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 (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_ _ _ _ _ _ _ ~ ~ ~ Contemporary Organic Synthesis Editorial Board Professor G.Pattenden, FRS (Chairman), University of Nottingham Professor P. D. Bailey, Heriot- Watt University Dr S. E. Gibson (nee Thomas), Imperial College of Science, Technology, and Medicine Professor P. J. Kocienski, University of Southampton Professor C. J. Moody, Loughborough University of Technology Professor E. J. Thomas, University of Manchester International Advisory Board Prbfessor E. J. Corey, Harvard University Professor S. Hanessian, Universiti de Montrial Professor M. Julia, Universiti de Paris X I (Paris-Sud) Professor P. D. Magnus, University of Texas at Austin Professor G. Mehta, University of Hyderabad Professor K. C. Nicolaou, The Scripps Research Institute and University of Professor R. Noyori, Nagoya University Professor L. E. Overman, University of California, Iwine Professor L.F. Tietze, University of Gottingen California at San Diego, La Jolla Contemporary Organic Synthesis is a bimonthly journal which aims to review and provide perspective in all aspects of methodology, selectivity and efficiency in contemporary synthesis. As well as covering all the principles and methods in functional group chemistry and interconversions, organometallic chemistry and asymmetric synthesis will feature prominently; so too will modern aspects of strategy and computer aided design, biotransformations and protecting group protocols. Special methods and techniques, such as sonochemistry, FVP, electroorganic synthesis and supported catalysis will be included as occasional articles, and the manner in which synthesis addresses problems and provides solutions in biology, medicine, agriculture, the environment and new materials, will also be encompassed.Contemporary Organic Synthesis aims to be proactive, drawing attention to new opportunities and new directions, providing timely information to the synthetic chemist who needs to keep abreast of developments in the field. Although the majority of articles are intended to be specially commissioned, the Society is always prepared to consider offers of articles for publication. In such cases a short synopsis, rather than the completed article, should be submitted to Dr S. R. Buxton, Managing Editor, Organic Publications, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF, UK.Tel +44 (0) 1223 420066 Fax +44 (0) 1223 420247 E-mail rscl@rsc.org RSC Server http://chemistry.rsc.org/rsc/ Members of The Royal Society of Chemistry may subscribe to Contemporary Organic Synthesis by placing their orders on the Annual Subscription renewal forms in the usual way. All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letchworth, Herts SG6 lHN, England. 1996 subscription rates: EEA E185, USA $350, Canada El90 (plus GST), Rest of the World &190. Contemporary Organic Synthesis is published 6 times a year in February, April, June, August, October and December. Airfreight and mailing in the USA by Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey, NJ 07001, USA and at additional mailing offices. Second class postage is paid at Rahway, NJ. USA Postmaster: Send address changes to Contemporary Organic Synthesis, c/o Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey 07001. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. 0 The Royal Society of Chemistry, 1996. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording or otherwise, without the prior permission of the publishers. Typeset in Great Britain by Unicus Graphics Ltd, Horsham, West Sussex Printed in Great Britain by Whitstable Litho Ltd, Whitstable, Kent

ISSN:1350-4894    

DOI:10.1039/CO99603FX009

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/CO99603BX011

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

ISSN 1350-4894 COGSE6 3 (3) 173-258 (1996) Contemporary Organic Synthesis A journal of current developments in Organic Synthesis VOLUME 3 NUMBER 3 CONTENTS NIWfOH OBz do Boc Recent developments in chemical oligosaccharide synthesis By Geert-Jan Boons Reviewing the literature published up to October 1995 Main group organometallics in synthesis By Martin Wills Reviewing the literature published between January 1994 and June 1995 Saturated oxygen heterocycles By Christopher J. Burns and Donald S. Middleton Reviewing the literature published between October 1994 and September 1995 Carboxylic acids and esters By Tammy Ladduwahetty Reviewing the literature published be 1 August 1994 and 31 July 1995 173 201 229 243 ween Boc ICumulative Contents of Volume 3 Number 1 1 Stoichiometric applications of organotransition metal complexes in organic synthesis (1 September 1994 to 30 April 1995) Timothy J.Donohoe 19 Saturated and partially unsaturated carbocycles (January 1994 to April 1995) Christopher D. J. Boden and Gerald Pattenden 41 The enediyne and dienediyne based antitumour antibiotics. Methodology and strategies for total synthesis and construction of bioactive analogues. Part 1 (up to 15 October 1995) Hem6 Lhermitte and David S. Grierson 65 Alcohols, ethers and phenols (August 1993 to February 1995) C. S. Hau, Ashley N. Jarvis and Joseph B. Sweeney Number 2 93 The enediyne and dienediyne based antitumour antibiotics. Methodology and strategies for total synthesis and construction of bioactive analogues. Part 2 (up to 15 November 1995) HervC Lhermitte and David S.Grierson 125 The discovery of fluconazole (up to December 1994) Ken Richardson 133 Organic halides (1 July 1994 to 30 June 1995) Stephen €! Marsden 151 Aldehydes and ketones (October 1994 to September 1995) Patrick G. Steel Number 3 173 Recent developments in chemical oligosaccharide synthesis (up to October 1995) Geert- Jan Boons 201 Main group organometallics in synthesis (January 1994 to June 1995) Martin Wills 229 Saturated oxygen heterocycles (October 1994 to September 1995) Christopher J. Burns and Donald S. Middleton 243 Carboxylic acids and esters (1 August 1994 to 31 July 1995) Tammy Ladduwahetty Articles that will appear in forthcoming issues include Saturated nitrogen heterocycles (1995) Timothy Harrison Catalytic applications of transition metals in organic synthesis (1 September 1994 to 31 October 1995) Graham J. Dawson, Justin F. Bower and Jonathan M. J. Williams Saturated and unsaturated lactones (1 August 1994 to 31 October 1995) Ian Collins Amines and amides (1995) Michael North Synthetic approaches to rapamycin Mark C. Norley Synthetic applications of flash vacuum pyrolysis (1990 to 1995) Hamish McNab Protecting groups (1995) Krzysztof Jarowicki and Philip Kocienski The synthesis of quinones (1 January 1991 to 31 December 1995) Peter T. Gallagher

