摘要:

Contemporary Organic Synthesis Editorial Board Professor G. Pattenden, FRS (Chairman), University of Nottingham Professor P. D. Bailey, Heriot- Watt University Professor P. J. Kocienski, University of Southampton Professor C. J. Moody, Loughborough University of Technology Dr S. E. Thomas, Imperial College of Science, Technology) and Medicine Professor E. J. Thomas, University of Manchester International Advisory Board Professor E. J. Corey, Harvard University Professor S. Hanessian, Universite' de Montre'al Professor M. Julia, Universite' 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, Scripps Research Institute, La Jolla Professor R. Noyori, Nagoya University Professor L.E. Overman, University of California, Irvine Professor L. F. Tietze, University of Gottingen Cmztemporary Organic Synthesis is a bimonthly journal which aims to review and provide perspective in all aspects of methodology, selectivity, and efficiency in contemporary synthesis. As well as covering all the principles and methods in functional group chemistry and interconversions, organometallic chemistry and asymmetric synthesis will feature prominently, so too will modern aspects of strategy and computer aided design, biotransformations, and protecting group protocols. Special methods and techniques, such as sonochemistry, FVP, electroorganic synthesis, and supported catalysis will be included as occasional articles, and the manner in which synthesis addresses problems and provides solutions in biology, medicine, agriculture, the environment, and new materials, will also be encompassed.Contemporary Organic Synthesis aims to be proactive, drawing attention to new opportunities and new directions, providing timely information to the synthetic chemist who needs to keep abreast of developments in the field. Although the,majority of articles are intended to be specially commissioned, the Society is always prepared to consider offers of articles for publication. In such cases a short synopsis, rather than the completed article, should be submitted to the Senior Editor (Reviews), Books and Reviews Department, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF. Members of the Royal Society of Chemistry may subscribe to Contemporary Organic Synthesis by placing their orders on the Annual Subscription renewal forms in the usual way.All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letchworth, Herts SG6 lHN, England. 1994 subscription rate: EC & 150, USA $282, Canada 2 169 (plus GST ), Rest of the World &16 1. Air freight and mailing in the USA by Publications Expediting Inc., 200 Meacham Avenue, Elmont 1 103; USA Postmaster, send address changes to C'oiztemporary Organic Synthesis, Publications Expediting Inc. Second class postage is paid at Jamaica, New York 1 143 1. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe.0 The Royal Society of Chemistry, 1994 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording, or otherwise, without the prior permission of the publishers. Typeset by Unicus Graphics Ltd Printed in Great Britain by Whitstable Litho LtdContemporary Organic Synthesis Editorial Board Professor G. Pattenden, FRS (Chairman), University of Nottingham Professor P. D. Bailey, Heriot- Watt University Professor P. J. Kocienski, University of Southampton Professor C. J. Moody, Loughborough University of Technology Dr S. E. Thomas, Imperial College of Science, Technology, and Medicine Professor E.J. Thomas, University of Manchester International Advisory Board Professor E. J. Corey, Harvard University Professor S. Hanessian, Universite' de Montrkal Professor M. Julia, UniversitP de Paris X I (Paris-Sud) Professor P. D. Magnus, University of Texas at Austin Professor G. Mehta, University of Hyderabad Professor K. C. Nicolaou, The Scripps Research Institute and University of California at Sun Diego, La Jolla Professor R. Noyori, Nagoya University Professor L. E. Overman, University of California, Irvine Professor L. F. Tietze, University of Gottingen Contemporary Organic Synthesis is a bimonthly journal which aims to review and provide perspective in all aspects of methodology, selectivity, and efficiency in contemporary synthesis. As well as covering all the principles and methods in functional group chemistry and interconversions, organometallic chemistry and asymmetric synthesis will feature prominently, so too will modern aspects of strategy and computer aided design, biotransformations, and protecting group protocols. Special methods and techniques, such as sonochemistry, FVP, electroorganic synthesis, and supported catalysis will be included as occasional articles, and the manner in which synthesis addresses problems and provides solutions in biology, medicine, agriculture, the environment, and new materials, will also be encompassed.Contemporary Organic Synthesis aims to be proactive, drawing attention to new opportunities and new directions, providing timely information to the synthetic chemist who needs to keep abreast of developments in the field.Although the majority of articles are intended to be specially commissioned, the Society is always prepared to consider offers of articles for publication. In such cases a short synopsis, rather than the completed article, should be submitted to the Senior Editor (Reviews), Books and Reviews Department, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF. Members of the Royal Society of Chemistry may subscribe to Contemporary Organic Synthesis by placing their orders on the Annual Subscription renewal forms in the usual way. All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letchworth, Herts SG6 lHN, England. 1994 subscription rate: EC &150, USA $282, Canada &169 (plus GST), Rest of the World &161. Air freight and mailing in the USA by Publications Expediting Inc., 200 Meacham Avenue, Elmont 1103; USA Postmaster, send address changes to Contemporary Organic Synthesis, Publications Expediting Inc. Second class postage is paid at Jamaica, New York 11431. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. 0 The Royal Society of Chemistry, 1994 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording, or otherwise, without the prior permission of the publishers. Typeset by Unicus Graphics Ltd Printed in Great Britain by Whitstable Litho Ltd

ISSN:1350-4894    

DOI:10.1039/CO99401FX017

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

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

ISSN:1350-4894    

DOI:10.1039/CO99401BX019

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

ISSN 1350-4894 COGSE6 l ( 5 ) 317-416 (1994) Contemporary Organic Synthesis ~ ~~ A journal of current developments in Organic Synthesis VOLUME 1 NUMBER 5 CONTENTS Me -TLi O Y O NPr', Recent developments in asymmetric aldol 3 17 methodology By Alison S. Franklin and Ian Paterson Reviewing the literature published up to the end of 1993 Main group organometallics in synthesis By Martin Wills Reviewing the literature published between July 1992 and December 1993 Synthesis of materials for molecular electronic applications By Martin C. Grossel* and Simon C. Weston Reviewing the literature published between mid-1 992 and December 1993 Control of asymmetry through conjugate addition reactions By John Leonard Reviewing the literature published up to the end of March 1994 339 367 387Cumulative Contents of Volume 1 Number 1 1 23 3 1 47 Aldehydes and ketones (July 1992 to June 1993) Patrick G.Steel Saturated oxygen heterocycles (January 1992 to March 1993) Christopher J. Burns Noncovalent design principles and the new synthesis Mark Mascal Recent progress in the synthesis of taxanes (January 1991 to July 1993) A. N. Boa, P. R. Jenkins, and N. J. Lawrence Number 2 77 Catalytic applications of transition metals in organic synthesis (1 July 1992 to 32 August 1993) Graham J. Dawson and Jonathan M. J. Williams 95 Saturated nitrogen heterocycles (January 1992 to May 1993) John Steele 1 13 Organic halides ( 1 July 1992 to 30 June 1993) P. L. Spargo 125 Stoichiometric applications of organotransition metal complexes in organic synthesis ( 1 July 1992 to 31 August 1993) Julian Blagg Number 3 145 173 191 205 Recent developments in indole ring synthesis-methodology and applications (1990 to 1993) Gordon W.Gribble Saturated and unsaturated hydrocarbons ( 1 July 1992 to 1 September 1993) R. P. C. Cousins Thiols, sulfides, sulfoxides, and sulfones (July 1992 to September 1993) Christopher M. Rayner Synthesis of five-membered aromatic heterocycles (July 1991 to June 1993) Thomas L. Gilchrist Number 4 2 19 243 259 287 The role of zinc carbenoids in organic synthesis (up to February 1994) W. B. Motherwell and C. J. Nutley Alcohols, phenols, and ethers (July 1992 to July 1993) Joseph Sweeney Synthetic developments in host-guest chemistry (July 1992 to December 1993) Jeremy D. Kilburn and Hitesh K. Patel Synthetic approaches to butenolides (1976 to 1992) D. W. Knight Number 5 317 Recent developments in asymmetric aldol methodology (up to the end of19.3) Alison S. Franklin and Ian Paterson 339 Main group organometallics in synthesis (July 1992 to December 1993) Martin Wills 367 Synthesis of materials for molecular electronic applications (mid-1992 to December 1993) Martin C. Grossel and Simon C. Weston 387 Control of asymmetry through conjugate addition reactions (up to the end of March 1994) John Leonard Articles that will appear in forthcoming issues include Recent developments in the synthesis of medium ring ethers (October I990 to June 1994) Mark C. Elliott Saturated and partially unsaturated carbocycles C. Boden and G. Pattenden Amines and amides (July 1992 to December 1993) Michael North The synthesis of natural 8-lactam antibiotics (up to February 1994) Robert Southgate

ISSN:1350-4894    

DOI:10.1039/CO99401FP021

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

MENDELEEV Mendeleev Communications &her stales nt the Camrnonwealh of lndepmdent %tes and elsehem COMMUNICATIONS Mendeleev Communications is a prestigious primary journal, produced as a collaborative venture between the Russian Academy of Sciences and the Royal Society of Chemistry. It publishes original papers directly in English, giving the international chemical community rapid access to important new research from Russia and the other states of the former Soviet Union in the shortest possible time. The journal contains preliminary accounts of novel and significant results of wide general appeal or exceptional specialist interest and covers all branches of chemistry. In format and range of subject matter it closely resembles its 'sister' publication, Chemical Communications. Important features include: Primary publication in English of original chemistry from Russia and other states of the CIS Two stages of rigorous refereeing - once in Moscow and once in the UK - to maintain the highest possible standards Editorial Boards in both Moscow and the UK composed of eminent scientists who will advise on refereeing policy Rapid publication - appearance of papers within 12 weeks of receipt in the UK High quality production and editing News section containing information about the Institutes of the Russian Academy of Sciences Essential reading to keep up-to-date with the current chemical research translation journal.NB Mendeleev Communications is NOT a A selection of recent papers Synthesis, IR Study and Crystal Structure of a Novel Mononuclear Tungstenwi) 0x0 Com lex with 1 -Hydroxyethylidenediphosphonic Icid, Exhibiting a W03 Core Elena 0 Tolkacheva, Vladimir S Sergienko and Andrei B llyukhin New Intercalation Compounds of Molybdenum Disulfide with Transition Metals Az(H20)yM~S2 (A=Fe, Co, Ni, Y, La, Er, Th) Alexander S Golub, Galina A Protzenko, lrina M Yanovskaya, Olga L Lependina and Yurii N Novikov Selective Non-catalytic Cyclopropanation of Methyl E-Pent-en-1 -yn-3-yl Carboxylates with Diazomethane Alexey V Kalinin, Evgeny A Shapiro,Yury V Tomilov, Bogdan I Ugrak and Oleg M Nefedov Carbonylation of Cyclopentane in the Presence of Aprotic Or anic Superacids lrena S Adrem, Stanislav Z Bernadyuk and Mark E Vol'pin Selective Homogeneous Catalytic Epoxidation of Alkenes b Hydrogen Peroxide Catalysed by Oxidativeb- and Solvolytically-resistant Polyoxometalate Complexes Alexander M Khenkin and Craig 1 Hill Send for further information or a free sample issue today! 1994 Subscription Published six times a year Back issues available on request.EC f 180.00 USA $300.00 Canada f 189.00 (+GST) Rest of World f 180.00 ISSN 0959-9436 To order please contact: Turpin Distribution Services Limited., Blackhorse Road, Letchworth, Herts SG6 1 HN, UK. I Tklephone: +44 (0) 462 672555. Fax: +44 (0) 462 480947. Telex:.825372 TURPIN' G. For further information please contact: Sales and Promotion Department, Royal Society of chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF, UK. Telephone: +44 (0) 223 420066. Fax: +44 (0) 223 423429. E-mail: (Internet) MendeleevC3RSC.ORG Information Services *&,&p rn-HZxMENDELEEV Mendeleev Communications &her stales nt the Camrnonwealh of lndepmdent %tes and elsehem COMMUNICATIONS Mendeleev Communications is a prestigious primary journal, produced as a collaborative venture between the Russian Academy of Sciences and the Royal Society of Chemistry.It publishes original papers directly in English, giving the international chemical community rapid access to important new research from Russia and the other states of the former Soviet Union in the shortest possible time. The journal contains preliminary accounts of novel and significant results of wide general appeal or exceptional specialist interest and covers all branches of chemistry. In format and range of subject matter it closely resembles its 'sister' publication, Chemical Communications.Important features include: Primary publication in English of original chemistry from Russia and other states of the CIS Two stages of rigorous refereeing - once in Moscow and once in the UK - to maintain the highest possible standards Editorial Boards in both Moscow and the UK composed of eminent scientists who will advise on refereeing policy Rapid publication - appearance of papers within 12 weeks of receipt in the UK High quality production and editing News section containing information about the Institutes of the Russian Academy of Sciences Essential reading to keep up-to-date with the current chemical research translation journal. NB Mendeleev Communications is NOT a A selection of recent papers Synthesis, IR Study and Crystal Structure of a Novel Mononuclear Tungstenwi) 0x0 Com lex with 1 -Hydroxyethylidenediphosphonic Icid, Exhibiting a W03 Core Elena 0 Tolkacheva, Vladimir S Sergienko and Andrei B llyukhin New Intercalation Compounds of Molybdenum Disulfide with Transition Metals Az(H20)yM~S2 (A=Fe, Co, Ni, Y, La, Er, Th) Alexander S Golub, Galina A Protzenko, lrina M Yanovskaya, Olga L Lependina and Yurii N Novikov Selective Non-catalytic Cyclopropanation of Methyl E-Pent-en-1 -yn-3-yl Carboxylates with Diazomethane Alexey V Kalinin, Evgeny A Shapiro,Yury V Tomilov, Bogdan I Ugrak and Oleg M Nefedov Carbonylation of Cyclopentane in the Presence of Aprotic Or anic Superacids lrena S Adrem, Stanislav Z Bernadyuk and Mark E Vol'pin Selective Homogeneous Catalytic Epoxidation of Alkenes b Hydrogen Peroxide Catalysed by Oxidativeb- and Solvolytically-resistant Polyoxometalate Complexes Alexander M Khenkin and Craig 1 Hill Send for further information or a free sample issue today! 1994 Subscription Published six times a year Back issues available on request.EC f 180.00 USA $300.00 Canada f 189.00 (+GST) Rest of World f 180.00 ISSN 0959-9436 To order please contact: Turpin Distribution Services Limited., Blackhorse Road, Letchworth, Herts SG6 1 HN, UK. I Tklephone: +44 (0) 462 672555. Fax: +44 (0) 462 480947. Telex:.825372 TURPIN' G. For further information please contact: Sales and Promotion Department, Royal Society of chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF, UK. Telephone: +44 (0) 223 420066. Fax: +44 (0) 223 423429. E-mail: (Internet) MendeleevC3RSC.ORG Information Services *&,&p rn-HZx

