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 (nek 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 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 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, and environment, and new materials, will also be encompassed.Contemporary Organic Synthesis aims to be proactive, drawing attention to new opportunities and new directions, providing timely information to the synthetic chemist who needs to keep abreast of developments in the field. Although the majority of articles are intended to be specially commissioned, the Society is always prepared to consider offers of articles for publication. In such cases a short synopsis, rather than the completed article, should be submitted to the Senior Editor (Reviews), Books and Reviews Department, The Royal Society of. Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF.Members of the Royal Society of Chemistry may subscribe to Contemporary Organic Synthesis by placing their orders on the Annual Subscription renewal forms in the usual way. All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letchworth, Herts SG6 lHN, England. 1995 subscription rate: EEA 2165, USA $303, Canada 2173 (plus GST), Rest of the World 2173. Air freight and mailing in the USA by Publications Expediting Inc., 200 Meacham Avenue, Elmont 1103; USA Postmaster, send address changes to Contemporary Organic Synthesis, Publications Expediting Inc. Second class postage is paid at Jamaica, New York 11431. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe.The Royal Society of Chemistry, 1995 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording, or otherwise, without the prior permission of the publishers. Typeset by Unicus Graphics Ltd Printed in Great Britain by Whitstable Litho LtdContemporary Organic Synthesis Editorial Board Professor G. Pattenden, FRS (Chairman), University of Nottingham Professor P. D. Bailey, Heriot- Watt University Dr S. E. Gibson (ne6 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 Professor E. J. Corey, Hawurd University Professor S. Hanessian, Universite' de Montre'al Professor M. Julia, Universitk de Paris XI (Paris-Sud) Professor P. D. Magnus, University of Taus 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 Gbttingen California at Sun 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 the Senior Editor (Reviews), Books and Reviews Department, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF. Members of the Royal Society of Chemistry may subscribe to Contemporary Organic Synthesis by placing their orders on the Annual Subscription renewal forms in the usual way. All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letchworth, Herts SG6 lHN, England.1995 subscription rate: EEA E165, USA $303, Canada El73 (plus GST), Rest of the World E173. Contemporary Organic Synthesis is published 6 times a year in February, April, June, August, October, December. Airfreight and mailing in the USA by Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey, NY 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 Armail within Europe and Accelerated Surface Post outside Europe. 0 The Royal Society of Chemistry, 1995 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording, or otherwise, without the prior permission of the publishers. Typeset by Unicus Graphics Ltd Printed in Great Britain by Whitstable Litho Ltd

ISSN:1350-4894    

DOI:10.1039/CO99502FX017

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

EUCHEM Conference on Tycloadditions and Related Reactions: Theory and Practice” Vulcano Island, Italy, 21-24 June, 1995 Address for Correspondence: Prof. Mario Gattuso - Universith di Messina Dpt di Chimica Organica e Biologica - Salita Spemne 31, S. Agata 98166 MESSINA, Italy - FAX +39 90 392840EUCHEM Conference on Tycloadditions and Related Reactions: Theory and Practice” Vulcano Island, Italy, 21-24 June, 1995 Address for Correspondence: Prof. Mario Gattuso - Universith di Messina Dpt di Chimica Organica e Biologica - Salita Spemne 31, S. Agata 98166 MESSINA, Italy - FAX +39 90 392840

ISSN:1350-4894    

DOI:10.1039/CO99502BX019

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

Saturated nitrogen heterocycles TIMOTHY HARRISON Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essa CM20 2QR Reviewing the literature published between June 1993 and December 1994 1 1.1 1.2 2 2.1.1 2.1.2 2.1.3 2.2 3 3.1.1 3.1.2 3.1.3 3.2 4 4.1 4.2 5 5.1 5.2 5.3 6 Three- and four-membered rings Aziridines Azetidines Five-membered rings Pyrrolidines via 1,3-dipolar cycloaddition reactions Pyrrolidines via intramolecular cyclization Pyrrolidines via miscellaneous methods Pyrrolidinones Six-membered rings Piperidines via [4 + 21 cycloaddition reactions Piperidines via intramolecular cyclization Piperidines via miscellaneous methods Piperidones General methods for the construction of nitrogen heterocycles of varying ring sizes Monocyclic heterocycles Bicyclic and polycyclic heterocycles Pyrrolizidine, indolizidine, and quinolizidine ring systems Pyrrolizidines Indolizidines Quinolizidines References 1 Three- and four-membered rings 1.1 Aziridines A review detailing the synthesis of chiral aziridines and their uses in stereoselective transformations has recently appeared.’ An improved procedure for the generation of the useful nitrene NC02Et has been described which proceeds via a-elimination from NsONHC0,Et using an inorganic base without a catalyst; this nitrene is a convenient aziridine precursor.2 Homochiral aziridine-2-carboxylates, which are useful building blocks for the syntheses of modified amino acids, can be prepared by the Michael addition of amines to the bromo-acrylate 1 using the Oppolzer sultam as a chiral auxiliary.The enantio-differentiating step is asymmetric si-face protonation of the Michael adduct, leading to ( S ) - aziridine carboxylates 2, after removal of the auxiliary using Mg(OMe)2 in MeOH.3 1 R @ OMe H 2 Two reports detailing the asymmetric aziridination of olefins using PhI=NTs and a chiral catalyst have appeared. Katsuki et aE. have used optically active (salen) manganese(II1) complexes for the aziridination of styrene derivatives; however, at present the levels of asymmetric induction and chemical yields are Evans et al. have reported that cinnamate derivatives undergo highly enantioselective aziridination using PhI-NTs and a chiral bis (oxazo1ine)-copper ~omplex.~ At this time, however, the optimal conditions identified for the aziridination of cinnamate esters cannot be extrapolated reliably to other olefinic substrates.1.2 Azetidines A straightfonvard but extremely useful synthesis of 3,3-disubstituted azetidines 4 starting from an appropriate ketone is outlined in Scheme 1; the one-pot reduction-cyclization of the cyano-tosylate intermediate 3 is noteworthy.6 Both cyclic and acyclic ketones have been used in this sequence. 4 3 Scheme 1 A novel route to 3-substituted azetidines involving the addition of a reagent X-Y across the highly strained a-bond of the unusual bicyclic amine 5 has been de~cribed.~ The presence of the ethyl group Harrison: Saturated nitrogen heterocycles 209limits the generality of this procedure at this time, but the methodology can be used to prepare potentially useful azetidin-3-one derivatives such as 6.Y 5 6 2 Five-membered rings 2.1.1 Pyrrolidines via 1,3-dipolar cycloaddition react ions The 1,3-dipolar cycloaddition of azomethine ylides with olefins continues to be one of the most effective and useful methods for the construction of the pyrrolidine ring. Since these reactions are highly stereospecific the identification of chiral controller groups would allow the preparation of enantiopure pyrrolidine derivatives. N-Acryloyl proline benzyl ester 7 functions as an excellent chiral auxiliary in the cycloaddition with azomethine ylides 8 (readily derived from amino acids). In all of the examples studied the cycloaddition proceeds with almost exclusive endo-selectivity and also with excellent facial discrimination, providing highly functionalized pyrrolidine derivatives 9 via a highly ordered, chelated transition state.8 Garner and Dogan have investigated the Oppolzer sultam as a dipole based chiral auxiliary in cycloaddition reactions with achiral dipolaraphiles." The desired carbonyl stabilized azomethine ylides 14 and 15 were generated by thermolytic ring-opening of the aziridine derivatives 12 or by condensation of the glycine derivative 13 with an aldehyde followed by tautomerization.The endo-ao selectivity and regioselectivity were found to be somewhat dependent on the structure of the dipolarophile; however, moderate to good face selectivity (5:l to 11:l) was achieved (Scheme 2). 13 Scheme 2 The dipolar cycloaddition reactions of non- stabilized azomethine ylides are generally restricted to reactions with electron-deficient alkenes.However, ethylenic compounds bearing a trifluoromethyl group are sufficiently activated to allow the formation of 3-trifluoromethylated pyrrolidines in good yield.'' A new method for the generation of non-stabilized azomethine ylides involves electrochemical oxidation of N , N- bis (trimet hylsilylmet hyl) benzylamine 16. Electrochemical reduction of enone receptors is a competing side-reaction.12 Alternatively, azomethine ylides can be generated under thermal conditions without using a catalyst starting from a benzotriazole derivative such as 17.13 Bn I TMS-N-TMS DMF An alternative approach to obtaining asymmetric induction in these cyclizations is to use an enone bearing a chiral alkoxy or amino substituent in the y-position, e.g.10, as the dipolarophile. In this way Patzel and co-workers' observed extremely high regio- and diastereo-selectivity in cycloaddition reactions with azomethine ylides, providing pyrrolidines 11 as single diastereoisomers. 0 14 9 16 10 11 15 H20 ? BtH + CH20 + Me3SiCH2NHR TMS-N-Bt r.t., 2h 17 toluene reflux L J The synthesis of pyrrolidines by the [n4s + n2s] cycloaddition between highly reactive non-stabilized 2-aza-ally1 anions and electron-rich alkenes complements azomethine ylide chemistry, where an electron deficient alkene is normally used. In an 210 Contemporary Organic Synthesisextension of earlier work, Pearson et al. have described the generation and cycloaddition reactions of heteroatom-substituted 2-aza-ally1 anions 19 with alkenes and alkynes leading to 1-pyrrolines 20.14 The aza ally1 anions are generated by tin-lithium exchange starting from stannyl imidates or thioimidates 18 (Scheme 3).E+Y+ -R * X I R 18 X = OR', SR' 19 Li I -x- t E = Ts, NO2, Ar R = alkyl, aryl, C02R' 24 X = OAc, OC02Me The intramolecular oxime-olefin cycloaddition of the unsaturated oxime 25 derived from L-serine provides the unusual tricyclic intermediate 26 in a highly stereoselective cyclization. l7 The tricycle 26 was then converted into the highly functionalized pyrrolidine 27, following reduction and hydrolysis. The reason for epimerization at C-2 during the $-k~ [ *R= *R hydrolysis is being investigated. t 20 ii Scheme 3 Jones et al. have reported an improvement to their earlier procedure for the preparation of pyrrolidines 23 by the 1,3-dipolar cycloaddition of 4,5-dihydroimidazolium ylides (21) with alkenes, followed by reduction of the resulting adduct 22.15 25 170 "C __c H N - 0 OK &*'= 0 26 27 This one-pot procedure utilizing a t-butyl ester as quarternizing agent provides experimental simplification and improved stability of the products 23.2.1.2 Pyrrolidines via intramolecular cyclization The propensity Of cyclizations onto proximate alkene bonds has made this an attractive method for pyrrolidine synthesis. to undergo I I rN< f02Me DBU (714b) L" \ 3'. 21 I But026 22 (60%) Thus Takano et al. have reported a highly diastereoselective radical cyclization of the densely functionalized precursor 28 leading to the pyrrolidine 29 en route to an enantiospecific synthesis of (-)-kainic acid.18 TMSl M e y i c e OTBDPS 602Me 28 Bu3SnH 23 Trost and Marrs have described a [3 + 21 cycloaddition approach to the synthesis of pyrrolidines via reaction of the extremely versatile all carbon 173-dipole synthon 24 with imines under Pd-catalysis.l6 Whereas simple imines fail to react, incorporation of electron-withdrawing groups at either the nitrogen or carbon centres enhance the electrophilicity of the imine sufficiently to make it an excellent acceptor. The results are consistent with a two-step addition process. COpMe 29 Shibuya et al. have described an approach to the trans-2,5-disubstituted pyrrolidine derivatives 31 via radical cyclization involving A4~s-oxazolidin-2-one precursors 30.The high diastereoselectivity is attributable to minimization of A',3 strain in the Harrison: Saturated nitrogen heterocycles 21 1preferred transition state 32.19 Shibuya has used an extension of this methodology in a useful synthesis of ( + )-bulgecinine 36 (Scheme 4).20 Thus, cyclization of the O-stannyl ketyl radical 34 derived from the aldehyde 33 proceeded with high face selectivity, but without diastereoselectivity at the alcohol bearing centre, to provide a 1 : 1 mixture of the alcohols 35. These two alcohols subsequently converged following oxidation - reduction of the unwanted epimer.” 30 32 RO OH 31 s, r 1 Bu,SnH, BnO 0 ::HN * 1 Bno>N7] 33 HO k - * C 0 2 H 36 34 I BnO 35 Scheme 4 An alternative approach to the stereoselective synthesis of trans-2,5-disubstituted pyrrolidines 38 involves cyclization of aminyl radicals generated from unsaturated amines 37.The high stereoselectivity is noteworthy and contrasts with the results obtained when aminyl radicals are generated by other means.*l Rate constants for the cyclization of aminyl radicals have been determined.22 ,i*R3 (ii) (i) BuoSnH NCS.PhH -AIBN. Ri--J!-&il rH R2 PhH, reflux Re A 37 38 Treatment of 1,6-dienes 39 with tributyltin hydride under CO pressure leads to stannyl- formylation with concomitant ring closure, leading to the substituted pyrrolidines 40 in moderate yield.23 A 39 A 40 The samarium(r1) iodide mediated ring closure of N-ally1 and N-propargyl substrates 41 derived from L-serine has been investigated by Baldwin et al., leading to 2,3,4-trisubstituted pyrrolidine derivatives 42.However, in general the reactions are not diastereo~elective.~~ 41 42 Hecht et al. have reported a concise synthesis of ( + )-preussin 44 utilizing a mercury mediated 5-endo-dig cyclization of the ynone 43, prepared in two steps from N-Boc-(S)-phenylalanine. The overall synthesis is complete in five steps.” 43 X = HgCl: H 8 : 1 ( i ) NaBH, Ph Me 44 2.1.3 Pyrrolidines via miscellaneous methods A number of alternative methods for the stereoselective synthesis of 2,5-disubstituted pyrrolidines have appeared during the period covered by this report. Thus, the bicycle 45, which is Ar (i) NaBH,. MeOH (iii) LiDBB, THF (i) Ar’MgX, THF (iii) LiDBB. THF (ii) (PhS),, Et3P THF H A r e H *-Ari 46 47 212 Contemporary Organic Synthesisreadily prepared by addition of Grignard reagents to phenylglycinol-derived imines, functions as a precursor to either (R)-Zaryl 46 or (R,R) 2,5-bis (aryl) pyrrolidines 47.26 Saski et al.have reported a general method for the chirospecific synthesis of any enantiomer of the 2,5-disubstituted pyrrolidine derivatives 50, by appropriate choice of the desired enantiomers of the starting glycidyl triflate 48 and the sulfone 49. The reactioin proceeds via regioselective ( > 92%) attack of the sulfonyl carbanion of 49 at C-1 of the glycidyl triflate, followed by 5-ao cyclization onto the adjacent e ~ o x i d e . ~ ~ ;9”,-c””” OTHP - 2 ~ i + 0 r -! OTH P I Li’ 48 49 L -I I Two reports describing the synthesis of optically active 2,5-trans-disubstituted pyrrolidines by reaction of amines with 1,4-dibromo and 1,4-mesyloxy derivatives have appeared.28729 The synthesis of 3-methylenepyrrolidines by [3 + 21 cycloaddition reactions involving activated imines has already been described. l6 In a conceptually similar approach, the addition of the allyzinc reagent 51 to activated imines 52 bearing a chiral group on nitrogen, followed by Pdo-catalysed cyclization of the adduct 53, allows the one-pot preparation of 3-methylene pyrrolidines with good to excellent diastereosele~tivity.~~ ‘C02Bn I 52 51 t r 1 L J Enantiomerically pure 3- and 3,3-disubstituted pyrrolidines 55 can be prepared by alkylation of the phenyl-glycinol derived bicyclic lactam 54, followed by reduction (Scheme 5).31 An alternative approach to 3,3- and 3,4-disubstituted pyrrolidines, reported by Denmark et al., involves the Lewis-acid promoted [4 + 21 cycloaddition of nitroalkenes with vinyl ethers to afford cyclic nitronates 56 in good yield, followed by reduction (Scheme 5).32 H H 54 55 \ [4 + 21 56 Scheme 5 N-Tosyl aziridines can be ring-opened with the dianion derived from a P-keto ester to provide pyrrolidine derivatives 57 after acid-mediated cyclization.In general the less-hindered (E)-isomers of 57 are formed.33 L C 0 2 M e + p - &co2Me NHTs - - amberlyst 15 PhMe, reflux I @C02Me 57 An interesting annulation reaction of N-Cbz- a-amino aldehydes with allyltrimethylsilane has been reported by Kiyooka et al., leading to all-cis 2,3,5-trisubstituted pyrrolidines 58. It is interesting that the si-face selection with F3B-OEt2 results in r 1 I 53 a x P h H Me C02Bn t C b z N y SiMe3 58 Hawison: Saturated nitrogen heterocycles 213the ‘chelation controlled’ stereochemistry; cyclization of the resulting silicon cationic intermediate then provides the pr~duct.’~ Taguchi et al.35 have described a highly stereoselective zirconium-mediated ring contraction reaction of vinyl morpholine derivatives 59 (readily prepared from amino acids) leading to 2,3,4-trisubstituted pyrrolidines 60.The stereochemistry of the final product is independent of diastereoisomers generated at any step in the synthesis of the starting vinyl morpholines 59, and depends only on the absolute configuration of the starting amino acid (Scheme 6).35 R2 r 2.2 Pyrrolidinones The use of radical chemistry for the preparation of lactams is currently undergoing a resurgence.In studies directed toward synthesis of the kainoids, Taylor et al. have investigated the radical cyclization of the serine-derived a-chloroamides 63. In general, radicals substituted at the a-position (R’, R2 = Me, H; Ph, H; Clz) were found to cyclize more efficiently than the unsubstituted derivative^.^^ Zard et al. have reported the remarkable reagent system of nickel powder and acetic acid for effecting a similar cyclization. This particularly mild and selective method extends the scope of radical cyclizations of a-halo amides by allowing atom transfer cyclizations and intermolecular trapping of the cyclized radicals with radical traps, i.e. cyanide, TEMPO, 02.39 r R2 63 6 2 60 Scheme 6 Panek et al.have described an asymmetric synthesis of the highly functionalized pyrrolidines 62 by low temperature condensation of chiral (E)-crotyl silanes 61 with in situ generated achiral N-acyl imines derived from aromatic aldehyde^.^' This study represents the first asymmetric addition of a chiral ally1 silane to in situ generated imines. F3B-, +,C02Me ?( + w C 0 2 M e th&iPh 61 X = H, OMe Ar x, A CH2C12 -78 “C \ MewsiMe2Ph CH2C12 -100-+-78°C OMe ‘ 0 Ar ArAOMe +H2N KOMe C02Me 62 Finally, a review detailing the hetero Diels-Alder reaction with nitroso dienophiles has been published.37 The adducts can be easily transformed into pyrrolidines via stereospecific reactions. Magnesium-methanol is a simple, yet selective, reagent for the reduction of a, P-unsaturated esters.This method has been used in a one-pot synthesis of 5-substituted 2-pyrrolidinones 65 from the N- alkoxycarbonyl y-amino a, P-unsaturated carboxylates 64 without ra~emization.~’ An alternative approach to pyrrolidinones starting from y-amino a, P-unsaturated carboxylates 66, involves Michael addition of nitromethane followed by reduction of the nitro group with Raney nickel. Reasonable diastereoselectivity is observed in the addition leading to 3-aminoethyl substituted pyrrolidines 67 after spontaneous ring closure (Scheme 7).41(a) Mg in MeOH - 0 H 64 65 66 Scheme 7 67 Finally, pyrrolidines can be prepared in good yield by cyclization of p, y-unsaturated amides using trifluoromethanesulfonic a ~ i d . ~ ’ ( ~ ) 3 Six-membered rings 3.1.1 Piperidines via [4 + 21 cycloaddition reactions The asymmetric hetero Diels-Alder reaction has recently been reviewed.42 For the construction of 214 Contemporary Organic Synthesispiperidine rings, either hetero-dienes or hetero- dienophiles (imines) can be employed.A number of papers have appeared describing chiral aldimines derived from amino acids, e.g. 68,43 from ethyl lactate, e.g. 69,44 and from chiral iron-tricarbonyl complexes, e.g. 70.45 These chiral dienophiles react with electron rich dienes, e.g. Danishefsky's diene, under Lewis acid catalysis to afford 4-piperidinone derivatives with good selectivity. 