ISSN:1350-4894    

DOI:10.1039/CO99603FP013

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Recent developments in chemical oligosaccharide synthesis GEERT-JAN BOONS The School of Chemistry, The University of Birmingham, Edgbaston, Birmingham B15 2Ti7 UK Reviewing the literature published up to October 1995 1 2 2.1 2.2 2.3 2.4 2.5 2.6 3 4 5 6 7 8 9 10 11 Introduction Methods for stereoselective glycosylation Glycosidic bond synthesis Neighbouring group assisted procedures In situ anomerisation Glycosylation with inversion of configuration Solvent participation Intramolecular aglycon delivery Glycosylation of 3-deoxy-2-ulopyranoso- nates (3-deoxy 2-ketoaldonic acids) Formation of 2-deoxy-glycosidic linkages Regioselective glycosylations Convergent block synthesis Chemoselective glycosylations Polycondensations and one-pot multi-step glycosylations Solid-phase oligosaccharide synthesis Concluding remarks References 1 Introduction Glycoconjugates are the most functionally and structurally diverse molecules in nature and it is now well established that protein- and lipid-bound saccharides play essential roles in many molecular processes impacting on eukaryotic biology and disease.' Examples of such processes include fertilisation, embryogenesis, neuronal development, hormone activities? the proliferation of cells and their organisation into specific tissues.Remarkable changes in the cell-surface carbohydrates occur with tumour progression, which appear to be intimately associated with the dreaded state of metastasis.' Furthermore, carbohydrates are capable of inducing a protective antibody response and this immunological reaction is a major contributor to the survival of the organism during infe~tion.~ Oligosaccharides have also been found to control the development and defence mechanisms of plank4 The increased appreciation of the role of carbohydrates in the biological and pharmaceutical sciences has resulted in a revival of interest in carbohydrate chemistry.The chemical synthesis of oligosaccharides is much more complicated than the synthesis of other biopolymers such as peptides and nucleic acids. The difficulties in the preparation of complex oligosaccharides are a result of a greater number of possibilities for the combination of monomeric units to form oligosaccharides. In addition, the glycosidic linkages have to be introduced stereospecifically ( a : p selectivity). To date, there are no general applicable methods or strategies for oligosaccharide synthesis and consequently the preparation of these molecules is very time consuming.Nevertheless, contemporary carbohydrate chemistry makes it now possible to execute complex multi-step synthetic sequences that give oligosaccharides consisting of as many as 20 monosaccharide units5 The preparation of oligosaccharides of this size is only possible when each synthetic step in the assembly of the oligosaccharide is high yielding and, furthermore, the formation of each glycosidic linkage is highly stereoselective. Apart from this, the assembly of the monomeric units should be highly convergent. This review describes the recent advances in chemical oligosaccharide synthesis. In the first part, methods for stereoselective glycosylation are reviewed and the scope and limitations are mentioned (Section 2).Next, the glycosylation of 3-deoxy-2-keto-ulo(pyranosyl)onates and 2-deoxy sugars are discussed (Sections 3 and 4). In Sections 5-8, examples of convergent oligosaccharide synthesis are presented and new glycosylation strategies for the facile preparation of saccharide building blocks are discussed. Finally, recent advances in solid supported oligosaccharide synthesis are summarised (Section 9). 2 Methods for stereoselective glycosylation 2.1 Glycosidic bond synthesis Inter-glycosidic bond formation is generally achieved by condensing a fully protected glycosyl donor, which bears a leaving group at its anomeric centre, with a suitably protected glycosyl acceptor that contains often only one free hydroxy group (Scheme l).637 Traditionally,Q the most widely used glycosylation methods utilised anomeric halide derivatives of carbohydrates as glycosyl donors.However, these compounds often suffer from instability and require relatively drastic conditions for their preparation. The introduction of the Boons: Recent developments in chemical oligosaccharide synthesis 173wo S / d X + HO-acceptor donor 1 promoter yo 0-acceptor s 4 4 R . . ors that tnfluence the a$ ratio 1. Substituent R: participating vs. non-padicipating 2. Orientation of substituent R: equatorial vs. axial 3. Type of substituents (S) in donor and acceptor 4. Type of leaving group (X) 5. Type of promoter 6. Solvent 7. Temperature 8. Pressure Scheme 1 orthoester' and imidate' procedures was the first attempt to fjnd alternatives to the glycosyl halide methodolegies.Since these original disclosures, many other leaving groups at the anomeric centre have been reported (Figure However, of these glycosyl donors, the anomeric fluorides, trichloroacetimidates and thioglycosides have been applied most widely. These compounds can be prepared under mild conditions, are sufficiently stable to be purified and stored for a considerable period of time, and undergo glycosylations under mild conditions. By selecting the appropriate reaction conditions, high yields and good a : /3 ratios can be obtained. The anomeric linkages can be classified according to the relative and absolute configuration at C-1 and C-2 (Figure 2) and they are: the 1,2-cis- and 1,2-trans-2-~-glycero series (allo-, gluco-, gulo- and galactopyranosides) and the 1,2-cis- and 1,2-trans- 2-~-glycero series (altro-, manno-, ido- and talo- galactopyranosides).Apart form these types, some miscellaneous glycosidic linkages can also be identified including: 2-deoxyglycosides and 3-deoxy- 2-keto-ulo(pyranosylic) acids. The stereoselective introduction of the glycosidic linkage is one of the most challenging aspects in oligosaccharide synthesis. The nature of the protecting group at C-2 of the glycosyl donor is a major determinant of the anomeric selectivity. A protecting group at C-2 which can perform neighbouring group participation during glycosylation will give 1,2-trans glycosidic linkages. On the other hand, when a non-assisting functionality is present at C-2 then the reaction conditions (e.g.solvent, temperature, promoter) will determine the anomeric selectivity. Also the constitution of the glycosyl donor and acceptor (e.g. type of saccharide, leaving group at the anomeric centre, protection and substitution pattern) have a major effect on the a : p selectivity. 2.2 Neighbouring group assisted procedures The most reliable method for the introduction of 1,2-trans-glycosidic linkages is based on I cosy1 halides = F, CI, Br) trichloroacetimidate !J selenoglycosides a S R thioglycosides (R = alkyl, aryl, cyanide, pyridyl) glycosyl xanthate glycosyl sulfoxide 1 ,2-epoxide lycosyl phoshorous e R = al I, Oalkyl; x = 0,'X lone pair) vinyl glycosides (R = H, Me) pentenyl glycoside N anomeric diazirines Figure 1 orthoester (R' = OR2, SR2, CN) anomeric acetate -OH reducing sugar X OR 0 pentenoyl glycoside 1 ,2-cis 1,2-mns 2-D-glycero 2-D-glycero 1 , 2 - m s 2-deoxy- 2-~-glycero glycosides Figure 2 1 ,Bcis 2-~-glycero OR 2-keto-3-deoxy- ulosonic acids 174 Contemporary Organic Synthesisneighbouring group participation of a 2-0-acyl functionality.The principle of this approach is schematically illustrated in Scheme 2. Thus, activation of the anomeric centre of 1 results in the formation of an oxonium ion 2. Subsequent neighbouring group participation of the 2-0-acetyl protecting group leads to a more stable acetoxonium ion 3. Attack of an alcohol at the anomeric centre results in the formation of a 1,2-trans-glycoside 4.Thus, in the case of glucosyl- type donors, P-linked products will be obtained and mannosides will give a-glycosides. The neighbouring group assisted glycosylation procedures are compatible with many different anomeric leaving groups and representative examples are depicted in Scheme 3. In some glycosylations, the alcohol will attack at the C-2 position of the dioxolane ring of 3 resulting in the formation of an undesired orthoester 6 (Scheme 2). For example, reaction of the glycosyl donor 7 with acceptor 8 gave only traces of coupling product 9 and a significant amount of orthoester 10 was isolated (Scheme 4).1° However, glycoconjugate 12 was isolated in a respectable 77% yield when glycosyl donor 11 was used. In this donor, the 2-0- BnO Bn:n* AcO + OAll O Y N H cc13 OBn + BzO BzO SMe BnO BzO BnO AcO AcO SMe +Ho& BnO OBn PhthN BnO PivO SPh + Q OH P i v 0 PivO ClAcO + CIA& HOB* SPh AcO PhthN R ' A o 1 R ' 4 0 4 1 HO-R' 6 5 Scheme 2 BF39Et2 - (73%) DMTST (85%) D CuBr2, Bu4NBr, AgOTf - (84%) Tf20 (80%) t SnC12, AgC104 w (72%) (All = allyl) (OBZ ,OBn B z o m i & O B n BzO BzO BnO PAC ,OBn OBn AcO PhthN BnO P i v o A o + PivO PivO PivO.PhthN BnO, Me3SiOTf,0°C ~ BnOB* + B n o & o ) BnO BnO BnO A&BnO&op BnO BnO AcO Brio Scheme 3 Boons: Recent developments in chemical oligosaccharide synthesis 175,OAc (OAc AcO F OAc AcO 7 R=Ac 11 R=PG + 'OAcw SnCI2, AgOTf 9 R=AC 12 R=Pw 10 Scheme 4 a Bz? Me I PhthN 14 AgOTf 1 13 PhthN BzO BzO 15 (43=2:1) b Bz? OBz I M e q B z + & ? ? HO SEt PhthN Br 14 I 16 a b AgOTf Figure 3 I 17 (a$ = 1:8.4) Scheme 5 acetyl protecting group has been replaced by a pivaloyl functionality.The increase in yield was explained as follows: the orthoester formation is disfavoured by the presence of the bulky rert-butyl group adjacent to the electrophilic carbon atom enhancing attack at the anomeric centre. A similar effect can be achieved by benzoyl protecting groups. In some cases, the glycosylation may also proceed via the oxonium ion 2 to give mixtures of anomers 5 (Scheme 2). For example, van Boeckel and co- workers showed" that coupling of bromide 13 with acceptor 14 in the presence of silver trifluoromethane sulfonate at -50 "C gave the dimer 15 with modest anomeric selectivity of a : /3 = 2 : 1 (Scheme 5a). Thus, although the participating benzoyl group present at C-2 of the glycosyl donor 13 should direct p-glycosidic bond formation, mainly the a-linked product was 18 (mismatched pair) I 19 (matched pair) obtained.It was reasoned that the transition state leading to the P-glycoside 18 was strongly disfavoured (mismatched pair) by severe steric hindrance (Figure 3a). It was anticipated that the use of glycosyl donor 16 with opposite chirality should give a different stereochemical outcome (double stereodifferentiation). Indeed, coupling of 16 with 14 under identical conditions afforded predominantly the P-linked dimer 17 (a: p = 1 : 8.4) (Scheme 5b). Computer modelling studies showed that in this case the transition state leading to the /?-product 19 is more favoured (matched pair, Figure 3b).In general, when in glycosylations unexpected a : P ratios or very low yields are obtained then unfavourable steric hindrance in the transition state should be considered. These unfavourable interactions may be reduced using sterically less demanding protecting groups. 2.3 In-situ anomerisation A major breakthrough in a-glycosidic bond synthesis came with the introduction of the in situ anomerisation procedure. This approach requires 176 Contemporuiy Organic Synthesisglycosyl donors with a non-participating protecting group at C-2. Lemieux and co-workers described'* that coupling of bromide 20 with glycosyl acceptor 21 in the presence of tetrabutylammonium bromide gave trisaccharide 22 mainly as the a-anomer (Scheme 6). The stereochemical outcome of this reaction was explained by the Curtin-Hammett prin~ip1e.l~ Thus, in this type of reaction, the tetrabutylammonium bromide catalyses the equilibration between the a- and /?-halides 23 and 24.This equilibrium is shifted strongly towards the a-bromide 23 since this compound is stabilised by the anomeric effect. However, the energy barrier for nucleophilic attack by an alcohol is lower for the P-halide 24. Therefore, glycosylation will take place from this intermediate and mainly x-glycosides 25 will be formed. However, an important requirement of this reaction is that the rate of equilibration is much faster than that of glycosylation. Furthermore, it is essential that the glycosylation is performed in a solvent of low polarity. In polar solvents, the reaction will proceed via an oxycarbonium ion and the anomeric selectivity will be reduced.Tetraalkylammonium halides react only with very reactive glycosyl halides. More reactive activators are required for more demanding glycosylations and nowadays a whole range of activators with different reactivities are available.6' High a-anomeric selectivities have been obtained with other anomeric leaving groups. For example, Ph ?r b @OBn + B z o w o : % AcHN OH 21 OBn BnO 20 Bu4NBr 1 Ph BzO b*o% OBn I F O B . 22 OBn BnO 26 Bn'O Bn\O I 23 Br 24 Brio Scheme 6 trimethylsilyl triflate mediated couplings of perbenzylated trichloroacetimidates at low temperature give in many cases excellent a-selectivities. Some examples have been reported in which thioglycosides and glycosyl fluorides also give high a-selectivities (Scheme 7).It has to be noted that the reaction mechanisms of these glycosylations have been less well studied. However, it is reasonable to assume that they proceed via an in situ anomerisation process. equilibration between the two ion pairs is faster than the glycosylation and many different parameters affect this requirement (see Scheme 2). Often many different reaction conditions have to be examined in order to obtain satisfactory results. Also small changes in the constitution of the glycosyl donor or acceptor may have a dramatic effect on the stereochemical outcome of a glycosylat ion. As mentioned above, it is very important that the 2.4 Glycosylation with inversion of configuration The in situ anomerisation procedure requires a fast equilibrium between an a- and P-ion pair.On the other hand, some glycosylation procedures are based on preventing this pre-equilibration and, hence, glycosylation will proceed via inversion of configuration. For example, glycosylation of a-halides 27 in the presence of an insoluble silver salt results mainly in P-glycoside formation 29.14 In this case, anomerisation of the halide is restricted because of lack of nucleophiles in the reaction mixture and therefore the reaction will proceed with inversion of configuration. A schematic illustration of the reaction mechanism is depicted in Scheme 8. Silver silicate and silver silicate-aluminate have often been applied as the heterogeneous catalyst. These catalysts have proven to be valuable in the preparation of P-linked mannosides which cannot be prepared by neighbouring group participation or in situ anomerisation.The presence of an non-participating substituent on C-2 is an important requirement for a glycosylation using a heterogenous catalyst. However, van Boeckel and co-workers have shown15 that the nature of the substituents at C-3, C-4 and C-6 also have a major effect on the anomeric ratios of the coupling products. As can be seen in Scheme 9, reaction of 30 with 31 gave dimer 32 as an mixture of anomers. However, when the acetyl group at C-3 was replaced by a benzyl group (33) then the dimer 34 was isolated mainly as the p-anomer. Reaction of a glycosyl donor having a trichloroacetyl group at C-3 (35) with 31 yielded dimer 36 as an anomeric mixture. When glycosyl donors with a 4-0-acyl group, 37 and 39, were used high levels of /?-products, 38 and 40, were obtained.Surprisingly, a glycosyl donor having a 4-0-alkyl group (41) gave 42 with lower levels of anomeric selectivity. Thus, these results indicate that an acyl group at C-3 decreases and at C-4 increases the P-selectivity. These observations were explained as Boons: Recent developments in chemical oligosaccharide synthesis 177BnoB% BnO MesSiOTf, Et20. room temp. BnO (83%, = 8:l) OBn BnO OBn BnO * o y " " BnO cc13 Brio% BnO OBn + HO BnO MeaSiOTf, Et20, mom temp. BnO (6670, a:B = %:I) v DI I U I m.n Bnb OBn BnO& BnO SEt + BnO N O M e IDCP. (83%. u J ~ Et2WCE = 5:l) .no$+ BnO BnO HoMe OBn BnO 0 OBn BnO ,OBn BZO Bn:% + H:* OTBS CuBr2, TBABr, AgOTf BnO A:%o& A d BnO * SMe (90%, a) BnO OTBS N3 SnCh.AgCIO,, -15 OC * Ad% (75%, a) BnO + H O T BnO Brio 0 7 OTPDPS BnO OTPDPS Scheme 7 Scheme 8 follows: anomeric mixtures will be obtained when the glycosylation proceeds via an oxonium ion and such an intermediate will be formed when the positive charge at the anomeric centre is well stabilised. A lone pair of the oxygen atom of the 4-O-acyl group can interact through bonds with the p(0) ring orbital. Thus, this interaction is stronger than expected with inductive effects only, and the electron withdrawing 4-O-acyl substituent suppresses oxy carbonium ion formation. Through- bond interactions are only significant when a succession of trans-bridges is available. Therefore, a 3-O-acyl group can interact only with the anomeric centre via inductive effects.Thus, destabilisation of 178 Contemporary Organic SynthesisR2tc% R'O + mo Br HO N3 30 R' = Ac; R2 = Bn 33 R' = R2 = Bn 35 R' = COCCI,; R2 = Bn 31 I 37 R' = Bn; R2 = Ac 39 R' = Bn; R2 = COCCIn silver silicate I 41 R' = Bn; R2 = All 1 7 0 (All = allyl) 32 R' = Ac; R2 = Bn; a$ = 1:l 34 R' = R2 = Bn; a:p = 1:6 36 R' = COCClj R2 = Bn; a:p = 1:l 38 R' = Bn; R2 = Ac; a$ = 1:9 40 R' = Bn; R2 = COCClj a$ = 1:lO 42 R' = Bn; R2 = All; a:P = 1:5 Scheme 9 an oxonium ion is less profound and hence more a-product will be obtained. P-Mannosides have also been prepared by direct substitution of an l-O-tosyl-a-mannoglycosyl donor.I6 However, this method has not been applied widely in oligosaccharide synthesis. Glycosylations may also proceed via inversion of configuration when performed in an apolar solvent and activated by a mild promotor.Schmidt and co- workers s h o ~ e d ' ~ that BF3 - Et,O mediated glycosylation of a-glucosyl and a-galactosyl trichloroacetimidate donors in dichloromethane or mixtures of dichloromethane-hexane give mainly P-glycosides. For example, BF3 Et20 mediated coupling of 43 with 44 in dichloromethane at -20 "C gave dimer 45 mainly as the p-anomer (Scheme 10). efficient approach for the synthesis of 1,2-cis- pyranosides employing l72-trans-g1ycosyl thiocyanates as glycosyl donors and tritylated sugar Kochetkov and co-workers have reported" an 44 CHzC12 I I 43 "'3 BF39Et2 Scheme 10 S-CEN + BnO 46 48 O-Tr d 49 S/-d + Tr-N=C=S + Tr+ Brio OR 50 Scheme 11 derivatives as glycosyl acceptors.For example, coupling of 46 with tritylated saccharide 47 gave dimer 48 as the a-anomer (Scheme 11). This coupling reaction is initiated by the reaction of the nitrogen atom of the thiocyanate 49 with a trityl cation with simultaneous nucleophilic attack by the oxygen atom of the trityl protected sugar alcohol at the anomeric centre to give an a-glycoside 50. It appears that this reaction proceeds by clean SN2 inversion at the anomeric centre. The substitution pattern of a glycosyl donor may also prevent in situ anomerisation and under appropriate conditions glycosylation will take place via SN2 substitution. For example, Danishefsky and co-workers have shown" that reaction of a 1,2-cis epoxide 52, obtained by epoxidation of a glucal 51 with dimethyldioxirane, with a sugar alcohol 53 in the presence of ZnC12 gives stereoselectively a 1,2-trans glycosidic linked product 54 (Scheme 12).However, van Boom and co-workers reported" that ZnC12 mediated glycosylation of 1,Zepoxides derived from galactal gives mixtures of anomers. Thus, in these cases, the reaction proceeds via a SN1 mechanism. Recently, Kiessling and co-workers used 172-cyclic sulfites as glycosyl donors.21 They argued that these compounds are more easily accessible and less labile than the corresponding epoxides and, hence, more appropriate glycosyl donors. Thus, osmylation of glucal 51 proceeded with high diastereofacial selectivity (19: 1) to give a 1,2-diol in high yield (91%) which upon treatment with thionyl Boons: Recent developments in chemical oligosaccharide synthesis 179BnO, BnO, 51 52 \o/ B n r a BnO / 53 BnO B n O a o BnO 7 OH I B n f n a 54 Scheme 12 Scheme 13 imidazolide stereospecifically gave the 1,2-cis cyclic sulfite 55 (Scheme 13).Exposure of 55 to lanthanide(I1r) triflate and reaction with benzyl alcohol resulted mainly in the formation of 1,2-trans glucoside 56 (10 : 1). It has not been reported whether 1,Zcyclic sulfites also give acceptable results with sugar alcohols as glycosyl acceptors. 2.5 Solvent participation The stereochemistry of a glycosylation can also be controlled by a participating marked example is the use of acetonitrile which in many cases leads to the formation of an equatorial glycosidic bond.23 Several groups have independently proposed24 that this reaction proceeds via an a-nitrilium ion 59 which is generated under SN1 conditions (Scheme 14).Nucleophilic substitution of the nitrilium ion by an alcohol will lead to P-glycosidic bond formation (60). An important requirement for the reaction is the absence of a participating functionality at C-2. donors (e.g trichloroacetimidates, fluorides, phosphates and pentenyl-, vinyl- and thio- glycosides) feature the ability to form the highly reactive nitrilium intermediates. As can be seen The most It has been shown that different types of glycosyl Scheme 14 from Scheme 15, the highest P-selectivities are obtained with reactive alcohols at low reaction temperatures. Unfortunately, mannosides give poor anomeric selectivities under these conditions. 2.6 Intramolecular aglycon delivery Recently, Stork2' and Hindsgau126 reported independently the preparation of P-mannosides in a highly stereoselective manner by an intramolecular aglycon delivery approach. In this approach, the sugar alcohol (ROH) is first linked via an acetal or silicon tether (Y = CH2 or SiMe2, respectively) to the C-2 position of a mannosyl donor and subsequent activation of the anomeric centre of this adduct 62 forces the aglycon to be delivered from the p-face of the glycosyl donor (Scheme 16).A silicon tether could easily be introduced as is shown in Scheme 17. Compound 66 was first converted to the corresponding chlorodimethyl silyl ether and subsequent reaction with 67 gave the tethered compound 68. Oxidation of the phenylsulfanyl group of 68 yielded phenyl sulfoxide 69 which on activation by the method of Kahne resulted in the selective formation of P-mannoside 70 in a 61% overall yield.The acetal tethered compound 72 could easily be prepared by treatment of equimolar amounts of 71 with 67 in the presence of a catalytic amount of acid (Scheme 18). Reaction of 72 with N-iodosuccinimide (NIS) in dichloromethane resulted in the formation of P-linked disaccharide 70 in 61% overall yield. In this reaction, no a-linked disaccharide could be detected. It is of interest to note that when this reaction was performed in the presence of methanol, no methyl glycoside was obtained. This experiment indicates that the glycosylation proceeds via a concerted reaction and not a free anomeric carbocation. Recently, Ogawa and co-workers showed2' that an intramolecular acetal can also be introduced by treatment of a mixture of a mannoside, having a methoxybenzyl protecting group at C-2 and an alcohol with DDQ.Intramolecular aglycon delivery has also been used for the preparation of 1,2-ci~-glucosides.~~ Furthermore, glycosyl acceptors have also been tethered via the hydroxy groups C-4 and C-6.29 However, in these cases the anomeric ratios in the glycosylations were rather disappointing. 180 Contemporary Organic SynthesisBnO Bno*OyNH BnO CCI3 BnO BnO BnO CCI, BnO BnO, Bn&+ow BnO Bnr%F BnO BnO BnO BnO O - 4 Bnb I B n ~ ~ o y N , , BnO Cct3 Scheme 15 Bnjn* Brio OMe .;+ Brio OMe Bg++ Brio OMe Bn3n* Brio OMe Me,SiOTf MeCN,-2O0C * Me3SiOTf MeCN, -20 'C NBS hner;~, room templ SiF4 MeCN, 0 "C - Me3SiOTf MeCN,-20°C * MesSiOTf MeCN.