摘要:

Contemporary Organic Synthesis Editorial Board Professor G. Pattenden, FRS (Chairman), University of Nottingham Professor P. D. Bailey, Heriot- Watt University Dr S. E. Gibson (nee Thomas), Imperial College of Science, Technology, and Medicine Professor P. J. Kocienski, University of Southampton Professor C. J. Moody, Loughborough University of Technology Professor E. J. Thomas, University of Manchester International Advisory Board Professor E. J. Corey, Haward University Professor S. Hanessian, Universiti! de Montre'al Professor M. Julia, Universite' 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, the environment and new materials, will also be encompassed.Contemporary Organic Synthesis aims to be proactive, drawing attention to new opportunities and new directions, providing timely information to the synthetic chemist who needs to keep abreast of developments in the field. Although the majority of articles are intended to be specially commissioned, the Society is always prepared to consider offers of articles for publication. In such cases a short synopsis, rather than the completed article, should be submitted to Dr S. R. Buxton, Managing Editor, Organic Publications, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF, UK.Members of The Royal Society of Chemistry may subscribe to Contemporary Organic Synthesis by placing their orders on the Annual Subscription renewal forms in the usual way. All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letchworth, Herts SG6 lHN, England. 1996 subscription rates: EEA f185, USA $350, Canada f190 (plus GST), Rest of the World f190. Contemporary Organic Synthesis is published 6 times a year in February, April, June, August, October and December. Airfreight and mailing in the USA by Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey, NJ 07001, USA and at additional mailing offices. Second class postage is paid at Rahway, NJ.USA Postmaster: Send address changes to Contemporary Organic Synthesis, c/o Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey 07001. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. Q The Royal Society of Chemistry, 1996 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording or otherwise, without the prior permission of the publishers. Typeset in Great Britain by Unicus Graphics Ltd Printed in Great Britain by Whitstable Litho Ltd~~ Contemporary Organic Synthesis Editorial Board Professor G. Pattenden, FRS (Chairman), University of Nottingham Professor P.D. Bailey, Heriot- Watt University Dr S . E. Gibson (neC Thomas), Imperial College of Science, Zchnology, and Medicine Professor P. J. Kocienski, University of Southampton Professor C . J. Moody, Loughhorough University of Technology Professor E. J. Thomas, University of Manchester International Advisory Board Professor E. J . Corey, Haward University Prifessor S. Hanessian, Universiti de Montrial Professor M. Julia, Universiti de Paris X I (Paris-Sud) Professor P. D. Magnus, University of Exas at Austin Professor G. Mehta, University of Hyderabad Professor K. C. Nicolaou, The Scripps Research Institute and University of Professor R. Noyori, Nagoya University Professor L,. E. Overman, University qf California, Iwine Professor L.F. Tietze, University of Guttingen 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 Dr S. R. Buxton, Managing Editor, Organic Publications, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF, UK. % 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 1 HN, England. 1996 subscription rates: EEA i18.5, USA $3.50, Canada El90 (plus GST), Rest of the World f190. Contemporary Organic Synthesis is published 6 times a year in February, April, June, August, October and December. Airfreight and mailing in the USA by Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey, NJ 07001, USA and at additional mailing offices. Second class postage is paid at Rahway, NJ. USA Postmaster: Send address changes to Contemporary Organic Synthesis, c/o Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey 07001. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. ((. The Royal Society of Chemistry, 1996 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording or otherwise, without the prior permission of the publishers. Typeset in Great Britain by Unicus Graphics Ltd Printed in Great Britain by Whitstable Litho Ltd