68 X = 0, H2 69 70 2-Amino-1,3-butadienes such as 71 react with non-activated achiral aldimines derived from aromatic aldehydes under the aegis of ZnClz to afford 4-piperidinone derivatives 72 after hydrolysis.The stereoselectivity of the reaction is very high but strongly dependent on the nature of the imine.46 Amino-dienes, such as 71 but bearing a proline- derived chiral amine, have been shown to undergo stereoselective aza-Diels-Alder cycloaddition with N-silyl aldimines to provide 4-piperidinone derivatives with high enantiomeric excess.47 (OR ,OR2 71 72 Unactivated imines, such as 73, derived from alkyl aldehydes and bearing a-hydrogens, react smoothly with 2-siloxy-l,3-butadienes using TMSOTf as catalyst.48 Gilchrist et al. have reported that the 2-azadiene 74 undergoes [4 + 21 cycloaddition with both electron rich (e.g. enamines) and electron poor dienophiles (eg. methyl vinyl ketone).In general yields are moderate to poor, and in all cases the cycloadditions were highly regioselective but not stereo~elective.~~ Y O z M e 'f " Ar 74 73 R', R2 = alkyl, H In an extension of his earlier work, Ghosez has reported that chiral aza-dienes 75 derived from a, /?-unsaturated aldehydes and Enders' hydrazines cycloadd to cyclic dienophiles with high facial selectivities. The adducts can be readily converted into enantiopure piperidine derivative^.^' To date, efforts to employ less reactive dienophiles, such as methyl acrylate or dimethyl fumarate, have proved unsuccessful. 4 0 3.1.2 Piperidines via intramolecular cyclization Cyclization of the homochiral urethane 76 under palladium catalysis occurs with efficient chirality transfer, affording the homochiral piperidine 77 in good yield." A Pdo-catalysed intramolecular N- alkylation forms the key step in a synthesis of piperidine alkaloids described by Tadano et al.Thus, treatment of the allylic chloride 78 with NaH in the presence of catalytic Pdo led to the piperidine derivative 79 with high dia~tereoselectivity.~~ 76 77 Alkaloids containing a 2,6-disubstituted piperidine system are ubiquitous in nature: in general the trans-isomers are less available than the corresponding cis-isomers. Asymmetric dihydroxylation of the N-alkenyl urethane 80 derived from D-alanine provides a mixture of (i) TBDMSCVimid (iii) H$Pd(OH), (ii) MSCIEt3N 1 82 Harrison: Saturated nitrogen heterocycles 215diastereoisomeric alcohols 81 which, after protection of the primary alcohol and activation of the secondary alcohol, undergo ring closure to afford the trans-2,6-disubstituted piperidine 82 as the major (3 : 1) isomer.53 4-Hydroxy-5hexenylamines such as 83 have hitherto proved fairly unreactive toward electrophilic cyclization.However, carbamates, sulfonamides, and amides of these precursors undergo efficient selenium-induced cyclization in the presence of silica gel and anhydrous KzCO3 to give predominantly tran~-2-(phenylselenomethyl)- 3-hydroxypiperidines 84 in moderate yield. The selenium moiety can be replaced by a hydroxyl group, following oxidation to the selenone and nucleophilic displacement with NaOH.54 83 84 major (3421) (I) MCPBA (ii) NaOH I U Y O H R An extremely versatile approach to either cis- or trans-2,6-disubstituted piperidines involves the stereoselective cyclization of an a-cyanoarnine containing a vinyl group induced by TiCI4.When the vinyl group is unsubstituted, the cis- diastereoisomer 85 is formed whereas when the vinyl group contains a silyl substituent the trans- isomer 86 is the exclusive 85 1 I Pr R = H, SiMe (R = SiMed 1 87 , I 88 PhsP, DEAD I K 8Q 3.1.3 Piperidines via miscellaneous methods Homes et al. have utilized an intramolecular nitrone cycloaddition to assemble the key piperidine ring in an enantioselective synthesis of the azasugar deoxynojirimycin 90." The aza-sugar skeleton is secured by the kinetic preference for a six- membered ring over a seven-membered ring during the initial carbon-carbon bond formation. ,OSiBu'Me, B d P h & i i R OBn OSiMe,Bu' OBn 2 - O The use of pyroglutamic acid as a starting material for natural product synthesis is well established.Thus, N-Boc pyroglutamate ethyl ester 91 can be ring-opened with the lithiated sulfoxide 92 91 - TFAAIPy i 1 Amino-alcohol derivatives such as 88 (obtained by sequential addition of the bis-metallic reagent 87 to an imine, then an aldehyde under Lewis acid catalysis) can be cyclized under Mitsunobu conditions to provide piperidines, e.g. 89 although diastereoselectivity is Scheme 8 TdS O n p;' C02Et Boc 94 2 16 Contemporary Organic Synthesisto first provide the adduct 93. This material then undergoes Pummerer rearrangement with concomitant intramolecular cyclization leading to the 5-0x0 pipecolic acid derivative 94 in near quantitative yield (Scheme 8).This route provides a new synthetic approach to this important class of natural products.58 homochiral piperidines such as 97 starting from the optically active enaminoester 95. The route involves conjugate addition of 95 to an a,p-enone, followed by reductive cyclization-fragmentation to octahydroimidazopyridines 96, and finally further reduction to remove the auxiliary atoms.59 In this sequence 95 functions as a homochiral 'ethanol enamine' equivalent. Jones et al. have reported a new route to (ii) BH3. THF then Ph" 50% aq. H2S0, Ph" [ H$ I; 96 \** Q H 97 3.2 Piperidones In a series of publications, Stille et al. have described a synthetic approach to the 2-piperidone derivatives 98 utilizing the aza-annulation of enamines with acryloyl chloride (Scheme 9).This strategy provides a convergent route for the construction of six-membered nitrogen heterocycles, and has been illustrated by the total synthesis of a range of alkaloid^.^'-^^ '0 *.-* ' 0 98 Scheme 9 Homochiral3-substituted-2-piperidinone derivatives such as 100 are obtained by alkylation of the corresponding hydroxy lactam 99; the excellent diastereoselection observed can be rationalized via the chelated amide enolate intermediate 101.64 An interesting approach to 2-piperidinone derivatives utilizes an intramolecular hetero Diels-Alder reaction from the chiral acylnitroso compound 102. The diastereoselectivity of the process is significantly enhanced when the reaction is carried out in a aqueous solvent system, producing the major trans-isomer 103 in a 4.5 : 1 ratio.The lactam 103 was subsequently converted into ( -)-pumiliotoxin C.65 99 L 100 101 L 102 I BnO H p o 103 Two reports detailing novel approaches to 3-piperidinones have appeared. In the first of these, West et al. have utilized the Stevens rearrangement of ammonium ylides 105 to generate 2-substituted- 3-piperidinones 106. The ylides 105 can be generated by rhodium(I1)-catalysed decomposition of amino-bearing diazo-carbonyl compounds 104. In all the cases studied the carbon with the best radical stabilizing substituent was found to undergo migrat ion.66 L 105 104 R' = CH2Ar2, CH2C02Me R2 = Me, Et 106 Alternatively, a-silylamino-enones and ynones 107, which are readily prepared from amino acids, undergo photoinduced radical cyclization under SET conditions to provide 3-piperidinone derivatives 108.This 6-endo cyclization has been shown to proceed with high levels of diastereoselectivity .67 108 Harrison: Saturated nitrogen heterocycles 217A particularly facile synthesis of 2,6-disubstituted 4-piperidinones 109 has been described by Edwards et al. where the condensation between an a, P-unsaturated ketone, an aldehyde, and an amine gives the products 109 with generally high cis- selectivity.68 The yields are poor (20-35%), but the operational simplicity of a one-pot reaction should make this a useful synthetic method. 109 Thermolyses of amino ethylalkynyl ether derivatives 110 at 150°C produce the corresponding ketenes which can be trapped intramolecularly, leading to the lactams 111. This methodology can be used to produce 6-15 membered lactams in good to excellent yield.69 NHBn Brl 111 110 (n= 1-10) 4 General methods for the construction of nitrogen heterocycles of varying ring sizes 4.1 Monocyclic heterocycles A review detailing the synthesis of medium-sized rings by ring expansion reactions has been p~blished.~' The use of iminophosphoranes as useful building blocks for the preparation of nitrogen heterocycles (ma-Wittig reaction) has also been reviewed.71 Beak et al.have reported a general approach to nitrogen heterocycles via a lithiation/ intramolecular cyclization sequence. Using this methodology a variety of easily prepared acyclic N- Boc amines 112 are transformed to the cyclic products 113.72 Epoxides as well as halides have been used as the leaving group X.112 113 Kim et al. have reported novel cyclizations involving alkyl azides leading to nitrogen heterocycle^.^' In this approach, the heterocycle is generated by direct carbon-nitrogen bond formation via addition of an alkyl radical to an azide (Scheme 10). Of key importance to the success of this approach was the finding that azides are relatively inert to tris(trimethylsily1)silyl radical, thus allowing chemoselective alkyl radical generation from an iodo a i d e 114 without concomitant azide reduction. 114 Scheme 10 The intramolecular cyclization of alkenes onto iminium ions provides a versatile method for the construction of nitrogen heterocycles. Mariano et al. have described the oxidation of a-silyl amines 115 as a mild, regioselective method of iminium ion generation.Both photoinduced single-electron transfer and metal-based oxidants can be used.74 In related work, Pandey et al. have demonstrated that a-silyl amines such as 116 undergo efficient cyclization upon photoinduced electron transfer leading to pyrrolidines and piperidines. These authors invoke a delocalizaed a-silylmethylamine radical cation as an intermediate (Scheme ll).75 I Ph I Ph 115 Scheme 11 Buchwald et al. have reported that cyclic amines 118 can be produced with very high e.e.3 by catalytic asymmetric hydrogenation of the corresponding cyclic imines 117 using a chiral titanocene catalyst. The reaction is general for cyclic imines of ring size 5-7 and exhibits a high degree of functional group ~ompatibility.~' 117 (if 2Bu"Li (ii) 2.5 - 3 PhSiH3 H2* chirai catalyst (1 -5 n?d%) R =Q" H 118 71 - 86% yield 95 - 99% e.e.n = 1-3. Cyclic imines such as 117 are conveniently prepared by the tandem addition-cyclization of Grignard reagents to co-bromonitriles 119. The use of hydrocarbodether solvent mixtures to suppress enolization of the nitrile is critical to the success of this reaction.77 218 Contemporary Organic Synthesis119 117 Cyclic imines bearing both C-2 and C-3 substituents such as 120 are useful precursors for the generation of cis-2,3-disubstituted pyrrolidines and piperidines 121. These imines undergo stereoselective reduction (NaCNBH3, AcOH, EtOH, OOC) from the less-hindered face of the heterocycle, leading to the cis-products 121 with high ~electivity.~’ Terminal alkenes containing a remote carbonyl group, e.g.122, react with iodobenzene diacetate, diphenyl diselenide, and sodium azide to afford the products of anti-Markovnikov azido- phenylselenenylation of the double bond, e.g. 123. Addition of triphenylphosphine to these products produces the corresponding imines 125 bearing a pendant phenylselenyl moiety via the iminophosphorane intermediate 124 (Scheme 12).79 122 123 Php, PhH 1 R = alkyl, aryl,OMe #= 1,2. L 125 124 Scheme 12 Nitrohydroxylated pyrrolidines and piperidines 127 are conveniently prepared through a one-pot procedure involving initial Michael addition of a nitrogen nucleophile bearing a latent aldehyde to nitroethylene. The latent aldehyde is directly trapped in a subsequent nitroaldolization step. Both the amino alcohols 126 and the amino esters 128 can function as the nitrogen nucleophile.’’ The products can be transformed into a range of useful products, including amino alcohols. Ph I (ii) Swern Ph/ C02Me ‘+iH Ph I 126n=1.2 127 128 Naito et al.have reported an alternative route to amino alcohols which involves intramolecular radical cyclization of oxime ethers which are tethered to an aldehyde or ketone 129. The reaction is mediated by tributyltin hydride, and in general the trans-isomers predominate. Yields are moderate.’l 0 NOMe OH NHOMe OH NHoMe 129m= 1,2,3 n= 1.2 In a useful extension to earlier work, Larock and Weinreb have described a versatile synthesis of the 2-( 1-alkeny1)pyrrolidine sulfonamides 130 starting from simple vinylic halides and unactivated olefinic sulfonamides.” The sequence proceeds via vinyl palladium addition to the olefin, followed by regioselective rearrangement to a .n-allylpalladium intermediate, and subsequent intramolecular nucleophilic displacement of palladium.NHTS R b X n - 1.2 X = Br, I, OTf Pdo i Ts 130 4.2 Bicyclic and polycyclic heterocycles trans-Fused bicyclic pyrrolidines and piperidines such as 132 can be prepared from a-halogenoalkyldichloroboranes 131, following amination with benzylazide and intramolecular nucleophilic substitution; the precursors 131 are readily prepared either by hydroboration or Diels-Alder reaction.g3 131 LPh 132 Viehe et al. have described a general, diastereoselective synthesis of the fused heterocycles 135 based on the ‘a-cyclization of tertiary arnine~.”~ The reaction is thought to proceed via initial [2+2] cycloaddition of DEAD to the enamine 133, followed by ring-opening and hydrogen shift to generate the cyclization precursor 134 (Scheme 13).Harrison: Saturated nitrogen heterocycles 219133 n = 1 - 4 El& c--- R 135 Scheme 13 134 The intramolecular cyclization of a tethered nucleophile onto an iminium ion provides one of the most useful methods for the synthesis of nitrogen heterocycles. By careful choice of the group on nitrogen, Overman et al. were able to selectively prepare either stereoisomer of the 1-substituted octahydroisoquinoline 137 by reaction of the allylsilane 136 with an aldehyde.” The reversal of selectivity is attributed to non-bonded interactions between R’ and R2 in the cyclization transition state when R’ is large. + eCH0 R’HN 136 I 137 favoured with favoured with large R’ small R’ Rigby et al.have utilized a relatively uncommon 7-endo radical cyclization process for construction of the hydroapoerysopine ring system 138. None of the corresponding product derived from a 6-ex0 pathway was detected, and the formation of the trans-fused product is noteworthy.86 The cyclization was unsuccessful under palladium-mediated cyclization conditions. Bu”3SnH AIBN (65%) J$ / Me0 \ MeO Finally, Padwa et al. have described a powerful approach to polyheterocyclic ring synthesis based on a tandem cyclization-(dipolar cyc1oaddition)- cationic cyclization sequence.87 Thus the a-diazoimides 139 undergo cyclization-cycloaddition under the aegis of Rh2+ to provide oxabicyclic amides 140.These useful cycloadducts contain a ‘masked’ N-acyliminium ion which is able to further react with an internal tethered nucleophile leading to more-complex heterocyclic systems (141). The approach is specifically illustrated by conversion of the a-diazoimide 142 into the tricycle 143 (Scheme 14). 1 39 1 40 141 Bn 142 143 Scheme 14 5 Pyrrolizidine, indolizidine, and quinolizidine ring systems 5.1 Pyrrolizidines Aminyl radicals generated from sulfenamide precursors, e.g. 144, undergo tandem radical cyclization in the presence of low concentrations of C02Me GN+ OMe R h 2 ( 0 A ~ ) 2 ~ PhMe,A e0 (73%) 0 0 146 147 OMe 138 148 220 Contemporary Organic SynthesisBu3SnH to provide the pyrrolizidine skeleton 145.88 Kim et al. have utilized a diazoketo ester-thioimide cyclization of the precursor 146 to generate the bicyclic lactam 147, which was readily converted into ( & )-supinidine 14tLs9 An unusual approach to the pyrrolizidine skeleton involves the photocatalysed addition of N- substituted pyrrolidines to the butenolide 149.The adduct 150 undergoes cyclization in the presence of KOBu' to provide the lactam 151, which has the ring skeleton and stereochemistry of the pyrrolizidine alkaloid lindel~fidine.'~ I SiMe3 bnzophenone MeCN 149 p (N) TBDMSO "OH 150 KOBd THF I 151 5.2 Indolizidines Shibasaki et al. have used a catalytic asymmetric Heck reaction for the synthesis of the indolizidine derivative 153 starting from the prochiral alkenyl iodide 152. Enantiomeric efficiencies of up to 86% have been obtained." An alternative approach to homochiral indolizidine derivatives involves thermal rearrangement of isoxazolines, e.g. 155, which are H 0 152 0 153 L N 0 2 Ph PhNCO, EtaN, Et& 154 155 1 A 156 prepared from homochiral (R)-( - )-2-chloro- Snitropentane 154, via nitrile oxide cy~loaddition.~~ The diastereoisomeric indolizidines 156 are obtained with 96% e.e.The enantioselectivity of the thermal rearrangement is dependent on the experimental conditions and on the structures of the chiral isoxazolines. indolizidine skeleton involve substituted pyrroles as precursors. Thus, diethyl-L-glutamate. HCl (157) undergoes reaction with 2,5-dimethoxy tetrahydrofuran to provide the pyrrole 158 without racemization. Following Friedel-Crafts acylation (BBr,), the homochiral keto-pyrrole 159 can be reduced to either the indolizidine 160 or the hydroxy derivative 161 depending on the catalyst used (Scheme 15).93 A similar approach using L- glutamic acid and HCl/MeOH for the Friedel- Crafts step has previously been described by Taylor et aZ.94 A number of synthetic approaches to the 157 Me0 158 161 160 159 Scheme 15 Pipecolic acid derivatives contain useful functionality for further elaboration to the indolizidine skeleton.As the key step in a total synthesis of ( + )-monomorine (164) Angle et al. have used the conformationally restricted Claisen rearrangement of the lactone 162 to produce the pipecolic acid derivative 163. This intermediate was transformed into the natural product in just three operation^.^' 162 1 63 1 64 Both K e ~ k ~ ~ and Kibaya~hi~~ have described a new chiral route to (-)-swainsonine (168) and related compounds based on an intramolecular acylnitroso cycloaddition.The Kibayashi approach is summarized in Scheme 16. In both cases the diastereomeric ratio of the product 1,2-oxazines 166 and 167 was low when CH2C12 or CHC13 was used as solvent. However, some improvement in diastereoselectivity and yield was achieved when the reaction was conducted under aqueous condition^.^^ Harrison: Saturated nitrogen heterocycles 2210 0 0 165 168 Scheme 16 CHCI,; 1.3 : 1 H20 4.1 : 1 + BnO Q-3 u 167 Wasserman et al. have further extended the use of vicinal tricarbonyls to the synthesis of the indolizidine alkaloid ( f )-slaframine. The key step in the synthesis is the intramolecular alkylation of the N-substituted 3-hydroxypyrrole derivative 171 to provide the indolizidine skeleton 172.The hydroxy pyrrole 171 was itself prepared in a single step by reaction of the primary amine 169 with the vicinal tricarbonyl 170.98 OH silica gel &OBn OTBS 0 0 1 70 5-40.. Y OTBS 172 Finally, Pearson et al. have developed an intramolecular variant of the Schmidt reaction of azides with carbocations for the construction of nitrogen heterocycles. Thus, upon treatment with triflic acid the alcohol 173 undergoes ionization and the resulting carbocation is captured intramolecularly to produce an aminodiazonium ion intermediate. Carbon-to-nitrogen bond rearrangement then occurs providing the indolizidine 174 in 47% yield.99 By appropriate choice of starting material a range of interesting bridged or fused nitrogen heterocycles (e.g.quinuclidines) can be prepared with reasonable efficiency. HO '' Q N3 b f 2 173 1 74 5.3 Quinolizidines Beckwith et al. have described the highly diastereoselective formation of substituted indolizidines and quinolizidines 176 by intramolecular radical cyclization starting from the bromides 175. In all cases studied the radical intermediate approaches the side of the double bond anti-to the substituent at C-2 with high selectivity.lW 175 1 76 In an extension of earlier work. West et al. have utilized the Stevens [l, 21-shift of cyclic ammonium ylides in an enantioselective route to the quinolizidine ( - )-epilupinine. Thus, treatment of the diazo ketone 177 with Cu(acac)2 provided the bicyclic ketone 179 with high diastereoselectivity (178: 179 = 5 : 95) and 65-75% e.e.(Scheme 17). Much lower diastereoselectivity (178 : 179 = 1 : 3) was obtained using Rh2(OAc)4 as the catalyst.'" 177 1-0 0 L J Bn02C H 0 (35 Bno& 178 179 Scheme 17 Finally, Martin et al. have disclosed a novel technique for the efficient synthesis of fused nitrogen heterocycles based on the molybdenum alkylidene-catalysed 'metathesis of the a, cu-dienes 180. These precursors are readily prepared from succinimide and glutarimide in three steps, and they undergo efficient ring-closing methathesis in the presence of the catalyst 182 to provide the corresponding bicycles 181 in 65-90% yields.lo2 222 Contemporary Organic Synthesis1 8 0 ~ = 1,2 n=0-3 20 Y. Yuasa, J.Ando, and S. Shibuya, J. Chem. SOC., 21 M. Tokuda, H. Fujita, and H. Suginome, J. Chem. 22 M. Newcomb, J.H. Horner, and H. Shahin, 23 I. Ryu, A. Kurihara, H. Muraoka, S. Tsunoi, N. 24 (a) J.E. Baldwin, S.C. MacKenzie Turner, and M.G. Chem. Commun., 1994,1383. SOC., Perkin Trans. 1, 1994, 777. Tetrahedron Lett., 1993,34, 5523. Kambe, and N. 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ISSN:1350-4894    