-2O0C * Me3SiOTf MeCN, -20 OC * .. T h o , BnO B ' o E $ q p:a = 16:l Brio OMe p:a = 24:l p:a = 1.6:l BnO p:a = 3:l p:a = 16:l BnOBnO BnO yoBn BnO -kL, p:a = 6:l BnbF2% Brio OMe B n : a o , BnO Scheme 16 Bnb AMe 61 62 1 64 63 J 65 3 Glycosylation of 3-deoxy-2-ulopyranoso- nates (3-deoxy 2-ketoaldonic acids) The above discussed methods for stereoselective glycosylations are mainly applicable to aldoses with a substituent at C-2. However, there are other types of glycosides, the preparation of which requires special consideration. ketoaldonic acid which frequently terminates oligosaccharide chains of glycoproteins and N-Acetyl-a-neuraminic acid (NeuSAc) is a cyclic I BnO AMe SPh 67 i. C12SiMe2 ii. Then67 66 I \ / BnO BnO BnO x Bnb AMe 68 X = SPh ( 69 X = S(0)Ph Bn;*o, BnO 70 OMe Scheme 17 Boons: Recent developments in chemical oligosaccharide synthesis 181BnO SEt 71 BnO SEt 72 I NIS BnO O - 7 Bnb I OMe BnO- BnO 70 BIIO I OMe Scheme 18 0 HQ II > HO HO -OH C-OH OH Kacetylneuraminic acid 3-deoxyoct-2-ulopyranosonic acid (KDO) HO YH OH 3-deoxynon-2-ulopyranosonic acid W N ) Figure 4 Some important cyclic ketoaldonic acids glycolipids of cell membranes and plays vital roles in their biological activities (Figure 4).Iy2 The use of derivatives of Neu5Ac as glycosyl donors is complicated by the fact that no C-3 functionality is present to direct the stereochemical outcome of the glycosylations. Furthermore, the electron withdrawing carboxylic acid at the anomeric centre makes these derivatives prone to undergo elimination.Finally, the glycosylation of NeuSAc has to be performed at a tertiary oxy carbonium ion. Silver or mercury salt promoted activation of bromides and chlorides of N , 0-acylated neuraminic acid esters gives, particularly with secondary sugar hydroxy groups as acceptors, only modest yields of the desired a-linked coupling product^.^' Recently, thioglycosides of neuraminic acid derivatives have been used as sialyl donors.31 These compounds are 67 PhSeOTf 73 C02Me A C O v O A c I 7 5 - Scheme 19 74 BnO% + ACO, ,OAc OMe readily available, stable under many different chemical conditions but undergo glycosylation in the presence of a thiophilic reagent [N-iodosuccinimide (NIS), dimet hyl( methylt hio)sulfonium trifluoro- methanesulfonate (DMTST) or phenyl selenyl triflate (PhSeOTf)].For example, PhSeOTf mediated coupling of 73 with 67 in acetonitrile gave mainly the a-linked product 74 (a : p = 82: 18) in a 78% yield (Scheme 19). The P-product predominated when the glycosylation was performed in dichloromethane (63%, a : p = 16:84). Apart from the coupling products glycal 75 was also isolated. Recently, effective sialylations have been reported using phosphites'* or xanthate~~~ as the anomeric leaving group. It is important to note that the anomeric phosphite group can be activated by catalytic amounts of promoter. Some indirect glycosylation methods have been described which take advantage of a temporary stereocontrolling functionality at C-3 of N e ~ 5 A c . ~ ~ For example, Ogawa and co-workers employed glycosyl donors such as 79 and it was expected that during glycosylation an intermediate episelenium ion 80 would be formed, nucleophilic substitution of which should lead to a-glycosides (Scheme 20).Essential for this strategy is the steroselective introduction of a C-3p substituent. The synthesis of 79 was started from the readily available 2,3-dehydro derivative 76. Thus, reaction of 76 with phenylselenyl acetate afforded a mixture of 77 and 78 in which the axial adduct predominated over the equatorial one. Treatment of this mixture of compounds with sodium methoxide resulted in epimerisation at C-3 (77 : 78 = 2 : 1). The epimers could easily be separated by silica gel column chromatography to afford pure 77. The undesired epimer 78 could be equilibrated to a mixture of 77 and 78.Treatment of 77 with DAST afforded the glycosyl donor 79. Silver triflate/tin(Ir) chloride mediated glycosylation in carbon tetrachloride with the secondary sugar alcohol 81 gave clean formation 182 Contemporary Organic Synthesis76 + c-- OBn AcHN OBn OBn 77 X=SePh;Y=H NaoMe c 78 X = H; Y = SePh BnO BnO- - AcHN 79 r 1 1 AgOTf, SnCI2 BuBSnH Scheme 20 82 R=SePh c 83 R = H L 81 J 80 of a-linked product 82. Finally, the phenylselenyl group could easily be removed by reduction with tributyl tin hydride to give the desired disaccharide 83. Despite the fact that this method provides a reliable approach for the preparation of a-sialic acid derivatives, it is hampered by the fact that the synthetic sequence is rather laborious. It is important to note that efficient enzymatic methods have been developed for the glycosylation of sialic acid.35 Other important 3-deoxy-2-ulopyranosonic acids are KDO and KDN (Figure 4).The glycosylation of these compounds is hampered by the same difficulties as for NeuSAc, but for these compounds no enzymatic approaches have been described yet. 4 Formation of 2-deoxy glycosidic linkages The macrolides, anthracyclines, cardiac glycosides and aureolic acids are important classes of glycosylated compounds which share the same feature; i.e. they contain 2,6-dideoxy glycosides. The introduction of a 2-deoxy : P-glycosidic linkage requires special considerations since the absence of a functionality at C-2 excludes neighbouring group assisted glycosylation procedures and furthermore enhances the lability of the corresponding glycosyl donors.36 2-Deoxy glycosyl halides have been employed in glycosidic bond synthesis; however, yields and stereochemical outcomes were often rather disappointing.36 The increased stability, ease of preparation and excellent reactivity of 2-deoxy thioalkyl (or thiophenyl) glycosyl donors makes them an ideal choice to be used as glycosyl donors.37 For example, it has been reported that reaction of thioglycoside 84 with 85 in acetonitrile in the presence of NBS gave disaccharide 86 in a good yield with high /?-selectivity (72%, a : P = 1/9) (Scheme 21).In this case, the P-selectivity probably arises from a solvent effect (participation of acetonitrile). On the other hand, Wiesner and co-workers used a participating 3-0-p- methoxybenzoyl protecting group to obtain P-selectivity (Scheme 22).38 Thus, mercury-ion assisted glycosylation of 87 gave high levels of 0 + '\% OMe Me 84 85 NBS-MeCN 0 86 OMe Scheme 21 - OMe H O W 88 ODig OpMBz ~ M B Z O V : ~ * ODig OpMBz OpMBz pMBz = para-methoxybenzyl Scheme 22 P-selectivity and it was assumed that this glycosylation proceeds via intermediate 89.However, Binkley and co-workers suggested that neighbouring group participation of a C-3 acetoxy functionality is not a major determinant of stereochemical outcome of this type of Boons: Recent developments in chemical oligosaccharide synthesis 183glyco~ylation.~~ Thiem and co-workers showed4" that S-( 2-deoxyglycosyl) p hosp horodit hioat es are also relatively stable donors for 2-deoxy-glycosyl preparation.a temporary directional functionality at C-2.41 For example, treatment of glucal 91 with NIS as an electrophile leads to the formation of intermediate 92 which is favoured by an inverse anomeric effect (Scheme 23). Nucleophilic attack by 93 from the opposite side provided the a-glycosidic linked dimer 94. The iodo derivative could be reduced with tributyl tin hydride to give the corresponding 2-deoxy glycoside 95. Recently, it was observed that treatment of various 2-hydroxy sugars with diethylaminosulfur trifluoride (DAST) resulted in a stereoselective 1,2-rnigrati0n.~~ For example, treatment of 96 with DAST gave the glycosyl fluoride 97 as mixture of anomers. Compound 97 could be used as a glycosyl donor and, depending on the solvent, a- and P-glycosides could be prepared (Scheme 24).The thiophenyl group of a coupling product 99 could be Other reliable approaches are based on the use of r 1 92 A&oBn X I Bu3SnH 94 95 X = H 93 Scheme 23 TPDPSO OH TBDMSO Meo%sph A!:* 98 OMe I OMe removed by reduction with Raney Ni to afford a corresponding 2-deoxy glycoside 100. A similar type of migration was observed when a thioglycoside having a phenoxythiocarbonyl ester on C-2 was activated with iodonium ions.43 For example, treatment of a mixture of 101(a or b) and 104 with NISRfOH gave the formation of 1,2-truns P-glucoside 105 (a or b) (Scheme 25). The reaction proceeds probably via the intermediate 102 (a or b) and 103 (a or b) which are formed after iodonium ion activation of the phenoxythiocarbonyl ester of 101 (a or b).It was noted that the glycosylation with an SEt glycosyl donor is more effective then for the SPh donor (85% and 75% respectively). However, it is well known that Raney nickel mediated desulfurisation of the SEt derivative 105a is less facile (50%, 5 d) than of SPh derivative 105b (81%, 2 h). When in this reaction a glucose-type of glycosyl donor is used then a-linked 2-deoxy glyco- sides can be obtained. tionally rigid glycosyl donors which possess a thioether bridge between the C-2 and C-6 position and these compounds have been used for the stereoselective synthesis of 2,6-dideoxy glycosides (Scheme 26).44 Chemoselective activation of the anomeric thiophenyl moiety of 107 with NIS/ TMSOTf and reaction with the hydroxy group of 108 gave mainly formation of the or-linked dimer 109 in high yield (89%).The chemoselectivity of this reaction is based on the greater reactivity of the 2,6-anhydro-2-thio glycosyl donor 107 compared to that of the 2,6-anhydrosulfenyl sugar 108 (for Toshiba and co-workers have designed conforma- s-l 101a R = E t 102a R = E t b R=Ph b R=Ph 1 [2qR 103a R = E t b R=Ph BnO 105a X = SEt OMe Bu3SnH( 106 X = H Bu3snH( 106 X = H 105b X = SPh Scheme 24 184 Contemporary Organic Synthesis Scheme 25OSE TPSO SPh HO SPh SMe + AcHN OAc TPSO 108 107 TPSO & A d I OTPS O p ? SPh 110 1 cyclothtanol NIS-Me3SiOTf 1 TPSO dk RO NW* I OTPS SPh 109 R = cyclohexyl 112 O R Scheme 26 chemoselective glycosylations see paragraph 7). The sulfoxide moiety of 109 was reduced with lithium aluminium hydride to afford 110 which was glycosylated with cyclohexanol to yield 111.Finally, reductive cleavage of the thioethers of 111 gave the 2,6-dideoxy glycoside 112. In an interesting approach to glycosides of 2-deoxy sugars, Giese and co-workers reported45 that treatment of a 2-O-phosphoryl bromide and a sugar alcohol with Bu3SnH under conditions of photochemical initiation gave the corresponding 2-deoxy glycoside. In this reaction, the phosphoryl bromide rearranges to give a 2-deoxy derivative which undergoes glycosylation. The anomeric ratios in this approach were disappointing. 5 Regioselective glycosylations In most glycosylations, the glycosyl acceptor contains only one free hydroxy group. However, when two or more hydroxy groups differ significantly in reactivity then a regioselective glycosylation can be considered.For example, 115 Scheme 27 iodonium ion promoted glycosylation of the thioglycoside 113 derived from neuraminic acid with trio1 114 in acetonitrile gave dimer 115 in a 61% yield, exclusively as the a-anomer (Scheme 27).4h The regioselectivity of this reaction is due to the greater reactivity of the equatorial alcohol compared to the axial hydroxy group. Furthermore, a C-2 hydroxy group has generally a lower nucleophilicity due to the electron withdrawing effect of the anomeric centre. It is of interest to note that the yield of this reaction is significantly higher than when performed on a galactosyl acceptor having only a free C-3 hydroxy group. It should also be realised that the procedures for the preparation of glycosyl acceptors having several free hydroxyls are often easier to conduct and, hence, may offer shorter routes to oligosaccharides.Recently, Garegg and co-workers reported4’ that glycosidation of the tin acetal of unprotected methyl galactoside gave regioselectively 1,6 linked dimers in yields of 44-81% (Scheme 28). For example, the main product obtained when methyl /?a- galactopyranoside 116 was treated first with dibutyltin oxide and then reacted with 2,3,4,6-tetra- 0-benzyl-a-D-glucopyranosyl bromide 117 in the presence of tetrabutylammonium bromide was the a-linked dimer 118 in a 78% yield. Glycosidation of the same stannylene derivative with thioglycosides 119 and 121 in the presence of dimethyl- (methy1thio)sulfonium triflate (DMTST) as the thiophilic promotor gave the 1,6 linked products 120 and 122, respectively.Owing to the participating group at C-2, the products had the expected /?-configuration. No orthoester formation was observed in these reactions. Furthermore, when the reactions were performed in the absence of stannylene activation, no reaction products or mixtures of oligomers were obtained. Ziegler and co-workers have that 1,1,3,3-tetraisopropyldisiloxane-1,3-diyl (TIPS) protected glycosides can be regioselectively glycosylated by glycosyl fluorides using BF3 - OEt, as the promoter (Scheme 29). For example, treatment of 124 with 2,3,4,6-tetra-O-acetyl-a-~-glucopyranosyl Boons: Recent developments in chemical oligosaccharide synthesis 185B n & + , BnO HO 116 Scheme 28 AcO F 123 B n & $ , BnO Brio Br 117 Bu4NBr, CH2CI2 (78%) m Bu2SnO/ I MeOH 119 * DMTST, CH2C12 (69%) I Bz:* BzO I '*' ;El DMTST, CH2C12 (64%) + BFs.OEt2 AcO BzO TBAF ( 125 R = TIPSF Bzo /JMe 126 R = H AcO A& 128 R = TIPSF TBAF 129 R = H Scheme 29 OMe HO OMe HO HO BzoB% BzO OMe HO HO fluoride 123 in the presence a catalytic amount of BF3 * OEt, in dichloromethane resulted exclusively in glycosylation at the C-6 position to give the P-linked disaccharide 125 in a 71% yield.Apart from the dimer, a small amount of the partial hydrolysed monomer was isolated. Thus, in this reaction the BF3 hydrolyses partially the silyl diether as well as activates the anomeric fluoride. The silyl group at C-4 of dimer 125 could easily be removed by treatment with a catalytic amount tetrabutyl- ammonium fluoride to give 126.When the 2,3-TIPS- protected methyl glycoside 127 was treated with 123 in the presence of BF3 - Et,O the corresponding laminaribioside 128 was solely formed. On the other hand, predominantly C-2 glycosylation was observed when methyl 4,6-O-benzylidene-a-~-glucopyranoside was coupled under various conditions with 2,3,4,6-tetra-O-acetyl-a-~-glucopyranosyl bromide. Thus, in the latter example, the TIPS-protecting group completely reverses the regioselectivity. This observation was explained by the fact that the C-2 position of 127 is sterically very congested forcing the glycosylation to take place at the C-3 position. other approach to invert expected regioselectivity (Scheme 30). They showed that mainly the 1,4-linked disaccharide 132 was formed when the cyanoethylidene glycosyl donor 130 was coupled with the di-tritylated glycosyl acceptor 131 in the presence of a catalytic amount of TrC104.The opposite reactivity of primary and secondary trityl ethers in comparison with the corresponding alcohols could be explained by the formation of an earlier transition state upon glycosylation of trityl ethers compared to that of alcohols. Thus, in such a glycosylation the electron density at the oxygen atom and not steric factors determines the regioselectivity. Recently, Kochetkov and coworkers an 186 Contemporary Organic SynthesisScheme 30 6 Convergent block synthesis Oligosaccharides can be prepared by a linear glycosylation strategy or by block synthesis.In a linear glycosylation strategy, monomeric glycosyl donors are added to a growing saccharide chain. Such an approach is less efficient than when oligosaccharide building blocks are used as glycosyl donors and acceptors (convergent approach). Glycosyl bromides have been used in block synthesis; however, results were often rather disappointing especially with labile bromide^.^" Nowadays a variety of glycosyl donors are available which can be prepared under mild conditions, are sufficiently stable to be purified and stored for a considerable period of time, undergo glycosylations under mild conditions, and by selecting the appropriate reaction conditions give high yields and good a : p ratios. These features allow the preparation of oligosaccharides by efficient block syntheses.acetimidate methodology have been exploited in the block synthesis of the prominent tumour associated dimeric antigen Lewis X (Le’).” The retrosynthetic strategy is depicted in Figure 5. In order to make efficient use of common building blocks, it was decided to disconnect the octasaccharide into two trimeric units and a lactoside residue. The trisaccharide was further disconnected into a fucose The favourable properties of the trichloro- and a lactosamine moiety and the latter was readily available from lactose. Thus, the strategy was designed in such a manner that optimal use could be made of the cheaply available disaccharide lactose. In such an approach, the number of glycosylation steps is considerably reduced. The key building blocks for the preparation of the target compound I were 133, 134 and 135.The azido-lactose building block 134 was prepared by azidonitration of lactal, followed by selective protection. The selectively protected lactoside 135 was readily available from lactose via a sophisticated protecting group interconversion strategy. a-Fucosylation of acceptor 134 with the very reactive fucosyl donor 133, under ‘inverted procedure’ condition^,^^ gave trisaccharide 136 in a 89% yield (Scheme 31). The trisaccharide 136 was converted into the required glycosyl donor 137 and acceptor 138. Thus, removal of the TBDMS protecting group of 136 with TBAF and treatment of the resulting lactol with trichloroacetonitrile in the presence of DBU afforded trichloroacetimidate 137 in a good overall yield.On the other hand, cleavage of the isopropylidene moiety of 136 under mild acidic conditions furnished 138. Coupling of glycosyl donor 137 with acceptor 138 in the presence of BF,-Et20 as catalyst gave the hexasaccharide 139 in a 78% yield. In the latter reaction, the higher acceptor reactivity of the equatorial 3-OH group with respect to the axial 4-OH was exploited. The synthesis of octasaccharide 142 required the repetition of the above described strategy, i.e. conversion of the anomeric TBDMS group into a trichloroacetimidate functionality (139441) and coupling of the trichloroacetimidate 141 with lactoside unit 135 (64%). Finally, target molecule I was obtained by reduction of the azido group of 142, followed by acetylation of the amino group and hydrogenation under acidic conditions.Using a similar approach, spacers containing dimeric and trimeric Lewis X antigens have been synthesised.”“ The described glycosylation strategy is highly convergent and makes optimal use of the common trisaccharide 136. Furthermore, efficient use was made of the commercially available dimer lactose. Finally, the trichloroacetimidates could be prepared Galp~-(l4)-GlcNacp~-(l-3)-Galp~-(l-4)-GlcNacp~-(l-3)-Galp~-(l-4)-Glc a Galpp-(14)-GlcNac + lactose t I Fucpa-( 1-3) t Fucpa-( 1-3) t Fucpa-(1-3) J 11 fucose + lactosamine cc5 135 OBn 134 Figure 5 Boons: Recent developments in chemical oligosaccharide synthesis 187BnO 1 42 i. HzS. PY ii. AczO iii. Pd-c, H2, HOAc I I Scheme 31 in high yield and these donors behaved very well in the glycosylation reactions (high yields and anomeric selectivities).The latter point requires some attention. It should be realised that some types of glycosidic linkages can be constructed rather easily whereas others impose great difficulties. In planning a synthetic scheme, the disconnections should be chosen in such a way that the block assembly will not impose problems. Furthermore, difficult glycosylations should be performed in an early stage of the synthesis. Nicoiaou and co-workers have prepared5' a trimeric LeX antigen exploiting the favourable properties of anomeric phenylthio groups (Scheme 32). As in the approach of Schmidt and co-workers, the target molecule is disconnected into a common trisaccharide (151) and a lactoside building block (152).In this case, the trisaccharide intermediate is assembled from monomers, 143, 144 and 147. Furthermore, the building blocks are assembled in a different order. Thus, coupling of 143 with 144 in the presence of silver perchlorate and tin(I1) chloride gave stereospecifically the P-glycoside 145 in a 72% yield. Selective removal of the ally1 protecting group of 145 furnished glycosyl acceptor 146 which was coupled with the fully benzylated fucosyl fluoride 147 to yield trisaccharide 148 in a 87% yield. Thioglycoside 148 was converted into a glycosyl fluoride 149 by treatment with N- bromosuccinimide (NBS) and DAST which was followed by a protecting group exchange to give glycosyl donor 151 in a 84% overall yield. presence of silver triflate (AgOTf) and HfCp2C12 Coupling of 151 with lactoside 152 in the 188 Contemporary Organic SynthesisOAc Brio 2,$? C l C H 2 C O O m ; & SPh ClCH2COO&F + H;h SPh NPhth CICH2C00 OAc NPhth CICH2C00 OPiv 143 i.H2Ru(PPh ii. TsOH. Me8H ( 146 R = H 145 R = All 144 (All = allyl) C l A c O f l ~ ~ & ~ ClAcO OwoR NPhth OR RO AcpO, py ( 151 R = Ac; X = F A OTf, Hf8p2CI2 I-- + AgC104 + SnCI2 @lBn Brio 147 H o @ i h O R OPiv HO OBZ OBZ 152 R = FC,3H27 N3 BzO, t OR thiourea ( 153 R' = OCOCH2CI 154 R'=H 151, AgOTf, HfCp2C12 r I 1 0 PivO OR OPiv CICH2C00 OAc OAc AcO 155 R = 1 AcO 156 R =2 Scheme 32 occurred regioselectively at the more reactive 3-position to give stereoselectively the penta- saccharide 153 (91%). The chloroacetyl groups of 153 were removed by treatment with thiourea and two reiterations of the coupling and deprotection procedure led to the isolation of undecasaccharide 156.Compound 156 was deprotected to yield the desired trimeric LeX antigen. This described strategy is highly convergent and minimises the number of manipulations which have to be executed at the oligosaccharide stage. Attractive features of the strategy are: (i) the stability of thioglycosides under many different chemical conditions, (ii) the ease of activation of thioglycosides by conversion into glycosyl fluorides, (iii) the high efficiency of glycosyl fluorides in glycosidic bond formation and, (iv) the excellent behaviour of thioglycosides as glycosyl acceptors. Apart from these synthetic approaches, several alternative synthetic routes for LeX have been reported.54 Martin-Lomas and co-workers reported55 a highly convergent approach for the preparation of the fully protected tetragalactoside moiety of the GPI anchor of Trypanosome brucei.In this approach the tetra- saccharide 162 was prepared from the common building block 157 (Scheme 33). Thus, the common building block 157 could be converted into the glycosyl acceptor 158 by base-mediated removal of the acetyl protecting group. Treatment of 157 with MCPBA gave the anomeric sulfoxide 159 which was coupled under the conditions described by Kahne to give dimer 160 (78%, a : p = 86 : 14). Dimer 160 was converted into the glycosyl acceptor 161 which was coupled with 159 to give the tetrasaccharide 162. The phenylthio group of 162 could be oxidised to the corresponding anomeric sulfoxide and is ready for further glycosylation.anomeric leaving group has been used. However, for the successful preparation of complex oligo- In the examples discussed above only one type of Boons: Recent developments in chemical oligosaccharide synthesis 189Thus, coupling of armed donor 163 with disarmed acceptor 164, in the presence of the mild activator iodonium di-collidine perchlorate (IDCP), gave the dimer 165 as an anomeric mixture in a yield of 62% (Scheme 34). Next, the disarmed dimer 165 could be further glycosylated with acceptor 166, using the more powerful activating system N-iodo- succinimide-catalytic triflic acid (NIS-TfOH) to yield the trisaccharide 167 (60%). Thus, this chemoselective glycosylation approach allows the preparation of a trisaccharide without a single protecting group manipulation between the glycosylations. The C-2 acyl protecting group of compound 165 performs neighbouring group participation in the glycosylation and therefore only a 1,2-trans linked product will be formed.When a 1,2-cis glycosidic linkage is required, the acyl group has to be replaced by an ether type protecting group, hence introducing additional manipulations at the oligosaccharide stage. It has also been found that cyclic acetals reduce the reactivity of pentenyl glycoside~.