ISSN:1350-4894    

DOI:10.1039/CO99603FX005

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

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

ISSN:1350-4894    

DOI:10.1039/CO99603BX007

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

The enediyne and dienediyne based antiturnour antibiotics. Methodology and strategies for total synthesis and construction of bioactive analogues. Part 2 HERVE LHERMITTE and DAVID S. GRIERSON* Institut de Chimie des Substances Naturelles, F-91198 Gifsur-Yvette, France Reviewing the literature published up to 15 November 1995 Concluding the coverage which commenced in Part 1, Contemporary Organic Synthesis, 1996, 3, 41 1 2 3 4 4.1 4.2 4.3 5 5.1 5.2 5.3 6 7 Introduction Approaches to the total synthesis of the neocarzinostatin chromophore Nine-membered enediynes: kedarcidin and The total synthesis of calicheamicinl esperamicin Central core structure Synthesis of the glycone Total synthesis of ( - )-calicheamicin ylI Dynemicin analogues and the total synthesis of dynemicin A A-ring 'biomimetic' approach Anthraquinone 'platform' assembly Nor-D,E dynemicin analogues: the total synthesis of dynemicin A Conclusion References and notes C- 1027 1 Introduction The discovery and structure elucidation of the highly potent antitumour antibiotics neocarzino- statin 1,' calicheamicin yll 2,* esperamicin Al 33 and dynemicin A 44 (Scheme 1) created a wave of Me I MeO OH MeHN HO neocarzinostatin chrornophore 1 \ ? I HO 2 calicheamicin-y: R' = H, R2 = Et, R3 3 esperamicin-Alb R' = 0, R2 = Pr', R3 = Me M e o y O OH 0 wonder and amazement amongst scientists as to the neverending power of nature to innovate in the constitution of complex multifunctional molecules, and the mechanism through which they exert their biological activity.Antibiotics 1-4 associate with their intracellular target DNA and are converted to high energy diradical species which effect single and/or double strand cleavages through hydrogen abstractions from the deoxyribose ba~kbone.~ These multistep processes are unprecedented.In response to this stimulus, the chemical community quickly set out to demonstrate that modern synthetic methodology and thinking could rise to the C02H OMe OH 0 OH dynernicin A 4 Scheme 1 Lhermitte and Grierson: Enediyne based antitumour antibiotics. Part 2 93challenge that efficient construction of these sensitive and complex molecules represents. In part 1 of this review,6 an overview was given of the research that was initiated to synthesize simpler, more readily accessible enediyne-dienediyne systems and to examine their capacity to undergo Bergman or Myers type cycloaromatization7~R to diradical and polar intermediates.intense efforts to attain the natural products themselves by total synthesis. To date, significant progress has been made to construct the labile core structure of neocarzinostatin 1 and esperamicin 3, and two successful approaches to the aglycone of calicheamicin have been developed. Several routes to the sugar components of 2 and 3 have similarly been devised, and through the coupling of advanced intermediates to both the aryl tetrasaccharide of calicheamicin and its aglycone (calicheamicinone) both Nicolaou and Danishefsky have achieved the total synthesis of natural (-)-2. A considerable body of work has also gone into constructing simplified bioactive analogues of dynemicin A 4, and these efforts have formed a solid basis for the two syntheses of this enediyne antibiotic that have very recently appeared.A description of these ground breaking achievements, in conjunction with many other approaches and strategies that are under development for the total synthesis of the enediyne- dienediyne antitumour antibiotics is given here in Part 2 of this review. Concurrent with these studies, have been equally i. EtMgBr, CH20 ii. - 0 PdO-CuI 0 ~ ~ s - 2 Approaches to the total synthesis of the neocarzinostatin chromophore Wender's group was the first to achieve the construction of the neocarzinostatin chromophore skeleton. In this work they popularized the use of 2-bromocyclopent -2-enone 5 as an A-ring synthon onto which the B-ring propargyl and acetylene units can be conveniently attached (Scheme 2).9,'0 Also central to their strategy is the photochemically induced extrusion of SO, from 6, which effects ring contraction to the strained 9-membered neocarzinostatin intermediate 7.This choice was made in view of the sensitivity of 1 to high pH and certain nucleophiles, as well as to decouple the enthalpic and entropic problems which otherwise combine to make direct closure of the 9-membered ring difficult. The fragile bicyclic dienediyne 8 was obtained by treatment of alcohol 7 with MsCl and DMAP. Elements of this strategy appear in Mikami's ene reaction approach to the construction of 10 from aldehyde 9 (Scheme 3). However, under the thermal conditions employed this intermediate undergoes dehydration and cycloaromatization giving tricycle 11." reaction of an ally1 chromium reagent, generated from 12, as a means to achieve 9-membered ring formation (77-88% yields) (Scheme 4),I2-l4 as well as the 2,3-Wittig ring contraction of the Wender also explored the intramolecular Nozaki iii.TBAF iV.M&I.TEA HO' 5 6 hv 10min,l5% I 7 0 Scheme 2 0 9 10 11 Scheme 3 12-membered ether 13 (R=H) to compound 14.12 However, the yields in the latter study were only moderate, and difficulties were encountered during purification of the mixture of diastereoisomeric products. Krebbs et al. found that the corresponding 0- MEM protected ether 13 (R=MEM) fails to undergo the 2,3-Wittig ring c~ntraction.'~ In contrast, Doi and Takahashi showed that ether 13 (R = TBS) does rearrange efficiently (ButLi, THF, -100 "C, 10 min), and with a high degree of 'cis' selectivity to give the neocarzinostatin derivative 14 (66% yield).16 Further, simple, but delicate transformations gave the dienediyne 15.Takahashi's group have built upon this result to synthesize compound 21 in which the two hydroxy groups are present in the cyclopentene ring with the correct relative stereochemistry (Scheme 5).'7,18 This involved reaction of epoxy ketone 16 with the lithium acetylide 17, followed by dehydration, regioselective Pd(0) catalysed opening of allylic 94 Contemporary Organic SynthesisGOTBS HO R' = Br, R2 = OH R1 = OH, R2 = Br / \ RO . _ _ 12 13 CrC12, THF / 4,5-cis products 77-8770 2,SWittig @OH RO 14 15 Scheme 4 epoxide 18 in the presence of benzoic acid, and elaboration of ketone 19.2,3-Wittig rearrangement of ether 20 produced the neocarzinostatin analogue 21 in greater than 60% yield. Magnus and collaborators have shown that their strategy employing q2-dicobalt hexacarbonyl alkyne complexes can be applied to the synthesis of the bicyclic skeleton of neocarzinostatin 1 (Schemes 6-8).19,20 Their initial plan was to close the C,-& bond in an intramolecular aldol reaction involving the enol (enolate) form 23 of the masked enediyne 22. However, exploratory experiments revealed an unexpected reaction pathway leading to 24 (Scheme 6). This problem could be countered through cyclization of intermediate 25, but in this case, subsequent decomplexation of 26 was accompanied by cycloaromatization of the highly reactive 9-membered enediyne product (Scheme 7).to install the sensitive epoxide trigger of 1 prior to Analysis of the situation led to the audacious plan 16 18 I. PdO, Phcofi ii. TBSCl iii. KSOs MeOH hr. PCC -*. / Br TB TBSO THF, -100 OC 10 min, 62% 20 Scheme 5 21 J 6 R 2 24 Scheme 6 the Lewis acid promoted aldol type cyclization step (Scheme 8). Fortunately, it was found that aldehyde 27, obtained as a mixture of monochiral diastereoisomers, underwent smooth ring closure on treatment with BuzBOTf and Et,N to give 28 in Lhemitte and Grierson: Enediyne based antiturnour antibiotics. Part 2 9525 26 Scheme 7 57% yield. Oxidative decomplexation then gave the desired 9-membered diyne epoxide 29 (69-75% yield), which was a stable product! of the neocarzinostatin chromophore 1 in enantiomerically pure form has been made by Myers et al.(Scheme 9).21,22 They showed that condensation of the chiral epoxy functionalized 1,5-diyne unit 30 with optically pure keto acetal31 led to selective (18:l) formation of the desired 1,Zaddition product 32. Subsequent ring closure of aldehyde 33 to 34 was achieved using LHMDS in the presence of CeC13 (87%). The remarkable aspect of this, and similar ring closures discussed further on, is that the highly strained 9-membered ring is formed via a reaction which is potentially reversible. At this stage it was found that the delicate allylic transposition of 35 to 36 could be effected by brief exposure to trifluoroacetic acid. Hydrolysis of trifluoroacetate 36 was then followed by hydroxy protection and vinylogous elimination of MsOH to give the dienediyne product 37.The most significant progress toward construction E t O & Y B r Br i. -TMS,P$ ii. DlBAL iii. Na(OMe)3BH c bEt I. (-)- DET iL Phrcl Ill. F A 1 V OEt 27 28 29 Scheme 8 rl Snaphth 31 L 32 i. mCPBA iv. TMSOTf i. MeOH, c--- 49% I TMSO HO 0 37 -36 R=H- R=TMS EtSNeHF 35 34 33 Scheme 9 96 Contemporary Organic Synthesis4% o \ NHP C-1027 38 H O M W Me kedarcidin 39 T 0 0 I - Scheme 10 3 Nine-membered enediynes: kedarcidin and C-1027 Recently, Hirama et al. have reported an approach to the 9-membered enediyne core of the enediyne C-1027 3823 and kedarcidin 3924 (Schemes 10 and ll).25926 Fundamental to their strategy is the idea that these highly unstable molecules may exist as nucleophilic addition adducts (Serine-OH) in the apoprotein (Scheme lo), and that liberation of the chromophores is accompanied by enediyne double bond formation.25 antibiotics is unknown, racemic 40 was condensed with optically pure diyne 41 to give 42 (and its C-9 diastereomer as shown in Scheme 11).Both diastereomers were separately carried through to aldehydes 43 and reacted with LHMDS in the presence of CeCI,. Interestingly, ring closure to 43 was succeeded by a facile Cope rearrangement to the bis-allene 44.27 This undesired transformation was suppressed during the corresponding cyclization As the absolute stereochemistry of the two of the enyne intermediate 45 to the point where the target compound 46 could be isolated and characterized (46 can be stored at - 20 "C).was converted to the enediynes 47 and 48 (Scheme 11). Compound 47 underwent rapid cycloaromatization (tg at 20 "C = 11 min), but epoxide 48 could be purified by silica column chromatography. The pronounced dependency of the cycloaromatization rate of 48 on solvent [ti ( CD2C12) = 680 min; ti ( CD2C12/CHD) = 23 min] led to the suggestion that 48 may be virtually in equilibrium with the diradical intermediate 49 due to a very low energy barrier to interconversion, and to a higher barrier to radical neutralization by hydrogen abstraction. Several reports have also appeared concerning preparation of the aromatic and sugar components present in 38 and 39.28,29 By a short sequence of reactions this intermediate 4 The total synthesis of calicheamicin/esperamicin 4.1 Central core structure As with any large molecule, a vast number of retrosynthetic pathways can be envisaged for the preparation of calicheamicidesperamicin. However, in view of the ready availability of enediyne 50,30 the bond disconnection shown in Scheme 12, involving condensation of its dianion across a keto aldehyde platform synthon 51, has attracted particular attention.Given this choice, the problem of constructing the aglycones calicheamicinone 52 and esperamicinone 53 can be reduced to deciding how much of the molecules functionality (and in what form) should be present in the starting platform synthon, and at what moment either direct condensation or stepwise construction of the bridging enediyne system should intervene.Kende achieved the synthesis of the bicyclo[7.3. lltridecane compound 56, possessing the crucial C,-C,, bridgehead double bond of calicheamicinone which prevents cycloaromatization (Scheme 13).31 In this work the aldehyde function in 54 served as a latent ethynyl substituent, and the keto group was elaborated into the a,P-unsaturated aldehyde system found in 55. In the final step the enediyne bridge was successfully buckled together to produce 56 along with its C-8 epimer. Detailed NMR studies of these products permitted reattribution of the stereochemistry initially proposed for the C-8 centre in 2. In the first synthesis of calicheamicinone by Danishefsky et al., the concept of reacting the dianion of enediyne 50 with a fully functionalized platform structure was taken to the letter (Scheme 14).32 Indeed a projected key step was the condensation of 50 with the keto aldehyde synthon 59, obtained by Becker-Alder,, dearomatization of the phenol intermediate 57 and a Dess-Martin periodinane mediated oxidation34 of the resultant alcohol 58.Preliminary studies of this process pointed to the inescapable necessity of having the Lhermitte and Grierson: Enediyne based antitumour antibiotics. Part 2 9740 I 0 Y O ! + LAIH4 iii. TBAF vi. Dess-Martin periodinane 54% periodinane T& 45 TES 42 Y 0 0 MO M = Ce* or ti+ cope rearrangement 72% v H6 h 0 P iii. TBSOTf TBSo' i. MsCl ii. TBAF iv. MsCl v. DBU, 25 O C HO 46 i. TBAF ii. TBSOTf iii. MsCl iv. DBU, 25 OC v TBSO 47 49 44 Scheme 11 MeSSS 51 50 R = H calicheamicinone 52 R = OH esperamicinone 53 PdO-CuI t Scheme 12 98 Contemporaly Organic SynthesisOMe OMe I I 0 54 n 0 55 Scheme 13 Nas 71 96 R-H - R-Ek * n i.HO OH, PPTS ii. OsO,, NMO iii. NaI0, LiHMDS (inverse addition) MF,2O0C * HOW-- H 56 dianion react first with the less reactive keto group in 59. This was achieved by a clever application of the Comins procedure for in situ aldehyde p r ~ t e c t i o n ~ ~ wherein the 1,2-addition product 60 was formed regio- and stereo-selectively. Despite the large distance between the reacting centres in this acyclic intermediate (-6.5 A) ring closure was extraordinarily efficient giving the strained enediyne intermediate 61 with the correct C-8 hydroxy stereochemistry in 60% yield. ether function to the corresponding ketal, elaboration of the C-13 ketone function through epoxide ring opening and oxidative cleavage of the resultant diol, and introduction of azide ion at C-10 in a Michael reaction process.At this stage the exocyclic double bond was stereospecifically introduced into 62 by an intramolecular Wittig reaction, and the azido group was reduced and carbomethoxylated giving lactone 63. The final operations included reductive opening of the lactone ring, and conversion of the derived alcohol to thiol 64, which on treatment with Harpp's disulfide reagent 6536 gave the allylic methyl trisulfide intermediate 66. Selective reaction of 66 with CSA at room temperature touched only the ketal function, completing the synthesis of ( f )-calicheamicinone 52. Scheme 12 are also found in Nicolaou's first synthesis of ( - )-calicheamicinone (Scheme 15).37 Particularly appealing in this work is the idea of capturing in latent form the urethane nitrogen and the C-9 aldehyde function within the Subsequent steps involved conversion of the enol The essential elements of the strategy depicted in L 1 5 0 1 iLTMS0Tf !BR=CH@H 5@R=CHO HO-- 0 L (EtO)Q(O)CHflOCI ii.LiEk iv. (CLJCO)&O v. M H RS 63 I i.DlEAL 61 i. HO(CH&OH, CSA ii. KOAo, AcOH, DMSO hr. Nd04 v. NaN, iii. M a , NH3 56% 6 2 " 3 P'zSSMe 64 R=H 66 R=SSMe Scheme 14 dihydroisoxazole ring of the highly functionalized monochiral intermediate 67. Note also that stereoselective reaction of the keto group in 67 with lithium (trimethylsily1)acetylide to give 68 Lhermitte and Grierson: Enediyne based antitumour antibiotics.Part 2 99n 0 JF HO M*2c--o:L NaOCl (4 : 1 mixture) ii. Naom iii. Jones oxidation c OH i.m/ ii. NaBH4 76 y y W 3 ~ M E M 67 n I OH A OH Dess-Martin I TMS P X 69 x = o Ph"=C:%h 68 70 X=CHC02Me i. K@3, MeOH ii. TESOTI iii. WO-CUI (cat.) n NPhth iv. s i r i ge~ v. AC-p c 97% 78 i. 71, Pdo-CuI ii. DIBAL iii. Dess-Martin iv. CsF TMS 0 I ? Q 73 I KHMDS, -90 "C 72 + 44% i. MsCl ii. silica, py - iil MeNHNH2 74 NHC02Me 75 79 80 ii. M n 4 OH j/ (-)-calicheamicinone 52 Scheme 15 81 Scheme 16 82 R = 83 R = established the chirality at C-1 of the target molecule. In the following steps Swern oxidation of the O-MEM deprotected derivative of 68 effected both oxidation of the liberated secondary alcohol and aromatization of the isoxazole ring giving 69. Reaction of this intermediate with methyl(tripheny1- phosphoranylidene) acetate produced the a,P-unsaturated ester 70 as a single isomer.The enediyne system was then assembled by Pdo-CuI catalysed coupling with cis chloro enyne 71, and the amino aldehyde functionality contained in the 100 Contemporary Organic Synthesisisoxazole ring of 72 was released by N-0 bond cleavage using molybdenum hexacarbonyl. Ring closure of phthalamide derivative 73 to a 9:l mixture of alcohol 74 and lactone 75 (44% combined yield) was achieved through reaction with KHMDS in toluene at - 90 "C. Taking advantage of proximity effects, alcohol 74 possessing the incorrect stereochemistry at C-8 was converted via its mesylate derivative to lactone 75. Reductive ring opening of this lactone, and its elaboration to (-)-calicheamicinone 52 was achieved using the chemistry developed by Danishefsky and Magnus.To gain access to esperamicinone 53 in both its natural (1S,8R)3s and antipodal forms for biological testing,39 Grierson and co-workers employed the two enantiomers of keto ester 77, obtained from the quinic acid derivative 76, as the pivotal intermediate (Scheme 16).4"741 For the natural series, elaboration of seco aldehyde 79 began by stereospecific acetylene addition to (+)-77 using weakly basic dichlorocerium (trimethylsilyl)acetylide, and 0- silylation of the derived alcohol to block intermediate 78 in the conformation having the acetylene function axial. Cyclization of 79 gave the desired bicyclic enediyne product having the correct C-8 stereochemistry ( > 60%).However, to avoid retrocondensation during subsequent operations the cyclized alcohol was converted to its methyl ether 80 before work-up. Introduction of the urethane nitrogen was then achieved by reaction of enone 81 with Ph2S=NH. In this transformation cyclization of 88 Scheme 17 84 TESOTf D the presumed intermediate Michael addition adduct to aziridine 82 is sufficiently rapid that cycloaromatization does not occur. Various conditions can be envisaged to effect ring opening of the N-carbomethoxylated aziridine derivative 83 such that the C9-Clo double bond is reinstalled, and the C-13 centre is activated with respect to construction of the allylic trisulfide system. In a closely related fashion Kadow and Isobe have elaborated the simpler esperamicin intermediates 86 and 87 from keto ester 84 (Scheme 17).42,43 Interesting in Kadow's study is the contrasting dependence of product C-8 stereochemistry on reaction temperature in the ring closure of aldehyde 85, and the analogous cyclization of 90 to 91.Aldehyde 90 was obtained in four steps from Isobe's epoxide 88 (see Scheme 36) by TESOTf induced ring opening to the exocyclic enol ether 89 and regioselective thermal selenoxide cis elimination.44 With respect to the strategy depicted in Scheme 12, Magnus and co-workers approached the problem of synthesizing 52 from almost the opposite viewpoint, i.e. by introducing the functionality onto the 6-membered ring platform after assembly of the bicyclic enediyne skeleton (Scheme 18). In particular, from their work on the preparation of different cobalt complexed bicyclic enediyne structures (see Scheme 12 in Part 1 of this review6), it was observed that the ketone 94 obtained after decomplexation of 93 was sufficiently stable to permit chemical manip~lation.~~-~~ This result is remarkable, in view of the fact that the crucial 0 TBAF ProtO 1 85 86 R' = H, R2 = OTMS 87a R' = OH, R2 = H (25 "C) I 87b R' = H, R2 = OH (0 "C) R3=H 91a R' = H, R2 = OH (20 "C) 91b R'=OH,R2=H R3 = OTES (91-1 b = 1.2:l at -78 "C) t i.PhSeCl ii. mCPBA iii. K2C03 I MeOH - TMS TESO'~ 30% I LHMDS, THF 89 90 Lhermitte and Grierson: Enediyne based antitumour antibiotics. Part 2 101R = Me or H 93 92 R=OMeorH 12. THF, 82% 1 r 1 L -I 95 94 i. DlBAL R=CN 1 ii. MsCl iii. NaSAc iv. LiAIH4 Scheme 18 bridgehead double bond is absent in enediyne 94.The cobalt complexed enediyne 93 was prepared via a ring closure reaction involving reaction of the enol ether system in 92 with a formal carbocation generated by departure of the OMe or OH group under Lewis acid conditions (the Nicholas reaction). conformation in which the C-9 hydrogen is in the plane of the carbonyl system, the enol silyl ether 95 could be generated. This opened the way to a selenium based protocol for creation of the C9-Clo double bond in 96.48949 At this point oxygen functionality can be further introduced at C-11 under SeOz allylic oxidation conditions giving 97, and through a stereocontrolled Wittig-Horner reaction using diethyl cyanomethylphosphonate elaboration of the allylic trisulfide unit in 98 was achieved.48i50 To incorporate the C-8 alcohol function in the molecule the cobalt complexed aldehyde 99 was cyclized through an aldol reaction to 100 (Scheme 19).” Kadow,’* and subsequently R ~ t h ~ ~ and M a g n ~ s , ~ ~ have modified this approach showing that Since 94 adopts preferentially a boat treatment of 101 with PhS-/Ti(OPr’)4 initiates ring closure through a Michael addition-enolate trapping mechanism to give alcohol 102 (Scheme 20).Subsequent oxidative elimination of PhSOH and decomplexation then provides a simple alternative means to access compound 96. At a later stage it was shown that diketone 103 can be converted to the enaminoketone 104 through reaction with either PhZS=NH or the azide ion in DMF (Scheme 21).