ISSN:1350-4894    

DOI:10.1039/CO99401BP023

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Recent developments in asymmetric aldol methodology ~~ ALISON S . FRANKLIN and IAN PATERSON University Chemical Laboratory, Lensfield Road, Cambridge, CB2 1E W, UK Reviewing the literature published up to the end of 1993 1 1.1 2 3 3.1 3.2 3.3 4 4.1 4.2 4.3 5 6 7 Introduction Controlling factors in the stereochemical outcome of aldol additions to aldehydes Asymmetric induction from the aldehyde Asymmetric induction from the enolate Ligand-mediated Auxiliary-mediated Substrate-mediated using chiral ketones Asymmetric induction in Mukaiyama aldol reactions from the Lewis acid Boron Lewis acids Tin( 11) Lewis acids Other Lewis acids Asymmetric induction by transition metal complexat ion Aldol reactions of a-isocyanocarboxylates References 1 Introduction The ability to form new carbon-carbon bonds in a regio-, stereo-, and enantio-selective fashion plays a fundamental role in modern organic synthesis.Over the last decade or so, the aldol reaction has been developed into one of the most powerful and versatile methods for the control of acyclic stereochemistry and the efficient assembly of complex natural products. Control of the absolute and relative stereochemistry of the aldol addition is possible using a range of techniques. A chiral auxiliary or reagent is frequently employed to direct enolization and n-face selectivity. More recently, chiral Lewis acids have been introduced to promote enantioselective Mukaiyama aldol additions. These methods rely on reagent control. An alternative strategy depends on substrate control using a chiral ketone or aldehyde component, where appropriate choice of the metal and the enolate geometry enables high levels of n-face selectivity to be attained in the absence of any auxiliary group.generally applicable methods for absolute stereocontrol in the aldol reaction developed in recent years (predominantly 1990-1993).1,2 While mechanistic issues and molecular modelling of aldol This review provides an overview of the many transition states are also active areas of current r e s e a r ~ h , ~ ? ~ they are not dealt with here. The reader is referred to some excellent comprehensive reviews on the aldol reaction, which provide an account of transition state models.’ The emphasis of this review is given to those aldol methods which have seen some application in total synthesis, as well as state-of-the-art methods which appear to offer considerable potential for future development.In the latter case, an important area is catalytic aldol processes using sub-stoichiometric chiral Lewis acids. While aldolase enzymes have been used synthetically, particularly for carbohydrates, they are not covered in this particular review. 1.1 Controlling factors in the stereochemical outcome of aldol additions to aldehydes For the aldol reactions of substituted enolates with aldehydes, a fundamental consideration is the relationship between the two adjacent stereocentres created in the addition. Early work on lithium and boron enolates showed that the disastereoselectivity of aldol reactions performed under kinetic conditions is predominantlyt dependent on the geometry of the enolate component? Thus, 2-enolates 1 give rise to syn aldol products 2 whilst E-enolates 3 provide anti adducts 4 (Scheme l).’ 1 me2 3 me4 Scheme 1 More recently, extensive studies8 have explored the factors governing the selective generation of 2- or E-enol borinates of ethyl ketones using electrophilic boron reagents of the type bBX and an amine base.In general, sterically demanding ligands (e.g. c-hex) and a tNote that the diastereoselectivity of Mukaiyama aldol reactions of silyl enolates with aldehydes is frequently unaffected by their E/Z geometry. Franklin and Paterson: Recent developments in asymmetric aldol methodology 317poor leaving group on boron (e.g. C1) combined with a small amine base (eg. Et,N) provide the E-enolate, whilst small ligands (e.g.Bun), a good leaving group (e.g.OTf) and a hindered amine (e.g. Pr',NEt), give 2-selective enolization. Thus, selective access to syn or anti aldol adducts can often be obtained by appropriate choice of the boron reagent and enolization conditions. These trends have been rationalized by computer modelling of the intermediate ate complexes formed between the ketone carbonyl oxygen and the Lewis acidic boron reagent.4 Titanium(1v) enolates may be generated either by transmetallation of lithium enolates or, more simply, using the TiCl,/Pr\NEt system developed by Evans et al.' both approaches give rise to syn products, often in higher yields than the boron counterpart. In general, boron performs better for simple unbranched or a-branched ethyl ketones, whilst titanium-mediated aldol reactions give improved selectivity for chiral ethyl ketones, particularly in auxiliary based systems.'" Tin( 11) enolates, generated using tin( 11) triflate and an amine base, also afford syn aldol products with high selectivity.' a much greater challenge than the control of simple syn /anti diastereoselectivity, requiring significant stereodifferentiation of the x-faces of the enolate and the aldehyde.Three main strategies have been actively pursued: (i) Induction from the aldehyde component. (ii) Induction from covalently-bound ligands or auxiliaries in the enolate component or, in its simplest form, inherent chirality in the ketone substrate. Induction from a chiral Lewis acid in Mukaiyama aldol reactions.Asymmetric induction in aldol reactions represents (iii) Where the formation of new stereogenic centres may be influenced by two or more sources of induction, possibilities exist for both the enhancement and reduction of selectivity. Overall, when these influences are in the same stereochemical sense, this constitutes a 'matched' pair, leading to increased selectivity. However, those known to have opposing influences undergo 'mismatched' reactions with a concomitant reduction in overall selectivity.' * Double (and triple) asymmetric induction effects are generally seen to be additive, however, reactants with a very high diastereofacial preference may control the stereochemical course of a reaction regardless of the influence of other components. It is important to stress that these are simple guidelines for what to expect and that, particularly in the combination of chiral reactants, interactions which do not play a significant role in simple systems may cause unforeseen selectivity.2 Asymmetric induction from the aldehyde Aldol reactions between achiral enolates and a-chiral aldehydes provide the least general route to the diastereoselective synthesis of @-hydroxy carbonyl compounds. Although a-methyl, a-alkoxy, and a-amino aldehydes exhibit high diastereofacial preferences in Mukaiyama aldol reactions with enol silanes (vide infra),13 additions of other metal enolates exhibit considerable ~ariability.'~ The reaction of a-methyl aldehydes 5 with achiral E-enolates usually gives adduct 6 as predicted by the Felkin-Anh model (Scheme 2).15 However, additions to 2-boron, lithium, and titanium enolates exhibit anti-Felkin facial selectivity, yielding 7, provided the steric requirements of R' are greater than that of the a-methyl group, with an increase in selectivity observed for larger R1.l6 High anti-Felkin selectivity is also observed in the reactions of a-methyl-P-alkoxy aldehydes with achiral Z-enolates.However, lithium enolates 8 add to a ,@-epoxyaldehydes 9 with good diastereofacial selectivity to give 10 as predicted by the Felkin-Anh m0de1.I~ In studies directed towards the synthesis of calyculin A (Scheme 3), Evans et al. showed that 5 6 5 7 9 0 R' = H, Ph; R2= H, Me; R3 = CH20Bn, CH20TBS; R4 = H, Me; Z = OBut, OEt, But Scheme 2 H G5 10 1 FSB.OEt2 OH OTES BU' But I I 12 (82% d.s.) 13 (98%d.s.) Scheme 3 3 I8 Contemporary Organic Synthesis?Me complementary 1,2-asymrnetric induction may be obtained for the addition of pinacolone to aldehyde 11.'* The lithium enolate gives rise to anti-Felkin product 12, whilst a Lewis acid mediated Mukaiyama addition using the silyl enol ether gives Felkin product 13.In certain cases, synthetically useful levels of 1,3-~tereocontrol may be obtained in additions to B-chiral aldehydes, particularly where chelation can be exploited under Mukaiyama aldol conditions. l 9 In studies directed towards the synthesis of swinholide A, Paterson et al. found that the vinylogous Mukaiyama aldol reaction of silyl dienol ether 14 with aldehyde 15 proceeded with high diastereoselectivity (Scheme 4).*" However, here the best Lewis acid was boron trifluoride etherate, which precludes chelation by the dihydropyran oxygen.The stereoselectivity in aldol a-methylene-P-alkoxy aldehydes mediated by boron, tin( II), and titanium( I V ) enolates have been examined.*' Useful levels of 1,3-asymmetric induction from the aldehyde are possible, where the sense and level of induction varies with the nature of the enolate and the substitution in the aldehyde. For example, the titanium-mediated aldol addition of diethylketone to 16 gives adduct 17 with 95% d.s., whereas addition to 18 gives predominantly 19 (Scheme 5). I I I reactions of methyl and ethyl ketones with OMe swinholide A pO/l-'' wH + T S i M e , 15 14 .~ P = Bn. Bz F3B.OEt2 I Po-'. nJv=+" 81 - 90% d.S. Scheme 4 TiCI4, Pt2NEt + 3 Asymmetric induction from the enolate 3.1 Ligand-mediated The use of chiral ligands on the metal of an enolate provides a mean of differentiating the two diastereotopic x-faces.Work in this area has concentrated mainly on the use of chiral boron reagents for the enolization of simple ketones, esters, and thioesters [( - )-Ipc,BOTf and 20-231. di-isopinocampheylboron triflate [( + )- or ( - )-Ipc,BOTf] have been shown by Paterson et al. to The a-pinene-derived reagents 18 TBDPSO OH 0 17 (95% d.s.) PMBO % Scheme 5 Franklin and Paterson: Recent developments in asymmetric aldol methodology 19 (70% d.s.) 31926 97% d.s. 67 - W h 8.8. Me&iiTf, Pr'flEt 1 22 23 provide access to either enantiomer of syn aldol product 24 from the addition of ethyl ketones to sterically undemanding aldehydes (Scheme 6).22 The use of enol di-isopinocampheyl borinates generated from the 1,4-addition of Ipc2BH to E-a,/?-unsaturated ketones in the synthesis of enantiomerically enriched syn aldols has also been reported.23 This approach allows regioselective enolization of unsymmetrical ketones and gives exclusively the syn product in good enantiomeric purity (60-90% e.e.).Ipc2BCl or Ipc2BOTf can also be used for enantioselective aldol reactions of methyl ketones.22 /3-Hydroxyketones 25 are produced with reduced levels of enantioselectivity and with the opposite hydroxyl configuration to that observed in the ethyl ketone aldols for a given reagent configuration. 24 (66 - 93% 8.8. 95 - 98% d.S.) R' = Et, Ph, Pr', Pr'CH2, Me f? = Me, H2C=C(Me), P f , E-MeCH=CH, P-furyl, Ph Scheme 6 An asymmetric synthesis of dihydropyrones 27 has been developed using the Ipc-controlled boron aldol reactions of /3-chloroenones 26 with aldehydes, followed by cyclization (Scheme 7).24 This method has been used in the synthesis of 27 ( R2 = H, R2 = CH2CH20Bz), a key intermediate for the synthesis of swinholide A and scytophycin C.2" X = OTf, CI R' = H, Me R2 = P f , H&=C(Me), Ph, BnOCH2, E-MeCH=CH, c-Hex, CH2CH208z 27 Scheme 7 The corresponding anti aldol reactions of E-enolates generated from ketones using Ipc,BCl proceed with little enantioselectivity.22 In contrast, the computer-designed boron reagent [( menth)CH212BC1 20 (X = C1) introduced by Gennari et al.has been shown25 to enolize a range of cyclic and acyclic ketones leading to anti aldols 28 with high diastereoselectivity in good enantiomeric purity (Scheme 8 ).Methyl ketone derived enolates exhibit the same aldehyde enantioface preference (in contrast with the Ipc case) giving 29, again with reduced enantioselec tivity. 28 (56 - 88% 8.8. 86 - 100% d.S.) (9 =I. Et3N (A) R2CH0 29 (55 - 76% 8.e.) R' = Et, Ph, PS, -(CH2)3-, -(CH,),-,BU', Bu', Me R2 = Et, H&=C(Me), c-Hex, Pr' R ' = H , M ~ 30 R' = H 85 - 97% 8.e. f? = Bu', CEt3, Ph, 30 R' = Me 74 - 297% d.s. @ = c-Hex, Ph, Pt, 290% e.8. P f , H2C=C(Me) Scheme 8 This methodology has been extended to the enolization of thioacetates and thiopropionates by modification of the reagent to its bromo derivative (the 320 Contemporary Organic Synthesisboron chloride was found to be ineffective for the enolization of thioesters).26 Thioacetates give enantiomerically enriched /3-hydroxythioesters 30 ( R1 = H) whilst the thiopropionates react with high enantio- and diastereo-selectivity.The reagent 24 (X = Br) was also shown to be marginally more anti selective than the corresponding chloride for the aldolization of ketones. The two closely related chiral boranes 21 and 22 have been employed by the groups of Masamune and Reetz respectively for the enolization of ketones and thioesters. The diphenyl derivative 22 performs better in thioacetate aldols (92- > 95% e.e.)27,28 whilst the dimethyl reagent 2 1 is superior for thiopropionate systems (98- 100% e.e.)29 although the differences are small. The reactions of thioesters with chiral a-amino aldehydes mediated by 22 have been shown to proceed with a high level of reagent control.27 Reagent 2 1 follows the rules of double asymmetric induction (Scheme 9), thus the addition of thioester enolates 31 to chiral aldehyde 32 giving adducts 33-36 provides both matched and mismatched product ratios, although the reagent chirality dictates the overall facial selectivity.* 9 32 31 33 R' = H; R2 =OH; R3 = H 34 R' = H; R2 = H; R3 = OH 33 : 34 (FIR)-21 13:l (SS)-21 1 : 7 Scheme 9 35 R' = Me; R2 = OH; R3 = H 36 R' = Me; R2 = H; R3 = OH 35 : 36 (R@-21 >200: 1 (sen1 1 : 55 Corey et al. have employed bromoborane 23 in the enantioselective aldols of propionates and thioesters (Scheme 1 O ) . 3 0 9 3 1 Enolization of phenylthioesters with 23 and Pr',NEt leads to syn products 37 whilst t-butyl esters and Et3N as base give rise to anti isomers 38. Acetate derivatives 39 can be accessed via t-butyl br~moacetate~~ with Bu;SnH/AIBN being used for debromination of the initially formed anti bromohydrin 40. 4 1 to transmetallate acetate33 and p r ~ p i o n a t e ~ ~ ester lithium enolates, leading to significant levels of enantioselectivity in their reactions with aldehydes to give 42 and 43 (Scheme 11).The same species has been used in the aldol additions of menthyl acetate enolates to give 44, where the influence of the ligands on the titanium is dominant in determining the facial ~electivity.~~ deprotonation agents for ketones provides potential access to optically active aldol products. Although Duthaler et al.have used the chiral titanium reagent The use of chiral lithium amides as enantioselective 37 (83 - 97% 8.8. 98 - 99% d.s.) 38 (87 - 98% 8.8. 94 - 99% d.s.) 40 R = c-Hex, E-PM=H=CH, AIBN, Bun3SnH I Ph, PhCH2CH2, Pr' OH 0 R 4 A o B " t 39 (90 - 98% e.9.) Scheme 10 (i) LDA ir, (ii) 41 ~ Bub (iii) RCHO Bub 42 (90 - 96% e.e.) (i) LDA vo3 ____) (ii)41 iii) RCHO vov R 43 (92 - 97% d.s. 91 - 97% e.e.) I a 44 Scheme 11 Franklin and Paterson: Recent developments in asymmetric aldol methodology 32 1good enantiomeric excesses (up to 86% e.e.) have been achieved, the origins of selectivity in these reactions are not well understood, limiting their application at the present time to a few, specific systems based on sterically demanding acyclic and cyclic ketones.36 stereocontrol, and be easily cleaved, under high yielding and mild conditions, without loss of stereochemical integrity at the newly formed centres.The initial formation of diastereomeric products in these reactions should allow facile separation prior to cleavage to essentially enantiopure products, of the protected a-hydroxy ketones 45 (Scheme 12) where aldol addition, deprotection, and periodate cleavage yields the corresponding a -me th y 1- /3- h y d roxy car boxy lic acid. H ea thcoc k et af. have shown that all four possible diastereoisomers 46-49 are available from one enantiomer of 45 (R = But, P= TMS or TBS) by appropriate choice of enolization conditions.38 The N-propionyl imides 50 and 5 1, derived from (S)-valine and ( 1 S, 2R)-norephedrine respectively were introduced by Evans et af.in 198 1 and allow highly enantiocontrolled synthesis of both syn and anti aldol products (Scheme 13). The Z-enol borinate of 50, generated using di-n-butylboron triflate, reacts with aldehydes to give syn aldol52. Similarly, the 2-boron enolate of 5 1 gives syn isomer 53 arising from complementary asymmetric induction. In both cases, treatment with sodium methoxide in methanol gives the corresponding methyl ester in > 99% enantiomeric purity.39 Alternatively, access to the second syn isomer from a given auxiliary is possible via the titanium enolate. Transmetallation of the lithium enolate of 50 with ClTi( OR'), and subsequent addition of aldehyde gives the 'non-Evans' syn product 53 (85-92% d.s.).,O Direct generation of the more reactive chlorotitanium enolates by deprotonation of the TiC1,-complexed imide with di-isopropylethylamine simplifies this approach.g Addition of TiC1, to the preformed boron enolate prior to reaction with the aldehyde also gives the 'non-Evans' syn product 53 in 87-94% d.s.,' A more significant application of Lewis acid additives developed by Heathcock et af.gives anti isomers 54 or 55 with good diastereoselectivity (74 : 26-95 : 5) from the addition of the boron enolates of 50 or 5 1 to aldehydes precomplexed with Et,AlCl. Again the two auxiliaries exhibit opposite facial selectivities:' Perhaps the simplest chiral auxiliary system consists 3.2 Auxiliary-mediated A common means of controlling asymmetric aldol additions is through the use of a chiral auxiliary attached to the enolate component.These must be readily synthesized, impart a high level of R = c-H~x, Bu'; OP COPh, CHzOMe 45 But& R TMSO ' (I) LDA, TMEDA (ii) RCHO 1 46 (>95% d.s.) But# TMSO R 47 (>95% d.s.) TMSO (ii) RCHO 48 (92 - 95% d.s.) But* R TBSO (i) BrMgNR2 (ii) Ti(OPi)&l, HMPA * OTBS (iii) RCHO 49 (>95% d.s.) R = Me, Pi, But, Ph, PhCH20CH2CH2 Scheme 12 0 0 0 OH Bu",BOTf, R,N RCHO/Et$iICI Bu"pBOTf, R3N I RC H OlTii Id, 52 54 50 A Ti enolate 0 L N L U x* U R I X * Y R * BU"@OTf, R3N - RCHO/EtfiICI I I 55 53 51 Scheme 13 Contemporary Organic Synthesis 322Reversal of the simple syn selectivity of these boron enolates to give both anti and 'non-Evans' syn products has also been observed in a small number of substrate-specific cases, particularly in the presence of excess di-n-butylboron t~iflate.,~ The corresponding acetate aldol reactions of these oxazolidinone systems have proved disappointing.However, Nagao et al. have shown that the closely related thiocarbonyl species 56 and 57 induce diastereoselectivity in both propionate (R' =Me) and acetate ( R1 = H) aldol additions via their tin( 11) enolates, whilst 58 functions solely as an acetate equivalent (Scheme 14 ):3 Et 86 - 91% d.s. 'Bn 'Bn 59 56 'Bn O w N 4 R' ' \ Ph' Me (ii) R~CHO 57 R' = H, Me R2 = Me, Pr', Bu,' Ph w,K sq R' 58 R' = Et, Pr' R2 = a,B-unsat A' 76 - 90% d.S. 89 - 98% d.s. Scheme 14 Stereocontrolled acylation of 59 to give P-ketoimides 60 and 6144 provides further opportunities for directing aldol additions, leading to dipropionate units.Evans et al. have shown that three of the four possible stereochemical courses of the aldol additions of these substrates can be achieved by variation of the enolization conditions (Scheme 15). Titanium( IV ) chloride/di-isopropylethylamine enolization of 61 leads to the all syn product 62, whilst the second syn aldol isomer 63 is available using tin( 11) triflate/trieth~lamine.~~ The anti isomer 64 arises from reaction of the E-enol borinate, generated from 6 1 using dicyclohexylboron chloride and dimethylethylamine, with aldehyde^.,^ Reactions of these B-ketoimides with a-chiral aldehydes have been shown to follow the rules of double asymmetric induction. A number of possibilities for auxiliary cleavage beyond simple hydrolysis (which may also be performed under milder conditions with LiOOH) exist, allowing ready access to aldehydes, Weinreb amide~,4~ thioesters, benzyl esters, and alcohols, 61 Scheme 15 62 (98 - >99% d.S.) X' W R 63 (79 - 95% d.s.) 64 (80 - 92% d.s.) facilitating further functionalization.Numerous examples of the use of these highly effective auxiliaries in the synthesis of complex targets have been reported, particularly those containing polypropionate fragment~.~~-~O Often a large proportion of the stereocentres are introduced by asymmetric aldol reactions with further induction by these centres then playing an important role in subsequent steps. One such synthesis is that of cytovaricin from the Evans Here, a total of five aldol connections were made (Scheme 16).It should also be noted that the aldol addition of 65 to 66 (C,-C,) proceeded with unprecedented anti selectivity to give 67, apparently due to the high n-facial bias of the aldehyde component. by Oppolzer et al. for asymmetric aldol reactions (Scheme 17). Enolization of 68 ( R1 = Me) with diethylboron triflate and di-isopropylethylamine followed by addition of aldehyde gives the syn aldol product 69. In contrast, the lithium or tin(1v) enolates of 68 ( R1 = Me) react with aldehydes to give the other syn isomer 70.52 anti-Aldols 7 1 can be accessed either via ketene acetal 7253, or directly by addition of TiC1,-complexed aldehyde to the boron enolate of 68 ( R1 = Me).54 In all cases, products are obtained in > 99% d.s. after recrystallization. Bornane-sultam 68 ( R1 = Me) has been employed Franklin and Paterson: Recent developments in asymmetric aldol methodology 32365 66 Bu",BOTf, Et3N k4 67 Scheme 16 69 I R' 70 EtSOTf, Pr'aEt A' 71 72 73 Scheme 17 324 Contemporary Organic Synthesis The corresponding acetate aldols of 68 (R1 = H) again proceed via the ketene acetal7 2 ( R1 = H) although selectivities are lower (79 : 21-95 : 5) than the corresponding propionate systems.55 Cleavage of recrystallized aldol products occurs readily with alkaline peroxide,53 ally1 alcohol/Ti( or dilithiated methyl phenyl sulfones7 to give enantiopure /3-hydroxy carbonyl derivatives.The anti and syn selective aldols of 68 (R1 = Me) and sultam 7358 respectively have been used in the asymmetric synthesis of ~erricorole.