DOI:10.1039/CO9950200209

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

Synthesis and use of cyclic peroxides K. J. McCULLOUGH Department of Chemistry, Heriot- Watt University, Riccarton, Edinburgh EH14 4AS, UK being used in the treatment of some drug-resistant forms of malaria, especially Plasmodium falcipamm. A second, lesser-known, peroxidic antimalarial agent, (+)-yinghaosu A (4), with an unusual dioxabicyclo[3.3.l]nonane ring system has been isolated from the leaves of Artabotrys uncinatus (L.) This review covers primarily the literature published between January 1992 and January 1995 inclusive although selected Papers appearing in 1991 are also cited. 1 2 3 4 5 5.1 5.2 6 7 8 Introduction 1,2-Dioxetanes traditional Chinese herbal remedy."' 1,2-Dioxolanes Mew. which are also used as the basis of a 1,2-Dioxanes and related compounds Ye OH Polycyclic 1,2,4-trioxanes related to artemisinin I .*H Ketone cyclic peroxides Hb Miscellaneous endoperoxides 0 Me Simple 1,2,4-Trioxanes 1,2,4-trioxanes and related compounds Me? 6y9' Me OH Me I 3 4 Cyclic peroxides derived from ozonolysis reactions In addition to considerations of their biological 9 References 1 Introduction A resurgence in the chemistry of cyclic peroxides and related compounds has been stimulated by the isolation and characterization of several natural products which not only have a cyclic peroxide unit incorporated into their structure but also possess attractive pharmacological properties. A range of naturally occurring cyclic peroxides, as exemplified by plakortin (1) and muqublin (2), have been isolated from a variety of marine organisms; many of these compounds have considerable potential as antibiotics.' activity and structural novelty, cyclic peroxides of various types have also been employed extensively as key intermediates for the introduction of oxygen functionality into organic compounds with a high degree of stereo- and regio- selectivity. In most of the strategies which have been developed for the synthesis of cyclic peroxides, irrespective of their structural complexity, the peroxide group is preformed, being introduced into the molecule as either molecular oxygen or hydrogen peroxide or, in some cases, ozone.Moreover? since they are intrinsically thermally labile and are highly susceptible to attack by reducing agents, the range of reagents compatible with cyclic peroxides is generally limited. This review will attempt to highlight recent developments in the synthesis of cyclic peroxides with ring sizes from four upwards, and, where appropriate, their subsequent chemical transformation into other classes of organic compounds. 2 1,2-Dioxetanes Although the four-membered ring 1,2-dioxetanes hyperenergetic (i.e.they generate electronically excited fragments on thermal decomposition), several stable derivatives have been synthesized by either intramolecular cyclization of P-halo hydroperoxides (Kopecky method), or by [2 + 21 cycloaddition of singlet oxygen to alkene~.~ Treatment of 1,l-disubstituted alkenes with concentrated hydrogen peroxide and 1,3-dibromo- 5,5-dimethylhydantoin (DDH) affords the Me0& m ; T 0 0 Me Me are highly strained and, as a consequence? Me The 1,2,4-trioxane derivative ( + )-artemisinin (qinghaosu) (3), which has been identified as the active component of a traditional Chinese herbal medicine obtained from leaves of Aternisia annua L., has attracted a great deal of recent On account of their high potency and low human toxicity, artemisinin and related compounds are now McCullough: Synthesis and use of cyclic peroxides 225corresponding /?-bromo hydroperoxide which subsequently undergoes base-catalysed cyclization to the 3,3-disubstituted 1,2-dioxetane 5 (Scheme 1).* 1,ZDioxetanes derived from a-styrene derivatives have been prepared in low yield (10-15%) by a similar method.’ 5 Scheme 1 Although the [2 + 21 cycloaddition of singlet oxygen to simple alkenes can provide a direct synthetic route to l,Zdioxetanes, alternative processes, including the formation of hydroperoxides via the ene reaction or [4 + 21 cycloaddition, often compete readily.7.lo The formation of dioxetanes is, however, generally more favoured with electron-rich alkenes such as enol ethers. been prepared in high yield by the photosensitized oxygenation of the enol ethers 6 using 9,lO-dicyanoanthracene (DCA) as the sensitizer.’ The reaction of enol ethers 6 with ground state molecular oxygen at -78°C in the presence of either tris(p-bromopheny1)- or tris(o,p- dibromopheny1)-ammoninium hexachloro- antimonate also gives rise to 1,Zdioxetanes 7.12 In both cases, the reaction proceeds via the appropriate radical cation derived from 6 which is generated by single electron transfer (SET).A series of thermally stable 1,Zdioxetanes 7 have e R 1 R2 or cat. I O2 I -78 “c 7 6 R‘ = Me, CH2Ph, R2 = aryl On photooxygenation of the dicyclopropyl enol ether 8, the corresponding dioxetane 9 is only obtained as the major product when the reaction is carried out at -78°C. At higher reaction temperatures, the hydroperoxide 10 is the major product. l3 8 Ar = 3-MeOC6H4 9 10 Photooxygenation of the cadinene derivatives 11 and 12 has resulted in the formation of the novel ring-cleaved dioxetanes 13 and 14 respectively which exhibit modest antimalarial activity.14 r- 11 X=AC 12 X = H H ? 0 I1 M”;o\,,, OH ps 13 Me 0-- ?--U 14 & The comparatively rare diastereoisomeric bisdioxetanes 15 (68%) and 16 (20%) along with the endoperoxide 17 (12%) are obtained from the photooxygenation of the electron-rich tetramethoxybenzobarrelene at - 30°C with tetraphenylporphyrin (?TP) as sensitizer.l5 OMe 0-0 15 16 17 Thermolyses of 1,2-dioxetanes, which give rise to electronically excited carbonyl fragments, have been extensively studied because of their mechanistic importance in bioluminescent processes and their potential application in molecular biology for imrn~noassay.~ More recent studies have been directed towards chemical transformations of 1,Zdioxetanes. The thermal decomposition of 3,3-dibenzyl- 1,2-dioxetane 18 has afforded, in addition to the expected dibenzyl ketone (ca. 70%), a novel rearrangement product 19 (ca. 30%) which arises from a benzyl radical induced decomposition 0-0 VHZPh CHzPh 18 I A Scheme 2 ,CH,Ph A O 1 * CH2Ph + o PKH2 0oaCH2Ph 19 Me0 OMe OMe P h C H 2 L I z o M e OMe OMe PhCHz 226 Contemporary Organic Synthesispathway.l67l7 The intermediate 1,4-dioxy diradicals from 18 and other 3,3-disubstituted dioxetanes form cycloadducts with electron-rich alkenes such as tetramethoxyethene and 1,4-dioxene (Scheme In addition to appreciable quantities of ring cleavage products, 3,3-disubstituted dioxetanes 20 react with n-butyllithium, via a regioselective SN2 displacement process on the peroxide bond, to yield the corresponding fl-hydroxy ether 21 and, if X = Br or C1, epoxy ether 22 (Scheme 3).* Heteroatom nucleophiles, including amines, sulfides, cyanide, thiocyanate, hydroxide, and halide ions, are also considered to attack the 3,3-disubstituted dioxetanes 20 at the less-hindered oxygen atom of the peroxide bond, giving rise to addition, deoxygenation, and fragmentation product^.'^ With secondary amines, dioxetanes 20 are transformed into hydroxylamine derivatives 23.Moreover, the formation of the N- alkoxyammonium bromide salt 24 from the reaction of 20 (X = Br) with triethylamine is consistent with the SN2 mechanism proposed (Scheme 3). 2). 16, l8 Scheme 3 In a similar fashion, enamines react with dioxetane 18 to yield, after hydrolytic work-up, a-alkoxy ketones 25 in moderate to good yield (Scheme 4).20 0-0 + q C H 2 P h CH2Ph 18 (i) CH2CI, -20 to 0 "c (ii) dil. HCI, 40 "C OH 1 0 25 Scheme 4 McCullough: Synthesis and use of cyclic peroxides 1,3-Dioxolanes 26, which are formally products derived from carbene insertion into the peroxide bond, have been obtained from the reaction between 1,Zdioxetanes and diazoalkanes.21 Since these reactions were carried out at low temperature, carbenes are considered unlikely to be involved.It is proposed that the reaction proceeds by an initial nucleophilic attack of the negatively charged pole of the diazoalkane on the peroxide bond followed by ring closure with concomitant elimination of nitrogen (Scheme 5). 26 R' = Me, Ph t? = Me, CH2Ph Scheme 5 Triphenylalkylidenephosphoranes, being nucleophilic in character, also insert into the peroxide bond of a 1,Zdioxetane to give phosphonium alkoxides 27 which exist in equilibrium with their ring-closed isomers.22 On deprotonation, the phosphonium alkoxide 28 participates in a Wittig reaction with benzaldehyde to give the hydroxy enol ether 29 in moderate yield.R3 R4 E1& or + toluene b P h 3 -78 "c Me Me 27 11 Ph fo\ (i) NaH, THF. A L Me+OH Me+O+bph3 (ii) PhCHO, THF, 20% 29 Me Me 28 The synthesis and chemical transformation of dioxetanes derived from heterocyclic compounds, particular benzofurans and indoles, has attracted some attention. photooxygenation of the furan 30 affords initially the endoperoxide 31 in quantitative yield which rearranges in solution or on silica gel to give the first isolable furan derived 1,Zdioxetane 32.23 On treatment with catalytic quantities of Consistent with its diene character, in 227tetraethylammonium bromide, 32 rearranges cleanly to the spiroepoxide 33. Deoxygenation of 32 using either diphenyl sulfide or triphenylphosphine gives the enedione 34 (Scheme 6).M.. - Me- /A or silica gel Me Scheme 6 Benzofuran dioxetanes 35 undergo an unprecedented bromide ion catalysed rearrangement to yield the novel spiroepoxides 36 as the major products unless either of the substituents R', R2 are phenyl groups, in which case fragmentation products 37 pred~minate.~~ The labile epoxides 36 dimerize at low temperature in solution to give 38, form [4 + 21 cycloadducts 39 with 4-methyl-l,2,4-triazoline-3,5-dione (MTAD), and rearrange to benzodioxoles 40 on thermolysis (Scheme 7). 35 R1, R2 = Me, Ph 37 + 40 36 R1 39 Scheme 7 0 38 Photosensitized oxygenation of N-acyl indoles results in the formation of comparatively stable 1,Zdioxetanes 41 though hydroperoxides 42 are also formed if there is an abstractable allylic hydrogen on the 3-s~bstituent.~~-*~ Since N-acylation deactivates the indole ring nitrogen, the 1,Zdioxetanes 41 are stable enough to be isolated and characterized at low temperature by spectroscopic techniques.At moderate temperatures, the 1,Zdioxetanes 41 decompose quantitatively, producing keto amides 43, accompanied by intense chemiluminescence.26 On treatment with dimethylsulfide or trimethyl phosphite, dioxetanes 41 are deoxygenated to the corresponding epoxides 44 which subsequently rearrange to either 2-methyleneindolines 45 or 2-indolinones 46 depending on the nature of the substituents R' and R2 (Scheme 8).27-29 AC 41 AC 42 R2 I 41 AC Scheme 8 45 AC 46 Epoxides analogous to 44, which are known to be highly mutagenic, have been shown to be key intermediates in the deoxygenation of dioxetanes derived from 2,3-dimethylbenzofuran, 2,3-dimethylindene, and 2,3-dimethylindole by triphenylphosphine (Scheme 9).30 I X = 0, CHz, N-BOC Scheme 9 228 Contemporary Organic Synthesis3 1,2-Dioxolanes 1,2-Dioxolanes are usually synthesized by a variety of radical-mediated oxygenation reactions or by intramolecular cyclization of allylic or homoallylic hydroperoxides.vinylcyclopropyl esters in the presence of diphenyl diselenide and AIBN affords mixtures of the diastereoisomeric 1,2-dioxolanes 47 and 48 via the radical-catalysed oxygenation sequence outlined in Scheme The stereoselectivity, which generally lies in favour of the trans-isomer 48, is particularly pronounced when the ester group substituent is strongly electron-withdrawing [e.g X = CH(CF3),].Irradiation of oxygenated solutions of 0-0 d c 0 , x ---co2x 0-0 PhSe . co*x P h S e ~ C 0 2 X 0 2 11 'ObQ _L P h S e w M C 0 2 X --- PhSe Scheme 10 1,2-Dioxolanes 50 are obtained from the photosensitized oxygenation of the electron-rich tetraaryl cyclopropanes 49 using hydroxyanthraquinones as sensitizers; DCA has also been used as a photosensitizer in analogous reactions.32 These reactions proceed via the corresponding intermediate radical cation, generated by an electron-transfer-induced process, which subsequently combines with molecular oxygen or superoxide (Oi-) to form 50 (Scheme 11). Singlet oxygen, generated thermally or photochemically, also reacts with similar cyclopropanes 51a,b in a non-stereospecific fashion to yield the dioxolanes 52a,b via 1,5-zwitterionic intermediates (Scheme 1 I A?--;$ + A+ 0-0 0-0 52a 52b Scheme 12 When solutions of the 2-cholesten-5a-01 derivative 53 are irradiated with visible light in the presence of di(acetoxyiodo)benzene (DIB), iodine, and molecular oxygen (2-5 atm.) the resulting alkoxy radical derived from 53 undergoes p-C-C bond scission followed by cycloperoxyiodination, affording the cyclic peroxide 54 as a mixture of isomers (ca.50% in total) (Scheme 13).34*35 Treatment of the product mixture with silica gel yields the enone 55. Under similar conditions, the hydroxy lactone 56 Droduces a mixture of iodo- and hydroxy-cyclic beroxides 57.35 OH 53 @ 0 55 Scheme 13 .NvT DIE, 12 hv - silica gel, pentane -HI - - I @ 0 5 4 Scheme 11 McCullough: Synthesis and use of cyclic peroxides 56 0 57 X=I,OH Instead of peroxides analogous to 54 and 57, the peroxylactones 58 and 59 are obtained from the photochemical reactions of the cyclic hydroxy ketones 60 and 61 with DIB or mercury(I1) oxide, iodine, and molecular oxygen."" Although the initial stages of the reaction mechanism are postulated to be similar to those described in Scheme 13 the corresponding oxy radical intermediates must 229undergo ring cleavage, thereby forming the peroxylactone moiety (Scheme 14).0 7 3 0 I 0 O 59 58 Scheme 14 The intramolecular addition of a peroxy radical to a double bond to give a 1,2-dioxolane ring is a key step in each of the sequences outlined in Schemes 13 and 14 and also in the biosynthesis of prostaglandins and related compounds.Synthetic application of this concept has now been partially realized in the conversion of arachidonic acid, via the hydroperoxy ester 62, into the methyl ester of PGGz 63 along with the 1Zepi-isomer 64 (15%, isomer ratio 1:3) (Scheme 15).37 For its success, this procedure required the development of a new catalyst, obtained from samarium(f1) iodide and molecular oxygen, to effect the efficient generation of peroxy radicals from the hydroperoxide 62. Although the overall yield is low and the product is obtained as a mixture of isomers, this procedure is commended by its inherent simplicity and represents the first biomimetic synthesis of PGG2. 63 W H 64 60H 15% yield, ratio 6354 1:3 Scheme 15 Thermal decomposition of a series of pyrazoline hydroperoxides 65 in the presence of molecular oxygen (1 atm.) yields the corresponding 3-hydroxy- 1,2-dioxolanes 66 in moderate yield (35-50%).388-40 The thermally stable cyclic hemiperketals 66 do not apparently exist in equilibrium in solution with the open chain forms at room temperature but decompose under acidic conditions, particularly with phenyl groups at the 5-position, to give pentane- 2,4-diones and phenols or alcohols (Scheme 16).40 65 R', R2, R3= Me, Ph Scheme 16 66 I H+ + Trapping of the relatively long lived triplet diradical derived from diazoalkane 67 by molecular oxygen (5 atm.) affords the dioxolane 68 as a 1:l mixture of diastereoisomers together with lesser quantities of the ring expanded endoperoxide 69 (Scheme 17).4' Photolysis of the bis-azoalkane 70 yields in a similar fashion the structurally novel bis- dioxolane 71.42 67 I O2 (5 atm.) 68 69 70 71 Scheme 17 On treatment with mercury(rr) acetate or nitrate, the allylic hydroperoxides 72 undergo 5-endo cyclization to give the intermediate mercuriated 1,2-dioxolanes 73 which are reductively demercuriated to yield in turn the 3-substituted- 1,2-dioxolanes 74 (Scheme 18).43 Homoallylic hydroperoxides 75 and 77 are transformed, via a similar reaction sequence, into 3,4- and 3,5-disubsituted dioxolanes 76 and 78 respectively.The cycloperoxymercuration step is highly regioselective with the mercury substituent invariably being placed on the least substituted 230 Contemporary Organic Synthesiscarbon. In the formation of 3,4- and 3,5-disubstituted dioxolanes 76 and 78, the reaction stereoselectivity varies with the nature of the mercury(I1) salt used and the steric requirements of the substituents.Generally, however, the trans- isomer tends to predominate for compounds 76 whereas there is a marked preference for the cis- isomer in 78. R = Pr', But, Ph, allyl X = OAc, NO3 72 73 74 - - 75 R = Me, allyl 76 HgX HgX2 NaBH4, H O - R o h k - OOH 5-exo-t@ 0-0 0-0 77 R = Me, ethenyl 78 Scheme 18 Cycloperoxymercuration-de hydridomercuration of the allylic hydroperoxide 79 affords 3-ethyl-5-n- propyl-1,2-dioxolane 80 exclusively as the cis-isomer in high yield (Scheme 19). Moreover, treatment of 79 with either NBS or bromine gives the 4-bromo derivative 81 directly (39% yield).44 I OOH 79 Scheme 19 80 Pr ePyy/ 0-0 81 4 1,2-Dioxanes and related compounds The six-membered 1,2-dioxane and 3,6-dihydrodioxine rings are found to be common structural features in many peroxy natural products.' Recent examples include the mycaperoxides A (82) and B (83) which have been extracted from a Thai sponge of genus Mycale and found to exhibit marked cytotoxicity and antiviral and a series of peroxyketal acids 84 and 85 which have been isolated from sponges of the Plakortis genus and shown to possess strong an tifungal act i ~ i t y .~ ~ 82 X = Me, Y = OH 83 X= OH, Y = Me ?Me Me H02C+ H 84 8 4 a R = -Me Me b R = dMe c R = 4 H02C H+ 85 a-b h e The [4+2] cycloaddition of singlet oxygen to an acyclic 1,3-diene, which would be expected to offer the most direct synthetic route to an unsaturated six-membered cyclic peroxide, yields predominantly dioxetanes, or their fragmentation products, and/or ene-products. Nonetheless, photosentitized oxygenation of the diene 86 using a sun lamp and rose bengal (RB) as sensitizer affords a mixture of the isomeric hemiperketals 88 and 89 in moderate yield (Scheme 20).47 More surprisingly, a mixture of 88 and 89 is obtained in high yield ( 7 5 4 5 % ) from the enone 87 under similar conditions using either RB or copper(r1) sulfate as sensitizer.In these reactions, superoxide rather than singlet oxygen is considered to be the reactive oxygenating species. Moreover, any enone or enal capable of undergoing photoenolization to give an intermediate dienol can 36 'c0,Me R = alkyl X R LC02Me 87 88 89 90 91 Reagents: (i) hv (sun lamp), RB, CH2Cl2-MeOH (19:l) Scheme 20 (ii) MeOH, TsOH, 25 *C McCullough: Synthesis and use of cyclic peroxides 231be transformed by this latter procedure into the corresponding hemiperketal. Subsequent acid- catalysed methanolysis of 88 and 89 yields a mixture of the methoxy compounds 90 and 91 which are readily separable by chromatography. Racemic chondrillin (90, R = n-C16H33) and plakortin (91, R = n-C16H33) have been successfully synthesized by this meth~dology.~~ Irradiation (sun lamp) of the y-hydroperoxy enone 92 results in double bond isomerization followed by spontaneous cyclization to produce the hemiperketal93 (60-90%, 1 : 1 isomeric mixture) which on treatment with methanol and pyridinium p-toluenesulfonate (PPTS) affords the perketal94 (Scheme 21).48 92 60H 93 (ii) I 94 Reagents: (i) hv (sun lamp), RB, CH2Ch-MeOH (19:l) Scheme 21 (ii) MeOH, PPTS Enal95 can be transformed into perketal 96 by a similar reaction sequence.On subsequent reaction of 96 with either titanium(1v) chloride or tin(1v) chloride and allyltrimethylsilane at - 78°C the 3-ally1 endoperoxides 97 are obtained in moderate yield (40-59%, cis:trans ratio 3:2) (Scheme 22).49 m S i M e 3 Or 0 SnC14 I Scheme 22 97 The reaction of a 1,l-diarylethene with tris(2,4- pentanedionato)-manganese(~~~)(Mn(acac)~) in the presence of air at room temperature affords the corresponding 4-acety1-3-hydroxy-1,Zdioxane 98 in high yield.50 More generally, oxidative free-radical cyclization reactions take place readily when Mn(a~ac)~ is replaced by a 1,3-dicarbonyl compound and manganese(II1) acetate, giving rise to a series of hemiperacetals 99 (Scheme 23).50-54 Typical substrates include 1 , 3 - d i k e t o n e ~ , ~ ~ ~ ~ ~ P-keto e s t e r ~ ; ~ .~ ~ and acetoa~etamides.~~ Active methylene compounds such as P-keto sulfoxides, sulfones, and phosphinates can also be employed as substrates to give dioxanes ,COMe (i) Mn(acac)3/ air or (ii) Mn(OAc)3/Oz/ pentane-i .3-dione . .. 99 X = alky, aryl, OR, NH2 Me Ar>ckMB Ar 0-0 OH 100 Y = SOPh, SO,Ph, P(0)(OMe)2 Scheme 23 With cyclopentane- 1,3-dione, the bis-hemiperketals 101 are ~btained.'~ Although manganese(rI1) acetate is generally used as the oxidation catalyst in these reactions, manganese(I1) acetate gives higher yields with active methine compound^.^^ 1 101 Photosensitized oxygenation of 1,l-diarylethenes using DCA as sensitizer affords the 3,3,6,6-tetraaryl- 1,2-dioxanes 102 in high yield ( > 85%) providing that one of the aryl substituents has an electron- donating group at either the para- or ortho-position (Scheme 24).32955 The 1,Zdioxanes are produced in a radical chain-reaction involving the radical cation derived from the 1,l-diarylethene and ground state molecular ~ x y g e n .~ ~ . ~ ~ Under similar conditions, the 1,a-bis(diarylalkeny1)alkanes 103 (n = 3 or 4) are transformed into the corresponding trans-fused bicyclic dioxanes 104.57758 CCA, hv 02.MBCN * A? DCA' 1 Ar' 102 to, Ar' + DCA-* Scheme 24 232 Contemporary Organic Synthesis3,6-Dihydrodioxines decompose under both basic and acidic conditions.The base-catalysed cleavage of peroxyketals shows a strong stereochemical dependence; thus 3,ti-dihydrodioxines 112 with a hydrogen atom in a pseudo equatorial position undergo a rapid, antiperiplanar E2 elimination to yield initially an enedione 113 whereas the isomeric compounds with a pseudo axial hydrogen atom form the enolate which participates in an intramolecular SN2 displacement to give an epoxide 114 (Scheme 27).60 Ar Ar Ar 103 104 Hex-5-enyl hydroperoxide derivatives 105 have been cyclized to the 1,2-dioxane derivatives 106 by the cycloperoxymercuration/reductive demercuration sequence mentioned above for the preparation of 1,3-dioxolanes (Scheme 25).43 On treatment of the hydroperoxide 107 with a recently developed samarium peroxide reagent in the presence of molecular oxygen, the dioxane 108 is obtained (70%) via a radical cyclization process.37 The samarium peroxide reagent is claimed to be highly effective for the generation of an intermediate peroxy radical from the corresponding hydroperoxide.\=/ 113 R2 Rw 114 105 Scheme 27 106 In addition to tile ac-J-catalysed formation of methyl perketals from the corresponding hemiperketals (vide supra), the 3,6-dihydrodioxine 115, derived from pulegone, is transformed into the 1,3-dione 116 on treatment with concentrated hydrochloric acid in methanol (Scheme 28).47 Reduction of 115 with zinc in acetic acid afforded the menthofuran 117 in 90% yield (68% overall from p ~ l e g o n e ) . ~ ~ Scheme 25 samarium peroxide (-)YOOH _____.t 0 2 0-0 Me 108 OOH Me 107 The trimethylsilyl triflate catalysed reaction between the endoperoxide 109 and either 1,4-diphenylcyclopentadiene or 2,5-diphenylfuran results in the diastereoselective formation of the tricyclic 1,2-dioxane 110 (Scheme 26).59 Under similar reaction conditions, styrene and 1 ,Zdiphenylethene produce the analogous cis-fused bicyclic dioxanes 111 though the acyclic olefinic moiety is incorporated with the opposite regiochemistry .conc. HCI / MeOH 116 Me 115 ph*ph Ph Ph 117 Scheme 28 8; Ph 109 110 X = CH2,O --I The saturated hemiperketals 98 and 99 have been transformed into the corresponding dihydrofurans 118,50952 tetrahydrofuranols 119, and furans 1205' as outlined in Scheme 29. More remarkably, the dioxanes 98 were de-acylated on treatment with 5% methanolic potassium hydroxide at reflux to yield 121 (ca.70-80%).51 111 Scheme 26 McCullough: Synthesis and use of cyclic peroxides 233cox / Ar Ar9&3 118 .cox Ph3P or Pd/C, Hz, HOAc Ar 2M HCI, HOAc. A \ COMe 98 X=Me 99 X = alky, aryl, OR, NH2 which on subsequent condensation with a cycloalkanone affords the corresponding dispiro- 1,2,4-trioxane derivative 125 (Scheme 31).62 ' Scheme 31 Ar 5% KOH, MeOH. A 121 Scheme 29 125 n = 5.6,7,12 By analogy, the unsaturated /3-hydroxyhydroperoxides 126, derived from a regioselective ene reaction between singlet oxygen and the appropriate allylic alcohol, have also been transformed into the 1,2,4-trioxanes 127 which are found to be effective antimalarial agents (Scheme 32).63 Treatment of 126 with concentrated On treatment with cobalt( 11) tetraphenylporphyrin acid in dichloromethane at room (CoTPP), the unsaturated endoperoxides 122 and 123 rearrange to form the corresponding furan derivatives (Scheme 30).61 temperature 3,6-bis(a-styryl) trioxane derivatives 128, presumably via a-arylacroleins generated in situ.64 in the formation Of the 123 Scheme 30 5 1,2,4-~ioxanes and related compounds Until the recognition of artemisinin (3) as a potent antimalarial agent, 1,2,dtrioxanes were virtually unknown as a class of corn pound^.^-^ Although ( + )-artemisinin (3) and its derivatives have proved to be attractive synthetic targets, there have also been significant developments in the chemistry of the structurally simpler monocyclic and bicyclic 1,2,4-trioxanes since several examples of these also possess attractive pharmacological properties.5.1 Simple 1,2,4-trioxanes The acid catalysed perhydrolysis of methylenecyclohexane oxide under anhydrous conditions yields the P-hydroxyhydroperoxide 124 Me 126 127 1 28 Scheme 32 In an alternative synthetic strategy, polysubstituted 1,2,4-trioxanes 130 have been conveniently prepared by the mercury( 11)-mediated cyclization of hemiperacetals 129 formed in situ from allylic hydroperoxides and aldehydes or ketones as outlined in Scheme 33.65766 Since tetra(ally1peroxy)tin compounds, readily obtained by photooxygenation of the corresponding tetra(ally1)tin compounds via metalloene reactions, behave similarly to ally1 hydroperoxides, they can be transformed into trioxanes 131 by the oxymercuration procedure (Scheme 34).67 The use of intermediate tetra(ally1)tin compounds is particularly commended for the preparation of trioxanes 131 ultimately derived from gaseous alkenes.234 Contemporary Organic SynthesisOH R H 0x0 I 130 R = alkyl, aryl Scheme 33 R1 snp#]4 R H RCHO, CF&02H HOxo - - H2C Me Me 129 4 NaBH,, NaOH '4 I MeCHo AZ 131 Scheme 34 When the oxymercuration reaction is carried out with the unsaturated hydroperoxides 126 (Ar = Ph) or their O-protected derivatives 132 as substrates, a series of new trioxanes 133 with an oxymethyl substituent at the 6-position is obtained (Scheme 35)?