& Nicolaou’s group turned to synthesizing esperamicinone 53.54 The main emphasis in the approach that was ultimately developed (Scheme 22) was to create the 1,Ztruns-diol system in the late stage intermediate 110 via Sharpless epoxidation of 108 (90% ee) and acid catalysed ring opening of the epoxide unit in acetylene 109.Key operations in the elaboration of allylic alcohol 108 involved nitration of the ketal 105, oxidation of the aromatic ring in 106 to give quinone 107, and ketone to cyanoethylene conversion (65 % overall, Having succeeded in obtaining calicheamicinone, Z : E = 10: 1). 99 loo Scheme 19 i. Pd(OAc), ii. H+ iii. Co2(CO)8 iv. Bu‘OMgBr. ADDP 101 Me2AISPh Ti(OPr’), 1 TBSO A 96 102 Scheme 20 ’& RO-- =. I orNaN3, Ph2S=NH DMF :& 2 2 I 103 Scheme 21 1 04 102 Contemporary Organic Synthesis?Me OMe i.KgO3 K. MsCl MeOH-H@ iii. Dw 55% L n. BUU. -18 "c J),, !i.s2Kfio3 c &HC02Me iii. COCl, then MeOH 56% OH O x 0 TBSo O x 0 II c II 106 i. Ce(NHd2(NO& ii. Silica gel iii. PMBBr OTBS v. TBSCI 111 /$ Ho Me 1 27% HO & . i. BuLi, MeCN ii. TFAA iii. HFQ 4 6 5 4 TBSO o 1 07 108 i. Sharpless epoxidation ii. Dess-Mattin 1 . L 112 Scheme 23 0 0 Scheme 22 4 ,-H@ PMB Schreiber et al. have adopted yet another entirely different strategy for the synthesis of the calicheamicin/esperamicin aglycone based upon an intramolecular Diels-Alder reaction in which the enediyne system acts as a structurally rigid chain connecting the diene and dienophile components (Schemes 23 and 24).55 This approach to the platform ring is astute in that the bridgehead double double bond is created during the Diels-Alder step rendering the cycloadduct thermally stable.Contrary to expectation, compound 111 did not cycloadd via a geometry imposed a o transition state to give the desired product 112 (Scheme 23). However, it was . found that the cycloadduct 114 obtained from Diels-Alder reaction of 113 could be readily converted to the mesylate derivative 115, and that Lewis acid promoted pinacol type rearrangement of this intermediate produces the esperamicin analogue 116 ( > 15 : 1,65%) (Scheme 24). \--I 113 Et*I 65% - 115 4.2 Synthesis of the glycone Sophisticated NMR, molecular modelling, and (bio)chemical studies have revealed much about how the oligosaccharide fragment in calicheamicin, and the trisaccharide and fucosyl anthranilate units in esperamicin, contribute to the interaction of these antibiotics with the minor groove of duplex DNA.56 From this work a detailed picture at the molecular level concerning the differences in site selectivity and capacity of the two compounds to 116 Scheme 24 Lhennitte and Grierson: Enediyne based antiturnour antibiotics. Part 2 103effect single versus double strand breaks in DNA through abstraction of specific hydrogens from the deoxyribose backbone has emerged. In particular, these studies point to the important role played by the hydroxylamino glycoside linkage between the A and B monosaccharide units in preorganizing the oligosaccharide into a conformation that compliments the shape of the minor groove.The development of strategies for the stereocontrolled formation of the /3-N-0 linkage, which joins the anomeric centre in the novel sulfur containing 2-deoxy B-ring sugar and C-4 of the A (or A-E) ring fragment, is therefore a central issue that must be addressed in any effort to construct the A-(E)-B trisaccharide structure common to calicheamicin 2 and esperamicin 3. The discussion will consequently be focused upon the problem of constructing the respective methyl glycosides 117 and 118 (Scheme 25).57-70 B-ring A-ring <Me R1 S .I OH 0 I 0 , OMe I H O W - D-ring '* OH 118 R' = Me, R2 = Pr' Scheme 25 Considering the presence of two 1,Zaminoalcohol systems in the otherwise sparsely functionalized E- ring of 117, Nicolaou, and more recently Roush, chose to construct this sugar from ~ - s e r i n e .~ l - ~ ~ The key step in both routes is the reaction of a serine derived aldehyde intermediate with a chiral ally1 borane reagent. In Nicolaou's synthesis (Scheme 26) this led to formation of compound 119 as a single isomer (75%). Methylation and subsequent ozonolysis gave a methoxy aldehyde intermediate, which was converted to acetal 120 (68% overall yield for the four steps). Cyclization of 120 in dry HCl-MeOH produced a mixture of separable methyl glycosides which were converted to the N- Fmoc (9-fluorenylmethoxycarbonyl) protected glycosyl fluoride 121 by treatment with Fmoc- chloride followed by reaction of the anomeric acetate derivatives with DAST. Coupling of 121 with the methyl D-fucopyranoside derivative 122 followed by deprotection and selective oxidation of the axial C-4 alcohol gave the A-E ketone 123.@ In Kahne's approach to the E-ring the Diels- Alder 124, obtained from reaction of the N-Boc- N, O-isopropylidene derivative of serine aldehyde with Danishefslty's diene, was oxidatively cleaved giving the /3-hydroxy ester 125 in 77% overall yield (Scheme 26).65 Methylation of the secondary alcohol, DIBAL reduction, deprotection under acidic methanolic conditions, and sequential N- acetylation and alkylation then gave 126.Anomeric activation involved OMe +SPh exchange and conversion of the derived thioglycoside to the corresponding sulfoxide 127. Reaction of this sulfoxide with methyl glycoside 128 in the presence of triflic anhydride in pyridine (the Kahne reaction%) gave a disaccharide intermediate which was elaborated to the A-E ring triflate intermediate 129 (64% overall yield).67 The use of glycals both as starting materials and intermediates in the sugar coupling reactions is a key feature of Danishefslty's synthesis of the calicheamicin/esperamicin oligosaccharides.6R~69 This is exemplified by the Theim type coupling (I+C10;)70 of glycal 130 with compound 131, itself derived from D-fucal, to give ultimately the disaccharide intermediate 132 with the 0-4 axial triflate function in 41% overall yield (Scheme 27).In a similar way Beau et al. showed that glycal 133, prepared in six steps from D-arabinal, condenses with the A-ring precursor 134 in a Theim reaction to give the A-E ring intermediate 135 (Scheme 28).71 Three major strategies have evolved to date for the coupling of A-E-ring intermediates to the B- ring via the N-0 bond such that the correct &a- BIQ configuration is obtained. In the initial phase of Nicolaou's synthesis of the calicheamicin glycone the idea was to use the C-2 oxygen substituent in compound 138 to direct selective formation of the P-glycoside 139 (Scheme 29).@~~~ Intermediate 138 was obtained in five steps from glycal 136, the most important operation of which was the stereoselective Zn(B&)2 reduction of ketone 137 from the P-face with concomitant ester migration.As planned, reaction of lactol 138 (a : /I = 8 : 1) with N-hydroxyp ht halamide (Mitsunobu conditions) produced the required /3-anomer 139 as the major product (5 : 1 to 7 : 1; 56% overall).Liberation of the amino group and coupling of the derived hydroxylamine 140 with the A-E ring ketone 123 under acidic conditions proved highly efficient, giving oxime 141 as a single isomer (83%). Conversion of compound 141 to thioniomidazolide 142 then set the stage for a thermal [3,3]-sigmatropic rearrangement to 143. In this step the B-ring C-4 sulfur substituent was introduced stereospecifically, and the C-2 position was deoxygenated. Subsequent condensation of 144 with the acid chloride derivative 145 gave the tetrasaccharide intermediate 146 in 80% yield. In the final steps to the calicheamicin methyl glycoside 117 the B-ring keto group was exposed and reduced, and the remaining protecting groups were removed. Most importantly, the oxime double 104 Contemporary Organic Synthesis20 O y N 7 0 t & O y N 7 0 119 "9 i.A@, Me1 ii. 03, P(0hW3 iii. H*. MeOH iv. NaOH 68% Scheme 26 P h t h N e MeO 130 Scheme 27 124 i. Ru04, NaI04 ii. K2CO3 iii. HCI 125 i. MeOTf, P.&di-teMUtyl- hethylpyridine ii. DIBAL iii. TsOH. ZnCh. MeOH iv. 40, PY v. KOH, Eti 67% OMe I i. HCI -i.LiAIH4 w pq 126 ii. Fm&1, K&03 - iii. AcOH iv. DAST iv. MPBA 65% 55% MeO ii. TFAA iii. PhSH, BF3.Et2O Me0 X=F,R=Fmoc 121 127 X = SOPh, R = COCF3 ii. NaH. HO(CH2)flH iii. Bu2Sn0, Br2, Bu$nOMe 45% 123 OTf - .. w OH i. IClO,, BM~o!&,$P BMPO 131 OH P ii. 41 Ph&H. % AlBN *PhthN ,@ Mi. Tf@, py Me0 132 \ k 6 U 3 0 ii. TsOH OMe Tf20,PY iii. BzCI, TEA, DMAP iv. Tf20, py 64% OSnBu3 ii. TsOH w MeO 129 133 Scheme 28 NIS. MeCN, 4 A molecular sieves 135 134 Lhennitte and Griemon: Enediyne based antiturnour antibiotics.Part 2 105OTBS 138 TBSO %YR2 . OCOAr 139 R =Phth 140 R:=H&~ OTBS 137 ii. TESOTf 83% OTBS 136 TBSO eo;L+ 6COAt' p$ 4N Me0 141 i. DIBAL ii. (Im)&S 79% ____c TBSO ; 142 o K l m S I TEsocg-?c( OTES PhMe, 110 "C 98% I 146 i. TBAF ii. K-Selectride iii. HFpy iv. Et2NH v. NaBH3CN, HCI 19% 117 Scheme 29 bond was reduced selectively such that the required C-N equatorial stereochemistry was obtained (86%; a : /3 = 6 : 1). By essentially the same route the esperamicin trisaccharide 118 was ~ynthesized.~~ The second approach to the calicheamicin aryl tetrasaccharide 117 was developed independently by Danishefsky and Kahne. Here, the B and A-E rings are joined through SN2 displacement of the axial triflate substituent in the A-E fragment by the anion generated from N-acylated B-ring anomeric hydroxyalmine intermediates (Schemes 30 and 31).The N-Teoc derivative 155 employed by ~~~i~h~f~ky68,69,74,75 was prepared by first converting tri-0-acetyl-D-galactal 147 to the a-phenylthio pseudoglycal 148 (82% overall) (Scheme 30). LiAlH4 reduction and mesylation of the remaining hydroxy group then afforded compound 149, which was converted to the disulfide 150. Treatment of 150 with m-CPBA at -40 "C resulted in sulfoxidation of the less hindered anomeric thiophenyl residue only. At room temperature this intermediate underwent clean [ 2,3]-sigmatropic rearrangement giving 151 (76% after 0-silylation). Reaction of this glycal with TMSCH2CH20C(0)NHOH (Teoc-NHOH) in the presence of Ph3P.HBr gave urethane 152 (57%) along with 37% of the undesired N-linked glycoside.The C-4 thiol was then liberated through reaction with EtSH/&CO, giving the B-ring thiol 153 in high yield.76 This intermediate was condensed with acid chloride 154 in the presence of Et,N-DMAP to give the N-Teoc protected B-C-D fragment 155 (85%). In the next step the crucial reaction of the urethane anion of 155 with the A-E ring triflate derivative 132 was effected producing the protected oligosaccharide intermediate 156 in 80% yield. Liberation of the E-ring amino function in 156 106 Contemporary Organic Synthesismb i. a. TEA, DMAP OTES 85% 4 OTBS 155 156 mo-? M* OTBS OMe I How OH oMe 117 Scheme 30 followed by reaction with acetaldehyde and NaBH3CN permitted introduction of the N-ethyl substituent (98%).Final cleavage of the p - methoxybenzyl, silyl and Teoc blocking groups through successive reaction with DDQ and TBAF provided the target glycone 117 in 40% overall yield. By the same sequence of reactions using the S-methyl derivative of thiol 153 the esperamicin glycone 118 was efficiently prepared. 151 TeocNHOH PhpHBr 5796 The requisite B-ring substrate 160 in Kahne's synthesis was prepared in six steps from the readily available D-lyxo-pyranoside 157 (Scheme 31).67 This involved two sequential displacement reactions, and stereoselective formation of the desired p-anomer in the reaction of the sulfoxide derived from 158 with 0-stannyl-N-hydroxyurethane 159 (12 : 1; 39%). N- Alkylation of urethane 160 with the A-E triflate 129 was then effected producing 161 in 81% yield.This Lhemitte and Grierson: Enediyne based antitumour antibiotics. Part 2 107+ i. m CPBA iii. EtO&HN-OSnBu3 . ii. TfzO KHMDS 129 81 % 161 intermediate was fully deprotected by successive treatment with TBAF and NaOMe to give the (A- (E)-B trisaccharide as its disulfide 161. Deprotection at this stage was judicious as the protected aryl tetrasaccharide otherwise obtained proved sensitive to base treatment, undergoing a number of interesting rearrangements. Selective formation of the calicheamicin methyl glycoside 117 from 162 was elegantly achieved by reacting the corresponding thiolate generated in situ (Bu3P) with the phosphate derivative 163 according to Masamune (79% for the two steps).77 Beau et al.showed that BF3 OEt2 assisted cyanoborohydride reduction of the oxime ether double bond in the A-E ring derivative 135 occurs selectively from the /?-face giving the hydroxylamine 164 (74%) (Scheme 32).71778 Preparation of this intermediate for attachment to the B-ring involved isopropylidene hydrolysis and conversion to the N- protected nitrone derivative 165. O-Alkylation of this nitrone, achieved by reaction with trichloroacetimidate 166 in the presence of silver triflate, was accompanied by N,O-acetal formation giving the trisacccharide 167 in 90% yield (/? : a = 5 : 1). After three further deprotection steps the esperamicin methyl glycoside 118 was obtained. In the third strategy for A-(E)-B ring assembly, 1 62 MeO 163 Meo OH t 1 0 \ How MeO OH oMe 117 Scheme 31 4 3 Total synthesis of (-)-calicheamicin ylI To complete the total synthesis of calicheamicin 2 in a convergent fashion required the coupling of an advanced stage optically pure central core intermediate with a suitably protected aryl oligosaccharide component, under conditions where both components and the derived product survive.Further, the coupled product must not be overly sensitive to any subsequent steps of deprotection and functional group elaboration. In particular, provision must be made to avoid the known rearrangement of N-unprotected free glycosides such as 167 to azafuranoses (Scheme 33).60 In Nicolaou’s first synthesis of 2, both the labile trisulfide system in the aglycone and the hydroxylamine system joining the A and B rings of the sugar component were elaborated after the coupling reaction (Scheme 34).79 Important to the success of this approach was the use of the 0-TES and N-Fmoc protected /?-Znitrobenzyl glycoside 168,” which could be converted photolytically to lactols 169 (1:l mixture) and coupled to the calicheamicinone derivative 171 via trichloroacetamide 170 using the exceptionally mild conditions of the Schmidt reaction (76%).’l allylic sulfur atoms was introduced at C-15 in the aglycone.To effect the crucial reduction of the oxime double bond in 173 (NaCNBH3, 4a:4b=2:1; 80% yield) the silyl protecting groups had to be removed. However, temporary reprotection of the sugar hydroxyls subsequently proved necessary in order to elaborate the allylic trisulfide unit. This was achieved through reaction of 174 with TESOTf and With compound 172 in hand, the first of the three 108 Contemporary Organic SynthesisMeS i.HCI, MeOK3120 ii. panisaldehyde, PhMe 135 97x NaBH3CN, BF39Et2 TBAF; THF 0°C I 74% AgOTf, CHzCIz. 90% c-- COCF3 4 A molecular sieves OH ii. KzCO3, MeOH iii. 5 M KOH, rt 32% Me0 118 167 Scheme 32 167 OTBS , 1 HoY Scheme 33 Hunig's base followed by treatment of the crude product mixture with excess HOAc-H20. Reduction of the thioacetate group with DIBAL at - 90 "C then gave the corresponding thiol which was reacted with Harpp's reagent giving 175 in 75% yield. Treatment of this intermediate with HF-pyridine afforded 176 (90%) which was further deprotected 164 165 in the last two steps through sequential treatment with TsOH (70%) and Et2NH (90%), completing the synthesis of (-)-calicheamicin 2.Exploratory studies by Danishefsb of the coupling of the free glycoside derivative of 155 with different forms of the calicheamicin aglycone revealed problems associated with the use of the 0- TBS and N-phthalimide protecting groups, and the potential incompatibility of the allylic trisulfide (and other functionality) during fluoride promoted removal of the N-Teoc hydroxylamine protecting group.69974 In light of these findings and Nicolaou's precedent, they also settled upon use of a 0-TESIN- FMOC substituted oligosaccharide as the glycone precursor to calicheamicin (Scheme 35).82 Coupling of the trichloroacetimidate derivative 178 of lactol 177 with (-)-(S)-acetate 179 under modified Schmidt conditions (AgOTf catalyst) gave the desired P-configured product 180 along with the a-isomer in 58% combined yield.83@ Only four steps were required to convert this coupling product to (-)-2.However, more impressive was the finding that AgOTf catalysed Schmidt coupling of trichloroimidate 178 with the calicheamicinone ketal 181 was possible giving 182 in 34% yield (P-isomer only). From this intermediate ( - )-calicheamicin 2 was obtained by successive treatment with CSA and TBAF. 5 Dynemicin analogues and the total synthesis of dynemicin A Dynemicin A 4 possesses an intriguing hybrid structure composed of a calicheamicin/esperamicin enediyne core structure condensed to an Lhermitte and Grierson: Enediyne based antiturnour antibiotics. Part 2 109Scheme 34 OMe BzO 171 BFNEt2 -40 'C, 76% OR I.DlBAL ii. Ph3P, DEAD, AcSH iii. HFpy 79% 173 R=H,X=SAc I NaBH3CN, BF3.0Et2 -40 oc, 80% T 174 R=H,X=SAc - I i.TESOTf I ii.DlBAL iii. PhthN-SSMe 175 R = TES, X = SSSMe 56% HC'W HO, Mx 18 h. 90% 1 e h N H C 0 2 M e MeSSS 110 Contemporary Organic SynthesisTeoc 0 0 Et(Frnoc)N@ Me0 R 4 2 0 2 M e 181 RrSSSMe ti\\ I HO' 179 R=SAc AgOTf, 4 A molecular CH&12,25 "C i. DIBAL ii. PhthN-SSMe 1 54% (58%) 180 R = SAC (34%) 182 R = SSSMe i. CSA, 25 "C ii. TBAF, 15 min 37% MeSSS EtNH Me0 OH (-)-calicheamicin 2 Scheme 35 anthraquinone unit characteristic of the anthracycline antibiotics. Between these two subunits is the epoxide trigger which is highly susceptible to ring opening in intermediates wherein the anthraquinone system is reduced to the hydroquinone level.Particular care must thus be taken during construction of dynemicin to either maintain the anthraquinone component in a protected form, and/or in the correct oxidation state. The strategies which have evolved for the synthesis of antibiotic 4 include a linear approach in which the pentacyclic 'platform' structure (rings A- E) is elaborated before attempting introduction of the epoxide ring, the enediyne bridge and other functionality onto the A-ring, and a second, more convergent 'biomimetic' approach in which the enediyne core structure is joined to an anthraquinone derivative via formation of the C8-C9 and C2-N1 bonds. However, the approach which has been most extensively developed to access dynemicin and simplified fully functional analogues involves the use of quinoline or phenanthridine derivatives as B-C and A-B-C ring precursors onto which the enediyne/epoxide system can be elaborated, followed by the D-E rings.This later strategy was adapted by Myers and Danishefsky in their respective total syntheses of dynemicin A, and by Schreiber et al. in their synthesis of the di-0- methyl ether-methyl ester of 4. Lhemzitte and Grierson: Enediyne based antitumour antibiotics. Part 2 1115.1 A-ring ‘biomimetic’ approach To access the enediyne core component of dynemicin equipped with the epoxide trigger, Isobe showed that the ketal enone 183 can be converted selectively via 184 to the epoxy diol intermediate 88 (Scheme 36).85 Cyclization of the corresponding aldehyde 185 to the bicyclic dynemicin analogue 186 proved feasible using the LHMDS/CeC13 combination.Note that treatment of the acetate derivative of 186 with TsOH gives 187, providing a convenient link to the calicheamicin series (see Scheme 17). i. TFA*H20 ii. NaBH4 iii. mCPBA * Me0 ii. K2C03. MeOH iii. 71, PdOGuI (cat.) 63% 0 LiHMDS 35% Cecla 183 184 OH 185 oTMS 1 a8 OH HO H.. fJ 0: I I OTMS 186 Scheme 36 AcO’ ! OTMS 1 87 In a more recent study Maier has synthesized the related enediyne 190 in which one of the connections is made to the oxygenated C-ring (Scheme 37).86 The starting ketal enone 189 for this study was prepared in five steps from acid chloride 188. Addressing the problem of making the c&9 connection and closing the B-ring in a biomimetic type synthesis of 4, Isobe showed that palladium based coupling of the more highly functionalized A- ring bromide 191 with the aryl tin derivative 192 OMe 188 Scheme O h R = OH R = CH(0Me)z 180 11 OMe 190 7 0 191 OTBS 1 0- 193 Scheme 38 could be achieved (Scheme 38).87 Treatment of intermediate 193 with TFA in CH2C12 then gave the A-B-C ring synthon 194 in 77% yield.5.2 Anthraquinone ‘platform’ assembly Construction of the anthraquinone portion of dynemicin A has been undertaken by several groups, with the idea in mind either to use this material as a synthetic intermediate on the way to 4, or to evaluate methodology which will subsequently be applied for the elaboration of the D-E rings in late stage intermediates which already contain the 112 Contemporary Organic Synthesisenediyne/epoxide moieties.The possibility that synthetically derived anthraquinones may themselves display antiturnour properties is of further interest. Within the latter synthetic context Schreiber developed a route to the angular anthraquinone 199, involving condensation of the quinoline derived aldehyde 195 with the lithiated benzamide derivative 196, followed by reduction of lactone 197 and intramolecular Friedel-Crafts cyclization to the air sensitive anthracenol 198 (Scheme 39).88 Treatment of this intermediate with DDQ provided 199 in 25% yield. & TsOH ii. PivcI 87% CI CI I I OMe 200 OMe 201 i. HP, Pd/C ii. Bu'Li, TMEDA iii. TsOH 2,5-(Me0)&H3CH0 M m jj.y+EoH iii. Jones o m oxidation OMe I II I Me0 0 OMe U o M e 202 203 OMe 195 Scheme 40 6; OMe 205 LDA, 95% - 199 198 OMe 0 MeO*C' Scheme 39 204 Nicolaou's route to the pentacyclic compound 203 (Scheme 40) began with directed metalation of the phenanthridine intermediate 200 and reaction with diethylcarbamoyl chloride (84%).89 Hydrogenolysis of the C-Cl bond in 201 was then followed by a second metalation reaction with 2,5-dimethoxybenzaldehyde and lactonization.Reduction of lactone 202, ring closure and oxidation with Jones reagent gave 203 (53% overall). Magnus et al. have also devised a synthesis of the B to E rings of dynemicin (Scheme 41) via a seven step sequence in which compound 206 is obtained by conjugate addition of the anion of lactone 205 to the a,P-unsaturated ester 204 followed by aromatization and 0-pivaloate formation (85% ~verall).