~' has also been used in asymmetric aldol reactions (Scheme 18).The boron enolate of 74 (X = 0 or S) gives syn isomer 7560 whilst the second syn isomer 76 is the product of addition of TiC1,-complexed aldehyde to the chlorotitanium enolate of 74 (X = S).61 The asymmetric syn aldols of a range of other N-propionyl derivatives have been reported with other chiral amine6* or camphor63 based auxiliaries. Di-N-propionyl derivatives of the general type 77 have also been employed, providing access to two identical aldol fragments from a single chiral s0urce.6~ The camphor-derived N-propionyloxazolidine 74 0 OH z o 75 OYN-.: i / 74 RCHO x = 0,s; R = Ph, p f , p i , Me. MeCH=CH 77 x = so,, c=o R = Ph, -(CH2)4- 76 Scheme 18 Chiral esters have been shown to provide ready access to asymmetric aldol products, often in an anti selective Of particular note in this area is 78 which was introduced by Braun et aZ.66 and has been used, as its TMS ether, by Corey et aZ.in a synthesis of lactacystin. The anti aldol of zirconium enolate 79 with aldehyde 80 proceeded with 86% d.s., whilst that of the achiral lithium enolate 81 showed only 60% d.s. (Scheme 1 9)?7 Other auxiliary-based approaches have employed chiral amides,6* sulfoxides,69 hydra zone^,^^ and oxazapho~phites~ to induce asymmetry in aldol reactions.'0 Ph R Ph Ph 3.3 Substrate-mediated using chiral ketones In certain cases, the inherent chirality of an a- or #&substituted ketone leads to useful x-facial 78 R=H,Me discrimination of its enolate without the requirement for a temporary chiral auxiliary or enolization reagent.Despite the potential for asymmetric induction in the aldol additions of a-chiral ethyl ketones, systematic study in this area has been limited to relatively few specific substrates. The a,B-substituted ketones 82 undergo diastereoselective boron-mediated additions to aldehydes (Scheme 20) and function as tripropionate equivalent^.'^-'^ This approach has been applied to the asymmetric synthesis of ebelactone A and B, where the key intermediate 83 was obtained by sequential aldol reactions on diethylket~ne.~~ The reactions of the structurally related ethyl ketones 84 have been reported by Evans et al. 80 with improved Ph Ph 79 Scheme 19 81 diastereoselictivities for the syn isomers, in the same stereochemical sense as boron, being obtained via their chlorotitanium enolates (Scheme 2 1 ).OP 0 OP 0 OP 0 OH 85 - 95% d.s. 08 - 90% d.s. 90 - 98% d.s. 295% d.s. P = TBS, TIPS, PMB, Bn L = Bun, SBBN Scheme 20 Franklin and Paterson: Recent developments in asymmetric aldol methodology 325TWO 0 TBSO 0 OH 0 TBSO 0 OH 94% d.s. Scheme 21 96% d.s. 96% d.s. 95% d.s. Ketones ( R ) - and (5)-85 have been introduced by Paterson et al. as versatile dipropionate equivalents for the construction of polyketide natural products (Scheme 22).73 Three out of the four diastereomeric aldol adducts can be obtained selectively for any aldehyde by using appropriate e n o l a t e ~ . ~ ~ The chiral ketones 85 have been widely used in the synthesis of complex polypropionate targets with the majority of the stereocentres being introduced by appropriate asymmetric aldol reaction^.^' Induction by these centres may then influence the selectivity of subsequent reactions: selective access to all possible (32) stereoisomers of the stereopentad sequence 86 may be achieved by or tin( 11) RCHO ( BnO I I I I I I I I I I I I I I I 1 I I I R C d RCHO 1 RCHO 1 I I I I I 1 I I I .1 90 - 95% d.s.88 - 90% d.s. 89 - 92% d.s. 95 - >98% d.s. Scheme 22 326 Contemporary Organic Synthesis a6Po k O B n 87 P = Bn, Me OH 0 OH 0 90 Scheme 23 m-89 P = TBDPS R*OBn (I) c-Hex,BCI, Et3N (ii) RCHO - OP 88 (>95%d.s.) stereoselective reduction and hydroboration of the appropriate aldol adducts of 85 and methacrolein.80 The anti aldol reactions of chiral alkoxymethyl ketones have also been studied.81 Simple aldehydes react with the E-enol borinate of 87 to give adduct 88 (Scheme 23).The enolate exhibits high n-facial selectivity in its reactions with ( R ) - and (S)-89 overriding any Felkin-Anh type influence from the aldehyde stereocentre to give the respective adducts 90 and 91 with 80% (mismatched) and 95% (matched) diastereoselectivity. This approach has been used in the synthesis of a polypropionate fragment of rapam ycin. reactions, methyl ketone aldols often provide a greater challenge than ethyl or higher alkyl ketones. The silyl enol ethers 92 of a-pivaloyloxy ketones react with aldehydes in the presence of a Lewis acid with good selectivity for 93,82 which has been used in the synthesis of ipsenol (Scheme 24).83 The chiral methyl ketone 94 undergoes boron-mediated aldol reactions to give predominantly 95 with useful levels of induction, which can be further enhanced by using appropriate Ipc l i g a n d ~ .~ ~ As in other approaches to asymmetric aldol (i) c-HexaCI. Et3N OHC BnO oms OH 0 OH 0 &R1 R % - ~ o ~ R2/,&,R' I + R 2 &R1 I i>h O h ow 92 93 (81-98%d.s.) 94 Scheme 24 95 (88% d.s. for c-Hex$XI 92% d.s. for (-)-Ipc&OTf) In certain cases, the key to obtaining useful levels of selectivity in a-chiral methyl ketone aldol reactions appears to be additional chelation by a suitably positioned heteroatom. For example, the lithium enolates of a -( N, N-dibenz ylamino )alkyl methyl ketones 96 add to aldehydes with high selectivity in favour of 97 (Scheme 25).84 Remote chelation has also (9-M 87 P - TBDPS 91 been shown to play a role in determining the stereoselectivity of methyl ketone aldol reactions.During studies on the synthesis of bafilomycin A,, Roush et al. found that methyl ketone 98 underwent a selective addition to aldehyde 99, to yield 100 and 10 1, only as its lithium enolate and in the absence of chelating solvent additives.85 Further studieP + R%HO - NBnz NBn, m 97 (So - >98% d.S.) I I -0Bz 99 98 LiN(TMS)2 THF 1 OBz 100 R' = H, R,= OH loo:lol 101 R' = OH, R2= H 102 103 P = TBS, TES, MPM Franklin and Paterson: Recent developments in asymmetric aldol methodology 327indicated that this selectivity was probably due to chelation by the C,, alkoxy substituent, with ketones of type 102 (P= MOM) reacting selectively (8: l), whilst those of type 102 (P=TES), 103, and 104 gave little selectivity (1.2 : 1-3 : 1).However, these chelation effects appear to be insignificant in the aldol reactions of the corresponding chlorotitanium enolates, with 102 (P= TES, Bz) undergoing highly selective ( 2 96% d.s.) reactions. Recent work by the Evans group has shown that asymmetric induction by a P-chiral centre in the ketone may also play a role in certain substrates. The aldol additions of a-unsubstituted-P-silyloxy ethyl ketones to a-methyl aldehydes have been studied as part of a synthetic approach to bafilomycin A, (Scheme 26).87 Best results were obtained with the enol borinate prepared using dichlorophenyl- borane.88 Ketone 105 reacted with high selectivity in favour of 106 (87% d.s.with Pr'CHO, 79% d.s. with I 1 111 llPR'=OPMB, I?=H also R1=OTBS,R2=H; R' = H, I? = OTBS, OPMB 92% d.s. OTBS OPMB TBSO*cHo 107). However, the nature of the silyl protecting group in the ketone proved crucial. Low selectivity was observed with 108 whilst silylene-protected 109 gave excellent diastereoselection ( > 99 : 1 for Pr'CHO and 110, > 9 5 : 5 for 107). I 105 106 107 P = TMS, TBS 108 109 Scheme 26 The high x-face selectivity associated with the enolates of certain chiral ketones often provides the controlling influence in aldol additions to chiral aldehydes. In many cases, the aldol reaction between two complex fragments has been shown to be a viable means of coupling large segments in total synthesis. In the coupling of such highly substituted components, subtle effects can have a dramatic (and often unpredictable) effect on the product stereochemistry. For example, the nature of the protecting group and stereochemistry of a b-alkoxy centre in an a-methyl chiral aldehyde have been shown to have a significant effect on the selectivity of its aldol reactions with a chiral ketone.During studies directed towards the total 116 113 114 Ticid. P+*NEt 2 I I I I 1 1 1 1 I 117 (80% e.e.) 1 i e I l l . 1 1 1 1 11 5 (97% ds.) 119 (83% d.s.) Scheme 27 328 Contemporary Organic Synthesissynthesis of rutamycin B, Evans et al. found that only the coupling of 11 1 and 112 proceeded with high diastereoselectivity (Scheme 27).49 The corresponding titanium-mediated coupling of fragments 113 and 1 14 also proceeded with high selectivity to give 1 15 despite apparently constituting a mismatched reaction.xY Similar selectivity ( > 93 : 7) has been observed by White et al.with the closely related aldehyde 116.'* A related mismatched aldol coupling between 1 17 and 1 18, reported by Paterson et a!. , proceeds with high diastereoselectivity to give adduct 119, leading to the stereocontrolled synthesis of denticulatin B."' ( R ) - and (S)-85 to aldehyde 18 have also been explored (Scheme 2 8).21 Unexpectedly high diastereoselectivities were obtained based on the low intrinsic facial biases of the two reactants. Thus, the matched pair gave adduct 120 with 95% d.s., while the mismatched pair gave 12 1 with 88% d.s. Here the chlorotitanium enolate from (S)-85, which shows a small preference (ca.2 : 1) for re-face attack on aldehydes, completely overrides the low (ca. 70 : 30) si-facial bias of 18. These results demonstrate that the accurate prediction of the product stereochemistry in such complex coupling situations remains largely elusive. The titanium-mediated aldol addition of the ketones PSoTiCI, Et3N TiC14, P+#JEt +l+ PMBO w m n 120 (95% ds.) 0 x 0 0 0 18 (*a PMBO' TiCI,, Pr'&Et 5- PMBO 121 (88% d.s.) Scheme 28 Frequently, the selection of the metal in the enolate has a significant effect on the stereochemical course of the aldol reaction. During studies on an aldol-macrocyclization approach to rapamycin (Scheme 29), Danishefsky et al. found that only a ,OTI PS 6. I 123 H U O B O M fi 124 125 126 IDA, ZnCl 3 Ho 127 Scheme 29 Franklin and Paterson: Recent developments in asymmetric aldol methodology 329titanium-mediated reaction of 122 provided the desired product 123, albeit in low yield (1 lo/o), despite investigating lithium, boron, tin, zinc, zirconium, and cerium enolates as alternatives.Y2 Martin et al.have noted that the diastereoselectivity of the aldol reactions of a-methyl aldehyde 124 with a-chiral ethyl ketones is dependent on the nature of the metal c~unter-ion.'~ Similarly, Evans et al. completed the synthesis of ferensimycin B by the addition of aldehyde 125 to the zinc enolate of 126 to give 127 in preference to the lithium- or magnesium-mediated reaction^.'^ The Ipc boron aldol reaction has been used in double asymmetric induction situations, in enhancing substrate-based stereoselectivity in the aldol reactions both of chiral ketones with achiral aldehydes and of achiral ketones with chiral aldehydes. In the former case, kinetic resolution in the aldol reactions of certain ethyl ketones has been demonstrated, where syn aldol 128 was obtained with high enantio- and diastereo- selectivity by starting from rac-82 (Scheme 30).Y5 This was converted into an ansa chain segment for the synthesis of rifamycin S.129 L$Cl, EtjN 5- 130 131 130 : 131 c-Hex,BCI 70 : 30 (+)-Ipc2BCI >95 : <5 (-)-IPC,BCI 77~23 *CHO rac-82 128 (98%d.s. 295% e.e.) Scheme 30 In studies directed towards the synthesis of swinholide A, Paterson et al. examined the Ipc-mediated boron aldol reactions of methyl and ethyl ketones with chiral a-methyl and /3-alkoxy aldehydes (Scheme 3 l).y6 The anti-Felkin selectivity obtained in enol borinate addition to 129 could be increased to > 95% d.s.for 130 by using the appropriate Ipc,BCl reagent. Note that use of the enantiomeric reagent failed to reduce the substrate-induced face selectivity from this particular aldehyde. #?-Alkoxy aldehyde 132 showed significant n-facial bias in favour of 134 in its reactions with 2-enol borinates, which could be overturned using ( + )-Ipc,BOTf. In a further example, reagent P, 132 133 134 133 : 134 BU"2BOTf 16 : 84 (+)-I&BOTf 75 25 9/s'\0 9PMBO (i)L,BOTf, PiflEt (ii) ECHO * 135 136 137 135 : 136 BunZB0Tf 33 : 67 (+)-Ip@OTf 88 12 (-)-ImBOTf 8 : 92 Scheme 31 330 Contemporary Organic Synthesis4 Asymmetric induction in Mukaiyama aldol reactions from the Lewis acid control was demonstrated for the selective formation of either 135 or 136 from the ethyl ketone 137.Work by Masamune et al. on the bryostatins and calyculins has provided examples of both double and triple asymmetric induction. The use of both enantiomers of boron triflate 2 1 in the coupling reactions of chiral aldehydes and chiral ketones leads to significant variation in selectivity compared to the corresponding achiral boron reagent mediated addition^.^^ In the aldol coupling of methyl ketones 138 and 139 with achiral aldehydes a useful level of reagent control is possible (Scheme 32). The substrate-based selectivity in favour of 144 and 145 in the aldol coupling of chiral methyl ketones 146 and 147 with chiral aldehydes can be enhanced by use of the appropriate chiral reagent, (RR)-2 1.However, in these triple asymmetric induction situations, the chiral reagent is largely ineffective for overturning the substrate-based selectivity. The Lewis acid mediated addition of a silyl enol ether to an aldehyde or ketone, the Mukaiyama aldol reaction, came to prominence as a useful asymmetric reaction in the 1980s. While the use of chiral silyl enol ethers and a-chiral aldehydes has been extensively explored,' 3,98 the opportunities presented by variation of the Lewis acid catalyst have only been exploited more recently. Work has been focused on the design of new chiral Lewis acids for asymmetric Mukaiyama reactions with emphasis being placed on the ability of reagents to act in sub-stoichiometric quantities.4.1 Boron Lewis acids Kiyooka et al. have used chiral boron Lewis acids prepared from the sulfonamides of a-amino acids to OXO OMOM i ~LOTBDPS 138 140 : 141 (RR)-2? 1 : 6 141 R'=OH;l?=H EtpBOTf 1 :2 140 R ~ = H ; R ~ = O H (ss)-21 2 : 1 139 142 : 143 (Rl3-21 1 : 4 142 R' =H; R ~ = O H (ss)-21 4 : 143 R' =OH; R2 = H (R9-21 1 : 1 146 144 : 148 147 Scheme 32 145 : 149 (Rrn-21 1 9 - 1 145 R' = H; R2= OH ( ~ 9 - 2 1 2 149 R' = OH; R2 = H Et2BOTf 8 : 1 Franklin and Paterson: Recent developments in asymmetric aldol methodology 331promote the reaction of silyl ketene acetals and aldehydes (Scheme 33). Initial studiesYy demonstrated that a variety of boranes, when used stoichiometrically, promoted the formation of #?-hydroxyesters 150 in 85-93% e.e.from silyl ketene acetal 151 ( R2 = R3 = Me, R4 = Et). Use of the analogous TBS ketene acetal gave improved enantioselectivities (92-98% e.e.) but led to the formation of acetal 152, apparently from the reduction of an intermediate ester by hydride transfer from the borane. Use of nitroethane as solvent in place of dichloromethane allowed the catalyst to be employed in sub-stoichiometric quantities without any reduction in enantioselectivity.loO /?-Hydroxyesters 150 were obtained in 8 1-96% e.e. in reactions promoted by 20 mol% of borane ( R5 = Pri, Rh = p-N0,Ph). An alternative approach employed by Masamune et al. uses a boron Lewis acid prepared from a,a-disubstituted glycine arenesulfonamides 153 and 154 inthereactionsof 151 (R2=R3=Me,R4=Et) to give /3-hydroxyesters 155 of > 97% e.e.with typical primary aldehydes and 84-96% e.e. with secondary aldehydes.'O This approach can be extended to unsubstituted and monosubstituted ketene acetalslo2 which give lower enantio-Y9 or diastereo-sele~tivity~~~ for similar 0 Lewis acids. When ligand 153 was used to form the chiral catalyst in addition of unsubstituted ketene acetals 156 (R2 = R3 = H, R4 = SEt, SBu', OPh) with a variety of aldehydes, the reactions proceeded with high enantioselection (81-93% e.e.). The reaction of monosubstituted ketene acetals 156 ( R2 = H, R3 = Me, R4 = SEt, SBd, OPh) with aromatic and a,#?-unsaturated aldehydes proceeded well in the presence of ligand 153, whilst 154 was found to be superior for primary aldehydes. In all cases anti products 157 were favoured? with both isomers being formed with good enantioselection.The tryptophan-derived oxazaborolidine 158 has been employed by Corey et al. as a catalyst in the asymmetric Mukaiyama aldol reaction (Scheme 34).lo4 This catalyst performed best with terminal trimethylsilyl enol ethers derived from methyl ketones and a range of aldehydes giving 159. The more substituted silyl enol ether 160 was found to react with benzaldehyde in the presence of 40 mol% of 158 to give predominantly 16 1. However, silyl ketene acetals were found to react with poor enantioselectivity under these catalytic conditions. 159 (86 - 93% e.e.) R' R2 R' = Ph, n-C4H9, = Ph, c-Hex, Pf', 2-fury1 151 150 160 152 153 154 151 155 156 Scheme 33 332 Contemporary Organic Synthesis 157 = H, R3 = Me 77 - 94% d.s.60 - >98% e.e. Scheme 34 161 (96% d.s. 86% e.e.) The chiral (acy1oxy)borane complex 162 (X = H), derived in situ from tartaric acid derivative 163 and H3B . THF (Scheme 35) promotes the Mukaiyama aldol reaction of silyl enol ethers and ketene acetals with various aldehydes when present in catalytic amounts (20 mol%). Using this catalyst system, Yamamoto et al. have established that silyl enol ethers 164 derived from ketones lead to aldol adducts 165 with high diastereo- and enantio-~electivity.~~~ Improved diastereoselectivities (9 1-99% d.s.) were observed in the analogous reactions of 162 (X = 3,5-bistrifluoromethylphenyl) with ethyl ketones, whilst 162 (X = o-phenoxyphenyl) led to increased enantioselectivity (88-94% e.e. versus 80-85% e.e.) with methyl ketones.lo6 Only phenyl ester derived silyl ketene acetals 166 gave reasonable levels of diastereoselectivity in the formation of 167, with a,/?-unsaturated aldehydes providing the best results.lo3 ?Note that this anti selectivity is in contrast to the syn selectivity observed by Yamamoto et al..rosH3B.THF __t 163 ic 162 0 oms 164 R' =H, Me, -(CH2)4-; 165 X=H 80->95%d.s.R2= Bu", Ph, Et, -(CH2)4-; R = Ph, Bu", Pr", PhCH=CH, 80 - 96% 8.8. 6MeCH=CH O O H R3 20 md% 162 R ' W o T M S + R3CH0 - R b 166 R' = Me; R2= Ph; Scheme 35 167 (64 - 96% d.s. 92 - 97%e.e.) 4.2 Tin(I1) Lewis acids The use of a tin( 11) triflate/diamine based system as a chiral promoter has been the subject of extensive study by Mukaiyama and Kobayashi et al. (Scheme 36).Early work involved the use of stoichiometric amounts of a three-component system consisting of tin( 11) triflate, tributyltin fluoride,lo7 or dibutyltin diacetatelo8 and diamine 168 or 169. This was shown to promote the reaction of aldehydes with ketene silyl acetals derived from acetic acid esterslog and thioesters of acetic and propionic acids.11o In all cases, the reactions proceeded with high enantioselectivity. The enol silanes of propionate thioesters 170 reacted with high diastereoselectivity to give the syn isomer 17 1. Selective synthesis of both syn and anti a,P-dihydroxyester derivatives can be achieved by variation of protecting group, where 172 (P= Bn) gives anti products 173"' whilst the corresponding TBS ether 172 (P=TBS) gives syn products 174.112 Catalyst turnover in these reactions occurs in propionitrile113 in the presence of 20 mol% tin(I1) triflate and chiral diamine. Enol silanes derived from both acetate114 and propionatells thioesters react with a range of aldehydes in a highly enantio- and diastereo-selective manner ( 6 8 -9 7% e.e., 86: 14-1OO:O syn:anti).The selectivity of the reaction of a-chiral aldehydes with thioacetate derived enol silanes has also been investigated.'16 It was found that the stereochemistry of the aldol addition is almost completely controlled by the chiral catalyst regardless of the inherent diastereofacial preference of the aldehyde with 2 94% d.s. in all cases. These reactions provide a highly selective approach to the asymmetric synthesis of polyoxygenated 'sugar' derivatives from achiral starting materials.ll7 R Me R = Me, Et, Pr" p!8 \ / 166 169 170 F?=H, Me 171 (99 - 1Wh d.s.78 - >98% e.e.) O h I 173 (91 -99% d.s. P=TBS L Rv OH 0 172 P=Bn,TBS SEt I OTBS 174 (88 - 97% d.s. 90 - 94% e.e.) Scheme 36 4.3 Other Lewis acids Although titanium( IV) chloride is one of the most commonly used Lewis acid catalysts in Mukaiyama aldol reactions, relatively few examples of chiral titanium derived catalysts exist. Binapthol-derived catalysts have been employed, where the oxide 175 catalyses the addition of silyl enol ether 176 to a$-unsaturated aldehydes (60-85% e.e., 20 mol% in toluene)' l8 whilst the dichloro species 177 catalyses the addition of glyoxylates 178 to ketone silyl enol ethers 179, giving 180 via an ene mechanism (Scheme 37)' l9 The latter reactions proceed with high selectivity. The use of lanthanide derived catalysts has 175 1 76 177 OSiR, 0 +R2 + R ' w c 0 2 R 3 R' R2 l7Q 1 78 Scheme 37 180 (>9Wo d.s.79~21-99:l Z E 299% e.e.) Franklin and Paterson: Recent developments in asymmetric aldol methodology 333also been explored with Ln( dppm), and Ln(fod), (Ln = Eu, Pr), inducing stereoselectivity in additions to a-chiral systems.120 5 complexation Metal complexation can provide asymmetry in either the aldehyde or enolate component in an aldol addition, with later decomplexation providing the free /3-hydroxy carbonyl compound. Acyclic acyl iron complexes 18 1, developed independently by the groups of Davies and Liebeskind, may be employed as ketone equivalents with their diethylaluminium and tin( 11) enolates providing high, complementary, levels of x-face selectivity for acetate systems (R = Me).Asymmetric induction by transition metal 181 R = Me, Et The boron trifluoride mediated reaction of o-trimethylsilyl benzaldehyde complexes 182 with cyclic silyl enol ethers' 24 and ketene silyl a c e t a l ~ ' ~ ~ leads to syn products 183. The corresponding reaction of enol silanes with ( + )- or ( - )-182 gives 183 or ent-183 in high e.e.126 The titanium tetrachloride mediated reaction of 182 (R = H), with enol silanes 184 proceeds with anti selectivity towards 185 irrespective of the initial double bond geometry.127 Reactions with resolved 182 give products of high enantiomeric excess after metal decomplexation. This general approach has been applied to the synthesis of a taxol side chain analogue, where the titanium enolate of thioester 186 gave the anti product 187 ready for further elaboration.128 Chromium complexation to an aromatic enolate component also influences aldol selectivity, where complex 188 undergoes aldol reactions via its enol borinate to give 189 (Scheme 3 9 ).I 29 (i) R'*BOTf, Pi2NEt &R2 Aluminium and copper( I) enolates induce anti and syn selectivity respectively in propionate (R = Et ) aldol reactions.l*' In reactions with chiral aldehydes, the high diastereofacial bias of the iron chiral auxiliary overrides the inherent selectivity of the aldehyde, allowing access to all possible diastereomers by variation of the auxiliary configuration and the enolate counter-ion.122 Tricarbonyl ( q6-arene) chromium complexes derived from substituted aromatic aldehydes are readily resolved,123 giving access to enantiomerically pure aldehydes with potential for exceptional n-facial selectivity (Scheme 38).OH 0 &(co)~ 182 R = H, OMe, CI 183 ( n = 1,2,3; X = CH2 90 - >98% d.S. X = 0 85 - 90% d.S. 90 - >98% e.e.) 182 184 R' = Me, Et; 185 (73 - 96% d.S. 92 - >98% e.e.) R2 = SBU', SPh OH 0 ocHo+ FSBut- (ii) TBAF &fS6Ut (iii) hu TMS OBn I 186 187 cr(co), 95% ds, ~ 9 8 % 88 Scheme 38 Scheme 39 6 Aldol reactions of a-isocyanocarboxylates The asymmetric aldol addition between isocyanoacetates 190 and aldehydes mediated by chiral gold(1) complexes was first reported in 1986.I3O The reaction proceeds with high diastereoselectivity to give trans-oxazolines 19 1 which may be converted into the corresponding syn p-hydroxy-a-amino acids 192 upon hydrolysis (Scheme 40).Detailed studies have been carried out on the effects of substitution patterns (Rl, R2, R3) within the substrates and on the nature of the terminal tertiary amino group in the ligand side chain of 193, which is believed to play a key role in transition state coordination. 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ISSN:1350-4894    

