (Fig. 50), derived from phenylalanine [281], which were designed on the basis of the structure of the reported b-lactam inhibitors [367] and the residues implicated in the active site of the HCMV protease [417]. These compounds have been evaluated against HCMV in human embryonic lung cells [418], and the results compared to those obtained for the reference compounds, which were the model b-lactam Ia of Fig. 49, the viral DNA polymerase inhibitors DHPG (ganciclovir), and HPMPC (cidofovir). The obtained results have shown that the trisubstituted b-lactams a–e of Fig. 50 exhibited some antiviral activity, slightly higher than that reported for the prototype 2-azetidinone Ia of Fig. 49. No appreciable influence of the absolute configuration, either at the C-4 or at the 1-phenylethyl substituent, on the inhibition of viral replication, was observed. The presence of an aromatic group at the 1-acyl

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substituent seemed to be important for the antiviral activity, as deduced from the lack of activity of the tert-butoxycarbonyl derivative g and the presence of activity of the benzyloxycarbonyl analog f, (Fig. 50). This latter compound showed the highest anti-HCMV activity within the b-lactam series, but with a very narrow therapeutic window, having a cell toxicity value close to the IC50 data for viral inhibition [263]. Interestingly, removal of the carbonyl group from the b-lactam ring, most likely acting as the serine trap, resulted in an azetidine derivative with anti-HCMV activity comparable to that of the reference compound ganciclovir [281, 419].

5 Concluding Remarks A comprehensive overview of the most significant and interesting developments on the synthesis of novel b-lactam compounds has been presented. The contributions examined are those published from 2000 till date; the literature survey was organized by type of reaction, and, among them, by year. The synthetic strategies reported are based either on novel methodologies or on already known but efficient and versatile protocols. An alternative methodology, reported in a separate paragraph, was the modification of preexisting groups linked at the different positions of the 2-azetidinone ring. Considering that the core structure of four-membered cyclic amide is the common feature of the antibacterial compounds, and that their biological and pharmacological activity are strictly related to the substituents linked to this small heterocycle, the modification of these linked groups not only afford new b-lactam derivatives, more complex and polyfunctionalized, but can produce molecules even more efficient in their activity. For this reason, a single paragraph of this chapter was focused on the studies reported in literature concerning the SARs of the b-lactams examined, with the aim of highlighting the possibility of designing new and even more efficient b-lactam compounds. We believe that this chapter can become an essential part of the knowledge of organic chemists who can plan the synthesis of novel substituted 2-azetidinones. Moreover, medicinal chemists can have an overview, covering the latest developments in the biological and pharmacological applications of these 2-azetidinone compounds, thereby giving focus to their future investigations.

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Top Heterocycl Chem (2010) 22: 211–259 DOI 10.1007/7081_2009_11 # Springer‐Verlag Berlin Heidelberg 2010 Published online: 22 January 2010

b-Lactam Ring Opening: A Useful Entry to Amino Acids and Relevant Nitrogen-Containing Compounds C. Palomo and M. Oiarbide

Abstract The main strategies for the ring opening of b-lactams by chemical means are described. The discovery of each approach is put into context, sometimes in connection to processes occurring in biological systems, and the synthetic opportunities each approach offers are shown. Thus, this b-lactam route affords a number of synthetically relevant building-blocks, including a-amino acids, b-amino acids, their derived peptides, and other nitrogen containing heterocycles and open chain molecules. The content, which encompases references to initial work, further major development, and the most relevant recent literature contributions, is categorized according to the ring bond cleavaged (N1–C2, C2–C3, C3–C4, N1–C4), to finish with ring opening strategies leading to large heterocyclic compounds. Within each category, distinction has been made according to the type of nucleophilic agent employed, principally O-, N-, and C-nucleophiles. Also, a variety of applications of the strategy to the synthesis of interesting target compounds are shown. Keywords a-Amino acids b-Amino acids b-Lactams Peptides Ring opening Contents 1 2

3

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 Ring Opening at N1–C2 Bond of b-Lactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214 2.1 Ring Opening by Oxygen Nucleophiles: b-Amino Esters and Related Products . . . 219 2.2 Ring Opening by Nitrogen Nucleophiles: b-Amino Amides and b-Amino Acid-Derived Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 2.3 Ring Opening by Carbon Nucleophiles: b-Amino Ketones and Related Products . . . 231 2.4 Ring Opening by Hydrides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 Ring Opening at C2–C3 Bond of b-Lactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236

C. Palomo (*) and M. Oiarbide Departamento de Quı´mica Orga´nica I, Facultad de Quı´mica, Universidad del Paı´s Vasco, Apdo. 1072, 20080, San Sebastia´n, Spain e-mail: [email protected]

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C. Palomo and M. Oiarbide

3.1 NCAs Bearing Side Chains from Nonproteinogenic a-Amino Acids . . . . . . . . . . . . . . . 3.2 NCAs of a, b-Diamino Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 NCAs of a-Branched a-Amino Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Ring Opening at C3–C4 Bond of b-Lactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Ring Opening at N1–C4 Bond of b-Lactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Large Ring Heterocycles from b-Lactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Concluding Remarks and Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abbreviations Ac AcOH AD Ar Bn Boc Bu Bz CAN Cbz cHex CSA DCC DIBAL DMAP DMD DMF DMSO Et Fmoc Gly HMDS HMPA HOBt LDA Leu LHMDS mCPBA Me MS NCA

Acetyl Acetic acid Asymmetric dihydroxylation Aryl Benzyl tert-butoxycarbonyl Butyl Benzoyl Ceric ammonium nitrate Benzyloxycarbonyl Cyclohexyl Camphorsulfonic acid N,N-dicyclohexylcarbodiimide Lithium diisobutylaluminium hydride 4-(dimethylamino)pyridine Dimethyldioxirane Dimethylformamide Dimethyl sulfoxide Ethyl 9-fluorenylmethoxycarbonyl Glycine (glycinyl) Hexamethyldisilazide Hexamethylphosphoric triamide N-hydroxyl benzotriazole Lithium diisopropylamide Leucine (leucinyl) Lithium hexamethyldisilazide 3-chloroperoxybenzoic acid Methyl Molecular sieves N-carboxy anhydride

238 241 242 243 244 249 252 255

b-Lactam Ring Opening: A Useful Entry to Amino Acids

NDC NMM Nu PDC Ph Phe PMP Pr p-Tos p-Tolyl SEM Succ TBAF TBDPS TBS TEMPO TES TFA THF Thz TIPS TMS TMSOTf UV Val

213

Nicotinium dichromate N-methyl morpholine Nucleophile Pyridinium dichromate Phenyl Phenylalanine (phenylalaninyl) 4-(methoxy)phenyl Propyl 4-(methylphenyl)sulfonyl 4-methylphenyl 2-(trimethylsilyl)ethoxymethyl Succinyl Tetrabutylammonium fluoride tert-butyldiphenylsilyl tert-butyldimethylsilyl 2,2,6,6-tetramethylpiperidinyl-1-oxyl Triethylsilyl Trifluoroacetic acid Tetrahydrofuran 2-thiazolyl Triisopropylsilyl Trimethylsilyl Trimethylsilyl trifluoromethanesulfonate Ultraviolet Valine (valinyl)

1 Introduction After the first successful attempts in 1928 to identify the active biochemicals found in antibacterial molds, followed the rediscovery of penicillin by Fleming, identification of its chemical structure by Hodgkin, and subsequent synthesis by Chain, Heatley, and Florey, which led to the commercial production of penicillin in the mid 1940s [1]. Since then, other families of b-lactam antibiotics have been developed [2, 3], and their massive use worldwide continues to be a forefront line of action against infectious pathogens [4–6]. In recent years, b-lactams have found other biomedical applications, such as inhibitors of serine protease ([7, 8]; for a review, see [9]) and inhibitors of acyl-CoA cholesterol acyltransferasa (ACAT) [10]. Encouraged by their bioactivity, the synthesis and chemistry of b-lactam antibiotics have been the focus of active research, and chemical modification of some basic structures available from biosynthesis (semisynthetic approaches) as well as the discovery of fully chemical routes to de novo synthesis of b-lactam

214 Fig. 1 Principal strategies for the selective ring opening of b-lactams

C. Palomo and M. Oiarbide R1 C2–C3 (R1= OH, O)

N O N1–C2

R2 N1–C4 (R2= Ar)

compounds, have been pursued ([11–13]; for synthetic strategies and medicinal properties of b–lactams, see [14]). Subsequent to this effort, a number of methods have become available for the delivery of the 2-azetidinone core ring present in all b-lactam compounds [15–20]: namely, the ketene-imine cycloaddition or Staudinger reaction ([21]; for reviews, see [22]; [23–25]), the ester enolate-imine condensation (for reviews, see [26]; [27–32]), the hydroxamate approach [33], the alkene-isocyanate cycloaddition [34], and the alkyne-nitrone cycloaddition (Kinugasa reaction) ([35–39]; for a highlight, see [40]). Complementing the interest in the formation of the 2-azetidinone ring, the cleavage of 2-azetidinones also bears important biological as well as chemical implications. On the one hand, the irreversible ring opening of the 2-azetidinone core accounts for one of the key biomolecular events during both the b-lactams antibiotic action [5, 12–14] and their inhibition by b-lactamases [12–14, 41–45]. On the other hand, the chemically controlled ring opening of the 2-azetidinone system has been demonstrated as a powerful tool for the synthesis of important building blocks, especially heterocycles, a- and b-amino acids, and derivatives (for chemical methods, see [46]; for a review on enzymatic methods, see [47]; [48–51]; for a recent example [52]; [53]). In this chapter, the most general approaches for the selective ring opening of the b-lactam unit are described and a selection of relevant developments are shown, including the most recent examples in the area. Three major bond breaking strategies of the b-lactam unit have been developed so far, Fig. 1. The most intuitive scission corresponds to that of the amide bond (N1–C2) cleavage, and involves the attack of some nucleophile species, most often N- and O-centered nucleophiles. A second strategy is feasible for b-lactams bearing a hydroxyl group attached at the C3 position (also for a-keto b-lactams), and consists of the oxidative Baeyer-Villiger type rearrangement of the derived a-keto b-lactams. The third strategy can be applied for b-lactams bearing an aryl group attached at the C4 position. The selective N1–C4 bond cleavage in these substrates can be achieved under hydrogenolytic conditions.

2 Ring Opening at N1–C2 Bond of b-Lactams b-Lactams can act as acylating agents to those nucleophiles that effect the cleavage of the b-lactam N1–C2 bond. Indeed, irreversible acylation of an enzyme amino acid unit belonging to a bacterial cell is the most common type of molecular mechanism for the b-lactam antibiotics mode of action. Similarly, the process is on grounds of

b-Lactam Ring Opening: A Useful Entry to Amino Acids Fig. 2 N1–C2 bond cleavage leading to b-amino acid derivatives

215 O

R2

R1

O

N

O

H N

Me

O

O

N

O

O

O

O

O O N

R2 R1

O

HN

NH

O

O O

Me

O O

NH

N H

Onchidin 1

O

MeOH, HCl (g) H3CO

NH O

NH2

2

3

Scheme 1 Acid methanolysis of b-lactam 2 in the synthesis of key b-amino acid unit of onchidin, 1

their inhibition by b-lactamases. This reactivity of the b-lactam ring has been exploited in the laboratory in the context of the synthesis of b-amino acid derivatives, Fig. 2. The majority of the early procedures for the cleavage of the b-lactams N1–C2 bond deal with hydrolysis and alcoholysis processes under rather harsh acid or basic reaction conditions. One example is the ring opening of b-lactam 2 under acidic conditions to afford almost quantitative b-amino ester 3, a component of the dimeric cyclic depsipeptide onchidin, 1, isolated from the marine mollusc Onchidium sp., Scheme 1 [54]. Similarly, the acid hydrolysis of b-lactam 7 has been described [55] to give the a-hydroxy b-amino acid 8, a suggested N-terminal component of angiotensinconverting enzyme inhibitor microginin 4, Scheme 2. The key precursor 7 was obtained through a Wittig olefination of the 4-formyl b-lactam 5, followed by simple elaboration of the resulting 6 (for a review on the use of 4–formyl b–lactams in synthesis, see [56]). In an intramolecular variation [57], the acid-promoted alcoholysis of the b-lactam ring in 10, Scheme 3, produced 2,3-aziridino-g-lactones 11, which are intermediates of glutamic acid derivatives with potential activity as excitatory neurotransmitter of the central nervous system.

216

C. Palomo and M. Oiarbide OH NH2 O

Me

H OH N

N H

O

N H

O

Me

CO2H

O

4

BnO

H H

O CH3(CH2)5PPh3Br

H N

O

BnO

5

1. H2, Pd/C (10%), 50 psi, 6 h, EtOAc, 90%

H H N

nBuLi, THF 0 °C, 6h, 75%

PMP

OH

O

2. Ce(NH4)2(NO3)6, CH3CN/H2O 0° C, 25 min, 85% 3. HCOONH4, Pd/C (10%), MeOH, reflux, 6 h, 95%

PMP 6

H H

HO

CO2H

2. Dowex 50W x 2-400 5% NH4OH, 70%.

N O

OH

1. 3M HCl, 60 °C, 6 h H

NH2 8

7

Scheme 2 Acid hydrolysis of NH-b-lactam 6 in the synthesis of microginin, 4

RO

H H

OR' MsO

R'' N

O

H H

OH R'' HCl, MeOH (20%)

N

PG

O

9

PG

H

reflux, 8-24 h

10

O

80–86%

PG N O

H H R''

11 R''= H, CH2OH

PG: Bn, PMP, p-tolyl

Scheme 3 Intramolecular acid alcoholysis of b-lactams leading to g-lactones

O NH

rac-12

CO2H NH2

aq. HCl (con.), r.t., 8 h, 90%

rac-13

Scheme 4 Acid hydrolysis of NH b-lactam to homoadamantyl b-amino acids

A further example of the use of acid hydrolysis of the b-lactam nucleus is the transformation of 12 into homoadamantyl b-amino acid derivatives like 13, which are precursors of potential candidates for treatment of cancer and degenerative brain diseases [58] (Scheme 4).

b-Lactam Ring Opening: A Useful Entry to Amino Acids

217 O

N

N O

O

PhO

O

N

PhOCH2COCl, Et3N

N O

CH2Cl2, –78 °C, 78%

OPh

O

14 15

O 10N HCl, H2O, 85%

PhO

OH

HO

HN

NH O

O OPh

O 16

Scheme 5 Synthesis and subsequent cleavage of azetidin-2-one ring of bis-b-lactams

Z N

1. LiOH, THF, H2O, 99% 2. Pd/C (10%), MeOH, H2, 93% N

O

Boc

3. Fmoc-Osucc, iPr2NEt, CH2Cl2, 68%

17

NHBoc CO2H N Fmoc 18

Scheme 6 Basic saponification of the b-lactam amide in compound 17

In a similar way, formation and subsequent hydrolysis of bis-b-lactams provide a route to peripheral functionalization of macrocyclic imines. For example, racemic bis-b-lactam 15, Scheme 5, which is formed upon Staudinger reaction of imine 14 and the ketene originated from phenoxyacetyl chloride and triethylamine, led to C2 symmetric amino acid 16 in high yield [59]. Most traditional methods use hydrochloric acid solutions as the acid reagent for the hydrolysis or alcoholysis of b-lactams. Methanolic solutions of trimethylchlorosilane are able to generate HCl in situ, and the trick has been employed successfully for the methanolysis of b-lactams in a route to aspartic acid derivatives [60, 61] and 2-oxazolidinones[62], respectively. Recently the use of silica-supported acid reagent has been reported as a convenient alternative. The reagent (SiO2–Cl) prepared from admixing silica gel and SOCl2 in dichloromethane and subjected to dryness, is able to run the methanolysis of b-lactams at room temperature in 20 min [63]. Alternative to the acid hydrolysis of the b-lactam amide system is the base promoted saponification reaction. Robinson and Pluschke [64] have employed the LiOH-promoted hydrolysis of the bicyclic b-lactam 17 as a means to the synthesis of key diamino acid residue 18, employed in the preparation of a malaria-vaccine candidate, Scheme 6. Saponification of the bicyclic b-lactam 21 to yield 22 has been employed by Corey [65] as an experimental evidence of the mechanism-based design of

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C. Palomo and M. Oiarbide

1. 1-Chloro-N,N,2-trimethyl1-propenylamine CH2Cl2, -78 ºC → 23 ºC

O BocN

O

O O BocN

2. Et3N, CH2Cl2, 23 ºC 43% (two steps)

HO2C

Me

19

PMP 5. Et3N·3HF, THF, 23 ºC, 1 h N H 86% (two steps) 6. Ph3PCl3, pyridine, CH3CN TMS Me 23 ºC, 3 h, 80% 20 7. CAN, 1:1 CH3CN/EtOAc, H2O 75 min, 89%

O PMP

N O

O

H N

TMS

OH O

1M LiOH

N H Cl

O

1. Cs2CO3, MeOH, 23 ºC, 3 h, 94% 2. 32% w/w CH3CO3H/CH3CO2H CH2Cl2, NaOAc, 23 ºC, 2 d, 70% 3. Pd-C, THF, H2, -20 ºC, 24 h, 91% 4. TMSOTf, 2,6-lutidine, CH2Cl2, 23ºC 2 h, MeOH, Et3N

1:1 MeOH/H2O 40 ºC, 3 h, 75%

O

H N

H

OH CO2Me H NH 22

21

Scheme 7 Saponification of bicyclic b-lactam 21 as a test for the proteasome inhibition activity of parent compound 20

R1

R2 H

OMe Ph

•

N O

PMP

Ph NaOMe MeOH, r.t., 8–96h 50–77%

R2 R1 MeO2C

N PMP

Me

23

Me R1 O H

•

R2

N O

PMP

R1

CO2Me

NaOMe MeOH, reflux, 2–54h 49– 68%

Me

N PMP

R2

24

Scheme 8 Opening of N-aryl b-lactams with methoxide leading to pyrroles

proteasome inhibition compound 20, Scheme 7. Synthesis of b-lactam 21 was carried out by the [2+2] cycloaddition reaction of ketene generated from acid 19 and the corresponding imine, and subsequent elaboration of the resulting b-lactam 20. When N-substituted b-lactams are involved, the ring opening effected by metal alcoxides is feasible if the substituent group on the nitrogen is a phenyl. In contrast, N-alkyl substituted b-lactams ring remained unaltered under such conditions [66]. By using the appropriate b-lactam substrate, such as allenyl derivatives 23 and 24 the ring opening effected by sodium methoxide in methanol yields tetrasubstituted pyrroles, Scheme 8. In these transformations, the evolving amine function adds to the allenyl moiety with concomitant aromatization of the newly formed fivemembered ring through b-elimination of an alkanol unit.

b-Lactam Ring Opening: A Useful Entry to Amino Acids

219

Class C b-lactamases

EnzOH

NuH

EnzO

N

NH

O

O

Nu

NH O

EnzOH

Chemical NuH

XH N O

X

NH O

Nu XH

NH O

Scheme 9 Enzymatic and chemical ring opening of b-lactams via N1–C2 bond cleavage

The examples discussed above constitute a selection of recent applications of the acid and basic hydrolysis of b-lactams in synthesis. Hydrolysis and alcoholysis of b-lactams can also be effected under roughly neutral reaction conditions when enzymes are the promoters [47]. The b-lactamases catalyzed hydrolysis of b-lactams is an efficient process for a broad spectrum of substrates, including those b-lactams with base or acid sensitive groups [12–14]. This process proceeds through an acyl enzyme intermediate to give ring opened b-amino acids. The class C b-lactamases in particular, in Scheme 9, have the ability to catalyze the alcoholysis reaction and hence b-amino esters are the products formed. Besides enzymes, other chemical promoters have been developed for the N1–C2 bond cleavage of activated b-lactams under not so drastic acid or basic conditions. To this end, the use of N-acyl b-lactams, i.e. N-Boc b-lactams, as activated substrates has assumed major importance. The N-acyl group on the substrate b-lactam serves not only to activate the b-lactam carbonyl towards the nucleophile attack, but also to protect the amino function in the resulting b-amino acid derivative product (for the application of this concept to g- and d- lactams, see [67]). A recent study has revealed N-sulfonyl b-lactams as another class of activated b-lactams towards the ring opening by both N- and O-nucleophiles [68].

2.1

Ring Opening by Oxygen Nucleophiles: b-Amino Esters and Related Products

The most representative example of the utility of b-lactams as acylating agents is the coupling reaction of the b-lactam 25 Scheme 10, with the sodium salt of vacatin III to give paclitaxel ([69–73]; for a recent example involving kinetic resolution of racemic b–lactams, see [74]), after mild deprotection of the TES group.

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C. Palomo and M. Oiarbide

O

AcO

Ph

O N

OH NaHMDS

+ HO O

O

HO

Ph

25

O

O H OBz OAc

THF, –30 °C, 30 min, 93%

vacatin III O 0.5% HCl

Ph

AcO

Ph

OH

O OH

25 °C, 36 h, 99%

O

NH O

O HO OBzHOAc

TaxolÒ (paclitaxel)

Scheme 10 N-acyl b-lactam 25 as acylating reagent of vacatin III in the last synthetic step towards paclitaxel

H H

ROH, NaN3 or KCN (10%)

AcO N O

Boc

DMF, r.t., 24-30 h, 70-90%

CO2R

BocN H

26 R: CH3

R: C6H5CH2CH2

R: C6H5CH2

R: (C6H5)2CH

R: 4-NO2C6H4CH2

R: c-C6H11

OAc 27

Scheme 11 Alcoholysis of b-lactams in the presence of NaN3 or KCN as the reaction promoters

In general, the ring opening of N-acyl b-lactams by the action of an alkoxylate salt produces the expected esters when the peripheral substituents on the b-lactam ring are not base sensitive. If free alcohols are used instead, with the aim of avoiding the strongly basic media, the coupling reaction is in general so slow that it is not useful. In this context, NaN3 and KCN were identified in the middle 90s as two very efficient promoters of the ring opening of N-Boc b-lactams with free alcohols. This trick permits couplings to take place under almost neutral conditions and makes the method more effective than the use of alkoxylate salts in some instances. For example, the alcoholysis of 26 to give 27, Scheme 11, in the absence of these additives is exceedingly slow, while in the presence of a 10 mol% of NaN3 or KCN, the coupling proceeds smoothly to give b-amino esters 27 in good to excellent yields. Interestingly, under these conditions the acetoxy group remains intact, whilst under the basic conditions of MeONa or EtONa, it is also cleaved [75]. Using spiro-b-lactams as substrates, Alonso [76] has applied this trick for the synthesis of a,a-cyclic disubstituted b-amino esters 29, Scheme 12, which might be useful units for the design of b-peptides with new folding patterns.

b-Lactam Ring Opening: A Useful Entry to Amino Acids Y

X

O

R

KCN, MeOH

N O

221

MeO

rt, 16 h, 93-95%

Boc 28

R NHBoc

X Y

X, Y= O, CH2

29

Scheme 12 KCN-promoted cleavage of b-lactams leading to a,a-cyclic disubstituted b-mino esters 29 AcO

I

Me H

Me

AcO

Me SnBu3

NBoc O OTBS

MeOH, KCN

Me

OTBS

SEMO

SnBu3

OTBS

Me

Me

30

AcO Me

I CO2Me OTBS

DMF, 89%

SEMO

Boc Me

HN Me

HN Me

31

Boc Me

OH Me 32

HN Me

O

O

Me

CO2Me OTBS SEMO

O

CO2Me

HO

Me

OH Me lankacidin C

Scheme 13 KCN-promoted methanolysis of b-lactam 30 en route to lankacidin C synthesis

The implementation of this methodology for a synthesis of advanced macrocyclic precursors of antitumor antibiotics lankacidins, which posses a carbocyclic structure, has been reported by Thomas [77]. In such a route, Scheme 13, one of the key steps is the ring opening of the b-lactam nucleus in 30 by methanol, assisted by KCN, to give the corresponding b-amino ester intermediate 31. The latter, upon cyclization and protecting group manipulation, renders 32, which on subsequent elaboration affords lankacidin C. Taking advantage of the same concept in an intramolecular variant, Romo has documented [78] the synthesis of ( )-panteamine A, Fig. 3, in which a b-lactam-based macrocyclization is the crucial step to construct the b-amino macrolactone 33. Of the different reaction conditions used for the intramolecular coupling of the secondary alcohol and the b-lactam unit in 34, Scheme 14, the use of KCN or Et4NCN as additives give the best results. Further elaboration of 35 leads to the immunosuppressive agent ( )-panteamine A. A related example (Scheme 15) of the utility of b-lactams as acylating agents for macrolactonization has been reported by Georg in an approach to the antimicotic agent cryptophycin 37 from precursor 36 [79, 80].

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C. Palomo and M. Oiarbide

Fig. 3 b-Amino acid unit constituent of panteamine A

Me S NMe2 N

Me

Me

O O

H2N

(–)-Panteamine A, 33

Me O

S Me

N

Me

b-Lactam-Based Macrocyclization

S

Br O

Me

Me

Br

N

O Me

O

BocN O

O

O

BocNH OH

Me O

Me

O

Me

34

35 Temp. ºC

Yield %

1.1 eq. NaHMDS, THF, 45min

Conditions

–40

37

1.1 eq. LiHMDS, THF, 2.5h

–40

11

1.1 eq. NaH, THF, 1h

–10

42

0.5-0.6M KCN, DMF, 1-2h

25

52-72

9.0 eq. Et4NCN, CH2Cl2, 4-9h

25

59-68

Scheme 14 b-lactams as intramolecular O-acylating reagents (I). A route to (-)-Panteamine macrolactone

O O

O

HN O

OH

N

OMe

O

36

1. BF3·Et2O, CHCl3 2. PhI, Pd(OAc)2, CH3CN 3. DMD

20%

O O

Scheme 15 b-Lactams as intramolecular O-acylating reagents (II). A route to Cryptophycin

O

HN

O

N H 37

O

OMe

b-Lactam Ring Opening: A Useful Entry to Amino Acids

223

More recently, Dondoni [81] has shown the methanolysis of N-Boc b-lactams in the presence of excess Et3N (5 equivalents) and DMAP (3 equivalents), Scheme 16. In this work, b-lactams containing a sugar residue as in 38 were transformed in the corresponding isoserine derivatives 39, in high yields and without compromising configurational integrity.

Ring Opening by Nitrogen Nucleophiles: b-Amino Amides and b-Amino Acid-Derived Peptides

2.2

From the ring opening of b-lactams by amines and a-amino acids, b-amino amides and b-amino acid derived peptides are generated. These structures are of interest because of their presence in several naturally occurring macrocyclic compounds [82, 83]. One example of the latter is the b-hydroxy aspartic acid derived tripeptide 45 found in the macrocyclic peptide lactone antibiotic lysobactin 40 [84], Fig. 4. The key step of the approach to 45 is the ring opening of N-Boc b-lactam 43 with ammonia, Scheme 17. The synthesis starts from the 4-carboxy azetidin-2-one 41, which is a b-hydroxy aspartic acid form possessing the b-carboxyl group and the a-amino moiety simultaneously protected. The dipeptide unit 42 is obtained in 95% overall yield after activation of the a-carboxy group with cyanuric fluoride and BnO H H

OBn OBn

Et3N, DMAP

AcO O

O N H Boc 38

OBn

O

BnO

MeOH, rt, 48 h, 90%

H

NHBoc CO2Me OH OBn

BnO

OBn 39

Scheme 16 Methanolysis of N-Boc b-lactams under basic conditions

O OH H N

H2 N O HO

NH O

NH

O

OH O

HN H H N

H2N O

Fig. 4 Structure of antibiotic lysobactin

Ph O N H

O

O H N

O

O HO lysobactin 40

N H

H HN N O H2N

NH N H

O

224

C. Palomo and M. Oiarbide

H H BnO N O

CO2H

Cyanuric fluoride, Py then L-(S)-Ser(OBn)OBn

PMP

CH2Cl2, NMM, r.t., 95%

BnO

H H N

O

OBn

O N H R

41 1. (NH4)2Ce(NO3)6, CH3CN-H2O 0 ºC, 85%

42 R: PMP

2. (Boc)2O, DMAP

43 R: Boc

O

DMF, 90% BnO

O OBn

H2N

NH4OH

CF3CO2H, CH2Cl2

O

NHBoc NH

OBn O

H2N O

then BocGlyF, NMM 70% BnO

CO2Bn

CO2Bn

NH CO2Bn

N H

NHBoc

45

44

Scheme 17 Ammonolysis of N-Boc b-lactams as a route to b-amino acid-containing peptides

subsequent coupling with O-benzyl L-(S)-serine benzyl ester. N-Dearylation followed by incorporation of the Boc group and ring opening with ammonia in DMF as solvent renders the carboxamide 44 in 90% yield. Subsequent N-Boc deprotection and coupling with Boc-GlyF provides tripeptide 45 in 70% yield [85]. Although aminolysis of N-acyl b-lactams can be effected in aqueous media by amines without the assistance of any additional promoter [86], the use of some additives can considerably speed up the process in ordinary organic solvents. For instance, although the ammonolysis of the b-lactam 43 proceeded efficiently even in the absence of any additive, the presence of NaN3 has been shown to be crucial for the coupling of b-lactams with a-amino esters to be efficient ([87]; for a related work, see [88]). It has been found that, for example, coupling of the N-Boc b-lactam 46 with (S)-LeuOBn, Scheme 18, to give the dipeptide product 47 in an appreciable yield necessitates a fourfold excess of the a-amino ester component, while the same reaction performed in DMF, and in the presence of NaN3, proceeds in high yield by using just an equimolar amount of both coupling components. Similarly, the reaction of 46 with the more sterically crowded (S)-ValOBn in DMF produces 48 in 22% yield when a 1:2 ratio of components is employed, respectively, and only traces of 48 are detected for a 1:1.3 ratio. In contrast, when NaN3 is used as an additive, the desired product is obtained in 80% yield under the same conditions. Both 47 and 48 can be transformed into bestatin 49 and phebestin 50, respectively, two low molecular weight peptides that show marked inhibition of aminopeptidases. The utility of these promoters to achieve an efficient coupling of a-amino b-lactams with a-amino acid esters has also been documented [89]. For example, b-lactam 51, Scheme 19, upon treatment with (S)-PheOMe and (S)-ValOMe in DMF, in the presence of NaN3, furnishes dipeptides 52 and 53 respectively, in good

b-Lactam Ring Opening: A Useful Entry to Amino Acids H H

BnO

(S)-LeuOBn or (S)-ValOBn NaN3 (1 equiv.)

N O

225

DMF, r.t., 16-20 h

Boc

N CO2Bn OBn H 47 R: CH2CH(CH3)2 83% 48 R: CH(CH3)2

1. F3CCO2H, CH2Cl2, 0 °C 2. H2, Pd/C, EtOH, r.t., 98%

O

OH

O N H

CO2H

R

BocN H

46

H2N

O

H2N OH

N H

80%

H N

CO2H

O

Ph

phebestin 50

bestatin 49

Scheme 18 NaN3-promoted opening of b-lactams with a-amino esters Ph H H

CbzN H

N O

Ph Boc

O

(S)-H2NCH(R)CO2Me, NaN3 DMF, r.t.

51

BocN H

N H NHCbz 52 R: CH2Ph

R CO2Me 73%

53 R: CH(CH3)2 77%

CbzN H

H Me Me N

O

Boc

(S)-PheOMe, KCN (1 equiv.) DMF, r.t., 10 h, 89%

Me BocN H

54

Me O N H NHCbz

Ph CO2Me

55

Scheme 19 NaN3- and KCN-promoted opening of N-boc b-lactams

yield. Nevertheless, the b-lactam 54, possessing a quaternary carbon center at C4, does not react with these a-amino acid esters even when a twofold excess of NaN3 is employed to promote the coupling reaction. In this and other instances that involve difficult coupling reactions, KCN may be the additive of choice. For example, dipeptide 55 is produced within about 10 h in 89% isolated yield when KCN is employed instead of NaN3. Further examples of the coupling of b-lactams with a-amino acid esters are shown in Scheme 20. For instance, 57, prepared from 56, reacts with a-amino acid esters in the presence of NaN3 to give tripeptides 58 and 59. In addition, simple exposure of 57 to hydrogen over Pd/C at room temperature produces the piperazinedione 60 in 90% yield. The effectiveness of KCN in promoting difficult couplings can be further shown in the reaction of a-amino a-branched b-lactams with a-amino esters [90].

226

C. Palomo and M. Oiarbide

H2N

H H

1. (S)-Z-LeuCOF, NMM, 80% 2. (Boc)2O, DMAP, CH3CN, 90%

NH O

CbzN H

56 (S)-H2NCH(R)CO2Me, NaN3 or KCN (1 equiv.) DMF, r.t.

HN

O

N

N H

H2, Pd/C, EtOH r.t., 14 h, 90%

CO2Me

O

H BocN H

Boc

O 57

R

O BocN H

H H H N

O NH

HN

NHCbz O 80% 58 R: CH2Ph 59 R: CH(CH3)2 75%

60

Scheme 20 Coupling of N-Boc b-lactams with a-amino acid esters

Ph O

BocN H

(S)-LeuOMe, KCN (1 equiv.) N

O 61

Boc

DMF, r.t., 19 h, 75%

H BocN BocN H

N H

CO2Me

Ph 62

Scheme 21 KCN-promoted opening of b-lactams leading to a,b-diamino acid containing peptides with a quaternary carbon

Whilst compound 61, Scheme 21, upon treatment with (S)-LeuOMe and NaN3 does not produce the corresponding dipeptide product, the reaction in the presence of KCN leads to dipeptide 62 in 75% isolated yield. The coupling reaction of a-unsubstituted b-lactams, bearing a quaternary carbon atom at C4, constitutes another good example of the ability of KCN to promote b-lactam ring opening, Scheme 22. In these instances, no coupling reaction from 63 is observed in appreciable extent under the reaction conditions noted above. However, the coupling takes place efficiently in DMF at 40 C in the presence of stoichiometric amounts of KCN to produce 64 in good yields. Under these conditions, even the bulky AibOBn efficiently couples with 63a to afford the dipeptide 65 in 70% yield. Interestingly, the 3-chloro b-lactam 66, Scheme 23, upon treatment with (S)LeuOBn in DMF as solvent, afforded detectable dipeptide formation (15%) in the absence of any promoter. When the same coupling is carried out under identical conditions but with the assistance of 1 equivalent of NaN3, the yield rises to 85%. Finally, by using KCN instead of NaN3, a complete reaction at room temperature is

b-Lactam Ring Opening: A Useful Entry to Amino Acids

227

(CH2)n

(CH2)n

O

(S)-LeuOBn N O

DMF, 16 h

Boc

BocN H

N H 64

63 Conditions

T, °C

Yield, %

1 equiv. NaN3

r.t.