~’ This deactivating effect is large enough to allow a chemoselect ive glycosylation of benzylat ed pent enyl glycosyl donor 168 with cyclic acetal protected glycosyl acceptor 169 to give dimer 170 as an anomeric mixture in a modest 52% yield (Scheme 35). It should be noted that compound 170 has a non-participating C-2 benzyl functionality and coupling of 170 with a glycosyl acceptor will allow the introduction of an a-glycosidic linkage.Deactivation by cyclic acetals reflects presumably the torsial strain inflicted upon the developing cyclic oxy carbonium ion, the planarity of which is opposed by the cyclic protecting group. The pentenyl methodology has been applied to the preparation of several complex oligosaccharides.5R kOo& SPh \ OTBDMS 1 57 \ \ OTBDMS OTBDMS 159 158 n ,OAc SPh RO 160 R = TBDMS ( 161 R = H 0 OAc 162 Scheme 33 saccharides, a range of different leaving groups often need to be examined. 7 C hemoselec t ive glycosy la tions BnO BnO 6 0 pent + A;&&+OPent OAc IDCP 164 disarmed I BnO 163 armed (OBn BnO-0, BnO (OBn Bn\O AcO-opent A& An important requirement of convergent oligosaccharide synthesis is ease of accessibility of oligosaccharide building blocks.Fraser-Reid and co-workers have a chemoselective glycosylation (armed-disarmed glycosylation strategy) which allows the preparation of this type of unit with a minimum of protecting group manipulations. They have shown that pentenyl glycosides having a C-2 ether protecting group can be coupled chemoselectively to C-2 benzoylated pentenyl glycosides. The chemoselectivity relies on the fact that an electron withdrawing C-2 ester deactivates (disarms) and an electron donating C-2 ether activates (arms) the anomeric centre. Scheme 34 OAc 165 NIS/TfOH 14- 167 3 190 Contemporary Organic SynthesisOPent OBn OBn 1 70 Scheme 35 Chemoselective glycosylations have also been developed for other types of glycosides.Van Boom and co-workers showeds9 that, similar to pentenyl glycosides, the reactivity of thioglycosides towards iodonium cations can be modulated by the choice of protecting groups and it was found that a C-2 ether group activates and a C-2 ester deactivates the sulfur atom at the anomeric centre. Thus, iodonium cation mediated coupling of 171 with 172 gave disaccharide 173 mainly as the a-anomer in a 84% yield (Scheme 36). In addition, it was established Bn:*sEt BnO + BzOH&sEt BzO BnO BzO 171 172 I IDCP Bn?&?+, BnO BnO BzO&&,SEt BzO 173 BzO Scheme 36 E3n:&&E, BnO OBn 171 174 BnO, that a disarmed thioglycoside (e.g.173) could be readily activated with the strong thiophilic promotor NISEfOH. It was also found that thioglycosides are more reactive than analogous pentenyl glycosides and give often better or-selectivities. In this case, the chemoselective glycosylation approach was rationalised as follows: the electron density on the anomeric sulfur atom in a 2-0-acyl ethyl thioglyco- side is decreased, due to the inductive effect of the electron withdrawing ester functionality at C-2 and as a result, the nucleophilic complexation of the anomeric thio group with iodonium ions decreases and the thioglycoside can be regarded as disarmed with respect to an armed 2-0-alkyl thi~glycoside.~" Ley and co-workers proposedm that the armed- disarmed glycosylation strategy could gain versatility by tuning the glycosyl donor leaving group ability further.They described that a dispiroketal protecting group (R-R) has a marked effect on the reactivity of the anomeric centre and it was found that a dispiroketal protected thioglycoside (eg. 174, Scheme 37) has a reactivity between an armed C-2 alkylated thioglycoside (eg. 171) and a disarmed C-2 acyl thioglycoside (e.g. 176). The three levels of anomeric reactivity were exploited in the prepara- tion of a protected pentasaccharide unit common to the variant surface glycoprotein of Trypanosome brucei. Thus, iodonium dicollidine perchlorate mediated chemoselective glycosylation of glycosyl donor 171 with dispiroketal protected acceptor 174 gave disaccharide 175 in an excellent yield (82%, LY : /? = 5 : 2).Further chemoselective glycosylation of the torsially deactivated donor 175 with electronically deactivated acceptor 176 in the presence of the more powerful activator NIS-TfOH gave trisaccharide 177 in 63% yield as one isomer. Finally, the pseudo-pentasaccharide 179 was obtained by condensation of glycosyl donor 177 with glycosyl acceptor 178. In the armed-disarmed glycosylation approach, the leaving group ability is controlled by protecting IDCP L BnO, 37 0-Ph 1 79 u- SEt 0 177 Scheme 37 Boons: Recent developments in chemical oligosaccharide synthesis 191groups (ether-dispiroketal-ester). It may, however, be advantageous to control the anomeric reactivity by means of modifying the leaving group itself. Boons and co-workers showed61 that the bulkiness of the anomeric thio group has a marked effect on glycosyl reactivity whereby a new range of differentially reactive coupling substrates could be produced (Schemes 38 and 39).glycosylation of glycosyl donor 171 with glycosyl acceptor 180 gave the disaccharide 181 in an excellent yield of 79% as one anomer. Further chemoselective coupling of sterically deactivated donor 181 with the electronically deactivated glycosyl acceptor 172 in the presence of the more powerful promoter system NIS-TfOH gave trisaccharide 182 in a 82% yield. In both coupling reactions, no self-condensed or polymeric products were detected. These experiments show that the reactivity of a C-2 benzylated dicyclohexylmethyl thioglycoside is of an order of magnitude between the reactivities of ethyl thioglycosides having a fully armed ether and disarmed ester protecting group on c-2.The new method to control the anomeric leaving group mobility allowed the generation of glycosyl donors or acceptors with new reactivities. It was envisaged that the sterically and electronically deactivated glycosyl acceptor 184 should have a lower reactivity than the electronically deactivated Thus, IDCP mediated chemoselective B n O a BnO SEt OBn 171 + BnO Bno*8 1 80 I I IDCP t B n O a BnO BnO 181 I .OH 8 172 + BnO ,o B20% BzO SEt OBz 182 Scheme 38 192 Contemporary Organic Synthesis B z O a BzO SEt + BzO&&S BzO OBZ 183 1 a7 OMe Scheme 39 glycosyl donor 183 (Scheme 39). Indeed, coupling of glycosyl donor 183 with glycosyl acceptor 184 in the presence of NIS-TfOH gave dimer 185 in a 61% yield.Glycosyl donor 185 was coupled with 186 in the presence of NIS-TfOH and trisaccharide 187 was isolated in a good yield. The latter reaction demonstrated that a sterically and electronically deactivated substrate is still a suitable glycosyl donor. This glycosylation approach offers the largest number of reactivity levels published to date. Investigations by Danishefsky and co-workers have revealed6* that chemoselective activation is also applicable to glycals and this methodology opened the way for the efficient preparation of 2-deoxy containing oligosaccharides (Scheme 40). Thus, IDCP mediated chemoselective oxidative coupling of ether protected glycal 188 with the partly acylated glycal 189 stereoselectively gave the disaccharide 190 in 58% yield.The dimer 190 could also be activated with IDCP and reaction with glycosyl acceptor 191 yielded trimer 192 (79%). Radical mediated dehalogenation of 192 afforded the 2-deoxy glucoside containing trisaccharide 193 (94%). In another strategy,63 glycals were activated by epoxidation followed by stereoselective condensation with a partly protected glycal. After protection of the 2-hydroxy group, this procedure could be repeated. The chemoselective glycosylations described in this section allow the facile preparation of di-, tri- and tetra-saccharides. These saccharides can be used in a convergent block synthesis of larger oligosaccharides. Often the monomeric units required for the preparation of the building block can be synthesised from a common unit.It should1 IDCP BzO 190 IDcpl-- Ph3SnH AlBN 0 191 x ( 192 R = I x 193 R = H Scheme 40 be noted also that other glycosylation strategies (e.g latent-active@ and orthog~nal~~ glycosylations) have been developed which allow efficient preparation of oligosaccharide building blocks. 8 Polycondensations and one-pot multi-step glycos yla t ions The glycosylations discussed above utilise a fully protected glycosyl donor which is condensed with an appropriately protected glycosyl acceptor to give a well defined product. On the other hand, the use of a glycosyl donor having a reactive alcohol or ether functionality will result in polymerisation.h6 For example, when an 0-trityl ether (Tr) and a cyano- ethylidene group are present in the same molecule ,OTr CN 1 94 Scheme 41 TrCIOd (e.g.194) then under glycosylation conditions polymerisation will take place. For example, treatment of 3,4-di-O-acetyl-l,2-O-cyanoethylidene- 6-O-trityl-a-~-glucopyranoside (194) with a catalytic amount of tritylium perchlorate (10-20 mol%) resulted in polycondensation giving 195. The reaction gave compounds with a molecular weight of approximately 3000-4000 (Scheme 41). It has been found that for some reactions an increase in the degree of polymerisation can be obtained by applying high pressure. It should be mentioned that also other substrates have been used in this type of polymerisation reaction. glycosylations have been reported. Kahne and co- workers described67 a glycosylation method that is based on activation of anomeric sulfoxides with triflic anhydride (Tf20) or triflic acid (TfOH).Mechanistic studies revealed that the rate limiting step in this reaction is triflation of the sulfoxide; therefore the reactivity of the glycosyl donor could be influenced by the substituent in thepara position of the phenyl ring and the following reactivity order was established OMe > H > NO2. The reactivity difference between a p-methoxyphenyl sulfonyl donor and an unsubstituted phenylsulfonyl glycosyl acceptor is large enough to permit selective activation. In addition, silyl ethers are good glycosyl acceptors when catalytic triflic acid is the activating agent but react more slowly than a corresponding alcohol. These features opened the way for a one-pot synthesis of a trisaccharide 200 from a mixture of monosaccharides 196,197 and 198 (Scheme 42).6* Thus, treatment of this mixture with triflic acid resulted in the formation of trisaccharide 200 in a 25% yield.No other trisaccharides were isolated and the only other coupling product was dimer 199. The products of the reaction indicate that the glycosylation takes place in a sequential manner. First, the most reactive p-methoxyphenylsulfenyl glycoside 197 was activated and reacts with alcohol 198 and not with the silyl ether 197. In the second stage of the reaction, the less reactive silyl ether of disaccharide 199 reacts with the less reactive sulfoxide 196 to give trisaccharide 200. The phenylthio group of trisaccharide 200 could be oxidised to a sulfoxide which was used in a subsequent glycosylation.The obtained trisaccharide Recently, more controlled methods for sequential HO AcO A&-:-]" ~ OAc AcO OH AcO OAc 195 (n = 15-20) Boons: Recent developments in chemical oligosaccharide synthesis 193W i P h W i G 0 . e wSph HO OBn 198 197 TMSO OBn O0 196 Slow HSPh - e0 0 wo 2oo Scheme 42 B n O w s E t OBn OBn &HsEt 201 OMe 202 OMe &H OMe 203 NISTTfOH 203 205 Scheme 43 is part of the natural product ciclumycin 0 and despite the relatively low yield of the coupling reactions, this methodology provides a very efficient route for this compound. It has, however, to be proven whether this methodology is applicable to a wide ranger of glycosyl donors and acceptors. Ley and co-workers reported" a facile one-pot two-step synthesis of a trisaccharide unit 205 which is derived from the common polysaccharide antigen of a group B Streptococci.The trisaccharide was assembled from the beiizylated rhamnoside 201 and the cyclohexane-1,Zdiacetal (CDA) protected rhamnosides 202 and 203 (Scheme 43). The preparation of 205 is based on the armed-disarmed glycosylation strategy and exploits the fact that the activated thioglycoside 201 is more reactive than the torsially deactivated CDA protected rhamnoside 202. Thus, NIS-TfOH mediated chemoselective coupling of 201 with 202 gave dimer 204. Next, the second acceptor 203 was added to the reaction mixture and the disaccharide 204 could be activated by the addition of another equivalent of NIS and a catalytic amount of triflic acid to afford the trisaccharide 205 in an excellent overall yield of 62%.It is of interest to note that a stepwise preparation of 205 resulted in a lower overall yield. This glycosylation approach was also employed for the preparation of a tetramannoside. Recently, one-pot multi-step glycosylations have been reported in which glycosyl donors and acceptors having different types of anomeric groups were used.70 The described glycosylation strategies allow the construction of several glycosidic linkages by a one- 194 Contemporary Organic Synthesispot procedure. It should, however, be realised that this type of reaction will give only satisfactory results when all the glycosylations are high yielding and highly diastereoselective. For example, it is generally known that rhamnoside donors often give very high a-selectivities.Furthermore, by exploiting neighbouring group participation it is easy to form 1,2-trans-glycosides. Other type of glycosidic linkages may impose problems. 9 Solid-phase oligosaccharide synthesis Inspired by the success of solid-phase peptide and oligonucleotide syntheses, in the early seventies several research groups attempted to develop methods for solid supported oligosaccharide ~ynthesis.~' However, since no powerful methods for glycosidic bond formation were available, the success of these methods were limited and only simple di- and tri-saccharides could be obtained. solid supported synthesis of a D-galactofuranosyl heptamer. The synthetic approach which was followed is illustrated in Scheme 44. The selectively protected L-homoserine 206 was linked to the Merrifield polymer chloromethyl polystyrene (PS = polystyrene) 207 to give the derivatised polymer 208.The loading capacity of the polymer was 0.5 mmol g-' resin. Acid hydrolysis of the trityl group of 208 gave 209 and coupling of the chloride In 1987, van Boom and co-workers reported7' the 206 207 (PS = polystyrene) 210 with the immobilised 209 under Koenigs-Knorr conditions afforded the polymer linked homoserine glycoside 211. It was observed that the coupling reaction had not gone to completion and to limit the formation of shorter fragments, the unreacted hydroxy groups were capped by treatment with acetic anhydride in the presence of pyridine and N,N-dimethylaminopyridine (DMAP). Elongation of 211 was performed as follows: the levulinoyl (Lev) group of 211 was removed by treatment with a hydrazine-pyridine-acetic acid mixture, the released alcohol was coupled with chloride 210 and the unreacted hydroxy groups were capped by acetylation.After repeating this procedure five times (n = 6), the heptasaccharide 216 was released from the resin by basic hydrolysis. Under these conditions also the benzoyl and pivaloyl (Piv) protecting groups were removed. Finally, cleavage of the benzyloxycarbonyl ( Z ) group by hydrogenolysis over Pd-C gave 217 in an overall yield of 23%. Kahne and co-workers described73 the solid supported synthesis of oligosaccharides using anomeric sulfoxides as donors. In the procedures of van Boom and Kahne, the anomeric centre of a saccharide is linked to the solid support and glycosyl donors are added to the growing chain.Recently, Danishefsky rep~rted'~ an inverse approach in which the incoming sugars are glycosyl acceptors. The basic strategy involves NHZ 208 R = Trit - c 209 R = H P 0 212 n = 2 213 n = 3 214 n = 4 215 n =5 216 n = 6 21 6 I (ii, iii, i) r 1 n times n t I NHZ w r i v OBz I r 1 Reagents : (i) Hs(CN)~, HgBr,, 144; (ii) Ae0, pyridine, DMAP; (iii) NH2NH2, HOAc, pyridine Z = benzyloxycarbonyl; Lev = levulinoyl; Piv = pivaloyl Scheme 44 Boons: Recent developments in chemical oligosaccharide synthesis 195attachment of a glycal to a polymer support, followed by epoxidation to provide a 1,Zanhydro- derivative. This polymer-bound glycosyl donor is then treated with a solution of a protected glycal, acting as a glycosyl acceptor, to give a polymer- bound disaccharide.Reiteration of this reaction sequence provides larger oligosaccharides which ultimately are retrieved from the support (Scheme A commercially available 1 % divinylbenzene- styrene copolymer was employed and the glycal was attached to this resin using a diisopropylsilyl ether linker. Such a linker is stable under the employed reaction conditions but can be cleaved by fluoride ion treatment. In previous studies a diphenyl- dichlorosilane linker was used; however, it was shown that this linker was inferior to the diisopropylsilyl linker.74b Lithiation of the copolymer followed by quench- ing with diisopropyldichlorosilane provided 218. The silylated polymer was reacted with a solution of galactal 219 in dichloromethane and Hunig's base to give the corresponding dialkylsilyl linked polymer construct 220.The loading of the solid support was 0.9 mmol g-' resin. The double bond of the polymer bound glycal 220 was activated by epoxidation with 45). i. BuLmEDA 21 8 1% divinylbenzene- styrene copolymer 0 OH 1 222 i. !A. 3,3-dimethyldioxirane and the epoxide 221, thus obtained, was reacted with a tetrahydrofuran solution of 219 in the presence of ZnC12 to give the polymer bound dimer 222. The glycosidation procedure required a 6-10 fold excess of solution based glycosyl acceptor and 2-3 equivalents of promoter. However, in some reactions less acceptor and shorter reaction times have been applied. It should also be noted that no glycosylation at the 2-position was observed.Twice repetition of this two-step procedure (epoxidation, glycosylation) provided a polymer bound tetrasaccharide 225 which was released from the solid support by treatment with tetrabutyl- ammonium fluoride (TBAF). The method allowed the preparation of the tetrasaccharide 226 in a 74% overall yield. An advantageous aspect of this solid supported approach is that no capping step is required because any unreacted epoxide will hydrolyse in the washing procedure. On the other hand, in the case of a very difficult glycosylation step, most of the solid supported linked glycosyl donor may decompose lowering the overall yield. In the procedures of van Boom and Kahne, excess of donor can be used to achieve acceptable yields in difficult glycosylation reactions. OSiPr',Ph(S) 0 21 9 220 t 21 9 ZnCh 4 C - ii. ZnC12.THF 224 221 '0 0 OH 1 BnO 225 R = SiPr12S 226 R = H Scheme 45 196 Contemporary Organic SynthesisPhthN ~0% BzO OMe OMe 230 OSuPEG 232 Scheme 46 The rate of reactions on a solid support are generally reduced compared to solution based methods. Krepinsky and co-workers addressed this problem by a polymer-supported solution synthesis of oligosaccharides (Scheme 46).75 This strategy is based on the fact that a polyethylene glycol polymer supported saccharide is soluble under conditions of glycosylation but insoluble during work-up. Poly(ethy1ene glycol) monomethyl ether (PEG) was coupled through a succinic (Su) ester linkage to a carbohydrate hydroxy group. When PEG is bound to a carbohydrate, a glycosylation reaction can be driven to completion by repeated addition of the glycosylating agent.For example, in the silver ion mediated coupling of 230 with 231 to give 232, several portions of the bromide were added until the reaction had gone to completion. The progress of the glycosylation could be monitored by NMR spectroscopy. After the reaction had finished, the PEG-bound product was precipitated by the addition of diethyl ether. Subsequently, the crude polymer was recrystallised from ethanol and after drying was used in the next synthetic step. The PEG-succinimide linkage could be cleaved by DBU- catalysed methanolysis in dichloromethane. Recently, PEG was bound to the anomeric centre of a saccharide via an a, a’-dioxyxylyl gly~oside.~~ This linkage is stable under many chemical conditions including glycosylation but can be cleaved by hydrogenolysis.The PEG-based methodology has been used for the preparation of a heptaglucoside having phyto-alexin elicitor and other oligosa~charides.~~~-~ eliminate time-consuming work-up procedures and purification steps. However, despite recent advances, only relatively simple oligosaccharides have been prepared by these methods and the glycosidic linkages of these oligosaccharide were 1,2-trans linked. The polymer support based glycosylation methods 10 Concluding remarks Nowadays a range of glycosyl donors, such as trichloroacetimidates, thioglycosides and fluorides, can be prepared by standard procedures and these compounds have a reasonable shelf-live and can be used confidently in glycosylations.Several methods have been developed to control the anomeric selectivity of glycosylation reactions. These approaches are in many cases unreliable and often modest CI : p selectivities are obtained. It should be realised that often many reaction conditions need to be examined to achieve acceptable results. Nevertheless, contemporary carbohydrate chemistry makes it now possible to execute multistep synthetic sequences that give complex oligosaccharides. Convergent strategies have been developed which make efficient use of common building blocks. In this respect, chemoselective glycosylations allow the preparation of saccharide building blocks without extensive protecting group manipulations. Several polymer support based glycosylation methods have been reported.However, only relatively simple oligosaccharides have been prepared by these methods and the glycosidic linkages of these oligosaccharide were often 1,Ztrans linked. Problems associated with basic glycosylation methodology need first to be addressed before solid oligosaccharide synthesis can be introduced as a general method. An attractive alternative for solid-phase oligosaccharide synthesis may be one-pot multi-step glycosylations. This type of methodology allows each glycosylation step to be monitored but reduces time-consuming work-up and purification steps. In order to overcome problems associated with chemically based methods, combined enzymatic approaches have been developed. In such an approach, glycosidic linkages which are very difficult to introduce chemically are introduced enzymati- cally and vice versa.The latter approach has proven to be extremely valuable for the introduction of neuramic acid units in an oligosaccharide. It should be realised that the number of enzymes available to perform these transformations are limited. 11 1 2 3 References A. Varki, Glycobiology, 1993,3, 97. ( a ) S. Hakomori, Cancer Res., 1985, 45, 2405; (b) J. Kellerman, F. Lottspeich, A. Henschen and W. Muller- Esterl, Eul: J. Biochem., 1986; 154, 471; (c) J. Montreuil, Adv. Carbohydr Chem. Biochem., 1980, 37, 157. ( a ) N. Sharon, Trends Biochem. Sci., 1984, 9, 198; (b) S. Hakomori and A, Kombata, in The Antigens, ed. M. Sela, 1974, vol. 11, p. 79. Boons: Recent developments in chemical oligosaccharide synthesis 1974 M. McNiel, A.G. Darvill, S. C. Fry and P. Albersheim, Annu. Rev. Biochem., 1984,53, 635. 5 For recent examples of convergent oligosaccharide synthesis see: (a) H. Paulsen, W. Rauwald and U. Weichert, Liebigs Ann. Chem., 1988, 75; (b) H. Paulsm, M. Heume and H. Niirnberger, Carbohydr: Res., 1990, 200, 127; ( c ) F. Yamazaki, S. Sato, T. Nukada, Y. Ito and T. Ogawa, Carbohydr: Res., 1990, 201, 31; (d) J. Alais and A. Veyrieres, Carbohydr: Res., 1990,207, 11; (e) H. Paulsen and C. Krogmann, Carbohydr: Res., 1990,205, 31; (f) N. Hong and T. Ogawa, Tetrahedron Lett., 1990,31, 3179; (g) M. Sasaki and K. Tachibana, Tetrahedron Lett., 1991,32, 6873; (h) M. K. Gyrjar and G. Viswanadham, Tetrahedron Lett., 1991,32, 6191; (i) C. Murakata and T. Ogawa, Carbohydr: Res., 1992, 234, 75; ( j ) N.M. Spijker, P. Westerduin and C. A. A. van Boeckel, Tetrahedron, 1992,30,6297; ( k ) K. Takeo, Carbohydr: Res., 1993, 245, 81; (1) R. K. Jain and K. Matta, Carbohydr: Res., 1992, 226, 91; (m) C. Unverzagt, Angew. Chem., Znt. Ed. Engl., 1994, 33, 1102. 6 (a) H. 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ISSN:1350-4894    

