摘要:

_ _ _ _ _ _ _ ~ ~ ~ Contemporary Organic Synthesis Editorial Board Professor G. Pattenden, FRS (Chairman), University of Nottingham Professor P. D. Bailey, Heriot- Watt University Dr S. E. Gibson (nee Thomas), Imperial College of Science, Technology, and Medicine Professor P. J. Kocienski, University of Southampton Professor C. J. Moody, Loughborough University of Technology Professor E. J. Thomas, University of Manchester International Advisory Board Prbfessor E. J. Corey, Harvard University Professor S. Hanessian, Universiti de Montrial Professor M. Julia, Universiti 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 Professor R.Noyori, Nagoya University Professor L. E. Overman, University of California, Iwine Professor L. F. Tietze, University of Gottingen California at San Diego, La Jolla 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 Dr S. R. Buxton, Managing Editor, Organic Publications, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF, UK.Tel +44 (0) 1223 420066 Fax +44 (0) 1223 420247 E-mail rscl@rsc.org RSC Server http://chemistry.rsc.org/rsc/ 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. 1996 subscription rates: EEA E185, USA $350, Canada El90 (plus GST), Rest of the World &190. Contemporary Organic Synthesis is published 6 times a year in February, April, June, August, October and December. Airfreight and mailing in the USA by Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey, NJ 07001, USA and at additional mailing offices.Second class postage is paid at Rahway, NJ. USA Postmaster: Send address changes to Contemporary Organic Synthesis, c/o Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey 07001. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. 0 The Royal Society of Chemistry, 1996. 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 in Great Britain by Unicus Graphics Ltd, Horsham, West Sussex Printed in Great Britain by Whitstable Litho Ltd, Whitstable, KentContemporary Organic Synthesis Editorial Board Professor G.Pattenden, FRS (Chairman), University of Nottingham Professor P. D. Bailey, Heriot- Watt University Dr S . E. Gibson (nee Thomas), Imperial College of Science, Technology, and Medicine Professor P. J . Kocienski, University of Southampton Professor C. J. Moody, Loughborocigh University uf Technology Professor E. J. Thomas, University qf Manchester International Advisory Board Professor E. J. Corey, Haward University Professor S . Hanessian, Universiti de Montrial Professor M. Julia, Universiti de Paris XI (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 Professor R. Noyori, Nagoya University Professor L. E. Overman, University qf California, lrvine Professor L. F. Tietze, University of Giittingen California at San Diego, La Jolla 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 Dr Sheila R.Buxton, Managing Editor, Organic Publications, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF, UK. Deputy Editor: Nicole Brooks. Production Editor: Nicola Coward. Technical Editor: Tony Breen. Tel +44 (0) 1223 420066 Fax +44 (0) 1223 420247 E-mail rsc 1 @rsc.org RSC Server http://chemistry.rsc.org/rsc/ Members of The Royal Society of Chemistry may subscribe to Confemporary 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 1 HN, England. 1996 subscription rates: EEA &185, USA $350, Canada El90 (plus GST), Rest of the World f190. Contemporary Organic Synthesis is published 6 times a year in February, April, June, August, October and December. Airfreight and mailing in the USA by Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey, NJ 07001, USA and at additional mailing offices. Periodicals postage is paid at Rahway, NJ. USA Postmaster: Send address changes to Contemporary Organic Synthesis, c/o Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey 07001. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. $3 The Royal Society of Chemistry, 1996. 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 in Great Britain by Unicus Graphics Ltd, Horsham, West Sussex Printed in Great Britain by Whitstable Litho Ltd, Whitstable, Kent

ISSN:1350-4894    

DOI:10.1039/CO99603FX013

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

ISSN 1350-4894 COGSE6 3 (4) 259-344 (1996) Contemporary Organic Synthesis A journal of current developments in Organic Synthesis V O L U M E 3 N U M B E R 4 C O N T E N T S 6' 4 I I R'R2NLi Saturated nitrogen heterocycles By Timothy Harrison Reviewing the literature published in 1995 Catalytic applications of transition metals in organic synthesis By Graham J. Dawson, Justin F. Bower and Jonathan M. J. Williams Reviewing the literature published between 1 September 1994 and 31 October 1995 259 277 Saturated and unsaturated lactones 295 By Ian Collins Reviewing the literature published between 1 August 1994 and 31 October 1995 Amines and amides By Michael North Reviewing the literature published in 1995 323Cumulative Contents of Volume 3 Number 1 1 Stoichiometric applications of organotransition metal complexes in organic synthesis (1 September 1994 to 30 April 2995) Timothy J.Donohoe 19 Saturated and partially unsaturated carbocycles (January 1994 to April 1995) Christopher D. J. Boden and Gerald Pattenden 41 The enediyne and dienediyne based antitumour antibiotics. Methodology and strategies for total synthesis and construction of bioactive analogues. Part 1 (up to 15 October 1995) HervC Lhermitte and David S. Grierson 65 Alcohols,,ethers and phenols (August 1993 to Febncary 1995) C. S. Hau, Ashley N. Jarvis and Joseph B. Sweeney Number 2 93 The enediyne and dienediyne based antitumour antibiotics. Methodology and strategies for total synthesis and construction of bioactive analogues. Part 2 (up to 25 November 1995) HervC Lhermitte and David S.Grierson 125 The discovery of fluconazole (up to December 1994) Ken Richardson 133 Organic halides (1 July 1994 to 30 June 1995) Stephen €? Marsden 151 Aldehydes and ketones (October 2994 to September 2995) Patrick G. Steel Number 3 173 Recent developments in chemical oligosaccharide synthesis (up to October 2995) Geert-Jan Boons 201 Main group organometallics in synthesis (January 1994 to June 2995) Martin Wills 229 Saturated oxygen heterocycles (October 1994 to September 2995) Christopher J. Burns and Donald S. Middleton 243 Carboxylic acids and esters ( 1 August 1994 to 31 July 1995) Tammy Ladduwahetty Number 4 259 Saturated nitrogen heterocycles (1995) Timothy Harrison 277 Catalytic applications of transition metals in organic synthesis (2 September 1994 to 31 October 1995) Graham J. Dawson, Justin E Bower and Jonathan M. J. Williams 295 Saturated and unsaturated lactones (1 August 1994 to 31 October 2995) Ian Collins 323 Amines and amides (1995) Michael North Articles that will appear in forthcoming issues include Synthetic approaches to rapamycin Mark C. Norley Synthetic applications of flash vacuum pyrolysis (2990 to 1995) Hamish McNab Protecting groups (2995) Knysztof Jarowicki and Philip Kocienski The synthesis of quinones (1 January 1991 to 31 December 1995) Peter T. Gallagher The intramolecular Heck reaction (up to the end of 1995) Susan E. Gibson (n& Thomas) and Richard J. Middleton

ISSN:1350-4894    

DOI:10.1039/CO99603FP015

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

280 H. Tani, S. Irie, K. Masumoto and N. Ono, Hetero- 281 S. Dhanalekshmi, C. S. Venkatachalam and K. K. cycles, 1993, 36, 1783. Balasubramian, J. Chem. SOC., Chem. Commun., 1994, 511. Chem. Soc., 1994, 116,6713. 1993,36, 1795. J. Chem. SOC., Perkin Fans. 1, 1995, 2855. 1994,352299. Chem., 1992,45, 1639. 282 W. Adam, M. Ahnveiler and D. Reinhardt, J. Am. 283 B. Alcaide, C. Biurran and J. Plumet, Heterocycles, 284 M. A. Brimble, S. J. Phythian and H. Prabaharan, 285 D. G. Barrett and S.H. Gellman, Tetrahedron Lett., 286 D. B. Clarke, J. R. Guild and R. T. Weavers, Aust. J. Williams: The synthesis of carbocyclic aromatic systems 287 H. R. Sonawane, S. N. Bellur and S. G. Sudrik, Ind. J. 288 E. V. Dehmlow and C. Bollmann, Tetrahedron, 1995, 289 G. P. Shkil and R. S. Sagitullin, Tetrahedron Lett., 290 H.A. Etman, Ind. J. Chem., Sect. B, 1995,34, 285. 291 T. Nakazawa, M. Ishihara, M. Jiguji, M. Yamaguici, Y. Sugihara and I. Murata, Tetrahedron Lett., 1992, 33, 6487. 292 H. Nishino, S. Kajikawa, Y. Hamada and K. Kuro- sawa, Tetrahedron Lett., 1995, 36, 5753. 293 R. F. C. Brown, F. W. Eastwood and J. M. Horvath, Aust. J. Chem., 1995, 48, 1055. Chem., Sect. B, 1992, 31, 606. 51, 3755. 1994,35, 2075. 567280 H. Tani, S. Irie, K. Masumoto and N. Ono, Hetero- 281 S. Dhanalekshmi, C. S. Venkatachalam and K. K. cycles, 1993, 36, 1783. Balasubramian, J. Chem. SOC., Chem. Commun., 1994, 511. Chem. Soc., 1994, 116,6713. 1993,36, 1795. J. Chem. SOC., Perkin Fans. 1, 1995, 2855. 1994,352299. Chem., 1992,45, 1639. 282 W. Adam, M. Ahnveiler and D. Reinhardt, J. Am. 283 B. Alcaide, C. Biurran and J. Plumet, Heterocycles, 284 M. A. Brimble, S. J. Phythian and H. Prabaharan, 285 D. G. Barrett and S.H. Gellman, Tetrahedron Lett., 286 D. B. Clarke, J. R. Guild and R. T. Weavers, Aust. J. Williams: The synthesis of carbocyclic aromatic systems 287 H. R. Sonawane, S. N. Bellur and S. G. Sudrik, Ind. J. 288 E. V. Dehmlow and C. Bollmann, Tetrahedron, 1995, 289 G. P. Shkil and R. S. Sagitullin, Tetrahedron Lett., 290 H. A. Etman, Ind. J. Chem., Sect. B, 1995,34, 285. 291 T. Nakazawa, M. Ishihara, M. Jiguji, M. Yamaguici, Y. Sugihara and I. Murata, Tetrahedron Lett., 1992, 33, 6487. 292 H. Nishino, S. Kajikawa, Y. Hamada and K. Kuro- sawa, Tetrahedron Lett., 1995, 36, 5753. 293 R. F. C. Brown, F. W. Eastwood and J. M. Horvath, Aust. J. Chem., 1995, 48, 1055. Chem., Sect. B, 1992, 31, 606. 51, 3755. 1994,35, 2075. 567