* R1 R2 CH2 yH (i) R'RkO, Hg(02CCF& 0x0 phv (ii) KBr; (iii) NaBH,, NaOH L L t ) Lox 1 32 X = H, Ac, CONHPh pti 133 ox Scheme 35 Employing N- halogenosuccinimides (NIS or NBS) instead of mercury(I1) salts, hemiperacetals 134 can be cyclized to give the 5-(halogenomethyl) trioxane derivatives 135 (Scheme 36).69 This latter procedure is less versatile than the oxymercuration procedure because it is restricted to hemiperacetals derived from aliphatic aldehydes.R H Me ?H 134 (if) NBS or NIS 135 R = alkyl X = Br, I Scheme 36 1,2,4-Trioxan-5-ones 137, which might be expected to be relatively unstable, have been in fact readily synthesized by the trimethylsilyl triflate catalysed condensation of trimethylsilyl ct [ (trimet hylsilyl)peroxy]alkanoates 136 with aldehydes or ketones (Scheme 37).70 R2 R2Me3 OSiMe3 \('I H R'+CO,H Reagents: (i) lo2; (iii) 3 ~ 2 , R2 Scheme 37 R1 O-OSiMe3 (iv) R' 0-0 R3 -R$6)(R4 137 (ii) LDA (2 eq.) Me3SiCI; (iv) R 3 ~ C O , Me3SiOTf Although zwitterionic intermediates, generated by the photooxygenation of electron-rich olefins, can be trapped by carbonyl compounds to yield trioxanes, lo the analogous reactions involving either indene or 1,2-dihydronaphthalene under aqueous conditions, even in the presence of a large excess of acetaldehyde or acetone, afforded a preponderance of the trans-hydroxy hydroperoxides 138 and 139 respectively (Scheme 38).7' Only compound 139 condensed with aldehydes or ketones to produce the trans-fused trioxanes 140.cis-Fused trioxanes 141 and 142 have been obtained from the respective 1,Zdioxetanes derived from indene and 1,2-dihydronaphthalene. Thermolysis of 1,2,4-trioxan-5-ones 137 in solution or under flash-vacuum pyrolysis (FVP) results in extensive ring fragmentation with loss of carbon dioxide and the formation of carbonyl be accompanied by chemilumine~cence.~~ The thermal decomposition may also McCullough: Synthesis and use of cyclic peroxides 235139 (29%) Ambedvt- 15 or MgSlOTf R’ R2 O X 0 140 Scheme 38 Me 141 Me 142 In addition to ring fragmentation, the dispiro trioxanes 125, on thermolysis at 190°C in solution, undergo radical-mediated ring-expansion reactions yielding the oxalactones 143 and ketolactones 144 depending on the nature of the spiro substitutents (Scheme 39).62 125 n 143 144 Scheme 39 An efficient kinetic resolution of a racemic mixture of the enantiomeric cis-fused cyclopententeno-l,2,4-trioxanes 145 and 146 can be achieved by treatment of the respective racemic mixtures with catalytic quantities of potassium osmate, N-methylmorpholine-N-oxide (NMO), and either l74-bis(dihydroquinidine)phtha1azine [(DHQD),PHAL] or bis(dihydr0quinine)phthalazine [(DHQ),PHAL] as indicated in Scheme 40.74 (-)-la I (+)-146 “I + (-)-145 30% yield (e.e.95%) + (+)-146 25% yield (95%e.e.) Reagents: (i) K20s04, (DHQD),PHAL, NMO, aq. Me2C0, 20 “C, 2h (ii) K20s0,, (DHQ),PHAL, NMO, aq. Me,CO, 20 “C, 2.7h Scheme 40 5.2 Polycyclic 1,2,4-trioxanes related to artemisin Acid-catalysed cyclization of the hydroperoxides 147, derived from the corresponding hydrazines, has afforded the bicyclic 1,2,4-trioxanes 148 along with the 1,Zdioxanes 149 if R’ = H.75 On treatment with perchloric acid in dichloromethane, a mixture of the isomeric methoxyhydroperoxides 150 was converted quantitatively into the bicyclic ring system 151, the putative pharmacophore of artemisinin (3).76 0 I---- R’ 148 MeOAO” 147 R’=H,Me R2 ”H, Me 149 0 150 151 The exo-bicyclic ozonide 152a rearranges smoothly into trioxabicyclo[2.2.2]octane derivative 153 (90% yield) in acetonitrile buffered with sodium hydrogen carbonate via a cationic ring-expansion process operating under stereoelectronic control; the endo-isomer 152b does not rearrange under similar condition^.^^ 236 Contemporary Organic Synthesis(0 MeCN.NaHCO, (2 eq.). 25 "C 152a (I) MeCN, NaHCO, (2 eq.), 25 TMS 152b In each of the total stereoselective syntheses of ( + )-artemisinin (3) and its derivatives, a readily available terpene, which will ultimately serve as ring A in 3, is elaborated in a linear fashion (8-15 steps) to give a key sesquiterpene intermediate. Subsequent oxygenation of this intermediate followed by acid-catalysed rearrangement of the resulting peroxide species affords 3.Since several of the synthetic strategies adopted have been discussed in detail el~ewhere,~.' this review will focus on The Lewis acid catalysed Diels-Alder reaction between enone ester 157, derived from (-)-P-pinene and isoprene, yields the adduct 158 which is transformed into the regioisomeric methyl esters 159. Photooxygenation of the inseparable mixture of regioisomers 159 followed by treatment of the crude product with trifluoroacetic acid affords 3 in 30% yield based on 159b (Scheme 42).79 157 E = C02Me 158 several I I steps 11 recent developments in the construction of the peroxide-containing rings c and D of 3.In the shortest total synthesis of 3 reported to date (ten steps), the vinyl silane 154, obtained from (R)-( + )-pulegone, undergoes an anomalous ozonolysis reaction to yield an intermediate siloxy- 1,2-dioxetane which rearranges on treatment with acid to give 3 in 35% yield (Scheme 41).78 The 9-desmethyl derivative 156 (61%) is obtained from 155 in a similar fashion. Scheme 42 15% (isomec ratio 59) 159b (i) 02. CH2CIa methylene blue (ii) CF3C02H, O,, pet. ether 1 hv, 20 "C 3 Mx- I I several deps - - Me,Si 0 (i) 03, CH2Cb, - 78 "C (ii) SIO,, aq. H#O, (3 M) / 0 3 (R=Me) 16 (R= H) Scheme 41 McCullough: Synthesis and use of cyclic peroxides A shorter, improved synthesis of a pivotal keto aldehyde (160) from A3-carene has been reported (Scheme 43).80 Artemisinin 3 can be obtained from 160 in six steps5 Me Me -0 the A3-carene Scheme 43 Me Me 0 160 Treatment of a mixture of 6-methylcyclohexenone and hexa-3,5-dien-l-ol in dichloromethane with aluminium(II1) chloride or in acetonitrile with copper( 11) triflate yields the tricyclic hemiacetal 161 which is readily converted into the methyl ester of desdimethyldihydroartemisinic acid (162, Scheme 44).Subsequent photooxygenation followed by a catalysed ring cleavage-oxygenation process provides the desdimethylartemisinin analogue 163.81 237H A *'H h Me02C / +H Me QH v 162 163 Reagents: (i)AIC13, MeCN, Cu(OTf)2, -20 "C; (ii) H2, PdrC, EtOAc; (iii) H2CT03, acetone; (iv) CH2N2.Et20; (v) NaBH4, MeOH; (vi) POC13, pyridine; (vii) '02; (viii) Fe(~hen)~ (0.02 eq.) then Cu(OTf), (0.1 eq.), MeCN, 02,-30 "C; (ix) p -TsOH, CH&I2 Scheme 44 - Me q --H - wq *-H H02C OHC Me I R'MgBr 164 + Me HO Me R' (+epimer) A' 165 R' = alkyl, alkenyl, aryl, Reagents: (i) 02, MeCN.CH2C12, sens, hv; (ii) Cu(0Tf)p. MeCN, 0 2 , -20 "C Scheme 45 he 'OH Artemisinic acid 164, which is more abundant than 3 in the plant Artemisia annua, has proved to be a useful precursor in the synthesis of a variety of artemisinin derivatives. Thus, several novel artemisinin derivatives functionalized at C-( 12) and C-(13) have been prepared from 164 as outlined in Schemes 45 and 46 re~pectively.~~-~~ The 12-n-butyl derivative 165 (R' = n-C4H,) shows promising antiviral activity against ~ 1 v - 1 .~ ~ followed by treatment with trimethylsilyl triflate yields the corresponding desoxyartemisinin derivatives 167.86 Steroidal analogues 168a and b are prepared in modest yield (16% and 20% respectively) by similar proced~res.'~ Photooxygenation of the cyclic enol ethers 166 1 67 166 R=H,Et Reagents: (i) O,, CH2C12, sens, hv, -78 "C; (ii) TMSOTf 1- 168b R = bmethylhept-2-yl By adapting a strategy used in the total synthesis of 3,78 low temperature ozonolysis of the vinylsilane 169 followed by treatment of the resulting product mixture with either acetone or acetaldehyde and Amberlyst- 15 resin affords the tricyclic analogues 170 in which ring D is missing.88 Me Me 169 0 170 R' = H, Me R2= HI Me Reagents: (i) Oar CH2C12, -78 "C (ii) Me2C0 or MeCHO, Amberlyst-l5,22 "C Reagents: (i) MeLi, Et20; (ii) KCN, NH4CI, aq.DMA, 120 "C; (iii) NaBH4; (iv) 0 2 , CH2C12, sens, hv; (v) CFaCOsH, Et20: (vi) LiAiH4, Et20; (vii) 0 2 , CHzCg, sens, hv; (viii) Dowex-H*, hexane Scheme 46 Acid-catalysed ring-opening of 1 ,Zdioxetanes derived from the photooxygenation of the cyclic enol ether precursors with sequential intra- or inter- molecular incorporation of a carbonyl moiety yields the tricyclic analogues 171 and 172 respectively." 238 Contemporary Organic SynthesisH ? A 171 R = H, Me, Ph Reagents: (i) '02, CH2CI2. -78 "C; (ii) Amberlyst-15 (iii) R2C0, Amberiyst-15 The use of triethylsilyl hydrotrioxide provides an alternative method to photooxygenation for the synthesis of 1,2-dioxetanes from electron-rich vinyl ethers." Thus, the keto vinyl ethers 173 are conveniently transformed into the alkoxy tricyclic 1,2,4-trioxanes 174 as outlined in Scheme 47.91992 From structure-activity studies on the trioxane derivatives 174 it is found that only compound 174a with a C-3 a-hydrogen atom, which is potentially available to participate in a 1,5-hydrogen abstraction process, exhibits antimalarial activity (almost twice as potent as 3).92 (i) Et,SiOOOH or '4 (ii) Bu'Me$iOR (iii) Et3N Me I 173 OH 174 a: R' = H, R2 = Me b: R' = Me, R2 = H c: R'=R2=Me Scheme 47 Treatment of dihydroartemisinin 175 with either triethylsilane and boron trifluoride etherate or H,B-NEt, and trimethylsilyl chloride affords deoxyartemisinin 176, a more active antimalarial than 3, in high yield (Scheme 48).93,94 Deoxyartemisinin 176 rearranges to 177 in the presence of a large excess of boron trifluoride etherate with cleavage of the peroxide bond resulting in contraction of rings c and D and concomitant expansion of rings A and B .~ ~ The peroxide bond of dihydroartemisinin 175 is also cleaved during its silica gel catalysed transformation into the lactone 178.95 Anhydrodihydroartemisinin 179 has been found to be a useful compound for the introduction of additional functionality into ring B of 3. Osmylation of 179 with stoichiometric quantities of osmium tetroxide in pyridine yields a 1 : 1 mixture of the isomeric diols 180 and 181,96 whereas 180 is the major isomer using catalytic quantities of osmium tetroxide with NMO as co-oxidant (180:181 7:197 and 10:198) (Scheme 49).Further oxidation of 180 Me? --H Me H o OH 175 0 178 176 (iii) 177 Reagents: (i) EtaSiH, BF3-OEt2, CH2CI2, -20 "C; (ii) BH3NEt3, Me3SiCI. DME, r.t.; (iii) BF3-OEt2 (30 eq.), MeCN, 0 "C; (IV) SiOp, benzene, A, 6h. Scheme 48 and 181 with either Jones or PCC- alumina97 affords the corresponding 1 l-a- and 1 l-P-hydroxy derivatives 182 and 183 respectively. On treatment with thionyl chloride in pyridine, compound 180 is transformed into 11-P-chloroartemisinin 184.97 Ye 179 (i) or (ii) I M e T c , Me H 6 1 1 "H 0 tie 184 t + M e 9 I --H Me H O 181 OHOH 182 R' = Me, $ = OH 183 R' = OH, R2 = Me Reagents: (i) Os04 (1 eq.). pyridine; (ii) OSO4 (cat.), NMO, aq. acetone or Bu'OH; (iii) Jones reagent or PCC-alumina; (iv) SOC12, pyridine Scheme 49 McCullough: Synthesis and use of cyclic peroxides 239Epoxidation of 179 using either m- chloroperbenzoic acid (mCPBA) buffered with aqueous sodium hydrogen carbonate96 or a complex of mCPBA and potassium fluoride95y98 yields the isomeric epoxides 185/186 in various ratios depending on conditions but 185 is always the major The acid-catalysed ring-opening of 185 yields 1 1P-hydroxy 1 1-epihydroartemisinin 187 which rearranges in the presence of silica gel to give the ring contacted product 188 (Scheme 50) (cf.Scheme 48,175+178 and 176+177)?' OH 187 un 188 Reagents: (i) H2S04 (1 M), aq. acetone; (ii) Si02, benzene, A, 10 min. Scheme 50 The reaction of 179 with absolute ethanol in the presence of p-toluenesulfonic acid as catalyst yields the pharmacologically important arteether 189 together with the C-( 11)-epimer 190 (3: 1).'O0 Surprisingly, when the reaction solvent is changed to dichloromethane, the epimeric ratio 189: 190 inverts (1 :3), Treatment of 189 with equimolar quantities of iron(m) chloride affords an equilibrium mixture of 189 and the C-(12)-epimer 191 (ca.1:l).lo1 Me M e T H .'Me H t , OEt 190 Base-catalysed dehydrobromination of the bromoacetal 192 results in ring contraction of ring B to give the aldehyde 193 (Scheme 51).lo2 Oxidation of 192 with PCC in dichloromethane followed by treatment with DBU affords iso-artemistene 194 (overall yield of 70%) which on subsequent radical bromination with NBS gives the allylic bromo compound 195 (65% yield).lo3 1 93 0 0 194 195 Reagents: (i) DBU, CH2C12, r.t.; (ii) PCC, CH2CI2 then DBU; (iii) NBS, (PhC02)2 Scheme 51 On reduction with tri-n-butyltin hydride, the bromopropargyl ethers 196 and 198 are transformed into the cis-fused ao-methylene compounds 197 and 199 respectively via intramolecular radical 196 -CECH 1 97 Me Br 6.198 199 200 \-CH=CH* 201 191 240 Contemporary Organic Synthesis Reagents: (i) Bu",SnH, AIBN, toluene, 115 O Ccyclization reactions. Under similar reaction conditions, the corresponding bromoallylic ethers also undergo analogous cyclization reactions (e.g 200 + 201). 6 Ketone cyclic peroxides The acid-catalysed peroxidation of the cyclohexanone derivatives 202 in aqueous alcohol has afforded the corresponding dimeric cyclic ketone peroxides (1,2,4,5-tetroxanes) 203 in good yield (ca. 70%).'05 Since such ketone peroxides are readily synthesized and exhibit antimalarial activity comparable with artemisinin 3 combined with low toxicity, they have considerable potential as inexpensive antimalarial drugs.Reagents: (i) H202 (30%), H2S04, aq. EtOH, 0 "C Although tetroxanes do not usually participate in O-atom transfer reactions, trifluoroacetone diperoxide 204 is found to oxidize thioanisole to the corresponding sulfoxide and 3-methylpent-2-ene to the (E)-epoxide in quantitative yield.lo6 F,C 0-0 Me Me x x 0-0 CF, 204 In addition to dimeric cyclic peroxides, peroxidation of ketones may also yield cyclic trimeric peroxides (1,2,4,5,7,8-hexoxonanes) depending on the nature of the ketone, the reaction solvent, and pH. Thus, on addition of diethyl ketone to a mixture hydrogen peroxide and sulfuric acid at - 10°C, in the absence of solvent, the trimeric cyclic peroxide 205 is obtained (80% yield).lo7 Et 0-0 Et Et x x p ? Et 205 7 Miscellaneous endoperoxides Oxygenation of cyclic conjugated dienes generally produces the corresponding bicyclic endoperoxide."' Although their fundamental structural and chemical properties continue to attract interest, such endoperoxides are frequently exploited as intermediates for the stereospecific introduction of cis-1,4-oxygen functionality into unsaturated organic molecules.Thus, several highly efficient and versatile synthetic routes to the biologically important inositols and related compounds have been developed. Photooxygenation of the protected trans- cyclohexa-3,5-diene-1,2-diol206 yields the endoperoxide 207 which is reduced by thiourea to the cis-1,4-diol208 (Scheme 52).Osmylation of 208 affords the chiro-inositol derivative 209 as a single isomer. OH 209 Reagents: (i) 02, sens., hv, CH2CI2, -70 "C; (ii) thiourea, MeOH, r. 1.; (iii) Os04, NMO, aq. acetone, r. t. Scheme 52 R Mas: HO 210 a: R = H b:R=Me OH HO 2qH2 (v), (xi) OH OH Reagents: (i) 02, sens., hv, CH2CI2, -70 "C; (ii) thiourea, MeOH, r. t.; (iii) Os04, NMO, aq. acetone, r. 1.; (iv) mCPBA; (v) H30*, A; (vi) NaH, BnBr, DMF; (vii) BnOH, NaH, DMF, 130 "C; (viii) NaH, Mel; (ix) P&C, H,; (x) AqO, py; (xi) K2CO3, MeOH; (xii) MeC03H, MeC02H Scheme 53 McCullough: Synthesis and use of cyclic peroxides 241The cis-cyclohexa-3,5-diene-l,Zdiols 210, which are readily obtained from the microbial cis- dihydroxylation of the corresponding aromatic compounds, have also proved to be suitable substrates for the synthesis of a range of inositols.l10 Cycloaddition of singlet oxygen to the commercially available diol2lOa gives a readily separable mixture of the anti- and syn-endoproxides (39% and 15% yield respectively) which have been reductively cleaved to conduritol A (211) and conduritol D (212).'11 Tetrols 211 and 212 are in turn convenient precursors of a series of inositol stereoisomers and ( k )-quebrachitol213 (Scheme 53).By analogous chemical steps, the homochiral azidoinosoitol214 and aminocyclitol215 have been enantiospecifically synthesized from the diol21Ob (Scheme 54).l12 OH 214 X=N3 215 X=NH, Scheme 54 Partial deoxygenation of the endoperoxide 216 with triethyl phosphite has been shown to provide the epoxide 217 (55% yield) which is a convenient precursor of conduritol F (218) and conduramine F4 (219) (Scheme 55).11' + o - $$:ye (i) acetone.H' (19 02. sens., hv, CH2CI2, -70 "c 21 Oa Me 21 6 d (iv) H3O+, r. t., BaCq OH 218 Scheme 55 217 (v) NH3, MeOH J (iv) H3O'. r. t.. BaCO3 6: OH 219 Photooxygenation of 1,4-cyclohexadiene affords the hydroperoxy endoperoxide 220 (70%) which is readily transformed into the cyclohexanepentol ( f )-proto-quercitol 221 in three simple chemical steps (Scheme 56).l14 0 220 OH 221 Scheme 56 Treatment of the endoperoxide 222, derived from tropanone, with CoTPP yields the bisepoxide 223 (40%) whereas 222 is deoxygenated by triphenylphosphine to give the monoepoxide 224 (20%); both 223 and 224 can be converted into tris- epoxide 225 (Scheme 57).'15 (i) ColTP (ii) PPhS CH2CI, (iv) Bu'OOH, Triton\ .*9 (lii) 02, sens..hv. CH&, -70 "c J (i) CoTTP 225 Scheme 57 Epoxy endoperoxide 227, obtained as the sole product of the photosensitized oxygenation of 226, undergoes CoTPP-catalysed rearrangement to give the hydroxy aldehyde 228 (Scheme 58).'16 0 CCl4, r. t. 226 227 I CoTPP Scheme 58 Thermolysis of the fulvene endoperoxide 229 affords the oxepinone 230 as the major product whereas the mono unsaturated endoperoxide 231, obtained by diimide reduction of 229, rearranges to the stable allene oxide 232 on heating at 80°C (Scheme 59).'17 242 Contemporary Organic Synthesis229 231 0 &'"' HYf-fO H 230 232 Scheme 59 The 4-acetoxyazetidone derivative 233 has been synthesized from methyl 3(R)-hydroxybutyrate via the endoperoxide 234 (Scheme 60).'18 Although thermal rearrangement of 234 in the presence of sodium acetate provides 233 (22%), improved yields of 233 can be obtained by treatment of 234 with hydrogen peroxide followed by acetic anhydride prior to thermolysis.OAOMe 0 k-fi I '0, -30 "C methyl 3(R)-hydroxybutyrate TBSO TBSO 233 234 Reagents: (i) 0 "C, KOAc; (ii) H202 then AqO / py; (iii) MeCN, A, 50 "C Scheme 60 The [4+2] cycloaddition of singlet oxygen to a protected guanosine derivative affords the corresponding thermally labile adduct 235 as a mixture of isomers.' l9 Endoperoxides related to 235 are considered to be responsible for photosensitized modifications of DNA. Photooxygenation of the salt 236, derived from the quaternization of thebaine by methyl triflate, yields a stable endoperoxide 237 which on thermolysis at 75°C is converted into the 14-hydroxycodeinone salt 238 (Scheme Under similar conditions, thebaine itself produces the dihydrodibenzofuran 239 via a complex oxidative rearrangement process. (I) 0, TPP, Me MeO 236 Scheme 61 239 237 (iii) TFA, A, 75 "c M e 238 In the [4+2] cycloaddition of singlet oxygen to chiral naphthalene derivatives 240, highest diastereoisomeric ratios for adducts 241 are observed when X = OH as a result of the steering effect of the OH group on the incoming singlet oxygen species.'*l Me a X Me a X &$q$+&$ 4 4 R R R 241 a 241b X = OH, ratio 241 a:241 b > 4:l 240 R=H,Me [aR',l Rg.4S*] [aR*, 1 S*,4R*] The dicyanodiphenylsemibullvalene 242 reacts readily with triplet oxygen in solution to yield the stable endoperoxide 243 (26%).122 Oxygenation of a 242 243 H2 H2 CH2 c-0-0-c Q &I+ c-0-0-c H2 H2 244 CH2 McCullough: Synthesis and use of cyclic peroxides 243solution of 2,s-dime t hylene-2,5-dihydrot hiop hene in dichloromethane affords the macrocyclic bis- peroxide 244 in high yield.123 The antimalarial natural product yinghaosu A (4) has been synthesized from (R)-( -)-cawone 245 via a multi-step sequence in which the dioxabicyclo[3.3.l]nonane ring system of 4 is constructed by an ene reaction between the cyclohexenone derivative 246 and singlet oxygen followed by spontaneous cyclization of the resulting hydroperoxide in the presence of p-toluenesulfonic acid to yield 247 (Scheme 62).596 Me 245 Me 246 4 tie tie 247 Scheme 62 Using similar synthetic strategies, a series of enantiomeric dioxabicyclo[3.3.l]nonan-7-one analogues, e.g. 248 and 249, has been prepared from 245 and its enantiomer (Scheme The structurally related compound 4,4,8-Trimethyl- 2,3-dioxabicyclo[3.3.l]nonan-8-ol250 has been identified as a significant component (ca.20%) of the product mixture (after treatment with sodium sulfite) arising from the autooxidation of cis-pinane at 130°C (Scheme 64).12' 8 Cyclic peroxides derived from ozonolysis reactions Carbonyl oxides 251, generated in situ as key intermediates in the ozonolysis of alkenes and other unsaturated compounds, generally react with carbonyl compounds via [3 + 21 cycloaddition processes to form ozonides (1,2,4-trioxolanes) 253 or, in the presence of protic solvents (S-H), the hydroperoxides 252 (Scheme 65).126*127 Although normally considered to be thermally labile and hazardous to handle, several stable ozonides have been isolated and fully characterized, including the 1,2,4-trioxolane derivative 255, obtained by ozonolysis of alkene 254,12' and the polycylic ozonides 256 which have been shown to have significant antimalarial activity,lZ9 and the diozonide 257, as exclusively the endo, endo-isomer, derived from hexamethyl(Dewar benzene).13* MevCH2 0 Me 248 NaOMe, MeOH 1 OOH Me+ Me Me Me-0 I 8 I Me (i) ' 0 2 , MeCN (a) pTsOH,MeCN I 0 tie 249 Scheme 63 Me Me Me li '02 t aq.Na#03 Scheme 64 Ozonolysis of cycloalkenes, illustrated by cyclohexene, in the presence of methyl pyruvate affords the corresponding trisubstituted ozonide 258.1313132 Since the trioxolane moiety is stable enough to function as a protected aldehyde or carboxylic acid group, the adduct 258 is terminally 244 Contemporaly Organic Synthesis+ -o'%o CHO I J P+21 w/ 252 253 Scheme 65 0 0 endo.ende257 differentiated with reaction taking place selectively at the aldehyde group in a variety of subsequent chemical transformations, e.g. Mukaiyama-type aldol condensation reactions (Scheme 66). Acidolysis of indene ozonide 259 results in formation of the crystalline cyclic tetramer 260 (20% yield) which contains a novel 20-membered dodecaoxacycloicosane ring. 133 Under similar reaction conditions, the bicyclic ozonide 261, derived from l-phenylcyclopentene, dimerizes to yield the 2,3,5,6,1 l-pentoxabicycloundecane 262 or, in the presence of 259, forms the cross-dimerization product 263.133 The tricyclic peroxide 265 is isolated in 5% yield from the acid-catalysed rearrangement of the cyclic hemiperacetal264 obtained from the ozonolysis of l-methylcyclopentene in methanol; dimeric bicyclic peroxides analogous to 262 have also been isolated (Scheme 67).134 Treatment of the solvent-derived ozonolysis products, a-hydroperoxyisochromanes 266, with formaldehyde under acidic conditions affords mixtures of the bicyclic 1,2,4,6-tetroxepanes 267 and 1,2,4,6,8-pentoxonanes 268 which have incorporated either one or two molecules of formaldehyde 0 258 Y Y C C H O C .O 2 H Reagents: (i) 03, methyl pyruvate (1.5 eq.).CH2C12, -78 "C; (ii) EtpZn (1.5 eq.), BF3-OEt2 (1.5 eq.), CH2CI2, -78 OC; (iii) CH2=CHCH2SiMe3, Tic4 (0.5 eq.), CH2CI2, -78 "C; (iv) BF3-OEt2 (2.3 eq.), CH2C12, r. t.; (v) Ph3P, CH2CI2, r. 1.; (vi) Scheme 66 EtaN, CHzCI2, r. t. do H CIS03H (0.1 q.) / 259 Ph 261 260 L + 259 Ph Ql--:)(: H 262 263 R = (CH2)3COPh McCullough: Synthesis and use of cyclic peroxides 245Me 265 Scheme 67 respectively. 135 When formaldehyde is replaced by acetaldehyde, only the corresponding 1,2,4,6-tetroxepanes 267 (R2 = Me) are obtained (Scheme 68). 267 0 1 Scheme 68 In addition to commonly observed recombination reactions with carbonyl compounds to form ozonides, carbonyl oxide intermediates may participate, with suitable co-reactants, in a variety of other cycloaddition reaction types, thus offering the prospect of alternative synthetic routes to several novel cyclic peroxide systems.'26 Carbonyl oxides, generated by the selective ozonolysis of vinyl ethers, readily undergo [3 + 21 cycloaddition reactions with imines to provide the corresponding 1,2,4-dioxazolidines 269.136 Photooxygenation of furan derivatives 270 in the presence of phenyl isocyanate produces the 1,2,4-dioxazolidin-3-ones 271 in ca.20% ~ie1d.l~' In this latter case, the required carbonyl oxides are formed by spontaneous rearrangement of the unstable ozonide intermediates (Scheme 69). H H Ar $ OMe "[ Ar&OMe 0-0 ] 270 E=C02Me rearrangement I Ph 271 Scheme 69 The [3 + 31 cycloaddition reactions between carbonyl oxides and nitrones have been shown to proceed in a non-concerted fashion to yield the dihydro-l,2,4,5trioxazines 272.'38 The ozonolysis of cyclopenta-1,3-dienes generally yields monomeric products consisting of either the unsaturated bicyclic endoperoxides 273 containing 1,2,4-trioxepine ring, or the unsaturated ozonides 274, or mixtures of 273 and 274 (Scheme The bicyclic endoperoxides 273 are considered to arise from a stepwise intramolecular [3 + 41 cycloaddition process.R', R2 = Me, Ph R YWRI I 0 3 R2 R2 R2 R2 4 1 273 Scheme 70 4' 274 Polycyclic 1,2,4,6-tetroxepane derivatives, analogous to 267, are also obtained from reactions between formaldehyde 0-oxide and 1,5-dicarbonyl compounds via extended [3 + 2 + 21 cycloaddition proces~es.'~~ Thus, the keto aldehydes 275 and formaldehyde 0-oxide yield mixtures of the regioisomeric compounds 276 and 277 whereas with the keto aldehydes 278, the adducts 279 are obtained as mixtures of exo- and endo-isomers (Scheme 71).246 Contemporary Organic SynthesisO/O7O + a .2+21r 276 0 0 /-% 0 + 277 [3 + 2 + 21 - R3 'R2 278 R3 = H, Me, Ph R' = H, Ph; R2 = H, Ph Scheme 71 279 9 Conclusions Recent developments in the chemistry of organic cyclic peroxides demonstrate that such compounds should no longer be regarded as chemical curiosities. 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ISSN:1350-4894    