–

1 equiv. KCN

r.t.

–

1 equiv. KCN

40-60

80-90

CO2Bn

a n=1 90% b n=2 80% c n=3 86%

O BocN H

N CO2Bn H 65, 70%

Scheme 22 Opening of spiro b-lactams with a-amino esters

Cl N O

O

(S)-LeuOBn, KCN (1 equiv.) 66

Boc

DMF, r.t., 16 h, 83%

BocN H

Cl

N H 67

CO2Bn

Scheme 23 Opening of a-chloro spiro b-lactams facilitated by KCN

observed and the dipeptide 67 is obtained in 83% isolated yield. These results suggest that the presence of electron-withdrawing substituents at the Ca position of the b-lactam nucleus is an additional element that facilitates the coupling reaction [91]. Following a similar strategy, Miller [92] has documented the ring opening of a-azido b-lactams with a-amino acid esters, Scheme 24. Treatment of a-azido b-lactams 68/69 with glycine methyl ester thus afforded dipeptides 70/71 with differentially protected amino groups. From dipeptide 70, a synthesis of the rhodopeptin B5 analogue 72 was further demonstrated. McCarthy and coworkers have used this strategy en route to ADDA conjugates [93, 94], residues that are found in the cyclic peptides microcystin LA 73, microcystin LR 74, and nodularin R 75, Fig. 5. In particular, the ADDA-containing analogue 77 can be prepared from the coupling of 76 with glycine methyl ester, Scheme 25. In another application of the approach, Nuss and coworkers have reported the preparation of a-keto amides 79 from 78, Scheme 26. Again, the best results, particularly with hindered nucleophiles, are attained by performing the ring opening in the presence of KCN [95]. The same authors have shown that activation of the b-lactam ring towards nucleophilic opening can be achieved by sulfonylation of the nitrogen atom.

228

C. Palomo and M. Oiarbide O

R

N3

Gly-NH2HCl, iPr2NEt, NaN3 (cat.)

N

DMF, 78%

O Boc 68 R: (CH2)10CH3 69 R: (CH2)5NHCbz O H2N

O

O H N H N

N H

CH3(CH2)10

N3 N H BocHN R 70 R: (CH2)10CH3 71 R: (CH2)5NHCbz

MeO2C

N H O

(CH2)4NH2 R1

2 HCl

O

O H N H N

N H N H O

(CH2)4NH2

O

R1: (CH3)2CH(CH2)9

72

Rhodopeptin B5

Scheme 24 Ring opening of a-azido b-lactams with a-amino acid esters

CO2H HN Me R

O

O N H

O

Me N

NH

O

N H NH

O

Me Me

Y

O Me R NH

H N

O

CO2H O Me

H N

Y: Ala, microcystin LA 73

Me

O NH

O CO2HO

Me N

CO2H

nodularin R 75

Y: Arg, microcystin LR 74

MeO Ph

=R Me

Me

Fig. 5 Cyclic peptides containing ADDA-conjugates

Me

H H

Me

Me N O

GlyOMe, NaN3 (2 equiv.)

Ph Boc

OMe

DMF, r.t.

76 OMe

BocNH

O

Ph Me

Me

77

Me

N H

CO2Me

Scheme 25 NaN3-promoted opening of N-Boc b-lactams leading to ADDA-containing analogues

b-Lactam Ring Opening: A Useful Entry to Amino Acids EtO EtO N

O

O H RN EtO

Conditions

+ RNH2

229

O

O NH OEt

O

O

79

rac-78

RNH2

Conditions*

Yield, %

Ph H2N H2N

OH

CO2Me

KCN, DMF, r.t., 4h

87

KCN, DMF, 70°C

68

KCN, NMP, 90°C

61

Ph H2N

CO2-Wang

* No coupling observed in the absence of KCN

Scheme 26 Opening of b-lactams with amines leading to a-keto aminoamides

OEt EtO N O

O

1. P-Val-(R)-Leu-H, THF, 60 °C 2. PhSH, K2CO3, DMF

O S

P -Val-(R)-Leu

NH2 EtO OEt

O

81

NO2

rac-80

H N

H2N O

O

O N H

O

N H

H N

O OH

O

poststatin 82

Scheme 27 Ring opening of N-sulfonyl b-lactams

In this respect, Scheme 27, the ring opening of N-sulfonyl b-lactam 80 with a dipeptide affords a-keto amide precursor 81. Subsequent elaboration of 81 and final hydrolysis of the ketal moiety affords poststatin 82, a naturally occurring pentapeptide which shows inhibitory activity against prolyl endopeptidase. Although no conclusive evidence has been found yet for this assumption, it is postulated that the b-lactam opening reactions promoted by CN or N3 -containing additives proceed via an acyl azide or an acyl cyanide intermediate. The mode of action of some b-lactamases and the fact that no b-lactam ring opening usually takes place in the absence of such additives support this hypothesis. Complementing the capacity of CN or N3 -containing additives, Dondoni [81] has shown that the combination of Et3N (excess equivalents) and DMAP

230

C. Palomo and M. Oiarbide OBn

BnO H H AcO O

O N H Boc

H-Phe-OMe·HCl(2.0equiv.) Et3N (4.5equiv.), DMAP (0.5equiv.)

OBn

BocNH OH

BnO

CH2Cl2, rt, 48 h, 92%

O

N OAc H

BnO

83

OBn

Ph CO2Me

84

Scheme 28 Opening of b-lactam ring with amines promoted by the Et3N/DMAP system

H3C OHC N O

F

O O N

N H

N O

Mg2+

2

85

nBu +

N O

O

H N

F

O

2-Ethylhexanoic acid N H

N

THF, 72 °C, 7 h, >96%

87

86

nBu H N

O N

O

F

O N H

N

85

88

Scheme 29 Acid-promoted opening of N-benzyloxy b-lactams

(0.5 equivalents) also promotes the ring opening of N-acyl b-lactams by amine nucleophiles. In a recent work, Scheme 28, treatment of b-lactam 83 with phenyl alanine methyl ester under the above conditions was described to provide compound 84 in 92% yield. In an effort to access peptide-deformylase inhibitor 85, Prasad [96] has described the aminolysis of N-benzyloxy b-lactam 86 with proline derivative 87 to give the b-(O-benzyl hydroxylamine) amide 88. It is worth noting that no acyl activation of the b-lactam nitrogen is operating in this case. After examination of an array of solvents and additives for the ring opening, the best result (>96% yield) was finally obtained with 2-ethylhexanoic acid as the catalyst, and THF was the preferred solvent at 72 C (Scheme 29).

b-Lactam Ring Opening: A Useful Entry to Amino Acids

2.3

231

Ring Opening by Carbon Nucleophiles: b-Amino Ketones and Related Products

By analogy with the above reactions that use O- and N-nucleophiles, it has been shown that ring opening of N-Boc b-lactams can be achieved by reaction with metallated carbon nucleophiles. For instance, Baldwin developed the reaction of a-lithiated sulfones, Scheme 30, with b-lactams, such as 89, to provide access to g-keto a-amino esters 90, after desulfonation of the resulting intermediates. In particular, the angiotensin converting enzyme inhibitor WF-10129 91 has been synthesized by this route [97]. In a more recent example of this methodology, the ring opening of b-lactam 92, Scheme 31, with a lithiated sulfone proceeds to give after desulfonation compound OTBS 1.

Cbz

2. Al/Hg, deoxygenated THF:H2O 9:1 3. H2, 5% Pd/CaCO3, EtOAc

N O

PhSO2 BuLi, THF, –78 °C, 10 min

CO2tBu

89

O Me

CO2 HMe N H

OH

O Me

CO2tBu NH2

OTBS

90

H N

O

CO2H

OH

91

Scheme 30 Opening of N-Cbz b-lactams by a a-lithium sulfonyl anion

t

BuPh2SiO

1. n-C13H26CH2SO2C6H4Me-p, n-BuLi THF, –78 °C, 1 h, 86% 2. Li-naphthalenide OTIPS THF, –78 °C, 20 min, 93%

H H

OSiPh2tBu n-C13H27

N O

Boc

OTIPS O

92

NHBoc

93 1. LiEt3BH, THF, –78 °C, 2 h then n-Bu4NF, THF,r.t., 2 h 2. 10% HCl in MeOH (w/v) 40 °C, 9 h, 82%

OH

1. KN(SiMe3)2, (CF3SO2)2NPh THF, –23 °C, 20 min, 99% 2. HCO2H, Et3N, Pd(OAc)2(PPh3)2 cat. DMF, 60 °C, 7 h then n-Bu4NF THF, r.t., 2h, 63%

OH

n-C13H27 OH

NH2

94

OH n-C13H27

OH

95

NHBoc

Scheme 31 Access to phytosphingosines through b-lactam ring opening by lithiated sulfones

232

C. Palomo and M. Oiarbide

BnO

O

H H

O

OBn O

RMgX, THF, –40 °C, 1 h

O

R N O

Boc

O

NHBoc

96

RMgX

97

Ratio of 96:97:98

Yield, % of 97

OBn O

ArMgBr

--:>99:--

≥90

R

MeMgBr

13:45:42

40

R

EtMgBr

12:67:21

60

nBuMgBr

--:90:10

80

nHexMgBr

--:89:11

85

OH

O

NHBoc 98

Ar: C6H5, 4-FC6H4 4-MeC6H4, 4-MeOC6H6

Scheme 32 b-lactam ring opening by Grignard reagents

93, which is then converted into L-lyxo-phytosphingosine 94. The same route has been employed to prepare D-erythro-sphingosine 95, a potent inhibitory agent against protein kinase C [98, 99]. Other carbon nucleophiles may also be employed in such a coupling reaction that provides b-amino ketones and polyol intermediates. As shown in Scheme 32, aryl-Grignard reagents react at low temperature with the N-Boc b-lactam 96 to afford b-aminoketones 97 in 90–96% yields as the exclusive products. In no case over-addition is observed, even when an excess of the Grignard reagent is present in the reaction medium. On the other hand, when the reaction is performed at room temperature, only tertiary carbinols 98 are produced. In contrast to these observations, reaction of 96 with primary alkylmagnesium halides leads to a mixture of the corresponding b-amino ketone and b-amino carbinols in variable amounts, depending upon the size of the alkyl moiety as well as the nature of the counterion. As shown in Scheme 33, almost exclusive formation of the corresponding ketones 99, 100, and 101 (ketone:carbinol ratio >99:1) takes place when lithium enolates and alkyl magnesium chlorides are the reagents employed [100]. A further interesting example in the context of natural products is shown, in the transformation of the b-lactam 102 into the b-amino ketone 103, Scheme 34, which upon carbonyl reduction provides the amino lactone 104, the cyclized form of the N-terminal amino acid residue found in the antibiotic family of nikkomycins, Fig. 6 [101]. Thereafter, the groups of Spero and Ojima have independently demonstrated the utility of this approach to the efficient preparation of aminopolyols and hydroxy (keto)ethylene dipeptide isosteres, respectively. Thus, as shown in Scheme 35, the

b-Lactam Ring Opening: A Useful Entry to Amino Acids

OBn O

iPrMgCl or c-HexMgCl

233

OBn O

O

O

NHBoc 99 > 99:1, 85%

O

O NHBoc 100 > 99:1, 83%

96

OBn O

O

MeO

CH2C(OLi)OMe

O

O

NHBoc

101 >99:1, 73%

Scheme 33 Acylation of Mg- and Li-carbanions with N-Boc b-lactam

Me

H H N

O

CO2Me Boc

MeO

Me

4-MeOC6H4MgBr

CO2Me

THF, –40 °C, 72%

O

102

NHBoc

103

L-Selectride

NHBoc

Me

NHBoc

Me

+

THF, -78 °C (62:38)

Ar

OH

O

Ar

O

O

104 ee>99%

PDC or NDC, 76% (nicotinic acid-CrO3/H2O)

Scheme 34 Opening of b-lactams with a Grignard reagent as an entry to precursors of nikkomycins O HO

CH3 O

–

CO2

N OH NH3+H HO

NH

R:

O

R OH

N OHC R:

nikkomycin B

O NH nikkomycin Bx O

Fig. 6 Structure of nikkomicyn B and Bx antibiotics

b-lactam 105 upon treatment with isobutylmagnesium chloride and subsequent desilylation furnishes the b-amino ketone 106 in 95% yield. This product on reduction provides 1,2,3-aminodiol 107, a constituent of the potent inhibitor of human renin A-725-17 108, with essentially complete diastereoselectivity [102].

234

C. Palomo and M. Oiarbide H H

Et3SiO

HNBoc O

1. iBuMgCl, Et2O, –10 °C, 95% N

2. TBAF, THF, 0 °C, 96%

Boc

O

OH

105

106

S N O Ph

H N

N H SO2 N

O

OH

NaBH4 OH

OH BocN H

OH 108

N H3C

107

Scheme 35 A route to a fragment of A-725-17 (108), a potent inhibitor of human renin

OLi TIPSO

O

O

EtO N Boc

O

THF, –78 °C, 96%

BocHN

OEt OTIPS

109

110

Scheme 36 b-lactam ring opening with Li-enolates of esters. An access to the hydroxy (keto) ethylene dipeptide isostere

H

BnO CO2Bn

N O

Boc 111

+ BnO BnO

THF, –65 °C

O Li AcNLi 112

BnO BnO BnO

O

O

AcNH 113

NHBoc CO2Bn

Scheme 37 An approach to C-linked glycosyl amino acids

In its turn, the hydroxy(keto)ethylene dipeptide isostere 110 has also been prepared in a straightforward manner from b-lactam 109, Scheme 36 [103]. Three further interesting examples, which delineate the utility of b-lactams in synthesis, have been described recently. In an approach to C-linked glycosyl amino acids, Scheme 37, addition of the lithium dianion 112 to the corresponding N-Boc b-lactam 111 provides the b-amino ketone 113 [104]. The sodium anion of trimethylsilyl diazomethane has also been used to open N-acyl b-lactams 114, Scheme 38. The resulting intermediate a-diazoketones 115 affords, after photolytic Wolff rearrangement, the corresponding g-lactams 116 [105].

b-Lactam Ring Opening: A Useful Entry to Amino Acids

R1

R2 N

O

235 R1

R2

TMSCHN2, NaN(TMS)2 O

THF, –78 °C,1 h

Boc

NHBoc

N2

114 R1: iPr

115

R2: PhCH2CH2

65%

R1: BnO R2: 4-MeO-C6H4 61%

R1

R2

UV, benzene, 6h

NBoc O 1 i

116

2

R : Pr

R : PhCH2CH2

R1: BnO

R2: 4-MeO-C6H4 62%

75%

Scheme 38 b-lactams opening with the sodium anion of TMSCHN2

Ph

O N MeLi

Ph

N

O

H O N

THF,–25 °C,1 h O rac-117

Anatoxin–a (rac)

HO 118

Scheme 39 Synthesis of anatoxin-a precursor 118 via MeLi mediated b-lactam ring opening

In a development involving racemic products, nonactivated N-benzyl b-lactam 117, is shown to be opened selectively with methyllithium to yield, after intramolecular oxirane opening, the methyl ketone 118, Scheme 39. This compound is transformed through several steps into the nicotinic acetylcholine receptor agonist anatoxin-a [106].

2.4

Ring Opening by Hydrides

Although more rare, the ring opening of N-acyl b-lactams has also been realized by using hydrides, giving rise to the corresponding reduction products. In this context, Scheme 40, Lee and Pak [107] have described the treatment of N-Boc b-lactam 119 with lithium aluminium hydride to give N-protected amino alcohol 120. Compound 120 could serve as potential intermediate for the synthesis of various hydroxylated indolizidine alkaloids. Apart from alanes [108–110], and monochloroalanes ([111]; for use of monochloroalanes in the reduction of 2–azetidinones to azetidines, see [112]), boranes have also been employed for the b-lactams N1–C2 bond cleavage. Baldwin had reported the sodium borohydride promoted ring opening of N-Cbz b-lactams

236

C. Palomo and M. Oiarbide BnO

OR

BnO

LiAlH4

N O

THF, 0 °C,10 min, 97%

Boc 119

OR

HO

NHBoc 120

(Z–119 --> Z–120, 95%)

Scheme 40 Reductive ring opening of b-lactams leading to aminoalcohols

R1

R= Ph

PhO

NHPMP

15–87%

OH

RO R1

N O

PMP 121

122

NaBH4 iPrOH/H2O (v/v, 11:2) 20 h R= Ac 74–95%

HO

R1 N

O

R1

HO

NHPMP

PMP 123

OH 124

Scheme 41 Cleavage of b-lactams ring with NaBH4

leading to open chain g-amino alcohols [113]. Reductive opening of the 2-azetidinone ring by sodium borohydride has also been reported with b-lactams lacking the N-acyl activating group. Thus, Scheme 41 [114], Buttero has described the reaction of N-p-methoxyphenyl b-lactams 121 to yield amino alcohols 122 and 124, respectively. The same strategy has been used by Alcaide and Almendros en route to optically active trisubstituted piperidines, employing lithium borohydride as the reducing agent of the respective N-p-methoxyphenyl b-lactam [115].

3 Ring Opening at C2–C3 Bond of b-Lactams Work from this laboratory has demonstrated the synthetic potential of the ring opening at C2–C3 bond of a-hydroxy b-lactams to produce a-amino acid derivatives, Fig. 7. Ring opening of b-lactams at C2–C3 with application in peptide synthesis was first reported on a-keto b-lactams 126 ([116]; for applications of a-keto b-lactams, see [117]), Scheme 42. These b-lactams, readily available via oxidation of 3-hydroxy b-lactams 125, undergoes a Baeyer-Villiger reaction upon exposure to m-CPBA and affords N-carboxy a-amino acid anhydrides (NCAs) 127 [118]. Shortly after, it was discovered that a more direct, one pot route to these NCAs is feasible by treatment of 3-hydroxy b-lactams with a solution of commercial bleach

b-Lactam Ring Opening: A Useful Entry to Amino Acids Fig. 7 C2–C3 bond cleavage leading to a-amino acids

237 O

HO

R

R

HO N

HN

O H O [O]

R

O

[O] [–CO2]

N O

R1

O DMSO, P2O5 16 h, r.t., 80-90%

N O

R2 mCPBA, CH2Cl2 –40 C, 1 h, 80-95%

3

R

126

HO

R1 N

O

O R2 R3

NaClO-TEMPO

O

1-2 min, >95% O

125

1

R

R2 N

R3

127

NaClO-TEMPO: 1M NaOCl, TEMPO cat., KBr NaHCO3, KH2PO4-K2HPO4, pH=6.9 CH2Cl2, H2O

Scheme 42 The b-lactam route to NCA’s

O

H

H 2

R N

O 128

R1

R3NH2, 90 C

O

O

H

N R3 129

R2 NHR1

H

–CO O

R2

NHR1 NHR3 130

Scheme 43 Amine promoted transformation of a-keto b-lactams to a-amino acid derivatives

in combination with a catalytic amount of 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO). More recently, the direct reaction of amines and amino esters with azetidin2,3-diones 128 at 90 C, Scheme 43, leading to peptides 130, has also been reported. The reaction is believed to occur through formation of an aziridine intermediate 129 which then rearranges to the amino amide with coextrusion [119, 120]. NCAs are well known forms of a-amino acids which present the amino group protected and the carboxylic group activated for a peptide coupling step. The most common access to NCAs is based on dehydration procedures of a-amino acids involving carbonic acid equivalents, which has limited the method to proteinogenic

238

C. Palomo and M. Oiarbide

a-amino acid-derived NCAs [121]. The availability of a concise and general access to enantiopure NCAs from nona-amino acid precursors has been beneficial in the context of the synthesis of peptides, as will be illustrated below.

3.1

NCAs Bearing Side Chains from Nonproteinogenic a-Amino Acids

An attractive application of this strategy can be visualized in the synthesis of the tripeptide segment 136, Scheme 44, present in the macrocyclic antibiotic lysobactin 40, Fig. 4. It was reported that b-lactams 131 and 132, upon ring expansion under the NaOCl-TEMPO conditions indicated above, afford NCAs 133 and 134, respectively. Coupling of the NCA 133 with (S)-LeuOMe results in the formation of 135 which upon exposure to 134 provides tripeptide 136 in high overall yield [122]. A related example, Scheme 45, is the synthesis of the NCA 138 from the b-lactam 137, which proceeds with excellent yields and without epimerization at the a-amino stereocenter. H H

HO

OR2 R

N O

70%

132 R: Ph

78%

N H

CO2Me

O

OR2 R

N

O

Bn

i

133 R: Pr

(S)-LeuOMe, CH2Cl2 then H2, Pd/C, 95%

95%

134 R: Ph 96%

OTBS H N

1. 134, NaN3 (1 equiv.) DMF, r.t., 70% 2. H2, Pd/C, (Boc)2O EtOH, 78%

TBDPSO

H

NaOCl-TEMPO

Bn

131 R: iPr

O H2N

O

BocN H

O N H

O TBDPSO

135

CO2Me

136

Scheme 44 Ring expansion of 3-hydroxy b-lactams leading to NCA’s formally derived from serine analogues

AcO

H H

OBn N

O

O

O Bn

137

1. LiOH, H2O2, 95% 2. NaOCl-TEMPO, 95%

O

O H OBn

O

NBn

O

Scheme 45 The b-lactam route to NCA’s with polyoxygenated side chains

138

O

b-Lactam Ring Opening: A Useful Entry to Amino Acids

239

Fig. 8 Structure of some polyoxins

R2

H2N

O OH

NH2

O

CO2R1 O

OH O

O

N H

N

NH O

HO

OH

139

OH

O

RO

OH OH

NH2

R1: OH,

N

2

CO2H

R : CO2H, CH2OH, CH3, H

140 R: NH2CO

O O O

H

O OCONH2

NBn O 141

O

OMe

O O O O

H

O

NBn

O O

142

O O O

H

O O

NBn O 143

Fig. 9 Polyoxygenated NCAs affordable from b-lactams

The NCA 138 represents the amino-protected and carboxy-activated form of polyoxamic acid 140, the hydroxylic amino acid portion of the antifungal family of polyoxins 139, Fig. 8. Other polyolic NCAs such as 141, 142, and 143, Fig. 9, have also been prepared from the corresponding a-hydroxy b-lactams with equal success [123, 124]. The feasibility of the illustrated strategy for the access to oxyalkyl substituted NCAs relies primarily on the high yields and diasteroselectivities generally attained with [2+2] alkoxyketene-imine cycloaddition reactions when a-oxyaldehydederived imines are involved. In this respect, nonracemic a-oxyaldehydes are readily available from the chiral pool [125–127] or they can be easily prepared in an enantiodivergent way by the Sharpless AD technique [128]. The exploitation of the latter possibility is shown in the approach to NCAs of b,g-dihydroxy a-amino acids, Scheme 46, starting from the imines 145, readily accessible from the respective a,b-unsaturated ester 144. The cycloaddition of these imines with acetoxyketene occurs with essentially perfect stereocontrol to give, after deprotection, the a-hydroxy b-lactams 146 that undergo ring expansion to provide NCAs 147 in almost quantitative yields. One example of the utilization of this approach for the synthesis of natural products is the facile access, Fig. 10, to the southwest tripeptide segment of echinocandin B, 148, a cyclic hexapeptide that is characterized by its antifungal and antiyeast activity. As Scheme 47 illustrates, the threonine derivative 149 is coupled with 147b to furnish the dipeptide 150, which, after protecting group manipulation and further

240

C. Palomo and M. Oiarbide

O

O H

R

CO2Me

R

O

NBn

144

O 1. AD-mix , r.t., overnight, 85%, ee>99% 2. Me2C(OMe)2, C6H6, reflux, 85-93% 3. DIBAL, toluene, -78 C, 86-97% 4. PhCH2NH2, 4A MS, CH2Cl2, 0 C, 87-94% O

NBn

R

H O 145

O

147

NaClO-TEMPO (R=4-CH3OC6H4, 98%)

1. AcOCH2COCl, Et3N CH2Cl2, -78 ºC r.t.

HO

H H N

2. LiOH, H2O2 THF-H2O, r.t.

O

O R O Bn

146 a R: Ph b R: 4-CH3OC6H4 (84%) c R: 4-CH3C6H4

Scheme 46 NCA’s of b,g-dihydroxy a-amino acids

HO O

Me

HO N H

N Me HO

Fig. 10 Structure of echinocandin B which shows antifungal and antiyeast activity

OH

O

HO O

NH

HO

OH

NHCOR4 O HN OH

O

H N

N O

OH

Echinocandin B, 148

peptide coupling with the 4-hydroxyproline derivative 151, gives rise to the protected tripeptide 152 in good yield [129]. A combination of the Sharpless AD technique and the ring expansion of 3-hydroxy b-lactams to NCAs has also been applied on compounds 153, Scheme 48, to provide a route to NCAs 155. The requisite b-lactams 154, which exhibit a relative unlike configuration between stereocenters C4 and Ca’, are not directly accessible via [2+2] cycloaddition reaction [130]. One important issue in these developments concerns the degree of isomerization during the coupling of NCAs with a-amino acid esters (for observations by other authors regarding partial isomerization, or absence of isomerization, during the NCA– amine couplings, see, respectively [131, 132]). In this respect, both the substitution pattern on the NCA and the nature of the solvent used have been identified as key elements. For instance, while in methylene chloride the isomerization degree during

b-Lactam Ring Opening: A Useful Entry to Amino Acids 147b CH2Cl2, r.t., overnight, 73% then H2, Pd(OH)2

OSitBuPh2 CH3

CO2Me

241

CH3O

NH2 149

O

OSitBuPh2

O

O

NH2

N H

CO2Me

150

CH3 Ph2tBuSiO CH3O O

O

Ph2tBuSiO

CO2Me NH Cbz N H N O

t

OSi BuPh2

N

CO2H

Cbz

151

DCC, HOBt, 80%

O 152

Scheme 47 NCA route to echinocandin tripeptide segment

BnO

H H

R 1. AD-mix b, 0 C or 20 C 70-82%, d.r.>98:2

BnO

H H

NBn O

153

2. (CH3O)2C(CH3)2, p-TosOH 77-80% O

H

2. NaOCl-TEMPO, 95-96%

R NBn O

O

154

O

1. H2, Pd/C, EtOAc, 99% O

O

R a R: Ph NBn O

O

b R: 4-CH3OC6H4 c R: 4-CH3C6H4

155

Scheme 48 Reversal of reactions sequence to produce compounds with unlike configuration

coupling of 138 (Scheme 45) with LeuOBn is below the limit of detection (less than 0.5%), it is significant in more polar solvents such as MeCN (~15%), MeNO2 (~8%), DMF (~50%), and HMPA (~70%) [122, 129]. On the other hand, when NCAs bearing linear chain substituents, Scheme 49, such as 157, are involved, the coupling reaction with amines or a-amino acid esters is accompanied by racemization to some extent, regardless of the solvent used. Interestingly, even in the latter case, no racemization is observed at all when the methanolysis of 157 to give 158 is performed [133].

3.2

NCAs of a, b-Diamino Acids

a, b-Diamino carboxylic acids are uncommon naturally occurring amino acids which attracted considerable interest. An approach to their NCAs 160, Scheme 50, takes advantage of the highly diastereoselective cycloaddition of ketenes to imines derived from N-Boc a-amino aldehydes, to provide 159 [134].

242

C. Palomo and M. Oiarbide

HO

H H

Ph

O NaOCl-TEMPO

NBn O

O

>95%

156

O

MeOH, r.t. then H2, Pd/C

Ph

H

Ph

NBn 157

CO2Me NH2 158

Scheme 49 NCA’s of alkyl chain a-amino acids

HO

H H

NHBoc R

N O 159

Bn

O

H

NHBoc

NaOCl-TEMPO O CH2Cl2, r.t., 10-15 min 90-98%

O

R N

Bn

160

Scheme 50 NCA’s of a,b-diamino acids

In this development, both amino moieties are differentially protected and thus, incorporation of these amino acids into peptide chains either at the a- or b-position is possible. This procedure has also been applied to the synthesis of piperazine2-carboxylic acids and derived peptides [135], Scheme 51. For example, the bicyclic a-hydroxy b-lactam 161, upon ring expansion and subsequent coupling of the resulting NCA 162 with a-amino esters, affords 163 in good yield.

3.3

NCAs of a-Branched a-Amino Acids

Another application of this approach for access to nontrivial NCAs and peptides derived thereof is shown in Scheme 52. The a-hydroxy b-lactams 164 and 165, bearing a quaternary stereogenic center at C4 position, upon treatment with NaOClTEMPO, lead to NCAs 166 and 167 in yields higher than 95%. In a first observation, the coupling of these NCAs with a-amino acid esters under usual conditions generally gave rise to yields below 10%. Much improvement was observed when the corresponding coupling reactions were carried out using potassium cyanide as additive to furnish the expected dipeptide products 168, 169, and 170 in 95, 93, and 95% yield, respectively. Remarkably, the bulky Aib-benzyl ester is also coupled with 167 to afford 171 in 79% yield [136]. The transformation of a-hydroxy b-lactams 173a–c, Scheme 53, readily available from the 4-formyl 2-azetidinone 172, into their corresponding NCAs illustrates the scope of the present approach. NCAs 174a and 174b, upon treatment with (S)-PheOMe and (S)-ValOMe in the presence of KCN as promoter, render

b-Lactam Ring Opening: A Useful Entry to Amino Acids

HO

H H

R1 N

O

Boc

N

H

R1

NaOCl-TEMPO

N

O O

Ph

Boc

N

CH2Cl2, r.t., 5-10 min

O 161

243

Ph 162

Boc N R1

2

(S)-H2NCH(R )CO2Me CH2Cl2, r.t., 70-85%

Ph

O

H N

N H

R1: Me, iPr 2 i i OMe R : Pr, Bu, Bn

2

O

R

163

Scheme 51 Synthesis of piperazine-2-carboxylic acid peptides OTBS Me R 166 R: Bn 167 R: iPr NBn

O

OTBS H Me NaOCl-TEMPO HO R 5 min, >95% NBn O

O O

164 R: Bn i

KCN (1 equiv.), DMF r.t., overnight, >90% R2

165 R: Pr

R1

Ph TBSO H N

CO2Bn BnN 2 H Me 1 O R R 168 R1: Bn R2: H

H2N

CO2Bn

R: Bn

R: iPr TBSO

169 R1: iPr R2: H

BnN H Me O

H N R1

CO2Bn R2

170 R1: Bn R2: H 171 R1: Me R2: Me

Scheme 52 The b-lactam/NCA route to a-branched b-substituted serine-derived peptides

dipeptides 175a and 176b in 78 and 71% yields, respectively. Again, even the Aibbenzyl ester did couple with 174c to give the corresponding dipeptide product which, upon N,O-didebenzylation, afforded 177c in 70% yield [137].

4 Ring Opening at C3–C4 Bond of b-Lactams The ring opening of the b-lactam ring by selective cleavage of the C3–C4 bond has been explored to a much lesser extent. A thermally induced [3, 3] sigmatropic

244

C. Palomo and M. Oiarbide

BnO

H Me CHO 1. Ph3P=CHR, THF, r.t., 2 h

H Me

2. H2, Pd/C, EtOH, r.t., 14-16 h, >75%

NBn O

HO

R

NBn O

172

173

NaOCl-TEMPO, >95% O O O

Me

R

1. (S)-H2NC(R1R2)CO2R3, KCN (1 equiv.), DMF

R

NBn 174

H2N

2. H2, Pd/C, EtOH

a R: H, b R: Ph, c R: Me

Me H N

CO2R3

2 1 O R R

1

175 R : Bn R2: H R3: Me 1 i 176 R : Pr R2: H R3: H 1 177 R : Me R2: Me R3: H

Scheme 53 NCA’s formally derived from quaternary a-amino acids

rearrangement on cis-2-azetidinone-tethered dienes 178 has led to the tetrahydroazocinones 179, Scheme 54 [138]. Of practical interest, this Cope-type reaction proceeds stereospecifically to afford the eight-membered lactams. Hydrogenation of 4-formyl spiro-b-lactams like 180, Scheme 55, accessible from cyclic amino acids and chiral imines, resulted in the formation of bicyclic system like 181, which was reduced to piperazine 182 [139]. The reductive rearrangement leading to 181 proceeds in high yield and the scission of the C3–C4 bond is rationalized in terms of a retro-Mannich process. Unfortunately, however, isomerization occurs during rearrangement, leading to racemic products. Cis 4-formyl-b-lactams like 183, Scheme 56, overcome a ring expansion to the corresponding g-lactams 184 when treated with tert-butyl dimethylsilyl cyanide and 10 mol% iodine at room temperature [140, 141]. The parent trans b-lactams remain unchanged under the same conditions. A mechanism has been postulated that implies cationic intermediates in which iodine acts as a Lewis acid. Rearrangement of b-lactams, bearing a bromo-iso-alkyl group at C4, to g-lactams via N-acyliminium intermediates has been described by De Kimpe [142–144]. Besides the major trans g-lactam product 187 and 188, respectively, traces of the corresponding cis diastereomer and minor quantities of the dehydrohalogenated b-lactam, are also obtained (Scheme 57). Application to the synthesis of bicyclic g-lactams from monocyclic b-lactams has been described [144].

