摘要:

Contemporary Organic Synthesis Editorial Board Professor G. Pattenden, FRS (Chairman), University of Nottingham Professor P. D. Bailey, Heriot- Watt University Professor P. J. Kocienski, University of Southampton Professor C. J. Moody, Loughborough University of Technology Dr S. E. Thomas, Imperial College of Science, Technology, and Medicine Professor E. J. Thomas, University of Manchester International Advisory Board Professor E. J. Corey, Harvard University Professor S. Hanessian, Universite' de Montrkal Professor M. Julia, UniversitP de Paris X I (Paris-Sud) Professor P. D. Magnus, University of Texas at Austin Professor G. Mehta, University of Hyderabad Professor K. C. Nicolaou, The Scripps Research Institute and University of California at Sun Diego, La Jolla Professor R.Noyori, Nagoya University Professor L. E. Overman, University of California, Irvine Professor L. F. Tietze, University of Gottingen Contemporary Organic Synthesis is a bimonthly journal which aims to review and provide perspective in all aspects of methodology, selectivity, and efficiency in contemporary synthesis. As well as covering all the principles and methods in functional group chemistry and interconversions, organometallic chemistry and asymmetric synthesis will feature prominently, so too will modern aspects of strategy and computer aided design, biotransformations, and protecting group protocols. Special methods and techniques, such as sonochemistry, FVP, electroorganic synthesis, and supported catalysis will be included as occasional articles, and the manner in which synthesis addresses problems and provides solutions in biology, medicine, agriculture, the environment, and new materials, will also be encompassed. Contemporary Organic Synthesis aims to be proactive, drawing attention to new opportunities and new directions, providing timely information to the synthetic chemist who needs to keep abreast of developments in the field. Although the majority of articles are intended to be specially commissioned, the Society is always prepared to consider offers of articles for publication. In such cases a short synopsis, rather than the completed article, should be submitted to the Senior Editor (Reviews), Books and Reviews Department, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF.Members of the Royal Society of Chemistry may subscribe to Contemporary Organic Synthesis by placing their orders on the Annual Subscription renewal forms in the usual way. All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letchworth, Herts SG6 lHN, England. 1994 subscription rate: EC &150, USA $282, Canada &169 (plus GST), Rest of the World &161. Air freight and mailing in the USA by Publications Expediting Inc., 200 Meacham Avenue, Elmont 1103; USA Postmaster, send address changes to Contemporary Organic Synthesis, Publications Expediting Inc. Second class postage is paid at Jamaica, New York 11431. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe.0 The Royal Society of Chemistry, 1994 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording, or otherwise, without the prior permission of the publishers. Typeset by Unicus Graphics Ltd Printed in Great Britain by Whitstable Litho LtdContemporary Organic Synthesis Editorial Board Professor G. Pattenden, FRS (Chairman), University of Nottingham Professor P. D. Bailey, Heriot- Watt University Professor P. J. Kocienski, University of Southampton Professor C. J. Moody, Loughborough University of Technology Dr S. E. Thomas, Imperial College of Science, Technology, and Medicine Professor E.J. Thomas, University of Manchester International Advisory Board Professor E. J. Corey, Harvard University Professor S. Hanessian, Universite' de Montrkal Professor M. Julia, UniversitP de Paris X I (Paris-Sud) Professor P. D. Magnus, University of Texas at Austin Professor G. Mehta, University of Hyderabad Professor K. C. Nicolaou, The Scripps Research Institute and University of California at Sun Diego, La Jolla Professor R. Noyori, Nagoya University Professor L. E. Overman, University of California, Irvine Professor L. F. Tietze, University of Gottingen Contemporary Organic Synthesis is a bimonthly journal which aims to review and provide perspective in all aspects of methodology, selectivity, and efficiency in contemporary synthesis.As well as covering all the principles and methods in functional group chemistry and interconversions, organometallic chemistry and asymmetric synthesis will feature prominently, so too will modern aspects of strategy and computer aided design, biotransformations, and protecting group protocols. Special methods and techniques, such as sonochemistry, FVP, electroorganic synthesis, and supported catalysis will be included as occasional articles, and the manner in which synthesis addresses problems and provides solutions in biology, medicine, agriculture, the environment, and new materials, will also be encompassed. Contemporary Organic Synthesis aims to be proactive, drawing attention to new opportunities and new directions, providing timely information to the synthetic chemist who needs to keep abreast of developments in the field.Although the majority of articles are intended to be specially commissioned, the Society is always prepared to consider offers of articles for publication. In such cases a short synopsis, rather than the completed article, should be submitted to the Senior Editor (Reviews), Books and Reviews Department, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF. Members of the Royal Society of Chemistry may subscribe to Contemporary Organic Synthesis by placing their orders on the Annual Subscription renewal forms in the usual way. All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letchworth, Herts SG6 lHN, England. 1994 subscription rate: EC &150, USA $282, Canada &169 (plus GST), Rest of the World &161. Air freight and mailing in the USA by Publications Expediting Inc., 200 Meacham Avenue, Elmont 1103; USA Postmaster, send address changes to Contemporary Organic Synthesis, Publications Expediting Inc. Second class postage is paid at Jamaica, New York 11431. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. 0 The Royal Society of Chemistry, 1994 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording, or otherwise, without the prior permission of the publishers. Typeset by Unicus Graphics Ltd Printed in Great Britain by Whitstable Litho Ltd

ISSN:1350-4894    

DOI:10.1039/CO99401FX021

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

HAZARDS IN THE CHEMICAL LABORATORY Royal Society of Chemistry, Turpin Distribution Services Ltd, Blackhorse Road, Letchworth, Herts SG6 IHN, United Kingdom. CHEMISTRY Information Services II I 5th Edition ‘. . . easy to read, an excellent reference text, and a worthwhile investment .’ Journal of the American Chemical Society reviewing the 4th Edition. The new edition of this essential laboratory handbook is the ‘key’ requirement for all research, development, production, analytical and teaching laboratories worldwide. The 5th Edition provides: 0 a quick guide to the hazardous properties of 1339 substances (over 800 more than were covered in the previous edition) details of the latest UK and EC regulations an extremely useful emergency action check list - users can fill in their own key contacts for hospitals, fire etc.handy tables, symbols and statistics for ease of reference 0 a description of the American scene, including US legislation and safety practices - highlighting differences between the UWEC and USA PVC Protective Binding xx + 676 pages New features include: expanded ‘Yellow Pages’ section on hazardous substances, providing immediate information on hazardous properties, recommended control procedures and safety measures complete guide to labelling requirements to comply with EC directives and UK legislation, including the risk and safety phrases that must appear 0 chapter on electrical hazards 0 index to ‘Yellow Pages’ section, with synonyms of compounds 0 index to CAS Registry Numbers ISBN 0 85186 229 2 (1992) Price f45.00 If you have not yet ordered your copy of the NEW edition, do so now! Why take chances? Be informed and safe.5I To order, please contact: Telephone: +44 (0)462 672555 Fax: +44 (0)462 486947. 1350-4894C199411.1-9HAZARDS IN THE CHEMICAL LABORATORY Royal Society of Chemistry, Turpin Distribution Services Ltd, Blackhorse Road, Letchworth, Herts SG6 IHN, United Kingdom. CHEMISTRY Information Services II I 5th Edition ‘. . . easy to read, an excellent reference text, and a worthwhile investment .’ Journal of the American Chemical Society reviewing the 4th Edition. The new edition of this essential laboratory handbook is the ‘key’ requirement for all research, development, production, analytical and teaching laboratories worldwide. The 5th Edition provides: 0 a quick guide to the hazardous properties of 1339 substances (over 800 more than were covered in the previous edition) details of the latest UK and EC regulations an extremely useful emergency action check list - users can fill in their own key contacts for hospitals, fire etc.handy tables, symbols and statistics for ease of reference 0 a description of the American scene, including US legislation and safety practices - highlighting differences between the UWEC and USA PVC Protective Binding xx + 676 pages New features include: expanded ‘Yellow Pages’ section on hazardous substances, providing immediate information on hazardous properties, recommended control procedures and safety measures complete guide to labelling requirements to comply with EC directives and UK legislation, including the risk and safety phrases that must appear 0 chapter on electrical hazards 0 index to ‘Yellow Pages’ section, with synonyms of compounds 0 index to CAS Registry Numbers ISBN 0 85186 229 2 (1992) Price f45.00 If you have not yet ordered your copy of the NEW edition, do so now! Why take chances? Be informed and safe. 5I To order, please contact: Telephone: +44 (0)462 672555 Fax: +44 (0)462 486947. 1350-4894C199411.1-9

ISSN:1350-4894    

DOI:10.1039/CO99401BX023

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

ISSN 1350-4894 COGSE6 1 (6) 417-494 (1994) Contemporary Organic Synthesis A journal of current developments in Organic Synthesis VOLUME 1 NUMBER 6 C O N T E N T S 89% (Soo/, e.e.) R 0 RCHO tSml2 Ph-N=C=O PhCH#r. RCHO. SmI2 fTh p:2H2Br'/ \ 7 Ph-N,Ph P h 7 N y R 0 0 OH 417 The synthesis of natural p-lactam antibiotics By Robert Southgate Reviewing the literature published up to February I994 Saturated and partially unsaturated 433 carbocycles By Christopher D. J. Boden and Gerald Pattenden Reviewing the literature published between August I992 and January 1994 Recent developments in the synthesis 457 of medium-ring ethers By Mark C. Elliott Reviewing the literature published between 1 October 1990 and 30 June I994 Amines and amides By Michael North Reviewing the literature published between July I992 and December I993 475Cumulative Contents of Volume 1 Number 1 1 23 3 1 47 Aldehydes and ketones (July 1992 to June 1993) Patrick G.Steel Saturated oxygen heterocycles (January 1992 to March 1993) Christopher J. Burns Noncovalent design principles and the new synthesis Mark Mascal Recent progress in the synthesis of taxanes (January 1991 to July 1993) A. N. Boa, P. R. Jenkins, and N. J. Lawrence Number 2 77 Catalytic applications of transition metals in organic synthesis ( 1 July 1992 to 31 August 1993) Graham J. Dawson and Jonathan M. J. Williams 95 1 13 Saturated nitrogen heterocycles (January 1992 to May 1993) John Steele Organic halides ( 1 July 1992 to 30 June 1993) P. L. Spargo 125 Stoichiometric applications of organotransition metal complexes in organic synthesis ( 1 July 1992 to 31 August 1993) Julian Blagg Number 3 145 173 191 205 Recent developments in indole ring synthesis-methodology and applications (1990 to 1993) Gordon W.Gribble Saturated and unsaturated hydrocarbons ( 1 July I992 to 1 September 1993) R. P. C. Cousins Thiols, sulfides, sulfoxides, and sulfones (July 1992 to September 1993) Christopher M. Rayner Synthesis of five-membered aromatic heterocycles (July 1991 to June 1993) Thomas L. Gilchrist Number 4 2 19 243 259 287 The role of zinc carbenoids in organic synthesis (up to February 1994) W. B. Motherwell and C. J. Nutley Alcohols, phenols, and ethers (July 1992 to July 1993) Joseph Sweeney Synthetic developments in host-guest chemistry (July 1992 to December 1993) Jeremy D.Kilburn and Hitesh K. Patel Synthetic approaches to butenolides (1976 to 1992) D. W. Knight Number 5 3 17 339 Recent developments in asymmetric aldol methodology (up to the end of1993) Alison S. Franklin and Ian Paterson Main group organometallics in synthesis (July 1992 to December 1993) Martin Wills 367 Synthesis of materials for molecular electronic applications (mid-1992 to December 1993) Martin C. Grossel and Simon C. Weston 387 Control of asymmetry through conjugate addition reactions (up to the end ofMarch 1994) John Leonard Number 6 41 7 433 457 475 The synthesis of natural P-lactam antibiotics (up to February 1994) Robert Southgate Saturated and partially unsaturated carbocycles (August 1992 to January 1994) C. Boden and G. Pattenden Recent developments in the synthesis of medium ring ethers (October 1990 to June 1994) Mark C. Elliott Amines and amides (July 1992 to December 1993) Michael North Articles that will appear in forthcoming issues include The hydrometallation, carbometallation, and metallometallation of heteroalkynes Sharon Casson and Philip Kocienski Serotonin, sumatriptan and the management of migraine Alexander W. Oxford Aromatic heterocycles as intermediates in natural product synthesis (up to December 1993) M. Shipman Stoichiometric organotransition metal complexes in organic synthesis ( 1 September 1993 to 31 August 1994) Julian Blagg