ISSN:1350-4894    

DOI:10.1039/CO99603BX019

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Saturated nitrogen heterocycles TIMOTHY HARRISON Merck Sharp and Dohme Reseurch Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Hurlow, Essex CM20 2QR, UK Reviewing the literature published in 1995 Continuing the coverage in Contemporary Organic Synthesis, 1995, 2, 209 Three-membered rings Four-membered rings Five-membered rings Six-membered rings Pyrrolizidines, indolizidines and quinolizidines Tetrahydroquinolines and tetrahydroisoquinolines Miscellaneous methods for the synthesis of nitrogen heterocycles of varying ring sizes Medium and large ring nitrogen heterocycles References 1 Three-membered rings Heteroaryl aziridines 2 (Het = 2-pyridy1, 2-quinolyl and 2-benzathiazoyl) of (E)-configuration have been prepared by the diastereoselective Darzens-type reaction of (heteroaryIchloromethy1)lithiums 1 with imines.The (heteroarylch1oromethyI)lithium species are readily available by lithiation of the corre- sponding chloromethyl heterocycles (LDA, THF, -78 "C), and the addition works well with both nonenolizable and enolizable imines.' Diary1 aziri- dines 4 can be prepared in moderate to good yields by reaction of cis-p-sultams 3 with SnCl,. The desired product is accompanied by smaller amounts of benzophenone derivative 5 . If the truns-/hultams are used, then the benzophenone derivatives predominate .2 1 2 n 3 4 5 Relatively sensitive N-tosyl vinyl aziridines 7 can be prepared in moderate to high yield by the Cu(acac)2-catalysed aziridination of 1,3-dienes using PhI=NTs. Both acyclic and cyclic dienes can be used, and in some cases the reactions appear to be stereospecific with retention of double bond geometry.For unsymmetrical dienes, the more electron rich double bond undergoes aziridination, and when two double bonds are electronically similar, steric factors govern the selectivity.3 Matano et al. have reported a direct route to 2-acylaziridines 11 starting from imines 10 utilising a bismuthonium ylide 9 generated in situ from bismuth salt 8. This mode of reaction stands in marked contrast to that of phosphonium ylides, and the cisltruns stereo- chemistry of the products can be controlled by proper choice of base and additi~e.~ -78 *c II c) 8 9 1 R2CH;NS0,R3 5 0 ~ ~ 3 r% R' + Ph3Bi 0 11 A number of papers detailing asymmetric syntheses of aziridines have appeared.Thus, Jorgensen et al. have reported the preparation of aziridines 13 via the addition of ethyl diazoacetate to imines 12 catalysed by simple copper complexes. The diastereoselectivity and yield of the reaction is very dependant on the nitrogen substituent R2, with phenyl giving the highest yields and silicon the highest diastereoselectivity. The incorporation of a chiral auxilliary in the diazoacetate portion produced products with a low de, and the use of Harrison : Sot ura ted nitrogen heterocycles 259Cu(OTf), in the presence of a chiral oxazoline ligand produced aziridines with low eek5 In a related study Jacobsen et al. have reported the same reaction using N-aryl benzylidine imines 14 as precursors and copper( I) hexafluorophosphate as the catalyst in the presence of homochiral bis-oxazo- lines.At present enantiomeric excesses are low to moderate, and efforts to extend this aziridination methodology to other classes of imines have not been fruitful. In some instances racemic pyrrolidines 15 are also produced in the reaction.6 HkZ2 R' 12 t 13 R' = Ph, Bu', H R2 = Ph, Pr', But, SiMe H 14 ' g - - H C02Et + Ar'--fyCO2Et c' N Ar' 'A? EtQC 'C02Et major (1 147% ee) mc -1 5 Both Davis7 and Ruano8 have reported the asymmetric synthesis of 2-substituted aziridines by addition of dimethyloxosulfonium methylide to enantiomerically pure sulfinimines 16. In the Davis work the de's proved to be relatively insensitive to the reaction conditions (58-70% de). After separa- tion of the diastereoisomers, the N-sulfinyl group can be removed by treatment with 1.5 equiv.of methyllithium at - 78 "C followed by quenching with sat. NH4Cl. Davis et al. have also reported an asymmetric synthesis of 2H-azirine 2-carboxylic acid derivatives 18 by LDA-induced deprotonation of aziridines 17 in the presence of iodomethane.' The 2H-azirine structural unit is found in a number of natural antibiotics. Me3S(0)CI, base H N A2 (W+)-16 MeLi. M F R2 = S(0)Ar -78°C H i. LDA, -78 "C ii. Me1 H Y H iii. H20, THF R H RXco2Me S(0)-tolyl-p 17 18 2 Four-membered rings Seebach et al. have described a new synthetic approach to the relatively unexplored azetidine- 3-one derivatives 20. Thus amino acid derived diazo ketone 19 undergoes Rh"-catalysed cyclisation to provide the products in 5040% yield after chromatography." R 19 20 3 Five-membered rings The asymmetric synthesis of pyrrolidine derivatives by 1'3-dipolar cycloaddition of azomethine ylides with alkenes in the presence of chiral controller groups continues to attract attention.Grigg et aZ. have shown that metallo-azomethine ylides 21, generated from imines by the action of amine bases, undergo cycloaddition with menthyl acrylate 22a at room temperature to give homochiral pyrrolidines 23 in excellent yield. The absolute configuration of the newly established pyrrolidine stereocentres is independent of the metal salt and the size of the pyrrolidine C(2)-substituent for a series of aryl aliphatic imines. In addition, other electron- withdrawing groups can replace the ester in the starting imine (e.g 24)." Similar work has also been reported by Waldmann et aZ.in which N-metallated azomethine ylides 21 add to N-acryloyl-(S)-proline 0 21 I R'OC- 0 R* I? . 24 23 260 Contemporary Organic Synthesisesters 22b again with high diastereoselectivity furnishing pyrrolidines 23. l2 The homochiral oxazolidinone 25, which is a useful precursor for the synthesis of non-proteino- genic amino acids via Diels-Alder reactions, allenyl radical and nitronate anion 1 ,Zadditions, and cyclo- propanation, undergoes highly exo-diastereoselective 1,3-dipolar cycloadditions with azomethine ylides 26 derived from a-amino acids to provide cycloadducts 27. These are readily converted to polyfunctional prolines 28 (Na2C03, MeOH) with high enantio- meric purity.13 R' LiBr, DBU, THF PhANk:02R2 -780c L J 26 4 25 0 H 28 27 '*- -I- R2\[rNAF1' AgOAc, DBU R:, 0 0 THF 29 R ~ O C ~ R' H A full account of the diastereoselective synthesis of pyrrolidines by reaction of homochiral a, p- unsaturated ketones 29 bearing alkoxy or amino substituents in the y-position with azomethine ylides has appeared.I4 Harwood et al.have extended the scope of dipolar cycloadditions based on the morpholinone 30 by using ethyl glyoxylate as the condensing agent. The resulting (E)-ylide 31 under- goes highly diastereoselective cycloaddition with a range of dipolarophiles, and removal of the template from the cycloadducts 32 furnishes enantiomerically pure pyrrolidine-2,5-dicarboxylate derivative^."^ The use of formaldehyde as the condensing agent has also been de~cribed.'~~ Coldham et al.have described the synthesis of pyrrolidines by 1,3-dipolar cycloaddition of con- jugated azomethine ylides 34. These are generated in situ from a mixture of azido alcohols 33 by treat- ment with Ph3P to form the aziridine and then thermal ring opening. The ring opening is conrota- tory generating cis-2,5-disubstituted pyrrolidines 35. In all cases the endo-cycloaddition products were observed. l6 H H 30 31 32 Ph v C 0 2 E t ?H + Ph& .-' C02Et N3 33 OH 34 1 M e o 2 C ~ C o 2 M e Ph %CO2Et H Me02C 35 1,3-Dipolar cycloadditions using dipoles other than azomethine ylides can be used to prepare pyrrolidines. Treatment of aldehyde 36 with N-alkyl hydroxylamine gives the nitrone 37 which undergoes intramolecular cyclisation yielding the bicycles 38. The reaction proceeds with high diastereoselectivity.Cleavage of the cycloadducts with zinc in acetic acid-H20 at 70 "C provides the homochiral pyrro- lidin-2-ones 39, while reduction with LiAlH, provides pyrrolidines 40.17 Hassner et al. have described the Michael addition of secondary allylamines to nitroalkenes and subsequent trapping as the 0-silyl a-allylamino- alkylnitronates 41. These undergo stereoselective intramolecular silylnitronate-olefin 1,3-dipolar cycloaddition to provide highly functionalised pyrro- lidines in a one-pot operation.l8 The dithiolane-isocyanate imminium methylide 43, generated by desilylation of readily available salt 42, undergoes efficient cycloaddition to electron deficient dipolarophiles to yield lactams 44 following hydrolysis of the intermediate dithiolanes.l9 Enantiomerically enriched pyrrolidines 48 can be prepared by the Lewis acid promoted [4+2] cyclo- Harrison: Saturated nitrogen heterocycles 2610 L 36 37 39 40 addition with chiral vinyl ethers 46.20 The resulting cyclic nitronates 47 are reduced with H2 (160 psi) in the presence of PtO,. Yields are generally good. Coldham et al. have reported a new route to pyrrolidines by MeLi-promoted anionic cyclisation of the (aminomethy1)stannane 49 onto the proximal unactivated alkene. The resulting organolithium reincorporates trimethyltin to give the function- alised pyrrolidine 50. Cleavage of the trimethyltin group with ceric ammonium nitrate in MeOH provides the acetal 51.,' I 0.2 eq MeLi N,SnMe3 THF, %Me4 * LPh (70%) 49 50 i. HCI ii.CAN, MeOH I cat. TsOH MxoMe 51 41 In a reversal of the normal reactivity pattern, pyrrolidines 53 can be prepared by intramolecular R' R' ?SiMe3 nucleophilic substitution on nitrogen by a carbon- based anion, using the diphenylphosphinoxyl group as leaving group. The cyclisation precursors 52 are readily prepared from oximes.2' I R2Nb-FH * BU4NFSTHF R ~ N 3o R3 R3 42 + - 42? 0":: - o,+ 0 H& R' 43 hydrolysis 1 E Me t F?? Tco2Et B"'oK_ or LDA pzo2Et ox R 53 0 I I X = H Et3N Ph2PCL I X = P(O)Ph2 52 44 In an extension of their work on the chemistry of diene-magnesium reagents, Rieke et al. have described a facile one-pot synthesis of y-lactams from conjugated dienes and imines (Scheme 1). The bis-organomagnesium reagent 54 reacts with complete regioselectivity in the 2-position in the initial step to give intermediate 55.Carboxylation and acidic hydrolysis provides lactams 56. The imine derived from cyclohexanone has also been used in this ~equence.'~ 0 + 0 R' R2 'V? .R2 -k 1:; LA R3 45 46 47 I %02 H The direct electrophile induced cyclisation of alkenylamines to nitrogen heterocycles has been R' R' 48 rarely employed in synthesis due to competing side- reactions associated with the process. However, 262 Contemporaly Organic Synthesis54 55 56 Scheme 1 imines 57, readily derived from primary homoallylic amines and aldehydes, undergo regioselective cycli- sation in the presence of electrophiles (Brz or phenylselenyl bromide) to provide pyrrolidines 58 in good yield. The bromine or selenium substituent is readily removed under radical reduction condi- tions.24 Electrophilic cyclisation can also be used to prepare bis-trifluoromethyl substituted 2-aryl pyrro- lidines 61.Thus ene reaction of 4-ally1 anisole 59 with N-tosylhexafluoroacetone imine provides the amine 60, which cyclises in the presence of toluene- p-sulfonic acid to give the pyrrolidine 61. The reaction appears to be limited to a-aryl substituted amines 61 which are able to form a benzylic cation.2s 57 9 Br2 or PhSeBr R'# R1' 50 Bu3SnH or Ph3SnH, E = Br, SePh PhCHB E = H "TS 'ene' @ + F3CACF3 N HTs OMe 59 60 gTsOH xylene I Ph q 2 3 I Ts 61 Radical-based methodologies for the synthesis of pyrrolidines continue to prove fruitful. Ikeda et al. have reported a 5-endo-trig radical cyclisation of acetamide derivatives 62 providing pyrrolidinones 63.In order for the cyclisation to proceed effect- ively, it is necessary that the developing x-acylamino radical in the transition state of the cyclisation must be stabilised by an aryl or an alkyl group (ie. R' is not H), otherwise simple reduction of the substrate is observed.26 Murphy et al. have described an elegant approach to the ABCE tetracycle of aspido- spermidine and related alkaloids 65 by tandem radical cyclisation of the iodo azide precursor 64, mediated by tris(trimethylsily1)silane (TTMSS) and AIBN. This work further demonstrates than an aryl C-I bond can be selectively reduced in the presence of an azide using TTMSS.27 * b0 R21Ni;;l R' Me AIBN R' Me Bu3SnH 62 (R' # H) 63 r N 3 r N H alyJ :;:s- Q-(J Y " 80 "C, PhH (95%) S02Me Y S02Me 64 65 Buchwald et al.have demonstrated that the pyrro- lidine ring system 67 can be assembled by reductive cyclisation of the enone 66 by a titanium catalyst.28 The key to the success of this approach is the use of Ph2SiH2 to cleave the Ti-0 bond in the metallocycle and regenerate the catalyst. The product is formed as a 1 : 1 mixture of diastereoisomers. lidines 69 through a five-step sequence which is formally equivalent to a disfavoured direct 5-endo- Homoallylic amines 68 can be converted to pyrro- 66 Ph 67 60 69 Harrison : Saturated nitrogen heterocycles 263Ph MeH R3R2NH pt+ ( R = I R2NH2 * C P f R 1 ')$-$NR2R3 * (R R' = = Me, Ph) R' =Me) 0 0 0 70 71 ,NR2R3 H N b 73 74 1 F' Scheme 2 trig ring closure from 68." The approach involves epoxidation, intramolecular epoxide opening by a carbamate group and a final zinc mediated reductive cleavage-reductive amination from an intermediate 1,3-0xazine-2-one.A series of publications by Meyers et al. has described the synthesis of pyrrolidine derivatives using the chiral bicyclic lactam 70 as starting material (Scheme 2). Thus, reaction of 70 (R =I) with a variety of primary amines afforded endo-aziri- dinolactams 71 (60-92% yield). Treatment of these lactams with AlH, provided the N-substituted pyrro- lidines 72 in which the angular methyl group has undergone facial inversion in the major diastereo- isomers (95 : 5). The N-substituent can be removed by hydrogenoly~is.'~ Alternatively, bicyclic lactam 70 (R = H) undergoes highly diastereoselective conjugate addition of primary amines to afford homochiral 3-amino pyrrolidines 73 after reductive cleavage.Typical yields ranged from 80-90% with facial diastereoselectivities ranging from 95 : 5 to =- 98 : L3' Finally, addition of methylenedithiolane to 70 (R =H) occurred with very high endu-selectivity to give the cyclobutane adduct 74. Reductive removal of the sulfur (Raney Ni), cleavage of the chiral auxilliary with inversion of the angular methyl group (Et3SiH, TiC14) and removal of the phenyl glycinol moiety (Na-NH,) provided the enantio- merically pure pyrrolidine 75 (R' = Me).32 The ruthenium catalyst [Clz(PCy3)2Ru=CH- CH=CPh2], introduced by Grubbs for olefin metathesis, effects clean metathesis of the diene 76 leading to the unsaturated pyrrolidine 77.33 2-Substi- tuted pyrrolines can be prepared using the intra- molecular 'carbocation' version of the Schmidt reaction.Thus, 4-substituted but-3-enyl azides 78, CI~(PC~&RU=CH-CH=CP~~ (cat.) PhH, rt, 32 h - Bu'O (95%) 'OH 77 bH 76 78 R = Ar, ~r*' ArQ I A r G + NEN 79 upon treatment with CF3S02H at 0 "C, provide cyclic imines 79.34 Alper et nl. have described the Pd"-catalysed cycloaddition of stereochemically defined aziridines (e.g 80) with heterocumulenes (carbodiimides, isocyanates and isothiocyanates), leading to 5-membered ring heterocycles 81. The reaction is both regio- and stereo-specific, the cycloaddition occurring with retention of stereochemistry at the Wo2" Y + 1 80 X=C=Y R02C L Y 20 h, g-psi N2 a1 X Y ArN Am 0 ArN ArN S 264 Contemporay Organic Synthesisaziridine carbon centres, providing an enantio- specific general method for the synthesis of imidazolidinones, imidazolidinimines and thiazoli- dinimine~.~~ Finally, Watanabe et al.have utilised the deoxy- genating capability of carbon monoxide to effect a novel synthesis of 1 -pyrroline derivative 83 from aliphatic y-nitrocarbonyl compounds 82. The reaction is catalysed by a Ru3(CO),,-l,10-phen- anthroline system and is thought to proceed via a ruthenium nitrene intermediate.36 + 3 co 83 Ph Ph 88 R' ,-Qco2B"H b"' 89 90 4 Six-membered rings Ghosez et al. have described the Diels-Alder reaction of a, P-unsaturated hydrazones 84 bearing an ester or a nitrile at C-2 with electron-deficient dienophiles. Dramatic rate enhancements are observed if reactions are conducted in concentrated 2Ph3PCH3Br ~ f), R C02Bu' dph Bu;,DME Bu""2c> H R organic solutions of LiNTf, (a useful replacement for LiC104).37 Electron deficient 2-azadienes 86, which are prepared by aza-Wittig reaction of N-vinylic phosphazenes 85 with carbonyl com- pounds, undergo inverse electron demand Diels- Alder reaction with alkenes leading to the formation of tetrahydropyridines 87.38 x x 'y NMe2 84 X = CN, C02R 85 86 87 Trova et al.have utilised an asymmetric aza- Diels-Alder reaction in the construction of the bicyclic piperidine 88, a substructure found in a number of HIV-1 protease inhibitor^.^^ Both S ~ m f a i ~ ' ~ ~ ~ and C l d h a m ~ ~ ~ ~ ~ have used the aza-[2,3]-Wittig rearrangement for the construction of tetrahydropyridines. In the Somfai work, treat- ment of vinyl aziridines 89 with LDA resulted in smooth and rapid ( < 5 min) conversion to tetra- hydropyridines 90 in high yield and as a single diastereoisomer.Coldham et al. have utilised 2-keto 91 92 R = Me, Bu, Pt' aziridines 91 as starting materials. Treatment with 2 equiv. of a phosphonium ylide again generates vinyl aziridines which rearrange to provide cis-2,6-disub- stituted tetrahydropyridines 92. Muzart et al. have described the stereoselective synthesis of vinylmorpholines 94 by the palladium- catalysed tandem allylic substitution of butenediol derivatives 93 with enantiopure amino In a similar approach Achiwa et al. have demonstrated that both vinyl morpholines and vinyl piperazines 95 can be prepared with low to moderate ee's by reaction of the bis-acetate 93 with achiral amino alcohols and diamines in the presence of a chiral palladi~m(O)-catalyst.~~ Rhodium catalysts have also been used for construction of the piperidine ring system.Thus, intramolecular cyclohydrocarbonyla- tion of the unsaturated amine 96 in the presence of Rh(acac)(CO)2 (1 mol%) and BIPHEPHOS (2 mol%) provided the pipecolate derivative 97 in quantitative yield. The alkoxy group of 97 undergoes highly diastereoselective substitu- tion with cuprate reagents via an iminium ion inter- mediate to give trans-2,6-disubstituted MeNH kPh OH Pdo THF + - AcO Me-N kPh 93 94 95 Harrison: Saturated nitrogen heterocycles 265Rh(aca~)(CO)~ 96 97 Deziel et al. have described a very facile synthesis of heterocycles via asymmetric ring closure mediated by the chiral C2 symmetrical organo- selenium reagent 99.Thus, treatment of the carba- mate 98 with 99 in CH2C12 in the presence of 2.5% v/v methanol provides the piperidine 100 in 89% yield and with 25 : 1 diastereoselectivity. The selenium moiety is readily removed under radical conditions (Ph,SnH, AIBN).47 Ph- NHBoc 98 + OTf I w CHpClp cat. MeOH -78 + -90 "C I BOC 100 99 Overman et al. have described a carboxylate- terminated N-acyl iminium ion bis-cyclisation 101-+102 for construction of the D and E rings of the heteroyohimbine alkaloid ( - )-ajmalicine en route to a total ~ynthesis.~' A related cyclisation provides the central step in an approach to ( + )-e~iajmalicine.~' W N J Ar (HCHO), Tf 0- 1 : 1 TFA-CHC13 Tf "=Lm Tf "Go C02R 101 102 iq- 0 3-Hydroxy piperidines 104, which may contain a quaternary centre at C-3, can be easily prepared with ee's up to 97% by ring expansion of prolinol derivatives 103.The reaction likely proceeds via an aziridinium intermediate.49 Alternatively, optically pure cyclic enamides 105, available via a three-step sequence starting with Oppolzer sultams, undergo trans-selective hydroborations providing 3-hydroxy piperidine derivatives 106 in good yield and with high diastereoselectivity." Altenbach et al. have described a concise route to the highly functionalised dihydropyridine derivative 108, an intermediate which should prove to be useful in the synthesis of a range of polyhydroxy- lated piperidines (azasugars). Thus, the readily available protected amino alcohol 107 undergoes stereocontrolled oxidative cyclization in the presence of MCPBA providing 108 after acetal formation." i.(CF3CO)p0, THF, reflux ii. Et3N iii. NaOH (10%) R R OH R &OH I 103 104 i. BH3*SMe2, THF "O'G>- * R2 'R2 ii. H202,NaOH O A R ' OAR1 105 106 i. MCPBA CH Clp 30 "C, 4.k h (270%) OAc ii. EtOH, * EtO'. CdNH4)2(N02)6 Ts OAc rt, (95%) NHTs 1 07 108 The use of homochiral bicyclic lactams 110 for the synthesis of homochiral 2-substituted piperidines has been described by Meyers et al. Reduction of 110 using Red-A1 in refluxing THF provides N-substi- tuted piperidines 111 in high yield and with excellent diastereoselectivity. The N-benzyl substituent can be easily removed by hydrogenation. In order to improve the generality of this method Meyers has demonstrated that a range of 1,5-keto acids 109, the condensing partners with phenyl- glycinol in the preparation of bicyclic lactams 110, are readily prepared by low temperature addition of Grignard reagents to commercially available methyl 4- (chloroformy 1) butyrat e (Scheme 3).'* 0 C02Me 109 (S)-phenyl I glycinol t Red-Al, THF R' H OH 111 0 110 Scheme 3 Bicyclic lactam chemistry can be extended to provide a novel asymmetric route to homochiral cis- 2,6-disubstituted piperidines such as 114. Thus, the vinylogous urethane 113, which can be prepared from the bicyclic thiolactam 112 via Eschenmoser contraction, undergoes highly diastereoselective hydrogenation in the presence of Pd(OH),-C to provide 114 in a single step.53 266 Contemporary Organic SynthesisS 112 113 ‘C02Me C02Me H R’ 114 Finally, Jacobsen et al.have described methodo- logy (diastereoselective triflate alkylation and novel intramolecular Mitsunobu reaction) for the asymmetric synthesis of the complete series of enantiopure 2,6-methylated pipera~ines.~~ 5 Pyrrolizidines, indolizidines and quinolizidines Denmark et al. have described a general strategy for the synthesis of cis-substituted pyrrolizidine based alkaloids such as (-)-rosmarinecine 119. The key feature of this strategy is a tandem [4 + 2]/[3 + 21 cycloaddition sequence involving the fumarate- derived nitroalkene 115 and the chiral vinyl ether 116. The reaction proceeds with very high diaster- eoselectivity (25 : 1 exolendo) and in high yield (96%). The tricycle 117 is readily converted to the lactam 118 with recovery of the chiral auxiliary, and thence to (-)-rosmarinecine 119 following Mitsunobu inversion of the alcohol at C-6 (Scheme 4).’5 115 + ” v 116 U 117 Ph Ph 119 Scheme 4 118 Petrin et al.have used the homochiral nitrone 120, which is readily available in five steps from L-tartaric acid, in a stereoselective total synthesis of ( + )-lentiginosine 123. Addition of the Grignard reagent 121 to this nitrone proceeds with 90% de and in 82% yield to yield the hydroxylamine 122. Reduction and cyclisation then provides the natural product.’‘ 0- OH 120 122 It 1 23 Both the indolizidine and pyrrolizidine frame- works can be accessed via [2+2] cycloaddition of endocyclic enecarbamates 124 to alkyl ketenes 125. The endolexo ratio in the cycloadduct 126 is dependent on the reaction conditions and the struc- ture of the ketene.The exo-cycloadduct 126 (n = 1) undergoes highly regioselective Baeyer-Villiger ring expansion with MCPBA and the resultant lactone 127 is converted to the new, nonnatural indolizidine 128 (n = 1) in two simple stepss7 F? H \ ___) hexane *Ho reflux Z” Q + H t CI )n 124 125 c’ 126 n =0,1 MCPBA I 128 127 Both the amide 129a (X=O, R = H ) and the carbamate 129b (X = HZ, R = Boc) undergo highly diastereoselective intramolecular conjugate addition leading to piperidines 130, which are useful inter- mediates for the total synthesis of (+)-swainso- nine.58 Pilli et al. have described a one-pot preparation of quinolizidine-2-one and indolizidin- 7-one ring systems based on the addition of dienes 131 to cyclic N-acyliminium ions 132.59 Harrison: Saturated nitrogen heterocycles 267TBSO BU'OK, THF t &CO,Me 129a X=O,R=H 129b X = H2, R = BOC ir".- -55 "C X 130 The indolizidine (-)-slaframine 135 can be accessed via the bicyclic lactam 134 which in turn can be prepared by intramolecular aldol reaction of ketoaldehyde 133.60 The ketone carbonyl in 134 can be reduced with high diastereoselectivity using the Corey oxazaborolidine. Suitably activated proline derivatives such as 136 undergo 5-exo-trig cyclisation to provide the pyrrolizidine ring system 137 with retention of optical integrity. If the corresponding methyl ester is used in the cyclisation then racemisa- tion occurs.61 do 0 uo HNZ 133 piperidine, THF, t 6 ~ rt, 24 h then H30+, 1 h 0 NH2 HNZ 134 135 t 'N' y" THF.-78 "C 0 A 2h 0 P 136 137 The lactam 139 is a pivotal intermediate which can be used to prepare a range of indolizidines containing alkyl substituents at the 3-, 5- and 8-positions. This intermediate is readily prepared from the dianion of 4-(phenylsulfonyl)butanoic acid 138.62 f alkylation/deprotection cyclisation, 0 chain extension 138 chain introduction 139 The umpolung of reactivity offered by electron transfer has been utilised in an approach to indolizi- dine and quinolizidine derivatives based on cathodic cyclisation. Thus the pyridinium salt 140 undergoes diastereoselective cathodic cyclisation to give a mixture of regioisomeric hydroxy alkenes 142 with the same relative stereochemistry. The diastereose- lectivity of the reaction may occur through the hydrogen-bonded transition structure 141.63 U 1 40 - le- t ___) %OH+% H 141 1 42 6 Tetrahydroquinolines and tetrahydroiso- quinolines Kobayashi et al.have demonstrated that rare earth metal triflates [Ln(OTf)3 or Sc(OTf),] are excellent catalysts for the reaction of imines with silyl enolates and for the Diels-Alder reaction of imines with d i e n e ~ . ~ ~ , ~ ~ The latter reaction can provide tetrahydroquinolines 143 in good yield. Alterna- tively, cationic 2-azabutadienes 144, which are considerably more reactive and selective than their neutral counterparts, undergo highly regio- and diastereo-selective [4n+ + 2n] cycloaddition with various dienophiles to give tetrahydroquinolines 145 in good yield.66 Sc(0Tf)s (20 mot%) MeCN,rt, "Ph A,, + Ph 85% Ph 143 R QNfisR Tic14:pph3*[ Q,] L pJ$ I I 144 1 45 l-Formyl-1,2-dihydroquinolines 148 are readily accessed in a reasonably efficient manner by the BF3-catalysed cyclisation of phenyl isocyanides 147.These intermediates are in turn prepared from (0-acylpheny1)formamides 146 following Grignard addition and dehydrati~n.~~ 268 Conternporaly Organic Synthesisp3 R3 0 146 1 47 0.1 BF39Et2 1 CH2CI2,O O C t I CHO 148 Over the years, the Pictet-Spengler reaction has developed into one of the most important methods for the synthesis of nitrogen heterocycles. Nakagawa et al. have reported that the homochiral tryptamine derivative 149 undergoes diastereoselective Pictet - Spengler reaction providing tetrahydro-P-carbolines 150 with de's of up to 72%.68 Waldmann et al.have reported that diastereoisomeric ratios of > 99 : 1 can be achieved in the same reaction by using N-acyli- minium salts such as 151 which bear an N,N-phtha- loyl amino acid as chiral auxiliary which can be readily removed by reduction of the amide bond 'using LiAlH4.69 Two reports from Katritzky describe novel routes to both 1,3- and 1,4-disubstituted tetrahydroq~inolines~' and 4-(dialky1amino)tetra- hydroq~inolines~' starting from benzotriazole-based precursors. (S )-149 1 50 + c1;- 0 0 cr Meyers et al. have extended their chiral bicyclic lactam chemistry to provide a general route to 1-alkyl- and 1-aryl-tetrahydroisoquinolines. The application of this chemistry to the synthesis of the isoquinoline alkaloid ( + )-cryptostyline 154 is outlined in Scheme 5.Condensation of the keto acid 152 with (S)-phenylglycinol provides the diastereo- isomerically pure bicyclic lactam 153 in 61% yield. Reduction (LiAlH4, 14 : 1 mixture of diastereo- isomers) followed by debenzylation and methylation provides 154 in exellent yield.72 Finally, Heaney et al. have provided a full account of their work on the synthesis of N-(arylmethy1)tetrahydroisoquinolines starting from bis-amino1 ethers.73 (S )-phenylglycinol OMe Me0 t PhCH3, reflux I OMe 152 Scheme 5 It 0 153 i. LAH, THF ii. HP, Pd-C iii. H2C0, HC02H 1 I OMe Me0 Q OMe 154 7 Miscellaneous methods for the synthesis of nitrogen heterocycles of varying ring size The use of N-acylnitroso Diels-Alder methodology for the synthesis of nitrogenous natural and the use of amino acid esters as chiral auxiliaries for the asymmetric synthesis of nitrogen hetero- c y c l e ~ ~ ~ has recently been reviewed.Pearson et al. have utilised their 2-azaallyl cycloaddition methodology in an extremely concise synthesis of the amaryllidaceae alkaloids ( - )-amabiline and (-)-augustamine. In a key step the 2-(azaally1)- stannane 155 undergoes intramolecular cyclo- addition upon transmetallation at - 78°C to provide a 5 : 1 mixture of the diastereoisomeric hexahydro- indoles 156. The major isomer undergoes further cyclisation in the presence of Eschenmo~ers~s salt to give (-)-amabiline 157 in excellent yield.76 In a series of two publications Livinghouse et al. have described the scope of acynitrilium ion initi- ated cyclisations in heterocycle s y n t h e ~ i s .~ ~ , ~ ~ The application of this methodology to alkaloid synthesis is demonstrated by the spiroannulation of the iso- nitrile 158 to provide bicycle 159, a potentially Harrison: Saturated nitrogen heterocycles 269xo&NvSnBu3 0 155 i. 1.9 eq BuLi ii. H20 THF, -78 "C 74% I H I H + ) L o O.C;;;? H I H 5 1 156 i. Me2N=CH2 r, MeCN, A ii. HCI, MeOH, I + 85% Hwo \ / 9 1 57 L + 'R 158 Me0 (-yo 0 159 useful intermediate for the synthesis of the alkaloid serratine. An alternative entry into polycyclic alkaloid skeleta has been reported by Feldman in which the unique ability of an iodonium species to form two bonds in tandem by nucleophile capture and subse- quent C-H insertion is exploited. The reactive iodonium species 160b is generated from the stannane 160a and undergoes cyclisation-insertion to provide bicycles 161.The reaction is successful for n = 1-3 (but not 4) and subsequent alkylidine carbene insertion occurs into a range of C-H bonds (primary, secondary and tertiary) in line with the high reactivity of these specie^.'^ Negishi et al. have reported an approach to bicyclic and tricyclic lactams 163 in which acyl palladium intermediates, the products of carbo- palladation of alkynes 162, are trapped intra- molecularly using an internal nitrogen nucleophile. I 160a X = SnBu3, A = H 160b X = IPh' OTf, A =a ii. Bu'OK, THF i. PhICNOTf Ts H 161 9' I - R' CO, cat. PdL,, base LNHZ d 162 163 R', R2 = 2 or 3 atom tether 2 = H, alkyl, acyl, sulfonyl Scheme 6 Both modes of cyclisation have been demonstrated (Scheme 6).80 A similar approach to a, P-unsaturated lactams 165 by Pd-catalysed intramolecular carbonylative coupling of amino vinyl triflates 164 has been described by Crisp." 0 Pd(Ph3P)o Bu~N c or CO (1 am) or MeCN, 65 "C OTf &;HBn 164 0 h k n 165 An unusual synthesis of lactams has been described by Mori et al.in which alkynyl amino derivatives 166 react with Fischer chromium carbene complex 167 to generate a vinyl ketene complex which is attacked by the tethered sulfonarnide. Yields are good for the synthesis of 4-7 membered ring lactams.82 The use of zirconium y2-imine complexes for the construction of nitrogen hetero- cycles has been reported by W h i t b ~ . ~ ~ 270 Contemporary Organic SynthesisOEt Me i. (co),cr=( 167 THF, reflux ii.[FeClp(DMF)d[Fe&] ( I HF;' Ts Ts 166 X The intramolecular aza-Wittig reaction is a powerful method for the construction of nitrogen heterocycles and has recently been used to prepare 174-benzodiazepin-5-one derivatives 168 in moderate to good yield, (Scheme 7).84 Pearson et al. have extended the scope of the intramolecular Schmidt reaction of carbocations with azides to include aliphatic azides. This method can be used to prepare a variety of saturated nitrogen heterocycles of varying ring sizesE5 168 Scheme 7 Scheme 8 169 The synthesis of azacycles using radical based methodology continues to attract interest. Lee et al. have reported an efficient synthesis of 5- and 6-membered heterocycles 170 by radical cyclization onto @-amino acrylates 169. In general diastereo- selection is not high, and 7- and &membered rings are not readily accessible.However, starting with cyclic amino acids as precursor the indolizidine and pyrrolizidine skeleta can be readily accessed, and stannyl ketyl radical precursors 171 can be employed in the radical cyclization although the reaction is slower (Scheme In contrast to aryl radicals, which prefer to cyclise onto imines in a 6-endo sense, sp3 carbon-centred radicals undergo predominantly 5-exo or 6-ex0 cycli- sation onto either the carbon or nitrogen atom of imines. This finding has been utilised in a synthesis of nitrogen heterocycles 172 using tandem radical cyclisation of imines. Addition of Lewis acid facili- tates the tandem reaction, and a number of cyclisa- tion modes have been demonstrated leading to a variety of ring systems (Scheme 9).87 Ikeda et al.have described a synthesis of the bridged azabicyclic compounds 174 and 175 using radical translocation of the proline-derived bromo- benzoyl derivatives 173. The regiochemistry (5-exo vs. 6-endo) of this cyclization can be controlled by 170 I C02Me 171 Bu3SnH, AIBN, PhH (0.025 mol dm -3), reflux, 24 h C02Me C02Me 65% 32% (mR1 / \ * (mR, ' \ R2 MgBr2 R2 MgBr2 A2 1 72 . Scheme 9 substitution of the prop-2-enyl group, and substituents at the 2- and/or 4-position(s) of the pyrrolidine ring play an imporant role in this cyclisation." Harrison: Saturated nitrogen heterocycles 271Me02C NBz &Me 10-20% Pd(0AC)p NaHC03 (2.5 eq) Bu~NCI (1 .O eq) 3 A molecular sieves, MeCN, 95 "C, 16.5 h Bu3SnH, AIBN, 174 c PhCH3, reflux and/or 173 175 8 Medium and large ring nitrogen heterocycles A range of methods have been reported over the last year for the construction of medium and large ring nitrogen heterocycles. Aryl iodides tethered to dehydroalanine units by two to four methylene units 176 undergo endo-selective Heck cyclisation under anhydrous Jeffrey conditions to provide 7-, 8- and 9-membered heterocycles 177.89 Rigby et al.hav 176 n =1-3 Qco2Me 177 reported that the enamide 178 undergoes predominantly the expected exo-cyclisa- tion under 'standard' Heck conditions [Pd( OAc)* (10 mol%), (o-Tol)'P (20 mol%), Et,N (2 equiv.), MeCN-H20 (10: l), 80 "C] to give the six- membered ring product 179 but remarkably under- goes exclusively endo-cyclisation under Jeffrey conditions [Pd(OAc):! (10 mol%), Bu,NCl (2 equiv.), KOAc (5.5 equiv.), DMF (0.2 mol dm-'), 100 "C)] to provide the seven-membered ring product 180 (Scheme 10).Thus the possibility exists for affecting either endo- or exo-selective Heck reaction from the same substrate by appropriate choice of reaction condition^.^^ Clark et al. have described an enantioselective approach to the CE ring system of the manzamines in which the spiro-fused bicyclic ylide 182, generated from a copper carbenoid, undergoes [2,3]-sigma- tropic rearrangement generating the bicycle 183 with >98% ee.91 and 13-membered rings) from protected amino The synthesis of medium ring lactams (7-, 9-, 11- n M e O & v N t i R Me0 0 179 Conditions 'Jeff ery' - 'standard' 46% Scheme 10 Cu(acac)p (2 mot %) C6H6;, reflux 56 /o 1 78 I NHR I Me0 180 26% 48% 183 acids via cyclization using polymer bound l-hydroxy- benzotriazole (HOBt) has been reported.92 Grubbs et al.have shown that eight-membered rings (e.g. 185) can be formed from acyclic precursors 184 by ring closing metathesis provided the cyclisation precursor contains a suitable conformational constraint to facilitate cyclisation (in this case an aromatic ring). Structures related to 185 can be converted to the anticancer agents mitomycin and FR-900482.93 Ph OTBS r i rd @- yJ= 59% OTBS Boc Boc 184 185 Optically active nine-membered lactams 187 can be prepared in good yield and with complete 1,3-chirality transfer starting from allylic amines 186 by a zwitterionic aza-Claisen reaction.94 The reaction can be carried out in the presence of acidic protons without epimerisation. Johnson et al.have utilised a Pd-mediated 71-ally1 alkylation for the synthesis of the ten-membered lactam 189 starting from allylic acetate 188. The use of benzyltrimethylammonium methyl carbonate 272 Contemporary Organic Synthesis?2 R ' c t 7 ?-fOEt 0 1 86 1 87 N AC02Me Me02C,,pNJ Pd(Ph3P)* (cat.) - O H O H Me02C 1 88 189 (BTMC) as a source of slowly generated methoxide is crucial to the success of this cyclisation. The allylic acetate moiety of 188 is generated by Ag' catalysed addition of NaOAc to the corresponding allene.95 A number of reports deal with the synthesis of nitrogen-containing macrocycles. Thus Kise et al. have described the synthesis of diazacrown ethers 191 by intramolecular coupling of bis(imino ethers) 190 promoted either by electroreduction or chemical reduction with Zn powder in the presence of methanesulfonic acid.Proton-bridged inter- mediate diiminium salts have been invoked to explain the relatively high yields in these cyclisa- tions.96 More highly functionalised systems have been examined and the diastereoselectivity of these cyclisations is discussed. / Ph-NWo reduction MsOH 190 191 The 17-membered ring of the macrocyclic spermi- dine alkaloid ( - )-oncinotine has been successfully closed using an iminium cyclization as the key step. Thus, treatment of the aldehyde 192 with H2 over a Pd(OH)2 catalyst under high dilution (4 x lo-' mol dm-' in MeOH) leads to in situ generation of the transient iminium ion 193 which is further hydro- genated to provide 194 in 66% yield in a single step .97 Finally, Vogtle et al.have described the synthesis of l-aza[2.2]metacyclophane 196, the hitherto most strained cyclophane with a free NH group in the NHBOC 192 L NHBOC J NHBOC 193 194 PhLi (exces. EtpO rt, 58% Br-0NKCF3 / o H' 195 196 bridge, from dibromide 195. Crucial to the success of this synthesis is the use of the trifluoroacetate group for N-protection, with subsequent C-C bond formation via a phenyllithium coupling reaction. Under these conditions the N-protecting group is removed following C-C bond formation, and the product is formed in a remarkable 58% yield." 9 References 1 S. Florio, L. Troisi and V. Capriati, J. Org. Chem., 2 T. Kataoka and T. Iwama, Tetrahedron Lett., 1995,36, 3 J.G. Knight and M. P. 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ISSN:1350-4894    