~' Reaction of 207 with LDA then leads to ethyl ether 208 which is converted to 209 after oxidation (CAN), deprotection and reaction with acetic anhydride.derivative 210, Isobe and co-workers prepared the pentacycle 215 (Scheme 42).9' Remarkably, all efforts to cyclize the conjugated amide intermediate 211 to a 6-membered ring product led instead to spirocycle 212. This situation was countered by effecting a Pd catalysed Heck type reaction of the Starting from the readily available anthraquinone 1 @$ C0,Bu' c--- LDA, 95% bMe kOBu' I 4 207 (J.$ 0 0 i. CAN n. HBr HI. AQO 56% - QJJy OAc 0 OAc OMe &I OEt 208 209 Scheme 41 Lhermitte and Grierson: Enediyne based antiturnour antibiotics. Part 2 113Nicolaou and co-workers, who have focused their activity on the synthesis of dynemicin analogues lacking the D and E ring^.^^-"^ In many respects this effort has been fuelled by the fact that diversely functionalized derivatives of phenanthridines 0 OMe 21 1 t 21 0 0 0 OMe 212 0 c CuBq 64% 0 OMe 21 3 Pd(dba)p, CH,C13 ~(O-TOI)~, P1'2NEt DMF, BSA 67% 1 n 215 I 21 4 21 6 Scheme 42 corresponding p, y-unsaturated amide 213, which proceeds through the preferred ao-trig pathway giving the pentacyclic amide 214 (9 : 1 with double bond isomer). Reaction of this product with NBS- AIBN and base then permitted conversion to pyridone 215.Attempts to close the enediyne bridge across carbons 2 and 7 (dynemicin numbering) in this product through reaction at the amide carbonyl centre failed.92 However, Isobe's group has recently developed Pd catalysis conditions for replacement of the triflate group in 216 by an acetylene function.93 Note the mild conditions of this reaction, plus the fact that no inorganic salt additives are required.5.3 Nor-D,E dynemicin analogues: the total synthesis of dynemicin A An impressive contribution to the chemistry and biological study of dynemicin has been made by 217a-d and 226a,b could readily be obtained as starting substrates'" (Schemes 43 and 44), and by the fact that the derived model compounds retain the capacity to undergo epoxide opening-Bergman cycloaromatization, displaying potent DNA cleaving power. Introduction of oxygen functionality at C-10 in compounds 217a-d was achieved by acetic anhydride promoted rearrangement of their N-oxide derivatives (Scheme 43).94-96,'05 For the next step, Yamaguchi type reaction of compounds 218 with ethynyl magnesium bromide and benzoyl chloride proved to be a very effective means for introduction of the acetylene unit at C-6 in 219 (3 : 1 mixture, 97%).loh Epoxidation of this intermediate occurred uniquely from the face opposite the ethynyl group, giving ketone 220 (after 0-desilylation and PCC oxidation).The acyclic enediyne unit was then constructed through Pdo-CuI catalysed reaction with cis-chloro enyne 71 and TMS cleavage (AgN0,-KCN). Cyclization of compounds 221 to the dynemicin analogues 222a-d was achieved using LDA at -78 "C ( > 60%). It should be emphasized that it was necessary to install the epoxide unit before this ring closure, otherwise a strained product would be formed in which the olefinic double bond is severely distorted.Notice also that, in contrast to studies on calicheamicin, the reactivity of the ketone carbonyl in 21 was sufficient for closure of the enediyne bridge to take place. In a similar manner the synthetic strategy was extended to include benzodiyne analogues of dynemicin in which the central double bond of the enediyne system in 222 was replaced by a phenyl and a naphthalene ring.97j98 Reaction of the ketone derived from 219a with (2R,3R)-butane-2,3-diol also permitted access to enediyne 222a in enantiomerically pure form.99 Further reductive removal of the C-7 hydroxy group in compounds 222 gave the analogues 223. Compound 222a did not display any DNA cleavage activity when incubated with DNA. However, the corresponding free amine caused significant damage to DNA.This observation was pursued and confirmed in tumour culture assays using the base labile N-2-(phenylsulfonyl)- ethoxycarbonyl derivatives 224."'"-'u2 These results indicate that in its free form the amine nitrogen assists epoxide ring opening producing an o-quinone methide type intermediate 225 which picks up a nucleophile and cycloaromatizes. For preparation of the dynemicin analogues 229a,b the synthetic plan had to be modified such that the enediyne system was assembled first, in order to allow for the sensitivity of the epoxide system to the presence of the C-12 oxygen substituent (Scheme 44).'03 In fact the epoxide system in 227 is opened and reformed giving 228 114 Contemporary Organic Synthesis1 mcPBA 218 R 217a R=H b R=We A 219 L 71, PdO-CuI il.&Nos KCN 0:: pm?+Q A 221 I R 225 R = H, OMe, O(CHd20H, 1-i OH X = H, OW, O(CHd20H Scheme 43 prior to cyclization. Compounds 229 were also shown to be mechanism based analogues of dynemicin, their free phenol form 230 rearranging to the p-quinone methide intermediate 231 which reacts with added nucleophiles giving a species which spontaneously cycloaromatizes.'"''~102 226 R I I r"\'. TMS 0:: pho% R 0 227 TBS 22g4b 230 R=OH 3 Scheme 44 231 Wender and Isobe have also been very actively involved in the synthesis of truncated analogues of dynemicin which display potent DNA cleaving power (Scheme 45). Wender's group has developed a synthesis of the enediyne 234 from the readily available quinoline carbinol 232.'07-"0 The Yamaguchi procedure was again employed to introduce the acetylene unit next to nitrogen, and epoxide formation preceded experiments to effect ring closure of aldehyde 233.Isobe's group studied the preparation of the corresponding ketone 236 from quinoline 235 in both racemic and monochiral forms."'-"4 An important innovation by both groups in the enediyne field was the finding that direct condensation of the TMS protected acetylene with the carbonyl function in 233 and 236 could be achieved upon treatment with fluoride ion. Wender further showed that the yield of this transformation could be markedly improved by reacting the cyclized alkoxide intermediate with Ac20 (or other electrophiles) prior to extractive work-up.'" Lhemitte and Grierson: Enediyne based antiturnour antibiotics.Part 2 115232R1=H 235 R' = Me R' F I. M P B A ii. 71, PdO-CuI ill. oxldatbn I 'N iz z: 1 ie } R2 = C02Me 233 R' = H 236 R' = Me Scheme 45 Photochemical cleavage of the o-nitrobenzyl- carbamate protecting group in 238 proved to be a very effective way to generate and study the cycloaromatization chemistry of the derived amine. 109,110 Starting from the TBS ether 239 of 3-hydroxyquinoline, Magnus et al. achieved regioselective introduction of the entire enediyne chain giving 240 after cobalt carbonyl complexation (Scheme 46).I15 Providing nitromethane, a polar cation solvating solvent, was employed in the subsequent cyclization step (a Nicholas reaction), the desired product 241 was obtained in 43% yield. Liberation of the acetylene moiety gave the dynemicin analogue 242, which proved to be remarkably stable to Bergman cyclization compared to 94.In a closely related fashion formation of enediyne 244 from the 6-methoxyquinoline derivative 243 was achieved. However, the difficulty in accessing the starting material for this study led Magnus to conceive an alternative strategy involving epoxidation and selenoxide elimination (245 +246) to introduce the C-3 oxygen substituent (Scheme Two other relevant aspects of the chemistry of these dynemicin systems is the observed isomerization of the bridgehead selenoxide 247 to the corresponding selenite ester 249, via, most probably, the iminium quinomethide 248 (Scheme 48), and the discovery of a nonradical cycloaromatization pathway upon treatment of enediyne 242 with the thiolate ion (2424250, Scheme 49)."6,117 Recently, Takahashi has developed a promising new approach to the dynemicin system in which the 47).239 R' = H 243 R' = OMe A' 242 R' = H 244 R' = OMe Scheme 46 LJ 1 R' R' 241 Ado&, 8" ii. i. Ph2Se2, HP m-CPBA, NaBH4 K2C03 Ad02C&rp - SePh iii. TBSCl / / OMe 245 I OMe 246 m-CPBA, KzC03 (C0)3 1 OTBS N I R"O*C, q R' 240 Scheme 47 2,3-Wittig rearrangement reaction of 251 is employed to generate the tetrahydroquinoline intermediate 252 (Scheme 50)."* Dehydration of this intermediate to diene 253 (a Z,E:Z,Z mixture which is isomerized totally to Z,Z-253 using 12) opened the way to construction of compound 254, 116 Contemporary Organic Synthesisand its conversion to 255 in an intramolecular Diels-Alder reaction.Alternatively, compound 253 was reacted with dimethyl acetylenedicarboxylate in an intermolecular cycloaddition sequence to give the compound 256. Notice that both routes permit control of the C-2,4,7 stereochemistry. In a manner similar to Danishefsky (see Scheme 53), the i. Me02C-C02Me (3:2 mixture), 80% ii. m-CPBA iii. AgN03, NIS 60% AdOzC, p R = Se(0)Ph R 247 R = Se(0)Ph 249 R = OSePh Scheme 48 d= OSePh (pi TBS %OH Me02C, 255 Scheme 50 bis(iodoa1kyne) intermediate 256 was coupled with 2-bis( trimethylstanny1)et hylene to give the dynemicin analogue 257. workers have adapted their Diels-Alder approach in the enediyne field to access di-0-methyl dynemicin methyl ester 271. In the initial phase, In a very elegant fashion, Schreiber and co- 250 242 Scheme 49 TMS TMS I Me02C, T M S e M g B r \ -- ’ \\ CIC02Me (3:l mixture) 95% 251 TBS 252 :BS ii.DBU 67% i. MsCl iii. I2 1 h TMS iii. TsOH 254 68% iBS TBS 253 257 256 Lhermitte and Grierson: Enediyne based antiturnour antibiotics. Part 2 117i. (y-3 TBSO Me Pd’, 85% ii. BtMg SiMeThexyl iii. TBAF c OH Me Br 258 259 i. BrCH=CHC02Me BrCH=CHC02Me PdO4lI (cat.) w Br Me 260 i. Et3SiH I MeAICI2 ii. (COCl)2 iii. TMSOTf iv. D W 51% 261 CI c’v Cocl DMAP, 50% rTpyrmliiino 0s onium exa luorophosphate 51 % B201 1 s’ I OMe i. MeAIC12 ii. Mesityl-SO2NHNHp 4 262 263 R’ = OH, R2 = U-H, R3= ~ O B Z iii. Protect R‘ = H, R2 = &H, R3 = Me ,1 li.”c”A”N 92% I 90% 264 R0 OMe Br 267 AgOTf c ii. K2CO3, Me2S04 57% OMe 266 -0Me 268 OMe 265 i. mCPBA ii. DBU, MeOH iii. CAN - OMe OH OMe OMe OH 0 OMe 0 OH - - 270 269 271 Scheme 51 118 Contemporary Organic Synthesis3-bromo-6-met hoxyquinoline 258 was converted to the acyclic enediyne intermediate 259, which was in turn elaborated to compounds 260 and 261 (Scheme 51).'19 Subjection of these intermediates to conditions aimed at achieving macrocyclization led directly to formation of a common product 262, resulting from an apparent room temperature [4 + 21 cycloaddition.Further experimentation revealed the necessity to epimerize the lactone ring of 262 such that repositioning the double bond to the A-B ring junction position would produce the correct C-4 methyl stereochemistry. Thus, after N-protecting group modification, reaction with DBU and oxidation with CAN gave 263, which was reacted with EtAlCl, at low temperature followed by quenching with mesitylenesulfonylhydrazide. In this way the desired product 265 was produced via a [ 1,5]-sigmatropic rearrangement of the diazene intermediate 264.At this point the A-ring enol ester !i.g;,yg * Me0 # 0Me 04% Tf20 heat. 180°C_ @;:: / NHBoc m -CPBA \ OH 0 0 iii. Pdo, ArB(OH)* 272 273 bR3 274 R2 = OTf; R3 = Me [IIR2=H; R3=TBS S OTBS i. TsOH ii. (Im)&S 65% - OTBS 277 Bu3SnH, AlBN 97% 1 OTBS 278 i. C02, MgBr2. TEA ii. KOBu', MeOTf 49% i. mCPBA ii. TBAF iii. TBSCl iv. Swem oxidation v. KHMDS, CeCI3 rt All0 OMe OH OTBS 276 275 OTBS 0 279 280 PdO 60% (+)-dynemicin A 4 Scheme 52 OTMS 283 OTMS 282 KHMDS 0 281 Lhemitte und Grierson: Enediyne bused antiturnour antibiotics. Part 2 119system of 266 was elaborated by oxidative cleavage of the lactone ring, and the N-protecting group was further modified to enhance its base lability.Under precise conditions, the silver triflate promoted Freidel-Crafts reaction of 266 with 267 produced compounds 268 (1 : 1 mixture) in 57% yield. This intermediate was then converted to the hexacyclic ketol269 (51% overall) exploiting i. @:2 MOMO technology developed for a model system (see Scheme 39). In the final, delicate steps of the synthesis the epoxide unit was introduced, the D-ring nitrogen was deprotected, and the resultant intermediate was oxidized using CAN to give the target molecule 271. It is remarkable that the N- deprotected compound could be converted to the iminoquinone intermediate 270 before total loss of ii.Ph(OTFA)2 i. OsO.,, NMO ii. Ph2(0Me)2 1 M e 3 S n q SnMe3 TIPS ROAN 0 8 0: =OAc *oA&..okph \ ’-0 Ph (.&> OTBS OTBS *‘OAc 0 \ 0 OTBS 288 OTBS 287 COPMOM b Teoc, COZMOM iii. Dess-Mattin periodinane iv Cr2CI v.’C02 hfgBr, TEA vi. MOMCI OMe OMe OTBS OTBS 0 289 290 291 MOMO I (+)-dynemicin A 4 293 Scheme 53 120 Contemporary Organic Synthesisthe molecule occurred through the competing dynemicin cycloaromatization pathway. In their first synthesis of (+)-dynemicin A, Myers et al. settled the problem of the C-4 methyl stereochemistry in the first steps through the use of monochiral diketone 272 as the A-ring precursor (Scheme 52).lZ0 Pdo catalysed condensation of the enol triflate of this intermediate with tert-butyl- 2-borono-4-methoxycarbinolate gave compound 273, which was ring closed and converted to hydroxy ketal274.Introduction of the epoxide unit and enediyne bridge was then undertaken giving 276. Note that the alcohol function and one of the methoxy oxygens played a critical role in directing acetylene addition to the same face of 275 as the methyl substituent. At this juncture ketal deprotection and reaction of cyclic thiocarbonate 277 with tin hydride produced ketone 278. In a very expeditious manner this ketone was converted in two steps (COz, MgBr2, Et,N then KOBu', MeOTf) to the enol methyl ether carboxylic acid 279. Reaction of the desilylated phenol derivative of 279 with iodosobenzene afforded compound 280, which on N-deprotection was transformed to the stable quinone imine 281. To build up the A-B rings of dynemicin a series of different isobenzofurans derivatives were evaluated as Diels-Alder dienophiles. The combination which led to (+)-dynemicin A 4 involved cycloaddition of quinone imine 281 with the tris(trimethylsily1- oxy)isobenzofuran 282 followed by air oxidation and deprotection of the derived Diels-Alder adduct 283.In Danishefsky's total synthesis of ( f )-dynemicin, Diels-Alder chemistry was used in the initial steps to fix the stereochemistry of the C-4 and C-7 centres (Scheme 53).12' This involved Lewis acid mediated intramolecular cycloaddition of compound 284, oxidation of the derived hydroquinone 285 and B- ring closure giving 286. cis-Dihydroxylation of 286 and ketal formation encumbered the lower face of the molecule, thereby directing introduction of the acetylene at C-2 in the required fashion (7 : 1 mixture) to give 287.Seven steps were subsequently needed to construct the C-7 acetylene, modify the hydroxy protection and iodinate both alkyne units giving 288. In a new innovation brought to the dynemicin field, the enediyne bridge was then installed by Pdo coupling of 288 with 2- bis(trimethylstanny1)ethylene producing the enediyne product 289. After subsequent acetate cleavage and removal of the C-5 hydroxy group, the resultant intermediate, the C-5,6 enol ether-ester system of 290 was elaborated. 0-TBS deprotection and treatment with PhI(OAc)2 then produced the key iminoquinone product 291. The D-E rings were built onto this substrate through reaction with the lithium anion of the homophthalic anhydride 292, followed by oxidation of the derived adduct.Exposure of this product to oxygen and light followed by 0-MOM deprotection of quinone 293 completed the synthesis of dynemicin A 4. 6 Conclusion The total synthesis of dynemicin A by Myers and Danishefsky, like the accomplishments in the calicheamicin/esperamicin and neocarzinostatin area, marks just the beginning of what will be a rich harvest of knowledge which synthetic chemists will employ in the construction of the enediyne- and dienediyne-containing molecules that nature still has in waiting. 7 References and notes 1 N. Ishida, K. Miyazaki, K. Kumagai and M. Rikimaru, J. Antibiot., 1965, 18, 68; K. Edo, M. Mizugaki, Y. Koide, H. Seto, K. Furihata, N. Otake and N. Ishida, Tetrahedron Lett., 1985, 26, 331.2 M. D. Lee, T. S. Dunne, M. M. Siegel, C. C. Chang, G. 0. Morton and D. B. Borders, J. Am. Chem. SOC., 1987, 109,3464; M. D. Lee, T. S. Dunne, C. C. Chang, G. A. Ellestad, M. M. Siegel, G. 0. Morton, W. J. McGahren and D. B. Borders, J. Am. Chem. SOC., 1987, 109, 3466. 3 J. Golik, J. Clardy, G. Dubay, G. Groenewold, H. Kawaguchi, M. Konishi, B. Krishnan, H. Ohkuma, K.-I. Saitoh and T. W. Doyle, J. Am. Chem. SOC., 1987, 109, 3461; J. Golik, G. Dubay, G. Groenewold, H. Kawaguchi, M. Konishi, B. Krishnan, H. Ohkuma, K.-I. Saitoh and T. W. Doyle, J. Am. Chem. SOC., 1987, 109,3462. 4 M. Konishi, H. Ohkuma, T. Tsuno, T. Oki, G. D. VanDuyne and J. Clardy, J. Am. Chem. Soc., 1990, 112,3715. 5 G. Pratviel, J. Bernadou and B. Meunier, Angew. Chem., Int.Ed. Engl., 1995, 34, 746; Enediyne Antibiotics as Antitumor Agents, ed. D. B. Broders and T. W. Doyle, Marcel Dekker, New York, 1994. 6 See Part 1 of this review: H. Lhermitte and D. S. Grierson, Contemp. 0%. Synth., 1996,3,41. 7 R. R. Jones and R. G. Bergman, J. Am. Chem. SOC., 1972, 94,660; R. G. Bergman, Acc. Chem. Res., 1973, 6, 25; T. P. Lockhart, P. B. Comita and R. G. Bergman, J. Am. Chem. SOC., 1981, 103, 4082; T. P. Lockhart and R. G. Bergman, J. Am. Chem. SOC., 1981, 103, 4091. 8 A. G. Myers, Tetrahedron Lett., 1987, 28, 4493; I. H. Goldberg,Acc. Chem. Res., 1991, 24, 191. 9 P. A. Wender, M. Harmata, D. Jeffrey, C. Mukai and J. Suffert, Tetrahedron Lett., 1988, 29, 909. review.'j 23. Chem. SOC., 1990, 112,5369. Mah, Tetrahedron Lett., 1990, 31, 6605.J. Am. Chem. SOC., 1977, 99, 3179. Lett., 1990, 31, 3533. 3465. Yamada, T. Shiraki and Y. Sugiura, Angew. Chem., Int. Ed. Engl,, 1993, 32, 1657. 10 See Scheme 36 and reference 74 in Part 1 of this 11 K. Mikami, H. Matsueda and T. Nakai, Synlett, 1993, 12 P. A. Wender, J. A. McKinney and C. Mukai, J. Am. 13 P. A. Wender, J. W. Grissom, U. Hoffmann and R. 14 Y. Okude, S. Hirano, T. Hiyama and H. Nozaki, 15 A. Krebs, T. Wehlage and C.-P. Kramer, Tetrahedron 16 T. Doi and T. Takahashi, J. OR. Chem., 1991,56, 17 T. Takahashi, H. Tanaka, Y. Hirai, T. Doi, H. 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SOC., 1995,117,8074. 57 Syntheses of the C-ring, the D-ring and the C-D ring fragment of calicheamicin 2 include: K. C. Nicolaou, T. Ebata, N. A. Stylianides, R. D. Groneberg and P. J. Carro1,Angew. Chem., Int. Ed. Engl., 1988, 27, 1097; K. V. Laak and H.-D. Scharf, Tetrahedron, 1989, 45,5511; K. V. Laak, H. Rainer and H.-D. Scharf, Etrahedron Lett., 1990,31, 4113; S. H. Olson and S. J.Danishefsky, Tetrahedron Lett., 1994,30, 7901; see also: references 61,69 and 74. 58 Two syntheses of the A-ring sugar equipped with the C-4 hydroxylamine substituent have also been developed: H. Rainer and H.-D. Scharf, Liebigs Ann. Chem., 1993, 117; see also: Golik et al., reference 60. 59 For preparation of the C-D aryl monosaccharide unit in esperamicin 3; see reference 73. 60 In instances where the C-4 hydroxylamine nitrogen and the anomeric centre in ring A are unprotected, very facile rearrangement to a nitrone intermediate occurs: J. Golik, H. Wong, B. Krishnan, D. M. Vyas and T. W. 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Y. Chu- Moyer, S. H. Boyer, S. H. Olson and S. J. Danishefsky, J. Am. Chem. SOC., 1995, 117, 5750. 83 For papers on the enzymatic resolution of synthetic intermediates toward calicheamicinone, see: D. S. Yamashita, V. P. Rocco and S. J. Danishefsky, Tetrahedron Lett., 1991,32, 6667; V.P. Rocco, S. J. Danishefsky and G . K. Schulte, Tetrahedron Lett., 1991,32,6671. 84 Concerning the reactivity of compounds related to calicheamicin precursor 180, see also: K. C. Nicolaou, T. Li, M. Nakada, C. W. Hummel, A. Hiatt and W. Wrasidlo,Angew. Chem., Int. Ed. Engl., 1994,33, 183. 85 T. Nishikawa, M. Isobe and T. Goto, Synlett, 1991, 393. 86 M. E. Maier and U. Abel, Synlett, 1994, 38. 87 T. Nishikawa and M. Isobe, Tetrahedron, 1994, 50, 5621. 88 H. Chikashita, J. A. Porco Jr, T. J. Stout, J. Clardy and S. L. Schreiber, J. 0%. Chem., 1991,56, 1692. 89 K. C. Nicolaou, J. L. Gross, M. A. Kerr, R. H. Lemus, K. Ikeda and K. Ohe, Angew. Chem., Int. Ed. Engl., 1994,33, 781. 90 M. Magnus, S. A. 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ISSN:1350-4894    