ISSN:1350-4894    

DOI:10.1039/CO99401FP025

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

The synthesis of natural P-lactam antibiotics ROBERT SOUTHGATE SmithKline Beecham Pharmaceuticals, Research Divison, Brockham Park, Betchworth, Surrey, RH3 7A4 UK Reviewing the literature published up to February 1994 1 2 2.1 2.2 2.3 3 3.1 3.2 3.3 3.4 4 5 5.1 5.2 5.3 5.4 5.5 6 Introduction Monocyclic B-lactams Nocardicins Monobactams Formadicins Penicillins and cephalosporins Penicillins Cephalosporins Cephamycins Cephabacins Clavulanic acid Carbapenems Thienamycin Olivanic acids PS-5 Carpetimycins As parenomy cins References 1 Introduction Up to 1970 most P-lactam research was concerned with the penicillin 1 and cephalosporin 2 families of antibiotics.' In 1970 elucidation of the structure of the p-lactamase stable cephamycins 32 was quickly followed by the isolation from natural sources of several new /3-lactams structurally distinct from the penicillins and cephalosporins.These were the nocardicins 4,3 clavulanic acid 5,4 thienamycin 65 and the olivanic acids 7.h This diversity of structural types, coupled with potent antibacterial or B-lactamase inhibitory activity, provided a new incentive for expansion in the area of /3-lactam chemistry directed COpH 602H 1 2 X = H 3 X=OMe CO2H C02H 4 5 6 0' I C02H 7 towards semi- or total-synthesis of these new agents and analogues. Over the next two decades these efforts saw the emergence of many new methodologies for the synthesis of such structures, involving aspects of stereo control, 8-lactam ring construction and protecting group strategies. Subsequently, the isolation of the so called monobactams 8 from bacterial sources provided a further impetus to synthesis in the area.',* More recently the cephabacins 9y and formadicins 1 O l o have provided further variations of naturally occurring cephalosporins and monocyclic structures.In addition to the discovery of these new natural products a substantial effort has been devoted to the synthesis of numerous P-lactams of various structural RCONH x 8 X=H,OMe 9 RCONH NHCHo DJyoH ! 0 CO2H 10 Southgate: The synthesis of natural /3-lactarn antibiotics 417types which have not been found in nature. Although these do not strictly fall within the scope of this review, significant structures of synthetic interest have been included. racemization, the Miller synthesis provides a high yielding process which is applicable to almost any p-lactam.The key to this approach lies in the selective intramolecular displacement of X in intermediates 16 by the nitrogen atom of the hydroxamic acid derivative 2 Monocyclic B-lactarns giving the azetidinone 17 with inversion of configuration at C-4 and retention at C-3. Thus, 2.1 Nocardicins base-catalysed cyclization of /?-halo hydroxamates or While semi-synthetic approaches to the nocardicins from penicillin derived P-lactams have been described,", I * only the totally synthetic methods are covered here. One of the first made use of the classical keten-imine reaction for the construction of the P-lactam 12 by reaction of phthalimido acetyl chloride with the thioimidate 1 1. Subsequent removal of the S-substituent and deprotection afforded 3-aminonocardicinic acid 13 which could be acylated to afford nocardicins A and D.I3 The Lilly group reported a synthesis starting from the L-cysteine derived thiazolidine 14 followed by one of the first examples of N-C-4 bond ring closure via the chloride 15.14 OCHZPh 11 0 6OpH 13 b02Me 12 PhCON X S H - - t / CO2H 14 602CH2Ph 15 A much more direct synthesis of functionalized P-lactams involving the biomimetic N-C-4 cyclization approach is by the highly versatile and widely used hydroxamate method developed by Mil1er.l5 Further, it provides the opportunity to use readily accessible chiral amino-acids to form the P-lactam. Whereas N-C-4 cyclizations of amino-acids with P-leaving groups are normally low yielding due to competing side-reactions such as elimination or use of the Mitsunobu procedure readily provided good yields of the cyclic products 17 ( R3 = CH2Ph).I6 Conversion to the free N-hydroxy /?-lactam 17 (R' = H) was followed by reduction with TiC1317 to provide an efficient synthesis of P-lactams 18 and applicable to a wide variety of structural variations.16 17 i a This methodology was used by Miller for the synthesis of the nocardicin ring-system starting from tBoc-L-serine. This provided /?-lactam 19, which on treatment with the diazophenylacetate 20 and rhodium acetate gave a mixture of C-5 disastereoisomers from which the protected 3-aminonorcardicinic acid (3-ANA) nucleus could be separated. Fortunately, the wrong diastereoisomer of 2 1 could be isomerized with base to allow almost complete conversion into 2 1 in an overall yield of 45% from the protected amino-acid.Ix 19 20 C02CH2Ph 21 The total synthesis of nocardicins A-G, also by a biomimetic N-C-4 ring closure has been comprehensively described by Townsend.19 In this case intermediate 22 was cyclized smoothly in a modified Mitsunobu cyclodehydration procedure, substituting triethylphosphite for triphenylphosphine to give a high yield of cyclic product with virtually none of the opposite C-5 diastereoisomer which has plagued many other approaches, even under the mildest conditons of cyclization such as demonstrated by Hanessian using the imidazoylsulfonate leaving group.*" The use of the 4,5-diphenyl-4-oxazoline-2- one (Ox) protecting group for nitrogen also showed several advantages compared to the more conventionally used phthalimido, being readily removed by hydrogenation with less competing side-reactions. Differential deprotection of the cyclic product provided 23 which by a variety of procedures, 4 18 Contemporary Organic SynthesisPh H 2 N p N s O H H 0 kOpBu' C02Bu' 3 Penicillins and cephalosporins 22 23 29 30 3.1 Penicillins using the appropriate side-chains, was converted into the natural nocardicins A-G.For example, nocardicin A was produced in an overall yield of 22% from L-serine and D-( p-hydroxyphenyl) glycine. The first synthesis of a natural penicillin (potassium penicillin V ) was described by Sheehan in 1957 following his early pioneering work in this area.26 Condensation of 3 1 with D-penicillamine 32 to give 33 was followed by progression to the penicilloate 34 which was cyclized to the natural product 35 using the then newly introduced DCCI (dicyclohexylcarbodiimide) reagent.Subsequent reports outlined the application of such methods to the general synthesis of penicillin^.^^ Keten-imine cycloaddition reactions for p-lactam construction as used by Bose also allowed the construction of the penicillin ring-system but gave the unnatural 5,6 2.2 Monobactams As in the case of the nocardicins, initial approaches to the monobactams were from penicillin derived P-lactams.21 Total synthesis of the naturally occurring nucleus 25 was achieved by direct base-catalysed cyclization of the acyl sulfamate 24.22 RNH H RNH t! trans-configuration of the P-lactam protons.2x 0 XC' 'SO,-M+ 0 @' S03-M+ ""5 H2N kO,H 24 25 gN.""" COpBu' With the monobactams, however, it was found that non-naturally occurring C-4 substituted p-lactam 31 32 derivatives showed some advantage in their biological properties compared to the natural products.Thus, cyclization of the threonine derived mesylate 26 and "p----c02H PhOCHpCONH H ! deprotection gave 3-amino-4-methylmonobactamic 0 acid 27 from which the highly potent antibiotic aztreonam 28 was obtained.23 0 COpBU' H 28 2.3 Formadicins Of the most recently discovered naturally occurring 3-formamido substituted nocardicins of type 10, no syntheses have been reported, although formamido monobactam analogues 29 have been synthesized from the penicillin derived sulfone 30.24 A wide ranging review of the synthesis of many other analogues of the nocardicins and monobactam family has also been published.2s 33 (diastereoisomers separated) 34 PhOCH2CONH H H C02H 35 However, a method for correcting this stereochemistry was developed by the Merck group and used in a total synthesis of Penicillin G.2y Thus, using the keten derived from azido-acetyl chloride and the chiral thiazoline 36 yielded (98%) the a-azido bicyclic system 37.Elaboration to the Schiff's base 38 allowed ready deprotonation at the C-6 position. Subsequent kinetic reprotonation provided a 2 : 1 ratio of cis: trans p-lactam isomers which could be progressed and separated to give synthetic penicillin G 39. The only highly stereoselective synthesis of the penicillin ring-system remains that described by Baldwin in 1976, using the peptide precursor 4 1 obtained from the cysteine derived thiazolidine 40 and D-isodehydrovaline methyl ester.") Base-catalysed cyclization of the chloride 42 to 43 was followed by a multi-step conversion into the sulfoxide 44. Generation of the sulfenic acid 45 resulted in Southgate: The synthesis of natural P-lactam antibiotics 41936 37 PhCHPCONH t! y 38 39 PhCON 'S PhCON H a A COR 0 PhCON'S PhCON'S (!OR'x 0- CHO OH PhCONH H H ' k02Me &02Me 44 45 PhCONH H C02Me 46 n = l 47 n = O ring-closure to the sulfoxide 46 which on deoxygenation gave the penicillin ester 47.3.2 Cephalosporins While a large number of nuclear analogues of the cephalosporin ring-system have been synthesized, approaches to the natural products have been limited, the major emphasis being focused on acylamino-derivatives of 7-amino-cephalosporanic acid (7-ACA). Both the Squibb3' and R o ~ s s e l ~ ~ groups used intermediates of type 48 to produce the amino-acid 49 which could be cyclized as in the Sheehan penicillin synthesis to provide the cephalosporin lactone ring-system 50.Deprotection and acylation of the amino-function provided 50 (R = &co ) in which the lactone ring could be opened, giving dea~etylcephalothin.~~ Another approach to the lactone made use of the cycloaddition reaction between the thiazine 5 1 and the keten generated from azido-acetyl chloride.34 In a similar manner the Merck group used thiazine 52 to complete a total synthesis of racemic ~ephalothin.~~ 48 49 50 51 52 In contrast to these approaches the earlier total synthesis of cephalosporin C described by Woodward in 1966 provides one of the classic examples of natural product synthesis.", 37 Protection of the nitrogen, sulfur, and carboxylic acid functions of L( + )-cysteine provided the cyclic intermediate 53 which was ideally suited for introduction of the amino-function-this in turn was to become the nitrogen atom of the key p-lactam intermediate 57.This was achieved in a stereocontrolled manner by introduction of the hydrazino-substituent 54 followed by oxidation and conversion into the trans-hydroxy ester 55. Conversion into the mesylate, inversion of the stereochemistry by displacement with azide, and reduction gave the p-amino-ester 56 which was cyclized to the p-lactam 57 using triisobutylaluminium, the stereochemistry being confirmed by X-ray crystallography.C02Me 53 54 55 56 57 Addition of 57 in a Michael-like manner to the dialdehyde 58 to form 59 was followed by treatment with trifluoroacetic acid to remove both nitrogen and sulfur protecting groups and effect cyclization to the bicyclic cephalosporin precursor 60. The amino group was acylated with the protected D-a-amino adipic acid side-chain in forming 6 1. Reduction, acylation of the primary hydroxyl, and equilibrium provided the cephalosporin C ester 62. The then novel and subsequently much used trichloroethyl protecting groups were removed using zinc to give the free acid 63 (identical with authenic natural cephalosporin C). 420 Contemporary Organic Synthesis' T Z H O C02CH2CC13 CHO sa &02CH&C 13 59 CHO 60 R = H !JH C02CH2CCl3 62 R' = CH2CCI3, R2 = C02CH2CC13 63 R' = R2= H Although not directed specifically towards natural product synthesis, many subsequent outstanding contributions were made by the Woodward group to the area of p-lactam chemistry. None more so than the intramolecular phosphorane cyclization methodology initial developed for constructing novel cephalosporins 65 from 64,3* and then the highly active hybrid penicillin-cephalosporin penem ring system 6 7 by way of 66.39 This mild, neutral, and high yielding method has been universally used for constructing an immense variety of bicyclic P-lactam ring-structures over the past twenty years.64 65 C02H 68 R=Me 69 R=NH2 the a-amino-adipic acid side-chain but vary in the substitution pattern at C-3.As a family they are intrinsically more resistant to degradation by P-lactamases compared to the unsubstituted compounds. As in the case of cephalosporins one of the main areas of chemistry has been concerned with the introduction of new acyl-amino side-chains. However, much effort has also been devoted to methods for synthesizing the 7( a)-methoxy cephalosporin ring-system present in the natural products. Initial approaches were based on the displacement of halogen from intermediates such as the bromo-azide 70 derived from the C-7-diazo Many other methods were subsequently developed for the stereoselective addition of methoxide to acylimine intermediates such as 7 1 ,J3 while addition to sulfenimines 72 is also possible.44 A common methodology is to use a Schiff's base 7 3 to facilitate C-7 anion formation, followed by reaction with an electrophile such as methyl methanethiosulfonate to provide 74.Introduction of the acylamino side-chain followed by solvolysis in methanol in the presence of a mercury salt gives the methoxycephem in good ~ i e l d . ~ ~ - ~ * Other methods of generating imines followed by addition of methanol make use of 7S4' and the quinonoid intermediate 76.50 In all cases, addition to the imine is from the less-hindered face of the bicyclic ring-system to provide the required a-orientation of the methoxy substituent. R'N 0 ' E A O A c 0 R A O A c COpC H Ph2 70 &O2R2 71 R'=RCO 72 R' = RS 66 67 73 RLH 74 R' =SMe 75 k02R2 3.3 Cephamycins In 197 1 the isolation and structural elucidation of two naturally occurring cephalosporins 68 and 69 possessing a 7 a-methoxy group was rep~rted.~" Further examples of this type of natural product were subsequently obtained from a variety of Streptomycete strain^.^' Known as the cephamycins, they all possess Southgate: The synthesis of natural p-lactam antibiotics 421Cycloaddition using the previously described thiazine 52 and the keten from azido-acetyl chloride produced the azido-cephem 77, which was progressed to the thiomethyl derivative 78.This was ideally suited for conversion into 79 and ultimately to provide a total synthesis of ( f ) cefoxitin 80.35 N3H 0 P & O A c C02PMB 77 602R2 78 R' = SMe, R2 = PMB (p -methoxybenzyl) 79 R' = OMe, R2 = PMB 80 R' = OMe, R2 = H The only other total synthesis of a methoxylated cephalosporin is that reported by Kishisl and mimics a possible biogenetic route for p-lactam synthesiss2 N-Acetyl-bromodehydroalanine t-butyl ester was converted in five steps into the bromothioamide 8 1.This was successfully used in a double cyclization to give the p-lactam thiazoline 82. The allylic bromide 83 could then by cyclized to 84 by merely allowing a methylene chloride solution of the bromide to evaporate to dryness at room temperature over three days. HN MeO- CHBr2 0 2, - Me02C Me 81 82 R = H 83 R=Br MeCONHMeO ? p > M e C02Me 84 Although not discovered as natural products, considerable effort has also been devoted to the synthesis and development of 6( a)-methoxy substituted penicillins such as temocillin 85 and other variants,". 54 while mention must also be made of the methoxylated oxacephem moxalactam 86 developed by Shionogi and Lilly, using a multi-stage synthesis starting from the penicillin nucleus.55 Me0 H ( - F H - c o N H - ~ - - - - Me ' ' C02Na 0 CO2Na 85 3.4 Cephabacins In 1984 several groups reported on the isolation of naturally occurring 7( a)-formamido substituent cephalosporins 9 from bacterial sources.9* 56.57 Interestingly, during the course of examining a range of 6( a)-substituted penicillins and 7( a)-substituted cephalosporins, the Beecham group had already discovered that this substituent, with an appropriate side-chain, provided a series of highly active antibiotics.sx, sy Conversion of the unsubstituted cephalosporin ring-system into the formamido nucleus could conveniently be carried out starting from the readily available t-butyl7P-amino-7a- (methy1thio)cephalosporanate 87 used for methoxylated analogues?" Acylation provides 88 from which the methylthio group is readily displaced by ammonia in the presence of a mercury (11) salt; subsequent formylation with acetic-formic anhydride provides 89.Alternatively, the formamido group can be introduced directly by treatment of 88 with N, N-bis( trimethylsily1)formamide in the presence of mercuric acetate. Removal of the acid protecting t-butyl group from 89 affords the appropriate 7( a)-formamido cephalosporin acid. Other methods for introducing the formamido substituent have been described,h1vh2 together with a review of the structural variations prepared.63 H Me? 7 OHCN 7 'lNH 0 Z A O A c R c o N H F & O A ~ k02Bu' 87 R' = H 88 R' = R2C0 602Bu' 89 A highly convenient large scale preparation of the 7( a)-formamido nucleus 90 was also developed to provide a readily available intermediate for semi-synthetic manip~lation.'~ Protection of 7-ACA 9 1 as the trimethylsilyl ester was followed by conversion into the Schiff's base 92.Oxidation in situ with DDQ gave the quinone methide 93, which readily reacted with N, N-bis( trimethylsilyl)formamide, forming 94. Subsequent hydrolysis to remove the side-chain and silyl protecting group followed by crystallization gave the pure 7 a-formamido nucleus 90. This 'one-pot' procedure provided an overall yield 422 Con temporaly Organic SynthesisC02H 90 R = NHCHO 91 R = H C02SiMe3 92 R=H 94 R=NHCHO C02SiMe3 93 of 46% of 90 from 91 on a 1 kg scale, while the DDQ and aldehyde used for oxidation and Schiff's base formation are both recoverable. 99 R=C02Me 100 R = CH20H 101 R=CH=CH2 5 Carbapenems Discovered in the mid- 1970's the first compounds to be reported were thienamycin 6s from Streptomyces cattleya and a group of interrelated metabolites from S.olivaceus such as MM 13902 (7; R = SO,H)h and MM 22382 (7; R = H)h9 known as the olivanic acids. HO 6 7 4 Clavulanic acid Streptomyces clavziligerzis produces a number of natural products containing the 7-oxo-4-oxa- 1 -azabicyclo[ 3.2.0lheptane (clavam) ring system, the best known of these being the clinically important P-lactamase inhibitor clavulanic acid 5.6,hs,66 Although many derivatives and synthetic analogues of this agent have been de~cribed,"~ syntheses directed towards the natural product itself have been minimal.Starting from the simple azetidinone 95, alkylation to provide the keto-ester 96 was followed by conversion into the chloride 97 and base-catalysed cyclization to 98. The geometry of the double bond was corrected by ultra-violet irradiation and the resulting diester 99 selectively reduced with di-isobutylaluminium hydride to give a low yield of the racemic methyl ester 100 of clavulanic acid.h7 In a second approach the diene 10 1 was prepared by cyclization of the appropriate keto-ester. The terminal double bond was converted into the ozonide, which on hydrogenation also provided the racemic ester 1 OO.'# Since the methyl ester of the natural product can be readily hydrolysed to the parent compound both syntheses constitute a formal total synthesis of racemic 5 .95 96 R=SMe 97 R=CI 98 Thienamycin has the 8R configuration of the hydroxy group with a trans- arrangement of p-lactam protons, whereas in the olivanic acids the stereochemistry is 8s with a cis-substituted p-lactam in the sulfated series and both cis- and trans-p-lactams in the hydroxy cases. Subsequently, several other structural variations represented by PS-5 102,70 carpetimycin A 103,7' asparenomycin C 104,72 and pluracidomycin C 105,73 were reported. To date over forty variations of these natural products with differing C-2 and C-6 substituents have been de~cribed.~ * The simplest 102 OH 103 OH 1 04 Southgate: The synthesis of natural p-lactam antibiotics 423member of the series is the rather unstable parent nucleus 106, shown to occur in certain bacterial strains of Serratia and Erwinia.74 Fermentation yields of these Streptomycete metabolites are low and total synthesis methodology has been extensively developed to provide both natural products and analogues. The most common strategy has been to construct an appropriately substituted monocyclic B-lactam with the correct stereochemistry, followed by cyclization to form the highly-strained bicyclic carbapenem ring-system in the last step of the synthesis. S03H C02H 105 0 q CO2H 106 The basic ring system 106 was synthesized in racemic form by several groups prior to the disclosure of the natural product. M e r ~ k ~ ~ made use of the azetidinone 107 derived from chlorosulfonyl isocyanate (CSI) and 1,4-acetoxybutadiene.After reduction of the double bond, progression was by way of the phosphorane 108 and 109. Oxidation and cyclization gave a good yield of the ester 110. Subsequent removal of the photolabile protecting group provided the unstable sodium salt of racemic 106. Also, using phosphorane methodology, the CSI derived 4-allylazetidinone 1 1 1 76 was converted, via the p-nitrobenzyl or acetonyl ester 1 12, into the racemic natural product 106; in this case oxidation of the terminal methylene grouping by ozonolysis provided the aldehyde for the intramolecular Wittig rea~tion.~', 78 0 JdR NO2 108 R=Ac 109 R = H 0 JQ C02R 5.1 Thienamycin Since its discovery, the highly potent broad spectrum antibiotic thienamycin 6 has been the focal point for a multitude of synthetic studies in the carbapenem area.79y880 While several novel methods have been developed, many of the original contributions from Merck are still widely used.The first synthesis of racemic material made use of the previously described azetidinone 107.81,82 This was converted into the 1,3-tetrahydrooxazine 11 3 and then by an aldol condensation to the appropriately substituted truns-/?-lactam 114. This was elaborated by a lengthy process to the dibromide 1 15, which on cyclization, decarboxylation, and elimination gave the ester 1 16; deprotection led to ( k )-thienamycin. 113 R = H 11 4 R = MeCH(0H) 11 5 R = PNB (p -nitrobenzyl) 116 R = PNB A chiral synthesis soon followed, starting from the L-aspartate derived P-lactam 1 17.83 In this case introduction of the hydroxyethyl side-chain was via an acetyl substituent which was subsequently reduced, by a stereocontrolled manner using potassium SelectrideIM, to the alcohol.Homologation to the acid 118 was followed by conversion into the keto-ester, silyl group removal, and diazo-exchange to form 119. C-3-N-4 cyclization using a catalytic amount of rhodium acetate proceeded extremely efficiently to produce the bicyclic keto-ester 120. Activation at C-2 by conversion into the enol phosphate allowed the introduction of the cysteamine side-chain and final deprotection afforded ( + )-thienamycin. Another 117 118 R' = R3 = H, R2 I SiMe2But 129 R' = SiMe2But, @ c R3 = H 130 R' 5 SiMe2But, @ E H, R3 = Me 119 120 approach to the intermediate 118 starts from the lactone 12 1 derived from acetone dicarboxylic acid.x4 Conversion of the side-chain stereochemistry from S to R was required, but nevertheless the overall yield to final product was greater than 10% and offered a practical synthesis of ( f )-thienamycin.The method 424 Contemporary Organic Synthesiswas later modified to produce homochiral material.*5 The synthesis of 12 1 from ( - )-carvone has also been reported.x6 0 4 Me'. G N H C H z P h 6OpH 121 Further refinements using the 4-acetoxy or 4-chloro azetidinone 122 and the silyl enol ether 123 in the presence of Lewis acid provided a method for the direct incorporation of the diazo-ketone residue.87, 88 A convenient method for the synthesis of trimethylsilyl and t-butyldimethylsilyl enol ethers of various esters of a-diazoacetoacetic acid for use in this procedure has been reported.*' Azetidinones 1 18 and 122 (X = OAc) have become universally recognized as being the key intermediate for the synthesis not only of thienamycin but also of many analogues.Methodology therefore has concentrated on developing routes to these versatile P-lactams. Two of the most conceptually appealing procedures make use of simple readily available chiral starting materials derived from 3-hydroxybutyric or lactic acid. u OR N2 122 X=OAc,CI R = H, SiMe2Bu' 123 Thus, using a dianion-imine cycloaddition approach, 122 (X = OAc, R = SiMe,But) was synthesized in an overall yield of 44% in eight steps from (S)-( + )-ethyl-3-hydroxy-butyrate 124 and the N-arylaldimine 125.'" A comprehensive account of cyclo-addition procedures using R or S 3-hydroxybutyric acid derivatives directed towards thienamycin synthesis has been published.Y1 The (S)-enantiomer of ethyl lactate 126 can be converted into (.~)-2-benzyloxypropanal which, with di-p-anisylmethylamine, gives a chiral imine 12 7 suitable for a [2 + 2lcycloaddition reaction with diketen.This proceeds in a highly stereoselective manner to the 3,4-trans-3-acetyl P-lactam 128 which was elaborated in high yield to either 129 or 122 Me XAOEL Ar-p -0Me N, 124 125 P" A Me"C02E 126 -. .. ,. 127 128 (X = OAc, R = SiMe2But).92 Synthesis of the latter has advanced to a stage where it is readily available commerically for both carbapenem and penem ~ynthesis.'~ Efficient syntheses of the 4-benzoyloxy analogue 122 (X = OCOPh, R = H) have made use of the intramolecular cyclization of a threonine derived N-protected epoxy amideY4 or keten-imine methodol~gy.