5 Ring Opening at N1–C4 Bond of b-Lactams The palladium catalyzed hydrogenolysis of 3-amino 4-aryl azetidin-2-ones, Fig. 11, constitutes an excellent and reliable strategy to access a-amino acid derived peptides. The discovery, development, and synthetic opportunities of this approach have been reviewed by Ojima [145–148], and will not be covered here. Only the

b-Lactam Ring Opening: A Useful Entry to Amino Acids

245

Ph H H

Et3N (CH3)2CCHCOCl

N

CH2Cl2, D, 57%

Ph

N

Ph

CH3

H H N

Ph

CH3

CH3 178

Ph

O

O

CH3

Ph

CH3

64:36

Toluene, D 83% Ph CH3 N O

Ph CH3

179

Scheme 54 Eight-membered lactams from b-lactams H

O N

N PMP 180

N

H2, Pd/C

H

N Cbz O

AlH2Cl

EtOAc/MeOH 3:1 r.t., overnight, 70%

O

N THF, 70% PMP

N PMP rac–182

rac–181

Scheme 55 Piperazines from b-lactams O R1O

H N

O 183

R2

TBSCN, I2 (10 mol%) MeCN, r.t., 1-3h 46–89%

R1: Me, Bn R2: PMP, Bn, Allyl,CH2CCH, CH2CO2Me

R1O O

OTBS N R2

CN

184

Scheme 56 Dihydroxylated g-lactams from b-lactams

general concept and a representative example to illustrate the potential of the approach will be outlined. The potential of the method is best demonstrated when the ring opening is preceded by chemo- and stereoselective alkylation reactions. As Fig. 12 shows, two main types of alkylation events can be carried out on the designed b-lactam precursor. Type 1 alkylation takes place at the C3 position of the b-lactam ring, with entrance of the electrophile R group from the side opposite to the Ar group at C4. The second one (type 2) takes place at the exocyclic carbon directly bonded to the

246

C. Palomo and M. Oiarbide Br

RO

20% H2O in DMSO 18 h, r.t

RO N

N

N

O

O

O

minor

185 R: Me 186 R: Bn

OH

RO +

187 R: Me (54%) 188 R: Bn (58%)

OH

RO H2O

RO RO

N

N O

N O traces

O

Scheme 57 Cationic rearrangemente of b-lactams to g-lactams

Fig. 11 N1–C4 bond cleavage leading to a-amino acids

Ar H2N

Ar

H2N

N

O

O

Fig. 12 Asymmetric alkylation of C3 carbon (type 1) and of a side-chain carbon bonding to the b-lactam nitrogen (type 2)

E+

X Li

X

Ar N

O Type 1

N H

Ar N

R1

O

OR2

O R

Li

E+

Type 2

N1 nitrogen. In the example in Scheme 58 [149], the realization of the full strategy that combines type 1 and type 2 alkylations with the final ring opening of the b-lactam, is shown. After completion of the asymmetric double alkylation of the glycinate moiety with methyl iodide and allyl bromide, the side chain of the resulting b-lactam ester 191 does not have any acidic proton. Thus a type 1 enolate is generated and the third alkyl substituent (methyl) is introduced to the C3 position of 191; hence, the whole process constitutes a unique and highly selective sequential asymmetric triple alkylation to give 192. Deprotection of the tert-butyl ester of 192 by TFA in dichloromethane at 20 C, followed by cleavage of the b-lactam ring as well as removal of the N-protection with Li/NH3/t-BuOH at 78 C, gave (S)-a-methylphenyl-alanyl-(R)-a-allylalanine, (S,R)-193, in 62% yield after purification on an ion-exchange column.

b-Lactam Ring Opening: A Useful Entry to Amino Acids O

O

O Ph

N N

THF, -78 ºC then MeI, 95%

O

O

O N

LHMDS

Ph

Ph

Ph

N

CO2tBu

189

THF, -78 ºC then CH2=CHCH2Br 85%

N

Me Ph

191

N O

Me

1. TFA, 20 ºC

Ph

THF, -20 ºC then MeI, 100%

Me

O

CO2tBu

O N

LHMDS

Ph

Ph

190 O

O N

LHMDS Me

O

CO2tBu

247

Me 192 CO2tBu

2. Li/NH3/THF/tBuOH, -78 ºC 3. Dowex 50X-2 62% (three steps)

H2N

Ph CONH

Me CO2H

(S,R) –193

Scheme 58 Dipeptides with quaternary a-amino acids from b-lactams

R

R

LDA, THF, r.t

R N O

194

R O

N H 195 R= Ph R= Me R= (CH2)5

65% 67% 63%

Scheme 59 LDA-promoted ring enlargement of b-lactams to g-lactams

Other strategies for the ring opening of b-lactams via N1–C4 bond cleavage have seldom appeared in literature. Ahn [150] has reported the LDA-promoted ring enlargement of N-benzyl b-lactams 194 to the corresponding N-H g-lactams, Scheme 59. The reaction proceeds diastereoselectively to provide exclusively the trans-4,5-disubstituted g-lactams 195. McMurray [151] has described the acid-assisted cleavage of the N1–C4 bond in trans 4-hydroxyphenyl b-lactams. The ring opening reaction may proceed with concomitant reduction or formation of carbon–carbon coupling products, as a function of the reagent employed. For instance, Scheme 60, treatment of 196 with 4 equivalents of triethylsilane in neat trifluoroacetic acid led to compound 197. On the contrary, treatment with anisole in trifluoroacetic acid led to compound 198. Unfortunately, no data are provided by authors regarding process yield or final diastereomeric ratio. On the other hand, several nucleophilic reagents and catalysts have been found capable of promoting the ring expansion of 4-formyl b-lactams, and/or their imine derivatives, to afford open chain acyl thiazole or succinimide derivatives. For example, treatment of 4-formyl b-lactam 199 with 2-(trimethylsilyl)thiazole,

248

C. Palomo and M. Oiarbide OH TES (4 equiv.), TFA OH

O

H N

Me

OMe

O Me

197

O

N O

OMe

OH OMe anisole (2 equiv.), TFA Me

trans–196

O

H N

OMe

O 198

Scheme 60 N1–C4 bond cleavage of b-lactams under acidic conditions

2-trimethylsilyl thiazole CH2Cl2, 0 °C MeO

H H

MeO O

H O Thz

PMPHN

O

MeO +

H H

OH Thz

N O

200 (52%)

PMP 201 (15%)

H N

O 199

PMP 1. PMP-NH2, 4Å MS CH3CN, D, 4 h 2. Bu4NCN (20 mol%), r.t., 2 h 3. aq. 20% HCl, r.t., 4.5 h

MeO O

NPMP N PMP 202 (55%)

Scheme 61 Nucleophilic bond cleavage of b-lactam’s N1–C4 bond

Scheme 61, yielded thiazole 200 as the major product, along with minor amounts of carbinol 201 [152]. On the other hand, treatment of the imine formed from 199 and p-methoxyphenylamine with catalytic tetrabutylammonium cyanide, produced succinimide derivative 202. In both cases, the process is initiated by nucleophilic attack to the carbaldehyde C=O (or azomethine’s C=N) group, which is followed up by an anionic rearrangement. A variation of the above process using as catalysts N-heterocyclic carbenes (NHC) derived from base treatment of azolium, imidazolium, or triazolium salts, has also been developed to access gem-disubstituted succinimides [153, 154]. Unfortunately, an attempt of kinetic resolution of racemic 4-formyl b-lactams by using chiral NHC resulted in moderate selectivities only [154].

b-Lactam Ring Opening: A Useful Entry to Amino Acids

249

6 Large Ring Heterocycles from b-Lactams Cycloexpansion of the four-membered b-lactam ring to either medium or large ring heterocycles can be achieved through N1–C2 bond cleavage by intramolecular nucleophilic attack from a suitable peripheral substituent, Fig. 13. Some medium rings have been already discussed, and others, like pyrrolidines, pyrrolizidines, piperidines, morpholines, etc. have been reviewed elsewhere [11, 155–158]. Some more recent cases from the literature, including examples leading to cyclopeptidomimetics, spermine backbone containing alkaloids, cyclams, and cycloaromatization processes, have been chosen here for illustration. In this context, Greene and coworkers [159, 160] have reported the first lowmolecular-mass immunoglobulin mimetic 207, Scheme 62, developed on the basis of an X-ray structure analysis of the antigen–antibody complex. Compound 207 is resistant toward proteases and imitates the binding and functional properties of the native antibody. The synthesis of 207 is based on an intramolecular aminolysis of the b-lactam ring in 206. This latter compound was prepared by stereoselective alkylation of 203 with 1-bromo-3-butene and subsequent oxidative cleavage of the double bond to give the carboxylic acid 204, which next was coupled with 205. The resulting peptide product 206 rapidly cyclized to a ten-membered ring compound, on reductive deprotection of the hydrazine group, and then coupled with N-carbobenzoxytyrosine to give 207. Another example is compound 214, which imitates the trombin-bound structure of the fibrin peptide A, and is an inhibitor of this protease. The first step of this synthesis, Scheme 63, involves opening of 208 to the seven-membered ring compound 209. Subsequent acylation with 210 to form 211 is followed by an intramolecular oxidative cycloaddition to provide tricyclic lactam 212. Nucleophilic ring opening proceeds readily with glycine methyl ester to afford lactam 213 in 88% yield, which was transformed into 214 using solid-phase protocols [161]. The same group has also reported the synthesis of the nonpeptide enkephalin b-turn mimetic 216 [162]. The key step of the approach, Scheme 64, involves the simultaneous intramolecular cyclization/b-lactam ring cleavage in derivative 215 leading to compound 216. b-Amino acid fragments containing large heterocycles also occur in some alkaloids, and approaches to these compounds using b-lactams as key intermediates have long been known since the pioneering contributions of Wasserman [163] and, later on, of Hesse [164, 165]. In Fig. 14, some of the heterocyclic compounds

NH

Fig. 13 Types of intramolecular nucleophilic attack on b-lactams leading to expanded rings

N1 O

4

N O

HN

3

N O HN

250

C. Palomo and M. Oiarbide BnO O BnO H OTBS N

O

TBS

1. LDA, -78 ºC HO2C then homoallyl bromide O

205

iBuOCOCl, NMM, 64%

TBS 204

BnO O

N

NHCbz

O

N OTBS

N

2. RuO2, NaIO4

203

BnO

H H

NH2 N

O

N H N NHCbz O

H H OTBS N O

H O N H N N

HO

TBS

1. H2, Pd/C, 95% 2. Cbz-Tyr, iBuOCOCl NMM, 58% 3. H2, Pd/C, 92%

O O

H O

N

HN

OH O

OH NH3 Cl

206 207 OH

Scheme 62 b-lactam approach to iminoglobulin mimetics

(217–224) synthesized through b-lactam intermediacy are represented [166]. Using this strategy, Crombie and Jones [167–169] have described the internal rearrangements on N-(o-haloalkyl) b-lactams as a valuable method for the total synthesis of several homalium alkaloids containing a spermine structural backbone. These include (S,S)-( )-homaline 225, rac-hopromine 226, rac-hoprominol 227, and rac-hopromalinol 228, Scheme 65. As an example, the enantiopure b-lactam 230, prepared from 229, experiences a transamidative ring expansion on prolonged standing in liquid ammonia to afford the macrocyclic b-amino amide 231, which is converted into (S,S)-( )-homaline 225. Other large cycles containing b-amino acid fragments include dioxocyclams 232 and bis-dioxocyclams 233. Analogues of the latter, bearing nitrogen atoms attached through a three carbon bridge, display high and selective anti-HIV activity [170]. Hegedus has described [171, 172] a very short and original access to these dioxocyclams and bis-dioxocyclams using either optically active or racemic 1-N-Boc-azapenams 236 as key intermediates. The approach, Scheme 66, involves the photolysis of chromium alkoxycarbene complexes 234 with N-Boc-imidazolines 235 to give the expected azapenams 236 in a fully stereoselective way. Remarkably, the hydrogenolysis reaction is very sensitive to the acidity of the medium. Thus the reaction in the presence of camphorsulfonic acid leads to the seven-membered hexahydrodiazepinones 237, while in the presence of triethylamine, it results in the fourteen-membered dioxocyclams 232. An extension of this methodology has been reported by the same author to prepare the five-atom

b-Lactam Ring Opening: A Useful Entry to Amino Acids

251 O Cl

O

H H

EtO

BnHN Ph

N O

O

N2H4

NH NH

H

84%

Bn

210

208

O

209

O O

Bn

BnN

O

N

PhI(OAc)2

NH H NH

94%

GlyOMe

H

O

211

O

88%

N N O

212

O BnHN

O

CO2Me

N H N N

H

213

O BnHN

O N N

H

O

214

Gly-Val-Arg-CH2Cl

O

Scheme 63 A b-lactam approach to fibrin peptide A protease inhibitors

TBS N

HN O O

O N H

TBSO

CO2Me 1. F3CCO2H, CH2Cl2, 0 °C

Ph N-NHBoc

2. TBAF, THF

O

215

CO2H HO 3. HCl, EtOAc 94% (three steps)

H2N

O

O H N

H

NH Ph

N O

O 216

Scheme 64 A b-lactam approach to enkephalin mimetics

N H

252

C. Palomo and M. Oiarbide O

O N H

N

N H

Ph

217

N H Ph

218

OH

O R:

N H

Ph H

N H

N N Ac

N H

N

Ph

N H Ph

Ph

O

O

O

O

N H

R

220

HO

221

O

OH

H

222

219

OMe

OMe O

O

H HN

N N Ac

223

O

H

O

O H N

HN

O NH N H

N

224

Fig. 14 Some representative large heterocycles accessible from b-lactam compounds

system bridged [–O(CH2)3O–] 233 from bis-chromium alkoxycarbene complexes 238 [172]. Intramolecular transamidation in b-lactam enediynes can induce concomitant Bergman type cycloaromatization. For instance, Scheme 67, amine 239, which can be stored as its hydrochloride salt in the freezer, reacts in THF at reflux in the presence of cyclohexadiene as a hydrogen donor to produce only trace amounts of the expanded lactam 240 along with aromatic compound 241 as the major compound [173].

7 Concluding Remarks and Prospects The interest in b-lactams had been driven traditionally by the pre-eminence of b-lactam antibiotics, which has over the years fuelled a huge effort devoted to the search for synthetic routes to b-lactams and the subsequent manipulation of the attached groups. The development of improved routes to b-lactams is still appealing, particularly because of the appearance of b-lactam resistance and new

b-Lactam Ring Opening: A Useful Entry to Amino Acids R1

R2

O

MeN

O

N

225

H

R1: Ph

R2: Ph

1

226

R : (CH2)4CH3

R2: (CH2)6CH3

227

R1: (CH2)4CH3

R2: CH2CH(OH)(CH2)4CH3

228

R1:

R2: CH2CH(OH)(CH2)4CH3

Ph

Br

NH O

Cl N

KOH, DMSO, 75%

Ph

NH3 (liq.), 3 d, 20 °C Cl

O

229

O

NMe N

H

Ph

253

(sealed tube), 67%

230

H Ph

HN

NH

Br

Br

KOH, DMSO, 54%

CH2O, NaBH3CN

225

MeCN, AcOH, 61%

231

Scheme 65 Internal rearrangement on b-lactams leading to homalium alkaloids containing spermine backbones

biomedical applications of b-lactam compounds. However, b-lactams also constitute versatile precursors of a variety of nonb-lactam compounds, particularly a- and b-amino acids, their derived peptides, and an array of small and large heterocyclic compounds. All these transformations imply the cleavage of the 2-azetidinone ring, through any of its four bonds. Like enzymes do during the phenomenon of antibiotic action or antibiotic inhibition, selective ring opening of b-lactams is currently a chemically affordable task. Several strategies have been developed for the b-lactam ring scission that proceed under sufficiently smooth conditions to tolerate both functional groups and stereocenters sensibly. This fact, in combination with the arsenal of methods for the stereocontrolled synthesis of b-lactams, enables the b-lactam approach to account for as one realistic option for accessing some functionally and stereochemically complex molecules. The examples included here illustrate this potential and show the maturity of the approach. However, the possibilities b-lactams offer as versatile intermediates in synthesis are not fully addressed yet, and new contributions in the area are foreseen for the near future. Acknowledgements We thank the following institutions for financial support of our b-lactam program: Ministerio de Educacio´n y Ciencia (Spanish Government), Eusko Jaurlaritza (Basque Government), Euskal Herriko Unibertsitatea-Universidad del Paı´s Vasco (University of the Basque Country), and Diputacio´n Foral de Gipuzkoa. All team members cited within the references are also acknowledged.

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C. Palomo and M. Oiarbide R2O

R1

R3

R3 NH HN

R4

O R1

NH HN

NH HN

NH HN

O Me

OR2

O

+

Cr(CO)5

N

R2O H Boc N R1

hu

N

MeCN, 12 h 41-90%

4

R3

234

O Me

O rac-233

Boc N

R1

O

NH HN

232

R2O

O Me O

R4

NH HN

O

Me

O

R

O

R

R3 236

235

1. H2 (45psi), Pd/C MeOH, Et3N, 4 min 4

232

2. CSA (1.1 eq.) 3. H2 (45psi), Pd/C, MeOH, 2 d 70-96%

CSA (1.1 eq.), H2 (45psi), Pd/C THF, 20 h, 59-71% Me

O

O

Cr(CO)5

R2O

Me

NH

R1

Cr(CO)5

R4

O

238

N H

R

3

237

Scheme 66 Synthesis of large cycles containing b-amino acid fragments: dioxocyclams and bis-dioxocyclams

1,4-cyclohexadiene OTBS

THF, reflux

N O

OTBS O

NH HN

NH2

240

239

OTBS O

NH HN 241

Scheme 67 Intramolecular transamidation on b-lactams as a trigger of Bergman type cycloaromatization

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Top Heterocycl Chem (2010) 22: 261–311 DOI 10.1007/7081_2009_9 # Springer‐Verlag Berlin Heidelberg 2010 Published online: 22 January 2010

Recent Approaches Toward Solid Phase Synthesis of b-Lactams Bablee Mandal, Pranab Ghosh, and Basudeb Basu

Abstract Since the discovery of penicillin in 1929, b-lactam antibiotics have been recognized as potentially chemotherapeutic drugs of incomparable effectiveness, conjugating a broad spectrum of activity with very low toxicity. The primary motif azetidin-2-one ring (b-lactam) has been considered as specific pharmacophores and scaffolds. With the advent of combinatorial chemistry and automated parallel synthesis coupled with ample interests from the pharmaceutical industries, recent trends have been driven mostly by adopting solid phase techniques and polymersupported synthesis of b-lactams. The present survey will present an overview of the developments on the polymer-supported and solid phase techniques for the preparation of b-lactam ring or b-lactam containing antibiotics published over the last decade. Both unsubstituted and substitutions with different functional groups at various positions of b-lactams have been synthesized using solid phase technology. However, Wang resin and application of Staudinger [2+2] cycloaddition reaction have remained hitherto the major choice. It may be expected that other solid phase approaches involving different resins would be developed in the coming years. Keywords Azitidinone Penicillin Solid phase synthesis b-Lactam b-Sultam Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Solid-Phase Techniques for b-Lactam Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Solid-Phase Synthesis of b-Lactam by Staudinger Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Solid-Phase Synthesis of b-Lactam by Gilman-Speeter Reaction . . . . . . . . . . . . . . . . . . . . . . . . 5 Solid-Phase Synthesis of b-Lactams by Miller’s Hydroxamate Approach . . . . . . . . . . . . . . . . 6 Other Solid-Phase Synthetic Approaches to b-Lactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

B. Mandal, P. Ghosh, and B. Basu (*) Department of Chemistry, North Bengal University, Darjeeling 734 013, India e-mail: [email protected]

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Abbreviations AM-resin BAL BEMP resin BOBA BQ CAN DCC DEAD DIPEA DMAP DMF DMTMM EDC FDPP Fmoc HOBt LiHMDS MAMP MCPBA MeOPEG NCA NMP PAL PASP PBP PEG SASRIN TEA TFA TMAD

Aminomethylated polystyrene Backbone amide linker Resin 2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro1,3,2-diazaphosphorine immobilized on polystyrene resin Benzyloxybenzyl amine Benzoylquinine Cerric ammonium nitrate N,N0 -Dicyclo-hexylcarbodiimide Diethylazodicarboxylate Diisopropylethyl amine 4-Dimethylaminopyridine N,N-Dimethylformamide (4,6-Dimethoxy-[1,3,5]-triazin-2-yl)-4-methyl-morpholinium chloride N-Ethyl-N0 -[3-(dimethylamino)propyl]-carbodiimide hydrochloride Pentafluoro phenyldiphenyl phosphate 9-Fluorenylmethoxycarbonyl Hydroxybenzotriazol Lithium hexamethyldisilazane Merrifield, alpha methoxy phenyl resin m-Chloroperbenzoic acid Methoxy polyethylene glycol N-Carboxy a-aminoacid anhydride N-Methylpyrrolidone Peptide amide linker Polymer assisted solution phase Penicillin-binding proteins Polyethylene glycol Super acid sensitive resin Triethylamine Trifluoroacetic acid Tetramethylamine azodicarboxylate.

1 Introduction The discovery of penicillin by Sir Alexander Fleming in 1929 has been recognized as one of the most fortunate discoveries in modern times [1]. The b-lactam ring is the key component of commonly used antibiotics such as penicillins, cephalosporins, carbapenems, and monobactams [2]. The development of b-lactam antibiotics

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help to combat several lethal diseases such as plague, wound sepsis, and tuberculosis [3, 4]. The penicillin antibiotics inhibit transpeptidase enzymes (penicillin-binding proteins (PBPs)) by acylation of the serinyl residue at their active site, which leads to cell wall lysis, since blocking PBPs circumvents proper murein membrane formation [3]. Several peptides and peptidomimetics containing the b-lactam ring have been recently described as effective protease inhibitors and, consequently, as potential drugs for a wide range of diseases implicating proteases [5–8]. Since their introduction, b-lactam antibiotics proved to be chemotherapeutics of incomparable effectiveness, conjugating a broad spectrum of activity with low toxicity [9]. b-Lactams are a large class of antibiotics characterized by the presence of the azetidin-2-one ring, which is the core of the biological activity, and differentiated by side chains, unsaturations, heteroatoms, and in many cases, by the presence of another five- or six- membered ring. The great vivacity of research in this field led to the development of classical b-lactam substrates such as penicillins and cephalosporins together with nonclassical ones such as carbapenems and monobactams obtained via semi or total syntheses. To complete and increase the importance of b-lactams, nonclassical bicyclic and monocyclic b-lactam substrates with different biological activities have appeared in recent literature: serine-dependent enzyme inhibitors [10–13], matrix-metalloprotease inhibitors [14], and even apoptosis inductors [15]. The problem of microbial resistance, related to the use of these agents over the last 50 years, is nowadays widely recognized, and treatment options in clinical practice are limited by multidrug-resistant bacteria [16]. Despite the need for new antibiotics, large pharmaceutical companies are devoting fewer resources to their development because these agents do not provide as great a return on investment relative to that of compounds for some other therapies [17]. However, the phenomenon of bacterial resistance forces the continuous modification of side chains and structures of known active compounds and the development of new ones.

2 Solid-Phase Techniques for b-Lactam Synthesis The wide spectrum of activities of b-lactam containing organic molecules has led to the consideration of the motif azetidin-2-one ring (b-lactam) as a general lead structure for the design of new antibiotics [18, 19] and novel inhibitors of enzymes containing a nucleophilic serine in their active site [20–22]. Several intelligent strategies and attractive approaches for the preparation of b-lactam moiety have been developed and reported in the literature. However, with the advent of combinatorial chemistry and automated parallel synthesis, recent trends have been driven mostly by adopting solid phase techniques and polymer-supported synthesis of b-lactam. A considerable number of novel methodologies involving solid supports for the synthesis of azetidinones and its derivatives have been reported in the literature, besides regular reports of solution phase methods applying known and classical methods [23–39]. This chapter will present an overview of the developments on the

264

B. Mandal et al.

polymer-supported and solid phase techniques for the preparation of b-lactam ring or b-lactam containing antibiotics published over the last decade. The advent of combinatorial techniques and solid phase organic synthesis may lead to preparation of large numbers of structurally related molecules in short periods of time. This is important especially for the optimization of lead structures in the pharmaceutical industry [40]. It is now well established and documented that the combinatorial technology and solid phase techniques could offer sufficient latitude for preparation of corresponding chemical libraries with broad structural diversity. The diverse potentiality of b-lactam moiety as specific pharmacophores and scaffolds has attracted ample interests from pharmaceutical industries for the synthetic methods based on polymer-supported techniques. The development of efficient routes to synthesize b-lactams is an area of significant research interest [41–45]. This has been driven, in large part, by the importance of these molecules as constituents of antibiotics, ranging from penicillin-based substrates to a number of more recently developed compounds (e.g., penems, cephems, monobactams, carbapenems, and trinems) [46–51]. b-Lactams have also been demonstrated to be important synthons in organic synthesis (Fig. 1) [52, 53] and to be monomers in the generation of polyamides [e.g., poly(b-peptides)] [54, 55]. In principle, an attractive approach to prepare molecules such as b-lactams would be to consider their structure. Because of the b-lactams’ highly strained four-member ring, the cleavage of any of the four bonds is possible (Scheme 1). The N1–C2 bond can be easily cleaved by nucleophiles (e.g., oxygen, nitrogen, and carbon) to obtain b-amino acid derivatives as products [56]. When R2 is an amino group and R3 is an aryl group, palladium-catalyzed hydrogenolysis is a good way to H N

R O

H N

R

S

S

O

N O

N O

OH O Penicillin

R' COOH

Cephalosporin

S

NH2 N

N N

O

O

O O

OH

OH

O HN N O

Carbapenem

Fig. 1 Examples of few familiar antibiotics

CH3 SO3H

Aztreonam (Monobactam)

Recent Approaches Toward Solid Phase Synthesis of b-Lactams Scheme 1 Possible cleavage of any of the four bonds in b-lactam

R2 3 4 R3 2

N

O

265

O N1-C2 cleavage

1

R1

HN

R3

O R2

R1

Ar H2N 3 4 Ar 2

O

HO 3 4 R2 2

N1-C4 cleavage

N1 R1

N

O

1

H2N N R1 H

O

O C2-C3 cleavage

R2

HO HN

R1 H O

R2

[O]

N R1

[–CO2]

[O] O

R1

O

break N1–C4 bond and get a-amino acid-derived peptides [57]. The ring-opening at C2–C3 bond of a-hydroxy b-lactams can also produce a-amino acid derivatives via N-carboxy a-amino acid anhydride (NCA) intermediates [58]. Selective cleavage of the C3–C4 bond is, however, rare. Intensive research has generated numerous methods of synthesizing the b-lactam skeleton [59]. The strained four-member ring, which constitutes the core structure of all b-lactam antibiotics, is the main challenging point in the synthetic efforts for preparation of these compounds. The four-member ring of b-lactam can be constructed by any of the four single-bond formations or by [2 + 2] cycloaddition (Scheme 2). The formation of the amide (N1–C2) bond is the most obvious approach and was utilized in the synthesis of penicillin [60]. Among the four singlebond constructions, C2–C3 bond formation was rare. One methodology involving a tributylstannane-mediated ring closure has been reported [61]. In a simple sense, the C–C bond construction (C3–C4) involves the formation of a nucleophilic center at C3 and an electrophilic center at C4, or vice versa [62]. The biosynthetic route to b-lactam has been focused primarily on the C4–N1 bond formation [63]. Several approaches have been developed to construct this bond. The idea is to displace a leaving group attached to C4 intramolecularly with activated nitrogen [64]. Compared with the single-bond construction approach of b-lactam synthesis, the ketene-imine cycloaddition, which includes carbenoid insertion and the Staudinger reaction, have been widely used [56, 65]. Due to the ready availability of both imines and ketenes, the Staudinger reaction has provided a useful and economical approach for the synthesis of b-lactams. In addition, the ketene-imine cycloaddition is efficient, which constructs the b-lactam four-member ring in just one-step

266

B. Mandal et al. R2

O

R2

R2 X R1

R1 X NH R3

R1

N

N-C2 bond

HN O OH R3

O

N-C4 bond formation

C3-C4 bond formation

R2 3 2

formation

R1

[2+2]

4

N

C2-C3 bond formation

+ O C N R3

olefin & isocyanate

1 R3

O

R2

R3

[2+2] imine & ketene

R1

X

N

O

R2

R3

R1 C O

+ R3

N

(Staudinger Reaction)

Scheme 2 Possible methods for b-lactam ring construction N O C R

R' R

X X N

H fast

R

O

X R

H R

O N

R'

R R

Scheme 3 Mechanism for the Staudinger reaction

reaction. The mechanism for the Staudinger reaction is that the electrophilic ketene is attacked by lone pair electrons of imine nitrogen and the zwitterionic enolate is formed followed by conrotatory ring closure forming the b-lactam (Scheme 3) [66]. The ester enolate-imine condensation, also called Gilman-Speeter reaction, is another well-accepted method for b-lactam synthesis (Scheme 4) [67–69]. In 1997, Tomioka reported the first example of a direct catalytic enantioselective synthesis of b-lactam by using this method [70]. The active reagent is a ternary complex (comprising LDA, the ester enolate, and tridentate amino diether), which finally affords the b-lactam compounds in high yields and good ee values.

3 Solid-Phase Synthesis of b-Lactam by Staudinger Reaction Between the above two methods for the synthesis of b-lactam derivatives, the venerable Staudinger [2+2] imine-ketene cycloaddition [36] is by far the most versatile and simplest entry to the lactam fragment. Application of Staudinger

Recent Approaches Toward Solid Phase Synthesis of b-Lactams

267

R2 O

O R

base

R

X

R2

NR2 X

R1

H Ph

Me O

Me O

PMP

N

X

O

O MeO

Ph

R2

10% PMP

N

R1

R

O

Ph

Me2N +

N

LDA 4 equiv. toluene, –20 °C, 1.5h

O N

H Ph

Me Me

99% yield 88% ee

Scheme 4 Gilman-Speeter reaction in b-lactam synthesis

reaction in polymer assisted solution phase (PASP) technique [71] was reported by Dondoni et al. [72]. They reported for the first time the synthesis of C-glycosyl b-lactams by generation of the cycloaddition partners in the same reaction vessel from mixtures of sugar aldehyde, amine, and acyl chloride. The unreacted p-methoxybenzyl amine (PMBA) was sequestered by treatment with resin-supported sulfonyl chloride. To the resulting heterogeneous mixture was then added (acetoxy)acetyl chloride and triethyl amine to produce the corresponding acetoxy-substituted ketene. After a suitable period of time, the reaction mixture was treated with nucleophilic aminomethylated polystyrene (AM-resin) to remove the excess of ketene and its precursor acetyl chloride, as well as the acid arising from the hydrolysis of the latter (Scheme 5). Simple workup (filtration and washing with water) of the resulting suspension and solvent evaporation afforded a mixture of 4-(C-ribosyl)-b-lactam stereoisomers (3R,4S) (major, 83%) and (3S,4R) (minor, 9%). Similar protocols were also adopted by Gordeev et al. [73] for the synthesis of b-sultams (1,2-thiazetidine 1,1-dioxides), which have attracted attention due to their apparent structural analogy to the b-lactams [74]. Their synthetic strategy was based on the [2 + 2] cycloaddition of activated sulfenes with imines as the key step (Scheme 6). Methyl (chlorosulfonyl) acetate was used as a reactive sulfene precursor, which was reacted with the imine generated from Sasrin resin, [75] and immobilized alanine derivatives, in the presence of pyridine as a base. The reaction sequence, intermediates, and products were robust enough to tolerate other types of linkers [e.g., poly(ethylene glycol) (PEG)] and cleavage conditions. The resulting b-sultams were released from the polymeric supports by acidic cleavage (TFA) or photocleavage. The first synthesis of b-lactams bound to a soluble/insoluble polyethylene glycol monomethylether polymeric matrix has been realized by standard reactions carried out on immobilized imines. From the polymer, b-lactams were removed under acidic and basic conditions [76, 77]. The reactivity of the immobilized reagent was tested by synthesizing b-1actam from imines and an enolate 8a and the

268

B. Mandal et al.

BnO

O

BnO

H CHO CH2Cl2

OBn

O

H

BnO

CH N PMB

+ BnO PMB NH2 p-methoxybenzyl amine (1.5 equiv)

OBn 1 (crude)

O S Cl O

BnO

PMB H N O

O S NH PMB O

O OAc

H H BnO

1.Et3N (6.0 equiv) 2.AcOCH2COCl (3.5 equiv)

OBn 83%

BnO

PMB H N O H H

BnO

O OAc

NHCOR

1 (pure)

NH2 aminomethylated polystyrene(AM-resin)

OBn 9%

Scheme 5 Application of polymer-assisted solution phase (PASP) technique in Staudinger reaction

cycloaddition with a ketene 8b, (Scheme 7). While 1H NMR analysis allowed a satisfactory determination of the stereoisomeric composition of the products bound to the polymer, the yield of the b-lactam was better determined by releasing the azetidinone from the MeOPEG matrix, a reaction that served to establish a possible synthetic application of the polymer-supported synthesis of b-lactam. Singh and Nuss [78] described the synthesis of b-1actams via [2 + 2] Staudinger reaction [79] on solid supports with the aim of developing methodology for the rapid synthesis of combinatorial libraries (Scheme 8) [79]. The polymer-supported imine (20) was reacted with a-acetoxy acetyl chloride in the presence of triethyl amine to produce the b-lactam (21), which was eventually released from the polymeric surface by treatment with 3% TFA in CH2Cl2 (Scheme 8). Typically in solution phase this cycloaddition occurs favorably at 0 C and requires chromatographic purification. This problem is however eliminated in solid phase synthesis. The reaction in general was able to tolerate a large excess of amine with no undesirable cleavage of the azetidinone amide bond being observed.

Recent Approaches Toward Solid Phase Synthesis of b-Lactams

269 O

1) Piperidine, DMF 2) R2CHO

O Fmoc HN

O L R1 L = acid or photocleavable linker

R2

O N

HC(OMe)4, CH2Cl2

R3 O L

O O S Cl

Py, THF, -78 °C to rt

R1

O R2

R3 O S N O

O O O L

TFA, DCM or hν 365 nm

R2

R3 O S N O

R1

O OH

R1

DBU, DMF R3=OFm Cl O R2

HO O S N O

Cl O

O O L

CF3CO2C6F5 Py, NMP

hν 365 nm R1 = C6H11CH2 R2 = 3-(3,4-Cl2C6H3O)C6H4

R1

O

HO

O O S N O

OH

C-3 = 13C

O PfpO O S N O

R2

O O L

R1

1)Ph(CH2)2NH2 2)TFA, CH2Cl2 R1 = Me R2 = Ph

O N H

O O S N O

OH Me

Scheme 6 Synthesis of b-sultams on solid support

Although yields of the azetidinones from the imines that were generated from a range of amines such as alkyl, aryl, and anilines were obtained in satisfactory ranges, electron deficient heterocyclic amines were found to be problematic. However, as compared to the homogeneous counterpart, undesirable product formation can be avoided and side products resulting from the reaction solution can be washed away from the solid supports. Thus, a successful application of the Staudinger cycloaddition on solid supports has been demonstrated. This group is currently investigating the application of this methodology to the generation of diverse combinatorial libraries. Gallop et al. [80] reported the preparation of b-lactams via a [2+2] cycloaddition reaction of ketenes with resin-bound imines derived from amino acids (Scheme 9). This is another solid-phase adaptation of the Staudinger reaction, which could lead to the synthesis of structurally diverse 3,4-bis-substituted 2-azetidinones [81]. In addition, a novel approach to the synthesis of N-unsubstituted-b-lactams, important building blocks for the preparation of b-lactam antibiotics, and useful precursors of chiral b-amino acids was described [82].