DOI:10.1039/CO9960300259

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Catalytic applications of transition metals in organic synthesis GRAHAM J. DAWSON, JUSTIN F. BOWER AND JONATHAN M. J. WILLIAMS Department of Chemistry, Loughborough University, Loughborough, Leicestershire LEI 1 3TU, UK Reviewing the literature published between 1 September 1994 and 31 October 1995 Continuing the coverage in Contemporary Organic Synthesis, 1995, 2, 65 1 2 2.1 2.2 2.3 3 3.1 3.2 3.3 3.4 4 4.1 5 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 6 6.1 6.2 6.3 7 7.1 7.2 7.3 7.4 8 9 Introduction Oxidation Epoxidation Dihydroxylation Other oxidations Hydrogenation and related processes Hydrogenation Hydrosilylation Hydroboration Hydro formy lation Lewis acids Diels-Alder reactions Coupling reactions Heck reactions Suzuki coupling Stille coupling Other coupling reactions Allylic substitution reactions Carbonylation Cyclisation reactions Reactions involving alkynes Reactions involving metal carbenoids Cyclopropanation and related processes Carbene insertion reactions Metathesis reactions Miscellaneous Al kene hydrome t allat ion and carbome t alla t ion Isomerisat ion reactions Conversion of aldehydes to ketones Catalysed Michael addition Conclusion References included in this review, since it cannot be fully comprehensive.Many transition metal catalysed reactions are being pursued in an asymmetric fashion, and there have been new ligands and new applications of ligands reported in recent months. However, not all research involves asymmetry, and this review has attempted to describe the recent advances in transi- tion metal catalysed reactions as a whole.2 Oxidation There has been a long standing interest in the catalytic oxidation of organic substrates. Catalysis by transition metals allows for stereoselective and chemoselective processes to take place. Each year new advances are made in tuning the selectivity of such catalysed processes. For example, in the last year, several groups have reported allylic oxidation reactions proceeding with good enantioselectivity (see Section 2.3). 2.1 Epoxidation The use of manganese salen complexes 1 and related sytems for the enantioselective epoxidation of alkenes has continued to be a useful process. Jacobsen and co-workers have reported that with an oxidising system comprising of mCPBA (meta- chloroperbenzoic acid) and NMO (N-methyl- morpholine oxide), it is possible to run the epoxida- tion reactions at low temperatures.' The low temperature has a beneficial effect on the enantio- selectivity, allowing the epoxidation of styrene 2 to occur with 86% ee in the formation of styrene oxide 3.This research group has also reported its NMO, CHpCI2, -78 "C 89% 2 2-8 mol% 1 3 86% ee 1 Introduction This review highlights the recent advances in transi- tion metal catalysis for the period 1 September 1994 to 31 October 1995. The review deals with homo- geneous transition metal catalysed reactions - an area which over the 14 months covered represents a large number of research papers. Consequently, a great deal of high quality chemistry cannot be (pi),sio phxph 'But But' 1 Dawson, Bower and Williams: Catalytic applications of transition metals in organic syrtthesis 277successful results using salen manganese complexes in the asymmetric epoxidation of tetrasubstituted alkenes2 and in the kinetic resolution of racemic chr~menes.~ Bosquet and Gilheaney have reported that chromium salen complexes are also effective as asymmetric epoxidat ion cat aly~ts.~ 2.2 Dihydroxylation The asymmetric dihydroxylation (AD) reaction of alkenes now leads the field of asymmetric catalysis in terms of generality and synthetic utility.The asymmetric dihydroxylation reaction is an example of a catalytic reaction which is accelerated by the presence of the ligand, and such reactions have recently been re~iewed.~ The pseudo-enantiomeric ligands 4 and 5 are the most widely employed, although many other variations have also been described.From a practical standpoint, one of the most useful developments of this reaction is the procedure developed by Wang and Sharpless for the conversion of stilbene 6 into the diol 7 with 99% ee and 87% yield on a one kilogram scale.6 Remark- ably, even on this scale, the reaction was achieved in a five-litre flask!! I moMe WoMe X=DHQ X 4 X=DHQD 5 DHQ DHQD OH Ph/.cph 0.25 mol% (DHQD)2-PHAL 5 0.2 mol% K20~02(OH)4 p/=bPh NMO (60% in water), 6H 6 BdOH, r.t., 14 h 87% _ . . 7 (99% ee) The Sharpless group have also reported a multi- gram synthesis of the taxol side-chain 8.7 Methyl cinnamate 9 underwent asymmetric dihydroxylation to afford the diol 10, which was further manipulated to provide the taxol side-chain 8. Additionally, Sharpless and co-workers have reported the selective dihydroxylation of polyenes.' 0 OH 0 P h d O M e 10 ,(99% ee) 0.5 molX (DHQ)rPHAL 4 Ph &OMe 0.2 mol% K20~04(OH)4 NMO (60% in water), OH BdOH, r.t., 23 h 72% 9 0 1/...I t PhKNH 0 P h 4 O t - I OH 8 23% yield from 9 Corey and co-workers have reported that whilst allylic alcohols are not good substrates for asymmetric dihydroxylation reactions, the corre- sponding methoxybenzoate derivatives can be employed to provide highly enantioselective dihydroxylation.' For homoallyl ethers, the methoxy- phenyl ether was found to be the best derivative." Warren and co-workers have revealed a racemic version of the Sharpless AD reaction." The alkenes are converted into the corresponding diols upon treatment with OsC13 and K3Fe(CN), with quinucli- dine as the accelerating ligand, using added potas- sium carbonate and methylsulfonamide in a two-phase system of tert-butyl alcohol and water.This can be useful in the preparation of racemic diols which can be used as analytical standards. A remarkable photochemically induced, osmium tetroxide catalysed reaction has been reported by Motherwell and Williams.12 Benzene 11 was converted into a mixture of do-inositol and condur- itol E, which were isolated as their peracylated derivatives 12 and 13. i. 1.3 mot% 0~0~. OAc OAc 11 12 13 2.3 Other oxidations Several groups have independently reported enantioselective allylic oxidation reactions catalysed by copper complexes. Thus, Andrus and co-workers have described the conversion of cyclohexene 14 into cyclohexenyl benzoate 15 with 80% ee in the presence of an enantiomerically pure bis-oxazoline copper complex 16 and the perester 17.13 A related system employing bis-oxazolines had also been reported by Pfaltz.14 Additionally, copper complexes of proline and related amino acids have been employed in asymmetric allylic oxidation reaction^'^^'^"^ 14 5 equiv.17 1 equiv. Enantiomerically pure 0 0 APh 5 moPh 16 MeCN, -20 O C 43% 15 80% 88 copper complexes have also been employed in catalytic asymmetric Baeyer- Villiger reactions, such as the conversion of 2-phenylcyclohexanone 18 into the lactone 19, wherein a kinetic resolution takes place using the catalyst 20.'s,19 Ruthenium dioxide and manganese dioxide have also been shown to be catalysts for Baeyer-Villiger reactions in the presence of oxygen and benzaldehyde.*O 278 Contemporary Organic Synthesis1 mol%20 1 atm.O2 0.5 equiv. Bu'CHO 1969Y0ee 18 PhH, H20 41% 6 "C, 16 h, i a 16 20 Larock and co-workers have reported an oxida- tion reaction involving the conversion of silyl enol ethers into a, P-unsaturated carbonyl compounds.21 For example, the cyclic silyl enol ether 21 was converted into cyclooctenone 22 in high yield upon treatment with catalytic amounts of palladium acetate in the presence of oxygen with Me2S0 as the solvent. OSiMe3 0 / // 0 10 md% Pd(OAc), 1 atm 0 DMSO 25"C? 12 h c 82% 0 21 22 3 Hydrogenation and related processes Transition metal catalysed hydrogenation reactions are historically amongst the first practical processes which were achieved with homogeneous transition metal catalysts.Hydrogenation and the related processes discussed in this section are still being actively researched, and significant discoveries are still being uncovered. 3.1 Hydrogenation Transition metal catalysed hydrogenation reactions are usually associated with the conversion of alkenes into alkanes, and normally this procedure can be conducted without affecting carbonyl groups. How- ever, Noyori and co-workers have demonstrated that it is possible to selectively hydrogenate aldehydes and ketones in the presence of alkenes!" Critical to this selectivity is the addition of catalytic amounts of potassium hydroxide and 1,3-diaminopropane to the ruthenium catalyst." Thus, benzylideneacetone 23 is converted into the corresponding alcohol 24.0 OH 0.2 mol% RuC12[PPh& Ph O . ~ ~ O I % N H ~ ( C H ~ ) ~ N H ~ * Ph 24 0.4 molO/oKOH-- - 8 atm. HP, 28 OC, 1.5 h C3HSOH/PhMe, (61) 98% 23 These workers also describe competitive experi- ments, where acetophenone reacts 1500 times more quickly than a-me t hylstyrene. A ruthenium catalysed asymmetric hydrogenation of P-keto esters which proceeds at atmospheric pressure has been reported by Genet and co-workers." Thus the P-keto ester 25 was reduced to the P-hydroxy ester 26 in good yield and enantio- selectivity with the ruthenium catalyst 27 under atmospheric pressure of hydrogen. Burk and co-workers also reported mild conditions for the enantioselective ruthenium catalysed hydrogenation of 8-keto esters.25 0 0 OH 0 uOMe 2 mol% RuBr,J(S)-binapl27 HP, MeOH, r.t., 48 h * 25 80% 26 97% ee The research group of Buchwald has continued its investigations into the hydrogenation of imines with the enantiomerically pure titanium catalyst 28.26,27 For example, this group has performed a kinetic resolution on the racemic pyrroline 29, one enantiomer of which is selectively hydrogenated to give the cis-pyrrolidine 30." 5 mol% 28 X p 1,l'-binaphth- 2,2'-diolale n i, 10 molob BuLi ii, 15 mol% PhSiHo 29 iii, 80 psi H2 Me**'& Ph 37% H 30 34% 99% ee Interest in the hydrogenation of a-aminoacylacry- lates to yield amino acid derivatives is a reaction which has been investigated with many ligands.Recent additions to this research include the use of the ligand 31,29 which is proposed to function as a trans-chelating ligand, and the ligand 32 employed by Burk and co-workers.Ligand 32 has been used to provide high enantioselectivities in the rhodium catalysed hydrogenation of P-branched substrates, such as 33, which is converted into a P-branched amino ester derivative 34.30 This group have also \ C02Me 0.2 mol% L*Rh(cod)]OTf *&C02Me 90 psi H2, PhH, 25 OC, 24 h 100Y0 conversion I NHCOMe 34 97.2% ee N(H)Ac 0, 33 31 L* 32 Dawson, Bower and Williams: Catalytic applications of transition metals in organic synthesis 279reported related reduction reactions performed in supercritical carbon Hydrogenation using two-phase catalysis and glass beads to support one of the phases has been reported. The catalyst is dissolved in a polar phase which binds to the surface of the glass bead, whilst the substrate remains in the organic phase.This overcomes some of the problems associated with catalyst contamination found with conventional homogeneous catalysis. Some of the recent advances have been summarised in a short review.32 3.2 Hydrosilylation The stereocontrolled hydrosilylation of terminal alkynes has been reported by Takeuchi and T a n ~ u c h i . ~ ~ Depending upon the conditions employed, the reaction pathway could be directed towards the formation of either the (E)- or the (2)-vinylsilane. The hydrosilylation of hex-1-yne 35 with [Rh(cod)C1I2 in the absence of a phosphine affords predominantly the (2)-vinylsilane 36 whereas using a cationic rhodium catalyst in the presence of a phosphine affords predominantly the (E)-vinylsilane 37.C H 4 9\=/SiEt3 36 0.5 mol% [Rh(cod)CII2 80% 97% this isomer C4HgCECH 4 mot% PPh3, Et3SiH C4H9 _. SiEt3 \ 37 99:l (E):(Z) acetone, r.t., 30 min, 99% The enantioselective hydrosilylation of prochiral ketones is well known with rhodium catalysts - ligand 31 has recently been used for this purpose.34 Additionally, Buchwald and co-workers have applied their titanocene derived catalysts 28 to this reaction and obtained excellent enantioselectivity for the reduction of a range of aryl alkyl ketones.35 Takaya and co-workers have demonstrated that hydrosilyla- tion of symmetrical ketones can lead to excellent asymmetric induction at the silicon centre when a suitable prochiral silane is employed.36 Treatment of naphthylphenylsilane 38 with pentan-3-one and a catalytic system comprising of the Cybinap ligand 39 and [Rh(cod)Cl], affords the hydrosilylation product 40 with >99% ee.Hayashi and co-workers have developed ligands which are indisputably mono- dentate ligands, and yet still provide very high asymmetric induction in the palladium catalysed hydrosilylation of alkene~.~' Styrene 2 undergoes hydrosilylation in the presence of 0.1 mol% of a palladium complex of the monodentate phosphine 41 and subsequent conversion into the correspond- ing alcohol 42 with high levels of asymmetric induction. are known, and Ito and co-workers have demon- As well as hydrosilylation, bis-silylation reactions Ph 5 mal% 39 Ph . .. - . . . -. , - - - . .. I 5 mol% [RhCl(cod)]2 I ,Si--H + Et2CO i-NP 'H THF, -20 OC, 18h 97% 38 40 R-(+) >99% 88 (R)-Cybinap 39 H-MOP 41 sicI3 H2°2 ?H 0.1 mol% 41 0.1 mol% [PdCl(lr-C3H5)I2 KF, KHC03 PhA >90%yield %tlA overall Ph- - O°C, 12h 42 93% ee strated that palladium catalysed intramolecular bis-silylation reactions can occur with good diastereo~ontrol.~~ The single stereocentre of the cyclisation precursor 43 controls the stereochemistry of two further stereocentres formed in the cyclisa- tion products 44 and 45.Intramolecular cyanosilyla- tion has also been described by Ito and co-workers. The alkyne 46 undergoes palladium catalysed cyano- silylation to afford the silatetrahydrofuran product 47.39 PhMqSi %$ Bu2Si: 0 XMe 44 33 mol% 1-OcNC 2 mot% Pd(OAc), + \\ PhMe2Si, Me PhMe, r.t. si--d Bu2 43 92% PhMe2Si BU2Sj XMe 0 45 44:45 90: 10 2 mol% Pd(a~ac)~ 0-SiPh2CI 1.2 equiv.Me3SiCN LMe PhMe, reflux, 5 h * Me 84% 46 47 Esters are usually inert to catalysed hydrosilyla- tion reactions. However, Cutler and co-workers have reported that esters can be converted into the corresponding ethers upon treatment with phenyl- silane and manganese cataly~t.~' 3.3 Hydroboration Togni and co-workers have shown that pyrazole- containing ferrocenyl ligands 48 can be used for rhodium catalysed asymmetric hydroboration reactions, as exemplified by the hydroboration of styrene 2.41 After oxidative work-up the hydrated 280 Contempora y Organic Synthesis1 mol% [Rh(cod)2)BF4, ligand 48, THF, 20 %,3-5 h + 91% 2 42 66% 95.1% ee OH b 49 34% 48 products 42 and 49 are obtained with reasonable regioselectivity and good enantioselectivity.3.4 Hydroformylation A recent review has provided valuable coverage of the latest developments in enantioselective hydro- formylation reactions.42 The reaction of an alkene 50 with HdCO affords the branched aldehyde 51 and linear aldehyde 52, and the branched chain aldehyde has the possibility of being formed with asymmetric induction. This process has been the subject of much research, and recently, excellent regiocontrol and enantiocontrol have both been achieved. The review describes the factors which affect this stereocontrol. H catalyst E H + R L C H O R H R *CH2 - 50 51 branched 52 linear Buchwald and co-workers have examined the rhodium catalysed hydroformylation of internal alkyne~."~ Under suitable conditions, these workers have been able to form the conjugated aldehyde with only small amounts of isomeric or saturated aldehydes.Oct-4-yne 53 is converted into the unsat- urated aldehyde 54 using a rhodium catalyst in conjunction with ligand 55. 2 mol% [Rh(CO)2(acac)] C3H7 C3H7 C3H7 2.2 mol% 55 CO/H, (1 atm.) C3H7- - . , 53 CH2C12, r.t. 54 85% 55 4 Lewis acids Lewis acids are able to catalyse a wide range of organic transformations. In particular, interest in catalytic asymmetric synthesis with Lewis acids has been great. The Mukaiyama aldol reaction employing silyl enol ethers 56 and a carbonyl compound 57 catalysed by a Lewis acid provides a synthetically useful route to aldol adducts 58. Many enantiomerically pure ligands have been successfully employed with this reaction, especially titanium catalysts, including ligand 59 recently reported by Carreira and co-w~rkers."~ Additionally, these workers have described a carbonyl-ene equivalent of this reaction which proceeds with remarkable selec- tivity, especially for acetylenic aldehyde^."^ In t he presence of a titanium complex of ligand 59, methoxypropene 60 and the aldehyde 61 are converted into the 'aldol adduct' 62 with excellent enantiocontrol and yield.Simple hydrolysis converts the adduct into the corresponding /3-hydroxy ketone. Berrisford and Bolm have written a short review detailing Some of the current highlights of carbonyl- ene reaction^."^ OSiMe3 Me3Si0 catalyst * d R R 8,' b R R Br 59 The desymmetrisation of meso-epoxides is another reaction which has been catalysed by enantiomerically pure Lewis acids.Jacobsen and co-workers have employed (salen)chromium(rrr) complexes 63 as Lewis acids to desymmetrise meso- epoxides by nucleophilic ring opening with tri- methylsilyl a ~ i d e . ~ ~ For example, cyclopentene oxide 64 was converted [after removal of the silyl group with camphorsulfonic acid (CSA) in methanol], into the azido alcohol 65 with high levels of enantiocontrol. The allylation of aldehydes such as benzaldehyde 66 with allyltributyltin 67 to give the adduct 68 has been catalysed by a zirconium BINOL complex 69.48 4.1 Diels-Alder reactions Diels Alder reactions have also been catalysed by transition metal complexes. A lot of research has Dawson, Bower and Williams: Catalytic applications of transition metals in organic synthesis 281i, 2 motoh 63 ii, CSA, MeOH + Me3SiN3 EbO, r.L 28 h 80% 64 65 94% ee H Q H OH -40 OCr 6 h 66 67 79% 68 92.0% ee 69 centred around the use of titanium complexes of tartrate-derived TADDOL ligands, and two detailed reports concerning the mechanism of these com- plexes in Diels-Alder reactions have Evans and co-workers have continued to employ copper(I1) bis-oxazoline complexes such as 70 to catalyse Diels-Alder reactions with excellent enantioselectivity, as demonstrated by the catalysed addition of cyclopentadiene 71 to methacrolein 72 to give the cycloadducts 73 and 74.51 Mikami and co-workers have shown that the 6,6’-dibromo- BINOL titanium complex 75 provides better results 73 92% ee bH: 74 72 73:74 97:3 L 70 75 U 76 than the parent BINOL titanium complex in catalysed Diels-Alder reactions?2 The enantio- merically pure iron complex 76 has also been highly successful as an asymmetric Lewis acid catalyst in Diels-Alder reactions,53 and even oxo(sa1en)manga- nese(v) complexes have been used as Lewis acid catalysts for Diels-Alder reactions.54 Keck and co-workers have reported a catalytic enantioselective hetero Diels-Alder reaction using titanium BINOL c~mplexes.~~ The adducts are formed with up to 97% ee.The mechanism is probably not concerted and is thought to proceed via a two-step aldol-Michael sequence. zirconocene catalysed Diels-Alder reaction which does not proceed via a simple Lewis acid catalysed me~hanism.~~ The dienophile 77 is activated to reaction by the formation of a cationic intermediate 78 which reacts with the diene 79 and after hydro- lysis of the cycloadduct esters affords compound 80.Wipf and co-workers have reported an interesting i, 10 mot% CHrC12 I 9 77 /\//\ / 79 80 51% overall yield 5 Coupling reactions Transition metal catalysed coupling reactions cover a wide range of synthetically useful processes. Coupling reactions often provide a method for the formation of new C-C bonds, although there are also applications to the formation of carbon- heteroatom bonds. Additionally, many coupling reactions may be conducted in an asymmetric fashion. 5.1 Heck reactions The Heck reaction between aryl or vinyl halides with alkenes is a valuable method for the construc- tion of C-C bonds, as are variants of the Heck reaction. Hillers and Reiser have shown that the Heck reaction of 4-alkyl substituted 2,3-dihydrofurans, such as compound 81, with a coupling partner such as iodobenzene 82 occurs diastereoselectively to give the trans-configured product 83.57 3 mol% P~(OAC)~ 6mol%PPh3 9 d, 66% Me’ Phl82, NEt3, DMF, 65 “C Me 81 83 282 Contemporary Oeanic SynthesisMasters, Danishefsky and co-workers have employed a Heck cyclisation as a key step in the total synthesis of tax01.~' The vinyl triflate 84 was cyclised to afford the advanced intermediate 85 in a yield of 49%, which is remarkable considering the density of functional groups in this molecule.0 0 84 0 85 Other Heck cyclisation reactions have been reported. Gibson and co-workers have prepared 7-, 8-, and 9-membered rings by endo-Heck cyclisa- tion reaction^.^^ Thus, the cyclisation precursor 86 underwent Heck cyclisation to afford the 9-membered ring 87.Macrocyclisation Heck reactions providing 18-, 20- and 22-membered macrocycles have also been reported." Ac 10 mot% Pd(OAt& \ ~ N T c o 2 ~ ~ Bu~NCI, eq. NaHC03 3 A MS ~ - NAc \ C02Me MGN, 95 "C, 16.5 h 58% 86 87 Diazotisation of anilines provides suitable sub- strates for Heck reactions, and the intermediate diazo compounds can be used without isolation in either a one-pot procedure or by a tandem in situ reaction."' Sengupta and Bhattacharyya have converted the aniline 88 into the Heck product 89 using the sequential one-pot procedure."' Heck reactions of polymer bound aryl iodides with alkenes have been reported, and have applications in combinatorial ~ynthesis."~.'~ Me? Me? 0""" A NHC02Me 88 A NHC02Me 89 5.2 Suzuki coupling Polymer bound aryl iodides have also been subjected to Suzuki reactions. This is exemplified in the conversion of the polymer bound aryl iodide 90 into the coupled product 91 on palladium catalysed coupling with the arylboronic acid 92.65 0 t o 92 Baldwin and co-workers have used the Suzuki coupling reaction to generate a range of acromelic acid analogues."6 The vinyl triflate 93 was coupled with arylboronic acids including phenylboronic acid 94, to give the coupled product 95.Percec and co-workers have provided a detailed account of the use of nickel catalysts in Suzuki-type reactions of aryl mesylates and aryl arenesulfonates with arylboronic Ph ,-C02But TfolL-Co2Bu' PhB(0H)z 94 . . COPh 73% COPh 93 95 An interesting example of a double Suzuki coupl- ing which results in cyclisation has been reported by Soderquist and co-workers.68 The diene 96 is doubly hydroborated, and then undergoes a double Suzuki coupling with the dibromoalkene 97, which affords the cyclic product 98.___) NaOH (3 mol dms) I OTBDMS 96 97 98 BBN = 9-borabicyclo[3.3.1]nonane Fiirstner and Seidel have described a new approach to the preparation of borates for Suzuki coupling reaction^."^ Rather than adding methoxide to a trialkylboron compound, these workers add polar organometallics to 9-methov-9-bora- bicyclo[3.3.l]nonane 99. For example, addition of phenylacetylide affords the borate 100, which was MeO-BBN 9P I Ph-Cf CK Br MeO, - 101 RRhl 100 82% 102 Dawson, Bower and Williams: Catalytic applications of transition metals in organic synthesis 283coupled with 2-bromopyridine 101 to give the 5.4 Other coupling reactions Suzuki product 102.By slow addition of the organo- metallic species, it was possible to use catalytic amounts (30 mol%) of the boron compound 99. 5.3 Stille coupling The synthetic utility of the Stille coupling is demon- strated by an example reported by Hodgson and co-~orkers.~~ The functionalised vinyl stannane 103 underwent Stille coupling with various aryl halides including compound 104 to give the product 105. The presence of copper iodide as a co-catalyst was found to be essential. The role of copper(1) co-catalysts was also discussed in detail el~ewhere.