~~ Approaches to non-naturally occurring carbapenems also make use of displacement reactions with 122 (X = OAc, R = SiMe,Bu').Many of these have been particularly directed towards 1 P-methyl substituted compounds which show a decreased susceptibility to degradation by the renal dehydropeptidase-I (DHP-I) enzyme compared to thienamycin.96 Examples include the use of tin or boron enolates producing 130 in yields of 70-80% with a ratio of p: a isomers ranging from 24 : 1 to 60: 1.97-99 Other formal syntheses of thienamycin, using P-lactams derived from carbohdyrates,lo0-lo2 arnino-acid~'~~, Io4 and isoxazolidines,105 have been reported.Alternative methods for bicyclic ring construction include the Dieckmann type cyclization, using the S-pyridylthioester 13 1 (60-65O/0)~~~ which gives the keto-ester directly, and an intramolecular Michael cyclization with 132 to form the saturated ring-system 133 (57%); the latter being elaborated to the bicyclic keto-ester via a nitrolefin and ozon~lysis.~~~~ Novel approaches making use of organo-iron or cobalt complexes have been described. Bu'Me2Si0 Me NO2 I C02PNB 133 131 R' = Me, # =cos 132 R' = PNB, R2 = CH=CHNOz Oxidation of the n-allyl-tricarbonyliron lactarn complex 134, derived from (S)-( - )-a-methylbenzylamine and the n-allyl-tricarbonyliron lactone, gave a 85% yield of the P-lactam 135 which could be converted into a known thienamycin intermediate.lo8 Most recently, Pattenden has shown that heating the carbamoylcobalt salophen 136 in toluene affords a stereoselective cyclization with dehydrocobaltation to the racemic P-lactam 137; this has also been converted into a known thienamycin precursor.lDy 0 tie 134 135 Southgate: The synthesis of natural P-lactam antibiotics 425PNBCO,? ... Ph 136 [Co] = Co(sa1ophen) 137 5.2 Olivanic acids The discovery that thiol esters could participate in the intramolecular Wittig cyclization to form the carbapenem ring-system provided a basis for the total synthesis of the olivanic acid derivative MM 22383 146."0, Tetrahydrooxazine 138 was converted into the diazo-intermediate 139 by reaction with diketen and then tosyl azide.Rhodium acetate catalysed cyclization provided the more thermodynamically favoured trans-substituted P-lactam 140. Borohydride reduction gave a 1 : 1 mixture of hydroxy epimers. n 140 ::: :::ek Protection of the hydroxy group and removal of the nitrogen-oxygen blocking group gave the P-lactam 14 1 in which the primary hydroxyl was oxidized and converted into the Wittig product 142. This was progressed to the phosphorane 143, and, after oxidation to the acid, to the thio-ester 144 possessing the required ( E)-acetamidoethenylthio side-chain. Heating in boiling toluene gave the two epimers of the cyclic product 145 (23%) which were separated and deprotected to afford ( +_ )-MM 22383 146 and ( k )-N-acetyldehydrothienamycin 147."' Later, the use of a 1,3-tetrahydroxazine derived from an optically active cyclohexanone or aminopropanol provided the opportunity for the chiral synthesis of other analogues.113s114 PNBC020 PNBC020 Me Hw?7 Me H w f i C 0 2 M e k N H OH 0 141 142 R = H 143 R = yPPh3 PNBC020 C02PNB I COZPNB 144 C02PNB 145 H H Me 146 R = ,,:A (S) OH 147 R = ( R ) One other reported synthesis in the olivanic acid series was of the benzyl ester of racemic MM 22381 148 by way of thiol addition of the appropriate C-( 2)-side-chain to the unsubstituted nucleus 149.110."s This gave, in high yield, the saturated carbapenam isomers 150, which by a process of oxidation (PhIC1,) and double bond isomerization, could be converted into 148.C02CH2Ph C02CH2Ph 148 149 S/\/NHA~ COzCH2Ph 150 5.3 PS-5 PS-5 lO2"and other members of this group (PS-6, PS-7, and PS-8)41 differ from thienamycin and the olivanic acids in having an unsubstituted ethyl or isopropyl group at C-6 in combination with the acetamidoethylthio or acetamidoethenylthio- substituent at C-2.Synthesis has been primarily directed towards PS-5. One of the earliest successes made use of the thiol addition procedure described for MM 2238 1 .I 16, I ' Allylazetidinone 11 1 was alkylated a-to the p-lactam carbonyl and the trans-P-lactam 15 1 converted into the phosphorane 152 and then cyclized to 153. Addition of acetamidoethanethiol gave a 70% yield of isomers of 154, which on reintroduction of the double bond and deprotection, afforded ( f )-PS-5. Most other methods have concentrated on using the C-2 to N-4 carbene insertion procedure after the synthesis of an appropriately substituted monocyclic p-lactam.One early synthesis which illustrates this was by Kametani' Ix using the 4-acetoxy substituted P-lactam 155 derived from the vinyl acetate 156 and 426 Contemporary Organic Synthesis" 0 w 151 R = H 152 R = ypPb COPNB CO2PNB 153 C02PNB 154 Et w : O 2 R 0 Et -0Ac U 155 156 157 CSI. Enolate displacement of the acetate to 157 was followed by cyclization and conversion into ( k )-PS-5. A variety of ester-imine condensations have also been used to provide 155 in racemic or chiral form. Thus, a Reformatsky-type reaction with a bromo-ester and imine gave racemic 158,''y while a lithium enolate-imine condenstion using a chiral ester gave a 92% e.e. of 159;120 both were converted by oxidative procedures into 155. Similarly, using the lithium enolate of t-butyl butanoate and the silylimine 160 from S-lactic aldehyde provided trans-P-lactam 16 1 (96 : 4 trans:cis) which after deprotection, conversion into the ketone and Baeyer-Villiger oxidation again gave the acetoxy azetidinone 155.12' Alternatively, ester enolate additions to imines can give P-amino-acids such as 162 or 163 suitable for elaboration to either racemic or chiral PS-5.'22-1 24 Boron or tin( 11) enolate-imine condensations also provide suitable P-lactam precursors.l 2s.2h E t g OSiMe2Bu' 0 Me OMe 158 R = Me 160 159 R=H 161 E t w O S i P h 2 B u ' H H Et+C02E1 ROpC NHBoc H0pC NH2 163 162 An elegant and novel approach which uses a 3-substituted anisole as a masked P-keto ester synthon has been used by Evans127 in an enantioselective synthesis.Reaction of the chiral boron enolate 164 with the aldehyde 165 established the correct stereochemistry in 166 required for the P-lactam ring 168. This was achieved after conversion into the hydroxamate 167 and cyclization using the Miller 164 165 b40 167 R = MeONH methodology. In the next step, a dissolving metal reduction effected both N-0 bond cleavage and aromatic ring reduction. The dihydroanisole derivative 169 was subjected to ozonolysis to give, after reductive work-up, the P-keto-ester 170. This was converted by the standard procedure into 17 1, and the synthesis completed by introduction of the N-acetyl-cysteamine side-chain and deprotection to the acid. The route provides enantiomerically pure ( + )-PS-5 in 13% overall yield from 3 -me thox ymet h y Ip hen ylacet aldehyde.0 'OMe Etm 0 OCH20Me bCH20Me 1 68 169 &H20Me C02CH20Me 170 171 One of the most recent routes makes use of a stereoselective addition of thiophenol to the double bond of the chiral imide 172.12x The desired 2S, 3s adduct 173 was then converted into the hydroxamate 174. Formation of the p-lactam 175 was accomplished in this case through S-alkylation and base-catalysed cyclization (83%). Further elaboration provided 176 in 1 72 175 R' = OMe, R2 = CH2Ph 176 R' = R2 = SiMepBu' fl' K 173 R = O N, 0 174 R = MeONH Southgate: The synthesis of natural /3- Iactam antibiotics 42742% overall yield from the acid precursor of 172. A An alternative synthesis which introduces chiralilty photochemical synthesis of the cis-B-lactam 177 from the pyrazolidin-3-one 178 has also been described.129 Since this can be epimerized to the trans-isomer it also affords another route to PS-5.An extensive review of synthetic procedures directed towards PS-5 and PS-6 has been pub1i~hed.l~~ SiMe3 177 178 5.4 Carpetimycins Several syntheses of the naturally occurring sulfoxide carpetimycin A 103 have been reported. In contrast to the synthesis of thienamycin, a major problem in this series is the establishment of the cis stereochemistry of the p-lactam ring. In one approach131 mono-sulfenylation of the tetrahydrooxazine 1 13 to 179 was followed by an aldol reaction with acetone giving a mixture of cis- and trans-products 180. Reductive desulfurization using tri-n-butyltin hydride in the presence of a radical initiator gave predominantly the cis-azetidinone 18 1 (7 1% cis:22% trans).The same ratio of isomers was obtained irrespective of the stereochemistry of 180, indicating that the same radical intermediate is formed and that hydrogen transfer from the bulky hydride reagent takes place from the less-hindered a-face. A sequence of protection and oxidation reactions to the acid 182 was followed by conversion into 183. Cyclization to the bicyclic keto-ester, introduction of the C-2-side-chain, oxidation to the sulfoxide, and deprotection then gave ( f )-carpetimycin A 103. Two other approaches to the cis-substituted intermediate 18 1 also utilize radical reduction methods. One uses the isonitrile 1 84'32 obtained from a penicillin-derived /?-lactam, the second uses the bromohydrin 185 which originates from a /?-lactam obtained by reaction of an allenyl sulfide with CSI.133 phsQo :ko 0 179 181 180 R=SPh 184 R=NC 185 R=Br 182 R = COpH 183 R = COCHpCOpPNB into the sequence makes use of the enzymic hydrolysis of the prochiral ester 186 to the acid 187 (98% e.e.).Borohydride reduction resulted in formation of the lactone 188. Stereocontrolled incorporation of the hydroxyisopropyl substituent giving 189 was followed by ring-opening and conversion into the amino-acid 190. This could be cyclized using the Grignard reagent to the p-lactam and then by known procedures to ( - )-carpetimycin A.134 M e O 2 C V 2 M e H 0 2 C T p M e NHCOzCH2Ph NHCOpCHpPh 186 1 87 188 R = H 190 189 R = Me2C(OH) A neat example of a directed aldol condensation has also been used starting from the optically pure methoxyethoxymethoxy (MEM) protected azetidinone 191.135 These authors reasoned that on formation of the P-lactam enolate, metal-ion chelation with the neighbouring MEM group on the /?-face of the molecule would allow for predominant formation of the cis-p-lactam.Thus, condensation with acetone using the titanium enolate and bulky silyl group on nitrogen gave 59% of the cis- product 192 and only 22% of trans-isomer. 0 4-Y SiPh2But 191 R = H 192 R = Me2C(OH) 5.5 Asparenomycins The asparenomycin natural products have an alkylidene substituent at the C-6 position. Synthesis has followed the familiar carbapenem approach by way of a bicyclic keto-ester (e.g. 195) derived from an appropriately functionalized monocyclic azetidinone.The first synthesis of ( - )-asparenomycin C utilized 193. This underwent an aldol condensation with methylthiomethoxyacetone followed by elimination to the desired (E)-double bond isomer 194 ( 9 8 O / 0 ) . ~ ~ ~ This was readily progressed to 195. Introduction of the (E)-acetamidoethenylthio side-chain and deprotection led to ( - )-asparenomycin C (104). Using the allylazetidinone 196 the aldol product from hydroxyacetone, as a mixture of isomers, was readily converted into the carbonate 197, and ultimately the bicyclic analogues 198.13', 13x Treatment with DBU gave a single (E)-isomer and removal of the p-methoxybenzyl group with aluminium trichloride-anisole gave the various racemic asparenomycin natural products.A slightly different 428 Contemporary Organic SynthesisH 193 R = CH20SiMe2But 196 R=CH=CH;! /OCOZPNB 195 OCHfiMe W.L. Parker, P.A. Principe, M.L. Rathnum, W.A. Slusarchyk, W.H. Trejo, and J.S. Wells, Nature, 198 1, OSiMe2Bu' 291,489. 9 S. Tsubotani, T. Hida, F. Kasahara, Y. Wada, and S. Harada, J. Antibiot., 1984,37, 1546. 194 Harada, J. Antibiot., 1985,38,1128. b4*+ OZO+ Me 1101. N'siMe2But 10 T. Hida, S. Tsubotani, N. Katayama, H. Okazaki, and S. 11 T. Kamiya, 'Recent Advances in the Chemistry of j3-Lactam Antibiotics' ed. J. Elks, Special Publication No. 28, The Royal Society of Chemistry, 1977, pp. 281-294. 12 M. Foglio, G. Franceshi, P. Lombardi, C. Scarafile, and F. Arcamone, J. Chem. SOC., Chem. Commun., 1978, 13 T. Kamiya, M.Hashimoto, 0. Nakaguchi, and T. Oku, 14 G.A. Koppel, L. McShane, F. Jose, and R.D.G. Cooper, 15 M.J.Miller,Acc. Chem. Res., 1986,19,49-56. 16 M.J. Miller, P.G. Mattingley, M.A. Morrison, and J.F. Tetrahedron, 1979,35,323. J. Am. Chem. SOC., 1978,100,3933. 197 Kervin, J. Am. Chem. SOC., 1980,102,7026. 1 99 200 R = Br 201 R=OC02PNB approach uses the acetoxy azetidinone 199 derived from l-acetoxy-3-methylbuta- 1,2-diene and CSI.' 35, This was converted by way of the allylic bromide 200 into the azetidinone 20 1, and then progressed by the diazo-route to ( k )-asparenomycin C. 6 References 'Cephalosporins and Penicillins' ed. E.H. Flynn, Academic Press., London and New York, 1972. R. Nagarajan, L.D. Boeck, M. Gorman, R.L. Hamill, C.E. Higgens, M.M. Hoehn, W.M. Stark, and J.G.Whitney, J.Am. Chem. SOC., 1971,93,2308. H. Aoki, H. Sakai, M. Kohsaka, T. Konami, J. Hosoda, Y. Kubochi, E. Iguchi, and H. Imanaka, J. Antibiot., 1976,29,890. T.T. Howarth, A.G. Brown, T.J. King, J. Chem. SOC., Chem. Commun., 1976,267. G. Albers-Schonberg, B.H. Arison, T.O. Hensens, K. Hirshfield, E. Hoogsteen, A. Kaczka, R.E. Rhodes, J.S. Kahan, R.W. Ratcliffe, E. Walton, L.J. Ruswinkle, R.B. Morin, and B.G. Christensen, J. Am. Chem. SOC., 1978, 100,6491. A.G. Brown, D.F. Corbett, A.J. Eglington, and T.T. Howarth, J. Chem. SOC., Chem. Commun., 1977,523; 1979,953. A. Imada, K. Kitano, K. Kintaka, M. Muroi, and M. Asai, Nature, 1981,289,590. R.B. Sykes, C.M. Cimarusti, D.P. Bonner, K. Bush, D.M. Floyd, N.H. Georgopapadakou, W.H. Koster, W.C. Liu, 17 P.G.Mattingley and M.J. Miller, J. Org. Chem., 1980, 45,410. 18 P.G. Mattingley and M.J. Miller, J. Org. Chem., 1981, 46,1557. 19 G.M. Salituro and C.A. Townsend, J. Am. Chem. SOC., 1990,112,760. 20 S. Hanessian, C. Coutrive, and H. Wyss, Can. J. Chem., 1985,63,3613. 2 1 C.M.Cimarusti, H.E. Applegate, H.W. Chang, D.M. Floyd, W.H. Koster, W.A. Slusarchyk, and M.G. Young, J. Org. Chem., 1982,47,179. 22 D.M. Floyd, A.W. Fritz, and C.M. Cimarusti, J. Org. Chem., 1982,47,176. 23 C.M. Cimarusti, D.P. Bonner, H. Breuer, H.W. Chang, A.W. Fritz, D.M. Floyd,T.P. Kissick, W.H. Koster, D. Knonenthal, F. Massa, R.H. Mueller, J. Pluscec, W.A. Slusarchyk, R.B. Sykes, M. Taylor, and E.R. Weaver, Tetrahedron, 1983,39,2577. 24 C.L. Branch, S.C. Finch, and M.J. Pearson, Tetrahedron Lett., 1989,30,3219.25 R.C. Thomas, 'Recent Progress in the Chemical Synthesis of Antibiotics', ed. G. Lukacs and M. Ohno, Springer-Verlag, 1990, pp. 534-564. 26 J.C. Sheehan and K.R. Henery-Logan, J. Am. Chem. SOC., 1957,79,1262; 1959,81,3089. 27 J.C. Sheehan and K.R. Henery-Logan, J. Am. Chem. SOC., 1959,81,5836; 1962,84,2983. 28 A.J. Bose, G. Spiegelman, and M.S. Manhas, J. Am. Chem. SOC., 1968,90,4506. 29 R.A. Firestone, N.S. Maciejewicz, R.W. Ratcliffe, and B.G. Christensen, J. Org. Chem., 1974,39,437. 30 J.E. Baldwin, M.A. Christie, S.B. Maker, and L.I. Kruse, J. Am. Chem., 1976,98,3045. 31 J.E. Dolfini, J. Schwartz, and F. Weisenborn, J. Org. Chem., 1969,34,1582. 32 R. Heymes, G. Amiard, and G. Nomine, Bull. Soc. Chim. Fr., 1974,563. 33 S.L. Neidleman, S.C.Pan, L.A. Last, and J.E. Dolfini, J. Med. Chem., 1970,13,386. 34 J.A. Edwards, A. Guzman, R. Johnson, P.J. Beeby, and J.H. Fried, Tetrahedron Lett., 1974,203 1. 35 R.W. Ratcliffe and B.G. Christensen, Tetrahedron Lett., 1973,4649. 36 R.B. Woodward, Science, 1966,153,487. 37 R.B. Woodward, K. Heusler, J. Gostelli, P. Naegeli, W. Oppolzer, R. Ramage, S. Ranganathan, and H. Vorbriiggen, J. Am. Chem. Soc., 1966,88,852. 38 R. Scartazzini, H. Peter, H. Bicknell, K. Heusler, and R.B. Woodward, Helv. Chim. Acta, 1972,55,408. Southgate: The synthesis of natural p-lactam antibiotics 42939 I. Ernest, ‘The Penems’ in ‘Chemistry and Biology of 8-Lactam Antibiotics’, ed. R.B. Morin and M. Gorman, Academic Press, NY, 1982. 40 R. Nagarajan, L.D. Boeck, M. Gorman, R.L.Hamill, C.E. Higgens, M.M. Hoehn, W.M. Stark, and J.G. Whitney, J. Am. Chem. SOC., 1971,93,2308. 41 R. Southgate and S. Elson, ‘Progress in the Chemistry of Organic Natural Products’, Springer-Verlag, 1985,47, 1-89. 42 L.D. Cama, W.J. Leanza,T.R. Beattie,and B.G. Christensen, J. Am. Chem. SOC., 1972,94,1408. 43 G.A. Koppel and R.E. Koehler, J. Am. Chem. SOC., 1973,95,2403. 44 E.W. Gordon, H.W. Chang, C.M. Cimarusti, B. Toeplitz, and J.Z. Gougoutas, J. Am. Chem. SOC., 1980,102, 1690. Koster, M.S. Puar, M. Young, and J.E. Dolfini, J. Org. Chem., 1973,38,943. Slusarchyk, and B. Toeplitz, J. Org. Chem., 1974,39, 2794. Funke, W.H. Koster, M.S. Puar, W.A. Slusarchyk, and M.G.Young, J. Org. Chem., 1979,44,811. 48 T. Jen, T. Frazee, and J.R.E. Hoover, J. Org. Chem., 1973,38,2857.49 Y. Sugimura, K. Iino, Y. Iwano, T. Saito, and T. Hiraoka, Tetrahedron Lett., 1976, 1 3 10. 50 W. Yanagisawa, M. Fukushima, A. Ando, and H. Nakao, Tetrahedron Lett., 1975,2705. 51 S. Nakatsuka, H. Tanino, and Y. Kishi, J. Am. Chem. SOC., 1975,97,5008. 52 R.D.G.Cooper, J. Am. Chem. Soc., 1972,94,1018. 53 G. Burton, M.J. Basker, P.H. Bentley, D.J. Best, R.A. Dixon, F.P. Harrington, R.F. Kenyon, A.G. Lashford, and A.W. Taylor, J. Antibiot., 1985,38,721. 54 G. Burton, D.J. Best, R.A. Dixon, R.F. Kenyon, and A.G. Lashford, J. Antibiot., 1986,39, 1419. 55 H. Otsuka, W. Nagata, M. Toshioka, M. Narisada, T. Yashida, Y. Harada, and H. Yamada, Medicinal Research Reviews, 198 1, 1 , 2 17, John Wiley & Sons Inc. 56 P.D. Singh, M.G. Young, J.H. Johnson, C.M. Cimarusti, and R.B.Sykes, J. Antibiot., 1984,37, 773. 57 J. Shoji, T.Kato, R. Sakazaki, W. Nagata, Y. Terui, Y. Nakagawa, M. Shiro, K. Matsumoto, T. Hattori, T. Yoshida, and E. Kondo, J. Antibiot., 1984,37, 1486. 58 P.H. Milner, A.W. Guest, F.P. Harrington, R.J. Ponsford, T.C. Smale, and A.V. Stachulski, J. Chem. SOC., Chem. Comrnun., 1984,1335. 59 R.J. Ponsford, M.J. Basker, G. Burton, A.W. Guest, F.P. Harrington, P.H. Milner, M.J. Pearson, T.C. Smale, A.V. Stachulski, in ‘Recent Advances in the Chemistry of p- Lactam Antibiotics’, ed. A.G. Brown and S.M. Roberts, Special Publication No. 52, The Royal Society of Chemistry, 1985, p.p. 32-57. 60 A.W. Guest, C.L. Branch, S.C. Finch, A.C.Kaura, P.H. Milner, M.J. Pearson, R.J. Ponsford, and T.C. Smale, J. Chem. SOC., Perkin Trans.1, 1987,45. 6 1 C.L. Branch, M.J. Pearson, and T.C. Smale, J . Chem. SOC., Perkin Trans. I , 1988, 2865. 62 A.C. Kaura and M.J. Pearson, Tetrahedron Lett., 1985, 26, 2597. 63 R. Southgate, C. Branch, S. Coulton, and E. Hunt, in ‘Recent Progress in the Chemical Synthesis of Antibiotics’, ed. G. Lukacs and M. Ohno, Springer- Verlag, 1993, p.p. 622-675. 64 P.D. Berry, A.C. Brown, J.C. Hanson, A.C. Kaura, P.H. Milner, C.J. Moores, J.K. Quick, R.N. Saunders, R. 45 W.A. Slusarchyk, M.E. Applegate, P. Funke, W.H. 46 H.E. Applegate, J.E. Dolfini, M.S. Puar, W.A. 47 H.E. Applegate, C.M. Cimarusti, J.E. Dolfini, P.T. Southgate, and N. Whittall, Tetrahedron Lett., 199 1,32, 2683. 65 A.G. Brown, D. Buttenvorth, M. Cole, G. Hanscomb, J.D. Hood, C. Reading, and G.N.Rolinson, J. Antibiot., 1976,29,668. 66 P.A. Hunter, K. Coleman, J. Fisher, and D. Taylor, J. Antimicrob., Agents Chemother., 1980,6,455. 67 P.H. Bentley, P.D. Berry, G. Brooks, M.L. Gilpin, E. Hunt, and I. Zomaya, J. Chem. SOC., Chem. Commun., 1977,748. Tetrahedron Lett., 1979, 1889. Howarth, J. Antibiot., 1979,32,96 1. Okamura, Y. Shimauchi, and T. Ishikura, J. Antibiot., 1980,32,796. 7 1 Y. Nakayama, S. Kimura, S. Tanabe, T. Mizoguchi, I. Watanabe, T. Mori, K. Mori, K. Miyahara, and T. Kawasaki, J. Antibiot., 198 1,34,8 18. 72 N. Tsuji, K. Nagashima, M. Kobayashi, J. Shoji, T. Kato, Y. Terui, H. Nakai, and M. Shiro, J. Antibiot., 1982,35, 24. 73 N. Tsuji, K. Nagashima, M. Kobayashi, Y. Terui, K. Matsumoto, and E. Kondo, J. Antibiot., 1982,35, 1255. 74 W.L.Parker, M.L. Rathnum, J.S. Wells, W.H. Trejo, P.A. Principe, and R.B. Sykes, J. Antibiot., 1982,35,653. 75 L.D. Camaand B.G. Christensen, J. Am. Chem. SOC., 1978,100,8006. 76 A.J.G. Baxter, K.H. Dickinson, P.M. Roberts,T.C. Smale, and R. Southgate, J. Chem. Soc., Chem. Commun., 1979,236. and R. Southgate, J. Chem. SOC., Perkin Trans. 1, 198 1, 3242. 78 H.R. Pfaendler, J. Gosteli, R.B. Woodward, and G. Rihs, J. Am. Chem. Soc., 198 1,103,4526. 79 R.W. Ratcliffe and G. Albers-Schioberg, in ‘Chemistry and Biology of P-Lactam Antibiotics’, ed. R.B. Morin and M. Gorman, Vol. 2, Academic Press, 1982, 68 P.H. Bentley, G. Brooks, M.L. Gilpin, and E. Hunt, 69 A.G. Brown, D.F. Corbett, A.J.E. Eglington, and T.T. 70 K. Yamamoto, T. Yoshioda, Y. Kato, N. Shibamoto, K. 77 J.H.Bateson, A.J.G. Baxter, P.M. Roberts, T.C. Smale, P.P. 227-3 13. 80 T. Nagahara and T. Kametani, Heterocycles, 1987, 25, 729. 81 D.B.R. Johnston, S.M. Schmitt, F.A. Bouffard, and B.G. Christensen, J.Am. Chem. SOC., 1978,100,313. 82 S.M. Schmitt, D.B.R. Johnston, and B.G. Christensen, J. Org. Chem., 1980,45, 1142. 83 T.N. Salzmann, R.W. Ratcliffe, B.G. Christensen, and F.A. Bouffard, J. Am. Chem. SOC., 1980,102, 6161. 84 D.G. Melillo, I. Shinkai, T. Liu, K. Ryan, and M. Sletzinger, Tetrahedron Lett., 1980,21,2783. 85 D.G. Melillo, R.J. Cuetovich, K.M. Ryan, and M. Sletzinger, J. Org. Chem., 1986,51, 1498. 86 T. Kametani, T. Honda, H. Ishizone, K. Kanada, N. Naito, and Y. Suzuki, J. Chem. SOC., Chem. Comrniin., 1989,646. 87 S. Karady, J.S.Amato, R.A. Reamer, and L.M.Weinstock, J. Am. Chem. SOC., 198 1, 103,6765. 88 P.J. Reider and E.J.J. Grabowski, Tetrahedron Lett., 1982,23,2293. 89 Y. Ueda, G. Roberge, and V. Vinet, Can. J. Chem., 1984,68,2936. 90 G.I. Georg, J. Kant, and H.S. Gill, J . Am. Chem. SOC., 1987,109, I 129. 91 G.I. Georg, ‘Studies in Natural Product Chemistry’, ed. Atta-ur-Rahman, Elsevier, 1989, p.p. 43 1-487. 92 Y. Ito, Y. Kobayashi, T. Kawabata, M. Takase, and S. Terashima, Tetrahedron, 1989,45,5767. 430 Contemporary Organic Synthesis93 Nippon Soda Co. Ltd, 2-2- 1 Ohtemachi, Chiyoda-Ku, Tokyo 100, Japan. 94 A. Afonso, S. Chackalamannil, N. Fett, A.K. Ganguly, and M. Kirkup, ‘Recent Advances in the Chemistry of P-Lactam Antibiotics’, ed. P.H. Bentley and R. Southgate, Special Publication No. 70, The Royal Society of Chemistry, 1989, pp.295-303. 95 D.M. Tschaen, L.M. Fuentes, J.E. Lynch, W.L. Laswell, R.P. Volante, and I. Shinkai, Tetrahedron Lett., 1988, 29,2779. Heterocycles, 1984,2 1,29. 5687. 96 D.H. Shih, F. Baker, L.D. Cama, and B.G. Christensen, 97 R. Deziel and D. Faureau, Tetrahedron Lett., 1986,47, 98 F. Shirai and T. Nakai, J. Org. Chem., 1987,52, 5491. 99 T. Shibata and Y. Sugimura, J. Antibiot., 1989,42,374. 100 M. Miyashita, M.N. Chida, and A. Yoshikoshi, J. Chem. SOC., Chem. Commun., 1982,1354. 10 1 N. Ikota, 0. Yashimo, and K. Koga, Chem. Pharm. Bull., 1982,30, 1929; 1991,39,2201. 102 A. Knierzinger and A. Vasella, J. Chem. SOC., Chem. Commun., 1985,9. 103 H. Maruyama, M. Shiozaki, and T. Hiraoka, Bull. Chem. SOC. Jpn., 1985,58,3264. 104 M.Shiozaki, N. Ishida, H. Maruyama, and T. Hiraoka, Tetrahedron, 1983,39,2399. 105 T. Kameta, T. Nagahara, and T. Honda, J. Org. Chem., 1985,50,2327. 106 A.I. Meyers, T.J. Sowin, S. Scholz, and Y. Ueda, Tetrahedron Lett., 1987,28,5103. 107 S. Hanessian, D. Desilets, and Y.L. Bennani, J. Org. Chem., 1990,55,3098. 108 S.T. Hodgson, D.M. Hollinshead, and S.V. Ley, Tetrahedron, 1985,41,587 1. 109 G. Pattenden and S.J. Reynolds, J. Chem. SOC., Perkin Trans. I , 1994,379. 110 J.H. Bateson, A.J.G. Baxter, K.H. Dickinson, R.I. Hickling, R.J. Ponsford, P.M. Roberts, T.C. Smale, and R. Southgate, ‘Recent Advances in the Chemistry of B-Lactam Antibiotics’, ed. G.I. Gregory, Special Publication, No. 38, The Royal Society of Chemistry 1 1 1 R.J. Ponsford and R. Southgate, J. Chem. Soc., Chem. Commun., 1980,1085. 11 2 J.S. Kahan, U.S. Patent 4 162 323, 1979. 1 1 3 T.C. Smale, Tetrahedron Lett.. 1984,25, 29 1 3. 114 P. Brown and R. Southgate, Tetrahedron Lett., 1986, 27,247. 1 15 J.H. Bateson, P.M. Roberts, T.C. Smale, and R. Southgate, J. Chem. SOC., Perkin Trans. I , 1990,1541. 1981,pp. 291-313. 116 J.H. Bateson, R.I. Hickling, P.M. Roberts, T.C. Smale, and R. Southgate, J. Chem. SOC. Chem. Commun., 1980,1084. 117 J.H. Bateson, R.I. Hickling, T.C. Smale, and R. Southgate, J. Chem. SOC., Perkin Trans. I , 1990, 1793. 11 8 T. Kametani, T. Honda, A. Nakayama, and K. Fukumoto, Heterocycles, 1980,14,1967. 119 J.M. Odriozola, F.P. Cossio, and C. Paloma, J. Chem. SOC., Chem. Commun., 1988,809. 120 D.J. Hart and Chin-Shone Lee, J. Am. Chem. SOC., 1986,106,6054. 121 G. Cainelli and M. Panunzio, J. Am. Chem. Soc., 1988, 110,6879. 122 T. Shono, N. Kise, F. Sanda, S. Ohi, and K. Yoshioka, Tetrahedron Lett., 1989,30, 1253. 123 C. Gennari, G. Schimperna, and I. Venturini, Tetrahedron, 1988,44,4221. 124 K. Hattori, M. Miyata, and H. Yamamoto, J. Am. Chem. SOC., 1993,115,1151. 125 M. Shibasaki, Y. Ishida, G. Iwasaki, and T. Imori, J. Org. Chem., 1987,52,3488. 126 T. Yamada, H. Suzuki, and T. Mukaiyama, Chem. Lett., 1987,293. 127 D.A. Evans and E.B. Sjogren, Tetrahedron Lett., 1986, 27,3119. 128 0. Miyata, Y. Fujiwara, I. Ninomiya, and T. Naito, J. Chem. SOC., Perkin Trans. I , 1993,2861. 129 J.D. White and S.G. Toste, Tetrahedron Lett., 1993,34, 207. 130 C. Palomo in reference 25 pp. 565-6 12. 13 1 H. Natsugari, Y. Matsushita, N. Tamura, K. Yoshioka, and M. Ochiai, J. Chem. Soc., Perkin Trans. I , 1983, 403. 132 M. Aratani, H. Hirai, K. Sawada, A. Yamada, and M. Hashimoto, Tetrahedron Lett., 1985,26,223. 133 J.D. Buynak and M.N. Rao, J. Org. Chem., 1986,51, 1571. 134 T. Iimori, Y. Takahashi, T. Izawa, S. Kabayashi, and M. Ohno, J. Am. Chem. SOC., 1983,105,1659. 135 M. Shibasaki, Y. Ishida, and N. Okabe, Tetrahedron Lett., 1985,26,2217. 136 K. Okano, Y. Kyotani H., Ishihama, S. Kobayashi, and M.Ohno, J.Am. Chem. SOC., 1983,105,7186. 137 H. Ona and S. Uyeo, Tetrahedron Lett., 1984,25, 2237. 138 H. Ona, S. Uyeo, K. Motakawa, and T. Yoshida, Chem. Pharm. Bull., 1985,33,4346. 139 J.D. Buynak, M.N. Rao, H. Pajouhesh, R.Y. Chandrasekaran, K. Finn, P. de Meester, and S.C. Chu, J. Org. Chem., 1985,50,4245. Southgate: The synthesis of natural B-lactam antibiotics 4 3 1