DOI:10.1039/CO9960300093

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

The discovery of fluconazole KEN RICHARDSON Central Research, pfizer Limited, Sandwich, Kent CT13 9NJ, UK Reviewing the literature up to December 1994 1 2 Lead discovery 3 Synthetic chemistry 4 Summary 5 References Background on the fungal diseases 1 Background on the fungal diseases The treatment of fungal infections, particularly in immune-compromised patients, is an increasingly difficult problem facing the medical profession.’ Fungi are all around us. They are present in the soil, in the air and in most peoples gastrointestinal tracts, but they don’t usually cause serious problems because our natural defence system protects us. However, there are a growing number of patients who have deficient immune systems and they are at risk of life threatening infections.’ The patients particularly at risk are those being treated for leukaemia and certain types of cancer, and those receiving organ transplants.In addition, AIDS patients are particularly susceptible to fungal infections. In the early 1970s a research programme was set up at Pfizer Central Research in Sandwich with the objective of discovering a drug to treat serious systemic fungal infections. Although the incidence of such infections was quite low at that time, we believed that there would be increasing numbers of susceptible patients in the future. Advances in medical practice, such as organ and bone marrow transplantation, and increasingly aggressive cancer chemotherapy were resulting in a slow but sure increase in the number of serious fungal infection^.^-^ had made the search for safe and effective antifungal drugs very difficult.The only available drugs at the time were amphotericin B and 5-fluorocytosine. Amphotericin B 1 is a polyene antibiotic which binds to the fungal sterol ergosterol 4, in the cell membrane, and promotes the loss of vital ions from the cell. Unfortunately, amphotericin also has affinity for the mammalian sterol cholesterol and this lack of selectivity results in a number of side-effects in man, including shaking, chills, fever, nausea and renal failure6 These side- The very similar biochemistry of fungi and man effects, together with the fact that amphotericin has to be given by intravenous infusion over several hours, made clinicians reluctant to use it and frequently amphotericin was used as a last resort, when it was too late.The only other widely available systemically-effective drug was 5-fluorocytosine 2, which had the major advantages of good oral bioavailability and low toxicity, but was only active against a limited range of fungi and resistance frequently arose during long-term treatment.7 OH HO ..OH H Hod.:: OH OH COOH HO’ NH* amphotericin B 1 y 2 O J h +JF H Sfluorocytosine 2 Clearly, there was a need for a safe, effective agent that could be given on suspicion of a fungal infection and we felt that demand would increase in the future. We believed that the ideal agent would be one that could be administered both orally and intravenously because, although the oral route would be most frequently used, certain cancer patients had difficulty with oral dosing and the availability of an intravenous dosage form would therefore be a considerable advantage. We also wanted our agent to be effective against a wide range of fungal species and it must have a good safety profile.We believed that an agent with these properties would represent a considerable advance in antifungal chemotherapy, and would be used extensively . 2 Lead discovery There were a number of potential chemical starting points for our research programme because many Richardson: The discovery of jhconazole 125different structural classes had been reported to show antifungal activity. However, most of these chemicals were not selective for fungi and so we chose to work on imidazole compounds because these were known8 to possess potent and selective in vitro activity against a wide range of fungal pathogens.Their antifungal action was known to be due to inhibition of fungal C-14 demethylase (Scheme l), a cytochrome P450-containing enzyme essential for the production of the principal fungal sterol ergosterol 4.9 Ergosterol is essential for the fluidity of the fungal membrane, and therefore the viability of fungi. H =-- lanosterol 3 I H O W **, H demethylate I - ergosterol 4 Scheme 1 / The imidazole compounds could be remarkably selective for the fungal C-14 demethylase, rather than the closely related mammalian enzyme, which encouraged us to believe that these compounds were inherently safe. Our early work led to tioconazole 5, which proved to be very effective clinically when administered topically against fungal infection of the skin and the vagina.' However, it was poorly effective in animal models of fungal infections when administered by either the oral or intravenous routes.Our studies suggested that these imidazole antifungals were highly susceptible to metabolic inactivation, resulting in low oral bioavailability and low, poorly-sustained plasma levels. In addition, tioconazole was lipophilic (log P - 5 ) and highly bound to plasma proteins resulting in very low circulating levels of the unbound, active form. Therefore, the approach that we decided to adopt was to make the compounds as metabolically stable as possible whilst minimising their overall lipophilicity. We believed that metabolic stability would lead to improved oral bioavailability, while reduced lipophilicity would result in lower protein binding, with the overall effect of producing high sustained plasma levels of unbound drug.Cl (f)-tioconazole 5 Our initial modifications of tioconazole included introduction of a range of polar-substituted alkyl, phenyl and heterocyclic groups in place of the chlorothiophene moiety, as an approach to compounds with reduced lipophilicity. Some progress was being made but our plans were modified following the report that orally adminis- tered ketoconazole 6 was active in several animal models of fungal infection." Examination of ketoconazole showed that although it was less metabolically vulnerable than earlier imidazole antifungal derivatives, resulting in good oral bioavailability, it was still vulnerable to metabolism and very low levels of unchanged drug were excreted in the urine.Ketoconazole was also less lipophilic than earlier imidazole derivatives, resulting in higher blood levels, but it was still highly bound to plasma proteins, with < 1% being in the unbound form. Clearly, ketoconazole was an important advance from the earlier imidazole antifungal derivatives2 but it left considerable scope for improvement" and fell short of the target that we had set ourselves. (Ketoconazole 6 has a cis arrangement of the imidazole and substituted phenolry group and, like tioconazole, is a racemic mixture). CI (*)-ketoconazole 6 3 26 Contemporary Organic SynthesisKetoconazole was, however, an important structure-activity step and our plans were adjusted to take account of it.We prepared a range of structural types which were influenced by the structure of ketoconazole, including the dioxolanes, dithiolanes, tetrahydrofurans and hydroxy deriva- tives shown in Figure 1. We investigated a wide range of modifications as we pursued our goal of reduced lipophilicity and increased metabolic stability. The introduction of polar functionality such as carboxamide, sulfone, nitrile and polar heterocycles was usually well tolerated, but ionised groups such as amino and carboxylic acid resulted in a marked loss of both in vitro and in vivo antifungal activity. non-cyclic series and was therefore most structurally-distinct from ketoconazole, the presence of a hydroxy group lowered the lipophilicity, and this series was readily synthesised and therefore ideas could be rapidly evaluated.compounds (Figure 2) and many showed ketoconazole-like activity, but we were unable to improve upon the in vivo activity of ketoconazole. Pharmacokinetic evaluation of 30 of these derivatives in the mouse showed that, despite the wide range of structural variations, they all remained metabolically-vulnerable and had, at best, a ketoconazole-like pharmacokinetic profile, with a half-life of - 1 hour and < 1% being excreted unchanged in urine. Over the following year, we prepared almost 300 OH OH Cl 7 CI 8 CI 0 Figure 1 Cl 10 In vitro activity was assessed on agar plates" against all of the major fungal pathogens (Candidu, Cryptococcus, Aspergillus and dermatophytes). In vivo efficacy was evaluated initially against a systemic Candidu infection in mice, where animals had been given a potentially lethal infection and test compounds could be given either orally or by intravenous inje~ti0n.l~ Efficacy was assessed when all saline-treated animals were dead, and the dose of compound required to protect 50% of the animals was calculated.Ketoconazole was used as a comparative agent, and compounds showing ketoconazole-like levels of activity were progressed to studies in other animal models, including those in immune-suppressed animals. Particularly good compounds were also advanced to pharmacokinetic studies in mice and dogs. In each of the structural series shown in Figure 1, it proved possible to obtain compounds showing in vivo efficacy similar to that of ketoconazole, but none of these derivatives showed the clear advantage that we were seeking. In order to increase our rate of progress we decided to concentrate our efforts on one series, the hydroxy series.We chose this series because it was the only Figure 2 The only consistent structural feature of all the compounds that we had synthesised was the presence of the imidazole moiety and we therefore concluded that it was possible that this group could be one of the reasons for the metabolic vulnerability of these compounds. This view received support from our discovery that in tioconazole the imidazole group was a site for metabolic inactivation, as we later rep~rted.'~ We therefore came to the conclusion that the imidazole had to be replaced and we chose a range of groups (Figure 3) which we believed might interact with cytochrome P450, in place of the imidazole unit.We chose this particular series to evaluate potential replacements because compounds were readily synthesised, as shown and the corresponding imidazole derivative demonstrated in vitro and in vivo activity equivalent to that of ketoconazole. Therefore, we believed that qcl Cl Figure 3 Richardson: The discovery of JEuconazole 127any improvement in metabolic stability would lead to in vivo efficacy superior to that of ketoconazole. Twenty groups were examined as potential replacements, including a range of substituted imidazole derivatives, several other heterocycles and a number of basic groups, but the only group offering encouragement was 1,2,4-triazole when attached by the 1-position.Replacement of imidazole by a 1,2,4-triazol-l-y1 unit gave UK-46,245 11 which was twice as potent in our standard murine systemic candidosis model as the corresponding imidazole analogue, despite being approximately six times less potent against Candida in vitro. These data suggested that the triazole group was less susceptible to metabolic inactivation than an imidazole moiety, but yet it retained the ability to interact with the cytochrome P450 unit in the fungal C-14 demethylase enzyme. However, in UK-46,245 there remained a lipophilic, metabolically-vulnerable hexyl group and therefore we considered how we could replace this moiety and achieve our original objective of a compound which would combine good metabolic stability with low lipophilicity.A number of potential replacements were chosen but the first to be aamined was a 1,2,4-triazol-l-y1 unit to yield the symmetrical bis-triazole compound UK-47,265 12. CI UK-46,245 11 Cl UK-47,265 12 UK-47,265 was a most remarkable compound! When examined in the mouse systemic candidosis model it was almost 100 times more potent than ketoconazole following administration by either oral or intravenous dosing. This level of activity was completely unprecedented. Further evaluation against vaginal candidosis in mice and rats and against dermatophytosis in mice and guinea pigs showed impressive efficacy, as did examination against systemic candidosis in immune-compromised mice and rats. These findings were even more remarkable when it was shown that UK-47,265 had only modest activity against fungi when examined using standard in vitro assay methods." Pharmacokinetic studies in rodents indicated that the in vivo activity was not due to the formation of active metabolites since UK-47,265 was extremely stable, showing high and persistent levels of unchanged drug with approximately 30% being excreted intact in the urine, in marked contrast to the < 1% observed with ketoconazole.'6 efficacy was well recognised with the imidazole This poor correlation between in vitro and in vivo antifungal compounds, and UK-47,265 appeared to represent a rather extreme example.However, we believed that in vitro assessment of antifungal activity would be essential for the development of UK-47,265, since it would be necessary to examine its activity against many clinical isolates and against examples of all important species of fungal pathogens. Therefore, we commenced an investigation of the possible reasons for the very low levels of in vitro antifungal activity seen with this compound.The activity of UK-47,265 in over 30 different agar and liquid-based growth media was evaluated and it became clear that complex media, especially those containing peptones, antagonised the activity of UK-47,265 whereas good in vitro activity was observed when a tissue culture-based medium similar to SAAMF medium17 was used. UK-47,265 showed outstanding activity in a wide range of systemic and superficial infection models. The systemic infections were due to Candida, Cryptococcus and Aspergillus species, and were in a range of infection sites including the kidney, liver, brain, gut and lung.The animals used were both normal and those which had been immune- compromised with immune suppressants which are used in patients such as cyclophosphamide and steroids. The superficial infections were dermatophytosis in mice and guinea pigs, and vaginal candidosis in mice and rats. Pharmacokinetic evaluation in several species (mouse, rat, guinea pig, rabbit, dog) showed excellent oral bioavailability together with a long plasma half-life and therefore UK-47,265 was progressed into pre-clinical safety evaluation. The results were extremely disappointing since UK-47,265 proved to be hepatotoxic in mice and dogs, and teratogenic in rats. This obviously precluded further progression and we therefore turned our attention to the search for a replacement.antifungal, pharmacokinetic and safety studies, an intensive follow-up programme had been in progress resulting in the synthesis of over 100 bis-triazole analogues. All of the derivatives were examined in the mouse model of systemic candidosis and a particularly interesting series of compounds resulted from replacement of the dichlorophenyl moiety by a range of aryl and heteroaryl groups (Table 1). Many of these derivatives showed very good in vivo anti- Candida activity and the best of these were progressed to evaluation in mouse models of vaginal candidosis and dermatophytosis (Table 2). The best three compounds, the 2,4-difluorophenyl, 2-chloro- 4-fluorophenyl and 4-chlorophenyl analogues were progressed to pharmacokinetic evaluation in the mouse (Table 3) and the outstanding compound was obviously the 2,4-difluorophenyl analogue.It had a plasma half-life of 5.1 hours, 75% of drug was excreted unchanged in the urine and, in addition, it was water-soluble (8 mg ml-' at room temperature), a property that would greatly facilitate its formulation for intravenous administration. This derivative, UK-49,858, showed outstanding activity While UK-47,265 was being evaluated in 128 Contemporary Organic SynthesisTable 1 OH Table 2 R f$F($, F 'bF F hF hF F F 4 F 4 F F CI Br Cl Cl ~ F CF3 I CI F CI F F Me OMe OH CF3 I Cl F F F F Table 3 R +cl F Tlkmice 3.6 % in urine (h) 29.4 Water solubility <1 (mg rn1-l) F 5.1 75 8 CI 4.0 12.5 <1 in our full range of fungal infection models in both animals with normal immune function and those with suppressed immune fun~tion.'~''~ Safety evaluation showed that UK-49,858 13, now known F lluconazole 13 (UK-49,858) as fluconazole, was not teratogenic or hepatotoxic and it was therefore progressed to studies in man.excellent oral absorption, and food did not affect the bioavailability. The plasma half-life was approximately 30 hours leading to predictable accumulation following daily dosing, with a steady state being reached within 4-5 days.'' Approxi- mately 90% of orally-administered fluconazole was excreted unchanged in the urine, as predicted from studies in animals, and there were no adverse side- effects. Fluconazole was therefore progressed to evaluation against fungal infections in man.with acute vaginal candidosis, with half being given a 150 mg single oral dose of fluconazole and half being dosed intravaginally (200 mg daily for three consecutive days) with commercial Canesten (chlotrimazole 14) vaginal tablets. Both drugs In healthy human volunteers, fluconazole showed Initial efficacy studies were carried out in patients Ph ' "Ph chlotrimazole 14 Richardson: The discovery of JEuconazole 129produced excellent clinical responses (Fluconazole 100%; Canesten 97%) with no side-effects:’ and therefore fluconazole was progressed to studies in immune-compromised patients. The large majority of these were AIDS patients with oropharyngeal candidosis infections and ‘spectacular’ clinical efficacy was reported, with a 100% success rate after 5-7 days treatmenfl and there were no clinically significant side-effects.A later studf showed that fluconazole was more co$t effective than either ketoconazole or ketoconazole 6 followed by fluconazole in HIV-positive patients. These extremely promising results encouraged progression to studies of potentially life-threatening infections. Cohen2” reported the treatment of Candida infections in five patients who were immune-suppressed because of chemotherapy for cancer or after organ transplantation, and all five patients were cured of their infections after two weeks of therapy. Further studies showed very good efficacy against Candida infections at a wide range of body sites in AIDS, cancer, leukaemia and organ transplant fungal infection in up to 30% of AIDS patients, and Dupont and Drouhet28 achieved remarkable clinical success with fluconazole, which was confirmed by Dismukes et aZ.29 A recent study”’ showed that fluconazole combined with 5-fluorocytosine 2 led to improved clinical success compared with either fluconazole alone or amphotericin B 1 alone.Patients with AIDS will require some form of maintenance antifungal therapy to prevent relapsel re-infection and a stud?’ showed that prophylaxis with fluconazole was highly effective and fluconazole is now the drug of choice for these patients. Fluconazole (orally) was recently shown to be superior to weekly intravenous amphotericin B as therapy to prevent relapse in AIDS patients with cryptococcal meningitis, after primary treatment with amphotericin B.”’ Cryptococcal meningitis is a life-threatening 3 Synthetic chemistry Synthesis of the imidazole derivatives went via the key keto-derivative UK-10,990 15. This was readily synthesised and easily manipulated to give access to several series of active compounds (Scheme 2).The change to triazole derivatives increased the chemical difficulty because of the opportunity for the triazole to react at both the 1- and 4-positions. In all cases, the product resulting from reaction at the l-position dominated, but a significant amount of the 4-substituted product was always produced, and had to be removed by either chromatography or crystallisation. The overall yield of the bis-triazole derivatives was approximately 20% in each case. with the usual ones being as shown in Scheme 3.The bis-triazoles can be formed in three positional isomers, namely 1,4-, 1,l- and 4,4-bis-triazoles. Only the compounds with both triazoles attached through The bis-triazoles were prepared by several routes, R Cl CI CI UK-l0,990 15 I CI OH R CI N3T Cl Scheme 2 the l-position showed good in vivo antifungal activity. 4 Summary The discovery of fluconazole serves to illustrate several important points. It demonstrates how long the discovery of a drug can take, since it was almost 20 years from the start of the programme until its market launch in 1988. It also shows how one can take a very potent and selective agent like tioconazole 5, and modify it to overcome its weaknesses of high lipophilicity and metabolic vulnerability. In the process, almost every aspect of tioconazole’s structure has been modified, as can be seen by an examination of their chemical structures (below).It also demonstrates that, occasionally in drug discovery one may achieve more than one realised was possible. When we started the research programme that eventually led to fluconazole, we believed that by lowering lipophilicity and decreasing metabolic vulnerability we would obtain a significant improvement in antifungal efficacy. We had not anticipated that such a remarkable 130 Contemporary Organic SynthesisCI-fO R triazole EtOAc reflux NEt3 - N PyY0 W N R OH DMF BULL Et20 R .MF R = b’ F Scheme 3 tiaconazole 5 CI i fluconazole 13 (UK-49,858) \ OH combination of efficacy, safety and outstanding pharmacokinetic properties would result.Acknowledgements The author wishes to acknowledge scientific colleagues and collaborators, too many to mention individually, for their invaluable contributions to the fluconazole programme in all its phases. 5 References P. A. Robinson, A. K. Knirsch and J. A. Joseph, Rev. lnfect. Dis., 1990, 12, 5439. J. Heeres, in Medicinal Chemistry. The Role of Organic Chemistry in Drug Research, ed. S. M. Roberts and B. J. Price, Academic Press, London, 1985, p. 249. T. Eilard and R. Norrby, Scand. J. Infect. Dis., 1978 (Suppl. 16), 15. P. Hart, E. Russel and J. Remington, J. Infect. Dis., 1969, 120, 169. R. C. Young, J. E. Bennett, G. Geelhoed and A. S . Levine,Ann. Intern. Med., 1974, 80, 605. M. S. Maddux and S. L. Barriere, Drug Intell. Clin. Pharm., 1980, 14, 177.E. R. Block, A. E. Jennings and J. S . Bennett, Antimicrob. Agents Chemother., 1973, 3, 649. Richardson: The discovery of fluconatole 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 S. Jevons, G. E. Gymer, K. W. Brammer, D. A. Cox and M. R. G. Leeming, Antimicrob. Agents Chemother., 1979, 15, 597. H. Van den Bossche, G. Willemsens, W. Cools, W. F. J. Lauwers and L. LeJeune, Chem.-Biol. Interact., 1978, 21, 59. D. Thienpont, J. Van Cutsem, F. Van Gerven, J. Heeres and P. A. J. Janssen, Experentia, 1979,35, 606. R. J. Holt, in Antifungal Chemotherapy, ed. D. C. E. Speller, John Wiley, New York, 1980, p. 107. G. S. Kobayashi and G. Medoff, in Fungi Pathogenic for Humans and Animals, ed. D. H. Howard, Marcel Dekker Inc., New York, 1983, p. 357. K. Richardson, K.W. Brammer, M. S. Marriott and P. F. Troke, Antimicrob. Agents Chemother., 1985,27, 832. P. V. Macrae, M. Kinns, F. S. Pullen and M. H. Tarbit, Drug Metab. and Dispos., 1990, 18, 1100. P. F. Troke, R. J. Andrews, G. W. Pye and K. Richardson, Rev. Infect. Dis., 1990, 12 (Suppl. 3), S276. K. Richardson, K. Cooper, M. S . Marriott, M. H. Tarbit, P. F. Troke and P. J. Whittle, Rev. Infect. Dis., 1990, 12 (Suppl. 3), S267. P. D. Hoeprich and P. D. Finn, J. Infect. Dis., 1972, 126, 353. P. F. Troke, R. J. Andrews, K. W. Brammer, M. S. Marriott and K. Richardson, Antimicrob. Agents Chemother., 1985, 28, 815. K. W. Brammer, P. R. Farrow and J. K. Faulkner, Rev. Infect. Dis., 1990, 12 (Suppl. 3), S318. K. W. Brammer and L. J. Lees, in Recent Trends in the Discovery, Development and Evaluation of Antifungal Agents, ed. R. A. Fromtling, J. R. Prous, Barcelona, 1987, p. 151. B. Dupont and E. Drouhet, J. Med. Vet. Mycol., 1988, 26, 67. L. Rabeneck and L. Laine, Arch. Intern. Med., 1994, 154,2705. J. Cohen, J. Antimicrob. Chemother., 1989, 23, 294. P. Kujath and K. Lerch, Infection, 1989, 17, 111. J. W. Van’t Wout, H. Mattie and R. van Furth, J. Antimicrob. Chemother., 1988, 21, 655. F. M. Gritti, E. Raise, L. Bonazzi, V. Vannini, G. Di Giandomenico, G. Lanzoni and A. M. Cucci, Cun: Ther: Res., 1990, 47, 1049. 13127 C. A. Kauffman, S. F. Bradley, S. C. Ross and D. R. Weber, Am. J. Med., 1991,91, 137. 28 B. Dupont and E. Drouhet,Ann. Intern. Med., 1987, 106, 778. 29 W. Dismukes, G. Cloud, S. Thompson, A. Sugar and C. Tuazon, in Proceedings of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy at Houston, American Society for Microbiology, 1325 Massachusetts Avenue, NW, Washington DC 20005, 1989, Abstract 1065. 1992,326,793. 30 R. A. Larson, S. A. Bazette, B. E. Jones, D. Haghighat, M. A. Leal, D. Forthal, M. Bauer, J. G. Tilles, J. A. McCutchan and J. M. Leedom, Clin. Infect. Dis., 1994, 19, 741. 31 R. D. Diamond, Rev. Infect. Dis., 1991, 13,480. 32 W. G. Powderly, M. S. Saag, G. A. Cloud, P. Robinson, R. D. Meyer, J. M. Jacobson, J. R. Graybill, A. M. Sugar, V. J. McAuliffe, S. E. Follansbee, C. U. Tuazon, J. J. Stern, J. Feinberg, R. Hafner and W. E. Dismukes, New England J. Med., 132 Contemporary Organic Synthesis