DOI:10.1039/CO9940100317

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Main group organometallics in synthesis MARTIN WILLS School of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK Reviewing the literature published between July 1992 and December 1993 1 1.1 1.1.1 1.1.2 1.1.3 1.1.4 1.1.5 1.1.6 1.2 1.3 2 2.1 2.2 2.3 3 3.1 3.1.1 3.1.2 3.1.3 3.1.4 3.2 4 4.1 4.1.1 4.1.2 4.2 5 5.1 5.2 6 6.1 6.2 7 Group 1 Lithium Lithium amides and enolates Non-stabilized organolithium reagents Lithiated aromatic and heteroaromatic groups Benzylic and allylic lithium anions Alkenyl and alkynyl anions Di- and tri-lithiated anions Sodium and potassium Anions stabilized by sulfur, silicon, and other heteroatoms Group 2 Magnesium Barium Zinc, cadmium, and mercury Group 13 Boron Alkyl boranes Allyl, allenic, and alkenyl boranes Hydroboration and carbon reduction by boranes Borane catalysts Aluminium and thallium Group 14 Silicon Allyl, benzyl, and alkenyl silanes and their derivatives Other classes of organosilyl reagent Tin Group 15 Phosphorus Arsenic, antimony, and bismuth Group 16 Sulfur Selenium and tellurium References Due to the extensive scope of the subject area this review will concentrate on synthetic aspects rather than mechanistic and structural properties of organometallic compounds and complexes. Whilst every effort has been made to be comprehensive, the emphasis of the review will be on novel methodology rather than applications of widely accepted methods.Furthermore, in some cases the number of references have been necessarily minimized by the exclusion of papers which contain closely related work to that specifically discussed in the review.1 Group1 1.1 Lithium 1.1.1 Lithium amides and enolates The study of chiral, non-racemic, lithium amide bases for the asymmetric deprotonation of prochiral ketones and in kinetic resolution reactions continues to be a productive research area.' Additives, such as lithium chloride, can have a dramatic and beneficial effect on the enantioselectivity of asymmetric deprotonations of several classes of ketone, for reasons that are yet to be fully explained.' A recent development in the field has been the use of dilithiated derivatives of amino alcohols, such as 1, for the enantioselective ring-opening of epoxides (Scheme 1 ).* The advantage of these reagents is that the reaction takes place at much lower temperatures than those traditionally required for monolithiated amide bases.6 0 OBn HO + 7:93 4 HO MeNLi OLi Reagents (i) 1. THF, -78 "C to rA., 16h 1 Scheme 1 The remarkably diastereoselective addition of chiral lithium amides 2 derived from a-methylbenzylamine to a,#?-unsaturated esters3 has been employed in a concise synthesis of the side-chain 4 of the anti-tumour drug taxol, via oxidation of the intermediate enolate with the chiral oxaziridine 3 (Scheme 2).3(a) A diastereoselective cyclization of lithium amides onto non-activated double bonds has been employed for the synthesis of pyrrolidine alkaloids! The nickel-catalysed isomerization of lithiated allylic alcohols to enolates has been optimized by refinement of the catalyst to the point where essentially a single regioisomer of enolate can be formed and alkylated in the one The extremely hindered lithiated amide derived from diadamantylamine has Wills: Main group organometallics in synthesis 339R R x 2 3 U 7 8 OH 92% d.e I 1 I l o t OH 4 Reagents (i) 2; (ii) 3.Scheme 2 been shown to exist as a monomeric species even in the presence of donor solvents and is capable of generating E-enolates of greater than 50 : 1 diastereoisomeric purity.6 An excellent review has been published describing the use of chiral diamines to control the asymmetric reactions of enolates with aldehydes and a,B-unsaturated ketone^.^ 1.1.2 Non-stabilized organolithium reagents The reaction of alkyl lithium reagents with carbon dioxide is known to give gem-dialkoxides, and subsequently ketones upon hydrolysis.A report has appeared describing a synthesis of unsymmetric ketones from two different alkyl lithiums in a one-pot reaction, thereby considerably increasing the scope of the process.8 Substrate controlled stereoselective synthesis is by no means a novel concept. This year, however, a detailed investigation has been reported on 'Cram' selective additions of alkyl lithium reagents to chiral ketones, in which optimization of solvent, temperature, and addition rate serves to produce higher diastereoselectivities than have previously been achieved for this class of reaction.9 Following an initial breakthrough some years ago, intramolecular cycloaddition reactions of non-stabilized alkyl lithiums have continued to be a productive area of research. Full papers have appeared on tandem cyclizations, which have been featured in previous reviews,'O and new applications have been reported, such as the cyclization of allenyl organo-lithiums as illustrated by the conversion of 5 into 7 and of 6 into 8." In each case there is strong preference for the formation of a five-membered ring, providing an 'allowed' cyclization pathway is available.5 n = l 6 n = 2 Dramatic solvent-effects in such reactions are not unusual. Cyclization of 9 (generated from the phenylselenyl reagent using n-butyllithium) in THF at - 110°C gives a 54% yield of the cyclized products 10 and 1 1 in a 1 : 9 ratio. The same reaction in ether at - 30°C gives exclusively Similar cyclization reactions have been employed for the synthesis of tetra hydro fur an^.'^ In each of the cases discussed above, the alkyl-lithium reagents were generated by an exchange reaction with n-butyllithium. However, it is noteworthy that the recent development of polyaryl- catalysed reductive lithiations of halides, ethers, and sulfides present attractive alternative methods,14 several more of which will be featured in this review.9 10 11 Acyl anions are probably the most widely employed class of 'umpolung' reagents. Whilst several equivalents of such species, e.g. dithianes and cyanide anion, are known, true acyl anions have not been widely exploited due primarily to their high reactivity. However, two recent reports have described the in situ preparation of such reagents by low-temperature ( - 110°C) addition of alkyl lithiums to carbon monoxide15 and by direct reduction of N,N-di- isopropylcarbamoyl chlorides using lithium powder and a catalytic amount of naphthalene (3 molo/o).In the latter case the acyl lithium reagents are immediately trapped by a carbonyl compound (Scheme 3). l h 0 0 0 OH Reagents (i) Li, C,,H8(3 md%), THF, -78 "C 4 20 "C; (ii) H20 Scheme 3 Lithiation adjacent to an oxygen atom may be achieved by direct deprotonation with the aid of a carbamate directing group, which serves to simultaneously activate the protons and to direct deprotonation. In the presence of the chiral diamine ( - )-sparteine 12, one of a pair of prochiral protons can be removed with high selectivity (Scheme 41.' This is a remarkable transformation as much for its versatility as well as selectivity.The symmetrical substrate 13 has been converted in a two stage process into the C2-symmetric adduct 1418 and the 340 Contemporary Organic SynthesisReagents (i) Bu'Li; 12, EtzO, -78 "C, 16h; (ii) CH31, -78 "C, 4h Scheme 4 13 R = H 14 R=Me 15 R = H 16 R=CO,Me amine-substituted 15 has been converted into a series of enantiomerically enriched derivatives such as 1 6.1Y In the latter case it is essential that the dibenzyl derivative is employed, since the less hindered Carbamates also make excellent directing groups for deprotonations adjacent to nitrogen24 and, together with for ma mi dine^,^^ dominate the chemistry of such transformations. The two directing groups appear to be in many respects complementary in terms of directing effect and stereochemical control.26 For example, lithiation of formamidine 19 ( n = 1 or 2, Bu'Li, - 20"C, ether) gives predominantly the 2-substituted product 2 1 after addition of an electrophile whilst the same transformation on carbamate 20 ( n = 1 or 2, BusLi, TMEDA, - 78"C, ether, followed by addition of an electrophile) gives the aromatic substitution product 22.26(a) a R m E I p I E o+o t +N 19 R=CH=NBU' 20 R=CO@' 21 22 Trialkyltin/lithium exchange has also been used extensively to generate lithio-anions adjacent to nitrogen.27 The enantiomerically enriched species 23, generated from 24, has been shown to be configurationally stable for at least 45 minutes at - 40"C.27(a) A preparation of lithiated aziridines 25 via trialkyltin/lithium exchange has been reported.28 dimethylamino compound competes with the carbamate for chelation sites and gives products of low 1.1.3 Lithiated aromatic and heteroaromatic groups enantiomeric excess. Apart from the enantio-directing effect, a chiral diamine also serves to maintain configurational stability in the anion.Without this, such anions have been demonstrated to be reasonably stable at low temperatures ( - 78°C) but rapidly epimerize if they are warmed ( - 20°C).20 Amides and are two of the most effective directors of ortho lithiation of aromatic rings when a butyllithium is employed as the base. Whilst the directing ability of amides is largely due to the combination of a strong directing effect and the ability to increase the acidity of the aromatic protons, the ability of the amide to achieve a coplanar geometry is the comparative compounds 26-28, in which the increasingly large ortho-substituent hinders the achievement of coplanarity (Figure ).z9 Whilst all the alkylations of carbamate stabilized retention of configuration, there is conflicting evidence from the results of certain Wittig reactions.21.22 Treatment of 17 with n-butyllithium gives the rearrangement product 18 with 88% stereoselectivity, whilst the diastereoisomer of 17 gives the opposite anions discussed above are Postulated to Proceed with also essential.This factor is clearly demonstrated by of lithiation of the series of diastereoisomer as the major product.2 18 Assuming that the trialkyltin/lithium exchange proceeds with retention the only explanation is predominant inversion of configuration at the lithiated carbon atom.In fact the energy difference between the retention and inversion pathways is small, and highly dependent on the nature of the electrophile; examples of such sensitivity have featured in previous reviews and an example is given in a following section, The related [ 2,3]-Wittig rearrangement22 has been successfully employed in a number of total syntheses of natural products such as raparny~in.~~ C Ph3 A a : n B " n 3 A R A ~ ~ 23 24 25 Compound Relative Rate 26 (R = H) 200 0 R 27 (R=Pr') 17 &- 28 (R = Bu') 9 Figure 1 Relative rate of dithiation An additional advantage of the amide group is that it may be subsequently employed for the creation of further functionality in the molecule, or for intramolecular c y c l i z a t i ~ n s .~ ~ ~ ~ ~ An excellent example Wills: Main group organometallics in synthesis 34 1is provided by a very concise synthesis of a pancratistatin model compound via addition of a functionalized aryl lithium to an unsaturated nitro-compound (Scheme 5).30 Amides bearing homochiral groups have been shown to be capable of generating moderate diastereomeric excesses in addition reactions to aldehyde^.^' H 02N'rl 0 CONEt2 0 CONEt2 OIBDMS OIBDMS I t Reagents (i) Busti, TMEDA, THF, -78 "C, (ii)@02 (iii) AcOH, ( i ) Et3N, EtOH, reflux Scheme 5 Recently, lithiated amides have emerged as suitable bases for aromatic lithiations of suitably activated compounds. Remarkably, competition studies have shown that fluorine is one of the best directing groups in this situation.In contrast it is inferior to many other groups when an alkyl lithium base is employed to create the aryl small change in the nature of the base employed for ortho-lithiation can be dramatic. Reaction of 29 with BunLi alone results in aromatic lithiation whilst, in contrast, deprotonation using BunLi with ButOK (i.e. a 'superbase') gives a benzylically-lithiated anion (Figure 2).33 This result serves to underline the contention that such a combination of alkyl lithium and a metal alkoxide gives a base which is of fundamentally different reactivity to either component and not simply a highly reactive derivative. The effect of an apparently 29 Figure 2, Position of lithiation in a thioether. Intramolecular cyclization reactions of aryl lithiums generated by in situ exchange of a halide for lithium can be powerful synthetic tools.34 This is amply illustrated by the conversion of 30 into 3 1 (Bu'Li, TMEDA, THF, - 78"C, 67%) and subsequently into 32, a potential precursor of the anti-tumour compound taxol and its derivative^.^^(^) The asymmetric addition of l-lithio naphthyl derivatives to appropriately substituted naphthyl acceptors, mediated by the chiral diether 33, has been demonstrated to be capable of giving binaphthyl products with enantiomeric purities of up to 90% e.e.when 1.1 equivalents of 33 are employed (Scheme 6).35 Rather more impressive is the observation that when only 2.5 mol% of diether 33 is used an e.e. of 82% is still generated. 32 F NAr I Li Ar = 2,6(P+)2CeH3 Me0 phAph OMe 33 90% e.e. Reagents: (i) l.leq 33; (ii) H+, H20, toluene, -45 "C Scheme 6 Lithiation of N-phenyl pyrrolidine occurs selectively at the 2-position, as expected.Rather less expected is the observation that the lithiation process involves an initial kinetic preference for formation of a dilithiated intermediate (also lithiated on the phenyl group) followed by a slow eq~ilibrium.~~ Such a process in which one lithiated group directs a second rapid lithiation is not unusual, and an example of a detailed study of a related system will be described in the section on dilithiated anions. The reaction of alkyl lithium bases with aromatic or heterocyclic iodides invariably results in iodine/lithium exchange. If lithium diisopropylamide is used as the base, however, it is possible to lithiate adjacent to iodine.In the case of 34, lithiation is followed by iodine migration to give a more stabilized heteroaryl lithium which subsequently reacts with an electrophile to give substitution products 35.37 the generation of heteroaryl lithium compounds, but the rate of the reactions is generally very high, and Lithium/halide exchange is an effective method for 342 Contemporary Organic Synthesis34 (X=F,CI) 35 (X=F,CI) selective bromide exchanges can be difficult to control. An ingenious example where control is possible is in the lithiation of 36 (a purine building block), the substitution pattern of which permits the three iodines to be distinguished in sequential lithium/iodine exchange processes. The first exchange is of the iodine between the nitrogen atoms and the second involves the iodine proximal to the directing ether A similar sequence has been reported for a tribromo analogue .3 of polar allylic organometallic corn pound^.^^ Cyclopropane synthesis via intramolecular cyclizations of tributyltin-derived benzylically stabilized anions with displacement of a p-toluenesulfonate group has been reported, but the pattern of stereochemical control in such reactions is highly sensitive to the reaction c0nditions.4~ the structure 42 are formally allylic reagents, they react in many ways as localized anions.As for the related structures previously discussed, such anions may be created in enantiomerically pure form using a combination of the chiral diamine base ( - )-sparteine and an alkyl lithium (see Scheme 4).45 One of the most valuable applications of allylic anions 42 are in additions to aldehydes, which are generally most selective after exchange of lithium for a titanium( iv ) deri~ative.~~ If titanium tetrachloride is used, the transmetallation proceeds to give the inversion product 43 and subsequently 44 in 80-90% e.e.after reaction with an aldehyde. An inversion of configuration is also observed in the reaction of homochiral anion 45 with methyl chloroformate (or Although the carbamate-stabilized anions based on carbon dioxide then diazomethane) to give 46.47 (Note that the sparteine ligand has been omitted from all One of the most versatile lithiated heterocyclic terms of applications, is the lithiated thiazole anion 37.40-41 This is a valuable formyl anion equivalent and it has been employed in the synthesis of numerous and One Of the most Prolific in illustrations of chiral anions for reasons of clarity.) R 4 n o F N ? $ , R4*0kNpt2 classes of target compound, including a-amino L i O i i O aldehydes, which may be accessed via addition of 37 (OPr'), to nitrone~.~' 43 42 Me c0,Me v y&q -T"i O Y O O Y O NPi2 OKNP+, NPi2 37 0 46 Finally, in this section, a very short synthesis of the important anti-tumour compound ellipticine 38 has 44 45 been reported in which the key step isthe addition of lithiated indole 39 to the anhydride 40.The addition product 4 1 is formed in 92% yield and the remaining mass balance is accounted for by the unwanted regioisomer. From 4 1, the synthesis of 38 requires only five further steps.42 38 39 Several examples of the synthetic application of Wittig rearrangements of allylic anions have been reported.48 Perhaps the most impressive of these is the contraction of enediyne 47 into 48 following treatment with lithium tetramethylpyrolidine for five minutes at - 25°C.48 I I I I ~ T B S ~ T B S 47 48 0 Asymmetric benzylic lithiations adjacent to tetra- 40 41 hydroisoquinolines may be achieved if a chiral formamidine is employed as the directing group, as in 1.1.4 Benzylic and allylic lithium anions 49.4' Meyers has demonstrated that initial lithiation of 49 removes the a-proton to give 50 which is An excellent review has been published on the preparation and regio- and stereo-control of reactions subsequently alkylated (El isthe electrophile) from the top face (as illustrated) to give 5 1.The second Wills: Main group organometallics in synthesis 343J Me0 51 52 lithiation process gives 52 with the lithium on the lower face again, but alkylation ( E2 is the electrophile) of this anion occurs from the lower face to give 53, with retention of config~ration.~~(~) Although the lithiated species are illustrated with tetrahedral geometry the anion has a significant amount of sp2 character due to benzylic overlap, with the lithium atom predominantly lying on one side due to stabilization by donation from oxygen and nitrogen atoms of the side chain. The sense of alkylation is in each case controlled by steric effects from the chiral formamidine group. central atom is nitrogen have been generated by trialkyltin/lithium exchange and by direct deprotonation and give pyrrolidines 55 upon reaction with appropriately substituted a l k e n e ~ .~ ~ Allylic organo-lithium compounds 54 in which the hi yyT 54 55 1.1.5 Alkenyl and alkynyl anions Lithiation of the position adjacent to the oxygen atom of enol ethers is a relatively facile process which has been employed extensively in synthetic applications. For example, the vinyl lithium 56 (generated using Bu'Li, THF/HMPA, - 78°C) is a key component in a total synthesis of breynolide reported this year by A. B. Smith.s1 The potential for asymmetric synthesis in the addition of such reagents to aldehydes has been realised by the incorporation of a homochiral group as in 57, which reacts with the ketone 58 to give a 4.5 : 1 ratio of diastereoisomeric adducts in which 59 predominates.The nature of the aromatic ring on the ether is critical-reaction of the corresponding anion in which a phenyl has replaced the 2,4,6- trimethylphenyl group with the same ketone gives a 1 : 1 mixture of adducts.52 Both prolinol and diacetone glucose groups have been employed as chiral auxiliaries in related addition reactions of lithiated allenyl ethers.53 56 57 58 50 Lithium/bromineS4 or tributyltin/lithi~rn~~ exchange are reactive processes which allow reactive organometallic reagents to be created in the presence of functional groups that may become subsequently involved in, for example, intramolecular cyclization reactions. Two examples of such applications are provided by the conversion of 60 into 6 1 ( 8 6 O / 0 ) ~ ~ and 62 into 63 ( 8 1 O / 0 ) ~ ~ via intramolecular reactions of a#-unsaturated sulfones and ketones respectively.0 6 S02Ph 60 61 0 OH 62 63 The combination of alkenyl lithium compounds with an ally1 magnesium bromide in the presence of zinc( 11) bromide results in zinc( 11 )-mediated allylation of the vinylic compound. As illustrated in Scheme 7, this is achieved by initially generating, through a chair-like transition state, a dimetallic intermediate which upon quenching with a source of protons gives 344 Contemporary Organic SynthesisL J 1 Reagents (i) ZnBr2, THF; (ii) H30i Scheme 7 the hydrocarbon product (M1 and M2 represent two non-identical metal counter-ions which may be zinc, lithium, or rnagne~ium).~~ This 'mixed-organometallic' chemistry has recently been extended to a synthetic approach to cyclopropane rings5' In this case the starting material, the vinyl lithium reagent 64, contains a methoxymethylether function which acts as a leaving group for cyclopropane formation following the allylation process.The final product, after quenching of the reaction, is the cis-cyclopropane 65. A \n-C,H, L- 64 65 The combination of an alkyl lithium, a tertiary amide, and a terminal alkyne results in the formation of propargylic alcohols in a one-pot process (Scheme 8).58 In this process the reaction of the alkyl lithium with the amide gives a ketone and a lithium amide. The latter deprotonates the terminal alkyne, which subsequently adds to the newly formed ketone. 0 RLi + R 1 4 OH + Ph-CEC-H ---Ph-C3--((Rl R N R22 Scheme 8 1.1.6 Di- and tri-lithiated anions Treatment of amide 66 with two equivalents of BusLi in the presence of ( - )-sparteine 12 ( - 78"C, THF/methyl-t-butyl ether solvent) results in enantioselective benzylic lithiation to give 67.Such a mode of lithiation, in a situation where enolate formation is also possible, is very unusual and underlines the importance of the amide group as a director of lithiati~n.~~ Reaction of 67 with an electrophile gives enantiomerically enriched products 68 (80-94% e.e.) in high yield (77-86%). -0- Li, E O Ph dNHMe Ph -NMe Ph 4NHMe 68 E =TMS, Me, Bun Bn, Ph,C(OH) 66 67 Dilithiation of allylic secondary amines has been shown to be an effective method for the generation of alkenyl lithiums.60 However, like many similar reactions this is very sensitive to the exact solvent conditions.Treatment of 69 with BunLi in ether at - 50 to - 30°C followed by Bu'Li at - 30 to 20°C gives the expected dilithium 70. Should the same reaction be carried out in the presence of a coordinating di- or tri-amine, such as pentamethyl- diethylenetriamine (PMTEDA, 7 1 ), then allylically dilithiated anion 72 is formed.60(a) The nature of the directing group is critical in lithiations of compounds based on the structure 73. Dilithiation (BusLi) of carbamate 73a gives exclusively the benzylically substituted 74 (79% yield after reaction with carbon dioxide) whilst the same transformation of urea 73b gives exclusively the aryl lithium 75 (82% yield after reaction with carbon dioxide). The N-pivaloyl compound gives a mixture of lithiation at both positions.6 Several other reports have appeared describing aromatic lithiations directed by carbamate groups,62 including a very valuable one detailing the relative stabilities of BunLi and Bu'Li in ether and THF solutions.R-YH Y Y 69 (R = Ph, allyl, 70 c- hex) Li RN -Li 0 72 73 a, R = OCMe3 b, R = NM% C, R = CMe3 I I 71 ii- OLi 74 75 76 The reaction of 76 with BunLi has been investigated in great detail by Beak et al. since there is some controversy over the relative rates of lithium/bromine exchange compared to amine deprot~nation.~~ It has been concluded that amide deprotonation is the faster reaction and that this initially gives a complex with several molecules of BunLi, i.e. 77a. This has the effect of producing a very high local concentration of BunLi in the region of the deprotonated amide, and bromine/lithium exchange takes place (to give 77b) within the complex at a rate faster than mixing of the 0 0 77a T7b Wills: Main group organornetallies in synthesis 345BunLi within the reactive solution.The result then is that (theoretically) 50% of the substrate is rapidly dilithiated, whilst the other 50% is not lithiated at all. that at least one aromatic substituent on the ketone is essential for a clean reaction. Providing this is the case, ketals may also be used as substrates for this reduction Some of the species 77 acts to deprotonate unchanged 76. This can be proved by deuterium labelling studies-the use of N-deuterio-77 results in formation of a quantity of 78 in the final reaction mixture.63 & NHMe 78 Aldehydes normally react rapidly with alkyl lithium reagents, but prior treatment with a monolithiated diamine results in the formation of a-amino alkoxides, which are themselves good directing groups for further lithiation.The resulting dianions 79 may be alkylated with a number of electrophiles and are converted back into the parent aldehyde upon w0rkup.6~ This methodology appears to be excellent for alkylation reactions of heterocyclic compounds such as pyridines and fur an^.^^ 79 Dianions localized on adjacent atoms are difficult to make by deprotonation, for obvious reasons. One solution is to stabilize the charge at each location as in 80, which may be prepared by direct deprotonation of the benzylically substituted amide precursor ( BusLi, THF, TMEDA)-note that aryl lithiation is not fav0ured.~5 0% I NAOLi PhALi 80 An attractive, alternative method is the direct reduction of a double bond using lithium metal in the presence of a catalytic amount of a polyaromatic such as naphthalene.In this way aromatic ketones such as 8 1 can be reduced (lithium, 8mol% naphthalene) to dianions 82 which subsequently react with a variety of electrophiles to give adducts 83.66 Addition of such dianions to imines gives a-amino alcohols in good ~ields.6~ The literature coverage suggests, predictably, 0 Ph 81 82 83 E = Me,Et, Pr'CH(OH), PhCH(0H) process.68 A similar reductive dilithiation may be achieved using strained oxygen-containing rings as substrates (three- or four-membered)."Y In this case a carbon-oxygen bond is cleaved, as illustrated by the conversion of epoxide 84 into dianion 85 (a side chain component in a total synthesis) using lithium 4,4'- di( t-buty1)dibenzene ( LDDB).hY(") Reactions of similar dianions with chromium-arene complexes have been used for the synthesis of lactones.6Y(byc) Analogous reductions of aziridines, such as 86, lead to dilithiated species 87, which are useful building blocks for alkaloid synthesis.70 84 85 86 87 The combination of lithium metal with a catalytic amount of naphthalene may also be used for the reductive conversion of chlorides such as 88 into alkyl lithiums 89 (the amide is first deprotonated using n-butyllithi~m).~~?~~ The lithio-anions thus formed may be alkylated with a variety of electrophiles or, as in recent reports, coupled with aryl or vinyl halides7* Finally, in this section, is the report that mono-N-protected amino acids may be tri-lithiated with excess LDA to give highly reactive species such as 90, which have been used as intermediates for the synthesis of a number of functionalized amino acid derivative^.^^ 0 OLi O-LP PhKNH %oyN&o-Li OX+ 88 89 90 1.2 Sodium and potassium The use of a combination of alkyl lithium and potassium alkoxide, or 'superbase' can lead to the formation of highly reactive alkyl potassium reagents.Such reagents have been employed recently in the synthesis of a-santalol, using a displacement of a bromide by an ally1 potassium as the key step74 and, via an epoxide opening by a benzyl potassium reagent, a chiral auxiliary.75 The reductive generation of a benzyl potassium reagent, by treatment of a cyclic aminal with potassium metal, has also been reported (see previous section).76 1.3 Anions stabilized by sulfur, silicon, and other heteroatoms The synthesis of natural products via the addition of sulfur-stabilized anions to a,P-unsaturated carbonyl reagents has been investigated in some depth.A novel 346 Contemporary Organic Synthesisvariation on this is in the 'cascade' reaction of anion 9 1 with 92 to give adduct 93 in one step. Subsequent transformations yield the natural product analogue 94.77 91 92 93 An excellent and comprehensive review has been published describing the scope of carbon-carbon bond forming reactions using lithiated sulfoxides such as 95.7* Such anions have potential for asymmetric synthesis if enantiomerically pure sulfoxides are used and many applications have been reported in previous reviews.Additions to nitrones, in which diastereoisomeric ratios of up to 92 : 8 (in the case of 96) may be realized, have been reported this year.79 Reductive removal of the sulfoxide from the major adduct (after separation) derived from 96, using Raney nickel, furnishes the enantiomerically pure tetrahydro- isoquinoline 97.79 ?" 94 96 he 97 Lithiated sulfones are very versatile reagents for synthesis, and several examples of their application have been reported this They appear to be particularly useful as P-lithio enone equivalents, since the sulfone can be removed by elimination to give the double bond. Reagents 9gxota) and 9980(b) are both equivalents of the synthon 100, and have been used to prepare a$-unsaturated- y-lactones via reactions with aldehydes.Funkx2 has reported a novel method for intramolecular cyclization which relies on a lithiated sulfone. It was found that 10 1, generated by deprotonation (Bu"Li, THF, OOC) gave the cyclized compound 102 upon quenching with iodomethane. Li pT0I!3O2&OBn pTolS02 L O & 98 99 100 101 1 02 The proposed mechanism for this transformation involves the initial formation of anion 103 followed by translithiation to the more stabilized anion 104.82 The process also works for other anion stabilizing groups such as esters and phosphonium salts. OEt 0 Et 103 104 Synthetic applications of a-lithiated-a,P- unsaturated sulfones 105 have also been extensively reported this year.Such reagents often contain a donating group on the P-substituent, as in 106, to improve the configurational stability of the Li R2 phso'Y-7 LF OR 105 106 a-Lithiated organosilanes may be employed as tools for asymmetric synthesis if an appropriate chiral directing group is incorporated into the s u b ~ t r a t e . ~ ~ ~ * ~ Lithiation of 107 (2eq. BusLi) followed by the addition of excess alkyl halide ( R2X = MeI, EtI, ally1 bromide) results in formation of the alkylated derivatives 108 in diastereoisomeric ratios of up to 98 : 2. Subsequent oxidative desilylation (20% H202, MeOH, THF, KF, KHCO,) then gives propargylic alcohols 109 in up to 97% enantiomeric excess.g4 Studies of the configurational stability of such compounds have been reported.g5 Synthetic applications of trialkyl-stabilized allylic reagents have been reported, including additions to ketonesg6 and to activated naphthyl systems.g7 R2 R' /b 109 Arylselenyl-stabilized organo-lithium compounds have been employed in a small number of transformations and are generally prepared by reaction of the gem-diselenated precursors with an n-butyl-lithium.g8 Configurational stability studies have been reported.88(c) Ally1 lithiums substituted by chiral phosphorus groups may be employed in asymmetric Wittig reactions of 4-monosubstituted cyclohexanonesxY and in asymmetric Michael addition reactions.yo The Wills: Main group organometallics in synthesis 347addition reaction of 110 with cyclic /3-methyl enones gives adducts of up to 90% diastereoisomeric excess (n = 1 or 2; only two out of a possible four products are formed) in which 11 1 predominates.9o 0 110 111 Lithiated trialkylboranes are relatively rare in synthesis.Recently, however, a large number of papers have been published by Pelter’s group describing the synthesis, structural properties, and reactivity of the lithiated boranes of general structure 1 1 2.y’ (Mes),BCH,Li 112 2 Group2 2.1 Magnesium Magnesium activated by association with aromatic compounds has been used to good effect in the preparation of other finely divided metals.y* The reaction of activated magnesium (‘Reike’ magnesium) with 1,3-dienes results in cycloaddition to magnesium- containing five-membered organometallics ( 1 13). Subsequent reaction with a n-C,-alkyl ( x = 3, dibromide gives spirocyclic products 1 14.93 4, dr 5) 113 114 A related transformation is the conversion of 1,6-dienes into trans-di-Grignard reagents using a combination of butylmagnesium bromide and catalysis by a zirconium complex (Scheme 9).94 This is only one example of a large number of zirconium-catalysed transformations of Grignard reagents reported in recent years.Q 115 * 117 116 The nickel-catalysed reaction of methyl magnesium bromide with dithianes such as 118 results in the formation of the alkene 1 19.y6 Conversely, the same reaction with a substrate bearing a double bond adjacent to the dithiane, such as 120, results in formation of the gem-dimethyl adduct 12 1 .97(a) Transmetallation to the zinc reagent has been reported to give a cleaner reaction in a similar proce~s.”~(~) 118 119 120 121 Asymmetric catalysis of the addition of Grignard reagents to aldehydes, to give products of up to 75% e.e., has been achieved with the use of the chiral diamine ligand 1 22.98 Slightly higher e.e.s have been obtained in the asymmetric catalysis of the Michael addition of Grignard reagents to cyclic enones mediated by the chiral catalyst 123 (Scheme 1 O).99 123 .R n= 1 1 6 4 7 % e.e.n = 2 60 - 72% 8.8. n = 3 53-87%e.e. Reagents: (i) WBr, 5 md% 123, -78 “C Scheme 10 Reagents: ( i ) 3-4eq. Bu”MgBr, Cp2ZrC12(!5-10 mol%); (ii) H30+ Scheme 9 The reaction of 2,5-dihydrofuran 115 with ethyl magnesium bromide mediated by 10 molo/o of homochiral zirconium complex 116 gives the ring-opened adduct 11 7 in 65% yield and > 97% e.e.”5 Mixed sulfur/nitrogen donor ligands based on the chiral oxazole system are ideal for this application because of the combination of an excellent copper ligand (sulfur) and a stereochemically well-defined asymmetric environment, More applications of such ligands in asymmetric Michael additions are certain to be reported in the near future. 348 Contemporary Organic SynthesisThe addition of Grignard reagents to pyridinium salts 124 bearing a chiral group on the carbamate has proved to be a highly versatile and valuable synthetic process for the asymmetric synthesis of alkaloids.loO The bulky trialkylsilyl group in 124 assists in the control of the regioselectivity of the addition and high diastereoselectivities have been observed in the addition products.lo0 Adduct 125 has been converted into ( - )-pumiliotoxin C,lOO(a) adduct 126 into ( + )-myrtine 128,100(b) and adduct 127 has been elaborated to the intramolecular Diels-Alder precursor 129 and subsequently the lycopodine alkaloid skeletal molecule 130.100(c) OMe 124 128 R'?bc' R2 132 Corey has used allyl bariums to good effect in the synthesis of open chain precursors for cyclization to steroids (Scheme 1 1).Io3 F O T B D P S Br ' I (OTBDPS 0 Scheme 11 125 R = CH2CH2CH2CHCH2 126 R = CHZCH2CH2CHzCI 127 R = (CH2)40CHCH30CH2Me 129 130 Whilst the majority of Grignard reagents add to 124 to give adducts of the absolute configuration shown in 125.A triphenylsilyl Grignard reagent gives the product of opposite configuration 13 1, for reasons that are not fully understood.loo(d) 131 2.2 Barium Allyl barium reagents 132 are presently the subject of significant interest from the synthetic community.101~102 Prepared by the reaction of barium metal with allyl chloride, these reagents show a high selectivity for alkylation at the less substituted terminus.This is in contrast to the reactivity of most other allyl metals, such as magnesium reagents. Compatible electrophiles include carbon dioxide101 and allylic bromides.lo2 2.3 Zinc, cadmium, and mercury The chemistry of the versatile reducing agent zinc borohydride has been reviewed. lo4 Intramolecular cycloadditions of non-stabilized alkyl zinc reagents onto unactivated double bonds have been found to proceed in a manner analogous to the alkyl lithium compounds 5,7, and 9 described at the start of this review, with a preference for the 5-endo-tet mode of cycli~ation.