ISSN:1350-4894    

DOI:10.1039/CO9940100417

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Saturated and partially unsaturated carbocycles CHRISTOPHER D. J. BODEN and GERALD PATTENDEN Department of Chemistry, The University, Nottingham NG7 2RD, UK Reviewing the literature published between August 1992 and January 1994 1 1.1 1.2 1.3 2 2.1 2.2 2.3 3 3.1 3.2 3.3 3.4 4 4.1 4.2 4.3 4.4 4.5 5 6 7 8 9 T hree-membered rings Simmons-Smith cyclopropanations Diazoester cyclopropanations Other routes to three-membered carbocycles Four-membered rings Transition metal based methods Photochemical and free radical methods Other routes to four-membered carbocycles Five-membered rings Free radical cyclizations Transition metal mediated cyclizations Other routes to five-membered carbocycles Pol yquinanes Six-membered rings Diels-Alder reactions Transition metal mediated cyclizations Free radical cyclizations Other routes to six-membered rings Fused six-membered rings Seven-membered rings Eight-membered rings Ten-membered and larger rings General carbocyclic ring synthesis References 1 Three-membered rings 1.1 Simmons-Smith cyclopropanations The Simmons-Smith reaction remains one of the most useful procedures for the synthesis of cyclopropane derivatives, and a wide range of chiral auxiliaries for asymmetric Simmons-Smith reactions have been described.In extensions of earlier work, Ukaji et al. have now shown that optically active silicon-substituted cyclopropylmethanols can be synthesized using the Simmons-Smith procedure utilizing diethyl tartrate as a chiral auxiliary, e.g. 1 -+ 2 in 92% e.e. Similarly, Charette et al. have developed a new and simple auxiliary derived from 1,2-trans cyclohexanediol for the Simmons-Smith cyclo- propanation of substituted alcohols, viz.3 -+ 4 ( > 20 : 1 d.s.); related work by the same research group using 2-hydroxy-~-~-glucopyranose as the chiral auxiliary has also been developed this year.3 1 2 02% (92% e.e.) wowpr Etgn, CH$ woT Pr OH CsH&de;-20"Cr 3h OH 3 4 By analogy with the Simmons-Smith reaction, Motherwell and Roberts have extended their earlier work on the deoxygenation of carbonyl compounds and shown that organozinc carbenoid species derived from zinc and chloroalkyl silanes can be trapped with alkenes leading to cyclopropanes in good to excellent yields." The reaction works particularly well using aryl and, in some cases, a,B-unsaturated carbonyl compounds as precursors of the organozinc carbenoid species (Scheme 1).IPh- 99% (cis : trans 25 : 1) Scheme 1 1.2 Diazoester cyclopropanations A very wide range of metal complexes are known to catalyse the cyclopropanations of alkenes by diazoesters. Rhodium( 111) porphyrin complexes are especially interesting in view of the scope that chiral porphyrins offer in asymmetric cyclopropanations. A transition state model has now been developed for these rhodium-catalysed reactions which provides some level of stereochemical predictive power.5 In a similar vein, the copper complex of the optically active bipyridine 56 and the chiral cobalt( 11) complex 6 from 1( R )-3-hydroxymethylenebornane-2-thione' have been used as chiral catalysts for the asymmetric cyclopropanations of styrenes and oct- 1-ene with ethyl diazoacetate.Boden and Pattenden: Saturated and partially unsaturated carbocycles 433n . .4 SiMe, Me38 O Y R MevMe 0 5 6 Scheme 3 Two novel cyclopropane ring-forming sequences have been employed in the synthesis of the natural products 13 and 14. Thus the cyclization step 11 -. 12 was used by White and Jensen14 in their biogenetically patterned synthesis of the cyclopropane-containing eicosanoid 13 produced by the coral Hexaura homomalla. Furthermore, the cyclopropane 17 has The homoallylic diazoacetates 9 have been shown to undergo enantioselective intramolecular cyclopropanation with the rhodium catalyst 7 leading to the bicyclic cyclopropane 10 in 7 1-90% e.e. and in 5 5-80°/0 chemical yield.8 Other related studies have been described, with ally1 diazomalonates, using the chiral phenylalaninol-derived copper catalyst 8.9 n U 7 coj2 Et - 9 8 10 80% (90% e.e.) been produced in one step from the mesylate 15, presumably via the intermediate 16, during Danishefsky 's synthesis of the unusual pentacyclic diterpene mycorin 14.lS 11 12 14 13 1.3 Other routes to three-membered carbocycles Meyers and his colleagues'" have described full details of their elegant studies on the synthesis of enantiomerically pure 172,3-trisubstituted cyclopropanes based on cycloaddition reactions of sulfur ylides to chiral unsaturated lactams (Scheme 2).Ho 'OH Reagents: (i) Ph,S=CHMe; (ii) Red-AI; (iii) BuCH=PPh3; (iv) H30+ 15 16 17 Scheme 2 In related work, Krief and Lecomte" have outlined further extensions of their studies of the stereoselective synthesis of cyclopropane derivatives from y-alkoxy- a, B-unsaturated carbonyl compounds derived from D-glyceraldehyde and sulfur ylides (Scheme 3).Developments of earlier strategies towards the synthesis of cyclopropanes, based on a 1,3-elimination protocol, have also been described.'*? l 3 A novel method for the synthesis of cyclopropanols has been described whereby solutions of a$-unsaturated aldehydes in DMF are simply treated with 2.2 mol of chromium chloride in the presence of 2 mol O/O nickel(n) chloride at room temperature, viz. 18 - 19.16 1,2-Cyclopropanediols are produced when acylsilanes are reacted with ketone enolates; the reaction proceeds via Brook rearrangement of the initial 1,2-adduct and subsequent aldol reaction (Scheme 4).17 434 Contemporary Organic Synthesiscrc12 R2 R'&o NiCIz, DMF * 16 \OH 19 OSiMe, HO ,OH Me,SiO 0- .. . , (ii) . , P h r n P i - PhmPi 0 Reagents: (i)+Pi, -80 O to -30 OC; (ii), MeOH Scheme 4 Substituted cyclopropanes of constitution 2 1 are produced via a novel rearrangement when the hydroxylated cyclobutane derivatives 20 are treated with F,B.OEt,-POCl, in the presence of pyridine or Raney nickel.' Another unusual atom-reorganization sequence has been used by Dowd et al. in their synthesis of the p, y-cyclopropyl ketones 23 by treatment of substituted cyclobutanones of constitution 22 with Bu,SnH-AIBN (Scheme 5).ly 20 21 22 23 Scheme 5 2 Four-membered rings 2.1 Transition metal based methods Transition metal based methods form the bulk of new work published in the area of cyclobutane ring synthesis during the period under review.Stille has reported the intramolecular addition of alkyl titanocene complexes to alkynes under Lewis acid catalysis, leading to four-membered rings 24 bearing an exocyclic trisubstituted alkene.20 Ph EtAICI2 c r8Tic12cp21 -78 "C AcOH I HZO ph& 24 A number of metal-catalysed [2 + 21 methods have also been reported, of which the most interesting is probably that of Narasaka in which sulfur-bearing alkenes, allenes, or alkynes may be reacted with electron-deficient alkenes in the presence of a chiral titanium catalyst to give the corresponding cyclobutanes 25, exo-methylene cyclobutanes 26, and cyclobutenes 27 with good to excellent enantioselectivity.2' The use of ketene thiocetals, followed by desulfurization of the resulting adduct, makes for a useful synthesis of cyclobutanones 28, as does the work of Wulff, which utilizes the reaction of 1,Genynes with Fischer carbene complexes to give cis-[3.2.0]bicycloheptanones 29 in good yields and with good diastereoselectivity for positions a- to the ring junction.*, Where a is *;to 0 0 25 (%%, >98% e.e.) SiMe, d N K o + =*< SMe Me02C \ u , a, TiCI2(0Pi)p PhMe, 0 "C 1 OOV0, >9Wo e.e.I 26 Boden and Pattenden: Saturated and partially unsaturated carbocycles 4350 0 'NAO R2 SMe 27 S M e 28 2.2 Photochemical and free radical methods Wagner et al. have reported an interesting synthesis of bicyclo[4.2.0]cyclo-octadienes, based on the intramolecular photoaddition of tethered alkenes to triplet benzenes 30,23 and Galatsis et al.have devised a modification of the de Mayo reaction which allows the synthesis of bicyclo[4.2.0]cyclooctenones.24 hv Two unusual examples of cyclobutane ring formation by radical methods have appeared. The first, described by Jung et al., constitutes a route to cyclobutanones 3 1 via the corresponding ketal; 4- exo-trig cyclization of the radical onto an alkenoate occurs in the presence of a di-alkoxy substituent but with the free ketone only the product of reduction is formed.25 The second example relies on electronic rather than steric effects, with the stabilizing effect of methythio- and sulfone-substituents on an intermediate radical promoting 4-ex0 cyclization, to 32, rather than to the 5-endo cyclization products.26 Bu&nH, AlBN PhH, rdlux \C02E1 \CO2Et 31 32 2.3 Other routes to four-membered carbocycles Barber0 et al. have reported a remarkable synthesis of both endo and ex0 cyclobutenes, based on the fast transmetalation of ally1 and vinyl stannanes with alkyl-lithiums at low temperature (Scheme 55% / TsO R Tsd R=HorPh 61 -72% Scheme 6 Tin-lithium exchange is so rapid that the reaction can be carried out with Bu"Li in the presence of ketone groups, viz.33 --* 34. Nagasawa and Suzuki have published an effective method for the synthesis of cyclopropyl cyclobutanes and cyclobutenes based on the high stability of cyclopropyl carbocations (Scheme 7).28 Finally, Fukumoto et al. have extended their work on tandem intramolecular Michael-aldol reactions to allow the synthesis of polycyclic cyclobutane derivatives 35 which are commonly found in nature.29 0 33 34 (65%) 3 Five-membered rings A very wide range of methods leading to isolated and to ring-fused substituted cyclopentanes, published 436 Contemporary Organic SynthesisL R = alkyl -76% 1 NuH R ?? 8048% Nu = OH, OMe Scheme 7 Me02C OTMS TMS-I, (TMS)ZNH Mm2cw 1 ,Pdbhbroethane, 25 O C ' 35 during the period under review, have been based on free radical or transition metal mediated cyclizations.Furthermore, many of these methods have been applied in the area of total synthesis amongst naturally occurring polyquinanes. 3.1 Free radical cyclizations The enormous scope for oxidative free-radical cyclizations of /3-keto esters, 1,3-diones, and 1,3-diesters containing proximate alkene residues, in the presence of Mn( OAc), and Cu( OAc), has been further delineated, e.g.36 -+ 37,30 and the effects of solvent and ligand on the efficacy of the process have been discussed.31 Mn(OAc), - 36 1 37 Consecutive treatment of appropriately substituted alkenyl malonates with sodium hydride and iodine in THF provides excellent yields of cyclopentanes, e.g. 38 -+ 39.32 The reaction also works well in three- and six-, but not four-membered ring formations. Further developments of cobalt( 1)-mediated radical cyclization~~~ leading to cyclopentanes have been described, and Schafer et al. 34 have described more details of their novel use of CrC1, [and Cr( OAC),] in the radical cyclizations of /3-halo esters. Thus, after performing the desired radical cyclization, the product radical can be trapped to produce an organochromium intermediate which can then react with electrophiles, e.g. aldehydes, leading to substituted adducts (Scheme 8).EtO2C Ezu N;: t Et02C-f1 38 30 Reagents: (i) CrC13, LiAIH4, 0 "C; (ii) PhCHO, N2 25 "C Scheme 8 The relatively unexplored area of the use of phosphorus-centred radicals in cyclization reactions involving 1,6-diene systems has now been investigated, viz. 40 -+ 41;35 so too has the use of arenesulfonyl hydrazones as radical acceptors in the synthesis of unsaturated five-membered carbocycles, 4 2 -+ 4 3.36 EtO2C PhPPH pph2% ,CO2Et AIBN, C&ls A 40 41 BuSnH I NHS02Ar 42 / 43 A beautiful illustration of the scope for 5-exo-dig radical cyclizations in meaningful target synthesis is contained in the synthesis of the intermediate 45 from 44, en route to the anti-tumour agent fredericamycin A 46.,' In addition, the scope for cyclizations of unsaturated ketyl radical anions in natural product synthesis has been neatly summarized by COSSY.~~ Tellurium derivatives, viz.47, have featured in approaches to substituted cyclopentanes from carbohydrates described by Barton et aZ.,39 and other approaches to carbocycles from carbohydrates have been published during the period under review.40 a range of substituted five-membered ring synthesis. Thus, enone radicals generated from the corresponding iodoenones have been found to undergo intramolecular cyclization to tethered trimethylsilyl acetylene side-chains, leading to highly unsaturated cyclic products, viz.48 -. 49.41 Allenes and acetylenes have featured prominently in Boden and Pattenden: Saturated and partially unsaturated carbocycles 437OMe MeO *;h SePh \\ i)SiPh,Bu' 44 Ph3SnH 1 E~,B 46 6COMe 47 7 . 76% q, (fast :r addition) - (q fMS 48 1 TMS 49 (85%) Intramolecular reductive coupling reactions involving carbonyl and allene units have been carried out using either samarium( 11) iodide4* or cathodic redu~tion:~ leading to cyclopentenes, e.g. 50 .+ 5 1 and 52 .+ 53. U 50 51 (82%) 52 53 (96%) In addition, Blechert et u Z . ~ ~ have shown that allenylic radicals, generated from propargylic precursors undergo cyclizations onto proximate alkene electrophores, providing a facile synthesis of vinylidene-substituted cyclopentanes, e.g.54 .+ 5 5 . 55 (44%) 54 A neat combination of epoxide ring fragmentation triggered from a ketyl radical, followed by a 1,5-hydrogen abstraction and cyclization provides the basis of a synthesis of ring-fused carbocycles from cyclic a$-epoxyketones described by R a ~ a l ~ ~ and by Kim46 and their respective collaborators (Scheme 9). 0 OSnBu3 OSnBu3 OH OH 57 Scheme 9 OH In extensions of their studies with radical induced epoxide-fragmentations, Rawal and his colleagues have also shown that atom-transfer cyclizations of iodo-epoxides lead to similar angular hydroxy substituted cyclopentanes, whereas Kim and colleagues have demonstrated that treatment of epoxy silyl enol ethers derived from 56 with Bu,SnH-AIBN also provides a useful synthesis of cis-fused bicycles of constitution 57.A 1,5-hdyrogen abstraction protocol, involving a vinyl radical intermediate and an ally1 rnethylene residue, has featured in an approach to 5-ring fused bicycles described by Parsons et al.49 (Scheme 1 0 ) , and Motherwell et al. 50 have summarized their novel approach to the construction of bicyclic systems, based on a tandem free radical cyclopropylcarbinyl rearrangement- cyclization strategy, highlighted in Scheme 1 1. y p """'\p NaCNBH3 __c @ OH OH OH 63% Scheme 10 438 Contemporary Organic SynthesisS Scheme 11 A number of other interesting radical-induced cyclizations, leading to five-membered carbocycles, have been published during the period under review. These include the double ring expansion of the allylidenecyclopropane 58 to 59 at 1 70"C,51 the intramolecular cyclization/ring expansion/radical trap sequence 60 --+ 6 1 --* 62 whereby the cyclopropanol60 is converted into 62 in the presence of manganese( 111) tris-2-pyridine carboxylate5* or ferric chloride,53 and the cyclization of the tosylhydrazone derived from 63 in the presence of NaBH,CN-ZnCl, leading to the bicyclic ester 64.54 A further interesting development in cyclopentane ring synthesis is shown by the divergent reaction pathways followed by o-bromo acylgermanes and acylsilanes in their radical induced cyclizations (Scheme 1 2).55 58 59 60 Mn3* DMF, 0 "C - w H 62 (i) TsNH,NH, (ii) NaBH,CN H ', 63 64 OSiPh2Me MR3 = GePhs MR, = SiPh,Me Bu3SnH/AIBN (X = I or Br) Scheme 12 3.2 Transition metal mediated cyclizations In recent years the Pauson-Khand reaction has emerged as one of the most powerful methods for the synthesis of cyclopentenones.The reaction has also undergone substantial development since its initial report in 1973, including the introduction of new promoters and new metal carbonyl precursors for the source of CO. Dimethyl sulfoxide can now be added to the list of promoters for the reaction,56 so too can W(CO),.THF,57 MO(CO),,~~ and MO,C~,(CO),~~ as precursors to the intermediate alkyne complexes and source of CO. The effects of coordinating ligands in the homo and bis-homopropargylic position of a 1,6-diene precursor have also been exarnined;,O so too has a solid phase variant of the Pauson-Khand reaction.6 Reports of successful Pauson-Khand reactions with electron-deficient alkynes have been p~blished,h~,~~ and the reaction has played a pivotal role in the recent synthesis of ( - )-a-kainic acid 6564 and of ( k )-loganin 6665 (Scheme 13).0 I I 65 76% o+$ OH C 0 2 k 66 Scheme 13 Applications of palladium-catalysed reactions leading to polycycle constructions are ubiquitous in contemporary organic synthesis. Thus, Trost and his colleagues have published more details of their atom-economical cyclo-isomerizations of enediynes,66 and of their zipper reactions67 leading to ring-fused cyclopentanes, under palladium catalysis. They have also demonstrated the compatibility and effect of Boden and Pattenden: Saturated and partially unsaturated carbocycles 439carbonyl, carboxylic acid, and ketal functionality in these catalysed enyne cyclizations.68.6y Overman has published a useful review of his early work on Heck-type polyene cyclizations of organopalladium intermediate^,^^ and has also described a neat total synthesis of ( k )-scopadulcic acid A 67 using an intramolecular double-Heck cyclization to form the B-D rings in this complex tetracyclic diterpene structure, with complete stereochemical control (Scheme 1 4).7 1, 72 Grigg et aZ. have also published full details of their contemporaneous synthetic studies on the intramolecular Heck reaction, featuring anion capture,73 which adds further credence to this powerful method for the construction of novel polycycles. 67 Scheme 14 10% Pd(0AC)Z PPh3, \ THF. rdlux 1 OR TBAF, THF A OH Buchwald et 75 have highlighted the use of a combination of Cp,TiCl, with two equivalents of EtMgBr as an effective cocktail for the reductive cyclization of enynes to bicyclic titanacyclopentanes; reactions of the latter with CO then lead to cyclopentenones in good yield (Scheme 15).The cyclocarbonylation of acyclic 1,3-dienes via their tricarbonyl iron complexes has also resurfaced as a route to cyclopentenones, viz. 68 -+ 69.76 TiCp, CO2Et CPlTiCh 2EtMgBr EtO2C E t O 2 C w 0 Scheme 15 440 Contemporary Organic Synthesis (0c)3Fx A 20 "C j& 0 68 69 (>95%) Further details on the scope and limitations of the synthesis of cyclopentenones involving reactions between c yclopropylcarbene-chromium complexes and alkynes have been disclosed,77 and highly diastereo- and enantio-selective cyclizations of substituted penten-4-als using a chiral rhodium( I) complex leading to cyclopentanones have been published (Scheme 16).78 Rh'C104 d BlNAP Scheme 16 A number of [ 3 + 21 type cycloaddition reactions bear witness to the use of this strategy in the synthesis of cyclopentenones (Scheme 1 7),7y-81 and the use of the molybdenum alkylide 70 in effecting the novel olefin metathesis/carbonyl olefination route to cyclopentenes is, to say the least, intriguing.82 Ni(CO), base, MeOH I R' i"" C02Me Scheme 17 Q L O ( C H 2 ) a P h 06%3.3 Other routes to five-membered carbocycles The scope for intramolecular additions of the carbon-to-lithium bond into unactivated & Zn/Et20t & - I2 & 20 "C, 20 min.carbon-to-carbon double bonds, leading to attention in recent years. 5-exo-dig Cyclizations are also possible, and these reactions can be effected in tandem with 5-exo-trig processes (Scheme 18).83 cyclopentylmethyl lithiums, has received considerable 73% Scheme 21 OBu OBu N Bu'Li U Scheme 18 I (I) +20 "C, 2h (ii) MeOH (iniii) 65% Reagents: (i) Et2Zn(2 eq.), PdCln(dppf)(P d%), 20 "C.5-20h: (ii) CuCN, 2LiCI; (iii) 85% Scheme 22 In a similar vein Krief et al. 84 have shown that o-alkenyl allyl-lithiums also undergo facile cyclizations with high regio- and stereo-control (Scheme 19), and usefully functionalized cyclopentanes are produced when stabilized organolithiums are added intramolecularly to alkoxyacetylenes (Scheme 20).8s A number of methods are available for the synthesis of cyclopentane derivatives via ring expansion processes of three- and four-membered ring systems.To add to this list are the rearrangement of cobalt complexed alkynyl cyclopropanols shown in (Scheme 23)90,91 and the ring expansions of alk- 1 -enyl-cyclobutan- 1-01s under Hg2 + catalysis illustrated in the conversion of 71 into 72.36 Ph Ph P r 2 s i t co CO), P r ~ ~ i ~ k c o 2 ~ c o ) 6 reflux 4 2( - Ph # , DME or THF ; BuYi MF. -1 10 "c. then warm c Scheme 19 # , Scheme 20 Recent advances in the accessibility of organozinc compounds have prompted Normant, and others, to examine the intramolecular cyclizations of a range of suitably functionalized alkenyl zinc derivatives, with some interesting and useful results emerging (Scheme 2 1 ).86, 87 Related studies by Knochel et al. 88, 89 have shown that intramolecular carbozincation reactions of alkenes can be dramatically accelerated by the addition of small amounts of Pd'I or Ni" complexes.These novel ring closures, which are probably radical in nature, lead to organometallic intermediates which can subsequently be trapped with a range of electrophiles (Scheme 22). Scheme 23 0 71 72 The novel use of an anionic oxy-Cope rearrangement, from 73, in combination with a transannular cyclization has culminated in a neat synthesis of the 5,7-ring-fused terpene ( k )-africanol 74, described by White et al. (Scheme 24).92393 Danheiser and his colleague^^^^ 95 have extended their studies of [3 + 21 annulation reactions involving allenylsilanes, and now shown that ally1 and propargyl silanes can take part in the reactions, leading to usefully functionalized cyclopentanes, e.g.75 -, 76. Boden and Pattenden: Saturated and partially unsaturated carbocycles 441SnBu3 73 rh" 1st.. 74 Scheme 26 Reagents: (i) KH, ether, 25 "C, 3h; (ii) Na/CloHe, THF; (iii) CH212, EtpZn, 0 "C Scheme 24 OSiMe:, I 0 OHo 70 OMe 75 76 3.4 Polyquinanes Interest in the biological activity and structural novelty of natural products like hirsutic acid, pentalenene, and modhephene has sustained activity in the synthesis of linear, angular, and propellane-type triquinanes. Furthermore, a number of the strategies used towards these intriguing compounds have been very much based on the burgeoning interests in free radical and transition metal mediated cyclopentane ring-forming reactions, discussed earlier in this section. Thus, Curran and Shen have published full details of their approach to ( f )-modhephene 77 based on tandem transannular radical cyclizations (Scheme 25),96 and Weinges et al.have demonstrated the scope for radical cyclizations in the presence of samarium iodide in their approach to coriolin 78 (Scheme 26).97 Reagents: (i) CICOCOCI; (ii) Scheme 25 (iii) 100 "C; (iv) steps A Pd2+ promoted cyclization provides a cornerstone in Fukumoto's synthesis of ( +_ )-hirsutene (79, Scheme 27),"," and an asymmetric Heck-reaction/anion-capture process features in an approach to capnellenols, via 80, presented by Shibasaki et al. (Scheme 28).Io0 Both the H H H H 79 Scheme 27 89% (80% e.e.) -OH H Scheme 28 80 Pauson-Khand'"' reaction and tandem cyclizations of 5-hexenyl lithiums"'* have been used in other approaches to angular and linear polyquinanes.The interesting ring cleavage reaction 8 1 --, 82 is the key step in a new synthesis of ( f )-pentalenene 83 presented by Franck-Neumann et al.,103 and an unusual oxyradical fragmentation radical-transannulation-cyclization sequence, i. e. 84 --, 85 -, 86, has been investigated as an alternative approach to 83.1°4 A range of other routes to polyquinane constructions have been published during the period under review,lo5-lo9 and a total synthesis of ( f )-crinipellin B 87 has also been described.lIo 442 Contemporary Organic SynthesisSiMelBu' & yAi0A- * CO2Et H H 81 82 OAc i steps 83 84 05 H 86 mx 89 90 COMe X, Y = H,CHO, CO,Me, difficult to obtain. Welker has reported similar results with cobalt-substituted butadienes.' l 3 Konopelski has extended his work on vinylketene acetals to 3-substituted cases 9 1, although quite reactive dienophiles are still needed.' The useful 2-pyrone equivalent 92 has been prepared and investigated in Diels-Alder reactions, where the conditions for the cycloadditions are much milder than is usual for pyrone additions.' The conversion of the product 94 obtained on acidolysis of the adduct 93 into an intermediate in the synthesis of a vitamin D, analogue has also been described.An example of the use of tethered vinylallenes and dienes (which allows the construction of two rings simultaneously) has been reported.' I h OH 0 1 n 87 An interesting new approach towards the tricyclo [5.3.1.01.s]undecane ring system found in a-cedrene 88 relies on the tandem radical cyclization reaction shown in Scheme 29, which proceeds via an addition-elimination mechanism.' 91 X = SPh, OTBS NC4HaO 80-95% single isomer 'FSph Bu3SnH 'fl @CHO, then NaBH,, 25 MeOH "C, 96h 0 AIBN, A, CeHe I 88 Scheme 29 4 Six-membered rings 4.1 Diels-Alder reactions The Diels-Alder reaction retains its central role in the synthesis of six-membered rings, with several new modifications being developed, particularly in the field of asymmetric synthesis.reported, of which the most generally useful may prove to be the butadienyl boronate species 89 described by Miyaura and Suzuki.' l 2 This highly reactive diene leads to adducts of the type 90, and provides a useful route into cyclic alkenyl boronates which are otherwise A number of new diene variants have been CSA, MeOH 25 "C, 15h I 94 As with dienes, the use of boron-substituted dienophiles such as 95, followed by appropriate manipulation of the adducts 96, has been reported, most notably by both this and the related work of Vaultier'21 are beset by problems of regioselectivity, although there are indications that these problems can be overcome.If this is indeed the case the method provides a useful route to cyclic boranes. Saigo and his co-workers have reported a novel method for producing highly electron-deficient dienophiles whereby the acrylate-acetal97 is first converted into the species 98, which then reacts readily with a range of dienes under milder conditions Boden and Pattenden: Saturated and partially unsaturated carbocycles 443,25"C,THF &OH BX, then oxidative work-up \ 95 96 (75%, single regioisomer) than are usually needed for Lewis acid catalysed acrylate cycloadditions.122 The related cationic species 100 may be formed in situ from the ketone 99 by the action of TMS-OTf and TMS-OMe and then used in a similar manner.123 Sieburth et al.have described the use of in situ formed vinylsilane dienophiles such as 10 1 in intramolecular Diels-Alder reactions; by careful choice of the alkyl groups on silicon, excellent exo:endo selectivity can be obtained.i24 Roush has prepared the unusual dienophile 102 as an intermediate in the synthesis of kijan01ide.l~' Lewis add CHzCl OMe OMe -78% Me0 97 98 6649% &.ex0 2 25:l I 0 Me0 v v 1 % SiRa A Two examples of the use of the allenes 103 and 104 as dienophiles in natural product synthesis have been reported,126y127 and Kim has investigated the scope for cyclic sugar-derived dienophiles such as 105.These dienophiles react with five- or six-membered ring cycloalkadienes to give single stereoisomers of the resulting adducts, which can then be converted into highly substituted cyclopentanols or cyclohexanols such as 106.128 1 02 103 1 05 A 104 ACO Hd 106 A number of new chiral auxiliaries for dienophiles have been reported.12Y,130 Thus, Hoffmann et al. have described the use of N-sulfonyloxazolidines in conjunction with cyclopentanones, illustrated by 107 -. 108, and Nouguier et al. have used arabinose derivatives such as 109. In addition, Yamamoto et al. have described a strategy for increasing the effectiveness of chiral menthyl esters by the use of bulky Lewis acids.131 101 108 109 0- SiR2 endo:exo = 1:4 (R = Me), 1:20 (R = But) Interestingly, the less usual course of placing chiral auxiliaries on the diene component has also seen significant progress this year.Enders has used chiral, proline-derived 2-amino- 1,3-butadienes, such as 1 10, 444 Contemporary Organic SynthesisO y O M . N 110 for both carbo- and hetero-cycl~additions,~ 32 whilst Jones and Aversa have studied the use of chiral sulfoxide-bearing d i e n e ~ . ' ~ ~ The latter researchers obtained excellent results in the optimization of Lewis acid conditions in the case of 1 1 1. 0- & Ho@ ' L e I 111 70%, enhexo = 100: 0 Liclo,, CH2C12, 25 oc 9% e.e. (after sulfoxide removal) Q e c o 2 M e " d V C O 2 M e OMe Perhaps one of the most interesting general developments in the area of Diels-Alder reactions is the demonstration by Pandey that reactions between cyclic dienes and dienophiles can be forced to give predominantly the product of exo-addition ( e.g.1 13) by carrying out the reaction under photolytic ~0nditions.l~~ If this method proves to have general application it should be of considerable value, given the normal tendency towards predominantly endu-addition products, e.g. 1 12. A number of new or improved Lewis acid catalysts for Diels-Alder reactions have been reported; these include the bulky MAD and MABr aryloxyaluminium reagents of Yamarnot~,'~~ examples of catalysis on solid support^,^^^^ 137 and the use of scandium triflate.138 Asymmetric catalysis has seen little genuinely new work; however, the basic staples of metal-complexed chiral binaphth~ls'~'~ 140 and the chiral 0 0 + Q 0 1 111:llB > 4Q:l (cf.c 1 :49 under thermal conditions) hv, EtsN, EtOH v 112 113 oxaborolidinone work of Corey141 have seen further development. The latter has been extended to reactions with furan, providing a useful route into chiral cycl~hexanols.~ l 4.2 Transition metal mediated cyclizations As in previous years palladium has been the dominant metal used in transition-metal based syntheses of six-membered rings published during the period covered by this report, with several descriptions of coupling to sp2 centres. Trost has published a study of intramolecular palladium-catalysed intramolecular carbametalations of 1,6-enynes, wherein the regioselectivity of addition is shown to be dependent on the substitution pattern of the alkyne, with monosubstituted alkynes such as 114 giving exclusively the product 1 15 of 6-endo cy~lization.'~~ Another example of endo cyclization of alkenyl palladium intermediates has been reported by Negishi, viz.116 -+ 11 7, although evidence is presented which indicates that the reaction in fact proceeds via the exo-mode of bicyclization followed by cyclopropanation and then ~earrangement.'~~ 114 TPh H 115 - :y PdCI2(PPH&, EtpNH-EtsN, DMF, 80 "C 94% E EcBun 116 117 Bun The recent revival of synthetic interest in the vitamin D carbon skeleton (following the discovery of immunosuppressant and anti-cancer properties in analogues) has led several research groups to approach the A-ring (with its two exo-alkene groups) via palladium-based methodology of similar type to that described above for 1 14 -+ 1 15.144 Interestingly, attempts to form the triene system in 119 via the cycloisomerization of a suitable enyne 1 18 followed by trapping of the intermediate vinyl palladium species with a vinyl halide were hampered by a tendency towards isomerization in the product, viz.1 19 -. 