270

B. Mandal et al. O

O OH

O

a

O

O O

NHR

O

2

3 R= COOCH2Ph

= MeOPEG O

R

c

O

O

4

b

4 R= H N

R1 + Me

O

O

5, R1 = Ph

SPy

6, R = H 7, R = OSiMe2Bu-t

+ OR

d 10, R = Ph 11, R = PhCH2

C O

R1

R

d

N O OR2

8, R = PHCH2O, R1= Ph, R2 = CO(CH2)2COOPEGOMe; 9, R = Et, R1 = Ph, R2 = H; 10, R = (R)-MeCH(OH), R1 = Ph, R2 = H; 11, R = PhO, R1 = Ph, R2 = H Reagents. a: 4-PhCH2OCONH-C6H4-OH, DCC, DMAP; b: H2, 10% Pd/C; c: R1CHO; d: CH2Cl2, 15h, 23 °C

OTBS

OTBS H HR

1) TiCl4 / (C8H17)3N

Me

Me SPy

O

O

O

N CHR

R = Ph or (E)-CH=CHPh

7

O O

O

N O

Ce(NH4)2(NO3)6

OTBS H HR Me N

1

R

O

12, 13

O

O

OHC NH2

H 14, 15

O

O

O

N

(MeO)3CH 16

Et O

1) TiCl4 / (C8H17)3N SPy

Et H H

2) 16

N O

O

R1

O

Ce(NH4)2(NO3)6

Et H H

O

O

N O

17

H 18

12,14 R = Ph; 13,15 R = (E)-PhCh=CH R1 = -C6H4O(CH2)3C6H4O-

Scheme 7 (a) Synthesis of b-lactam bound to a soluble/insoluble polyethylene glycol monomethylether polymeric mallix. (b) Stereoselective and solid phase synthesis of b-1actam

Recent Approaches Toward Solid Phase Synthesis of b-Lactams

271 O

O RNH2

N H

H

N H

4Å sieves, CH2Cl2 or (CH3O)3CH

O 19

H N 20

R

O AcO O

20

N H

AcO

Cl

O

K2CO3 CH3OH, CH2Cl2 RT

N

Et3N, CH2Cl2 RT

O

R 21

N H

HO N O

R 22

(iPr)2NEt p-Nitrophenyl chloroformate CH2Cl2 RT O

R1

H N

OH H O

O NH2

N

1. R1NH2, CH2Cl2 RT

ArO O

2. 3% TFA/CH2Cl2

O

R 24 cis- racemic

N H

O N O

23

R

Scheme 8 Synthesis of b-1actams using polymer supported imine (20)

O FmocHN

O a, b

O

R2

R1

N

c

O 1

R

Resin is sasrin

R3

R3

R2

N O R1

R2

+

d

O N O

R3

R2 CO2H

O R1

N

CO2H

O R1

(a) 30% piperidine in NMP, 45 min; (b) 0.8 M R2CHO in 1:1 (MeO)3CH:CH2Cl2, 3 hrs; (c) 0.8 M R3CH2COCl, 1.1 M NEt3 in CH2Cl2, 0°C to 25°C, 16hrs; (d) 3% TFA in CH2Cl2, 45 min

Scheme 9 Use of Sasrin resin bound amino acid for the preparation of b-lactam via [2+2] cycloaddition

272

B. Mandal et al.

The participation of imines derived from amino acid esters in the Staudinger reaction is well known in homogeneous solution. For solid-phase b-lactam synthesis, the carboxylic acid residue of an amino acid is conveniently tethered as an ester or amide to the support. Among several commercially available polystyrene peptide synthesis resins preloaded with Fmoc protected amino acids that were investigated by the authors as supports for solid-phase b-lactam synthesis, the highly acid-labile resin, Sasrin, proved particularly suitable. After removal of the Fmoc protecting group by treatment with piperidine in NMP, the resulting amines were condensed with a 10–15-fold molar excess of an alkyl, aromatic, or a,b-unsaturated aldehyde in a 1/1 mixture of (MeO)3CH/CH2Cl2, to yield the resin-bound imines quantitatively [83]. b-Lactam intermediates were constructed through [2 + 2] cycloadditions between ketenes and imines on the solid-phase by Pei et al. [84]. A library of 4,140 dihydroquinolinones has been produced using this synthetic process and is used to prepare 3,4-dihydro-2(1H)-quinolinones through the rearrangement of blactam intermediates on the solid-phase. The reported reaction conditions involved in the synthesis of blactams in solution-phase are mild enough to tolerate a large variety of functional groups. Therefore, it is possible to incorporate various substituents into the final products through b-lactam intermediates. In this report, they described the synthesis of 4-amino-3,4-dihydro-2(1H)-quinolinones from amino acids, aldehydes, and acid chlorides, through the rearrangement of b-lactam intermediates on the solid-phase. The synthesis of 4-amino-3,4-dihydro-2(1H)-quinolinones were carried out on the solid-phase using the tea-bag technology [85]. The reaction sequence has been illustrated in Scheme 10. Resin bound amines 26 were condensed with ortho-nitrobenzaldehyde in dichloromethane in the presence of anhydrous sodium sulfate as drying agent to furnish the imines 27. Cycloaddition [2 + 2] of 27 with ketene was carried out in dichloromethane at 78 C. The ketene was generated in situ from corresponding phenoxyacetyl chloride in the presence of triethylamine. In all cases, cis-b-lactams OHC

O 1) HO

NH2

25

R1

NH2 O N 2

1

NH

R

NH

N H

R2 31

R

R

N R

1

1

2

27

NO2

CO-NH SnCl2

N H

O

R3OCH2COCl 28 TEA CH2Cl2 –78 oC - rt

R O O

O2N

2

NH

3

HF/anisole

R

Na2SO4, CH2Cl2

26

CONH2

R3O O

R

O

2) 55% TFA 3) 5% DIEA

MBHA Resin

NH

t 1 NH- Boc

R2

R2

DMF, rt

30

Scheme 10 Synthesis of dihydroquinolinones on MBHA Resin

OR3 O

NH

N R1

O 29

Recent Approaches Toward Solid Phase Synthesis of b-Lactams

273

were obtained as single products in almost quantitative yield. From L-Boc-AIa-OH, a mixture of two diastereomers of the cis-b-lactam 29b was obtained in about 1:1 ratio. The nitro groups of the b-lactam intermediate 29 were reduced to amines using tin(II) chloride (2.0 M) in DMF at room temperature [86]. Under the reaction conditions, the b-lactam ring underwent rearrangement to produce trans-3,4-dihydro-2(1H)-quinolinones 30, through an intramolecular nucleophilic attack of the blactam amide moiety by newly generated amino groups. Dihydroquinolinones 31 were obtained in excellent yields after cleavage using HF/anisole (95/5). In a program to synthesize biologically interesting mono- and multicyclic b-lactam compounds by applying solid-phase methodologies Mata et al. [87] have carried out the polymer-supported Staudinger reaction smoothly under mild conditions to give the corresponding b-lactams in good to high overall yields with excellent cis-selectivity using the cost-effective Wang resin as the solid-support. Application of this method constituted an efficient asymmetric synthesis of b-lactams, when chiral acid chlorides or chiral aldehydes were used. These optically active b-lactams are useful precursors for the generation of combinatorial libraries of potential antibiotics and enzyme. There are a number of amide releasing linkers [88], which possess an amino group for incorporation as –NHCO– into their products. Such linkers include Rink [89], Sieber amide [90], PAL [91], SASRIN [92], BAL [93], and MAMP [94]. These linkers rely on acid-induced SN1 cleavage mechanisms and incorporate extended aromatic systems to stabilize the resulting cations. A drawback of such systems is that their amino groups are sterically hindered by methoxy groups included in their aromatic systems. For example, the acylation of Rink amide secondary amines with amino acids possessing bulky side chains was reported to occur in only modest yields (60%) [95]. The authors have reported a new amine linker of this category that is cleaved using ceric [96] ammonium nitrate [Ce(NO3)6(NH4)2, CAN]. The linker has been designed for the release of secondary amides and, in particular, b-lactams but will have broader application. Monocyclic b-lactams such as the nocardicins [97] and monobactams [98] are of interest as they have been found to exhibit antibiotic properties. In solution-phase syntheses CAN has been utilized to remove the p-methoxyphenyl group from the amide nitrogen of b-lactams to generate their N-unsubstituted analogues [99, 100]. Exploitation of CAN in a solid-phase cleavage strategy offers mild, rapid, and selective cleavage conditions. The linker is based on resin bound aniline and is free from steric hindrance and easy to prepare. The benzyloxyaniline linker is also acid stable, which contrasts with the CAN or TFA cleavable benzyloxybenzylamine (BOBA) linker [101] (Schemes 11 and 12) (Table 1). In continuation of the research on solid-phase synthesis of biologically interesting b-lactam compounds towards the development of combinatorial libraries, Mata et al. [102] investigated use of 2-chloro-1-methylpyridinium iodide (Mukaiyama’s reagent) as a key reagent for the construction of the b-lactam ring in a stereoselective manner. The popular explanation involves the reaction of ketene B with the imine to form a zwitterionic intermediate D (Scheme 13). Alternatively, it is the activated acid A that acylates the imine to form the zwitterion D by abstraction of proton with

274

B. Mandal et al. NH2 HO

NHBoc

a

NHR

b c

HO

O 32

33 R = Boc, 34 R = H

(a)Et3N (1 equiv), Boc2O (1 equiv), DMF, 12 h, 0 °C to room temperature, 99%; (b) NaH (3 equiv), 1(3 equiv), DMF, 0 °C, 1 h then add to Br TentaGel resin (1 equiv), DMF, rt, 12 h, 97%; (c) 10% TFA/DCM, rt, 12 h then filter and wash with Et3N/DCM.

Scheme 11 Protection of amine followed by attachment to resin via esterification

NH2 H H OPh

a, b, c

O

N R

O

35 R = OBn, 36 R = H (a) t-Hexenal (1 equiv), 4 Å molecular sieves, DCM, rt, 1 h; (b) Et3N (5 equiv), phenoxyacetyl chloride (2 equiv), DCM, 0 °C to room temperature, 18 h, 67% for two steps; (c) CAN (3 equiv), MeCN/H2O (2:1), 0 °C to room temperature, 1 h, 59%.

Scheme 12 Resin-supported free amine and subsequent Staudinger reaction Table 1 Use of CAN in the solid-phase cleavage of linker R1 H H OPh NH2

R1 H H OPh

c

a, b

N O

O

H

O

34 38

%purity a

%yield b

a

CH3(CH2)2CH=CH–

98

83

b

4-nitrophenyl

93

88

c

3-chlorophenyl

98

62

d

2-bromophenyl

99

56

e

(CH3)3C–

96

45

f

4-methoxyphenyl

97

85

a b

O

38a-f

37a-f R1

N

Determined by HPLC with UV detection at 220 nm. Calculated from the loading of resin 34

Recent Approaches Toward Solid Phase Synthesis of b-Lactams

275

I N Me

Cl O

+ R1

I

N Me

R1

O A

NEt3

R1 O H

B

R2

CO2H N

2 H H R H 1 R N O

NEt3

R1

H R2

H

N O

D

C

R1

R2 N

O 39

Scheme 13 Mechanistic explanation of Staudinger reaction using Mukaiyama’s reagent

a base. The intermediate eventually undergoes a conrotatory ring closure to generate the thermodynamically less stable cis-b-lactam 39. Lower temperatures led to products with better cis selectivity without decreasing the overall yield. Solid-phase preparation of trans 3-alkyl b-lactams was reported by Mata et al. recently (Scheme 14) [103]. The synthetic sequence involved the start from Fmocglycine tethered to Wang resin, followed by addition of a controlled excess of 43 (4 equiv) and triethylamine (8 equiv) to the resin bound imine 42 in refluxing toluene. Cleavage form resin surface and esterification afforded the 3-alkyl b-lactams, 45, as a single product with excellent trans-selectivity. Solid-phase synthesis of 3,4-disubstituted b-lactams was accomplished [104] via reaction of in situ generated ketenes with immobilized aldimines under mild conditions. Initially Fmoc-protected Wang resin strategy was followed (Scheme 15) and the [2+2] cycloaddition was performed by adding phenoxylacetyl chloride (49, R1 = phenoxy) and triethylamine in excess to a suspension of 48 in dichloromethane. The yields ranged from good to very good for the five-step synthetic sequence and exclusive formation of the cis isomer was detected in all cases. A similar reaction sequence was attempted using a Merrifield resin-Boc strategy starting with commercially available Boc-glycine linked to Merrifield resin (52) (Scheme 16).

276

B. Mandal et al. MeO FmocHN

i) 30% piperidine in DMF

O

N

O

ii) 4-CH3OPhCHO 41 1% v/v AcOH in DMF

40

R2

R2CH2COCl (43) (4 eq)

R1

R2

N

R1 N

O

ii) CH2N2 O

O

i) 10% TFA

O

Et3N (8 eq)

O

42

CO2Me

O

45

44 R1 = 4-OMeC6H4

Scheme 14 Solid-phase preparation of trans 3-alkyl b-lactams R2

PHN b

N

O

O

O

46 P = Fmoc a

O 48

47 P = H c

= Wang resin

R1

R1

R2 d N

R2 N

O

O O

OMe

O

O 50

51 (a) 30 % piperidine in DMF. (b) R2CHO (3) (5 equiv), 1% v/v AcOH in DMF. (c) Et3N (20 equiv), R1CH2COCl (49) (15 equiv), 0 °C then r.t. overnight. (d) (i) 10% TFA in CH2Cl2. (ii) CH2N2.

Scheme 15 Synthesis of b-lactam using Fmoc-Wang resin

This research group further carried out an asymmetric version of the solidphase Staudinger reaction using a chiral auxiliary at C-3 for the generation of active carbacephems and other multicyclic b-lactam. Thus, the homochiral (S)-4

Recent Approaches Toward Solid Phase Synthesis of b-Lactams

277

R5 R4 BocHN O

a

O 52

N O

O = Merrifield, PAM resin

53a: R4, R5 = OMe 53b: R4, R5= H

b R4

R4 R5

R5

PhO

PhO c N

N

O

O O

OMe

55aa R4, R5 = OMe 55ab R4, R5 = H

O

O 54 aa 54 ab

(a) (i) 25% TFA in CH2Cl2, 50 min. (ii) aldehyde (5 equiv), 1% v/v AcOH in DMF. (b) Et3N (20 equiv), PhOCH2COCl (15 equiv), 0 °C then r.t. overnight. (c) (i) TMTOH, (ii) CH2N2

Scheme 16 Synthesis of b-lactam using N-Boc protected Merrifield resin

phenyloxazolidinylacetic acid (56) was prepared according to the Evans procedure (Scheme 17). [105] The asymmetric Staudinger reaction on solid support was then performed by adding (S)-(4-phenyloxazolidinyl) ketene, generated in situ by treating the crude acid chloride 57 with triethylamine at low temperature, to suspensions of different resin-bound aldimines 48 yielding the optically active b-lactams (59) (Scheme 17, path b). Good to very good overall isolated yields were achieved with very high diastereoselectivity. In another approach, Mata et al. [106] described synthesis of b-lactam analogues of cholesterol absorption inhibitors with excellent geometrical selectivity involving an efficient cross-metathesis on solid support and thus illustrated excellent methodology for introduction of diversity at C-3 and C-4 positions of the b-lactam ring with excellent 3,4-trans selectivity and complete E selectivity at the C-3 side chain. The efficiency of the cross-metathesis on solid phase and its application to the generation of biologically interesting 3-(aryl)-alkenyl-b-lactam was established by this method. The key intermediate in this protocol was the resin-bound 3-vinyl-b-lactam 65. The attachment of Fmoc protected p-aminophenol to Wang resin was however achieved by using tetramethylamine azodicarboxylate (TMAD) and Bu3P [107]

278

B. Mandal et al. R2 N

48

O

N

O b or c

Ph O

R2

N

O

O

O

O

Ph

N O

R

O 58

= Wang resin a

O

56 R = OH d

57 R = Cl

O

O

R2

N Ph

N O 59

CO2Me

(a) (COCl)2, toluene, 3 h, 60 °C. (b) 48: CH2Cl2, Et3N (20 equiv), 57 (15 equiv), 0 °C then r.t. overnight. (c) 48: CHCl3,56 (2.5 equiv), Et3N (6 equiv), then 74, r.t. 24 h. (d) (i) 10% TFA in CH2Cl2. (ii) CH2N2.

Scheme 17 Asymmetric solid-phase synthesis of carbacephems

instead of classical Mitsunobu conditions [108] (DEAD, Ph3P). The resin-bound aniline 62 was deprotected following standard procedure and converted to the aldimine 64 by condensation with aldehyde 63. The synthesis of the b-lactam ring was accomplished through solid-supported Staudinger reaction using the Mukaiyama’s reagent as acid activating agent [102]. Thus, the reaction of crotonic acid with the corresponding imine 64, effectively yielded the supported 3-vinyl-b-lactam 60 (Scheme 18). Treatment of the resin with 10% trifluoroacetic acid in CH2Cl2 at room temperature was found to be an efficient procedure for the cleavage of resin, affording the 3-vinyl-b-lactam 65 in 32% overall isolated yield (based on the manufacturer’s loading of the Wang resin). Subsequently, attention was focused on the cross-metathesis reaction on solidsupport. The advantages of using olefin cross-metathesis include mild reaction conditions, tolerance to a wide range of functional groups, and availability of a wide variety of commercial olefin partners. The olefin cross-metathesis on solid support using second-generation Grubbs precatalyst, has been conducted to generate a library of analogues of cholesterol absorption inhibitors. (Fig. 2) (Scheme 19) Recently, Mata et al. [109] described the first solid-phase Staudinger reaction based on immobilization of the activated carboxylic acid, which led to the development of a strategy for the preparation of C3-anchored b-lactam derivatives. In this approach, two linkers, viz. the diethylsilyloxy linker (PS-DES resin) and the Wang resin were tested, of which the latter was found to offer better results.

Recent Approaches Toward Solid Phase Synthesis of b-Lactams NHFmoc HO

279

FmocHN

OH

O

TMAD, Bu3P

61

62

R1 1) piperidine 30% DMF

O

2) R1

N

63

I

64

O

OH

N Me

O

R1

Cl

R1 10% TFA in CH2Cl2

N

N

O

O 60

O

65

OH

Scheme 18 Solid-Phase synthesis of 3-Vinyl-b-lactams

MesN

NMes

Cl

Fig. 2 Precatalysts defined as Grubbs (62) and HoveydaGrubbs (65)

Ru Cl PCy Ph 3 62

MesN

NMes

Cl

Ru Cl i-PrO 65

Coupling of 69 with methyl 4-hydroxyphenoxyacetate 70 was carried out in the presence of imidazole and confirmed by gel-phase 13C NMR of PSDES resin 71. The hydrolysis of resin-bound ester was efficiently achieved using trimethyltin hydroxide (TMTOH) [110–114] to give the corresponding immobilized carboxylic acid 72. For the key Staudinger reaction, activation of the carboxylic acid 72 by Mukaiyama’s reagent 74 was employed (Scheme 20) [115–117]. The cis-b-lactam 76 was obtained in a 12–14% isolated yield. Because of the low yield, the reaction was carried out by using the Wang resin as the polymeric support. The methyl 4-hydroxyphenoxyacetate (77) was immobilized to Wang resin under modified Mitsunobu conditions (TMAD, Bu3P) to yield the

280

B. Mandal et al. R1

R2

R2

R1 n n

N

Grubbs precatalyst

O

N O

O

O

60

66

R2 R1 n 3

TFA 10% CH2Cl2

4

N O 67

OH

Scheme 19 Synthesis of 3-(Aryl)-alkenyl-b-lactams by olefin cross-Metathesis on solid support

resin-bound ester 78 (Scheme 21). The expected products were obtained in good overall isolated yields for the five reaction steps on solid phase (25–57%). This methodology is based on the Staudinger reaction between an immobilized ketene and different imines. Of the two linkers tested, the Wang resin proved to be better than the diethylsilyloxy linker, allowing an efficient reaction sequence giving good overall isolated yields of the desired b-lactams. Solid phase synthesis of b-lactams with high degree of chiral selectivity and on a larger scale has been developed by Lectka et al. [118]. The general features of their process are based on a design involving the use of solid-phase reagents and catalysts that constitute the packing of a series of “reaction columns”. The assembly designed for this purpose consists of two jacketed columns linked together by a ground glass joint; the top column is packed with a polymer-supported dehydrohalogenating agent that produces analytically pure, extremely reactive ketenes from inexpensive and widely available acid chlorides. The middle column is packed with a nucleophile-based solid-phase asymmetric catalyst. Between the two columns, an imine is added to the system. An optional third column is packed with a scavenger resin to remove any unreacted ketene or imine from the eluent [119]. Several advantages of this column-based technique include: (1) obviating the need to isolate and/or manipulate highly reactive ketenes, (2) separating the different solid-phase components easily, (3) recycling the polymer-supported reagents and catalysts for additional catalytic reactions, and, finally, (4) avoiding vigorous agitation that can degrade resin beads. The well precedented in situ generation of ketenes [36, 120]

Recent Approaches Toward Solid Phase Synthesis of b-Lactams

281 CO2Me

*

*

Et Si H 4 Et 68

NCS

*

CH2Cl2

Et Si O 4 Et

Et Si Cl 4 Et 69

HO

O 70 imidazole CH2Cl2, r.t. Et Si O 4 Et

CO2Me O

* TMTOH

71

72 OMe *

Bn

N

CO2H O

Et Si O 4 Et

OMe

73 O

Mukaiyama's reagent (74) Et3N, CHCl3, reflux

N O

HO

Bn 75

TBAF or HF/py

OMe O

3

N O

Bn 76

Scheme 20 Synthesis of C-3 anchored b-lactam using diethylsilyloxy linker (PS-DES resin)

using triethylamine (or other tertiary amines such as Hu€nig’s base) is problematic because the amine itself catalyzes the cycloaddition of ketene 85 and imino ester 86 [121–123]. Additionally, the by-product hydrochloride salts also interfere with the catalytic, asymmetric reaction [124]. To overcome these difficulties, Lectka et al. employed resin-bound dehydrohalogenation reagents to allow for the simple isolation of the ketene solution under inert atmosphere at reduced temperature. Standard solid-phase bases such as Amberlite IRA-67, a tertiary amine-based polymer, failed to promote ketene formation to any appreciable extent when phenylacetyl chloride in THF was passed through it in a jacketed column at 78 C. However, the extremely basic resin BEMP (Fig. 3) [125], containing a triaminophosphoamide imine bound to a polymeric support, [126] was found to produce ketenes rapidly and quantitatively. At low temperature (78 C), a solution of phenylketene reacts with the imino ester 86 in the presence of 10 mol% of benzoylquinine (BQ) to afford the desired b-lactam 87 in 65% yield, 98% de, and 96% ee after purification by column chromatography (Schemes 22 and 23) [121–123]. It is significant to note that the length of the catalyst-solid-phase linker is crucial to the success

282

B. Mandal et al.

OH

O

O

OH

KOSiMe3 THF

TMAD Bu3P

O

O

CO2Me 77

O CO2Me 78

CO2H 79

R1 O R2

N

80 R1 O

Mukaiyama's reagent (74) Et3N, CHCl3, reflux

TFA 10% N O

R2

CH2Cl2

81 HO R1 O

3

N O

R2

82

Scheme 21 Synthesis of C-3 anchored b-lactam using Wang resin

t-Bu N NEt2 P CH3 N N

Fig. 3 BEMP Resin

of the reaction; short linkers give inferior results, presumably due to the steric encumbrance of the polymeric support [127, 128]. In the extreme, the reaction has been successfully run through the catalyst column 20 times with no significant loss in stereoselectivity or yield (90% ee and 62% yield for run 20). One can envision practical applications for the synthesis of enantio-pure compounds using this methodology. Reactants can be passed through discrete columns containing recyclable reagents, which upon degradation can be swapped out of the production stream and regenerated. The use of reagents on solid support greatly simplifies the purification of the crude reaction mixture, allowing for shorter production times and thus lower costs under certain circumstances (Fig. 3). A polymer-supported synthesis of an array of a chirally pure b-lactams in high purity has been demonstrated [129] from a resin-bound chiral oxazolidine aldehyde. Application of resin-bound chiral oxazolidine aldehyde equivalent was explored

Recent Approaches Toward Solid Phase Synthesis of b-Lactams

283

Scheme 22 Synthesis of solid-phase chiral catalyst 83 O

O

Cl

O

O

Cl

OH + Wang resin

O

n-Bu

quinine

OMe N N O

O

83 SP base O

O C

Cl

Ph

H

Ph

84

H 85

SP catalyst

Scheme 23 Synthesis of optically enriched b-lactams through dual solid-phase reagents

O C Ph

Ts

Ts + H

H

COOEt 86

O N

N

H Ph

EtOOC 87

for the synthesis of a small array of b-lactams. The reaction, which is believed to occur via a two-step mechanism, can be controlled exclusively to the generation of b-lactams with cis stereochemistry [130]. The aldehyde 89 was thus condensed with four different amines representing varying electronic and steric properties, and the resulting resin-bound imines subsequently underwent cycloaddition with ketenes, which were formed in situ from their corresponding acid chlorides. Finally, the resin-bound b-lactams 90a-g were treated with 10% TFA in DCM to remove the N-Boc-protecting group and to cleave the now unstable oxazolidine moiety to unmask the amino alcohol functionality. (Scheme 24) Asymmetric synthesis on solid support is crucial for the generation of combinatorial libraries of novel optically active carbacephems and other polycyclic b-lactam derivatives [44]. Solid-phase Staudinger reaction of the homochiral

284

B. Mandal et al. H

O OH

NO2

O

i O

ii

O

O O

88 O

O

89

HO

O N Boc

O

R2

H H

iii

O

N Boc

O

N R1

iv

H H R2

H2N

O

R1

N

90

O 91a-g

Reagents and conditions: (i) 4-nitrophenylchloroformate/DIPEA/DMAP/DCM; (ii) Linker A/DIPEA/DMAP/DMF; (iii) R1NH2/DCM/4 Å sieves then DCM/Et3N/ R2CH2COCl/DCM; (iv) 10% TFA/DCM H

O Linker A = R

N Boc

O

Scheme 24 Application of chiral oxazolidine aldehyde in the synthesis of b-lactam library

I

N Ph

+ CO2H

92

N Me

R2

O

O

N

O

O

Cl 74

R2

N Ph

N

NEt3, CHCl3

O

C O O 93

C O O

94 i) 10% TFA ii) CH2N2 O

O

R2

N Ph

N O 95 CO2Me

Scheme 25 Synthesis of novel optically active carbacephems

4-phenyloxazolidinylacetic acid 92 [105] with several aldimines, using Mukaiyama’s reagent (74) as activating agent (Scheme 25) were explored and high diastereoselectivity was observed in all cases.

Recent Approaches Toward Solid Phase Synthesis of b-Lactams (a) Piperidine, DMF (b) 4-X-ArCHO, CH2Cl2 (c) Phenoxy ketene CH2Cl2

O FmocHN

285 X

PhO O

O

N

O

O

Me

Me 96a: X = I 96b: X = Br 96c: X = B(OH)2 (a) RB(OH)2 or RIa DMF, Pd-cat. (b) TFA, CH2Cl2

R

R

PhO

PhO +

O N O

O N

OH

O

Me

OH

Me 97a-g

aRB(OH) 2

used with 96a and 96b, RI used with 96c

Scheme 26 Synthesis b-lactam and arylation by using Suzuki coupling with aryl boronic acid

R I PhO

O Me 96

PhO O N

O N

(a) Olefin, TEA, TBAI, Pd-cat., DMF, H2O (b) TFA, CH2Cl2

O O

OH

Me 98

Scheme 27 Synthesis of b-lactam and olefination by Heck coupling reaction

Applications of Suzuki and Heck cross-coupling reactions were adopted by Gallop and coworkers [131] to prepare diverse biaryl- and styryl-substituted b-lactams on solid support. The catalyst system, [PdCl2(dppf)]-TEA, was found to be efficient to promote C–C bond formation around a b-lactam template (Schemes 26 and 27). Stella et al. [132] considered the use of imines coming from commercially available fluorinated a-amino-acids and applied the following synthetic pathway. The acid function is used to anchor the substrate on a Merrifield or Wang resin and the fluorine atom is used as an analytical probe for the recording of NMR spectra. Thus, each of the chemical products linked to the resin is characterized by a

286

B. Mandal et al. O HOOC

NHBoc

O

M

1) TFA/ CH2Cl2

NH2

O

M

2) DIEA 5% CH2Cl2

Ar

NEt3, dioxane, 96h

Ar

O

Cl

M

NHBoc

Ar

20 equiv PhCHO TMOF, CH2Cl2 (1:1) 24h, rt Ar Ph

MeO

N O

3

O

R

3

Ar

1M NaOMe M MeOH: THF (1:4)

Ph

O

N O

rt, 18h

3

O

O

R CH2 COCl NEt3, CH2Cl2

R

M

–78 °C->rt 18h

N

O

Ph

Ar 97 Ar = oFC6H4 98 Ar = pFC6H4CH2

Scheme 28 Synthesis of b-lactam using Merrifield resin

O HOOC

NHFmoc

W

OH W

2 x 20min 25 ° C

Ar

DIC,DMAP, CH2Cl2,DMF 25 ° C, 2h

Ar

O

piperidine 20% DMF

NHFmoc

O

W

NH2

O Ar

20 equiv PhCHO TMOF, CH2Cl2 (1:1) 24h, rt CH2(pFC6H4) Ph HOOC N O

OCH2Ph

1.5h, 25 °C

O

CH2(p FC6H4) PhCH2OCH2COCl NEt3, CH2Cl2 Ph N W –78 °C, T.A., O O OCH Ph 18h 2

SOCl2, MeOH reflux, 18h, 38 %

M

TFA aq. 95 %

H3COOC

O N

O

Ph

Ar Ar = p-FC6H4CH2

CH2(pFC6H4) Ph N O

OCH2Ph

Scheme 29 Synthesis of b-lactam using Wang resin

single 19F NMR-signal while the respective chemical shift value is related to each chemical step according to the close group modifications. Thus, 19F NMR has been used as a simple means to monitor the solid phase synthesis, as shown in schemes 48 and 49 (Schemes 28 and 29). The N-unsubstituted b-lactams are important building blocks for the synthesis of several biologically active antibiotics. However, solution phase techniques normally include acidic conditions, which are not tolerable with acid-sensitive functionalities. In an elegant approach, Banik et al. [133] developed a solid phase synthetic route to access N-unsubstituted b-lactams directly using Rink resin as the solid support. The method for construction of b-lactam ring was based on Staudinger reaction and subsequent cleavage from the solid support was done with TFA in dichloromethane (Scheme 30).

Recent Approaches Toward Solid Phase Synthesis of b-Lactams

287

4 Solid-Phase Synthesis of b-Lactam by Gilman-Speeter Reaction Schunk and Enders [134] disclosed the first solid-phase synthesis of b-lactams via ester enolate-imine condensation employing an immobilized ester enolate in a simple three-step procedure (Scheme 31). The protocol showed high purity, excellent diastereoselectivity, and good yields of the product. The substrates were attached to the polymer with a T1-triazene linker, which was cleaved traceless. The

NH2

R

CH(OMe)3

+ RCHO

Z

ZCH2COCl

N

TEA, CH2Cl2

R

Z

50% TFA

N

NH

in CH2Cl2

O

O (60 – 68%)

Z = OAc, OBn, OPh, O-Pthalimide

Scheme 30 Synthesis of N-unsubstituted b-lactam using Rink resin

N N N (a)

N H

O

101

O HNEt3 102 (b)

CF3CO2

N N

N N

N

(c) R1 O

N H 104

R1 OCH3

O

O

N H

R

OCH3 O

103 t

Reagents: (a) p-Aminobenzoic acid, BF3.Et2O, BuONO,THF, -10 °C, 1h; 2. 101, pyridine/DMF (1:1), rt, 1h; (b) 102, 3 eq. of amino acid methyl ester.HCl, 2-Chloro-1-methylpyridinium iodide, NEt3, CH2Cl2, rt, 12h; (c) 5% TFA/CH2Cl2.

Scheme 31 Preparation of diazonium salt immobilized on T1 triazine linker resin

288

B. Mandal et al.

group is currently employing the established synthesis for the preparation of highly diverse b-lactam libraries. Starting from benzylamine resin 101 via 102 gave ester resins 103 with high loading and excellent purity of the corresponding cleavage products 104. Treatment of 101 with 4-carboxybenzenediazonium tetrafluoroborate yielded T1-benzoic acid resin 102. This reaction was carried out under basic conditions, but only pyridine and lutidine were found to be reasonable bases. Other bases, e.g., triethylamine, Hunˇig’s base, DMAP, and t-BuOK, resulted in decomposition of the diazonium salt. Several peptide-coupling reagents (e.g., 2-chloro-1-methylpyridinium iodide, N-ethyl-N0 -[3-(dimethylamino)propyl]-carbodiimid hydrochloride/hydroxyl-benzotriazol (EDC/ HOBt), and pentafluorophenyl diphenylphosphinate (FDPP) were tested in the synthesis of resins 103 (step b). Resin 103b affords diazonium salt 104b after treatment with 5% TFA/CH2Cl2. To obtain pure cleavage products 104, the triazene formation reaction (step a) had to be carried out at room temperature. Lower temperatures resulted in lower purity of 104 and lower loading of 103. The ester enolate-imine condensation was initially tested in the liquid phase (Scheme 32) on model compound 105. This reaction gave b-lactam 106 in 71% yield having trans-configuration. The base, LiHMDS, was found to give best results for the generation of dianion. The liquid-phase reaction conditions were followed on the solid phase (Scheme 33) without any problems. It is most probable that the reaction proceeds, as in liquid phase, via a dianion [135]. The condensation reaction of 103b was carried out with a range of imines, all of which gave very good results concerning loading of the lactam resin 107 and purity of the cleaved diazonium salt 108 (Scheme 34). Conditions published to date [136] for traceless cleavage from a

N N

N N

N

N (a) R1 O

N H

OCH3 O

105

O

R1

O

NH N

106

(a) 1. 2.2 eq. of LiHMDS, THF, -78 °C, 20 min; 2.3 eq, of PhCH=NPh, -78 °C to rt, 23h; 3. H2O Scheme 32 T1 triazine linker resin for b-lactam synthesis

Recent Approaches Toward Solid Phase Synthesis of b-Lactams

289

N N

N N

N

N (a) CH3 O

OCH3

N H

O NH H3C

O

O

103b

R2

N

107

(a) 1. 2.2 eq. of LiHMDS, THF, -78 °C,1.5h min; 2. 3 eq, of R2CH=NPh, -78 °C to rt, 23h; 3. H2O

Scheme 33 T1 triazine linker resin for substituted b-lactam synthesis

N N N

N

CF3CO2 N H N

(a)

CH3

O O NH H3C O

R2

R2

N

108 O

N (b)

107 H N O

CH3

R2

N O 109 o

(a) 5% TFA/CH2Cl2; (b) THF/DMF (5/2), 60 C, 15 min.