~~~ be a useful reagent for certain transformations.106 In the selective lithiumlbromine exchange of the 1,l-dibromoalkenes 134, for example, 133 exhibits a much higher selectivity for exchange of the halide cis-to the larger group, to give 135, than n-butyl-lithium alone.This may be due to the higher level of relief of steric interactions in lengthening and breaking of this C-Br bond than that cis-to the small group. Allyl zincs may be prepared by alkyl lithium deprotonation followed by transmetallation with a source of Zn", as in the case of 136.107 Subsequent reactions of 136 with aldehydes are rather more selective than the parent allyl lithium reagents. The direct reduction of allyl bromides or allyl ethers with an activated source of zinc also provides an attractive method for allyl zinc synthesis.1o8 Reactions of thus derived allyl zinc reagents with aldehydes and ketones are valuable reactions, which have been used extensively in synthesis.lo8 Rather more interesting is the reported cycloaddition of this class of organometallic with trialkylsilyl substituted acetylenes.In this sequence the synthesis of a five-membered carbocycle is completed by a palladium-catalysed cyclization of the initially formed alkenyl zinc (Scheme Alkenyl zinc reagents have been used extensively in palladium-catalysed coupling reactions with aryl- and The mixed lithium/zinc reagent 133 has proved to 12).'09 Wills: Main group organometallics in synthesis 349Bu",ZnLi RLHBr Rs Br 133 RL = Large group R' = Small group 134 R' OR^ 135 136 Me3Sik /I3 + Me3SifC-R3 - (i) B r Z n 2 R 1 I ZnBr 137 130 139 Reagents: (i) Ligand Scheme 13 140 Reagents: (i) THF, 100 "C, 30h; (ii) Pd(PPh3), (510%) 24h 65 "C Scheme 12 vinyl-halides.l10 However, a note of caution was expressed in a recent report that the in situ rearrangement of 137 to the ally1 zinc 138 occurred in the presence of a Lewis acid catalyst.'ll Although this rearrangement was not observed in a nickel(I1)- catalysed coupling process, it may be a source of unwanted side-products in some cases.Palladium- catalysed coupling reactions of the a-amino-acid derived organozinc reagents 139 with P-bromoenones,l12 acyl chlorides,l13 and heteroaromatic iodides have been reported recently.' l 4 It is a remarkable feature of zinc organometallics that reagents which contain both a reactive carbon-metal bond and a source of reasonably acidic protons may be prepared and manipulated with such ease, and this underlines their synthetic importance.The Knochel group has reported extensively the results of its studies on the synthesis and applications of organozinc reagents functionalized with esters, amides, ethers, sulfides, and halides.ll5>ll6 Most of the work has been summarized in an excellent review.I The majority of applications developed by Knochel have involved the prior conversion of the zinc reagent to a mixed copper/zinc species, thus providing an entry to functionalized cuprate compounds.l17 A detailed comparison of analogous zinc and copper reagents has been reported.l18 Few would argue, if the number of related publications is taken as a measure of the level of interest, that the single most important development in organozinc chemistry has been the asymmetric catalysis of their addition to carbonyl groups (Scheme 13).'19 Although most commonly reported for the case of diethylzinc, more functionalized organozincs have been employed, some of which will be discussed later in this section.The breakthrough in terms of asymmetric induction in this reaction was achieved using the conformationally restricted amino alcohol DAIB (140) and was reported some years ago by Noyori. Since this report, several new amino alcohols have been screened as catalysts. The structures and maximum asymmetric inductions for the reaction in Scheme 13, for these and other catalysts, are shown in Figure 3, along with the appropriate reference source.Many of the compounds are obvious structures which derive from ( - )-DAIB. Organometallic reagents such as 142 and 143 have been very successful in terms of asymmetric induction, and some effective nitrogen heterocycle derivatives, such as 144- 146, have been investigated. Sulfoxide and sulfoximine catalysts 148 and 149 have not proved to be as effective as might have been expected. The N-protected ephedrine derivatives 150 and 15 1 appear to be promising reagents, since they are readily available and give high e.e.s in the addition reaction. Most recently a class of C2-symmetric titanium( iv ) complexes, represented by 152 and 153, have emerged and are rapidly gaining momentum in terms of their level of synthetic application.beyond the use of simple dialkyl zincs has lagged somewhat behind the rate at which new ligands have been screened. A study of the use of N,N-diallyl-( - )- ephedrine as a catalyst for the addition of a zinc( 11) enolate to acetophenone failed to give an e.e. in excess of 74'/0.'~~ On the other hand an induction of 99% e.e. was achieved for the addition of a simple dialkyl zinc to ferrocenal using (S)-154 as the ligand.134 For the addition of functionalized (remote ethers and esters) zinc reagents to aldehydes, Knochel has found that best results are obtained with the newer titanium(1v )-based complexes based on 1 5 2 F In contrast, Oppolzer has found that the original aminoalcohol DAIB (140) was the catalyst of choice for the impressive intramolecular cyclization of 155 to 156, a precursor of the perfume ingredient ( R)-muscone.136 This inconsistency serves to underscore the need for studies of the mechanism of this important asymmetric reaction, rather than continued empirical studies.The related addition reaction to imines, to give chiral arnines, has been achieved via addition to the Extension of the asymmetric addition methodology 350 Contemporary Organic Synthesis&Ph Ph H OH 141 100% e.e.) OH 145124(67% e.e.) %Me HO NMe, 14212'(>99% e.e.) 143'=(87% e.e.) AoH 144'23(82% e.e.) ?- OH I I I I ph*-Pfph Ph jR YPh pTol 0S++R 146lS(98% e.e.) 147'28(35% e.e.) 14812'(55% e.e.) Ph Ph Me, Ph (-J$(0Pi)2 XI$ H > i ( o ~ i ) ~ S02C F3 Ph Ph 1 *Ht S02C F3 0 NH OH H O q e HN, ,OMe 2 4 p h Ph l,OMe pTolSOzNH OH.Ti(OPr')4 Ph' S 15213'(99% e.e.) 1 53'32(98% e.e.) 14912a(88% e.e.) 150'=(95% e.e.) 151130(97% e.e.) Figure 3 Catalysts for diethyl zinc addition to benzaldehyde with 8.8.obtained and reference diphenylphosphonyl protected imine 15 7. Here asymmetric inductions in excess of 90% have been obtained in the product 158 using the ephedrine-derived catalyst 159.137 The protecting group can be removed after the reaction by treatment with mild aqueous acid. diethylzinc with enones gave products of e.e.s greater than 95% when the polymer supported nickel catalyst 160 was employed (Scheme 14).138 Given the level of recent activity in carbonyl addition chemistry, it is likely that this preliminary observation will be followed in the near future by the screening of various chiral nickel( acac) complexes for improved asymmetric induction, versatility, and reactivity.cadmium reagents has been reported. Additions of these reagents to aldehydes were also described.139 intramolecular cyclization reactions have been employed in the synthesis of functionalized tetra hydro fur an^,'^^' pyrrolidine rings,141 and cyclic peroxides.14* In certain cases, mercuration can lead to ring expansion if no cyclization pathway is available. 143 Organomercury( 11) compounds have been employed in palladium-catalysed coupling reactions with allylic substrates144 and allyl mercury compounds have been employed in substitution reactions with acyl chlorides.14s On a slightly different subject, the reaction of A Barbier-type procedure for the synthesis of allyl P henylmercuric chloride mediated stereoselective 3 Group 13 3.1 Boron 3.1.1 Alkyl boranes The steroechemistry of enol boration of ketones is remarkably sensitive to the nature of the borating 157 158 (>90% e.e) 159 160 8.8.up to 95% Reagents (i) 160 (5-1 0 moPh), Et2Zn, hexane. Scheme 14 agent. In a series of in-depth studies, Brown has found that in the case of formation of the di( cyclohexy1)boron enolate of propiophenone the combination of dialkylboron chloride and triethylamine gives predominantly the E-enolate 16 1, whilst the use of the Wills: Main group orgunometullics in synthesis 351dialkyl iodide or triflate favours formation of the 2-enolate 162.146 In many cases the selectivity can exceed 97 : 3.An attempt has been made to rationalize this effect with the aid of molecular modelling.147 OB(c-hex), OB(c-hex), Fph 4 P h 161 162 The importance of boron enolates as tools for stereoselective synthesis has been underlined by the publication of a number of total and partial synthesis such as that of bafilomycin A, reported by Evans,148 and rapamicin14' and ( + )-m~amvatin'~~ (163) reported by Paterson. The synthesis of 163, a marine polypropionate, involved several aldol reactions of chiral boron enolates and was completed by an impressive cyclization from the open-chain precursor under conditions of mild catalysis.150 A series of molecular modelling studies on such aldol reactions have been reported.lS1 163 Chloromethylboranes 164 are useful intermediates for synthesis because nucleophilic substitutions may be achieved using a variety of nucleophiles to give the derivatives 165.Such reactions take place via initial addition of the nucleophile to boron, followed by a migration.lS2 The order of addition may be reversed; addition of chloromethyllithium to 166 gives the allyl borane 167, and subsequently 168 upon oxidative hydr01ysis.l~~ Related methodology has been applied to the synthesis of a$-unsaturated esters,lS4 a-aminoboronic acids, and the beetle pheromone stegobiol, in which all of the four chiral centres were created via chloromethylborane intermediates.1ss 164 165 166 167 160 3.1.2 Allyl, allenic, and alkenyl boranes Like boron enolates, allylic boranes are well established reagents for asymmetric and stereoselective synthesis, offering almost unparalleled control over relative and absolute steroechemistry in the creation of at least two new chiral centres in addition reactions to aldehydes.Probably the most commonly used chiral allyl boranes are derivatives of the diisopinocampheylborane, (Ipc),B, system, as typified by 169.156-15s The reactions of two classes of heteroatom substituted derivatives serve to illustrate the synthetic scope and sense of the selectivity in additions to aldehydes. Addition of 169a to an aldehyde gives the product 170, of syn-stereochemistry,lS7 whilst the same reaction of 169b gives the anti-product 171.158 169 a, X = H, Y = OSEM 170 b, X = NMe2, Y = H 171 Additions to propargylic aldehydes are generally less selective than most other aldehydes or ketones.This situation can be remedied, however, by complexation of the alkyne to dicobalt-hexacarbonyl prior to the addition reaction.lSY The alternative chiral allyl boranes of choice are B-allylbis( 2-isocarany1)- boranes 172, which have been applied in a small number of papers.16* In some cases these reagents give improved stereochemical control compared to the (Ipc)*B reagents. Another class of promising reagents are boronic esters derived from C2 symmetric alcohols, generally tartrate derivatives, based on the structure 173.161,1h2 In terms of relative stereochemistry these compounds add to aldehydes to give analogous products to those derived from dialkyl boranes, but additionally generate asymmetric inductions routinely in excess of 90°/0, in a predictable sense.Of particular note is the application of 173b to a key step in the synthesis of an erythronolide analogue.162 1 72 173 a, E = COzP~'sl b. E = c-hexls2 Related reagents are the allenyl boranes 174, which act as propargylic anion donors, furnishing products 175 upon reaction with an palladium-catalysed asymmetric synthesis of allenyl boranes may be achieved using the mixed phosphorus/oxygen donor ligand 176 to mediate the reaction of catecholborane with an enyne substrate. Addition of the resultant enantiomerically enriched boranes to ketones gives addition products in up to 6 1% e.e. (Scheme 1 5).Ih4 4-borated cyclohexenes. In a detailed comparative study of the structural requirements of the borane component it was found that whilst trivinylborane was the most reactive, borane 177a was the most The Cycloadditions of alkenyl boranes with dienes gives 352 Contemporary Organic Synthesisused in the catalyst is critical. Tiiphenylphosphine can in some cases transfer a phenyl group, in which event R2BT\* YR 3- the use of tri( 2-methoxyphenyl)phosphine, which has OH P P ~ z less tendency to do this, is recomrnended.l7l \\ 174 a, R2B= a : B 175 b, bB=B-BBN 1 76 3.1.3 Hydroboration and carbon reduction by boranes R H I w R M e Ph+ OH 61% 8.8.Reagents (i) Cat. 176, Pd(dba)2, CH2C12; (ii)PhCHO Scheme 15 regioselective and 178 was the most stable and endo-selective in reactions with cyc10pentadiene.I~~ A Asymmetric hydroboration of alkenes by (Ipc),BH 184 continues to find synthetic applications.Recent examples include the asymmetric synthesis of a-amino alcohols by the reaction of 184 with enamine~'~~ and the preparation of enantiomerically pure enones 185 by hydroboration of but-2-ene followed by a sequence of reactions featuring a combined carbonylation/alkylation elimination sequence from a borane complex.173 Alkene hydroboration can be catalysed by rhodium and ruthenium complexes, which provides an obvious potential for asymmetric catalysis.'74 Although many of the popular diphosphines have been screened they only give moderate results, but this potential has been realized by the use of the mixed nitrogen/phosphorus donor ligand 186, which is capable of generating enantiomeric excesses of up to 94% in the reaction of styrene with catecholborane (Scheme 16).175 sterically-driven regioselectivity can be overriden in some cases by electronic factors.Cycloaddition of 177b with 179 gives mainly 180 after oxidation, whilst the bromo-substituted borane 18 1 reacts to give exclusively the opposite regioisomer 182 in the same sequence.Ih6 Similar cycloadditions of alkynyl silanes reactions between 1,3-dienes substituted at the (&* PPhz with dienes have been reported,'67 as have the 184 185 / 0 2-position with a boronic ester ( 183) and 186 electron-poor alkenes.lh8 177a, R = H b, R=Me up to 94% e.e Ar = Ph, 69%, 88% 8.8 Ar = pMeOCsH4, !3%, 94% e.e 1 78 Reagents: ( i ) Rh complex, 195, (ii) H202/HO- Scheme 16 For the asymmetric reduction of carbonyl groups, B-chlorodiisopinocampheyl borane (DIP-Cl) 18 7 is a 179 180 181 superior reagent to the-more established hydride analogue in terms of reactivity and selectivity.Asymmetric inductions of > 98% may be routinely obtained with this reagent.176 Chiral boronic esters are capable of directing the asymmetric reductions of carbonyl groups three177 or fourI7* carbon atoms of 188 gives 189, a precursor of chiral tetrahydrofurans, in 93% e.e. and 97% yield after oxidation.178 The combination of a stereoselective carbonyl reduction followed by an intramolecular hydroboration of the intermediate boronic ester provides a means for the creation of two new chiral alcohols in a single synthetic m O H +)' 1 182 183 distant, using borane as the reducing agent.Reduction Vinyl- and aryl-boranes and boronic acids make excellent substrates for palladium-catalysed coupling reactions with aryl-( viny1)triflates or halides.169 Recently this process has been applied to a very concise synthesis of i b ~ p r 0 f e n . l ~ ~ However, a note of caution-the nature of the triarylphosphine ligand Wills: Muin group orgunometullics in synthesis 3531 87 188 189 r Chiral oxazaborolidines have proved to be excellent catalysts for the asymmetric reductions of ketones, and two excellent reviews have been published recently on the subject which serve to summarize much of the recent research.lsO A number of reports have appeared describing new methods for the proline-derived catalyst 190, which has been developed and used extensively by Corey.lsl Corey himself has reported a method for the in situ formation of this compound from the amino alcohol precursor and alkylbis- (2,2,2-trifluoroethoxy)borane which allows ketone reductions to be undertaken directly and with equal asymmetric inductions, as are obtained when isolated 190 is employed.lX2 A group of Merck chemists have also invested a great deal of effort in this area and have found that whilst 190 is a rather labile material, the borane complex 19 1 is a relatively stable, free-flowing material for which an X-ray crystal structure determination has been obtained.lX3 The Merck team have also employed 190 in a range of synthetic applications and have investigated the means by which enantioselectivity is generated.ls4 One intriguing observation is that the addition of triethylamine to the reduction medium results in an increase in the enantioselectivity of the Although these studies concentrated on the stoichiometric reduction (using 19 1 ), in the case of acetophenone the enantioselectivity improved from 96% to 99.2% e.e.$oLh $oLh NIB' Y'B' Me Me H3B 190 191 Perhaps the most remarkable development in this area is contained in the report that, at elevated temperature ( 1 10°C), catalytic quantities of prolinol are capable of generation of e.e.s in excess of 95% for acetophenone reduction by borane, presumably via intermediacy of the oxazaborolidine 192.1g6 At low temperatures the enantioselectivity is much lower (8-59% e.e.), in contrast to 190. A possible explanation is provided by the observation that at low temperature 193 dimerizes to the non-catalytic species 194, a process that is reversed at high ternperature~.'~~ If this is the case with 192 then this may help to explain the temperature dependence.This is a very important observation, since the two phenyl groups in 190 are considered to be important contributors to the enantioselectivity of the reduction4 may be that they simply increase the bulk of the oxazaborolidine and prevent an unproductive dimerization. Ketones which contain heterocycles with donor groups are generally good substrates for asymmetric reduction, although an excess of borane may be required in certain cases due to complexation with the he teroatoms. ** Reduction of tric hloromet hyl ketones gives products of high enantiopurity which may be subsequently converted into a-hydroxy or a-amino acids.189 Novel classes of catalysts for asymmetric borane reduction of ketones include the amino alcohols l95l9O and 196,19' which are capable of generating eves of 94% and > 99% respectively, the sulfoximine 1971g2 and the phosphinamide 198.lY3 Ph 193 196 Ph, Ph Me- N d k N Me2N OH P h ~ o - ~ - o l ~ e H2 Me Me 1 94 195 NH OH P h - - - : A p h Ph ,!Ph2 O" Ph H 197 198 3.1.4 Borane catalysts The borane complex 199, formed between a tartrate derivative and borane, has been used for the asymmetric catalysis of Diels-Alder reactions,lY4 the reactions of trialkyltin ally1 reagents with a1dehydes,ly5 and aldol reactions of trimethylsilyl enol ethers.196 The enantiomerically pure BINOL-derived reagent 200 has been used for asymmetric catalysis of hetero Diels-Alder reactions1y7 and the additions of trimethylsilyl enol ethers to imines.198 The tryptophan derived borane complex 201, and related reagents, have been used for the catalysis of Diels-A1derJy9 and aldol reactions.200 &, C02H 192 199 200 354 Contemporary Organic SynthesispTolSOpN, ,O 7 BU" 20 1 3.2 Aluminium and thallium The use of chiral ligands for the modification of lithium aluminium hydride can lead to the generation of highly selective carbonyl reduction catalysts.20 Whilst this is by no means a new concept, a novel application of the R-BINAL hydride reagent 202 is in the selective reduction of one carbonyl group of the C2-symmetric anhydride 203 into 204 (up to 90% e.e.), a precursor of biotin analogues.202 0 - 202 203 204 Stereoselective cleavage of chiral cyclic acetals by alkyl aluminium reagents has been the subject of a considerable amount of synthetic interest.Recently, the use of perfluoroalkoxy substituted aluminium reagents for this process has been shown to be capable of generating higher levels of stereoselectivity than the simple trialkylaluminium compounds.203 The zirconium-catalysed addition of trimethylaluminium to terminal alkynes, to give terminal alkenes, proceeds at a much faster rate, and at lower temperatures, in the presence of an equivalent of water than under dry conditions.204 The chiral aluminium complexes 205205 and 20620h have been employed to good effect in the asymmetric catalysis of Diels-Alder reactions.The reaction of one equivalent of a nucleophile to one equivalent of a straight-chain and a branched-chain aldehyde in the presence of the aluminium alkoxide complex 207 results in predominant addition to the latter.207 This is believed to be due to the preferential complexation of the smaller aldehyde to the aluminium complex, which serves to sterically 'protect' the carbonyl group as illustrated in Figure 4. Synthetic applications of the related aluminium ( III) complex 208, mainly for the catalysis of cycloaddition reactions, have also been described.20x Figure 4 208 The level of synthetic interest in thallium reagents is declining, possibly as a consequence of their known high toxicity, and recent reported applications of these organometals are as catalysts.Grigg has reported that the intramolecular cyclization of aryl palladiums onto double bonds gives much higher yields in the presence of thallium acetate (86% compared to 15% under a typical set of reaction conditions).209 4 Group14 4.1 Silicon The importance of the cation-stabilizing effect (the '/?-effect') of chloroalkylsilyl groups compared to trialkylsilyl groups has been reviewed,210 as have the synthetic applications of trialkylsilyl substituted dienes211 and the use of silyl protecting groups for alcohols.212 4.1.1 Allyl, benzyl, and alkenyl silanes and their derivatives A method for the synthesis of enantiomerically enriched (90-98% e.e.) allyl silanes via a Wittig reaction of a-trialkylsilylaldehydes of similar enantiomeric purity has been reported.213 Fleming has reported the synthesis of allyl silanes 209 of greater than 99.9% e.e.and greater than 99.95% geometric purity using a chiral auxiliary directed Trichloroallylsilanes have been reported to be as good, if not superior, sources of anionic allyl groups to trialkylallyl silanes in terms of yields and addition stereoselectivity.21s The alkoxide formed by deprotonation of the hydroxy group in 2 10 can form a 205 207 209 21 0 Wills: Main group organornetallies in synthesk 355bond to the silyl group, giving a hypervalent reagent which is activated towards allyl transfer to electrophiles under mild conditions.216 iminium cations has been used to great effect in the total synthesis of alkaloid^.^'^-^^' Treatment of 2 11 with iron(n1) chloride results in cyclization to 2 12, a key step in the synthesis of sarain A in 6 1% yield.217 The intramolecular cyclization of allylic silanes with I TMS 21 1 /\Ph H 21 2 Even more remarkable is the reaction between 2 13 and 2 14 to give the major cyclized product 2 15, a precursor of ( - )-morphine, in 82% yield (a 20 : 1 mixture of diastereoisomers is formed).,CHO TBDPSN m - Reagents: (i) TCI,, CH,C12, -78 "C Scheme 17 Alkenyl silanes may be prepared by the reaction of terminal acetylenes with triethyl~ilane.~~~ This reaction is remarkably sensitive to the reaction conditions. Using [Rh(cod)Cl,] as the catalyst in ethanol/DMF solvent the major product is the Z-isomer whilst use of the same catalyst in the presence of added triphenylphosphine in acetonitrile favours formation of the E-isomer.Intramolecular reactions of alkenylsilanes are very valuable in ~ y n t h e s i s . ~ ~ ~ - ~ ~ ~ Treatment of 220 with ethylaluminium dichloride gives the seven-membered ether 22 1,224 whilst treatment of 222 with a source of acid results in cyclization to the alkaloid precursor 223.225 Lewis acid catalysed additions of allenyl silanes to aldehydes have been described,227 as have subsitution reactions of alkynyl silanes with glycosides.228 mT"" 'R2 21 4 21 5 TMS 21 3 le The cyclization presumably takes place via a transition state similar to 216.218 A remarkable series of cyclization reactions converts a mixture of the allyl silane 2 17 and silyl en01 ether 2 18 into 2 19 (n = 1,2) N A N 0n 222 under conditions of mild Lewis acid catalysis.220 R fl 'Me Bn 223 Ph, / H <@ TBDMS 4.1.2 Other classes of organosilyl reagent The synthesis and addition chemistry of the unusual but remarkably stable formylsilane 224 has been described.229 In the previous section the example of a trialkylsilyl-migration mediated cycloaddition was 21 6 21 7 21 0 described.Similar processes operate in the conversion of 225 into 226 (DEAD, PPh,)230 and the reaction of a$-unsaturated acyl-silane 2 2 7 with an enolate (of RCOCH,) to give 228.2313232 c0,Me oHcG7;h @OTMS WQ 0 21 Q Remaining with the theme of cyclization reactions, 225 OSiR, there have been a number of reports of the addition of allyl silanes to enones, which involves subsequent silyl migration appear to be and quite ring wide closure in scope (Scheme and 1 stereoselective, 7).22 Reactions fSiR3 6 with a preference for formation of the trans- product.been reported.222 220 R R OH 227 A related transformation of propargylic silanes has Ph 22s 356 Contemporary Organic SynthesisSilicon-based groups make excellent tethering groups for intramolecular Diels-Alder reactions233 and intramolecular radical cyclization~~~~ due to their ease of removal or potential for conversion into other functional groups after use. Several examples of applications have been reported recently. Asymmetric catalysis of hydrosilylation reactions is an area which has lagged behind the related subject of asymmetric hydrogenations, for reasons that are not readily obvious, since both reactions have a similar range of potential applications. Polydentate oxazoline ligands such as 229235 and 230236 have proved to be valuable ligands for the reduction of carbonyl groups (Scheme 1 S), and have been reported in previous reviews; a novel ligand for this application, however, is the C2 symmetric phosphorus donor 231, reported by Seeba~h.~~' The homochiral titanium complex 116 229 230 231 OH 0).Oi) PhK Me P h h M e 0 229 (90% e.e.) 230 (94% e.e.) 231 (97% e.e.) Reagents: (i) catalyst 229,230, or 231 ; (ii) H30+, Ph2SH2 Scheme 18 (see section on magnesium chemistry) is an excellent catalyst for the asymmetric hydrosilylation of imines, although the best results are obtained using cyclic imine substrates.238 The mixed oxygen/phosphorus ligand 176, which has already been described, has been employed in the asymmetric hydrosilylation of alkenes such as 232 (silyl trichloride, palladium catalyst) to give 233 in 96% e.e.after oxidation.239 Intramolecular hydrosilylation reactions of carbon- carbon double bonds have been used in the stereoselective synthesis of di01s.~~" 232 233 4.2 Tin Tributyltin compounds can act as nucleophiles in reactions with powerful electrophiles. This property has been employed for the phenylselenyl cation promoted intramolecular cyclization reactions241 and for stereoselective opening of chiral cyclic a m i n a l ~ . ~ ~ ~ Appropriately-located donor groups can activate nucleophilic transfers from the resultant hypervalent tin complex. The tin hydride 234 shows an improved reducing ability243 and 235 is highly activated towards transfer of an alkyl group in palladium-catalysed coupling reactions with aryl bromides244 as a result of such effects. 234 235 Alkenyl stannanes are important synthetic reagents which may be prepared by hydrostannylation of alkynes in a reaction which may be catalysed by zirconium (for Z-vinyl stannanes) or palladium complexes.245 E-Alkenyl stannanes 236 may be prepared by the chromium dichloride mediated reaction of 237 with aldehydes.246 a$-Unsaturated y-lactones substituted at the a- or B-position by tributyltin groups have been prepared by a regiospecific exchange reaction with thiophenyl precursors.247 Vinyl tributyltin compounds formed in this way have been applied to an asymmetric synthesis of allenes 238, via elimination from the homochiral alcohol 239.248 Alkenyl tin compounds are more widely employed in palladium-catalysed coupling reactions than any other single process.249 The Br 237 236 OH H 238 239 intramolecular variant of this process has been employed to good effect in the synthesis of macrocyclic natural products250 of which perhaps the most impressive is the concluding sequence of a synthesis of rapamycin 240.251 Cyclization is achieved using 1,2-distannane 24 1, which provides the central double bond in the triene, via coupling to the corresponding bis-vinyl iodide.The role of Lewis acids in the reactions of ally1 tin compounds with electrophiles such as aldehydes and ketones (Scheme 19) has been reviewed.252 Using lanthanide catalysts or acid catalysis these reactions can be performed in aqueous media.253 Wills: Main group organornetallies in synthesis 357R OMOM % 1 240 Reagents: (i) Lewis acid Scheme 19 An investigation of perchlorate salts has revealed that the cations (Li, Mg, Ca, etc.) often do not act as Lewis acids but assist the reaction by mediating development of the six-membered transition states.2s4 High pressures (up to 800 kbar!) are reported to be capable of accelerating this class of reaction.2ss A chiral titanium(1v 1 catalyst 242 derived from enantiomerically pure BINOL has been employed for the asymmetric catalysis of the reaction, giving products with e.e.s of up to 99'/0.~~' Rather unexpectedly it was found that the addition of a trace of triflic or trifluoroacetic acid improves the enantioselec tivity sharply. 242 y-Alkoxyallylstannanes 243, the 2-isomers of which may be simply prepared by isomerization of the a-alkoxyallyl precursors, have been employed in the total syntheses of complex target molecules such as the alkaloid diepicastanospermine (using 243, R = H)257 and the marine sponge metabolite bergamide E (using 243, R = iso-propyl).2sX Reaction of ally1 stannanes 244 with aldehydes using tin tetrachloride as catalyst essentially gives exclusively the adduc t 2 4 5, presumably a result of tin( 1v ) exchange to intermediate 246, which is stabilized by the donation from the adjacent alkoxy group.2s9 Bun3Sn Ad 243 Bun3Sn-OR 1 224 I CI,Sn-OR Ph L O R I d I 245 246 Under conditions of titanium tetrachloride catalysis, trialkyl lead reagents will transfer alkyl groups to aldehydes.2h0 Aryl lead triacetates have been employed as aryl transfer reagents in reactions with nucleophiles.2h 5 Group 15 5.1 Phosphorus The use of borane as a protecting group to prevent oxidation of phosphines is an established method.262 A recent paper has described the in situ removal of the borane from a chiral diphosphine ligand which circumvents the need to isolate the pho~phine.~'~ A new method for the synthesis of mixed phosphorus/heteroatom donor ligands involves the reaction of potassium diphenylphosphide with o-substituted aryl fluorides.264 Cycloaddition reactions mediated by diphenylphosphinyl radicals have been described.265 generally give 2-alkenes.In contrast, ylids derived from the reagent 9-phenylphosphabicyclo [4.2.1] nonane 247 show a strong preference for the formation of E-alkenes.266 Better 2-selectivity is achieved in the reaction of the stabilized ylid 248 with aldehydes than is obtained using the triphenyl- phosphine analogue^.^' Wittig reactions of non-stabilized phosphorus ylids 247 H 248 Enantiomerically pure phosphorus reagents based on the structure 249 have been used as chiral auxiliaries for the stereoselective alkylation of attached enolates ( 249a)2h8 and the reduction of attached /3-carbonyl groups ( 249b).269 The alcohols derived from the latter reaction have been converted into stereochemically pure alkenes via a phosphonate elimination.: =;? 249 a, R = COCH2Me b, R=CH,COR 358 Contemporary Organic Synthesis5.2 Arsenic, antimony, and bismuth The addition of triphenyl-arsenic, -antimony, or -bismuth to the titanium tetrachloride catalysed reaction of cyclopentadiene with a chiral acrylate (dichloromethane, - 78°C) reduces the level of polymerized diene which is formed as a side product.These additives also have a mediating effect on the reaction of ally1 tin compounds with aldehydes.270 The arsenic reagent 250 acts as a precursor for the formation of 251, a powerful electrophile for additions to alkenes under mild conditions (NBS, dichloromethane, - 78°C).271 0 0 RKSeAsPh2 RK%& 250 251 A triaryl-bismuth diazide has been reported to react, under photochemical conditions, with alkynes to give 1,2,3-triazide~~~~ whilst in another application triphenylbismuth has been used as a leaving group in a-keto derivatives.273 The in situ formation of alkyl bismuth compounds, from metallic bismuth and an alkyl halide, and their addition reactions with imines have been reported.274 6 Group 16 6.1 Sulfur The asymmetric synthesis of sulfoxides by sulfide oxidation gives products of up to 95% e.e. using a combination of enantiomerically pure BINOL, titanium isopropoxide and t-butyl hydrogen peroxide275 and up to 47% e.e.using a manganese-salen complex with sodium hyp~chlorite.~~~ The stereoselective synthesis of sulfoxides proximal to epoxides, and their subsequent intramolecular reactions, have been described.277 Enantiomerically pure sulfoxides may also be prepared by displacement of a chiral leaving group from a diastereoisomerically pure sulfinate ester with a Grignard reagent. Although this is generally thought to involve inversion of configuration at sulfur, recent evidence has revealed that in some cases retention of configuration is observed.278 The displacement of homochiral oxazolidinones from the diastereoisomerically pure sulfinamides such as 25 2, which must be purified by flash chromatography, represents an attractive alternative to the use of sulfinate esters.279 The related homochiral cyclic sulfinamide 253 reacts with a range of nucleophiles with inversion of configuration at sulfur to give intermediates which may be subsequently converted into enantiomerically enriched alcohols and amines.280 252 253 Sulfoxides have been shown to be excellent directing groups for cycloaddition r e a c t i ~ n s ~ ~ l - ~ * ~ as illustrated by the reaction of 254 with cyclopentadiene under conditions of boron trifluoride catalysis, to give a 25 : 1 mixture of cycloadducts, in which 255 predominates.281 254 255 The known ability of Z ~ ~ C ( I I ) bromide to invert the selectivity of sulfoxide-directed reductions has been extended to the reduction of i m i n e ~ ~ ~ ~ and carbonyl groups proximal to cyclic s ~ l f o x i d e s .~ ~ ~ Chiral sulfoxides have been used as leaving groups; the Grignard reagent derived from 1 -bromonaphthalene adds to 256 to give the biaryl product 257 in up to 60% e.e.28h 256 257 6.2 Selenium and tellurium Triphenylselenium( iv ) chloride has proved to be an excellent catalyst for phase-transfer cyclopropanation of alkenes by dichlorocarbene. Five mol% of this additive gives a 92% yield of product in one reaction with cyclohexene, 10 molo/o gives a 99% yield.287 Cyclopropanes are also the products of the reactions of cations 258 with active methylene compounds.288 Homochiral a-phenylselenyl ketones have been prepared using 'Evans' enolates with phenylselenyl chloride.28y Asymmetric addition of phenylselenyl chlorides across double bonds may be achieved using a chiral auxiliary290 or a homochiral selenating reagent, such as 259, to give addition products in diastereoisomeric ratios of up to 66 : 1 (methanol is used to trap the intermediate selenium cation).291 OEt S e h ?Et fiPh ' pR BF,' 258 259 Oxidation of selenium( 11) compounds to the selenoxides followed by elimination provides double bonds under mild conditions. A valuable application of this reaction is the synthesis of vinyl esters 260 (which are used extensively in esterification reactions) from Wills: Main group organometallics in synthesis 359the ester 261, itself prepared from a carboxylic acid and /3-phenylselenylethanol.292 Holmes has reported further examples of the use of a mild selenoxide elimination for the preparation of enol ethers, precursors of medium ring amides and esters, which are formed via intramolecular [ 3,3] sigmatropic rearrangements.293 0 0 RKO% 260 261 The reaction of dilithium tellurolate ( Li2Te) with 1,2-ditosylates such as 262 results in formation of a three-membered selenium-containing ring (263) from which metallic tellurium is readily extruded to give the alkene 264. This reaction is stereospecific;-the cis-dimesylate gives the ~ i s - a l k e n e .~ ~ ~ MsO OMS \ I 262 263 264 A similar reductive transformation of epoxy alcohols295 and stereospecific debromination/cyclopropyl ring-opening296 has been reported. The reaction of a-bromo esters with lithium benzene tellurate in the presence of cerium trichloride cleanly generates the cerium enolate, which goes on to react with carbonyl compounds.297 2-Alkenyl tellurides, generated from acetylenes, have been used as precursors for stereochemically pure cuprates29* whilst cyclic tellurides, such as 265, have been converted into the dilithium reagents 266 upon reaction with two equivalents of n-butyl-lithium.2yy WLi Li 265 266 Tellurium ylids 267a and b, formed by deprotonation of the salt by a lithium amide, react with ketones to give e p o x i d e ~ ~ ~ ~ and with a#-unsaturated esters to give cyclopr~panes.~~~ Attempts to form the tellurium ylids using n-butyl-lithium, however, results in tellurium/lithium e~change.~O'(~) The stabilized tellurium ylid 267c gives alkenes upon reaction with ketones.302 Chiral aryltellurolates containing R Ph$€?--(- H 267 a, R = CH=CHR' b, R=C,CR' C, R=CO2R' 360 Contemporary Organic Synthesis binaphthyl groups have been reported to react with a$-unsaturated esters in a 1,4-fashion to give adducts in up to 70% d.e.303 P henyl-selenium and -tellurium compounds are excellent substrates for radical cyclization reaction^.^^^,^^^ In this respect they are especially effective as sources of acyl radicals.304 7 References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 (a) B.J.BUM and N.S.Simpkins, J. 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ISSN:1350-4894    