120; however, less ambitious approaches based on initial formation of the exo-diene structure followed by triene Boden and Pattenden: Saturated and partially unsaturated carbocycles 445synthesis by more conventional methods have been more s u c c e s s f ~ l . ' ~ ~ - ' ~ ~ Other metal-mediated research of note includes Kim's ring expansion method for 1 -alkenyl cyclopentanols 12 1 via the corresponding mercurinium ion 122.'48 The method may also be applied to the synthesis of five-, seven-, and eight-membered rings (see Section 3.2).Br p Pd(OAc),, PhaP Et3N - PhMe, reflux then desilylation 5 HO" 119 118 m s o G P h 121 120 122 & Ph 4.3 Free radical cyclizations Cyclizations of simple heptenyl radicals are, in general, an unreliable method of forming six-membered rings, owing to a tendency for competing side-reactions (7-endo cyclization, 1,Shydrogen abstraction, and simple reduction) to both decrease the chemical yield and possibly introduce problems in purification. However, by attaching suitable substituents to either the radical centre of the acceptor site, it is possible to minimize or even eliminate such complications.For example, the propensity of acyl carbon atoms, acting as either radical centres or radical acceptors, to selectively form six-membered-ring cyclic ketones is emerging as a useful addition to more established methods of annulation. Crich has described the use of the acyl radial cyclization route in an alternative approach, viz. 123 -* 124, to the vitamin D A-ring discussed in Section 4.2.'49 The clean 6-ex0 addition to the alkene 123 seen here is also apparent in other work. so 0 123 0 Bu3SnH, AlBN PhH. reflux 125 In a related study, Crich has demonstrated that (at least in arylacyl cases) acyl tellurides are a viable alternative to acyl selenides as a source of acyl radi~a1s.l~~ Another case in point is the use of copper-manganese reagents to generate radicals at P-dicarbonyl centres.This method has been investigated by Snider, yielding some fascinating results. Such radicals favour 6-endo cyclization over 5-exo in many circumstances, and as such are a potentially useful tool for the synthesis of cyclohexanones. In the case of 126 a tandem process occurs, giving the product 127 via the mechanism indicated in Scheme 30.15* By careful choice of the chiral auxiliary 'X' in 126 synthetically useful yields and diastereomeric excesses can be obtained. Snider has also described the control of regioselectivity by the use of chloroalkenes for cases where either 7-endo or 5-exo cyclizations are serious ~ide-reacti0ns.l~~ The case of the latter is exemplified by the conversion of 128 into 129.Finally, an unusual route to six-membered rings has been reported by Kilburn,lS4 based on radical addition to methylene cyclopropanes such as 130. 0 I 126 1 0 127 90%, fwX= 86% d.e. & 0 Scheme 30 446 Contemporary Organic Synthesis0 R 128 0 COpEt 129 Bu$nH,AlBN Ph PhMe. reflux Ip,,*1 130 L J I.'. ph+ 4.4 Other routes to six-membered rings Anionic methods remain popular in six-membered ring constructions, with the familiar Michael and Dieckmann reactions seeing further development. Periasamy has described a general method for the introduction of cyclohexyl rings at the a-methylene centre in ketones, esters, lactones, and nitriles, utilizing a one-pot combination of the two, e.g. 131 + 132.155 Na2Fe(CO),, H,C=CHCO,Me, THF 53% 131 132 New ring-expansion methods have also been reported. Thus, McNelis has shown that treatment of alkynyl cyclopentanols 133 with iodine and Koser's reagent gives cleanly and in good yield the methylene cyclohexanone 134 with a doubly halogenated alkene.Subsequent selective reduction of the iodine moiety in 134 gives the stereodefined bromide 135.15h Schick has reported an unusual ring-expansion of the 1,3-~yclopentanediones 136 to the corresponding 1,4-~yclohexanediones 137;' 57 the reaction is unusual in that cleavage of 1,3-~yclopentanediones is usually seen under alkaline conditions. OH 133 12. HTlB MGN, 25 "C 55-7% NaOMe. MeOH (j+ -70% * 0 0 136 137 (R = 1 O alkyl) Cationic methods, particularly those mediated by Lewis acids, are increasing in popularity.Thus Booker-Milburn has reported the preparation of cyclohexenones 140 from cyclopentenones 138 by iron-catalysed ring expansion of siloxybicyclo- [ 3.1 .O]cyclohexane intermediates 1 39,15* and Overman has demonstrated that the Prins-pinacol rearrangement can be usefully applied to the synthesis of quite complex structures such as 142 following simple treatment of the vinyl (siloxycylopentane) 14 1 with tin tetrachl~ride.~~' Finally, Lewis-acid catalysed asymmetric enelh0 and carbonyl ene reactions have seen further development, the latter forming part of a remarkable (and highly stereoselective) tandem process with the Sakurai reaction (Scheme 3 l ) . I h 1 (I) RMgX, CuI, Me3SiCI (ii) CH& Etsn, Et20 R = alkyl, allyl, benzyl THF-HMPA, -78 "C R 139 138 or aryl FeClS DMF, 0 "C NaOAc, MeOH 1 45-71 % 0 R 140 OMe OMe -78OCt0-23"C SnCI.,, CH&IR & 57% OMe 141 142 Scheme 31 4.5 Fused six-membered rings The majority of the methods used for six-membered-ring annulation are equally applicable to the synthesis of six-membered-ring containing bicycles and polycycles, by the simple expedient of using a cyclic substrate.Such simplicities are not Boden and Pattenden: Saturated and partially unsaturated carbocycles 447covered in this section, which instead highlights cases of 'one-pot' formation of two or more rings, where at least one is six-membered. Transannular ring contractions of medium-rings provide one such approach, as illustrated by the work of White,162 in which treatment of the cyclododecenone 143 with acid gives the trans-decalin system 144.Note that under radical conditions (Bu,SnH or SmI,) the 7,5-ring system is favoured. Other transannular work includes the continuing research of Deslongchamps into intramolecular Diels-Alder syntheses of polycycles, which has been self-su~nmarized.~~~ Roush has also made a recent contribution to this field.164 An increasingly popular alternative to transannulation reactions for polycycle synthesis is the use of 'cascade' cyclizations, as described for five-membered rings in Section 3. An excellent example of this has been reported by D e m ~ t h , ' ~ ~ wherein the polyene 145 is cyclized to the tricycle 146 under single-electron transfer conditions. This fascinating process is suggested to proceed via radical cation intermediates (as would be expected from the reaction conditions), and represents an alternative to the classical cationic means of achieving 'biomimetic' polycyclization. Although the yield of 146 is low, there remains considerable scope for optimization.02CCF3 1 C02Bu' BunLi, THF, -78 Dct I 1 94% single isomer 147 c02Bu' BunLi, THF. -78 "c I 148 p C02Me CF&O2H, CH& 0 "C 64% (single isomer) 0 143 144 OH 63 OH 145 146 18%. + 6% of c-14 epimer A 'tandem' approach to decalins 147 and spiro 6,5-systems 148 has been described by Cooke.166 The method is dependent on the rapid halogen-metal exchange (presumably via single-electron transfer) between alkyl iodides and Bu"Li, and appears to be remarkably efficient. Another route (asymmetric in this case) to spiro-bicycles has been reported by Sakai,167 utilizing chiral diol auxiliaries to allow the synthesis of 149 in chral form.A method for the selective formation of cis or trans decalins via samarium-mediated c yclization has been reported, 68 where the stereocontrol is proposed to arise by intramolecular samarium chelate formation between the carbonyl and hydroxyl groups; thus the hydroxyl groups in 150,151, and 152 are all syn, to each other. I 149 (86% yield 85% e.e.) Me0& p Sda THF, MeOH, -78 "C El%, single isomer (6H c0,Me 150 c02Me \ Sd2, THF, MeOH, -78 "C 151 + * 70%. 151:152 = 5 1 152 'Appendage' bicyclization ( i.e. attaching a bifunctional synthon to a monocycle and then closing a second ring in situ) continues to attract interest. Fuchs has developed the four carbon appendage 153 as a means of preparing highly functionalized allylic stannanes such as 154 via the classical Robinson annulation.169 The survival of 154 under the alkaline conditions of the annulation is noteworthy (the equivalent silane is hydrolyzed). Finally, Piers has 153 154 448 Contemporary Organic Synthesisreported a simple method of exo-alkenyl cyclohexane synthesis based, like that of Pulido mentioned in Section 2, on the fast transmetalation of vinyl stannanes with alkyl-lithiums.' 70 5 Seven-membered rings Without doubt one of the most effective methods for the synthesis of seven-membered rings to be utilized in recent years has been the Cope rearrangement of cis-divinylcyclopropanes, e.g.155 -+ 156. The only limitation to this method of synthesis is the availability of the cis-divinylcyclopropanes.In a concise review Davies17' has now drawn together the main features of the conversions to demonstrate how the cis-divinylcyclopropanation/Cope-rearrangement can be effected in tandem, leading to highly functionalized seven-membered rings, often with excellent control of both relative and absolute stereochemistry. Me0 LOBn 155 156 (8Wo) The equally familiar Claisen rearrangement, but used in the form of a ring-contraction strategy, has been used in a most elegant fashion to elaborate the novel 7,7-fused bicyclic ring portion 159 in the ingenane family of natural products, viz. 157 -, 158 -, 159.17* 157 E=C02Me 158 ! I 1 (i) LiHMDS. Bu'M+SK;i (ii) 95C.3h (iii) HF. 0 "c 43 H02C 159 (88%) Cycloaddition reactions based on [4 + 31 and [5 + 21 annulations leading to seven-membered rings have featured prominently in the recent literature, and two further examples of these reactions described during the period under review are collected in Scheme 32.173-176 The unusual reaction between 2-aminobuta- 1,3-dienes and vinylchromium Fischer TBSO 145 'c 1 Raney-Ni 0 OpJH Scheme 32 type carbenes, which can be regarded as a [4 + 31 cycloaddition, also provides an interesting route to seven-membered rings (Scheme 33).' 77 Furthermore, in a modification of the more familiar Dotz reaction, Herndon et al.17*, 17y have now shown that cycloheptadienones can be obtained by the reaction of cyclopropylcarbene molybdenum or tungsten complexes with alkynes according to Scheme 34.MeCN 25 'c c IEF] OM* Fu = furan Scheme 33 D-tM0(c0)5 O(CHJ& ECPh Scheme 34 81 Yo 1 0 q 0 55% Boden and Pattenden: Saturated and partially unsaturated carbocycles 449Ring-enlargement reactions are often used in synthesis, and two new sequences used in seven-membered ring constructions are the rhodium( 1)-catalysed ring fusion 160 -+ 16 1 free-radical ring expansion of fused cyclobutanones described by Dowd et ~ 1 . ' ~ ' and highlighted in Scheme 35. and the Majetich et al. L8s have published full details of their allylsilane-based annulation strategy to construct perhydroazulenes, viz. 164 -+ 165, and Jones et al. 18h have described an approach to the same ring system based on some novel cyclizations involving sulfones, e.g. 166 - 167. H (i) THF (ii) aq.HCI . 160 Cu (C N) L 161 H 0 Scheme 35 A further illustration of the scope for tandem free-radical reactions in seven-membered ring synthesis is shown by the cascade fragmentation-transannulation process triggered by treatment of the bicyclic dienol 162 with iodosylbenzene diacetate/iodine, leading to the 7,5,5,-tricycle 163 in 80% yield (Scheme 36).IX2 Other radical-based procedures, involving acyl radical' x3 and organocobalt intermediate^,'^^ leading to the synthesis of linear fused seven-membered ring systems have also been described. 162 163 (81%) SiMes 164 165 I . -0 graveolide 166 167 Ring-opening reactions of oxabicyclo[ 3.2.1 ]octanes leading to functionalized cycloheptenes and cycloheptadienes have been summarized,' 87 and the neat metathesis reaction 168 -, 169 has been highlighted as a route to h.ydroazulenes.'8x 169 (58%) 168 6 Eight-membered rings Much of the recent spate of activity in approaches to the synthesis of eight-membered rings stems from interest in taxol 170 and its promising anticancer activity.A concise review of approaches to taxanes has recently been published in Contemporary Organic Synthesis.lX' Recent additions to these approaches are Scheme 36 170 450 Contemporary Organic Synthesisthe intramolecular Ni"-Cr" mediated coupling reaction shown by 171 -+ l72,lYo and the intramolecular nucleophilic allylic bromide-aldehyde addition reaction 173 -+ 174 promoted by a Zn-Cu couple."' 0 It 1%NiCIfirC12 DMSO, 2 0 d 171 172 (50%) 173 174 OR 1 C02Me C02Me OMOM The Claisen rearrangement of 175 -.+ 176 has featured in Paquette's approach to the 5,8,5-ring fused diterpene ( + )-ceroplastol I 177,ly2 and Myers and CondroskilY3 have outlined a neat radical-based transannular strategy in their novel synthesis of the tobacco isolate ( k )-7,8-epoxy-4-basnien-6-one 178 (Scheme 37).constructions published during the period covered by this review, efficient intramolecular [4 + 41 photocycloadditions between 2-pyrones and furan have been pre~ented,"~ Funk has extended his work on Claisen rearrangements to enol phosphates,' y5 and Inoue et al. Iy6 have used a modified de Mayo photochemical reaction in an approach to ( f )-precapnelladiene found in marine coral. In other approaches to eight-membered ring 175 176 i steps \ 177 178 Reagent: ( i ) N-methylcarbazole, 1,6cyclohexadiene, THF-H,O, hv Scheme 37 7 Ten-membered and larger rings In so-called higher order cycloaddition reactions, Rigby and co-worker~~~' have summarized numerous examples of [6n + 4n] cycloadditions which can be effected either thermally, photochemically, or by employing a chromium metal catalyst (Scheme 38); related [6n + 2271 cycloaddition reactions have also been highlighted by Rigby and co-workers.198 6 + OAc 0 % A xylene 59% 66% 0 52% Scheme 38 The directed ring-opening of epoxycarbinyl radicals set in decalin ring systems, followed by fragmentation of the resulting oxy-centred radicals, has been used as an approach to substituted cyclodecanones (Scheme 39),"'? 2oo and related work involving radical intermediates from homoallylic alcohols has been presented.*O' from farnesol has been described by Corey et al.202 which incorporates the trick of utilizing an allylic A biogenetically inspired synthesis of humulene 180 Boden and Pattenden: Saturated and partially unsaturated carbocycles 45 1cb] COpEt C02Et c3 CO2Et Scheme 39 Bu,Sn to lower the activation energy in the cyclization of 179 -+ 180 in the presence of dimethylaluminium chloride at - 78°C. The cyclization of 181 to the eleven-membered ring intermediate 182 has been used in the biogenetically patterned synthesis of the clavularanes 183 described by Williams et al. 203 SFBU:, toluene, -78 "C 179 180 I Po-& ' 1 e i 182 i steps i 183 In Paquette's synthesis of the fourteen-membered furanocembrane acerosolide 185, the crucial cyclization step was achieved by treatment of the allylic bromide 184 with the reducing cocktail of CrCI, and LiAlH, .204 8 General carbocyclic ring synthesis In addition to those reviews already sited, Tietze and Beifuss2OS have produced a useful review of sequential (tandem/domino/cascade) ring-forming reactions in organic synthesis, which nicely complements the book written by T.-L.Ho covering the same area.2o6 Roxburgh has reviewed the synthesis of medium-sized rings by ring expansion reactions,2o7 and Paquette and CCl* THF 20% c 0 0 184 I 0 185 Stirling208 have presented a useful expose of the intramolecular S,l reaction and some of its applications to ring synthesis. A general account of stereo-electronic effects in the formation of five- and six-membered rings, and the role of so-called Baldwin's rules, has been presented,20y and Petasis and Patane2l0 have provided an excellent account of the synthesis of eight-membered carbocycles. 9 References 1 Y.Ukaji, K. Sada, and K. Inomata, Chem. Lett,, 1993, 2 A.B. Charette and J.-F. Marcoux, Tetrahedron Lett., 3 A.B. Charette and B. Cbte, J. Org. Chem., 1993,58, 4 W.B. Motherwell and L.R. Roberts, J. Chem. SOC., 1227. 1993,34,7157. 933. Chem. Commun., 1992,1582; cf. R.M. Vargas, R.D. Theys, and M.M. Hossain, J. Am. Chem. SOC., 1992, 114,777. 5 K.C. Brown and T. Kodadek, J. Am. Chem. Soc., 1992, 114,8336. 6 K. Ito and T. Katsuki, Tetrahedron Lett., 1992,34, 2661; Synlett, 1993,638. 7 G. Jommi, R. Pagliarin, G. Rizzi, and M. Sisti, Synlett, 1993,833. 8 S.F. Martin, C.J. Oalmann, and S.Liras, Tetrahedron Lett., 1992,33,6727. 9 A.M.P. Koskinen and H. Hassila, J. Org. Chem., 1993, 58,4479. 10 D. Romo and A.I. Meyers, J. Org. Chem., 1992,57, 6265. 11 A. Krief and P. Lecomte, Tetrahedron Lett., 1993,34, 2695. 12 K. Tanaka and H. Suzuki, J. Chem. SOC., Perkin Trans. I, 1992,2071. 13 A.R. Katritzky and M.F. Gordeev, Synlett, 1993,213. 14 J.D. White and M.S. Jensen, J. Am. Chem. SOC., 1993, 15 M.Y. Chu-Moyer and S.J. Danishefsky, J. Am. Chem. 16 D. Montgomery, K. Reynolds, and P. Stevenson, J. 115,2970. SOC., 1992, 114,8333. Chem. SOC., Chem. Commun., 1993,363. 452 Contemporary Organic Synthesis17 K. Takeda, J. Nakatani, H. Nakamura, K. Sako, E. Yoshii, and K. Yamaguchi, Synlett, 1993,841. 18 M. Ihara, T. Taniguchi, N. Taniguchi, and K.Fukomoto, J. Chem. SOC., Chem. Commun., 1993,1477. 19 W. Zhang and P. Dowd, Tetrahedron Lett., 1992,33, 7307. 20 A.E. Harms and J.R. Stille, Tetrahedron Lett., 1992,33, 6565. 2 1 K. Narasaka, Y. Hayashi, H. Shimadzu, and S. Niihata, J.Am. Chem. SOC., 1992,114,8869. 22 O.K. Kim, W.D. Wulff, W. Jiang, and R.G. Ball, J. Org. Chem. 1993,58,5571. 23 P.J. Wagner, M. Sakamoto, and A.E. Madkour, J. Am. Chem. SOC., 1992,114,7298. 24 P. Galatsis, K.J. Ashbourne, J.J. Manwell, P. Wendling, R. Dufault, K.L. Hatt, G. Ferguson, and J.F. Gallagher, J. Org. Chem., 1993,58,1491. 25 M.E. Jung, I.D. Trifunovich, and N. Lensen, Tetrahedron Lett., 1992,33,6719. 26 K. Ogura, N. Sumitami, A. Kayano, H. Iguchi, and M. Fujita, Chem. Lett., 1992, 1487. 27 A. Barbero, P. Cuadrado, A.M. Gonza'lez, F.J.Pulido, R. Rubio, and I. Fleming, Tetrahedron Lett., 1992,33, 5841. 28 T. Nagasawa and K. Suzuki, Synlett, 1993,29. 29 M. Ihara, T. Taniguchi, K. Mamita, M. Tukano, M. Ohnishi, N. Taniguchi, K. Fukumoto, and C. Kabuto, J. Am. Chem.Soc., 1993,115,8107. 30 B.B. Snider, L. Armanetti, and R. Baggio, Tetrahedron Lett., 1993,34, 1701; for a review see: G.G. Melikyan, Synthesis, 1993,833. 31 B.B. Snider and B.A. McCarthy, J. Org. Chem., 1993, 58,62 17. 32 A.L.J. Beckwith and M.J. Tozer, Tetrahedron Lett., 1992,33,4975. 33 B.Giese, P. Erdmann, T. Gobel, and R. Springer, Tetrahedron Lett., 1992,33,4545. 34 T. Lubbers and H.J. Schafer, Synlett, 1992,743. 35 J.E. Brumwell, N.S. Simpkins, and N.K. Terrett, Tetrahedron Lett., 1993,34, 1215. 36 S. Kim and J.R. Cho, Synlett, 1992,629.37 D.L.J. Clive, Y. Tao, A. Khodabocus, Y.-J. Wu, A.G. Angoh, S.M. Bennett, C.N. Boddy, L. Bordeleau, D. Kellner, G. Kleiner, D.S. Middleton, C.J. Nichols, S.R. Richardson, and P.G. Vernon, J. Chem. SOC., Chem. Commun., 1992,1489. 38 J. Cossy, Pure Appl. Chem., 1992,64,1883. 39 D.H.R. Barton, J. Camara, X. Cheng, S.D. Gero, J.C. Jaszberenyi, and B. Quiclet-Sire, Tetrahedron, 1992, 48,926 1. 40 J. Marco-Contelles, P. Ruiz, L. Martinez, and A. Martinez-Grau, Tetrahedron, 1993,49,6669. 41 C.-K. Sha, C.-Y. Shen,T.-S. Jean, R.-T. Chiu,and W.-H. Tseng, Tetrahedron Lett., 1993,34,7641. 42 T. Gillmann, Tetrahedron Lett., 1993,34,607. For a concise review on mechanistic insights into radical reactions using samarium( 11) iodide see; D.P. Curran, T.L.Fevig, C.P. Jasperse, and M.J. Totleben, Synlett, 1992,943. Synlett, 1992,72 1. Tetrahedron Lett., 1993,34,5251. Tetrahedron Lett., 1993,34,2899. 1992,1377. 4687. 43 S. Toni, H. Okumoto, M.A. Rashid, and M. Mohri, 44 F.-H. Wartenberg, H. Junga, and S. Blechert, 45 V.H. Rawal, V. Krishnamurthy, and A. Fabre, 46 S. Kim and J.S. Koh, J. Chem. SOC., Chem. Commun., 47 V.H. Rawal and S. Iwasa, Tetrahedron Lett., 1992,33, 48 S. Kim and J.S. Koh, Tetrahedron Lett., 1992,33,7391. 49 A.D. Borthwick, S. Caddick, and P.J. Parsons, Tetrahedron, 1992,48,10655. 50 R.A. Batey, J.D. Harling, and W.B. Motherwell, Tetrahedron, 1992,48,8031. 51 C.A. Shook, M.L. Romberger, S.-H. Jung, M. Xiao, J.P. Sherbine, B. Zhang, F.-T. Lin, and T. Cohen, J. Am. Chem. SOC., 1993,115,lO 754. 52 N.Iwasawa, M. Funahashi, S. Hayakawa, and K. Narasaka, Chem. Lett., 1993,545. 53 K.I. Booker-Milburn, Synlett, 1992,809; K.I. Booker-Milburn and D.F. Thompson, ibid., 1993,592. 54 D.F. Taber, Y, Wang, and S.J. Stachel, Tetrahedron Lett., 1993,34,6209. 55 D.P. Curran, W.-T. Jiaang, M. Palovich, and Y.-M. Tsai, Synlett, 1993,403; D.P. Curran and M. Palovich, ibid., 1992,631. 56 Y.K. Chung, B.Y. Lee, N. Jeong, M. Hudecek, and P.L. Pauson, Organometallics, 1993,12,220. 57 T.R. Hoyeand J.A. Suriano,J. Am. Chem. SOC., 1993, 115,1154. 58 N. Jeong, S.J. Lee, B.Y. Lee, and Y.K. Chung, Tetrahedron Lett., 1993,34,4027. 59 C. Mukai, M. Uchiyama, and M. Hanaoka, J. Chem. SOC., Chem. Commun., 1992,1014. 60 M.E. Krafft, I.L. Scott, and R.H. Romero, Tetrahedron Lett., 1992,33,3829.6 1 D.P. Becker and D.L. Flynn, Tetrahedron Lett., 1993, 34,2087. 62 T.R. Hoye and J.A. Suriano, J. Org. Chem., 1993,58, 1659. 63 M.E. Krafft, R.H. Romero, and I.L. Scott, J. 0%. Chem., 1992,57,5277. 64 S. Yoo, S.-H. Lee, N. Jeong, and I. Cho, Tetrahedron Lett., 1993,34,3435. 65 N. Jeong, B.Y. Lee, S.M. Lee, Y. K. Chung, and S.-G. Lee, Tetrahedron Lett., 1993,34,4023. 66 B.M. Trost and Y. Shi, J. Am. Chem. SOC., 1993,115, 12491. 67 B.M. Trost and Y. Shi, JAm. Chem. SOC., 1993,115, 942 1. 68 B.M. Trost and O.J. Gelling, Tetrahedron Lett., 1993, 34,8233. 69 B.M. Trost and L.T. Phan, Tetrahedron Lett., 1993,34, 4735; see also F.-H. Wartenberg, B. Hellendahl, and S. Blechert, Synlett, 1993,. 539. 70 L.E. Overman, M.M. Abelman, D.J. Kucera, V.D. Tran, and D.J. Ricca, Pure Appl.Chem., 1992,64,1813. 71 L.E. Overman, D.J. Ricca, and V.D. Tran, J. Am. Chem. Soc., 1993,115,2042. 72 D.J. Kucera, S.J. O'Connor, and L.E. Overman, J. Org. Chem., 1993,58,5304. 73 B. Burns, R. Grigg, V. Santhakumar, V. Sridharan, P. Stevenson, and T. Worakun, Tetrahedron, 1992,48, 7297. 74 R.B. Grossman and S.L. Buchwald, J. Org. Chem., 1992,57,5803. 75 S.C. Berk, R.B. Grossman, and S.L. Buchwald, J. Am. Chem. SOC., 1993,115,4912. 76 D. Schinzer, J. Kabbara, and K. Ringe, Tetrahedron Lett., 1992,33,80 17. 77 S.U. Turner, J.W. Herndon, and L.A. McMullen, J. Am. Chem. SOC., 1992,114,8394. 78 X.-M. Wu, K. Funakoshi, and K. Sakai, Tetrahedron Lett., 1992,33,6331; ibid., 1993,34,5927. 79 A. Llebana, F. Camps, and J.M. Moreto, Tetrahedron, 1993,49,1283. 80 M.Yamaguchi, M. Sehata, A. Hayashi, and M. Hirama, J. Chem. SOC., Chem. Commun., 1993,1708. 8 1 J. van der Louw, J.L. van der Baan, C.M.D. Komen, A. Knol, F.J.J. de Kanter, F. Bickelhaupt, and G.W. Boden and Pattenden: Saturated and partially unsaturated carbocycles 453Klumpp, Tetrahedron, 1992,48,6105. 115,3800. Am. Chem. SOC., 1993,115,3080. 907. Ellestad, and J.B. Stallman, J. Am. Chem. SOC., 1993, 115,7023. 86 C. Meyer, I. Marek, G. Courtemanche, and J.-F. Normant, Synlett, 1993,266. 87 C. Meyer, H. Marek, G. Courtemanche, and J.-F. Normant, Tetrahedron Lett., 1993,34,6053. 88 H. Stadmiiller, C.E. Tucker, A. Vaupel, and P. Knochel, Tetrahedron Lett., 1993,34,7911. 89 H. Stadtmuller, R. Lenz, C.E. Tucker, T. Studemann, W. Dorner, and P. Knochel, J. Am.Chem. SOC., 1993,115, 7027. 90 N. Iwasawa and T. Matsuo, Chem. Lett., 1993,997. 91 N. Iwasawa and M. Iwamoto, Chem. Lett., 1993,1257. 92 W. Fan and J.B. White, J. Org. Chem., 1993,58,3557. 93 W. Fan and J.B. White, Tetrahedron Lett., 1993,34, 957. 94 R.L. Danheiser, B.R. Dixon, and R.W. Gleason, J. Org. Chem., 1992,57,6094. 95 R.L. Danheiser, T. Takahashi, B. Bertok, and B.R. Dixon, Tetrahedron Lett., 1993,34,3845. 96 D.P. Curran and W. Shen, Tetrahedron, 1993,49,75. 97 K. Weinges, R. Braun, U. Huber-Patz, and H. 98 M. Toyota, Y. Nishikawa, K. Motoki, N. Yoshida, and K. 99 M. Toyota, Y. Nishikawa, K. Motoki, N. Yoshida, and K. 82 G.C. Fu and R.H. Grubbs, J. Am. Chem. SOC., 1993, 83 W.F. Bailey and T.V. Ovaska, Chem. Lett., 1993,819; J. 84 A. Krief, D. Derouane, and W.Dumont, Synlett, 1992, 85 R.L. Funk,G.L.Bolton, K.M. Brummond, K.E. Imgartinger, LiebigsAnn. Chem., 1993, 1133. Fukumoto, Tetrahedron Lett., 1993,34,6099. Fukumoto, Tetrahedron, 1993,49,11 189. 100 K. Kagechika, T. Ohshima, and M. Shibasaki, Tetrahedron, 1993,49,1773. 101 E.G. Rowley and N.E. Schore, J. Org. Chem., 1992,57, 6853. 102 W.F. Bailey, A.D. Khanolkar, and K.V. Gavaskar, J. Am. Chem. SOC., 1992,114,8053. 103 M. Franck-Neumann, M. Miesch, and L. Gross, Tetrahedron Lett., 1992,33,3879. 104 G. Pattenden and D.J. Schulz, Tetrahedron Lett., 1993, 34,6787. 105 D.L.J. Clive and H.W. Manning, J. Chem. SOC., Chem. Commun., 1993,666. 106 M.-C.P. Yeh, B.-A. Sheu, H.-W. Fu, S.-I. Tau, and L.-W. Chuang, J.Am. Chem. SOC., 1993,115,5941. 107 T. Shono, N. Kise, T.Fujimoto, N. Tominaga, and H. Morita,J. Org. Chem., 1992,57,7175. 108 T. Cohen, K. McNamara, M.A. Kuzemko, K. Ramig, J.J. Landi, Jr., and Y. Dong, Tetrahedron, 1993,49,7931. 109 T.K. Sarkar, S.K. Ghosh, P.S.V. Subba Rao, T.K. Satapathi, and V.R. Mamdapur, Tetrahedron, 1992,48, 6897. 110 E. Piers and J. Renaud, J. Org. Chem., 1993,58, 11. 11 1 Y.-J. Chen, C.-M. Chen, and W.-Y. Lin, Tetrahedron Lett., 1993,34,2961. 1 12 A. Kamabuchi, N. Miyaura, and A. Suzuki, Tetrahedron Lett., 1993,34,4827. 113 J.T.L. Smalley, M.W. Wright, S.A. Garmon, M.E. Welker, and A.L. Rheingold, Organometallics, 1993, 12, 998. 1993,34,4587. 33,7839. Chem. Commun., 1993,270. 114 J.P. Konopelski and R.A. Kasar, Tetrahedron Lett., 1 15 K. Afarinkia and G.H. Posner, Tetrahedron Lett., 1992, 116 J.P.Dulcere, V. Agati, and R.J. Faure, J. Chem. SOC., 11 7 D.A. Singleton, J.P. Martinez, J.V. Watson, and G.M. Ndip, Tetrahedron, 1992,48,5831. 118 D.A. Singleton, J.P. Martinez, and G.M. Ndip, J. Org. Chem., 1992,57,5768. 119 D.A. Singleton and S.-W. Leung, J. Org. Chem., 1992, 57,4796. 120 D.A. Singleton, K. Kim, and J.P. Martinez, Tetrahedron Lett., 1993,34,3071. 121 N. Noiret, A. Youssofi, B. Carboni, and M.J. Vaultier, J. Chem. SOC., Chem. Commun., 1992,1105. 122 Y. Hashimoto, T. Nagashima, K. Kobayashi, M. Hasegawa, and K. Saigo, Tetrahedron, 1993,49,6349, 123 Y. Hashimoto, T. Nagashima, M. Hasegawa, and K. Saigo, Chem. Lett., 1992, 1353. 124 S.M. Sieburth and L. Densterbank, J. Org. Chem., 1992, 57,5279. 125 W.R. Roush and B.B. Brown, J. Org. Chem., 1993,58, 2152.126 M.E. Jung, C.N. Zimmerman, G.T. Lowen, and S.I. Khan, Tetrahedron Lett., 1993,34,4453. 127 J. De Schrijver and P.J. De Clerq, Tetrahedron Lett., 1993,34,4369. 128 K.S.Kim,I.H. Ch0,Y.H. Joo,I.Y.Yoo, J.H. Song,and J.K. KO, Tetrahedron Lett., 1992,33,4029. 129 H. Hoffmann, M. Bolte, B. Berger, and D. Hoppe, Tetrahedron Lett., 1993,34,6537. 130 R. Nouguier, J.-L. Gras, B. Giraud, and A. Virgili, Tetrahedron 1992,48,6245. 13 1 K. Maruoka, K. Shiohara, M. Oishi, S. Saito, and H. Yamamoto, Synlett, 1993,42 1. 132 D. Enders, 0. Meyer, and G. Raabe, Synthesis, 1992, 1242. 133 H. Adams, D.N. Jones, M.C. Aversa, P. Bonaccorsi, and P. Giannetto, Tetrahedron Lett., 1993,34,6481. 134 B. Pandey and P.V. Dalvi, Angew. Chem., Znt. Ed. Engl., 1993,32,1612. 135 K.Maruoka, M. Oishi, and H. Yamamoto, Synlett, 1993,683. 136 C. Cativiela, J.M. Fraile, J.L. Garcia, J.A. Mayoral, E. Pires, A.J. Royo, F. Figueras, and L.C. de Menorval, Tetrahedron, 1993,49,4073; see also idem., Tetrahedron, 1992,48,6467. 137 A.K. Saha and M.M. Hossain, Tetrahedron Lett., 1993, 34,3833. 138 S. Kobayashi, I. Hachiya, M. Araki, and H. Ishitani, Tetrahedron Lett., 1993,34,3755. 139 Y. Hong, B.A. Kunz, and S. Collins, Organometallics, 1993, 12,964. 140 K. Maruoka, A.B. Concepcion, and H. Yamamoto, Bull. Chem. SOC. Jpn., 1992,65,3501. 141 E.J. Corey and T.P. Loh, J. Am. Chem. SOC., 1991,113, 8966; E.J. Corey and T.-P. Loh, Tetrahedron Lett., 1993,34,3979. 142 B.M. Trost and J. Dumas, Tetrahedron Lett., 1993,34, 19. 143 Z . Owczarczyk, F. Lamaty, E.J.Vawter, and E.-I. Negishi,J.Arn. Chem. SOC., 1992,114,10091. 144 B.M. Trost, J. Dumas, and M.J. Villa, J. Am. Chem. SOC., 1992,114,9836. 145 J.M.Nuss, M.M. Murphy, R.A. Rennels, M.H. Haravi, and B.J. Mohr, Tetrahedron Lett., 1993,34,3079. 146 T. Takahashi and M. Nakazawa, Synlett, 1993,37. 147 J.L. Mascareiias, A.M. Garcia, L. Castedo, and A. Mouriiio, Tetrahedron Lett., 1992,33,4365. 148 S. Kim and K.H. Uh, Tetrahedron Lett., 1992,33,4325. 149 C. Chen and D. Crich, Tetrahedron, 1993,49,7943. 150 D. Batty and D. Crich, J. Chem. Soc., Perkin Trans I , 1992,3205. 15 1 C. Chen, D. Crich, and A.J. Papadatos, J. Am. Chem. Soc., 1922,114,8313. 454 Contemporary Organic Synthesis152 B.B. Snider and Q. Zhang, Tetrahedron Lett., 1992,33, 5921. 153 B.B.Snider, Q. Zhang, and M.A.Dombroski, J. Org. Chem., 1992,57,4196. 154 C.Destabe1, J.D. Kilburn, and J. Knight, Tetrahedron Lett., 1993,34,3151. 15 5 M. Periasamy, M.R. Reddy, U.Radhakrishnan, and A. Devasagayaraj, J. Org. Chem., 1993,58,4997. 156 P. Bovonsombat and E. McNelis, Tetrahedron, 1993, 49, 1525. 157 S. Schramm, B. Roatsch, E. Grundemann, and H. Schick, Tetrahedron Lett., 1993,34,4759. 158 K.I. Booker-Milburn and D.F. Thompson, Tetrahedron Lett., 1993,34,7291. 159 G.C. first, T.O. Johnson, Jr., and L.E. Overman, J. Am. Chem. Soc., 1993,115,2992. 160 K. Hiroi and M. Umemara, Tetrahedron, 1993,49, 1831. 16 1 L.F. Tietze and M. Rischer, Angew. Chem., Znt. Ed. Engl., 1992,31, 1221. 162 D. Colclough, J.B.White, W.B. Smith, and Y.J. Chu, J. Org. Chem., 1993,58,6303. 163 P.Deslongchamps, Pure Appl. Chem., 1992,64,1831. Ten other related papers have been published by this author. Lett., 1993,34,4427. Warzecha, C. Druger, H.D. Roth, and M. Demuth, J. Am. Chem. SOC., 1993,115,10358. 164 W.R. Roush, J.S. Warmus, and A.B. Works, Tetrahedron 165 U. Hoffmann, Y. Gao, B. Pandey, S. Hinge, K.-D. 166 M.P. Cooke, Jr,J. Org. Chem., 1993,58,2910. 167 H. Suemune, Y. Takahashi, and KJ. Sakai, J. Chem. 168 M. Kito, T. Sakai, K. Yamada, F. Matsuda, and H. 169 S. Kim and P.L. Fuchs, J. Am. Chem. SOC., 1993,115, 170 E. Piers, B.W.A. Yeung, and F.A. Fleming, Can. J. 171 H.M.L. Davies, Tetrahedron, 1993,49,5203. 172 R.L. Funk,T.A. Olmstead, M. Parvez, and J.B. Stallman, J. 0%. Chem., 1993,58,5873. 173 M. Harmata and B.F. Herron, Tetrahedron Lett., 1993, 34,5381.174 M. Harmata and B.F. Herron, J. Org. Chem., 1993,58, 7383. 175 M. Harmata, C.B. Gamlath, and C.L. Barnes, Tetrahedron Lett., 1993,34,265. 176 A. Rumbo, L. Castedo, A. Mourifio, and J.L. Mascerefias, J. Org. Chem., 1993,58,5585. 177 J. Barluenga, F. Aznar, A. Martin, S. Garcia-Granda, M.A. Salvado, and P. Pertierra, J. Chem. SOC., Chem. Commun., 1993,319. 178 J.W. Herndon,M. Zora, P.P. Patel, G. Chatterjee, J.N. Matasi, and S.U. Turner, Tetrahedron, 1993,49, 5507. 179 J.W. Herndon and M. Zora, Synlett, 1993,363. 180 M.A. Huffman and L.S. Liebeskind, J. Am. Chem. SOC., 1993,115,4895. 181 P. Dowd and W. Zhang, J. Org. Chem., 1992,57,7171.. 182 C.E. Mowbray and G. Pattenden, Tetrahedron Lett., 1993,34,127. 183 D. Batty and D. Crich, J. Chem. SOC., Perkin Trans. I , 1992,3 193. Soc., Chem. Commun., 1993,1858. Shirahama, Synlett, 1993,158. 5934. Chem., 1993,71,280. 184 A. Ali, D.C. Harrowven, and G. Pattenden, Tetrahedron Lett., 1992,33,2851. 185 G. Majetich, J.-S. Song, A.J. Leigh, and S.M. Condon, J. Org. Chem., 1993,58,1030. 186 D.N. Jones, M.W.J. Maybury, S. Swallow, and N.C.O. Tomkinson, Tetrahedron Lett., 1993,34,8533. 187 (a) M. Lautens, Synlett, 1993, 177; (b) M. Lautens and C. Gajda, Tetrahedron Lett., 1993,34,4591; (c) M. Lautens, C. Gajda, and P. Chiu, J. Chem. SOC., Chem. Commun., 1993, 1193; (d) M. Lautens, P. Chiu, and J.T. Colucci,Angew. Chem., Znt. Ed. Engl., 1993,32,281. 188 H. Junga and S. Blechert, Tetrahedron Lett., 1993,34, 3731. 189 A.N. Boa, P.R. Jenkins, and N.J. Lawrence, Contemp. Org. Synth., 1994,1,47. 190 M.H. Kress, R. Ruel, W.H. Miller, and Y. Kishi, Tetrahedron Lett., 1993,34,6003. 191 Z. Wang, S.E. Warder, H. Perrier, E.L. Grimm, and M.A. Bernstein,J. Org. Chem., 1993,58,2931. 192 L.A. Paquette, T.-Z. Wang, and N.H. Vo, J. Am. Chem. SOC., 1993,115,1676. 193 A.G. Myers and K.R. Condroski, J. Am. Chem. SOC., 1993,115,7926. 194 F.G. West, C.E. Chase, and A.M. Arif, J. Org. Chem., 1993,58,3794. 195 R.L. Funk, J.B. Stallman, and J.A. Wos, J. Am. Chem. SOC., 1993,115,8847. 196 Y. Inoue, M. Shirai, T. Michino, and H. Kakisawa, Bull. Chem. SOC. Jpn., 1993,66,324. 197 (a) J.H. Rigby,K.M. Short, H.S. Ateeq, and J.A. Henshilwood, J. Org. Chem., 1992,57,5290; (b) J.H. Rigby and S.V. Cuisiat, J. 0%. Chem., 1993,58,6286; (c) J.H. Rigby, H.S. Ateeq, and A.C. Kruegar, Tetrahedron Lett., 1992,33,5873; (d) J.H. Rigby, Ace. Chem. Rex, 1993,26,579; (e) J.H. Rigby and V.P. Sandanayaka, Tetrahedron Lett., 1993,34,935. Tetrahedron Lett., 1993,34,5397; (b) J.H. Rigby, H.S. Ateeq, N.R. Charles, J.A. Henshilwood, K.M. Short, and P.M. Sugathapala, Tetrahedron, 1993,49,5495. 199 V.H. Rawal and H.M. Zhong, Tetrahedron Lett., 1993, 34,5 197. 200 D.A. Corser, B.A. Marples, and R. Kinsey Dart, Synlett, 1992,987. 20 1 A. Boto, C. Betancor, T. Prange, and E. Suarez, Tetrahedron Lett., 1992,33,6687. 202 E.J. Corey, S. Daigneault, and B.R. Dixon, Tetrahedron Lett., 1993,34,3675. 203 D.R. Williams, P.J. Coleman, and S.S. Henry, J. Am. Chem. SOC., 1993,115,11654. 204 L.A. Paquette and P.C. Astles, J. Org. Chem., 1993,58, 165. 205 L.E. Tietze and U. Beifuss, Angew. Chem., Znt. Ed. Engl., 1993,32, 131. 206 T.-L. Ho, ‘Tandem Organic Reactions’, Wiley Interscience, 1992. 207 C.J. Roxburgh, Tetrahedron, 1993,49,10 749. 208 L.A. Paquette and C.J. M. Stirling, Tetrahedron, 1992, 209 C.D. Johnson, Acc. Chem. Res., 1993,26,476. 210 N.A. Petasis and M.A. Patane, Tetrahedron, 1992,48, 198 (a) J.H. Rigby, G. Ahmed, and M.D. Ferguson, 48,7383. 5757. Boden and Pattenden: Saturated and partially unsaturated carbocycles 455