DOI:10.1039/CO9950200225

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

Recent advances in organofluorine chemistry ~ ~~~ JONATHAN M. PERCY School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT Reviewing the literature published between January 1992 and April 1995 1 2 2.1 2.2 2.3 2.4 2.5 3 3.1 3.2 3.3 3.4 3.5 3.6 4 4.1 4.2 5 6 Introduction Fluorinated carbon nucleophiles Perfluoroalkyl organometallic reagents Fluoroalkenyl organometallic reagents Met allat ed fluoroenol derivatives Fluoroenolates and enol silyl ethers Phosphonyl- and sulfonyl-stabilized carbanions Fluorinated carbon electrophiles Fluoroalkyl ketones a-Fluoro-a$-unsaturated carbonyl compounds P-Fluoro-a,p-unsaturated carbonyl compounds y-Fluoro-a,P-unsaturated carbonyl compounds Fluoroalkyl epoxides Fluoroallylic electrophiles Pericyclic reactions Diels-Alder and dipolar cycloadditions Sigmatropic rearrangements and ene reactions Free radical reactions References 1 Introduction This Review deals with advances in the chemistry of fluorinated building blocks which are small, readily- available, and manipulable molecules that already contain one or more fluorine atoms.The article concentrates on aliphatic chemistry wherein lies the main intellectual challenge. No effort will be made to cover the burgeoning literature describing functional group transformations with reagents such as DAST, elemental fluorine, or xenon difluoride.lP2 Recent more specialized reviews have discussed routes to fluorinated amino acids3 and aspects of the electrochemistry of organofluorine compound^.^ The material is organized under fairly broad headings reflecting the relative youth of much of the chemistry.2 Fluorinated carbon nucleophiles 2.1 Perfluoroalkyl organometallic reagents A multitude of methods exist for the trifluoromethylation of organic substrates, forming the subject of a recent specialized re vie^.^ One particularly accessible method uses commercially- available (trifluoromethyl) trimethylsilane (Ruppert’s reagent) 1 which adds efficiently to carbonyl electrophiles in the presence of fluorine ion sources. The reactive species is presumably the silicon-ate complex 3 and recent applications have included syntheses of deoxysugars in both hexose6 and pentose7 series. Scheme 1 shows a typical sequence from protected ribonolactone 2 through to D-lyxose ketal 4; yields of adducts are high but the reagent usually shows low diastereoselectivity in the addition step.Other peduoroalkylation reactions (i) 2. THF (ii) EtNF (cat.) (iii) TBAF 4 1 Me3SiCF3 Scheme 1 4 (69%) have been described by Uno and co-workers.8 Readily-available perfluoroalkyl iodides undergo halogen-metal exchange at low temperature. The first formed perfluoroalkyllithium reagent reacted with the iodide precursor to afford iodinate complex 5 (Scheme 2). The ate-complex was believed to act as a reservoir for the reactive perhoroalkyllithium reagents. When the complexes were generated in the presence of electrophiles, good yields of adducts could be obtained via the removal of the reactive but thermally-unstable perfluoroalkyllithium reagent 6 from the equilibrium. Scheme 2 In the presence of boron trifluoride etherate, good yields of adducts with imines were obtained.’ Scheme 3 depicts the addition of perffuorohexyl iodide to imine 7 affording 8 in moderate chemical yield but with high diastereoselectivity.Percy: Recent advances in organofluorine chemistry 251Scheme 3 2.2 Fluoroalkenyl organometallic reagents The pioneering work of Normant, Burton, and others has formed the subject of a recent review." Readily available 2-bromo-l,l,l-trifluoropropene can be used in a range of organometallic reactions. Scheme 4 shows a Barbier reaction with aldehydes mediated by a zinc-copper couple to afford allylic alcohols 9.'' RCHO F3CA& ZWCU co~pIe, OM; F3C HO 50 OC, 4-8 hours 9 R = Pr, Pr', Ph (7045%) Scheme 4 Interestingly, the vinylzinc reagent 10, prepared by stoichiometric chemistry in THF or DMF, failed to react with aldehydes.The reactive species in the Barbier reaction was believed to be an unsolvated vinylorganometallic reagent. Hu and co-workers have described coupling reactions of 10 with (bromoviny1)-dialkylboranes (Scheme 5), leading to triene 11.12 The bromide reacted directly with alkynes under palladium catalysis in the presence of copper( I) iodide to afford trifluoromethyl enynes in good yield. PdC12(PPh& NaOEt, PhH 60 %, 3 hours 1 F3C h n - h x 11 (68%) Scheme 5 An analogue 12 of the fungal metabolite siccayne has been prepared in this way (Scheme 6).13 Enynyl silane 13 has been added to aldehydes in the presence of a fluoride source to afford allylic alcohols 14. Aromatic aldehydes give high (70-80%) yields of adducts but additions to aliphatic aldehydes were less efficient (Scheme 7).Treatment of 2-bromo-l,l,l-trifluoropropene with LDA (2 equivalents) afforded lithio trifluoropropyne 15 OMOM PdCl2(PPh& CUI, EtaN, THF c r.t., 10 hours OMOM OMOM 12 (85%) Scheme 6 13 CSF, 1- THF, -20 OC RCHo I F3c\R OH 14 R = 4MeO-Ph. Ps, Et !jO-8!j% Scheme 7 which was trapped in situ, with 3-(benzyloxy)propanal at the start of a synthesis of 2,6-dideoxy-6,6,6-trifluorosugars. l4 Lipase-catalysed resolution of 16 allowed the isolation of the enantiomer 17 in high ( > 99%) e.e. (Scheme 8). The protected L-oliose analogue 18 was obtained following standard manipulations. 18 Scheme 8 17 (40%; >99% e.e.) Difluorovinylboranes (see Section 2.3 for their synthesis) are versatile carbon nucleophiles; Scheme 9 shows some of the products available from borane 19. Transmetallation with copper(1) salts in HMPA affords a reactive difluorovinylcopper reagent.Phosphine oxide 20 was obtained in good yield following transmetallation of 19, reaction with the phosphorus electrophile, and oxidation with excess hydrogen per~xide.'~ Vinyl halides16 and aryl iodides17 coupled efficiently with 19 under palladium catalysis to afford styrenes 21 (with retention of alkene configuration) and dienes 22 252 Contemporary Organic Synthesisrespectively. The vinylcopper reagent was sufficiently reactive to afford good yields of enones 23 upon treatment wth acid chlorides." R' P' ( i ) Cul, HMPA * F+RI 20 (88%) (ii) Arl. PddbasPPh3 I F 21 Ar = 4-02NPh, 4-MeOPh 90-94% F 19 R = Bu".Bus P' CuI, HMPA Pd2dbao.PP h3 I (i)Cul,HMPA ~ FhR2 (ii) R~COCI F O 23 Scheme 9 Because of the low reactivity of fluorovinylcopper reagents, conjugate addition of fluoroalkenyl units to enones had not been reported until the publication of a solution by Yamamoto and co- w o r k e r ~ . ~ ~ When complexed with a tris( ary1oxy)aluminium complex (ATPH 24), enones underwent 1,4-addition with an excess of fluoroalkenyllithium reagents at low temperature, affording adducts 25 and 26 in good yield (Schemes 10 and 11). The procedure therefore avoided transmetallation (and consequent loss of reactivity) of the fluoroalkenyl nucleophile. Ph 24 (ATPH) (9 ATPH, CHzCh, hexane c (i9 C2F5LI c2F5 25 (51%) Scheme 10 -bF (9 ATPH, CH&, hexarm (I9 F,C=CFLI, -78 "C F 26 (75%) 6 Chromium carbene chemistry has been found to accommodate fluoroalkenyl components. A highly substituted fluorophenol27 has been formed in a low yielding carbene annulation sequence (Scheme 12).20 Less reactive fluoroalkenyllithium reagents, or alkynes bearing sterically demanding substituents, failed to yield phenolic products.(i) PhGCPh, Bu'OMe, 55 "c (i9 FOCI, DMF 1 OH Ph I OMe 27 (35%) Scheme 12 McCarthy and co-workers have described chemistry that affords synthetic equivalents to a-fluoroalkenyl anions.21 A squalene epoxidase inhibitor (28) has been prepared using a modified Suzuki coupling from an a-fluoroalkenyl iodide (Scheme 13).22 Interestingly, the iodide was prepared from a vinylstannane precursor which presumably failed to undergo Stille coupling.This result suggests that such species are relatively poor coupling partners in palladium-catalysed procedures. Nevertheless, a Stille coupling was used successfully during the synthesis of thymidylate synthetase inhibitor 31 (Scheme 14), though DMF was required as the solvent and the reaction occurred slowly.23 Coupling was also achieved with acid chlorides and aryl iodides. Mild protodesilylation of 30 completed the synthesis of 31. The synthesis of the a-fluoroalkenyl anion equivalent 29 is discussed in Section 2.5. Vinylphosphonates have also been prepared from the corresponding iodides by a coupling reaction.24 0 -0.1 R NaOH, Pd(PPh& F F 28 (82%) R=T*- Scheme 11 Scheme 13 Percy: Recent advances in organofluorine chemistry 25329 Pd(PPhd4 _I_c DMF 30 R = SiM% (28%) F M e 3 s i d s n B " 3 25 O C 29 Scheme 14 2.3 Metallated fluoroenol derivatives A dehydrofluorination/metallation sequence from commercial 2,2,2-trifluoroethyl tosylate (32) provides the entry point to Ichikawa's versatile borane 19 via 1,Zrnetal-ate rearrangement (Scheme 15) of complex 33.18 More recently, two groups have ,"" Bu"Li F3C THF,-78OC - 32 F F u F When 35 adds to aldehydes or ketones, the first- formed alkoxide undergoes a rapid transacylation reaction,26(a) releasing basic enolate 37 which can be trapped with non-enolizable aldehydes, to afford aldol products 38 in high yield though with low stereoselectivity (Scheme 17).26(b) OLi -78 to 0 oc F oCONEt2 37 (€)-H&CH=CHCHO 1 OH 0 38 (62% 1:l syn:anfi) Scheme 17 2.4 Fluoroenolates and enol silyl ethers The Reformatsky reaction of ethyl bromodifluoroacetate (39) with aldehydes (Scheme 18) is a ubiquitous process for the synthesis of compounds containing a difluoromethylene group.The zinc-promoted reaction appears to be BRI -78 OC [ '9;R2] 33 1 Ooc R F+BR2 t 19 R = Bu", BU8, (CHd3Ph Scheme 18 Scheme 15 developed chemistry of the metallated enol carbamate 35, derived from 34, in independent s t u d i e ~ . ~ ~ , ~ ~ ( ~ ) The intermediate is a versatile carbon nucleophile; the reaction with (trimethylsily1)methyl triflate affords an ally1 silane 36 that adds to aldehydes in the presence of a fluoride ion source (Scheme 16).25 OCON Et2 OCONEt2 34 i. 35 R+ JCHo F+SiMer TBAF F F THF,O°C F 36 R = Pr', Ph 3844% ?H BrF2CCO2Et - Zn, THF 39 Aor ))) 0 fl: 40 39 Zn, THF A I '1 41 II Scheme 16 Scheme 19 254 Contemporary Oqanic Synthesisparticularly amenable to scale-up; indeed the Eli Lilly plant scale route to the anti-tumour nucleoside gemcitabine is based upon the rea~tion.'~ The addition reaction displays low diastereoselectivity.On a large-scale, the unwanted diastereoisomer was removed by recrystallization of a benzoate derivative. On smaller-scales, chromatographic separation or recrystallization may be possible. An inhibitor of interleukin-lfl converting enzyme has been prepared28 from 39 and lactam aldehyde 40. The highly electron-withdrawing nature of the CF2 group was evinced by the coexistence of 41 with hemiacylal42 (Scheme 19). Doherty and co-workers have explored the ultrasound promoted Reformatsky reaction to prepare renin inhibitors." On a small-scale, sonication conditions minimized racemization of the sensitive aldehyde 43, though attempts to use the procedure on a large-scale were unsuccessful.Instead, (R)-diastereoisomer 44 was obtained in high purity (>95% d.e. after crystallization) via the thermal reaction, though an excess of 39 was required to obtain reproducible yields (Scheme 20). 44 II 45 HCJ&O&i DCC,DMSO I I CH&, 0 O C to r.t. 46 (7&Q5%) Scheme 20 Percy: Recent advances in organofluorine chemistry An interesting, modified Pfitzer-Moffat oxidation procedure has been developed which allows conversion of the secondary alcohol 45 into ketone 46 in good yield (75-90%) with minimal epimerization a- to the ketonic carbonyl group.Scheme 21 shows the synthesis of a 4,4-difluoro-~- arginine analogue 49.30 Reformatsky reaction with Garner's aldehyde (47) was followed by treatment with thiocarbonyldiimidazole and free radical deoxygenation to afford 48 in good yield. h i d e reduction proceeded smoothly with Red-Al, followed by protection of the primary amino group and manipulation to 49. 47 O (i) 39 Zn. THF ))) o O C to r.t. (ii) I@=S ' d y C F & O & t OCSlm 48 ( i ) NH3. Et20,-78 OC (ii) Red-AI, PhMe, r.t (iii) Cbz-CI. NaHQ. EtOAc Scheme 21 An extended ester enolate has been generated and trapped in high yield when chlorodifluorocrotonate (50) was treated with aldehydes in the presence of a zinc-copper couple (Scheme 22).31 The crotonate was prepared by Wadsworth-Horner-Emmons reaction upon chlorodifluoroacetaldehyde and the extended (i) LIAIH., Et&, -78 OC c'F2cco2Et (ii) ( E t 0 ) ~ P O C H ~ O g ~ c ' F 2 c ~ C 0 2 E t Et3N, LiEr.THF 50 (&I%) Zn(Cu) couple PhCHO I THF, 0 % 51 (61%; 1:l syn:anti) Scheme 22 255Reformatsky reaction gave good yields of y,y-difluoro homoallyl alcohols 51 with a range of aldehydes. Yields with ketone electrophiles were relatively poor. An aldol reaction between ketone 52 and paraformaldehyde was used recently in the synthesis of a potential myristoyl transferase inhibitor 54 (Scheme 23).32 The reaction was catalytic in titanium tetrachloride and, though direct, occurred in modest yield. Aldol53 was elaborated by activation to the triflate and displacement by a thiolate nucleophile.Scheme 23 More efficient Mukaiyama aldol reactions have been performed with difluoroenoxysilanes. Newer methods for their synthesis have exploited the Brook rearrangement. Treatment of acylsilane 55 with a Grignard reagent affords an adduct 56 that collapses to silic-ate species, 57 (Scheme 24). The carbon-silicon bond is then sufficiently reactive to cause cleavage of an antiperiplanar carbon-fluorine bond, forming the enoxysilane 58.33 Using isopropylmagnesium bromide as the nucleophile allowed 59 to be isolated in excellent yield. 55 56 57 Scheme 24 OSiPh3 OSiPh3 F+H F$h F F 59 58 (8&100%) A similar approach was followed by P ~ r t e l l a ~ ~ who introduced a trifluoromethyl nucleophile using Rupperts reagent 1 and the non-hygroscopic fluoride source, 60, described by Gingras (Scheme 25).35 The difluoroenoxysilanes undergo Mukaiyama aldol reactions when treated with titanium tetrachloride in the presence of aldehydes.A brassinosteroid analogue has been synthesized via this approach.33 Lithium difluoroenolates have also been deployed in the aldol reaction though only low diastereoselectivities have been reported to date.26(b) [Ph3SnF2]NBu4 60 OH 0 0 OSiMe2R2 F+Rl TCI4- phvR PhCHO RiKSiMe2R2 - TclF . . .. R’ = odyl, Ph -78 to -30 Dc F CH2CI2 F7 ‘F R2 = Me, But R = Ph, 71% 4d79yo -78 O C to r.t. Scheme 25 2.5 Phosphonyl- and sulfonyl-stabilized carbanions McCarthy36 has described a range of useful reactions based upon fluoromethylphenylsulfone (61). Though the preparation of the compound is non-trivial, it can be used to prepare a-fluorovinylsulfones with interesting properties.Treatment of 61 with an amide base in the presence of diethylphosphochloridate affords a highly stabilized carbanion that is still sufficiently reactive to undergo a Wadsworth-Horner-Emmons reaction with aldehydes and ketones (Scheme 26). Mixtures of (E)- and (Z)-vinylsulfones are obtained, which have been separated in some cases.37 Treatment with tributyltin hydride/AIBN results in stannylative desulfonylat ion2’ with retention of configuration to afford 62. The stannyl group can then be used to introduce an iodine, fluorine, or hydrogen atom (Scheme 27). Protodestannylation22 occurred on treatment with sodium methoxide, ammonia in methanol, or TBAF, while reaction with SelectfluorTM 63 in acetonitrile resulted in a high yielding tidfluorine exchange,38 The chemistry has been used in the syntheses of an antitumour nucleoside 64,39 and analogues of eugenol methyl ether 65, a sex attractant of the Oriental Fruit Fly.40 Scheme 26 62 MeCN.80 % F q R F Scheme 27 63 256 Contemporary Organic SynthesisH O T c Me0 MeorF HO i 64 65 An interesting application of sulfone 61 involves trapping the lithium anion with (chloromethy1)dimethylphenylsilane to afford 66 as a stable crystalline solid in good yield.4' Retreatment with butyllithium, followed by the addition of an aldehyde triggered a Peterson-type elimination in which carbon-sulfur bond cleavage occurred from the silic-ate to afford an allylic silylether 67 (Scheme 28).Silane 66 is therefore an extremely useful alternative synthetic equivalent for the a-fluoroethenyl anion. 66 i OSiMe2Ph 67 Scheme 28 Fluorinated phosphonate carbanions have been used to prepare mimics of biologically important phosphate esters. O'Hagan and Nie~chalk~~ have described a synthesis of 70 (Scheme 29) involving the alkylation of the fluorophosphonate carbanion 68 with the primary alkyl triflate 69. Free radical deoxygenation provides an attractive alternative to alkylation chemistry. Bu"Li, Me3SiCI Me3SY PO(OEt)2 BrF2CPO(OEt)2 THF, -78 OC ti 68 (0 69 (ii) LiOEt. EtOH (iii) NH4Ci 83% OTf (iv) Me3SiBr (v) C6HllNH2 I Martin and c o - ~ o r k e r s ~ ~ have described the basic methodology which was used in a recent syntheses of the phosphoserine analogue* 71 (Scheme 30) and nucleotide 5'-deoxy- 5'-difl~oromethylphosphonates~~ 72.The OCSOPh 86% PhMe 68% (iii) HCI. EtOH (iv) RuCI~, NaIO4 (XI4. MeCN 1 phosphate buffer H02CeCF2PO(OEt)2 NHBOC 71 (32%) Scheme 30 attachment of the difluoromethylenephosphonato group to secondary carbon centres remains a problem, though two potentially general solutions have emerged. Addition of a lithiodifluorophosphonate to methyl vinyl ketone, followed by rearrangement of the allylic alcohol product afforded 73 in good yield as a single stereoisomer (Scheme 31).46 Scheme 32 shows a conjugate addition solution to the pr~blem.~' In the presence of cerium(m) chloride, the lithiodifluorophosphonate added to nitroalkenes in acceptable yield to produce 74. $ 8 H d \OH 72 (B= U, C, A) Scheme 29 73 (82%) Scheme 31 Percy: Recent advances in organofluorine chernistty 257I addition of iododifluoromethyl ketone 78 to N,AJ- dimethylacrylamide afforded the ketoamide in good yield.Treatment with aqueous ammonia converted the reactive difluoromethylene ketone into the corresponding imine. Cyclization followed by dehydrofluorination completed the synthesis of pyrrole 79. (I) LDA. Cec!, THF, -78 OC RqNo2 'F~cpo(oEt)2 (ii) (E)-RHC=CHNG - (iii) HOAc CFpPO(OEt);! 74 R = Et, Pi, But, t% 25-62% Scheme 32 3 Fluorinated carbon electrophiles 3.1 Fluoroalkyl ketones Fluoroalkyl ketones and related carbonyl compounds are reactive carbon electrophiles with diverse synthetic and medicinal chemistry. Fluoroalkyl ketones form the subject of a recent review.48 Fluoromethyl ketones were prepared by a sequence involving a sulfoxide elimination (Scheme 33).The conjugate base of 75 added to aldehydes in excellent yield. Flash vacuum pyrolysis of the adducts has afforded ketones 76 in moderate yield.49 Simple compounds of this type should be available from the reaction between silyl enol ethers and the Selectfluorm reagent?' Alternatively, the N,N- diisopropylcarbamate of difluoroethanol functions as an acyl anion equivalent (77) upon treatment with strong base (Scheme 34)' Difluoromethyl ketones have been prepared from trifluoroethanol by a similar but higher yielding route.26(a) 0 0 I I II LDA. -78 OC F 1O:l THF:HMPA Ph0'? - F 7s 1 PhCH2CH0 76 (45%) 9lYo Scheme 33 OR 40% Scheme 34 Difluoromethylene ketones are usually prepared by the Reformatsky chemistry described in Section 2.4.An alternative approach was recently described by Burton and Qiu?' and deployed in syntheses of B-fluoropyrroles (Scheme 35).53 Palladium-catalysed 79 (9o-Yo.f Scheme 35 Trifluoromethyl ketones have been prepared in good yield using a new method described by Zard and co-w~rkers.~~ The reaction proceeds via an acyl ketene intermediate but requires the formation of an acid chloride (Scheme 36), which limits the range of functionality that can be present. Kitazume and (F3CCO)20 T F3c9 H217 c1p(CH2)7 0 759/0 0 Scheme 36 co-workers have prepared furanyl trifluoromethyl ketones en route to a range of 6-deoxy- 6,6,6-trifluoro~ugars.