Scheme 34 Removal of T1 triazine linker resin after the synthesis of substituted b-lactam

T1-triazene linker resulted in decomposition of the sensitive b-lactams. The relative configuration of b-lactams, was determined by NOE experiments to be the transconfiguration as observed in solution-phase synthesis [137].

290

B. Mandal et al.

Employing an immobilized ester-enolate moiety Schunk and Enders [138] reported the solid-phase synthesis of diverse monocyclic b-lactams via the ester-enolate imine condensation route. The ester-enolate imine condensation route is a readily developed synthetic methodology for the preparation of b-lactams [69, 139, 140]. However, the main advantage of this approach, from a solid-phase chemists’ point of view, is the wide variety of easily available imines and its precursors, which might allow variation of every position of the azetidin-2-one ring [135, 141–144]. The ester-enolate was immobilized by a triazene linker system and found stable under the required basic conditions [136, 145]. The linker paves the way for introduction of a variety of functionalities by applying different cleavage procedures [146]. Monocyclic b-lactams were obtained in good purities after simple workup. Although the method does not provide all desired substitution patterns, it is a versatile tool for the preparation of diverse b-lactam libraries. The possibility of the triazene linking system for the ester-enolate imine condensation was initially investigated on model compounds 110 and 111 (Scheme 35). Dibenzyltriazene 110 was used as a model compound for monobactam derivatives and prepared by diazotization of hippuric acid methyl ester. Dibenzyltriazene 111 was used as a model compound for 3-phenyl-substituted azetidin-2-ones and prepared by diazotization of 2-(4-aminophenyl)-propionic acid methyl ester and conversion with dibenzylamine in 64% overall yield. The low yields of N-unsubstituted lactams, during the model studies, hint at a problematic transfer to solid support. The triazene linker can be used for the immobilization of aromatic diazonium salts, and therefore for aromatic amines, but not for aliphatic amines due to the instability of their diazonium salts. Cleavage of the linker can be achieved under mild acidic conditions to yield the benzylamine resin and the corresponding diazonium salt [136, 145, 146]. The main difference between the preparation of triazenes in solution and triazenes on solid support is the respective amine, namely bisbenzylamine and polymer-supported benzylamine 114. In solution, it was used in excess to quench unstable diazonium salts and force the reaction to completion. In the solid-phase approach it was immobilized and cannot be used in excess with respect to low loadings. A simple three-step procedure (Scheme 36) starting from benzylamine resin 114 via carboxylate 115 led to the successful preparation of ester resins 116 in essentially higher loadings. Treatment of resin 114 with 4-carboxybenzene diazonium tetrafluoroborate yielded benzoic acid resin 115. Larger amounts of pyridine drastically enhanced the coupling reaction and loading of 118, but also led to an increased formation of Japp-Klingemann type by-products 120. Several procedures to transform the diazonium salts into traceless products were explored before the formation of pure b-lactams. The best conditions for traceless cleavage turned out to be simplified Keumi conditions [147]. (Scheme 37–38) 1,4-Bisaryl b-Lactams. The liquid-phase reaction conditions were employed for the preparation of monobactam like 1,4-bisaryl b-lactams in solid-phase system (Scheme 39) without any difficulties. It was believed that the reaction pathway proceeds via dianion, as in the liquid phase.

Recent Approaches Toward Solid Phase Synthesis of b-Lactams

291

N N

N N

N

N

(a) R1

O

N H

O

OCH3 O

R1

O

R1=H

NH N

110a, 110b, R1=CH3

112a, R1=H, R2=Ph, R3=Ph 112b, R1=CH3, R2=Ph, R3=Ph 112c, R1=CH3, R2=Ph, R3=H

N N

N N

N N (b) H3C OCH3

H3C O 111

O

R2 N R3

113a, R2=Ph, R3=Ph 113b, R2=H, R3=Ph

Reagents and conditions : (a) (1) LiHMDS (2.2eq.),THF, -78°C,1h; (2)R2CH=NR3 (1-3eq), THF, -78 °C to rt, 23h. (b) (1) LiHMDS (1.2equiv), THF, -78°C, 1h; (2) R2CH=NR3 (1-3eq), THF,- 78°C to rt,23h.

Scheme 35 Use of T1 triazine linker for solid phase synthesis of b-lactam

1,4-Bisaryl b-Lactams (125). The preparation of 4-phenyl-substituted b-lactams 127 on the solid phase was performed in an analogous manner, beginning with the bisarylimines (Scheme 40). Excellent results have been obtained concerning loading of the lactam resins 125 and purity of the cleaved diazonium salts 126. 1,4-Bisaryl b-lactams 127 obtained by traceless cleavage were easily separated from the by-products by dissolving in Et2O/n-pentane and eluting through silica gel. Nine different b-lactams 127 were prepared in reasonable to high purities (68–98%), medium to high diastereomeric excesses (48–96%), and reasonable to good yields (35–92%).

292

B. Mandal et al.

N N N (a)

N H

O

114

O HNEt3 115 (b)

CF3CO2

N N

N N

N

(c) R1 O

N H O 117

R1 OCH3

O

N H

OCH3 O

116

Reagents: (a) (1) 5 eq. of p-aminobenzoic acid, 10 eq. of BF3.Et2O, 10 eq. of tBuONO, THF, -10 oC, 1h 114, pyridine/DMF (1:1), rt, 1h; (b) 111, 3 eq. of amino acid methyl ester.HCl, 2 eq. of 2-Chloro-1-methylpyridinium iodide, 20 eq. of NEt3, CH2Cl2, rt, 12h; (c) 5% TFA/CH2Cl2.

Scheme 36 Use of T1 triazine linker for solid phase synthesis

Keeping in view the biological and synthetic importance of the b-lactams and the potential of solvent-free microwave chemistry, Kidwai et al. [148] prepared b-lactams via an ester-imine based synthesis under solvent-free microwave irradiation. The trans-4-aminocyclohexanol (128) was condensed with different aromatic aldehyde to give the respective Schiff base. The Schiff-base was then reacted with ethyl a-mercapto/a-cyano acetate, in the presence of basic alumina, to afford the required 3-mercapto/cyano b-lactams respectively, outlined in Scheme 41.

5 Solid-Phase Synthesis of b-Lactams by Miller’s Hydroxamate Approach On the basis of the Miller approach, Meloni and Taddei synthesized b-lactams on solid phase starting from serine, threonine, or other b-hydroxyacids derived from naturally occurring amino acids and a resin-bound hydroxylamine [149]. The ring-

Recent Approaches Toward Solid Phase Synthesis of b-Lactams

293

N N N

(a)

N H 114

OCH3

R1 O 118

(b) N N

CF3CHO2

N N

CF3CO2

R1 N N

OCH3

+

O

OCH3

R1

R1

O 120

119

OCH3

O

Reagents and conditions: (a) (1) 2-(4-Aminophenyl)propionic acid methyl ester (6 equiv), BF3.Et2O (12 equiv), isoamylnitrite (12 equiv), THF, -10 °C, 1 h. (2) 6 (1equiv), pyridine (6 equiv), THF, -10 °C, add diazonium salt (3 equiv), -5 °C, 25 min. (3) filtration of resin under argon, wash with dry THF (x1), suspend in dry THF, repeat step 2. (b) 5% TFA in CH2Cl2.

Scheme 37 Use of T1 triazine linker for solid phase synthesis

N N

R4

N

(a) R1

R1 O

N H

OCH3

O

O

116

N H O 121

Reagents and conditions: (a) 5%TFA in CH2Cl2.

Scheme 38 Use of T1 triazine linker for solid phase synthesis

OCH3

294

B. Mandal et al. N N

N N

N

N

(a) R1

O

OCH3

N H

O

R1

NH R2

O O

N 3 122 R

116

(b)

N HN 124

O

R1 R2 N

O

R3

N

CF3CO2

(c)

HN 123

O

R1 R2 N

O

R3

Reagents and conditions: (a) (1) LiHMDS (2.2 equiv), THF, -78 oC, 1.5h. (2) R2CH=NR3 (3 equiv.), THF, -78 oC to room temperature, 23h. (3) H2O. (b) (1) 5%TFA in CH2Cl2. (c) THF/DMF (5:2), 60 oC, 15 min.

Scheme 39 Use of T1 triazine linker for solid phase synthesis

closure was carried out under Mitsunobu conditions. The amino group present on the b-lactam was used to assemble a short peptide. After a reductive cleavage with SmI2, b-lactam-containing peptides were obtained. They have claimed the first example of Miller hydroxamate synthesis of b-lactams [150] carried out on solid phase. The strategy was chosen to: (1) link the amino acid derivative to a polystyrenesupported hydroxylamine, (2) carry out the cyclization under Mitsunobu conditions, and (3) assemble a short peptide on the free amino group present in the ring. This approach has been shown to be suitable particularly for solid-phase synthesis, as the supported b-lactam could be easily separated from the by-products of the Mitsunobu reaction. The linker employed was a polystyrene resin carrying O-tritylhydroxylamine linker, prepared according to the literature procedure [151]. After the deprotection of Fmoc group carried out with 20% piperidine in DMF, the L-cbzserine (or L-cbz-threonine) was coupled using (4,6-Dimethoxy-[1, 3, 5]-triazin2-yl)-4-methyl-morpholinium chloride (DMTMM) [152] in N-methylpyrrolidone (NMP) in the presence of N,N-diisopropylethylamine (DIPEA) (Schemes 42–45).

Recent Approaches Toward Solid Phase Synthesis of b-Lactams

295 N N

N N

N

N

(a)

H3C

OCH3

H3C

O

O 118b

125

R2 N R3

(b)

N CH3 N O

R2

N

CF3CO2 CH3

(c)

N

R3

O

127

R2 R3

126

Reagents and conditions: (a) (1) LiHMDS (1.5 equiv), THF, -78 oC, 1.5h. (2) R2CH=NR3 (3 equiv.), THF, -78 oC to room temperature, 23h. (3) H2O. (b) (1) 5% TFA in CH2Cl2. (c) THF/DMF (5:2), 60 oC, 15 min.

Scheme 40 Use of T1 triazine linker for solid phase synthesis

HO

NH2

+ OHC

128

129

R

EtOH MWI

EtOOC-CH2X HO

N CH 130

R

Basic Alumina MWI

H HO

N O

H X 131

R

Scheme 41 Synthesis of b-lactam on basic alumina surface under microwave irradiation

6 Other Solid-Phase Synthetic Approaches to b-Lactams The chemistry of carbonylation has long been known and widely applied in organic synthesis as a convenient, versatile, and powerful method [153–205]. Recently, Lu and Alper [206] investigated the catalytic efficiency of dendrimer-supported

296

B. Mandal et al. b

a Cl

O 133

132 HO O

O

NHFmoc

c

134 R

R d

NH

NH2

O

NHCbz

NHCbz N O

O 137 R=H 138 R=Me

135 R=H 136 R=Me

R

NHCbz

e HN

137 or 138 f

O 139 R=H 140 R=Me

R

NHCbz N

HO

O 141 R=H 142 R=Me

a) FmocNHOH, 2eq. DIPEA, rt, 48h.b) piperidine,DMF, rt, 20min. c) (L)-Cbz-Ser-OH or (L)-Cbz-Thr-OH, 4eq. DMTMM, 4eq. DIPEA, NMP,rt, 12h.d) 5eq. DEAD, 10eq. PPh3, THF, rt, 24h.e) SmI2 0.1M in THF, rt,4h.f) 5%TFA in CH2Cl2, rt

Scheme 42 b-Lactams on solid phase using the Miller’s hydroxamate approach

Rh-complexes in carbonylative ring expansion reactions of a variety of aziridines with carbon monoxide, which resulted in the formation of b-lactams in good yields. It was reported that the catalytic system could be easily recovered by simple filtration and recycled without significant loss of activity. The first account on the carbonylation of heterocyclic compounds with metallodendrimers was recently reported by Lu and Alper using Rh-complexed dendrimers on a resin [207]. The building-block techniques of solid-phase chemistry were used to synthesize dendrimers, followed by phosphonation of the dendrimers with diphenylphosphinomethanol. The resulting phosphonated dendrimers were then reacted with chloro(dicarbonyl)rhodium(I) dimer to give dendritic catalysts A and B (31P NMR, d = 25 ppm; loading of rhodium: A, 0.74 mmol g1; B, 0.83 mmol g1). As a model study, the reaction of 1-tert-butyl-2-phenylaziridine with carbon monoxide in catalytic presence of A afforded the desired b-lactam

Recent Approaches Toward Solid Phase Synthesis of b-Lactams Ph H N

NHFmoc 134

a O

b

N 143

O N H

O

HN

O

O

Ph H N

c

O

297

H N

O

O

N

H N

N H

NHBoc O

O

144

NHBoc O

145

(a) N-Fmoc-Ser-OH, DMTMM, NMM, NMP, rt, 4 h followed by DEAD, PPh3, THF, rt, 24 h. (b) Fmoc deprotections with 25% piperidine in DMF followed by couplings using DMTMM in NMP with N-Fmoc-Phe-OH; N-FmocAla-OH, and N-Boc-Val-OH. (c) SmI2 0.1 M in THF, rt, 4 h.

Scheme 43 Solid phase synthesis of b-lactam tetrapeptide O COOH

COOEt

a

b

NHBoc

NHBoc

146

147 OH

OH COOEt

COOH

c

d

NHBoc

NHBoc 149

148 OH O

NHBoc

O H

N O H

N

e

O NHBoc

150

151 O H NH

f

NHBoc 152

(a) CDI, THF, rt, 24 h followed by EtAc/LDA in THF, -78 °C, 1 h. (b) TiCl4 in CH2Cl2, 30 min, followed by BH3.Py, -78°C, 1 h. (c) LiOH, THF/H2O, 24 h, followed by aqueous citric acid. (d) 134, NMP, DMTMM, NMM, 2 h. (e) DEAD, uiv PPh3, THF, rt, 24 h. (f) SmI2 0.1 M in THF, rt, 4 h.

Scheme 44 Application of Mitsonobu reaction and use of SmI2 for detachment

298

B. Mandal et al. OH

OH

COOH

COOEt a, b, c

d

NHFmoc

NHBoc 148

153 O

OH O

NHFmoc

N H

H

O e

154

N

O NHFmoc

f, g

155 O

O BocHN

N H

HH N O

NH Ph

156

(a) LiOH, THF/H2O, 24h. (b) HCOOH (assolvent), rt, 6h. (c) Fmoc-Cl, Na2CO3, dioxane/water, rt, 12h. (d) 134 , NMP, DMTMM, NMM, 2h. (e) 5 equiv of DEAD, 10 equiv of PPh3, THF, rt, 24h. (f) Series of Fmoc deprotections with 25% piperidine in DMF followed by couplings using DMTMM in NMP with N-Fmoc-Val-OH and N-Boc-Ala-OH. (g) SmI2 0.1 M in THF, rt, 4h.

Scheme 45 Application of Mitsunobu reaction in solid phase synthesis of b-lactam

(Schemes 46 and 47). Variation of the Rh-complexed dendrimers A to B and generalization with a range of aziridines constituted a generalized and attractive methodology for solid phase b-lactam synthesis. Chmielewski et al. [208] described a new resin-based chemistry for the straightforward construction of 1-oxacephams, which represent a class of compounds with potential biological activity [209]. The synthetic strategy, outlined in Scheme 48, began with commercially available Wang resin 157 utilizing the cyclization/cleavage approach. The 1-oxacephams 169 and 170 were obtained in good overall yield and high diastereomeric purity was obtained by the cyclization/cleavage step from the corresponding resins 167 or 168 with BF3.Et2O in CH2Cl2. The good yield and purity of the products, and simple procedure for both reaction sequences make this a very attractive method for the synthesis of 1-oxacephams. Mata et al. also described a new and robust protocol for the solid-phase synthesis of 2b-methyl substituted penam derivatives using Merrifield resin as support [210]. The work begins with immobilization of 6,6-dibromopenicillanic acid (171) onto Merrifield resin followed by oxidation with m-chloroperbenzoic acid (MCPBA) to obtain the resin-bound sulfoxide (173). The key-step involves the thermal rearrangement of the corresponding penicillin sulfoxide (Scheme 49).

Recent Approaches Toward Solid Phase Synthesis of b-Lactams Ph N t-Bu

Ph P Cl(OC)2Rh Ph

N P Ph Ph

+

CO

299

Ph

A 400 psi, C6H6

N O

(CO)2Cl (CO)2Cl Ph Ph Rh Rh Ph P P P P Ph Ph Ph N N O O HN

t-Bu

N

NH Ph O

Ph Ph P Rh(CO)2Cl

P Ph

NH O

Catalyst A

Scheme 46 Carbonylative ring expansion of 1-tert-Butyl-2-phenylaziridine using Rh-complexed dendrimers

An efficient and convenient solid-phase method for the synthesis of 2b-methyl substituted penicillins using commercially available resins was developed by Mata et al. [211]. Functionalization of the Merrifield and Wang resin bound penam derivatives was performed by penicillin sulfoxide rearrangement and the products were released from the supports under mild conditions. Merrifield (178) and Wang (179) resins were selected as polymer supports for the immobilization of penicillins and it was found that both could be used to tether the 6,6-dibromopenicillanic acid (177) starting material. However, potassium fluoride in DMF or DCC with catalytic amount of DMAP was used respectively for coupling with resins. The Merrifield resin-bound penicillin 180(M) and the Wang resin-bound compound 180(W) were then subjected to solid phase oxidation using m-chloroperbenzoic acid followed by mild cleavage conditions, such as AlCl3 and 10% trifluoroacetic acid (Schemes 50 and 51). Synthesis of thietane-fused b-lactam was reported by Sakamoto et al. [212] involving solid-state photoreaction of N-(a,b-unsaturated carbonyl) thiobenzanilide demonstrating a single-step photochemical route to b-lactam, as outlined in Scheme 52. A series of piperidine containing N1 activated C4-carboxy azetidinone tryptase inhibitors was prepared by Sutton et al. [213] adopting solid-phase technology. Wang resin was used to attach with the carboxyl group of the b-lactam moiety and removal from the resin surface was achieved as usually by 20% TFA in CH2Cl2.

300

B. Mandal et al.

R2

R2 N R1

+

catalyst A or B CO 400 psi, C6H6

N O

R1

Ph Cl(OC)2Rh P Ph Ph P N (CO)2Cl Ph Ph Rh Ph P P Ph Ph Ph Ph N P Rh(CO)2Cl N O P Ph Ph O NH Ph Ph P Cl(OC)2Rh

N

Ph Cl(OC)2Rh P Ph Ph P Ph N

Rh(CO)2Cl

N P

Ph Ph O

NH

O

NH NH

P

NH O

HN

P Ph Ph

Ph

Ph

NH O

O

Ph Ph P Cl(OC)2Rh

HN O O

HN

Ph

Ph

O

N

P Rh(CO)2Cl

N P Ph Ph

P Ph

Ph

NH O Ph Cl(OC)2Rh P Ph Ph P Ph N

HN O HN Ph Cl(OC)2Rh P Ph Ph P Ph N HN

O NH

Ph

P

P

Ph Rh P Ph (CO)2Cl

Ph

Ph Ph P Cl(OC)2Rh

Ph

O

O

O NH

Rh(CO)2Cl

N

N

Ph

Ph P

O

P

NH NH

O

Rh(CO)2Cl

N Ph

NH

NH Ph

P

O

O

Ph

Ph

Ph

Ph Ph Ph P Cl(OC)2Rh

Ph

P

N

Rh(CO)2Cl

N P Ph Ph

P Ph

Ph

N P Ph Ph Catalyst B

Scheme 47 Carbonylative ring expansion of aziridines using Rh-complexed dendrimers

The preparation of the azetidinone core and the coupling to resin is outlined in Scheme 53. The first expeditious solid-phase procedure for the preparation of optically active quaternary cis-b-lactams with an innovative substitution pattern is reported by Gonza´lez-Mun˜iz et al. [214]. They describe an operationally simple four-step procedure for the solid-phase synthesis of chiral (3S,4S)-1,3,4,4-tetrasubstituted b-lactams. Taking into account the recurrence of 1,3,4-trisubstituted pattern in bioactive monocyclic b-lactams, the development of an environment friendly method for the synthesis of this 1,3,4,4-analogues may be of major interest. The key step to the four-member ring formation is the enantioselective phosphazene base-assisted cyclization of the resin-bound N-(alkyl)-N-[(S)-2-chloropropionyl]

Recent Approaches Toward Solid Phase Synthesis of b-Lactams

301

OH 157

O a

NH O CCl3 158

O b

c 159

160

RO

CO2Me

O

O O

O

O O

161 O

162 R = Piv 163 R = H

d

e

f O

OR TfO

O O

O O

164 R = H 165 R = Tf

O O

f 166 O g,

g

NH O O O

O 167

O

O

N

O

N

O O

O

O O

168 h

H

O

h

H

H

N

O

HH O O H

N

O

O 169

H 170

a)CCl3CN, DBU, CH2Cl2 , 20 oC, 3 h; b) methyl (S)-3-hydroxybutyrate (159), BF3.Et2O, CH2Cl2/cyclohexane 1/1, 20 oC, 5 min; c) 1,2-O-isopropylidene-5-O-pivaloyla-d-xylofuranose (160), BF3.Et2O, CH2Cl2/cyclohexane 1/1, 20 oC, 5 min; d) DIBAL-H, THF, 20 oC, 4 h; e) MeONa, MeOH, 20 oC, 2 h; f) Tf2O, 2,6lutidine, CH2Cl2, 0 oC, 6 h; g) nBuLi, Bu4NHSO4, THF, -70 oC- 20 oC, 12 h; h) BF3.Et2O, CH2Cl2, 20 oC, 3 h. Piv.=pivaloyl, DBU.=1,8-diazabicyclo[ 5.4.0]undec-7-ene, DIBAL-H.=diisobutylaluminum hydride.

Scheme 48 Solid-phase synthesis of 1-oxacephams

302

B. Mandal et al. S

S H

Br

S

Br

Br

N O

O O

171

N O O

172 n = 0

C O 174

MCPBA (1.4 eq.) 20h, 0 °C

173 n = 1

N

S

Br

Benzene reflux 12h

C O

S

H

Br

N (1.5 eq.)

N

KF/ DMF 60 °C, 24h

CO2H

SH

H (O)n S

Br

Cl

SO2Cl2, CH2Cl2, –40 °C or Br2, acetamide, rt

H

Br Br

S 6

N O

7

Br

1)AlCl3, CH2Cl2/MeNO2

X

5

2 3

S

S

Br

O 175 O

176

H

Br

X

N

2) CH2N2, Et2O

CO2R

H

Br

X

N

C O

O O

C O

Scheme 49 Solid-phase synthesis of 2-b-methyl substituted penam derivatives

M

Br

S

Br O

Br N

a

N

O

177 CO2H

W

b

O

OH 179

(O)n S

Br Br

d

c

e or f

C

O 180(M) n = 0 181(M) n= 1 182(M) n= 2

M e

(O)n S

Br Br

N

N

O O c

(O)n S

Br

Cl 178

C

O

W

O O

C

OH

180(W) n = 0 181(W) n = 1

(a) 3, KF, DMF, 60 °C, 24 h; (b)179, DCC, DMAP (cat.), CH2Cl2–DMF, r.t., 4 h; (c) MCPBA (1.4equiv), CH2Cl2, 0 °C, 20 h; (d) MCPBA (5 equiv), CH2Cl2, r.t., 96 h; (e) AlCl3, CH2Cl2/MeNO2, 0 °C, 30 min; (f) 10% TFA in CH2Cl2, r.t., 30 min.

Scheme 50 Solid phase synthesis of penicillin using Merrifield resin and Wang resin

amino acid derivatives. The route does not require any chiral auxiliary or catalyst, since the high enantioselectivity which is obtained is solely directed by the configuration of 2-chloroalkanoyl substituent. This also permits different configurations of

Recent Approaches Toward Solid Phase Synthesis of b-Lactams

303

O S

Br Br N O

W

C O O 181(W)

a S N

S

Br

O

C

O

S

Br

S N

N

+

N O

S

Br

S

Br

O

W

O

C

183(W)

S

Br

O

O

C

N C

OR

OR

185(W) R = W 186 R = Me

c

S

N O

+

N O

S

Br

Cl

S

Br

W

184(W)

b

Br

O

184(W) R = W 187 R = Me

c

(a) 2-MBT (4 equiv), toluene, reflux, 4 h; (b) Cl2SO2, CH2Cl2,–40 °C; (c) (i) 10% TFA in CH2Cl2, r.t., 30 min; (ii) CH2N2, Et2O.

Scheme 51 Solid phase synthesis of penicillin using Wang resin

R1

S

R1

Ph hn N

R2 O

R3

R1

S R2

Ph N

O

R3

+

R2

H N

S Ph

O Me Me

Scheme 52 Synthesis of thietane-fused b-lactam

the final b-lactam just by changing the configuration of the 2-chloroalkyl carboxylic acid incorporated in second step. This procedure is highly notable compared to other approaches for the synthesis of highly substituted b-lactams (Scheme 54).

304

B. Mandal et al. 190 CO2H

HN

CO2Et

I

a-c

N O

CO2H

Boc N

TBS

Boc N N

d

O

189

188

TBS 191 e

193

O Boc N

Cl

O O

N

Boc N

N

O

O

N

O

O N

O

O

N

N

O f

O

O 194

O

O HN

O

OH

h or i, j

N

O

NH

N

HN

OH

OH

O

N N 197 O

N R' R

O

O

O

N

196 O

195 O

HN

O

N

N O

TBS

= Wang resin

g

Boc N

192

O

N O

N O R

198

N O

N R

(a) Boc2O, Et3N, DMAP, CH2Cl2, 98%; (b) LiAlH4, THF, 0 oC, 94%; (c) (i) Ph3P, imidazole, CH2Cl2, (ii) I2, 0 oC, 74%; (d) (i) LDA, THF, -78 to -20 oC, (ii) add compound 7, -78 to -20 oC, 43%; (e) WangResin, MSNT (1-mesitylene-2 sulfonyl)-3-nitro- 1H-1,2,4-triazole), N-methyl-imidazole, CH2Cl2, THF; (f) compound 5, Et3N, DMAP, CH2Cl2; (g) Pd(Ph3P)4, PhSiH3, CH2Cl2; (h) isocyanate or chloroformate, Et3N, DMAP, CH2Cl2; (i) carboxylic acid, DIC, HOAT, CH2Cl2–dimethylacetamide (1:1); (j) 20% TFA in CH2Cl2.

Scheme 53 Preparation of N1 activated C4-carboxy azetidinone tryptase inhibitors using Wang resin

A survey of the literature reports regarding the synthesis of b-lactam using carbohydrate precursors has recently been published by Furman et al. [215]. They have shown that the carbohydrates were used either as chiral tools or chiral auxiliaries. A few solid phase approaches have been outlined in the survey using the vinyl ether bound to the polymeric support through a sulfonyl linker. Two alternative modes of attachment of the vinyl ethers to the resin have been reported.

Recent Approaches Toward Solid Phase Synthesis of b-Lactams

N H

R2CHO/ HC(OMe)3

O

2S-Me(Cl)CHCO2H

O

HN

NaBH3CN

O

R

Me

Cl

R1

R1 Fmoc

305

O

N

O

coupling reactions

O 2

R1

R

O 2

Fmoc-Xaa-Wang-resin R1

Me

R1

Me

O

TFA

CO2H N

Base

O

N

DCM

O

O

199

2 200 R

R2

R1 = Me. benzyl, (CH2)4NHBoc, (CH2 )2CO2 -t-Bu R2 = 4-methoxyphenyl, CH(CH3 )2 ,

(CH3)3, 2,4-dichlorophenyl, benzyl

Scheme 54 A solid-phase synthetic approach showing diversity incorporated at R1 and R2 202 202 202 PivOC6H4SO2O O

O

O

Na, MeOH

OMe

then Wang resin, DEAD, PPh3

O O

H

O

H

NH

+

OMe

H

O

BEMP or DBU

OMe

O O 202

O O

203

O O

O

O

O

O OMe

then Red-Al

O

O H

N

O O

204

OMe

O O

+

OMe

N

SO2O O

CSI, Na2CO3 O

201

H

O H

O

SO2O O

Scheme 55 Vinyl ether linked through Wang resin followed by cleavage to yield b-lactam

MsO

O O

LiCH2SO2O BuLi, THF/DMPU

O O O O

O O

SO2O

BEMP

CSI, Na2CO3 then Red-Al

O O

NH

O O

O O

+

O

O O 206

Merrifield resin

SO2O

O O

205

H H N O

O

HH O O H 207

H H O H

O

O O

HH O

+ N O

O

O H

H 208

Scheme 56 Vinyl ether linked through Merrifield resin followed by cleavage to yield b-lactam

306

B. Mandal et al.

The first one (Scheme 55) uses the p-oxyphenylsulfonyl linker attached to the Wang resin by the Mitsunobu procedure [216, 217] whereas the second one (Scheme 56) utilizes alkylation of the lithium salt of a mesylate [218] with the terminal of the Merrifield resin [216, 219].

7 Conclusion In conclusion, the present review on the synthesis of b-lactams and analogues performed on solid surface covers several intelligent approaches. Although various resins have been employed, Wang resin and application of Staudinger [2+2] cycloaddition reaction have remained the major choice so far. Both unsubstituted and substitutions with different functional groups at various positions of b-lactams have been synthesized using solid phase technology. It may be expected that other solid phase approaches involving different resins would be developed in the coming years. Acknowledgments Partial financial support from the Department of Science & Technology, New Delhi, India (Grant No. SR/S1/OC–49/2006) is gratefully acknowledged. BM thanks CSIR, New Delhi for Senior Research Fellowship.

References 1. Fleming A (1929) Br J Exp Pathol 10:226 2. Mandell GL, Petri WA, Jr (1996) In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Goodman Gilman, A (eds) Goodman & Gilman’s the pharmacological basis of therapeutics. McGraw-Hill, New York 3. Manhas MS, Bose AK (1971) b-Lactams: natural and synthetic. Wiley, New York 4. Page MI (1987) In: Bethell D (ed) Advances in physical organic chemistry. Academic Press, London 5. Yoakim C, Ogilvie WW, Cameron DR, Chabot C, Guse I, Hache´ B, Naud J, O’Meara JA, Plante R, De´ziel R (1998) J Med Chem 41:2882 6. Linder MR, Podlech J (1999) Org Lett 1:869 7. Abell AD, Gardiner J (1999) J Org Chem 64:9668 8. Palomo C, Aizpurua JM, Benito A, Galarza R, Khamrai UK, Vasquez J, de Pascual-Teresa B, Nieto PM, Linden A (1999) Angew Chem Int Ed 38:3056 9. Wright AJ (1999) Mayo Clin Proc 74:290 10. Konaklieva MI (2002) Curr Med Chem: Anti-Infect Agents 1:215 11. Singh R, Micetich RGI (2000) Drugs 3:512 As recent examples of beta-lactam inhibitors of HLE see 12. Clemente A, Domingos A, Grancho AP, Iley J, Moreira R, Neres J, Palma N, Santana AB, Valente E (2001) Bioorg Med Chem Lett 11:1065 13. Koteva KP, Cantin AM, Neugebauer WA, Escher E (2001) Can J Chem 79:377 14. Cainelli G, Galletti P, Garbisa S, Giacomini D, Sartor L, Quintavalla A (2003) Bioorg Med Chem 11:5391 15. Kazi A, Hill R, Long TE, Kuhn DJ, Turos E, Dou QP (2004) Biochem Pharmacol 67:365

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Top Heterocycl Chem (2010) 22: 313–347 DOI 10.1007/7081_2009_10 # Springer‐Verlag Berlin Heidelberg 2010 Published online: 22 January 2010

Computational Studies on the Synthesis of b-Lactams via [2þ2] Thermal Cycloadditions Ana Arrieta, Begon˜a Lecea, and Fernando P. Cossı´o

Abstract The main computational studies on the formation of b-lactams through [2þ2] cycloadditions published during 1992–2008 are reported with special emphasis on the mechanistic and selectivity aspects of these reactions. Disconnection of the N1-C2 and C3–C4 bonds of the azetidin-2-one ring leads to the reaction between ketenes and imines. Computational and experimental results point to a stepwise mechanism for this reaction. The first step consists of a nucleophilic attack of the iminic nitrogen on the sp-hybridized carbon atom of the ketene. The zwitterionic intermediate thus formed yields the corresponding b-lactam by means of a four-electron conrotatoty electrocyclization. The steroecontrol and the periselectivity of the reaction support this two-step mechanism. The [2þ2] cycloaddition between isocyanates and alkenes takes place via a concerted (but asynchronous) mechanism that can be interpreted in terms of a [p2s þ (p2s þ p2s)] interaction between both reactants. Both the regio and the stereochemistry observed are compatible with this computational model. However, the combination of solvent and substituent effects can result in a stepwise mechanism. Keywords b-lactams ab initio calculations Alkenes Imines Isocyanates Ketenes Ketenimines Semiempirical calculations

A. Arrieta, B. Lecea, and F.P. Cossı´o (*) Departamento de Quı´mica Orga´nica I, Kimika Organikoa Saila I, Universidad del Paı´s Vasco – Euskal Herriko Unibertsitatea, P.O. Box 1072, 20080 San Sebastia´n-Donostia, Spain e-mail: [email protected] DIPC, Po Manuel de Lardizabal 4, Universidad del Paı´s Vasco – Euskal Herriko Unibertsitatea, 20018 San Sebastia´n-Donostia, Spain

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Contents 1 2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314 The Reaction Between Ketenes and Imines and Related Transformations . . . . . . . . . . . . . . . 316 2.1 Reaction Between Ketenes and Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316 2.2 Reaction Between Thioketenes and Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330 2.3 Reaction Between Ketenimines and Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331 2.4 Reactions Involving Metalated Ketenes and/or Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334 2.5 Catalytic Versions of the [2þ2] Cycloaddition Between Ketenes and Imines . . . . . . 337 3 The [2þ2] Cycloaddition Between Isocyanates and Alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338 3.1 General Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338 3.2 Regiochemistry and Sterochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340 4 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

Abbreviations AM1 B3LYP CASSCF CI-HE DFT ECP MNDO MO MPn PCM PM3 RHF SCF SCRF UHF ZPVE

Austin Model 1 Hybrid three-parameter functional derived by Becke, Lee, Yang and Parr Completely active space self-consistent field Configuration interaction-half electron method Density-functional theory Effective core potential Minor neglect of differential overlap Molecular orbital nth order Møller-Plesset expansion Polarization continuum model Third parametrization of MNDO Restricted Hartree-Fock Self-consistent field Self-consistent reaction field Unrestricted Hartree-Fock Zero-point vibrational energy

1 Introduction Given the importance of b-lactams in heterocyclic and medicinal chemistry [1–3], many different methods for the synthesis of these compounds have been developed [4, 5]. Among them, those involving [2þ2] cycloadditions are of special relevance because of the convergent nature of these methodologies, the readily accessible reagents required, and the wide range of b-lactams thus available [6–9].