ISSN:1350-4894    

DOI:10.1039/CO9940100433

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Recent developments in the synthesis of medium-ring ethers MARK C. ELLIOTT Department of Chemistry, Loughborough University of Technology, Loughborough, Leicestershire, LEI 1 3TU, UK Reviewing the literature published between 1 October 1990 and 30 June 1994' 1 Introduction 2 3 4 Rearrangement reactions 5 Ring expansions 6 Modification of lactones 7 Conclusion 8 References Cyclization by C-0 bond formation Cyclization by C-C bond formation have been included elsewhere in the appropriate section. 2 Cyclization by C-0 bond formation V. S. Martin et al. have shown6 that oxepanes can be formed in good yield by an intramolecular hetero-Michael reaction (Scheme I), although the cis-double bond in the substrate proved necessary for cyclization to occur. 1 Introduction Medium-sized rings, both carbocyclic and heterocyclic, are widely recognized as being difficult to prepare,2 and methods which work well for five- and six-membered rings are often unsatisfactory when applied to seven-membered rings and larger. The synthesis of cyclic ethers is no exception, and although the subject has been reviewed in general,3 the special problems posed by medium rings, together with the discovery of an ever increasing array of natural products containing such rings, merits a separate article.Many syntheses of seven- to nine-membered cyclic ethers have been reported since this subject was last reviewed.' Much of the impetus behind this work has been influenced by the structures of the monocyclic (Laurencia derived, etc.) and polycyclic (bre~etoxin,~?~ ciguatoxin) natural products containing these functionalities.This review covers the literature on medium-ring ether synthesis from 1 October 1990 to 30 June 1994, with emphasis on methods specifically designed for the synthesis of such compounds rather than extensions of tetrahydropyran synthesis to larger ring sizes. Examples of six-membered ring formation have, however, been included in some cases in order to explain mechanistic points. involving C-0 bond formation, C-C bond formation, rearrangement and ring expansion as the cyclic ether forming step. Also a number of groups have developed general methods for the conversion of lactones into cyclic ethers, and a section on these reactions has been included. However, in cases where the lactone has been formed using novel chemistry these reactions The reactions have been classified into those BU'PhSii H Scheme 1 Nevertheless since the oxepane ring in natural products is often unsaturated, any methodology which permits the inclusion of a double bond is valuable. The stereochemistry of the cyclization can be controlled by the double bond geometry of the Michael acceptor, and therefore either diastereomer of the oxepane can be readily accessed.This methodology is versatile, and has also been applied to the preparation of tetrahydropyrans and tetrahydrofurans. As expected, in these cases no cis-double bond was required for cyclization to O C C U ~ . ~ ' ~ ambitious program towards the development of methodology for the synthesis of polycyclic medium-ring ethers9 The symmetrical unsaturated oxepane 1 has been prepared by the route shown in Scheme 2.1° of the cyclooct-3-enone-7,8-epoxide 2.Its silyl enol ether 4 was hydroborated and oxidized to give 5. Further oxidation followed by a diastereocontrolled reduction and deprotection gave the cis-diol6. Treatment with DBU led to the formation of diene 7, the diol moiety of which was cleaved with periodate to J. D. Martin and colleagues have embarked upon an The bicyclic ketone 3 was prepared ' by iodination Elliott: Recent developments in the synthesis of medium-ring ethers 457The final hydrogenation reaction can be carried out to give either stereoisomer of the ornithine derivative depending upon the reagent used.loO of the classical Strecker amino acid synthesis, and a number of chiral versions of this reaction using chiral auxiliaries on the amine have been developed.In the latest example, phenylglycidol is used as the chiral auxiliary as shown in Scheme 27. (R)-Phenylglycidol induces predominant formation of the ( S)-isomer at the new chiral centre, and the auxiliary can be cleaved either by reduction or oxidation, allowing a wide range of amino acids to be prepared in this way.lol The formation of the a-C-CO, bond is at the heart NaHS03 (OHR - /OH PhANACN H (OHR R Ph A H N k O 2 H /OHm - I I A H2NhC02H H Scheme 27 A stereoselective synthesis of P-hydroxy-a -amino acids based on the Strecker reaction has also been reported (Scheme 28). Thus 0-protected optically pure cyanohydrins, which are readily available,lo2 are reduced by DIBAL-H to the corresponding imines.The latter compounds undergo imine exchange when treated with an amine, followed by stereoselective addition of hydrogen cyanide giving P-hydroxy-a -amino acids after further manipulation. OCMe20Me PhXCN (i) (ii) DIBAL-H RNHz, P h q c N p h q c o 2 H NHR NHR (iii) HCN (iv) HCI Scheme 28 Baldwin et al. have shown that aspartic acid derived P-lactams 23 react with both organocuprates and sulfur stabilized carbanions to give y-keto-a -amino acids by nucleophile induced ring-opening of the p-lactam ring.lo4 23 2.3.4 Synthesis of #?-amino acids 2.3.4.1 Racemic syntheses of #?-amino acids Reaction of diethylenetriamine with ReNCl,( PPh,), results in oxidative cleavage of the C-N bonds to give p-alanine.Io5 A racemic synthesis of norbornane-containing p-amino acids of type 24 and their derivatives by the Diels-Alder reaction of maleic acid derivatives followed by a Curtius rearrangement has been reported.lo6 The use of penicillin acylase to resolve the N-phenylacetyl derivatives of a variety of p-amino acids has been reported, and enantiomeric excesses of > 99% were obtained.'" dNH2 CO2H 24 X = 0, CH2 An attractive approach for the synthesis of P-amino acids involves the addition of an ester or acid enolate to an imine.However, this reaction is more difficult than the corresponding enolate addition to carbonyl compounds due mainly to the lower electrophilicity of the C=N double bond compared to C=O. The introduction of sulfonyl groups onto the imine nitrogen raises the electrophilicity of the imine, and reaction with Reformatsky reagents then provides a route to p-amino esters and acids.'OX An asymmetric version of this reaction has also been pub1ishedlo9 (see Section 2.3.4.2).In an alternative approach, lithium perchlorate' catalyse the addition of silylketene acetals to aldimines, giving p-amino esters. or zinc bromide' I can be used to 2.3.4.2 Asymmetric syntheses of B-amino acids A synthesis of p-amino acids and p-hydroxylamino acids based on the Lewis acid catalysed reaction of a silylketene acetal with a nitrone has been developed by Murahashi and Otake."* An asymmetric example of this reaction is shown in Scheme 29. OSiEt3 + PhAN+#O- II b y A P h Me026 OH Scheme 29 An asymmetric p-amino acid synthesis based on the stereoselective ring opening of chiral oxazolidines by Reformatsky reagents has been developed by Pedrosa et ~ 7 E .l ' ~ (Scheme 30). The degree of asymmetric induction depends upon the size of the R group. An almost identical approach to these compounds uses ethyl tributylstannylacetate in the presence of ZnC1, and F3B.0Et2.114 The addition of organocerium reagents to the RAMP or SAMP hydrazones of 3,3-ethylene- 484 Contemporay Organic SynthesisMe OBn OAllyl I 15 Me KCHfiOMe THF, r.t. 16 17 80% total yield Scheme 5 a-anomer produced a 1.7: 1 mixture of oxepane and tetrahydropyran (Scheme 5).Is ketals in medium-ring ether synthesis.16 Fotsch and Chamberlin ' have described a novel variant of this method which involves the intramolecular opening of an epoxide by a carbonyl oxygen (Scheme 6).Kotsuki has previously described the use of bicyclic I Scheme 6 Moody et al. have shown that some of the earlier described rhodium( 11) acetate catalysed cyclizations leading to oxepanes can be carried out under milder conditions using the more active catalyst rhodium( 11) trifluoroacetamide.18 The reaction shown (Scheme 7 ) can be carried out at room temperature in Scheme 7 dichloromethane, whereas using rhodium( 11) acetate as catalyst, heating under reflux in benzene was required to effect conversion.' diazophosphonate 18 resulted in the formation of the corresponding oxepane-2-phosphonate 19, which was transformed into the cis-2,7-disubstituted oxepanes 20 and 2 1 using standard chemistry. Cyclization to the 7-6 and 7-7 bicyclic systems 22 and 23 was effected by treatment with TMSOTf and triethylsilane, conditions originally developed by Olah2' and used to great effect by Nicolaou (see later). Although the reaction predominantly gave the trans-ring fused ethers, the stereoselectivity was at best 3:l (Scheme 8).In related work,20 the cyclization of the ia 19 Scheme 8 20 n = l 21 n = 2 Me3SiOTf Et3SiH CHfil2 1 22 n = 1(78?h) 23 n = 2 (51%) The rhodium carbenoid cyclization can also be used for the formation of eight-membered rings. Meier et al. have improved on the earlier reported yield22 for the synthesis of the oxocane 24 by the use of high dilution techniques and slow addition.23 A fivefold increase in dilution led to an increase in yield from 3 1% to 77% (Scheme 9). 0 0 24 'OH Scheme 9 In an alternative procedure, intermolecular rhodium( 11) catalysed O-H insertion reactions were used; these were followed by a Wadsworth-Emmons reaction and simple acid catalysed cyclization (Scheme 10).*4 A further carbenoid-based approach to medium-ring ether synthesis has been described by Elliott: Recent developments in the synthesis of medium-ring ethers 459HO(CHd4 CS4 benzene * reflux.81 % P,,, Scheme 10 Clark and co-workers (Scheme 1 1).25 The oxonium ylide 26 formed by transition metal catalysed decomposition of the diazo compound 25 rearranges by a [2,3]-sigmatropic shift to give the oxepane 27. This process also gives, albeit in lower yield, the oxocane 28. b Scheme 11 26 1 27 reflux, 404L \*- 28 Copper( 11) hexafluoroacetylacetonate is the catalyst of choice since, rhodium(1r) acetate, the more commonly used catalyst for such reactions, is less selective in that C-H insertion products are also obtained, resulting in a lower yield of the desired cyclic ethers, Pirrung has described a sequence of photochemical reactions which involve medium-ring ethers at two stages.26 Irradiation of cyclopentanone enol ethers 29 and 30 gave the fused cyclobutanes 3 1 and 32 containing oxepane and oxocane rings respectively (Scheme 12).29 n = 1 30 n - 2 Scheme 12 31 n = 1 (73%) 32 n = 2 (3040%) Baeyer-Villiger oxidation of 3 1 and 32 followed by hydrolysis and esterification gave the cyclobutanones 33 and 34 respectively. Photolysis of cyclobutanones is believed to proceed via a 2-tetrahydrofuranylidene7 e.g. 35 and 36. This oxacarbene then inserts into 0-H bonds to give moderate yields of the oxepane 37 and oxocane 38 acetals as shown in Scheme 13.31 n = l 32 n = 2 33 n = l 34 n = 2 35 n = l 3 6 n = 2 Meo2cq 37 n = 1(53%) 30 n =2(49%) Scheme 13 A simple two step procedure has been used to prepare the functionalized oxepane 39 from 1,7-0ctadiene.~~ Cycloaddition of triphenylacetonitrile oxide 40 with 177-octadiene 4 1 gave the isoxazoline 42 in almost quantitative yield. Treatment with iodine then gave the oxepane 39 in 80% overall yield (Scheme 14). However, following the same protocol using 1 ,8-nonadiene resulted in none of the corresponding oxocane. 41 benzene fiN- pbc 40 >5N phc 42 NC a1 Scheme 14 39 Intramolecular 7-ex0 cyclization of an alcohol onto an thiiranium ion 43 gave a mixture of diastereomeric oxepanes 44 and 45 along with a single isomer of the oxocane 46.As expected, oxepane formation was the predominant process (Scheme 15).28 Five- to eight-membered ring lactol ethers, e.g. 48, are formed in good yield by the intramolecular cyclization of o-hydroxy- a -sulfonylmethanoethers 4 7 (Scheme 1 6).2y 460 Contemporary Organic SynthesisAlthough direct cyclization of 1,6-diols is not generally an efficient method for the production of oxepanes, Tagliavini et al. have shown3' that a catalytic amount of butyltin trichloride promotes this cyclization by way of an organotin alkoxide. Water and the product oxepane 54 are co-distilled out of the reaction (Scheme 19). 43 - 0 5 mol% BuSnCI:, 40% QOH 54 Scheme 19 46 (21%) 45 (35%) 44 (20%) Scheme 15 Cyclization of diols can, however, be efficient if the conformational mobility of the substrate is reduced.The presence of two cis-alkene moieties in the diols 55 facilitates the cyclization to the dihydrooxepins 56 (Scheme 20).32 t Br,Mg.0Et2 N a H a , ultrasound 6796 BnO 48 PhS02 BnO nOH 47 Scheme 16 Exchange with benzenesulfinic acid gave the 2-phenylsulfonyloxepane 49 which was allowed to react with benzylmagnesium chloride to give 2-benzyloxepane 50 (Scheme 1 7).29 55 56 R' = Bu', I? = H R' = H. R2 = But 87% 85% Scheme 20 48 49 1E.J' The hydroxyaldehydes 58, prepared as shown in Scheme 2 1 , cyclize efficiently to the oxepanes 59 upon treatment with trimethylsilyl cyanide. The yields shown are for the three step process from 57.33 Bn 0 n n 0 0 (i) LI.naphthalene CI AH (ii)R'RkO * R 2 R w H 50 Scheme 17 OH 57 Dimethyldioxirane oxidation of the o-hydroxyallene 5 1 gave the isolable bis-epoxide 52. Simply heating this compound at 60°C for 10 days in the presence of potassium carbonate gave a 78% yield of the oxepane 53 (Scheme 18).30 HCI, H@ 1 A 58 59 Me Me&H R' = H, I? = Ph 36% R'=R2=Et 39% R1R2 = -(CH2)5- 34% R'=R2=Me 22% 98% 51 52 K&.60"C 10 d. 78% Scheme 21 Thallium(xxx) acetate has been found to promote the intramolecular cyclization of hydroxyakenes 60. This reaction works best for the formation of tetrahydropyrans, but is still efficient for the preparation of tetrahydrofurans and oxepanes, e.g. 6 1 (Scheme 22).34 HO 0 53 Scheme 18 Elliott: Recent developments in the synthesis of medium-ring ethers 46 1Scheme 22 However, oxocane formation was unsuccessful, as was oxepane formation from citronellol62.These observations suggest that the reaction proceeds via Markovnikov addition of thallium( 111) acetate to give the more stable carbenium ion 63. Thus, in the case of citronellol, cyclization would give the oxocane 64, which is presumably disfavoured on entropic grounds (Scheme 23). Terpenoid oxepanes 67 and 68, isolated from quince fruit, have been synthesized from the corresponding diols 65 and 66. The primary alcohol was selectively tosylated and cyclization was effected using sodium hydride in DMPU (Scheme 24).35 Surprisingly, in this case the inclusion of a double bond in the acyclic precursor 65 actually resulted in a lower yield of the cyclized product 67.The 8-8-6-6-6 fused system 7 1 which corresponds to the FGHI and J rings of brevetoxin A has been synthesized by the Nicolaou group. Both oxocanes were formed by cyclization of an alcohol onto a dithioketal. One of the cyclizations (69 to 70) is shown in Scheme 25.36 Ph 70 OTBDPS H H H 71 Scheme 25 P O H 65 P O H 67 TsCI. PY I NaH.DMPU $:, Scheme 24 Contemporary Organic Synthesis 68 The same workers have prepared hemibrevetoxin B (see later) and its epimer, (7aa)-epi-hemibrevetoxin B using a range of cyclization chemistry developed for this purpose. The c-ring was prepared by the simple but effective reductive cyclization of a hydroxyketone (72 to 73) as shown in Scheme 26.37 OBn H Me 72 OBn H Me 73 Scheme 26 3 Cyclization by C-C bond formation The wring of (7aa)-epi-hemibrevetoxin B was prepared using the photochemical cyclization of a bis-thioester (Scheme 27).37 462Me3S/ OBn Scheme 27 Yamamoto's group have developed an efficient route to P-alkoxy substituted cyclic ethers related to the brevetoxin natural products.Lewis acid treatment of the stannane 74 gave a 59% yield of 75 as a single trans-diastereoisomer (Scheme 28).3x 74 75 Scheme 28 A similar cyclization was used to prepare the m-ring fragment of gambiertoxin 4B. Treatment of chiral non-racemic 76 with boron trifluoride etherate gave an essentially quantitative yield of the fused oxepane 77.39 An earlier report3* suggested that the fusion of a cyclohexyl ring makes cyclization more favourable by reducing the conformational mobility of the acyclic precursor.Presumably the tetrahydropyran ring exerts the same effect in this case (Scheme 29). 76 77 Scheme 29 The cyclization onto aldehydes is generally accompanied by higher stereocontrol than the acetal cyclizations. In cases where diastereoselectivity is low, the use of titanium( IV ) chloride in conjunction with triphenylphosphine can be advantage~us.~" The aldehyde cyclizations have been used to prepare 6-7-7-6 and 7-7-6-6 fused systems related to brevetoxin B and hemibrevetoxin re~pectively.~ 1,42 This methodology is equally applicable to the synthesis of tetrahydropyrans. In this case the reaction has been studied under a wide range of condition^.^^ It has been found that if a protic acid is used, the sense of diastereocontrol is determined by the double bond geometry (Scheme 30).However Lewis acid promoted cyclization of E or 2 78 produced the same trans-isomer 80. U 2-70 79 U 678 80 Scheme 30 Martin has shown that this type of cyclization can be applied to the preparation of the heavily functionalized 8-6-7 fused system 83. The protected diol81 (the diacetate analogue of which was earlier used in the preparation of the 6-6-7 fused system 14, see Scheme 4) was converted into the bis-stannane 82. This was then oxidized and cyclized to 83 in a one-pot process (Scheme 3 1 ).44 HO, ,OH SnBy Bu3Sn' \ 81 82 B u4N+104- then F3B.OEt2.63'% 1 H H HO 83 Scheme 31 Cyclization of allylsilanes onto acetals proceeds similarly to the analogous allylstannane cyclizations (Scheme 32).45 In this case an acyclic acetal84 was used, such that one of the acetal oxygen atoms is retained in the oxacyclic ring 85.This is therefore an endo cyclization rather than an ex0 acetal cyclization as described by Yamamoto. chromium-mediated cyclization of bromo aldehydes 86 and 87 to give fused oxepanes 88 and oxocanes 89 (Scheme 33).46 Attempted production of a benzopyran A further, similar example is provided by the Elliott: Recent developments in the synthesis of medium-ring ethers 463SiMea phso2&7 5396- EtAICI, OMe 84 Scheme 32 86 87 Scheme 33 85 OH 88 -0 4 lpcydohexadiene chbrobentene 5 f OTBDMS 90 An elegant approach to oxepanes and oxocanes from a common precursor has recently been reported by Mujica et ~ 1 . ~ ~ whereby the alcohol 94 was transformed into the halides 95 and 96. These were then cyclized to the oxepane 97 and oxocane 98 in 21% and 80% yields respectively (Scheme 35).The lower yield in the oxepane cyclization was rationalized in terms of the known difficulty in displacing halides with /3-alkoxy substituents. 89 J TBDPSO 95 [a? OTBDMS ] 92 a OTBDMS 93 1.7:l diastereoisomer mix Scheme 34 (I) NaH. Me1 (i) TsCI, DMAP, Et3N / \WBAFFF (iii) TsCI, DMAP. Et3N (ii) NaI, acetone 85% (hr) NaI, acetone by this method failed as elimination gives predominately the phenol (salicylaldehyde). by the process shown in Scheme 34.47 Bergman cyclization of the enediyne 90 gives the diradical9 1 which rearranges by two [ 1,5] shifts to the diradical92. Recombination then gives the oxocane 93. A similar oxocane 93 is formed, albeit in low yield, LO Y , TBDMSO 91 / Ts 94 Me0 <\ 96 OMe I LDA.THF I LDA,THF 1 21% Ts 1 " 97 98 Scheme 35 In connection with the rhodium( 11) acetate catalysed cyclizations of diazo alcohols, it has been shown that it is also possible to use an intermolecular 0-H insertion of a rhodium carbenoid, followed by an intramolecular Wadsworth-Emmons reaction as the cyclization step.24,4y The reaction is quite general, and works with both aldehydes and ketones as the carbonyl component, and for phosphonyl-ketones, -sulfones, and bis-phosphonates, as well as phosphonoacetates (as shown in Scheme 36).Rhodium( 11) acetate catalysed insertion into a secondary alcohol led to the 2,7-disubstituted oxepane 99. A similar intramolecular Wittig reaction has been used by Bestmann et al. to prepare the oxepane 102.Oxidation of the bis-phosphonium ylide 100 gave a 24% yield of the oxepane 102, presumably via the aldehyde 10 1 (Scheme 37).50 Overman et al. have demonstrated the power of their acetal-alkene cyclizations5' with an elegant first total synthesis of the marine natural product isolaurepinnacin. The precursor 103, with most of the required functionality in place, was cyclized to the oxepane 104 in 90% yield (Scheme 38). This 464 Contemporary Organic SynthesisQ C z E t Me Qo2, 99 Scheme 36 100 101 0 0 ° 102 Scheme 37 intermediate was converted into isolaurepinnacin (105) in five simple steps.52 by Speckamp and c o - ~ o r k e r s ~ ~ to provide the unsaturated oxepane shown in Scheme 39. been shown to provide oxepanes 106 in moderate yields (Scheme 40).Use of a chiral titanium BINOL complex led to high levels of asymmetric induction.s4 Oxocanes 107 can also be formed by this process although the yields are lower, reflecting the greater difficulty of eight-membered ring formation. Addition of silver perchlorate led to a slight increase in enantioselectivity, although the yields were again decreased. When the organozinc compound 108 is heated under forcing conditions a similar intramolecular ene reaction takes place to give the oxepane 109 as a mixture of geometrical isomers (Scheme 4 1).55 A small amount of an oxocane, produced by endo cyclization, was also obtained. An acetal-alkyne cyclization has recently been used The Lewis acid catalysed carbonyl-ene reaction has Scheme 38 103 r= 105 idaurepinnacin Scheme 39 dc02M 106 n = 1 (64%; 88% e.e.) 107 n = 2 (1 2%; 34% 8.e.) Scheme 40 sealed tube, 130 "c a h .40% 1 08 109 Scheme 41 Radical reactions to form medium-sized rings are often accompanied by hydrogen abstraction processes which lead to overall reduction of the radical. Crich has shown that in the case of the cyclization of the acyl radical 110 the favoured process is a 7-endo-cyclization, to give the fused oxepane 11 1. The yield is low due to the rapidity of decarbonylation of 110 to give the stabilized radical 112 which cyclizes to the tetrahydrofuran 113 (Scheme 42). Elliott: Recent developments in the synthesis of rnediurn-ring ethers 465Bu3SnH, hv 1 H 110 p1 112 Q H 111 (25') H 113 (32%) Scheme 42 Although a tetrahydropyran would be produced by exo-cyclization of the acyl radical 110, one was not observed.s6 become easier because of the lack of transannular strain present in these molecules.Ohtsuka et al. have used this to good effect in their preparation of oxocanes and azocanes (Scheme 43). Cyclizations to give rings larger than ten-membered 114 X=O,Y=CHp 115 X=CH*,Y=O Ph 116 X=O,Y=CH2,93% 117 X = CH2, Y = 0,86% (i) LDA then PhCHfir (ii) Nd04 I 0 120 X=O,Y=CHz 121 X = CH2, Y = 0 1 Raney Ni 122 X = 0, Y = CH2, 85%from 118 123 X = CH2, Y = 0,93%from 119 Scheme 43 8 118 X = 0, Y = CH2,59% 119 X = CH2, Y = 0,92% Macrocyclization of 1 14 and 1 15 gave the 12-membered ring amides 1 16 and 1 17 in good yields. This functionality then 'holds' the reacting sites together so that the actual cyclization steps (1 18 to 120, 119 to 12 1) proceeded in almost quantitative yield.Having served its purpose, the temporary connection was then reductively removed to give the oxocanes 122 and 123." enjoying increased popularity.s8 Anodic oxidation of a-stannylethers has been demonstrated to be effective in the synthesis of tetrahydropyrans and oxepanes. The proposed mechanism is illustrated for the formation of a tetrahydropyran 130 (Scheme 44). Single electron oxidation of the substrate 124 leads to the formation of the radical cation 125. Loss of tin can be heterolytic, leading to the oxygen stabilized radical 126, or homolytic leading to the oxonium ion 127. Since the radical 126 would be expected to cyclize onto the double bond in a 5-exo-trig manner, to give a tetrahydrofuran 128, then it is proposed that if this intermediate is formed, it must be rapidly oxidized to the oxonium ion 127.This ion undergoes a 6-endo-trig cyclization to give the more stable (as opposed to the primary carbenium ion which would be formed by 5-exo cyclization) carbenium ion 129 which is quenched by the tetra-n-butylammonium tetrafluoroborate present in the reaction mixture.59 Electrochemical synthesis has recently been ynBu3 124 + SnBy I 125 126 128 \ J - 127 JJ+ c7H15 F 130 (83%) 129 Scheme 44 The carbenium ion 129 can also lose a proton to give an alkene. Thus in the case of 13 1, the fluorinated oxepane 132 and the tetrahydrooxepin 133 are obtained in a combined yield of 89% (Scheme 45). 466 Contemporary Organic Synthesis131 132 (61%) Scheme 45 133 (28%) A nitrone cycloaddition of a glucose derivative provides access to either enantiomer of the chiral oxepane derivative 1 36.60>61 Treatment of 3- 0-allyl-~-( + )-glucose 134 with N-benzylhydroxylamine, followed by acetylation gave a 55-60% yield of oxepane 135, oxidative cleavage of the side chain of which gave 136 which contains two of the original chiral centres of the glucose (Scheme 46).DGlucose I yH2Ph A& 136 135 Scheme 46 Alternatively,61 a one-carbon degradation of glucose provided the aldehyde 138 (via 137) in which the two chiral centres to be retained have the opposite stereochemistry to those in the original glucose derivative 134. Thus, formation of the nitrone followed by cycloaddition and modification gave the oxepane 139, the enantiomer of 136.Finally, the isoxazolidine ring was reductively cleaved to give the chiral oxepane 140 (Scheme 47). A further example of a nitrone cycloaddition to give oxepanes has been reported by Aurich and co-workers (Scheme 48).h2 This reaction is extremely substrate dependent. Nitrone 14 1 gives only the oxepane 142 (92% yield) while the isomeric nitrone 143 gives the tetrahydropyran 144 exclusively. This is in agreement with the observations of Shing et al. who have noted that for systems related to 138, minor structural modifications can lead to the formation of tetrahydropyrans at the expense of oxepane~.~~ Olefin metathesis has received little attention from synthetic organic chemists. The metathetic ring closure of 1,6- 1,7- and 1,g-dienes has been recently investigated and found to be efficient and mild.Oxepane formation by this method is shown in Scheme 49.64 137 OHC FHpPh PhCHdHOH 55% from 137 0 CH2Ph I 138 NHAc 140 139 Scheme 47 p' %fi&A 0- I O - Y Me toluene, 92% reflux * M e 0 141 142 Bu: 143 M l 144 Scheme 48 benzene. 25 OC Ph 75% Ph /I Ph R = CMe(CF3)2 M&Me RO'I Me RO Scheme 49 Elliott: Recent developments in the synthesis of medium-ring ethers 467The same authors have more recently reported a ruthenium-based catalyst which gives comparable yields, with the advantage of being less air 4 Rearrangement reactions Holmes has shown that his earlier described Claisen rearrangement of ketene acetals can be readily extended to the synthesis of nine-membered lactones. The easily prepared (79% over six steps) selenyl ether 145 was isolated as a mixture of three diastereoisomers. These were oxidized to the selenoxide and immediately heated to give the ketene acetall46 which underwent Claisen rearrangement to give the lactone 147.The ketene acetal is presumably a mixture of diastereoisomers. However, both isomers react to give the same lactone via chair transition states 148 and 149. Reaction through a boat transition state 150 would give rise to a product containing a trans-double bond, and is not observed (Scheme 50).66 OTBDPS MeOH. H@ . * (il) DBU, toluene 939L Phse) 145 - El TBDPSO 148 Scheme 50 146 1 O ' \ 147 149 150 This lactone has been converted into an advanced intermediate for the synthesis of obtusenyne (Scheme 5 1).67)68 A highly diastereoselective oxidation of the enolate of 147 followed by Tebbe methylenation gave 15 1. This was then subjected to intramolecular hydrosilylation followed by oxidation to give 152.A similar sequence of reactions starting from dimethyl ( R )-malate 153 via a six-membered cyclic acetal 154 has resulted in an elegant total synthesis of ( + )-laurencin 155, another of the many Laurencia metabolites, (Scheme 52).69 of the selenyl ether precursor can result in a diastereoselective Claisen rearrangement; e.g. 156 to 157 (Scheme 53).'" Incorporation of substituents onto the double bond (i) KHMOS 147 (i) Tebbe reagent (11) NaOH (li) TBAF 89% I 151 152 Scheme 51 0 OH oAo U O T B D P S Me0 153 similar to HO" Ho> 0 8 , OTBDPS =Q, 0 OTBDPS 155, (+)-laurencin Scheme 52 OBn 156 Scheme 53 157 468 Contemporary Organic SynthesisThis methodology has also been applied to the synthesis of the proposed nine-membered lactone structure of ascidiatrienolide A, leading to a revision of the structure of this natural product.71 Cope rearrangement of cis-divinylepoxides gives rise to dihydrooxepins in synthetically useful yields (Scheme 54).72 poM Me3si Me3Si pc0m Me3Si 50% I I 66% t-p Me3Si 66% Pdo C02Me Me3si.82% M = Me3Si, 78% M=Tf, 77%0 Scheme 57 Scheme 54 (steric constraints due to the epoxide preclude the normally favoured chair transition state), the E-isomer 159 rearranges smoothly to give the 4,5-cis-dihydrooxepin 161, whereas the Z-isomer 160 requires a longer reaction time, giving only the 4,5-trans-dihydrooxepin 1 62.73 Where one of the double bonds forms part of a Silyl enol ether or an enol triflate the dihydrooxepins formed are amenable to further modification.The silyl enol ether can be converted into the lithium enolate, which then undergoes aldol reactions with aliphatic, aromatic, and a ,/-?-unsaturated aldehydes (Scheme 5q.72 Me3Si BH I Me3Si R = Ph 56% R = (CH3)sCH 69'Yo R = (E)-CH&H=CH- 76% Scheme 55 The triflate group can be replaced by an alkyl group via a cuprate displacement (Scheme 56).72 Bu Bu&uLi,THF 50% Scheme 56 Palladium-catalysed Stille and Heck type couplings Wadsworth-Emmons olefination of the can also be carried out on the triflate (Scheme 57).72 2,3-epoxyketone 158 gave a mixture of cis- and trans-divinylepoxides 159 and 160 which were readily separated and subjected to Cope rearrangement (Scheme 58).Assuming a boat-like transition state Me3Si 159 (51%) 158 I 160 (34%) /'I: t I QM Q Me Me3Si CN Me3Si kN 161 (85%) 162 (85') Scheme 58 A similar [3,3]-sigmatropic shift has been used by Hofmann and R e i ~ s i g ~ ~ and by Boeckman et al.75 to prepare 2,5-dihydrooxepins. Since the product is an ally1 vinyl ether, this reaction is formally a retro-Claisen rearrangement. The cyclopropane ester 163 (prepared by a selective metal-catalysed cyclopropanation of a 2-siloxy diene with methyl diazoacetate) was reduced to the alcohol 164 in high yield. Partial oxidation under Swern conditions gave only the dihydrooxepin 166. Since the cyclopropane ring in 165 is substituted by both an electron donor Elliott: Recent developments in the synthesis of medium-ring ethers 469and an electron-acceptor, one would expect the central C-C bond to be weakened (see resonance structures 165a and 165b), thereby favouring dihydrooxepin formation (Scheme 59).74 TBDMSO P C 0 2 M e 163 TBDMSO 0 166 TBDMSO) 6 165a Scheme 59 TBDMSO 6- LIAIH4, Et@ 96% ___c 164 Swern oxidation 91% 1 165 165b A similar oxidation of cyclopropane derivative 167 gave the 2,5-dihydrooxepin-6-aldehyde 168 (Scheme 60).As expected, if the cyclopropane is enantiomerically enriched, then the dihydrooxepin is formed with no loss of stereochemical integrity.7s 0 167 168 Scheme 60 5 Ring expansions Another total synthesis of ( + )-laurencin 155 shows an interesting approach to oxocane synthesis (Scheme 6 1 ). Treatment of the cyclobutanone 169 with acid led to the hemi-ketal 170.Selective protection of the primary alcohol was followed by oxidative cleavage of the diol to give the keto-lactone 171 in high yield. Conversion to the diene-triflate 172 was followed by cuprate displacement to give 173. Finally, the silyl en01 ether 173 was converted into the silyl ether 174 which was hydroborated and oxidized to give the oxocane ketone 175, obtained as the 2,8-cis- isomer after epimerization with triethylamine. Conversion into ( + )-laurencin was accomplished in a further 11 steps.76 &+ %.+-$ OH OH 169 170 (0 p e l (11) Pb(OAc), 76% from 169 P!l6 1 74 Scheme 61 Pvb 175 Feng and Murai have also developed a novel approach to the c- and D-rings of hemibrevetoxin B based on a double Baeyer-Villiger oxidation of the decalin-dione 176.Oxidation of 176 gave the lactone 177 which was converted into the oxepane 178 using a cuprate displacement of a triflate in a similar manner to the above. Almost identical modification of the other ring gave the fused bis-oxepane system 179 (Scheme 62).77 A recent approach to the anti-fertility agent zoapatanol uses a cyclopropanation-ring expansion strategy to provide the key oxepane ring (Scheme 63). Thus the silyl enol ether 181 of the ketone 180 was cyclopropanated using bromoform in the presence of base. Acidic treatment led to the oxepane 182 (65% overall yield) which was further elaborated to provide the advanced intermediate 1 83.78 than direct free radical cyclizations where medium-sized rings are desired. Dowd and Choi have used a one-carbon ring expansion to prepare the oxepane 184 in 66% yield.Slow addition of the substrate to tributyltin hydride was required (Scheme 64).7y Directed cleavage of oxiranylcarbinyl radicals, e.g. 189, derived from thiocarbamates 185 and 186 leads to the formation of oxepanes 187 and oxocanes 188 in good yields. The phenyl group is required to stabilize the radical 190, and so favour C-C bond cleavage over C-0 bond cleavage (Scheme 65).*O monocyclic systems is a common tactic in organic synthesis. We have recently showns' that oxonanes Free radical ring expansions are much more efficient Cleavage of bicyclic systems to give ring-enlarged 470 Contemporary Organic SynthesisS &p Ph 185 n = 1 186 n = 2 Bu3SnH. AlBN 1 76 177 187 n = 1 (72%) 188 n = 2 (66%) % Et O( C H2) 2 0 H ATBS 185 189 1 90 Et O( C H2)20 0 Scheme 65 192 can be readily prepared by the oxidative cleavage of tetrahydrophthalans 19 1 (Scheme 66).The dialkyl oxonane 193, prepared by this method, was deoxygenated in three steps to give obtusan 194 containing the carbon skeleton of the Laurencia metabolite obtusenyne. (9 MOMCI RuCIs NaIO4 58% 191 192 0 \ 70% EtO( CH2) 2 0 1 79 Sd Scheme 62 193 194 L MeiOTf. Et3N Scheme 66 During the course of studies towards nigericin, Holmes and Bartlett discovered that the reaction of silyl enol ether 196 with the cyclic acetal 195 is strongly dependent on the stereochemistry of the substrate (Scheme 67). Thus a 78:22 a$ mixture gave 180 181 CHBr3, BubK then HCI. THF 65% from 180 I Scheme 63 I 195 ““‘Y 0 0 - * DOH x: 196 , C02Me - 889c 184 198 Scheme 64 Scheme 67 Elliott: Recent developments in the synthesis of medium-ring ethers 471a 23:77 mixture of tetrahydropyran 197 and oxocane 198 (78% total yield), whereas pure ( > 95%) a-acetal gave mainly the oxocane 198, with less than 5% of the tetrahydropyran being formed.Both products were formed as single stereoisomers. This suggests that each isomer of acetal gives rise to the formation of a single product.s2 It has been suggested that the methyl group directs approach of the titanium tetrachloride to the least hindered acetal oxygen. This dictates the direction of acetal opening and hence the product formed (Scheme 68).s2 cr Scheme 68 +O D O H Finally, thermolysis of the cyclopropanated tetrahydropyran 199 in the presence of magnesium and chlorotrimethylsilane led to a one-carbon ring expansion, giving the oxepane 200 in 40% yield (Scheme 69).s3 1 99 200 Scheme 69 6 Modification of lactones Petasis and Bzowej have reporteds4 that dibenzyltitanocene reacts with ketones, esters, and amides in the same way as the Tebbe reagent to give the corresponding benzylidene compounds. In the case of the lactone 201 this was immediately followed by hydrogenation to give the oxepane 202 (Scheme 70).201 202 Scheme 70 Mukaiyama has described a Lewis acid mediated reaction of lactones with silyl ketene acetals. E-caprolactone 201 has been converted in this way to 203,204, and 205 in good yields (Scheme 71).s5 Qo 201 +OTBDMS OEt 203 R = Et, NU = H 90% 204 R = Me, Nu = ally1 67% 205 R = Me, Nu = CN 62% Scheme 71 Lactones can also be converted into six- and seven-membered cyclic enol ethers.Palladium( 0)-catalysed cross-coupling of the triflate 206, derived from E-caprolactone, with hexamethylditin gave the oxepane 207 in 78% overall yield (Scheme 72).86 206 207 Scheme 72 The final, and most spectacular, example of lactone modification is provided by Nicolaou’s synthesis of hemibrevetoxin B (Scheme 73). Cyclization of the hydroxy-acid 208 provided the lactone 209 which was first converted into the thiolactone 2 10. Cuprate alkylation gave the cyclic enol ether 2 1 1. The required oxygen atom was introduced via a hydroboration/oxidation sequence followed by standard chemistry to give the hydroxy-acid 212. This was then elaborated in a similar manner to provide the tetracyclic 7-7-6-6 ring system of b r e v e t o ~ i n .~ ~ , ~ ~ 7 Conclusion The last four years have seen a wide range of new methods for the synthesis of oxepanes, oxocanes, and oxonanes. These methods are generally mild and tolerant of other functionality in the molecule, as required by the complex natural products which often contain these moieties. A number of total syntheses have been reported, and no doubt more will be achieved in the near future. 472 Contemporary Organic SynthesisOBn Z4,Btrkhbrabenzayl chloride OBn OBn Lawesson's reagent + OBn 92% OBn 209 21 0 1 TBSO(CH&CH,(Z-Th)(CN)CuLI, I(CH&)I. pempidine, 85% OBn 3 Hoe OBn Hf.THFthenHf12.NaOH 89% OBn OBn 0 R H H H HOH H H H02C R = TBSO(CH2)3CHz 21 1 R = TBSO(CH2)3CH2 21 2 Scheme 73 8 References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 , C.J.Moody, and M.J. Davies, Stud. Nut. Prod. Chem., 1992,10,201. G. Illuminati, and L. Mandolini, Acc. Chem. Res., 1981, 14,95. C.J. Burns, Contemp. Org. Synth., 1994,23. K.S. Rein, D.G. Baden, and R.E. Gawley, J. 0%. Chem., 1994,59,2101. K.S. Rein, B. Lynn, R.E. Gawley, and D.G. Baden, J. Org. Chem., 1994,59,2 107. M.A. Soler, J.M. Palazon, and V.S. Martin, Tetrahedron Lett., 1993,34,547 1. J.M. Palazon, M.A. Soler, M.A. Ramirez, and V.S. Martin, Tetrahedron Lett., 1993,34,5467. V.S. Martin, and J.M. Palazon, Tetrahedron Lett., 1992, 33,2399. E. Alvarez, M.T. Diaz, R. Perez, J.L. Ravelo, A. Regueiro, J.A. Vera, D. Zurita, and J.D. Martin, J. Org. Chem., 1994,59,2848.E. Alvarez, M.T. Diaz, R. Perez, and J.D. Martin, Tetrahedron Lett., 1991,32,2241. E. Alvarez, M.T. Diaz, M.L. Rodriguez, and J.D. Martin, Tetrahedron Lett., 1990,31,1629. E. Alvarez, D. Zurita, and J.D. Martin, Tetrahedron Lett., 1991,32,2245. M. Zarraga, and J.D. Martin, Tetrahedron Lett., 1991, 32,2249. E. Alvarez, M. Rico, R.M. Rodriguez, D. Zurita, and J.D. Martin, Tetrahedron Lett., 1992,33,3385. M. Sasaki, M. Inoue, and K. Tachibana, J. 0%. Chem., 1994,59,715. H. Kotsuki, Synlett, 1992,97. C.H. Fotsch, and A.R. Chamberlin, J. Org. Chem., 1991, 56,4141. G.G. Cox, J.J. Kulagowski, C.J. Moody, and E.-R.H.B. Sie, Synlett, 1992,975. M.J. Davies, C.J. Moody, and R.J. Taylor, J. Chem. SOC., Perkin Trans. I, 1991,l. C.J. Moody, E.-R.H.B. Sie, and J.J.Kulagowski, J. Chem. SOC., Perkin Trans. I, 1994,501. M.B. Sassaman, G.K.S. Prakask, and G.A. Olah, Tetrahedron, 1988,44,3771. C.J. Moody, and R.J. Taylor, J. Chem. Soc., Perkin Trans. I, 1989,721. H. Meier, E. Stavridou, S. Roth, and W. Mayer, Chem. Ber., 1990,123, 14 1 1. C.J. Moody,E.-R.H.B. Sie, and J.J. Kulagowski, Tetrahedron, 1992,48,3991. 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 J.S. Clark, S.A. Krowiak, and L.J. Street, Tetrahedron Lett., 1993,34,4385. M.C. Pirrung, V.K. Chang, and C.V. DeAmicis, J. Am. Chem. Soc., 1989,111,5824. M.J. Kurth, M.J. Rodriguez, and M.M. Olmstead, J. Org. Chem., 1990,555,283. P.L. Lopez-Tudanca, K. Jones, and P. Brownbridge, Tetrahedron Lett., 1991,32,2261.The structure of oxocane 46 was incorrectly drawn in the original report.K. Jones, personal communication. P. Charreau, S.V. Ley, T.M. Vettiger, and S. Vile, Synlett, 1991,415. J.K. Crandall, D.J. Batal, F. Lin, T. Reix, G.S. Nadol, and R.A. Ng, Tetrahedron, 1992,48,1427. G. Tagliavini, D. Marton, and D. Furlani, Tetrahedron, 1989,45,1187. J.G. Walsh, P.J. Furlong, and D.G. Gilheany, J. Chem. SOC., Chem. Commun., 1994,67. J.F. Gil, D.J. Ramon, and M. Yus, Tetrahedron, 1993,49, 4923. M.L. Mihailovic, R. Vukicevic, S. Konstantinovic, S. Milosavljevic, and G. Schroth, Liebigs Ann. Chem., 1992,305. S. Escher, and Y. Niclass, Helv. Chim. Acta, 1991,74, 179. K.C. Nicolaou, C.A. Veale, C.-K. Hwang, J. Hutchinson, C.V.C. Prasad, and W.W. Ogilvie, Angew. Chem. Znt. Ed. Engl., 1991,30,299. K.C. Nicolaou, K.R. Reddy, G.Skokotas, F. Sato, X.-Y. Xiao, and C.-K. Hwang, J. Am. Chem. SOC., 1993,115, 3558. J. Yamada, T. Asano, I. Kadota, and Y. Yamamoto, J. Org. Chem., 1990,55,6066. T. Suzuki, 0. Sato, M. Hirama, Y. Yamamoto, M. Murata, T. Yasumoto, and N. Harada, Tetrahedron Lett., 199 1, 32,4505. I. Kadota, V. Gevorgyan, J. Yamada, and Y. Yamamoto, Synlett, 1991,823. I. Kadota, Y. Matsukawa, and Y. Yamamoto, J. Chem. SOC., Chem. Commun., 1993,1638. Y. Yamamoto, J. Yamada, and I. Kadota, Tetrahedron Lett., 1991,32,7069. V. Gevorgyan, I. Kadota, and Y. Yamamoto, Tetrahedron Lett., 1993,34,1313. J. L. Ravelo, A. Regueiro, and J. D. Martin, Tetrahedron Lett., 1992,33,3389. R. Chakraborty, and N.S. Simpkins, Tetrahedron, 1991, 47,7689. Elliott: Recent developments in the synthesis of medium-ring ethers 47346 P.A.Wender, J.W. Grissom, U. Hoffmann, and R. Mah, 47 J.W. Grissom, T.L. Calkins, D. Huang, and H. McMillen, 48 M.T. Mujica, M.M. Afonso, A. Galindo, and J.A. 49 C.J. Moody, E.-R.H.B. Sie, and J. J. Kulagowski, 50 H.J. Bestmann, R. Pichl, and R. Zimmermann, Chem. 5 1 D. Berger, and L.E. Overman, Synlett, 1992,8 1 1. 52 D. Berger, L.E. Overman, and P.A. Renhowe, J. Am. 53 L.D.M. Lolkema, H. Hiemstra, C. Semeyn, and W.N. 54 K. Mikami, E. Sawa, and M. Terada, Tetrahedron: 55 J. van der Louw, J.L. van der Baan, C.M.D. Komen, A. Tetrahedron Lett., 1990,31,6605. Tetrahedron, 1994,50,4635. Palenzuela, Tetrahedron Lett., 1994,35,340 1. Tetrahedron Lett., 1991,32,6947. Ber., 1993,126,725. Chem. SOC., 1993,115,9305. Speckarnp, Tetrahedron, 1994,50,7 1 15.Asymmetry, 1991,2,1403. Knol, F.J.J. de Kanter, F. Bickelhaupt, and G.W. Klumpp, Tetrahedron, 1992,48,6105. 56 D. Crich, K.A. Eustace, S.M. Fortt, and T.J. Ritchie, Tetrahedron, 1990,46,2135. 57 Y. Ohtsuka, K. Fushihara, S. Kobayashi, K. Kawamura, T. Iimori, and T. Oishi, Chem. Pharm. Bull., 1992,40, 617. 58 A.J. Fry, Aldrichimica Acta, 1993,26, 3. 59 J. Yoshida, Y. Ishichi, and S. Isoe, J. Am. Chem. SOC., 60 A. Bhattacharjya, P. Chattopadhyay, A.T. McPhail, and 1992,114,7594. D.R. McPhail, J. Chem. SOC., Chem. Commun., 1990, 1508. 6 1 S. Datta, P. Chattopadhyay, R. Mukhopadhyay, and A. Bhattacharjya, Tetrahedron Lett., 1993,34,3585. 62 H.G. Aurich, M. Boutahar, H. Koster, K.-D. Mobus, and L. Ruiz, Chem. Ber., 1990, 123, 1999. 63 T.K.M. Shing, W.-C. Fung, and C.-H. Wong, J. Chem. SOC., Chem. Commun., 1994,449. 64 G.C. Fu, and R.H. Grubbs, J. Am. Chem. SOC., 1992, 114,5426. 65 G.C. Fu, S.T. Nguyen, and R.H. Grubbs, J. Am. Chem. SOC., 1993,115,9856. 66 N.R. Curtis, A.B. Holmes, and M.G. Looney, 67 N.R. Curtis, A.B. Holmes, and M.G. Looney, 68 N.R. Curtis, and A.B. Holmes, Tetrahedron Lett., 1992, 69 R.A. Robinson, J.S. Clark, and A.B. Holmes, J. Am. 70 M.A.M. Fuhry, A.B. Holmes, and D.R. Marshall, J. 71 M.S. Congreve, A.B. Holmes, A.B. Hughes, and M.G. 72 W.-N. Chou, and J.B. White, Tetrahedron Lett., 1991,32, 73 W.-N. Chou, J.B. White, and W.B. Smith, J. A m .Chem. 74 B. Hofmann, and H.-U. Reissig, Synlett, 1993,27. 75 R.K. Boeckman Jr., M.D. Shair, J.R. Vargas, and L.A. 76 K. Tsushima, and A. Murai, Tetrahedron Lett., 1992,33, 77 F. Feng, and A. Murai, Chem. Lett., 1992,1587. 78 G. Pain, D. Desmaaele, and J. d’Angelo, Tetrahedron 79 P. Dowd, and S.-C. Choi, Tetrahedron, 1991,47,4847. 80 D.A. Corser, B.A. Marples, and R.K. Dart, Synlett, 1992, 987. 81 M.C. Elliott, C.J. Moody, and T.J. Mowlem, Synlett, 1993,909. 82 C.P. Holrnes, and P.A. Bartlett, J. Org. Chem., 1989,54, 98. 83 M. Grignon-Dubois, M. Fialeix, and C. Biran, Can. J. Chem., 1991,69,2014. 84 N.A. Petasis, and E.I. Bzowej, J. Org. Chem., 1992,57, 1327. 85 K. Homma, H. Takenoshita, and T. Mukaiyama, Bull. Chem. SOC. Jpn., 1990,63,1898. 86 C. Barber, K. Jarowicki, and P. Kocienski, Synlett, 1991, 197. 87 K.C. Nicolaou, K.R. Reddy, G. Skokotas, F. Sato, and X.-Y. Xiao, J. Am. Chem. SOC., 1992,114,7935. Tetrahedron, 1991,47,7171. Tetrahedron Lett., 1992,33,671. 33,675. Chem. SOC., 1993,115,10400. Chem. SOC., Perkin Trans. 1, 1993,2743. Looney,J.Am. Chem. Soc., 1993,115,5815. 157. SOC., 1992,114,4658. Stoltz, J. Org. Chem., 1993,58, 1295. 4345. Lett., 1994,35,3085. 474 Contemporary Organic Synthesis