~~ Arylbenzoic acids may be employed without protection in the Stille reaction, and with suitable tin-containing reagents, such reactions can be conducted in ~ a t e r .~ ~ ' ~ ~ 104 75 mol% Cul * X O M e Me02C 8 mol% Pdzdba3 103 22 mol% AsPh, N -methylpyrrolidinone Me02C 105 50 "C, 48 h 82% Sometimes, the Stille reaction produces unexpected coupling products. For example, the coupling of the vinyl stannane 106 with iodobenzene 107 affords very little of the expected product 108, and instead provides methyl cinnamate 109.74 A mechanistic rationale involving the formation of a palladium carbene intermediate is proposed. Chenard and co-workers have reported that phenyl groups from triphenylphosphine can become incor- porated into the coupled products via a scrambling of aryl groups within the intermediate palladium(1r) complex.75 For electron-rich aryl halides the effect is substantial, and in the coupling of arylstannanes 110 with 4-bromoanisole 111, the expected product 112 is present in smaller amounts than the 'scrambled' product 113.Norton and co-workers have described related results.76 Very often organozinc reagents prove to be amongst the best partners in metal catalysed coupling pro- cesses. In the preparation of the vitamin D skeleton 114 the organozinc derivative 115 was found to provide a higher yield than other organometallics when coupled with the vinyl iodide 116.77 p 115 BrZn 116 THF, 25 "c, 2 h 95% ? OTBDMS 114 There are also many examples of the use of Grignard reagents in coupling reactions. An inter- esting method for the preparation of thioamides employs Grignard reagents, as illustrated by the nickel-catalysed coupling between phenylmagnesium bromide 117 and N,N-dimethylthiocarbamoyl chloride 118 to give the thioamide 119.78 Cai and co-workers have reported a useful preparation of BINAP 120 by direct nickel catalysed coupling between binaphthol ditriflate 121 and diphenyl- pho~phine.~~," This reaction proceeds without loss of stereochemical integrity. S S N%$;e) ~ &NMe2 PhMgBr +ClKNMe2 THF, r.1, 1 h 80% 117 118 119 PPh2 q o - r f Ph DAkC6 PH 5.75 (4 eq.) eq.) (Ph3P)2NiCb (10 mol%) 2-3d *mpph2 121 120 Hartwig and Louie have developed the palladium C02Me 108 catalysed synthesis of arylamines 122 from aryl- bromides 123.*l Whilst initial results had required the use of aminostannanes, it has now proved to be possible to use simple amines such as compound 124 as the coupling partner.82 Ph, + 107 106 70% rco2Me cat.PddbaB 50 "C, THF SnBu3 cat. AsPhs 109 108:109 1:254 Me0 Me? 5 mol% Me3SnAr+ 0 - 0 9 105 "C 110 Br Ar Ar 111 112 21.9~~ 113 54.8% 5 mol% Pd[P(@MeC6H4)$2 LiN(SiMe3)2 toluene, 100 "C, 2 h * A r - N 3 ArBr + HN 123 124 84% 122 3 Hayashi and co-workers have reported an unusual asymmetric palladium catalysed coupling process.83 The achiral precursor 125 undergoes an enantio- selective reaction where one of the enantiotopic 284 Contemporary Organic SynthesisOTf 5 molK Ph PdC12 127 TfO OTf 2.1 equiv. PhMgBrRiBr 48 h, 87% &) Et20PhCH3, -30 "c Me, .Me 126 93% ee 125 PhcH2*" Ph"'Ph 1 27 triflate groups undergoes preferential reaction to provide the coupled product 126 with high enantio- selectivity in the presence of ligand 127.There is a substantial interest in the use of allenes in metal catalysed coupling reactions. The reactivity of the alkoxyallene 128 is particularly interesting because the regioselectivity of the palladium catalysed addition is strongly dependent upon the nucleophile employed.84 Thus, using the pronucleo- phile 129 leads to the a-addition product 130, whereas the use of the pronucleophile 131 affords the alternative y-addition product 132. .CN h(CH2)30 x Me--(C02Et 129 5 mol% Pd2dba3.CHCI3 26 mol% dppb Me THF. 75 "C. 24 h C02Et 130 H' 128 5 mol% Pd2dba3.CHCI3 26 mol% dppb I THF, 75 OC, 24 h CN 77% -<CO*Et 131 Ph+CN C02Et 1 32 Murai and co-workers have reported the ruthenium catalysed addition of C-H bonds in an enone to an alkene.85 Thus, the enone 133 under- goes catalysed elaboration into the coupled product 134 on treatment with triethoxyvinylsilane 135 and a ruthenium catalyst. Trost and co-workers have reported related results.86 Si(OEt)3 12 mol% Ru(H)~(CO)(PP~~)~ @ @Si(OEt)3 135 2 equiv.I toluene, 135 OC. 10 h I 134 96% 133 5.5 Allylic substitution reactions There is still a substantial interest in asymmetric allylic substitution reactions. The ligand 136 has been shown to provide high asymmetric induction in the palladium catalysed formation of cyclic allylic sulfones from cyclic allylic acetates.87 The same ligand has been used in the asymmetric alkylation of the gem-diacetate 137, which is converted into the substitution product 138.88 -'NH PPh2 '"0 136 M e 0 2 Me0 .PPh2 PPh2 ' 1 - 1 45 149 C02Me OAc Ph 2.5 m~l~/&l~C~H~PdCi]~ 137 7.5 mol% 136 138 Ph >95% ee 92% Pfaltz and co-workers have reported the use of ligand 139 in tungsten catalysed allylic substitution reactions.89 Thus, cinnamyl phosphate 140 is converted into 141 and 142 with excellent enantio- selectivity and good regioselectivity.Williams and co-workers have used the same ligand in palladium catalysed asymmetric allylic substitution of the acetate 143 which provides the substitution product 144 with excellent enantio~electivity.~~ Helmchen and co-workers have shown that whilst ligand 139 is not ideally suited to inducing high enantioselectivity for cyclic substrate^,^^ the new ligand 145 is outstanding for such reactions. Thus, the cyclic acetate 146 is converted into the substitution product 147 with excellent enantio~electivity.'~ Indeed, there are now many ligands available which provide excellent enantioselectivity for palladium catalysed allylic substitution reactions, including ligands 14Sg3 and 149.94 140 C02Me 1 42 2.5 mol%[q3C3H5PdClk 10mol% 139 Ph Ph NaCH(CO2Meh * P h y V P h Ph OAc DMF.2O0C,24h Ph CH(C02Me)2 88% 143 144 99% 08 Dawson, Bower and Williams: Catalytic applications of transition metals in organic synthesis 285Tamaru and co-workers have reported a synthesis of unsymmetrical ketones by carbonylative coupling.lO' For example, the allyl phosphate 154 is coupled with the zinc reagent 155 in the presence of carbon monoxide and a palladium catalyst to give the ketone 156 with inversion of stereochemistry.Li' CH(C02B~'2 ooAc 9my;;mg145 * THF, 25 "C, 2 h, 73% 146 147 ~ 9 9 % ee Brandes and Hoffmann have reported a diastereoselective intramolecular palladium catalysed allylic substitution reaction leading to functionalised 9-membered rings." Kocovsky and co-workers have reported a molyb- denum catalysed allylic substitution reaction which proceeds with overall retention of stereo~hemistry.~~ These workers present evidence for a mechanism which proceeds via a syn-syn pathway, since neither the molybdenum nor the nucleophile are believed to be able to approach from the endo face of substrate 148 in its conversion into product 149. research into cobalt catalysed substitution reactions of allyl alcohols.97 The allyl alcohol 150 is converted into the amide 151 by treatment with acetonitrile and acetic anhydride in the presence of a cobalt(1r) catalyst.98 Iqbal and co-workers have continued their Ph Ac20 1.2 equiv., dry MeCN Ph 80 "C, 20 h, 57% 150 151 C02Me PhB(0H)p 10 mol% [Ni(acac)p] 40 mol% PPh3 20 mol% AIEt3 toluene, 60 "C, 17 h * b * - p h NEt2 152 54% 153 Trost and Spagnol have reported the nickel catalysed reaction between allylamines and boronic acidsw Furthermore, they have reported that the reaction proceeds by retention of configuration, as demonstrated by the conversion of the cyclic allyl- amine 152 into the phenyl-substituted product 153.The use of soft nucleophiles such as dimethyl malonate in nickel catalysed allylic substitution reactions has also been reported.Im , -0P03Et2 5 mol% Pd(PPh3)4 1 atm.CO HMPA (1 1 equiv.) THF, r.t., 72 h * 59% 154 + IZn -C02Et 155 156 Other carbonylation reactions of allylic com- pounds have also been reported. Cinnamyl methyl carbonate 157 undergoes ruthenium catalysed carbonylation to give the methyl ester 158, where the methoxy group has come from the original starting material.'02 Overall, the reaction involves loss of C02 and gain of CO. Crudden and Alper have reported the insertion of carbon monoxide into allylic C-S bonds."' Using a palladium catalyst, the substrate 159 is converted into the product 160 with concomitant isomerisation of the alkene. However, using a ruthenium catalyst, there is no such isomerisation, and the P,y-thioester 161 was isolated. reactions can provide a useful route to lactones and lactams.'04 Crisp and Meyer have used this strategy in the synthesis of the ct,P-unsaturated lactam 162 from the vinyl triflate 163.'05 Palladium catalysed carbonylative coupling 0 A r O S e 10 mol% Pd(OAc)2 20 mol% DPPP 68 atm.CO toluene, 140 "C 160 Ar = p-MeC6H4- 159 44 h, 73% 0 159 toluene, 140 "C 161 44 h. 50% 5.6 Carbonylation Many transition metals bind well to carbon monoxide, and consequently, there is a rich - (QBn 10 mol% Pd(PPh3)4 NBu3, MeCN. 65 "C 1 atm. CO chemistry associated with transition metal catalysed 1 w/o 0 reactions in the presence of carbon monoxide. 163 162 286 Contemporary Organic SynthesisGrigg and co-workers have reported a remarkable cascade reaction involving the incorporation of 2 equiv. of carbon monoxide.'06 The coupling partners 164 and 165 underwent palladium catalysed carbonylation to give the product 166.I 0 10 mol% Pd(OAc)2 164 kMe 20 mol% PPh3 c ELNCI. CO 0 + PhM; 1 10°C, 18 h 70% 166 Bu3Sn 165 5.7 Cyclisation reactions In the preceding sections, a number of cyclisation reactions are discussed. However, some cyclisation reactions were not easy to allocate to one section, and so have been included here. The conversion of enantiomerically enriched nitriles 167 into the corresponding pyridines 168 using cobalt catalysts has been the subject of a review. lo' cat. CpCo(c0d) acetylene, solvent 167 168 R ~ C N The research groups of Crowe'os and Bu~hwald'~' have independently reported the titanium catalysed reductive cyclisation of unsaturated ketones and aldehydes. The aldehyde 169 undergoes reductive cyclisation upon treatment with triethoxysilane and the titanium catalyst 170 to give the cyclisation product 171.pentane, r.t., 3.5 h 5-H 73% I Me 169 171 Buchwald and co-workers had earlier reported the use of the same catalyst in the enyne cyclisation reaction where an isocyanide is inserted into the substrate."' The enyne 172 is converted into the intermediate 173 which is hydrolysed directly into the bicyclic ketone 174. The palladium catalysed 1,4-addition to dienes has been performed in an intramolecular sense,"' and the latest addition to this family of reactions, involves the use of an allylsilane as the tethered nucleophile.1'2 Thus, the allylsilane 175 undergoes palladium catalysed oxidative cyclisation to the diastereomers 176 and 177.Ph /N- -b 10 mol% 170 R3Si Bu'Me2SiCN, PhMe, / 173 45 "C, 10-24 h 172 /HOAc/NaOAc (1:l) P F , 0 OC, 2 4 h Ph 174 66% yield tie C02Me Me C02Me C02Me H H 10 mol% Li2PdC14 176 + * benzoquinone, LiCl acetone-HOAc (2:l) SiMe2Ph r.t., 16 h, 68% cl@ Me H 7 175 H 'i= 177 1763177 (1:3) Grigg and co-workers have reported a cascade cyclisation reaction which terminates in a formal Friedel-Crafts alkylation.113 The substrate 178 undergoes a cascade cyclisation to afford the tetra- cyclic product 179. 1 78 w 10 mol% P~(OAC)~ 20 mol% PPh,, T12C03 PhMe, llO°C, 15h 179 5.8 Reactions involving alkynes The number of transition metal catalysed reactions involving alkynes is large. This section deals with only a few of these reactions. Buszek and Jeong have reported the arylation of the propargylic alcohol 180 under cross-coupling conditions.' l4 The triphenylphosphine employed as a ligand was found to be the source of the aryl group, and by employing excess triphenylphosphine, a good yield of the arylated product 181 was obtained.Kocienski and co-workers have reported the silyl- stannylation of alk~xyalkynes."~ The ethoxyalkyne 182 was converted into the adduct 183, which could H 180 10 m o l l Pd(PPh& 3 q. PPh3 3 q. NH(P& 1 mol% Cul THF, r.t., 12 h Ph 181 87% Dawson, Bower and Williams: Catalytic applications of transition metals in organic synthesis 287e c l + Bu-H + Ph*SnBu3 r3 OEt 182 2 mol% Pd(PPh& Me3SiSnMe3 cat. galvinoxyl PhH, r.t., 3 h 90% * EtO TiSiMe3 SnMe3 1 83 subsequently be employed in Stille coupling reactions. In addition to the already well-documented hydrometallation reactions of alkynes, Sat0 and co-workers have reported a titanium catalysed hydrozincation of internal alkynes."' The stereo- defined alkenylzinc reagents can be further exploited in palladium catalysed coupling reactions.Inoue and co-workers have provided a direct synthesis of alkylalkynoates using copper or silver catalyst^.''^ For example, treatment of oct-1-yne with hexyl bromide and carbon dioxide with potassium carbonate and a copper catalyst directly provides the ester 184 without the need for any other co-catalyst. McDonald and Schultz have reported an unusual molybdenum pentacarbonyl catalysed cyclisation of alkynols.1'8 The alkynol 185 is treated with the molybdenum catalyst, and undergoes reaction to afford the dihydrofuran 186.The mechanism is postulated to proceed by intramolecular attack of the hydroxy group on a vinylidene carbene species. In the presence of tributyltin triflate, a-stannyl vinyl ethers can be prepared."' NEt3, 26 mol% Et20, MO(CO)~ hu, 20 min* b P h HO then 18 h, r.t. 185 89% 186 Three-component coupling reactions are always of interest because of the rapid construction of more complex molecules. An example is provided by Murai and co-workers, where the alkyne 187, tri- methylsilyl iodide 188 and dimethylzinc 189 are converted with a palladium catalyst into the coupled product 190.120 Another example is provided by Sat0 and co-workers, who have reported that ally1 chloride 191, hex-1-yne 192 and the alkynyltin com- pound 193 are coupled with a palladium catalyst to give the product 194.12' 5 mol%- Ph+ +Me3% + Me2Zn 8 h, 61% Me 187 188 189 1 90 Trost and co-workers have reported a ruthenium catalysed synthesis of butenolides.'22 The diene 195 is converted in one step into the bis-butenolide 196 191 1 93 10 mol% Ni(acac)flIBALH (1:l) THF, reflux, 1 h 70% Ph' 1 94 Eto2c\.+ 197 OH 0 4 O / ; 195 10 mol% (cod)CpRuCI 198 MeOH, reflux, 5.5 h 75% I upon reaction with the prop-Zynylic alcohol 197 in the presence of the ruthenium catalyst 198. 6 Reactions involving metal carbenoids 6.1 Cyclopropanation and related processes Whilst the enantioselective cyclopropanation of alkenes has become a reasonably familiar reaction over recent Doyle and co-workers have reported an enantioselective cyclopropenation rea~ti0n.l~~ Using rhodium MEPY catalyst 199, they were able to convert the alkyne 200 into the corre- sponding cyclopropene 201 with reasonably good enantioselectivity. 199 Several groups have reported enantioselective intramolecular cyclopropanation reactions.Pfaltz and co-workers have employed their enantio- merically pure semicorrin copper complexes 202 as catalysts for the conversion of the diazoketone 203 into the bicyclic product 204.'26 Doyle and Proto- popova have used their rhodium MEPY catalyst 199 to effect the intramolecular cyclisation of 205 into the product 206.'27 Interestingly, when rhodium( 11) perfluorobutyrate (pfb) was employed as the catalyst, the reaction pathway changed from intra- molecular cyclopropanation to intramolecular C-H insertion, affording the alternative product 207.288 Contemporary Organic Synthesis0 0 5 mol% 202 CICH&H&I, 23 "C * 57% 203 204 95% ee CN 202 Me, M e v 0 y C H N 2 Me 205 0 1 motyo "1J \35yo CHpCl2,25 1 mol% Rh2(pfb)4 "C CHpClp,25 C 79% n 206 93% ee 207 Doyle and co-workers have published other examples of intramolecular cyclopropanation reaction^.'^^.'^^ of aziridines from imines and diazo esters. Rasmussen and Jorgensen have shown that using aniline derived imines, they can generate the corre- sponding aziridines with up to 95% ~ie1d.I~' Jacobsen and co-workers have reported an asymmetric variant of this reaction, although the yields and enantioselectvities are only modest .'jl Using the bis-oxazoline 208 and a copper(1) catalyst, the imine 209 was converted into the aziridines 210 and 211.Two groups have reported the catalytic formation H p h A " P h 209 + 6 mot% [CUPF,~(M~CN)~] 15 mot% 208 CH2CI2, r.t.. 1 h * 37%,cidtrans 4: 1 .d- Pti 'Ph - Co2Et 21 0 cis 44% ee I \ph trans 35% ee Ph 208 6.2 Carbene insertion reactions Transition metal catalysed carbenoid reactions may undergo reaction pathways involving addition to double bonds, insertion into single bonds or addition to heteroatoms. Padwa and Austin have provided a useful review discussing the factors which influence the chemoselectivity of these ~eacti0ns.l~~ Doyle and co-workers have continued their research into highly enantioselective C-H insertion reactions, including an example of a route to P-lactams via intramolecular C-H insertion rea~ti0ns.l~~ Hashimoto and co-workers have reported an effective route to the formation of quaternary centres with high asymmetric induction by an enantiotopically selective C-H insertion of the substrate 212 to give the cyclised product 213 catalysed by the rhodium complex 214.134 Insertion into other single bonds is also possible, and Moody and Miller have reviewed the synthetic applications of 0-H insertion reaction^.'^^ Additionally, Moody and co-workers have reported an N-H insertion reaction of amides, carbamates and ureas with the diazo compound 215 which affords the N-acylamino- phosphonoacetate 216 when decomposed in the presence of carbamate 217.'36 Landais and co-workers have provided another example of a rhodium catalysed Si-H insertion rea~ti0n.I~' The vinyldiazocarbonyl compounds employed were found to retain their geometry, thereby providing a stereospecific route to allylsilanes. Katsuki and Ito have used enantiomerically pure bipyridine copper complexes to effect enantioselective C-0 insertion reactions.'38 0 2 mol% 214 Ph N2 C-h 86% Et p* 213 95% ee 21 2 21 4 NPhth 4 PO(OW2 2 mol% Rh2(OAck EtO,C$ PO(OEt);! * N2 PhMe, Bu'OCONH2 reflux, 217 16 h NHCOOBU' 21 5 75% 21 6 Transition metal carbenoid intermediates can also react with suitable substrates to form 1,3-dipole and ylide intermediates.Padwa and Price have used this to great effect in the rhodium(I1) catalysed conver- sion of 218 into 219.'39 The reaction is presumed to proceed via the intermediate 220. Agganval and co-workers have continued to develop their rhodium tetra-acetate catalysed epoxi- dation reaction of aldehydes using sub-stoichio- metric quantities of a sulfide.'4' These reactions probably proceed via a sulfur ylide intermediate.These workers have demonstrated that the reaction is suitable for the preparation of epoxides 221 from base-sensitive aldehydes such as p henylace t alde hyde. 14' Dawson, Bower and Williams: Catalytic applications of transition metals in organic synthesis 28921 8 / 220 Qy$: Y ' C02Me Me 21 9 95% Me2S (0.5 equiv.) Rhp(0Ac)d (0.01 WUiV.) ph 4 ph PhnCHo N2CHPh addition * over 24 h, r.t., CH2Cl2 80% 221 9:l (transcis) 6.3 Metathesis reactions Catalytic ring-closing metathesis reactions have continued to be popular. Schmalz has written a short review of the recent deve10pments.l~~ Grubbs and co-workers have reported the ring-closing metathesis of dienynes in the formation of fused bicyclic rings.'13 Thus, treatment of the dienyne 222 with the ruthenium catalyst 223 affords the cyclisa- tion product 224.This research group has also reported the ring-closing metathesis reaction of dienes in the formation of eight-membered rings. 144 The tungsten catalyst 225, which is readily prepared from tungsten(v1) oxychloride and 2,6-dibromo- phenol is also an active catalyst for ring-closing rnetathesi~.'~~ This catalyst has been employed in the conversion of the diene 226 into the cyclisation product 227 with little or no loss of enantiomeric purity. The mechanism is believed to proceed via tungsten carbene complexes. 0 Cl..iu:x Ph ArO,II,CI CI* I Ar= 2,6-dibromophenyl ph CIOW'OAr PCY3 223 225 8h25"C 95% Me Me 222 224 1 -Q+K 2 mol% 225 4mol% Et4Pb 1,2,4-trichlorobenzene 226 90 "C, 1 h, 68% 227 97% ee 7 Miscellaneous 7.1 Alkene hydrometallation and carbometallation In earlier sections, reactions involving the hydro- boration and hydrosilylation of alkenes were discussed.However, the hydrometallation of alkenes can also be catalysed by transition metal catalysts. Lautens and co-workers have reported the nickel catalysed hydroalumination of the oxabicyclic alkene 228.146 With the addition of an enantiomerically pure ligand, the hydroalumination process occurs via the intermediate 229, thereby affording the isolated product 230 also with excellent enantio- selectivity. (OMe 21 14 mol% mol% (R)-BINAP Ni(cod)p &:Me 1.1 equiv.BuiAIH (over 1 h) r.t., 1-3 h, 97% 228 230 97% ee f OM= via WM~ Bui2Al 229 Knochel and co-workers have reported further examples of nickel catalysed hydro~incation,'~~ as well as an interesting use of nickel catalysed carbo- ~incati0n.l~~ The bromide 231 is converted into the corresponding zinc reagent which undergoes an intramolecular carbozincation reaction to give the intermediate 232, which upon treatment with oxygen in the presence of trimethylsilyl chloride affords the cyclic aldehyde 233. SiMe3 \I ,Br SiMea I XZn-CH 5 mol% Ni(acac)2 OBU THF, 40°C, 12 h Etgn, 0.25 equiv. Lil* p e n t G o B u C!jHll 231 232 02, 2 equiv. TMSCI 55% overall O W - C5Hll &Low 233 7.2 Isomerisation reactions Isomerisation reactions encompass a wide range of reaction types.They are particularly appealing in terms of 'atom economy'.'49 Three interesting examples are described in this section. Cyclopropanes are a rich source of isomerisation chemistry. Ryu and Sonoda have reported the nickel catalysed rearrangement of the 1-siloxy-1 -vinylcyclo- propane 234 into the cyclic silyl enol ether 235.l5' 290 Contemporary Organic SynthesisH OTBDMS OTBDMS 7.4 Catalysed Michael addition The trans-chelating diphosphine 244 has been used to provide asymmetric induction in a rhodium catalysed Michael addition reaction. The a, p-usatu- rated ketone 245 undergoes conjugate addition with the a-cyano Weinreb amide 246 with excellent yield and enantioselectivity in the formation of the product 247.'54 2.5 mol% NiClz(PPh3)~ 5 mol% Zn Bu toluene, 110 "C, 20 h 90% 234 235 Alkenes are also susceptible to isomerisation in the presence of transition metal catalysts.Miyaura and co-workers have employed ruthenium and iridium catalysts in the conversion of the vinyl- boronate 236 into the allylboronate 237.15' 236 3 mol% (IrHz(thf)z(PPhzMe)z1PF~ r.t., 56%, (f ):(Z) = 923 237 Nakai and co-workers have developed a palla- dium( 11) catalysed Claisen rearrangement in which the enol ether is generated by the addition of trifluoroacetic acid as a co-catalyst.lS2 The enol ether 238 and the ally1 alcohol 239 were directly trans- formed into the ketone 240 without isolation of the intermediate enol ether. OMe Et o w 10 mol% PdC12(PhCN)z A +Ho%\ 10mol%TFA < toluene, r.1.. 12 h 61% u 238 239 240 >99% anti 7.3 Conversion of aldehydes to ketones The in situ conversion of aldehydes into ketones has been achieved by Zheng and Srebnik in an interest- ing manner.ls3 As an example, the zinc bromide catalysed addition of the alkylzirconocene chloride complex 241 to benzaldehyde 66 affords an inter- mediate 242 which in the presence of additional benzaldehyde undergoes an Oppenauer-type oxida- tion to the ketone 243.20 mol% ZnBr2 THF (0.8 mol dm-3) C8H17 C8H1~zZrCppCI -+ PhCHO 241 66 25 "C, 3 h 242 PhCHO 25 "C, 6 h 83% 0 C8H17 A P h 243 Ph 245 0 the Me 246 1 mol% Rh(acac)(CO)z 1 mol% 244 PhH, 3 OC, 18 h 99% 247 94% ee 8 Conclusion The use of transition metal catalysed reactions is still increasing and transformations are being reported with higher levels of chemoselectivity and enantioselectivity. 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ISSN:1350-4894    