DOI:10.1039/CO9960300173

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Main group organometallics in synthesis MARTIN WILLS Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK Reviewing the literature published between January 1994andJune1995 Continuing the coverage in Contemporary Organic Synthesis, 1994, 1, 339 1 2 2.1 2.1.1 2.1.2 2.1.3 2.1.4 2.1.5 2.2 3 3.1 3.2 3.3 4 4.1 4.1.1 4.1.2 4.1.3 4.2 5 5.1 5.1.1 5.1.2 5.1.3 5.2 5.3 6 6.1 6.2 7 7.1 7.2 8 Introduction Group 1 Lithium Lithium amides and enolates Non-stabilised organolithium reagents Lithiated aromatic and heteroaromatic groups Benzylic and allylic lithium anions Alkenyl and alkynyl anions Anions stabilised by sulfur, silicon and other heteroatoms Group 2 Magnesium Barium Zinc and mercury Group 13 Boron Boron enol ethers, borane catalysts and alkylboranes Allyl-, allenic and alkenylboranes Hydroboration and carbonyl reduction by boranes Aluminium, gallium and thallium Group 14 Silicon Silyl enol ethers Allyl-, benzyl- and alkenylsilanes and their derivatives Other classes of silicon reagent Germanium Tin Group 15 Phosphorus Arsenic, antimony and bismuth Group 16 Selenium Tellurium References 1 Introduction As with previous reviews the emphasis will be on synthetic aspects, rather than mechanistic and structural properties, of the organometallic compounds in the following discussion.2. Group 1 2.1 Lithium 2.1.1 Lithium amides and enolates Under certain conditions, and provided P-hydrogen atoms are available, lithiated amines can act as reducing agents; this aspect of their reactivity has been reviewed recently.' The use of homochiral lithium amides in asymmetric deprotonation chemistry is now a mature area of research and most reports now detail refinements and improvements to known systems.A striking recent application of this methodology has been in the asymmetric ortho-lithiation of certain activated arene-chromium tricarbonyl complexes, where enantiomeric excesses (ee7s) of up to 90% have been recorded.2 Lithium enolate chemistry is pivotal to organic synthesis and a comprehensive coverage would not be possible in a review of this type. However attention will be drawn to recent developments in the area of asymmetric protonations of racemic enolates, which have in some cases been refined to give ee's of up to 98%.3 With the aid of an appropriate chiral ligand, similar selectivities may be achieved in alkylation reactions of certain c~mpounds.~ 2.1.2 Non-s tabilised organolithium reagents Due to their high reactivity, organolithium compounds are rarely used in catalytic asymmetric reactions, since reaction acceleration is difficult to achieve.This feature is reflected in the report by Denmark on the asymmetric addition of alkyllithiums to imines catalysed by diamines, in which ee's of up to 82% are achieved, but only when a stoichiometric amount of ligand is empl~yed.~ Whilst halide-lithium exchange reactions remain the predominant method for formation of complex organolithium building blocks,6 the use of lithium metal, together with a catalytic amount of a polyaromatic, is gaining popularity. In a recent development it has been demonstrated that aryl sulfones can serve as suitable precursors for this ~hemistry.~ The same Barbier-type process can be achieved using sonochemical methods.' In recent years intramolecular cyclisations of organolithiums onto unactivated double' or triple" bonds has been developed into a versatile and reasonably general procedure.In one example a very simple diene synthesis has been achieved Wills: Main group organornetallics in synthesis 201(Scheme l).'O" Related cyclisations onto activated multiple bonds are also synthetically valuable, especially when the process can be achieved in a tandem sense by setting up an appropriate sequence of five- and six-membered rings. This has been illustrated by the stereoselective conversion of iodide 1 into the bicycle 2 upon treatment with butyllithium. ' ' Reagents: i, 2.0 eq.Bu'Li, C5HI2, Et20, -78 "C to r.t.; ii, H30t Scheme 1 r( co2Bu' 1 2 3 Lithium anions may be created adjacent to heteroatoms by a variety of methods. In a large scale (2.2 kg) example of the 'reductive' method, an excess of lithium metal is employed to generate 3 and subsequently 4 upon reaction with the appropriate chiral aldehyde." This synthesis clearly underlines the value of such methodology to process development as well as to small scale synthetic work. In other cases, however, the process of lithium-bromine exchange via the use of an alkyllithium is fav0~red.l~ In some cases this can be a stereoselective process, as illustrated by the low temperature reaction of 5 with butyllithium to give predominantly the isomer .-.6, which was trapped as a Gc, T 7 1 p : Bn2N Br HO 4 5 74- TBDMS-O TBDMS-O o\B,o &Br W B r 6 7 TBDMS-O OH 0 +ok 8 boronic ester derivative 7.IJb This reaction formed the basis for the synthesis of the bryostatin subunit 8 via reaction with the dianion of tert-butyl acetoacetate. The corresponding reaction of butyllithiums with alkyl chlorides does not result in lithium-chlorine exchange; deprotonation adjacent to the chlorine is favoured. This process may also be employed to synthetic ad~antage.'~ Lithiation may be achieved by deprotonation a- to a nitrogen atom;I5 however some form of activation or a directing group is invariably required. In some cases polyamines, which are often employed to activate alkyllithium bases, can direct their own self- lithiation.In some cases this can be a troublesome side reaction, as illustrated by a report of tetramethylethylenediamine (TMEDA) lithiation,I6 but may also be employed to useful effect, for example in a methylene transfer reaction (Scheme 2).17 Carbamates are perhaps the most widely used directing groups for lithiation adjacent to nitrogen,'* and a full paper has appeared describing formation and applications of enantiomerically enriched complexes such as 9. These valuable homochiral building blocks are formed by the action of butyllithium complexed with a chiral ligand such as the diamine sparteine." Applications of these and related compounds have been extensively explored; however a very attractive recent addition to the repertoire is a very valuable palladium coupling with aryl halides to give the 2-aryl derivatives Directed lithiation adjacent to a nitrogen atom may also be achieved by using a complex with carbon disufide, as in 11, which collapses back to the amine upon work-up of the reaction.21 Reagent: i, pentane, 0 "C Scheme 2 9 10 11 Trialkyltin-lithium exchange is another of the popular methods for formation of lithiated anions adjacent to nitrogen." Rather milder conditions are required to achieve this than for direct deprotonation, which has obvious advantages.This 202 Contemporay Organic Synthesisprocess has formed the basis of an interesting cyclisation reported by Coldham, in which a five- membered heterocycle formation is terminated by re-addition of trimethyltin (Scheme 3).” As well as the bonus that is afforded by the further manipulation of the trialkyltin group (for example to give an acetal), the process also benefits from the fact that only a catalytic amount of methyllithium is required. Reagent: i, MeLi Scheme 3 Formyl anion equivalents22 are of great use in synthesis and will feature at various points throughout this report.Less common however are the nitrogen equivalents - imines lithiated at the a-position such as 12.24 Such compounds may be simply generated by the addition of tert-butyllithium to the appropriate isonitrile and, in the example referenced here, add to carbon monoxide and then cyclise in an intramolecular sense onto the aromatic ring to form indoles. The trifluoroacetimidoyl lithium compounds 13 may be generated from the corresponding iodides using butyllithium25“ and a related compound has been prepared by a similar treatment of a trialkylstannane precursor.25’ 12 13 14 n =1,2 15 n =1,2 Much of the discussion above is also applicable to the preparation and use of lithium anions adjacent to oxygen.Reductive methods using lithium metal and catalytic amounts of a polyaromatic are again popular, and have been successfully employed for the formation of lithiated tetrahydrofurans and pyrans 14 from the precursors 15 in high yields.26 Useful chiral building blocks such as 16 are available in the same way.27 Whatever the method of generation, anions adjacent to oxygen atoms have been employed extensively in Wittig rearrangements to great effect,28 as illustrated by the impressive ring expansion of 17 to give the bicyclic product 18 (the 16 17 18 lithiated species is generated from the trimethyltin precursor).’& Hoppe has reported further results from his studies on the asymmetric directed lithiations of carbamates using the chiral base sparteine as a directing group.29 Such reactions show remarkable dependence on the nature of the deprotonation conditions and the nature of additives.Reaction of 19 with 1.5 equiv. of sec-butyllithium in ether at -78 “C involves a directing effect by the dibenzylamine group to give the lithiated species 20. In contrast, use of the same conditions in the presence of 1.5 equiv. of (-)-sparteine gives the regioisomeric complex 21 (sparteine is omitted for clarity), presumably due to the overriding directing effect of the chiral diamine-alkyllithium complex.29a 0 - Cy2N K O ~ o ~ NCy2 NBn2 0 19 20 X = L i , Y = H 21 X = H .Y = L i 2.1.3 Lithiated aromatic and heteroaromatic groups Of all the functional groups known to be effective at directing the ortho-lithiation of aromatic rings, methoxy and amide groups are two of the most effective. However even a catalytic amount of TMEDA can generate a dramatic rate increase in this process, an effect which has been studied in detail recently.” The presence of a para-fluoro atom has also been shown to provide a dramatic rate enhancing effect, presumably due to activation via inductive electron withdrawaL3* Bromine-lithium exchange provides a milder alternative to deprotonation and is the method of choice provided a suitable substrate is available.In the total synthesis of balanol, Nicolaou employed such a process to convert ester 22 to the ketone 23 via an intramolecular reaction initiated by treatment with b~tyllithium.~’ After oxidation with TPAP and further steps, 23 was converted to the side chain of the synthetic target molecule. In another intramolecular example, rapid bromine-lithium exchange outpaces attack by phenyllithium on the epoxide in 24, allowing intramolecular ring opening to be achieved to give the product 25.33 The relatively facile 2-lithiation of furan rings has been studied in some detail. This process has been employed recently in a key step in the total synthesis of salinomycin, where fragment 26 was coupled cleanly with another of equal complexity to provide the C( 11)-C(30) portion of the target molecule.34 One-pot furan lithiation and acylation may also be achieved using the sonochemical Barbier reaction in Wills: Main group organometallics in synthesis 2030 OBn qco%oTp.Br OBn OBn 22 23 24 25 26 ph# + PhCO21i+ - i Ph&Ph OH OH 0 Reagent: i, Bu'CI, TMEDA, THF, 3 9 , r.t., 15 min. Scheme 4 which the lithium salt of a carboxylic acid is irradiated in the presence of tert-butyl chloride and lithium metal, presumably resulting in in situ formation of tert-butyllithium (Scheme 4).35 Direct thiofuran lithiation favours the 2-position; however 3-lithiothiofuran my be prepared from the appropriate bromide precursor.36 The use of thiofuran as a 4-carbon fragment (via exhaustive reduction to the hydrocarbon) is well established. An excellent example of this has recently been described in which the coupling of 2-lithiothiofuran and bromide 27 provides a key step in the synthesis of the C2 symmetric target (+)-xestospongin A 2tL3' The thiofuran in this case provides the atoms in the two chains linking the heterocyclic units.Treatment of tetrabromothiofuran may be selectively controlled so that one bromide is predominantly exchanged for lithium, as described in some detail by I d d ~ n . ~ * CI 27 28 LiQ 29 Lithiated pyridines are valuable synthetic intermediates which have been the subject of a good deal of detailed studies recently. A good example is the use of 34ithiopyridine 29 to provide the heterocyclic ring in a recent short synthesis of epibatidine 30.39 Comins4' has reported further results from his studies on directed lithiations of pyridines using lithiated hemiaminals, which may be introduced via reaction of the lithiated pyridine with a formamide (Scheme 5).In the sequence illustrated, which is part of a camptothecin total synthesis, further lithiation is achieved directly, 30 1 iv, v I CI &OH 0-0- Reagents: i, Bu"Li; ii, Me2NCH2CH2N(Me)CHO; iii, Bu"Li; iv, 12; v, NaBH4. H20 Scheme 5 followed by iodination and then reduction of the intermediate aldehyde. In a related sequence, the synthesis of parvifoline has been achieved, although not on a pyridine ring in this case.41 Finally in this section, the synthesis of atpenin B, 31, via a sequence of four sequential lithiations of 2-chloropyridine, working clockwise around the ring as drawn, is highlighted.42 2.1.4 Benzylic and allylic lithium anions Alkylations of unsymmetric allyllithium compounds can occur with low regioselectivity if the steric differentiation between the 1- and 3-positions is not great.A useful solution to this problem is to perform the alkylation in an intramolecular sense. This idea is illustrated by the formation of allylsilanes 32 via a [1,4]-Brook rearrangement of the silyloxy precursor anion 33, which may be formed by either reduction of an allylic thioether, as in this example,43 or tin-lithium exchange.44 In either case the anti product dominates (>90% this isomer) and the resultant double bond is invariably 204 Contemporay Otganic SynthesisOH 0 OH Si(Bu’)Ph2 P h A : L MeOANAOH 31 32 Li+ OSi(Bu’)Ph2 Li+ I - Ph- 33 34 35 36 37 38 trans irrespective of the geometry of the starting material.Katritzky has reported further examples of the applications of allylic anions based on benzotriazoles 34. Such reagents are highly versatile and may be used to prepare cyclopropanes or unsaturated ketone derivatives depending on the exact conditions empl~yed.~’ chloromethyl substituted aromatic or heteroaromatic compound generally results in deprotonation to form a benzylic anion. Such anions may subsequently be employed in the formation of epoxides upon reaction with ketones or aldehyde^.^^ The reduction of chloromethyl ketones with lithium metal and a polyaromatic, on the other hand, provides an excellent method for the formation of non-stabilised benzylic anions, which are often otherwise difficult to prepare.47 When there are activating or directing groups on the aromatic ring, such as a phosphate48 or an amide,49 direct benzylic deprotonation can be achieved under relatively mild conditions.When (-)-sparteine was used in collaboration with an alkyllithium base for the deprotonation of 35, an asymmetric complex 36 was formed. The enantioselectivity of alkylation of 36 shows a remarkable dependence on the nature of the alkylating agent; 37 (up to 97% ee) is the product when alkyl tosylates are used whereas the enantiomer 38 (up to 92% ee) is the product when alkyl halides are employed.49 Heteroallylic anions featuring a central nitrogen atom have been developed into valuable synthetic reagents in recent years5’ Pearson has reported a number of inter- and intra-molecular cyclisation reactions directed at the synthesis of alkaloids which feature these reagents (Scheme 6).’O“ Trialkyltin- lithium exchange appears to be the method of choice for their generation.A related series of reagents featuring an additional stabilisation by an enolate has also been reported.” The reaction of a strong base such as LDA with a *‘\ 1- MOM Ar 80% yield Reagent; i, 2.1 eq. Bu”Li, THF, -78 OC, 1 h. Scheme 6 2.1.5 Alkenyl and alkynyl anions The formation of alkenyllithiums by direct deprotonation is only efficient if a suitable activating” or directing group is available to assist the reaction; if not then a reductive method (vinyl chloride, lithium powder, catalytic polyaromatic c~mpound)”~ or a trialkyltin-lithium exchange methods4 may be used.Of all the possible activating groups, a-alkoxy functions are especially effective at promoting deprotonation at vinylic carbon atoms.” Several examples of the lithiation of enol ethers and related materials have been reported recently. Applications of diverse alkyllithium species thus formed, represented by 39,51a*h 40”“ and 4l5Id have also been described. The difluoro substituted reagent 42 has been the subject of considerable recent interest. In a recent paper the tandem reaction of 42 with two carbonyl compounds, reacting first as a vinyl anion equivalent and then as an enolate anion, has featured.” 39 40 41 42 Vinylic anions have seen many applications in organic synthesis. The reaction of 1 equiv. of 43 with cyclobutenedione 44 is a key step in the synthesis of isochromaquinones; a ring expansion of product 45 gives the required quinone addition-rearrangement sequence was used by Paquette in the synthesis of a tricyclic natural produ~t.’~ Lithiated dihydrofurans, e.g.46, provide useful building blocks for complex synthetic targets.” Upon reaction with cuprate 47 and a subsequent ring opening reaction and methylation, the C(16)-C(23) region of FK506 48 is prepared.57u Perhaps one of the most exciting applications of vinyl anions however has been in the area of Taxol@ was the reaction between 49 and 50 (the latter formed by a Shapiro reaction of the sulfonated hydrazone precursor) to give, in 85% yield, adduct A similar A key step in the Nicolaou synthesis Wills: Main group organometallics in synthesis 205, , OTIPS 43 i i 46 49 R' R2 G: 44 R' R2%o.OTIPS 45 I OMOM 47 48 50 51 5L5' In another synthetic approach, a vinyllithium was employed to set up an intramolecular Diels- Alder reaction in a very concise sequence leading to the Taxol@ ABC ring Alkynyl anions have also found many applications in synthesis, one of which has been as a building block in the spiroketal subunit of milbemycins.60 An impressive enantioselectivity (up to 97%) was achieved in the addition of a lithiated 2-acetylenic pyridine to a heterocyclic electrophile using a lithiated quinine to provide the directing effect (Scheme 7).61 cdio R Li R = i 93% - Reagent: i, quinine, Li, THF, -25 "C Scheme 7 2.1.6 Di- and tri-lithiated anions In the presence of a suitable directing group, dilithiated dianions such as 52 may be prepared by direct deprotonation.Whilst it has always been assumed that the directing group was in some way responsible for directing the base to the benzylic position, it is only recently that direct evidence for this has been obtained.62 Related compounds 5363 and 5461 featuring further additional stabilisation from a sulfone group have also been reported. In particular these reagents have been employed in the synthesis of nitrogen heterocycles and lactones respectively. Without the additional stabilisation or directing effects, preparation of dianions such as 5565 and 5666 generally requires an alternative approach. In most cases a variation upon the reductive method is favoured, chlorinated precursors may be employed as the starting materials6576Q or, for compounds of type 56, aziridines.6@ The reductive cleavage of a sulfide in an intramolecular sense was employed to create the dianion 57.67 Li 0 pTolS02 Li NLi 1 Li OLi Ph ANA Me NLiMe 'Ph 52 53 54 LiJR2 L i ~ R , SLi Li R 55 56 57 The lithium salt formed by the reaction of lithium methyl(meth0xy)amide with an aldehyde serves to protect the sensitive functional group from attack by nucleophiles.In one recent example of the use of this strategy a further deprotonation was undertaken to give dianion 58 which was then converted to the ally1 borane 59. After work-up of the reaction and regeneration of the aldehyde an intramolecular addition reaction completed the synthesis of target molecule 60.68 Noteworthy in this sequence is the fact that all the transformations, from the precursor to 58 to target 60, were carried out as part of a one pot process.0-Li 58 59 60 Dianions in which one or more of the anions is located on an sp2 carbon atom may be created most readily by exchange reactions, and in particular the exchange of trialkyltin groups for lithium using an alkyllithium base has proved to be the most effective method. Allylamine derivatives of general structure 61 may be prepared by such a strategy.69 Presumably 206 Contemporary Organic Synthesisthe trialkyltin precursor 62 has a finely balanced reactivity so that the exchange does not precede deprotonation at nitrogen, as is often a problem in bromine-lithium exchange reactions. A number of related trianionic compounds such as 63, prepared by similar methods, have been rep~rted.~' 61 R = alkyl, TMS 62 R = alkyl, TMS 63 64 Dilithiations of aromatic compounds are generally less troublesome, and may usually be achieved with direct reaction with a healthy excess of alkyllithium base.71*72 Whilst directing groups such as carbamates are well known to promote this type of lithiation71 carboxylic acid salts, traditionally themselves rather prone to nucleophilic attack, can under certain conditions promote ortho-lithiation reactions to give, for example, 64.72 2.2 Anions stabilised by sulfur, silicon and other heteroatoms The configurational stability of anions adjacent to sulfur in dibenzyl sulfide has been investigated by Hoffman, who has found that racemisation begins to occur at very low temperature^.^^ Whilst this rather limits applications of such compounds to asymmetric synthesis, there is sufficient stability to permit very low temperature ( - 100 "C) intramolecular reactions to take place in a stereoselective manner (Scheme 8).74 MEMO S-Ph MEMO SH __c Reagent: i, Bu"Li, -100 OC, 1 h Scheme 8 In the example shown the reaction is believed to proceed with essentially 100% inversion of configuration.The rather more configurationally stable anion 65, flanked by both sulfur and silicon, may be formed directly from the enantiomerically pure precursor using sec-butyllithium activated by TMEDA ; both the deprotonation and subsequent reaction of this anion with MeOD proceed with retention of c~nfiguration.~~ Anions stabilised by two sulfur atoms are very important in synthetic chemistry due to their value as reverse-polarity reagents.76 A lithiated dithiane has been employed in the total synthesis of FK506.7Q Further examples of lignan syntheses facilitated by the stereoselective additions of anions such as 66 to a$-unsaturated-d-lactones have been rep~rted.'~ Allylic anions stabilised by sulfur such as 67 react cleanly and regioselectively with epoxides 68 to give adducts which cyclise (to 69).A short \ I N. 65 66 67 SPh 68 69 70 series of transformations completes the synthesis of a,P-unsaturated-&lactones 70 for which they were r e q ~ i r e d . ~ ~ Allylic anions stabilised by sulfones rather than sulfides may be employed for the synthesis of enones in related proces~es.~"~ Whilst the reaction of 67 with 68 was regioselective due in part to the effect of the methoxy group, addition a- to the sulfur atom is often observed.If this is not the required isomer then it is possible to rearrange the adduct via a 1,3-shift promoted by heating to 160 "C in xylene in the presence of diphenyl disulfide (Scheme 9).79 i,ii - m S P h ox HO Reagents: i, Bu"Li, TMEDA, HMPA, THF, -78 "C+ 0 "C; ii, (PhS)2, xylene, 160 "C Scheme 9 Lithium anions adjacent to sulfoxides are important reagents for asymmetric synthesis because the sulfoxide group may in principle be resolved into enantiomers. Several applications of such anions have been reported recently, and a full paper on the synthesis and reactivity of homochiral 1,3-dithiane-1,3-dioxide 71 has appeared.Anions of 71 react with high diastereoselectivity with aldehydes ( > 95 : 5 ) and may be cleaved to a-alkoxy esters using a short sequence of reactions featuring a Pummerer reaction at a key point." Addition of the anion 72 to the cyclic nitrone 73 proceeds with a Me0 0- 71 72 73 Wills: Main group organometallics in synthesis 207face selectivity of 96 : 4, the highest yet achieved in this type of reaction. The use of other sulfoxides, such as lithiated methyl p-tolyl sulfoxide, has already been reported to give selectivities of up to 92 : A more unusual application is the ring opening of either diastereoisomer of ketal74, to give 75 as the major product, upon treatment with LDA. This strategy, the stereochemistry of which is controlled entirely by the sulfoxide, provides an alternative to enzymatic differentiation of meso- diols.82 Sulfoximines such as 76 also feature robust stereochemical centres and have found many applications in asymmetric synthesis. A full paper has appeared on the synthesis and uses of 76 itself,83 whilst conjugate addition reactions of the related compound 77 to enones have also been described.In the latter example the highly diastereoselective reaction gives 78 as the major product isomer.84 , NpTs Ph, ,-Li !.. Ph O/ /s; 'NSi(But)Ph2 e s * N p T s , .+ Ph I \\ LI - 76 77 78 Anions adjacent to sulfones 79 are generally prepared by direct deprotonation but can in some cases be formed by reductive methods.85 Such anions have been widely employed in synthesis and appear particularly compatible with synthetic approaches to large complex target molecules.Recent applications include key carbon-carbon bond forming steps in the synthesis of rapamycin, which features epoxide opening by a sulfone anion86 and aplyronine A.87 In the latter example three important bonds are formed between large fragments of the target, one by a Julia olefination process, the others by displacement of a triflate and an iodide respectively by sulfone anions. Lit hiated sulfones which form part of a three membered ring, e.g. 80, have been substituted by a range of electrophiles and then employed to form alkenes by extrusion of sulfur dioxide.88 A one pot process permits the synthesis of allylic alcohols 81 from lithiated j-silyl sulfones 82, which therefore acts as a vinyl-isoprenyl anion equivalent.89 K PhSO2-R - Li+ Li 0 2 79 80 81 R', R2 = H, alkyl Allylic sulfones may be prepared very readily by deprotonation and display a versatile reactivity pattern.Alkylation of 83 with isoprenyl bromide furnishes 84, a convenient precursor of a Diels- Alder reagent for apoyohimbine syntheskgO In another application a sequence of epoxide opening reactions was employed to form a key building block of brefeldin A in an impressive one pot process (Scheme Reagent: i, BuLi, THF, -78 "C to r.t. Scheme 10 Silicon stabilised anions have not been as extensively investigated as the sulfur analogues; however some very valuable processes have been developed. The reaction of 85 (formed by lithium metal-polyaromatic reduction of the a-sulfide) with addition to give 86.Oxidation by a conventional method then completes a very effective synthesis of enantiomerically pure cis-diol 87.92 Other silyl stabilised building blocks include the heterocycle 8893 which was used for the synthesis of epoxy diols and the silacyclopentane 89, a starting material for the synthesis of y-hydroxy ketones.94 adjacent anions and applications to alkene formation methodology are rather too numerous to comprehensively feature in an article of this type. Attention should be drawn however to the recent studies of the reactions of homochiral derivatives of this type such as 90, lithiation of which, followed by reaction with an aryl sulfonyl azide, gives 91 in high stereoselectivity. Azides of general structure 91 may be converted via a short sequence to the corresponding enantiomerically enriched a-amino Numerous phosphorus derivatives stabilise SiPh3 OH SiPha PhALi Ph 4Ph Ph 85 86 87 U I \i PhS02 $,,SiR3 Ma2cd I so2 Me02C Li 88 89 90 82 83 84 91 92 208 Contemporary Organic Synthesisphosphonic acids.95 Related allylic anions 92 have also been reported, and display remarkably high selectivities in addition reactions to ct,P-unsaturated Finally, in this section, an intriguing report has appeared describing the deprotonation of racemic phosphine oxide 93, followed by asymmetric reprotonation of the anion 94.Use of the chiral amine 95 to supply the proton returns enantiomerically enriched 93 in up to 83% ee, which can be increased to over 100% by recry~tallisation.~~ Very few examples of deracemisation methodology of this type have been reported.0 95 93 94 3 Group2 3.1 Magnesium Reviews have appeared recently describing the reactions of alkylmagnesium compounds in gene~al,~' and also the effects of alkylzirconium species on Grignard reagents in parti~ular.~~ necessarily be dominated by the enormously versatile Grignard reagents, and this article is no exception to this. One feature that makes such reagents attractive to synthetic chemists is their applicability to stereoselective addition reactions. The reaction of phenylmagnesium bromide with dimine 96, for example, results in highly selective formation of the useful protected diamine 97.'" Additions of Grignard reagents to pyridinium salts bearing chiral directing groups are highly stereoselective provided the correct substitution pattern is present on the heterocyclic ring, i.e.3-trialkylsilyl-4-methoxy. lo' Such reactions have been employed extensively by Comins for the asymmetric synthesis of alkaloids; the representative example Any review of organomagnesium chemistry will 96 OMe H H 81 Reagents: i, Me(CH2),,MgBr; ii, H30+ Scheme 11 shown in Scheme 11 features the key step in the synthesis of ( - )-solenopsin An ally1 Grignard addition fulfils a key role in a reported synthesis of the zaragozic acid-squalestatin core model structure 98 from lactol99."' Following the addition of the allylic anion (to the hydroxy aldehyde), the resulting alcohol is oxidised to the ketone level and a careful acid catalysed cyclisation reaction leads to 98. BnQ ,OPMB MBq8F?oBn -d I \ OTBS 98 99 Another target molecule which has excited a great deal of recent interest is that class based on the dynemicin structure.Alkynyl Grignard reagents have played an important role in establishing the enediyne structure in these corn pound^.'^^ In the example shown in Scheme 12 the introduction of the unsaturated bridge is completed by an acid catalysed cyclisation of the dicobalt hexacarbonyl derivative,lok a strategy also successfully applied to the synthesis of the related calcheamicins. . m g q LOTHP Reagent: i, AdOCOCl Scheme 12 Y OMe The use of chiral ligand 100 to modify the reactivity of Grignard reagents with aldehydes gives only modest enantiosele~tivities.~~~ Rather more interesting however is the remarkable observation that the ee induced increases with temperature (Scheme 13), a rare but not unknown phenomenon.Modest to good ee's (65-80%) were also obtained in the titanium-chiral diol mediated reaction of certain Grignard reagents with esters, a process which gives chiral cyclopropanes as product^.''^ The nickel catalysed reaction of cyclopropyl Grignard reagents with dithianes results in the formation of 1-substituted b~ta-1,3-dienes."~ Whilst Grignard reagents are usually formed from alkyl halides and magnesium metal, transmetallation can sometimes be a viable alternative. Hoffman has examined the stereoselectivity of the formation of derivatives 101 Main group organornetallies in Jynthesis 209phyN*N<h H F M g B r 1 00 101 OTMS I 7- 1 02 -40 "C : up to 9% e.e. 35 "C : up to42% e.e.Reagent: i, 100 Scheme 13 of gem-diiodides 102 formed upon reaction with isopropylmagnesium bromide.107 The conjugate addition reaction of chiral amines with unsaturated esters has been extensively studied by Davies, who has concentrated on the use of lithium amide nucleophiles. It appears that excellent results may also be obtained when the corresponding magnesium reagents are employed."' Intramolecular cycloaddition reactions often proceed with excellent diastereoselectivity, an advantage over intermolecular reactions which are often less selective. This disparity can be rectified by connecting the two reagents in the latter reaction using a temporary 'tether' group. Stork has reported that an alkenyl alkoxy magnesium tether can be used effectively in this capacity: 103, formed in situ by the reaction of an alkoxide with vinyl magnesium bromide, cyclised readily to 104.'09 R'TBaC' R2 103 104 105 3.2 Barium Ally1 barium reagents 105 have benefitted from a considerable level of recent research activity due to their high regioselectivity in addition reactions to electrophiles."' Such compounds are generally prepared by the reaction between an activated form of barium metal and the allyl chloride.A very comprehensive full paper has recently described their use in addition reactions to aldehydes and in conjugate addition reactions to enones. Of particular note are: (i) the consistent observation of addition to the least hindered terminus of the allyl group, (ii) the full conservation of double bond geometry and (iii) high selectivity for 1,4- over 1,2-addition ( > 99 : 1).3.3 Zinc and mercury Tremendous recent progress has been made in organozinc chemistry, thanks mainly to the efforts of the Knochel group, who have developed methods for the preparation of several classes of functionalised zinc reagents."' Recently reported methods include the reactions of alkyl bromides with either diethylzinc"' activated by copper(1)- manganese(I1) or zinc metal activated on titanium di0~ide.l'~ Benzylic zinc reagents, which are somewhat more difficult to prepare than alkylzincs, have been made in good yields from the bromides using an electrochemical meth~d.''~ Organozinc derivatives of a-amino acids such as 106 have been the subject of particular attention in recent years. Of particular note, in addition to versatility in reactions, is the compatibility of the zinc reagent to the usual protecting groups associated with amino acid chemistry.The reagents are configurationally stable and the nitrogen atom remains protonated throughout the sequence of reagent formation and during nucleophilic reactions. Jack~on"~ and others have reported full details of much of his communicated research in this area as well as new applications including palladium catalysed coupling reactions with aryl iodides116 and cc,P-unsaturated acid chloride^"^ to give 107 and 108 respectively. Further examples of palladium catalysed coupling reactions will feature throughout this section. The preparation and reactions of closely related, configurationally stable organozinc reagents of type 109 have been reported by Knochel.' '' COpBn ArYozBn NHBoc 0 COzBn I Z n p NHBoc 106 107 108 0 A Z n E t / K < ZnI 0 NH 109 110 Allylzinc reagents may be prepared by the reaction between diethylzinc and either an allyl palladium c~mplex"~ or a benzoyl protected allyl alcohol.120 In the former example, reported by Julia, an allyl sulfone was employed together with an appropriate source of palladium(0) to supply the allylic complex which then formed the allylzinc 110 in an in situ process.Reactions of 110 with carbonyl compounds were described. In the latter process (Scheme 14), which also featured stereoselective reactions with carbonyl compounds, a formal polarity reversal of the n-ally1 group was achieved.I2' A further development of allylzincs such as 111 is for the diastereoselective carbometallation of 210 Contemporary Organic SynthesisQ- TMS C5Hll leading to 118.'23 The resulting alkylzinc may then be quenched upon acidic work-up or employed in .OBz - i EEnQ - pph] Zn---0 further reactions with electrophiles.Since its first report this reaction has proved to be very versatile and may be applied to cyclisations with triple disubstituted tetra hydro fur an^.'^^ Oppolzer, who has successfully employed a palladium catalysed process to assist in situ formation of precursors 119 to intramolecular zinc- ene reactions from allylic acetates 120. Cyclisation again favours the cis-products 121, which may again be quenched by acid or further reacted with electrophiles."' and to the stereoselective formation of cis- A related cyclisation has been investigated by I TMS C5H1 1 QOBu u n 4 , Reagents: i, Etgn; ii, PhCHO Scheme 14 Li ZnBr I 111 112 113 vinyllithums.For example; reaction of 111 with 112 gives the gem dimetallated adduct 113 and subsequently the aliphatic derivative 114 upon quenching with aqueous acid.121 Several examples have recently been reported by Normant, who has proposed that the stereochemical control is the result of reaction via a transition structure such as 115. In certain cases intermediate 113 can be converted effectively to cyclopropane derivatives, again with control of stereochemistry.'22 Organozinc compounds also make excellent substrates for intramolecular cyclisation reactions. Building on the work described in the previous section, Normant has examined cyclisations of trialkylsilylalkynes such as 116; deprotonation with an alkyllithium and zinc-lithium exchange results in formation of the metallated allenic species 117 which then undergoes the intramolecular reaction M 119 Y = C(S02Ph)2, NTs, M = ZnEt 121 Y = C(S02Ph)2, NTs 120 Y = C(S02Ph)2, NTs, M = OAC The approach taken by Knochel to intramolecular cyclisations of alkylzinc reagents onto double bonds requires the use of a nickel(I1) ~ata1yst.l~~ In the representative example selected (Scheme 15), the stereoselective formation of a tetrahydrofuran ring results from a concise sequence of reactions.127u It is also noteworthy that the enantiomerically enriched starting material in Scheme 15 was itself formed by an asymmetric addition of a dipentylzinc to an a,/?-unsaturated aldehyde.L -1 1 ii, 55% OHC, C5H11 QOBu Reagents: i, Et2Zn, Lil, cat. Ni(a~ac)~, THF, 40 "C; ii, 02, TMSCI, THF, -5 "C 114 \ OMe 115 One example of a catalysed (usually by -0Me 116 palladium) coupling reaction of an organozinc has Me0 TMS TMS 117 118 already been described in this section? l6 However the literature is replete with further examples of this valuable class of reaction. In general arylzinc derivatives 122 are most commonly prepared by exchange with aryllithium reagents, which in turn originate from directed aromatic metallation'** or a halide exchange process.129 Reaction partners in Wills: Main group organometallics in synthesis 21 1125 such processes are commonly aryl halides, vinyl halides, acyl chlorides and allylic halides.129~130 In some cases the use of arylzincate reagents is favoured, one advantage being their ease of formation directly from the aryl iodides upon reaction with Me3ZnLi.13' Vinylzinc reagents 123 react in an analogous fashion but benefit from the additional benefit of ease of formation from the alkyne precursor^.'