ISSN:1350-4894    

DOI:10.1039/CO9940100457

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Amnes and amdes MICHAEL NORTH Department of Chemistry, University of Wales, Bangor, Gwyriedd, LL572U W, UK Reviewing the literature published between July 1992 and December 1993 1 2 2.1 2.2 2.3 2.3.1 2.3.2 2.3.3 2.3.3.1 2.3.3.2 2.3.4 2.3.4.1 2.3.4.2 2.3.5 3 3.1 3.2 3.2.1 3.2.2 3.3 4 5 Introduction, scope, and coverage Preparation of amines Synthesis of achiral and racemic amines Synthesis of optically active amines Synthesis of amines bearing additional functional groups Synthetic routes to P-hydroxyamines Synthesis of a-amino aldehydes Synthesis of a-amino acids Racemic syntheses of a -amino acids Asymmetric syntheses of a-amino acids Synthesis of p-amino acids Racemic syntheses of p-amino acids Asymmetric syntheses of P-amino acids Synthesis of y- and higher amino acids Preparation of amides General methods, and the synthesis of acyclic amides Synthesis of lactams Synthesis of P-lactams Synthesis of other lactams Synthesis of peptides Summary References 1 Introduction, scope, and coverage This review covers the literature published in the second half of 1992, and all of 1993. Papers were selected from the on-line science citation index for 1992 and 1993, so some papers published at the end of 1993 which are cited in the 1994 index have not been included but will be covered in the next review of this topic. This is not intended to be a comprehensive review of the literature, rather it is intended to highlight novel and potentially useful approaches to the synthesis of the title compounds.The review is split into two main sections, dealing with amines and amides.2 Preparation of amines 2.1 Synthesis of achiral and racemic amines A number of reagents are known to reduce nitriles to amines, although there is still a need for reagents which can achieve this transformation chemoselectively. A recently reported method utilizing Raney cobalt, manganese, or nickel in the presence of methanol and potassium methoxide at high temperatures and pressures’ may be of use in this respect. It has also been reported was that chromium or nickel promoted Raney cobalt in the presence of ammonia will catalyse the hydrogenation of polynitriles, to give polyamines.’ Amines can also be prepared by the reduction of amides, and this can be accomplished by use of 10% Pd-C under H2 (50 psi), in the presence of aqueous HC1.3 A less obvious route to N-methyl secondary amines is the hydrogenation of tris-N-substituted triazines.However, this transformation can be achieved by using a CuO/Cr,O, catalyst at 200°C under H2 (850 psi).4 A synthesis of primary amines by the reductive amination of an aromatic aldehyde, using tritylamine as a protected synthetic eqivalent to ammonia, in the presence of sodium cyanoborohydride, has been reported, and used to prepare the PAL handle for solid phase peptide synthesis.s N-MethyI amines have been prepared from primary or secondary amines by reaction with diazomethane in the presence of Co(BF4),.6 A route to N-Boc protected amines has been developed by Genet et a1.’ Thus, reaction of n-Boc-O-tosyl hydroxylamine with BuLi or potassium hexamethyldisilazide results in the formation of a nitrogen anion which reacts with primary or secondary trialkylboranes to produce N-Boc amines.Propargyl amines can be prepared by the reaction of allenyl bromides with amines in the presence of a catalytic amount of copper( I ) bromide.x Addition of Grignard reagents to bis-imines is highly stereoselective,9 giving mainly the Zk-isomer of the diamine. Thus, addition of allylmagnesium bromide to bis-imine 1 gives the diamine shown in Scheme 1 contaminated with < 5% of the meso isomer. 1,2-Diamines can also be prepared from oximes by a -bromination with NBS, bromide displacement with an amine or azide, and LiAIH, reduction. Scheme 1 North: Amines and amides 475A reported specific method for converting the readily available 2-( 2-thieny1)ethanol into the corresponding amine is described in Scheme 2.Reaction of the alcohol with cyanuric chloride gives the tris- 0-( 2-thieny1)ethyl derivative which on heating in the presence of tetrabutylphosphonium bromide isomerizes to the tris- N-( 2-thieny1)ethyl compound, and hydrolysis then provides 2-( 2-thienyl) ethylamine.' CI A 0 OANAO NaoH * h N H 2 Scheme 2 A route to a-cyclic amines based on the radical cyclization of an a-amino radical has been developed (Scheme 3). Thus, treatment of an aldehyde with a secondary amine and benzotriazole results in formation of the corresponding a -amino- benzotriazole derivative from which the a -amino radical can be generated by treatment with samarium iodide. Best results are obtained with 5-ex0 and 6-ex0 cyclizations.I* A synthesis of aminocyclopropanes from chloroenamines has also been reported,13 and the synthesis of 1 -amino- 1 -( aminomethy1)cyclopropane R' HR2 and its derivatives, by alkylation of the benzophenone imine of amino acetonitrile, has been described.', Piperidine derivatives can be prepared by the Diels-Alder reaction of imines with electron-rich dienes.2.2 Synthesis of optically active amines The preparation of racemic amines by the Gabriel synthesis (reaction of an alkyl bromide with potassium phthalimide) followed by their resolution by crystallization of the complex formed with ( S , S ) - 1,6-( o-chloropheny1)- 1,6-diphenylhexa-2,4- diyne- 1,6-diol or ( - )- 10,lO'-dihydroxy-9,9'- biphenanthryl has been reported.lh This may be of value when the more traditional resolution by salt formation with a chiral acid fails.Optically pure primary amines can be selectively monoalkylated with an alkyl halide using DMPU as the solvent, and sodium carbonate as base. Under these conditions, no over alkylation or racemization OCCU~S.~' A general asymmetric synthesis of primary amines utilizing ephedrine derivatives as chiral auxiliaries has been described as illustrated in Scheme 4. Treatment of an N , N-dialkylephedrine with methanesulfonyl chloride followed by N-hydroxyphthalimide and removal of the phthalimide group with hydrazine gives the chiral auxiliary 2. Reaction of 2 with an aldehyde produces the oxime ether to which organolithium reagents add stereospecifically. The oxime should be free to rotate about the N-0 bond, but the stereochemistry of the resulting amines suggests that the organolithium reagents attack the least-hindered face of the conformer shown in Scheme 4.Presumably, the organolithium reagent coordinates to the tertiary amine and then delivers the alkyl group ( R2) intramolecularly to the less-hindered face; LiAlH, reduction then provides the chiral primary amines.Ix A route to chiral amines based on asymmetric conjugate addition of primary and secondary amines to the chiral pyrrolin-2-one 3 has also been reported; addition of the amine occurs on the face opposite the isopropoxy substituent. PhyOH (i) (ii) MsCl PhthNOH Ph (iii) HzNNH2 (i) R*U/BF~ (it) LiAlH, 1 Scheme 4 Me2C"O--Q0 I Ac 3 476 Scheme 3 Contemporary Organic Synthesisa -Amino acids have been converted into optically pure &amino allylsilanes, which reacted with aldehydes to give optically active piperidine derivatives, and with acid chlorides to give, after further manipulation, chiral pyrrolidines.20 A synthesis of optically active 172-diamines from a -amino acids has been described.21 Thus, reduction of an N-protected a -amino acid to the corresponding p-amino alcohol followed by activation of the alcohol by reaction with methanesulfonyl chloride and displacement with either an amine or azide and reduction, if necessary, gives optically active 1,2-diamines.2.3 Synthesis of amines bearing additional functional groups A racemic synthesis and resolution of proline boronic acid 4 derivatives by the lithiation of N-Boc-pyrrole, trapping with triethylborate, acid hydrolysis, and hydrogenation has been reported.22 It is unfortunate that an asymmetric hydrogenation methodology could not be utilized to avoid the final resolution.Palladium oxide has been reported to catalyse the deamination of primary (silyloxy )alkylamines, giving the corresponding secondary and tertiary a m i n e ~ , ~ ~ e.g. Scheme 5. A synthetic route to optically active y-silyl-allylamines by the reaction of nitrogen nucleophiles with y-silyl-n-palladium complexes has been described.24 a -Amino isocyanides derived from morpholine have been prepared by dehydration of the corresponding f~rmamides.~~ Q{; I H 4 I PdO Scheme 5 There is currently much interest in synthesizing a -amino phosphonates, as when incorporated into peptides these compounds function as transition state analogues of reactions involving nucleophilic attack onto the amide bond.Thus the synthesis of various cyclic and acyclic a-amino phosphonates by the addition of ammonia and diethyl phosphite to ketones has been described.26 The diastereoselective synthesis of 1 -aminocyclopropylphosphonic acids has been reported by Schollkopf et a/. as shown in Scheme 6 .27 The stereochemistry of the cyclopropane is determined by that of the epoxide. An asymmetric synthesis of a -amino phosphonates utilizing camphor-imine methodology initially developed for asymmetric amino acid synthesis has been described and is outlined in Scheme 7.2x /?-Amino phosphines can be prepared from /?-hydroxyazides as shown in R' (i) MsCl (ii) L C 6 ~ 1 , ~ ~ (iii) HCUMeOH I Scheme 6 I .(iii) H30' 1 1 - H2!l*FW(OEt)2 Scheme 7 Ph2P 2 NH2 Scheme 8 Scheme 8.2y The reaction involves migration of nitrogen via an aziridinium salt which lithium diphenylphosphine opens at the least-hindered end. A synthetic equivalent to the /?-trifluoro- ethylamine-a -cation has been prepared electrochemically from P-trifluoroethylamine and a diary1 disulfide, as shown in Scheme 9.30 Reaction with a variety of carbanions, including enolates, then provides access to trifluoromethylamines. Treatment of N-Boc cyclic amines with BusLi results in a -deprotonation, and the resulting carbanion can be trapped with a wide variety of electrophiles, including aldehydes, amides, TMS-C1, and tributyltin chloride, to give a -functionalized cyclic amines .3 (i) R- SAr (ii) HCJ ,!, F3C-NH2 + ArSSAr %.F3C-N' F3C NH2 Scheme 9 a -Amino carbanion equivalents can also be prepared from a -chloro phthalimide derivatives (Scheme 10). The derived copper/zinc reagent undergoes Michael additions and displaces allylic, vinylic, and alkynic halides, whilst the chromium derivative reacts with aldehydes.32 North: Amines and amides 477I R2CH0 I OH 0 R2 @N."' Cu(CN)ZnCI 0 IE' ($N<R1 E 0 Scheme 10 A number of routes have been developed for the synthesis of amines adjacent to aromatic or heteroaromatic rings. Thus, reaction of an optically active a-amino nitrile, derived from an a-amino acid, with acetylene and CpCo( COD) results in a [2 + 2 + 21 cycloaddition between the nitrile and acetylene to give 1-( 2-pyridyl)alkylamine~.~~ The synthesis of 1 -amino-2-tetralones and the corresponding amides by the photolysis of 2-alkoxynaphthalenes has been reported (Scheme 1 1 ).34 2-Amino thiazoles and selenazoles can be prepared by the condensation of a P-diketone with thioureas or selenoureas, respectively, in the presence of [hydroxy( tosyloxy)iodo]benzene.35 NHF? moR1 R2NH2, hv 1,3dicyanobenzene Scheme 11 2.3.1 Synthetic routes to /?-hydroxyamines A bewildering array of methodologies for synthesizing P-hydroxyamines have been reported during the period under review.This interest in P-hydroxyamines reflects current interest in natural products which contain this fragment, and the versatility of P-hydroxyamines in the synthesis of other functionalities. Those methods which permit control of the diastereo- and/or enantio-selectivity are likely to prove the most useful, and this section will concentrate mainly on such routes.Treatment of epoxides with amines,36 or with reagents of the type LiAl( NHR),, which are derived from lithium aluminium hydride and four equivalents of an a m i r ~ , ~ ' gives P-hydroxyamines. Reaction occurs at the least-hindered end of the epoxide. The ring-opening of oxazolidines by treatment with potassium has also been used to prepare P-alkoxyamines as shown in Scheme 12.3x K no- MeI- RNYo - 9 Ar Ar Ar Scheme 12 A diastereoselective approach to syn-P-hydroxyamines based on the reduction of p-hydroxy-oximino ethers by tetramethylammonium triacetoxyborohydride has been reported.39 A complementary route, allowing the preparation of anti-p-hydroxyamines, was derived from the samarium iodide induced reaction between an isocyanide, an alkyl halide, and an aldehyde (Scheme 13). Hydride reduction of the resulting adduct furnishes predominantly the anti-isomer of the p-hydr~xyamine.~" The diastereoselective reduction of homochiral a-amino ketones derived from serine has also been investigated; most reducing agents gave mainly the syn-diastereomer of the P-hydroxyamine whilst DIBAL-H gave mainly the anti-diastereomer but in low yield.41 Another reductive approach to P-hydroxyamines involves the reaction of an O-protected cyanohydrin with diisobutylaluminium hydride to give an N-diisobutylaluminium imine to which organometallic reagents add.The stereoselectivity of the addition of the organometallic derivative is variable, depending upon both the oxygen protecting group and the organometallic species.42 The addition of organometallic reagents to O-protected a-hydroxyimines normally gives the syn-isomer of the P-hydroxyamine due to the formation of a chelated intermediate but Cainelli eta!.have reported that addition of RCuMgX,.BF, reagents to O-protected-N-TMS- a -hydroxyimines yields anti-P-hydroxyamines, usually with excellent diastereo~electivity.~~ Ri I R2 NHAr R'?* OH Scheme 13 Optically pure P-hydroxyamines have been prepared from a -amino acids either by reduction of the acid group or by the addition of Grignard reagents to the acid. This methodology was extended to S-alkylated cysteine derivatives, giving access to a new class of chiral ligand~.~, Similarly, treatment of the 478 Con temporary Organic Synthesisbenzophenone imine of an amino acid methyl ester with DIBAL-H followed by addition of an organolithium reagent and hydrolysis gave syn-P-hydroxyamines as shown in Scheme 14.4s -.. t Scheme 14 Enamines have been converted into optically active P-hydroxyamines by hydroboration with diisopinocamphenylborane followed by treatment with hydrogen peroxide and sodium hydroxide."> Similarly, hydroboration of optically active allylic amine derivatives with borane gives, after a standard work-up, p-hydroxyamines with predominantly an~i-config~ration.~~ A reported procedure for the conversion of N-Boc allylic amines into P-hydroxy- y,G-unsaturated amines involved treatment with methyl dimethoxyacetate followed by palladium-catalysed oxidative cyclization to give an oxazolidine 5 which could be further manipulated into P-hydroxyamines.4'H Meo2cyYR' BocN \ 5 R2 An asymmetric approach to P-hydroxyamines based upon the functionalization of the carbon-carbon double bond in oxazolones of type 6 has appeared." 6 The same methodology can be used to prepare p-hydroxy-a-amino acids.Another diastereoselective chiral auxiliary approach to optically active P-hydroxyamines utilizes the Evans auxiliary (Scheme 15). Thus, aldol condensation of the Evans auxiliary derivative of propionic acid with an aromatic aldehyde gives a-methyl-P-hydroxy amides. Removal of the chiral auxiliary followed by a Curtius rearrangement gives cyclic carbamates which, on reduction, give a -methyl-/3-aryl-/3-hydroxyamines.so Both enantiomers of 1 -amino-2-propanol are readily available by the decarboxylation of threonine upon heating to 150°C in the presence of DMPU." Since a number of methodologies for the asymmetric 0 0 K Scheme 15 synthesis of P-hydroxy-a-amino acids exist, this decarboxylation may have more general applicability.Reduction of optically active 4-amino-2,3-epoxy-alcohols by DIBAL-H occurs exclusively at the 2-position, giving P-hydroxyamines. Using this methodology, the same starting materials can be used to prepare both P, y,G-trihydroxyamines and P, y-dihydroxyaziridines stereoselectively.5' A route to optically pure p- and y-hydroxyamines from aspartic acid has been published, in which N,N-dibenzyl aspartate is reduced with LiAlH, to give the corresponding diol as the key intermediate.The two hydroxyl groups can then be regiospecifically protected, activated, and manipulated to give various hydroxyamines.53 The synthesis of a range of /3-hydroxyamines (and amino acids) based upon ring-opening of the readily prepared homochiral aziridine 7 has been described,5J and a general synthesis of p-amino- y-hydroxysulfoxides derived from the reaction of an oxazoline enolate with a chiral sulfinate was also reported.55 Ts HO L O Ac 7 An asymmetric synthesis of p- or y-amino alcohols via the formation of a carbanion adjacent to the protected alcohol has been published and is shown in Scheme 1 Deprotonation of carbamates 8 by Bu'Li in the presence of ( - )-sparteine yields the configurationally stable carbanion adjacent to the masked alcohol which can be trapped by electrophiles giving, after removal of the carbamate group, y-amino alcohols with 77 to > 98"/0 e.e.2.3.2 Synthesis of a-amino aldehydes Reports of synthetic protocols which can be used to prepare either a -amino aldehydes or a -amino acids are described in the section on a-amino acids. a-Amino aldehydes are normally prepared by the reduction of a -amino acid derivatives. This is often not straightforward as it is frequently necessary to produce first the amino alcohol and then reoxidize this to the corresponding aldehyde. In this context, the North: Amines and amides 4798 /I =0,1 (i) Bu*Wsparteine (ii) E' (I) MeSaH (ii) Ba(OH), 1 Scheme 16 Moffat-Swern reaction has been described as the method of choice for oxidizing the amino alcohol derived from N-Boc-cyclohexylalanine to the corresponding aldehyde.s7 A catalytic amount of TEMPO in the presence of bleach and sodium bromide has also been reported to oxidize a range of optically active N-protected amino alcohols to the corresponding aldehydes in good yield and without racemization.sx The oxidation step has been avoided by converting an FMOC-amino acid into the corresponding benzylthio ester.Reduction of the thioester with triethylsilane in the presence of Pd-C then gave FMOC-a -amino aldehydes.5y In a different approach, a synthesis of N-Boc-glycinal has been reported which used 2,3-dihydroxypropylamine as the starting material. Protection of the amine followed by oxidative cleavage of the 1,2-dihydroxy group with potassium periodate gave N-Boc glycidal which underwent reductive amination with glycine to give peptide analogues.'" A route to both a-amino aldehydes and a -amino acetals based upon the asymmetric addition of organocerium reagents to the RAMP or SAMP hydrazones of glyoxal monoacetals has been described.' ' a -Amino glyoxals of general structure 9 are potentially versatile starting materials for the construction of a wide variety of amine derivatives, and an asymmetric synthesis of these compounds, by manipulation of a-amino acids, has been reported.62 0 9 2.3.3 Synthesis of a-amino acids Purely because of the extent of the publications in this area, no attempt is made here to cover all methods reported for the synthesis of a-amino acids.Only those methods involving formation of the C-N bond, or in which the amine functionality plays an important role in the chemistry, are included. Unfortunately, this meant excluding recent developments in a number of extremely useful and versatile amino acid syntheses. The same selectivity has been applied to the sections on P- and y-amino acids. 2.3.3.1 Racemic syntheses of a -amino acids Reaction of an a -bromo ester with an amine (or equivalent) is a classical method for the preparation of racemic amino acids. This has now been extended to the use of fluoroalkylamines by carrying out the reaction in acetonitrile with potassium carbonate as the base and benzyl triethylammonium chloride as a phase-transfer cataly~t."~ The use of trichloroacetamide as the amine component has also been preparation of a range of 15N and I3C labelled glycine derivative^.^^ synthesis of a-amino-P-keto esters by the reaction of the benzophenone imine of glycine methyl ester with an acid chloride in the presence of potassium t-butoxide.h6 Organozinc compounds add chemoselectively to the imine functionality of a-imino esters without affecting the ester, thus providing a racemic synthesis of a-amino a~ids.6~ The Strecker reaction, which was first reported in 1850, still provides convenient and simple access to a wide range of amino acids.It has been used in a synthesis of racemic a -monofluoromethyl amino acids from fluoromethyl ketones.68 Oxaziridine 10 acts as a source of BocN + , and reacts with ester enolates to give N-Boc-a-amino esters.6y The same reagent reacts with ketone enolates to give N-Boc-a-amino ketones, and with amines to give N-Boc hydrazines.as has the use of BoczN- in the Amino acid imine chemistry was utilized in a T-CN 0 10 Over recent years, Schollkopf et al. have developed a very successful asymmetric amino acid synthesis based on the formation of an enolate of a chiral bis-lactim ether. In an interesting continuation of this work, the authors have adapted the methodology to provide a racemic amino acid synthesis, as shown in Scheme 17. Thus the bis-lactim ether derived from glycine can be aromatized by treatment with N-chlorosuccinimide, and addition of organolithium reagents to the resulting pyrazine, followed by hydrolysis, provides racemic amino acids.'O This methodology represents the umpolung of the authors' previous work.a ,a -Disubstituted amino acids can be prepared via a -alkoxyamino acid derivatives 1 1, as shown in Scheme 18. Thus, compounds 11 (which can be prepared electrochemically from amino acid derivatives) react as a -cation synthons with allysilanes 480 Contemporary Organic SynthesisR2U 1 Scheme 17 11 R' /ip<o$ 0 Scheme 18 in the presence of TMS-OTf to give a , a -disubstituted amino acid derivative^.^' Another racemic synthesis of a , a -dialkylated amino acids starts from a-diazoesters (Scheme 19). Hence treatment of an a -diazoester with copper and a tertiary amine gives a nitrogen ylid, which undergoes an N-C migration of the most labile nitrogen substituent, giving a ,a -disubstituted amino esters.72 a-Amino ketones can be prepared in the same way, by starting with diazoketones. 0 0 0 Scheme 19 a -Fluoroalkyl amino acids have been prepared from perfluorohaloimidates, as shown in Scheme 20.73 In a palladium-catalysed process, treatment of an allylic acetate with a dialkylamino anion gives the corresponding allylic amine without allylic transposition.Ozonolysis in the presence of sodium hydroxide and methanol then gives N,N-disubstituted amino acid methyl esters.74 N-Arylidene imines of dehydroalanine esters undergo Diels-Alder reactions with themselves, giving adducts which can be further manipulated into a range of cyclic amino acids.75 X = CI, Br Scheme 20 2.3.3.2 Asymmetric syntheses of a -amino acids Whilst many methods have been developed for the direct synthesis of a single enantiomer of amino acids, the use of enzymes to resolve racemic amino acid derivatives remains widely used for the preparation of homochiral amino acids.The continued popularity of what is often perceived to be out-dated technology is due to various factors: the simplicity of the methods for synthesizing racemic amino acids, the commercial availability of a large number of enzymes which will resolve amino acid derivatives (esterases, lipases, and acylases), the broad substrate specificity of these enzymes, and the generally excellent enantiomeric excesses that they produce. A number of recent developments in this field have been published. Treatment of an amino acid with deuterated acetic acid in the presence of a catalytic amount of benzaldehyde gives a -deuterated racemic amino acids, via formation of the N-benzylidene-amino acid and the corresponding oxa~olone.~~ Esterification (MeOH/SOCl,) followed by resolution with an acylase enzyme then gives homochiral a -deuterated amino acids. Racemic oxazolidinones are easily prepared, and treatment of them with a lipase enzyme results in the formation of optically active N-benzoyl amino acids.77 Porcine pancreatic lipase gives (S)-amino acids whilst the lipase from Aspergillus niger results in the formation of (R)-amino acids.Treatment of an oxazolidinone with a lipase in methanol results in formation of the corresponding N-acyl amino acid methyl ester. This esterification is stereoselective for the (S)-enantiomer of the amino acid, and as the oxazolidinone can be racemized under the reaction conditions, a greater than 50% yield of the optically active methyl ester can be obtained.The optical purity of the product is then increased by hydrolysis of the methyl ester with a protease enzyme, giving an efficient two step enzymatic synthesis of N-acyl amino acids from racemic oxazolidinone~.~~ A well established approach to the asymmetric synthesis of a -amino acids is the hydrogenation of a ,P-didehydroamino acids. This can be carried out either by using a chiral catalyst for the hydrogenation, or by the hydrogenation of a didehydroamino acid containing a chiral auxiliary. PROPRAPHOS ( 12) has been investigated as an asymmetric catalyst for the production of arylalanines from 2- a -N- benzoylamino-P-arylacrylic acids, and gave the amino acids with e.e.'s of 63-92'/0.~~ A methodology based on the latter approach has been reported by Cativiela et al.(Scheme 21).80 Thus, condensation of the 2-hydroxypinan-3-one derivative 13 with an aldehyde gives a chiral didehydroamino acid derivative which can be hydrogenated and hydrolysed to give optically active a -amino acids. Alternatively, condensation of an a-keto-acid with a chiral amine in the presence of Na,PdCl, gives complexes of the type 14, which can be hydrogenated to give amino acids with up to 36% e.e.81 Rhodium complexes can also be employed, as can hydroxylamines. an N-sulfonylimine generates an allylic amine which on ozonolysis in the presence of methanol results in The addition of a homochiral bromovinyl anion to North: Amines and amides 48 114 12 13 Scheme 21 the formation of optically pure amino acid derivatives, as shown in Scheme 22.Ozonolysis in the absence of methanol provides the corresponding a -amino aldehydesx2 Another synthetic route to both a -amino acids and a -amino aldehydes is the addition of organometallic reagents to RAMP or SAMP hydrazones. Thus addition of organocerium reagents to the SAMP hydrazone of diethoxyacetaldehyde followed by a hydrolytic procedure gives a-amino aldehydes, whilst an oxidative continuation gives a-amino acids.83 iHS02Ar 0 0 Scheme 22 Sharpless has developed two of the most useful, catalytic, asymmetric methodologies, namely his epoxidation and bishydroxylation protocols. Both have been utilized in the asymmetric synthesis of a-amino acids.Optically active epoxy alcohols are readily available via the Sharpless epoxidation of allylic alcohols, and this methodology has been applied to asymmetric amino acid synthesis. Reaction of an epoxy alcohol with benzhydrylamine results in ring-opening at the end of the epoxide remote from the alcohol, oxidative cleavage of the resulting 1,2-diol with ruthenium trichloride and sodium periodate then giving optically active amino acids.x4 A synthesis of C-a -~-glucosyl-a -amino acids from a -D-gluco- pyranoside has been reported, in which the Sharpless asymmetric dihydroxylation methodology is used to introduce the amino acid functionality onto the sugar.85 A highly stereocontrolled synthesis of any of the four stereoisomers of a /I, y-unsaturated amino acid starting from the Sharpless epoxidation of an allylic alcohol has also been reported.x6 Hruby et al.have developed an asymmetric synthesis of P-methyltyrosine and P-methyltryptophan derivatives based upon the asymmetric Michael addition of methyl cuprates to homochiral enones of structure 15, followed by further manipulation to stereospecifically introduce the a -amino group via the enolate and a -azido cornp~unds.~~ In the case of P-alkyl tryptophan derivatives, a more direct route is available by the addition of higher order organocuprates to homochiral indole derivatives of type 16. Compound 16 can also be used to prepare 2,3-methanotryptophan derivatives by addition of trimethylsulfoxonium iodide to the C-C double bond.xx 15 16 An asymmetric synthesis of either enantiomer of 2-amino-2-methylbutanoic acid based on the alkylation of an isobornyl sulfonamide derived chiral cyanoacetate followed by a Curtius rearrangement has been reported.xY The same methodology should be suitable for the preparation of other a ,a-disubstituted amino acids.Concerted processes are a popular way of carrying out asymmetric synthesis, since they occur via transition states of well defined geometry, and hence usually result in excellent asymmetric transfer to the newly formed chiral centre( s). An asymmetric amino acid synthesis based on the ene reaction of an a-imino ester 17 has been reported (Scheme 23). Thus reaction of 8-phenylmenthyl glyoxylate imines with alkenes in the presence of a Lewis acid catalyst results in the formation of y,d-unsaturated amino acids.”) 0 0 17 Scheme 23 Grignard reagents also add stereospecifically to the imines ( 17, R’ Boc), providing chiral amino acids after an acidic work-up.” The aza-Claisen rearrangement of glycinamide derivatives of type 18 also provides a route for the synthesis of y ,d -unsaturated amino acids, and if chiral amides (R = 1-phenethyl) are used then asymmetric induction occurs during the rearrangement, giving optically active amino acids.y2 The aza-Cope rearrangement of chiral imine 19 can be followed by hydrolysis and a tandem ene-iminium ion 482 Con temporary Organic Synthesiscyclization (or a Mannich cyclization) to provide (i) KOBU' (ii) MeSO&I, access Allyltrichloroacetimidates to various proline and of homoserine type 20 undergo derivative^.^' a f---+y Et3N palladium-catalysed [ 3,3]-sigmatropic shift to give after further manipulation the E-isomers of H H NO2 KH, Bu'OOH P, y -unsaturated amino acids with high enantiomeric purity.93 0 C0,y"" R y Q Q P O T B D P S YNH H2NJIN,R ph'* A4 Ng ccg 18 19 20 H H In recent years, a number of groups have developed asymmetric amino acid syntheses based on formation of the C,-N bond.Oppolzer et al. have utilized their sultam derived chiral acetate equivalent in a synthesis of N-alkyl-a-amino acids, as shown in Scheme 24. Enolate formation, and trapping with l-chloro- 1 -nitrosocyclohexane results in stereospecific incorporation of an a -hydroxylamine group. Depending upon the subsequent steps, both a-amino acids and N-alkylated-a-amino acids can then be prepared.94 I (i) R2 CHO/NaBH3CN (ii) Zn/AcOH (iii) L i H HOG:R2 0 Scheme 24 In an alternative methodology, pantolactone esters of a-bromoacids have been reported to react with amines to give a -amino esters with retention of configuration at the a -carbon.9s Reaction of an a -bromo-ester with potassium phthalimide in the presence of N-benzyl-cinchonium (or quininium) chloride as phase-transfer catalysts also gives optically active amino acids (the enantiomeric excess being raised if an a -bromo-ester derived from bornyl alcohol is also used).96 Evans's chiral auxiliary has been used to prepare optically active fluorinated amino acids, since bromination of an acyl group adjacent to the auxiliary followed displacement of bromide by azide occurs stereoselectively.y7 Jackson et al.have developed a synthesis of hydroxy amino acids from glyceraldehyde (Scheme 25). Thus, reaction of isopropylidene glyceraldehyde with (p-toly1)nitromethane gives a 1 -tolylthio- 1 -nitroalkene which undergoes a stereoselective epoxidation to give 2 1 or 22 depending upon the epoxidation reagent. 22 I / 21 AH, Scheme 25 Ring-opening of the epoxide with amines occurs regiospecifically to give thioesters of protected amino acids which can then be deprotected to provide an asymmetric synthesis of a -amino acids.98 5N-Labelled phenylalanine and leucine have been prepared from the unlabelled amino acids by a route involving diazotization of the amino acid to the corresponding hydroxy acid with retention of configuration, followed by esterification. Conversion of the alcohol into the corresponding triflate followed by displacement with (Boc),"N - and deprotection gives the labelled amino acids with overall inversion of configuration.y9 A synthesis of ornithine derivatives based on the ring-opening of 1,2-didehydroprolines has been reported.This provides an asymmetric approach to ornithine derivatives only if an additional chiral centre is present in the proline starting material as in the case of 4-hydroxyproline (Scheme 26). (i) BU'OCI HQ (ii) Et$l (iii) NaOH HO., * Q-co2w QC02Me H NH@R.HCI I ?JH;Cr *C02H OH NH2 Scheme 26 *C02H OH NH, North: Amines and amides 483The final hydrogenation reaction can be carried out to give either stereoisomer of the ornithine derivative depending upon the reagent used.loO of the classical Strecker amino acid synthesis, and a number of chiral versions of this reaction using chiral auxiliaries on the amine have been developed. In the latest example, phenylglycidol is used as the chiral auxiliary as shown in Scheme 27.(R)-Phenylglycidol induces predominant formation of the ( S)-isomer at the new chiral centre, and the auxiliary can be cleaved either by reduction or oxidation, allowing a wide range of amino acids to be prepared in this way.lol The formation of the a-C-CO, bond is at the heart NaHS03 (OHR - /OH PhANACN H (OHR R Ph A H N k O 2 H /OHm - I I A H2NhC02H H Scheme 27 A stereoselective synthesis of P-hydroxy-a -amino acids based on the Strecker reaction has also been reported (Scheme 28).Thus 0-protected optically pure cyanohydrins, which are readily available,lo2 are reduced by DIBAL-H to the corresponding imines. The latter compounds undergo imine exchange when treated with an amine, followed by stereoselective addition of hydrogen cyanide giving P-hydroxy-a -amino acids after further manipulation. OCMe20Me PhXCN (i) (ii) DIBAL-H RNHz, P h q c N p h q c o 2 H NHR NHR (iii) HCN (iv) HCI Scheme 28 Baldwin et al. have shown that aspartic acid derived P-lactams 23 react with both organocuprates and sulfur stabilized carbanions to give y-keto-a -amino acids by nucleophile induced ring-opening of the p-lactam ring.lo4 23 2.3.4 Synthesis of #?-amino acids 2.3.4.1 Racemic syntheses of #?-amino acids Reaction of diethylenetriamine with ReNCl,( PPh,), results in oxidative cleavage of the C-N bonds to give p-alanine.Io5 A racemic synthesis of norbornane-containing p-amino acids of type 24 and their derivatives by the Diels-Alder reaction of maleic acid derivatives followed by a Curtius rearrangement has been reported.lo6 The use of penicillin acylase to resolve the N-phenylacetyl derivatives of a variety of p-amino acids has been reported, and enantiomeric excesses of > 99% were obtained.'" dNH2 CO2H 24 X = 0, CH2 An attractive approach for the synthesis of P-amino acids involves the addition of an ester or acid enolate to an imine. However, this reaction is more difficult than the corresponding enolate addition to carbonyl compounds due mainly to the lower electrophilicity of the C=N double bond compared to C=O.The introduction of sulfonyl groups onto the imine nitrogen raises the electrophilicity of the imine, and reaction with Reformatsky reagents then provides a route to p-amino esters and acids.'OX An asymmetric version of this reaction has also been pub1ishedlo9 (see Section 2.3.4.2). In an alternative approach, lithium perchlorate' catalyse the addition of silylketene acetals to aldimines, giving p-amino esters. or zinc bromide' I can be used to 2.3.4.2 Asymmetric syntheses of B-amino acids A synthesis of p-amino acids and p-hydroxylamino acids based on the Lewis acid catalysed reaction of a silylketene acetal with a nitrone has been developed by Murahashi and Otake."* An asymmetric example of this reaction is shown in Scheme 29. OSiEt3 + PhAN+#O- II b y A P h Me026 OH Scheme 29 An asymmetric p-amino acid synthesis based on the stereoselective ring opening of chiral oxazolidines by Reformatsky reagents has been developed by Pedrosa et ~ 7 E .l ' ~ (Scheme 30). The degree of asymmetric induction depends upon the size of the R group. An almost identical approach to these compounds uses ethyl tributylstannylacetate in the presence of ZnC1, and F3B.0Et2.114 The addition of organocerium reagents to the RAMP or SAMP hydrazones of 3,3-ethylene- 484 Contemporay Organic SynthesisRCHO Ph" Bn BrZnCH&Ogt 0 I 2.3.5 Synthesis of y- and higher amino acids y-Aminobutyric acid (GABA) is an important neurotransmitter, and a large number of analogues of this amino acid have been synthesized. An asymmetric synthesis of compounds of type 26 has been reported in which N-Boc-2-TBDMSO-pyrrole is used as a precursor to the y-aminobutyric acid unit.I2' Scheme 30 dioxypropanal, followed by ozonolysis of the acetal and removal of the RAMP/SAMP auxiliary gives p-amino acids in greater than 80% e.e.l15 An asymmetric p-amino acid synthesis derived from the addition of an ester enolate to a chiral sulfinimine has been described as shown in Scheme 3 1.Thus, asymmetric oxidation of a sulfenimine with chiral oxaziridine 2 5 gives the corresponding chiral sulfinimine which reacts with the lithium enolate of methyl acetate to give a /?-amino acid precursor. The resulting steps can be varied to allow access to either a-unsubstituted or a-hydroxy-8-amino acids.''* 25 H2N Cco2Me Ph hZO 0 2 S' 25a Scheme 31 P-Amino acids can also be prepared by the ring-opening of P-lactams, since nucleophiles such as alcohols attack N-acyl-P-lactams at the ring carbonyl,'16 and this approach has been used to prepare analogues of the phenylisoserine (norstatine) side-chain found in taxol.'" The same approach has been used to prepare B-hydroxyaspartates and P-hydroxymethylserines.' l 8 The ring-opening of optically active cis-2-benzyloxy-3- alkoxyalkyl-/I-lactams by chlorotrimethylsilane and methanol has been used to prepare a -benzyloxy-P-amino- y-alkoxy-acids.' 19 26 An asymmetric synthesis of P-hydroxy- y -amino acids which utilizes a -amino acids as chiral starting materials has been described as shown in Scheme 32.Thus, N-Z a-amino acids can be converted into P-keto esters by a number of routes; hydrogenation of these results in cyclization to tetramic acids which can be further reduced and ring-opened to P-hydroxy- y-amino acids.12' A process for removing the hydroxyl group from the intermediates, thus providing y-amino acids has also been described.Optically active a ,P-unsaturated- y-amino esters can be prepared from a ,/?-unsaturated- y-benzyloxyesters by treatment with Fe,( CO), to form an iron ally1 species, followed by addition of an amine and oxidative removal of the iron group.'22 An asymmetric route to various P-hydroxy-w -carboxy-amines, based upon the enzymatic resolution of cyanohydrin acetates or the derived B-amino acetates, has been r e ~ 0 r t e d . l ~ ~ R' R' WNAC02H Z H N W * 0 0 0 Scheme 32 3 Preparation of amides 3.1 General methods, and the synthesis of acyclic amides There are many well established methods for coupling an acid and an amine to produce an amide.However, new reagents for this transformation are still being developed which are more tolerant of other functional groups, and allow the reaction to be conducted under milder conditions. In this context, the controlled reaction of phosphoryl chloride with one equivalent of ethanol gives a reagent, EtOPOCl,, which has been reported to be useful for the coupling of amines and acids to give amide~.',~ Reagent 27 has also been considered useful for this reaction, and in addition to North: Amines and amides 485simple amines, a-amino esters can be used as the amine component, or if the acid contains a p-amino group then p-lactams can be formed.125 The oxadiazaphosphole 28 acted as a condensing agent for acids and amines, and was reported to give good results even in sterically hindered cases.126 For the conversion of acids containing very sensitive functional groups, such as p-lactams into amides, a two-step process involving treatment first with di-2-pyridyldisulfide and triphenylphosphine (or tributylphosphine or triethylphosphite) to form the 2-thiopyridyl ester followed by reaction with an N-silylamine has been deve10ped.I~~ The use of polymer supported EDC to couple acids and amines has also been investigated.l** 27 28 The tin reagent 29 converts esters into amides.12’ The bis-trimethylsilylamine group is not transferred, and best results are obtained with methyl esters.The same transformation can be achieved with reagents of the type LiAl(NHR), which are derived from lithium aluminium hydride and four equivalents of an amine. Reaction occurs with both ethyl esters and lac tone^.