DOI:10.1039/CO9940100339

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Synthesis of materials for molecular electronic apphcations MARTIN C. GROSSEL" and SIMON C. WESTON Department of Chemistiy, University of Southampton, Highfield, Southampton, SO9 5NH, UK of activity from synthetic chemists keen to improve modification of the TTF skeleton. Key points of attention include variation of the heteroatoms and Reviewing the literature published between mid- 1992 synthetic routes to and investigate structural and December 1993 1 2 2.1 2.1.1 2.1.2 2.1.3 2.1.4 2.2 2.3 3 3.1 3.1.1 3.1.2 3.1.3 3.2 4 4.1 4.2 5 6 Introduction Electron-donor systems Tetrathiafulvalene, its derivatives and analogues Peripheral substitution of the TTF skeleton Fused TTF analogues Centrally spacered, i.e. 'stretched' TTF's Vinylogous TTF derivatives Tetrachalcogenofulvalenes Other novel donor systems Electron-acceptors 7,7,8,8-Tetracyano-p-quinodimethane (TCNQ) and related systems Ring substitution of TCNQ and its analogues Extended x-systems TCNQ systems containing heterocyclic rings Electron-acceptors DCID and DCNQ Approaches to devices Donor-acceptor complexes Molecular switches and rectifiers Conclusions References peripheral substituents, modification of the bridge between the dithiolium rings, and the properties of unsymmetrical structures.Whilst the properties of TCNQ salts played a key role in the development of organic metals, more recent work has focused on their use as components for organic devices (ferromagnetic, non-linear optical, and molecular rectification). However, the TCNQ skeleton has until recently proved less amenable to structural modification, but the development of cyano-imino derivatives has greatly increased the repertoire of structural variation available.Incorporation of donor and acceptor moieties into one molecule provides an important approach to optical and electronic devices and there is increasing interest in the construction of such structures. Another important area involves the design of molecular optical and electronic switching systems and important developments are underway in this area. 2 Electron-donor systems 2.1 Tetrathiafulvalene, its derivatives and analogues 1 Introduction The discovery of the high electronic conductivity of salts of the electron-donor tetrathiafulvalene (TTF, 1) and the electron-acceptor 7,7',8,8'-tetracyano-p- quinodimethane (TCNQ, 2) provided a key stimulus for the development of electronically active materials. More recently there has been an explosion of interest in the behaviour of TTF derivatives since the discovery that its salts can behave as organic metals and superconductors' and this has stimulated a wealth [;XsTx S la, X=H b, X = U c, X = C(S)NHMe 8, X=Se- d, X=S- f, X = SCH2CH20H NC NC 2 Within the period covered by this review (mid- 1992 to the end of 1993) there has been considerable activity in the synthesis of new donors and acceptors and, though there has been comparatively little innovative synthetic work, important strides have been made in the control of, for example, unsymmetrical TTF analogues.The application of TTF moieties as structural building blocks in supramolecular chemistry has been reviewed.* 2.1.1 Peripheral substitution of the TTF skeleton Several new reactions of the mono-lithiated TTF 1 b have been reported.That with methyl thiocyanate affords the thioamide which forms a highly conducting 1 : 1 stoichiometry TCNQ ~omplex,~ whilst addition to Eschenmoser salts (CH2=N + R2) affords tertiary aminomethyltetrathiafulvalenes which give semiconducting paramagnetic TCNQ charge-transfer complexes! TTF-Li is readily converted into the thiolate Id and selenolate le. The former has been used as an intermediate in the preparation of bis- and Grossel and Weston: Synthesis of materials for molecular electronic applications 367tris-(TTF) derivatives such as 3 [by reaction with tris( bromomethyl)benzene] and lf, formed when TTF-S- is treated with 2-bromoethanol, has proved a particularly versatile building block for the formation of a range of esters, ethers, urethanes, and vinylthio derivatives5 Reaction of the mono-anions ld,e with bromoethane provides a one-pot route to the known unsymmetrical donors EDT-TTF (4, X = S) and EDS-TTF (4, X = Se)? P(OEt)% neat 125 'c 4 3 DIBAL-H reduction of the methyl ester moiety in 5 affords the corresponding alcohols which are readily converted into their corresponding phosphonium salts.The latter provide useful Wittig reagents for the preparation of sulfur-rich and space-extended TTF derivatives such as 6.' TTF-bridged cryptand 9, that with the homologous dibromodithianonane gives exclusively the macro- cyclic monomer 10, a precursor to the bis-macrocylic TTF derivative 11 (Scheme 1).This latter shows a marked cyclic voltamometric response in the presence of AgClO, but is unaffected by alkali metal perchlorates.8 (aryl = 2,3,4,5-tetramethylbenzyl, 1,4-benzo- dithian-6-yl, 2-naphthyl, and biphenyl-4-y1), all showing good donor behaviour, have been prepared by reaction of the chloroacetylarene with sodium t-butylthiocarbonate, followed by acid-catalysed cyclization to the 4-aryl- 1,3-dithiole-2-thione and phosphite-mediated coupling, though neither the 3,4-dialkoxyphenyl nor the indol-3-yl thione could be converted into the corresponding TTF derivative.g Novel x-donors 12 having three-fold symmetry have been constructedL0 by attaching TTF units to a 1,3,5-trisubstituted benzene core using Wittig and Horner-Wittig techniques (Scheme 2).Yields from the Wittig route to 12a were poor, the product being very insoluble, and significant improvements were achieved through the use of a more flexible spacer between the TTF units and the core. Introduction of the iminium unit 13 and A series of bis( ary1)-substituted tetrathiafulvalenes subsequent reaction with a phosphonate ylid gave the unsymmetrical tris(TTF) structure 12b in 23% yield. Similar yields [ 50% for ( 12c, R' = Me, R2 = H)] were achieved by reaction of phosphonate ylids with 5 x=s.o 6 1,3,5 -triformyl- and 1,3,5 -triacetyl-benzene. Of particular interest is 12b which can be reversibly oxidized electrochemically to its tri- and hexa-cation and forms a paramagnetic mixed valence salt ( 1 2b2 + ) * ( M0,C114~ - ).~ ~ x s ~ s ~ x S S Whilst reaction of dithiolate 7 with 1,5-dibromo-3- thiapentane gives as major product the macrocyclic dimer 8 which has been converted into the novel Br nn a- 's- 7 dmit 10 (100%) 8 (81%) P(OEt)& xylene, reflux 1 T " ? S Xsxs1 hSHS 9 (20%) <5% 368 Contemporary Organic SynthesisCH2Br R 12a, R = b, R = ws)$4e (23%) Me Me Scheme 2 Covalent attachment of ferrocene to the TTF skeleton has also been investigated, systems so far prepared having the two separated by one, two, or five spacer atoms.' Mono- and di-substituted ferrocenyl esters (14b-d, 15b, and 16) are readily obtained by reaction of the appropriate alcohols with the acid chlorides 14a and 15a in variable ( 12-80%) yields. The trans-linked ferrocenylvinyl-TTF ( 17) is obtained in good yield (58% after isomer separation) by Wittig reaction of ferrocene-CH=PPh, with TTF-CHO.Electrochemical studies of these materials suggest three independent reversible single-electron oxidation 15 a, X=COCl 14 b, X=-C(O)-TTF 0 II 0 II C, X = C C T T F d, X = COCHpCH2GTTF K" s-0 0 16 Fc = ferrocenyl 17 processes (TTF" -, TTF + , TTF + -, TTF2 + , and Fc" -, Fc + ). In addition, ferrocene has been inserted into the central alkenyl bridge of the TTF skeleton. For example, the derivatives 15e have been prepared in 60-70% yield from 1 ,1'-diacetylferrocene using the appropriate 1,3-dithiole Horner-Wittig reagents. These compounds form charge-transfer salts with TCNQ ( 1 donor : 2 TCNQ) which have high room- temperature conductivities [ a,, (compressed powder)= ca.0.1 S cm-'1. chains to the TTF skeleton affords a room-temperature melt which freely dissolves electrolytes like LiClO, to give an ionically conductive liquid.I2 The introduction of peripheral sulfur substituents provides the most important precursors to superconducting salts. bis-( Ethy1enedithio)-Tetra- thiafulvalene (BEDT-TTF or ET, 18) is perhaps the most important of these and a novel and facile two-step synthesis of this material has recently been reported13 which has the additional merits of using exclusively commerically available starting materials, requiring short reaction times, reliably giving good yields of high purity products, and avoiding hazardous procedures. Contrary to previous reports the key intermediate 4,5-dimercapto- 1,3-dithio1-2-one 20 is readily generated by base-catalysed cleavage of the bicyclic lactone 19 (Scheme 3).It is then bis-alkylated using dibromoethane to give the dithiolone which is converted into ET (18) most efficiently using triethyl phosphite. The authors have further demonstrated that the controlled cleavage of 19 provides a good general route to tetrakis( a1kylthio)-TTF derivatives such as 2 1. The attachment of four short oligo( ethyleneglycol) 19 20 /"&Ir MeOH, r.t.. 3h 0=(ISR 4f) S S S R 1 55% (recyst.) I 18 (85%) 21 R=PhCHZ Scheme 3 The stereoselective synthesis of the methylated ET derivatives 22 has been achieved from optically pure (2&3S)-2,3-butanediol (obtained by reduction of L-threitol- 1,4-ditosylate) (Scheme 4).14 Reaction with thionyl chloride and subsequent oxidation gives the cyclic sulfate 23 which is then converted into the bicyclic dithiolone 24 in moderate yield.This is Grossel and Weston: Synthesis of materials for molecular electronic applications 369homocoupled to give 22bRR (74%). Cross-coupling with 24 (R = H) gave the expected but separable ( 1 :2:l)mixtureof 18:22aR:22b,,. 24, R2=Me 18, R1=R2=H 22a, R' = H, R2 = Me b, R'=R2=Me Scheme 4 The electrochemical behaviour of these materials is similar to that of ET itself, but intermolecular steric interference arising from the presence of four methyl substituents changes the molecular packing behaviour in the solid-state. 22bRR has a conformational preference for di-equatorial location of the methyl groups within each dihydrodithiin ring whereas the substituents prefer a diaxial geometry in 22aR.the synthesis of the twin donor 25 which forms a crystalline charge-transfer salt with DDQ in which columns of 'U'-conformation donor pairs sandwich DDQ - units.lS Such materials are of particular interest as potentially ferromagnetic organic metals. Linking of two ET units has been achieved through 25 Until recently, little information has been available on the effect of the introduction of additional heteroatoms (0 or S) into the peripheral alkyl chains of the ET skeleton. Reports have now appeared of the synthesis of several such structures. Introduction of both an oxygen and a sulfur link to give 27a,b was readily achievedI6 by alkylation of the intermediate 20 generated as described aboveI3 with bis( chloro- methyl) ether or the corresponding sulfide.Coupling with triethyl phosphite gave BOBMT-TTF (27a) and its thio-analogue BTBMT-TTF (27b) in ca. 80% yield whereas the more common approach involving phosphite coupling of the 1,3-dithiole-2-thione 26 (X = Y = S) gives much more modest yields ( 5 30%) (Scheme 5). X I 0 . S 3h, r.t.. 45% x = 0,s 45% 27a, X = 0; BOBMT-TTF b, X = S BTBMT-lTF Scheme 5 The relatively high oxidation potentials of BOBMT- TTF, 27a, (relative to 18 and 27b) restrict the choice of anions suitable for electrocrystallization experi- ments but it forms a black crystalline (1 : 1) charge- transfer complex, when reacted with TCNQ in chloro- benzene, which has a very high room-temperature conductivity ( opowder = 10 S cm- I ) making it an attractive candidate for further investigation.In contrast, the insolubility of the thio-analogue 27b would appear to limit its use. In a related study a series of unsymmetrical derivatives 30 have been prepared by coupling of the thiones 28 with ketones 29.17 Good yields were obtained in several cases and the cross-coupled products are readily separated from the symmetrical analogues by silica-gel chromatography (Scheme 6). 30 + homo-coupled products a, X=CH,,Y=Z=H;MVT b, X = (CH2)3, Y = Z = H; TMVT 58% C, X = CH&H2, Y = Z = H; TMTVT 45% d, X=(CH2)2,Y=HIZ=M8;EMVT6l% 8, X = (CH2)2r Y = Z = Me; EDMVT 49% Scheme 6 There is considerable interest in unsymmetrical structures in which half of a TTF moeity and half of a BEDT-TTF moiety are linked.The preparation of 31 is of particular interest since it exploits the coupling of two 1,3-dithiole-2-thiones using Co2( CO)*, and allows 370 Contemporary Organic Synthesis31 R=H,CHzOH the possibility of hydrogen-bonded structural organization through the presence of the hydroxyl substituent.18 The novel donor BETE-DMB (32), which has been obtained in high yield by Wittig coupling of 2,3 -et hylenedithio-6 -formyltet rathia- fulvalene with 2,5 -dimethyl-p-xylylidene-bis- (triphenylphosphonium chloride), forms highly conducting radical cation salts. For example, ( 32-12Br) has oRT (single crystal) = 80 S cm-1.19 32 The TTF-bridged cyclophane 34, formed in the trialkyl phosphite mediated coupling of the dithione 33, undergoes a surprising electrochemically induced metathesis-like dimerization to give the expanded electron-rich cage 35 (Scheme 7) which forms OR OR 33 I OR 34 35 Scheme 7 charge-transfer complexes with 12, DDQ, and TCNQ-F,, but not with TCNE or TCNQ itself.20 bis-Alkylation of dmit (7) leads to monomer, dimer, and higher oligomeric dithiolone-bridged crown ethers which are readily coupled (30-40%) to give the bis-crown substituted TTF's 36 (Scheme 8).The 15-crown-5 and 18-crown-6 analogues 36 (n = 3) and 36 ( n = 4) are readily prepared without resorting to high-dilution techniques and both show significant selective spectroscopic and electrochemical responses towards alkali metal cations.21 s- 7 dmit P(OEt)3 neat 110-130 "C Scheme 8 The p-acetoxybenzylthio- protecting group is stable to triethyl phosphite-mediated cross-coupling of 4,5-dialkylthio- 1,3-dithiol-2-ones thereby providing a convenient source of the dithiolates 37a and 37b, both valuable precursors to unsymmetrical tetrathioalkyl-TTF derivatives.22 RS Rsx"#"Xs- S- 37a, R=Me b, R=Bu" Replacement of the peripheral sulfur atoms by oxygen gives bis-( ethy1enedioxo)-tetrathiafulvalene (BEDO-TTF ) 38, two superconducting salts of which are known.Several synthetic routes to 38 have been explored, of which the self-coupling of 4,7-ethylene- dioxo- 1,3-dithiolium tetrafluoroborate was the most satisfactory (Scheme 9 )' some literature methods having proved to be poorly repr~ducible.~~ Two new charge-transfer salts were prepared, the most interesting of which is (BEDO-TTF )*. CF3S03 which is the first Ic-phase material obtained from 38 and is metallic at room temperature.However, whilst the crystal structure suggests that it should be a good candidate for superconductive behaviour this is not Grossel and Weston: Synthesis of materials for molecular electronic applications 37 1observed, the material reverting to an insulating state at low temperatures. Wittig and Wittig-Horner coupling reactions give improved yields of unsymmetrical BEDO-TFF analogues, e.g. 39a-d.24 38 BEDO-TTF 40% Rx)==Q(o) R 0 39a, X = S, R-R = -O(CH2)+ b, X=S,R=Me d, X=Se,R=Me C, X=S,R=H Scheme 9 2.1.2 Fused TTF analogues Four alkyl derivatives of bis-( 2-methylidene- 1,3- dithiolo[ 4,5-d])-tetrathiafulvalene, BDT-TTF, (4 2a-d), have been prepared,25 a Wittig-Horner reaction being used to introduce the exocyclic alkenyl unit of the dithiolo-dithiol-thione 4 1 (Scheme 10).41a, R=Me b, R = Et 42 Scheme 10 The first oxidation potentials of 42b and 42c are similar to that of BEDT-TTF and semiconducting charge-transfer salts are obtained with DDQ and TCNQ-F,, though no reaction has been observed with TCNQ itself. Both 42a and 42d proved too insoluble for study. Highly conductive complexes have been obtained from the tetrathiapentalene-cored donor 43 which has been prepared from the phosphonate 40 by Horner-Wittig reaction followed by phosphite- induced cross-coupling (Scheme 1 1).26 Whilst the diester 43a is very insoluble, it has been successfully decarboxylated (LiBr, HMPA, 90°C 1 h; then l3O0C, 30 min.; 45%) to the parent donor 43c. The first oxidation potential observed for the latter is equal to that of TTF but the dication is formed more easily, reflecting reduced Coulombic repulsion in 43c2 + .(i) LDATHF R S (i) x &S, (EtO)sP, 80 “c. 2h R S J (ii) DDQ. xylene. reflux. 30 min. (-30%) 43a, R = COOMe b, R=MeS C, R=H Scheme 11 A similar approach (but employing a sulfur ylid) has been used to prepare the linear ‘fused’ dibenzo-TTF dimers 44 and their bent isomers.27 The linear structures are more readily oxidized and form the more conductive (1 : 2) charge-transfer salts with TCNQ and TCNQF,. bridged TTF derivatives have been r e p ~ r t e d . ~ ~ - ~ ’ The syntheses of a number of tetrathiapentalene- 44 R‘ = H, Me, S. EtS R2 = OEt, 0-hexyl, 0-dodecyl, SMe, S-isoamyl 2.1.3 Centrally spacered i.e. ‘stretched’ TTF’s There have been a number of reports describing the incorporation of unsaturated, particularly heterocyclic, spacers into the TTF skeleton.The phosphonate carbanion 45 reacts with anthraquinone to give the anthracene-spacered TTF 46 which is the first p-quinodimethane analogue of BEDT-TTF to have been reported (Scheme 1 2).32 Several substituted derivatives of 47 have now been prepared in a similar fashion. Reaction of phosphonates 48 with, for example, cyclopenten-l,3-dione has been used to prepare several cyclopentene-bridged derivatives 49 in variable yields (8-46%) (Scheme 13).33 These latter are readily oxidized by NOBF, to give cations 50 which are very stable and give semiconducting (1 : 1) charge-transfer complexes with TCNQ. Trimethyl phosphite induced coupling of thiosuccinic anhydride with dithiolethiones has provided an efficient route to BDTT ( 5 1) and some novel unsymmetrical derivatives e.g.EDT-BDTT ( 52).34 BDTT is one of the most powerful donors of the TTF class and alkylthio-substitution as in 52 leads to a slight reduction in its electron-donor ability though TCNQ salts of the latter show significantly 3 72 Contemporary Organic Synthesis45 @ = P(0)(OMe)2 or P*Ph3 0 46 svs H MeS SMe 47 0 Scheme 12 6. 0 R = Me, MeS, -S(CH2)$3- a CN CN : = CH2, C3( R \ a 49 50 Scheme 13 higher conductivity (by ca. lo2- lo3), reflecting enhancement of intra- and inter-stack interactions produced by the sulfur atoms at the edges of the donor skeleton. 51 BDTT 52 EDT-BDTT Horner-Wittig coupling provides an efficient route to oligothiophene-bridged dibenzo-TTF analogues such as 53.35 The presence of an alkyl substituent in the median thiophene ring significantly increases solubility of such materials, although the introduction of more than one thiophene spacer does not produce any further dramatic changes in the redox behaviour of these systems.53 R' = H; R2 = H, Me, octyl, Me(OCH2CH2)r R' = Me; R2 = Me Conjugation-extended TTF analogues (54) incorporating a central furan or thiophene ring have been prepared by Wittig condensation of the appropriate heterocyclic 2,5-dialdehyde with 1,3-dithiol-2-ylidenetributylphosphorane and its 4,5-bis( methoxycarbonyl) derivati~e.~~ This approach giving significantly improved yields over the Wittig-Horner route, particularly when BuLi in THF is used to form the ylid.Ha, X=O,R=H b, X=S,R=H C, X S , R=C02Me Similar conclusions are drawn from a more detailed study of routes to symmetrical 55 and unsymmetrical 56 derivatives, good yields (ca. 70%) of the thiophene and N-methylpyrrole-bridged compounds being obtained.37 Significantly improved yields are gained from the Wittig-Horner route if the base (Bu"Li) is added dropwise to a mixture of phosphonate and ylid at O- 10°C.38 These materials show ready oxidation to the dication [the mono( radical)cation] not very stable two close or coincident one-electron processes are seen. Charge-transfer complexes of 54b with I, and DDQ have moderately high conductivities B = ca. S cm-'. X = 0. S. NMe 2.1.4 Vinylogous TTF derivatives Wittig coupling provides a convenient method for the synthesis of the novel TTF derivatives 57 from formyl and acetyl-TTE3' Vilsmeier formylation of 5 7 followed by phosphonate coupling affords the Grossel and Weston: Synthesis of materials for molecular electronic applications 373cross-conjugated vinylogous TTF derivatives 58 (the Wittig reaction failing in this case) (Scheme 14).Both 59b and 59c show remarkably strong and reversible two-electron donor behaviour whereas 59a is surprisingly unstable to electrochemical oxidation. R - H Me&J=CHCI c;)==(p S % \ / 0 4.# 0 0 THF, l 4 h . -78 "c then 13h, rl. (67%) (ii) 180 %, (Mh (73%) I 61 Scheme 15 [3]- and [4]-Dendralenes such as 62 have been prepared in good yields by combinations of Horner-Wittig and Vilsmeier elaboration of 63, this Scheme 14 latter derivingfrom reaction of 2-thiomethyl- 1,3-dithiolium salts with malondialdehyde m0noanion.4~ Several tetra-( 1,4-dithia-fulven-6-yl)-substituted TTF-derivatives and vinylogues such as 60 have been reported, the latter being obtained via cycloaddition of 3-thioxo- 1,2-dithioles onto electrophilic alkynes followed by thermally induced dimerization of the resulting thials and subsequent peripheral Wittig ~lefination!~.~' Once again such compounds are very strong 2 n-electron donors which readily react with TCNQ to form electroconductive charge-transfer salts.w R2 R2 60 R' = H, Ph, p -MeC*H,- R2 = H, C02Me. -(CH=CH)r 62 R'=R2=MeS (R1)2 = -S-(CH2)TS-; R2 = Me 2.2 Tetrachalcogenofulvalenes An efficient synthesis of BETS (64), the tetraseleno analogue of BEDT-TTF is still being sought, though progress had been made through thiabenzylation of tetralithiotetra~elenafulvalene.4~ This material is an attractive target since it retains the sulfur periphery which plays a major role in the superconductive behaviour of BEDT-TTF salts but the addition of core selenium atoms should enhance transverse intermolecular interactions.Thienyl-substituted fulvalene and TTF-vinylogues such as 6 1 which have been prepared using a Diels-Alder/retro-Diels-Alder protection sequence (Scheme 15) have even lower, reversible, first oxidation potentials and form stable and well-defied TCNQ salts despite expected non-planarity of the donor skeleton.42 64 BETS 374 Contemporary Organic SynthesisA number of other tetraselenafulvalene derivatives of this type have been prepared using the titanocene route to 1,3-diseleno1-2-ones which were then coupled in neat triethyl phosphite!s Unsymmetrical donors such as 65 (ETIT) were also prepared by cross-coupling methods though in rather poor yield.65 ETIT The titanocene-route has also been successfully exploited in the synthesis of 66 (TMET-STF) (Scheme 1 6).46 A number of novel unsymmetrically substituted dithiadiselena- and tetraselena-fulvalenes bearing one or two functionalities such as diethylacetal, formyl, or hydroxymethyl substituents have been and routes to TTF analogues in which one sulfur atom has been replaced by selenium have been described.48 (i) Bu' Li (ii) Se se aBr - Br (iii) Cp2TiC12 69% -60% 66 TMET-TSF (27%) Scheme 16 2.3 Other novel donor systems bis-( thiadiazo1e)Tetrathiafulvalene (BTDA-TTF ) (67) which has been prepared in low yield by triethyl phosphite induced coupling (Scheme 17), is poorly soluble in common organic solvents and undergoes single-electron irreversible oxidation impeding the formation of charge-transfer CI 67 Reagents: (i) Na2S, H20, EtOH; (ii) CSCI2, 20 "C, 30min., Ne; Scheme 17 (iii) (Et0)3P, 100-130 "C,15 min.Wittig-Horner coupling has been used to prepare in good yields the bithiopheno-TTF analogues 68 bearing a variety of electron-withdrawing and donating substituents.50 Electrochemical oxidation of these compounds is also irreversible and leads to the formation of semiconducting polymers. dithiadiazafulvalenes," diazatetrathiafulvalenes,'2. s3 and bis-[ 1,2,5]-thiadiazolo-p-quino-bis-( 173-dithiole) Routes to other novel TTF analogues such as (BTQBT ), 69,s4 and its selenium analogues have been reported.Single crystals of 69 show unusually high conductivity ( oRT - 10-4-10-6 S cm- l ) for a single component organic materiaLSs 2-( thiopyran-4-y1idene)- 1,3-dithiole (TPDT ) 70a and its selenium analogues 70b-d have been prepared by phosphite coupling of 2-thioxo-l,3-dithioles with 4-oxo-tetrahydrothianes or selenanes, followed by chloranil-induced dehydr~genation.