^^ The reactions of vinylzincs with allylic bromides, with or without palladium catalysis, have been described in of palladium catalysed couplings of unsaturated organozinc reagents has generated some powerful methodology. For example sequential reaction of an alkynylzinc and then an allenylzinc with 124 provide a means for the effective synthesis of the complex unsaturated product 125.'34 asymmetric catalytic dialkylzinc addition reactions to aldehydes (Scheme 16) has continued to grow unabated.Noyori, who first reported the rate enhancing effect of an amino alcohol derivative on this reaction less than a decade ago, has reported an ab initio study of the reaction135 and a very detailed account of the remarkable non-linear chirality transfer effects which are 0b~erved.l~~ A comprehensive account of all the new ligands reported within the date range of this account will not be attempted; however representative examples and novel applications will be highlighted. The combined use The number of examples of ligands for chiral ligand 0 phKH + Et2Zn seetext Ph Scheme 16 Starting first with new catalysts, the results of which are summarised in Figure 1, amino alcohols 12613' and 12713* are reported to give ee's of up to 68 and 96% respectively for the prototype reaction shown in Scheme 16.Whilst this suggests that pyridylamines are rather poor catalysts, rather better results have been obtained using the slightly more complex alcohols 128139 and 129,I4O which furnish ee's of up to 93 and 88% respectively. The exact contributions of each of the chiral components in 129 to the overall selectivity is not fully delineated; however the current enthusiasm of researchers for 126 (up to 68% ee) H O A P h Ph 128 (up to 93% ee) 127 (up to 97% ee) Ph 129 (up to 88% ee) 132 (up to 94% ee) 130 1 3 1 u (up to 94% ee) (up to 83% ee) Ph, Me 7+ 0; ,Ti(OP+), Tf 133 134 (up to 94% ee) HS 0 (up to 100% ee) Figure 1 Maximum enantioselectivity for the reaction shown in Scheme 16 catalysis by chiral oxazolines essentially ensures their inclusion in most applications.The use of amino alcohol 128 to control the addition of alkynylzinc reagents to aldehydes gives slightly better results than with dialkylzincs: up to 95% ee.I4l Further reports have appeared on the use of polymer supported chiral amino alcohols in this application, some of which give results which are almost competitive with the homogeneous reaction^.'^^ Organometallic reagents containing n-complexed metals can introduce an extra steric or stereochemical element to a ligand which can improve their catalytic properties. Referring again to the prototype reaction of Scheme 16, the chiral ferrocene derivative 130 generates inductions of up to 83% ee.143 Certain chromium tricarbonyl derivatives of chiral amino alcohols have also been examined and found to be slightly better than the uncomplexed reagents.lU However perhaps the most interesting new reagent in this class is the selenium derivative 131 of ferrocene, which can give ee's of up to 94% for the prototype ~eacti0n.l~~ Whilst rather more complex than the simple ligands with which this work is normally associated, results of this type help to expand the horizons of this important asymmetric process.212 Contemporary Organic SynthesisReplacement of the oxygen atom in the asymmetric ligands with sulfur has been the subject of some attention. Whilst the change is a logical one given the need to coordinate to zinc, slight but important improvements to ee's have only been observed for a limited number of cases.Van Koten's reagent 132 gives up to 94% thioamino ligand 133 is reported to give up to 110% ee!147 Knochel has chosen to concentrate his asymmetric alkylzinc addition studies on the use of titanium derived complexes such as 134 as catalysts (formed in situ from the reaction between the ditriflated diamines and titanium tetraisopropoxide). Such catalysts, which are believed to be rather better than aminoalcohols for reactions of functionalised organozincs, give ee's in the region of 90-99% for the prototype reaction of Scheme 16 and related tran~formations.'~~ The Knochel system is particularly applicable to addition reactions to a,P-unsaturated aldehydes, several examples of which have been reported re~ent1y.I~~ Some impressive ee's (up to 90%) have also been obtained when 134 was used to mediate reactions of dialkylzincs with aliphatic aldehydes, a traditionally difficult process with all currently available chiral 1igands.l5' Other researchers have chosen to examine the versatility of ligand-accelerated alkylzinc addition reactions.Conditions have been found for control of the addition of diisopropylzinc to aldehydes, a hindered reagent which is normally ineffective in additions due to competing hydride transfer proce~ses.'~~ In a detailed study of mixed dialkylzincs it has been found that methyl and tert- butyl are remarkably inactive to transfer to the carbonyl compared to other alkyl groups, and therefore have potential value as non-transferable ligands in more complex In some cases the products of addition can themselves act as catalysts, thus permitting autocatalytic processes to take ~ 1 a c e .l ~ ~ This can be useful provided that all catalytic species favour formation of the same enantiomer of product. A study of the catalysed reaction of dialkylzincs with chiral aldehydes revealed that the ligand effect greatly dominates that of the chiral substrate, even when it bears an a-chiral centre.154 In terms of applications to total synthesis, perhaps the most impressive is the cyclisation of 135 to 136 in 91% de ('matched' directing effects operate) using only 1 mol% of the chiral aminoalcohol 137.15' Product 136 was taken whilst the simple on to complete an impressive synthesis of ( + )-aspicillin. Asymmetric additions of diethylzinc to C=N double bonds are rather rare.One excellent example is provided by the phosphorus protected imine 138, which gives enantiomerically enriched phosphinamides 139 (up to 85% ee) upon reaction in the presence of a polymer bound chiral amino alcoh01.l~~ Free amines may be generated from 139 upon exposure to relatively mild acid. cuprates, organozinc reagents have been employed in conjugate addition reactions to enone and related reagents.157 Together with an appropriate nickel(I1) catalyst and a suitable chiral ligand such as 140, such addition reactions have been reported to be capable of proceeding with very high ee (Scheme 17).158 An example of a related 'one-off asymmetric reaction is the combination of diethylzinc with (+)-diisopropyltartrate to give a reagent capable of promoting the asymmetric ring opening of symmetrical aziridines by thiols in up to 88% ee.'59 Whilst by no means as widely exploited as OH 138 R = Ph, 2-Np 139 R = Ph, 2-Np 1 40 Reagent: i, Ni(aca~)~, ligand 140 Scheme 17 To complete this section on zinc attention is drawn to the remarkable cyclopropanation reactions of allylic alcohols by bis(iodomethy1)zinc when used in the presence of borate esters such as 141 (Scheme 18).This methodology, first reported by Me2NOCh CONMe2 Bu 141 o p 0 R' ,++OH - .&OH R3 91-94% ee 80% yield R3 Reagent: i, 2.2 eq. Zn(CH21)2, 25 "C, CH2CI2, 2 h, ligand 141 0 135 136 (-)-DUB 137 Scheme 18 Wills: Main group organornetallies in synthesis 213Charette, has since been further developed by this author'60 and others.'61 In independent work, Denmark'62 and K~bayashil~~ have discovered that diethylzinc and diiodomethane is also an effective OEt the complex formed between protected amine 142, 1 47 148 149 material for asymmetric allylic alcohol cyclopropanation, although it is not quite as effective as the Charette method. their ability to promote cyclisation reactions onto triple'61,'65 and doublelM bonds.Spirocyclisations may be carried out using silyl enol ethers as the nucleophilic components as in the conversion of 143 to 144 after demercuration (N.B. the epimer is also formed).16% A good example of the value of this methodology is provided by the biscyclisation of 145 to 146 upon treatment with mercury(I1) triflate.'% Organomercury reagents are most remarkable for TMSO NHS02R 'NHSO~R 142 R = Me, CF3 143 144 145 146 4 Group 13 4.1 Boron In view of the marginal nature of boron as a 'metallic' compound, this section will be somewhat shorter than in previous reviews and will highlight important aspects of organoborane reactivity.4.1.1 Boron enol ethers, borane catalysts and a1 kylboranes Boron enol ethers continue to be of great synthetic significance due to their remarkable versatility and ability to introduce several stereogenic centres in one process. Their application however does require the control of two aspects; enolate geometry and diastereoselectivity of additions to aldehydes. The first has been studied in detail by Brown, who has published a series of articles on enolboration. 167 Above all, these reveal the remarkable sensitivity of the process to substrate structure and reaction conditions; treatment of 147 with dicyclohexylboron iodide and triethylamine in carbon tetrachloride gives the isomer 148 when R=Me but 149 when R=Ph.'67a In each case the selectivity in each direction is in the region of > 97: < 3.chiral boron enol ethers 150, it is perhaps the group Of those who have studied aldol reactions of of Paterson who have made the greatest use of these remarkable reagents.16' The majority of the factors controlling the selectivity of these reagents has largely now been delineated by this group, who have turned their attention to synthetic applications. Whilst a comprehensive review of the achievements of this group is not possible in an article of this type, attention is drawn to the syntheses of target molecules as diverse as ~leandomycin,'~~ swinholide been reported recently.Whilst the diisopinocampheylborane group is perhaps the most widely studied directing group, other chiral modifications of boron enol ethers may be made. For example the moderately enantioselective [2,3] Wittig rearrangement of 151 to 152 (83 : 17 in favour of this isomer) takes place via the diamine-derived enol 153.17* Menthyl-derived dichloroborane 154 has previously been shown to be a remarkable catalyst for the asymmetric Diels- Alder reaction, giving ee's of up to 99.5%! For the first time an X-ray crystal structure of a complex of this catalyst with a ketone has provided evidence to support the speculation that this stereocontrol is the result of a two point binding effect, rather than simply complexation of a lone pair on the ketone.'73 and ebelactone A and B,171 all of which have 1 50 151 1 52 fy0Me Ts Ts Ph 153 154 Alkylboranes have numerous applications in synthesis, although alkyl transfers to electrophilic reagents are not so common.One interesting recent example has been reported of such a transfer to a cyclic nitrone, a process which is promoted by initial association of a trialkylborane with the nitrone oxygen atom.'74 Chloromethylborate esters are also valuable synthetic reagents which have application in homologation reactions. The results of a detailed study of this class of reaction employing in situ generated alkyllithiums have been reported this year by 214 Contemporary Organic Synthesis4.1.2 Allyl-, allenic and alkenylboranes Allylboranes are remarkable synthetic reagents, capable of the generation of high regio- and diastereo-selectivities in addition reactions to carbonyl compounds.Asymmetric modification of these reagents renders valuable chiral reagents such as 155, a reagent which adds to acyl silanes to give products of up to 92% ee.176 These reagents may alternatively be of a complex structure, for example 156, which supplies an a-aminoallyl group in additions to aldehydes to give the product 157 with both de's and ee's in excess of 90%.'77 The related allylboronic esters 158 and 159 have probably received even further attention, Hoffman having recently examined the reactions of diol derived 158 B-Allenyl-9-BBN, a useful reagent for regio- and chemo-selective formation of homopropargylic alcohols upon reaction with aldehydes, has recently been described in a detailed publication by Brown.I8* Related vinylic boron reagents, excellent substrates for palladium catalysed coupling reactions with aryl and vinyl halides,'83 may themselves be formed by coupling reactions of boronic halides with trialkyltin alkenes.Is4 The 1,2-diborated alkene 164 is a suitable partner for cycloaddition reactions with unactivated dienes such as 165; oxidation of the primary cycloadduct then yields 1,2-trans diols 166.'@ Alkenylboranes bearing halides at the a-position react with allylic nucleophiles to give substitution products and subsequently ketones after oxidation.lg5 155 156 N Y P h Ph 1 57 158 with chiral aldehydes'78 and R o u s ~ ' ~ ~ and others180 the reactions of the tartrate derived versions 159.A versatile derivative is the menthofuran derived compound 160, which adds to aldehydes RCHO to give the trans products 161 and subsequently diols 162 upon oxidation.'79b The brominated allylic reagent 163 adds to aldehydes to give products with ee's of up to 9O%.ls0 Recently Roush has reported that improved results can in some cases be achieved using a related reagent containing an ethylene bridged tartramide in place of the ester groups in 159.18' 1 59 160 I OH 161 163 OH 162 QO; B ' 0 0 164 165 166 4.1.3 Hydroboration and carbonyl reduction by boranes Hydroboration is a pivotal transformation in boron chemistry. Few monoalkyl boranes are available to the synthetic chemist, however, the hindered thexylborane being the most widely used derivative.Another hindered compound, 2,4,6-trimethyl- phenylborane, has been reported to be a viable alternative, and benefits from relative ease of preparation and hand1ing.ls6 In terms of chiral alkylboranes, monoisopinocampheylborane 167 is well established. However minor modifications to the structure, as in the case of 168, have been reported to give reagents with dramatically improved selectivities in hydroboration reactions of representative alkenes.ls7 A potential problem with such reagents, however, is their non-availability in consistently enantiomerically pure form. To solve this problem a number of upgrading methods have been developed, one based on the formation of a 2: 1 complex with a diamine (as used to upgrade 167)'88 and the other based on the temporary formation of a trialkylb~rane.'~~ Further examples of transit ion met a1 complex mediated hydrobora t ion reactions have been reported."" 1 Y 1 167 168 169 170 R = H 1 72 171 R=Me 1 73 Wilks: Main group organometallics in synthesis 215Bis( isopinocamphey1)chloroborane 169 is an outstanding reagent for the asymmetric reduct ion ketones.Recent reports have appeared on the reductions of fluorinated ketones, which in some cases show improved or even inverted absolute asymmetric induction.'" The reagent is extremely well suited to the reduction of p-amino ketones, which may be reduced in up to 99% ee in some cases.'92 A remarkable reversal of selectivity was observed in the reduction of the closelv related of ketones 170 and 171 with 169.'93 The fbrmer gives the R-enantiomer 172 in 90% ee while the latter gives the S-enantiomer 173 in 92% ee, suggestive of an important coordination effect involving the hydroxy group.Highly selective asymmetric intramolecular reductions by chiral boranes have also been de~cribed.'~~ 4.2 Aluminium, gallium and thallium Carboalumination of terminal alkynes by trimethylaluminium may be catalysed by organozirconium complexes, the resultant vinylaluminium reagents 174 then being effective substrates for palladium catalysed coupling reactions with a-amino acetates 175 to give amino ester derivatives 176.'95 The combination of trimethylaluminium with dimethylamine gives a reagent which is highly effective for the formation of amides from esters196 whilst the use of trimethylsilyl triflate effectively activates trimethylaluminium towards gern-dimethylation of ketones.197 Although not as well established as the boron complexes described above, aluminium complexes 177 of diamines are effective catalysts of allylic acid cyclopropanation by diethylzinc and dii~domethane.'~~ Highly hindered alkoxyalkylaluminium complexes are effective Lewis acids for the promotion of several classes of transformations including hetero Diels-Alder reactions. However, most remarkable is their exquisite chemoselectivity; in certain cases straight chain aldehydes can benefit from the Lewis acid activation in the presence of more hindered derivatives due to the high level of steric hindrance around the aluminium centre.'99 In a similar way, 1,Zaddition to cyclic enones can be suppressed compared to 1,4-addition by the steric hindrance in the complex.'99 AIMe2 P h2C=NyC02R h2cT C02R H OAc R' R' 1 75 176 +H 174 H S02Ar aN\A,R BrGa/TMS BrGa-TMS " H S02Ar Gallium reagents have seen a handful of important applications.The reducing agent formed by the combination of gallium trihydride with a tertiary amine or phosphine is selective for reduction of the carbonyl group of bromoacetophenone.200 In contrast many aluminium hydride reagents would have cleaved the C-Br bond. Tetraalkylgalate complexes, formed by the reaction of an alkyllithium with a trialkylgallium, transfer a single alkyl group to acid chlorides to give ketones, a process which invariably results in formation of tertiary alcohol when other organometallics are used.201 Prop-2-ynylic and allylic organogallium compounds 178 and 179 may be prepared from the appropriate bromide precursors and react cleanly with carbonyl compounds.202 Organothallium reagents have always been somewhat underexploited in synthesis due to their toxicity.An interesting recent application of a trimethylthallium-methyllithium combination for nucleophilic additions to ketones revealed an interesting chemoselectivity; enones were considerably more reactive than the corresponding saturated compounds towards methylation, the reverse of the expected reactivity.203 5 Group4 5.1 Silicon 5.1.1 Silyl enol ethers The full range of applications of silyl enol ethers in any review period is far too vast to detail comprehensively, and therefore attention here will merely be focused on a small number of interesting studies of the stereochemistry of the reactions of these compounds with aldehydes.The great difficulty in the study of such reactions has always been in delineating all of the various effects - solvent, temperature, counterions, etc. - which contribute to a given result. Denmark has devised and studied an ingenious model based on the structure 180 which reduces the problem to that of an intramolecular reaction within a very well defined steric framework. The results of cyclisation studies of 180 have painted a complex picture however: there appears to be an inherent modest preference for an open, anti-periplanar reaction 1 80 HO 181 0 OH M e O v P h Me Me 182 177 178 179 1 83 216 Contemporary Organic Synthesismode (to give 181) in the presence of a range of Lewis acids and fluoride sources.2o4 In other cases the selectivity can be reversed, suggesting a chelation between the reaction partners. Denmark has also reported recently on the use of silacyclobutane derived enol ethers 182, which give predominantly (93 : 7-99 : 1) the syn aldol products 183 upon reaction with aldehydes.205 The incorporation of a chiral alkoxy group on silicon also results in asymmetric inductions of up to 97% in the case of ( - )-tralzs-2-cumylcyclohexanol.205 5.1.2 Allyl-, benzy- and alkenylsilanes and their derivatives Allylsilanes 184 may be made efficiently by the palladium catalysed reduction of allylic acetates 185 by sodium formate; regioselective hydride transfer to the terminal position of the intermediate complex is observed.206 Another method which allows full control of regio- and stereo-selectivity is the nickel catalysed coupling reaction of vinylselenides with a-trimethylsilylmethyl Grignard reagent^.^" In a series of systematic studies on a stereochemically well-defined substrate 186, which follow on from previous work, Denmark has examined the intramolecular Lewis acid catalysed cyclisations of allylsilanes and stannanes with aldehydes2'* These studies suggest that an anti electrophilic substitution process operates, i.e.the trialkylsilyl group is anti to the face of the ally1 group which reacts with the aldehyde. f CHo R S i P h M e , D TMS RFTMS R- OAc 184 185 186 Unlike allylboranes, allylsilanes generally require assistance from a Lewis acid to react with aldehydes.Allylsilacyclobutanes 187 appear to be rather more reactive than average and undergo non-catalysed additions at 130 O C . * 0 9 A rare example of Lewis base catalysed addition of allyltrichlorosilane to aldehydes has also been reported; phosphinamides act as the Lewis bases of choice in this This process also benefits from the fact that a homochiral phosphinamide may be employed to induce asymmetry in the reaction. In practice 188 was found to be the best reagent: 1 equivalent of 188 gave an ee of 63% for the reaction shown in Scheme 19. It is noteworthy that the two studies 187 1 88 i Ph c,3siN + PhCHO - Reagent: i, 1 eq. 188, -78 "C, CH2CI2 63% ee Scheme 19 above also came from Denmark's laboratory, which underlines his very important contributions to this area.In contrast to aldehydes, oxonium cations react rapidly with allylsilanes, a process which can be used to advantage in intramolecular cyclisation reactions.21 In the acid catalysed reaction between 189 and acetal 190, the intermediate 191 cyclised via the corresponding oxonium cation to give 192 with a high degree of diastereocontrol.212 Addition reactions, in the presence of a suitable Lewis acid, of allylsilanes to carbon-nitrogen double bonds have been rep~rted.~'" A related intramolecular cyclisation process featured an allylsilane cyclisation onto the cationic intermediate in a Beckmann Epoxide opening reactions can promote intramolecular allylsilane-terminated processes, an excellent example of which is the conversion of 193 to 194 upon activation by dichloromethylaluminium at -78 0C.215 The silyl group is essential for the success of this transformation. Rl+o"2 OR2 OH 190 MeSSi 189 R 2 0 q 0 'R II 191 1 92 193 In some cases Lewis acid catalysed allylsilane additions to electrophiles can give rearrangement products.The use of niobium pentachloride, for example, results in the formation of a product containing a cyclopropane ring.216 Reactions with Wills: Main group organornetallies in synthesis 217alkynes bearing electron withdrawing groups may give products of overall [3 + 21-cy~loaddition.~~~ Scheme 20 features a remarkable example in which two sequential reactions of this type take place.217a A similar process can on occasions take place in additions to ketones;218 however in some cases [2 + 21-cycloaddition reactions can compete.219 Reagent: i, TiC14, CH2CI2.-78-20 "C Scheme 20 Palladium(0) complexes can assist the reactions of allylsilanes with allylic acetates220 and aryl triflates.221 The incorporation of a chiral diphosphine can render this process asymmetric. An example is the formation of 195 in 91% yield and 92% ee from 196 when R-BINAP is employed as the ligand in the catalyst.222 Coupling of allylsilanes with benzylsilanes may be achieved by oxidative HO HO I L S i M e 3 \\ 195 1 96 Pr0p-2-ynylic~~~ and allenic ~ i l a n e s ~ ~ ~ may participate in intramolecular cyclisation reactions. The reaction of 197 with benzylamine in the presence of tin tetrachloride gives 198 with a high degree of stereocontrol via cycloaddition onto the intermediate imine.225 Compound 198 is an advanced intermediate in the synthesis of the C2 symmetric compound papuamine.An alkynylsilane, 199, is an advanced intermediate employed in the key step of the synthesis of a cyclic enediyne compound 200; dry caesium fluoride is employed to promote the reaction.226 H 1 97 R 198 A silicon atom has been used as part of a temporary 'tether' to mediate the intramolecular [2 + 21-cycloaddition between an alkenylsilyl group and the carbon-carbon double bond of an enone. Following the reaction the silicon was removed in an oxidative process to give a d i 0 1 . ~ ~ ~ Stereoselective epoxidation of an allylsilyane followed by a concerted intramolecular cyclisation, silyl migration and epoxide opening provided a means for the stereoselective formation of y-lactones, precursors of building blocks for nonactin.228 5.1.3 Other classes of silicon reagent Trialkylsilanes are ubiquitous reagents for the protection of alcohols.Whilst it is not possible to present a comprehensive review, the ability to selectively remove a tert-butyldimethylsilyl group from either an aliphatic or phenolic position, depending on the exact conditions used, is noteworthy . 229 double bonds may be employed to promote intramolecular cyclisations of 1,5-dienes, provided an ytterbium catalyst is Intramolecular asymmetric hydrosilylation of 201, using a combination of rhodium(1) with S-BINAP gives the siloxacycle 202 in up to 96% ee.231 Rhodium catalysed hydrosilylation of N-acyl enamines results in introduction of the silyl group a- to the nitrogen atom, as in 203.232 Asymmetric ketone hydrosilylation may also be achieved by the use of appropriate complexes of rhodium ( I ) ~ ~ ~ and a similar asymmetric reduction process of nitrones by the use of a ruthenium-BINAP combination (ee's up to 91%).234 This hydrosilylation process can also be used to prepare silanes which are chiralat silicon; reaction of 1-naphthylphenylsilane with symmetrical ketones, catalysed by a rhodium(1) BINAP catalyst, is reported to give products 204 of up to 99% ee. Subsequent reaction of 204 with methylmagnesium bromide results in conversion to the corresponding chiral silane 205 in equally high ee.235 The insertion reaction of carbenes into silicon-hydrogen bonds has been shown to be an effective method for the preparation of alkylsilanes.236 Hydrosilylation reactions of carbon-carbon R A 0 - p H 201 199 200 R 204 0 H- R P - 202 Yh Si Me I-Np' 1 "H 205 R' 203 PhMe2Si-Li 206 218 Contemporary Organic SynthesisAcylsilanes may be prepared by the ring opening of silylated epoxides, followed by oxidation of the a-hydroxy silane product.237 The addition of carbanionic nucleophiles to chiral acylsilanes can in some cases be a diastereoselective although in some cases a synthetically useful silyl migration from carbon to oxygen takes place.239 Lithiated silanes 206 may be formed from the and participate in stereocontrolled conjugate addition reactions to chiral electrophiles such as 207.24’ Oxidation of the intermediate adduct 208 gives the enantiomerically enriched P-hydroxy product 209.Ph 207 208 209 5.2 Germanium The germanium equivalent of the Peterson reaction has been known for some time. Recently however the X-ray crystal structure of the ketone addition intermediate has been solved.242 Ally1 germanium reagents, formed in situ from ally1 bromides, react efficiently with aldehydes via the tetra-coordinated intermediate 210.243 Alkenylgermaniums have been prepared from terminal alkynyl~ilanes.’~~ 21 0 5.3 Tin Asymmetric aldol reactions may be mediated by the combination of a tin(ii) complex with an appropriate chiral diamine, a process which has now been refined for a wide range of asymmetric addition of tributyltin to aldehydes may be catalysed by chiral quaternary amine salts, although in rather modest ee (up to 24%).246 The intramolecular cyclisation of a vinyl iodide with an aldehyde may be mediated by tributyltin anion generated in situ by the reaction between trimethylsilyltributyl tin and caesium (generated in situ from the bromides) with aldehydes may be catalysed effectively by copper( I) In most cases, however, allyltin compounds may be prepared by a variety of methods, and isolated before use. The most common application of allyltins is in reactions with aldehydes, in which high stereoselectivities are invariably achieved.In some cases palladium salts provide a conveniently mild form of catalysis.249 Studies of the The The Barbier coupling reaction of allyltins functionalised reagents 211250 and 212251 have been reported.Remote functional groups can have a dramatic stereodirecting effect,252 an example of which is 1,7-asymrnetric induction in the addition reaction of 213 to aldehydes RCHO, upon SnBu3 & R 4 q S n M e 3 R2 OBn 21 1 21 2 B u 3 S n v OH OH 21 3 21 4 21 5 21 6 21 7 treatment with tin tetrabromide, to give 214 in high de.252” In this reaction the tin tetrabromide exchanges with the organometallic to give a terminal alkene which then adds to the aldehyde via a chelated transition state 215. A similar chelating effect operates in a very attractive example of an ally la t ion of an unprotected a- hydroxy ketone. 253 a-Alkoxyallylstannanes such as 216 can be prepared by the insertion of carbenes into tin- hydrogen of acyltin reagent^."^ The reactions of these compounds with aldehydes to give products 217 are highly selective, although rearrangement to y-alkoxyallyltin compounds 218 usually precedes the addition reaction.In the case of 216 indium trichloride catalysis was employed to give products with ee’s in excess of 95%.256 Full details of the additions of this class of reagent to numerous classes of aldehyde have been reported by Allyltin reagents such as 218 may be made by the SN2’ reaction of cuprates with vinyltin reagents such as 219.258 A word of caution regarding the catalysis of the addition reactions - the use of a fluoride source along with boron trifluoride has been reported to effect conversion of the enol ether unit of 218 to the corresponding aldehyde, an unexpected An asymmetric version, containing a carbohydrate derived directing group, has been reported by Roush.260 Intramolecular reactions of allyltin reagents onto aldehydes26’ and oxonium cations,262 have been or by the asymmetric reduction Me3uM0M Me B u 3 s n ~ o E t OEt 21 8 21 9 Wills: Main group organornetallies in synthesis 219reported. Typical is the stereoselective conversion of bromide 220 to 221 upon reaction with excess activated tin(0).261" Allyltin compounds also react with alkyl iodides (a radical process)263 and in cycloaddition reactions with singlet oxygen.264 Allenyltin compounds 222 undergo stereoselective additions to aldehydes, the selectivity of which depends on the method of catalysis; using boron trifluoride, 223 is formed whilst the isomer 224 results from the same reaction in the presence of tin tetrachloride.265 220 221 222 223 224 a-Alkoxymethyltin derivatives 225 may be prepared by a number of methods, and in enantiomerically pure form by the reduction of acyltin compounds or the corresponding acetals.266 Oxidation of these reagents by ozone provides a means for the synthesis of most synthetically powerful when used as a-alkoxymethyl anion equivalents, a process which can in some cases be assisted by palladium(0) catalysis.26s Such compounds also participate in intramolecular cyclisation reactions onto bromonium cations269 and couple to allyltrimethylsilanes under anodic oxidation conditions.270 Transmetallation of trialkyltin substituted epoxides has been reported,271 as have a series of studies on the 2-trialkyltin substituted tetrahydrofurans 226.272 A synthesis of a-aminotributyltin compounds 227 has been although they are SnBu3 RR'N-( OR1 R RASnBu3 R2 225 226 227 RIX RYiMe3 SnMe3 R2 Ill XR' 228 X = 0, S; R', R2 = alkyl 229 X = 0, S; R1, R2 = alkyl \SnBu3 230 231 reagent.276 Another versatile approach to the synthesis of trans-vinylstannanes, in this case from aldehydes, has been described by Hodgson (Scheme 2 1) .277 + Bu3SnCHBr2 i * R4SnBu3 H Reagent: i, 4 eq.CrCI2, LII, DMF, THF, 25 "C Scheme 21 Vinylstannanes are most commody employed in palladium catalysed coupling reactions with a range of reaction partners including acid aryl halides279 or each other.280 In the field of natural product synthesis cis-1,2-bis(trimethyltin) 232 is an excellent reagent for the late-stage formation of enediyne units in the synthesis of the dynemicin antitumour antibiotics.281 In a synthesis by Danishefsky the two alkynyl iodides in 233 were connected, to give 234, using this reagent.In his synthesis of strychnine, Overman employed a palladium catalysed carboarylation reaction between a vinyltin, an aromatic iodide and carbon monoxide as a key step.282 232 Although vinyltin reagents may be prepared from alkynes using palladium catalysed additions of various tin sources,274 the regiochemistry of this process can often be difficult to One example of a regioselective reaction, however, is the exclusive formation of the useful building block 228 from 229.275a The preceding example was reported by the Kocienski group, who have also described a regio- and stereo-selective formation of vinylstannane 230 by treatment of the lithiated I dihydrofuran 231 with a tributylstannane cuprate 233 OMe 234 220 Contemporary Organic Synthesis6 Group 15 6.1 Phosphorus The area of ligands which are chiral at phosphorus has been reviewed recently.28' The protection of phosphines with borane, which may then simply be removed by treatment with excess amine, is an idea which has received increased attention recently.284 Such ligands, for example 235, may be prepared directly by the reaction of borane-coordinated phosphorus anions 236 with appropriate electrophiles, in this case 237.284" Knochel has described the preparation of functionalised phosphines via the reaction between functionalised organozincs and chloropho~phines.~~~ Once again the borane-protected phsophines are actually isolated./ PhSe, ,, 235 236 237 6.2 Arsenic, antimony and bismuth Together with a palladium source, salts of all three of the metals in this section have been shown to be capable of catalysis of the conjugate addition reaction of sodium tetraphenylborate with enones.286 Arsenic ylides have been employed for the synthesis of a-phenylselenyl acrylatesZR7 and for the synthesis of 3-hydroxy leukotrienes from lactol precursors.288 In the latter case, the olefination reaction proceeded with a high degree of trans-selectivity. sources of aryl groups in conjugate addition reactions to en one^^^^ or in carboxylation reactions2w in the presence of an appropriate palladium catalyst. Allenylantimony reagents have been used in addition reactions to aldehydes.291 Triaryldibromobismut h compounds have been used effectively as reagents for the dehydration of secondary and tertiary alcohols.292 Bismuth ylides give epoxides upon reaction with aldehyde^.^^' Triarylbismuth reagents can be activated towards N- arylation of cyclic a m i n e ~ .~ ~ ~ Triarylantimony reagents may be employed as 238 239 I Boc Boc 240 241 1 -p henylselenyl-2-trime t hylsilylet hene with enones gives a cyclopropane as the product via a selenium assisted 1,241~1 shift.299 Homochiral selenium reagents can give enantiomerically enriched alkene addition produ~ts.'~ The reaction of styrene with 242 results in the formation of 243 and subsequently 244 in 98% ee after reductive cleavage of the carbon- selenium bond."& A similar directing group was employed for the synthesis of ally1 amines from chiral selenium compounds in ee's of 77 to 87%.'"' I 242 PhAOMe 244 243 Alkylselenium reagents may be employed in radical reactions; several recent examples of intramolecular cyclisations onto double and triple bonds have been reported.These reactions may be terminated by tributyltin h~dride,~'~ resulting in a reductive cyclisation, or by the alkylselenyl radical, to give the product of addition across the unsaturated bond.'03 In the case of enol ethers the radical addition invariably takes place at the P-position (hence the alkylselenium is incorporated adjacent to the alkoxy and good diastereoselectivity may be obtained if the substrate is ~ h i r a l .~ ' ~ The radical generated from sulfoxide 245 may be trapped with allyltin compounds to give 246 as a mixture of isomers.306 A Pauson-Khand 7.1 Selenium &SePh ?- Ci"; 7 Group 16 0- 0- Phenylselenium halides are excellent reagents for the promotion of intramolecular cyclisation 245 246 247 reactions.295 A 6-exo-trig cyclisation of O-ally1 oximes provides an efficient entry to the quinolizidine J& If' o&H alkaloids;296 however most of the reported as in the representative conversions of oxime 238 to 239297 and tryptophan derivative 240 to 241.298 The H SePh tin tetrachloride catalysed reaction of trans- 248 249 250 R2SiH cyclisations proceed through the 5-endo m ~ d e , ~ ~ ~ . ~ ~ ~ 0 --OH H-- Wills: Main group organometallics in synthesis 221reaction followed by a radical cyclisation transforms 247 into tricyclic product 248 in two steps - a powerful reaction c~mbination.~’~ A sequence involving radical addition across a triple bond, hydride abstraction from silicon and further cyclisation converts 249 into the silacycle product 250 in one remarkable by the oxidative reaction of an alkylselenyl- aluminium complex with aldehydes,m also participate in radical cyclisation reactions.310 An outstanding example is the conversion of 251 to the tetracycle 252 (a 1 : 1 mixture, 53%) in one step with a combination of tributyltin hydride and AIBN.310” Acylselenium compounds, which may be prepared COSePh 251 252 The preparation and use of selenoglycosides as reagents for the synthesis of polysaccharides has been described in some detail.These reagents provide an excellent balance between stability and reactivity and are excellent synthetic reagents.”’ Intramolecular cyclisations onto a-seleno carbenium ions formed from selenium-oxygen heteroacetals have been described.312 7.2 Tellurium Sodium hydrogen telluride, and close derivatives thereof, are powerful reducing agents for double and triple bonds313 and are particularly efficient at the conversion of epoxides such as 253 into the corresponding allylic alcohols 254.314 Other leaving groups may be used in place of tosylate in this sequence which permits the asymmetric synthesis of allylic alcohols from readily available Sharpless epoxidation products. 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Sonoda, J. 0%. 322 D. Crich, C. Chen, J.-T. Hwang, H. Yuan, 228 Contemporary Oqanic Synthesis