DOI:10.1039/CO9960300277

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Saturated and unsaturated lactones IAN COLLINS Merck Sharp and Dohme, Research Laboratories, Neuroscience Research Centre, Erlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK Reviewing the literature published between 1 August 1994 and 31 October 1995 Continuing the coverage in Contemporary Organic Synthesis, 1995, 2, 133 1 2 3 4 5 6 7 8 9 10 Introduction P-Lactones Macrolides y-Lactones Medium ring lactones b-lactones S pirolactones a-Methylenebutyrolactones But-2-enolides and tetronic acids References 1 Introduction This review covers the literature relating to saturated and unsaturated lactones, including macrolides, tetronic acids and a-methylenebutyro- lactones. The classification of the chemistry described follows the pattern of the previous survey in Contemporary Organic Synthesis.' 2 fl-Lactones The high reactivity of the P-lactone group severely limits the number of successful lactonisation techniques available for its formation.Schick et aZ. have recently demonstrated the direct lactonisation of the P-hydroxyalkanoate intermediates formed during indium-mediated Reformatsky reactions. In its prototypical form this synthesis is restricted to a, a, p, P-tetrasubstituted p-lactones, relying on a strong gem-dialkyl effect to close the ring, but can be extended to less substituted systems by simply using the phenyl esters in place of the original ethyl alkanoates Scheme 1.2 The more reactive phenoxide leaving group mitigates a diminution in the gem- dialkyl effect and good yields of simple trisubsti- tuted P-lactones are obtained. If branched alkyl substituents are present in the ester 1, or aldehydes are used in place of ketones, the yields of the reaction become unsatisfactory. uses the condensation of the lithium enolates of phenyl esters with both ketones and aldehydes, representing a convenient alternative to the A more general development of this procedure 0 OPh 1 Scheme 1 A3 (51-81%) Danheiser alkanthioate meth~dology.~ The phenyl esters are sufficiently activated to eliminate lithium phenoxide at low temperatures to generate tri- substituted P-lactones in good yields (60-75%).In contrast to the indium-mediated reaction, this variant is successful with P-branched ester substituents. With aldehydes in place of ketones lower, but acceptable, yields are observed and a, P-disubstituted p-lactones are accessible with this procedure (Scheme 2).Mixtures of cis- and trans- disubstituted products are recovered, with the stereoselectivity dependent on whether a branched or a straight-chain substituent is present in the ester component 2. 2 R = Et, 3 1 (32%) R=Pr' 0 1 (40%) Scheme 2 The same interception of the normal pathway occurs in the Darzens reaction of phenyl 2-chloro- alkanoates with carbonyl compounds (Scheme 3).4 Here, lithium phenoxide eliminates more readily than lithium chloride from the intermediate P-alkoxyester 3 leading to the a-chloro P-lactone 4 instead of the usual glycidic ester 5 . The presence of the a-chloro atom contributes to a gem-dialkyl effect and good yields are seen with both ketones and aldehydes, although in certain cases enolisation of the aldehyde component can lead to complicated mixtures.The low diastereoselectivities in the reaction of unsymmetrical substrates parallels the poor selectivity of the Darzens reaction itself. Collins: Saturated and unsaturated lactones 295+ Et+(oLi CI OPh THF, -78 O C I 3 5 Scheme 3 4 (4043%) The [2+2] cycloaddition of ketenes and alde- hydes is an attractive direct route to substituted p-lactones and is realised in a highly diastereo- selective chelation-controlled cycloaddition of tri- methylsilylketene to a- and p-alkoxy aldehyde^.^ The choice of Lewis acid is critical; monodentate species such as boron trifluoride are unselective as they do not coordinate the alkoxy group, whereas bidentate Lewis acids form rigid chelate structures such as 6 (Scheme 4).This leads to a high bias for attack on the n-face opposite to the a-substituent of the aldehyde. The major product has the anti configura- tion in all cases examined, consistent with the proposed chelation control. Unfortunately, optically pure aldehydes undergo partial racemisation at the a-substituent in these conditions (typically product of 88% ee is obtained), and the reaction as it stands does not lead to single enantiomers without an additional enrichment step. BnO 0 1 + Y H H SiMea (Yield) Lewis acid (*)-anti (*)-sun BF *Et20 62 : 38 Mgbr2*Et20 98 : 2 Scheme 4 296 Contemporary Organic Synthesis Bn 6 Enantiomerically pure P-lactones can be synthe- sised via the classical Adam’s lactonisation provided the appropriate P-hydroxy acid precursors are avail- able.A new route to these key intermediates starts with the condensation of hydroxylaminoborneol7 and trimethyl orthoformate to generate the oxazo- line-N-oxide 8 (Scheme 5).6 A highly regio- and stereo-selective in situ [2 + 31 cycloaddition of 8 with an a, P-unsaturated ester follows. The cycloadduct 9 contains differentiated functionality that should lead to both cis and trans a, P-disubstituted P-lactones. In practise it is not yet possible to oxidatively cleave the auxiliary in the presence of the ester group, denying access to the cis substituted targets. However, prior reduction of the ester and protec- tion of the primary alcohol permits successful cleavage (and recovery) of the auxiliary. Lactonisa- tion of the p-hydroxy acid 10 furnishes the enantio- merically pure trans p-lactone 11 in 42% yield over eight steps.7 HO U P , Bno>’pr 11 (52%,7 steps) CaC03 PhMe steps - - 1 80°C 9 ~ 9 5 % de (80%) + Scheme 5 A conventional Reformatsky reaction followed by mild hydrolysis provides P-hydroxy acids which can be cyclised to give highly reactive a, a-difluoro p-lactones (Scheme 6).7 Since these materials react very rapidly with water and other nucleophiles a modified non-aqueous work-up is essential after lactonisation to provide good yields of pure products. The a, a-difluoro p-lactones are decarboq- lated smoothly to the corresponding 1,l-difluoro- alkenes on heating in solution, a sequence that constitutes a viable alternative to ylide chemistry. This highly stereoselective decarboxylation of P-lactones underlies the use of a-methylene p-lactones as allene equivalents in organic synthesis.BrCF&OCI OH n n n - i.Zn. THF ::%COzH ii. aq NaOH F F 0 II BnABn (85%) B n ~ F 15OOC BnsroF - co, (95%) (1 00%) Bn F Bn F Scheme 6 Stereochemically defined allyl amines and allyl sulfides are accessible with such a strategy through recent work by Adam et aL8 Conjugate additions of both amines and sulfides to a-methylene P-lactones occur under mild conditions but show a dramatic solvent dependent stereoselectivity (Scheme 7). Mixtures of cis and trans isomers are formed in aprotic solvents, but overwhelmingly the thermo- dynamically favoured trans isomers dominate when methanol is the reaction medium. Two competing protonation pathways are evoked to explain this observation.Proton transfer from solvent occurs preferentially on the opposite face of the p-lactone to the incoming nucleophile (path a), whereas in aprotic conditions the nucleophile may also serve as the proton source and the cis isomer is formed (path b). The initial mixtures of Michael adducts can be isomerised to essentially pure trans disub- stituted p-lactones with LDA at low temperature (Scheme 8). Subsequent thermal decarboxylation is generally high yielding and stereoselective, provided the substituents are not too bulky, and generates the E-allylamines and allyl sulfides. A further development of this methodology uses the addition of prochiral ester enolates to the a-methylene P-lactones to generate y, &unsaturated \ Solvent cis trans (Yield) THF 77 : 23 (69Yo MeOH 7 : 93 (84%1 Scheme 7 I \ I \ -)Y i.LDA, -78 "C ii. aqNH4CI -2 -4 aq NH4CI cis ltrans 65/35 95% de (60%) Scheme 8 esters of defined geometry after decarboxylation of the intermediate P-lactones (Scheme 9).9 The configurations of the Michael adducts correspond to the initial ester enolate geometry and can be seen as arising from attack of the coordinated enolate on the less hindered z-face of the a-methylene p-lactone. Good stereoselectivities are possible if enolates of well-defined geometry are used and provided the reaction is quenched at low tempera- ture (giving the trans products) to avoid electrocyclic ring opening of the intermediate P-lactone enolates. Bu'02cYMe -$* * 89% de (63%) Scheme 9 3 Macrolides An elegant and efficient asymmetric macrocyclisa- tion introduced by Oppolzer et al.is the central ring closure step in a synthesis of the macrolide ( + )-aspicilin (Scheme lo).'' Hydroboration of the cu-alkynyl ester 12 and transmetallation with diethyl- zinc generates an E-vinylzinc species that attacks the aldehyde in the presence of catalytic amounts of (-) dimethylaminoisoborneol (DAIB) to give the R allylic alcohol with good diastereoselectivity. This key chiral centre is exploited further through a directed epoxidation to build up the remaining stereocentres in the target. Despite its remoteness from the forming bond, the existing chiral substituent of the substrate 12 exerts a moderate influence on the topicity of the cyclisation. The alliance of 12 and (-)-DAIB constitutes a matched pair of stereodirecting effects (82% de).The contrast is seen when the enantiomeric ligand (+)-DAIB is used to generate the S alcohol and the bias of the catalyst and substrate are in opposition (70% de). The condensation between aldehydes and sulfinyl activated methylene compounds generates y-hydroxy a, P-unsaturated esters, As with many systems, this reaction encompasses macrolide synthesis only when Collins: Saturated and unsaturated lactones 2970 Me'' i. B(c-Hex)pH ii. E t a 82% de (60%) Scheme 10 high dilutions and extensive reaction times are applied." A Knoevenagel condensation initiates the sequence, to be followed by a double bond shift and [2,3] sigmatropic rearrangement of the sulfinyl group. In this manner the E allylic alcohol is formed after hydrolysis, but as yet no control over the absolute stereochemistry of the hydroxy group has been attempted (Scheme 11).carbon atoms is a valuable route to esters, and preliminary investigations show that it may apply within macrolide syntheses also.I2 The cyclisation of o-alkynyl alcohols requires two equivalents of palladium acetate with carbon monoxide at Palladium catalysed carbonylation at unsaturated 0% 04 ArS=O kH 0 ?+l)n n t(days) (Yield) 3 81%) 4 130%) OH Scheme 11 298 Contemporary Organic Synthesis atmospheric pressure to give modest yields (11-39%) of simple, unsubstituted 15- to 20-membered lactones. The low conversion of starting material and high stoichiometry of the metal reagent are formidable barriers to the practical use of this procedure, but the mild condi- tions make this an attractive area for further study. A more successful approach to the incorporation of carbon monoxide as a C1 unit in macrolactonisa- tions uses a sequential radical annulation (Scheme 12)" A terminal alkyl radical is generated from tris(trimethylsily1)silane and a terminal iodide, although selenides have also been used.To avoid Porter type cyclisation of the initial alkyl radical directly onto the alkenyl acceptor, high pressures (30 atmospheres) of carbon monoxide and high dilution conditions are necessary. In this way the carbon monoxide intercepts the alkyl radical and the intermediate acyl radical then cyclises. Some competitive reduction of the acyl radical by tris(tri- methylsily1)silane is observed but this does not seriously reduce the yields of the lactones.Ten- membered rings can also be formed, but yields are superior with larger systems. Of course, Porter type macrocyclisations are useful processes in their own right, and a new method of generating the primary alkyl radical involves photoirradiation of an iodoalkane in the presence of metal hydride c~mplexes.'~ Sodium cyanoborohydride in methanol seems to be the optimal reagent for high conversion and selectivity over dimeric products. 0 n =1-8 (28-78%) Scheme 12 Ring expansions offer an alternative strategy to the cyclisation of linear substrates for macrolactone synthesis. In practice, though, such approaches are often dogged by a complex dependence on substituents and reaction conditions, a point illus- trated in the double ring expansion by P-fragmenta- tion of alkoxyl radicals (Scheme 13).15 The alkoxyl radical generated from the tertiary alcohol 13 undergoes hydride abstraction unless the pendant primary alcohol is suitably protected, in which case the P-fragmentation product 14 is formed.The yield of the ring expansion is also very sensitive to temperature, reagent stoichiometry and choice of oxidising agent. Deprotection of the primary alcohol and a second radical fragmentation of the inter- mediate hemiacetal gives a low yield of the 13-membered lactone as a complicated mixture of double bond positional and geometrical isomers. In part, this is due to competing transannular cyclisa- tions, and a better yield of the ring expanded material (63%) is achieved if the alkene 14 is reduced prior to radical generation.H!3Q I2 Me0 q- hv, 0 "C OAc 13 Me0 (30%) Scheme 13 OAc 14 (85%) i.NaHC03 ii. HgO, 12. hv I Me0 @'I -1 In a similar vein, Grob fragmentation of medium ring ketones to macrolactones can be triggered by hemiacetal formation (Scheme 14)." Since the stereochemical outcome correlates to the relative orientations of the ester and epoxide, a concerted mechanism is implicated. However, although the trans oriented isomer 15 leads exclusively to the E alkene 17, the unexpected formation of some of the E product from the substrate 16 which has the epoxide and ester in the cis orientation suggests that a competing two-step ionic pathway may be operating. continues to throw new light on the substrate dependence of classical macrolactonisation techniques. The allylic alcohol 18, an intermediate in a synthesis of the cytotoxic comb rest at in^,'^ does not cyclise to the strained lactone under any of the conditions tried, including Steglich's modified Mitsunobu reaction.This may be due to SN1- initiated side-reactions in the very electron rich system. To address this problem, the double bond is The exploration of natural product syntheses WH 'CO2Prl QJ0doH C02Pr' 0 0 H h 15 16 1% 0ydJlH q + 17 0 17 (52%) (57%) (1 9%) QMe OMe CO2H O\'o 18 X = H, alkene 19 X = PhS, alkane (0% : (89%{ Scheme 15 masked as the phenyl sulfide 19, a change which also removes a conformational restraint from the molecule, and efficient lactonisation of 19 then proceeds (Scheme 15). The synthesis of the swinholide A family of macrolides by the Paterson group exemplifies the powerful influence that the preorganisation of acyclic substrates may have in enhancing the selec- tivity and yield of macrocyclisations.'' The integral tetrahydropyran of the seco acid and the cyclic acetal protecting group appear to provide conforma- tional anchors that bring together the two ends of the chain and lead to efficient cyclisation, without the need for full hydroxy group protection (Scheme OMe +OM.A Go..+c02H OTBS 20 Me0 I 21 22 Conditions 21 : 22 (Yield) Yarnaguchi, toluene 82: 18 (92% Keck, CHC13 5 : 95 Keck, toluene 40 : 60 (73%) Scheme 14 Scheme 16 Collins: Saturated and unsaturated lactones 29916). The regioselectivity of the cyclisation shows a suprising dependence on the reagents used.For example, the seco acid 20 mainly cyclises to the 22-membered lactone hemiswinholide A 21 under Y amaguchi conditions, but predominantly the 24-membered product isohemiswinholide A 22 results if Keck's reagents are employed. Intriguingly there is also a sensitivity to solvent polarity, as demonstrated by the reduction in selectivity when the Keck cyclisation is carried out in toluene instead of chloroform. This suggests that solvent polarity has a role in determining the conformational prefer- ence of the seco acid and hence the regiochemistry of the cyclisation. The same impressive degree of reagent control is exerted in the cyclisation of the dimeric seco acid precursor to the 44-membered macrodiolide swinholide A or the 46-membered isoswinholide A.Both protocols are efficient at ambient temperature and without the need for high dilution. 4 y-Lactones Intramolecular Michael addition of an a-phenylthio stabilised enolate should be a valuable method for the construction of highly functionalised, enantio- merically pure y-lactones, offering complete control over the stereochemistry of substituents, particularly at quaternary centres (Scheme 17a).I9 Epoxides obtained by Sharpless oxidation are opened regio- selectively with a-phenylthioacetic acid in the presence of titanium( IV) isopropoxide. The product diols 23 are susceptible to acyl migration but can be converted directly into the cyclisation precursors 24 without isolation. The choice of DMF as solvent for the intramolecular Michael reaction is critical since the esters 24 are prone to hydrolysis in most other solvents, through the elimination of 2-phenylthio- ketene.The cyclisation is also dependent on the temperature and base employed, with sodium hydride at -50 "C being optimal for selective formation of the major product 25 (R=H). A wide range of substituents is tolerated and neither the geometry of the double bond nor the presence of quarternary centres at the P- and y-carbons of the nascent lactone influence the outcome. Molecular modelling suggests that the stereoselectivity is kinetic in origin and the all-trans product 25 is a result of si face attack of the E enolate through transition state 27. One striking observation is that introduction of an a-substituent in the enolate completely reverses the configuration of the product lactone 26 at the a-carbon and calculations support the apparent re face attack of the more hindered enolate 28.The a-phenylthio group provides a versatile handle for further transformations, and the same authors demonstrate this in a complementary route to a-quaternary y-lactones.20 Oxidation of the sulfide 25 (R=H) to the sulfone 29, followed by enolisation and alkylation, goes with overall reten- tion of configuration to generate the y-lactone which has the opposite configuration at the a-carbon to the product 26 of the direct cyclisation (Scheme a PhSCH(R)CO*H TH Ti(OPS)4 * -2.1 OH 23 i. NaI04 ii. Wittig k P h 1 Pr uC02Me 24 NaH, -50 "C, DMF/ 0 0 &Jh + fiPh Pr '-C02Me Pr ,,i '-C02Me 25 26 R = H 100 0 (95%) R=Me 0 100 (95%) n via : Me 27 28 b 0 0 29 (88%) Scheme 17 17b).Models indicate that the diastereofacial bias arises from coordination of the metal counterion by a sulfone oxygen and shielding of one face of the enolate of 29 by the phenyl group. This is supported by the observation of unselective alkylation when the sulfide itself is used. y-Lactones can be derived in one step by the radical cycloaddition of malonate derivatives and olefins. A novel parallel approach proceeds through the copper-promoted addition of a sulfonyl ylide to an alkene (Scheme 18).*l Such reactions usually lead to cyclopropanation or reductive alkyl- ation, but in this case the nonafluorobutylsulfonyl (nonaflyl, Nf) group present in the ylide stabilises the intermediate zwitterion 30 sufficiently to allow P-hydrogen elimination from the ethyl ester and closure through oxygen to the lactone.The addition 300 Contemporary Organic SynthesisNf 1 - 1 I I L CUL, J 30 X I Nf (60%) Nf = nonafluorobutylsuifonyI (nonaflyl) Scheme 18 of the catalytic copper species is essential to suppress reductive alkylation, presumably by stabilising the positive charge of the zwitterion through coordination. Not suprisingly the methyl esters, which cannot undergo the P-hydrogen elimi- nation, produce the usual cyclopropanes. A conse- quence of increasing the life-time of the zwitterion is to permit rotation about the C4-C5 bond with subsequent loss of the double bond stereochemistry for acyclic alkenes. The a-nonaflyl group adopts the sterically favoured trans relationship to the P-substituent in all the systems studied and thus this represents a rapid and stereospecific entry into fused bicyclic lactones.Novel tricyclic bislactones originate from the conventional syn-endo Diels-Alder adduct 31 (Scheme 19).22 Functionalisation of the cycloadduct to the diol32 is followed by cleavage of the double bond to reveal two aldehydes, from which the two fused lactones are constructed. In the oxidation step one of the aldehydes epimerises but this is corrected in a subsequent basic cyclisation to form the highly concave lactol-lactone 33. Treatment with Grignard reagents makes good use of the rigid scaffold to give a single diastereoisomer of the dilactone 34 after oxidation. Previous investigations by Greene et al. into the cycloaddition of dichloroketene and alkenes, followed by regiospecific Baeyer-Villiger oxidation of the a, x-dichlorocyclobutanones to y-lactones, uncovered a troublesome side reaction in the reduc- tion of the a, a-dichlorolactones 36 (Scheme 20).This precluded the use of non-aryl substituents if reductive cleavage of the pendant ether auxiliary was to be successful. Now that difference in reactivity has been turned to advantage for the synthesis of P-hydroxybutyrolactones of the blast- mycinone class.23 Excellent diastereoselectivity is seen in the cycloaddition of dichloroketene with the benzylic enol ether 35. The dichlorolactone product of subsequent Baeyer-Villiger oxidation is reduced steps -OH 31 32 U 33 (88%) i. RMgCl ii. (Ph3P)3RuCI iii. TBAF I R H &:H O O 34 (36%) Scheme 19 35 Me (+)-blastmycinone Scheme 20 OSiPh,Bu' HO (62%) 0 * % 0-- I Me i.C13COCl, Zn ii. MCPBA A~T--H Me 36 Zn, CH3C02HI Me (50%, 3 steps) to the P-alkoxy lactone on treatment with zinc in acetic acid. Further manipulation gives blast- mycinone and its congeners as single enantiomers. Magnesium and trimethylsilyl chloride is a new reagent combination for the reductive cross- coupling of CI, P-unsaturated esters with aldehydes (Scheme 21).24 Electroreduction and samarium iodide have been used in this context but the new method promises to be easier to apply and also shows complementary substrate specificity. Whereas samarium iodide is only successful with P-aliphatic Collins: Saturated and unsaturated lactones 301isomers, indicating that the chiral ligand investigated A,&C02Et + RAo M:i:p' - ArDo may not be the best choice for strong reagent D control.n (39-94%) Scheme 21 a, P-unsaturated esters, the new technique is limited to the coupling of P-aryl substituted compounds. Although the trans P, y-disubstituted lactone is the major isomer recovered, selectivities are. generally low. Trimethylsilyl chloride is essential in the reaction and may play a dual role in activating both the metal and carbonyl substrates for single electron transfer. Preliminary work on the asymmetric halocarbo- cyclisation of 4-pentenylmalonates using titanium enolates prepares fused bicyclic y-lactones in modest to good enantiomeric purity.25 As with the standard racemic synthesis, activation of the olefin with iodine in the presence of the enolate achieves high yields and excellent regioselectivity in the first cycli- sation to the cyclopentane, followed by smooth lactonisation on heating (Scheme 22).The chair-like transition state 37 is postulated, where one face of the enolate is shielded by the metal ligands, and the stereospecific transformation of 2 and E alkenes supports the anti mode of attack shown. The enantioselectivity of the reaction is currently very substrate dependent, for example E alkenes give consistently poorer optical purities than the 2 702Bn M C02Bn Me 12, CUO, CH2Cl2 ii. 140 "C I Me Me E alkene 1 Z alkene 92 via: OBn I 1 37 u 45 (82%) 45% t?e 1 (1 00%) 76% ee A thiazincolidine complex previously developed for the asymmetric addition of alkylzincs to aldehydes can function as a catalyst for the enantio- selective reduction of cyclic N-phenyl meso-imides (Scheme 23).26 The desymmetrised products are cleaved by further reduction and recyclised to the y-lactones with good to excellent enantiomeric purity.These conditions do not yet apply efficiently to anhydrides. N-Phenyl substitution leads to approximately double the optical purity of other substituents such as benzyl, suggesting that an orthogonal arrangement of this substituent relative to the imide is involved in the differentiation of the two carbonyls by the catalyst. With this in mind, the extended array 38 is proposed as a model of the catalyst-substrate interaction, implying that the reducing agent attacks the indirectly activated carbonyl rather than that coordinated by zinc.A divergent synthesis of two epimeric a-alkyl y-lactones from the same allylsilane is created by simply reversing the order of the reaction ~equence.~' Alkylation of the allylsilane 39 gives essentially one diastereoisomer which can be lacto- nised after dihydroxylation of the double bond (Scheme 24a). If the same allylsilane is first subject to a Sharpless asymmetric dihydroxylation, the corresponding unsubstituted lactone 40 can be formed with good selectivity (Scheme 24b). Alkyl- ation of the p-silyl lactone 40 takes place on the face opposite to the bulky silyl group, a reaction that is successful only when the hydroxy substituent is unprotected. The insertion of carbon monoxide into the termini of simple ally1 alcohols will generate y-lactones (Scheme 25).28 A catalytically active 16-electron species [HCO(CO)~] is generated with triplet-excited xanthone during photoirradiation under carbon monoxide.Initial metallation of the alkene, prior to carbonyl transfer, is reversible and so provides an opportunity for double bond migra- tion. This is observed when terminally substituted Et A ?n-e I i. NaBH4 ii. H2SO4 84% ee (69%) postulated intermediate: Ph 38 Scheme 22 Scheme 23 302 Contemporary Organic Synthesisa Me0 f i R 2 39 i. alkylation ii. dihydroxylation 0 b fiR2 AD-mix-P Me0 ' 0 87: 13 diastereoselectivity 40 LDA 1 ;? z; O' H 0 (5 1-87%) Scheme 24 & ___.I hv, 5 "C & ___L MCPBA o& 0 "C (85%) (75%) (60-70%) Scheme 26 (OH R = H 1 0 (53%) 1 (63%) 1 17°C R=Me 2 0°C R=Me 9 Scheme 25 allylic alcohols undergo the process, yielding signifi- cant amounts of the 6-lactones.The isomerisation is thermal rather photochemical and is suppressed at lower temperatures. Spirolactones can also be formed with this procedure, but its use must be limited to relatively unfunctionalised materials because of the high reactivity of the triplet xanthone. The need for efficient and practical syntheses of the Taxol@ class of antitumour agents continues to stimulate research efforts in this area. Two sequen- tial photochemical rearrangements of a readily available (R)-( + )-verbone derivative are used to quickly construct a highly substituted y-lactone as an intermediate in the synthesis of the Taxol@ A-ring {Scheme 26).29 The first irradiation leads to a 1,3-shift of the bridging methine and is followed by a very chemo- and stereo-selective epoxidation of the ex0 face of the internal double bond.The epoxide and cyclobutanone groups fragment in the second photochemical step and rearrange to the bicyclic lactone. A novel rhodium catalysed ring restriction is harnessed with a hydrogen transfer process in a tandem sequence for the oxidation of glucopyra- noses to glycono-1,4-lactones (Scheme 27)." Under these conditions only the anomeric hydroxy group of the glucopyranose is oxidised, followed by a very hv, 5-10 "C I R =OH (90%) R = NHAc (62%) rapid rearrangement to the furanone. The mechanism may involve metal coordination of the lactone and 4-hydroxy groups to promote ring opening and isomerisation to the thermodynamically favoured furanone.The system runs efficiently with either free or protected hydroxy substituents at positions other than C-4 and no influence of stereochemistry is observed. Heretofore difficult substrates, such as N-acetyl-D-glucosamine, are readily converted in good yield by this new procedure. The ketene-Claisen rearrangement of acyclic allylamines has been mainly restricted to the highly activated dichloroketene and a limited scope of amines, often with disappointingly low yields. A thorough investigation of the rearrangement of the allylamine 41 shows that this is an extremely demanding reaction (Scheme 2tQ3' Virtually all standard methods for the ketene-Claisen process fail, giving only polymeric products or the ally1 chloride 42 which arises from SN2' attack by chloride on the initial acylammonium ion.A very specific two-step process is successful in suppressing this decomposition. Following acylation of the amine in the presence of solid potassium carbonate, trimethylaluminium is added to deprotonate the acyl group. The zwitterionic intermediate rearranges preferentially through the 6-membered chair confor- mation 43 in which 1,3-diaxial and other steric inter- actions are minimised. In keeping with the outcome of other variants of the Claisen rearrangement, the zwitterion derived from acetyl chloride shows only limited diastereoselectivity. In comparison, the Collins: Saturated and unsaturated lactones 303.. I ii. AIMe3, 0 "C vs steric hindrance 0- 43 o[sil R 9 \ o 9 /jK" \\O +TN 1 (84%) 1 (73%) R = H 2 R=Me >15 0 o A .M e 44 (93%) Scheme 28 bulkier methyl substituent of the 2 amide enolate generated from propionyl chloride ensures almost complete 1,2-induction of stereochemistry. Depro- tection of the silyl ether product and lactonisation with trifluoroacetic acid provides a mild and practical synthesis of a single enantiomer of the trisubstituted all-cis y-lactone 44. able in both enantiomeric forms, has an impressive pedigree as a starting material for natural product synthesis. In particular, radical additions to 45 proceed with complete ex0 selectivity and this is the basis of a new, divergent preparation of fused bicyclic y-lactones related to the Corey lactone and designed for use in prostanoid syntheses." The electrophilic radical generated photolytically from dimethyl a-phenylselenylmalonate adds preferen- tially to the more electron rich C-5 atom of the double bond.This initial adduct isomerises slowly on prolonged irradiation by a 1,3-acyl migration with concomitant phenylselenyl transfer. Functional group manipulation of the new bicycle provides an intermediate 46 that can be converted to two complementary lactones. Oxidation of the selenium acetal and lactonisation in base promotes epimerisa- tion of the pendant formyl group to furnish a product related to the Corey lactone. In contrast, The bicyclic ketone 45 (Scheme 29), readily avail- PhSe ?O2Me f 46 (73%) I i.H202 ii: P P T ~ ii. Na2C03, MeOH [Silo QCHO (95%) Scheme 29 (88%) acidic lactonisation preserves the integrity of all the stereocentres in 46 to generate the all-cis formyl lactone.The (diaroy1oxyiodo)benzene intermediates formed in situ from aromatic carboxylic acids and Ibis( trifluoroacetoxy)iodo]benzene dissociate to form oxygen-centred carbonyloxy radicals upon ph~toirradiation.~~ The fate of the radical depends on the substitution pattern of the aromatic ring. Alkyl groups in the ortho position undergo a 1,5-hydrogen abstraction which leads to phthalides in moderate yields (Scheme 30). Alternatively, if an o-aryl substituent is present, benzocoumarins are generated by addition of the radical to the pendant aromatic ring (Scheme 31). In all cases it is neces- sary to add iodine to the reaction mixture to re- oxidise the hydrogen iodide generated in the lactonisation step, which otherwise reduces the initial (diaroy1oxyiodo)benzenes. the a-radicals generated from ally1 a-bromo- a,a-difluoroacetates are thwarted by the low reactivity of these stabilised systems and only reduc- tion products are Attempts to form lactones by the cyclisation of This is overcome by (5-72%) Scheme 30 304 Contemporary Organic Synthesis0 0 TBDMSO- p (90%) Scheme 31 47 Bu3SnH slow addition I Ph dF Me 96%de (57%) Scheme 32 the application of a general solution first proposed by Stork and others (Scheme 32).Prior reduction of the ester to the corresponding silylated acetal suffi- ciently enhances the reactivity of the or-radical to allow smooth 5-exo-trig cyclisation. Exclusively the 5-membered lactols are obtained with good stereo- chemical control, and simple oxidation affords the or,cr-difluoro-y-lactones. The strong stereoelectronic preference for 5-exo ring closure is a drawback in the reaction of related homoallyl esters, where very poor yields of 8-lactols are observed.One practical problem is the volatility of the lactol cyclisation products, which can compromise the isolated yields, and might be addressed by a change in the silylating agent. A preference for the 5-exo-trig mode of cyclisa- tion is also seen when furanose radicals add intra- molecularly in an ‘anti-Michael’ fashion to pendant or, P-unsaturated esters, making fused bicyclic lactones as intermediates for nucleoside ~yntheses.~~ Unfortunately, reduction of the carbon radicals competes with the cyclisation even when slow addition of tributyltin hydride is employed, and yields are only modest (Scheme 33). The umpolung nature of the addition is implicit in the observation that good acceptor groups (e.g.phenyl) at the terminus of the double bond are required for the most efficient reactions. For the 2’-deoxynucleoside radical generated from 47 only one diastereo- isomeric lactone is isolated, corresponding to the approach of the radical to the ester in the less hindered s-cis conformation 48. The related 3’-deoxynucleoside radical shows a reduced selec- tivity and products from the addition to both s-cis and s-trans conformations of the cinammate are isolated. 48 H TBDMso% 0 0 Ph B = adenil-9-yl (30%) Scheme 33 The tandem rearrangement-biscyclisation of vinyl- cyclopropane esters to give fused bicyclic y-lactones also demonstrates the preeminence of 5-exo radical cyclisations (Scheme 34).36a Conjugate attack of phenylthio radical on the vinylcyclopropane initiates the cascade and is followed by two ring closures leading to the cis lactone 49 as the major product.The minor component 50 was originally reported as the bridged adduct 51 arising from equilibration of the radicals and an alternative 6-endo cyclisation. A subsequent erratum36b revises the identity of this material to the trans fused y-lactone 50, indicating that the reaction sequence is in fact under kinetic control. 1 I ‘SPh 51 82 18 Scheme 34 Collins: Saturated and unsaturated lactones 3050 The asymmetric nitroolefination of a-alkyl 6-lactones can be extended to cover the five- membered series with an improved choice of chiral auxiliary (Scheme 35).37 Substantial increases in both yields and optical purities are secured when the bulk of the oxygen substituent in the pyrro- lidinol auxiliary is increased.The new silylated nitroenamines are crystalline and are therefore more readily obtained as single enantiomers. Substi- tution of the nitroenamine double bond also improves enantioselectivity, consistent with the key role of steric interactions between the two compo- nents in determining stereoselectivity. An interesting temperature dependent stoichiometry is observed, with three equivalents of the enolate required at -78 "C as opposed to only two equivalents at -40 "C. This is postulated to be a result of the loss of a coordinated zinc enolate at the higher tempera- ture, raising the possibility that the oxygen substituent may also control the stereoselectivity through interference in the degree of metal coordi- nation.Another improved methodology for a-functionalisation of y-lactones concerns the tandem conjugate addition of silylcyanohydrin anions to chiral butenolides and reaction of the intermediate enolate with aromatic aldehydes (Scheme 36)." The cyanohydrin acyl anion equiva- lent is more versatile than the previously reported bis sulfide 52. The kinetic resolution of the racemic 4-hydroxy ester (+)-53 (Scheme 37) by lactonisation with porcine pancreatic lipase (PPL) is only capable of OznCl I 0 THF or DME -7a Oc Scheme 35 Omenthyl Q 0 R' R2 ee(%) weld) Me H TBDMS H rz] TBDMS Me 98 9996) TBSO CN i. L1.LDA ~~ - ii.A?CHO iii. TBAF HO- - A? 9 Pmenthyl (80%) phsYsph Ar' 52 Scheme 36 306 Contemporary Organic Synthesis Me 53 (46%)90%ee 98% ee at 61% conversion Scheme 37 giving high optical purities at low conversions (<30%) since longer reaction times allow the enzyme to convert appreciable quantities of the less reactive substrate. This common feature of biocata- lytic kinetic resolutions may be circumvented by coupling with a complementary enantioselective biotran~formation.~~ An initial Bakers' yeast reduc- tion produces material enriched in one enantiomer of the alcohol (S)-53, which is the faster reacting substrate for PPL. As a consequence, the lactonisa- tion is run to ~ 5 0 % conversion without loss of optical purity. The two reactions can be incor- porated into a one-pot protocol to give the y-lactone in 21% overall chemical yield and very high enantio- meric excess.Desymmetrisation of a meso-diol by acylation with a lipase enzyme is the starting point for the synthesis of single enantiomers of y-lactones by a multiple oxidation strategy (Scheme 38).40 Epoxidation of the olefin, directed by the free hydroxy group of the diol, is succeeded by conver- sion to the epoxy ketone 54 which undergoes a totally regioselective Baeyer-Villiger oxidation. The epoxy lactone product is water sensitive and this necessitates the use of a dried dichloromethane solution of the oxidant. Acidic methanolysis of the lactone opens the epoxide and promotes re-closure to the five-membered ring, although some of the acyclic material is also isolated.prop-2-enyl-173-dithiane involves a six-membered, chair-like transition state that generates the anti relationship of the product 55 (Scheme 39).41 With the relative stereochemistry thus secured a kinetic resolution of the acetate 55 catalysed by a lipase The condensation of aldehydes with the anion of OTBDMS OTBDMS 1 OH Scheme 38I- -. OAc H- (?)