~~ These are strong electron-donors which in some cases form highly conducting TCNQ complexes. A large number of derivatives of 68 70a, X = Y = S b, X = S, Y = Se c, X=Se,Y=S d, X=Y=Se 69 R = H, BTOBT Introduction of sulfur atoms into the periphery of polynuclear aromatic systems provides a useful means of lowering the oxidation potentials of such structures.Photocyclization of substituted 172-dithienylethenes provides a versatile synthetic route to naphtho[ 1 ,S-bc; 4,5-bfc']dithiophene 7 P7 Other interesting donors which have recently been prepared include 1 ,6-diselena-pyrenes8 and 2,3,8,9-tetrahydro- 1,4,7,1 O-tetrathiachrysene.s9 @; Me 71 3 Electron-acceptors 3.1 7,7,8,8-Te trac yano-p-quinodime t hane (TCNQ) and related systems The majority of TCNQ derivatives undergo two reversible single-electron reductions, the intermediate radical anion having high thermal stability and the presence of dicyanomethylene groups makes TCNQ a far stronger electron-acceptor than benzoquinone. the manipulation of the TCNQ structure, thereby modifying its properties: (a) Ring substitution, allowing fine tuning of the redox behaviour through careful choice of substituents.Extension of the n-system which reduces intramolecular Coulomb repulsion in the dianion state. Three general synthetic approaches are available for (b) Grossel and Weston: Synthesis of materials for molecular electronic applications 375(c) Incorporation of heteroatoms or heterocyclic rings into the TCNQ skeleton, leading to greater intra- and inter-stack interactions which increase dimensionality, stabilize the conductivity, and enhance the metallic state. However, the synthesis of the majority of TCNQ derivatives remains difficult and this has restricted the use of these acceptors in the development of new organic materials.Early routes proceeded via cyclohexanedione60 or 1,4-bis( cyano-methy1)benzene derivatives?’ In the latter, introduction of the cyan0 substituents was a painstaking, multistep procedure involving the use of highly toxic cyanogen chloride as the electrophilic cyanating reagent, but in recent years the advent of new synthetic methods has made the preparation of TCNQ analogues more viable. Techniques of particular importance are: The Lehnert procedure which involves direct bis( dicyanomethylation) of the quinone using malononitrile and TiC1, in pyridine; this method which works best for tetrasubstituted TCNQ’s, e.g 2b. Reaction of 1,4-di-iodobenzenes with malononitrile anion in the presence of a palladium catalyst, leading to phenylene-dimalononitrile derivatives which are then oxidized to TCNQ’s.A two-step approach in which terephthaloyl chlorides are reacted with cyanotrimethylsilane-pyridine followed by phosphorus oxychloride-pyridine to give TCNQ’s. Use of 2-chlorobenzyl thiocyanate 72 as a cyanogen chloride substitute. The Hiinig procedure for making DCNQI 73 derivatives. Direct reaction of quinones with bis( trimethylsily1)carbodiimide (BTC) in the presence of TiC1,. R’ NCRN 73a, R’= R2=H b, R’=R2=Me c, R’ = R2 = Br d, R‘ = Me, R2 = Br 3.1.1 Ring substitution of TCNQ and its analogues An example of the difficulties in synthesizing TCNQ derivatives is exemplified by Bryce’s6* largely unsuccessful use of the Lehnert reagent to prepare a series of ring substituted TCNQ derivatives, the notable exception being the known preparation of tetramethyl-TCNQ (TMTCNQ) 2b ( 5 5% reported yield from duroquinone) (Scheme 18).Small scale reactions (1-3 mmol) produced no TCNQ products while on a large scale ( 2 6 mmol) a maximum yield of 15% of 2b was obtained. In all other cases only a monocyanomethylated intermediate (25-40%) 74 and a phenolic side product ( 15-30°/0) 75 were isolated. These results contrast with those previously reported for the synthesis of TCNQ and 9,9,10,1 O-tetracyano- anthraquinodimethane (9,lO-TCAQ) 2k. however, be reacted with BTC/TiCl, to afford novel N,7,7-tricyano-p-quinomethanimine (TCNQI) hybrid acceptor 76(a-d, k-m) in typical yields of 65-80%. The quinomethide intermediates 74 could, pyridine (Lehnert) 72 + CN N“CN 76 R’ R2 s(E2) H H b Me Me c H Me d H Me e CI H f Br H g Me0 H h C02Me H I CI CI k -(CH=CH)2- i H H I -fHCH2)243- m -(CH=CH)2- n F F Scheme 18 R3 H Me Me Me CI Br Me0 H CI OH 75 R4 H Me Me H H H H H CI 376 Contemporary Organic SynthesisElectrochemical studies on each of these TCNQ derivatives showed a reversible first reduction wave. As expected TCNQI shows behavioural trends similar to those seen for TCNQ and DCNQI derivatives, progressive methyl substitution reducing the electron affinity. Use of 2-chlorobenzyl thiocyanate 72 as a source of electrophilic cyanide provides a significantly improved synthetic approach to several TCNQ derivative^,^^ e.g.2e-h which were previously difficult to prepare, and allows a wide variety of substituents to be incorporated into the TCNQ ring in yields of 35-45%, including for the first time a functionalized carbon group, i.e.C02Me. However, this new methodology fails to produce the elusive tetrachloro-TCNQ 2i. The current holder of the title of strongest electron-acceptor is claimed to be the di-positive electron-acceptor ( [TCNQF2L,)I2+ 77, L= DMAP+ ), a result of the electron-withdrawing power of the onio fun~tionality.~~ This is prepared from TCNQF, by onio substitution (Scheme 19). Cyclic voltammetry has confirmed the first reduction potential for 77 as 0.96 V ( versus Ag/AgCl in MeCN). However, TCNQ( CN)4 has a first reduction potential of 1.3 1 V although this latter compound is not stable in its oxidized form. NC 72n NC CN 0 78 2+ *2C F3 SO3- 77 I Y'"2 L NC+N J Scheme 19 The strongest uncharged electron-acceptor based on the TCNQ system remains 2,5,7,7',8,8'-hexacyano- p-quinodimethane [TCNQ(CN),, E , = 0.67 V versus Ag/AgCl in MeCN].However, tetracyano- 1,4-benzo- quinone (cyanil) (78) is the strongest known uncharged electron-acceptor [three electrochemcially quasi- reversible single-electron reductions at potentials of 0.90, 1.09, and - 1.81 V (versus SCE in MeCN)] and can now be easily prepared from various commerically available benzoquin~nes.~~ Following the discovery of a metal-insulator-metal transition (re-entrant behaviour) in ( Me2DCNQI),Cu [( 73b),Cu] at low pressure, and the subsequent discovery of an ambient pressure giant re-entrant state in the disordered alloys [ ( Me2), -,( MeBr),- DCNQI],Cu ([(73b),-,(73d),]2Cu) and (Br,DCNQI),Cu, - ,Li, [ (73c),Cu, - ,Li,] the search for re-entrant phenomena in a non-alloy at ambient pressure has attracted much interest.Workers have recently found giant re-entrant behaviour in the alloy [(Me2DCNQI-d,),-x(Me2DCNQI-d,),]2- Cu ([( 73b), -,( 79h),],Cu] in which the only disorder arises simply from the fact that some hydrogens have been replaced by deuterium.h6 Seven of the possible thirty five deuterated versions of Me,DCNQI (73b) have been synthesized6' (79a-h). Electrical studies on the copper salts of the deuterated DCNQI's [Me,DCNQI-d,],Cu (where n is the number of deuteriums present) reveal giant re-entrant behaviour for the first time in ordered (non-alloys) at ambient pressure (79e-g). The methyl ,D's are introduced by the reduction of the corresponding a-chlorinated p-xylenes by zinc powder in AcOD.Deuterations of the ring protons were performed by applying 'H/,D exchange reactions in acidic media. It seems that selective deuteration of the methyl groups plays a much greater role than deuteration of the ring protons. Me' Me2 Z' Z2 73b CH3 CH3 H H a CH3 CH3 D H bCH3 CH3 D D c CHPD CH3 H H z' Me2 d CH2D CH3 DRI e CHPD CH2D H H f CH2D CH2D D H g CH2D CH2D D D hCD3 CD3 D D NCMN 79 Me*z2 3.1.2 Extended jc-systems In general the acceptor ability of the benzene-fused TCNQ derivatives is poorer than that of TCNQ itself. Some TCNQ derivatives containing fused aromatic rings afford highly distorted molecular structures arising from steric interference between the cyano groups and the peri-hydrogens of the fused benzene rings.Planarity of donor and acceptor molecules is recognized as being one of the most important prerequisites in the search for organic conductors and it is this non-planarity that is blamed for the decrease in El with the increase in benzannelation in the series benzo > naphtho > anthraquino derivatives. Three approaches are now known in the fight to keep such extended systems planar: (a) P-substitution as in 9,9,10,1 O-tetracyano-2,6-naphtho-quinodi- methane (TNAP, 80) and 1 1 ,l 1,12,12-tetracyano-2,6-anthraquinodimeth- ane (TANT, 81) leads to truly n-extended, as opposed to fused systems, which do not suffer from peri-hydrogen interference. (b) Replacement of the dicyanomethylene groups with the less sterically demanding imine group. (c) Replacement of the carbon bearing the peri-hydrogen on the fused aromatic ring with a hydrogen-free heteroatom.Grossel and Weston: Synthesis of materials for molecular electronic applications 377An improved synthesis of the established Jt-extended systems TNAP (80, Scheme 20) and benzo-TCNQ 2j has recently been reported by Bryceh3 using the less arduous method (iv) above in improved overall yields of 20 and 45% respectively. CN NC NC 80 TNAP Scheme 20 TANT (8 1) has been prepared for the first time, using method (ii) in four steps from commercially available 2,6-diaminoanthraquinone in a 12% overall yield (Scheme 2 l).hX Cyclic voltammetry studies on TANT show two reversible single-electron reductions at 0.20 and - 0.12 V (versus Ag/AgCl in benzonitrile). Although the first reduction potential is equivalent to that of TCNQ 2a (0.20 V) and TNAP (0.23 V) under identical conditions the second reduction is higher, demonstrating the extensive conjugated nature of the structure. Deep-purple 1 : 1 complexes are formed with tetrathiatetracene (TTT ) and hexamethylene- tetratellurafulvalene (HMTTeF ) both of which are highly conductive ( a = 7.0 and 1 1.5 S cm- respectively).I Pd(PPh3)d NaH, CH,(CN), THF. reflux 20h NC NC 81 TANT Scheme 21 Four fused-aromatic DCNQI derivatives 82a-c, and 83 which have been prepared in order to study the effects of benzannulation on the DCNQI moietyh9 were obtained in the usual way by treating the appropriate quinone with BTC Ibis( trimethylsily1)- carbodiimide]/TiCl,. In each case cyclic voltammetry measurements showed two reversible single-electron reductions (whereas similarly annulated TCNQ /CN R5 N &?a, R1/R2 = R3/d = -(CH=CH)r, R5 = H b, R’ = R2 = H, #-R4 = -(CH=CHr, R5 = H C, R1 = R2 = R3 = H, R4-P = -(CH=CH)z- NCHN a3 derivatives, e.g.TCAQ, exhibit only a single two-electron reduction) and, as expected, the acceptor ability decreases as the fused aromatic groups become larger (reflecting non-planarity, even for cyanoimine substituents). polycyclic TCNQI derivative 84 from benz[ alanthraquinonone by Lehnert condensation of malononitrile with the less hindered carbonyl group followed by reaction with BTC/TiCl,. In this case cyclic voltammetry shows a single two-electron reduction in keeping with the increased steric hindrance. tetracyanoanthraquinodimethane (TANT ) analogues, aseriesofTCNQ-(85a,b)andDCNQI-based(86a,b) structures incorporating dioxan and dithian spacers have been prepared7* from the corresponding quinones using either the Lehnert procedure (yields of ca.40%) or standard Hunig conditions (yields of ca. 80%) (Scheme 22). However, attempts to prepare the oxygen-oxygen bridged TCNQ derivative yielded only the phenolic side product 87. Electrochemical studies on the TCNQ analogues reveal a single two-electron reduction potential (similar to TCAQ), whereas the DCNQI materials show two single-electron reduction potentials (similar to 82 and 83). These materials are being investigated as potential one-component donor-a-linked-acceptor (D-a-A) systems. Several pyrazino-TCNQs, 88a-i, have also been prepared from 1,2-phenylene-diamine in nine steps with widely varying yields (Scheme 23).The pyridyl- substituted derivatives were converted into stable neutral radicals (89d-f) by treatment with methyl triflate followed by Bu,”Ni with a view to obtaining single-component organic conductors, conduction electrons being provided by internal charge-transfer within the conjugated D-A system.71 Attachment of the donor moiety to the pyrazino ring rather than the TCNQ ring minimizes steric interference and the associated non-planarity of similar fused systems. The same workers69 have also prepared the In an attempt to reduce steric interference in 378 Contemporary Organic Synthesis0 86a, X = S, 83% b. X = 0,87Yo 85a. X = S, 40% b, X = 0.37% !? ?H Scheme 22 " F C N NC 87 Pyrazino TCNQ 88a forms highly conductive 1 : 1 charge-transfer salts with TTF and TMTSeF, with powder electrical conductivities of 1.4 and 0.9 1 S cm- respectively.Similar studies on the substituted materials (88b-c) afforded low conductivity salts as did other donors with 88a. The powder conductivities of the neutral radicals are much higher ( 0 = 10 - s- 10 -4, S cm- l ) than is normal for a single component organic solid. Several 1,4-anthraquinone-derived TCNQ (90) and DCNQI (9 1) derivatives bearing quinoidal ring substituents have been prepared72 by standard Lehnert and Hunig procedures. These 2,3-fused structures are stronger acceptors than other similar 2,3,5,6-fused materials. NC+N 90 91 R' = H, OMe R2 = Me, OMe, Br R3 = H, Br, Me R2 R' or NC Wa, R'=R2=H b, R ' = R2= Me d, R' = 2-pyridyl, R2 = H C, R1= R2=Ph 8, R' =3-pyridyl, R2= H f, R' = 4-pyridy1, R~ = H g R' = R2 = 2-pyridyl I I NC MeOSO&F3 R' = pyridyi Scheme 23 Grossel and Weston: Synthesis of materials for molecular electronic applications 3793.1.3 TCNQ systems containing heterocyclic rings In the late 1980'~'~ multiple-ring TCNQ heterocycles were made, both fused 94 and quinoidal93, based on thiophene-TCNQ 92.Such conjugated hetero-TCNQ derivatives should have reduced on-site Coulomb repulsion and strong intermolecular interactions which favour greater dimensionality and thus greater conductivity. NcmcN NC CN 92 93 NC@I: NC 94 Extended vinylogous thiopheno-TCNQ derivatives have now been synthesized in order to further investigate this postulate.74 Three extended hetero-TCNQ derivatives, 95a-c, were prepared by the coupling of two thiophene units using Wittig procedures (Scheme 24).All three acceptors were obtained as deep violet fine crystals, for 95a, b, albeit in poor overall yield (4% and < 1% respectively) R4 CHO a 46% b 5% c 39% R' R3 / a 48% b 41% though that for 95c was rather better (16% via a two-step process). Cyclic voltammetry studies ( versus Ag/AgCl in DMF ) indicate a single reversible two-electron reduction ( E , = 0.1 3 V) for 95a, demonstrating the extensive conjugation present here (the first and second reduction potentials coalesce). This electron affinity compares poorly with that for thiophene-TCNQ 94 which exhibits two reversible single-electron reductions (at 0.08 and - 0.50 V).However, the dibromo derivatives 95b,c show similar behaviour to 94, the symmetrical isomer being reduced at 0.07 and the unsymmetrical derivative at 0.02 and - 0.18 V, and thus have reduced energy gaps. Both 95a and 95b are symmetrical and suffer from poor solubility in organic solvents whereas 95c is soluble in hot chlorobenzene and forms charge-transfer complexes with TTT and 2,3- dimethyl- 1,4,9,1 O-tetraselenoanthracene each of which show high conductivity, o = 0.01 1 and 0.3 S cm- respectively. Compound 95c also forms a poorly conducting charge-transfer complex with tetra- phenyl-bipyranylidene (o= 4.3 X S cm-I). Another approach for increasing dimensionality is to fuse the heterocyclic rings to the main ring of the acceptor. Several TCNQ (97,102), DCNQI (99,104), TCNQI ( loo), and mono-reacted derivatives (98, 103) have been prepared75 from the appropriate thieno- quinones (96, 10 1, 105) using combinations of the Lehnert procedure and the Hunig condensation (Schemes 25 and 26).then HCI R W (ii) PCIG PhNO, AlCb R S 0 n U 96 flI2 Pyridine 1 97a, R = H (26%) X = C(CN)2, Y = 0 + b, R = CI (31%) X = 0, Y = C(CN)2 Nm I I I II NCYN 99a, R = H (68%) b, R=C1(40%) 95a, 37% b, 19% C, 41% N-CN 100 Scheme 24 Scheme 25 380 Contemporary Organic SynthesisNC-CN (Lehnert) /CHO CHz(CN)z TCI, pyridine Y (s&HO (QF$ri OH ’ s 0 \($ 5% K: EtOH a-J!JD 0 101 \ (M%SiN)& 105 + 5isomer S NC/N 104 I NC+N X (y-$-J$+m S 0 ’ s Scheme 26 Y 103 X = 0, Y = C(CN)2 X = C(CN)p, Y = 0 The thieno-quinones were approached by multi-step pathways appropriate to the particular quinone.UV spectroscopy suggests a lack of planarity in the TCNQ derivatives and this is borne out by the electrochemical studies which reveal only single two-electron reductions to the dianions. The DCNQI derivatives, however, exhibit two single-electron reductions consistent with more planar structures. The hybrid TCNQI compound 100 also shows two single-electron reductions and the greatest electron accepting ability. The isothianaphthene core has also provided a starting point for incorporation of a heterocyclic ring into an electron-acceptor.76 Two examples have been prepared from tetrachlorothionaphthalene 106 both of which show two reversible one-electron redox potentials (cyclic voltammetry versus Ag/AgCl in CH,Cl,) (Scheme 27).The benzothiophene derivative 107 has E = 0.31 and E = - 0.78 V whereas those for the benzothiophene analogue 108 are - 0.25 and - 0.62 V respectively, values which are much lower than those found for thiophene-TCNQ 94. 3.2 Electron acceptors DCID and DCNQ Attempts to prepare charge-transfer salts of the electron acceptor 2-dicyanomethyleneindane- 1,3-dione (DCID, 109a) with TTF or TMTTF were hampered by the rearrangement of the DCID radical anion into the DCNQ (2,3-dicyano- 1,4-naphthoquinone) radical anion 1 1 Oa.77 Similar behaviour was observed for 106 (i) Bu‘Li (ii) DMF.TMEDA heme, 0 “c %cN NC 107 CI Bu‘Li, TMEDA. hexane,O “c (ii) DMF CHO Y 108 CN DBU = 1,8-diazabicydo[5.4.O]undeo7-ene TCEO = tetracyanoethylene oxide Scheme 27 109 a, X = H (DCIBD) 110 a, X = H (DCNQ) b, X = CI b , X = CI tetrachloro-DCID ( 109b), this time giving, however, tetrachloro-DCNQ ( 1 1 Ob).Other electron-acceptors based on an indane core have been synthesized all of which are weaker acceptors than DCID. 4 Approaches to devices 4.1 Donor-acceptor complexes Perhaps one of the most imaginative uses of C60 to date has been its incorporation into the ‘ball-and-chain’ type donor-acceptor array 11 1,78 attachment to the fullerene being achieved through a Diels-Alder process (Scheme 28). The rigid spacer is itself prepared in several steps from the Diels-Alder adduct of p-benzoquinone and cyclopentadiene and has also been used to construct other arrays in which the acceptor is a 1,2-dicyanoethene or dialkyl maleate unit.7’ has involved the use of a diaza- 18-crown-6 ‘active spacer’ through which inclusion of metal ions should modulate the donor-acceptor interaction.80 A number of unsymmetrical structures ( 112) have been prepared; unsymmetrical alkylation of the diaza-crown being achieved through efficient chromatographic separation of the mixture of mono- and bis-alkylation products Another novel approach to donor-acceptor systems Grossel and Weston: Synthesis of materials for molecular electronic applications 381Me3 OMe Me0 Cso, toluene, reflux, 6h t CI CI xylene.140 'c, 2d THF. reflux. 18h 25 'c. 24h (il) Na Pr'OH ($ HCO1H, m (i) Me02C+CqMe toluene, reflux. 2d (ii) Ha P d 4 t (I) LIAIH4. M F , 12h C02Me (19 TsCI, PV. 4 'c, 2d (iii) KOBu', OMS0 c02Me 25 "c. I d Scheme 28 obtained when molar equivalents of diaza-crown ether and alkylating agent are reacted.Such structures offer an interesting approach to ion-selective molecular switching devices. Ar cono3 L N N-R 112 R = etc n = 3,4 Fully conjugated polyene-linked donor-acceptor systems have large molecular non-linearities, a property of potential importance in molecular electronic devices. A number of syntheses of materials of this type have been reported. These include tricyanovinyl thiophene derivatives such as 113 which have dramatically enhanced molecular non-linearities (@A - 6000-7000) in comparison with simple aromtic analogues such as 114 (&u - 700) (Scheme 29).81 NcHcN DMF, r.t.. 24h NC CN I N C ~ C N 114 (90%) DMF. f.t., 24h NC+N 113 n = 1.80% Scheme 29 The imino-dithioles 115, which are readily prepared by reaction of various mines with 2-amino- 173-dithiolium cations,x2 are also potentially interesting push-pull polarized systems.6-P henylt hio- and 6,8 -bis( phenyl thio )- benzo- cycloheptene- 174,7-triones 1 16 have been synthesi~ed.~~ In the solid state the bis( phenylthio) derivative 116b adopts a segregated column structure with considerable overlap of the x-acceptor systems and seems to be a potential candidate for a new type of organic conductor containing a donor-acceptor- donor molecular unit. 4.2 Molecular switches and rectifiers The syntheses of two structurally related photochromic switching devices have been 382 Contemporary Organic SynthesissYs NMe2 115a, R=Me 116a, R = H b, R=SPh described.84 Compound 1 17 (Scheme 30) is the prototype of a photo-switchable molecular wire displaying light-triggered reversible changes in optical and electrical properties. In the open form cyclic voltammetry shows no electrochemical process in the region f 0.6 volts, whereas the closed structure has a reversible one-electron reduction for which = - 0.23 volts.118 (and its symmetrical analogues) are readily prepared from the dialdehyde 119 by Wittig reaction and/or base-catalyzed condensation with malononitrile (Scheme 3 1). 84% I(1) BuLi. THF 117+pen hv (365nm) hv (6OOnm) ll Scheme 30 Irradiation of 1 18-open results in effectively complete ring closure ( > 98%) to give the conjugated donor-acceptor structure 118-closed which has A,,, 828 nm with a very high interest for possible use as non-linear optical materials.Multiply-bridged dyes such as 120, which are readily prepared from the corresponding triaryl methanes by Eglinton coupling, act as pH-sensitive optical switches (Scheme 32).8s The water-soluble Such systems are of H 119 H CN 11-n F2 C F2C’ ‘CF2 \ I 11 %closed Scheme 31 120 miourless lH+ orange Scheme 32 azo-benzenoid macrocycles 12 1 are photochemically switched molecular hosts for small molecules such as benzene and naphthalene derivatives (Scheme 33).86 Grossel and Weston: Synthesis of materials for molecular electronic applications 3836 References NH2T ICSC, 0 y - - N h e 3 c r 121 n = 13-6 Scheme 33 5 Conclusions The development of improved and more versatile synthetic routes to symmetrical and unsymmetrical tetrathiafulvalene derivatives and analogues remains a major objective for the production of highly conducting organic materials.Of particular interest are structures incorporating heterocyclic (particularly sulfur-containing ) units as central spacers and novel systems such as the dendralenes. 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ISSN:1350-4894    