~~ Trifluoroacetylation of lithio- 2-trimethylsilylfuran afforded ketone 80; reduction of the ketone afforded alcohol 81 as a racemic modification in excellent overall yield from furan (Scheme 37).Lipase resolution followed by furan oxidation afforded optically pure butenolide 82 which was converted into a range of optically-pure 6-deoxy-6,6,6-trifluorosugars, including 83 (Scheme The direct perfluoroacylation of alkynes has been achieved using an interesting procedure (Scheme 38).56 Presumably, the sequence involves the initial formation of a vinyl cation which is intercepted by the sulfur nucleophilic to afford vinyl sulfonium salt 84. Demethylation affords 85 in which some isomerization has occurred. Peracetic acid oxidation led to the formation of 86 in excellent chemical yield as the single (Z)-stereoisomer. Analogues of vitamin E have been prepared using Wittig 37).2 5 8 Contemporary Otganic SynthesisF3C* TMS HO 81 (82%; 5 steps) .I TBSO F3cYr HO' 83 Scheme 37 C0CF.q CH2C12. -40 OC 84 [95% ( E ) : ( Z ) = 2:3] H202 COCFS Ph 9 HOAc P h F C O C F , reflux S0,Me SMe 86 (88%) 85 (95% ( E ) : ( Z ) = 1 :3] Scheme 38 reactions of trifluoromethylketones, which show high reactivity towards phosphorus ylidsS7 Scheme 39 shows the preparation of an intermediate 87 from ethyl trifluoroacetoacetate which displays the usual (Z)-selectivity in the reaction of trifluoromethyl ketones with unstablized ylids. A useful aldehyde equivalent has been prepared from ethyl trifluoroacetate. Dibal-H reduction gave 88 in situ. Further treatment with an allylstannane and zinc bromide afforded good yields of homoallylic alcohols (Scheme 40).58 h- 87 [(E ):(Z) = 23:7n Scheme 39 Scheme 40 3.2 a-Fluoro-a, fl-unsaturated carbonyl compounds The standard method for the preparation of a-fluoro-enals and -enones involves the fragmentation of chlorofluorocyclopropanes, obtained by halocarbene additions to enol ethers.59 A full discussion of this methodology lies outside the range of this review and few applications in target synthesis have been reported in the open literature.However, the extensive use made of this methodology by Johnson and co-workers is discussed later in this review. The synthesis of a-fluoroenoate esters by Wadsworth-Horner- Emmons methodology has been described by Burton and Thennapan.60 A recent application Piva (Scheme 41) displayed the usual selective formation of the (E)-alkene diastereoisomer.61 Photoisomerization of adduct 89 afforded P,y-unsaturated ester 90 as a mixture of diastereoisomers in moderate yield.A bY complementary procedure has been described by F i c o 2 E t PO( OEt), (i) Bunti, THF, -78 OC - (ii) TBSO(CH2)2CH0 89 F [80%; ( E ) : ( Z ) = 98:2] h, Et3N CH&. 0 O C I Scheme 41 Clemenceau and Cousseau.62 Sodium salt 91 reacted with aldehydes to afford (Z)-fluoroenoates in moderate chemical yield. High diastereoselectivities resulted when bulky aldehydes were used in the reaction. Scheme 42 shows the most selective example. (Z)-Fluorothioenoates were prepared using the a-fluoroacrylate-P-cation equivalent 92 prepared from fluoroacetonitrile by a simple procedure (Scheme 43). Grignard reagents added at the carbonyl group and treatment with acid initiated dehydration with double bond migration and formation of an allylic thioacetal; thioacetal hydrolysis affords 93.63 Percy: Recent advances in olganojluorine chemistry 2590 Scheme 42 F /CN- MeS,&,, THF.HMPA hne6 83YO -78 OC Dibal-H CH& 0 OC (ili) Pr'MgCI.Et$, r.t. I (hr) HgCIz. MeCN (a%) M e S A CHO reflux mcosMe ' F 93 (67%) Me& 92 (70%) Scheme 43 A palladium-catalysed route to a-fluoroenones (Scheme 44) was published recently,64 based upon chemistry developed by Tsuji. In acetonitrile, ketoester 94 underwent decarboxylative elimination to afford enone 95 in good chemical yield. More highly substituted derivatives have been prepared from (2H)tetrafluoropropanol. Conversion into the tosylate and brief exposure to n-butyllithium yielded enol tosylate 96 as a mixture of diastereoisomers.Treatment with a secondary amine in the presence of a fluoride ion source led to the formation of /?-aminoenal97 in excellent yield (Scheme 45).65 94 Scheme 44 95 (74%) HF~CCF~CH~OTS B""Li_ THF HF&$OTs+ ph/(,,,H2 -78% 10% TBAF EtSN. THF 97 (94%) 3 3 fl-Fluoro-a, /?-unsaturated carbonyl compounds Fluorine atoms located on the /&carbon of an a,fl-unsaturated carbonyl compound are replaced readily in additiodelimination reactions with nucleophiles. Ichikawa has used difluoroenones to prepare highly substituted enones shows a recent example. There is a significant difference in reactivity between the di- and mono- fluoroenones 98 and 99, allowing the incremental replacement of the two fluorine atoms with different carbon nucleophiles.Carbon nucleophiles were delivered via cuprate and zincate reagents. A similar sequential displacement with heteroatom nucleophiles has also been described.67 Scheme 46 98 99 [79%; ( E ) : ( Z ) = 89:11] PhfiuMgI O V P h +B" Bu 100 [85%; (E):(Z) = 1:1] Scheme 46 3.4 y-Fluoro-a, fl-unsaturated carbonyl compounds Seebach and co-workers have described a range of useful reactions based upon chiral dioxinone 101 derived from trifluoroacetoacetate.68 Scheme 47 shows a diastereoselective conjugate addition of a Gilman reagent. Conjugate additions of alkyllithium reagents to y,y,y-trifluoroenones in the presence of the ATPH complex were described by Yamamoto and c o - ~ o r k e r s .~ ~ Taguchi and co-workers have described the preparation and reactions of the interesting bromodifluorocrotonate ester 102, which underwent Michael additions with lithium enolates to furnish adducts 103 (Scheme 4Q7' However, when the intermediate enolate was treated with triethylborane and oxygen, trans-cyclopropane 104 was formed in good yield. The reaction is interesting because it presumably involves alkylation of a boron enolate, rather than a free radical reaction. The product cyclopropanes were produced in high e.e. when chiral enolates were used in the Michael addition." 101 85% 3(5):3(R) >98:2 Scheme 45 260 Contemporary Organic Synthesis Scheme 47CO2TMP F F PO(OEt)2 NaHMDS BrF2CCH0 + CF,Br 1 02 R = Bu' B u b , C T 2 T M P (THF,DMI CF2Br 103 (70%) OLi THF.DMI 104 (73%) (TMP = 2,4,6-trimethylphenyl) Scheme 48 An efficient preparation of y,y,y-trifluoro- crotonates has been reported by Shen and G ~ o . ~ ~ Treatment of 105 with Grignard reagents followed by acidic work-up led to the formation of esters 106 in good yield with high (E)-selectivity (Scheme 49). (0 PhCkCMgBr Et@. 25 "c F 3 c r o 2 f 3 ~ t Ph3P<c0cF3 c C02But (ii) HOAc, r.t. 105 Scheme 49 Ph 106 [88%; (Z):(€) = 1288 3.5 Fluoroalkyl epoxides Epoxides are useful building blocks for the synthesis of fluorinated compounds; fluoroalkyl epoxides are more resistant to cleavage under acidic conditions than their non-fluorinated congeners but undergo nucleophilic ring opening. The fluoroalkyl epoxide 108 was formed when the corresponding ketone 107 was treated with diazomethane in ether.Bravo and co-workers have used this approach to prepare a range of optically-enriched building blocks,73 achieving asymmetric induction with a chiral sulfoxide auxiliary. Scheme 50 shows elaboration via Pummerer rearrangement and hemithioacetal hydrolysis which afforded reactive epoxyaldehyde 109. A range of related epoxides containing different fluoroalkyl groups have been prepared.74 Nucleophiles open the product epoxides in the usual way, via attack at the less-hindered carbon atom. Trifluoromethyl epoxides have been prepared from trifluoromethyl ketones and from trifluoromethyl enol ethers. 107 109 Scheme 50 BCguC and co-workers have reported that trifluoromethylenol ethers underwent oxidation with mCPBA in high yield to afford isolable epoxides 110 (Scheme 51).75 When treated with magnesium bromide etherate, bromotrifluoromethylketones were obtained in good yield.Nucleophilic ring- opening with azide was used in the preparation of human leukocyte elastase inhibitor^.^^ 110 (90%) Scheme 51 Ring-opening of chlorodifluoromethyl epoxides 111, obtained via epoxidation of the corresponding, easily-prepared enol ethers, was achieved upon treatment with t-butyllithium in THF at low temperature, affording difluoroallylic alcohols, including 112, in good yield (Scheme 52).77 Seebach R = CH&H(OEt)2 1 1 1 (60 '10) Scheme 52 and co-workers have developed a route to the optically-pure epoxyester 114 from 4,4,4-trifluoro- 3-oxobutanoate 113 (Scheme 53).78 Phenylcuprate nucleophiles attacked the epoxyester at C-(2), phenylmagnesium bromide attacked competitively at C-(2) and C-( 1) while organolithium reagents and alkyl Grignard reagents attacked at the carbonyl carbon leaving the epoxide intact.(i) LDA 0 F ~ c * * ~ c o ~ E ~ &C02Et - OH (ii) I2 (iii) H@ (N) DBU F3C 113 114 Scheme 53 Percy: Recent advances in organofluorine chemistry 26 13.6 Fluoroallylic electrophiles Though unusual, electrophiles of this type feature in some interesting processes. Difluoroallylic acetates react with Grignard reagents with copper(1) catalysis to afford sN2’ alkylation products in good yield though with variable stereoselectivity. Tellier and Sauvetre have studied the reaction extensively and a recent publication provides some experimental detail^.'^ The rates of competing processes may be very similar.Scheme 54 shows a situation in which nucleophilic attack occurs competitively at fluorinated and non-fluorinated allylic termini. The identical proportions of 115 and 116 illustrate the similar reactivities of the two allylic systems. Diene 117 arises from nucleophilic attack on 115 with loss of fluoride. Exposure of difluoroallylic alcohols to DAST provides a useful synthesis of trifluoromethylalkenes. Yields were not reported but a range of alkenes were prepared. Scheme 55 depicts a typical procedure.80 116 (25%) + 117 (30%) Scheme 54 HO Et&, M F Boc Qtj BOC Scheme 55 The fluoride ion can also function as a leaving group in sN2’ displacements. Lithium amides have been added to cx-trifluoromethylstyrene to afford useful yields of difluoroallylic amines.8’ The lithium cation may provide some assistance to the C-F bond cleavage; an attractive six-centre transition state has been written for the reaction (Scheme 56).Difluoroallylic amines were of some interest as MA0 inhibitors and have been prepared by a less efficient route. F*F Scheme 56 4. Pericyclic reactions 4.1 Diels-Alder and dipolar cycloadditions Dienophiles bearing fluorine atoms attached directly to the carbon-carbon double bond are rare; the propensity for thermal [2 + 21 cycloaddition displayed by fluoroalkenes is well known. 5-Fluorodioxinone 118 has been employed as a component in a Diels-Alder reaction; 118 reacted with Danishefsky’s diene to afford the expected cycloadduct in moderate yield under high pressure conditions (Scheme 57).Dioxinones with an additional substituent at the 6-position failed to react under these conditions. A more efficient reaction was reported with the more electron- deficient trifluoromethyl congener.82 0 36 H Scheme 57 A reactive dienophile, prepared from 119, has been prepared in situ from bromotrifluoropropene via an efficient sequence. High yields of cycloadducts were obtained with electron rich dienes, including furan under mild conditions (Scheme 58).83 119 Scheme 58 Tipping and co-worke~s~~ have reported the smooth cycloaddition reactions of trifluoromethyl propiolate derivative 120 with furan. Pyrolysis of the cycloadduct 121 led to the elimination of ethene, setting the stage for a second cycloaddition reaction between furan 122 and hexafluorobutyne (Scheme 59).262 Contemporary Organic SynthesisCOpEt !! 6 F3 120 Scheme 59 a-Trifluoromethyl styrene added to Danishefsky's diene under high pressure conditions, leading to cyclohexenone derivative 123 after hydrolysis (Scheme 60).85 The reaction was used to prepare the steroidal A-c ring system with an angular trifluoromethyl group. Fluoroalkyl imines have been explored as building blocks for the synthesis of nitrogen heterocycles with fluoroalkyl substituents. In the presence of boron trifluoride etherate, 124 added efficiently to Danishefsky's diene to afford a separable mixture of dihydropyridinones (Scheme 61).86 The chemical yield and diastereoisomeric purity of each adduct were high. OMe I Ph + phTcF3 15kBa - n c F 3 50 OC hydroquinol TMSO 123 (80%) Scheme 60 0 OMe I I F3B .O Et2 g :""?I - N Ph CH2C12 HF~C** TMSO Y -78% I fi Ph 1 124 82% (81 : 1 9 anfisyn ) Scheme 61 Homo- and hetero-dienes displaying useful reactivity have been described.Azadiene 125 was prepared from readily-available 2-fluoroacrolein by Schlosser and Ghosh (Scheme 62)87 and added smoothly to DMAD to afford fluoropyridine 126 after hydrolysis. Reissig has described a wide range of cycloaddition reactions of nitrosoalkene 127.*' The heterodiene is reactive and easy to prepare; Scheme 63 depicts a high yielding reaction with l-methoxyallene to afford cyclo adduct 128 in excellent yield. F rw (1) 80 %* Fqco2w C O * k $ + (ii) H30+ I c02Me NMe2 125 126 (70%) Scheme 62 Me0 127 128 (92%) Scheme 63 The LUMO-lowering effects exerted by the trifluoromethyl and carboxylic ester groups are similar.89 Pyrrolidines have been prepared via the reaction of an azomethine ylid with a range of trifluoromethylalkenes.a-Trifluoromethylstyrene reacted smoothly to afford cycloadduct 129 in good yield (Scheme 64). a-Methylstyrene failed to react under the same conditions. The formal [2 + 21 cycloaddition between fluoroketene and the optically-pure imine 130 was exploited in an efficient asymmetric synthesis of a fluorinated P-lactam (Scheme 65).90 Fluoroketene was generated in situ from fluoroacetyl chloride and triethylamine. Lactam 131 was obtained in moderate chemical yield though in high e.e. (299%). Lactam 132 was converted into a configurationally fixed alkylmalonamide component of an HIV protease inhibitor." CH&I2 r.t.+ phwcF3 Bn 129 (80%) Scheme 64 HzFCCOCl NPMP 130 131 R = H 132 R = Bn Scheme 65 4.2 Sigmatropic rearrangements and ene reactions A recent review describes the many applications of [3,3]-rearrangements in organofluorine chemistry.92 Perhaps the most developed methodology uses the Ireland silyl ketene acetal rearrangement. This has Percy: Recent advances in organojluorine chemistry 263proved to be a powerful tool in the hands of Welch and co-~orkers.~~ Allylic fluoroacetate 133 was prepared from highly toxic fluoroacetyl chloride; the (Z)-silyl ketene acetal was formed upon treatment with bulky triisopropyl silyl triflate. Scheme 66 shows a diastereoselective rearrangement. The rearrangement products have been utilized in syntheses of 2,3-dideoxy-2-fluoro-3-C-methyl pentose nucle~sides.~~ In a tetrasubstituted series, alcohol 140 was converted into acetate 141 and tributylstannyl methyl ether 142 (Scheme 69).Ireland rearrangement of 141 afforded a 4 : 1 mixture of acids 143 and 145, whereas Still-Wittig rearrangement of 142 led to the formation of homoallyl alcohols 144 and 146 in a 3 : 7 ratio.97 133 >95% (151 symanri ) Scheme 66 143 R2 = C02H 144 R ~ = O H OPr' pN (i) PrbH.HCI F (ii) - PrbH &;' + Ph F 134 (27%) B u ' C ~ ~ H 1 T L ~ 145'C FYco2pi Ph -eA4 Scheme 67 135 1 36 1 37 in sitv 1 139 Scheme 68 + X R'0 - Orthoester 134 was prepared from fluoroacetonitrile and used in the Johnson-Claisen rearrangement (Scheme 67). A range of a-fluoroesters was prepared in this way though the yields were low.The formation of the product ester as a 1 : 1 mixture of diastereoisomers implied that ketene acetal formation did not occur in a stereoselective manner.95 Johnson and c o - ~ o r k e r s ~ ~ have explored a range of rearrangements for the stereoselective construction of highly substituted fluoroalkenes. Fragmentation of cyclcopropane 136 in the presence of alcohol 135 led to the formation of 137 which rearranged to 138 in situ. Reduction with Dibal followed by orthoester Claisen rearrangement afforded 139 as a single alkene diastereoisomer (Scheme 68).96 Scheme 69 138 (71%) $111 140 R' = H 141 R' =Ac 142 R' = CH2SnBu3 F R* 145 R2=C02H 146 R2=OH A number of less common rearrangements have produced interesting results. A Brown Algae pheromone has been prepared by a Cope rearrangement in which strain relief and the weakness of the distal bond within a difluorocyclopropane contributed to an unusually facile conversion9' of divinylcyclopropane 147 into cycloheptadiene 148 (Scheme 70).Difluoroallylic 6 Bun 147 148 (78%) Scheme 70 alcohols have been transposed via the [2,3]-Wittig rearrangement shown in Scheme 71. Trifluoroethanol has been converted into a highly functionalized species containing a CF2 group in this way.w Mikami and co-workersl" have described a catalytic asymmetric ene reaction using trifluoroacetaldehyde (Scheme 72). The ene reaction proceeded in high e.e., though the efficiency was lower when 2-methyl-2-butene was used in the reaction. 264 Contemporaly Organic SynthesisOH OMEM LDA, THF -78 to -30 OC F F 0- Scheme 71 982 syn:anfi MY0 8.8.Scheme 72 5. Free radical reactions The high strength of the C-F bond renders it virtually inert under the conditions used to trap and generate free radicals. Fluorine atoms may exert a significant effect on the course of free radical reactions though the magnitude and direction of the effects remain far from clear. Recent physical organic studies have demonstrated the highly electrophilic a-nature of perfluoroalkyl radicals. The SOMO energy is relatively low because of delocalization of the unpaired spin into the ,8 C-F o* orbitals, and the inductive electron withdrawal exerted by the perfluoroalkyl group. Set against this effect is the SOMO raising interaction with the non- bonding electron pairs on the fluorine atoms borne on the radical centre.The trifluoromethyl radical therefore has ~r-character.'~'-~~~ Buttle and Motherwell have demonstrated that difluoromethyl radicals display some nucleophilic character. '04 Higher yields of cyclization products were obtained when an electrophilic alkene was present to trap the difluoromethyl radical. Scheme 73 shows a successful cyclizat ion. C02Me C02Me F5 BrF2C Bu3SnH Me02C L AIBN, PhMe Me02c Me02C reflux J 65% Me02C Scheme 73 The precursor was constructed by bromodifluoromethylation of a malonate carbanion in moderate yield. According to Bravo and co- workers, difluoromethyl radicals are electrophilic and highly reactive though their studies do not provide evidence either in support of or against this view.lo5 Cyclization of 149 afforded 150 as a single stereoisomer in moderate yield.The preference for the halomethyl group to assume an equatorial orientation is presumably reinforced by the necessity to avoid a 1,3-diaxial repulsion with the axial hydroxyl group (Scheme 74). A range of enantiomerically pure difluorocyclohexanes were prepared from 150. Similar routes to monofluorocyclohexaneslo6 and difluorocyclopentanes107 have been described by these authors. Bu3SnH reflux OH -O OH 150 (500/,) 149 Scheme 74 Takeuchi has described a general free radical route to tertiary alkyl fluorides from esters of dibromofluoroacetic acid.''* The allylstannane fragmentation method was used to prepare adduct 151 which underwent free radical addition to acrylonitrile (Scheme 75), or Reformatsky reaction with aldehydes.A high yielding bromodecarboxylation was achieved using Barton methodology; iodidebromide exchange set the stage for a second radical allylation affording 152. D H&=CHCH,SnBu3 Br2FCC02Et AlBN 151 H&=CHCN Bu3SnH, AIBN vCN F C02Et CN H2C=CMeCH2SnBu3 \ 4 TCN F I AlBN 152 Scheme 75 Radicals generated at the position fl to C-F bonds are expected to be more electrophilic than analogous alkyl radicals. Shimizu and co-w~rkers'~~ have described a useful bromofluorinationhadical cyclization sequence (Scheme 76). Bromofluoride 153 and the cyclized product 154 were obtained as single stereoisomers. The catalytic conditions described by Stork proved effective in the cyclizat ion. Percy: Recent advances in organofluorine chemistry 265153 (61%) 154 Scheme 76 Taguchi has explored the scope of cyclizations involving primary and secondary Q,Q-difluoroalkyl radicals.' lo Difluorotetrahydropyrans and cyclohexanes were prepared; Scheme 77 shows an efficient cyclization.Precursor 155 was prepared via a lengthy sequence involving the elaboration of a Reformatsky adduct of 39. The cyclic product 156 was obtained as a 1.2: 1 mixture of cis and trans isomers. The presence of the fluorine atoms had no effect on the efficiency of the cyclization reaction. A subsequent study extended the range of cyclizations to include trifluoromethyl alkyl and alkenyl radicals (Scheme 78)."' 155 Scheme 77 OMOM Bu3SnH AIBN, PhH ____c reflux 86% Scheme 78 6 References 1 J.A. Wilkinson, Chem. Rev., 1992, 92, 505.2 O.A. 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ISSN:1350-4894    