-55 (83%) lipase AY-30 pH 7.5 DMF-HZO 1 (92%) 98% ee (25%) Scheme 39 enzyme introduces absolute stereochemistry. The hydrolysis can be run in either direction but the highest optical purities are seen for the forward reaction. Changing the degree of branching in the carbon chain of the acetate can lead to a change in the configuration of the major product. The hydro- lysed enantiomer is lactonised after mercur);-assisted hydrolysis of the dithioketene acetal.Dithioketene- acetals also play a pivotal role in the unselective synthesis of a-trifluoromethyl y-lactone~.~~ Aliphatic enolates displace the vinylic fluoride from perfluoro- dithioketene acetals by an addition-elimination mechanism. The resulting ketones are reduced or subject to 172-addition by organometallics before lactonisation. These dithioketene acetals undergo acid hydrolysis without the aid of mercury salts, but this fails if an aryl substituent is introduced at C-4 since the initial carbocation adjacent to sulfur rearranges to the more stable benzylic cation (Scheme 40). i. KH, THF ~ cFcII i.MeLi :F3$0 F SEt Me ii. HCI, MeOH (78%) (85%) P i Ph/ Scheme 40 Excellent simple diastereoselection is observed in the reduction of the ketones 56 (Scheme 41) which are synthesised from tartaric anhydride^.^^ The sense of the addition is consistent with the non-chelated Felkin-Anh model.It is noteworthy that the pivalate protecting groups are essential to the practical success of the sequence since the 56 Piv= +.. 0 Scheme 41 i. NaBH4, -78 "C, [ pivos R h ii. HCI, -78 "C C02M( b i v I OH k (9&97%) (8&88%) >98% de analogous acetates are too water soluble to give readily isolated materials. Lactonisation is best carried out under anhydrous conditions and with careful monitoring as the highly oxygenated products appear to be sensitive to prolonged exposure to acid. Aqueous hypobromous acid generated in situ from sodium perbromate and sodium hydrogen sulfite oxidises primary alcohols to also be applied to the lactonisation of simple o-diols in moderate yield (Scheme 42).The mechanism, elucidated by cross-coupling experiments, is a two step oxidation via an intermediate lactol. The scope of the reaction is currently limited to y- and b-lactones, and temperature control is required to avoid over-oxidation. and can 0 (62%) Scheme 42 Oxygen insertion into racemic, aliphatic bicyclo- butanones catalysed by the chiral copper complex 57 takes place in an enantiodivergent fashion, reminis- cent of the related biocatalytic systems (Scheme 43).45 One enantiomer of the cyclic ketone leads to the usual Baeyer-Villiger product 58 whilst the other forms the regioisomeric lactone 59, where the oxygen inserts at the less substituted carbon atom.The two lactones are formed in a 1 : 1 ratio as evinced by GC analysis but the lactone 59 may be more susceptible to hydrolysis on work-up. The enantiodivergent nature of the transformation is revealed by the optical activity of the residual starting material (16% ee) which remains essen- tially racemic. The phenomenon is general for a range of bicyclic and bridged cyclobutanones but the optical activities of the lactones corresponding to 58 are consistently lower than those of the regio- isomers, implying that a competing uncatalysed Collins: Saturated and unsaturated lactones 30759 0 58 3 : 1 (61%) 67% ee 92% ee (85%) Scheme 43 pathway that converts racemic ketone to racemic lactone 58 is operating. The cyclopropylidene-ethanol60 undergoes a tandem asymmetric epoxidation and stereospecific 1 ,Zrearrangement when subject to Sharpless’ condi- tions (Scheme 44).46 After elaboration of the benzylic quaternary centre, conversion of the cyclo- butanone 61 to the silyl enol ether 62 permits Scheme 45 -+ i.AgBF4 ii. NaOH 0 63 ozonolytic lactone formation in the presence of the terminal olefin. The Baeyer-Villiger oxidation of a I steps derivative of levoglucosenone, a readily available chiral pool material prepared by the pyrolysis of cellulose, occurs regioselectively to give an ortho- ester which cleaves on hydrolysis to produce a hydroxylated y-lactone (Scheme 45).47 Me0 & , Me0 Me0 H Ti(OP& 1 ~ @ 0 ] \ \ 60 I Ar’O(?O OH (33%) (82%) Scheme 46 i. 0 3 - 61 62 (30%) Scheme 44 The Schmid azaallyl [4 + 31 cycloaddition provides a possible entry into natural products containing medium ring carbocycles, but a stumbling block is the resistance of some of the product bridgehead ketones to direct oxidative cleavage, as exemplified by the ketone 63 (Scheme 46).Cha et al. circumvent 64 65 (65%, two steps) this problem in two ways4* The bicyclic lactone 65 can be generated indirectly by Criegee rearrange- ment of the ozonolysis product of the homologated ally1 alcohol 64. This sequence is compromised by the formation of significant amounts of the epoxide by-product during the ozonolysis. Alternatively, the more substituted Schmid cycloadduct 66 (Scheme 47) is transformed by Mitsunobu inversion of the alcohol to the keto alcohol 67 which is set up for lactol formation.Although the lactol tautomer of 67 is present in only 10% abundance, generation of the oxygen centred radical is successful and smooth P-fragmen t at ion provides the attractively function- alised bridge-opened lactone in good yield. 308 Contemporary Organic Synthesisa 0 0 66 67 v +3 0 (82%) pk] ‘0 Scheme 47 A similar fragmentation is the basis for a novel replacement for the Baeyer-Villiger oxidation49 of unsaturated bicyclobutanones typified by 68 (Scheme 48). Bromination of the alkene on the convex face of the bicycle dictates regioselective opening of the bromonium ion at the more accessible C-3 atom. The geometry of the resultant halohydrin 69 is ideal for trans coplanar fragmenta- tion on heating, which is followed by spontaneous lactonisation to the isolated product 70.When the alkene is unsubstituted the intermediate halohydrins can also be isolated. The reaction is notably superior to the conventional oxidation of 68 where selectivity is moderate and reaction times much longer. 70 71 (9WO) (0%) Scheme 48 The tricyclic lactone core of the cytotoxin alliacd A is constructed rapidly but unselectively by the tandem aldol-SN2’-lactonisation of dilithioacetate and the y-mesyloxy enone 72 (Scheme 49a).50 The lack of diastereofacial selectivity in the initial THF, HMPA 0 OC * LO LO 0 )= 72 9 O H 0 1 : 1 (47%) b C I MF, HMPA -78 Oc 0 HO ‘-C02But 73 74 (95%) 75 dOH 0 h alliacol A (85%) Scheme 49 addition to the rather planar bicycle 72 is overcome if the structure 73 with a more pronounced curva- ture is employed (Scheme 49b).However, lactonisa- tion of the product 74 after double bond migration is compromised by competing retro-Claisen fragmentation of the pendant carboxylate. This is avoided by cyclisation of the 2-chloroacetate 75 at the alcohol oxidation level, where both syn and anti modes of the sN2’ reaction occur with equal facility (Scheme 49c). Reoxidation of the tetrahydrofuran furnishes the desired lactone. 5 Medium ring lactones A two step procedure is found to be the most efficient method of oxidative cleavage of the bicyclic Collins: Saturated and unsaturated lactones 309enol ether 76 to the 10-membered keto lactone product, an intermediate in the synthesis of pyreno- lide B (Scheme 50).5' In a related strategy, bicyclic enol ethers are assembled by the regio- and stereo- specific opening of spirocyclic 1,3-dioxolanes and their subsequent reclosure through an SN2 reaction (Scheme 51).52 The regiochemistry of the elimina- tion from the intermediate triflate 77 is base and solvent dependent, favouring the kinetic product 78 with hindered bases in toluene.The unstable enol ethers are cleaved by ozonolysis to give a reasonably controlled route to 10-membered keto lactones from the thermodynamic elimination product 79 or to d-lactones from the other regioiosomer. Medium ring keto lactones are also produced by the oxidation of carbocyclic homoallyl alcohols with permanganate under phase transfer catalysis (Scheme 52).53 The rearrangement pathway of the metallooxetane 80, leading to epoxides or medium ring lactones, varies with the size of the carbocycle and may be governed by the overall lipophilicity of the substrates.Improved selectivity for the forma- tion of the keto lactones is observed when Me Me 76 (73%) Scheme 50 c^"" TfpO ___c R3N -78 "C (1 00%) rfo&.. 77 -78 + 25 "C 1 1 (52%) 78 79 Solvent R3N 78 : 79 toluene Pi2EtN 91 : 9 OHC (54%) CH2CI2 Bu~N 9 : 91 r a b (Yield) KMn04 Q-phase C us046 H20 I 1 I Scheme 52 montmorillonite clay replaces copper sulfate as the solid support. chain of co-alkenyl carboxylates facilitates iodolacto- nisation to seven-, eight- and nine-membered rings by reducing transannular CH - - - CH interactions. Rou~seau~~ postulates that there may also be a favourable entropic effect resulting from neigh- bouring group participation by the oxygen atom in the cyclisation (Scheme 53).The regioselectivity of this cyclisation depends on the position of the oxygen in the tether, though a o ring closure is generally predominant. The pseudo-bicyclic coordi- nated iodonium ion 81 or the oxonium species 82 The introduction of an oxygen atom into the 8, 0 \ / x-Y via : Scheme 51 310 Contemporary Organic Synthesis Scheme 53 qY 0 OH Or 81 A endo (23%) (5%) OH 82are representative of the proposed mediators of this selectivity. A template effect of the metal catalyst is the driving force for the exclusively endo radical cyclisa- tion of alkenyl di- and tri-chloroacetates to eight and nine-membered rings developed by Speckamp et al.55756 This methodology is extended to 10- and 1 l-membered rings when a conformational constraint is included within the tethering chain, although forcing conditions sometimes become necessary (Scheme 54a,b).The sensitivity of the reaction to these constraints and to substitution within the chain reflects the close association of the radical and metal centres in this process. (37%) (51%) Scheme 54 6 &Lactones Further characterisation of the portfolio of mono- oxidase enzymes (MO) produced by the Pseudo- rnonas putida microorganism reveals their complementary substrate ~pecificity.~~ Whereas the NADH-dependent enzyme M01 is efficient for the biocatalytic oxidation of bicyclic ketones, the NADPH-dependent fraction M02 is especially suited to the production of monocyclic b-lactones (Scheme 55).58 Although excellent resolutions are seen with small, polar side chains the enzyme is intolerant of more lipophilic substituents, a limita- tion ascribed to its original metabolic role.The low yields are a result of competing dehydrogenase activities in the partially purified protein and better recoveries are achieved with more rigorously pure J i l n R ee (%) (Yield) ee (%) (Yield) Scheme 55 Collins: Saturated and unsaturated lactones material. Preliminary experiments show that M02 is not proficient at the oxidation of prochiral 3-substi- tuted cyclobutanones and in this case the whole-cell Acinetobacter calcoaceticus system is superior.59 The aerobic oxidation of cyclic ketones is also possible with transition metal oxides as catalysts.m Manganese dioxide is the best choice and a three- fold excess of an aryl aldehyde is necessary for complete conversion (Scheme 56).Olefins are not oxidised in these reactions, and in fact inhibit the reaction completely. Although aromatic peracid can be detected in the medium its importance to the mechanism is not clear. b C7H15 MnOP, PhCHO (79%) Scheme 56 The oxidative P-scission of cyclobutanols with lead tetraacetate generates alkyl radicals that can be trapped in high pressures of carbon monoxide to give 1,5-keto acids (Scheme 57a and b). Only in the case of 3-substituted cyclobutanols does the reactive intermediate oxidation product 83 cyclise to give the b-lactones.61 The analogous reductive ring opening of cyclopropyl ketones is promoted by samarium iodide and, with the addition of iron species to enhance the reducing power of the reagents, this chemistry is extended to cyclopropane- 1,l -dicarboxylates.62 Efficient trapping of the alkyl radicals in the presence of aliphatic ketones gives good yields of the corresponding b-lactones (Scheme 58).As yet the reaction is only poorly applicable to aldehydes and aromatic ketones. Enantiomerically pure b-lactones are synthesised by a highly st ereoselect ive chelat ion-con trolled reduction of homochiral sulfinyl 0x0 acids (Scheme 59).63 The addition of zinc bromide is required for satisfactory control over the reduction of the keto acids 84. One drawback at present is the inseparable mixture of substituted keto acids 84 (R # H) a co, 100 O C Bu b CO, 80 "C Bu (53%) Bu OAc (62%) cis: trans = 1 : 4 83 Scheme 57 311r 0- 1 dbm = dibenzoylmethiodo Scheme 58 R 84 DIB AL-H ZnBr2 I OH 0 H02C*!kl pTol R 0 Meo2cfk pTsOH ___c (6576%) & <* pTol R (73%) R=H 100%de Scheme 59 produced in the initial stages of the synthesis.However, the extra stereocentre shows only marginal influence on the selectivity of the reduc- tion and the diastereoisomeric ratio is carried through to the product lactones. Fused bicyclic y- and d-lactones are obtained in good yield by the photoirradiation of pyran-4-ones bearing a pendant carboxylic development of existing annellation processes involving the oxyallyl zwitterion 85 and is an attrac- tive reaction for applications in natural product synthesis. Although several substitution patterns are tolerated in the reaction the highest yields are seen with peralkylated pyran-4-ones (Scheme 60).Building on the work of Roush and others with macrocyclic ketones, a tandem macrolactonisation and transannular Diels-Alder cycloaddition gives rise to the tricyclic lactone 86 (Scheme 61) as the sole conditions are needed to avoid competing dimerisa- tion during the Horner-Emmons ring closure. The endo selective cycloaddition goes in the opposite stereochemical sense to that of the acyclic diene 87 and under milder conditions. An efficient trans- annular reaction is also seen in Fraser-Reid's approach to part of the insect antifeedant aza- dirachtin.66 A highly strained tricyclic lactone is formed by intramolecular conjugate radical addition to the a, P-unsaturated d-lactone 88 (Scheme 62). This is a High dilution and slow addition Scheme 60 L 85 1 (70%) 1 I4 + 21 H H@ 0 86 (63%) O[Si] toluene, 170 "C a7 Scheme 61 [Silo OMe 0 1 de 88 (87%) Scheme 62 Again, slow addition and high dilution conditions are the key to the success of the reaction.Thomas et al. rely on the transacylation of activated azetidinones to construct the 6-lactone portion of the macrocylic lankacidin antitumour antibiotic^.^' Careful choice of the exact substrate and protecting group array must be made to avoid side reactions, such as the formation of the seven- membered lactone 89 (Scheme 63). A very stereo- selective acylation of an azetidinone enolate is used to put together the cyclisation precursors. The 312 Contemporaly Organic SynthesisNHCOEt TBDMSO "* O[Si] 89 (35%) pTsOH R = CH20TBDMS \ Jfy Sil R '\O OTBDMS BF39Et2 R = CH2CH=CH2 \ NHCOEt O[Si] / .* ~ o ~ o (75%) / Scheme 63 unstable S-lactone 90, related to a fragment of the important HMG-CoA reductase inhibitor mevinolin, is rapidly constructed by sequential Sharpless asymmetric epoxidation and a stereospecific telluride transposition (Scheme 64).68 The acyclic precursor can be prepared as a single diastereo- isomer from the same reagent Combination on a simpler allylic alcohol. TBDMSoYYo TBDMSO vC02Me (Te27 -D . . Te, Na02SCH20H aq NaOH i\ 90 (76%) OTs Scheme 64 The ex0 mode of cyclisation observed in the intra- molecular ring closure of nucleophilic rnetallo- carbenes onto epoxides in the presence of Lewis acids69 is governed by the development of positive charge on the most substituted oxirane carbon (Scheme 65). The carbenoid is derived from the readily prepared, but unstable alkylmolybdenurn 91.Both y- and b-lactones are available from this reaction. A preliminary report suggests a promising new route to fused bicyclic &lactones through the intramolecular Sakurai-Hosorni allylation of epoxides, with 5-exo attack again dominant over 6-endo cyclisation (Scheme 66).70 The presence of the deactivating ester group on the allylsilane does not interfere with the efficiency of the process. reversed when the y-hydroxy enol ether 92 (Scheme 67) is subject to acid catalysed cyclisation, since the The preference for 5-exo cyclisation over 6-endo is 91 0 6- (40%) Scheme 65 (78%) (6%) 1 : 1 CIS: frans Scheme 66 SPh SPh 92 (85%) (32%) Scheme 67 incipient positive charge is stabilised by the methoxy ~ubstituent.~' The cyclisation precursors come from the coupling of a sulfur-stabilised anion and epoxides.Since the epoxides are readily available in enantiomerically pure form, this route is a general and rapid approach to optically active saturated and unsaturated 8-lactones. Another effective, if expen- sive, way of ensuring 6-endo cyclisation is to raise a catalytic antibody for the unfavourable proce~s.~' The cyclic sulfoxide hapten 93 secures an acidic residue in the antibody suitably placed to protonate only the internal carbon of the olefinic substrate (Scheme 68). 0 93 Scheme 68 catalytic antibody 1 (58%) >94% ee 6 : y =93:7 Collins: Saturated and unsaturated lactones 3137 Spirolactones The formation of allylic spiro-y-lactones such as 94 (Scheme 69) by the direct oxidation of Barbier-type addition products is not normally feasible due to competing internal double bond oxidations and the propensity of tertiary allylic alcohols to eliminate.The use of phase transfer catalysis to modify the reactivity of pe~manganate~~ overcomes these restrictions and gives good yields of the spiro- lactones. Another direct route to these compounds involves the reductive coupling of ketones and acryl- ate^^^ using the samarium( 11) species generated from samarium metal and a trimethylsilyl halide as a convenient alternative to Kagan's method for samarium diiodide formation (Scheme 70). unencumbered cyclohexyl diazoesters insert into the activated axial methine C-H bond to give spiro- cyclic P-lactones but introduction of a flanking substituent redirects the insertion to the less hindered methylene C-H (Scheme 72).N24c02R (68%) (80%) Scheme 72 (!& KMn04, CuS046H20, Bu'OH-H20 R-phase \ Single enantiomers of spirocyclic y-lactones are produced in good yield by coupling a diastereo- selective aldol addition with Warren's stereospecific cy~lisation~~ via an asymmetric episulfonium ion (Scheme 73a). The chiral auxiliaries from the aldol step are cleaved during the cyclisation and for the anti aldol 95 this gives a single spirocycle. Develop- ing 1,2-strain in the nascent five-membered ring formed from the syn aldol96 results in a partial epimerisation at the centre adjacent to the carbonyl group and two products are isolated (Scheme 73b). This epimerisation is not seen if the auxiliary is cleaved to the more nucleophilic carboxylate before cyclisa t ion.94 (62%) Scheme 69 8 Sm, TMSI, MeCN (53%) Scheme 70 The C-H insertion reactions of rhodium carbenoids show a clear general preference for five- membered ring formation, and both this selectivity and chemical yield are enhanced when rhodium(i1) carboxamide catalysts are used in place of di- rhodium acetate to generate the carbenes from diazoesters (Scheme 71).75 The activation of C-H bonds by adjacent oxygen atoms can sometimes override the preference for five-membered ring formation, but it is also important to consider steric factors. For example, the rhodium carbenoids derived from dicyclohexyldiazomalonates exhibit two intramolecular cyclisation pathway^.^' The sterically 95 1 Phs\J QoLo (62%) >98%ee b PhS, ,' 'U' (57%) ~ 9 8 % ee WNAO - + U &o < Ph 96 (27%) >98% ee Scheme 73 9 J! Rh2(caprolactam)4 100 : 0 60%) Rh2(OAc)4 50 : 50 [47%) Scheme 71 3 14 Contemporary Organic SynthesisAn investigation of the ex0 selectivity in Diels- Alder cycloadditions of a-methylene lactones shows that the conformation of the dienophile is the controlling factor7* rather than secondary orbital interactions (Scheme 74).The endo cycloadducts are usually, but not exclusively, isolated as the fused bicyclic transacylation products. With small rings reasonably selective formation of the spirocyclic ex0 adducts is observed. The orientation of the two components is governed by the drive to minimise the overall dipole of the transition state.For the smaller lactones, constrained to the s-cis conforma- tion, this is achieved in the ex0 addition mode 97, but as the rings become larger the competing endo transition state 98 with the s-trans conformation is possible. An unusual stereospecific rearrangement, corresponding formally to a 'transannular ene' reaction, is seen when the 10-membered lactone 99 (Scheme 75) is heated in acid.79 The precursor to 0 I TMsod--boTMS 1 A, echlorobenzene endo ex0 ~~ n endo : ex0 (Yield) 1 18 : 82 (59%) 5 42 : 58 (77%) 97 s-cisexo Scheme 74 -i- 98 s-trans endo R this reaction comes from successive oxidative /?-fragmentation of a steroid nucleus. 8 a-Methylenebutyrolactones Several syntheses of a-methylenebutyrolactones make use of palladium-mediated couplings to assemble the acyclic carbon skeleton.For example, carbonylation of the vinyl triflate 101 (Scheme 76), obtained by regioselective kinetic enolisation of the Bakers' yeast reduction product 100, produces an ester suitable for acidic lactonisation to a homo- chiral lactone.*' The carbonylation and desilylation steps have to be carried out as two separate opera- tions as the addition of fluoride ion to the carbonyl- ation medium completely inhibits the reaction, and also fails to remove the silyl group. A preliminary communication outlines how the synthesis of lactones can sometimes be achieved by starting with intermolecular 1,2-acryloylpalladation of olefins (Scheme 77)." This reaction is presently limited to modest yields because of polymerisation of the acrylate component.A more serious problem is the competitive formation of n-ally1 palladium complexes through /?-abstraction of labile allylic hydrogens, a pathway that leads to ally1 acrylate esters. This currently restricts the practical applica- tion of the reaction to systems with less easily removed allylic protons. The palladium(0)- copper( I ) catalysed coupling of 2-haloalk-2-enoates with vinyl stannanes generates intermediates that * TBDMx TBDMSO 2 i.KHMDS ii. PhNTf2 1 00 101 (97%) i. (Ph3PkPd CO. MeOH 1 ii. CF3C02H (36%) Scheme 76 f l / A 0 I 99 Scheme 75 0 Scheme 77 (40%) Collins: Saturated and unsaturated lactones 315can be elaborated to a-ylidenebutyrolactones.82 Both the E and 2 alkenoate coupling partners are themselves constructed with palladium chemistry, allowing complete control over the geometry of the trisubstituted exocyclic double bond of the final lactones (Scheme 78). \ Bf i R' R A f C02Et \\ (85%) (c-hex) BH pTsOd R' = H, R2 = Ph (65%) R' = Ph, R2 = H (62%) Scheme 78 The intramolecular cyclisation of ally1 but- 2-ynoates is also mediated by palladium.83 Although previously reported for the production of chlorome- thy1 substituted lactones, the procedure now extends to the more synthetically versatile bromo analogues (Scheme 79).The terminal substituent of the triple bond controls both the diastereoselectivity of the cyclisation and the geometry of the product double bond. The cis bromopalladation of unsubstituted propiolates (R = H) is followed by cyclisation through the pseudo-chair transition state 102 to give predominantly the trans p, y-substituted lactone. In contrast, internal triple bonds (R =Me) undergo a trans bromopalladation and cyclisation via the pseudo-boat conformation 103 to give mainly the cis lactone.The greater degree of steric interactions in the latter substrates is mirrored in the higher diastereoselectivity. By starting with homochiral secondary allylic alcohols, single enantiomers of the cis lactones are readily obtained.84 Thus far, attempts to incorporate the cyclisation into tandem sequences have been unsuccessful. R 0 loL R = H , X = H , Y=Br 75 : 25 93% R=Me, X=Br, Y = H 3 : 97 [%?%I 1 02 103 dba = dibenzylideneacetone Scheme 79 In a thorough investigation, Weavers et al. have tracked down the inefficiency of the radical cyclisa- tion of their unsubstituted alk-2-ynoate 104 (Scheme 80) to the slow transfer of iodine in the chain propa- gation step.85 The vinyl radical develops appreciable electrophilic character during the transfer which can be stabilised by electron donation from alkyl substituents, but is otherwise an unfavourable process.Only limited improvements in the efficiency of the transformation are seen from changes to the solvent and initiator, or from portion-wise addition of the latter. The most practical solution is to cyclise the trimethylsilyl substituted triple bond and to remove the silicon stereospecifically to give the desired a-iodomethylenebutyrolactones in good yield. The stereochemistry of radical additions to simple a-methylenebutyrolactones is determined at 0 104 R = H (91%) Scheme 80 316 Contemporary Organic Synthesisthe point of hydrogen transfer to the intermediate radical.Bulky reducing agents give high selectivity for approach on the less hindered face of the ring and this can be reversed to some degree by coordi- nation of the lactone with a Lewis acid (Scheme 81).8h 0 &pR Ph 0 @. Ph (60%) 96% de b=-. Ph (91%) 20%de formation of the spirolactones. The related cationic cyclisation of y, &unsaturated esters promoted by trimethylsilyl iodide shows the usual substituent influences on the regiochemistry of the ring closure, with formation of the initial cation directed to the most substituted olefinic carbon (Scheme 83).88 9 But-2-enolides and tetronic acids Najera et al. have described previously how the dianions of 3-tosylalkanoic acids 105 function as homoenolate equivalents in the synthesis of butenol- ides by aldol condensations; this approach can also be applied at the aldehyde oxidation level to generate butyrolactols (Scheme 84).” Although an additional oxidation step is now required, the overall yield of the transformation is improved over the direct route.Ts>(KoLi R Li 0 Scheme 81 105 A new method for the formation of spiro- or-methylenebutyrolactones has been uncovered during the investigation of the Ritter reaction of 2-(ethoxy~arbonyl)penta-2,4-dienylsilanes.~~ With hindered nitriles the normal Ritter reaction (path a) (Scheme 82) is intercepted in favour of intra- molecular participation of the ester group (path b). As yet this process is unoptimised for complete f SiMe3 U R=Me (57%) (0%) R = But (20%) (35%) Scheme 82 i.Jones ii. DBU I Me (80%) Scheme 84 106 ’ TMS phpo 7 OH (65%) Scheme 85 The stable vinyltitanium species 106 (Scheme 85) 9 Et ’- qi /$)& R also serves as a P-acylanion equivalent.” Initial R metallation of the homoprop-2-ynyl carbonate R=Me (0%) (78 h) by intramolecular acyl substitution to give 106. R R R = H (80%) ( o y produces an allenyltitanium structure which cyclises Scheme 83 Collins: Saturated and unsaturated lactones Simple acidic quenching affords the cx-rnethylene- butyrolactone whereas the reaction with benzalde- 317hyde triggers translactonisation to yield the substituted butenolide. The transformation is general for systems with up to four carbons between the carbonate and triple bond, but only disub- stituted alkynes will form the titanium reagent. Cyclopropanation of the exocyclic double bond of diketene with metal carbenoids furnishes the expected spirocyclopropyl p-lactones.In some cases, however, progression to substituted butenolides is observed and this has now been shown to be a metal catalysed reaction that can be driven to completion (Scheme 86).91 Metal insertion into and cleavage of the lactone C-0 bond is proposed as the starting point for the rearrangement, followed by lactonisa- tion with cyclopropane ring opening. The latter step is more selective when the trans spirolactone is used since the intermediate 107 experiences greater steric differentiation of the cyclopropane carbons than the analogous species 108 derived from the cis isomer.An unexpected ring expansion is observed when the hydroxycyclobutanone 109 is prepared by methanolysis (Scheme 87).92 The product 109 can be 0 cis or trans isolated in reasonable yield (51%) unless the reaction time, temperature or basicity are increased, whereupon the butenolide 110 is formed, presum- ably via electrocyclic ring opening and subsequent relactonisation with allylic substitution of the chloride, a mechanism that is precedented in the addition of enol silanes to squaric acid derivatives. Basic conditions are not essential for the rearrange- ment, which gives the highest yield (75%) in neutral refluxing methanol. Homochiral 4-substituted butenolides are valuable synthetic precursors to functionalised y-lactones through stereoselective reactions of the enone group.Elimination of the mesylate of alcohol 111 leads to partial racemisation due to formation of some of the intermediate enol lactone l12.93 This is overcome when the less reactive benzoate leaving group is used to ensure deprotonation of only the most acidic hydrogen in the elimination. Michael additions to the butenolide proceed with excellent diastereofacial selectivity on the least hindered side of the ring. The gem-disubstituted butenolide 113, prepared by Hegedus et al. with their chromium carbene technology, shows a more varied diastereo- facial bias.94 The sterically hindered molecule does not react with cuprates but the addition of thiolates and nucleophilic epoxidation occurs anti to the alkoxy group, as might be expected from application of the Felkin-Anh model to this vinylogous carbonyl addition (Scheme 89). Nitrones also have a strong 1.4 : (90-95%) 1 cis trans 2.1 via : + + J J-J; - 0 A o - 0 A o 1 07 108 Scheme 86 CI.Ph CI. F 1 09 I Scheme 87 3 18 Contemporary Organic Synthesis Ph 0 4 0 M e 110 (40%) 0 G B u -0QBu 111 MsCI, Et3N (57%) 71% ee PhCOCI, NH3, MeOH (49%) >99% ee 0 Bu 112 Scheme 88 n (75%) >99%ee 113 (89%) >97% de KMn0, I Scheme 89 (86%) >97%depreference for cycloaddition anti to the alkoxy group, reflecting the nucleophilic character of the nitrone in the addition to the electron-poor double bond. In contrast, azomethine ylides show a modest preference for the opposite sense of addition and permanganate dihydroxylation takes place exclu- sively from the same side as the alkoxy group.nates are the product of the Lewis acid promoted addition of silyloxyfurans to chiral acyl cation equivalents (Scheme 90).95 The silyloxyfuran approaches the least hindered face of the oxazoli- dinyl cation and the facial reactivity of the furan is determined by the level of 3-substitution. Thus the unsubstituted material shows only a modest discrimination between the two orientations 114 and 115, whilst the 3-methoxy-24lyoxyfuran avoids eclipsing interactions with the phenyl substituent of the oxazolidine in 114 and gives exclusively one diastereoisomer . tion permits the synthesis of a, y-disubstituted tetronic acids from allyl a-hydroxy esters (Scheme 91).96 The unrearranged product 116 can be isolated with adjustments to the reaction temperature, or by replacing allyl with simple alkyl groups.Excellent yields are obtained but attempts to apply the sequence to single enantiomers of the a-hydroxy esters presently run into problems with variable racemisation of the products. 4-Aryl-2-hydroxytetronates, which show activity as mimics of non-steroidal antiinflammatory compounds, are difficult to synthesise in optically pure form by conventional means due to the facile Single enantiomers of 4-substituted methyl tetro- A novel one-pot tandem Wittig-Claisen combina- R .. @OSiMe3 + Ph. 'n TsNXo Ph OMe BF3.OE12 -78 "C 1 P I2 + (84%) 0 +PPh, MeQO 0 4 - Wittig 1 Scheme 91 racemisation of the chiral centre. A route designed to overcome this uses pivalate protection to prevent the formation of easily racemised ketone tautomers adjacent to the stereocentre (Scheme 92).97 An unexpected migration of the pivalate group is observed when the keto ester 117 is lactonised, which appears to occur post-cyclisation as other more labile protected keto esters suffer retro-aldol degradation under these conditions.The most reliable deprotection of the 2-pivaloyltetronate is by hydride reduction which again avoids the acid catalysed keto-enol tautomerism that facilitates racemisation. TBDMSO TBDMSO C02Et Li R 114 115 Scheme 90 116 DIBAL-H &J WH R OH R via : Scheme 92 67 (62% 0 (38%{ R = H 33 R=Me 100 (50%) >96%ee (8590%) The highly reactive ketipic acid d i l a ~ t o n e ~ ~ is formed from the pyrolysis of the masked oxalyl- bisketene 118 (Scheme 93).The dilactone is opened by nucleophiles to give the (E)-y-alkylidenetetronic acids which show evidence of stabilisation by intramolecular hydrogen bonding. This nicely complements the selective synthesis of (Z)-y-alkylidenetetronic acids from ketipic acid itself. a new, mild and highly selective base for O-alkyl- Finally, caesium fluoride in dimethylformamide is Collins: Saturated and unsaturated lactones 3190 o A o * 118 Scheme 93 HO RO BnCl 92 : 8 (71%) Me02CCH2Br >99 : 1 (77%) e C 1 96 : 4 (72%) Scheme 94 ation of tetronic acids (Scheme 94).99 This system is not restricted to simple alkyl groups and is also effective for allylation, which is not possible with Mitsunobu conditions. Complete inversion of configuration is seen when a homochiral secondary mesylate is employed, although naturally the SN2 reaction does not extend to tertiary or neopentyl halides.Both unsubstituted and substituted tetro- nates are converted with equal facility and the traces of C-alkylation products are readily removed by chromatography. 10 References 1 2 3 4 5 6 7 8 9 10 11 T. Ladduwahetty, Contemp. 0%. Synth., 1995, 2, 133. H. Schick, R. Ludwig, K. Kleiner and A. Kunath, Tetra- hedron, 1995, 51, 2939. C. Wedler, A. Kunath and H. Schick, J. 0%. Chem., 1995, 60, 758. C. Wedler, A. Kunath and H. Schick, Angew. Chem., lnt. Ed. Engl., 1995, 34, 2028. R. Zemribo and D. Romo, Tetrahedron Lett., 1995,36, 4159. 0. Dirat, T. Berranger and Y. Langlois, Synlett, 1995, 935. W. R. Dolbier, Jr., R. Ocampo and R. Paredes, J.OR. Chem., 1995, 60,5378. W. Adam and V. 0. Nava-Salgado, J. 0%. Chem., 1995, 60, 578. V. 0. Nava-Salgado, E-M. Peters, K. Peters, H. G. von Schnering and W. Adam, J. 0%. 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Duhamel, Synlett, 1995, 431. guchi and Y. Ishii, Chem. Lett., 1995, 871. 320 Contemporary Organic Synthesis45 C. Bolm and G. Schlingloff, J. Chem. SOC., Chem. 46 H. Nemoto, T. Tanabe and K. Fukumoto, Tetrahedron 47 K. Matsumoto, T. Ebata, K. Koseki, K. Okano, Commun., 1995, 1247. Lett., 1994, 35, 6499. H. Kawakami and H. Matsushita, Bull. Chem. SOC. Jpn., 1995, 68, 670. 48 J. Lee, J. Oh, S. Jin, J.-R. Choi, J. L. Atwood and J. K. Cha, J. 0%. Chem., 1994, 59, 6955. 49 E. Marotta, B. Piombi, P. Righi and G. Rosini, J. 0%. Chern., 1994,59,7526. 50 J. J. La Clair, P. T. Lansbury, B. Zhi and K. Hoogsteen, J. 0%. Chem., 1995, 60,4822. 51 A. Moricz, E. Gassman, S. Bienz and M. Hesse, Helv. Chim. Acta, 1995, 78, 663. 52 K. Ishihara, N.Hanaki and H. Yashimoto, J. Chem. Soc., Chem. Commun., 1995, 11 17. 53 J. Das and S. Chandrasekaran, Tetrahedron, 1994, 50, 11 709. 54 B. Simonot and G. Rousseau, J. 0%. Chem., 1994,59, 591 2. 55 F. 0. H. Pirrung, H. Hiemstra, W. N. Speckamp, B. Kaptein and H. 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Warren, J. Chem. SOC., Perkin Trans. 1, 1995, 2411. 78 K. Takeda, I. Imaoka and E. Yoshii, Tetrahedron, 1994, 50, 10839. 79 L. Lorenc, L. Bondarenko-Gheorghiu, N. Krstic, H. Fuhrer, J. Kalvoda and M. L. Mihailovic, Hefv. Chim. Acta, 1995, 78, 891. 80 G. T. Crisp and A. G. Meyer, Tetrahedron, 1995,51, 5831. 81 N. Ferret, L. Mussate-Mathieu, J.-P. Zahra and B. Waegell, J. Chem. Soc., Chem. Comrnun.. 1994,2589. 82 F. Bellina, A. Carpita, M. De Santis and R. Rossi, Tetrahedron, 1994,50, 12 029. 83 J. Ji, C. Zhang and X. Lu, J. Org. Chern., 1995,60, 1160. 84 G. Zhu and X. Lu, Tetrahedron: Asymmetry, 1995,6, 345. 85 S. D. Mawson, A. Routledge and R. T. Weavers, Etra- hedron, 1995, 51,4665. 86 H. Urabe, K. Kobayashi and F. Sato, J. Chern. SOC., Chem. Cornrnun., 1995, 1043. 87 C. Kuroda and N. Mitsumata, Chem. Lett., 1994, 1375. 88 0. Piva, Tetrahedron, 1994, 50, 13687. 89 P. Bonete and C. Nrijera, Tetrahedron, 1995, 51,2763. 90 A. Kasatkin, S. Okamoto and F. Sato, Tetrahedron 91 N. W. A. Geraghty and P. A. Murphy, Tetrahedron 92 J. L. Dillon and Q. Gao, J. 0%. Chem., 1994, 59, 6868. 93 H. Takahata, Y. Uchida and T. Momose, J. 0%. 94 A. D. Reed and L. S. Hegedus, J. 0%. Chem., 1995,60, 95 A. Pelter, R. S. Ward and A. Sirit, Tetrahedron: 96 R. Schobert, S. Miiller and H.-J. Bestmann, Synfett, 97 A. T. Hopper and D. T. Witiak, J. 0%. Chem., 1995, 98 H.-D. Stachel, M. Jungkenn, C. Koser-Gnoss, Lett., 1995, 36, 6075. Lett., 1994, 35, 6737. Chem., 1995, 60, 5628. 3787. Asymmetry, 1994,5, 1745. 1995,425. 60, 3334. H. Poschenrieder and J. Redlin, Liebigs Ann. Chem., 1994, 961. 99 T. Sato, K. Yoshimatsu and J. Otera, Synlett, 1995, 843. Collins: Saturated and unsaturated lactones 321