ISSN:1350-4894    

DOI:10.1039/CO9960300125

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Organic halides STEPHEN P. MARSDEN Department of Chemistry, Imperial College of Science, Technology and Medicine, London SW7 2Ax UK Reviewing the literature published between 1 July 1994and30June1995 Continuing the coverage in Contemporary Organic Synthesis, 1995,2, 85 1 2 2.1 2.2 2.3 2.4 3 3.1 3.2 3.3 3.4 4 4.1 4.2 5 6 7 8 9 9.1 9.2 9.3 10 Introduction Alkyl halides By halogenation of alkanes By halogenation of alkenes By nucleophilic substitution By other methods Vinyl halides From alkynes From other vinyl derivatives By C=C bond formation By other methods Aryl halides By electrophilic substitution By nucleophilic substitution Alkynyl halides 1,1 -Dihalo compounds 1,l-Halohydrins and related compounds 1,2-Dihalo compounds 1,2-Halohydrins and related compounds By addition to alkenes By epoxide opening By other methods References 1 Introduction This review presents developments in the synthesis of organic halides which have appeared in the literature between 1 July 1994 and 30 June 1995.The strategic importance of organic halides as synthetic intermediates or as compounds in their own right is undiminished, and is reflected in the vast number of new or improved methods for their preparation since the last review in this series.' The methods highlighted here have been chosen as those most likely to gain recognition from the synthetic chemist, or those offering economic and/or environmental advantages over existing methods. As in the previous reviews,"2 the chemistry of perfluoroalkyl and hypervalent iodine compounds will not be discussed. A number of review articles covering aspects of organic halide chemistry have been published this year.These include articles concerning the bromination of olefins3 and synthetic applications of a-monohalo ether^.^ Additionally, advances in the synthesis of fluorinated heterocycles' and amino acids6 have both been reviewed, as have the synthetic applications of xenon difluoride7 and complexes of hydrogen fluoride.' fluorinating agents have been reported this year. Triphenylphosphine difluoride ( Ph3PF2) has been prepared in good yield by the ultrasonification of triphenylphosphine and potassium hydrogen fluoride in the presence of diisopropyl azodi~arboxylate,~ while anodic oxidation of aryl iodides in the presence of triethylamine/HF complex results in the formation of hypervalent iodobenzene difluoride derivatives." Additionally, DeShong has introduced tetrabutylammonium (triphenylsily1)- difluorosilicate [Bu4N+ (Ph3SiF2) -, TBAT] as a non- hygroscopic equivalent of tetrabutylammonium fluoride (TBAF)." Yields of a range of nucleophilic substitution reactions carried out with the new reagent were at least comparable to, and in many cases outstripped, those obtained with TBAF or potassium fluoride as the fluoride source. Another new, highly reactive nucleophilic fluoride ion source is cobaltocenium fluoride ( [Cp2Co]F), prepared by the reaction of cobaltocene with perfluorodecalin.'2 This reagent rapidly displaces chloride from alkyl or acyl chlorides and polychlorinated aromatics to yield the corresponding fluorides.Additions to the battery of polymer supported reagents include: (i) poly(styrene/4-~inylpyridine) supported bromine, which gave excellent yields in bromine addition to styrene derivatives, para- bromination of anisole and side chain bromination of toluene;13 and (ii) polystyryl diphenylphosphino iodine, which has been used in the efficient conversion of amino alcohols into P-iodoamines. l4 Convenient preparations of two useful 2 Alkyl halides 2.1 By halogenation of alkanes Reports on the halogenation of unactivated alkanes include a study of the iron(1rr) picolinate catalysed bromination of cyclooctane by bromotrichloro- methane from the Barton group,I3 and an interesting cobalt(1r) porphyrin mediated chlorination of alkanes using sulfuryl chloride.16 The regioselectivity of chlorination in the latter case was Marsden: Organic halides 133best explained by the intermediacy of an alkyl cobalt selectivity Cook (111) and species. of co-workers bromination examined of several the N-protected regio- &oTE::oT;:: * $0 then PhMe3N' Br3- 93% 3-methylimidazoles, achieving excellent regiocontrol (Scheme 1).l7 for side chain or ring bromination in some cases A# Scheme 3 TBDMSO * 9- "TBDMS b) a) NBS, NBS,CCl, CCl, , AlBN or Y 0 7 7 " -a77 Boc Boc a) X = H; Y = Br 95% TBDMSO b) X=Br;Y=H 92% LiN(SiMe& FN(PhS02)2 TBDMSO THF, -78 'C eF 95% "TBDMS 0 "TBDMS 9 Scheme 1 The synthesis of a-halocarbonyl compounds continues to be of interest. Moderate to good regiocontrol in the direct bromination of unsymmetrical ketones can be achieved by varying the order of addition of the reagents." Thus, addition of bromine to the ketone in refluxing methanol favours bromination at the least hindered carbon, while the more hindered carbon is brominated by addition of the ketone to a solution of bromine.An indirect but more rigorous solution to the problem of regiocontrol in bromination utilises P-keto-tert-butyl esters, the enolate of which Scheme 4 i) NaOMe, MeOH, 65 "C ii) AcOF, CFCS 00% Scheme 5 may be brominated with NBS and decarboxylated under anhydrous acidic conditions to furnish the unsymmetrical bromoketone (Scheme 2).19 The regioselective a-bromination of enones has been achieved in a one pot process, involving the quenching of a silyl enol ether with 0 0 Ph > QH*, PhCH:, 45% I Br Scheme 2 phenyl(trimethy1)ammonium tribromide.20 The latter brominating agent is sufficiently mild that the reaction is successful in the presence of additional unsaturation in the molecule (Scheme 3).A report in the Japanese patent literature shows that the a-iodination of amides may be achieved in the presence of remote olefins using iodine and 2,4,6-~ollidine.~~ In the area of diastereoselective halogenation of enolates, trapping of the lithium enolate of a 2-substituted cyclohexanone with N- fluorobenzenesulfonimide (PhSO,),NF gave exclusively the 2,6-trans-isomers in the synthesis of a fluorinated tribactam (Scheme 4),'* while modest control of the stereochemistry of bromination of ketones bearing the DiTOX auxiliary was shown to be possible through judicious choice of enolising agent.23 Related to the halogenation of enols and enolates, the fluorination of a nitro-stabilised anion using acetyl hypofluorite has been reported this year (Scheme 5).24 The fluorination of 173-dicarbonyl compounds has been achieved directly with gaseous fluorine (Scheme 6),25 and by the reaction of the derived enolates with the Selectfluor reagent (Scheme 7).26 Electrochemical oxidation of a-arylthio ketones and esters27728 and amide~*~ may be achieved using the triethylamine/hydrogen fluoride complex as an electrolyte (Scheme 8).The mechanism is proposed to involve the Pummerer-like rearrangement of a fluorosulfonium cation. t 80% Scheme 6 I- 10% 0 0 0 0 71% Scheme 7 Phs Phs Anodic oxidatbn EtH3HF. CH3CN 0 &\ Bn 92%J Scheme 8 134 Contemporary Organic Synthesis2.2 By halogenation of alkenes There have been some interesting developments in the area of atom transfer carbon-halogen addition to alkenes.Hiemstra and Speckamp have reviewed their success in the copper catalysed cyclisation of o-alkenyl di- and tri-chloroa~etates~~ and reported the high yielding synthesis of eight- and nine- membered lactones by this method.31 A related intermolecular coupling, utilising a copper(I)/iron couple, was also successful (Scheme 9),32 as was the photolytic radical atom transfer cyclisation of an o-alkenyl-a-iodo-nitro 58% Scheme 9 Taguchi has investigated two approaches to asymmetric iodocarbocyclisation reactions. The use of chiral ester groups as auxiliaries allowed the preparation of a cyclopropyl iodide with a good diastereoisomeric excess (Scheme while a chiral titanium catalyst promoted the analogous construction of a cyclopentane with a 76% enantiomeric excess (Scheme ll).35 R' = (-)-8-phenylmenthyl Scheme 10 Scheme 11 89% 30 : 1 CUO, 12, CH&I2 -78 OC to 0 OC 100% 76% ee Transition metal mediated cyclisations coupled with a halogen quench continue to be a valuable method for the construction of complex alkyl halides.In one such example, Luker and Whitby demonstrated a remarkable one pot sequence of reactions mediated by the Negishi reagent, leading to a highly functionalised iodide in excellent yield (Scheme 12).36 Halide ion terminated electrophilic olefin cyclisation reactions have also received much attention this year, leading to syntheses of halogenated tetrahydr~pyrans,'~ cy~lopentanes~~ and fused bicyclic systems (Scheme 13).39 The electrochemical difluorination of an enol camphanate ester followed by separation of the diastereoisomeric products and careful hydrolysis i) CP2ZTBU2 N) I2 ii) 1 -chbrel -1hhio-prop2-ene iii) PhCHO, B F & @ i - H OH I aG+ph H 80% Scheme 12 Scheme 13 0 Ph Scheme 14 0 I ..I ) 5% FaN2, CFCi3, CHCI,, -78 Dc t ii) sat. aq. NaHCO, ill) NH40H, MeOH iv) NaBH,, MeOH 6 : l b : a DI 30% provides an asymmetric route to a-fluoroketone~.~' Addition of molecular fluorine to azlactones provides a method of synthesising fluorinated amino acids by way of an intermediate fluorinated a-ketoacid (Scheme 14).4' 2.3 By nucleophilic substitution The in situ activation of alcohols and nucleophilic displacement by halide ions has again received significant attention this year.Diethylaminosulfur trifluoride (DAST) continues to be the most widely used reagent for the direct conversion of an alcohol to a fluoride and has been applied to the synthesis of, inter alia, fluorinated sugars,42 deoxythiopyrimidine nucleosides,4" t a x a n e ~ ~ ~ and, by an allylic transposition, 17-a-fluoroprogesterones (Scheme 15).45 A report on the fluorination of diols Me0 i) DAST, CH&ia -50 'C I) H30+ 72% Scheme 15 Marsden: Organic halides 135using DAST warns that, depending on the chain length separating the alcohols, cyclic sulfites or cyclic ethers can be formed as significant by- products or even major products.46 Other reagents which have been used for the direct synthesis of fluorides from alcohols include perfluorobutane- sulfonyl fluoride (Scheme 16),47 and (Zchloro- 1 , 1,2-trifluoroethyl)diethylamine (the Y arovenko reagent), which has again been demonstrated to be the superior reagent for the fluorination of benzylic alcohols (Scheme 17).48 The direct conversion of alcohols into iodides has been achieved in moderate yields by simple treatment with iodine in hydrocarbon solvents.49 & 0 Scheme 16 Scheme 17 CHCI, 38% br’ I F The conversion of silyl ethers to halides has been demonstrated on silylated cyclodextrins using triphenylphosphine dibromide” and in the synthesis of a potent anti-anginal prostaglandin with piperidino sulfurtrifluoride (Scheme 18).” T B S ~ : piperidino sutfurtrifluoride CIF&CFCIz 519“ I TEs*co2m TBSd C4H9 I , TBsb : ethylene glycol has been shown to be an excellent source of fluoride ion for such substitution reactions.’* There have also been two reports of the displacement of xanthates by halide ions.Motherwell describes the activation of simple S- alkyl xanthates with 4-methyl(difluoroiodo)benzene, with subsequent displacement by the liberated fluoride (Scheme 19).53 Zard employs propargyl xanthates, which undergo a thermal rearrangement to a betaine which may be trapped by mild acid and displaced by appropriate counterions such as fluoride or chloride (Scheme 20).54 S & F)-(C6H4-pMe) F CH2CIZ 58% Scheme 19 fll-pyridinium chloride x’O PhCH3. A X = F 60% X=CI 59% Scheme 20 The trimethylsilyl iodide (TMSI) mediated cleavage of lac tone^^^ and cyclic ether^'^ has again found widespread application in the synthesis of functionalised alkyl iodides.The unexpected participation of a benzoyl group allowed the synthesis of 6-iodo sugars from sugar lactones using this method (Scheme 21).57 Good regiocontrol in the acylative cleavage of 2,5-disubstituted tetrahydrofurans has been demonstrated if one of the substituents contains a mildly electron withdrawing group such as an alcohol (Scheme 22).58 Scheme 21 n I /(,L,,, AcCI, NaI, CH&N I V O A c as% OAc Scheme 22 Scheme 18 The nucleophilic displacement of sulfonates by halide ions continues to be a popular method, particularly in the case of chiral secondary sulfonates, where clean inversion of configuration is normally observed. Spray dried KF in warm 2.4 By other methods Kilburn has synthesised iodinated cyclohexanes in high yield using iodine atom transfer chemistry upon substrates containing methylene cyclopropanes (Scheme 23).59 The radical decarboxylation of 136 Contemporary Oganic Synthesis(k Br NBS, Bu'OH p;\ 54% - Scheme 23 Scheme 27 tricyclodecadienonesW and cyclopropanes61 via thiopyridylhydroxamate (Barton) esters, facilitates the synthesis of the corresponding bromide using bromotrichloromethane as the radical trap.the basis of a new homologative synthesis of a-chloroketones (Scheme 24).62 Lithiated (fluoromethy1)phenyl sulfoxide has been used to synthesise fluoromethylketones via addition to aldehydes followed by flash vacuum pyrolytic (FVP) sulfoxide eliminati~n.~~ The FVP step represents an improvement over a previously reported synthesis involving simple thermolysis in a sealed tube.In addition, allylation of the initially formed hydroxy sulfoxide gives a substrate which, on FVP, undergoes a tandem sulfoxide elimination/Claisen rearrangement to yield substituted fluoroketones (Scheme 25)." The Johnson variant of the Claisen rearrangement has also been employed in the synthesis of a-chloro-, bromo- and fluoro-esters (Scheme 26).65 Lithiated (dichloromethy1)phenyl sulfoxide forms Dibromination and dichlorination of propargylic selenides has been investigated, and leads to the production of halovinyl selenides bearing an allylic halide, the reaction proceeding via the addition of PhSeX to an intermediate haloallene (Scheme 2Q6' The synthesis of chlorinated allenic ketones may be achieved by the overall addition of acetyl chloride across a 1,3-enyne (Scheme 29).69 Finally, an interesting electrochemical oxidation of silylated azetidinones has been achieved, leading to the corresponding fluorinated heterocycle (Scheme 30).70 60 : 40 Scheme 20 0 ,/ ".I" ii) EtMgBr CI 68% Scheme 24 0 I) LDA, PhCHflHO II THFNMPA, -78 OC Ph") ii) LDA, crotyl iodide * ph' THFRIMPA. -78 OC 64% Scheme 25 / xylene,A 9% 1 : l Cl Scheme 26 The known ring-opening of cyclopropyl ketones with trimethylsilyl iodide has been spectacularly coupled with an intramolecular Michael addition reaction to yield complex fused tricyclic iodides.66 Cossy has reported the oxidative ring opening of cyclopropyl carbinols by NBS, which has been shown to proceed by nucleophilic addition to the corresponding ketone (Scheme 27).67 Scheme 29 /*'dSiMe3 Anodic Oxidation ~ /..J Bn Et$+3HF, CH&N &-N\ 88% 0 p.0 Bn 1 : 1 Scheme 30 3 Vinyl halides 3.1 From alkynes The stereoselective synthesis of (2) or (E)- 1,2-dibromoolefins by direct bromination of ethyl propynoate under controlled conditions has been reported (Scheme 31).71 The terminal bromide participates in palladium catalysed cross couplings with complete retention of stereochemistry, allowing access to the monobromides which could only be obtained as isomeric mixtures by Horner- Wadsworth-Emmons technology. Iodination of an alkene with intramolecular nucleophilic trapping by a sulfide was the key step in a synthesis of penem analogues (Scheme 32).72 Radical methods remain popular for the halo- functionalisation of alkynes.Interesting examples include the cyclisation/bromoselenation of an o-enyne (Scheme 33)73 and a synthesis of iodomethylene lactones involving the atom transfer Marsden: Organic halides 137Br 77% Ph /-<""" Br PhZnCI. Pd(PPh& THF Br 78% - PhAC02Et Scheme 31 Scheme 32 PhSeSePh, BuJNBr 'SBr oJ ' 1,4-dic~m1ht1alem * H 65% Scheme 33 Scheme 34 cyclisation of an iodo alkyne (Scheme 34).74 Weavers and co-workers have studied the latter reactions mechanistically and identified the optimal cyclisation condition^.^^ Normant and Marek have developed a stereoselective synthesis of iodomethylene cyclopentanes, involving the cyclisation of an organozinc species onto an alkyne and quenching of the resulting vinyl zinc with iodine (Scheme 35).76 The Sat0 group studied the nucleophilic addition of low valent titanium alkoxide alkyne complexes to carbonyl corn pound^.^^ Quenching the resulting a-bonded vinyl titanium with iodine yields functionalised (2)-vinyl iodides, the olefin geometry being controlled by complexation of the titanium to the allylic oxygen function (Scheme 36).Studies on R3Si = SiMe2(thexyl) Scheme 35 b-J R3Sid fi I OH Scheme 36 the synthesis of halomethylene y-lactones by the palladium mediated oxidative cyclisation of co-enynes have been extended this year.78779 In addition, a non-oxidative version of the reaction starting from an allylic acetate has also been demonstrated and employed in a synthesis of the antibiotic methylenolactone (Scheme 37).80 eoAc 5% Pd(OAc), LBr ''V I 1 c I \ Scheme 37 Finally, the stereoselective hydrohalogenation of alkynyl ketones may be achieved using sodium iodide/acetic acid under the optimised conditions of Piers,81 or through the conjugate addition of trimethylsilyl iodide followed by hydrolytic work up (Scheme 3tQ8* 0 TMSI, C H & , -78 'C then H$ 63% Scheme 38 3.2 &om other vinyl derivatives The popularity of vinyl silanes, stannanes and boranes as precursors to vinyl halides remains undiminished, and several significant examples reported this year illustrate the reasons for this popularity.A stannyl vinyl borane was exploited to achieve the stereospecific synthesis of a vinyl iodide intermediate on the way to an enediyne system (Scheme 39).83 Initial metallation takes place at the boronyl carbon, facilitating a copper catalysed cross coupling with a bromoalkyne, before final iodinative cleavage of the vinyl stannane.Complete control of regio- and stereochemistry was observed. Bromodienes were synthesised by the NBS mediated desilylation of l-silyl-l,3-diene~,~~ and bis(pyridine)iodonium tetrafluoroborate has been introduced as an agent for the stereoselective desilylation of vinyl ~ilanes.'~ Stewart and Whiting found that iodine monochloride was an effective agent for the cleavage of hindered pinacol 138 Contemporary Organic SynthesisI) BULi, THF, -78 ‘C Et Ph i9CuBrSMeb-78’% ~ w 63% Bd Scheme 39 boronates, where iodine had been shown to be unreactive.86 Retention or inversion of configuration can be attained cleanly by varying the order of addition of reagents (Scheme 40).Stereoselective fluorinative destannylation of vinyl stannanes can be achieved with silver triflate and xenon difluoride, the mechanism of which has been studied in detail this year.87 II) ICI, CH&I, I) ICI, CH&12 c \ Ph‘ii) NaOMe.MF 97 : 3 ’I 98 : 2 Ph Scheme 40 1,l- or 1,2-Dihaloalkenes are often used to prepare vinylic monohalides. Sequential treatment of 1,l-difluoroallylic alcohols with methyllithium and lithium aluminium hydride leads to @)-vinyl fluorides of excellent isomeric purity (Scheme 41).88 An interesting synthesis of cyclic vinyl fluorides exploits the /?-cation destabilising effect of a difluoromethylene unit to direct Nazarov cyclisations (Scheme 42).89 Fluorine substitution of 2,3-difluorobutenolides by organometallic or alkoxide nucleophiles provides entry to the corresponding 2-fluoro-3-substituted butenolides (Scheme 43).90 Clean a-iodination of enones can be achieved using iodine and catalytic pyridinium dichromate.” i) MeLi, Et@ PH L .L >95 : 5 Scheme 41 1,l-Dibromoolefins are valuable precursors to 1-bromovinyl radicals. The cyclisation of a bromovinyl radical onto a chiral a, /?-unsaturated ester occurred with a reasonable level of diastereoselectivity in the presence of the bulky Lewis acid MAD (Scheme 44).92 1-Fluoro- 1-tributylstannylethene 2 has been introduced for the incorporation of fluorovinyl units via palladium catalysed cross coupling reactions, exemplified by the synthesis of a modified nucleoside base (Scheme 45).93 Br * Scheme 44 Bu3SnH, Et3B MAD, toluene 73% C U 91 : 9 0 O F Pd(PPhd4.DMF H 45% Scheme 45 The Hunsdiecker reaction, the classical method for decarboxylative bromination, usually fails with unsaturated acids. Two alternative, non-radical based decarboxylative brominations have appeared this year. Both involve treatment of the unsaturated acid with NBS, with subsequent decarboxylation being promoted either by iodosyl benzene (Scheme 46)94 or potassium bicarbonate (Scheme 47).95 Scheme 46 0 o& HN5- (OH NBS, KHCO3 DMF H O q OH Scheme 47 5% 0 I OH Scheme 42 Novel iodovinyl sulfoxides have been synthesised by the addition of cuprates to alkynyl sulfoxides, trapping with N-iodosuccinimide (NIS), and also by dehydration of the iodohydrin of vinyl sulfoxides (Scheme 48).96 Finally, 3-chloro-2-sulfinyl- PhMgBt-CuBr, Scheme 43 1 ,Cbenzoquinones have been synthesised as asymmetric Diels-Alder dienophiles, by addition of Marsden: Organic halides 139II II Scheme 48 Scheme 49 chloride to the parent benzoquinone and subsequent oxidation of the intermediate dihydroquinone (Scheme 49).97 3.3 By C;L bond formation Vinyl halide synthesis via carbon-carbon double bond formation is a relatively little used strategy, largely due to the low levels of stereocontrol generally attainable through such approaches.For example, the synthesis of vinyl fluorides by the direct condensation of ethyl fluoroacetate with aldehydes proceeds with isomeric ratios typically of only 2 : l.98 The chromium(I1) chloride/iodoform system for the iodomethylenation of aldehydes has been utilised in a synthesis of bullaticin, but with E:2 ratios of only 4:1.99 Elsewhere, a fluorinated Peterson type reagent 3 (Scheme 50)lo0 and a chlorinated Horner-Wittig reagent 4 (Scheme 51)'" have been reported, but again variable degrees of stereocontrol in their reactions with carbonyl compounds limit their general use.Good levels of stereocontrol have been achieved, however, by the iodination of Schlosser type /.?-oxid0 ylides with 1,2-diiodoethane, followed by phosphine oxide elimination (Scheme 52).lo2 Another interesting Scheme 50 b LDA ii) dl oms F, OTBS 54% (+ 9% 2) 0 0 Ye II I) LO& THF, 4 0 "C CI li) 51% (+ 17% E ) 4 Scheme 51 44% Scheme 52 Z : E 9 8 : 2 r A " S Scheme 53 1. 74% OSiPhoMe syn : anti Ph 6.7 : 1 reagent is the silylated fluorosulfone 5, which achieves the overall addition of a fluorovinyl unit to aldehydes as shown (Scheme 53).'03 3.4 By other methods Vinyl fluorides are often produced during the attempted preparation of 1,l-difluorides from carbonyl compounds by treatment with DAST or synthetic equivalents. In some cases the vinyl fluoride is the exclusive product, a fact exploited in a synthesis of fluorodehydroepiandrosterones as potential antitumour agents.lM A related example, although not a vinyl fluoride, is the exclusive production of fluoro-imines from secondary amides (Scheme 54).'05 0 0 Scheme 54 Friesen has studied the iodination of allenic alcohols, and found that the excellent levels of stereocontrol for the (2)-isomer of the vinyl iodide observed are due to the isomerisation of an initial mixture rich in the (E)-isomer (Scheme 55).'06 Treatment of allenic esters with aqueous NBS leads, on cyclisation of the initially formed hydroxy ester, to /.?-bromobuten~lides.'~~ TIPSO I Initial: 0.6 : 1 Equilibrium: 13 : 1 Cd15 Scheme 55 E Vinyl iodides have been synthesised by the treatment of 1-trimethylsilyl epoxides with TMSI (Scheme 56).lo8 The production of a single geometric isomer from a mixture of (2)- and (E)- epoxides indicates that the reaction proceeds by the El elimination of hexamethyl disiloxane from an intermediate silylated iodohydrin. The elimination 140 Contemporary Organic SynthesisTMSX Ph A X x-CI 99% 22 : 78 X = Br 98% Z : E X = l 96% Ph Scheme 56 of water or hydrogen halide from 1,2-halohydrins and 1,Zdihalides respectively has been used in the synthesis of fluorinated analogues of abscisic acid"' and eugeno1.l" An improved method for the synthesis of a-chloro acrylates by lithium chloride promoted elimination of HCl from a-bromo- a-chloro esters has been reported, with Z : E ratios better than 20 : 1 observed in all cases examined (Scheme 57)."' Mechanistic studies show that it is the chloride ion which catalyses the elimination step, and that the lithium carbonate present simply neutralises the HCl thus formed.C3H7/xc02Et LICI, LJ2COs C 3 H 7 7 c 0 2 E t CI CI Br DMF 94% 2 : E 24 : 1 Scheme 57 The synthesis of P-iodo enones from cyclic 1,3-diones classically leads to iodination at the position corresponding to the most sterically accessible ketone.Kishi has developed a method for the synthesis of the regioisomeric iodo enones, involving silylation of the most reactive ketone, formation of the enol phosphonate of the remaining ketone and treatment with trimethylsilyl iodide (Scheme 58).It2 2-Chloro-1,3-dienes are formed stereoselectively and in good yield by the fluoride mediated ring opening of a-silyl dichlorocyclopropanes (Scheme 59).I13 Scheme 58 CI CI c*Hq - CsF, DMF z : E Cd13 J b s 72% * 1oo:o Scheme 59 4 Aryl halides 4.1 By electrophilic substitution The indiscriminate reactivity of molecular fluorine has led to it being comparatively little used in electrophilic aromatic fluorination reactions. Reports this year, however, have demonstrated that direct fluorination can indeed by performed in good yields, provided that a protic acidic solvent such as trifluoroethanol, trifluoroacetic acid114 or formic acid115 is used to temper the reactivity of the fluorine.Direct fluorination of an intact nucleoside with molecular fluorine has also been achieved, albeit in modest yield (Scheme 60).'16 Fluorination of a tyrosine analogue for PET studies has been achieved in excellent yield by the destannylation of an aryl stannane with fluorine (Scheme 61).'17 Elsewhere, the Selectfluor reagent has been used in the chemoselective fluorination of analogues of the antiarthritic agent rhein, again in modest yield (Scheme 62).'18 Scheme 60 ow OMe Scheme 61 OMe 0 OMe OMe 0 C02Me 0 2 2 % 0 Scheme 62 Reports this year show that the efficiency of NBS as a reagent for aromatic bromination can be greatly increased either by ultrasoni~ation"~ or by the addition of a zeolite catalyst.'*' Dibromodimethyl- hydantoin has been introduced as a more efficient synthetic equivalent of NBS, when used in conjunction with triflic acid.12' Developments in the area of aromatic chlorination include the use of calcium hypochlorite as an electrophilic chlorine source, in a cheap large scale preparation of 5-chloroanthranilic acid.'22 Thionyl chloride is often used to para-chlorinate phenols, but Sheldon has shown that the addition of catalytic amounts of a bulky secondary amine leads to a complete reversal Marsden: Organic halides 141of regioselectivity in favour of the ~rtho-isomer.'~~ He explains this result by invoking the formation of a chloramine, which hydrogen bonds to the phenolic hydroxy group.An interesting new aromatic chlorination procedure employs ammonium metavanadate in the presence of hydrogen peroxide and potassium chloride as the halide source & Bu'LkTHF -[&.I Cp2ZrM&l (MeO)BE/ (Scheme act as a mimic 63).lZ4 for The vanadate metavanadate dependent is proposed to &:;* &-.. B(OE02 metalloenzyme systems. 6 , Et2 I 3 M NaOH, H A 74% OH Br M e O u O M e 0.1 KCI, eq. NH4V03, H202 pH 4-5, WW20 45% Scheme 63 Aromatic iodination has been achieved with elemental iodine by bubbling gaseous fluorine through the reaction mixture.'25 The nature of the iodinating agent is not known, but is suggested to be either a hypervalent iodine species or iodine monofluoride.The latter species, created in situ by treatment of iodide salts with fluorine, has been used to incorporate radioactive iodine into aromatic rings for radiotracing applications.'26 Pyridine/iodine monochloride complex, in conjunction with mercury(I1) nitrate, provides a potent iodinating agent which successfully iodinates a wide range of aromatic substrate^.'^^ Finally, a mixture of iodine and periodic acid has been used to iodinate aromatic rings efficiently (Scheme 64).lZ8 Scheme 64 Directed lithiation protocols have proven extremely useful for the regiospecific synthesis of aromatic halides when used in conjunction with an electrophilic halogen quench. Chlorination and bromination of benzoic acids have been achieved, using the acid as a directing group for 1ithiati0n.l~' The presence of a halogen atom on the benzoic acid further directs lithiation to a single ortho-position, allowing the regioselective synthesis of 2,3-dihalo- benzoic acids (Scheme 65).l3' Buchwald has exploited the chemistry of zirconocenyl benzyne complexes to devise synthetic routes to isomeric halophenols (Scheme 66).131 Treatment of the complex with diethylmethoxyborane gives the BuLi.NEOAlMF -80 %, then C&le 61% Scheme 66 kinetic aryl boron species 6, while treatment with triethyoxyborane gives the thermodynamic isomer 7. Halogenative cleavage of the aryl-zirconium bond is followed by oxidation of the aryl-boron bond to furnish the isomeric halophenols. 4.2 By nucleophilic substitution The nucleophilic displacement of nitro groups from aromatic rings has been achieved with tetramethyl- ammonium fluoride'32 or potassium fluoride/ [2.2.2]~ryptand,'~~ the latter system being sufficiently rapid to be of use in the synthesis of 18F radiotracers.2-Fluoroimidazoles have been prepared from the corresponding bromides using spray dried KF as the fluoride source.'34 An interesting approach to the synthesis of fluorinated purine molecules involves the anodic oxidation of the parent compound in the presence of the triethylamine/HF complex (Scheme 67).'j5 Aryl triazenes are often employed as stable equivalents of diazonium salts in nucleophilic aromatic substitutions, but their activation usually requires strongly acidic conditions. A mild alternative reported this year involves the use of iodine in iodomethane at moderate temperatures (Scheme 68).136 0 0 Scheme 67 O(C H &OH 80 Oc, Sealed tube Br NEt2 I Scheme 65 Scheme 68 142 Contemporary Organic Synthesis5 Alkynyl halides The strategic value of alkynyl halides in organic synthesis, and particularly as partners in transition metal catalysed coupling reactions, has been highlighted by Danishefsky's preparation of a bisiodoalkyne for use in a synthesis of the core unit of dynemicin (Scheme 69).13' Practical improve- ments in the area this year include the introduction of bis(sym-collidine)iodine(I) hexafluorophosphate as a reagent for the direct iodination of alkyne~'~~ and a report of optimised conditions for the iodinative quenching of magnesium acetylides.139 I "OAC cat. AgNO:, ~ THF 100% OTBS I Scheme 69 6 1,l-Dihalo compounds Interest in the area of 1,l-dihalo compounds largely concerns 1,l-difluoro derivatives, undoubtedly stimulated by the potential use of such units as isosteric replacements for carbonyl groups in medicinal chemistry.Direct conversion of carbonyl groups into the -CF2- unit by treatment with DAST has again proved a popular m e t h ~ d . ~ ~ " ' ~ ~ Several new or improved protocols for the conversion of dithioketals into difluoromethylene groups have been reported, including the combinations of 1,3-dibrom0-5,5-dimethylhydantoin and (hexafluoro- propene)diethylamine (an in situ source of HF),142 and iodine and gaseous Anodic oxidation of p-methoxyiodobenzene in the presence of the triethylamine/hydrogen fluoride complex produces an iodosodifluoride derivative which carried out the difluorination in situ (Scheme 70)." An interesting electrochemical chlorination of an oxazoline has also been reported (Scheme 71).'44 Scheme 70 Ph.Ph . 1.25 V, LiCQ CH&N 95% Difluoroalkenes have proved to be competent radical acceptors, providing alternative routes to difluoromethylene containing carboxylic acids (Scheme 72)145 and carbohydrate analogues (Scheme 73).'46 Scheme 72 Scheme 73 OAc Lithiated diethyl (difluoromethy1)phosphonate [(EtO),P(O)CHF,] has been used as a nucleophile for the introduction of -CF2- units by the displace- ment of triflate~,'~~ addition to aldehydes14* and cerium(II1) mediated conjugate addition to nitro- olefins. 149 Synthetically useful aldol reactions of difluoroenolates, generated in situ by the addition of difluorovinyllithium 8 to aldehydes or ketones, have been demonstrated (Scheme 74).15' Treatment of chlorodifluoromethyl groups with samarium(I1) iodide generates a reactive entity, presumed to be either a free difluoromethyl radical or an organo- samarium(II1) species, which adds to ketones and olefins in reasonable yiel~ds.'~' Dichloromethylene Reformatsky type reagents have been formed from trichloroacetic esters using a lead(I1) chloride and gallium bimetallic redox system,"* and bromofluoro- methylene reagents from dibromofluoroacetic esters using a zinc/diethylaluminium chloride system.I5' Both reagents react cleanly with carbonyl compounds.Dibromomethyl lithium has been F&-OCONEt2 OH 0 2 eq. LDA, THF, -78 "C * 0 Scheme 71 Scheme 74 Marsden: Organic halides 143demonstrated to add in good yield to cyclic and in a 1,Zfashion to a cyclic e n ~ n e .' ~ ~ The use of difluoromethylene electrophiles has received somewhat less attention than their nucleophilic counterparts. The diastereoselective alblation of chiral oxazolidinone based enolates with ethyl difluoroiodoacetate and triethylborane has been reported, the reaction having been shown to proceed via a radical mechanism (Scheme 75).lS6 Michael addition of a chiral enolate to a bromo- difluoromethyl substituted acrylate leads to the asymmetric synthesis of a difluorocyclopropane (Scheme 76).'57 PS Pl' Scheme 75 chloride from dimethoxymethane and hexanoyl chloride has been reported, which gives material free from the normal impurity, the highly carcino- genic bis(chloromethy1) ether.16' In a similar vein, a new method for the N-bromomethylenation of imides and isothiazolones has been developed and applied to the synthesis of antiemphysemic compounds (Scheme 78).'62 A brominated aziridine required for a mitomycin synthesis has been prepared from the corresponding carboxylic acid via photolysis of its Barton ester and trapping of the resultant radical with bromotrichloromethane (Scheme 79).'63 L-J Pr" LDA, THF, then I BrFfi-OMesityl 0 Mesit y10 OBn 51% Pr" 92%& Scheme 76 1,l-Difluoroalkenes have been prepared by the SN2' displacement of fluoride from trifluoromethyl substituted alkenes with lithium arnide~.'~' Treat- ment of chlorodifluoromethyl substituted epoxides with Bu'Li leads to a surprisingly facile metal- halogen exchange with subsequent ring opening to furnish difluoroenol ethers (Scheme 77).'59 The high yielding dichloromethylenation of lactones has been achieved using triphenylphosphine and carbon tetrachloride,16' an improvement on previous methods which produced the carcinogenic hexamethylphosphoric triamide as a by-product. BU'LI, 90% -78 "c c F&Ph EtO k OH Scheme 77 7 1,l-Halohydrins and related compounds By far the most abundant examples of 1,l-halohydrin derivatives are the glycosyl halides.For reasons of brevity, these entities will not be discussed in this review. There have, however, been other significant developments in the area this year. A clean and safe preparation of methoxymethyl R = Br 88% Scheme 70 Scheme 79 hv, BrCCb 78% - cis: trans 8 1,a-Dihalo compounds The direct addition of fluorine to various aza[2.2.l]heptenes has been studied in the context of the synthesis of fluorinated carbocyclic nucleosides (Scheme 8O).lM Although the desired product dominated, the presence of several by- products demonstrates the indiscriminate reactivity of fluorine towards alkenes. Two novel metal mediated protocols for the 1,2-dibromination of alkenes have been reported.Clean trans-dibromina- tion has been achieved with trimethylsilyl bromide and tetradecyltrimethylammonium ~ermanganate.'~~ In a model for vanadium dependent bromoperoxi- dases (vide supra), ammonium vanadate will also achieve the dibromination of olefins in the presence of potassium bromide and hydrogen pero~ide.'~~~'~' bo BOC 5% FA, CHCl3, CHF, EtOH, -78 "C I F &To&. Boc & O b 0 BOC BOC 43% FF 5% F F 4% 2% Scheme 80 144 Contemporary Organic SynthesisThe bromofluorination and chlorofluorination of alkenes by the interception of halonium ions with fluoride has received much attention this year.Reagent combinations for this transformation include DBH/HF, pyridine,'68 DBH/K&F5,169 and N-ch1orosaccharinlHF~ pyridine. 170 In all cases, mixtures of stereo- and/or regio-isomers were obtained. a-chloroesters has been reported, mediated by a copper(I)/iron redox couple, leading to 1,Zdichlorides as shown in Scheme 81.'71,'72 A reductive homocoupling of a-bromo- Ph X c o 2 M e CuBr, Fe, DMSO Php:;" 89% Me02C CI CI Br Scheme 81 9 l,%-Halohydrins and related compounds 9.1 By addition to alkenes In the last review of this series, the application of caesium fluoroxysulfate (CsS04F) to the synthesis of vicinal fluoroethers was reported.This year a detailed study of the effect of alkene and alcohol on the rate and stereochemical outcome of this reaction has appeared.'73 An alternative approach to these compounds has been reported by Rozen and co-workers, who have investigated the reaction of alkenes with methyl hypofluoride (Scheme 82).'74 This compound, prepared by the reaction of methanol and fluorine at low temperatures, reacts as 'MeO+ F-', and is thus regiocomplementary to the CsS04F/MeOH system which has the opposite polarity. The use of chloroperoxidase enzymes for the synthesis of halohydrins has been extended to include higher sugar anomeric bromides (Scheme 83).'75 F F2, MeOH CHSCN, 4 5 'C W% Scheme 82 FOAC i) CPO, KBr, H202 A&* 'EO- ii) A@, py, DMAP * AdAco OAc 57% Br HO CPO = chloroperoxidase Scheme 83 Interest in halonium ion mediated electrophilic cyclisations remains intense.The use of bis(sym- collidine)iodine(r) hexafluorophosphate as an agent for medium ring iodolactonisations has been described, with excellent yields reported for seven- membered ring f0rmati0n.l~~ An interesting strategy for the asymmetric synthesis of iodolactones has been reported, involving the use of a C2-symmetric pyrrolidine as a chiral auxiliary for sequential alkylation and iodocyclisation reactions (Scheme 84), both proceeding with excellent stereoc~ntrol.~~~ The method has also been shown to be successful with the chiral auxiliary attached to a polymeric support, offering an attractively facile method of auxiliary re~ycling.'~~ In the related area of iodocarbonation, a remarkably diastereoselective cyclisation has been attributed to intramolecular delivery of iodine by an allylic aromatic group, prior to cyclisation (Scheme 85).'79 An interesting variation in halocarbonation reactions involving radicals rather than ionic species is shown in Scheme 86.'" The cyclisation proceeds with the same sense of asymmetric induction as the polar equivalent, but a greater level of selectivity (16 : 1, cf.4: 1). n " I ii) 12, THF 87% I i 1oo:o Scheme 84 eoH i) BuLi, THF I ii) COP 71% iii) I2 1oo:o Scheme 85 Scheme 86 Iodoetherification reactions have again been widely used in the preparation of tetrahydro- furans (including tetrasubstituted181 and 2,2,4-tris~bstituted'~~ examples) as well as in the synthesis of oxepanes (Scheme 87)'83 and oxetanes (Scheme 88).lW An interesting approach to the synthesis of functionalised tetrahydrofurans involves the use of ring oxygen of derivatised f~ranosyl'~~ and pyranosyl'86 sugars as the nucleophilic partner in iodocyclisations, with subsequent rupture of the sugar ring (Scheme 89). Scheme 87 Marsden: Organic halides 145Scheme 88 6 I Scheme 89 As in previous years, this review will not cover the co-addition of halides and heteroatoms such as sulfur and selenium to olefins.However, several interesting examples of the azahalogenation of olefins have appeared this year and are worthy of mention.The diastereoselective Michael addition of phthalimide to chiral enamides, trapping with a bromine source, leads to a mixture of three isomeric adducts, the major isomer having the stereochemistry shown in Scheme 90.'87 The nitrogen of P-lactams proves to be a competent nucleophile for halonium ions, facilitating a novel carbapenem synthesis (Scheme 91). Gallagher has investigated the synthesis of 8-11 membered azacycles by the iodocyclisation of sulfonamides onto allenes.lg9 Finally, an interesting formal addition of a nitrogen nucleophile and a halide across an olefin has been reported upon thermolysis of an azido olefin (Scheme 92).'% The reaction proceeds via interception of an intermediate aziridine by HCl produced by the chlorinated solvent.0 0 'N AN* then PhSOzBr pPh 05% 7 : l : 1 Scheme 90 Scheme 91 0 0 9.2 By epoxide opening Epoxide opening remains a popular method of halohydrin synthesis. A comparative study of the effects of fluoride source on the regioselectivity of ring opening of terminal epoxides reveals that good regiocontrol is possible in either sense by appropriate choice of reagent (Scheme 93).19' More challengingly, an investigation of the ring opening of 1,2-disubstituted epoxides has shown that chelation to nearby oxygen functionality can be used to direct halide delivery from metal halides with very high regiocontrol (Scheme 94).'92 Yttrium(n1) chloride and its dicyclopentadienyl analogue have been found to be excellent catalysts for the acylative ring opening of e~0xides.l~~ Using benzoyl chloride as the acylating agent, both chlorohydrins and, by the addition of sodium iodide, iodohydrins are formed in excellent yield (Scheme 95).0 m C 0 2 E t ~TOHF, CHzCI, KHFh 184-6, DMF a%, 92 : 8 00%. 18 : 82 Scheme 93 PS 75% Scheme 94 WithNaI: X = I , 99% Without NaI: X = CI, 99% Scheme 95 In the area of halide ion opening of aziridines, total control of the regiochemistry of ring opening of a bicyclic aziridine was demonstrated by appropriate choice of reagents (Scheme 96).194 .cr- TsH + N 6 c,..(5 Ts N 6 Cl NHTs -. 6.7 : 1 Scheme 92 HCI,CHCIs 98% 99 : 1 NaCI,DMF,A 75% 1 : 99 Scheme 96 146 Contemporary Organic Synthesis9.3 By other methods The regioselective formation of acetoxy chloride^'^^ and bromides'96 from diols via their derived orthoformates have been reported, the latter being employed in a large scale asymmetric synthesis of the Taxol@ side chain (Scheme 97).The addition of haloalkyl organometallic reagents to aldehydes and ketones provides an entry into l,Zhalohydrin~.'~~ In one report, the stereoselective addition of (chloromethy1)lithium to a-bromoketones furnishes glycidyl chlorides on warming the reaction mixture (Scheme 98).'98 Q" 60% Scheme 97 L Scheme 98 Finally, the G h e t group have achieved the dynamic resolution of a-chlorinated-P-ketoesters by catalytic asymmetric hydrogenation, leading to 1,2-halohydrins of reasonable purity (Scheme 99).'% cat' = [(R )-MeObiphep]RuBr2 72 : 28 9 0 % ~ 8 4 % ~ Scheme 99 10 References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 P.L. 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ISSN:1350-4894    