DOI:10.1039/CO9950200251

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

Amines and amides MICHAEL NORTH Department of Chemistry, University of Wales, Bangol; Gwynedd, LL57 2 W UK Reviewing the literature published in 1994 Continuing the coverage in Contempory Organic Synthesis, 1994, 1, 475 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 3 3.1 3.2 3.2.1 3.2.2 3.3 4 5 Introduction, scope and coverage Preparation of amines Synthesis of achiral and racemic amines Synthesis of optically active amines Synthesis of amines bearing additional functional groups Synthetic routes to p-hydroxyamines Synthesis of a-amino acids Racemic syntheses of a-amino acids Asymmetric syntheses of CI amino acids Synthesis of P-amino acids Racemic syntheses of P-amino acids Asymmetric syntheses of p-amino acids Preparation of amides General methods, and the synthesis of acyclic amides Synthesis of lactams Synthesis of P-lactams Synthesis of other lactams Synthesis of peptides Summary References 1 Introduction, scope and coverage This review covers the literature published during 1994.Papers were selected from the on-line science citation index for 1994, so some papers published at the end of 1994 which are cited in the 1995 index have not been included but will be covered in the next review of this topic. 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. However, the sections on 'Synthesis of y- and higher amino acids' and 'Synthesis of a-amino aldehydes' have been omitted from this year's review due to lack of suitable material.2 Preparation of amines 2.1 Synthesis of achiral and racemic amines The Mitsunobu reaction is an extremely versatile method for the synthesis of alcohols and their derivatives, but attempts to extend this chemistry to the synthesis of amines have in the past been thwarted by the low acidity of amines. Edwards et al. have now shown that p-toluenesulfonamides and t ri fluoromet hanesulfonamides are suit able substrates for use in the Mitsunobu reaction (using triphenylphosphine and diethyl azodicarboxylate), thus permitting the synthesis of a variety of amines from alcohol precursors.2 Exactly the same results were obtained by Tsunoda et al., using the more reactive Mitsunobu system composed of N, N , N',N'- t e tr ame t hy lazodicarboxam ide and t ributylp hosp hine .3 Treatment of N-trityl-3-chloro, bromo, or tosyl propane with a base results in cyclization to N-trityl azetidine.The trityl group can then be removed by treatment with perchloric acid, providing a short, convenient synthesis of a~etidine.~ The ring-opening of azetidines by lithium has then been reported to be catalysed by 4,4' di-t-butylbiphenyl. The resulting N,C-dianion can be trapped with a wide range of electrophiles, including deuterated water, carbonyl compounds, imines, carbon dioxide, and alkyl halides, producing a variety of amines with remote functional group^.^ Deprotonation of an N-Boc- methylalkylamine can also be achieved, and occurs regioselectively at the methyl group.The resulting carbanion can be trapped by a variety of electrophiles, including alkyl halides, aldehydes, silyl halides, tin halides, and deuterated water to provide a general synthesis of unsymmetrical secondary amines after cleavage of the Boc-group.6 A number of routes for the synthesis of amines which utilize organometallic chemistry have been reported. Thus, organozirconium chemistry has been used to prepare cyclopentylamines by the coupling of a diene and an i~ocyanide.~ Both pyrrolidines and piperidines have been prepared by a palladium- catalysed process involving the coupling of a vinyl halide (or triflate) with an olefinic sulfonamide.8 A synthesis of N-arylpiperidines using organobismuth chemistry has also been reported.Thus, reaction of a triaryl bismuth with piperidine derivatives in the presence of copper acetate results in formation of the aromatic-carbon to nitrogen bond, giving the N- aryl piperidines.' A synthetic route for the conversion of aldehydes into s-alkyl primary amines has been developed by Katritzky et al., as shown in Scheme 1. Thus, the aldehyde can be converted into an a-iminophosphorane benzotriazole derivative, from which the benzotriazole group can be eliminated by treatment with an organocerium reagent. Subsequent hydrolysis then provides the primary amine." Similar methodology has been reported by North: Amines and amides 269Katritzky et al., and simultaneously by Pearson and Stevens," for the synthesis of P-hydroxyalkyl tertiary amines, and a-stannylamines.Hence, condensation of an aldehyde, a secondary amine, and benzotriazole gives an a-benzotriazole tertiary amine, which upon treatment with tributylstannyl lithium gives an a-stannyl amine. Transmetallation of the latter species with butyl lithium gives an a-amino anion which will react with ketones to give P-hydroxyalkyl tertiary amines." Katritzky et al. have also shown that reaction of a-benzotriazole- tertiary amines with vinyl amides or vinyl amines provides a route for the synthesis of 1,3-diamines.l2 Scheme 1 The reaction between allyl chlorides and lithium hexamethyldisilazide is enhanced in the presence of silver iodide, providing a synthetic route to (N,N,- bis-trimethylsily1)allyl amines.l3 A stereospecific synthesis of (E)-allylic amines utilizing tantalium chemistry has been reported as shown in Scheme 2. Thus, addition of an organolithium reagent to an imine gives a nitrogen anion which will insert into a tantalium-alkyne complex, giving an allylic amine after aqueous ~ 0 r k - u p . l ~ Allylic amines can also be prepared stereoselectively from the corresponding bromides or mesylates by treatment with (BOC)~NH in the presence of caesium carbonate and lithium iodide followed by TFA to remove one or both of the Boc g r 0 ~ p s . l ~ N-Benql-allylic amines have been prepared by the addition of vinylmagnesium bromide to an N-benzyl nitrone, followed by reduction of the resulting hydroxylamine with zinc in acetic acid.16 the a-tosyl and N-anions undergo Michael additions onto the unsaturated ester.17 Reaction of an allenic bromide with an amine results in the formation of a propargylic amine via an SN2' reaction.18 By contrast, treatment of a propargyl ester (acetate or phosphate) with a secondary amine in the presence of catalytic copper(1) chloride results in the formation of propargylic amines without allylic rearrangement.l9 Ts Jc NHB" 1 Synthesis of monoprotected ethylenediamine derivatives can be difficult due to lack of selectivity in reaction at the two amino groups. A synthesis of N-Boc-ethylenediamine which avoids this problem has been reported which utilizes readily available amino-acetonitrile as the starting material. Introduction of the Boc group followed by reduction of the nitrile (RaNdEtOH/NH3/50 p.s.i.H2) gives the monoprot ect ed e t hylenediamine derivative .20 Photolysis of an N-phthaloyl a-amino acid in an acetone/D20 mixture results in decarboxylation along with deuterium incorporation to give N- phthaloyl deuterated amines. Removal of the phthaloyl protecting group then gives a-deuterated amines. 21 ( R1R2NCH2SR3) with an organolithium reagent results not in deprotonation, but in substitution of the thio-group, leaving a tertiary amine (R'R2NCH2R3).22 The reaction is thought to proceed via an imine or carbene intermediate. A synthetic route for the synthesis of fluorinated tertiary amines has been reported as shown in Scheme 3. Thus treatment of a secondary amine with either a fluorinated anhydride or fluorinated ester in the presence of a suitable base gives the corresponding amide.Treatment with Lawesson's reagent then gives the thioamide which undergoes an oxidative desulfurization-fluorination upon treatment with tetrabutylammonium dihydrotrifluoride in the presence of NBS or NIS.23 Reaction of an a-thio-tertiary amine Lawesson's reagent 1 S 'XF Ri Bun4NH2F3/ & N:# NBSorNIS 'R2 Scheme 2 Scheme 3 Treatment of allyl amine 1 with two equivalents of BuLi followed by the addition of a bis- electrophile allows the preparation of a wide range of cyclic amines. The bis-electrophile can either be a dihalide or ethyl propynoate, in the latter case both Electron-rich arenes (at least m-xylene) react with di(2,2,2-trichloroethyl) azodicarboxylate in the presence of Lewis acids to give the p-substituted-bis- Troc hydrazine.Reduction with zinc in acetic acid 270 Contemporary Organic SynthesisPh ,Ph TMS-CN F3B. OEtz or Ti Cl, then removes both Troc groups and reduces the hydrazine, providing a useful synthesis of arylamine~.~~ 2.2 Synthesis of optically active amines A method for the deracemization of racemic amines has been reported, in which the amine is condensed with a polymeric, chiral ketone to give an imine.25 Deprotonation of the imine with LDA followed by reprotonation with water and cleavage of the imine returns the amine in >75% e.e. In an alternative process, the racemic secondary amine is oxidized to the corresponding nitrone with hydrogen peroxide, this then undergoes asymmetric hydrosilylation upon treatment with diphenylsilane in the presence of catalytic Ru,C~~[(S)-~-TO~BINAP]~(E~~N) or other chiral ruthenium catalysts, giving optically active hydroxylamines as shown in Scheme 4. Reduction with zinc in hydrochloric acid then produces the optically active secondary amine.26 PhZSiHz/ RU&Id [(S)-~-TOIBINAP]~(E$+J) or other Ru" complex 1 Scheme 4 Macrocyclic polyamines (aza-crown ethers) are currently attracting much attention as complexing agents, however, these compounds are quite difficult to synthesize via traditional routes, especially if highly functionalized derivatives are required.Cyclic peptides are, by contrast, relatively easily prepared, the group of Aston et al. have used lithium aluminium hydride to reduce a cyclic pentapeptide to the corresponding macrocyclic ent tar nine.^^ In a similar reaction, the reduction of serine derived diketopiperazines with lithium aluminium hydride, followed by oxidation of the serine alcohol to the corresponding carboxylic acid has been used to prepare 5-alkylpiperazine-2-carboxylic acids.,' In the previous review of this area,' the highly diastereoselective addition of Grignard reagents to bis-imines was reported.Simpkins and co-workers have now extended this chemistry to the use of homochiral bis-imine 2 as shown in Scheme 5. The addition of phenylmagnesium bromide to compound 2 occurred with a diastereomeric ratio of 9: 1, giving the isomer shown in Scheme 5 as the major product as determined by X-ray ~rystallography.~~ The addition of methylmagnesium bromide was less diastereoselective (3 : 1). Yang et al. have investigated the addition of Grignard and organolithium reagents to homochiral thio-imines derived from camphor and aromatic 2 Scheme 5 aldehydes, producing optically active benzylamines as shown in Scheme 6.It was found that the corresponding sulfoxide and sulfone derivatives also gave good results, but attempts to extend the methodology to aliphatic aldehydes or ketones gave very low yields3' (i) NCS.NH3 (ii) PhCHO (i) R'MgBr or R'Li (ii) HCI I Ph Scheme 6 Also using imine chemistry, Reetz et al. have investigated the addition of TMS-CN to a-amino imines to produce a,P-diaminonitriles as shown in Scheme 7. Thus, condensation of readily available, optically pure N, N-dibenzyl-a-amino aldehydes with benzylamine, lithium hexamethyldisilazide, or Ts-N=S=O gave N-substituted imines, to which TMS-CN added diastereoselectively in the presence of a Lewis acid.3' The best results were obtained using boron trifluoride or titanium tetrachloride as Lewis acids, and the diastereomeric ratio of the products ranged from 1 : l to >95: 1.Enders et al. have shown that allyl cerium and allyl Grignard reagents will add to RAMP and SAMP hydrazones, leading eventually to &punsaturated amines with enantiomeric excesses of 90% or greater.32 Scheme 7 The asymmetric catalysis of the addition of organometallic reagents to carbonyl compounds has attracted considerable interest in recent years. By contrast, catalysis of the corresponding addition to imines has been rather neglected, though this is now starting to change. Hence, Inoue et al.reported that the dimethyl-dihydrobenzoin 3, and the North: Amines and amides 27 1phenylalanine derived ligand 4 both catalysed the asymmetric addition of organolithium reagents to aldehyde derived N-aryl-imines. It was necessary to use a full one equivalent of compound 3, but only 0.3% of catalyst 4 was required.”” Also in this area, the ephedrine derived polymer 5 has been found to catalyse the asymmetric addition of diethyl zinc to N-diphenylphosphinoylimines, giving optically active primary amines after an aqueous work-up. The best enantiomeric excesses were obtained in that the reaction should be of more general applicability. Indeed, it has now been shown that when a variety of a-amino acids containing two or more chiral centres are heated to 170°C in the presence of cyclohex-2-enone as a catalyst, smooth decarboxylation occurs to give optically active amines.Tetraethyleneglycol dimethyl ether is a convenient solvent for this reaction, as the amine products can then be distilled directly out of the reaction mixture as the free bases.”* alkylbenzene solvents, which appears to be related to the swelling of the polymeric catalyst in these ~olvents.”~ An asymmetric catalyst for the hydrogenation of cyclic imines has also been reported. Thus titanocene 6 catalyses the asymmetric addition of hydrogen to prochiral cyclic imines, providing cyclic secondary amines with > 95% enantiomeric excess.”’ Optically pure cyanohydrins can be prepared by a number of routes, and Chelucci et al. have shown that these compounds will undergo a cobalt(1)- catalysed [2 + 2 + 2) cycloaddition to give optically active a-hydroxymethyl pyridines from which a-aminomethyl pyridines can also be prepared.”’ 2 3 Synthesis of amines bearing additional functional groups A variety of methods have recently been developed for the synthesis of a-amino phosphonic acid derivatives, for eventual use as transition state analogues of peptide bond hydrolysis. The addition of phosphinates to heteroaromatic imines, leading eventually to a-heteroaromatic-a-amino phosphinic acids, as shown in Scheme 9, has been shown to occur much more readily when the reaction mixture is sonicated than when it is heated.40 O-Ethyl- 1-hydroxyalkylphosphinates undergo a Mitsunobu reaction with hydrogen azide, giving O-ethyl- 1-azidoalkylphosphinates which can be reduced with triphenylphosphine and water to O-ethyl- 1-aminoalkylphosphinates.4‘ M e 0 Me0 phxph OMe Me2N O D 3 4 Mewph OH y I Me 5 6 Reaction of a chiral allylsilane with the BF3- complex of an N-carbomethoxyimine provides a synthetic route to homochiral y,b-unsaturated amines.The reaction occurs with allylic rearrangement, and asymmetric induction can be achieved at both the imine and alkene prochiral centres.36 The Lewis acid promoted 3-aza-Cope rearrangement followed by reduction provides a convenient method for the synthesis of &&-unsaturated amines (Scheme 8). Cook and Stille have investigated the stereochemical consequences of substituents at various positions of the N-ally1 enamine, and concluded that only the nature of R2 has a significant infl~ence.”~ It appears that the R2 substituent acts as a conformational anchor during the transition state, thus permitting the formation of products with diastereomeric ratios > 95:5.Scheme 8 In last year’s review,’ the thermal decarboxylation of threonine to optically active 2-hydroxy- propylamine was described, and it was suggested I X = N,S Scheme 9 The enolate of a phosphonic diester can be trapped by di-t-butyl azodicarboxylate, giving initially an a-hydrazino phosphonic diester which can subsequently be converted into an a-amino phosphonic d i e ~ t e r . ~ ~ Another route to a-amino phosphonic acids has been developed by O’Donnell and c o - ~ o r k e r s ~ ~ (Scheme 10) and is also based on methodology originally developed for amino acid synthesis.Thus, treatment of the benzophenone imine of diethyl aminomethylphosphonate with dipyridyldisulfide and potassium t-butoxide gives the a-pyridylthio derivative, which upon treatment with organoboranes, again in the presence of potassium t-butoxide, gives a variety of a-amino phosphonic acid precursor^.^^ 272 Contemporary Organic SynthesisPh2C=N- P(OEt)2 8 Scheme 10 Also in an adaptation of work originally aimed at a-amino acid synthesis, it has been shown that treatment of an a-ketophosphonate with hydroxylamine followed by reduction with triactetoxyborohydride and titanium(rI1) chloride gives a-amino phosphonate esters.44 Musiol et al. have investigated the incorporation of Z-protected a-amino-phosphonates into peptides.They report that the best procedure for formation of the phosphoramide bond involves formation of the a-amino phosphoroyl chloride with oxalyl chloride/ DMF, followed by reaction with a peptide amine in the presence of either silver cyanide or HOAt.45 Sweeney and co-workers have investigated the ring-opening of optically pure N-diphenylphosphinyl aziridines which are readily prepared from p-amino alcohols (Scheme 11). Soft nucleophiles such as cuprates, cyanide, azide, thiols, and selinols all ring open the aziridine regiospecifically at the least- hindered end, providing a versatile approach to a variety of P-substituted amines after removal of the diphenylphosphinyl activating group by treatment with BF3 in methanol.46 (i) DPPCI / Et3N (ii) TsClIDMAP R R P (iii) NaH N u c - ~ R Y N u c N DPPNH NH2 DPP Nuc NH2 Scheme 11 A palladium-catalysed process for the synthesis of y-hydroxy-amines from carbonates has been reported as shown in Scheme 12.The key step in this methodology is the insertion of tosyl isocyanate into a carbonate, and the stereochemistry of this process depends upon the stereochemistry of the substituents on the carbonate but is always highly stereo~elective.~~ Warren and co-workers have described a diastereospecific synthesis of (E)-enol ethers of protected 4-amino aldehydes48 in which the key step is a 1,3-dipolar cycloaddition reaction of a nitrile oxide as shown in Scheme 13. R1 (\y<R2 O K 6 0 Scheme 12 Ts-N = C = 0 t Pdo R' (\y<R2 O K N T S 0 HO NHTs (i) NaBH,/ NiCIP (ii) Ac@ (iii) NaH NHAc I Scheme 13 As discussed in the previous review of this area,* 3-amino-2H-azirines 7 can be used as activated amines for peptide synthesis.A new synthesis of these compounds by successive treatment of a tertiary amide with LDA, diphenylphosphoryl chloride, and sodium azide has now been reported.49 The unusual heterocyclic secondary 8 and tertiary 9 amines have been prepared by reaction of the heterocyclic primary amine with the 2-fluoroimidazole deri~ative.~' Compound 9 was found to be completely non-basic, whilst compound 8 is an acid with a pK, of 4.2. Me 7 9 2.3.1 Synthetic routes to /I-hydroxyamines a-Amino acids have been quite widely used synthetic precursors to optically active as p-hydroxyamines. Usually, however, it is necessary to protect the amino group prior to reduction.Kamphuis and co-workers have now shown that sodium in propanol will reduce homochiral a,a-disubstituted-a-amino-amides to the corresponding enantiomerically pure p-hydroxyamines without the need to protect the amino group.51 North: Amines and amides 273Reaction of an optically pure P-hydroxy acid with diphenylphosphoryl azide results in formation of the corresponding oxazolidinone with retention of stereochemistry at both chiral centres. Subsequent manipulation gives enantiomerically and diastereomerically pure /?-hydroxy amines, including the amino acid statine.s2 Reaction of optically pure glycidol with benzyl isocyanate has been shown to provide a diastereoselective synthesis of y-hydroxy- /?-amino pure epoxy-amines, which are available via the Sharpless epoxidation, react with trimethylsilyl triflate to give an aziridinium ion as shown in Scheme 15.This undergoes regiospecific ring- opening with nitrogen nucleophiles, giving anti- /?- hydroxy-diamines. 54 as shown in Scheme 14. Optically 0 Scheme 14 HOJ Scheme 15 (i) Nuc. (ii) deprotect R4 $- R3 8 Photolysis of 2-alkoxynaphthalenes, in the presence of a primary amine and 1,3-dicyanobenzene, results in the formation of 1-alkylamino-2-alkoxy-1,4-dihydronaphthalenes.55 Reaction of a racemic epoxide with 2-propylamine has been shown to be catalysed by lipases and subtilisin, to give optically active (S)-propano- la mine^.^^ 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. This unfortunately means that many excellent syntheses have had to be omitted from this review.23.2.1 Racemic syntheses of a-amino acids Alkylation of the enolate of an imine of a glycine ester is one of the standard methods for amino acid synthesis via a glycine-anion synthon. It had been thought that whilst imines derived from aldehydes often gave the dialkylated glycine derivative as the major product, imines derived from benzophenone gave only the mono-alkylated product. However, Ezquerra and c o - ~ o r k e r s ~ ~ have shown that under appropriate reaction conditions (potassium hydroxide as base and a phase transfer catalyst), the benzophenone imine of glycine ethyl ester can be dialkylated as shown in Scheme 16.R R Ph2C=NXC02Et R R H2NXCO2H PRBr / KOH / BrNBu,/ MeCN 0°C * Ph2C = NAC02Et RBr / MeCN t K2CQ I A I R Scheme 16 A synthesis of N-Boc-cyclic amino acids based upon the reductive amination of glyoxylic acid with an cu-halo-amine, followed by N-protection and intramolecular alkylation of the derived glycine anion5' has been reported (Scheme 17). 0 0 CI-(CH2),-NH2.HCI + H MOH (i) NaCNBH3 (ii) B@ I Scheme 17 A reductive amination protocol was also utilized in a synthesis of N-Boc-N-alkyl glycines, which are building blocks for peptoid synthesis. Three separate synthetic routes were investigated: formation of an imine between glycine and an aldehyde, or imine formation between an a-ketoacid and an amine, followed in both cases by reduction and introduction of the Boc-group.The third approach involved alkylation of N-Boc glycine, with no one method being advantageous in all cases.59 cation synthon has been reported starting from the glyoxylic acid derivative 10 as shown in Scheme 18. Thus, consecutive treatment of compound 10 with BocNH2 and acetic anhydride gave the a-acyloxy A racemic synthesis of a-amino acids via a glycine 274 Contemporary Organic SynthesisOH 10 Scheme 18 11 R W N ‘&02h4e There are relatively few synthetic approaches to a-amino acids which utilize radical chemistry. In this regard, Clive and Etkin have reported that a-methoxy-a,P-dehydro-nitriles (readily prepared by the Wittig reaction between a ketone and the phosphorane derived from methoxyacetonitrile) will undergo addition to wide radicals generated from sodium azide and ceric ammonium nitrate as shown in Scheme 20.Hydrolysis and hydrogenation of the products then completes a synthesis of a-amino acidsw R2 OMe N3 ON02 glycine derivative 11. In the presence of zinc metal, reactive alkyl halides such as allyl, benzyl, and propargyl halides displaced the acetoxy group from amino1 11, giving racemic amino acids.60 An alternative glycine cation synthon utilizes readily available N-(0-nitrophenylsu1fenamine)glycine esters 12 as starting materials (Scheme 19). Hence, treatment with triethylamine and N-chloro- succinimide forms the sulfenimine, to which either enolates or Grignard reagents add, giving a-amino acids after acidic deprotection.61 An asymmetric version of this reaction was also reported, using imine 13.Scheme 20 a-Hydrovglycine is the biological precursor of peptide amides, and Brown and Ramage have reported the synthesis of a protected derivative of this amino acid suitable for use in FMOC-peptide 02N 6 synthesis as shown in Scheme 21. Et3N. NCS- R O O C ~ N - s H 12 (i) Nuc. (ii) TFA I NUC I OMe (i) glyoxylic acid (ii) MeOH / H$04 0 11 (iii) LiOH * FMOCHN &02H FMOC-O-C-NH2 ROOChNH2 Scheme 21 Scheme 19 w 13 Glycine t-butyl ester is usually prepared by a multi-step procedure, however, it has now been shown that reaction of t-butyl bromoacetate with excess ammonia in ether gives the t-butyl ester of glycine directly.The same approach can be used to prepare N-methyl-glycine t-butyl ester.62 Benzenediazonium tetrafluoroborate can react as an electrophilic nitrogen source, and treatment with silyl enol ethers gives either the derived imine or azo-compound. In either case hydrogenation provides a-amino esters.63 The methyl ether is converted into the corresponding alcohol under the standard acidolysis conditions used to cleave the final peptide from the resin. However, coupling of other amino acids to the 0-methyl-hydroxyglycine derivative was reported to occur only in low yield due to side-rea~tions.~~ Schmidt et al. have used protected a-hydroxyglycine derivatives as starting materials in a synthesis of differentially protected a-amino glycines. Thus, treatment of an N-urethane protected a-hydroxyglycine ester with diphenylphosphoryl azide substitutes an azido group for the alcohol, and subsequent reduction followed by N-protection with a second urethane group gives the desired derivatives. These manipulations can be carried out either at the amino acid or dipeptide stage, and the resulting a-amino glycine derivatives can be used in peptide synthesis.h6 Compound 14 has been utilized in a racemic synthesis of polyhydroxy-a-amino acids.Hence, condensation of pyrrole 14 with a polyhydroxylated North: Amines and amides 275aldehyde in the presence of tin tetrachloride results in condensation adjacent to the nitrogen, giving adducts 15 as shown in Scheme 22. Oxidative cleavage of the alkene in compounds 15, then leads to amino 14 SnCb I 15 Scheme 22 A synthesis of o-methyl and o,o-dimethyl- phenylalanine derivatives based upon the Pictet- Spengler condensation of a phenylalanine derivative and formaldehyde followed by hydrogenolysis has been reported. Unfortunately, whilst conditions were found under which the Pictet-Spengler reaction proceeded with retention of configuration at the amino acid a-centre, the hydrogenolysis was found to cause complete racemization, thus preventing the synthesis of optically active substituted phenylalanines using this methodology.68 A novel approach to the synthesis of a,/?-didehydroamino acids has been developed by Effenberger et al.Thus, treatment of an a-azido ester with NaReO, in the presence of an acid chloride (which can be an N-phthaloylamino acid chloride) gives N-acyl a$-didehydroamino esters or dipeptides incorporating an a$-didehydroamino acid residue.69 A variety of N-benzoyl- a$-didehydroamino acids, esters, and amides have also been prepared from readily available azlactones7’ by sonication in the presence of water, alcohols, or amines as shown in Scheme 23.a$-Didehydroamino acids, when incorporated into peptides, act as conformational constraints, for example a, b-didehydrolysine units have been incorporated into analogues of t~ftsin.~’ X = OH, OR2. NHR2 Scheme 23 A diastereoselective synthesis of cyclic, P,y-unsaturated a-amino acids using the Lewis acid catalysed [3,3] sigmatropic rearrangement of P,y-unsaturated esters of N-Boc glycine has been reported by Kazmaier as shown in Scheme 24, The best results were obtained with zinc chloride or magnesium chloride as Lewis For an (9 2.5eq.LDAI (ii) CH2N2 ZnCIz.MgClz m BocHNACO,Me MA? V + ‘Q BocHNAC02Me HNCe Scheme 24 asymmetric version of this reaction see Section 2.3.2.2. Cativiela et al. have developed a synthesis of 1-aminocyclopropane-carboxylic acids based upon the addition of a carbene or carbenoid to an imine of dehydroalanine methyl ester. Diazo-compounds used as carbene precursors gave very poor diastereoselectivity, whilst sulfoxonium salts gave a >9:1 diastereomeric ratio in favour of the (2)- isomer of the cy~lopropane.~~ An asymmetric variant of this reaction has also been 23.2.2. Asymmetric syntheses of a-amino acids For an asymmetric synthesis of 5-alkylpiperazine- 2-carboxylic acids see Section 2.2.Cox and Hanvood have prepared the homochiral a-amino-propanoic acid precursor 16 from an a-ketoacid and phenylglycinol. Hydrogenation of the imine (HJ PtO,) occurs from the less-hindered face, following which hydrogenolysis under more forcing conditions [HJPd(OH),, 6 atm.] gives the amino acid. The scope of this methodology is currently being further in~estigated.~~ Also using methodology originally developed by Harwood et al., Baldwin et al. have used a [3 + 21 cycloaddition between an (S)- phenylglycinol derived azomethine ylid and a variety of dipolarophiles to prepare highly functionalized proline derivative^.