ISSN:1350-4894    

DOI:10.1039/CO9960300201

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Saturated oxygen heterocycles CHRISTOPHER J. BURNS AND DONALD S. MIDDLETON Pfizer Central Research, Sandwich, Kent CTll 7NU, UK Reviewing the literature published between October 1994 and September 1995 Continuing the coverage in Contemporary Organic Synthesis, 1995, 2, 189 1 Three-membered rings 2 Four-membered rings 3 Five-membered rings 4 Six-membered rings 5 References 1 Three-membered rings There have been further illustrations of the use of manganese salen complexes in asymmetric epoxida- tions of unfunctionalised olefins published over the review period. Katsuki et al. have reported on two new manganese salen catalysts, 1 and 2, which show improved enantioselectivities in the epoxidations of a selected range of disubstituted olefins compared to their desmethyl analogues 3 and 4, The catalyst 2 has also been employed in the highly enantioselective epoxidatip of trisubstituted olefins where either iodosylbenzene 5 or sodium R - G R H-- 1 R=Me 3 R = H 2 R=Me 4 R = H hypochlorite was used as ~xidant.~ Thus, the dihydronaphthalene derivative 6 is transformed into the epoxide 7 in 96% ee.Good to excellent ee's are also obtained with the complex 2 in the epoxidations of cis-olefins4 and cis-enynes.' PhIO 5, 2, C N * - O - , :,e:N, 6 7,96% ee Brandes and Jacobsen have reported that certain tetrasubstituted olefins can be epoxidised with manganese salen catalysts with high enantio- selectivity.6 For example, the chromene derivative 8 is epoxidised with sodium hypochlorite in the presence of the catalyst 9, to afford the epoxide 10 with 96% ee.Under these conditions, Jacobsen et al. have previously shown that styrene is epoxidised with only moderate ee; however this group has recently demonstrated that low temperature ( - 78°C) epoxidation of styrene using either magnesium monoperoxyphthalate (MMPP) or MCPBA as oxidant with a salen catalyst such as 9 (and NMO as an essential additive) generates styrene oxide with good ee (59-86%).7 These conditions have recently been shown to be superior to the original aqueous bleach procedure in the epoxidation of a series of monosubstituted and cis- olefins.8 Adam and co-workers have demonstrated that dimethyldioxirane can also be used as the oxidant with manganese salen catalysts.' 9 c NaOCI, Ph<N*-O-, CH2C12.0 O C - 8 10,94% ee Amongst other routes to chiral epoxides, Hager and colleagues have demonstrated that 1,l-disubstituted olefins can be epoxidised with moderate to excellent enantioselectivity using chloroperoxidase (CPO).'o For example, the olefin 11 is converted into 12 in low yield but with good enantioselectivitv.Lasterra. Sanchez and Roberts Bums and Middleton: Saturated oxygen heterocycles 229have used catalytic poly-L-leucine to affect highly enantioselective epoxidations of a series of a, P-unsaturated ketones with H202-NaOH.l' Thus, the olefin 13 was converted into the epoxide 14 in both excellent yield and ee. Jayaraman et al. have prepared the chiral cis-vinyl epoxides 15 via the intermediacy of chiral chlorohydrins, generated by asymmetric chloroallylborations of aldehydes (Scheme l).I2 The product epoxides 15 are formed with excellent ee and in high yield.CPO, H202 H20, acetone, 11 12,89% ee example, Luthman and co-workers have shown that the allylic carbamates 18 are epoxidised with MCPBA to give predominantly the threo epoxides 19, largely independent of the allylic substituent R." Warren and his group have shown that epoxidations of the allylic phosphine oxides 20 with MCPBA leads preferentially to anti epoxides 21; however the presence of an allylic syn hydroxy group reverses this trend giving instead the syn-epoxides 22 as the major products.16 , Ph ,Ph 18 0 0 L-leucine Ph ____c \ / 85% 13 14,93% ee IpQBoMe ii. LiN(c -hex)p, THF iii. BF39Et2 I 15 R = alkyl, phenyl 90-98% ee Scheme 1 Mitrochkine et al. have employed a lipase catalysed transesterification in the asymmetric synthesis of (1S,2R)-epoxy indane 16.13 Thus, the racemic bromohydrin 17 was treated with vinyl acetate in the presence of the lipase LP 237.87, and after 8 days unreacted bromohydrin was obtained with very high optical purity.The epoxy indane 15 was then formed upon reaction of this chiral bromohydrin with sodium methoxide. The use of epoxide hydrolases in the kinetic resolutions of mono- and 2,2-di-substituted epoxides has also been e~amined.'~ A number of diastereoselective epoxidations have also been reported over the review period. For 19 threo lerythro R = C02Me 8: 1 R = CHpOH 7: 1 R = CH20Ac 5: 1 R2 R2 ~ l & ~ 3 MCPBA "'4 I R3+ "'4 I R3 PhpPO PhpPO PhpPO 20 21 22 R', R2, R3 = H, alkyl 21:22 = 66:34 -+ 91 :9 In an extension of previous work, Jackson et al.have shown that the stereochemistry of the sulfone epoxides 23 derived from 24 is significantly influenced by the nature of the allylic oxygen substituent; thus the free hydroxy compound (24, R' = H) gives predominantly syn epoxides while the silyloxy derivative (24, R' = SiPr;) affords largely the anti isomer.17 Interestingly, the opposite trend is seen for the substituted olefins 25. 20 R', R~ = H, alkyl 21 22 27:73 + 7:93 A 24 R = alkyl R 23 R1 = H; synlanti = 25:l R' = syn /anti = 1 :4 -+ 1 :25 PH S02Ph 0 PH & O k 03- Br ~ d ~ a W - 0 - MR' Ph R Ph R BrL- THF a d 85% / hexandether R' = H; synlanti = 1:12 + 1:25 R' = Sip+,; syn /anti = 2:l -+ 5:l 20% 25 me17 16,9$5% 88 230 Contemporary Organic SynthesisIn related work, epoxidation of the olefin 26 is shown to generate predominantly the syn epoxide 27 unless the hydroxy protecting group is methoxy- ethoxymethyl or the alkyl substituent is bulky (e.g. Pri), when the anti epoxide 28 is favoured." Linderman et al.19 have demonstrated that the epoxidation of cyclohexenyl ketones 29 with tert- butyl hydroperoxide/Triton B gives preferentially the anti epoxides 30, the ratio being largely independent of alkyl group R, or oxygen protecting group R'.OR1 LiOOBu' A OR' OR1 R b S O 2 P h x R S02Ph+ R 26 R = alkyl R~ = silyl, MEM 27 28 251 + 1:25 0 0 0 THF, r.t. 59-95% 29 R = alkyl R' = MOM, BOM, COBu', Bn 30 A number of significant reports on the use of dioxiranes in the synthesis of epoxides have been reported recently.Denmark and co-workers have reported the first catalytic epoxidation of alkenes with dioxiranes using the rationally designed phase transfer catalyst 31.20 The optimised conditions for the reaction include careful control of pH (7.5-8.0), slow addition of Oxone@ and the use of the triflate salt of 31, conditions which allow for high yielding epoxidations as shown in the conversion of 32 into 33. O j G N < : E 5 . Oxone 0 31 -OBn CH~CIfl20,O'C a OBn 33 91 Yo 32 34 - 35'6 36 37 mixture of cis and trans epoxides 39 and 40 is formed in acetone, and a 6 : 94 ratio is obtained in carbon tetrachloride/acetone (95 : 5).24 Interestingly, when the hydroxy group in 38 is protected, altering the reaction solvent has little effect on the diastereoisomeric ratio. 38 Solvent 39 : 40 acetone 54 : 46 CCl,,/acetone 6 : 94 While the formation of epoxides from the reaction of sulfur ylides and aldehydes has been known for some time, Agganval et al.have now shown that their recently disclosed catalytic process for sulfur ylide generation is sufficiently mild to be used with base sensitive aldehydes; the conversion of phenyl acetaldehyde 41 into the epoxide isomers 42 is representative." Hioki et al. have also reported a non-basic procedure for sulfur ylide generation.'6 Exposure of the sulfonium triflate salt 43 to caesium fluoride in the presence of aldehydes 44, furnishes the epoxides 45 in good to excellent yield. Matano has demonstrated that 2-oxobismuthonium ylides, prepared from the corresponding salts by treatment with base, also react with a range of aldehydes to give predominantly trans-substituted epoxides, as depicted for the conversion of salt 46 into the epoxide 47." The in situ generation of methyl(trifluoromethy1)- NZCHPh, Rhp(0AC)d CH2C12, r.t..80% 4; 9: 1, trans :cis /o" * Ph dioxirane 34 for use in epoxidations has been PhACHo Me2S, disclosed by Yang et aL2' The reactions are 42 41 conducted in a homogeneous mixture of water and acetonitrile at neutral pH generating epoxides in reactions of the chiral dioxiranes 35 and 36 has been can be formed efficiently with these reagents, asymmetric induction is poor (<20% ee). Similar results have been reported for chiral tetralone- derived dioxiranes such as 37.23 Murray et al. have shown that the diastereo- selectivity observed in the epoxidation of cyclohex- dramatically affected by reaction solvent; a 1 : 1 excellent yield.Similarly, the in situ generation and RCHO 44, CsF, Ph2+!3-CH2SiMe3 -0Tf DMSO, r.t. b R 58-94% reported by Curci and colleagues.'* While epoxides 43 45 R = alkyl, phenyl d 2-en-1-01 38 using dimethyldioxirane (DMDO) is 46 * .r"c( CI ++ Cl*; BiPh3 47 -78 "C + r.t. 70% trans :cis = 91:s Burns and Middleton: Saturated oxygen heterocycles 23 1Chiral sulfur ylides have been employed in the asymmetric synthesis of the aryl epoxides 48.** Thus, the ylide is generated from the salt 49 by treatment with a suitable base, and subsequent reaction with paraformaldehyde gives the desired products. Chiral sulfoximines, such as 50, have been used in asymmetric epoxidations of aryl aldehydes, with product ee's of 19-86%.29 Variable ee's (21-70%) have also been obtained for epoxides generated from the reactions of a series of aldehydes and ketones with the ylide derived from the sulfimide 51.30 % ii.HCHO, i.NaH THF, 4 0 O C * P Ar 49 48 73%, 96% ee Ar= 4 CI 61 Ar = m 5 5 % . 8 4 % ee 50 51 A review on the use of porphyrin and related transition metal complexes in the aerobic epoxida- tion of olefins has been published re~ently.~' Manganese porphinoid complexes such as 52 have also been examined as epoxidation catalysts using peracetic acid as the CI CI 9 CI 52 There have been a number of reports on the use of zeolites as catalysts for alkene epoxidation, and a review has also been published.33 Kumar et al. report that the titanium silicate TS-1 catalyses the epoxidation of allylic alcohols with hydrogen peroxide efficiently, leading predominantly to trans products in good yield.34 Catalysts related to TS-1 that can catalyse the epoxidation of large bulky alkenes have been reported by Fraile et aLJ5 and by Jorda et aZ.36 The catalysts used by each research group are readily prepared from silica and either titanium tetra-is~propoxide~~ or titanium tetra- fluoride.36 The synthetic anionic clay hydrotalcite has been shown to catalyse the epoxidation of a variety of electron deficient alkenes with hydrogen peroxide and the synthesis of the epoxide 53 from the olefin 54 is repre~entative.'~ 54 53 Three routes to epoxyalkylamines have been reported recently.Asensio and co-workers have demonstrated that protonation of the amino function in aminoalkenes with an arenesulfonic acid prior to epoxidation of the alkene moiety [with either DMDO, methyl(trifluoromethy1)dioxirane or MCPBA] leads to the corresponding aminoepoxides without the formation of any N - ~ x i d e .~ ~ The amino function can be similarly protected with boron trifluoride in diethyl ether prior to alkene epoxida- t i ~ n . ~ ~ Ibuka et al. have used the aza-Payne rearrangement of a variety of chiral hydroxy aziridines in the synthesis of chiral p-amino epoxide~.~' For example, treatment of the hydroxy aziridine 55 with potassium hydride under the conditions shown gives the epoxide 56 in excellent yield. KH 55 56 New methods for alkene epoxidation include the use of hydrogen peroxide in conjunction with organophosphorus ele~trophiles.~' For example, the epoxide 58 is prepared from the olefin 57 using hydrogen peroxide with the phosphorus anhydride 59 as promoter, though phosphoryl chlorides may also be used.Formamide has also been reported as a promoter of hydrogen peroxide epoxidations of a series of trisubstituted ole fin^.^* Lastly, Meyers and co-workers have reported that tertiary amine N- oxides alone may act as epoxidising reagents for a 0 0 II II Ph2POPPh2 H202* 59 t HzSTHF, K2C03 - 5 O 80% P 57 58 Ph Ph Ph 0 90% Ph 0 60 61 232 Contemporary Organic Synthesisselected range of lactams, as shown for the conversion of 60 into 61.43 2 Four-membered rings Akiyama and Kirino have disclosed a novel synthesis of oxetanes involving a titanium(1v) chloride promoted [2 + 21 cycloaddition process between a keto ester and an allyl silane.44 The procedure, shown for the conversion of keto ester 62 into the oxetane 63, has been carefully optimised to avoid formation of the simple allyl addition product and isomeric tetrahydrofurans.Bach has extended his work on the Paterno-Buchi reaction between benzaldehydes 64 and silyl enol ethers 65 leading to substituted 3-oxetanols 66.45 The reactions proceed with high diastereoselectivity largely independent of enol ether substitution, and they tolerate a variety of functionality on both the enol ether and the benzaldehyde. 63 96% 62 R3 0 0-f - OMe . OMe' R' = H, OBn, NHAc; R2 = alkyl, -co~B~~, )& , -( R3 = alkyl Reinecke and Hoffmann have published a synthesis of the oxetane-containing core 67 of the natural product dictyoxetane.The oxetane ring is formed in a one-pot fluoride induced desilylatiod cyclisation reaction generating 67 from the silyl ether 68 in moderate yield.46 Phase-transfer catalysis has been shown to be the best method for the synthesis of the oxetanes 69 by base-induced cyclisation of the hydroxy mesylates 70, the chiral centre being unaffected by these condition^.^' a TBAF THF 0 OC --f reflux OTBDMS 3p/o 68 67 3 Five-membered rings New and improved routes to tetrahydrofurans and tetrahydrofuran-containing natural products continue to be an active area of research, and there have been several important contributions over the review period. The synthesis of tetrahydrofurans via formation of a C-0 bond from an acyclic precursor is a particularly common approach to this ring system.Lipshutz and Gross have reported that the in situ generated selenium compound 71 converts homoallylic alcohols to tetrahydrofurans with remarkably high diastereoselectivity, particularly if the olefin is trans; the conversion of 72 into 73 is repre~entative.~' Similarly, DCziel and Malenfant have disclosed that the chiral C2 symmetric selenium compound 74 also effects cyclisation of homoallylic alcohols with high diastereo~lectivity.~~ The ability of silicon to stabilise a positive charge p to it has been exploited by a number of research groups in electrophile-induced cyclisations of alkenols. Thus, Schaumann and co-workers have reported that the vinyl silane 75 cyclises smoothly with either NBS or phenyl sulfenyl chloride as electrophile source, to generate tetrahydrofurans in good yield as shown for the synthesis of 76.50 Hosomi et al.have shown that tosic acid and titanium tetrachloride will also promote the cyclisation of a-hydroxy vinyl ~ilanes.~' PTf 74 75 76 The natural product (-)-trans-kumausyne 77 has been synthesised utilising the cyclisation of an incipient p-silyl carbocation as the key Thus, allyl silane addition to the chiral aldehyde 78 gives the intermediate 79 which then cyclises to the tetrahydrofuran 80. An allylic silicon substituent can also significantly effect the diastereoselectivity of ring formation, e.g. the tetrahydrofurans 82 are generated as the sole diastereomer from cyclisation of the silenols 81.53 Burns and Middleton: Saturated oxygen heterocycles 233-7L 04c: "% L 79 I ,.- \SiMe2Ph 77 SiMe2Ph PhhCI, K2CO3, Et20 -60 OC+ r.t.R 1 744% R &OH 81 R = phenyl, alkyl 82 The preparation of chiral 2,5-disubstituted tetrahydrofurans from monosaccharide alkenes has been reported by Mootoo et aZ.54 For example, exposure of the sugar derivative 83 to iodonium dicollidine perchiorate (IDCP) in wet dichloro- methane generates the unstable tetrahydrofuran 84 which is further reduced to the stable product 85. BnO 83 84 I NaBH4 T BnO goH HO 85 Other work has shown that increasing the size of the anomeric substituent improves the cis to trans ratio.s5 Trost and Li have disclosed a new route to tetrahydrofurans involving a phosphine catalysed intramolecular oxygen addition to 2-alkynoates as shown for the preparation of 86 from 87.s6 La Clair et al.have used an SNf process to generate the fused tetrahydrofuran 88 from the bicycle 89 in a synthesis of the fungal metabolite alliac01-A.~~ Sequential C and 0 alkylation of cyclic enolates forms the basis of a very efficient and diastereoselective formation of bicyclic lactols. Thus, treatment of the cyclo- hexanone 90 with excess potassium hydride followed by the dibromide 91 gives the enol ether 92, and after acidic work-up, the product 93.58 H 75%- H 87 86 HgSO,, PI"Et2 PhCH ' 110 02: 89 bPh 90 i. KH. THF J ii. B r w B r 91 "@Ph 93 New routes to tetrahydrofurans that involve C-C bond closure of acyclic systems have also been reported over the last twelve months by a number of workers using organozinc reagents.For example, Vaupel and Knochel have disclosed a novel nickel catalysed carbozincation reaction which generates 2-alkoqtetrahydrofurans such as 94, from bromo- acetals such as 95.59,60 The reaction proceeds through the organometallic reagent 96 which is readily functionalised as shown. Heathcock and co-workers have used an intramolecular Reformatsky reaction in the total synthesis of ( +)-codaph~~iphylline.~' Thus, treatment of the a-bromoester 97 with zinc generates the tricycle 98 234 Contemporary Otganic SynthesisEt2Zn D Ni(acac)p, THF, BuO AOh,h -78 "C 95 Y ,CHZnB( BuO J 2 - h J 96 i. CuCNQLEl 94 Zn. ZnCl THF, 0 "C 67% *9 97 98 in good yield. The use of allyl zinc reagents in the palladium mediated synthesis of 3-methylenetetrahydrofurans has been recently reviewed.62 tetrahydrofurans, Lautens and Kumanovic have utilised a-stannyl ethers as starting materials in an intramolecular SNt reaction of oxabicyclo[3.2.1] systems; the conversion of 99 into 100 is representative." In an alternative anionic approach to substituted OH Br3Sn MeLi THF, * -78 + 0 "C 71 yo 99 1 00 There have been a number of recent reports on the use of carbenoids in the synthesis of tetrahydrofurans.Padwa and his group have extended their work on the cycloaddition of isomunchnone dipoles, derived from reaction of a-diazo imides and catalytic rhodium(Ii), to include reactions with heteroaromatic n-systems.@ Thus, treatment of the imide 101 with rhodium acetate generates the complex polyheterocycle 102 in good yield and with complete diastereospecificity.An approach to lysergic acid, using an intramolecular isomunchnone cycloaddition reaction has also been ~ublished,~~ as have related dipolar cycloaddition routes to tigliane diterpenes66 and analogues of zaragozic acid A.67 In this latter work, the dipole 103, generated from the diazo compound 104, reacts intermolecularly with a variety of dipolarophiles, such as 105, as shown for the synthesis of 106. n 101 O A 1 02 .. - -1 Meu2b- u7 - - I 0 L J 104 1 03 I T;o;L TMSO ''% Me02C @ 0 106 Other cycloaddition routes to tetrahydrofurans have also been published. For example, Akiyama et al. have extended their work on the stannic chloride catalysed additions of allyl silanes to a-keto esters, and have shown that use of the chiral auxiliary L-quebrachitol leads to tetrahydrofurans of high optical purity, as shown for the conversion of ester 107 into 108 and after reductive removal of the auxiliary, 109.68 n SiBu'Me2 Ph D 107 108 de >98% LiBH4 I 'SiBu'Me2 109 Jiang and Turos have reported an alternative [3 + 21 cycloaddition route to tetrahydrofurans employing the allyl iron(i1) dicarbonyl complex 110.Reaction of 11069 with aldehydes or ketones, in the presence of zinc chloride or titanium tetrachloride, leads to the tetrahydrofuran esters 111, after oxidative destruction of the iron species 112. Bicyclic tetrahydrofurans, prepared by Molander's previously reported [3 + 41 cycloaddition protocol, have been shown to be useful precursors to cis- 2,5-disubstituted tetra hydro fur an^.^' The procedure, Bums and Middleton: Saturated oxygen heterocycles 235@ I co-Fe- co' ' 0 RJw ZnCl CH26I2, r.t.Q I 110 112 R = aryl, alkyl R' = H, alkyl lFH -78 "C Me0 4 111 which involves a Baeyer-Villager reaction of the bicycle 113, followed by oxygenation o! to the newly formed lactone 114 and subsequent reductive ring opening, is shown in Scheme 2. TMSOTf 0 CHpCI2, -78 "C ii. NaH, Me1 0 113 THF, + 0 "C 0 114 1 2 steps n Scheme 2 The related bicycle 115 can be prepared by the Lewis acid catalysed rearrangement of the epoxy cyclopropane 116, and can in turn be manipulated to give the tetrahydrofuran 117, as shown.71 BF39Et2 -78 "C 0 S02Ph 4A SO2Ph 60% 116 115 i. Os04 ii. NaI04 1 0HC--Q*.Jc02H 117 There have been a number of papers published in the last twelve months devoted to the synthesis of oligotetrahydrofurans, and a review has also been published in the area.72 Evans and co-workers have reported the first synthesis of lonomycin A, a naturally occurring antibiotic possessing three contiguous tetrahydrofuran ring^.^' The key ring forming process was achieved in three steps from the chiral diepoxy acid 118, firstly generating the bis-tetrahydrofuran 119 via a self-catalysed epoxide cascade, and then, after hydroxy directed epoxidation, acid catalysed ring closure to generate the tricycle 120 as shown.HO 0 118 4 A sieves CH2CI2, r.t. 1 119 i. MMPP, 4 A sieves, CH2CI2 ii. AcOH, CHpClp I 0 HO Me0 120 An epoxide ring opening process was also used in a synthesis of the bis-tetrahydrofuran portion of the natural product (+)-bullatacin, with Lewis acid catalysed removal of the acetonide in 121 and simultaneous epoxide ring opening giving 122.74 Koert and co-workers have also employed an acid- catalysed epoxide cascade reaction in the synthesis of tetrahydrof~rans.~~ Thus, the 1 : 1 mixture of the diepoxy alcohols 123 generated the two tetrahydro- furan oligomers 124 and 125 in excellent overall yield.This research group has also published alternative procedures for the synthesis of related tetrahydrofuran 01igomers.~~ F O P N B BFseEt20 MeOH-CH2CI2 0 "C + r.t. 92% JOPNB , OPNB HO 121 122 236 Contemporary Oiganic Synthesis123 124,45% 125,45% Paquette and his group have reported further examples of the use of oxonium ions in the synthesis of spirocyclic tetrahydrofurans, as in the syntheses of the natural products dactyloxene-B and -C,77 and grindelic In this latter work, exposure of the dihydrofuran 126 to acid led to the tetrahydrofurans 127 and 128 in the ratio shown, the major isomer being further converted into the natural product grindellic acid.126 I CSA 1 + CH2CI2,20 "C go/ 127 128 1 10.4 The rearrangement of epoxides to tetrahydro- furans has been reported by Itoh et al.; the conversion of 129 into 130 being repre~entative.'~ Petasis and Lu have disclosed a novel rearrangement of 4-methylene-l,3-dioxolanes to generate 3-hydroxy tetrahydrofurans in good yield and with good diastereoselectivity.*' For example, the dioxolane 131 rearranges to the tetrahydrofuran 132 predominantly as the syn diastereoisomer. Angle and his group have reported a novel reaction of B-benzyloxy aldehydes and ethyl diazoacetate generating substituted 3-hydroxy tetrahydrofurans.*' The reaction, illustrated for the conversion of aldehyde 133 into 134, generates only the anti diastereoisomer shown.Lastly, Schmitt and Reissig have shown that a range of organometallic reagents add to y-lactols in the presence of boron trifluoride etherate, to generate 2-substituted tetrahydrofurans.82 The diastereoselectivity of these additions is high for BF34Et2 Y O B n 0 Et20,73 X 129 1 30 Bu'fil Me x:yk' PhCH3,65 90% "C * Me 131 132 (71% S Y ~ ) CH2C12 BF34Et2 ZnEt2 -- 4--Et QoH Ph -78 "C + r.t. Ph 96% 135 136 80% de 3- and 4-substituted lactols (e.g 135 to 136), but poor for 5-substituted substrates. High pressure mediated intramolecular Diels- Alder reactions of furans tethered to a methylenecyclopropane moiety have recently been reported by de Meijere.83 Thus, heating a solution of the furan 137 in ethanol at 70 "C at 10 Kbar pressure for 24 h gave the spirocyclopropane 138 as a single diastereomer.The exocyclic double bond attached to the cyclopropane ring in 137 facilitates cycloaddition due to release of ring strain. The ex0 configuration of 138 was established by X-ray crystallographic analysis. Me% 10 Kbar EtOH,7O0C,24h * 74% 137 138 Engler has reported further examples of Lewis acid-promoted additions of styrenyl systems 139 to benzoquinones to yield dihydrobenz~furans'~ 140, and has extended the scope of the reaction to include 2-alkoxy-4-(N-phenylsulfonyl)-l,4-benzo- quinone monoimides 141.85 The regiochemistry of the cycloaddition in these cases may be controlled by the choice of Lewis acid.Use of BF, * OEt, favours formation of the dihydrobenzofuran 140, whereas use of excess Ti'" as the Lewis acid yields the dihydroindole 142. The first example of an addition reaction to a quinone bearing a chiral auxiliary has recently been reported, although the diastereoselectivity is poor.86 Reaction of the chiral sulfoxide 142, with 1 equiv. of silyloxyfuran 144 in acetonitrile at 0 "C for 2 h gave the cycloaddition products 145 and 146 as a separable 3.4 : 1 mixture of diastereoisomers in 86% yield. Bums and Middleton: Saturated oxygen heterocycles 2370 0 Tc14:Ti(OPi)4 (1:l) 10 equiv., -78 "C \ 139 141 BfsSEt? (1.2 eqUIV.) CH~CIP, 0 "C 142 X = 3,4-(OCH2O) R = Bu', 93% 140 X = 3,4-(OMe)2 R = Bn, 86% 1 45 1 46 3.4 : 1 Kims7 has shown that the thermolysis of a,P- epoxy-N-aziridinyl imines 147 yields the dihydrofuran derivatives 148 via the alkylidenecarbene 149.Whether the reaction proceeds via 1,5-0-Si insertion or initial oxonium ylide formation, remains to be elucidated. Attempts to extend the scope of the reaction to include 1,6- and 1,7-0-Si insertion yielded predominantly the product of C-H insertion. TBDMSO+R k2 kNfPh 1 47 -PhCH=CH2, N22 Toluene, A 149 1 48 6042% R = Ph, Et, PhCH2CH2 Pirrung has reported an extension of the Rh- mediated cycloaddition to diazocarbonyl compounds 15088 using vinyl ethers containing an allylic hydroxy f~nction.~' The allylic hydroxy group present in the vinyl ether 151 directs syn cycloaddition, forming 152 as a single diastereomer. " 152 151 40% 1 50 Hydroxy P-diketones, P-keto esters and P-diesters of general structure 153 have been shown to undergo stereoselective dehydrative alkylation/ annulation to yield cis-fused bicyclic dihydrofurans 154 under Mitsunobu-type condition^.'^ The reaction presumably proceeds via 5-en01 endo-exo- trig cyclisation.Y2 R2 6443% R' HO 153 1 54 R' = Me, OMe R2 = COMe, C02Me y, &Unsaturated ketones 155 bearing an electron- withdrawing group at the a-carbonyl position yield the dihydrofuran products 156 upon treatment with PhSeCl under basic conditions. In the absence of this functionality, regioselective cyclopropane formation to give 157 is the predominant pathway." 0 Me * *SePh NaH, THF, PhSeCl R' 155 156 R' = COMe (85%) R' = C02Et (79%) 0 NaH, THF, PhSeCl * *SePh R' 157 R' = H, 72% Yus9* and co-workers have reported further examples of DTBB-catalysed lithiation, to encompass the synthesis of the substituted furan derivatives 158.Thus, lithiation of 2,3-dichloro- propene 159 followed by reaction with ketones 160 gives intermediate diols 161 in modest to good yield. Acid-catalysed cyclisation then readily gives the furan product 158. The formation of 161 probably proceeds via two sequential lithiation in situ electrophilic quench cycles. Conducting the reaction at 0 "C suppresses allene formation. 4 Six-membered rings An interesting stereocontrolled radical cyclisation approach to the cis-fused pyranopyranyl skeleton of the dactomelynes has recently appeared.'.' Starting 238 Contemporary Organic SynthesisLcl + R ,J, R2 DTBB(5rnolG i.x.s. Li ' M R 2 THF, 0 "C OH ii. H 2 0 159 160 161 HCVEtPO 1 DTBB = 4,4'-di-tert-butylbiphenyl \\ 158 R' = Ph, Pr, Et; R2 = H, Me, Et R', R2 = (CHZ)", n = 4,5 50-9770 from ( -)-diethy1 tartrate, the radical cyclisation precursor 162 was prepared in 45% yield in seven steps. Initial radical cyclisation using tricyclohexyl- stannane under high dilution conditions gave the dichloro product in 67% yield. This intermediate was then dechlorinated stereoselectively using tris(trimethylsily1)silane in the presence of triethyl- borane to give a 13 : 1 mixture of diastereoisomers, with 163 as the major product; the stereoselective formation of 163 occurs via trapping of the intermediate radical 164.Conversion of 162 into the dibromo radical precursor 165 was then readily accomplished. Reaction of 165 with n-tributyl- stannane and AIBN in benzene, again under high dilution conditions, gave the product 166 as a single stereoisomer. The formation of 166 as a single isomer presumably reflects a high steric preference for the radical intermediate 167 in which the bromine substituent is orientated away from the existing tetrahydropyranyl ring. 1 62 i. (ehex)&nH, AIBN ii. (TMS)&H, Et$ 67% I 98% 13:: 1 64 Michael additions of alcohols to a, P-unsaturated esters or ketones continue to be a popular approach to the tetrahydropyran ring system, and their application in total synthesis has been reported by several research g r o ~ p s .~ ~ . ~ ~ Overman's elegant synthesis of the unusual guanidinium alkaloid 33oJ0JCO2Me PO 0 Br 165 Bu3SnH, AlBN CeH6,75% 1 C02Me PO 166 lpo 167 -I via ( - )-ptilomycalin A is illustrative of this approach.'6 The key step of establishing the spirocyclic central template 168 was optimally accomplished in two steps via TBDMS ether cleavage of 169 and subsequent cyclisation using tosic acid, to give a single product. Although epimeric with the natural material at C-4, the centre was readily epimerised later in the synthesis to give the natural configuration. TBDMS 0 C02R 169 i. PPTS, MeOH, 50 "C 1 ii. pTS~OICHCI,. r.t. R = (CH2)15C02All OH 168 Mohr has reported an extension to the acid- catalysed intramolecular addition of an allyl silane to an oxocarbenium ion, in a synthesis of tetrahydropyrans with high regiocontr01.~~ Treatment of the allyl silane 170 with 4-5 equiv.of the acetal 171 at room temperature gives the tetrahydropyran product 172 in moderate to good yields via in situ transacetalisation and subsequent ring closure. In each case the all-equatorial product predominated with > 95% diastereocontrol. Burns and Middleton: Saturated oxygen heterocycles 239-R ,,AOR!65171 OR' equiv.) ~lp..~ MeaSi - 0.33 equiv. TsOH*H20 OH 170 172 -80 "c-+ r.t. ii. MeLi, -80 "C iii. MeOH iv. silica gel 6445% During this review period, the report of Nicolaou's impressive total synthesis of the marine neurotoxin brevitoxin B is particularly n~teworthy.'~ The hetero Diels-Alder reaction continues to be a popular approach to the synthesis of dihydropyrans with numerous reports being described during the review period.Further developments of the asymmetric variant of this process have been reported using B I N O L - ~ ~ S ~ ~ ~ ' . ' ~ ~ and chiral lanthanide bis-trifylamide complexes.'o' High-pressure approaches via reactions of vinyl ethers with 3, P-unsaturated a1dehydeslo2 and enamino ketones"?' continue to be reported. The first efficient examples of heterocycloaddition involving styrene derivatives without the use of high pressure techniques have been disclosed.1M Treatment of activated heterodiene 173 with the styrene 174 in the presence of Eu(fod)3 (5 mol%) in hexane under reflux gave the cycloadduct 175 in good yield and with high endo selectivity. OMe I 173 174 \3.+oc* Eu(f0d)~(5 mol%) 0 OMe 175 >97:3 endo:exo High enantioselectivities have been reported recently for the Pd-catalysed hetero- and carbo- annulations of allenes with aryl and vinylic iodides.'05 For example, treatment of the vinyl iodide 176 with the allene 177 in the presence of 10 mol% of the bis-oxazoline 178 and 5 mol% Pd(OAc)2 in DMF gives the dihydropyran 179 in 79% ee.A recent report has described the highly syn- selective Michael addition of lithium enolates to optically active Fischer vinyl carbene complexes.'o6 Treatment of the Fischer carbene 180 [derived from ( - )-8-phenylmenthol] with the ketone lithium enolate 181, followed by treatment with 2 equiv. of methyllithium, led to the syn-Michael adducts 182 as a single diastereoisomer in all but one case.Dropwise addition of these carbenes to sodium methoxide in methanol under reflux then afforded 177 10 mot% 178 Pd(OAc), (5 mol%) DMF, 80 "C, 4 h 70% 176 I 9 rrC8H 17 179 79% ee 180a R=Ph 180b R = 2 - f u ~ l R2 182 99% de 178 R3 Me NaOMe, MeOH, 65 "C 40-58% * R1** R2 1 83 R1 = Ph, R2, R3 = (CH2)" (n = 3,4) R' = 2-futyl, R2 = Me, R3 = Ph 93-97% ee R' = 2-fu~l, R2, R3 = (CH2)4 the corresponding optically active enol ethers 183 in high enantiomeric excess. Yamamoto et al. have reported a highly regio- and stereo-selective annulation of cycloalkenyl- 3-hydroxypropyl ethers to yield dihydropyrans.'" The regioselectivity of the elimination step is highly base and solvent dependent. For example, treatment of the acyclic enol ether 184 with triflic anhydride in the presence of N, N-diisopropylet hylamine using toluene as solvent gave predominantly the endo- cyclic enol ether product 185.However, treatment of 184 under the same conditions using dichloromethane as the solvent yields predominantly 186. This methodology offers the first practical access to enol ethers of the type 186. OMOH I + solvent -78 OC+r.t. TfzO.Pi2NEt * @ + 8 184 W 185 1 86 toluene 97 3 CH2C12 13 : 87 240 Contemporary Organic SynthesisOverman et al. have reported extensions to the intramolecular Heck reaction to encompass the first examples of the synthesis of spirocyclic polyethers.'"' 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ISSN:1350-4894    