DOI:10.1039/CO9960300133

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Aldehydes and ketones PATRICK G. STEEL Department of Chemist% Science Laboratories, South Road, Durham DHl3LE, UK Reviewing the literature published between October 1994 and September 1995 Continuing the coverage in Contemporary Organic Synthesis, 1995,2, 151 1 1.1 1.2 1.3 2 3 4 5 5.1 5.2 5.3 6 6.1 6.2 7 Synthesis of saturated aldehydes and ketones Redox methods Umpolung methods General methods Synthesis of aromatic aldehydes and ketones Synthesis of cyclic ketones Protection and deprotection strategies Synthesis of functionalised aldehydes and ketones Unsaturated aldehydes and ketones a-Heteroatom substituted aldehydes and ketones Dicarbonyl compounds Reactions of aldehydes and ketones The aldol reaction and other enolate additions Conjugate addition reactions References 1 Synthesis of saturated aldehydes and ketones 1.1 Redox methods The Oppenauer oxidation forms a classical method for the conversion of alcohols to carbonyl compounds.Recent developments in the general area of Oppenauer-Meerwein-Ponndorf-Verley redox processes have been reviewed.' Oppenauer type oxidations can also be achieved through the mediation of zirconocene derived catalysts although this latter route does require the use of one equivalent of a sacrificial aldehyde.2 Chromium reagents retain a predominant role in this oxidation, although there is still demand for more convenient procedures. In this respect, the use of polychromates have been advocated as the reagents of ~hoice.~ These not only provide equivalent yields and selectivities, as do PCC and PDC, but are much cheaper.Similarly 18-crown-6 complexes of various chromate salts have been developed as more soluble, non-hygroscopic alternatives to PCC4 Other enhancements in this area have focused on the use of sub-stoichiometric quantities of chromium salts in the presence of co-oxidants such as sodium per~arbonate.'~~ In the second of these reports it has been found that the use of phase transfer catalysis provides enhanced efficiency although simple primary aliphatic alcohols are prone to over-oxidation. This proviso also applies to many of the reported alternatives to chromium catalysts which have included complexes based on palladium,' cobalt,' rhenium' and ruthenium." However, ruthenium porphyrin catalysts are suitable for the lo2 mediated oxidation of the complete spectrum of alcohols.'' C-H bond activation can be competitive with such ruthenium catalysts and this aspect has been exploited in the direct synthesis of carbonyl compounds from hydrocarbons.The use of peracids as the co-oxidant has been shown to provide much better conversions and ketone: alcohol selectivity than the previously favoured TBHP.12 Similar transformations, albeit with lower efficiencies, have been reported for a variety of other systems13 and in general, at present, the transformation is only synthetically viable for benzylic methylene ~ n i t s . ' ~ carbonyl groups - the Wacker reaction - have been reported. In particular, the use of j-cyclodextrins has been advocated for the oxidation of higher a-olefins. Whilst, as phase transfer catalysis, there is some precedent for this observation, this latest report utilises partially methylated cyclodextrins to provide optimal yields, rates and sele~tivities.'~ Interestingly, it has been shown that the regio- chemistry of the Wacker oxidation can be controlled by simple variations in substrate structure (Scheme 1).l6 today is the Dess-Martin periodinane.Recent reports have suggested that the addition of a stoichiometric amount of water can provide a more Modifications to the direct oxidation of alkenes to Amongst the more popular oxidants employed 90% ?\ 9\ Scheme 1 Steel: Aldehydes and ketones 15 1effective oxidant.17 The authors’ comment on the effect of prevailing humidity illustrate the difficulties that can arise. In this respect it has been noted that the use of o-iodoxybenzoic acid, which is the precursor to the Dess-Martin reagent, is not only an effective and selective oxidant but is less sensitive to moisture. The only drawback to this reagent is the requirement for DMSO as the solvent.18 in the conversion of sec-alkyl ethers into the corresponding ketones in good yield.Similar transformations have previously been reported with dimethyl dioxirane although this new modification appears more facile.” The latter reagent has been advocated as the reagent of choice for the selective oxidation of the secondary alcohol of cyclic and a- and p-linear diols. For saturated linear diols hydrogen peroxide in the presence of TS-1 zeolite proves more effective.20 This combina- tion is also effective for the oxidation of secondary benzylic amines although oxime formation is competitive.21 Oximes may be converted to the corresponding carbonyl compound on treatment with manganese dioxide; under these mild conditions a,P-unsaturated carbonyl groups do not suffer from olefin isomerisation.22 Similar conversions are also possible using copper nitrate or silver carbonate supported on silica or bentonite clay respectively” (see also Section 4).Enamines undergo oxidative cleavage to the homologous ketone upon treatment with a variety of reagents. A systematic survey on the use of potassium dichromate has shown that a biphasic solvent mixture can help inhibit over-oxidation which is a problem for substrates lacking P-sub~tituents.~~ Approaches that minimise side products are of interest and in this respect the electrochemically mediated oxidation of primary and secondary alcohols has been reported.25 In general these procedures appear to be more effective with benzylic alcohol substrates.26 In a similar vein, Pirrung has reported that the photolysis of substituted benzoylformate esters affords the corresponding ketones in good yield.27 The relatively long wavelength employed means that most common chromophores are unaffected by this transformation.Minimisation of the problems associated with heavy metal oxidants can also be achieved through the use of supported reagents: reviews on the use of silicates28 and ~ i r c o n i a ~ ~ have appeared. Enzymatic oxidation is also another possibility which can result in a kinetic resolution of suitably structured alcohols.30 Procedures €or the efficient, mild oxidative cleavage of 5-substituted furfurals to y-ketoester~~~ and nitroalkenes to the corresponding ketone32 have been published. Selective reduction of acid chlorides has been recognised as an efficient method for aldehyde synthesis.Excellent yields are obtained in the zinc- copper couple mediated reduction of an in situ generated acyl phosphonium salt .” Transfer hydrogenation remains a favourite method for the conjugate reduction of enones. Aqueous phase Perfluoroalkyl oxaziridines have been employed reductions are possible using the water soluble complex, Rh[(ptah)(pta)2Cl]C1 {where pta is 1,3,5 tria~a-7-phosphaadamantane}.~ Further reports have appeared on the use of the ammonium formate/Pd-C system which may be employed in the presence of both non-conjugated olefins and carbonyl group^.'^ Similar claims have been made for the use of sodium dithionate in water-dioxane solvent systems.Contrary to previous reports it is suggested that the use of phase transfer catalysis is detriment a1 to the c hemoselect ivity. 36 1.2 Umpolung methods Nucleophilic acyl radicals can be considered as umpolung reagents and this area remains one of some considerable activity. Aryl ~elenides~~ and chromium carbene cornplexe~’~ are both suitable precursors. The latter combine with most electrophilic acceptor olefins although efficient yields are only obtained with aromatic carbene complexes which lack ortho substituents. Electro- chemical reduction of an acyl chloride provides an alternative entry point and the resultant radical combines with carbon dioxide to produce a-keto- acids in moderate yield^.'^ Similar products can be more efficiently accessed through the use of lithiated ethoxyacetylene.Treatment of the initial adduct with neutral KMn04 affords the P-hydroxy a-keto ester. If aldehydes are used as the sub- strate this can provide a very rapid access to 1,2,3- tricarbonyl species.40 Collman’s reagent, Na2[Fe(C0)4], provides a number of routes to ketones. However, it is an extremely pyrophoric compound and this has restricted its use. The corresponding potassium salt, introduced by Yamashita, is much more stable and a simplified preparation has recently been published.41 co-workers have illustrated the use of protected 1,1,l-trifluoroethanol as a precursor to a variety of a, a-difluoro ketones (Scheme 2).42 a-Pefluoroalkyl aldehydes can be accessed from the treatment of perfluoroalkyl ketones with trimethylsilylthia~ole.~’ This represents the first reported addition of this In an elegant series of papers, Percy and r ODECI OH i.NaH, THF, 0 “C jDEc 2 eq. LDA l ~ f ~ ~ 1 THF, -78 “C, 20 rnin F3CJ ii.Et2NCOCI * F3C I i. ECHO ii. NH&I (aq.) F2CH Et ODEC 68% Scheme 2 152 Contemporary Organic Synthesisumpolung reagent to ketones and reflects the increased reactivity due to the perfluoroalkyl group. P-Chlorovinyl acetals undergo facile lithium- halogen exchange and as such represent a P-acyl vinyl anion eq~ivalent.~~ The generation of a-alkoxyvinyllithium is enhanced if tetrahydropyran is used as the solvent since this avoids contamination with acetaldehyde enolate which can be a problem in THF.45 Similarly 8-thio ketals can function as bis-homoenolate equivalent^.^^ Finally, cyanophosphonates may be employed as asymmetric cyanohydrin equivalents, undergoing alkylation with high diastereo~electivity.~~ 1.3 General methods Predominant in the modern repertoire for the preparation of ketones (and aldehydes) from a carboxylate function is the Weinreb amide, RC(=O)N(OMe)Me, and these can be efficiently prepared from the free acid using bromomethyl pyridinium iodide as a relatively inexpensive coupling agent."' Alternatively, esters may be directly converted to the corresponding ketone through consecutive treatment with the amine hydrochloride followed by 2 equiv.of the appropriate ~rganometallic.~~ The amide is sufficiently stable to be compatible with a number of other synthetic transformations. For example, the asymmetric aldol reaction of N-methoxy-N-methyl- cr-isocyanoacetamide 1 affords the corresponding oxazoline 2 which may subsequently be combined with a range of organometallic reagents to provide access to both amino and hydroxy substituted ketones and aldehydes (Scheme 3).50 1 2 t NHP R'q* P o 0 Scheme 3 A number of alternative leaving groups have been developed including piperidino carbamates which couple with the complete gamut of unhindered organolithiums to provide symmetrical ketones in excellent yield." Unsymmetrical ketones are accessible through the use of acyl-l,2-diazole~~~ or imidazole based hydra~ines.~~ The former also react with Reformatsky reagents to afford b-keto esters in moderate to good yield, whilst the latter, on reduction with DIBALH, provide aldehydes in excellent yield.Although acyl chlorides are normally too reactive to be used in this context it has been reported that in situ generated lithium tetra- alkylgallates do not add to ketones and can be employed in this respect. However, the difference in the migratory aptitude of the gallate substituents [Br > Ph > PhC = C > primary alkyl >secondary alkyl] is not always large and mixtures of products can result. In general, alkynyl transfer can be more effectively achieved using thallium reagents.54 sonochemical Barbier reaction have been p~blished.~' Trifluoromethyl ketones can be obtained through the in situ lithium-halogen exchange reaction between alkyl iodides and one equivalent of tert-butyllithium in the presence of a fluoroacyl cation eq~ivalent.~~ The stoichiometry of this process is crucial for good yields to be obtained.The same products are produced in the reaction of acid chlorides with trifluoroacetic anhydride.57 A similar synthesis of aliphatic P-keto esters can be achieved from the half ester of malonic Alternatively, a-bromo esters undergo a Claisen type condensation with concomitant reduction of the C-Br bond on treatment with samarium iodide (see also Section 6.1).59 These and other syntheses of P-keto esters have been reviewed.60 A trifluoromethoxy group is essential in the free radical mediated synthesis of a-keto esters from a-alkoxyacrylates." a-Epoxy esters undergo low temperature addition of organometallics to afford the corresponding ketone in good yield.h2 The presence of trimethylsilyl chloride is beneficial and becomes essential if Grignard reagents are used.2-Tetrahydrofuranyl carboxylate is converted to the corresponding ketone on reaction with 2 equiv. of an organometallic nucleophile; the various options for this particular conversion have been s~rveyed.~' The resultant tetrahydrofuranyl ketones are readily cleaved to the corresponding cu-hydroxy ketone on reaction with Sm12. This transformation proceeds via the samarium enolate which may be efficiently trapped with a range of electrophile~.~~ Homologous p-tetrahydrofuryl ketones can be accessed through a palladium mediated tandem radical cyclisation- carbonylation of alkyl 9-BBN derivatives. This report confirms the radical mediated nature of this previously reported route to acyclic ketones.65 P-Keto amides are produced in the lanthanide mediated coupling of azaketones and aldehydes.66 The intermediate cr-imino-oxetanes can also be used to produce P-lactams.A P-keto acylsilane is produced in the unusual aldol coupling of an acylsilane with excess benzaldehyde. However, the yield is only moderate and the generality was not stated.67 On treatment with lead tetraacetate and carbon monoxide, tertiary cyclobutanols undergo ring opening acylation to afford substituted 8-keto esters in moderate yields.68 Isomeric oxetanes undergo rhodium mediated carbonylative ring opening to produce the 8-silyloxy aldehyde.69 Unlike earlier Full details on the scope and limitations of the Steel: Aldehydes and ketones 153reports, this modification only requires stoichiometric quantities of the starting oxetane.Epoxides undergo rearrangement to carbonyl compounds on treatment with Lewis acids; there have been a number of reports in this area focusing on the aldehyde : ketone selectivity ~btainable.~' With styrene oxides, the use of strong Lewis acids may be avoided through the simple use of silica gel.71 Very high chemoselectivity is obtained via the utilisation of different phosphine ligands in the palladium acetate mediated version of this reaction (Scheme 4).72 A Pd(OAC)z, PPh3 PhH, reflux Scheme 4 Palladium catalysis is also effective in promoting the Claisen rearrangement and this can produce different stereochemical outcomes to that observed in the thermal modification (Scheme 5).73 In the presence of rhodium salts the Cope rearrangement can also be catalysed although under these conditions the product aldehyde is prone to undergo an intramolecular hydr~acylation.~~ PdCI,(PhCN)2, PhMe, rt, 0.5 h 55% 90 : 10 PhMe, 100 O C , 10 h 57% 11 : 89 Scheme 5 In the presence of TiC14, allylsilanes add to a-diketone ketals to afford a variety of ketonic products via simple acetal substitution followed by pinacol type rearrangement^.^^ Treatment of MEM ethers of 6-hydroxy-(E)-vinylsilanes with the same Lewis acid results in C - C bond cleavage and the production of ketones.76 The corresponding (2)- vinylsilane leads preferentially to dihydropyran products.Reactions of alkenyl sulfides 3 also occur with C-C bond cleavage and the Lewis acid mediated reactions of this nucleophile have been extended to include conjugate addition, which proceeds with excellent stereo~electivity.~~ Full details have appeared on the triaZky2- aluminium promoted homologation of aldehydes and ketones with diaz~alkanes,~' the aluminium ?TES SMe 3 trichloride induced rearrangement of aryl tert butyl ketones79 and the palladium mediated addition of alcohols to chiral methacrylates to afford a-chiral aldehydes masked as the corresponding acetal." Aldehydes and ketones masked as the enol ether are accessed through the coupling of an a-methoxy sulfone with a second lithiated sulfone.81 Mixed acetals are produced from the reaction of alcoholic solutions of allylic ethers with CO in the presence of dicobalt octacarbonyl.82 The free aldehyde is the product when water is used as the solvent.Alkynols are converted to ketones in a tandem hydrosilylation-isomerisation process catalysed by cationic rhodium(1) c~mplexes.~' Although the reaction can be carried out in a single pot the yields are better if each step is achieved separately. appear with a particular focus on the stereo- selectivity of the process.&4 Reports on the regioselectivity of diene~,'~ acrylateS6 and vinyl heterocycless7 have been published. However, the main body of work in this area has been concerned with control of the absolute stereochemistry and in this respect a number of new chiral ligands have been identified." Labile aldehydes can be masked as the acetal in situ through the use of triethyl orthoformate; further developments in this strategy allow this to be achieved at lower pressures and higher rates than had previously been rep~rted.'~ Other enhancements to the efficiency of the hydroformylation process have included hetero- genisation or biphasic/supported aqueous phase media." Developments in hydroformylation continue to 2 Synthesis of aromatic aldehydes and ketones Aryl carbonyl compounds can be accessed through benzylic hydrocarbon oxidation; a number of procedures in this area have been ~ublished.~' Whilst many of these suffer from competitive over- oxidation this is not the case for the enzymatic process utilising l a ~ c a s e .~ ~ In an interesting variant, trichloromethyl aryl groups can be converted to the corresponding aldehyde on reaction with pyridine; a mechanism for this transformation has been proposed.93 Oxidation of the corresponding benzyl alcohol is facile and new protocols and reagents for this conversion have been reported." Calcium borohydride-cyclooctadiene affords a reagent for the efficient reduction of aryl and other non-enolisable esters to the corresponding aldehyde?' popular options for the synthesis of aryl carbonyl Friedel-Crafts methods remain one of the most 154 Contemporay Organic Synthesisunits. Whereas most arenes undergo alkylation with lactones, N-methylpyrrole affords the acylated product in good yield.96 The regiochemistry of substitution of N-sulfonyl pyrroles can be controlled by the nature of the reaction solvent.97 For example, nitromethane favours a strongly dissociated acylium ion which leads to exclusive 3-substitution.Simple acylation can be achieved under very mild conditions using a combination of anhydride, dimethyl sulfide and boron trifluoride." This combination is equivalent in reactivity to acetyl triflate but is much cheaper and simpler in operation. Reports on the efficacy of a number of alternative Lewis acids have been published including rhenium pentacarbonyl bromide,99 hafnium triflate'"" and lanthanide salts of superacids."' The latter are claimed to be even more effective than the previously reported triflates.'02 reaction, scandium triflate is also an effective catalyst for the Fries rearrangement.lo3 This transformation can also be initiated photo- chemically; although this produces isomeric mixtures the product ratios can be enhanced through the appropriate choice of solvent.lW Similar problems befall the synthesis of o-hydroxyphenyl acetones via the Carroll rearrangement of aryl acetoacetates derived from the reaction of p-quinols and diketene.'05 be obtained through the generation of an aryl organometallic reagent which also overcomes problem or regiocontrol.Direct generation of halo aryl copper species is possible from haloiodoarenes and activated copper.lo6 Similar iodoarenes can be converted to the corresponding trifluoromethyl ketone via conversion to the aryl~tannane."~ This latter transformation is catalysed by palladium complexes and a variety of carbonylation processes are similarly promoted.1os A general review of the synthesis of diary1 ketones by such a strategy has been published.1o9 In related processes triaryl- bismuth may be employed as the arene source in a rhodium(1) catalysed coupling reaction,"' whilst iron pentacarbonyl can be used in an aqueous phase version of this synthesis.'" Directed metallation of the arene provides an alternative option for regio- control.'12 Such a process may then be combined with a transition metal catalysed acylation ~equence."~ In an interesting variant on this strategy activation of the ortho hydrogen of an aromatic ketone is possible on treatment with the ruthenium dihydro complex [Rh(H),CO(PPh,),], and a full account of this work has been p~blished."~ Benzyne combines with ketene silylacetals with high selectivity to provide access to benzocyclo- butanones with the regiochemistry controlled by the nature of the aryne ~ubstituents."~ The Lewis acid promoted rearrangement of 3-aryl-P-sultams provides aryl ketones or substituted arylethanals in good overall yield.'l6 Aryl methyl ketones are obtained through the reaction of Fischer carbene In addition to promoting the Friedel-Crafts Enhanced reactivity with acylating agents can complexes with chloromethyllithium.'17 Finally, two unusual transformations which produce aryl carbonyl units have appeared. Flash vacuum pyrolysis of 1 ,Zdialkoxybenzene affords mixtures of o-hydroxybenzaldehyde1l8 whilst treatment of a,P-epoxy ketones with the Vilsmeier reagent leads to moderate yields of 2,3-di~hlorobenzaldehydes.'~~ 3 Synthesis of cyclic ketones Cyclopropanone ketals are routinely accessed from ethyl P-halopropionate by treatment with sodium metal and trimethylchlorosilane.However, these conditions can cause difficulties with more complex substrates and the use of highly activated zinc has been advocated.'20 The ring strain associated with cyclopropanes also aids the oxidation of bicyclo [3.1 .O] hexanols to the corresponding 3-bromomethyl ketone.12' Fully protected glycols may be oxidised to 2,3-dihydropyranones by hypervalent iodine reagents.'" The same class of products are also accessible through the asymmetric heteroatom Diels-Alder rea~ti0n.I~~ Oxidation of allylic, benzylic or cyclic alcohols can be achieved by conversion to the diazoacetate followed by rhodium mediated diazoalkane decomp~sition.'~~ Although the yields are only moderate this represents the first reported examples of this particular pathway.The normal pathway for transition metal catalysed decomposition of diazocarbonyl compounds is via C-H insertion and this has been exploited in a number of cyclic ketone syntheses.l3 Cyclic a-diazo P-diketones undergo a photochemically induced ring contraction to the corresponding a-amido cyclic ketone.126 Full details have appeared on the thermolysis of bis(diazo- methyl ketones) to afford cyclic en one^.'^^ Both five- and six-membered rings can be generated with, notably, trans-hydroindenones being accessible in excellent yield, albeit with the proviso that non- symmetrical substrates produce isomeric mixtures.Owing to difficulties in the preparation of the corresponding bis(diazomethylketones), synthesis of cis-hydroindenones is limited in efficiency. However, these are routinely accessible by classical methods and consequently this represents a complementary study. The synthesis of cyclopentenones is dominated by the Pauson-Khand reaction and variants thereof.12' Developments have included the extension to different substrates including a11ene,129 electron deficient alkenes13' and terminal alkyne~.'~' The latter also appear in a catalytic rhodium mediated cyclisation of diyne~."~ Alkynes combine with /?-amino Fischer chromium carbene complexes to form enaminocy~lopentenones.~~~ Different isomeric products are obtained depending on the solvent used.Whereas the vinylcyclopropane-cyclopentene rearrangement proceeds with loss of stereochemical integrity, the corresponding rearrangement of cyclopropylchromium carbene complexes occur with retention of c~nfiguration.'~~ Steel: Aldehydes and ketones 155Cyclopropyl intermediates are also involved in the condensation of y-methoxy vinyl sulfones with a second vinyl sulfone to afford, after hydrolysis, P-cyclopentyl dienones (Scheme 6).i35 This is a further modification of previously reported methodology for the synthesis of P-alkylated cyclic en one^.'^^ Developments to this strategy have now extended this approach to the synthesis of cyclo- pentenone derivatives which previously underwent preferential self ~0ndensation.l~~ Sulfone stabilised anions are also employed in the annulation of a cyclopentanone ring to a pre-existing cyclic a-sulfonium e n ~ n e .' ~ ~ i. Bu'U SOpPh MeO' 1. 5% HCI, THF ii. DBU, MeCN, refiux I n $2" U - 95% Scheme 6 Nazarov cyclisations frequently produce complex mixtures of isomeric cyclopentenones. However, substrates containing a difluoromethylene unit react rapidly at room temperature to afford a single isomer in excellent yield, and this result is attributed to the p-cation destabilising effect of fluorine. However, for optimal yields the use of highly solvating 1,1,1,3,3,3-hexafluoropropanol is required as a co~olvent.'~~ 2,4-Diene- 1,6-diones undergo intramolecular Michael reactions to afford cyclopentenones in moderate yields although the substituent requirements for this pathway are high.140 The nature of the substitution pattern in 1,4-diketones can markedly effect the chemo- selectivity of the aldol cyclisation (Scheme 7).14' The basic nature of many of these cyclisations frequently results in isomerisation of the olefin. This can be avoided in a 'Robinson type annulation' of cyclo- pentenones through a strategy involving alkylation with (Z)-3-bromo-l-i0dopropene.'~~ One pot, five step (imine-enamine tautomerisa- tion, alkylation, aza-Cope rearrangement, Mannich cyclisation, elimination) strategy has been developed for the synthesis of cyclopentenones from aldehydes (Scheme 8). However, in the single example given the level of diastereoselection obtained at the newly formed chiral centre was 1 MeCNp800C rearrangement Mannich readion 1 J 40% overall Scheme 8 A number of Wittig based strategies have been developed for the synthesis of cycl~pentenones.~~~ Notably, stabilised Wittig reagents (e.g.Ph3P=CHC02But) couple with vinyl vicinal tricarbonyl units to produce a cyclic enone in good yield. In a similar fashion a variety of stabilised carbon nucleophiles react to produce cyclo- ~entanedi0nes.l~~ Such stabilised Wittig reagents i. Mg(OMe), MeOH ii. NaOH (aq.) 0 9 1 0 + 9 1 i. Mg(OMe)z, MeoH ii. NaOH (aq.) Me0& 0 7% Scheme 7 156 Contemporary Organic Synthesiscombine with cyclopropanones in a general ring expansion sequence to substituted cyclobutanones from cyclobuta-l,3-diones'48 whilst an efficient ultrasound promoted route to the 1,2-dione has been published.149 Ring expansion of cyclobutanones to cyclopentanones is simply and efficiently achieved upon treatment with samarium iodide-diiodo- methane, although mixtures of regioisomers occur with non-symmetrical Reaction of carbenoids with an alkyne affords 2-ynones in addition to the expected cyclopropenone. A recent report has developed this observation into a general method for the ring expansion of cyclic alkynes to the homologous 2-yn0nes.l~~ A large number of other reports have appeared, detailing ring expansion routes to cyclic ketones promoted by - amongst - Lewis oxidising agents'', and free radical initiator^."^ However, many of these involve multiple steps and/or are substrate specific, and although efficient, the overall yields are only moderate.Medium to large ring-fused tricyclic ketones can be prepared by a sequential Type 2 intramolecular Diels-Alder cycloaddition - ozonolysis - aldol condensation strategy.156 Polycyclic ketones are obtained with excellent control via tandem Diels- Alder rea~ti0ns.l~~ Similar products have also been prepared through a tandem radical cyclisation- Diels-Alder cycloaddition approach. Seven-membered ring ketones are approachable through the TiC1,-promoted intramolecular [4 + 31 cycloaddition reaction of oxyallyl cations. Harmata has examined the diastereoselectivity of this process.158 Oxyallyl cations also combine with olefins in a [3 + 21 cycloaddition to produce cyclo- pentenones. In contrast to most earlier reports, an excess of the olefin trap is not required when bis- sulfenyl ketones are used as the oxyallyl cation precursor.1s9 [6 + 21 Cycloadditions of chromium cycloheptatriene complexes with heterocumulenes are precedented.16' A recent report has demonstrated that chromium carbenes are also suitable 2n components in this process although the present yields are low.The development of efficient asymmetric ketene equivalents continues. The dithiolane dioxide 4 proves to be both accessible and selective.16' An alternative strategy is to use a chiral vinyl sulfate in an intramolecular cycloaddition.'62 +A -O - - "Y" ' O- 4 Bicyclic ketones have also been accessed from substituted cyclic ketones with the crucial bond formation achieved either by anionic16' or free radical cy~lisation.'~~ The latter, mediated by Mn(OAc)3, provides a method for free radical alkylation with alkenes, albeit one limited to products which cannot undergo enolisation.Bridgehead functionalisation of bicyclic ketones is normally difficult and Eaton has introduced the 1,2,4-trihydroxycyclopentane ketal as a controlling group for this operation (Scheme 9).165 I Scheme 9 PhI(0Ac)p d C " 0 & 87% Free radical cyclisation of 6-bromo-6-stannylacyl- silanes provides moderate to excellent yields of the cyclopentanone derived silyl enol ether via a Brook type rearrangement of an a-silyloxyl The anionic Brook rearrangement forms an integral part of the condensation of p-silyl a,P-unsaturated acylsilanes with the conjugated dienolate 5 (Scheme 10). 167 TBS 0 TBSO b \ --Ps 84% Scheme 10 Cyclohexanes are classically prepared by the Dieckman cyclisation.This can theoretically proceed to give two products. Control of the regiochemistry is possible through either base or Lewis acid Steel: Aldehydes and ketones 157bopB 74% 7096 scheme11 promotion (Scheme 11).'68 Attempts to achieve chemoselectivity through the use of Weinreb amides is not always successful with the product ratio depending on the precise conditions employed.'69 Although not intended, the Dieckman cyclisation of chiral bis-oxazolidinones can proceed with high diastereoselectivity and this can provide an efficient entry to enantiopure cyclohexan~nes.~~~ In a homologation of earlier reports cyclo- hexenones are prepared through the copper- catalysed addition of wester functionalised organozinc reagents to yn~ates.'