ISSN:1350-4894    

DOI:10.1039/CO9960300295

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Amines and amides MICHAEL NORTH Department of Chemistry, University of Wales, Bangol; Gwynedd LL57 2UW UK 2 Preparation of amines 2.1 Synthesis of achiral or racemic amines One of the well known problems with preparing tertiary amines by the alkylation of secondary Reviewing the literature published in 1995 Continuing the coverage in Contemporary OTanic Synthesis, 1995, 2, 269 1 2 2.1 2.2 2.3 2.3.1 2.3.2 2.3.2.1 2.3.2.2 2.3.3 2.3.3.1 2.3.3.2 2.3.4 3 Introduction, scope and coverage Preparation of amines Synthesis of achiral or racemic amines Synthesis of optically active amines Synthesis of amines bearing additional functional groups Synthetic routes to P-hydroxyamines 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 /I-amino acids Synthesis of y- and higher amino acids Preparation of amides 3.1 General methods, and the synthesis of acyclic amides 3.2 Synthesis of lactams 3.2.1 Synthesis of p-lactams 3.3 Synthesis of peptides 4 Summary 5 References 1 Introduction, scope and coverage This review covers the literature published during 1995.Papers were selected from the online science citation index for 1995, so some papers published at the end of 1995 which are cited in the 1996 index have not been included, but will be covered in the next review of this topic. Some papers which were published at the end of 1994, or the beginning of 1996 and which are included in the 1995 citation index have however been included.This is not 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 has the same format as that used last year,' and so is split into two main sections, amines and amides. The further subdivision of this review is somewhat arbitrary given the ease with which many of the derivatives (e.g. p-amino acids and P-lactams) can be easily interconverted. aminei is overalkylation to give ammonium salts. A solution to this problem has been reported, in which a secondary amine is treated with potassium hydride in the presence of an excess of an alkyl halide and triethylamine. The role of the triethylamine is to scavenge excess alkyl halide.2 Low valent titanium has been found to selectively cleave benzyl and allyl groups from tertiary amines, providing a convenient preparation of secondary amine~.~ A vinylogous Mannich reaction between an indole imine, acryloyl chloride and a 1-siloxybutadiene has been used to prepare a variety of alkaloids containing the tertiary amine group.4 The synthesis and crystal structures of the tetra-amines 1 and 2 have been reported, both amines being found to act as proton sponge^.^ 1 2 N-Benzyltriflamide (CF3S02NHBn) has been introduced as an amine generating reagent for the Mitsunobu reaction.The reagent is an air-stable solid which is easily prepared from triflic anhydride and benzylamine, and can be used in conjunction with the standard Mitsunobu reagents triphenyl- phosphine and diethyl azodicarboxylate.6 Also utilising a Mitsunobu reaction, a convenient procedure for the conversion of allyl alcohols into allylic primary amines which proceeds without allylic rearrangement has been reported.The allylic alcohol undergoes a Mitsunobu reaction ( PPh3- DIAD-phthalimide), following which treatment with hydrazine or methylamine cleaves the phthali- mide group, giving the allylic amine.' A palladium catalysed process for the synthesis of allylic amines from non-conjugated dienes has been developed, an example of which is shown in Scheme 1. The reaction is compatible with a range of dienes (not just 1,5-dienes) and primary or secondary amines.' Simply heating a homoallylic mesylate with a primary amine in DMSO at 80 "C is sufficient to form a homoallylic amine.9 North: Amines and amides 323Scheme 1 X=O,NH polymer = Wang, Rink, polystyrene Reductive amination of an aldehyde is a well known and effective strategy for the synthesis of secondary amines.This approach has recently been utilised in the synthesis of a number of polyamine- polyamide derived toxins including philanthoxins, JSTX-toxins and argiotoxin-636." A one-pot synthesis of 1-ferrocenylbenzylamine from ferro- cenyl phenyl ketone and which proceeds via a reduc- tive amination has been reported as shown in Scheme 2." The reductive amination of para- formaldehyde has also been achieved by treatment with a secondary amine in the presence of zinc chloride followed by sodium borohydride-zinc chloride.12 The reduction of aromatic oximes by borohydride exchange resin in the presence of nickel acetate has been used to prepare benzylic primary amines,I3 and the use of sodium boro- hydride and iodine to reduce oxime acetates to primary amines has been rep~rted.'~ i.piperidine ii. 2,5-dimethoxy- benzaldehyde, NaBH3CN NH2 i. ~ i ( o ~ i ) , i. NaBH4 ii. NH4CI, Et3N H2N OTi(Opi)3 ii. H30+ Fc - [ FcXPh ] - FcAPh Fc = ferrocene Scheme 2 A Strecker reaction, followed by cyanide displace- ment by phenylmagnesium bromide, is the key step in a synthesis of 3-amino-3-phenylazetidine as shown in Scheme 3.15 In another synthesis of 3-substituted azetidines, treatment of ditosylate 3 with excess of a primary amine was found to give azetidines in high yield.16 i. KCN, Bn2NH ii. PhMgBr iii. H@d Ph Scheme 3 Ts0- OBOM Total syntheses of the tertiary amine lavendustin-A have now been reported (Scheme 4), in which the use of a variety of polymeric supports was compared, and both alkylations and reductive alkylations were used to build up the tertiary amine.17 In related work, polymer bound aldehydes were shown to undergo imine formation followed by either addition of Grignard reagents, or reduction followed by tosylation.In both cases, the product amines could be cleaved from the silicon based polymeric support by treatment with TFA,'' Other authors, studying the solid phase reductive amina- tion of aldehydes and acylation of amines, have shown that gel phase 13C NMR can be used to monitor the progress of these reactions." A solid phase synthesis of 1,2,3,4-tetrahydro-P-carbolines has also been reported, in which a Pictet-Spengler reaction is carried out on polymer bound tryptophan derivatives.20 0 M e o s & ) M e -0Me i.2-methoxybenzyi qoH ,,.,FA/ bromide, DBU iii. BBr3 HO lavendustin-A Scheme 4 2.2 Synthesis of optically active amines In last years review of this area,' considerable atten- tion was paid to the asymmetric catalysis of the addition of organolithium reagents to imines. Work in this area has continued, and Itsuno et al. have studied the addition of butyllithium to a range of metallated imines as shown in Scheme 5. A number of catalysts were studied, including sparteine, 3 y 2 Buli, catalyst * Ph- Solid phase synthesis was once the preserve of biopolymer chemists, but the recent interest in combinatorial chemistry has resulted in a consider- able increase in the scope of this methodology.Scheme 5 324 Contemporary Organic Synthesisproline derivatives and polymer supported proline derivatives. Enantiomeric excesses ranged from 1-52%, with the best results being obtained with sparteine as the catalyst and aluminium as the metal.21 The asymmetric addition of methyllithium to p-methoxyphenyl benzyl imine has been further investigated this year, with a wide range of bi- and tri-dentate ligands being investigated as asymmetric catalysts for the reaction. In general, tridentate ligands (especially the amino acid derivatives 4 and 5 ) were found to give better asymmetric induction than bidentate ligands.22 Catalysts 4 and 5 both induce the formation of the (R)-enantiomer of the amine formed by the addition of organolithium reagents to imines.The related catalysts 6 and 7 have also been prepared, and whilst ligand 6 also gives the (R)-enantiomer of amines, catalyst 7 favours formation of the (S)-enanti~mer.~~ Me2N Me0 Me2N x, Me0 6 4 R=CH2Ph 5 R=Ph I 7 The addition of organometallic reagents to the chiral thioimines 8 has been studied: butyllithium and allylmagnesium bromide were found to give opposite senses of asymmetric induction, whilst diethylzinc gave a 1 : 1 mixture of diastereoisomers. Subsequent hydrolysis of the thio amines provided optically active a m i n e ~ . ~ ~ The asymmetric addition of organometallic reagents to chiral imines and chiral oxazolidines was also used in a general synthesis of bis( 1-arylethy1)amines (Scheme 6).25 The asymmetric addition of an allyl cerium reagent to a chiral imine has been carried out as shown in Scheme 7.The initial adduct was transformed into a phenylogous amino acid.26 The asymmetric addition of a wide variety of allyl metal reagents to valine derived imines has also been investigated (Scheme 8), the diastereoselectivity being dependent upon the metal used. Subsequent reduction and oxidative cleavage of the valine derived auxiliary provided an enantioselective synthesis of homoallylic amine~.~' Another application of the addition of organome- tallic reagents to imines is in the conversion of sugars to azasugars as shown in Scheme 9.28 &s.N& OMe 8 Scheme 6 Scheme 7 M = Mg, Pb, Bi, Cu, Al, Zn, In, Ti, Bi, Sn i. LiAIH., ii. HBIOB 1 Scheme 8 i.R'NH, iii. ii. Tf20 R2MgBr - fl - BnO Scheme 9 A total synthesis of (S)-carnegine and related compounds 9 has been reported this year, which employs a homochiral alkynyl sulfoxide as a chiral auxiliary in a Friedel-Crafts cyclisation of an iminium ion as shown in Scheme asymmetric hydrogenation of imines using the Buchwald chiral titanocene catalyst has been discussed in previous reviews of this area.' Recently, the kinetics and mechanism of this reaction have been in~estigated.~' A wide variety of chiral 1,Zdiamines as well as related amides and ureas have been prepared from (S)-pyroglutamic acid.31 The North: Amines and amides 3250 // MeorNHR + HCZC-S, Me0 Ar the newly formed chiral centre during the enamine reduction.37 The reduction of sulfoxide containing oximes 10 was rather more diastereoselective.Reduction with DIBALH and zinc salts gave the p-amino sulfoxide resulting from chelation controlled reduction, whilst reduction with L-Selec- i. TFA M e O p N R tride gave the diastereoisomeric P-amino sulfoxide ii. RaNi via non chelation control (Scheme 13).38 Treatment of a P-thioepoxide with trimethylsilyl triflate gener- ates a P-trimethylsilyloxy thiiranium ion, which upon 9 Ar opening to give a P-thio-y-oxy-amino ester as shown in Scheme 14.39 The same methodology can also be used starting with P-amino epoxides, thus producing p-amino-y-oxy-amino esters via an aziridinium ion.40 Me0 Me0 Me '&' treatment with an a-amino ester undergoes ring A Scheme 10 2.3 Synthesis of amines bearing additional functional groups Rrf50 ~ L-Selectride R7PIP A MeONH To1 MeON To1 In recent years, Katritzky and co-workers have been using benzotriazole chemistry to prepare a wide variety of functionalised amines as discussed in last years review.' Recent applications of this chemistry include the synthesis of N-alkyl prolines," ~x-phosphoamides~~ and ~tyrylamides.~~ Sharpless et al.have reported an asymmetric synthesis of a variety of P-heteroatom substituted amines starting from enantiomerically pure 1,2-diols. Thus conver- sion of the diol into a cyclic sulfonate, followed by reaction with a secondary amine gives an aziri- Scheme 1 R2 OSiMe3 R'*fR3 cF3s03- dinium salt which undergoes ring opening upon treatment with a second nucleophile as shown in R2 % )(R3 TMSOTf X=S,NH R' Scheme ll.35 As part of a synthesis of the thrombin homologation was employed to prepare a homochiral a-amino borane (Scheme 12).36 inhibitor DUP-714, an asymmetric Matteson 10 Nuc Scheme 11 i CHCl Li.ZnClp ii: KHMBS I Scheme 12 Homochiral sulfoxides have been used in a synthesis of optically pure y-fluoro-fi-amino sulfox- ides by the sodium borohydride induced reduction of y-fluoro-fi-enamino sulfoxides. Unfortunately, only a 3 : 1 ratio of stereoisomers was obtained at Scheme 14 The first synthesis of Amadori rearrangement products (a-amino keto tetraols, formed by the reaction of a sugar and an amino ester) to give pure products has been achieved by utilising protecting groups for all uninvolved functionalities. For the first time, the Amadori rearrangement product derived from a dipeptide has also been ~repared.~' In recent years, the acid chlorides of optically pure Fmoc-protected a-amino acids, and the correspond- ing acid fluorides of Boc and 2-protected amino acids have become readily available, and utilised as peptide coupling reagents.It has now been shown that reduction of any of these compounds by lithium tri(tert-butoxy)aluminium hydride provides an attrac- tive route for the synthesis of homochiral a-amino aldehyde^.^' The Mannich reaction between an aldehyde, amine and enol ether has been found to be catalysed by Yb(OTF)3 in a THF-water mixture, providing a convenient synthesis of P-amino 326 Contemporary Organic Synthesisketones.43 Trost et al. have reported an asymmetric synthesis of amine 11 from the meso-dibenzoate 12 as shown in Scheme 15.The key step is the enantio- selective displacement of one of the two benzoate groups by a chiral palladium complex (derived from ligand 13), forming a x-ally1 complex. The latter species is displaced by TMS-N3, giving the enantio- merically pure azide which can be reduced to the desired amine.44 BzoWNH2 + TMSN3 Pd, tabBz0WN3 PPh, H20* w 12 Scheme 15 A synthesis of perfluorotertiary amines (Scheme 17) has been reported, starting from a perfluoro- alkene. Thus reaction with a non-fluorinated secondary amine followed by fluorination with elemental fluorine gives perfluorotertiary amine~.~' Treatment of a urethane protected co-amino ester with formaldehyde, followed by trapping of the aminol with thionyl chloride gives a-chloro amines.Alternatively, the aminol can be trapped with dithio- phosphinates to give a-amino dithiophosphinates as shown in Scheme N4* Similarly, reaction of an a-amino ester with formaldehyde and an aryl amide provides a synthesis of N-acyl aminals (Scheme 11 Treatment of either a N-methoxymethylaryl- amine or N , N,N-triaryl-1,3,5-triazine with titanium tetrachloride and TMS-azide provides a synthesis of N-a~idomethylarylamines.~~ 0 Ph Ph 0 F3cHF HNR'2 F 3 c ~ ~ ' 2 F23 hv, R2F-N, P'F L 13 F3C CF2CF3 CF3CF2CF2 R'F A route for the conversion of a-amino acids into a-amino trifluoro ketones has also been developed as shown in Scheme 16. Thus the amino acids are Scheme l7 first converted into N-protected oxazolidinones, and , (CH2)&02R2 i. HZCO, K2CO3 )(AN/ (CH2)"C02R2 the latter react with trifluoromethyl trimethylsilane H';J ii.S0Cl2 or MeP(SH)(OEt)=S , in the presence of sonication and a catalytic amount co2R1 * C02R' of caesium fluoride to give an adduct which upon treatment with Amberlite IR-120 ion exchange resin gives the desired N-protected a-amino trifluoro ketones. An alternative route is also available, in which the a-amino acid is first converted into an N-protected a-amino aldehyde. Reaction of the aldehyde with (trifluoromethyl) trimethylsilane gives the corresponding /I-amino trifluoro alcohol, which can be oxidised to the corresponding ketone with the Dess-Martin perioindane reagent.45 The vinyl fluoride derivatives 14 and 15 have been prepared from ethyl (S)-prolinate, and investigated as poten- tial isosteres of the proline amide bond.46 X = CI or MeP(OEt)(=S)-S- Scheme 18 RO2CANH2-HCI + H2C0 + ArCONH2 0 1 R02CANANAAr H H Scheme 19 An asymmetric synthesis of a-aminophosphonic acids from aldehydes, which incorporates an enzymatic resolution and a Mitsunobu reaction to R' N< H2NACO*H R2 Prot = protecting group Scheme 16 introduce the nitrogen, has been reported, as outlined in Scheme 20.51 Similar methodology has been used to prepare P-hydroxy-a-amino phosphon- ates starting from a, P-dihydroxy pho~phonates.'~ 1 Amberlite IR-120 ProtHN &CF3 i.base A,?'' + HP03R2 ii. 0 0 OAc QY F Q-F Prot 14 15 Prot = BOC, Z ii. i. PPh3, lipase DEAD, HN3 iii. HTPd/C Scheme 20 North: Amines and amides 327Ph Ph Scheme 21 The synthetic route shown in Scheme 21 has been used to prcparc t .r-didcutero r-amino phosphonic acid. The synthesis is based upon previous work by the same authors, but with the introduction o f it transesterifcation step t o circumvent the harsh conditions required for the direct removal of the /I- t r i fl uo r o c t h y l c s t c rs." A synthesis o f co-amino r-hydroxy bisphosphon- atcs from (:)-amino acids has bccn rcportcd as shown i n Scheme 22.'' This short synthesis has bccn adapted for large scale work by the inclusion o f mcthancsulfonic acid as a solvcnt. t o avoid problems associated with the reaction mixture solidifying and generating cxccss heat. The alkylation o f the cnolatc o f an iminc of a glycinc cstcr is a commonly used route for the synthesis o f r-amino acids. This chcmistn has now been adapted to allow the sy n t hcsis o f z-a m i no p hos p ho n ic a nd p h osp h i n ic acids as shown in Scheme 23.' n =2-5 Scheme 22 AT.X X = R or OR Scheme 23 X I I x 16 17 Scheme 24 ketone with potassium phthalimidc or sodium azidc followed by hydrolysis or rcduction has been used t o prcparc a variety of C-2 symmetrical /I-hydroxy diamincs and r-keto diamincs as potential anti- IilV-1 protcasc inhibitors." A synthesis o f /j,/I'- dihydroxyamincs from an asymmctriscd tris(hydroxymcthy1)mcthanc derivative has also been rcportcd as shown in Scheme 25. Thus oxida- tion of thc unprotected OH group followed by it Curtius rearrangement gives the corresponding isocyanate with retention o f stcrcochcmistn. The isocyanate can then be trappcd with hcnzyl alcohol o r mcthyllithiuni, giving the N-Z- and acctamidc dcriva t ives rcspcct ive~y.~' P M B O M O ~ O T B D P S - P M B O M O ~ O T B D P S Nco - - \OH Scheme 25 0 R = Me orOBn A synthesis o f tcrbutalinc 18 has been reported in which the cyclic dipcptidc ~clo[-(S)-~iis-(S)-Ptic-] is used t o catalysc thc asymmetric addition of HC" t o an aldehyde.giving the derived cyanohydrin with very high cnantiomcric cxccss (Scheme 26). The synthesis continued by protection o f thc alcohol. conversion o f the nitrilc t o a rm-butyl amidc, and finally rcduction of thc amide t o the corresponding 2.3.1 Synthetic routes to P-hydroxyamines The asymmetric reduction o f r-amino phcnyl kctoncs using a rhodium catalyst with chiral ligands has been used t o prcparc enantiomcrically pure 2- hydroxy - 2 - p he ny Ic t hy l a m i nes .'6 H ydrogc na t ion o f homwhiral furan 16 using Rancy Nickel prtxxxdcd chcmoselcctivcly.giving chiral aminc 17, as shown in Scheme 24.'' Displacement o f an I , x'-dibrorno- Scheme 26 0 18 4O%ee R I mixture of H and Acamine. However, the final reduction step using lithium aluminium hydride was found to cause extensive (60%) racemisation of the benzylic centre.60 It is likely that the lithium aluminium hydride reduction of related systems will also have deleterious effects on stereochemical integrity. 2.3.2 Synthesis of a-amino acids This remains an area of much synthetic interest, and as with the previous review of this area,' only those methods that result in the formation of the carbon- nitrogen bond, or in which the nitrogen atom plays a pivotal role in the chemistry have been included.The emphasis of this review has been placed on those methods that allow the stereocontrolled synthesis of amino acids, as most applications of amino acids require stereoisomerically pure compounds. 2.3.2.1 Racemic syntheses of a-amino acids A synthesis of p, y-unsaturated-a-amino acids starting from P, y-unsaturated nitriles and incor- porating a Neber rearrangement has been reported as shown in Scheme 27.61 In a variation of well established glycine imine enolate alkylation reactions, O'Donnell et al. have also reported a synthesis of p, y-unsaturated a-amino acids, using organometallic methodology (Scheme 28).62 Also using organometallic reagents in a variation of well known chemistry, Maorgan and Pinhey have used organolead triacetates to alkylate ethyl acetamido- malonate as shown in Scheme 29.63 NH*HCI NCI P O M e NaOCl, P O M e - 1 -OH H27::H R2 Scheme 27 R' I R' Ph2C=NCH(OAc)C02R3 Cat.Pd(PPh3)4 Scheme 28 North: Amines and amides 0 C02Et i. TFAA ANAC02H H TFAA ii. H20 3H RPb(OAc)3 I R C02Et AcHNAC02H(Et) J ~ o 0 Scheme 29 A racemic, but erythro selective synthesis of P-fluoro a-amino acids has been reported (Scheme 30), in which the fluorine is introduced by the reaction of an azlactone with molecular fluorine. Subsequent ring opening and reductive amination gives the fluorinated amino Another stereo- selective synthesis of amino acids utilises a Claisen rearrangement. This was discussed in the last review of this area,' and recent developments have allowed the synthesis of wsubstituted y,b-unsaturated amino acids as shown in Scheme 31.65 F Ph Ph F i.NH40H ii. NaBH4 I Scheme 30 R' R3 CFSCON H ho+ R4 0 R2 i. 2.2 eq LDA ii. 1.2 eq ZnC12 or MgCI2 iii. H30 R3 I CF3CONH Scheme 31 Radiolabelled amino acids are important for a number of applications, and a synthesis of 2-amino- isobutyric acid specifically labelled with "C at the a-position has been reported. Thus addition of methyllithium to "C labelled CO, gives acetone with "C incorporated into the carbonyl group. A Strecker reaction and hydrolysis then gives the amino acid.66 329A synthesis of a, P-unsaturated amino acids from an a-bromoglycinate has been reported as shown in Scheme 32. Thus condensation of the a-bromo- glycinate with a nitro enolate followed by elimina- tion of the nitro group gives the desired a, P-didehydro amino The Michael addition of secondary amines onto N-Z- or N-Ac-a,P- didehydro amino esters and amides has been used in the synthesis of racemic 2,3-diaminopropanoic acid derivatives6* a,P-Didehydro amino esters also undergo Diels-Alder and other cycloaddition reactions.This chemistry has been utilised in a synthesis of a conformationally constrained analogue of homoserine as shown in Scheme 33.69 i. BuLi + RiR2CHN02 ii. Pr'2EtE Br PhCOHNAC02Me Scheme 32 TiCI4 butadiene, o \ r C 0 2 M e AcHN'COpMe NHAc i. NIS ii. Bu3SnH 0 c 0 2 M e 4 TFA,HzO C02Me Ho" NHp tion of one of the differentially protected alcohols followed by oxidation and final deprotection then gave the desired a-methyl ~erine.~* Seebach and co-workers have developed an effective methodology for the asymmetric synthesis of cx, a-disubstituted amino acids using his transfer of chirality approach.Alonso and Davies have now optimised this approach by replacing the originally used pivaldehyde with ferrocene carboxaldehyde as the prochiral species to which the chirality is trans- ferred.73 The main limitation of the transfer of chirality approach to a-amino acid synthesis developed by Seebach et al. is the hydrolysis of the final adducts, especially with sterically hindered a,a-disubstituted amino acids. However, a new two stage hydrolysis procedure which first forms an N-benzoyl amino acid methylamide (by treatment with MeOH and HC1 followed by PhCOCl and Et,N), then hydrolyses this with anhydrous followed by aqueous HCl, should overcome these difficul- ties.74 An asymmetric synthesis of fluorinated tyrosine and meta-tyrosines using Seebach's method- ology has also been modified his transfer of chirality methodology to provide an asymmetric synthesis of a variety of trifluorothreonine and allo-threonine analogues as shown in Scheme 34.For this synthesis, the cyclic template is formed between the acid and alcohol functionalities rather then between the acid and amino groups. Asymmetric induction is then achieved during the introduction of the a-amino group by reaction of the ester enolate with di-tert- butyl azodicarboxylate (DBAD).76 Seebach has Scheme 33 2.3.2.2 Asymmetric syntheses of a-amino acids Church and Young have developed a short asymmetric amino acid synthesis which proceeds via an alanine cation ~ynthon.~' Hence, ring opening of aziridine 19 by organocuprates occurs regiospecifi- cally at the least hindered position.Subsequent removal of the N-tosyl group (HBr, AcOH) then provides the desired amino acids. The same methodology has been used by Solomon et al. to prepare N-P-alkylated-diaminopropionic acid deriva- tives by the ring opening of aziridine 20 by primary arnine~.~' Similar methodology has also been used by Miller and co-workers in a synthesis of a-methyl serine derivatives. In this case, aziridine 21 was first protected with the P-trimethylsilylethylsulfonyl protecting group, then ring opened at the least hindered end by benzyl alcohol. Selective deprotec- Ts H N R0pC 19 R = H 21 20 R=Bu' BocN , NHBoc i.HCI, MeOH ii. H2-Pt20 iii. NaHC03 I HO ' R &C02Me CF3 I NH2 R = H, Me, Bu, Ph Scheme 34 The Oppolzer chiral sultam has been widely used in asymmetric amino acid synthesis over the last few years. In the latest application of this approach, Ayoub et al. have used the auxiliary to control the methylation of enolates of amino acid imines as shown in Scheme 35, leading to a synthesis of homochiral a-methyl amino acids.77 An asymmetric variant of the Ugi condensation has also been developed (Scheme 36). Thus condensation of tetra- pivaloylgalactosamine with an aldehyde, isocyanide and formic acid gives an adduct which on acid hydrolysis gives chiral amino 330 Contemporary Organic Synthesisreaction between an aldehyde and an a-isocyano- carbonyl derivative is catalysed by a gold catalyst in As discussed in last years review of this topic,' s*T--R base, MeI, S* the presence of chiral ligand 22.80 N-Ar N-Ar - +sop Ar = 4-CI-phenyl Scheme 35 OPiv PivO pivoLaNH2 + OPiv Scheme 36 there is currently much interest in the synthesis of ring substituted proline derivatives, due to their ability to function as conformationally constrained amino acids.Full experimental details of one of the syntheses of 3-carboxyproline mentioned last year have since been reported." This year, an asymmetric synthesis of highly substituted prolines via a 1,3-dipolar cycloaddition between an azomethine ylid and a chiral a,P-didehydro amino acid has been reported.** A related field is the synthesis of 4-oxaprolines derived from serine or threonine, and synthetic methodology for the preparation of a range of such compounds including derivatives where the acid has been reduced to an aldehyde or alcohol has been reported.8' trans-4-Hydroxyproline has been used as the starting material for a synthesis of cis-4-thioproline derivatives.The key inter- mediates in this synthesis are thiolactones 23 which undergo ring opening when treated with a m i n e ~ . ~ ~ O y H 0 R ~ H O + ZnC12 R2NC -sugar"d'N'R2 + H HC02H R' i. HCI, MeOH ii. H30* I I H2N vC02H R 1 Williams and co-workers have shown that treat- ment of a racemic allylic acetate with potassium phthalimide in the presence of a catalytic amount of a chiral palladium species gives optically active phthalimido protected allylic amines without allylic rearrangement.Subsequent oxidation of the alkene, and removal of the phthalimido protecting group leads to optically active amino acids.79 A stereo- controlled, asymmetric synthesis of P-hydroxy a-amino acids, along with the corresponding aldehydes and ketones, has been reported by Sawamura et al. (Scheme 37). Thus the aldol ,AH +CNJx X = OR, NR2, NROR r) NProt 23 Prot = protecting group Over recent years,1385 Hruby and co-workers have been synthesizing topographically constrained phenylalanine derivatives by the incorporation of methyl groups either in the ortho-positions of the aromatic ring or on the P-carbon; full details of this work has now been published.86 This methodology has now been extended to the synthesis of 2',6'-dimethyl and P-methyltyr~sines.'~ Another constrained amino acid i s decahydroisoquinoline 24, which has been synthesised by an asymmetric Diels- Alder reaction as shown in Scheme 3fkS8 The related constrained amino acid 25 has been prepared from diphenylalanine by a route involving a Pictet- Spenger reaction as shown in Scheme 39.The key cyclisation proceeds with a 2.8 : 1 selectivity between the two phenyl ringss9 The Diels-Alder reaction between cyclopentadiene and dehydro amino esters Ph Ph cts"" H -'C02Et 22 24 Scheme 37 North: Amines and amides Scheme 38 33125 Scheme 39 I C02R NHAC Scheme 40 (Scheme 40) is catalysed by a variety of silica based heterogeneous catalysts (using thermal or micro- wave activation), giving a mixture of the endo and a o isomers of the bicyclic amino acid.When a menthyl ester is used, asymmetric induction is observed, though this is greater in the case of the endo isomer (1OO:O) than in the a o isomer (best All four stereoisomers of the cyclic lant hionine derivative 26 have been prepared, and their confor- mations determined by X-ray and NMR techniques. Unlike the situation with the corresponding eight membered ring disulfides," all four stereoisomers of compound 26 were found to possess a cis amide bond, indicating that an eight membered ring disulfide is the smallest such ring capable of accom- modating a trans amide bond.92 Stereoisomers 27 and 28 which are conformationally constrained glutamine analogues, have both been prepared by multistep procedures from D-manitol.The key step in these syntheses is the introduction of the amino group from a carboxylic acid with retention of stereochemistry, utilising a Hoffmann or Curtius rea~rangement.'