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a a +

N

b

b N

N

O

+

O

O 2

1

3

4

5

Scheme 1 [2þ2] disconnections of the b-lactam ring

a

antara

supra

b

supra

antara

Fig. 1 [p2sþp2a] Mechanisms in the [2þ2] cycloaddition involving p-systems (a) and cumulenes (b)

Two possible [2þ2] cycloadditions can be envisaged for the synthesis of b-lactams (Scheme 1). Interestingly, the same fragmentations have been observed in the mass spectra of these compounds [10, 11]. One possibility consists of the [2þ2] cycloaddition between ketenes (2) and imines (3) to yield b-lactams (1). This reaction has been explored experimentally and it is also known as the Staudinger reaction between ketenes and imines [12–15]. In an alternative approach, the [2þ2] cycloaddition between alkenes (5) and isocyanates (4) leads to b-lactams (1). This reaction has been less extensively used, but it has proven to be useful in the chemical synthesis of interesting compounds [16–19]. The [2þ2] cycloadditions can be concerted under thermal conditions provided that the interaction between the p-systems takes place in a supra-antara mode (Fig. 1). This [2ps þ 2pa] mechanism [20] is sterically very demanding and, therefore, it should be facilitated by cumulenes possessing sp-hybridized electrophilic carbon atoms. This makes ketenes and isocyanates suitable candidates for concerted symmetry-allowed thermal [2þ2] cycloadditions. However, the presence of heteroatoms in both possible [2þ2] reactions leads in turn to different stepwise mechanisms in which the electrophilic nature of the sp-hybridized carbon atoms of ketenes and isocyanates plays a crucial role (Scheme 2). According to these mechanisms, zwitterionic intermediates (6) and (7) are plausible via formation of C–N or C–C bonds, respectively. All these concerted and stepwise mechanisms as well as the regio and stereochemical issues associated with these reactions pose complex mechanistic problems and make computational chemistry a suitable tool to analyze the different

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+

N

N O

O 2

6

3

N O 5

1 +

4

O

N

O

N

7

Scheme 2 Stepwise mechanisms in the reaction between ketenes and imines or isocyanates and alkenes to form b-lactams

reaction paths as well as to predict the stereochemical and regiochemical outcomes. In this review, the main contributions in this field during the 1992–2008 time span will be presented, although references to previous work will also be included when necessary. The aim of this review has not been to address a theoretical audience but organic chemists interested in the mechanistic aspects of these reactions.

2 The Reaction Between Ketenes and Imines and Related Transformations 2.1 2.1.1

Reaction Between Ketenes and Imines General Mechanism

Since the pioneering work of Boyd et al. [21], many studies have analyzed the Staudinger reaction. Although early ab initio works [22, 23] performed at the RHF/ 3-21G levels of theory predicted concerted but asynchronous mechanisms, these early claims were questioned on the basis of computational [24] and experimental arguments. Thus, Sordo et al. [25] and our group [26] concluded that the Staudinger reaction between ketenes and imines takes place via stepwise mechanisms, based on ab initio [25] and semiempirical [26] calculations at the AM1 level of theory [27]. According to this description of the mechanisms, the reaction starts with a nucleophilic attack of the iminic nitrogen atom on the sp-hybridized atom of the ketene to yield a zwitterionic intermediate. The chief features of the first transition structure associated with the reaction between ketene and methanimine as well as that corresponding to the zwitterionic intermediate can be found in Fig. 2.

Computational Studies on the Synthesis of b-Lactams via [2þ2] Thermal Cycloadditions

a [1.334] (1.333) [1.192] (1.222)

b

w=[180.0](180.0)

3

[1.745] (1.857) 2

3

[1.579] [1.342] (1.537) (1.360)

[1.250] (1.273)

1

317

1

2

[1.214] (1.255)

[1.254] (1.287)

4

4

w=[180.0](180.0)

[RHF/6-31G*] (RHF/AM1)

Fig. 2 Optimized geometric features of the first transition structure (a) and the intermediate (b) corresponding to the reaction between ketene and methanimine. Bond distances and angles are given and deg., respectively. o denotes the dihedral angle between the C4, N1, C2 and C3 atoms in A

C O

O

N

+

N

N H 8

N H

9 O

O C C C O

C

+

C

O

N

N

11

10

Scheme 3 Zwitterionic intermediates associated with the interaction between ketenes and nitrogen containing heterocycles R2 N R1

Base Cl

O 12

R1

14 C O

13

SiMe2R3

R1

R2 N O

SiMe2R3 15

D

R1

R2 N

O

SiMe2R3

16

Scheme 4 Stepwise mechanism corresponding to the reaction between ketenes and N-silyl imines

It is interesting to note that, under special conditions, these zwitterionic intermediates have been isolated (Scheme 3). Thus, the interaction of ketene (8) with imidazole showed an intermediate whose IR properties were attributed to zwitterion (9) [28]. More recently, Wentrup et al. [29] have calculated the stability of the complex formed by C3O2 (10) and pyridine and have found that at the B3LYP/ 6-31G* level at least a dielectric medium of relatively large dielectric permitivity (e = 40) is required to yield the zwitterionic intermediate (11). This result is in line

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A. Arrieta et al.

a

2.143 [2.129] (2.120)

b

1.427 [1.413] (1.428)

2.348 [2.355] (2.343) 1.431 [1.418] (1.432)

1.338 [1.307] (1.343)

2.348 [2.355] (2.343)

1.378 [1.369] (1.389) in

B3LYP(PCM)/6-31G* [RHF/6-31G*] (RHF/AM1)

1 3 2

out

4

3-out

1.440 [1.456] (1.446) 3-in 4-out 1

3

4

2

4-in w=20.6[22.0](18.7)

w=31.9[39.2](24.2)

Fig. 3 Optimized geometric features of the transition structure associated with the cyclobutene1,3-butadiene interconversion (a) and with the second transition structure of the reaction between and ketene and methanimine to yield azetidin-2-one. Bond distances and angles are given in A deg., respectively. o denotes the dihedral angle between the C4, N1, C2, and C3 atoms

with the difficulties found in the isolation of other zwitterionic intermediates of type (6, 9, 11). There is an exception, however. Panunzio et al. [30–33] have isolated 3-aza-1,3-dienes (15) in the reaction between ketenes (13) and N-silyl imines (14) (Scheme 4). These intermediates were fully characterized and transformed into the corresponding N-silyl-b-lactams (16). Therefore, 3-aza-1,3-dienes (15) can be considered as neutral isolable equivalents of zwitterionic intermediates (6). Given the preparative and mechanistic interest of this reaction, it has been studied computationally in detail (vide infra). Intermediates (6) can yield to the corresponding b-lactams via conrotatory electrocyclic closures (Fig. 3). The main features of these transition structures closely resemble those found for the thermal electrocyclic ring opening of cyclobutenes [34]. As a consequence, it has been proposed [35, 36] that the torquoelectronic model developed by Houk [35–37] for this latter reaction can be extended to the Staudinger reaction between ketenes and imines. This model relies on the nonequivalent positions of the substituents in the conrotatory transition structures, as shown in Fig. 3. In these transition structures the outward and inward positions are not equivalent, which has profound consequences on the stereochemical outcome of the reaction (vide infra). It is important to note that inclusion of solvent effects in the calculation of the mechanism is very important in order to reproduce correctly the reaction profile. Thus, if the electrostatic part of the free energy of solvation (DAsolv) is calculated in the form

Computational Studies on the Synthesis of b-Lactams via [2þ2] Thermal Cycloadditions

R1

R5

R2

R6

+

C O

R4 R3

17

R1

R4 N

N

R6

R5

O 18

R2

R2 +

319

R5 R6 R4

R1 N R3

O R3

20

19

Scheme 5 [2þ2] and [4þ2] periselectivity in the reaction between ketenes and a,b-unsaturated imines

N

[p4c]

N O

O 22b C O 2

R3

23

+ N 21 N

[p6d]

O

O 22d

N R3 24

Scheme 6 Stepwise mechanisms associated with the reaction between ketenes and a,b-unsaturated imines

DAsolv ¼

1 X X m mm0 m0 M f 0 M l0 2 l;l0 m;m0 l ll

(1) 0

where Mlm is a component of the multipole moment of order l and fllmm are the SCRF 0 factors, it has been found that at the MP2/6-31G* level the main contribution corresponds to the dipole term (l = 1), although higher multipoles have substantial contributions (l = 2,3), specially for the zwitterionic intermediate [38]. A more detailed study [39] (up to MP4/6-31G* level) showed the importance of solvent effects to stabilize the zwitterionic intermediate, as well as the relevance of ZPVE corrections. It is noteworthy that semiempirical calculations in the gas phase (RHF/ AM1) give similar potential energy surfaces to those obtained by ab initio methods included solvation effects [40]. 2.1.2

Periselectivity

When imines derived from a,b-unsaturated aldehydes react with ketenes, formal [2þ2] and [4þ2] cycloadditions are possible [11, 41] (Scheme 5). Although a [p2sþp4s] concerted (but not necessarily synchronous) mechanism is conceivable,

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A. Arrieta et al.

Fig. 4 Optimized geometric features of the electrocyclic transition structures associated with the conrotatory (a) and disrotatory (b) ring closure of the zwitterionic intermediates resulting from the interaction between ketene and prop-2-en-1-imine. Bond distances are given in A

both semiempirical RHF/AM1 [42] and SCF-MO [43] calculations suggest that both [2þ2] and [4þ2] reactions are stepwise. Thus, nucleophilic attack of the nitrogen of the a,b-unsaturated imine (21) (Scheme 6) on the electrophilic carbon atom of ketenes (2) leads to the formation of zwitterionic intermediates (22) in the b and d conformations. The thermally allowed [p4c] reaction (22b) leads to the formation of b-lactams (23), whereas the [p6d] electrocyclization of (22d) leads to the formation of the corresponding d-lactams (24) (Scheme 6). Figure 4 shows the main geometric features of the transition structures associated with the [p4c] and [p6d] steps in the reaction between ketene and prop2-en-1-imine. Experimental and computational studies [42, 43] showed that the periselectivity of this reaction is very sensitive to substituent effects. Thus, in general disubstituted ketenes and/or imines possessing bulky substituents at the b-position favor the formation of [2þ2] cycloadducts because of severe steric

Computational Studies on the Synthesis of b-Lactams via [2þ2] Thermal Cycloadditions

N

+

C

[p4s+p2s] O

N

O 2

N

(E )-25

X

N

N

O

26

N

+

C

321

2

(Z )-25

[p4s+p2s]

O

N

N

[3,3]s

N

N O

27

28

N N

[p4c] O

29

Scheme 7 Mechanisms of the reaction between ketenes and 1,3-diazabuta-1,3-dienes

interactions in the inward positions of the disrotatory transition states. (These positions are highlighted with asterisks in Fig. 4). The reaction between ketenes and 1,3-diazabuta-1,3-dienes [44–48] has also been studied computationally [48]. According to the MP2/6-31G* þ DZPVE results obtained by Bharatam et al. in the gas phase, there are at least three reaction paths leading to the [2þ2] and [4 þ 2] cycloadducts. Thus, ketenes (2) can react as dienophiles with (E)-1,3-diazabuta-1,3-dienes (E)-(25) to yield either [4 þ 2] cycloaducts (26) or (27) depending on the participation of the C = C or C = O moieties of the ketenes (Scheme 7). Claisen rearrangement of 3,6-dihydro-2-methylene-2H-1,3,5-oxadiazines (27) yields the b-lactams (28). Alternatively, reaction between ketenes (2) and (Z)-1,3-diazabuta-1,3-dienes (Z)-(25) leads to the usual zwitterionic intermediates (29), whose conrotatory electrocyclation leads to b-lactams (28). No computational data including solvent effects have been reported for these reactions.

2.1.3

Stereoselectivity

Despite its formal simplicity, the stepwise mechanism of the reaction between ketenes and imines raises a complex stereochemical situation since ketenes can be unsymmetrically substituted and imines can exist in either (E)- or (Z)-configurations [49]. As far as the first step of the reaction is concerned, the nucleophilic attack of the nitrogen atom of the imine can occur through the less hindered exo face, namely that which has the shortest substituent, or through the endo face, which incorporates the largest substituent (Scheme 8). In principle, the exo attack leads to second transition structures that exhibit the largest substituents at the 3-out position.

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A. Arrieta et al.

R2

R1 R3 N

L endo

31 endo attack

L S O

C O 30

exo

R1 N

R2 R3 31

exo attack

S

R1 N

S

R2

L

R2

N

R3

R3

O 33

32

[p4c]

[p4c]

L

R1

R3

S

R3

S

R2

N

R2

N

L R1

O 34

S

35

L R2 N

O

R1

O

R1

R3

36 trans-b-lactams (R1>R2) cis-b-lactams (R1
L

S R2

R1

N

R3 37 cis-b-lactams (R1>R2) trans-b-lactams (R1
Scheme 8 Stereochemistry of the reaction between ketenes and imines

According to the torquoelectronic theory [34–37], this should result in less energetic transition structures if the largest substitution is electron-releasing. In contrast, if this substituent is electron-withdrawing, the 3-inward position should be favored. This prediction was verified by computational studies carried out both in the gas phase and in dichloromethane solution. Table 1 shows some significant results [50–52]. According to this scheme, the Staudinger reaction between (E)-imines and ketenes should yield preferentially the kinetic cis-b-lactams, provided that the first step takes place via an exo attack, which leads to a second transition state in which the L substituent occupies the 3-out position (Scheme 8). Using the same argument, (Z)-imines should yield trans-b-lactams as main cycloadducts [26].

Computational Studies on the Synthesis of b-Lactams via [2þ2] Thermal Cycloadditions

323

Table 1 Torquoelectronic effectsa in the transition structures associated with the conrotatory ring closure of monosubstituted ketenes R2 R3 DEin–out R R1 e ¼ 1.00 e ¼ 0.93 14.0b OH H H H 12.1b b CH3 H H H 9.2 9.0b CH3 CH3 H H 7.2c 7.6c c CH3 H CH3 H 5.6 7.2c Cl H H H 12.7d Cl CH3 H H 8.2c 11.6c Cl H CH3 H 6.8c 9.1c c Cl CH ¼ CH2 H CH3 9.5 10.7c Cl H CH ¼ CH2 CH3 8.3c 9.8c b CN H H H 2.4 4.0b BH2 H H H 12.5b 11.5b a Measured as the difference in energy between the transition structures incorporating the substituent R in an inward and outward position b Data taken from [51] and computed at the MP2(SCRF)/6-31G*//RHF/6-31G* level c Data taken from [52] and computed at the B3LYP(SCRF)/6-31G* level d Data taken from [50] and computed at the MP2/6-31G*//RHF/6-31G* level

Hegedus et al. analyzed this model in detail and concluded that, in general, it agrees with the experimental evidence available [53]. There are some examples on diastereoslective reactions between ketenes and imines [54–61]. However, the number of computational studies dealing with these reactants is scarce [59, 62–64]. As an example of Staudinger reaction in which the chirality source is at the C4 position of the ring being formed, our group studied the reaction between methoxyketene (38) and imine (S)-(39) derived from (S)-a-alkoxyaldehydes to yield the corresponding cis-b-lactam (3S,4R)-(40) (Scheme 9). The RHF/AM1 transition structure (41) was found to be 1.5 kcal mol1 more stable than the saddle point (42), in good agreement with the experimental findings [62]. This large stereocontrol was attributed to the two-electron interaction between the p-AO of the CA atom and the CB-OC subunit, which acts as s-acceptor. In the case of transition structure (42), this conformation leads to a steric congestion between the 1,3-dioxolaryl group and the b-lactam ring being formed, thus resulting in a less stable structure (Scheme 9). The reaction between Evans-Sjo¨gren ketene (43) and the model (E)-imine (44) was also studied at the RHF/AM1 level (Scheme 10). The calculations indicated that in this case the dominant conformation is dictated by the anti orientation of the carbonyl groups of the oxazolidinone and azetidine rings [62]. In this case, the transition structure (47), which incorporates a destabilizing interaction between the phenyl group and the b-lactam being formed, was calculated to be 4.9 kcal mol1 higher in energy than saddle point (46). Therefore, exclusive formation of cisb-lactam (3S,4R)-(45) is predicted in good agreement with the experimental results [54].

324

A. Arrieta et al. Me

MeO

O

H H

Me

Me

O

X

38

(3R,4S)-40

H H

MeO H

+

C O

Me

Me

O

O

MeO

H

N O

Me

N

N

Me

O

(S)-39

Me

O

O

H Me

(3S,4R)-40 Me

Me H MeO

H

O b

b

MeO

c

O

O

Me

O

H

N

a

O

c

H

Me

a

O

N

H

Me

H

Me

41

42

(3S,4R)-40

(3R,4S)-40

Scheme 9 Stereochemistry of the reaction between methoxyketene (38) and imine (S)-(39)

O

O N Ph

H O

Ph H

X Me

N C O

+

H

N

H

O

O 46

(3S,4R)-45

Me

H H

H

N O

N

Me

(3S,4R)-45

H

H O

N

Ph

44

Me

O

N

(S)-43

(3R,4S)-45

Scheme 10

O

O

N

N

O

O

O

H H

O N

H

H

Me 47

(3R,4S)-45

Stereochemistry of the reaction between ketene (S)-(43) and imine (44)

Computational Studies on the Synthesis of b-Lactams via [2þ2] Thermal Cycloadditions

325

Gonza´lez et al. [63] investigated the model reaction between ketene (48) and imine (R)-(39) to yield b-lactam (3R,4S)-(49) (Scheme 11). These authors found that, at the B3LYP/6-31 þ G* level of theory, only cycloadducts (3R,4S)-(49) should be observed. Studies on imines possessing chiral groups at the nitrogen atom are scarce, mainly because of the lower stereocontrol usually achieved under these conditions. A recent exception consists of the computational study of the reaction between methoxyketene (38) and (E)-hydrazone (50) (Scheme 12) [64] to yield b-lactams (53). The second transition structures leading to the (3R,4S) and (3S,4R)-cycloadducts possess 3-outward methoxy groups and 4-inward methyl groups. However, in transition structure (51) there is a strong steric interaction between the C2-symmetric (R,R)-pyrrolidine moiety and the b-lactam ring being formed, thus resulting in the experimentally observed almost exclusive formation of cycloadducts (3R,4S). Me O

H N OHC O

Me O

Me

Scheme 11

MeO

H H

H

N

N

Me

O

(R)-39

Me O

H Me

(3R,4S)-49

Me

MeO

Me Me

X

MeO

Me C O

N

+

N

38

(3S,4R)-53 O

H Me

N N

O

H

N N

(3S,4R)-53

Me H

MeO Me

O 51

Me N

(3R,4S)-53

50

Me H Me

Me

Me

Me

MeO

H H N

N

Me

Me

Scheme 12

H H

O

Stereochemistry of the reaction between ketene (48) and imine (R)-(39)

N O

MeO

C + O 48

(3S,4R)-49

Me

O

O N CHO

X

H

N

Me

Me

52

(3R,4S)-53

Stereochemistry of the reaction between methoxyketene (38) and (E)-hydrazone (50)

326

A. Arrieta et al.

Very recently, an experimental study reported by Xu et al. [65] has highlighted the importance of the isomerization pathways in the reaction between ketenes and imines. According to this analysis, the cis/trans ratio is closely related to the rate constants of the direct ring closure (k1) and the isomerization of the zwitterionic intermediate (58) (k2), as indicated in (2) and Scheme 13. R k1 ½58dt ½cis 59 k1 ¼ R ½trans 59 k2 ½58dt ½60 k2

(2)

A similar scheme was investigated at the RHF/AM1 level for the reaction between methoxyketene (38) and methyl methylimidoformiate (58) [66]. The computational results showed that at the 3x3CI-HE/AM1 level the rotation about the N1-C4 bond in zwitterionic intermediate (59) to form the intermediate (61) was favored over direct formation of the cycloadduct cis-60, thus resulting in the exclusive formation of trans-60, in good agreement with the experimental evidence on related imidates [67] (Scheme 14). R1

R2 +

C O

ka N

13

kd

R3

R2 N

R1 O

k1

N

R3

O

55

54

k–2

k2

N O

k3

R2

O

R3

trans-56

Formation of cis- and trans-b-lactams (56) via zwitterionic intermediates (55) and (57)

H

MeO

MeO

C + O

N

38

58

Me

O

Me O H N Me

H MeO O

Me O H N Me

59

MeO

H H N

O

OMe Me

cis-60

Scheme 14

R2

R1 N

R3

57

MeO

R3

cis-56

R1

Scheme 13

R2

R1

H MeO O

H OMe N Me 61

H H

MeO

OMe

N O

Me

trans-60

Formation of cis- and trans-b-lactams (60) via zwitterionic intermediates (59) and (61)

Computational Studies on the Synthesis of b-Lactams via [2þ2] Thermal Cycloadditions

327

More recently, we have found that the role of the isomerization pathways in the reaction between ketenes and imines can be extended to the (E)/(Z) isomerization of imines themselves [68]. Thus, the stereocontrol observed in the reaction between methoxyketene 41 and (E)-imines (62a,b) was attributed to the competition between the energy barriers associated with the formation of intermediates (63a,b) and (65a,b) and the energies of activation corresponding to the isomerisation of (E)-imines (62a,b). Inclusion of isomerisation processes involving both imines (62a,b) and zwitterionic intermediates (63a,b) and (65a,b) led to a more complex kinetic analysis. As the final steps leading to b-lactams (64) can be considered irreversible, the formation of both cis- and trans-(64) can be described by (3) and (4): d ½cis 64 ¼ k1c ½63 dt

(3)

d ½trans 64 ¼ k2t ½65 dt

(4)

The concentration of intermediates (63) and (65) (Scheme 15) is determined by (5):

d A ¼ KA dt

(5)

where K is the matrix of reactants and reaction intermediates (6) and K is the rate matrix (7):

MeO

H C O 38

Ph N

E

H

k1

R

k –1

MeO

E

O

MeO

H

k–i

ki

H

Ph

k1

R

k –1

k –R

C O 38

(Z )-62a,b

c

k2

MeO

Z

kR

Z

O

N R

a: R=Phenyl b: R=1-Naphthyl

H Ph N R

65a,b

Ph

cis-64a,b

H MeO

H H

O

63a,b

(E )-62a,b

N

H Ph H N R

t

k2

MeO

H Ph

H

N O

R

trans-64a,b

Scheme 15 Formation of cis- and trans-b-lactams (64a,b) via zwitterionic intermediates (63a,b) and (65a,b)

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A. Arrieta et al.

1 0 ðEÞ 62 B ðZÞ 62 C B C A¼B C @ A 63 64 E ki þ k1E 38 k1 ki B ki k1 þ k1Z 38 0 B K¼B E @ k1E 38 0 k1 þ kR þ k2c 0 k1Z 38 kR 0

(6)

0 Z k1 kR Z k1 þ kR þ k2t

1 C C C A

(7)

Numerical simulations on (3)–(7) [68] led to results similar to those found experimentally. Thus, at the B3LYP(PCM)/6-31 þ G*//B3LYP(PCM)/6-31G* þ DZPVE level of theory, the isomerization barrier corresponding to the ðEÞ ! ðZÞ transformation of imine (62a) (R = Ph) was found to be larger than the activation energy associated with the formation of zwitterion (63a). This results in the formation of cycloadduct cis-(64a) as the only stereoisomer. In contrast, the situation was reversed in the case of (E)-N-benzylidenenaphtalene-1-amine (62b). In this case, it was calculated that the activation barrier leading to the formation of (63b) was higher than that leading to the isomerisation of (E)-(62b) to the more nucleophilic imine (Z)-(62b). This resulted in the exclusive formation of b-lactam trans-(64b) via intermediate (65b). These results were in good agreement with previous experimental findings [69, 70]. Another important issue of this reaction is the variable stereochemical outcome obtained depending upon the solvent used, the temperature, and the sequence of addition of the reactants. These aspects have been carefully studied experimentally by Xu et al. [71–73] in a brilliant series of papers. In particular, since one method for the generation of ketenes consists of the reaction between acyl chlorides (12) and bases (usually tertiary bases such as triethylamine), the direct reaction between compounds (12) with imines (66) was investigated at the B3LYP/6-31G* level of theory [52]. Under these conditions, it was calculated that formation trans-b-lactams (70) from enolates (69) is preferred, in agreement with the experimental results [74–76] and with the careful analysis of Xu et al. [72] (Scheme 16). In a complementary approach, the stereocontrolled [4-exo-tet] cyclization of enolates (71) in which the nucleophilic species attack from the C4-position of the b-lactam ring to be formed has been reported [77] (Scheme 17). B3LYP/6-311+ +G** calculations showed that the enolates (71) are preferred with respect to enolates (72) thus resulting in the formation of b-lactams (3S,4)-(73). Bisketenes can provide different reaction paths in the reaction with imines (Scheme 18). For example, bisketene (74) does not form b-lactam species like (76). Instead, DFT computations [78] indicate that zwitterionic intermediate (75) leads to the furane intermediate (77) whose cyclization yields aziridine (78). 1,2-, 1,3- and 1,4-bisketenyl benzene react normally to yield mainly bis (b-lactams) [78].

Computational Studies on the Synthesis of b-Lactams via [2þ2] Thermal Cycloadditions

R1

66

N

R3

O

R3

Cl

+ Cl

N

N

Cl 12

R1

R1

+ O

R2

R2

R2

329

R3

O

67

68 Base

R2

R2

R1

R1

[4-exo-tet] N O

R3

- Cl

Cl O

N R3 69

70

Scheme 16 Formation of b-lactams (70) form the direct reaction between acyl chlorides (12) and aldimines (66)

R1

Me

H N

Cl O

CO2R R2

70 Base

Me

R1

OR

N

O

H

Cl

R2

O

72

X

H R1 N

CO2R

R2

(3S,4S)-73

Scheme 17

R2

O

[4-exo-tet]

O

R1

N

71

Me

OR

O Me H Cl

Me

H R1 N

O

CO2R

R2

(3S,4R)-73

Formation of b-lactam (3S,4S)-(73) via [4-exo-tet] cyclization of intermediate (71)

330

A. Arrieta et al.

Me3Si

C

Ph +

O

C

N

Ph 74

C

Me3Si

O

O C Ph

O

Ph Ph

Ph

O

N

N

Ph

O

O

O

Me3Si

Ph 76

75

(E)-62a

Ph

Me3Si

Me3Si O

O Ph

Ph

N

N Ph

H

Ph

Ph 77

Ph

78

Scheme 18 Formation of bicyclic compound (78) in the reaction between bisketene (74) and imine (E)-(62a)

R1

Scheme 19 Formation of b-thiolactams from thioketenes and imines

2.2

R2 C S 79

R3 +

R1 N

R4

66

R2

R3 N

S

R4

80

Reaction Between Thioketenes and Imines

Sordo et al. [79] investigated computationally the reaction between thioketenes (79) and imines to yield b-thiolactams (80) (Scheme 19), a reaction investigated experimentally by Schaumann [80]. Several model reactions were studied by Sordo et al. at the MP2/6-31G*//RHF/ 6-31G*, B3LYP/6-31G*, and RHF/6-31G*//RHF/3-21G* levels of theory, both in the gas phase and in anisole (e = 4.33) and N,N-dimethylformamide (e = 37.0) solution, using SCRF procedures. Under these conditions, both concerted [p2s þ p2a] and stepwise mechanisms were found, although only the latter were obtained in solution (Scheme 20). According to the computational results, the stereochemical outcome of the reaction is determined by electronic effects related to the torquoelectronic model [34–37] rather than by steric effects. In contrast, the stereochemical outcome was not very sensitive to solvent polarity.

Computational Studies on the Synthesis of b-Lactams via [2þ2] Thermal Cycloadditions

R2

R1 C S 79

R3 +

[p2s+p2a] N

R1

R2

R3 N

R4

331

S

R4

80

66

[p4 c] R2 R3 N

R2 R1

R1

R4 N H

S

S

R3 81

Scheme 20

2.3

82

H R4

R1, R2 = H, i-Pr, t-Bu, OH, Me, CHO R3 = H, Ph R4 = H, Me

Concerted and stepwise mechanisms for the reaction between thioketenes and imines

Reaction Between Ketenimines and Imines

This transformation is in general not easily achieved and therefore, the first versions of this reaction involved the much more electrophilic keteniminium salts [81–83], usually generated from carboxamides (Scheme 21). The reaction profiles involving reactants, intermediates, and products shown in Scheme 21 were calculated at the RHF/6-31G*, MP2/6-31G*, B3LYP/6-31G*, and B3LYP(SCRF)/6-31G* levels of theory [84]. It was found that all the possible reaction paths are stepwise and involve the sequential formation of the N1-C2 and C3–C4 bonds. When the reaction takes place via intermediates (87), the second step consists of a electrocyclic ring closure to yield the products (88) (Scheme 21). However, when chloroenamines (84) (X = Cl) are used as precursors of the keteneimine ions, the step involving the formation of the C3–C4 bond can consist of an intramolecular SN2 reaction of type [4-exo-tet], thus yielding mainly the transcycloadducts (88) with low stereocontrol. These results are in good agreement with the experimental data available. The reaction between ketenimines and imines was found to be much more difficult to accomplish [85, 86]. However, Alajarı´n et al. [87, 88] discovered that the intramolecular version of the reaction proceeded smoothly and several previously unknown azeto[2,1-b] quinazolines (91)] were proposed (Scheme 22). Computational studies [89] on the model reactions shown in Scheme 22 at the RHF/6-31G*, MP2/6-31G*, B3LYP/6-31G* in vacuo and including solvent effects via SCRF methods showed that both processes take place via stepwise mechanisms similar to those found for the reaction between ketenes and imines. In both cases the nucleophilic attack of the iminic moiety was the rate-limiting step, the electrocyclic ring closure of intermediates (93, 96) being much faster. However, the first

332

A. Arrieta et al. R1

R1

H N R2

O

R2

83

H

COCl2 or N

X

(CF3SO2)2O

X

H

X

N R2

R2 84

R3 1.-

R2

R1 Base

N

R2

85

66 R4

2.- Base H

R3

H R3

H

R1

R1

X

N

N R2 N

R2 N

R4

N

R

X

87

R3

R1

R4

R2 N

R2

2

H C N

X R2

86

[p4c]

[4-exo -tet ]

R2 N

66

R4 R2

R2 89

R1

R1

H

R3 N

R4

X = Cl. CF3SO2 R1 = H, Me, Cl R2, R3 = H, Me R4 = H

R2

X 88

Scheme 21 nium salts

Possible reaction mechanisms for the reaction between imines (66) and ketenimi-

R1 n

N

Scheme 22 Intramolecular reaction between neutral ketenimines and imines

n

N

R2

C

R3

n = 1, 2

N N

R1 R2 R3 R4

R4 90

91

activation energy of reaction a (Scheme 23) was found to be 4.4 kcal mol1 (B3LYP(SCRF)/6-31G* results) higher than that computed for reaction b, in line with the experimental findings [87, 88]. In the same study, the stereochemical outcome of the model reaction depicted in Scheme 24 was analyzed. It was found that at the B3LYP(SCRF)/6-31G*//RHF/3-21G* level the energies associated with the conrotatory electrocyclizations of intermediates (99) and (100) were very similar. Therefore, the obtention of cycloadducts equivalent to cis-(101) was attributed to the preferential exo attack in reactant (98), thus surpassing the torquoelectronic effects operating in the second step of the reaction.

Computational Studies on the Synthesis of b-Lactams via [2þ2] Thermal Cycloadditions

a

H

H

H N

C NH

H

H

H

H

N

H

N H

HN

H

HN

92

b

H H

H H

H

93

H C

N N H

94 H H

H H

H

H H

H N

H

H

N

H H

N

H H

N

H

95

H

H

H

H H

333

H

H

96

97

Scheme 23 Model reactions for the computational study of intermolecular (a) and intramolecular (b) reaction between ketenimines and imines

Ph H

Ph endo

Me N N

Me

H

H

Ph N

C N H

H

[p4c]

H H

Ph-in Me-out

H

exo

N N H

H

[p4c]

H H

Ph-out Me-in

H 100

Scheme 24

H

Me H

Ph

98

H H

trans-101

Me

H

N N H

99

H H

Me

Ph N

H

N H

H H

cis-101

Formation of cis- and trans-(101) from precursor (98)

The stereochemical outcome of these reactions was also studied computationally by introducing several chirality sources at different positions [90], as shown in Scheme 25. The results obtained from reaction (a) in Scheme 25 at the B3LYP(SCRF)/ 6-31G* level showed a complete preference for cis-(103a, b) in good agreement with the experimental results obtained for related systems. The key element for the diastereoselectivity was the equatorial orientation of the methyl group of (102a, b) in the two transition structures, whereas in the case of trans-(103a, b) this methyl group occupies the axial position. This efficient diastereocontrol suggested that it could be exploited in systems such as that represented in Scheme 26 [91].

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A. Arrieta et al.

a

H H

R

H C

N

H

H a: R = Me b: R = Ph

O

N

N

H

N

H H

N H

H

104

Scheme 25

Ph R2 Me

H

OHC H H N

O

H +

N

H H

N

H

H

syn-105

O

H

anti-105

Chiral induction in the intramolecular reaction of ketenimines (102a,b) and (104)

R2

N

H R1

N

cis-107

Scheme 26

Me

trans-103a,b

H H

N

H

N H

H

H C

N

H

OHC H H N

H H

+

cis-103a,b

CHO

H

H

H Me

N

H 102a,b

b

N

H Me

N

H R R

H

H

H

Ph R2

Me R2 R2

Ph C N

N

106

H R1

Me N N

R2 H R1

R1 = Me, Ph R2 = SMe, Ph

trans-107

Remote chiral induction in the intramolecular reaction of ketenimine (106)

The computational prediction was confirmed since only cycloadducts trans-(107) were obtained in the experimental study.