^^ Oppolzer’s chiral sultam approach has previously been shown to be a versatile method for the asymmetric synthesis of a-amino acids. This methodology has now been used in an asymmetric synthesis of aziridine-2-carboxylic acid derivatives as shown in Scheme 25.However, starting from the corresponding crotonate derivative, a mixture of stereoisomers at the 3-position of 3-methyl- aziridine-2-carboxylic acid were obtained.77 Cativiela et al. have used a closely related chiral auxiliary in an asymmetric synthesis of a-methyl-b-phenyl- 276 Contemporary Organic Synthesis02s 4.. Br 1 RNH, 8 Br Scheme 25 phenylalanine, an unusual amino acid which may be of some interest as a phenylalanine analogue.78 An asymmetric synthesis of a-trifluoromethyl amino acids which uses another amino acid as a chiral auxiliary and proceeds via a glycine-cation synthon has been described (Scheme 26). The key step in the synthesis (the addition of the organometallic reagent to the putative imine intermediate) proceeds with very variable d.e.(5 to >99%) depending upon the structure of the organometallic reagent.79 Another synthetic equivalent to a glycine-cation synthon was discussed in Section 2.3.2.1. R’ 0 (i) TFAA (ii) R ~ M I Scheme 26 An asymmetric synthesis of P-methylphenylalanine derivatives has been described based upon the addition of a nitrene to a chiral silyl ketene acetal (Scheme 27). The best asymmetric induction was obtained when a chiral group (camphor sulfonamide derived) was attached to the ketene acetal, in addition to the chiral centre adjacent to the phenyl group.8o N HC02 Et N&O&t ---x-+ RoPf 0 Ph OTBDMS Scheme 27 Full details of the synthesis of all four stereoisomers of P-methyl-tryptophan described in last year’s review’ have now been reported by Hruby and co- workers,81 as has the synthesis of all four stereoisomers of ,!?-methyl-phenylalanine.R2 A synthetic route to all four stereoisomers of a-methyl- threonine, and both enantiomers of a-methyl-serine which uses phenylalanine as a chiral auxiliary has been developed as shown in Scheme 28.Thus, condensation of N-Boc phenylalanine with an a-hydroxyketone followed by removal of the Boc protecting group gives a cyclic imine to which cyanide adds stereospecifically, giving intermediate 17. In the case where R = Me, compound 17 is formed as an equilibrating mixture, thus allowing subsequent hydrolysis to furnish either diastereomer of a-methyl-thre~nine.’~ R = H,Me HO-R (i) F A (ii) NaCN Ph I CN 17 Scheme 28 N-Carboxyanhydrides are usually prepared from amino acids by treatment with phosgene or an equivalent reagent.Palomo et al., however, have now reported the alternative synthesis shown in Scheme 29. Thus the [2+2] cycloaddition of a homochiral imine with a benzyloxyketene gives a P-lactam. Hydrogenolysis of the benzyl protecting group followed by Swern oxidation gives the corresponding a-keto-P-lactam, which upon further oxidation with MCPBA gives an N-carboxy- anhydride.84 The authors have also shown that the /I-lactam 18 will undergo Wittig reactions and Grignard additions prior to oxidation, thus providing access to a variety of amino acids and P-hydroxy-amino acids via a synthetic equivalent to an alanine di-~ation.~’ (i) p a z I ~,i HCO, (ii) DMSO I P205 v Q MCPBA I\ - oKN-Bn 0 0 Scheme 29 North: Amines and amides 27718 Takano et aZ.86 have developed a method for obtaining optically pure enones 19, and have used these compounds as the starting materials in an ingenious asymmetric synthesis of glutamic and aminoadipic acids as shown in Scheme 30. Hence, selective reduction of the conjugated alkene, followed by imine formation, reduction from the outside face, and protection gives the chiral tricyclic amine 20.A retro-Diels-Alder reaction followed by oxidative cleavage of the newly formed alkene, and reductive deprotection of the amine protecting groups, then gives the amino acids.86 (iii) NaBH4 (iv) BnOCOCl H 0 19 20 (0 A (ii) RuCIaI NaI04 (iii) H,I Pd I C I C02H I (7H2)nr2 H2NhC02H n =0,1 Scheme 30 Kazmaier has investigated the synthesis of peptides containing C-terminal amino acids with allylic side-chains by a palladium-catalysed ester enolate Claisen rearrangement as shown in Scheme 31.It was found that this methodology caused no racemization at chiral centres elsewhere in the peptide, but the diastereomeric induction at the C- terminal amino acid was variable.87 A racemic version of this reaction was mentioned in Section 2.3.2.1. A - peptideK 1 3 0 cat. 2 x LDA Pd(PPhd4 I ZnCb - peptideK ‘&H ! R R = H.Me Scheme 31 0 YR The conformationally constrained aspartic acid analogue 3-carboxy-proline 21 has attracted considerable attention this year, with four independent asymmetric syntheses being reported.Three of these syntheses involve the generation of an aspartic acid p-enolate equivalent, reaction of this with a suitable bis-electrophile, and finally cyclization onto nitrogen to give the five-membered ring. The syntheses developed by North and co- workers,88 and by Chamberlin and c o - ~ o r k e r s ~ ~ both employ suitably protected aspartic acid derivatives as the p-enolate equivalent, whilst that of Potier and co-workersgO starts from a serine derivative. Of these three syntheses, that of Chamberlin gives best control over the stereochemistry at the new chiral centre, and allows both diastereomers of 3-carboxy-proline to be prepared, whilst the methodology of North also allows the preparation of hubstituted analogues of trans-3-carboxy-proline in addition to the parent molecule.The methodology of Potier produces only the trans-diastereomer of 3-carboxy-proline. The final asymmetric synthesis of 3-carboxy-proline reported this year,” uses a none-(amino acid) precursor, and can be controlled to give either diastereomer of 3-carboxy-proline. Regiospecific enolate formation was also utilized in a synthesis of y-amino glutamic acid derivatives which involved the generation of the y-enolate of a glutamate derivative and its trapping with 2,4,6-triisopropyl- benzenesulfonyl a ~ i d e . ~ ~ 6 ; l 2 H H 21 The addition of the lithium enolate of methyl bromoacetate to homochiral N-sulfinylimines 22 results in the asymmetric, stereoselective formation of the cis-isomer of an aziridine-2-carboxylic acid derivative 23 as shown in Scheme 32.Subsequent manipulation of compounds 23 provides aziridine- 2-carboxylic acids, a-amino acids, or P-hydroxy- a-amino acids.93 Bravo et aZ. have reported a synthesis of optically pure a-trifluoromethyl-alanine 22 I OMe OGS\ To1 ~ H T S 23 \ f? 702Me H ~ H n Scheme 32 278 Contemporary Organic Synthesisusing the asymmetric addition of (R)-methyl-p- tolylsulfoxide to N-alkoxycarbonyl-trifluoropyruvate i m i n e ~ . ~ ~ Whilst a large number of enzymes are known which will resolve racemic amino acid derivatives, many of these will not tolerate secondary amino acids as substrates. However, it has now been found that partially purified lipase from Aspergillus Niger will resolve the n-octyl ester of pipecolic acid." Chen et al. have shown that alcalase is very stable in supercritical carbon dioxide, and that N-protected amino acids can be resolved in this solvent in high yield and optical purity.'" A chemoenzymatic synthesis of 15N and 13C labelled amino acids using an appropriate amino acid dehydrogenase enzyme coupled to formate dehydrogenase to catalyse the asymmetric reductive amination of a ketoacid with ammonium formate has been described." The same approach has been used to prepare a variety of 15N, 13C, and 2H labelled glutamic acid derivatives from a-keto glutaric acid, using glutamic acid dehydr~genase.~~ It has also been shown that an artificial bilayer membrane incorporating (S)- histidine units and copper ions can exhibit aminotransferase activity, converting a-ketoacids into (R)-a-amino acids but in poor yield and with low enantiomeric exces~es.~' 2.3.3 Synthesis of 1-amino acids 2.3.3.1 Racemic syntheses of 1-amino acids A racemic synthesis of P-amino- 5-pyrimidinepropanoic acid by the Heck reaction of 5-bromopyrimidine and t-butyl acrylate followed by Michael addition of ammonia and deprotection has been reported'" (Scheme 33).The Michael addition of lithium hexamethyldisilazide onto an a,P-unsaturated li-lactone has also been used to prepare p-amino acid precursors."' For an asymmetric approach to /?-amino acids using similar methodology, see the work of Davis et al. discussed in the next section. O h ' (i) NH3/ Bu'OH (ii) TFA I Scheme 33 Ozonolysis of 2,3-dihydopyrroles has been shown to occur regiospecifically to give N-formyl-/?-amino esters as shown in Scheme 34.Ozonolysis of 1,2,3,4-tetrahydropyridines was less selective however, giving a mixture of N-formyl-y-amino R' 0 R' 0 + 0 C02Me A3 Scheme 34 esters and N-methyloxycarbonyl-y-amino aldehydes. lo2 2.3.3.2 Asymmetric syntheses of 1-amino acids Perhaps the most obvious retro-synthesis of a ,&amino acid involves cleavage of the central carbon-carbon bond, giving an imine and an acid enolate equivalent. However, synthetic approaches to this retrosynthesis are remarkably scarce, with the poor electrophilicity of an imine (compared to an aldehyde) being one contributing factor. Matsumura and Tomitalo3 have now reported an asymmetric P-amino acid synthesis using this synthetic approach, and utilizing compound 24 as a chiral auxiliary as shown in Scheme 35.Thus, treatment of compound 24 with TMS-azide in the presence of tin tetrachloride gives the corresponding azide which can be reduced, and the amine condensed with benzaldehyde to give the homochiral imine 25. Compound 25 reacts with a ketene acetal in the presence of zinc chloride to give, after an acidic work-up (MeOH/HCl), a /?-amino ester (e.e. 72-85%), and recycled chiral auxiliary 24. 24 (I) H*/ Pd / C (i) PhCHO I CM31; *02Ms $4 Ph Ph e.e. = 7 2 4 % Scheme 35 '0 25 North: Amines and amides 279An alternative solution to this problem has been developed by Jiang et al. starting from the optically pure sulfinate 26. Hence, displacement of the menthoxide group from 26 using lithium hexamethyldisilazide followed by conversion of the bis-silylamine into the corresponding imine with benzaldehyde gives optically pure imine 27.The sulfoxide group attached to the imine has an electron-withdrawing effect, increasing the susceptibility of the imine towards attack by nuclephiles, so that the sodium enolate of methyl acetate will add to the imine giving a p-amino acid after acidic work-up. '04 Unfortunately, unlike the method of Matsumura and Tomita, the chiral auxiliary cannot be recycled. Furthermore, use of the lithium enolate of methyl fluoroacetate in place of methyl acetate, gave the desired a-fluoro-p-amino acid but as an almost 1 : 1 ratio of diastereomers.lo5 For an approach to aziridine-2-carboxylic acid and a-amino acids using the same retrosynthetic analysis as that discussed above, see Section 2.3.3.2.26 27 A related synthesis of /?-amino acids has been developed by Wyatt et al. as shown in Scheme 36, though in this case the chiral auxiliary is attached to the ester component rather than to the imine. Again, it was found necessary to have a highly electron-withdrawing sulfonyl group in the imine to increase its susceptibility to nucleophilic attack.lo6 Scheme 36 A synthesis of fluorinated p-amino acids which incorporates an enzymatic resolution has been developed as shown in Scheme 37; condensation of a fluorinated p-keto-ester with benzylamine initially gives the a$-unsaturated ester which can, however, be isomerized with base to the benzylidene imine. Hydrogenation of the latter gives a racemic /?-amino acid which can be resolved by treatment of the N- phenacyl or N-benzoyl derivative with Penicillin a~yZase.'~~ Over the last few years, Davies and co-workers have developed a general, asymmetric synthesis of a variety of /?-amino acids based on the asymmetric Michael addition of a homochiral nitrogen anion 0 NHBn [ 2?l J \ NH2 - 1 Ph Scheme 37 lithium benzyl(a-methylbenzy1)amine to an a,/?-unsaturated ester. This approach has been taken up by Rico et al.in an asymmetric synthesis of P-3-pyridyl-P-alanine7 in this case using trimethylsily(a-methylbenzy1)amine as the chiral amine.lo8 If the a,p-unsaturated ester contains substituents at both the a- and P-positions then excellent asymmetric induction can be obtained at both new chiral centres, with the syn-diastereomer being formed diastereoselectively provided 2,6-di-t- butylphenol is used as the proton source to quench the reaction.'09 The corresponding anti- a,P-disubstituted p-amino acids are available by deprotonation of a-unsubstituted p-amino esters (prepared as described above) with LDA and reaction of the resulting enolate with an alkyl halide.'" P-Lactams can also be prepared using this methodology. Attempts to carry out a tandem Michael addition of the homochiral amine, followed by enolate trapping with an electrophile, resulted in much lower diastereomeric excesses than obtained in the two-step process described above. The enolate (generated either by the conjugate addition of a homochiral amine to an a,/? unsaturated ester, or by deprotonation of a /?-amino ester) can also be trapped with an electrophilic oxygen source, providing a synthesis of anti-/?-amino-a-hydroxy acids."' The authors have used this methodology in a synthesis of the taxol side-chain.ll2 A related procedure for the synthesis of both /?-amino acids and P-lactams has been reported by Asao et al.Thus, Michael addition of achiral lithium N-TMS-benzylamine to y-trityloxy a,/?-unsaturated esters gives p-amino acids with excellent asymmetric induction. The presence of a trityl or other bulky group on the y-hydroxy group is essential for good asymmetric induction.' l3 3 Preparation of amides 3.1 General methods, and the synthesis of acyclic amides Whilst a large number of reagents are known to be suitable for activating carboxylic acids for subsequent reaction with amines, the recently 280 Contemporary Organic Synthesisreported reagent phenyl dichlorophosphite has the advantage of being compatible with aqueous solvent systems.' l4 Alternatively, electron-rich triarylbismuthanes (MeOC6H&Bi have been shown to promote the direct reaction between primary carboxylic acids and amines.' '' Secondary, tertiary, and aromatic carboxylic acids are, however, inert to this reagent. Sodium diethyldiamidoaluminate has been used to convert esters into amides.l16 A general procedure for the synthesis of secondary amides by the iodotrichlorosilane- catalysed condensation of an aldehyde with a nitrile has been reported'17 as shown in Scheme 38.It has been stated that condensation of an a-amino ester hydrochloride salt with trimethyl- or triethyl- orthoformate results in the racemization free formation of N-formyl amino esters."' Scheme 38 Amides are often used as synthetic precursors to thioamides.The reverse reaction is less commonly encountered, but thioamides can be converted into amides by treatment with a silver carboxylate.' l9 Given the current degree of interest in fullerene chemistry it is not surprising that a method has been developed for attaching amides and amino acids onto c60. Thus, heating a toluene solution of c60 with a diazo derivative of the form R'R2NCOCHN2 (where R1 and R2 can be amino acid derived) results in the formation of fullerene derivatives attached to an amide via a cyclopropane.'20 A synthetic route for the diastereoselective alkylation of N,N-disubstituted amide enolates has been developed which uses phenylgycinol as a chiral auxiliary.'21 The asymmetric induction is thought to proceed through a chelated intermediate of type 28.Reaction of a ketenimine with a sulfenyl or selenyl chloride gives, after an aqueous work-up, a-sulfenyl or selenyl amides.122 28 Two approaches have been developed for the synthesis of amides via acyl cyanide intermediates. In the first of these (Scheme 39), reaction of an a,a-dicyano epoxide with a secondary amine results in regiospecific ring-opening and elimination of HCN to give an a-amino acyl cyanide, which reacts with a second equivalent of the secondary amine to give an a-amino amide.'23 The second route involves reaction of a (cyanomethy1ene)phosphorane with a carboxylic acid or acid chloride, followed by ozonolysis of the resulting phosphorane to give an a-ketoacyl cyanide as shown in Scheme 40.Reaction with an amino ester then leads to N-a-ketoamide- a-amino esters.'24 Scheme 39 X = CI,OH PPh, I o3 0 Scheme 40 Benzotriazole will undergo a Michael addition to a,P-unsaturated amides, and then has an acidifying effect on the P-carbon. Thus, deprotonation with butyllithium followed by addition of an electrophile gives the P-substituted-P-benzotriazole-amide as shown in Scheme 41. The benzotriazole group can then be eliminated by treatment with sodium ethoxide, leaving a P-substituted-a$-unsaturated amide.'25 0 a ' ; N N H + Y N H t v l e - B q N M e H (i) BuLi (2eq.) (ii) E 61 0 I Scheme 41 Treatment of an allylic amine with carbon monoxide in the presence of a palladium catalyst results in carbon monoxide insertion into the carbon-nitrogen North: Amines and amides 281bond, providing a convenient synthesis of P,y-unsaturated amides.126 Pattenden and co- worker~'~' have been investigating the chemistry of acyl radicals generated from acyl cobalt species, and this has resulted in a synthesis of a$-unsaturated amides: thermolysis of NJV-dialkylcarbamoyl cobalt(sa1ophen) complexes in the presence of styrene gives an (E/Z)-mixture of P-phenyl acrylamides. The acyl radical can also be trapped intramolecularly, providing a route to 4-6 membered ring 1 a ~ t a m s . l ~ ~ The lipase enzyme Candida antartica has been used to condense a variety of P-ketoesters with amines, giving optically active P-ketoamides.128 3.2 Synthesis of lactams 3.2.1 Synthesis of 6-lactams One of the standard methods for the synthesis of P-lactams is the [2 + 21 cycloaddition of an imine and a ketene usually derived from a thioester.The stereoselectivity of this process using N-a-methyl- benzyl imines has been investigated (Scheme 42).129 In general, the trans:cis ratio is greater than 9:l unless R1 or R2 is oxygenated, in which case the diastereomeric ratio is lowered. The asymmetric induction from the a-methylbenzyl group is, however, highly variable, with the diastereomeric excess ranging from 0 to >80%. The use of P-tosylethyl imines in the synthesis of P-lactams has also been investigated, as the P-tosylethyl protecting group can subsequently be cleaved from the P-lactam by treatment with potassium t-b~t0xide.l~' The zinc enolate of an a-amino ester can also be condensed with an imine to give p-lactams, and the stereochemistry of this condensation can be controlled by using appropriate groups attached to the ester and imine.131 Ph Scheme 42 Another established method for the synthesis of p-lactams is the cyclization of p-amino acids (see Section 2.3.3), and N-(chlorosulfiny1oxy)-N- methylmethanaminium chloride has been reported to be an effective condensing reagent for this transformation.The same reagent also allows the synthesis of P-lactams from unsaturated a m i d e ~ . ~ ~ ~ A rhodium(I1)-catalysed synthesis of p-lactams from diazoacetoacetamides and diazoacetamides has also been de~cribed.'~~ 3.2.2 Synthesis of other lactams A radical synthesis of lactams using xanthate chemistry has been reported'34 as shown in Scheme 43, and a synthesis of y-lactams using the nickel induced radical cyclization of a-carbamoyl radicals onto an N-ally1 substituent has been r e ~ 0 r t e d .I ~ ~ Similar methodology but utilizing tin chemistry has also been described,136 and cobalt based radical cyclizations were mentioned in Section 3.1. Cationic cyclizations have also been used to prepare lactams, with y- and &lactams being synthesized by the endo cyclization of P,y- and y,d-unsaturated amides respectively. 137 S Scheme 43 The rhodium-catalysed insertion of carbon monoxide into a y-alkynyl amine provides a short approach to the synthesis of a-methylene d-lactams as shown in Scheme 44. When the same reaction is carried out on a P-alkynyl amine, however, a mixture of y- and d-lactams are 0btai11ed.l~~ Treatment of FMOC-glutamic acid with thionyl chloride and a catalytic amount of DMF results in formation of FMOC-pyroglutamic acid chloride, which on reaction with HONSu gives the corresponding active ester.139 Scheme 44 3.3 Synthesis of peptides Whilst a whole armoury of reagents are now available for the coupling of amino acids, the formation of peptide bonds to sterically hindered a,a-disubstituted amino acids can still be problematical. In this respect the chloroimidazolium reagent 29 may be of use, since it has been reported14' that in the presence of a suitable additive (HOAt = HODhbt > DMAP > HOBt) this compound will form peptide bonds in good yields when amino isobutyric acid is either the amino or acid component.Alternatively, the m- trifluoromethyl analogues of BOP, pyBOP, and HBTU have been found to be especially good coupling reagents for reactions involving a-aminoisobutyric acid.141 The halogenophosphonium salts PyBrOP (30) and PyClPO (31) have been reported to be good coupling reagents for reactions involving N-methyl amino 282 Contemporary Organic SynthesisMe Mne 29 30 X = Br 31 X=CI 4-Methylthiophenyl esters provide a 'safety-catch' type activating group for peptide synthesis. Hence, whilst 4-methylthiophenolate is not a particularly good leaving group, electrolysis in acetonitrile/water in the presence of potassium chloride results in oxidation of the sulfide to the corresponding sulfone, and reaction with an amino acid then gives peptides by displacement of 4-methylsulfonyl- phenolate. 143 Pyrocarbonates are normally utilized in the preparation of the urethane protected amino acids needed for peptide synthesis, however, Pozdnev has shown that in the presence of base, pyrocarbonates can also function as coupling reagents.144 Despite the plethora of alternative reagents, DCC is still by far the most widely used activating reagent for carboxylic acids, and the mechanism of this reaction, including racemization and by-product formation, has been investigated by a kinetics The new water soluble analogue 32 of DCC has been introduced by Rapoport and co- workers, and has been shown to couple amino acids with similar yields and degrees of racemization to other carbodiimides. 146 'ds N 32 HOBt and derived reagents are probably the most widely used active esters/coupling reagents in peptide chemistry.In most cases, HOBt derived esters undergo peptide couplings in high yield and with very little racemization. However, in difficult cases both the chemical and optical yields can be lower than desired. Recently, therefore, Carpino et al. have been developing the azo analogue of HOBt (HOAt, 33). This active ester (and derived coupling agents) has been shown to cause significantly less racemization than HOBt and to be better for the synthesis of difficult sequences. 147 This comparison has also been extended to solid-phase peptide synthesis, and again HOAt and derived coupling reagents were found to give superior results to HOBt (including for the coupling of N-methyl amino with the additional advantage that the HOAt reagents change colour from yellow to colourless when the coupling reaction is complete, thus providing an in situ monitor for the progress of the coupling reaction. Peptide synthesis using either HOBt or HOAt usually requires the addition of a tertiary amine base.However, Indian workers have shown that for peptide synthesis using FMOC- amino acid chlorides, the potassium salt of HOBt can be used as both active ester forming reagent and base, and that the resulting peptide synthesis is racemization-free. 149 OH 33 Recently, there has been much interest in NJV- diurethane derivatives of amino acids, following the discovery that these compounds are relatively easily prepared. However, most activated NJV-diurethane protected amino acids racemize too readily to be utilized in peptide synthesis, in marked contrast to the N-monourethane protected amino acid derivatives.The acid fluorides appear to be an exception to this rule, and methods for preparing these compounds and their use in peptide synthesis have been reported, along with further studies on urethane protected N-~arboxyanhydrides.'~' N-Carboxyanhydrides have also been used in a synthesis of peptides containing N-alkyl- a-trifluoromethyl group."' is still being developed, and the enzyme Prolyl endopeptidase has been used to prepare peptides with C-terminal proline residues.'52 Chen et al. have reported the synthesis of a variety of proline- containing peptides using alcalase in anhydrous t- butanol to catalyse formation of the Xxx-Pro amide bond.The chemical yield was found to be dependent on the structure of the acyl donor, and on the amount of water present, though interestingly both L- and D-proline derivatives could be ~ti1ized.l~~ The use of immobilized pepsin to catalyse the formation of Z-Phe-Phe-OMe in solvent systems containing up to 5% water has been studied, and an attempt made to correlate the enzyme activity with factors such as solvent, concentration, and amino acid side-chain etc. 154 Ugi and co-workers have adapted his well known four component amino acid synthesis for the coupling of peptide fragments as shown in Scheme 45. Thus, treatment of two partially protected peptide fragments, one with a free acid and the other with a free amine, with t-butylisocyanide and N-t-butyl glyoxamide gives an intermediate which can be decomposed to the coupled ~ e p t i d e .' ~ ~ An unusual synthesis of N,N'-diaryldipeptide amides using an Ugi-type condensation between a carbonyl compound, an arylamine, and an isocyanide has been developed's6 as shown in Scheme 46. The use of enzymes to catalyse peptide synthesis North: Amines and amides 2830 Pept'- C02H H2N- Pep2 ___c 0 0 Scheme 45 R' R2 )=O + ArNH3+ C r + CN-CO;K+ Scheme 46 The oxime resin is amongst the most versatile resins for solid-phase peptide synthesis, as a wide range of cleavage conditions can be utilized to produce a variety of peptide derivatives. Voyer et aZ. have shown that peptide amides can be prepared directly from a peptide attached to an oxime resin by treatment with a variety of aliphatic or aromatic amines, provided only that the amine is not sterically hindered.'57 Whilst N-Z protecting groups are widely used in solution-phase peptide synthesis they are rarely used in solid phase work due to the lack of a suitable method of cleaving the protecting group from a peptide attached to a resin.The recent discovery that iodotrichlorosilane rapidly cleaves Z-groups under anhydrous conditions that are compatible with solid-phase peptide synthesis may change this situation.15* 2-hydroxy-4-methoxybenzyl amide protecting group developed by Sheppard et aZ. was discussed as a method for preventing the formation of P-sheeted networks during FMOC solid-phase peptide synthesis. Johnson and Quibell have now shown that the 2-hydroxybenzyl protecting group can serve the same purpose during solid-phase peptide synthesis using Boc methodology.159 The 2-hydroxybenzyl protecting group is more acid stable than the 2-hydroxy-4-methoxybenzyl group, and is not affected by TFA used to cleave the Boc groups. It is, however, cleaved by trifluoromethane sulfonic acid. A novel method for the synthesis of peptides incorporating P-amino acids has been reported which uses p-lactams as 'activated' /?-amino acid derivatives for the coupling reaction as shown in Scheme 47. This chemistry can be used in both solution- and solid-state peptide synthesis methodologies.16" In the previous review of this topic,' the R3 + H2N AC02R4 R'O,, ,R2 0 Scheme 47 4 Summary Probably the most striking feature of this review is the current prominence of imine chemistry in just about every section.This may reflect the transfer of methodologies developed initially for carbonyl compounds to this rather more demanding area; however, many of the results disclosed so far, especially concerning the asymmetric catalysis of the addition of nucleophiles to imines, have significant synthetic potential. Comparison of this review with the previous one shows that a number of areas have undergone a dramatic decrease in activity; this is especially apparent in the P-hydroxy-amine, a-amino aldehyde, P-lactam, and y-amino acid fields. 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ISSN:1350-4894    

DOI:10.1039/CO9950200269

出版商:RSC    

年代:1995

数据来源: RSC