~ 4 I 11.~0 fS\ NHBoc fCO2H *- dCONH2 26 27 28 In the first review of this area,85 the use of enantiomerically pure a-nitro vinyl sulfides as precursors to P-hydroxy a-amino acids reported by Jackson et al. was discussed. Full details of this chemistry have now been rep~rted.'~ A synthesis of 4-hydroxy-(S)-threonine which can be used to incor- porate I3C labels at both C2 and C3 has also been reported (Scheme 41). The enantiomerically pure epoxide required for this synthesis is available by a Sharpless ep0xidation.9~ Xue and Degrado have Scheme 41 reported a short, regiospecific synthesis of N-a-methyl-arginine and -0rnithine starting from N-a-Boc-glutamine.y6 Thus conversion of the amide to a nitrile (Ac20), followed by alkylation of the BocNH (NaH, MeI) and reduction of the nitrile (H2-Pt02), gives the desired ornithine derivative which can be further converted into the arginine derivative.The use of red yeast cells (in pH 10.5 aqueous buffer) to catalyse the addition of ammonia to ring substituted cinnamic acid derivatives, producing optically pure (S)-phenylalanine analogues, has been reported.97 Enzymatic resolution can still be an effective methodology for the synthesis of optically pure amino acids, and Bruce et al. have shown that leucine aminopeptidase will resolve piperazine derivative 29.98 Similarly, amidase enzymes were utilised by Kaptein et al.to resolve a-methyl amino amides. The a-substituted amino acids prepared in this way were then used to prepare chiral ligands for Lewis acid catalysts of the trimethylsilylcyanation of aldehydes, to prepare optically active cyanohydrins.% H ( T O N H 2 Boc 29 2.3.3 Synthesis of /?-amino acids 2.3.3.1 Racemic syntheses of /?-amino acids Reaction of the lithium enolate of an a-alkoxy- N,N-dimethylacetamide with an a-methoxyurethane gives a racemic a-hydroxy p-amino acid derivative in which the anti diastereoisomer predominates (up to 90%) as shown in Scheme 42. However, if R' is a TBDMS group and titanium tetraisopropoxide is added to transmetalate the lithium enolate, then the syn diastereomer is formed with up to 90% selec- tivity."' The stereochemistry of the reaction between zinc enolate 30 and imine 31 (Scheme 43) has been found to be solvent dependent.Usually, the trans diastereomer predominates, but in the presence of polar cosolvents (NMM, DMSO, NMP, Scheme 42 332 Contemporary Organic SynthesisP-cyanoamines can then be hydrolysed and depro- tected to give the desired p-amino acids. The same approach has been used to prepare 3,4-diamino- c B i M e 2 Me2Si -NwOZnCI + &\Ne Scheme 43 \ butanenitrile derivatives, starting from (S)-aspara- gine, the asparagine amide becoming the nitrile and the acid being converted into an amine.'05 The intui- tively more obvious approach of using the P-acid of aspartic acid as a P-amino acid has been exploited in a synthesis of iturinic acid 34 as outlined in Scheme 46.lo6 30 OEt 31 1 Bn02C BocHN - TMU, DMPU or optimally HMPA) the cis diastereoisomer becomes the major product.'" A one pot synthesis of p-amino esters (and p-lactams) from an aldehyde has also been reported. Thus addition of a lanthanide triflate catalysts to a mixture of an aldehyde, an amine and a silyl enolether gives p-amino esters.'" The intra- molecular Michael addition of an amine onto an a, P-unsaturated ester was employed in the synthesis of the bicyclic p-amino ester 32 as shown in Scheme 44.'03 Et02C i. BnNH2, NaBH3CN Bn C02Et 3 A H B ~ 32 0 Scheme 44 2.3.3.2 Asymmetric syntheses of /3-amino acids An asymmetric synthesis of P-amino acids starting from aspartic acid has been reported, in which the a-acid group of the aspartic acid becomes the acid of the p-amino acid.lW Thus aspartic acid is converted into the N,N-dibenzyl diol 33 using known methodology; this is then mesylated, which results in the formation of a mesylate aziridinium ion as shown in Scheme 45.The latter reacts regio- specifically with cyanide at the least hindered end of the aziridinium ion, followed by displacement of the mesylate by an organocuprate. The resulting C02H 33 i. LiCN ii. RU, CuI I BocHN r- 34 Scheme 46 The asymmetric Michael addition approach to p-amino acids developed by Davies and his co-workers was discussed in last year's review of this area.' This year, the methodology has been used to prepare the natural product (2S,3R)-3-amino- 2-hydroxydecanoic acid, as well as the 2-epimer and 2-deoxy deri~ative.''~ Davies et al.have also utilised this methodology [using (a-methylbenzy1)allylamine as the chiral amine] in a formal total synthesis of ( + )-thienamycin."' Related methodology has now been reported by Enders et al. which uses TMS- SAMP as the chiral amine equivalent,'" and by Sewald et al. using homochiral amidocuprates."' of hydroxylamines to a, @-unsaturated esters has been investigated as a route to asymmetric p-amino acid synthesis as shown in Scheme 47. Subsequent cyclisation of the hydroxylamine adduct to give an isoxazolidinone followed by hydrogenation gives the p-amino acids. The influence of chiral esters (R') and chiral hydroxylamines (R3) on the stereo- chemistry of the reaction was investigated."' Meyers et al. (Scheme 48), in which the Michael Also using similar chemistry, the Michael addition An alternative approach has been developed by LHMDS 1 Scheme 45 Scheme 47 North: Amines and amides 333l i d R I Prot = protecting group Scheme 48 addition of an achiral lithium amide to a chiral naphthyloxazoline is used to prepare cyclic P-amino acids."* The Michael addition of both chiral and achiral amines to homochiral a, P-unsaturated esters has also been investigated.'13 By the choice of a suitable pair of matched reagents, very high diastereoisomeric excesses could be obtained, and the adducts could be further manipulated by a-enolate formation (trapping with aldehydes) and cyclisation to P-lactams.Wyatt and co-workers have exploited the leaving group abilities of a benzotriazole (Bt) group in an Scheme 50 homologation of a-amino acids into p-amino acids has also been reported as shown in Scheme 51.Thus reduction of an N-protected a-amino acid to the corresponding /?-amino alcohol, conversion of the alcohol into an iodide, displacement with cyanide, hydrolysis and deprotection provides the desired 8-amino acid~.''~ R R ProtHNYCo2H R I i. EhN'CN- ii. HCI, MeOH ProtHN?foMe H N * F C 0 2 H - R R O asymmetric synthesis of 3-amino-2-phenylpropanoic acid, in which the enolate of a chiral imide is allowed to react with BtCH,NHZ as shown in Scheme 49. As a result of this synthesis, the absolute configuration of this p-amino acid was revised.' l 4 Prot = protecting group Scheme 51 i.LDA Z H N ~ fph 2.3.4 Synthesis of y- and higher amino acids In recent years, Williams and co-workers have Ph-Nyo P h 9 " f o developed an asymmetric synthesis of a-amino acids starting from the chiral template 35.This has now been extended into a synthesis of /3-hydroxy y-amino acids (Scheme 52) which are of importance as hydroxymethylene peptide bond isosteres."' An asymmetric synthesis of the template 35 has also been developed, in which the key step is the oxy- nitrilase catalysed addition of HCN to benzaldehyde ii. BtCH2NHZ ~ 0 0 0 0 i. LiOH ii. HrPd/C I 1 H2N, Ph*C02H Scheme 49 Diazoketones derived from a-amino acids undergo a Arndt -Eistert rearrangement upon treat- ment with a catalytic amount of silver benzoate in the presence of a nucleophile (Scheme SO), giving p-amino acid derivatives. Alternatively, in the presence of rhodium acetate azetidin-3-ones are produced.' l5 The Arndt-Eistert rearrangement has been shown not to cause any racemisation, except when the amino acid is phenylglycine, and it is possible to use the P-substituent to control the stereochemistry at the a-position during the alkyla- tion of an enolate subsequently formed from the p-amino ester.116 Alternative methodology for the i.NaN(TMS), ii. RX 35 R i. CH2=C(OMe)OTBDMS, ZnBr2 ii. KOH iii. Li. NH3 I Scheme 52 334 Contemporary Organic Synthesiscx, Scheme 53 giving optically pure mandelonitrile."' This synthesis improves upon the previous synthesis of the template which involved a resolution step. Another synthesis of P-hydroxy-y-aminobutanoic acid has also been reported, using malic acid as a chiral starting material.Iz0 A [3,3]-sigmatropic shift has been used in a synthesis of P, y-unsaturated S-amino acids (Scheme 53) which are also used as peptide bond isosteres.'21 The ring opening of a glucose derived N-Boc aziri- dine by phenylmagnesium bromide has been used in the synthesis of the hydroxyethyl peptide bond isostere of the Phe-Ala dipeptide unit as shown in Scheme 54.'22 BocN.___) -CO2Me , I , D-glucose -* OBn Me 1 PhMgBr NHBoc Ph -CO2Me I , OBn Me Scheme 54 A synthesis of a, P-unsaturated y-aminobutyric acids has been reported (Scheme 55) which starts from enamines. Thus reaction of an enamine with bromine followed by lithium tert-butyl acetate gives a p-amino y-bromo ester which undergoes elimina- tion of HBr with rearrangement via an aziridinium ion to give a, P-unsaturated y-aminobutyric acids. 123 i.Br, ii. 2 eq LiCH2C02Bu' 1 r C02Bu' CO~BU' B r 4 N R 1 2 R3 yR12 R3 R2 L 0 A racemic synthesis of 4-amino-3-(4-chlorophenyl)- butyric acid has also been reported, which proceeds via the ring opening of an aziridine as shown in Scheme 56.Iz4 Unlike all of the other examples of aziridine ring-opening cited in this review, in this case the ally1 group becomes attached to the more substituted carbon atom of the aziridine presumably due to its benzylic nature. A synthesis of the y-amino acid vigabatrin 36 specifically labelled with C in the terminal alkene position has also been r e ~ 0 r t e d . l ~ ~ 14 ""0, N- Ts allyl-MgBr - i. Na1O4 ii. Na, naphthalene I iii. HCI Scheme 56 36 3 Preparation of amides 3.1 General methods, and the synthesis of acyclic amides Reagent 37 has been used to convert a barrelene tetramethyl ester into the corresponding protected tetra-amide.Treatment with TFA subsequently removed the 2,4-dimethoxybenzyl protecting groups, giving the barrelene tetra-primary amide.126 p-Nitro- benzenesulfonyl chloride has been used as a condensing agent for carboxylic acids and secondary amines,'27 and 2-chloro-1-methylpyridinium iodide has been used to prepare N-methoxyamides from carboxylic acids and O-methyl hydroxylamine.'28 4'-Nitroanilides (4-nitrophenyl amides) are difficult to prepare, especially from amino acids as these cannot be highly activated due to the risk of racemi- sation. However, it has now been shown that N-Boc amino acids react with 4-nitrophenylisocyanate to give N-Boc amino anilide~.'~' The same 4'-nitro anilides can also be prepared by treating an N-protected (protecting group = Alloc, Boc, Fmoc, Tr or Z ) amino acid with 4-nitroaniline in the presence of phosphorus oxychloride and pyridine.13' Me2AIHN &OMe 37 Scheme 55 North: Amines and amides 335Reaction of a primary amide with an aldehyde in the presence of imidazole results in the formation of either an N-[(imidazol-1-yl)alkyl] amide or alkyl bridged bis-amide depending upon the structures of the amide and aldehyde as shown in Scheme 57.13' 0 R2 or Scheme 57 RCHO, Liar polymer, H 'R 1 TFA H2.4 R Scheme 58 Scheme 59 A solid state synthesis of a, P-unsaturated amides via a Wadsworth-Emmons reaction has been described (Schemes 58 and 59).The phosphonate amide can be attached to the solid support either through the phosphonate esters or via the amide, and the reaction can be monitored by gel phase 13C NMR."* The desymmetrisation of meso-anhydrides by homochiral amines is an attractive approach to the synthesis of enantiomerically pure compounds, as the adducts contain two versatile functional groups, an acid and an amide.The use of proline methyl ester as a cheap, readily available and efficient reagent to desymmetrise norbornene derived anhydrides (Scheme 60) has been r e ~ 0 r t e d . I ~ ~ The absolute stereochemistry of the amido acids was determined both by X-,ray crystallography, and by conversion to the known corresponding lactones. A related approach has also been used by Ward et al. to synthesise a lignan lactone utilising a-methyl- benzylamine as the chiral a m i r ~ e .' ~ ~ endo orexo Scheme 60 The use of the enzyme Candida antartica lipase (CAL) to catalyse the formation of amides from esters and amines has been investigated. In studies using dimethyl succinate, the product of the reaction was found to be solvent dependent (Scheme 61); the amido ester being formed in dioxane whilst the cyclic imide was produced in hexane. The reaction could also be used to resolve racemic amines, and was found to be regio- and stereo-specific when applied to dimethyl 2-methylbutanedioate. The latter reaction does not require a chiral amine, and gives predominantly the product of attack at the least hindered ~ a r b o n y l . ' ~ ~ The use of the same enzyme (in diisopropyl ether at elevated tempera- ture) to catalyse the formation of amides from N-Z-glutamate derivatives has also been investi- gated.With diesters (ethyl or benzyl) of (S)-glutamic acid, reaction with amines occurred regiospecifically at the a-carbonyl, whilst with diethyl N-Z-@)-glutamate amidation occurred regioselec- tively at the y-carbonyl. This reaction was also found to be enantioselective when a-methylbenzylamine was used as the amine.136 CAL, RNH2 Me02C- dioxane Me02C- CONHR C02Me CAL. RNH2 hexane I Scheme 61 Both lipase and protease enzymes have been investigated for the ammonation of methyl N-Z-a-amino esters. Whilst many amino acids were substrates for this reaction, most amino acid- enzyme combinations gave low to moderate enantiomeric excesses when the enzymes were used to resolve racemic amino esters.An exception was the resolution of methyl N-Z-phenylglycinate which when treated with lipase gave the amino amide with 91% ee.137 3.2 Synthesis of lactams A simple approach to the synthesis of macrocyclic diamides, by the condensation of a diacid chloride and a diamine which does not need to be carried out under high dilution conditions, has been 336 Contemporary Organic Synthesisreported. However, a similar cyclisation using meta-benzoic diacid chloride and para-di(amino- methy1)benzene lead to a catenane composed of the macrocyclic dimer.'39 A general procedure for the conversion of cyclic ketones into lactams via the Beckmann rearrange- ment which employs microwave irradiation of a mixture of the ketone, hydroxylamine sulfate and silica in the absence of any solvent has been rep~rted.'~' An intramolecular Schmidt reaction can also be used to prepare bicyclic lactams as shown in Scheme 62.The regio- and stereo-chemistry of this reaction has been studied using a wide range of sub~trates.'~' Scheme 64 Scheme 62 38 each bridge is as shown for the top bridge Olefin metathesis is enjoying a revival of interest 39 Scheme 65 at present, with particular interest being shown in both ring opening and ring closing metathesis. This activity has been largely stimulated by new catalysts 40 removed with TFA. Subsequent treatment with triethylamine results in cyclisation to give the macrocyclic lactam with lactam from the polymer support and regeneration of the polymer bound HOBt. The method has been used to prepare 7-13 membered rings.~46 which are tolerant of a wide range of functional groups.Nugent et al. have developed a tungsten based catalyst for ring closing metathesis which will tolerate amides; the catalyst was used to prepare nitrogen heterocycles as shown in Scheme 63.14* A synthesis of the N-norbornenyl derivatives of amino acids and their esters has been reported. These cleavage of the compounds undergo ring opening metathesis polymerisation to give polymers which are analogues of peptides and protein^.'^' Scheme 63 Reaction of an N-ally1 diazoamide with rhodium catalyst 38 results in asymmetric addition of the carbenoid onto the alkene, giving cyclopropyl plactams with up to 98% enantiomeric excess as shown in Scheme 64.'44 During the synthesis of 6,5-bicyclic lactams as peptide mimetics, the Lewis acid induced cyclisation of compound 39 was investi- gated.It was found that cyclisation occurred with rearrangement and concomitant removal of the benzyl protecting group (Scheme 65), giving lactam 40 as the The use of polymer bound HOBt (l-hydroxy- benzotriazole) in lactam synthesis has also been investigated. Thus reaction of an w-N-Boc amino acid with DCC and polymer bound HOBt results in the formation of a polymer bound cu-N-Boc amino activated ester. The N-Boc group can then be 3.2.1 Synthesis of b-lactams An asymmetric synthesis of either diastereomer of p-lactams has been reported which utilises 1,2,2-triphenylethane-1,2-diol as a chiral auxiliary in a condensation between an ester enolate and an imine as shown in Scheme 66.Interestingly, whilst normally the trans isomer of the p-lactam is obtained, simply protecting the alcohol as a methyl or silyl ether results in the formation of the cis diastereoisomer instead.'47 NProt Ph i. 2 eq LDA q o + r H ii. RCH=NProt Me'. ' 0 0 Ph Prot = protecting group Scheme 66 Perhaps the least utilised approach to p-lactam synthesis is formation of the N-C3 bond. However it has now been reported that P-mesyloxy amides can be cyclised to give b-lactams as shown in Scheme 67.14* Another approach to p-lactam synthesis uses a 4-exo-trig radical cyclisation to form the C2-C3 bond as outlined in Scheme 68. A variety North: Amines and arnides 3370 UMS II I RiN* 0 R’HN-R2 Scheme 67 R’ Br O’NYx R2 SPh * 0 VSPh Scheme 68 of racemic and optically active P-lactams have been prepared using this methodology, utilising chiral auxiliaries within R’ and R2 where appr~priate.’~’ 3.3 Synthesis of peptides Cabaret and Wakselman have introduced sulfonyl chloride 41 as a coupling reagent for peptide synthesis.The reagent is proposed to act through initial elimination of HCl, producing a sulfene which reacts with the carboxylic acid component to give initially a carboxylic-sulfonic mixed anhydride. This then undergoes an intramolecular rearrangement to give an aryl ester which reacts with the amine component to give the desired peptide bond as shown in Scheme 69.I5O ?H x 41 0 I1 L x X=CI, F x Scheme 69 Sulfonyloxybenzotriazole 42 has also been investi- gated as a coupling reagent in solid phase peptide ~ynthesis.’~’ As an alternative to solid phase peptide synthesis, polymer supported triphenylphosphine has been used as a peptide coupling reagent in the presence of iodine and irnidaz01e.I~~ Carpino and Elfaham have introduced (N, N, N ’, N ’-tetramethyl) fluoroformamidinium hexafluorophosphate 43 as a 42 43 convenient reagent for converting Fmoc amino acids into acid fluorides, which can be isolated or used in situ.153 Pent afluorophenyl dip henylphosp hate has been introduced as a reagent for the in situ forma- tion of pentafluorophenyl active esters for peptide synthesis, and is reported to give superior results to other reagents.’54 The use of water soluble carbodiimide in a two phase water-dichloromethane solvent system was found to give peptides in high yield and with low racemisation provided an additive was added.The best additives were HOBt, HOAt (l-hydroxy- 7-azabenzotriazole) and HOP0 (2-hydroxypyridine- N-oxide), whilst NHS (N-hydroxysuccinimide) was less effecti~e.”~ Gibson and Rapoport have intro- duced CBMIT [ 1,l ‘-carbonylbis(3-methylimida- zolium) triflate] 44 as a coupling reagent for peptide synthesis, and have shown that in the presence of copper(rr) salts it can be used for fragment conden- sations without causing significant racemi~ation.’~~ The chloro imidazolidinium salt 45 has been used as a coupling reagent (in the presence of HOAt or HODhbt) during the synthesis of Alamethicin-F30, a peptide which contains many Aib (a-aminoisobu- tyric acid) and other hindered residue^.'^' A theoretical study of peptide coupling via mixed anhydrides has been conducted using semiempirical methods, in an attempt to assess the importance of the various possible side reactions during this process.rl Me Peptide synthesis with a-trifluoromethyl amino acids is prone to numerous side reactions. However, the reaction of N-Boc a-trifluoromethyl amino acids with DCC has now been investigated in detail (Scheme 70). The initial product is a 4,5-dihydro- oxazol-5-one 46, which at room temperature elimi- nates isobutene giving Leuch’s anhydride 47. However, at lower temperatures the formation of 47 is inhibited and peptide synthesis can successfully be carried In the last review of this area, a novel synthesis of a, a-disubstituted enantiomerically pure Leuch’s anhydrides was discussed.’ It has now been R CF3 BocHNXC02H 46 47 amino ester low temperature I KBoc-protected dipeptide Scheme 70 338 Contemporary Organic Synthesisreported, that these Leuch's anhydrides react with a variety of amino esters (including other a, a-disub- stituted amino esters) to give dipeptides incor- porating an (R)-a-methyl-P-alkylserine residue.I6' in two separate steps during peptide synthesis.However, Roos et al. have shown that the Alloc group can be removed [Bu3SnH, cat. Pd(PPh3)4] from a protected amino acid in the presence of a second activated amino acid, giving dipeptides directly. Aminomethyl-polystyrene resins are widely used in solid phase peptide synthesis, and a synthesis of high capacity resins has recently been reported.Thus an FeC13 catalysed Friedel-Crafts reaction between polystyrene and phthalimidomethyl chloride 48 followed by hydrazinolysis gave the desired resin.'62 A general procedure for the synthesis of N-alkylamido peptides (H2N-peptide- C(0)NHR where R = alkyl) has been reported, in which an amine resin is first reductively aminated to give an N-alkylamino resin. Subsequent solid phase peptide synthesis, and cleavage of the peptide from the resin gives the desired N-alkylamido peptides.*63 The solid phase synthesis of peptide aldehydes has also been reported, using linker 49 between the resin and peptide chain. This methodology is compatible with either Boc or Fmoc protecting groups, and after the desired peptide has been assembled treatment with LiA1H4 cleaves the linker producing the peptide a1deh~de.l~~ Deprotection and coupling are usually carried out 0 48 49 0 C02Me 50 A hydrogenolysable solid support-linker 50 for solid phase peptide synthesis has also been reported. At the completion of peptide synthesis, hydrogenolysis produces a peptide with a C-terminal lysine methyl One of the most problematical steps in solid phase peptide synthesis is the attach- ment of the first amino acid to the resin. The use of Fmoc amino acid fluorides in the presence of DMAP [ (4-dimethy1amino)pyridinel has now been recommended for attaching amino acids to the acid labile Wang resin.166 An alternative procedure involving the reaction of Fmoc amino acids with the Wang resin in the presence of (Boc),O, pyridine and DMAP has also been r e ~ 0 r t e d .l ~ ~ Treatment of methyl (N-benzoy1)bromoglycine with ammonia gives the tertiary amine derivative 51 predominantly as the RRRISSS stereoisomer.'68 Saponification of the methyl esters from compound 51 followed by peptide synthesis provides a method [ PhCOHN Meo2c)+; 51 for the synthesis of peptides with three chains constrained to close proximity. Hegedus et al. have reported that photolysis of a chiral chromium amino carbene in the presence of an amino ester and carbon monoxide leads to the formation of a dipep- tide as shown in Scheme 71. The methodology can also be used to prepare dipeptides incorporating a,x-disubstituted amino acids.'69 Scheme 71 Peptide nucleic acids (PNAs) are compounds which consist of nucleic acid bases attached to a peptidic backbone, and have potential pharma- ceutical applications as they have greater in vivo stability than nucleic acids.Methodology has now been developed for the solid phase synthesis of PNA-DNA hybrids.17' Enzyme catalysed peptide synthesis continues to attract much research. Hence, trypsin has been used in a semisynthesis of salmon calcitonin, the enzyme being used to form the amide bond between amino acids 24 and 25, thus joining the two fragments of the peptide t~gether.'~' The use of wchymotrypsin immobilised on graft copolymers has also been investigated for peptide synthesis in organic fragment condensation, with the N-terminal peptide activated as a thioester of type 52.17' The enzyme subtiligase has been used to cyclise linear peptides, forming macrocyclic peptides containing between 12 and 16 amino acids.The main side reactions in this process are hydrolysis and dimeri~ation.'~~ The kinetics of thermolysin catalped peptide synthesis in a homogeneous aqueous-organic solvent system have been studied. 175 Alcalase or subtilisin Carlsberg have been used to form peptide bonds between proline or pyroglutamate derivatives (methyl or benzyl ester or amide), and the methyl esters of other Z-protected amino acids or pep tide^.'^^ One of the problems in enzyme catalysed peptide synthesis has been the specificity of the enzymes, resulting in couplings occurring slowly or not at all. This selectivity has now been turned to advantage in a synthesis of an octapeptide in which five different Thiolsubtilisin has been used in peptide 0 0 52 North: Amines and amides 339enzymes were used to selectively form the desired 5 References amide bond and avoid the use of protecting groups. 177 Standard peptide chemistry has been used to prepare peptides 53, which are of interest as they taste sweet, but are more stable than aspartame.17* 53 Solid phase peptide synthesis has been used to prepare both enantiomers of an enzyme (4-oxalo- crotonate tautomerase).Predictably, the two enantiomeric enzymes showed enantiomeric stereo- chemical preferences, but otherwise had identical pr0~erties.I~~ The 2-hydroxy-4-methoxybenzyl group has previously been shown to act as an amide protecting group for use in solid phase peptide synthesis using Fmoc amino acids. It was introduced to disrupt the formation of secondary structure whilst the peptide was attached to the solid support.It has now been shown that use of this amide protecting group also prevents aspartimide forma- tion and the subsequent rearrangement to a P-aspartate residue when used on sequences which are prone to this cyclisation-rearrangement.18' 4 Summary In last year's review, I commented on the increased prominence of imine chemistry; this has continued during the last twelve months. This year, however, an enormous expansion in the use of aziridines in synthesis is evident: there is hardly a section of this review where the chemistry of this functional group is not exploited. There appears to be a general realisation amongst the organic chemical community that chemistry developed for use with oxygen containing functional groups can be adapted to work with the corresponding nitrogen analogues. The main difference is that a protecting group will usually be required for.the nitrogen atom due to its higher valence than oxygen.In view of the wide variety of different protecting groups used in the work reported in this review, I would suggest that the ideal nitrogen protecting group (except for amines during peptide synthesis) has yet to be developed. The other notable feature of this year's review is the explosion of interest in solid phase synthesis. For the last thirty years, this area has been utilised only by biopolymer chemists. However, the recent interest in the preparation of compound libraries has resulted in a realisation that a far wider range of chemical reactions can be carried out on polymeric supports.Almost certainly, this activity will increase further in the coming years, and it may be that in the near future total syntheses of fairly complex natural products (other than biopolymers) will be conducted entirely on a polymeric support. 1 M. North, Contemp. 0%. 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ISSN:1350-4894    

DOI:10.1039/CO9960300323

出版商:RSC    

年代:1996

数据来源: RSC