2.4

Reactions Involving Metalated Ketenes and/or Imines

As we have indicated previously, the reaction between ketenes and N-silyl imines was described by Pannunzio et al. [30–33] and constitutes an interesting version of the Staudinger reaction between ketenes and imines because of the isolation of the intermediate of silyloxyazadienes. Given its interest, this reaction has been studied by different groups [92–94]. The parent reaction between ketene and N-silyl, N-stannyl and N-germanylimines (108a,c) has been studied at B3LYP/6-31G*, MP2/6-31G*, and B3LYP/ 6-311þG(d,p)&ECP levels of theory, both in the gas phase and in solution using

Computational Studies on the Synthesis of b-Lactams via [2þ2] Thermal Cycloadditions

H

H C O

H +

N

H H

H H

H

H

H N

MH3

H

[p4c]

108a-c

H H H

O MH3

O MH3 109a-c

335

H

N

H N

O

110a-c

MH3

111a-c

a: M=Si; b: M=Sn; c: M=Ge

Scheme 27 Model reactions between ketene and N-MH3 containing imines (108a-c) to form b-lactams (111a-c)

H N

SiH3 O H H2N

N H CH3 O SiH3 113

112a-d

4-out H H

[p4c]

H2N

H

N H3 C

H OH

R3M

a: M = Si, R = H b: M = Sn, R = H c: M = Ge, R = H d: M = Si, R = Me

3-out

H H

H N

MR3

108a-d

Scheme 28 Transition structures (112a-d) corresponding to the degenerate isomerization of imines (108a-d)

H2N

H

H

OH

114 3-out

HO H

CH3

N H

H2N

H

O SiH3

115

4-out

N

OH H

CH3

O H3Si (3R,4S)-116

H2N O H3Si

H H N

OH H

CH3

(3S,4R)-116

Scheme 29 Formation of intermediates (116) via conrotatory electrocyclization of homochiral azadiene (113)

SCRF methods [92–94] (Scheme 27). It was found that the first step of the reaction takes place with a concomitant N-O displacement of the MH3 moiety, thus yielding neutral azadienic intermediates (109), whose electrocyclic conrotatory reaction yields cycloadducts (110). The N-substituted-b-lactams (111) are formed via another O-N pseudopericyclic displacement of the MH3 unit.

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It is important to note that in imines (108a-d) (Scheme 28) the isomerization barrier was found to be significantly lower than the activation barrier leading to intermediates (109) [92–94]. This suggests that trans-b-lactams will be formed in all cases as sole or major products, in good agreement with the experimental evidence [30–33]. Finally, the effect of chiral groups at the 4-out position in the conrotatory transition structures (114, 115) was studied at the B3LYP/6-31G* level. It was found that both transition structures are almost isoenergetic, thus showing that in electrocyclic conrotatory transition structures the 4-outward disposition is much less efficient as a source of chirality, a result already observed by Pannunzio et al. in their experimental studies [32, 33] (Scheme 29). Another interesting example of the [2þ2] reaction involving N-metalated imines has been reported by Pe´rez et al. [95]. In this reaction, the nucleophilic part is an NRhenaimine, whose simplified computational model is the structure (117) reported in Scheme 30. Calculations at the B3LYP/6-31G þ G*(ECP) level of theory, revealed the known stepwise mechanism. However, the activation energy associated with the formation of the N1-C2 bond was found to be of only 3.1 kcal mol1 whereas the computed activation energy of the conrotatory ring closure of (118) was 15.2 kcal mol1. Thus, calculations indicate an enhancement of the nucleophilicity of the imine (117) with respect to nonmetallic analogues. Hegedus et al. discovered that irradiation of chromium–carbene complexes resulted in a photoinsertion of CO into the Cr–carbene bond to form Cr–ketene complexes [96, 97]. This opened novel routes to the preparation of valuable compounds via Cr–ketene chemistry. Among them, the reaction of metallated ketenes with imines was intensively explored [98–100]. Within this context, the reaction between several model Cr–ketenes (120) and imines was explored at the B3LYP/6-31G*&ECP level of theory [101, 102]. The mechanisms thus obtained are reported in Scheme 31. It was found that one possible mechanism, denoted as (A) in Scheme 31, consists of the nucleophilic attack of imine (66) in the chromacyclopropanone complex (120) to yield intermediate (121). Isomerization of this [Cr]-C complex leads to [Cr]-O zwitterionic intermediate (122), whose electrocyclic reaction yields O-coordinated b-lactam (123). Alternatively, isomerization of (120) to the O-complexed ketene (124) permits the direct formation of zwitterionic intermediate H

H C O

H

H CO N

+

Re

HN

CO CO

H N

Re

HN

117

H H

[p4c] CO

O

CO NH

H H

H

H CO

O

NH

H

Scheme 30

H H

H 118

Model reaction between ketene and N-metalated imine (117)

H CO

N

Re

HN

CO CO

NH

H H

119

Computational Studies on the Synthesis of b-Lactams via [2þ2] Thermal Cycloadditions H

R3 R2 R1

O OC OC

Cr

H N

R4

66

CO CO

R3 O

N R4 R1

R2

OC OC

A

Cr

L

CO CO

L

120

121

L: CO, OH2 R1: H, Me R2: H, OMe R3: H, Me, Ph R4: H, Me

B

R1

R3

R2 C Cr

H N

O OC OC

337

CO CO

66

R4

R4 R1 R2 OC OC

R2

H N

N

R3 O

O Cr

R1 H

CO CO

OC OC

Cr

L

L

L

124

122

123

R3 R4

CO CO

Scheme 31 Reaction between metalated ketenes (120) and (124) and imines (66) to yield coordinated b-lactams (123)

(122) (Scheme 31, Mechanism B). It was demonstrated that the experimental findings are better reproduced by Mechanism B [102].

2.5

Catalytic Versions of the [2þ2] Cycloaddition Between Ketenes and Imines

The development of catalytic versions of the [2þ2] version between ketenes and imines has attracted considerable attention in recent years because of the possibility of introducing chirality in the resulting cycloadducts in a very efficient manner [5, 6]. However, the number of computational papers dealing with this version of the reaction is scarce. Thus, Pons, Sordo et al. [103] studied at the B3LYP(PCM)/ 6-311 þ G(d,p) level the reaction of ketene (125) with imines (126a,b) in the presence of BF3 (Scheme 32). These authors found that the most likely mechanism involves the coordination of the Lewis acid with the ketene to yield a stepwise mechanism, which is led by the endo and exo attacks to the formation of trans- and cis-cycloadducts (129a,b) via intermediates (127a,b) and (128a,b), respectively. A factor that complicates the efficiency of the reaction is the interaction between the Lewis acid and the imine, thus resulting in stable intermediates that make difficult the completion of the cycloaddition and the catalytic cycle.

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A. Arrieta et al.

endo H3Si

R

H C O

+

H N

SiH3 R H N Me O BF3 127a,b

H R

N O Me BF3 trans-129a,b

H 126a,b

exo

H3Si

a: R = COOMe b: R = Me

R H N Me

[p4c]

H3Si H

H R

BF3

N O Me BF3

128a,b

cis-129a,b

O

Scheme 32 (129a, b)

[p4c]

H3Si H

Me

BF3

125

H

Reaction between ketene (125) and imines (126a, b) to yield cis- and trans-b-lactams

Another more efficient catalytic version of the reaction consists of the interaction of ketones with chiral amines [6] to form enolate-like intermediates that are able to react with electrophilic imines. It has been postulated that this reaction takes place via the catalytic cycle depicted in Scheme 33. The chiral amine (130) attacks the sp-hybridized carbon atom of ketene (2) to yield intermediate (131). The Mannich-like reaction between (131) and the imine (2) yields the intermediate (132), whose intramolecular addition–elimination reaction yields the b-lactam (1) and regenerates the catalyst (130). In spite of the practical interest in this reaction, little work on its mechanism has been reported [104, 105]. Thus, Lectka et al. have performed several MM and B3LYP/6-31G* calculations on structures such as (131a-c) in order to ascertain the nature of the intermediates and the origins of the stereocontrol (Scheme 33). According to their results, conformations like those depicted in Scheme 33 for intermediates (131) account for the chiral induction observed in the final cycloadducts.

3 The [2þ2] Cycloaddition Between Isocyanates and Alkenes 3.1

General Mechanism

As in the case of the reaction between ketenes and imines, the [2þ2] cycloaddition between isocyanates and alkenes [106, 107] can take place via concerted and stepwise mechanisms. However, with the exception of highly nucleophilic alkenes (vide infra), concerted mechanisms were postulated, since isocyanates are suitable candidates to act as antarafacial partners in thermal [2þ2] cycloadditions (Fig. 1). Aside from the [p2s þ p2a] mechanism, in principle [p2s þ (p2s þ p2s)] [108] and [p2s þ (p2s þ w2s)] [109] mechanisms can be envisaged (Fig. 5).

Computational Studies on the Synthesis of b-Lactams via [2þ2] Thermal Cycloadditions Scheme 33 General catalytic cycle for the reaction between ketenes and imines to yield b-lactams via zwitterionic intermediates (131a-c) and (132)

339

NR3 130

1

N

C O

2

O

O

131

132

N NR3

O

NR3

N

O

3

N

R1= H, CO2Ph R2= H, OMe H

N H O R1

R2

O

O

Ph

O

N 131a,b

a

O 131c

b 4

3

4

3

1 1

O

N

2

[π2s+(π2s+π2s)]

N1

N

2

O [π2s+(π2s+ω2s)]

4

4

ω=0

Fig. 5 Possible concerted mechanisms for the reaction between alkenes and isocyanates

ω=0

3

3

O

O

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A. Arrieta et al.

Fig. 6 Different geometries for the transition structure associated with the reaction between ˚ and deg., respectively. a Denotes ethylene and isocyanic acid. Bond distances and angles are in A the bond angle determined by N1, C2, and O5 atoms. o Stands for the dihedral angle formed by N1, C2, C3, and C4 atoms

If we consider the [p2s þ (p2s þ p2s)] mechanism, then the lateral overlap between N1 and C4 pAOs leads to a C1-symmetric transition structure and a nonzero value for the o = N1-C2-C3-C4 dihedral angle (Fig. 5), as well as to larger N1-C4 distances. In contrast, the [p2s þ (p2s þ o2s)] interaction leads to a Cs transition state for the reaction between ethylene and isocyanic acid. Both geometries were found for this reaction at different theoretical levels [109–111] (Fig. 6). Thus, at the RHF level the transition structure was found to be Cs-symmetric [110, 111], whereas the RHF(SCRF, MP2 and MP2(SCRF) leads to o values of ca. 40 deg. Thus, inclusion of solvent effects and/or electron correlation favor the [p2s þ (p2s þ p2s)] mechanism. This behavior was also observed with substituted alkenes [109]. Williams and Whitehead [112] reported a computational study on this reaction using semiempirical methods. They found that MNDO and AM1 geometries corresponding to these reactions are significantly different from ab initio geometries, whereas PM3 activation energy barriers were found to be in better agreement.

3.2

Regiochemistry and Sterochemistry

The regiochemistry of the reaction has been studied computationally (Scheme 34) [109]. It was found that the asynchronicity and the polar nature of the transition structures favor the formation of the 4-substituted cycloadducts (136) via transition structures (135) when electron-releasing groups are present. The alternative transition structures (137) were calculated to be of much higher energy.

Computational Studies on the Synthesis of b-Lactams via [2þ2] Thermal Cycloadditions H R1

H d+ H R1

d–

N

O

R2

133

H H

135

+ R2

X

H H

d+

H R1

d–

N

O

N

R2

136

O C N 134

R1

H O

341

R1

H H H N

O

R2 137

R2

138

Scheme 34 Formation of 4- and 3-substituted b-lactams via concerted [2þ2] cycloaddition between alkenes (133) and isocyanates (134)

H R=H R C H

H R

H

N

O

d–

H

H N

O

H

139 +

H

140

O C N H

Me R=Me

H

H

H

H d+ H

141 Me

d+ H Me

O

N

d–

H Me

H N

O

H

H 142

Scheme 35

143

Regiochemistry of the reaction between allenes (139) and isocyanic acid

The reaction between isocyanic acid and allenes was also studied and showed different regiochemistries depending on the substitution pattern (Scheme 35). Thus, in the simplest case (not studied experimentally), the formation of the 4-substituted cycloadduct (141) is predicted to be strongly favored, mainly because of the lower distortion of the allenic moiety at the transition structure (140). In contrast, substituted allenes such as 1,3-dimethylallene form the 3-alkylidene derivative (143) via a more stabilized transition structure like (142), in good agreement with the experimentally observed regiochemistry[113–115]. Some intramolecular [2þ2] cycloadditions of sulfonyl isocyanate-olefins have been studied by Metz et al. [116]. These authors found that the intramolecular reaction depicted in Scheme 36 was calculated to be endergonic at the B3LYP/6-31G* and B3LYP(PCM)/6-31G* levels, the corresponding free activation energies being in the

342

A. Arrieta et al. (n=1,2) Me

Me n

Me n

n

O C N

O

S O O

144

N

S O O

O

145

N S O O 146

Scheme 36 Intramolecular [2þ2] cycloaddition between alkenes and isocyanates via transition structures (145)

147 OH

OH

OH H

H + O C N SO2Cl

O

N SO2Cl

N O ClO2S

149

148

N O

SO2Cl 153

H O N ClO2S 151

150

OH H

OH

OH H O

N SO2Cl 152

Scheme 37 Stepwise mechanism computed for the reaction between ethenol (147) and chlorosulfonyl isocyanate (148)

range 43.0–50.1 kcal mol1, thus explaining the failure in the obtention of cycloadducts (146) by reaction of isocyanates (144) in refluxing benzene. The stereochemistry of the reaction between alkenes and isocyanates has been studied experimentally [117] and computationally [109]. It was found that the concerted nature of the reaction should result in retention of configuration of the starting olefin. However, in one case in which a strong p-donor was present it was possible to characterize a stepwise mechanism (Scheme 37). Reaction between vinyl alcohol (147) and chlorosulfonyl isocyanate (148) was calculated to proceed at the MP2(SCRF)/6-31G*//RHF(SCRF)/6-31G* level via zwitterionic intermediate (150), whose rotation about the C4-OH bond through transition structure (151) opens the possibility of a loss of stereoselectivity in this kind of reactions, a phenomenon observed in some cases in the reaction between (148) and vinyl ethers [118]. Although the reaction profiles of the reaction between isocyanates and chiral alkenes has not been studied computationally, some proposals have been made

Computational Studies on the Synthesis of b-Lactams via [2þ2] Thermal Cycloadditions

343

R Me

Me

H

R O C N

O

+

H

SO2Cl 154

2' 1'

H

SO2Cl 155

R

156 H

N O

148

H O

O H

Me 1

H

w(C1'-O-C1-Me)=195 deg.

O C N SO2Cl

Scheme 38 Formation of chiral b-lactams (155) from chlorosulfonyl isocyanate (148) and homochiral enol ethers (154)

based on early transition structures expected when a good matching between the nucleophilic character of the alkene and the electrophilicity of the isocyanate is achieved. Thus Chmielewski et al. [119] have proposed that the excellent stereocontrol observed in the reaction between (148) and chiral enol ethers (154) can be attributed to the minimum-energy (and NOE-compatible) conformations of type (156) (Scheme 38).

4 Concluding Remarks The mechanistic studies carried out on the [2þ2] cycloaddition reactions leading to the formation of b-lactams constitute a fruitful example of synergy between theory and experiment. There is a general agreement on the stepwise nature of the [2þ2] cycloaddition between ketenes and imines. The first step consists of a nucleophilic attack of the iminic lone pair on the sp-hybridized atom of the ketene to form a zwitterionic intermediate. The subsequent four-electron conrotatory electrocyclization leads to the corresponding b-lactam. The final stereochemical outcome of the reaction depends on the combination of the following features: (1) endo/exo attack of the imine on the ketene; (2) inward/outward disposition of the substituents at the conrotatory transition structure; and (3) relevance of the isomerization pathways, including those of the starting imines. In contrast, the [2þ2] cycloaddition between alkenes and isocyanates is in general concerted (although highly asynchronous) and consists of [p2s þ (p2s þ p2s)] mechanism rather than a [p2s þ p2a] process. The polarity of the transition

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state of this reaction determines the regiochemistry of the reaction, the most important ERG occupying the 4-position of the b-lactam ring in formation. In some cases where there are strong p-donating groups, solvent and substituent effects can lead to a stepwise mechanism. Further explorations on these reactions should lead to novel b-lactam rings showing interesting properties. We think that, in these developments, computational chemistry will be useful not only to explain but also to predict the behavior of novel substituents or catalysts.

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Top Heterocycl Chem (2010) 22: 349–373 DOI 10.1007/7081_2010_28 # Springer‐Verlag Berlin Heidelberg 2010 Published online: 14 April 2010

Novel Anticancer b-Lactams Bimal K. Banik, Indrani Banik, and Frederick F. Becker

Abstract Stereocontrolled synthesis of racemic and chiral novel b-lactams using polyaromatic imines has been accomplished. Domestic and automated microwaveinduced reactions have been investigated for the preparation of these types of b-lactams. A preliminary mechanism of this reaction has been advanced. Formation of trans-b-lactams has been explained through isomerization of the enolates formed during the reaction of acid chloride with imines in the presence of tertiary base. A donor–acceptor complex pathway has been believed to be involved in the formation of cis-b-lactams. The effect of a peri hydrogen has been found to be significant in controlling the stereochemistry of the b-lactams. Structure–activity relationship has identified b-lactams with anticancer activity. The presence of an acetoxy group has proven very important for anticancer activity. The preparation and mechanism of action of several other new anticancer b-lactams have also been explored. Keywords b-Lactams Anticancer agents Mechanism of action Staudinger reaction

Contents 1 2 3 4

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350 Preparation of Starting Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352 Synthesis of Novel b-Lactams with Polyaromatic Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354 Microwave-Induced Synthesis of b-Lactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355

B.K. Banik (*) Department of Chemistry, The University of Texas Pan American, 1201 West University Drive, Edinburg, TX 78539, USA e-mail: [email protected] I. Banik and F.F. Becker Department of Molecular Pathology, Unit 951, The University of Texas M. D. Anderson Cancer Center, 7435 Fannin Street, Houston, TX 77504, USA

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Mechanism of b-Lactam Formation with Polyaromatic Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357 6 Anticancer Activities of the b-Lactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 7 Asymmetric Synthesis of Anticancer b-Lactam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360 7.1 In Vitro Cytotoxicity of the Optically Active b-Lactams . . . . . . . . . . . . . . . . . . . . . . . . . 362 8 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363 9 Mutagenicity Assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364 10 Apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365 11 Interactions with Topoisomerases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365 12 Cell Cycle Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365 13 Anticancer b-Lactams from Other Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366 14 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369

5

Abbreviations DMF DMSO DNA h IC50 NMR PAH SN2

Dimethyl formamide Dimethyl sulfoxide Deoxyribonucleic acid Hour (s) Cell growth inhibition at 50% concentration Nuclear magnetic resonance Polyaromatic hydrocarbon Substitution nucleophilic bimolecular

1 Introduction The b-lactams have had a variety of clinical applications. In addition to penicillins and cephalosporins, a number of biologically relevant enzymes have been targeted by these types of compounds [1–4]. The usefulness of effective b-lactam antibiotics and b-lactamase inhibitors has motivated chemists and scientists to design and synthesize new b-lactams [5]. b-Lactams have also served as starting compounds in the synthesis of various heterocyclic compounds of biological importance [6–10]. Hydroxy b-lactam derivatives have been the key materials in the semi-synthesis of paclitaxel (Taxol) and docetaxel (Taxotere) [11]. The medicinal application of b-lactams as therapeutic agents for lowering plasma cholesterol levels has been published [12–15]. Synthetic and biological studies of human leukocyte elastase inhibitory mechanisms of these classes of compounds have also been reported [16]. A few remarkable developments, such as catalytic asymmetric [17–21] and polymersupported [22–29] synthesis of b-lactams, have been realized in recent years.

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On this basis of several developments, the searches for clinically useful b-lactams that are antibacterial and have other medicinal values have become the focus of intense investigations [30–34]. Various methods for the synthesis of b-lactams [35–52] and several biologically active compounds have been demonstrated by our group ([53–60]; also see [61]; [62–74]). In continuation of our research in this area, we reported stereocontrolled synthesis of novel anticancer b-lactams starting from imines, with pendent polyaromatic substituents [69–74]. Although chemistry of b-lactam as antibiotics is very rich, studies on these as anticancer agents have been very poor. Recently, a few other groups demonstrated the synthesis and studied the mechanism of action of anticancer b-lactams. In spite of the notable developments in the area of anticancer research, novel compounds with less toxicity are required. Based on our and others work, we realize that novel b-lactams can be identified as anticancer agents that may have less toxicity but increased activity against cancer cells. Analyzing the structures of the products and moderate anticancer activities of some of our compounds, it had come to our attention that more potent but less toxic analogues could be made by adopting principle of cyclic and noncyclic version of organic compounds. Structures 1 and 2 suggested that a ring closure reaction using N1 and C4 would result in b-lactam 3. On this basis, it was envisioned that b-lactam 3 of the general structure as shown in Fig. 1 would work as a conformationally constrained analogue of our open-chain compounds (1 and 2) that had shown anticancer activity against various cancer cell lines in vitro. The initial target for this study was to prepare substituted amines and amides with polyaromatic substituents, with the goal of investigating such compounds for potential anticancer activity. Based on the promising data on amides, it was then decided to extend the scope of study by including b-lactams. It has been confirmed that conformationally constrained molecules have a greater effect on biological properties when compared to the relatively flexible open-chain compounds in many cases (e.g., see [75–82]; for a few examples, see [83–92]). For example, UAB-8, a conformationally constrained analogue of

X

NHCOCH2CH2CON 2

1

5

4

3

6

1

NHCOCH2CH2CON

2 O 4 5

3

Fig. 1 Conformationally restricted compounds

O

2

N1 Ar

1

2

3

4

6

N

X 3

a: X = CH2 b: X = NCH3

5

6

X

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retinoic acid, had favorable toxicological properties relative to the nonrestricted structures. Tricyclic indole analogues of melatonin demonstrated superiority of the cis-constrained isomer over trans-constrained isomer as an agonist. Phenalene derivatives appeared to be promising restricted ligands for melatonin receptors. Anesthetic steroids that modulate GABAA receptors were investigated. The discovery of conformationally constrained Taxol analogues was reported. Conformationally restricted compounds that were more effective include antibiotic linezolide and nicotine derivatives. On the basis of these experiments, we anticipated that conformationally constrained analogues of our open chain diamides (1 and 2) may increase activity against cancer cell lines. In b-lactam chemistry, this kind of hypothesis had been tested, and it was established that certain b-lactams are more effective at lowering cholesterol in human plasma when compared to open-chain substrates [12–15]. Therefore, preparation of b-lactams of type 3 and related compounds was necessary to investigate a comparative study with diamides 1 and 2.

2 Preparation of Starting Compounds Many polycyclic aromatic amines and aldehydes are commercially available, but their supply is very limited. Preparation of these starting materials is necessary for studying the b-lactam formation reaction [93]. Nitro compounds are the precursors for the amines. An important task was to prepare polycyclic aromatic nitro compounds, particularly those of chrysene, phenanthrene, pyrene, and dibenzofluorene in good yield. Nitration of these hydrocarbons with concentrated nitric acid in sulfuric acid is a widely used reaction for this purpose. Our research culminated in facile synthesis of polyaromatic nitro derivative 9 starting from polyaromatic hydrocarbons (PAHs) 8 through the use of bismuth nitrate impregnated with clay (Scheme 1) ([94, 95]; for some examples of bismuth nitrate-catalyzed reactions OCH3

OCH3 Montmorilonite Bi(NO3 )3 . 5H2 O

NO2 5

4

NO2

Montmorilonite Bi(NO3 )3 . 5H2O

6

7 Montmorilonite

Scheme 1 Synthesis of polyaromatic nitro compounds

Bi(NO3 )3 . 5H2 O

8

NO2 9

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from our laboratory, see [66, 96–104]). The advantages of this method over the classical methods are numerous. Several methods can be used to prepare polyaromatic amines from polyaromatic nitro compounds. Catalytic hydrogenation, catalytic transfer hydrogenation, and several new methods have been found to be suitable for the reduction of polyaromatic nitro compound 9 to polyaromatic amine 14. However, these methods were not suitable with PAH derivatives. Indium- ([105, 106]; for some examples of indium-induced reactions from our laboratory, see [107–109]) and samariuminduced ([105–111]; for some examples of samarium-induced reactions from our laboratory, see [112–121]) reduction methods offered good opportunities to achieve this goal. For example, the indium-induced reaction was performed in water in the presence of ammonium chloride, while the samarium-induced reaction elicited a product within a few minutes of using ultrasound (Scheme 2). The indium-induced method was accomplished in 10 g scale. Synthesis of polyaromatic aldehydes, particularly phenanthrene 16a, chrysene 16b, and dibenzofluorene 16c, was performed using a previously described method [93] from their respective hydrocarbons 15, 8, and 19. Synthesis of dibenzofluorene hydrocarbon 19 was achieved following one-pot method by reacting b-tetralone 17 and naphthyl bromide 18 in the presence of sodium hydride and subsequent acid-induced reaction (Scheme 3). This process included alkylation, cyclodehydration, and aromatization in a one-pot operation.

OCH3

NO2

OCH3 In/NH4Cl/H2O/EtOH

or Sm/NH4Cl/EtOH

or Sm/NH4Cl/EtOH

NO2

NH2

In/NH4Cl/H2O/EtOH

7

NH2

11

10

5 NO2

In/NH4Cl/H2O/EtOH

NH2

In/NH4Cl/H2O/EtOH

or Sm/NH4Cl/EtOH

or Sm/NH4Cl/EtOH

NH2

NO2

13

12

14

9

Scheme 2 Synthesis of aromatic amino compounds

SnCl4, Cl2CHOCH3

SnCl4, Cl2CHOCH3

CH2Cl2, 70%

16a

15

8

CHO 16b

O

i) NaH/C6H6

+

17

CH2Cl2, 70%

CHO

Br

ii) MeSO3H 35%

18

SnCl4, Cl2CHOCH3

19 19

Scheme 3 Synthesis of dibenzofluorene

CH2Cl2, 70%

CHO 16c

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3 Synthesis of Novel b-Lactams with Polyaromatic Imines The Staudinger reaction has been extensively studied for the synthesis of monocyclic b-lactams (Scheme 4, e.g., 19 and 20) [37]. An imine 18, a tertiary base (triethylamine), and acid chloride 17 (or equivalent) are required for this reaction. The stereochemistry of the resulting b-lactams may vary depending upon the conditions (Scheme 5). The reaction of acyloxy, alkoxy, and nitrogen-containing acid chloride with diaryl imines produces cis-b-lactams under Staudinger reaction conditions [122]. In contrast, reaction of polyaromatic imines (21, 23, 25, 27, 29, and 36) with acetoxy, phenoxy, and phthalimido acid chloride in the presence of triethyl amine at 78 C to room temperature produced exclusively trans-b-lactams (22, 24, 26, 28, 30, and 33). cis-b-Lactams were expected according to the literature results [122]. The trans stereochemistry of the products was deduced from the nuclear magnetic resonance (NMR) data. The coupling constant of the C3 and C4 hydrogens in the cis-compounds is higher than that of in the trans-products. Isomeric polyaromatic imines (34, 36, and 38) in which the aromatic groups were interchanged produced exclusively cis-b-lactams (35, 37, and 39) (Scheme 6). However, imine 40 derived from cinnamaldehyde and 1-amino pyrene also afforded cis b-lactam 41 as the only product (Scheme 7). To investigate the reaction in more detail, isomeric naphthalenyl and anthracenyl imines were employed in the Staudinger reaction. The 1-substituted compounds (21 and 23) produced only the trans isomers (22 and 24). However, the 2substituted compounds (42 and 45) produced a mixture of cis (44 and 47) and trans isomers (43 and 46) in a ratio of 1:1 (Scheme 8). The reason for this observation is not clear. The peri hydrogen in 21 and 23 was closer to the imine bond than it was in 42 and 45. Further research is necessary to define the role of the peri hydrogen in this type of reaction. The preparation of b-lactams using the Staudinger reaction was discovered more than a century ago. Notably, the formation of trans-b-lactams as seen in the present investigation had not been described in the literature [37]. A few previous studies were performed toward the preparation of trans b-lactams. For example, synthesis of some trans-b-lactams was achieved using microwave irradiation and by changing the order in which the reagents were added [123–127]. Furthermore, trans b-lactams were formed as the only isolated products using cyclic imines. Structurally, those cyclic imines were completely different than the polyaromatic imines. Since microwave-irradiation was helpful in achieving the synthesis of transb-lactams, it was decided to test this approach.

Z

Y ZCH2COCl +

Scheme 4 Synthesis of b-lactam

N

N X

17

Z

Y

Y

Base

18

O

+ X

19

N O

X 20

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TEA ZCH 2 COCl +

O

C H 2C l2

N

_ 78 o C

17

a: Z = OAc b: Z = OPh

N

to RT

Z 21

+

17

22

O

TEA

N

a: Z = OAc b: Z = OPh

N

C H 2 C l2 _

78 o C to RT Z

23

24

O

TEA 17 +

N

N

_ 78 o C

Z

to RT

25

26

O

TEA

N

17 +

Z

a: b: c: d:

a: b: c: d:

Z= Z= Z= Z=

N

C H 2C l2

Ar

Ar _ 78 o C to RT 27

a: Z = OAc b: Z = OPh

C H 2 C l2

Z = OAc, Ar = phenyl Z = OPh, Ar = phenyl Z = Phthalimido, Ar = 2-Furyl Z = OAc, Ar = 2-Furyl

28 Ar N Z

Ar N

17 +

TEA

O

OAc, Ar = phenyl OPh, Ar = phenyl Phthalimido, Ar = phenyl OAc, Ar = 2-pyridyl

C H 2 C l2 _

29

78 o C to RT 30 TEA

A cO C H 2 C O C l

31

C H 2 C l2

+

_ 78 o C

N 32

N

to RT

Ph 33

Ph

O OAc

Scheme 5 Synthesis of b-lactams

4 Microwave-Induced Synthesis of b-Lactams The use of domestic microwave and automated oven in organic synthesis is well established (Microwave activation has become a very popular and useful technology in organic and medicinal chemistry. For some recent examples, see [128–131]). This is particularly very noteworthy because of the unconventional set up necessary for conducting the reaction. Microwave irradiation of a solution of imines 21, 23, and 29 with acetoxyacetyl chloride in chlorobenzene using a domestic and

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17

TEA CH2Cl2 _78oC to RT

+ 34

N

AcOCH2COCl + 31

N 35

TEA CH2Cl2 _78oC to RT

N 36

AcOCH2COCl +

N

38

31

Z

a: Z = OAc b: Z = OPh

O

OAc N

O 37

TEA CH2Cl2 _78oC to RT

OAc N O 39

Scheme 6 Synthesis of b-lactams

O N ZCH2COCl + 17

N

TEA/CH2Cl2 –78°C to RT

40

Ph

Ph

a: Z = OAc Z b: Z = OCH2Ph Ph = phenyl

41

Scheme 7 Synthesis of b-lactams

automated microwave oven afforded trans b-lactams 22a, 24a, and 30a, respectively (Scheme 9). When irradiated in a microwave oven using chlorobenzene and triethylamine, cis b-lactams 44 and 47 did not isomerize to trans b-lactams 43 and 46. These experiments clearly established that there is no isomerization of the cis b-lactams to the more stable trans b-lactams during reaction of imines with acid chlorides at a high temperature and under microwave irradiation. Irradiation of 21, 23, and 29 with 17 under identical conditions afforded the trans product 22a, 24a, and 30a as the only isomers. Therefore, the present study clearly indicated that microwave irradiation can accelerate the synthesis of b-lactams (e.g., see [132–139]). No

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17 +

N

O

Ph

42

CH2Cl2 –

78oC to

RT

O

+

N 43 Ph

44

Z

Z Ph

TEA

17 + N 45

Ph

N a: Z = OAc b: Z = OPh

O

CH2Cl2

O

N

– 78oC to RT 46

Ph

+ Z

N 47

Z Ph

Scheme 8 Synthesis of b-lactams

17 + 21

17 + 23

Chlorobenzene TEA, 60% MWI, 3 min Chlorobenzene

22a

24a

TEA, 60% MWI, 3 min Chlorobenzene 17 + 29

Scheme 9 Synthesis of b-lactams by microwave irradiation

TEA, 60% MWI, 3 min

30a

MWI = microwave irradiation

differences in the yields of the products could be detected in the domestic and automated microwave oven.

5 Mechanism of b-Lactam Formation with Polyaromatic Imines The mechanism of b-lactam formation has been investigated extensively. But the rationale for the observed diastereoselectivity in certain cases remains unknown. It has been demonstrated that the stereoselectivity depends on the structure of the imine, acid-chloride, order of addition of the reagents, solvent, temperature, bases, and many other conditions. In many cases, cis b-lactam was found to be the exclusive or major product when acid chloride (equivalent) was added drop-wise at low-to-room temperature to the solution of imines and a base. However, a trans b-lactam was the major or exclusive product obtained when a tertiary base was slowly added to the imine and acid chloride (equivalent) solution at high temperature. Georg and Ravikumar established a few rules regarding stereoselectivity in the formation of b-lactam rings [122]. Computer-assisted calculations were advanced to explain the stereochemical preferences [140–144]. Cossio et al. [140–143] and

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Sordo et al. [144] explained the stereoselectivity on the basis of torquoelectronic effects. Low-temperature infrared spectroscopy was also used to identify the reactive intermediates [145]. Two mechanisms were proposed to explain the product distribution in the b-lactam formation reaction. The ketene mechanism was observed in a low temperature infrared spectroscopy study [145], while the acylation of imine mechanism was believed to be involved in some [122]. Both mechanisms were supported by evidences. It had been hypothesized that cycloaddition of the imine occurs from the least hindered side of the ketene, and this process generates zwitterionic intermediates; conrotatory cyclization of these intermediates then produce cis- and trans-b-lactams. Acylation of the imine by the acid chloride to form N-acyliminium chloride also produced zwitterionic intermediates (Scheme 10). The formation of a trans-isomer could be explained through isomerization of the enolates (I–II). The electron-withdrawing polyaromatic group at the nitrogen had

Z

Y

H

Z

H

H H

N

C

Y

N

O

+ n

O

Z

Y

n

H

H

Z

Y

H

H N

O

Z

Y

O

N

O

N

n n

n

I

X N H Z H H IV

Y = monocyclic aromatic Z = O, N-containing group

Y

Y

O

III

II

H

X N H Z

/

H

O

/

V H

90° bond rotation and closure

/

Y

Y

n

X

X N H Z

X anion inversion

N N O

and closure

O

H VI

Z

O VII

Scheme 10 Mechanism of b-lactam formation reaction

H H VIII

Z / H

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stabilized the iminium ion. This process allowed rotation of the bond (I–II) and resulted in formation of trans-b-lactam III. This mechanism was supported by an observation reported by Just et al. [146]. In contrast, the exclusive formation of a cis-b-lactam with a polyaromatic group and cinnamyl at C4 prompted to propose a hypothesis previously described by Doyle et al. [147]. An extended conjugation of the cinnamyl and polyaromatic system may stabilize the acyliminium ion IV. The presence of the cinnamyl or polyaromatic system at C4 may outweigh the contribution of the N-polyaromatic system, resulting in cis-b-lactam formation. Subsequent proton abstraction from complex IV would lead to cis-b-lactam VII through V (90 bond rotation and closure) or VI (anion inversion and closure). This suggestion was further strengthened by the possible formation of donor–acceptor complex VIII proposed by Bose et al. [148]. This complex formation effectively stabilized the transition state of the reaction. Cossio et al. [140] described that the SN2 intramolecular mechanism favored the preferential or exclusive formation of trans b-lactams, particularly when the reactions were allowed to take place in the absence of a tertiary base in the initial stages of the reaction. The use of diisopropylethyl amine as the base could not improve the yield of products with polyaromatic systems. However, the stereochemistry of the products remained identical. Lassaletta et al. ([149]; for a similar and elegant contribution, also see [150]) explained the stereoselectivity of trans b-lactam formation following steric factors. It had been postulated that the isomerization of the imine bond prior to ring closure is a result of severe steric interactions between N-benzyloxycarbonyl-N-benzylamnio group and the alkyl group of hydrazone. This mechanism explained transselectivity, but could not explain the formation of cis-isomers with similar types of compounds. Formation of a mixture of cis- and trans- isomers with naphthalenyl and anthracenyl imines could not be explained using the mechanisms described earlier [140–150]. If the electron withdrawal properties or the steric crowding of the N-polyaromatic systems were solely responsible for the trans b-lactam formation, an identical stereochemical distribution would have been observed in the isomeric naphthalenyl and anthracenyl compounds. An examination of the N-polyaromatic systems in which trans isomers were the only products revealed a structural similarity. Imines 21 and 23 have a peri hydrogen very close to the C=N bond, whereas this peri hydrogen is relatively away from the same bond in imines 42 and 45. A critical role for a peri nitrogen atom in the biological activity of a number of carboxamides had been demonstrated. It appeared that stabilization of the positive charge by the extended conjugation is the main contributor in dictating the stereochemistry of the final b-lactams. These results also suggested that it is the nature of the C4 group that controls the isomeric distribution of the products.