^' Primary and secondary amides can be converted into the N-p-tolyl derivatives by treatment with p-tolyl-lead triacetate.l 3o R’ I+ (TMS)2N-Sn-( 29 Given the recent level of interest in the use of enzymes to catalyse organic reactions, it is not surprising that enzymatic routes to the synthesis of amides have been developed. Two main approaches have been investigated: the use of enzymes to catalyse condensation of an amine and an acid, and the enzymatic hydrolysis of a nitrile. The use of papain to catalyse the formation of various amides derived from N-( 2)-glycine methyl ester and amides has been reported,I3l and provides a route to a variety of peptide bond isosteres.Lipases have also been used to convert a ,P-unsaturated esters into the corresponding amides, and the kinetic resolution of racemic amines giving optically active amides has been achieved in this way.132 The use of Candida antartica lipase to catalyse the preparation of optically active P-hydroxy and P-epoxyamides from racemic esters and amines has also been published.133 An increasingly popular route to amides involves the use of enzymes to effect the hydrolysis of nitriles. This has been used to prepare a variety of a ~ h i r a l , ~ ~ ~ and optically active amides. ” A non-enzymatic method of achieving this transformation in the case of a-amino amides has also been reported.136 Thus, treatment of a racemic a-amino nitrile with a chiral, polymeric ketone in the presence of hydroxide results in formation of the (S)-a-amino amide.The unreacted (R)-a-amino nitrile is racemized under the reaction conditions, and then converted into the (S)-a-amino amide. rearrangement of chiral a -chloro-a -sulfonyl ketones has been reported, an amine being used as the nucleophile to ring-open the intermediate cyclopropanone. 37 Carbamates are widely used protecting groups for amines, and the conversion of carbamate to amine to amide can be carried out in one step by treatment of a carbamate and an acid chloride and sodium iodide.’3X Cyanohydrins can be oxidized to acylcyanides by treatment with t-butyl hydroperoxide in the presence of RuCl,(PPh,),.The resulting acylcyanides are good acylating agents and treatment with an amine gives the corresponding amide.’39 Overall this is a method for converting aldehydes into amides. A synthetic route to N-fluoroalkyl malonamides began with a fluoroalkyl isothiocyanate. Reaction with a stabilized phosphorane gives an iminoketene which on acidification yields the corresponding malonamide. The enolate of a tertiary amide is easily formed, but the corresponding enolate of a primary or secondary amide is not so readily accessible owing to the presence of acidic hydrogens on the nitrogen. A way of generating the enolate of a primary amide which uses an iminophosphorane group to protect the nitrogen atom has been reported, as shown in Scheme 33.Thus, treatment of an acid chloride with sodium azide followed by a trialkylphosphine gives the iminophosphorane. Enolate formation can then be achieved with BuLi, and after the enolate is trapped with a ketone the iminophosphorane group is cleaved by treatment with acid.14’ An asymmetric synthesis of amides via the Favorskii (0 BuLi (ii) fluorenone (iii) H30+ I #.- ‘ ’ OHo \ / Scheme 33 Whilst a carbanion adjacent to a tertiary amide can easily be formed, the corresponding carbocation is less accessible. Hoffman et al. have reported that O-mesyl hydroxamic acids 30 react with triethylamine to give a synthetic equivalent of this carbocation which can be reacted with nucleophiles such as halide, hydroxide, azide, or amines to give a-substituted amides.14* The reaction of phenylisocyanate with benzyl bromide and/or aldehydes in the presence of samarium iodide has been reported to form amides 486 Contemporary Organic SynthesisOMS (9 Tack.Zn (ii) R'-N=C=O (iii) I2 30 (Scheme 34).'43 Hence, reaction of phenylisocyanate with benzyl bromide gives N-phenyl-phenylacetamide whilst reaction with an aldehyde gives an N-phenyl- a -hydroxyamide. Reaction with both an aldehyde and benzyl bromide gives an N-phenyl- N - h ydroxyal k yl-phen ylacet amide. 7 Ph-N 0 PhCH2Br. RCHO. OH 7 sfl2 sm12 R+"Ph 0 .ph- Ph-N=C=O 0 (i) Tact5 Zn RI+y,R3 (ii) iii) R34=C=0 NaOH. H20 R'+R~ Scheme 36 7 PO( 0 Et) 2 J Yh Ph-NyR 0 OH Scheme 34 Scheme 37 A route to both saturated and a ,/?-unsaturated amides based on the Favorski rearrangement of a -chloro-a -sulfonyl ketones has been developed (Scheme 35).'44 a ,/?-Unsaturated nitriles can also be prepared from aldehydes by reaction with a tertiary amide of bromoacetic acid in the presence of zinc and tributylpho~phine.'~~ J L l t Rl+y,R3 *NaH.R3R4NH T0lS02 ,f,&R3 R2 f? R2 k NaW. I MeOH Scheme 35 An alternative route to a ,/?-unsaturated nitriles (including /?-iodo-a ,/?-unsaturated nitriles) based on tantalum chemistry is shown in Scheme 36.146 A synthesis of y- 6 -unsaturated amides has also been described (Scheme 37).147 Thus, treatment of a y-diethylphosphonyl carboxylic acid with LDA and an aldehyde results in formation of a lactone which on treatment with a -methylbenzylamine undergoes ring-opening and elimination of diethyl phosphonate to give the y,6-unsaturated amide.N-Ally1 acetamides can be prepared from allylic alcohols by reaction with (i) 2 x LDA (i9 RCHO (Eto)20p - (iii) H30+ RAOAO H acetonitrile in the presence of catalytic amounts of cobalt(1r) chloride and acetic acid.'4x The reaction proceeds with allylic rearrangement. two step p r o ~ e s s . ' ~ ' ~ Thus conversion of a lactam into the N-Boc derivative followed by reaction with an amine under high pressure ( 10 kbar) gives o-N-Boc-amino amides. A synthesis of all four stereoisomers of a /?-hydroxy- y-amino amide related to statine has been reported, starting from optically pure epoxy-alcohols and involving a Mitsunobu reaction to convert the alcohol into an azide, regioselective ring-opening of the epoxide by cyanide at the less-hindered end, hydrolysis, and finally reduction.' A synthesis of amidomethylphosphine oxides from secondary amides has been described.'s' Thus, reaction of a secondary amide with paraformaldehyde and TMS-Cl gives N-chloromethyl-amides which react with ethyl diphenylphosphinite to give amidomethylphosphine oxides. A versatile synthesis of heterocycle-containing amides as well as related amino acid derivatives has been reported (Scheme 38).sz Lactams can be converted into w-amino amides in a W 31 NaOH, K&03. or HCI/ 1 NH2Y 0 / OwNH: Y = H, NH2 Scheme 38 North: Amirzes and amides 487Hence, treatment of a heterocyclic nitrile oxide with an oxazolidinone gives the key intermediate 3 1 which reacts with acid or base to give amides, or with ammonia or hydrazine to give amino acid derivatives.Peptoids are defined as poly- N-alkylated glycine derivatives, and as such they are polyamides. A solid synthesis of these peptide analogues has been developed, as shown in Scheme 39. Thus, treatment of a RINK-amine resin with bromoacetic acid in the presence of diisopropylcarbodiimide gives the bromoacetylated derivative, which reacts with a primary amine to give the first peptoid residue. This process can then be repeated with different amines, to give peptoids of any length.153 BrCH2C02H RINK-RESIN-NH2 - RINK-RESIN-NHCOCH28r 1.N. (i) repeat (ii) cleave from resin H2N[CH2CONHRIn- RINK-RESIN-NHCOCH2NHR Scheme 39 3.2 Synthesis of lactams 3.2.1 Synthesis of p-lactams Microwave irradiation of a solid mixture of a silylketene acetal and an aldimine in the presence of montmorillonite clay or p-toluenesulfonic acid results in the formation of P-amino esters, whilst replacement of the acid catalyst with KF/18-crown-6 results in the synthesis of /3-1actams.ls4 p-Amino esters can be converted into p-lactams by treatment with Sn[N(TMS),],, and in difficult cases pivalic acid can be added to displace one of the TMS groups from the tin reagent, resulting in a more reactive species.lSs An asymmetric synthesis of 3-alkyl-3-benzyl-P-lactams starting from the chiral ester 32 has been reported.ls6 Thus, alkylation of the enolate of 32, followed by reduction of the nitrile to an amine and cyclization, gives p-lactams.A synthesis of optically active 3-amino-P-lactams by the addition of the zinc enolate of an N,N-bis-silyl-glycine ester to an imine derived from phenylglycine has also been described.lS7 Routes to chiral P-lactams based upon the condensation of the titanium enolate of a thiopyridyl ester with chiral imines derived either from the condensation of 1 -phenylethylamine with an achiral aldehyde158 or condensation of benzylamine with a chiral a -hydroxyaldehydel s9 have also been reported.Simple esters can also be used in this reaction, and the effect of introducing chiral groups at various sites on the ester or imine component has been investigated.I6O P-Lactams can also be prepared by the reaction of an imine with an acid chloride in the presence of triethylamine, a reaction considered to proceed via the [2 + 21 cycloaddition of the imine and the ketene derived from the acid chloride. Application of this methodology to optically active a -alkoxyaldimines and a-alkoxy acid chlorides gives optically active cis-2,3-disubstituted p-lactams,' 14, whilst the use of a bis-imine can give either a bis-P-lactam or a 4-formyl-/3-lactam. 0 S02N( c -Hex);! 32 In recent years, Hegedus et al.have reported a novel synthesis of both amino acids and P-lactams utilizing chromium carbene complexes. This methodology has been used by de-Meijere et al. to prepare a novel class of cyclopropane-containing P-lactams represented by structure 33.16, A novel synthesis of 1,3,4-tris- (trimethylsilyl)azetidine-2-one (34) by the ring-expansion of a silylated cyclopropanone has been described as outlined in Scheme 40. Compound 34 can then be converted into a variety of other P-1actams.l 33 SiMe3 @\ 0 34 Scheme 40 3.2.2 Synthesis of other lactams y-Lactams can be prepared from ally1 or propargyl amides of bromoacetic acid by nickel-catalysed electro-reductive c y c l i z a t i ~ n .~ ~ ~ The reaction can also be applied to the cyclization of o -bromophenylamides of propenoic acid. A route to both y- and d-lactams by the intramolecular ene reaction of azo compounds has been also developed (Scheme 41).lhS 9 Scheme 41 488 Contemporary Organic Synthesis3.3 Synthesis of peptides Only the development of new methodologies for peptide bond formation is discussed here. Unfortunately, lack of space prevents discussion of new protecting groups and methods for their removal, new resins for solid phase peptide synthesis, peptide conformation, or the synthesis and incorporation of conformationally-constrained peptides or amide bond surrogates.Whilst DCC and other carbodiimides are still by far the most popular coupling reagents for peptide synthesis, a number of alternatives are available which avoid the production of ureas as side-products. Acid chlorides were amongst the first peptide coupling reagents to be investigated, but their use rapidly diminished when it was realized that they caused extensive racemization. They are now enjoying something of a resurgence in popularity, since FMOC-amino acid chlorides have been found not to be significantly susceptible to racemization. Much interest has been expressed in the use of acid fluorides in peptide synthesis, as they have greater stability than acid chlorides so all three main amine protecting groups (FMOC, Boc, and Z) can be utilized.The preparation of both a - and side-chain acid fluorides of aspartic and glutamic acid derivatives has been reported. lh6 Active esters of amino acids are normally prepared using DCC activation, but this method suffers from the various disadvantages associated with DCC, and a route to active esters from mixed anhydrides has been reported which avoids these problems.lh7 Nagase et al. have described the synthesis of tripeptides from an N-Boc-dipeptide azide and the tetrabutylammonium salt of an amino acid, thus avoiding the need to deprotect the C-terminal amino acid.lh* In a comparative study of coupling reagents, BOP was found to give the best yields and least racemization.lhy However, the generality of such studies is questionable as previous investigations usually gave contradictory results.The efficiency of coupling reactions during solid phase peptide synthesis can be enhanced by microwave irradiation of the resin.l7(' investigated during the period of this review, the synthesis of 6-nitro-P-naphthalenesulfonyl- oxybenzotriazole and its use to produce 6-nitrohydroxybenzotriazole active esters for peptide synthesis has been described.171 3-Dimethylphosphinothioyl-2( 3H)-oxazolone MPTO (35) has been recommended for the racemization-free coupling of amino derivative 36 has also been used as a coupling reagent for the synthesis of dipeptides.173 p-Nitrobenzophenone oxime was used as an active ester coupling reagent in the synthesis of tetrapeptides.I 74 Amongst the many new peptide coupling agents and the saccharin I 7 SQ Me s ; q ( o M e o e N Sb2 35 36 Treatment of a carboxylic acid (including N-protected amino acids) with diphenyldiselenide in the presence of tributylphosphine and N-methyl-morpholine-N-oxide results in the formation of an acyl selenide which will react with amino acids to give peptides, without the need to protect the carboxyl group of the second amino acid.175 The use of polymer supported o-nitrophenol as an active ester for peptide synthesis has been reported,*76 as has the use of polymer bound 4-dimethylamino pyridine as a coupling agent in the presence of DCC.177 The use of carbohydrate derived esters for peptide synthesis has been investigated as they are activated by lithium bromide and a complex of type 37 is thought to be formed in which the amino group of a second amino acid can be delivered intramolecularly.78 I 37 There is still scope for the development of new coupling reagents for peptide synthesis, especially for use in fragment condensation reactions where traditional methods often result in significant racemization. In this respect, the reported use of a combination of 2-thiopyridyl trifluoroacetate and the sodium salt of HOBt for peptide synthesis appears to hold much promise, as both urethane and benzoyl protected amino acids were coupled to amino esters (including N-methylamino esters) with very low degrees of racemi~ation.~~~ Another area which still causes problems is the cyclization of linear peptides through their terminal amine and carboxyl groups to give cyclic peptides, although in the case of tetrapeptides molecular mechanics calculations have been used to predict the best linear precursor.180 In a study of a number of coupling reagents for formation of a cyclic hexapeptide, the combination of TBTU/HOBt/DIEA was found to give the best results,'*' although again this may not be a generally applicable conclusion.The formation of cyclic peptides on a solid support is an area that is attracting much interest at present, as generally higher yields are obtained than if the cyclization was carried out in solution (due to the effective high dilution conditions present within the polymer matrix). Albericio et al.have described a method of preparing cyclic peptides in this way in which the peptide is bound to the resin via the side-chains of aspartic or glutamic acids, and a triply orthogonal protecting group strategy (FMOC, t-butyl, allyl) is applied.182 A similar approach but with the peptide attached to the resin through an a-carboxyl North: Amines and amides 489group has been used by Bloomberg et al. to prepare branched cyclic peptides in which the side-chains of lysine and glutamic acid residues are connected via a peptide sequence.' x3 The formation of peptides containing multiple sterically hindered residues such as a -methylalanine (Aib) can be difficult, requiring the use of highly activated carboxylic acid derivatives. Both urethane protected N-carboxyanhydrides and the use of PyBroP as a coupling reagent gave good results with Aib-containing pep tide^.'^^ In the case of a ,a-diphenylglycine, it was found that the optimum choice of coupling agent depended upon whether the diphenylglycine residue was the amine or acid component.lS5 In the former case, EEDQ gave the best results and water soluble carbodiimide the worst, whilst in the latter case the order of efficiency of the coupling reagents was reversed.Methodology for the incorporation of P-trifluoroalanine residues into a preformed peptide amide has been developed. Thus, treatment of the peptide amide with methyl trifluoropyruvate followed by dehydration with TFAA gives an imine which is reduced by sodium borohydride to give the chain-extended peptide with a P-trifluoroalanine residue at the C-terminus.'8h The choice of solvent can also be important for peptide synthesis, as many protected oligopeptides are highly insoluble in common organic solvents. 1,1,1,3,3,3-Hexafluoro-2-propanol is a good solvent for protected peptides but not suitable for use in peptide synthesis; however, by adding a proton accepting solvent (DMF, DMSO, pyridine) an excellent solvent mixture for peptide synthesis is obtained.lX7 Solid phase fragment condensation is becoming a popular strategy for the preparation of large peptides, but unfortunately the method suffers from the disadvantage that extensive racemization can occur at the C-terminal amino acid residue of the activated fragment.The effect of solvent on this racemization has been investigated, and it was found that for diisopropylcarbodiimide mediated couplings, racemization was minimized in DMF/DCM and NMP/DCM solvent systems provided HOBt was also added.88 Enzyme-catalysed peptide synthesis continues to attract much attention. Kawashiro et al. have optimized the preparation of 2-Phe-Phe-NH, from Z-Phe-OEt and Phe-NH, using porcine pancreatic lipase in water/water miscible solvent systems.'" The use of chymotrypsin to catalyse the formation of a dipeptide in frozen, aqueous solution has been reported.Igo Freezing the reaction mixture appears to improve the yield of both kinetically and thermodynamically controlled enzymatic peptide synthesis. Protease enzymes have been used to couple N-2- a ,P-dehydroglutamic acid derivatives to a -amino arnides.lq1 Pepsin has been used in the synthesis of tetrapeptide p-nitroanilides.The enzyme was used to catalyse the coupling of N-Z-tripeptides with amino acid p-nitroani1ides.lq2 An enzymatic route to peptide amides utilizing o-nitrobenzylamine derivatives of type 38 has been developed in which the enzyme is used to convert a peptide into its o-nitrobenzylamine derivative, and the o-nitrobenzyl R 38 group is then cleaved by phot01ysis.l~~ A similar approach using 2,4,6-trimethoxybenzylamine has been reported in which papain or subtilisin is used to transform a protected peptide ester into the amide, the trimethoxybenzyl protecting group then being cleaved with TFA.lY4 reacting an activated carboxyl group with an amine. However, over the last few years Heimgartner has investigated the alternative approach, namely that of reacting an activated amine with an unactivated carboxylic acid.The activated amine takes the form of a 2H-azirine (which can be prepared from the enolate of a tertiary amide by reaction with diphenyl chlorophosphate followed by sodium azide) which on reaction with an amino acid or peptide gives rise to a peptide containing an a ,a -disubstituted amino acid. Such peptides can be difficult to prepare by more traditional methods as a ,a -disubstituted amino acids are sterically hindered and so react with carboxylic acid derivatives only slowly. In the latest example of this work,IYs a tripeptide containing two adjacent a ,a -disubstituted amino acids is constructed as illustrated in Scheme 42. Peptide synthesis is almost universally carried out by Scheme 42 Another occasional problem in solid phase peptide synthesis is the double incorporation of serine residues if the OH group is left unprotected, due to 0-acylation followed by a facile 0 - N acyl migration.This problem is traditionally circumvented by the use of 0-benzyl serine, but the benzyl group requires HF for its deprotection. Thus the use of 0-t-butyl-N-Boc serine has been recommended, as the t-butyl group temporarily protects the alcohol during acylation but is cleaved concomitantly with the Boc group.lY6 The incorporation of N-methyl amino acids into peptides is a popular way of investigating the 490 Contemporary Organic Synthesisconformational and H-bonding requirements of a peptide, and methodology to convert amino acids into N-methylamino acids whilst they are attached to peptide synthesis resin has been developed, as shown in Scheme 43. Thus, treatment of an N-deprotected peptide-resin adduct with dimethoxylbenzhydryl chloride followed by reductive amination with formaldehyde/NaBH, and deprotection of the dimethoxybenzhydryl group gives a terminal N-methyl amino acid, and peptide synthesis can then be continued.97 ( i ) (MeOPh),CHCI (ii) HSO, NaBH4 RESIN-PEPTIDE-NH, (iii) TFA c RESIN-PEPTIDE-NHMe Scheme 43 Whilst the standard conditions of solid state peptide synthesis have been optimized to give excellent yields of small model peptides, problems are often encountered in the synthesis of larger peptides which are thought to be due to the formation of extensively hydrogen bonded networks (P-sheets) within the peptide whilst it is attached to the resin.The obvious way to prevent this problem is to use an additional protecting group for the primary amide bonds during the synthesis. Unfortunately, N-alkyl amino acid derivatives are sterically-hindered which again reduces yields and causes problems during solid phase peptide synthesis. However, Sheppard et al. have devised a novel solution to this problem, by use of N,O-bis-FMOC derivatives of (2-hydroxy-4- methoxybenzy1)amino acids as shown in Scheme 44. R’ R’ (ii) deprotect FMOC c + H 2N-pept ide-resi n FMOC amino acid coupling reagent Me0 Me0 0 R’ Scheme 44 The substituted benzyl group protects the primary amide bond of subsequently formed peptides, and the next amino acid residue is coupled first to the phenol-OH and then transferred intramolecularly to the secondary amine, thus avoiding problems due to North: Amines and amides steric hindrance.The 2-hydroxy-4-methoxybenzyl protecting group is cleaved by TFA under the conditions normally used to cleave the peptide from the resin.198 An alternative solution to this problem, also due to Sheppard, is the use of DMSO as solvent during solid phase peptide synthesis, as this solvent strongly disrupts hydrogen bonds. 99 A set of aggregation parameters which can be used to predict problem sequences during solid state peptide synthesis have been derived,200 as have a set of parameters based on the ability of amino acid residues to stabilize /3-sheets.2n1 4 Summary In writing this review, a number of gends became apparent, some of which have been alluded to within the main text.As expected, the emphasis in amino acid synthesis (and to a lesser extent in amine synthesis) seems to be on the development of new asymmetric methodology, though a major change of direction from a- to p-amino acids is apparent. This probably reflects the saturation of a-amino acid methodology and the realization that much of the same chemistry can be modified for p-amino acid synthesis, along with the biological properties of p-amino acids. Work in the amide area seems to be far more diverse, though p-lactams remain attractive synthetic targets. The development of new methods for peptide synthesis continues to occupy many research groups, with increasing interest being exhibited in the use of enzymes.Future, annual reviews of amines and amides will follow developments in these areas with interest. 5 References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 N. Yamashita, T. Ishimaru, and S. Nishiyama, 1992, JP 04 117 348. Y.J. Lin, S.R. Schmidt, and R. Abhari, 1992, US 5 105 015. A.M. Tafesh, J.A. McDonough, and G.N. Mott, 1992, EP491 557. E.R. Carr, 1992 US 5 120 878. S.K. Sharma, M.F. Songster, T.L. Colpitts, P. Hegyes, G. Barany, and F.J. Castellino, J. Org. Chem., 1993, 58, 4993. V.A. Dokichev, U.M. Dzhemilev, 1.0. Maidanova, and G.A. Tolstikov, 199 1, SU 1 699 995. J-P. Genet, J. Hajicek, L. Bischoff, and C. Greck, Tetrahedron Lett., 1992,33,2677. A.M. Caporusso, R. Geri, C. Polizzi, and L. Lardicci, Tetrahedron Lett., 1992,33,747 1.W.L. Neumann, 1991, US 5 105 014. S. Shatzmiller and S. Bercovici, Liebigs Ann. Chem., 1992,1005. P.J. Harrington, and I.H. Sanchez, Synth. Commun., 1993,23,1307. J.M. Aurrecoechea and A. Fernandez-Acebes, Tetrahedron Lett., 1993,34,549. V. Butz and E. Vilsmaier, Tetrahedron, 1993,49,6031. F. Vergne, D.J. Aitken, and H.P. Husson, J. Org. Chem., 1992,57,6071. J. Barluenga, F. Aznar, C. Valdez, and M.P. Cabal, J. Org. Chem., 1993,58,3391; J. Barluenga, F. Aznar, C. Valdez, A. Martin, S. Garciagranda, and E. Martin, J. Am. Chem. Soc., 1993,115,4403. 49116 F. Toda, S. Soda, and I. Goldberg, J. Chem. SOC., Perkin 17 E. Juaristi, P. Murer, and D. Seebach, Synthesis, 1993, 18 R.K. Dieter and R. Datar, Can. J. Chem., 1993,71,8 14. 19 W-J. Koot, H.Hiemstra, and W.N. Speckamp, Tetrahedron Asymm., 1993,4, 1941. 20 M. Franciotti, A. Mann, A. Mordini, and M. Taddei, Tetrnhedron Lett., 1993,34, 1355. 2 1 G. Kokotos and V. Constantinou-Kokotou, J. Chem. Res. ( S ) , 1992,39 1. 22 T.A. Kelly, V.U. Fuchs, C.W. Perry, and R.J. Snow, Tetrahedron, 1993,49, 1009, 23 P.C. Dinh and P.Y.K. Lo, 1992, US 5 101 055. 24 H. Inami, T. Ito, H. Urabe, and F. Sato, Tetrahedron 25 A.R. Katritzky, L.H. Xie, and W.G. Fan, Synthesis, 26 J.P. Finet, C. Frejaville, R. Lauricella, F. Lemoigne, P. 27 U. Groth, L. Lehmann, L. Richter, and U. Schollkopf, 28 G. Jommi, G. Miglierini, R. Pagliarin, G. Sello, and M. 29 S.T. Liu and C.Y. Liu, J. Org. Chem., 1992,57,6079. 30 T. Fuchigami, S. Ichikawa, and A. Konno, Chem. Lett., 1992,2405. 31 P.Beakand W.K.Lee,J. Org. Chem., 1993,58,1109. 32 P. Knochel, T.S. Chou, C. Jubert, and D. Rajagopal, J. Org. Chem., 1993,58,588. 33 M. Falorni, G. Chelucci, S. Conti, and G. Giacomelli, Synthesis, 1992,845. 34 T. Yamashita, K. Yamano, M. Yasuda, and K. Shima, Chem. Lett., 1993,627. 35 R.M. Moriarty, B.K. Vaid, M.P. Duncan, S. G. Levy, 0. Prakash, and S. Goyal, Synthesis, 1992,845. 36 M.A. Allakhverdiev, A.B. Aliev, K.B. Kurbanov, V.M. Kerimov, and S.M. Omarov, J. Appl. Chem. USSR (Engl. Transl.), 1992,65, 1908. 37 A. Solladie-Cavallo and M. Bencheqroun, J. Org. Chem., 1992,57,5831. 38 U. Azzena, G. Melloni, and C. Nigra, J. 0%. Chem., 1993,58,6707. 39 D.R. Williams, M.H. Osterhout, and J.P. Reddy, Tetrahedron Lett., 1993,34,327 1. 40 M. Murakami, H. Ito, and Y. Ito, J.Org. Chem., 1993, 58,6766. 41 A.M.P. Koskinen and P.M. Koskinen, Tetruhedron Lett., 1993,34,6765. 42 G. Cainelli, M. Panunzio, M. Contento, D. Giacomini, E. Mezzina, and D. Giovagnoli, Tetrahedron, 1993,49, 3809. 43 G. Cainelli, D. Giacomini, M. Panunzio, and P. Zaranonello, Tetrahedron Lett., 1992,33,7783. 44 T. Mehler and J. Martens, Tetrahedron Asymm., 1993, 4,2299. 45 R. Polt, M.A. Peterson, and L. Deyoung, J. Org. Chem., 1992,57,5469. 46 G.B. Fisher, C.T. Goralski, L.W. Nicholson, and B. Singaram, Tetrahedron Lett., 1993,34,7693. 47 M.P. Sibi and B. Li, Tetrahedron Lett., 1992,33,4115. 48 R.A.T.M. Vanbenthem, H. Hiemstra,and W.N. Speckamp, J. Org. Chem., 1992,57,6083. 49 T. Ishizuka, S. Ishibuchi, and T. Kunieda, Tetrahedron, 1993,49, 1841; T. Ishizuka, M.Osaki, H. Ishihara, and T. Kunieda, Heterocycles, 1993,35, 90 1. 50 B.J.An, H.J. Kim, and J.K. Cha, J. Org. Chem., 1993, 58, 1273. 5 1 H. Urabe, Y. Aoyama, and F. Sato, Tetrahedron, 1992, 48,5639. Trans. I , 1993,2357. 1243. Lett., 1993,34, 591 9. 1993,45. Stipa, and P. Tordo, Phosphorus Sulphur, 1993,81, 17. Liebigs Ann. Chem., 1993,427. Sisti, Tetrahedron Asymm., 1992,3, 1 13 1. 52 K. Rossen, P.M. Simpson, and K.M. Wells, Synth. 53 P. Gmeiner, A. Kartner, and D. Jange, Tetrahedron Lett., 54 T. Kawabata, Y. Kiryu, Y. Sugiua, and K. Fuji, 5 5 N. Khiar, I. Fernandez, F. Alcudia, and D.H. Hua, 56 P. Sommerfeld and D. Hoppe, Synlett, 1992,764; J. Commun., 1993,23,1071. 1993,34,4325. Tetrahedron Lett., 1993,34,5 127. Tetrahedron Lett., 1993,34,699. Schwerdtfeger and D.Hoppe, Angew. Chem., Int. Ed. Engl., 1992,1505. Langridge, J.A. Menzia, B.A. Narayanan, R.J. Pariza, D.S. Reno, T.W. Rockway,T.L. Stuk, and J.H. Tien, Org. Prep. Proced. Int., 1993,25,437. 58 M.R. Leanna, T.J. Sowin, and H.E. Morton, Tetrahedron Lett., 1992,33,5029. 59 P.T. Ho and K.Y. Ngu, J. Org. Chem., 1993,58,2313. 60 K.L. Dueholm, M. Egholm, and 0. Buchardt, Org. Prep. 61 S.E. Denmark and 0. Nicaise, Synlett, 1993,359. 62 P. Darkins, N. McCarthy, M. A. McKervey, and T. Ye, J. Chem. SOC., Chem. Commun., 1993,1222. 63 M. Nasreddine, S. Szonyi, F. Szonyi, and A. Cambon, Synth. Commun., 1992,22,1547. 64 D. Albanese, D. Landini, and M. Penso, J. Org. Chem., 1992,57,1603. 65 L. Grehn, U. Bondesson, T. Pehk, and U. Ragnarsson, J. Chem Soc., Chem. Commun., 1992,1332.66 J. Singh, T.D. Gordon, W.G. Earley, and B.A. Morgan, Tetrahedron Lett., 1993,34,2 1 1. 67 G. Courtois and L. Miginiac, J. Organomet. Chem., 1993,450,33; G. Courtois and L. Miginiac, J. Organomet. C'hem., 1993,452,5. 68 L.V. Hijfte, V. Heydt, and M. Kolb, Tetrahedron Lett., 1993,34,4793. 69 J. Vidal, L. Guy, S. Sterin, and A. Collet, J. Org. Chem., 1993,58,4791. 70 U. Groth, T. Huhn, B. Porsch, C. Schmeck, and U. Schollkopf, Liebigs Ann. Chem., 1993,7 15. 71 C. Agami, F. Couty, J. Lin, A. Mikaeloff, and M. Poursoulis, Tetrahedron, 1993,49,7239. 72 F.G. West, K.W. Glaeske, and B.N. Naidu, Synthesis, 1993,977. 73 H. Watanabe, Y. Hashizume, and K. Uneyama, Tetrahedron Lett., 1992,33,4333. 74 R. Jumnah, J.M.J. Williams, and A.C. Williams, Tetrahedron Lett., 1993,34,66 19.75 G. Wulff and H.T. Klinken, Tetrahedron, 1992,48, 5985. 76 S.T. Chen, C.C. Tu, and K.T. Wang, Biotechnol. Lett., 1992,14,269. 77 R.L. Gu, I-S. Lee, and C.J. Sih, Tetrahedron Lett., 1992, 33, 1953. 78 J.Z. Crich, R. Brieva, P. Marquart, R.L. Gu, S. Flemming, and C.J. Sih, J. Org. Chem., 1993,58, 3252. Tetrahedron Asymm., 1993,4,73; C. Dobler, H-J. Kreuzfeld, H.W. Krause, and M. Michalik, Tetrahedron: Asymm., 1993,4, 1833. 80 C. Cativiela, M.D. Diaz-de-Villegas, and J.A. Galvez, Tetrahedron Asymm., 1992,3, 567. 81 R. Kramer, H. Wanjek, K. Polborn, and W. Beck, Chem. Ber., 1993, 126,242 1, 82 M. Braun and K. Opdenbusch, Angew. Chem., Int. Ed. Engl., 1993,32,578. 83 D. Enders, R. Funk, M. Klatt, G. Raabe, and E.R. Hovestreydt, Angew. Chem., Int. Ed.Engl., 1993,32, 418. 57 D.J. Krysan,A.R. Haight, J.E. Lallaman, D.C. Proced. Int., 1993,25,457. 79 S. Taudien, K. Schinkowski, and H-W. Krause, 492 Contemporary Organic Synthesis84 M. Poch, M. Alcon, A. Moyano, M.A. Pericas, and A. Riera, Tetrahedron Lett., 1993,34,778 1. 85 M.K. Gurjar, A.S. Mainkar, and M. Syamala, Tetrahedron Asymm., 1993,4,2343. 86 J. Claydon, E.W. Collington, and S. Warren, Tetrahedron Lett., 1993,34, 1327. 87 L.M. Boteju, K. Wegner, and V.J. Hruby, Tetrahedron Lett., 1992,33,7491; G. Li, K.C. Russell, M.A. Jarosinski, and V.J.Hruby, Tetrahedron Lett., 1993,34, 2565. 88 M. Bruncko, and D. Crich, Tetrahedron Lett., 1992,33, 6251. 89 C. Cativiela, M.D. Diaz-de-Villegas, and J.A. Galvez, Tetrahedron Asymm., 1993,4, 1445. 90 K. Mikami, M.Kaneko, and T. Yajima, Tetrahedron Lett., 1993,34,4841. 9 1 D.P.G. Hamon, R.A. Massywestropp, and P. Razzino, Tetrahedron, 1992,48,5163. 92 T. Tsunoda, S. Tatsuki, Y. Shiraishi, M. Akasaka, and S. Ito, Tetrahedron Lett., 1993,34,3297. 93 M. Mehmandoust, Y. Petit, and M. Larcheveque, Tetrahedron Lett., 1992,33,43 13. 94 W. Oppolzer, 0. Tamura, and J. Deerberg, Helv. Chim. Acta, 1992,75, 1965. W. Oppolzer, P. Cintasmoreno, 0. Tamura, and F. Cardinaux, Helv. Chim. Acta, 1993, 76, 187. 95 K. Koh, R.N. Ben, and T. Durst, Tetrahedron Lett., 1993,34,4473. 96 G.F. Su and L.C. Yu, Synth. Commun., 1993,23,1229. 97 U. Larsson, R. Carlson, and J. Leroy, Acta Chem. Scand., 1993,47,380. 98 R.F.W. Jackson, J.M. Kirk, N.J. Palmer, D. Waterson, and M.J. Wythes, J. Chem. SOC., Chem.Commun., 1993,889. 99 F. Degerbeck, B. Fransson, L. Grehn, and U. Ragnarsson, J. Chem. Soc., Perkin Trans. I , 1993, 1 1. 100 J. Hausler, Liebigs Ann. Chem., 1992, 123 1. 10 1 T. Inaba, I. Kozono, M. Fujita, and K. Ogura, Bull. Chem. SOC. Jpn., 1992,65,2359. 102 M. North, Synlett, 1993,807. 103 P. Zandbergen, J. Brussee, A. Vandergen, and C.G. Kruse, Tetrahedron Asymm., 1992,3, 769. 104 J.E. Baldwin, R.M. Adlington, C.R.A. Godfrey, D.W. Gollins, M.L. Smith, and A.T. Russel, Synlett, 1993,5 1. 105 R. Bernardi, M. Zanotti, G. Bernardi, and A. Duatti, J. Chem. SOC., Chem. Commun., 1992,101 5. 106 P. Canonne, M. Akssira, A. Dahdouh, H. Kasmi, and M. Boumzebra, Tetrahedron, 1993,49, 1985. 107 V.A. Soloshonok, V.K. Svedas, V.P. Kukhar, A.G. Kirilenko, A.V. Rybakova, V.A.Solodenko, N.A. Fokina, O.V. Kogut, I.Y. Galaev, E.V. Kozlova, I.P. Shishkina, and S.V. Galushko, Synlett, 1993,339. 108 A.J. Robinson and P.B. Wyatt, Tetrahedron, I993,49, 11329. 109 F.A. Davis, R.T. Reddy, and R.E. Reddy, J. Org. Chem., 1992,57,6387. 110 J. Ipaktschi and A. Heydari, Chem. Ber., 1993,126, 1905. 11 1 M. Mladenova and M. Bellassoued, Synth. Commun., 1993,23,725. 11 2 S. Murahashi and H. Otake, 1991, JP 03 291 259. 1 13 C. Andres, A. Gonzalez, R. Pedrosa, and A. Perez-Encabo, Tetrahedron Lett., 1992,33,2895. 1 14 M.K. Mokhallalati, M-J. Wu, and L.N. Pridgen, Tetrahedron Lett., 1993,34,47. 1 15 D. Enders, M. Klatt, and R. Funk, Synlett, 1993,226. 116 I. Ojima, C.M. Sun, M. Zucco, Y.H. Park, 0. Duclos, and S. Kuduk, Tetrahedron Lett., 1993,34,4149.1 17 I. Ojima, Y.H. Park, C.M. Sun, T. Brigaud, and M. Zhao, Tetrahedron Lett., 1992,33,5737; J.D. Bourzat and A. Commercon, Tetrahedron Lett., 1993,34,6049. 1 18 C. Palomo, F. Cabre, and J.M. Ontoria, Tetrahedron Lett., 1992,33,48 1 9. 1 19 C. Palomo, J.M. Aizpurua, R. Urchegui. and J.M. Garcia, J. Org. Chem., 1993,58, 1646. 120 G. Rassu, L. Pinna, P. Spanu, F. Ulgheri, M. Cornia, F. Zanardi, and G. Casiraghi, Tetrahedron, 1993,49, 6489. 12 1 U. Schmidt, B. Riedl, G. Haas, H. Griesser, A. Vetter, and S. Weinbrenner, Synthesis, 1993,2 16. 122 D. Enders and M. Finkam, Synlett, I993,40 I . 123 Y. Lu, C. Miet, N. Kunesch, and J.E. Poisson, 124 R.C. Rastogi, R.H. Khan, and K.R. Baruah, J. Znd. 125 M. Ueda and H. Mori, Bull. Chem. SOC. Jpn., 1992,65, 126 M. Metzulat and G.Simchen, Synthesis, 1993,62. 127 R. Di Fabio, V. Summa, and T. Rossi, Tetrahedron, 1993,49,2299. 128 M. C. Desai and L.M. Stephens Stramiello, Tetrahedron Lett., 1993,34,7685. 129 W-B. Wang and E.J. Roskamp, J. Org. Chem., 1992,57, 6101. I30 P. Lopez-Alvarado, C. Avendano, and J.C. Menendez, Tetrahedron Lett., 1992,33,6875. 13 1 M. Schuster, B. Munoz, W. Yuan, and C-H. Wong, Tetrahedron Lett., 1993,34,1247. 132 S. Puertas, R. Brieva, F. Rebolledo, and V. Gotor, Tetrahedron, 1993,49,4007. 133 M.J. Garcia, F. Rebolledo, and V. Gotor, Tetrahedron Asymm., 1993,4,2 199. 134 S. Yoshida, 1992, JP 04 197 189. 135 D.L. Anton, R.D. Fallon, W.J. Linn, and B. Stieglitz, 1992, W092 05 275. 136 J. Taillades, L. Garrel, P.H. Lagriffoul, and A. Commeyras, Bull. SOC.Chim. Fr., 1 992,129,19 1. 137 T. Satoh, S. Motohashi, S. Kimura, N. Tokutake, and K. Yamakawa, Tetrahedron Lett., 1993,34,4823. I38 M. Ihara, A. Hirabayashi, N. Taniguchi, and R. Fukumoto, Heterocycles, 1992,33,85 1 . 139 S.I. Murahashi and T. Naota, Synthesis, 1993,433. 140 E. Bollens, H. Trabelsi, J. Fayn, E. Rouvier, and A. Cambon, J. Fluorine Chem., 1993,63, 173. I41 P. Froyen, Phosphorus Sulphur, I993,78, 16 1. 142 R.V. Hoffman, N.K. Nayyar, and W. Chen, J. Org. Chem., 1992,57,5700; R.V. Hoffman, N.K. Nayyar, and B.W. Klinekole, J. Am. Chem. SOC., 1992,114, 6262; R.V. Hoffman, N.K. Nayyar, and W. Chen, J. Org. Chem., 1993,58,2355. 143 K. Abe, Y. Matsuo, T. Arime, and N. Mori, Chem. Express, 1992,7,645. 144 T. Satoh, K. Oguro, J-I. Shishikura, N. Kanetaka, R.Okada, and K. Yamakawa, Tetrahedron Lett., 1992,33, 1455. 145 J. Zheng, Z. Wang, and Y. Shen, Synth. Commun., 1992, 22, 161 1. I46 Y. Kataoka, Y. Oguchi, K. Yoshizumi, S. Miwatashi, K. Takai, and K. Utimoto, Bull. Chem. SOC. Jpn., 1992,65, 1543. Tetrahedron Asymm., 1993,4,893. Chem. Soc., I992,69,16 1. 1636. 147 T. Janecki, Synth. Cornmun., 1992,22,2063. 148 N.K. Nayyar, M.M. Reddy, and J. Iqbal, Tetrahedron Lett., 1991,32,6965. 149 H. Kotsuki, M. Iwasaki, and H. Nishizawa, Tetrahedron Lett., 1992,33,4945. 150 M. Bessodes, M. Saiah, and K. Antonakis, J. Org. Chem., 1992,57,444 1. 15 1 A. Couture, E. Deniau, and P. Grandclaudon, Synth. Commun., 1992,22,2381. 152 B.K. Jordan, B. Stanovnik, and M. Tisler, Heterocycles, North: Amines and amides 4931992,33,657.153 R.N. Zuckermann, J.M. Kerr, S.B.H. Kent, and W.H. Moos, J. Am. Chem. Soc., 1993,114,10646. 154 F. Texier-Boullet, R. Latouche, and J. Hamelin, Tetrahedron Lett., 1993,34,2 123. 155 W.B. Wang and E.J. Roskamp, J. Am. Chem. SOC., 1993, 115,9417. 156 C. Cativiela, M.D. Diaz-de-Villegas, and J.A. Galvez, Tetrahedron Asymm., 1992,3, 1 141 ; C. Cativiela, M.D. Diaz-de-Villegas, and J.A. Galvez, Tetrahedron Asymm., 1993,4,229. A.P.G. Kieboom, A.L. Spek, and G. van Koten, Tetrahedron Asymm., 1993,4, 1441. 158 R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi, and L. Raimondi, Tetrahedron Lett., 1993,34,6921. 159 R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi, and F. Ponzini, J. Org. Chem., 1993,58,4746. 160 F.H.Vandersteen, H. Kleijn,G.J.P.Britovsek, J.T.B.H. Jastrzebski, and G.Vankoten, J. Org. Chem., 1992,57, 3906. 161 B. Alcaide, Y. Martincantalejo, J. Perezcastells, J. Rodriguezlopez, M.A. Sierra, A. Monge, and V. Perezgarcia, J. Org. Chem., 1992,57,5921. 162 M. Es-Sayed, T. Heiner, and A. de-Meijere, Synlett, 1993,57. 163 K. Suda, K. Hotoda, F. Iemuro, and T. Takanami, J. Chem. Soc., Perkin Trans. 1, 1993, 1553. 164 S. Ozaki, H. Matsushita, and H. Ohmori, J. Chem. SOC., Perkin Trans. 1, 1993,2339. 165 M. Scartozzi. R. Grondin, and Y. Leblanc, Tetrahedroh Lett., 1992,33, 5717. 166 L.A. Carpino and E.S.M.E. Mansour, J. Org. Chem., 1992,57,6371. 167 N.L. Benoiton, Y.C. Lee, and F.M.F. Chen, Int. J. Pept. Protein Rex, 1993,42,278. 168 T. Nagase, T. Fukami, Y. Urakawa, U. Kumagai, and K. Ishikawa, Tetrahedron Lett., 1993,34,2495. 169 J. Dudash, J.J. Jiang, S.C. Mayer, and M.M. Joullie, Synth. Commun., 1993,23,349. 170 H.M. Yu, S.T. Chen, and K.T. Wang, J. Org. Chem., 1992,57,4781. 17 1 B. Devadas, I3. Kundu, A. Srivastava, and K.B. Mathur, Tetrahedron Lett.. 1993,34,6455. 172 T. Katoh and M. Ueki, Int. J. Pept. Protein Res., 1993, 42, 264. 173 A. Ahmed and H. Akhter, Ind. J. Chem., Sect. B., 1993, 32,564. 174 K. Kawasaki, K. Hirase, M. Miyano, T. Tsuji, and M. Wamoto, Chem. Pharrn. Bull., 1992,40,3253. 175 S.K. Ghosh, U. Singh, M.S. Chadra, and V.R. Mamdapur, Buff. Chem. SOC. Jpn., 1993,66, 1566. 176 S.C. Duh, H.Z. Hsieh, S.T. Chen, and K.T. Wang, J. Chin. Chem. SOC. (Taipei), 1993,40,475. 157 H.L. van Maanen, J.T.B.H. Jastrzebski, J. Verweij, 177 F.C. Frontin, F. Guendouz. R. Jacquier, and J. Verducci, Bull. Soc. Chim. Fr., 1992, 129,463. 178 H. Kunz and R. Kullmann, Tetrahedron Lett., 1992,33, 61 15. 179 U. Schmidt and H. Griesser, J. Chem. SOC., Chem. Commun., 1993,146 1. I80 F. Cavelierfrontin, G. Pepe, J. Verducci, D. Siri, and R. Jacquier, J. Am. Chem. Soc., 1992, 114,8885. 18 1 S. Zimmer, E. Hoffmann, G. Jung, and H. Kessler, Liebigs Ann. Chem., 1993,497. 182 S.A. Kates, N.A. Sole, C.R. Johnson, D. Hudson, G. Barany, and F. Albericio, Tetrahedron Lett., 1993,34, 1549. 183 G.B. Bloomberg, D. Askin, A.R. Gargaro, and M.J.A. Tanner, Tetrahedron Lett., 1993,34,4709. 184 C. Auvin-Guette, E. Frerot, J. Coste, S. Rebuffat, P. Jouin, and B. Bodo, Tetrahedron Lett., 1993,34,2481. 185 T. Yamada, Y. Ornote, Y. Nakamura, T. Miyazawa, and S. Kuwata, Chem. Lett., 1993, 1583. 186 E. Hoss, M. Rudolph, L. Seymour, C. Schierlinger, and K. Burger, J. Fluorine Chem., 1993,61, 163. 187 N. Nishino, H. Mihara, Y. Makinose, and T. Fujimoto, Tetrahedron Lett., 1992,33,7007. 188 A.C. Haver and D.D. Smith, Tetrahedron Lett., 1993, 34,2239. 189 K. Kawashiro, K. Kaiso, D. Minato, S. Sugiyama, and H. Hayashi, Tetrahedron, 1993,49,4541. 190 M. Schuster, G. Ullmann, U. Ullmann, H-D. Jakubke, Tetrahedron Lett., 1993,34,5701. 191 C. Shin, M. Seki, T. Kakusho, and N. Takahashi, Bull. Chem. SOC. Jpn., 1993,66,2048. 192 C.A.A. Malak, G.I. Lavrenova, E.N. Lysogorskaya, I.Y. Filippova, E.Y. Terenteva, and V.M. Stepanov, Int. J. Pept. Protein Res., 1993,4 1,97. 193 D.B. Henriksen, K. Breddam, and 0. Buchardt, Int. J. Pept. Protein Res., 1993,41, 169. 194 J. Green and A.L. Margolin, Tetrahedron Lett., 1992, 33,7759. 195 J.M. Villalgordo and H. Heimgartner, Helv. Chim. Acta, 1992,75, 1866; J.M. Villalgordo and H. Heimgartner, Tetruhedron, 1993,49,7215. Morgans, and J. Robinson, Int. J. Pept. Protein Res., 1993,41,342. 197 K. Kaljuste and A. Unden, Int. J. Pept. Protein Res., 1993,42, 118. 198 T. Johnson, M. Quibell, D. Owen, and R.C. Sheppard, J. Chem. Soc., Chem. Commun., 1993,369. 199 C. Hyde, T. Johnson, and R.C. Sheppard, J. Chem. Soc., Chem. Commun., 1992,1573. 200 V. Krchnak, Z . Flegelova, and J. Vagner, Int. J. Pept. Protein Res., 1993,42,450. 201 M. Narita, J.S. Lee, Y. Murakawa, and Y. Kojima, Bull. Chem. SOC. Jpn., 1993,66,483. 196 H.B. Arzeno, W. Bingenheimer, R. Blanchette, D.J. 494 Contemporary Organic Synthesis

ISSN:1350-4894    

DOI:10.1039/CO9940100475

出版商:RSC    

年代:1994

数据来源: RSC