~' Similar products are obtained in good yield from the ruthenium catalysed condensation of 2 equiv.of a P-ketoester with an allylic alcohol or amine.172 Finally, intramolecular umpolung strategies have been employed in the synthesis of cyclic ketones. Electrolytic reduction of a, co-ketoacids in the presence of tributylphosphine affords the corre- sponding a-hydroxycyclic ketone in moderate ~ie1ds.l~~ The reaction is believed to proceed via reduction of an acyl phosphonium salt. Treatment of the cyanohydrin 6 with KHMDS leads after hydrolytic workup to the keto lactol7 (Scheme 12), and this represents the first example of the reaction of a cyanohydrin anion with a lactone ele~trophile.'~~ TBSOyCN i. KHMDS, THF, -78 "C ii. TBAF, rt Ui.NaOH (aq.), E t g , rt HO 6 7 61% Scheme 12 4 Protection and deprotection strategies In the search for milder conditions for protection and deprotection, the use of diallyl acetals has been advocated. Selective deprotection is promoted by rhodium(1) catalysis whilst formation is routinely achieved following the Noyori protoc01.'~~ A modified version of this process has been developed for the mild introduction of the dioxolane a~eta1.l~' a, @-Unsaturated aldehydes are efficiently protected as the dioxolane in the presence of MgS04.177 A significant rate enhancement is observed in the formation of all dioxolanes through the use of microwave irradiati~n'~~ whilst substrate selectivity is obtained in the presence of mont- morillonite clays.'79 Methods for the selective protection of either component of cc-keto aldehydes have been published.18' Geminal diacetates have been advocated as acid-stable, base-labile protecting groups; their efficient synthesis can be achieved in the presence of a fl-zeolite.'81 Acetals may be converted to mixed acetals on treatment with appropriate nucleophiles (eg.thiols, etc.) in the presence of a dicyano ketene acetal as a novel n acid catalyst.182 Oxathiolanes can similarly be prepared through the use of TMSOTf or bismuth(rI1) salts as strong ~ata1ysts.l~~ These also promote the formation of dithioacetals. Selectivity in the preparation of the latter is observed through the use of catalytic amounts of CAN (ceric ammonium nitrate) as the promoter. Aldehydes react with ketones and cyclic ketones in preference to acyclic and aromatic ketones.'84 Selenium dioxide has been suggested as an efficient reagent for the deprotection of dithioacetals.However, an excess is required and the use of acetic acid as the solvent is e~sentia1.l~~ Oxathiolanes are much more labile and these can readily be exchanged with a polymer bound nitrobenzaldehyde residue. The same reagent is also effective for the conversion of thioketones to ketones."' Molybdenyl(v1) acetylacetonate proves to be a mild and efficient catalyst for the deprotection of a range of acetals and ketal~.'*~ The latter are efficiently cleaved by NO2 but acetals undergo oxidation to a-hydroxy esters.'88 a-Chloro acetals are converted to the corresponding a-chloro aldehyde upon treatment with a combination of acetic anhydride and acetyl chloride.Although a-bromo acetals are substrates, halogen exchange also occurs.189 Enol ethers represent an alternative mode of protection; an efficient mild synthesis of this functionality from chiral alcohols has been reported.'" Protection/deprotection strategies reduce synthetic efficiency; methodology which avoids this has been reported. Commins has previously reported that aldehydes could be masked in situ through the formation of amide base adducts. Higher stabilities in this process can be obtained through the use of Weinreb amide.'" In a similar vein Yamamoto has extended his work on the protection of carbonyl groups through the use of bulky aluminium Lewis acids. In these latest reports the promotion of 1,4 (conjugate) addition to enones in preference to 1,2-addition at alkyllithium reagents is 0ut1ined.l~~ 5 Synthesis of functionalised aldehydes and ketones 5.1 Unsaturated aldehydes and ketones Oxidation of enol silanes (silyl enol ethers) to the corresponding enone using stoichiometric palladium 158 Contemporary Organic Synthesisreagents is well established.Larock has developed a procedure in which this conversion can be achieved using catalytic quantities of the palladium Alternatively, this conversion can be efficiently realised using CAN in DMF.'94 Electrochemical oxidation of the corresponding enol acetate also provides the enone. However, this process is only efficient if a B-trimethylsilyl group is present.'" More traditionally, unsaturation is introduced in a two step procedure involving activation and elimination.This can be achieved in a one pot process using potassium enolates and methoxy- phenyl sulfoxide as the ele~trophile.'~~ Similarly the nitro group can function as the leaving group; this forms part of a multistep elongation of aldehydes to enedi~nes.'~~ Similar products can be obtained from the photochemical addition of 302 to fur an^.'^^ In this latter case the olefin is exclusively of cis geometry. Steroidal enediones are accessed through the PCC oxidation of the corresponding allylic alcohol." a, /3-Unsaturated aldehydes are formed on treatment of isoxazolines with methyl iodide. The yields are only moderate unless a second oxidation step follows.2oo Oxidative cyclisation of anisole containing oximes promoted by Bu4NRe04 affords good yields of spirocyclic dienones.201 Similar products are also obtained in the radical cyclisation of a functionalised quinol.202 Linear dienones are formed in the palladium catalysed rearrangement of 2-acyl- 3-vinyl a~iridines.~'~ Aliphatic Friedel-Crafts type acylations have been explored as routes to unsaturated ketones using acyl fluoroborate salts or electrolytic reduction of acid chlorides to provide the ele~trophile.~'~ Lewis acid catalysed addition of acid chlorides to enynes affords mixtures resulting from both 1,2- and 1,4-addition, with the allenyl ketone predominating as the degree of substitution of the enyne increase^.^'^ Alkynes also couple directly with aldehydes or ketones in the presence of tin halide- tertiary amine catalyst mixtures.Good EIZ selectivity is obtained whilst the use of trimethylsilyl chloride with ketone substrates affords the P, y-unsaturated product.206 Other P, y-unsaturated ketones are available through the condensation of dienylmagnesium complexes with esters and lac tone^,^'^ the trimethylsilyl chloride promoted deconjugation of P-bromo or P-iodo enones,208 or the palladium mediated carbonylative coupling of organozinc reagents with various alkylating agents.209 ruthenium catalysed coupling of alkynes with allylic alcohols.210 Dienol derivatives undergo palladium catalysed condensation with propargyl carbonates in both inter- and intra-molecular fashion to produce mixtures of isomeric enals in moderate to good yield."' Similar results are obtained using vinylic diol carbonates.212 Isomerisation of secondary prop- 2-ynylic alcohols is possible on treatment with Wilkinson's catalyst in the presence of tributyl- phosphine.The nature of the phosphine is important as triisopropylphosphine affords allylic y, &Unsaturated aldehydes arise from the alcohols.213 Rhodium catalysts are also important in the silaformylation of alkynes. A number of reports in this area have been forth~oming.~'~ In related work the first example of germaformylation has been noted.215 Hydroformylation of alkynes is frequently complicated by concomitant reduction to the saturated aldehyde. However, good yields of the desired enal can be obtained using the bisphosphite ligand 8 developed for alkene hydroformylation."6 However, with non-symmetrical alkenes the regio- chemistry is at best moderate.OMe OMe p 9 0 Full details have been published on the use of dioxolanyl salts as acyl equivalents for coupling with alkynyl b ~ r a t e s . ~ ~ ~ There have been a particularly large number of reports for the elaboration of unsaturated trifluoromethyl ketones: these have involved reagents based on boron,219 tellurium220 and phosphorus.221 Fluorine aids an efficient homologation of ketones to the corresponding enal through treatment with difluoromethyllithium.222 One of the most common methods for the generation of unsaturated ketones is via the Wittig reaction. The direct reaction of a stabilised Wittig reagent with the ozonide derived from a terminal alkene is possible but slow. This reaction is markedly accelerated by the addition of triethyl- amine.223 Non-stabilised Wittig reagents afford mixtures of stereoisomers. Cis enals can be isomerised to the corresponding trans isomer on treatment with catalytic potassium carbonate and thioacetamide in DMF.224 Conversion of unsymmetrical 1,3-diketones to the corresponding P-haloenone was first reported by Piers; this method affords the more sterically hindered ketone.225 The alternative regiochemistry can now be attained in moderate yields by one of the three methods.226 ct-Functionalisation of enones is readily achieved via the Bayliss-Hillman reaction.The first enantio- selective strategy for this conversion has recently been developed (Scheme 13).227 Related a-methylene ketones can be obtained through the iodine mediated oxidation of tertiary allylic alcohols228 or through the palladium mediated carbonylative alkylation of bis-homoallenic through the reaction with acyl tetracarbonyl A similar transformation is possible Steel: Aldehydes and ketones 159+ CH3CH0 0 Me3SiSP, MeCN, -78 OC AA PhS' 50%, 90% de, 93% ee 1 mCPBA, -10 "C then 130 "c 55%.09% ee Scheme 13 5.2 a-Heteroatom substituted aldehydes and ketones The most common strategy for the construction of a-hydroxy ketones is via enolate ~xidation.~~' Improved conditions for the Rubottom oxidation of bicyclic silyl enol ethers have been claimed.232 Oxidation of titanium enolates with tert- butylhydroperoxide (TBHP) is possible: this represents the first recorded use of this particular oxidant for this tran~formation.~~~ Interestingly, with chiral ketones, modest to excellent diastereoselectivities are obtained.Fluoroalkyl analogues of Koser's reagent, P ~ I ( O T S ) ~ provide a stable convenient oxidant for the conversion of enol ethers to a-tosyloxy Allenes are oxidised to a-ketols by hydrogen peroxide in the presence of catalytic peroxytungstoph~sphates~~~ whilst in the presence of a ruthenium catalyst and an oxygen atmosphere TEMPO selectively converts primary alcohols to the corresponding a-ald01.~~~ Dioxirane oxidation of symmetrical diols affords the corresponding ket01.~~~ Homologation of an aldehyde to an a-ketol can be achieved under non- oxidising conditions through the reaction with benzotria~olylphenoxymethane.~~~ Katritzky has also introduced other substituents into these benzotriazole based acylanion eq~ivalents.~' In addition to the reaction with carbonyl groups to afford functionalised ketols they also function as nucleophiles with a range of other electrophiles, e.g.enones. The use of functionalised methoxymethane derivatives is a development of the original procedure of Trost who introduced the phenylsulfenylmethoxymethane reagent for a-methoxy ketone synthesis. Improvements in this latter strategy are obtained thorugh the use of zirconium or hafnium tetrachloride to catalyse the pinacol type rearrangement.240 In a similar vein, a-chloro carbonyl compounds may be accessed via treatment of the homologous carbonyl compound with lit hiodichloromet hylp henyl sulfoxide."' Sterically hindered ketones may be directly converted to the a-methoxyketone on treatment with a MeI-CC14-KOH combination under phase transfer conditions.242 ing a-silyloxyarylketones occurs with no loss of stereochemical integrity on treatment with trimethylsilyl triflate in DMS0.243 In an approach to the bryostatins, an a-silyloxy epoxide is selectively converted to the corresponding a-keto diol in the presence of silver tetrafluoroborate,244 whilst on treatment with BF3.0Et2 bicyclo-a,P-epoxyacrylates undergo a regioselective rearrangement to a-acyloxy spirocycl~alkanones.~~~ a-Hydroxy-acids, on treatment with a perfluoro acid anhydride, regioselectively afford the acyl perfluoroalkyl carbin01.~~~ Although the mechanism of this process has not been elucidated it parallels that of the Dakin-West reaction of N-alkyl N-acyl amino the hydroxymethylene aldose is catalysed by nickel ethylenediamine c~mplexes."~ The Wittig rearrange- ment of chiral allyloxyhydrazones provides efficient routes to enantiomerically enriched (63-90% ee) a-hydroxycarbonyl compounds.249 Hydrazones also prove to be effective chiral auxiliaries for the alkylation of protected hydroxyacetaldehydes.250 A variety of other chiral auxiliary mediated strategies for the production of a-hydroxy or a-amino aldehydes and ketones have been delineated.251 Both protected a-hydroxy and a-amino carboxylates may be selectively converted to the aldehyde or ketone.252 In this respect the reaction of a-acetoxy acyl chlorides with organomanganese reagents to afford the a-acetoxy ketone with complete chemoselectivity and minimal stereochemical degradation is particularly n o t e w ~ r t h y .~ ~ The generation of quarternary a-amino ketones through the rearrangement of fl-hydroxy imines has been rendered enantio~elective.~~ Enantiomeric a-amino aldehydes are produced in situ on reaction with the phenylmenthol containing phosphonate 9.255 Similar dynamic kinetic resolution strategies have also been employed with other aldehydes.256 The direct conversion of an alkene to an a-keto azide is possible through the use of hypervalent iodine reagents in combination with trimethylsilylazide. The stable azido iodinananes 10-12 have been introduced as more convenient Conversion of an aryl epoxide to the correspond- The rearrangement of a ketose to Y3 0 10 11 12 160 Contemporary Otganic Synthesisreagents for this transf~rmation.~~~ However, some of these compounds have explosive tendencies and the use of chromyl azide which can be prepared in situ has been advocated.258 The same authors have also reported the analogous preparation of chromyl nitrate for the synthesis of a-nitro ketone from a l k e n e ~ .~ ~ a-Nitro ketones are also accessed through the tin( 11) chloride mediated reaction of trichloro- nitromethane with acid chlorides.260 Regiospecific diazo transfer to non-symmetrical ketones can be achieved from the corresponding a-phenacyl ketones (Scheme 14).261 Such decarbonylative procedures are also found in the regioselective bromination of tertiary #I-keto esters.262 Perfect regiocontrol is exhibited in the bromination of enol borinates prepared via the hydrozirconation-acylation of vinyl b~rinates.’~~ Asymmetric bromination is possible using an acyl dithiane oxide chiral auxiliary. The product may be converted to the corresponding a-aminoketone, albeit with some loss of optical purity.zu * P h q 1.K2C03, Bu,NBr, ii. Me1 PhH, reflux C8H17 61 % N2+ C8H17 70% Scheme 14 Although the initial addition is not particularly selective, electrolytic fluorination of camphanyl enol ethers affords routes to enantiomeric a-fluoro been introduced as a selective electrophilic fluorinating agent. Comparisons with similar existing reagents indicate that this provides a more effective method for enolate fluorination.266 P-Dicarbonyl compounds undergo a very facile enol fluorination on reaction with diluted fluorine.267 The same reagent system is useful for the synthesis of a- and a,P-difluoro enones.268 The corresponding a-iodo enones can be obtained through the reaction of an enone with trimethylsilyl azide and iodine.269 a,a-Difluoro ketones are produced in the reaction of acetylenes with Bank’s fluorinating reagent, through the palladium(0)-mediated addition of iododifluoro- methyl ketones to allenes and via the treatment of a-hydroxy orthodithioesters with Bu4NH2F3 and 1,3 dibromodimethylhydantoin.z70 ethylthiolate efficiently leads to an a-keto thioether, probably via an SET (single electron transfer) process.27’ The latter can also be prepared through N-Fluoro o-benzenedisulfonimide has Reaction of an a-dibromo ketones with the use of the hydrazone methodology developed by de Kimpe; full details of these procedures which provide access to a range of a-substituted carbonyl compounds have been published.”’ Equally good yields of a-keto dithianes result from the reaction of tris (t hiomet hyl) methyllithium with esters.273 In addition, several routes to the seleno analogues have been reported.274 Strategies for the synthesis of other a-sulfur containing carbonyl groups have appeared including a-keto sulfones and thi~cyanates.’~~ The stereochemistry of the acylation of chiral phosphine oxides has been elucidated,276 whilst the use of chiral auxiliaries in the rearrangement of vinyl phosphonates to P-keto phosphonates results in a small but measurable asymmetric 5.3 Dicarbonyl compounds The oxidation of acyclic 1,Zdiols to diketones can efficiently be achieved through the action of hydrogen peroxide in the presence of a peroxy- tungstophosphate catalyst.278 Cyclic substrates are more resistent to oxidation.The reaction proceeds via the intermediacy of the corresponding a-ketol and these are also suitable substrates. TEMPO derivatives have previously been used for simple alcohol oxidation and a recent report extends the scope of this reaction to include the diol to diketone conversion. In this respect the yields obtained are better than those found using the Swern However, the latter is an effective reagent system for the production of aromatic 1,2-carbox- aldehydes. 280 The double acylation of oxalic acid units provides a number of opportunities for 1,Zdiketone synthesis.Full accounts have been published on the use of bis-Weinreb amidesZ8l and cyclic oxamides.28’ Oxalyl chloride is a suitable substrate for condensation with two equivalents of a magnesio- cuprate provided additional lithium bromide is added.283 The electrochemical acyloin reaction proceeds directly to afford the symmetrical diketone with no requirement for an additional oxidation step. If trimethylsilylchloride is added then the a-ketol may be isolated.2w Monoprotected 1,2-dicarbonyl compounds are produced in a multistep a-oxidation of a, P-unsaturated the dioxirane oxidation of 1,4-dioxenes to a-ketal aldehydes,286 and in the rhodium mediated decomposition of a,d-diazo ketones in the presence of a primary alcohol. However, the latter is only an efficient process for the synthesis of indanedi~nes.~~~ 2,2-Dialkylindane-l,3-diones are accessed via the Wittig-Horner reaction of phthalide phos- phonates.288 1,3-Diketones are generally prepared through a Claisen type strategy as evidenced in a biomimetic polyketide synthesis using a tetramethyl- glycoluril template 13.289 Unsaturated acyl electro- philes are not always efficient although the use of the Weinreb amide analogue may help.zw Steel: Aldehydes and ketones 16113 Difficulties in the condensation of ketones with perfluoroalkyl acyl chlorides can be avoided through the use of the morpholino enamine.291 Cyclobutanes are a suitable electrophilic component in the vanadium(v) mediated reaction with silyl enol ethers although tetrahydrofuran formation can compete.292 Alkylation using p-lactams as substrates provides modest diastereoselectivity at C-3.293 A general approach to 3-unsubstituted diary1 pentane- 1,3-diones is available via isoxazolines derived from nitryloxide-alkene cycl~additions.~~~ Hexane-2,5-dione is efficiently generated via the dioxirane oxidation of cis-diamino-1,2-dimethyl- cyclobutane.Whether this is a general transforma- tion remains to be seen.295 The conjugate additionhrapping of trimethylsilylbenzotriazole 14 provides a novel acyl anion for the synthesis of 2-ene-l,4-diones (Scheme 15). This sequence is general for the p-enone functi~nalisation.~~~ 1'4-Diketones are produced when enones are combined with (i) aldehydes in a photochemical reaction,297 (ii) furans in the presence of Lewis acids298 and (iii) nickel acylate complexes.299 The last of these also couple with a variety of alternative Michael acceptors such as nitro alkenes to afford other 1,n-diketones.Enhancements have been developed for the synthesis of bis-enones from cycloalkenones via a tandem ozonolysis-Wittig reaction.300 have been recorded. These compounds can now be generated using phenylmanganese chloride and a catalytic amount of amine base.303 In the enantio- selective deprotonation of ketones with chiral amide bases the effect of added lithium chloride is normally to raise the enantioselectivity and allows for an efficient 'external quench'. Whilst this effect has been probed, the use of -0.4 mole equivalents of zinc chloride is found to produce enhanced levels of asymmetric i n d ~ c t i o n .~ ~ Koga's work on the enantioselective alkylation of tetralone enolates has been reviewed.305 This substrate is also a favourite for studies on asymmetric enolate protonation for which excellent selectivities ( ~ 9 4 % ee) can now be observed.306 It remains to be seen how general these procedures are. a-Substituted ketones may also be resolved through enzyme mediated hydrolysis of the corresponding oxime acetates.307 Antibodies have been raised for the hydrolysis of enol ethers and the origin and extent of the enantioselectivities obtained have been discussed in some The same authors have also recorded the first antibody catalysed aldol reaction albeit with fairly modest levels of asymmetric i n d u c t i ~ n . ~ ~ There have been a number of developments in auxiliary mediated asymmetric alkylation.This can be achieved electrochemically via the concomitant decarboxylation of a malonic ester derivatives an an ally1 carboxylic acid.310 Two auxiliaries 15 and 16, suitable for the direct conversion into the free chiral aldehyde or ketone with minimal racemisation, have been introduced.311 Enantioselective trifluoro- methylation of an achiral ketone enolates is now a possibility using the CF; equivalent 17 developed by Umemoto (Scheme 16).3'2 0 0 i. LDA, E+ 11. H30* Bt = benzotriazde E = RCOCI, RCHO, RX, etc. Scheme 15 Finally there have been a number of develop- ments in the search for high activity and stereo- regularity in the olefin-carbon monoxide copolymerisation.301 In a related study polycarbonyl compounds are produced in the lanthanide promoted polymerisation of cycloalkenones.302 6 Reactions of aldehydes and ketones 6.1 The aldol reaction and other enolate additions The advantages associated with the use of Mn enolates, e.g.regioselective monoalkylation, etc., 15 16 Ph & TO- 41%, 42% 88 17 Scheme 16 Both alkenes and dienes can function as electro- philes in the presence of manganese acetate or CAN re~pectively.~'~ The latter is also suitable for the allylation of P-diketones with allyltrimethylsilane under neutral conditions,314 whilst in the presence of 162 Contemporary Oiganic Synthesiscobalt salts a number of compounds such as allylic alcohols function as alkylating agents.315 The various methods for alkylation of these dicarbonyl substrates have been surveyed.316 A problem with many of these enolate alkylation sequences is the competition between C- and 0-alkylation; now conditions have been refined for selective C- alkylation of P-diket~nes.~’~ Related to this, Zhao has reported an unusual sequence for the synthesis of homologous aldols in high diastereoselectivity through the tandem C- and 0-alkylation of cyclo- hexanone enolates (Scheme 17).’lS P-Keto ester dianions can effectively formed in situ through the samarium iodide treatment of bromo esters.319 Such metal-halogen exchange provides an alternative route for enolate generation and whilst samarium seems to be the reagent of choice a number of alternatives have also been employed.320 Scheme 17 Syn aldols, and therefore (2)-enolates, are efficiently produced in the absence of base when ketones are treated with 5 mol% titanium tetra- fluoride in the presence of an acceptor aldehyde.The alternative anti diastereoisomer is obtained thorugh the use of PhTi(OR)4MgBr in a thermo- dynamically controlled process (Scheme 18).321 PhTi(OPr‘),MgBr 72% 2 : 98 5 mot% TiF4 63% 68: 32 Scheme 18 Similar control of diastereoselectivity can be observed in the use of antimony salts in the addition of tin enolates to 2-chlorocyclohexanone.322 Tin enolates are also generated in a neutral free radical mediated aldol type process reported by Enholm (Scheme 19),32 The diastereoselectivity observed in aldol processes involving various other enolates, TBSO OR TBSO 0 0 OH Scheme 19 including those from a-azido ketones,324 enones (both free325 and manganese ~omplexed~’~) and P-hydroxy ketones (ald~ls),~” has been studied.Various factors which affect the diastereo- selectivity of the double asymmetric aldol reaction have explored including the stereochemistry of the chiral aldehyde, the metal enolate utilised and the nature of the /3-substituent, including the particular protecting group employed. Through careful choice of the reaction conditions it is relatively easy to produce the opposite sense of diastereoselection commencing from the same starting material (Scheme 20).328 To help account for these factors, particularly 1,3-asymmetric induction, Evans has described modified aldol transition Similar control can be realised through the appropriate choice of ligand in the chiral Lewis acid mediated aldol presumably involved in the titanium mediated asymmetric aldol reaction utilising the cheap commodity chemical, 2-methoxypropene.”’ The chiral ligand is that previously employed by the same group in the asymmetric aldol reaction of ketene silyl acetals. Palladium catalysis is also effective for the asymmetric aldol reaction which proceeds via an oxygen bound enolate rather than the traditional Lewis acid catalysed rne~hanisrn.~~’ Multistep strategies for the synthesis of enantiomeric aldol products have been reported using chiral sulfoxide~~~~ and nitrile oxide cycloadd~cts.~” Similarly homochiral P-amino ketones are obtained via the asymmetric Michael addition to cc, /I-unsaturated Weinreb a m i d e ~ .~ ~ ~ These products are also accessible through a nickel catalysed ketone-imine and the lanthanide mediated addition of enol ethers to in situ generated i m i n e ~ .~ ~ ~ These reactions may be carried out in aqueous THF. Other water tolerant or water stable Lewis acids have been aldol reactions of unprotected sugars in aqueous methanol using calcium hydroxide as a base have also been reported.339 Not surprisingly, in view of these developments, the stereocontrolled aldol reaction retains a pivotal An ene type mechanism is The no nu r ) I TBSO OR OH 0 : ! ! I t TPS = ButPh2Si R = MOM LHMDS, M F 95% 97 : 3 R = MeSi Bu2BOTf, Et3N, CH2C12 74% 55 : 295 Scheme 20 Steel: Aldehydes and ketones 163role in natural product synthesis. As examples, the reader is directed to the synthesis of oleandolide reported by Paterson and an approach to taxol@ from the Mukaiyama group.34o 6.2 Conjugate addition reactions Organocopper species retain a pivotal role in conjugate addition reactions.The complex mixed salts Li2CuX3 are excellent sources of copper(r) for use in the catalysed addition of Grignard reagents to enones.”’ As with many of these procedures the use of trimethylsilylchloride is recommended for optimal yields. Alternatively, novel mixed thio-alkoxy ligands have been introduced as joint lithium- copper chelators to enhance the reactivity of these reagents.”2 This can also be achieved through the use of Lewis acid activators of the enone system; a rhenium complex proves to be effective both chemically and ~tereochemically.”~ An asymmetric Lewis acid catalysed Michael addition of silyl enol ethers is also possible which exhibits high diastereoselectivity if not particularly high enantioselectivity .” conjugate addition of alkylaluminium reagents including the higher organoalanes to enones.Enals, however, only couple efficiently with trimethylaluminium.” Nickel acetylacetonate is also an effective promotor, being particularly suitable for sterically hindered enones.% As with many transition metal catalysed processes, the use of alkyl groups containing /I-hydrogens is not possible. Since only one group is transferred from the aluminium, studies of the effect of the additional ligands have been undertaken which show that the use of dialkylethoxyaluminium does not require any promoter. The use of trimethylsilyl chloride minimises the amount of copper catalyst required, although trimethylsilyl bromide completely suppresses the conjugate addition.” Addition of a silyl triflate promotes the conjugate addition of organoaluminates.Whilst 1,Zaddition can compete when alkyl group transfer is attempted, both alkenyl and alkynyl delivery is very efficient.348 The latter is not normally possible using classical cuprate methodology. 1,4-Addition of aromatic units to enones may be achieved via the palladium catalysed coupling of amino boronic acids with enones in the presence of antimony tri~hloride.~~ The principal focus of much of the work in this area remains absolute stereoselectivity. Chiral auxiliaries have been employed in both and n~cleophile~~’ with moderate to excellent diastereoselectivity being obtained.Greater emphasis is currently placed on catalytic asymmetric synthesis; this is also true of conjugate addition. With one exception the successful examples of such a strategy have employed stabilised anions.”* The exception is a report by Tomioka who employed the proline based phosphines 18 and 19 to catalyse the conjugate addition of Grignard derived cycano- cup rate^.'^^ Interestingly these afford the enantio- Copper also acts as an effective catalyst for the meric products to those obtained from the corresponding lithium reagents (Scheme 21). New inexpensive accessible chiral ligand systems have also been identified for the nickel catalysed conjugate addition of dialkylzincs to e n o n e ~ . ~ ~ ~ 58-98%ee 7681% 88 Scheme 21 Finally, macrocyclisation via the caesium carbonate mediated Michael reaction of enones and ynones affords good yields of the 14-membered ring ketone without the need for slow addition or exceptionally high dilution (0.01 M), as shown in Scheme 22.Whilst an attractive strategy, there is some evidence that the process can be substrate specific, particularly in relation to enone geometry. 355 J0 C+COa, MeCN rt, [o.ory I 90% Scheme 22 7 References 1 C. F. de Graauw, J. A. Peters, H. van Bekkum and 2 B. Zheng and M. Srebnik, J. Og. Chem., 1995,60, 3 P. H. J. Carlsen, C. Kjaerstad and K. Aasb0,Acta 4 H. S. Kasmai, S. G. Mischke and T. J. Blake, J. 0%. 5 J. Muzart and S. fit-Mohand, New J. Chem., 1995, 6 S. Ait-Mohand and J. Muzart, Synth. Commun., 1995, 7 S. Ait-Mohand, F. HCnin and J.Muzart, Tetrahedron J. 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ISSN:1350-4894    

DOI:10.1039/CO9960300151

出版商:RSC    

年代:1996

数据来源: RSC