DOI:10.1039/CO9960300229

出版商:RSC    

年代:1996

数据来源: RSC

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Carboxylic acids and esters TAMMY LADDUWAHETTY Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM202QR, UK Reviewing the literature published between 1 August 1994 and 31 July 1995 Continuing the coverage in Contemporary Organic Synthesis, 1995, 2, 107 1 2 2.1 2.2 2.3 2.4 2.5 2.6 3 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 3.10 3.11 3.12 4 Introduction Carboxylic acids General Amino acids 0x0 acids Unsaturated acids Halo acids Miscellaneous Carboxylic acid esters General syntheses of esters a-Amino esters P-Amino esters 6-Amino esters (5-amino esters) a-Hydroxy esters P-Hydroxy esters Miscellaneous hydroxy esters Halo esters Keto esters Diesters Unsaturated esters Miscellaneous References 1 Introduction This review covers the literature pertaining to carboxylic acids and esters. Some chemistry of amino acids has also been included, although this area, as well as chemistries associated with amides and lactones is covered in separate articles in Contemporary Organic Synthesis.2 Carboxylic acids 2.1 General Directed ortho-lithiation is a powerful tool for the synthesis of polysubstituted aromatics. The carboxylic acid group, in particular, is a valuable ortho directing group due to the fact that it can be readily transformed into other useful functionalities, unlike the more traditionally used groups, e.g. amides and sulfonamides. An investigation into the competitive lithiation of substituted benzoic acids reveals that the carboxylic acid moiety is of intermediate capacity as an ortho director, being weaker than an amide, but stronger than methoxy and halo substituents.' acids are still being sought.Although the use of oxazolidinones as resolving agents for carboxylic acids is known, they have not yet gained wide popularity for this purpose due to the commercially available auxiliaries being too expensive for large scale resolutions. Thus the oxazolidinones 1 and 2 are valuable additions to the literature, being available on multigram scale from inexpensive D- xylose.' Their highly crystalline nature is an added bonus, enabling the separation of diastereoisomers by fractional crystallisation as well as by chromatography. An interesting resolution method for amino acids involves their initial coupling with the commercially available homochiral hydroxyketone 3, followed by cyclisation of the resulting ester to form the corresponding Schiff base.3 Only one of the diastereoisomers cyclises, enabling its separation (98% ee, after hydrolysis) by chromatography.The other diastereoisomer is not recoverable by this method (Scheme 1). Novel, inexpensive resolving agents for carboxylic O I l 0 1 R1=Ph;R2=H 2 R ' = R ~ = M ~ 3 0 i. 39"/. TFA, CH2CI2 ii. Pt2NEt 1 '0 overall yield 48% Scheme 1 Ladduwahetty: Carboq&'c acids and esters 243Homochiral a-arylpropanoic acids such as (R)- ibuprofan can be obtained in ~ 9 5 % ee by the diastereoselective addition of the (R)- or (S)- pyrrolidinone 4 to the ketene derived from a racemic acid ~hloride.~ Although this elegant chemistry has been reported previously using (R)- pantolactone, this particular auxiliary has a major advantage in that its full recovery is possible.Both enantiomers of the chiral pyrrolidinone 4 can be synthesised on a multigram scale (Scheme 2). 0 Et3N KO Y + - Ph Ph 4 74 to >99% de 87-93% yield HO OHH Ar 9599% ee Scheme 2 2.2 Amino acids Novel approaches towards the diastereoselective synthesis of amino acids continue to be a major focus in the area of carboxylic acid chemistry. The stereoselective Strecker reaction, involving the diastereoselective nucleophilic epoxidation of the 1-arylthio-1-nitroalkene 5, followed by regioselective ring opening with ammonia, provides a novel route to P-hydroxy amino acids in good yield (Scheme 3).5 This facial selectivity in the nucleophilic addition to protected glyceraldehyde derivatives is once again observed in the addition of lithiofuran to the nitrone 6, where the furan, which is later cleaved oxidatively, is a masked carboxylic acid synthon (Scheme 3b).6 synthon 7 reported earlier, Jackson et al.have In addition to the useful organozinc based alanine a \/ qAo sTol i. BU'OOK, -70 OC THF Hoq T B D M S O ~ - OH ii. NH3. (Boc)20 iii. TFA NH2 5 7 8 extended the scope of this chemistry to include the analogous zinc-copper reagent 8.' This new synthon, based on the Knochel methodology, has enhanced reactivity, undergoing facile SN2' alkylation with a variety of allylic and propargylic halides. The unprecedented use of a carboy group to direct the hydrosilation of P, y-unsaturated acyloxysilanes provides an efficient synthesis of cis- P-hydroxy acids.' This methodology finds its use in one of the shortest syntheses of (2S,3R)- hydroxyproline reported to date (Scheme 4).esters derived from acyclic' and cyclic'o allylic alcohols, undergo a diastereoselective Claisen rearrangement at 25 "C (- 20 "C in the case of cyclic esters) resulting in the formation of a-alkylated y,b-unsaturated acids. The lithium enolates do not undergo this rearrangement, since they decompose at 25 "C. The zinc enolate has also been shown to be superior to the ketene silyl acetal in terms of the diastereoselectivity obtained in the rearrangement (Scheme 5). Zinc and magnesium enolates of amino acid PtCODC12. DME 1 Boc 76% overall yield Scheme 4 0 R' 6 ~ H O H Bn' 92-96fh de 84% yield Scheme 3 Scheme 5 244 Contemporary Organic SynthesisThe enolate driven Claisen rearrangement has also been extended to the enantioselective synthesis of homochiral amino acids (79-90% ee), where the presence of the chiral ligand in the reaction (e.g.quinine) has the added effect of improving the diastereoselectivity obtained (Scheme 6)." i. H2, PdJC ii. RuC13, iii. Me3SiCI, MeOH H5106 0 RT 5eq. LiHMDS cF3,k 70 2.5 1.1 eq. eq. quinine A I ( O P ~ ) ~ cF3 H C02H H 0 6697% yield 98% de 79-90% ee i. BuLi, THF ii. HCI -90 "C, RX l Scheme 8 Scheme 6 COXN* p=4 ,COXN" 1. BuLi NYph i- '.=Qh ii. Pd2(dba)aC;C13 dppe, THF. 20 "C The products obtained from the enantioselective Ph palladium catalysed allylic substitution of 1,3-diphenylprop-2-enyl acetate can be converted into L-phenylglycine and D-glutamic acid derivatives with no loss of stereochemical integrity (Scheme Ph as%, > 90% de Scheme 9 7).12 P h L P h 65% 96% ee Meo2CY-Co2Me O K 0 \ / 96% ee Scheme 7 51% 96% ee (Scheme 9).15 In earlier reports concerning diastereoselective Pd catalysed allylations, the presence of a chiral phosphine ligand has been found to be necessary in order to achieve respectable levels of diastereoselectivity. 2.3 0x0 acids The arylsulfonamido derivative of the cis- l-amino- 2-hydroxyindan 9 can be coupled with a-keto acids and subsequently reduced to give the corresponding a-hydroxy acid of either enantiomer under different conditions (Scheme lo).'' Although this methodology has been reported previously with regard to more esoteric auxiliaries, the advantage of this work lies in the fact that both antipodes of the indan are commercially available.0 0 H:\S/: @ i. ArSO&I, EfN, DM,AP 'OH ii. RCOC02H, DCC, DMAP w0$ R 9 0 The Schijllkopf bis-lactim ether has found use in the enantioselective synthesis of P-branched13 and deuterated amino acids.I4 In the latter case, the judicious choice of deuteration conditions leads to the thermodynamically stable deuterated intermediate in >95% ee, which under kinetic conditions is alkylated exclusively on the opposite, less hindered, face of the auxiliary (Scheme 8). The palladium catalysed allylation of chiral glycine equivalents provides a-ally1 amino acids with good to excellent diastereoselectivity (67-90% de) Scheme 10 6H OH L-Selectride, ZnC12; 96% >99:1 K-Selectride, 18-crown-6; 96% 595 Ladduwahetty: Carboxylic acids and esters 245p-Keto esters can be alkylated with optically pure 2-triflyloxy esters without any loss of stereochemical integrity (Scheme l l ) , providing an elegant, simple method for the synthesis of y-keto acids.17 0 0 0 R2 OTf iii.TFA iv. LiOH Scheme 11 4572% yield 52-98% de It is well known that boron enolates of ‘propionate’ imides and thioimides undergo acylation with excellent diastereoselectivity. The corresponding boron enolates derived from ‘acetate’ imides and thioimides, on the other hand, give modest selectivity. There is an interesting difference in outcome when switching to the titanium enolate, however. Thus thioimide titanium enolates (Scheme 12) give excellent diastereoselectivities,’* whereas the imide enolates do not; this difference is probably due to towards sulfur.Scheme 12 the greater affinity of the titanium i. Pt2NEt, TiCI4 ii. RCHO iii. LiOH OH 0 8591% yield P-Keto esters and enolisable 2-substituted cycloalkane-1,3-diones can be cleaved oxidatively to give woxocarboxylic acids 0 0 Cu(C104)26H20 02, CH3CN * (Scheme 13).19 Scheme 14 2.4 Unsaturated acids Trisubstituted and disubstituted 1,3-dienes have been shown to undergo hydrocarboxylation at the least substituted double bond selectively (Scheme 15),*’ leading to y-unsaturated carboxylic acids. PdC PhaP C0,HCOOH * DME Scheme 15 60% A route that is complementary to the orthoester Claisen rearrangement, especially in the presence of base labile groups, involves simply heating an alcohol with the ketal 10 (Scheme 16) to give a rearranged a-hydroxy ketone, which is then oxidatively cleaved to reveal a carboxylic acid.22 OH I I (E ) selectivity >99% R = #&C02Me 72% #A/’oA, 78% Scheme 16 90% *OH 0 96% Scheme 13 4-Hydroxy-AL-butenolides derived from 2-furfural derivatives can be selectively reduced with zinc to give y-oxocarboxylic acids. The use of ultrasound in the reaction avoids the need to use activated Zn or high temperatures (Scheme 14).20 2.5 Halo acids The diastereoselectivity observed in the halogenation of chiral ester 11 (80-95% de for chlorination; 70-85% de for bromination) is surprisingly independent on the 2- or E- configuration of the starting silyl enol ether (Scheme 17).23 The addition of primary, secondary and tertiary alkyl radicals, generated from Barton esters, to electron deficient fluoroolefins, provides a new Arndt-Eistert type methylene group homologation leading to difluorocarboxylic acids (Scheme 18).24 246 Contemporary Organic SynthesisphYCoXN* DABCO Tic14 0 +25 "C 69% NCS (or NBS) 4 (S, S ) 100% ( R , R ) 0% (R, S) 0% 11 X = CI, 80-95% de X = Br, 7045% de LDA, 12 -78 + 25 "C w 80% Scheme 17 ( S , S ) 6% (R, S) 94% PhXcoxN* Ph COXN* (R, R ) 84% ( R , S ) 16% electrogenerated base L I 2 -50 + 0 "C 64% OTBDMS 0 bo Scheme 18 12 i.LiOhC02Bn ii. H2, Pd(OH)2 ii. H2. Pd(OH)2 2.6 Miscellaneous Chiral enolborinates of carboxylic, acids add to simple aldehydes leading to enantiomerically pure P-hydroxy acids (Scheme 19).25 Optically active succinic acids can be obtained by the novel oxidative homocoupling of chiral 3-acyl-2-oxazolidinones. The Ph 0 OTBDMS A J J 4 0 2 H TBDMSO 0 Ph Ho2C&0&02H H02C 0 base and oxidant can be chosen to give each diastereoisomer selectively (Scheme 20) .26 (3R, 2'R) 6l%, 99.9% de (35 2'5) 99.9% de Scheme 21 i.?.zeq R.' 0BL2* OH PhCHO R' - &CO2H OH- Ph R2 that enable the facile removal of by products R' 'R2 I continue to be developed. BDDC (bis-[4-(2,2- dimethyl-l,3-dioxalyl)-methyl]carbodiimide) 13, a distillable reagent,28 can be prepared on 200-300 g scale and promises to be an efficient reagent for esterification (77-93% yields). The urea byproduct can be removed with mild acid, the simultaneous cleavage of the ketal groups ensuring its water L* = 'p R' = R2 = Me, 90% yield, 99% ee Scheme 19 solubility.The desymmetrisation of the anhydride 12 with chiral (R)- or (S)-benzyl mandelate provides a neat route to glutaric acid derivatives of opposing chirality (Scheme 21).27 13 3 Carboxylic acid esters 3.1 General syntheses of esters EEDQ (2-ethoxy- 1-( ethoxycarbonyl)-l,2-dihydro- quinoline) 1429 can be used to couple primary, The currently available 'water soluble' carbodiimides that are used extensively for amide bond formation, cannot be used for esterification. Hence, efficient coupling reagents for carboxylic acids and alcohols secondary and tertiary alcohols, and the quinoline byproduct is once again removed with mild acid. No racemisation is observed with chiral substrates. Dialkyl carbonates (under DMAP and 247 Ladduwahetty: Carboxylic acids and estersOEt C i )’o EtO 14 0 R I diphosgene” have also been reported as efficient coupling reagents.A rare example of esterification under acidic conditions (57-99% yields) that does not require the presence of excess alcohol involves the use of (Me2Si0)4 with TiC1(OTf)3 ~atalysis.”~ The addition of BOP reagent 15 to a premixed solution of an amino acid and an alcohol at low temperature, leads to esterification in excellent (75-97%) yield^."^ The low temperature ensures the stability of the reactive phosphonate intermediate 16 and precludes the formation of the less reactive benzotriazole ester 17 (Scheme 22). 1 - 3 2 r -I Scheme 23 intermediate 18 undergoes SN2 displacement with various amines resulting in the formation of one a-amino acids with excellent enantiomeric excess The Negishi reagents 19 couple with the Schiff diastereoisomer predominantly, providing a route to 15 -20 o c 0 (Scheme 24).35 base acetate 20 to give substituted vinyl glycine esters (Scheme 25).36 (R)- and (S)-3-arylalanines involves the rhodium esters in the presence of optically pure diphosphines (Scheme 26).37 The disadvantage in this method lies in the need to use very high (60 bar) pressures.A short and efficient synthesis of optically pure catalysed hydrogenation of (2)-a-amino a,P-dehydro 17 7597% Scheme 22 Br The first reported one-pot procedure for the simultaneous protection of an amino acid with both carbamate and benzyl ester protecting groups,34 involves simply heating the acid in DMSO with benzyl chloroformate, (Scheme 23).The ester formation results from the DMAP induced fragmentation of the initially formed anhydride, followed by the in situ trapping of the resulting intermediate with benzyl alcohol. The reaction is limited to more lipophilic amino acids, probably due to their greater solubility in DMSO. 3.2 a-Amino esters The process of dynamic kinetic resolution, where under the reaction conditions the less reactive diastereoisomer in a mixture is epimerised to the more reactive one, is an attractive concept for the synthesis of homochiral compounds. Hence, the racemic N-( wbromoacy1)imidazolidinone R3 18 R’ 90% 99% ee Scheme 24 R3 (S, R):(S, S ) = (90:iO - 95:5) 248 Conternporaly Organic SynthesisScheme 25 ,C02Bu' R ' Y o 2 B u ' [R~(co~)L']BF~ - R' NH NHC02Bn k o H2, MeOH, 40 "C * 60 bar 0 LPh R' = awl Scheme 26 > 98% ee >98% yield anticancer drug Taxol@. A practical route to chiral anti-/?-amino-a-hydroxy acids involves the conjugate addition of a chiral amine to an a,/?-unsaturated ester, followed by the tandem (in situ) or stepwise reaction with a homochiral oxaziridine (Scheme 28).39 There are subtle differences in outcome depending on whether the stepwise or tandem approach is used.The chirality of the oxaziridine used in the reaction does not have a significant effect on the diastereoisomeric ratios obtained in the reaction, suggesting that it is the chirality of the substrate that is the stereodirecting feature in the hydroxylation step. 'OBU' ii. LiHMDS, Ph' P h d O B u ' Scheme 28 i.9-BBN or eMgBr ii. CF3C02H I CH3 A C O 2 E t H2N R R = H, 95% yield, >98% ee R = &i ,48% yield, >98% ee Scheme 27 Homochiral ct-substituted amino acid esters can be obtained from the sulfimine 21, by a chelation controlled reduction with 9-BBN (95% yield, > 98% ee) or Grignard addition with ally1 magnesium bromide (48%, >98% ee) (Scheme 27)." 3.3 b-Amino esters Practical approaches for the diastereoselective synthesis of P-amino-a-hydroxy acid derivatives are necessary due to the presence of this feature in a number important of natural products, e.g. the OH 90% yield 97% de P h y o s u ' OH 89% yield >98% de The presence of 1-(trimethylsilyl) benzotriazole during the addition of a Reformatsky reagent to imines ensures the exclusive formation of the corresponding /?-amino ester only; a mixture of the ester and p-lactam is obtained in the absence of the benzotriazole reagent (Scheme 29).40 of p-enamino esters 22 gives the corresponding cis- Sodium triacetoxyborohydride mediated reduction SiMea r RN=CHR' + 0 ' ; N ' N I TMS BrZnAC02Et I RNH y C 0 2 E t R' R = alkyl, benzyl 5244% Scheme 29 Ladduwahetty: Carboxylic acids and esters 24923 J n =1,2 Yield = 6149% p-amino the reaction. ether to the chiral aminal 25, gives two epimeric esters in a 9 : 1 ratio,45 with the cis-epimer predominating.(Scheme 32). This product distribution is due to the strain in the intermediate iminium ion. Some anti-selectivity is observed in The Lewis acid mediated addition of a silyl enol Scheme 30 Scheme 32 Ph Ph R,oqAMe NaHB(OAc)3 0 H'NAMe AcOH,MeCN R I O J - .~ 58-85'3'0 de cisltrans 12: 1 - 50: 1 56-73% ee Scheme 31 p-amino esters exclusively (Scheme 30).41 Reduction of the analogous homochiral p-enamino esters yields P-amino acids with good enantiomeric purity after debenzylation (Scheme 31).42 The stereoselectivity of the reduction arises due to the protonation of the intermediate diacetoxy enol ester 23 from the less hindered face. The reduction of acyclic p-enamino esters, however, is not stereoselective. The classical method for the synthesis of the starting enamino esters, involving the direct condensation of amines with P-keto esters, results in poor yields. An efficient route entails the acylation of lithiated enamines with diethyl carbonate or benzyl chl~roformate.~~ Tris(pentafluoropheny1)boron 24 is an efficient catalyst for the reactions of ketene silyl acetals with enolisable or non-enolisable imines leading to 24 i.4 O T B s , OEt BF39Et2 H CH3CN-OEt2, -78 OC, 8& pr**o*-ii. H2, PdC, 80% Sm" mediated regioselective reductions of 2-a~ylaziridines~~ provide a novel route to p-amino esters (Scheme 33). The ethanolamine present in the reaction functions both as a proton source and a chelator for the Lewis acidic Sm"', thus making the reaction stable to acid sensitive protecting groups, e.g. Boc (tert-butyloxycarbonyl). R4 Q20Rl 5.0eq. 2.5 eq. \N-OH Sm12 R 4 9 0 R 1 R5 R2 N R3 THF. 0 "C 87% Scheme 33 The Arndt-Eistert homologation of an amino acid, where the silver assisted decomposition of the intermediate diazoketone is quenched with methanol, provides a direct synthesis of the corresponding P-amino ester with retention of chirality (Scheme 34).47 0 0 ' jii.10% AgOCOPh, Et3N 0 ' 0 IV. MeOH Scheme 34 3.4 &-Amino esters (5-amino esters) Despite the several electrophilic sites available to alkenylaziridines, exemplified by 26 they react predominantly in a SN2' fashion with Yamamoto's alkyl copper reagent^,^^ dialkylzinc reagents and lower order cuprates (Scheme 35).49 The resulting 2-alkyl-4,5-substituted-5-amino-alk-3-enyl esters are formed in good yields and in excellent diastereoisomeric excess. 250 Contemporary Organic Synthesisfollowed by the DBU promoted diazo transfer (Scheme 37b).'" Methyl phenylglyoxylate, aniline and aromatic aldehydes undergo a three-component condensation reaction in the presence of Ti"' leading to syn- P-hydroxy esters (Scheme 38a).', The scope of this reaction has been extended to include aliphatic aldehydes and amines by the use of lanthanide triflates such as ytterbium triflate[Yb(OTf),] (Scheme 38b).', In contrast to the Ti"' catalysed R 2 & d O s l k y l 6 steps R 4 d O R 1 26 R5Cu(CN)Li BFa.OEt2 I 0 R3,R2 R4AE+OR method, aromatic aldehydes give anti adducts, while R' R5 syn adducts are obtained from aliphatic aldehydes.4690% vield 62-98% he Scheme 35 3.5 a-Hydroxy esters (S)-2-Aryloxy acids of >75% ee are accessible from racemic cx-bromo acids5' via their (R)-pantolactone esters (Scheme 36). The diastereoselectivity arises due to a dynamic equilibrium where the slower reacting diastereoisomer is rapidly converted into the faster reacting one by the halide ion generated in the reaction.Aliphatic acid nucleophiles do not give any diastereoselectivity. 55-769'0 yield (S, R):(R, R ) 8811 2 - 95~5 Scheme 36 0 OR 3 6 9 8 % yield 143% de O Y P h ?!2 6848% overall yield Scheme 37 The Rh(ri) mediated decomposition of chiral phenyldiazoacetates in the presence of simple alcohols provides cx-alkoxy esters in good yields, albeit with modest diastereoselectivity (Scheme 37a).51a A convenient preparation of the diazoesters, which is amenable to large scale synthesis, involves the initial activation of an ester by benzoylation, 0 0 a Me0 %ph + PhNH2 + HAAr 0 Ti'n, THF 1 OH H L pn 53-67% Yb(OTf)3 5 moly0 4 A molecular sieves, CH2C12,25 "C R'=Ph,7&90% 9 : 1 R' = C4H9, 90% 1 : 8 Scheme 38 3.6 fi-Hydroxy esters Aliphatic a,P-epoxyesters, which are readily available via the Sharpless methodology, ring open almost exclusively at the 2-position with NaI.54 The resulting halohydrins can be subsequently converted into synthetically useful intermediates such as P-hydroxy esters and syn-cx-amino-P-hydroxy esters (Scheme 39).Other halide salts (LiJ, KI) give lower regioselectivity in the ring opening reaction. cx,P-unsaturated esters can be dramatically enhanced by Lewis acid (EtAlCl,) c~mplexation.~~ P- and y-keto esters react smoothly with allylic halides, in the presence of Zn powder, with complete chemoselectivity to give hydroxyester adducts (Scheme 40).56 A significant advance in acyclic stereocontrol with respect to radical reactions involves the allylation of The slow rates of radical additions to Ladduwahetty: Carboxylic acids and esters 25 1? The Lewis acid mediated addition of the silyl ketene acetal27 to aldehydes can give the syn- or anti-2,3-dihydroxy esters 28 and 29 selectively, ester is crucial for the unique stereoselectivities observed (Scheme 43).0 NaI. Amberlyst 15 - R v C O 2 C H 2 C H 3 OH depending on the chiral ligand The phenyl X = I (C2:C3) 8911 1 X = Br (QC3) 9O:lO R -C02CH,CH3 0 ), ,25 "C NH2 Bu3SnH 6' i. NaN3, y C 0 2 E t - y C 0 2 E t DM_F C02Et ii. PdC OH OH OH 90% 85% Scheme 39 R2-r R2 &OEt R' OH 0 R'woEt Zn, NH4CI 0 0 n =1,2 6344% Scheme 40 OMe R$C02Me R T C 0 2 M e L C 0 2 M e - R , i H \ \ / / anti SYn MgBrOEt2 51-95% yield 38:l to >100:1 no Lewis acid 4444% 1:3 to 1:6 Scheme 41 P-methoxy-a-iodo esters in the presence of a Lewis to anti adducts predominantly, whereas in the absence of Lewis acids syn adducts are favoured to some degree (Scheme 41).Selective reductions of a-methyl-P-keto esters are achieved in the presence of tin hydride and titanium tetrachloride to give anti-a-methyl-P-hydroxy esters in good yields (Scheme 42).58 The chelation controlled transition state leads R v O M e Scheme 42 OH 0 R u O M e Bu3SnH, TiC14 I l h + R v O M e (antlsyn ) 81:19 - 99:l yield -97% 27 Sn(OTf)2, BU~S~(OAC)~ CH&, -78 "C R v O P h + R U O P h bB" OBn anti 29 syn 28 8&90% yield 95:5 - 99: 1 Lle K3 5148% yield 12:88 - 7:93 Scheme 43 A convenient source of Sm" can be generated in situ from Sm-Me3SiC1-NaI, and has been demonstrated to be a useful alternative to zinc in the Reformatsky reaction.60 SmI, in the presence of ethyl bromoacetate produces a P-keto ester equivalent 30, which in turn reacts with ketones and aldehydes to give 6-hydroxy-P-keto esters in excellent yields (Scheme 44).6' Scheme 44 3.7 Miscellaneous hydroxy esters Selective functionalisations of diols are a useful tool in protecting group chemistry. The regioselective cleavage of cyclic formal derivatives of 1,3-diols results in the formation of the least substituted acetate or pivalate exclusively (Scheme 45).62 The 252 Contemporaiy Organic SynthesisPh-OH A*a-o-ph 75% overall yield i.AcCI, ZnCI,, Et20 ii. MeOH, Pi2NEt, Et20 90% overall yield Scheme 45 resulting acetoxy-substituted chloromethyl ethers can be reacted in situ with various alcohols to give stable methoxymethyl (MOM) and benzyloxymethyl (BOM) ether derivatives.The analogous cleavage of 1,2-diols is less selective. Diols can also be acetylated selectively via hydrolysis of their cyclic ketene aceatal derivatives (Scheme 46).63 An inexpensive method for the large scale protection of symmetrical diols involves the oxidative cleavage of their cyclic acetals (Scheme 47)."4 80% Scheme 46 * R'O Na2C03, C6H6, 55 "C R+o) NaB03*4H20, Ac20 WoH 0 67-95%0 Scheme 47 Magnesium methoxide, generated from magnesium in methanol, is a useful reagent for the selective deprotection of a variety of diesters, e.g. p-nitrobenzoate in the presence of acetate (68%), and acetate in the presence of benzoate (76%).65 Ally1 and crotyl bicyclic phosphonamide anions are 'hydroxyalkyl' synthons that add to u,P-unsaturated esters to give mainly all-syn adducts in excellent yields (Scheme 48).66 3.8 Halo esters The study of organofluorine compounds is an ever increasing field within organic chemistry, spurred on i.BuLi, THFCo But ii. Ph- iii. Me1 iv. 03, then NaBH4 I I H O V rev Me CO2Bu' CO~BU' Ph 8 Ph 92 Scheme 48 0 R' KC02R2 DAST .- C02Et i. HCI(d, EtOH w ii. H2S04 OH 60-73% Dess-Martin periodinane I R,+02Et 0 Scheme 49 F F R' xC02R2 39-70% i. NaBH4, MeOH ii. KCN/KH2PO&O I &CN OH 62-73% 0 PhH 0 OH T O H +CF3KC02Et - 4 C02Et F. F PhH i. SOCi2, py 1 ii. :hFuI (cat.) h F 2- C02Et 80% F Scheme 50 no doubt by the demand for new fluorinated synthons in medicinal chemistry.A versatile route to P,P-difluoro-a-keto ester derivatives, by 'insertion' of a difluoromethylene group into an a-keto ester entails a simple four-step sequence (Scheme 49).67 The addition of allylic alcohols to ethyl trifluoropyruvate, followed by a Claisen rearrangement provides a route to unsaturated P,P-difluoro-a-keto esters (Scheme 50).68 Ladduwahetty: Carboxylic acids and esters 253a-Trifluoromethyl alkoxy- and aryloxy-acetates can mediated insertion of the diazo ester 31 into the 0-H bond of the starting alcohol (Scheme 51).69 (R)-3,3,3-Trifluoroalanine can be synthesised in moderate enantioselectivity by reduction of an aryl be obtained in good yields by a rhodium carbenoid dE: -78 OC t 40% imino ester with the (S)-oxazaborolidine-catechol borane combination (Scheme 52).70 -.32 Scheme 54 F3CKC02Et 56-81 70 33 80% Scheme 51 Scheme 55 4048% ee Scheme 52 The significantly lower LUMO in ethyl (E)- 3-(trifluoromethyl)acrylate, in comparison with ethyl crotonate, results in its greater reactivity towards nucleophiles, providing anti adducts selectively (Scheme 53).'l yield: 33-98% selectivity(anfi): 84-98% keto ester equivalents. Thus the mild potassium permanganate mediated oxidation of 33 to the corresponding P-hydroxy-a-keto ester is possible even in the presence of a double bond (Scheme The addition of the chiral enaminoester 34 to 55).73 methyl methacrylate gives a single keto ester product (> 95% de and ee), allowing the simultaneous control of both a quaternary and tertiary center in one step (Scheme 56).74 Carboxylic acids can be homologated directly to a-keto esters via the cyano phosphorane 35 (Scheme 57),75 and the (trimethylsily1)ethyl malonate 36, generated in situ, reacts with acyl imidazoles and chlorides to provide P-keto esters (Scheme 58).76 34 72% yield >95% de and ee Scheme 56 yield: 36-98% de: 30-9870 Scheme 53 R-CO~H + I;CN EDCI,DMAPt pph3 CH2Chfi (S)-( Trifluoromet hy1)dibenzo t hiop henium t riflate PPh3 32 is a new electrophilic source of the 35 03, -78 "C R 4 H , CH2CI2 1 trifluoromethyl cation, which can be used to alkylate the potassium enolate of phenylacetic acid ester in moderate yields (Scheme 54).72 3.9 Keto esters Alkynyl ethers, obtained by the condensation of lithioethoxyacetylene with ketones, can function as Scheme 57 254 Contemporary Organic SynthesisEtO JJR 53438% yield 96100% ee X = CI or imidazolyl Scheme 58 A hemiacetal, generated in situ from an aldehyde and an alcohol in the presence of a Lewis acid, has been shown to react with the acid sensitive ethyl 2-(trimethylsiloxy)acrylate 37, leading to the corresponding y-alkoxy-a-keto ester (Scheme 59).77 37 6443% Scheme 59 Tricarbonyliron coordinated acyclic dienes undergo Friedel-Crafts acylation to give (E,E)- 3,5-dienyl-2-keto esters selectively.The parent diene can then be obtained after decomplexation with cerium(1v) ammonium nitrate (Scheme 60).78 R3 i. AICln, R2J3 c0)3Fe7Y II. H2V, 0 "C " 2 C 0 2 E t Scheme 60 3.10 Diesters The caesium fluoride promoted displacement reactions of homochiral secondary mesylates take place with complete inversion to give chiral malonic ester derivatives (Scheme 61).79 Conventional malonic ester alkylation using stronger bases, or Mitsunobu reactions give these adducts in much Scheme 61 + O O M e - NO2 Bu4NF, 4 A molecuhr sieves, K2CO3, THF 0 -125 "C, 30 min 38 \ 62-90'3'0 yield Scheme 62 lower yield and enantiomeric excess.The fluoride- mediated additions of nitrotoluene anions to the a$-unsaturated ester 38 give the corresponding Michael adducts in good to excellent yield (Scheme 62)." Stronger bases such as LDA in this case result in dimerisations of the anions. The addition of nitroalkanes to dimethyl rnaleate, followed by the in situ elimination of nitrous acid, provides a direct synthesis of Stobbe type a, P-unsaturated diesters (Scheme 63).*' R2 C02Me CH3CN DBU R )=c,02Me /=\ R2Ti, + Me02C C02Me - Scheme 63 The catalytic organosamarium mediated coupling between vinyl esters and aldehydes lead to diesters of propane-1,3-diols (Scheme 64).82 The reaction is presumed to be due to the formation of an eight- coordinated alkoxy samarium species, which undergoes an intramolecular hydride shift.via I Scheme 64 Ladduwahety: Carboxylic acids and esters 255The addition-elimination reaction of the anion derived from the chiral synthon 39 with (E)-bromo acrylates takes place with excellent diastereo- selectivity [(R) : ( S ) > 20 : l)] (Scheme 65).83 i.LDA bo ii. Br% * I I C 4 R 39 %02R (€)-bromoacrylate, R = Me, 71% yield, ( R ) : ( S ) >20:1 (Z)-bromoacrylate, R = Et, 51% yield, ( R ) : ( S ) 6:l Aryl and alkenyl boronic acids react with carbon monoxide in the presence of 1-5 mol% Pdo and sodium acetate in methanol to give a$-unsaturated esters directly (Scheme 68).86 Aryl halides do not react under these conditions.This reaction has been reported previouly using stoichiometric amounts of Pd". C02Me e 0.1 mmol Pd(PPh& 1 atm. CO, MeOH NaOAc A@(OH)2 Scheme 65 Scheme 68 3.11 Unsaturated esters Stereochemically pure (2)- and (E)-2-bromo- 3-arylpropenoates have been prepared by the regioselective Pdo mediated cross coupling of (2)- and (E)-2,3-dibromopropenoates 40 and 41 with arylzinc halides (Scheme 66).84 The 2-bromopropenoates can then be reacted further with organostannyl reagents in a Stille type coupling to afford tri- and tetra-substituted a$-unsaturated esters (Scheme 67).85 C5H5NH+Br- CH2Cl2, 120 "C Br\_Fo2Et Br 40 90% I Ar-ZnX Pd(Pf'h3)4 THF, 20 "C Br 4:; 41 83% Ar-ZnX THF, 20 "C Pd(PPh314 I H Br Ar 52-79% 77-84% Scheme 66 (2)-En01 esters have been prepared by acylation reactions of ketones via their manganese enolate~,~' and by the reaction of silyl enol ethers with acyl fluorides.88 The conversion of a,P-unsaturated esters into silyl enol ethers under kinetic conditions leads to a single (2)-siloxydiene 42.89 Ri< iMe3 42 R2 3.12 Miscellaneous Secondary alcohols can be converted into benzoate esters with inversion of configuration via sequential reaction with the Vilsmeier reagent 43 and potassium benzoate (Scheme 69):' Although not suitable for chiral benzylic alcohols, this reaction has distinct advantages over the Mitsunobu reaction in terms of purification, the by-products being DMF and KCl.The displacement of the Vilsmeier intermediate, however, is very slow, taking up to three days in the examples cited. RiAR2 THF.O°C * LRiAR2 1 I PhCO K THF, i d OCOPh RiAR2 4648% yield 97-98% ee 20 "C 3&91% Scheme 67 Scheme 69 256 Contemporary Oiganic Synthesis4 References Inverse addition of the dianion of N-Boc iminodiacetic esters to a variety of electrophiles gives moderate to good yields of dialkylated products (Scheme 70).91 E E ~~ Me02Cfir;rAC02Me i. 2 eq. LDA Me02CAr;rAC02Me BOC BOC 3646% E = eBr, Ph-Br 1-1 A, I-' I 1 Scheme 70 The nickel promoted addition of the steroidal intermediate 44 to ethyl acrylate gives a good yield of adduct, whereas the corresponding tin radical mediated addition failed to yield any product (Scheme 71).92 Juiirr 44 'I C02Et 4 NiCb.*BH20.Zn pyri ne w 73% Scheme 71 The chemoselective reduction of a,a-unsaturated esters in the presence of isolated olefins is a useful process which can be achieved under transfer hydrogenation conditions (Scheme 72)93 and with borohydride exchange resin (BER).94 Metallic samarium, in the presence of iodine, has also been shown to reduce a,/?-unsaturated esters to the corresponding saturated analogues (Scheme 72).95 These conditions do not need the strictly anaerobic conditions necessary for Sm12. 94% 95% NHA* HCOO- R = H, OMe 92-95% Scheme 72 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 I B.Bennetau, J. Mortier, J. Moyroud and J. L. 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ISSN:1350-4894    

DOI:10.1039/CO9960300243

出版商:RSC    

年代:1996

数据来源: RSC