6 Anticancer Activities of the b-Lactams Several of these b-lactams were tested using nine human cancer cell lines with cisplatin and diamide 1b as controls. The results are shown in Table 1. The structure–activity study revealed that, regardless of the configuration of the b-lactams, neither naphthalene (22) and anthracene (24) nor pyrene derivatives (28)

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Table 1 In vitro cytotoxicity of b-lactams on human cancer cell lines (mM) Compounds BRO MCF-7 MDA-231 OVCAR SKOV PC-3 HL-60 K-562 HT-29 Cisplatin 7.66 10.05 12.33 3.99 5.99 4.66 1.66 2.33 16.99 1b 33.64 40.0 12.23 18.11 11.05 27.29 9.41 12.70 16.70 26a 10.48 10.09 12.49 18.0 18.00 9.3 5.21 4.0 10.49 30a 10.84 9.81 11.98 4.17 6.88 16.32 3.64 4.33 5.66 30d 11.00 14.93 14.46 – 9.0 – 2.5 2.5 15.90 22, 24, 26b, 28, >20 >20 >20 >20 >20 >20 >20 >20 >20 30b, 30c, 33, 35, 37, 39 All the in vitro cytotoxicity assays were performed using MTT assay

demonstrated activity against any of these cancer cell lines. The trans acetoxy phenanthrene and chrysene derivatives (26a, 30a, and 30d) demonstrated reasonable activity. Phenoxy and phthalimido (26b, 30b, and 30c) b-lactams were inactive. Interestingly, on the breast cancer cell line MCF-7, three compounds (cisplatin, 26a, and 30a) had identical activity, while on the colon cancer cell line HT-29, 30a was three times as active as cisplatin. Differences in cytotoxicity were also confirmed on the ovarian cancer cell line OVCAR, where cisplatin and 30a had equal activity and 26a had very little activity. This selectivity of cytotoxicity differences among compounds was very striking. A number of conclusions can be made from the results of the in vitro studies. It was clear that the minimal structural requirement of the aromatic system for cytotoxicity is at least three aromatic rings in an angular configuration. This was confirmed by the fact that only phenanthrene 26a and two chrysene derivatives 30a and 30d demonstrate cytotoxicity against the tumor cell lines. The other polyaromatic compounds derived from naphthalenes, anthracenes, and pyrene compounds (22, 24, 26b, 28, 30b-c, 35, and 37) were inactive. Interestingly, the presence of the acetoxy group proved to be very crucial for anticancer activity. Acetoxy is a wellestablished leaving group for reactions with a wide range of nucleophiles. This indicated that an enzymatic or other modification at this site is involved in the activation of these compounds (26a, 30a, and 30d). It was very important to note that only the trans b-lactams (26a and 30a vs. 35a and 37a) have antitumor activity. Our study supports that certain conformationally restricted compounds, indeed, can demonstrate better activity in biological systems. It has been confirmed that 26a, 30a, and 30d are more active than diamide 1b in many cancer cell lines in vitro.

7 Asymmetric Synthesis of Anticancer b-Lactam The anticancer activity of our racemic b-lactams has prompted us to devise method for the preparation of the optically active analogues. It is known that an optically active isomer of a racemic compound has better and much selective biological

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activity. Tremendous success has been achieved in the cycloaddition of optically active aminoketene with imines. In contrast, the analogous reaction of imines with chiral hydroxyketene equivalents has not been explored systematically. The reaction of achiral alkoxy ketenes with chiral imines derived from optically active a-oxy and a-amino carbonyl compounds had been investigated for the preparation of optically active b-lactams. Asymmetric synthesis of cis-hydroxy b-lactam (70% yield) derived from a-O-glycoside as the ketene component was reported with diaryl imine. The control of absolute stereochemistry was the most challenging part. The stereochemistry of the anomeric center of the carbohydrate is very crucial. Our hypothesis was to use the glycosides (a- and b-) as the ketene component. We predicted that the absolute stereochemistry of the anomeric center in the ketene component of the carbohydrate would be the most important, although the nature of the other center with different protective groups may play an important role in the formation of the b-lactam ring. Ferrier rearrangement was used for the preparation of the starting b-glycosides. Reaction of 3, 4, 5-tri-O-acetyl D-glucal (48) with benzyl glycolate (49) in the presence of iodine has produced a glycoside 50. Hydrogenolysis of the benzyl ester 50 and the hydrogenation of the alkene group had been performed by catalytic hydrogenation to afford acid 51 (Scheme 11). Reaction of the activated acid 51 with polyaromatic imine 29a in the presence of triethylamine produced a mixture of diastereomeric O-glycosides of trans blactams 54 and 55 in a ratio of 45:55. The diasteromers 54 and 55 were separated through column chromatography. Acid-mediated reaction was used to cleave the anomeric bond, and this process produced trans-hydroxy b-lactams (+)-56 and ()-57 in excellent yield. The hydroxy compounds were converted to the acetates (+)-58 and ()-59 (Scheme 12). The absolute stereochemistry of the trans-acetoxyb-lactam (+)-58 and ()-59 was confirmed by comparison with known transb-lactam described earlier [151]. An application of this chemistry was extended to a similar reaction with a b-glycoside. The synthesis of the acid with a b-glycoside bond was performed. Indium-induced reaction of acetobromoglucose (60) with 49 afforded an ester 61. Hydrogenolysis of the benzyl group produced the b-glycoside 62 (Scheme 13). Cycloaddition of the acid 62 with imine 29a was performed using imine in the presence of N-methyl-2-chloropyridiniumiodide (53) and triethylamine. NMR analyses of the crude reaction mixture showed the presence of two diasteromeric trans b-lactams 63 and 64 in 60:40 ratios. The diaseteromeric O-glycosides after OAc AcO

O

O

+ HO

I2 O

THF

AcO 48

49

OAc O O O O AcO 50

Scheme 11 Synthesis of starting acid for Staudinger reaction

H2 10% Pd-C EtOH

OAc O O O AcO 51

OH

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B.K. Banik et al.

N

OAc O

NEt3 /CH 2 Cl2

O

N

52 OH AcO AcO O H H O H 54

O

29a

AcO AcO

O H O HH

N

55

Chrysenyl

i) HCl/THF/CH 2 Cl2 ii) Ac 2 O/TEA/CH 2 Cl2

RO O

53

CH3 I

+

O

AcO

Cl

O

N Chrysenyl

i) HCl/THF/CH 2 Cl2 ii) Ac 2 O/TEA/CH 2 Cl2

H RO H

HH N

O

Chrysenyl (+)–56 R=H; (+)–58 R=Ac

N

Chrysenyl (–)–57 R=H; (–)–59 R=Ac

Scheme 12 Synthesis of chiral anticancer b-lactams

AcO HO AcO O O AcO + O AcO Br

Scheme 13 Synthesis of starting acid for Staudinger reaction

49

60 AcO AcO O AcO O AcO 61

In/THF or Ag(OTf)

O O

HCO2NH4 10% Pd-C EtOH

AcO AcO O AcO O AcO b 62

OH O

separation was treated with mild aqueous acid to the hydroxy compounds 65 and 67, and the resulting alcohols were converted to acetates. The absolute stereochemistry of the trans acetoxy-b-lactam 66 and 68 was confirmed by a comparison with known trans b-lactam as described earlier (Scheme 14).

7.1

In Vitro Cytotoxicity of the Optically Active b-Lactams

These optically active b-lactams were tested using seven human cancer cell lines against cisplatin and racemic b-lactam as controls, and the data is shown in Table 2.

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AcO AcO O AcO O AcO H 62

N Cl

CH3 I

+

NEt3 /CH 2 Cl2

CO2H

29a

AcO AcO O AcO H AcO O H H

AcO AcO O AcO H AcO O H H 63

N

O

N Chrysenyl

i) HCl/THF/CH2Cl2 ii) Ac2O/TEA/CH2Cl2

RO

HH

O

64

O

N Chrysenyl

i) HCl/THF/CH2Cl2 ii) Ac2O/TEA/CH2Cl2

H RO H

N Chrysenyl

65 R=H; 66 R=Ac

O

N Chrysenyl

67 R=H; 68 R=Ac

Scheme 14 Synthesis of chiral anticancer b-lactam Table 2 In vitro cytotoxicity of optically active b-lactams on human cancer cell lines (mM) Compounds BRO MDA-231 SKOV-3 PC-3 HL-60 K-562 HT-29 Cisplatin 7.66 12.33 5.99 4.66 1.66 2.33 16.99 (þ)-1 15.7 8.7 10.00 11.1 0.7 1.1 2.0 (þ)-66 and (þ)-(58) 6.1 0.8 6.8 1.4 0.7 1.1 0.7 ()-68 and ()-59 22.0 8.5 6.1 15.5 5.4 6.0 8.3

The cell growth inhibition data confirmed that, of the optically active b-lactam, 66 and 58 were extremely active (obtained from two different pathways), and the activity of the other optical isomer 68 and 59 (obtained from two different pathways) was reduced compared to the racemic b-lactam 1.

8 Mechanism of Action Because of the presence of the cyclic four-membered amide connected to the multicyclic ring systems, an effort to define their mechanism of action would be highly important. Despite a number of synthetic efforts, a relatively small amount of research had been focused on the use of compounds related to PAHs as anticancer agents. Bair et al. [152, 153] reported a close correlation between antitumor activity and the shape of the polyaromatic system. However, his group did not make a definitive correlation between the ability of these compounds to bind to deoxyribonucleic acid (DNA) and their cytotoxic activity. Bair’s group developed

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benzylic aminopropanediols from a structure–activity relationship study. These amino propanediols were believed to interact with DNA via intercalation and to be topoisomerase II inhibitors. The antitumor activity of two of the most active naphthalimides, amonafide, and mitonafide had been established due to intercalation to DNA. To improve its potency, naphthalene was modified to anthracene to serve as the chromophore. The resulting compound azonafide showed increased cytotoxic activity over naphthalene-based analogues. Not all azonafide derivatives, which had characteristic mechanistic properties when compared with existing classes of DNA intercalators, were localized in the nucleus. Other differences with existing DNA intercalators, such as mitoxantrone, had included a lack of inhibition of topoisomerase II enzymes at equicytotoxic concentrations. Improving cellular cytotoxic potency was adopted by linking two naphthalimide or anthralimide groups with a polyamine bridge. The mechanism of action of b-lactams as different types of biologically active compounds had been studied. However, investigations directed to define the mechanism of action of b-lactams as anticancer agents had not been explored. The active compounds may follow one of these mechanisms as described earlier or it may act on cancer cells through a novel mechanism.

9 Mutagenicity Assays Mutagenicity assays were performed by BioReliance Corporation as study AA65FL-FM.501.BTA. Compounds 26a and 30a were examined using the Salmonella Plate Incorporation, Mutagenicity Assay. The tester strains used were Salmonella typimurium histidine auxotrophs TA98 and TA100 [70]. Tester strain TA98 was reverted from auxotrophy to prototrophy by frame shift mutagens. Tester strain TA100 was reverted by mutagens that cause both frame shift and base pair substitution mutations. Both these compounds were exposed separately via the plate incorporation methodology. Each one of the b-lactam was tested at ten dose levels along with appropriate vehicle control and positive controls with tester strains TA98 and TA100 in the presence and absence of Aroclor-induced rat liver S9. All dose levels of test compounds, vehicle control and positive controls, were plated in duplicate. For each compound to be evaluated positive, it must have demonstrated a dose-related increase in the mean revertants per plate for at least one tester strain over a minimum of two increasing concentrations of the test article. Data sets for tester strains TA98 and TA100 were judged to be positive if the increase in mean revertants at the peak of the dose response was equal to or greater than twice the mean vehicle control value. The results of the mutagenicity assay indicated that neither 26a nor 30a demonstrated a positive response with these tester strains at any concentration in either the presence or the absence of Aroclor-induced rat liver S9, indicating that neither of these compounds demonstrate any mutagenicity. This is an important finding in the field of cancer research.

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365

Apoptosis

To determine whether exposure to 26a or 30a induced DNA cleavage in sensitive and resistant tumor cell lines, the APO-BRDU assay was performed. Compound 30a demonstrated no significant increase in BRDU insertion into the DNA of HL-60 cells exposed for 24 h. In two identical runs, 26a also failed to demonstrate an increase in BRDU insertion. These results were striking since, in all of these experiments, concentrations approximately twice that required for the IC50 of 26a and three times greater than that required for 30a were used. In one of these experiments, MDA-231, a human breast cancer line that was resistant in vitro to the effects of 30a, was tested for BRDU insertion. As expected from the above experiments, a significant increase was not detected. These results confirmed scanning electron microscopy studies of exposed cells that suggested the lack of alterations in these cancer cell lines, which were associated with the induction of apoptosis in the target cancer cells.

11

Interactions with Topoisomerases

TOPOGEN Inc. has the necessary kits to identify the interaction of organic compounds with topoisomerases. These kits contained reagents required for detection of topoisomerase I and II with DNA markers for detection of enzymatic action and standard topoisomerase inhibitors. The activity of 26a and 30a was determined using these systems. No inhibition of either topoisomerase I or topoisomerase II was detected in the HL-60 cancer cell lines using much higher concentration that were required to inhibit the growth of this cell lines in vitro. Therefore, there was no evidence that the active b-lactams had their cytotoxic activity in sensitive cell lines through interaction with DNA or DNA-associated enzyme systems. These compounds failed to increase BRDU insertion into DNA and display inhibitory action toward the two topoisomerase systems. The failure to induce apoptosis was consistent with these findings because in many instances this phenomenon was the putative result of such DNA interactions.

12

Cell Cycle Activity

Cell cycle activity of the active compounds was investigated. Propidium iodine (the marker for DNA content) was used as a marker of the cell cycle. This cytometric determination was calibrated separately and calculated for a related program to evaluate the percentage of cells in each phase of the cell cycle. The treated cells were compared with that of control HL-60 cancer cells for the percentage of cells in each cell cycle compartment over a period of 24 h. HL-60 cells treated with 10 mg

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of 30a demonstrated an increase in the percentage of cells in the G2 phase that was particularly predominating at 24 h. The average percentage of untreated cells in G2 was 17.2%, and that of cells treated with 30a and 26a was 38.4 and 23.6%, respectively. To determine whether alteration of the cell cycle occurred in a cell line that had repeatedly demonstrated resistance to the in vitro effect of 30a, the human breast cancer cell line MDA-231 was examined. HL-60 cells treated with 30a (1 mg) demonstrated a striking increase at 24 h (34.1%), but no increase was detected in MDA-231, which was identical to that in untreated MDA-231 cells (approximately 14%) [70].

13

Anticancer b-Lactams from Other Groups

Parallel to our group, a few other researchers also performed significant studies on anticancer b-lactams. For example, b-lactam derivatives (Fig. 2) induced DNA damage, inhibited DNA replication, and activated the apoptotic death program in human leukemic Jurkat T cells in a time and concentration-dependent manner. Importantly, b-lactam 69 also inhibited proliferation and induced apoptosis in other human solid tumor cell lines (breast, prostate, and head-and-neck). It was believed that induction of apoptosis by 69 is associated with activation of p38 mitogenactivated protein (MAP) kinase, release of mitochondrial cytochrome c, and activation of the caspases. It was reported that apoptosis is blocked by a specific inhibitor to p38 kinase, implicating p38 MAP kinase as the major factor in b-lactam-induced apoptosis [154]. This study was very significant. Turos and Ping found that two b-lactam analogs (73 and 74), both containing a branched-chain system at C3 of the ring, exhibited potent apoptosis-inducing activity. However, 73 exhibited superior in vitro activity over 74. (Fig. 3) The b-lactams with these side chains were able to inhibit the growth of mice bearing

Cl MeO

MeO

O

N

O

SMe

69

Cl

Cl

Cl

MeO

NH

O

Me O N

S 71

70

N

O

Me

Fig. 2 Structures of a few anticancer b-lactams

O

O O

5 3

O

N

SCH3

O 73

Fig. 3 Structures of a few anticancer b-lactams

O

O O

5 3

O

N

O 74

S

S

72

Me

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breast cancer xenografts as a result of the induction of DNA damage and apoptosis in tumor tissues [155]. Veinberg et al. reported synthesis and anticancer properties of 7a-chloro3-methyl-1,1-dioxoceph-3-EM-4-carboxylic acid esters. The tested esters were divided into two groups according to their anticancer effects. Interestingly, the n-butyl (75d), 2,2,2-trichloroethyl (75g) was characterized by LC50 values in the range 10–30 mg/mL and by active generation of nitric oxide radicals in the cell medium. But methyl ester 75a was characterized by a large cytotoxic effect in relation to both cancer cells and to normal cells. This was also confirmed by low LD50 values of 236 and 252 mg/kg for these compounds. It was crucial to note that an increase in the carbon chain in the ester group of compounds 75b, 75c, and 75e–g to 2 or 3 carbon atoms enabled a strengthening of the toxic effect in relation to cancer and a weakening of it in relation to normal cells. Surprisingly, the selectivity developed led to a more than twofold reduction in the toxicity index (Fig. 4). The results of this study indicated that the modification of the ester group in 7achloro-3-methyl-1,1-dioxoceph-3-em-4-carboxylic acid is promising in the search of new anticancer substances permitting action both on the cytotoxic effectiveness of compounds and on their selectivity in relation to cancer and normal cells [156]. With the goal of obtaining information on the potential antitumor activity of the new compounds, Ruf et al. synthesized and tested b-lactams at a concentration of 20 < mM in an in vitro screening method with the following human cancer cell lines: 5637 (urinary bladder carcinoma), RT-4 (urinary bladder carcinoma), A-427 (lung carcinoma), LCLC-103H (large cell lung carcinoma) (Fig. 5). While many compounds in this series were inactive, some compounds seem to form the most interesting group, as they exhibited a differentiated behavior [157]. Meegan et al. reported the synthesis of a number of b-lactams and these were evaluated in a series of in vitro assays, which determined their antiproliferative activity in MCF-7 and MDA-MB-231 breast cancer cell lines and also their affinity for the oestrogen receptor (Fig. 6). The cytotoxicity of the b-lactams was determined in the LDH assay to establish that the antiproliferative effects observed were due to cytostasis rather than cellular necrosis. Most of the compounds demonstreated low cytotoxicity, indicating that their action is cytostatic rather than cytotoxic. Cytotoxicity values considerably below that obtained for tamoxifen (13.4%, 10 mM) were observed with a most potent compound (3%, 10 mM in MCF-7 cell

Cl

O

O S

Cl CF3 COOH

N Me

O O

OBut

O

O S

Cl + [Me2 N=CHCl]Cl-

N

Me

O O

OH

O

O

Cl

S Me O

S

ROH

N

O Cl

O

O N

Me

O O

OR

75 a: R=Me, b: R=Et, c: R=i-Pr, d: R=n-Bu, e: R=CH2CH=CH2, f: R=CH2CH2Cl, g: R=CH2CCl3

Fig. 4 Structures of a few anticancer b-lactams

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R LDA/CTMS

O

O N

N Ph

Ph

76 R'-CHO Base

77

SiMe3

R'-CO-R" LDA

R

R - H2 O

O

O

N

N R'

Ph 78

R'

Ph

HO

79

R"

a: R = H; b: R = MeO; c: R = Br

Fig. 5 Structures of a few anticancer b-lactams

R2

R2 OH

N O

OH

N O

R2 N O

O R2

N

R2 O

O

80

R2 OH

N

N

R1

R1

81

R1

82

Fig. 6 Structures of a few anticancer b-lactams

line). A few b-lactams also showed low cytotoxicity in MDA-MB-231 cancer cell line [158].

14

Conclusion

We and others have demonstrated facile synthesis of a number of new anticancer active b-lactams. The b-lactam derivatives described herein are unique, and they demonstrate reasonable in vitro antitumor cytotoxicity. The stereochemical outcome of the Staudinger reaction as reported herein may offer our laboratory and others many additional opportunities to use b-lactams in the synthesis of biologically active compounds. Although the mechanism of action of the lead compounds has not been totally established, our research on cell cycle analysis offers intriguing

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possibilities. In the absence of effect upon DNA or DNA enzyme-systems, they produced a striking blockade. This “check point” in the cell cycle has attracted a considerable amount of attention recently. Studies are now underway to determine the exact site of this action and to utilize it in an effort to modify our b-lactams to obtain more potent compounds. It is our expectation that novel anticancer b-lactams with high potency and unique mechanism of action will be discovered by other researchers as well. Acknowledgment We gratefully acknowledge the financial support for this research project from National Institutes of Health-SCORE (2S06M008038-39).

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Index

A Ab initio calculations, 313 4-Acylamino-trans-b-lactams, 111 Acyl-CoA cholesterol acyl transferase (ACAT), 54, 189, 214 Adamantine-spiroheterocyclic b-lactams, 62 Alanes, 235 Alkenes, 313 trans-3-Alkyl b-lactams, 121 cis-3-Alkyl-1-benzyl-4-ethoxycarbonylb-lactams, 141 4-Alkyl-4-carboxy-2-azetidinones, 146 4-Alkylidene-2-azetidinones, 159 4-Alkyliden-b-lactams, 182 Allyl b-lactams, 140 Alper reaction, 107, 135 Amino acid-derived peptides, 223 a-Amino acids, 211 b-Amino acids, 211 b-Amino amides, 223 b-Amino esters, 219 b-Amino ketones, 231 a-Amino-2-azetidinones, 138 3-Amino-4-alkyl-2-azetidinones, 131 trans-3-Amino-4-alkylazetidin-2-ones, 122 a-Amino-b-lactams, 138 Amoxicillin, 3, 182 Anthrax, 180 Antibacterial activity, 104, 175 Antibacterial agents, 92 Anticancer activities, 106, 193, 359 Anticancer agents, 349

Anticancer b-lactam, asymmetric synthesis, 360 Antihyperglycemic activity, 106, 192 Antitubercular activity, 54 Antiviral activity, 106, 196 Antiviral agents, 91 Apoptosis, 365 inductors, 52, 106 3-(Aryl)-alkenyl-b-lactams, 279 4-Aryl-3-(3-chloropropyl)azetidin-2-ones, 130 Aspareomycins, 56 Atherosclerotic coronary heart disease (CHD), 90, 106 2-Aza-3-trimethylsilyloxybuta-1,3-diene, 145 N-a-Aza-heteroaryl substituted imines, 140 Azapenams, 165, 250 Aza-peptide, 137 5-Azaspiro[2.3]hexan-4-one, 7 Azatrinems, 57 2-Azetidinones, 1, 3, 105 Aziridine carbonylation, 137 Azirine-azomethine cycloaddition, 20 Azitidinone, 261 Aztreonam (monobactam), 264

B Bacillus subtilis, 182 BAL, 273 Benzocarbacephems, 22 Benzocarbapenems, 23

375

376

Benzodiazepine-fused b-lactams, 125 N-Benzyl-C-(methoxycarbonyl)nitrone, 7 Benzylisatin, 64, 89 N-Benzyloxy-4-aryl-3-(S)hydroxybutanamide, 137 3-Benzyl-b-lactam azapeptidomimetic, 137 Bicyclopropylidene, 7 Bis-(cyclophanyldiol)AlOTf complex, 118 1,4-Bisaryl b-lactams, 290 Bis-dioxocyclams, 250 Bisketenes, 328 Bis-b-lactams, macrocyclic, 126 1-N-Boc-azapenams, 250 Bromo-enamides, 147

C C-3 ferrocene-substituted 2-azetidinones, 134 Carbacepham, 13 Carbacephems, 276, 278, 284 Carbapenems, 51, 177, 264 Carbon nucleophiles, 231 Carbonylation, 295 Carbonylative ring expansion, 299 N-Carboxy a-amino acid anhydrides (NCAs), 236, 265 Carpetimycin, 56 Catalytic one-pot reaction, 129 Cathepsins, 186 Cefadroxil, 183 Cefoxitin, 175 Cell cycle activity, 365 Cephalosporanate sulfones, 7-alkylidene substituted, 195 Cephalosporinases, 2 Cephalosporins, 2, 51, 264 Chartelamides, 3 Chartellines, 3, 80 2-Chloro-1-methylpyridinium iodide (Mukaiyama’s reagent), 273 4-(1-Chloroethyl)-b-lactams, 131 Cholesterol absorption inhibitors (CAI), 49, 53, 70, 90, 189 Cholesterol acyl transferase inhibitors, 52 Cidofovir, 197 Cisplatin, 360

Index

Clavams, 156, 183 Clavulanic acid, 3, 51, 176, 177, 182 Cryptophycin, 221 Cyclization reaction, 101 Cycloadditions, 1, 49 Cyclopropane, b-lactam, spirocyclic, 8 Cysteine protease, 52, 106 inhibitors, 186 Cytotoxicity, in vitro, 362

D N,N-Dialkylhydrazones, 114 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 121 Diazepam derivatives, 5 Diazepan-b-lactam, spirocyclic, 5 Dibenzofluorene, 353 gem-Difluoro-b-lactams, 136 Dihydropyridine b-lactam, spirocyclic, 7 Dihydroquinolinones, 272 Dioxocyclams, 250 DNA intercalators, 364 Dynemicin, 195

E Echinocandin, 240 Elastase inhibitors, 52, 104, 185, 350 Electrochemical induction, 141 Enkephalin mimetics, 251 Enzyme inhibitors, 101, 105 Epigallocatechin-3-gallate (EGCG), 185 Epoxymonobactrams, 165 Escherichia coli, 182 Estrogen receptor, 196, 367 3-Ethoxycarbonyl b-lactams, 125

F Ferrocene-substituted 2-azetidinones, 143 Fibrin peptide A protease inhibitors, 251 Fluorescence-based penicillin, 178 Fmoc-Wang resin, 276 Fridricamycins, 92 Fused rings, 1

Index

G N-Galloxyl-4-alkyliden-b-lactam, 185 Ganciclovir, 197 Gilman-Speeter reaction, 107, 131, 266, 287 Glutamine synthetase, 93

H Hexahydrodiazepinones, 250 Homaline, 250 Hopromine, 250 Hoprominol, 250 Human cytomegalovirus (HCMV), 52, 106, 196, 198 Human leukocyte elastase (HLE), 52, 104, 184 Hydrides, ring opening, 235 7-Hydroxy-4-methylcoumarin, 178 1-Hydroxycarbacephams, 13 Hypocholesterolemic activity, 106

377

b-Lactamase inhibitors, 54 b-Lactamases, 2, 104 inhibitors, 49, 104, 175 b-Lactams, 1 bicyclic, 53, 56 monocyclic, 53 spirocyclic, 3, 4, 57 substituted, 109 synthesis, 107 tricyclic, 18, 53, 57 Lactenediynes, 195 Lankacidins, 221 Large ring heterocycles, 249 Leukocyte elastase (LE), 105 Lewis-acid catalysis, 145 Lithium diisopropylamide (LDA), 133 LY307174, 188 Lysobactin, 223, 237

M I Imines, 313 Iminoglobulin mimetics, 250 Imipenem, 56, 175 Indolenine spiro-b-lactams, 80 Intramolecular cyclization, 108, 141 Isocyanates, 313 [2þ2] cycloaddition with alkenes, 338 Isoxazolidine-b-lactams, 19 Isoxazolium anhydrobase, 144

K Ketene-imine, 49, 265, 316 Ketenes, 313 [2þ2] cycloaddition with imines, 337 1,3-diazabuta-1,3-dienes, 321 metalated, 334 Ketenimines, 313 imines, 331 Ketoconazole, 188 Keto-b-lactams, 111 Kinugasa reaction, 108, 137

L b-Lactam enolates, 132 cis-/trans-b-Lactam nucleosides, 138

MAMP, 273 Matrix metalloproteinase (MMP), 105 inhibitors, 52 Meropenem, 56 Merrifield resin-bound imine, 116 Metallo-b-lactamases, 2, 177 Metals, 1 7-a-Methoxycephalosporins, 51 a-Methylene-b-lactam, 5 N-Methylthio-substituted b-lactams, 179 Microginin, 215 Microwave-induced synthesis, 355 Miller’s hydroxamate approach, 292, 296 Mitsunobu reaction, 107, 137 Monobactams, 51, 53, 89, 175, 189, 262, 264, 273, 290 Monochloroalanes, 235 Moxalactam, 175 Mukaiyama’s salt, 117 Mutagenicity assays, 364

N NCAs, branched a-amino acids, 242 b-diamino acids, 241 side chains, nonproteinogenic a-amino acids, 238 Nikkomycins, 233

378

Nitrogen nucleophiles, 223 Nodularin, 228 Norcardicins, 53 1-Nosyl 3,3-dichloro-b-lactams, 130

O Olivanic acids, 56 Omuralide, 195 Onchidin, 215 Oxacephams, 51, 156, 298 Oxaciclopropane, 8 7-Oxanorbornene-b-lactam, spirocyclic, 6 Oxapenems, 51 Oxazolidinones, 217 Oxindole b-lactam, spirocyclic, 7 Oxirane b-lactam, spirocyclic, 8 a-Oxoamides, 143 4-Oxoazetidine-2-carbaldehydes, 33, 167 Oxygen nucleophiles, ring opening, 219

P Paclitaxel, 219 PAL, 273 Panipenem, 56 Panteamine, 221 Penam derivatives, 51, 109, 176 Penicillin, 2, 51, 261, 264 solid phase synthesis, 303 Penicillin-binding proteins (PBPs), 182 Penicillinases, 2 Peptide-deformylase inhibitor, 230 Peptides, 211 Peptidomimetics, 94 Periselectivity, 319 Phebestin, 224 Phenalene derivatives, 352 4-Phenoxymethylene-b-lactams, 130 2-Phenyliminoacenaphthenone, 59 N-Phenylsulfonyl-spiro-b-lactams, 77 Photoirradiation, 142 Phytosphingosines, 231 Picornaviruses, 91 Pilus formation, inhibition, 178 Piperazine-2-carboxylic acid peptides, 243 Pluracidomycin, 56 Polyaromatic imines, 354 Polyaromatic nitro compounds, 352

Index

Polymer-assisted solution phase (PASP) technique, 266 Polyoxins, 239 Poststatin, 229 Proline, spiro-b-lactams, 78 Prostate specific antigen inhibitor, 55 Protease inhibitors, 52, 105, 184, 196 Proteasome inhibitors, 81, 195

R Radical cyclizations, 1 Renal dehydropeptidase-I (DHP-I), 56 Renin, 235 Resistance, 2 N-Rhenaimine, 116 Ring opening, 211 C2–C3 bond, 236 C3–C4 bond, 243 carbon nucleophiles, 231 hydrides, 235 N1–C2 bond, 214 N1–C4 bond, 244 nitrogen nucleophiles, 223 Rink resin derived imines, 113

S Salinosporamide A, 195 SASRIN, 273 Selenopenams, 169 Semiempirical calculations, 313 Serine protease, 105, 107, 187, 214 prostate-specific antigen, 134 Sieber amide, 273 a-Silylketoamides, 144 Solid phase synthesis, 261 Spermine, 249, 253 Spiranic b-lactam, 3 Spiroazetidin-2-ones, 49, 66 Spirobarbiturates, 58 Spirocycles, 1 3-Spirocyclopropanated 2-azetidinones, 128 3-Spirocyclopropanated b-lactams, 127 4-Spirocyclopropylazetidin-2-one, 67 3-Spiro-epoxyazetidin-2-ones, 64 6-Spiro-epoxypenicillins, 63, 92 Spiroindolinone-b-lactams, antiviral Spiropenicillians, 60

Index

Spiro-b-lactam oxadiazolines, 65 Spiro-b-lactams, 49 a-Stannylketoamides, 144 Staphylococcus citrus, 182 Staudinger reaction, 4, 107, 109, 266, 349 Stereoselectivity, 321 Sulbactam, 51, 176 4-Sulphonamido-trans-b-lactams, 111 b-Sultam, 261, 267, 269 Synthetic intermediates, 49

T T1 triazine linker, 288 Tabtoxin, 93 Tabtoxinine-b-lactams, 93 Taxoids, 1, 3, 52 Tazobactam, 176 Tetrahydroazocinones, 244 Thienamycin, 51, 56 Thietane-fused b-lactam, 303 S-Thioesters, 131 Thioketenes, imines, 330 Thrombin inhibitors, 52, 55, 117, 187 Topoisomerases interactions, 365

379

Torii reaction, 108, 138 Transition metal-catalyzed reactions, 1 Triazene linker, 290 Trichloroethyl-6-diazopenicillanate, 59 Trinems, 3, 57 Tryptase inhibitors, 117, 187, 304 b-Turn mimics, 3, 4, 49, 54, 78, 94, 249 b-Turn nucleators, 49, 54, 95

V Vacatin, 219 Vancomycin, 183 Vasopressin V1a antagonists, 105, 188 3-Vinyl-b-lactams, 279 Virus-encoded proteinases, 91

W WF-10129, 231

Y Ynamide-Kinugasa reaction, 138 Ynolates, 132

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