DOI:10.1039/CO9940100367

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Control of asymmetry through conjugate addition reactions JOHN LEONARD Department of Chemistry, University of Salford, Salford M5 4WT, UK Reviewing the literature published up to end of March 1994 1 2 3 3.1 3.2 4 4.1 5 5.1 5.2 5.3 6 7 7.1 7.2 7.3 7.4 8 9 Introduction Stereoselectivity of enolate additions to acyclic a$-unsaturated carbonyl compounds Double Michael reactions and other processes in tandem with conjugate additions Conjugate addition followed by tandem enolate trapping Double Michael addition reactions Conjugate addition to acyclic a ,P-unsaturated systems bearing a chiral centre at the y-position Reactions with ester and amide chiral auxiliaries Conjugate additions to a ,B-unsaturated systems with chirality in the electron-withdrawing group Conjugate additions to a $-unsaturated esters and amides derived from chiral alcohols and chiral amines Chiral auxiliaries based on oxazolines and imines Conjugate addition to a ,#?-unsaturated systems bearing a chiral sulfoxide at the a-position Conjugate additions where the asymmetry is introduced via chiral centres covalently bonded within the nucleophile Conjugate additions of achiral nucleophiles to achiral a ,#?-unsaturated systems in the presence of chiral ligands or other chiral mediators Modification of cuprate and magnesium reagents Modification of organozinc reagents Modification of 1,3-dicarbonyls and other activated nucleophiles Other miscellaneous reactions Conclusion References (WE+ Susbstrate Enolate L\' ' I Product Scheme 1 When an a , B-unsaturated conjugate addition substrate has prochiral centres at the a and/or /3 positions there is potential for the creation of new chiral centres.There is also potential for new chiral centres to be formed in the nucleophile, or within the electrophile which reacts with the intermediate enolate ion. The relative and/or absolute stereochemistry generated at these positions can often be controlled efficiently, therefore conjugate addition reactions have gained a prominent role in the synthesis of chiral compounds. A number of recent reviews have covered various aspects of conjugate addition reactions,'-s and some have focused specifically on aspects of asymmetric conjugate addition reaction^.^^^(^),^^^ A short review on a subject of this breadth cannot be comprehensive and this review endeavours to provide an overview of where and how stereochemistry can be controlled through conjugate addition reactions.Sections 2 and 3 of this review will deal with some important aspects of the control of relative stereochemistry through conjugate addition reactions. The rest of the review will be devoted to ways in which the absolute stereochemistry at newly created chiral centres can be controlled. Figure 1 indicates the four most common sources of chirality which have been exploited for asymmetric induction at the a- and #?-positions. Each of these sources of chiral induction will be illustrated in turn in Sections 4-7. 1 Introduction Nucleophilic conjugate addition reactions, often referred to as Michael additions, comprise some of the most important structure building reactions for organic synthesis.The substrate for the nucleophilic attack is an alkene which can be conjugated to any mesomerically electron-withdrawing group. This group is most commonly a carbonyl (ketone, aldehyde, ester amide, etc.), but can be a nitro group, a nitrile, a sulfoxide, a sulfone, an electron-deficient heterocycle, etc. (Scheme 1). Nu- electron withdrawing +& R2 R2 E Figure 1 Sources of chirality for control of absolute stereochemisry: Chiral centre y to the electron withdrawing group Chiral centre(s) atached a- to the electron withdrawing group Chiral centre(s) at the electron withdrawing group Chiral centre(s) covalently bound to nucleophile Chiral centre(s) nort-covalently bound to nucleophile Leonard: Control of asymmetry through conjugate addition reactions 3872 Stereoselectivity of enolate additions to acyclic u, b-unsaturated carbonyl compounds When enolates or enamines react with a, B-unsaturated systems several new chiral centres can be generated and it is very useful to be able to carry out such reactions with good, predictable stereochemical control.It has been known for many years that the stereochemistry generated during these reactions can be highly dependent upon the solvent u ~ e d . ~ ( ~ ) Seebach et al. proposed a model to account for the observed stereoselectivity of additions of enamines to a, B-unsaturated systems. An example is shown in Scheme 2, where selective production of 1 can be accounted for by a 'closed transition state model 2. When chiral enamines, derived from prolinol, were used in such conjugate additions, products with up to 90% e.e.were produced (see Section 6).677 1 R = Me or Ph S O % d.e. U 2 Scheme 2 Heathcock et al. * and Yamaguchi et al. y, y4 investigated the stereochemistry generated when enolates add to a, B-unsaturated ketones and esters. Yamaguchi found that the lithium enolate of t-butyl acetate reacted with methyl crotonate in a conjugate manner, but the intermediate enolate generated 3 could only be alkylated after addition of HMPA and/or Bu'OK. Under such conditions the methylated product 4 was isolated with high syn selectivity (Scheme 3). Tomioka also found that conjugate addition to E-esters followed by methylation gave high syn selectivity.'" * C O ~ M ~ LDN THF Bub Bub 1 4 (70%, >80% d.e.) 3 Scheme 3 Heathcock et al.reacted the enolate of amide 5 with t-butyl crotonate, providing diastereoisomer 8 with high selectivity (Scheme 4).*(") This product was not in accord with previously proposed 'closed' transition state models and Heathcock proposed an 'open' transition state model 6 to account for the major stereoisomer. Heathcock et LIZ.*(") also reacted the enolate of amide 10 with t-butyl crotonate and Yamaguchi et aLY4 reacted the same enolate with ethyl crotonate. Neither reaction was particularly stereoselective and the direction of the selectivity was inconsistent. 0 OLi 5 6 I 7 1 8 9 : l l1 I 10 9 *C02R 12 13 a, R = Et 1 2 92% b,R=But 55 45 90% Scheme 4 A wide range of ester and ketone enolates have now been reacted with acyclic enones and enoates and the stereochemical outcome of such reactions can be predicted very well.In some of the earliest studies Heathcock et al. reacted the enolate of t-butyl propionate with a, B-unsaturated esters or ketones and found that without HMPA in the mixture syn diastereoisomer 16 was formed selectively ( - 90% d.e.), but with HMPA present the anti isomer 17 was formed selectively ( - 90% d.e.).8(b) Yamaguchi carried out similar studies using ethyl propionate and found a similar selectivity Yamaguchi ascribed the switch of selectivity with HMPA as a solvating effect, but Heathcock has shown from wide ranging studies that the stereoselectivity directly reflects the stereoselective formation of alternative geometrical enolate isomers 14 and 15 under the different reaction conditions.In general, Z-enolates such as 15 are formed with HMPA and react to give anti addition products, whereas E-enolates such as 14 are formed (kinetically) without HMPA and react to give syn addition products. Heathcock originally proposed an 388 Contemporary Organic Synthesis‘open’ transition state model to account for this stereoselectivity,”(b) but in a full report of their studies with both ketone and ester enolates they propose chelated transition both ketone and ester enolates proceed with high stereoselectivity when the substituent on the enolate is large and the enolates are formed with a high degree of geometrical selectivity, as in the examples shown in Scheme 5. It was suggested that the E-enolate reacts selectively via transition state 18a leading to syn product 16 when the enolate substituent is large.In general, the reactions of LDN THF o / OLj HMPA Bu’O1]7 U ) ~ F B~b5‘ 14 BUb 15 E-enolate Z-enohte E-enolate Zenolate -- Me H H 18a 18b 19b 19e he 16 (goyo d.e.) Scheme 5 he 17 (84Yod.e.) However, with small substituents (X) the E-enolate can react through transition state 18b to give some anti product. Similarly, Z-enolates with a bulky substituent will react via transition state 19a to give anti product 17 with high selectivity, unless the substituent (X) is small and transition state 19b becomes viable. Yamaguchi et al. have added the enolate of t-butyl propionate to enoate chains bearing a terminal halide. Thus, after initial conjugate addition, the intermediate enolate is trapped by intramolecular alkylation leading to cyclic products (Scheme 6).When enoate 20 was the substrate, stereoisomer 2 1 was the exclusive 20 21 22 No HMPA loo : 0 With HMPA 0 100 Scheme 6 product without added HMPA, whereas 22 was formed exclusively with HMPA Lewis acid catalysed Mukaiyama-type conjugate additions, using silyl enol ethers as precursors, also proceed with high stereoselectivity and have been reported by Heathcock et al.9(C) The mechanism of these reactions is quite different from those using lithium enolates, and the stereoselectivity does not appear to be related to enolate geometry. Bernardi and Scolastico have reported that titanium ‘ate’ enolates react selectively in conjugate additions, often with enhanced 1,4 versus 1,2-~electivity.~’ The control of relative stereochemistry shown in the reactions illustrated in this section is very important and a number of enantioselective procedures have been developed which utilize this diastereoselectivity.Examples of such processes are presented in other sections of this review. 3 Double Michael reactions and other processes in tandem with conjugate additions 3.1 Conjugate addition followed by tandem enolate trapping An enolate is generated when an anionic nucleophile is added to an a,P-unsaturated carbonyl compound and this has potential for reaction with an electrophile in a ‘one-pot’ process. One of the most attractive and convergent strategies for prostaglandin synthesis is stereoselective reaction of a cuprate reagent such as 24 with a chiral enone 23, followed by stereoselective trapping of enolate 25 with allylic halides 26.This process would provide the complete prostaglandin framework in one synthetic procedure. The main 0 t 0- I 1 0 25 OTBS ] (CH2)3C02Me 26 &L (CH2)3C02Me C5H 11 PhaSnC TBSO’ t OTBS k y ; F y 3 C o 2 M e 29 I TBSO‘ ~ T B S 27 Scheme 7 Leonard: Control of asymmetry through conjugate addition reactions 389problem is that the copper-lithium enolate 25 is not sufficiently reactive to add to an alkyl halide such as 26. A number of groups have worked on this problem and there are now several solutions, including two developed by Noyori et al. In the first strategy the highly electrophilic aldehyde 28 reacted with the enolate derived from addition of 24 to 23, providing 29 in 83% yield.12(a,b) This was readily converted into intermediate 27 via radical deoxygenation. In a later development it was discovered that if enolate intermediate 2 5 was treated with triphenyltin chloride and HMPA it would react efficiently with alkyl halide 26, providing 27 directly in 78% yield (Scheme 7).12(c) Negishi et al.also found a solution to the addition of the upper chain which involves a palladium coupling process.13 A spectacular example of a 'one-pot' tandem conjugate addition-alkylation process was part of Heathcock's masterful biomimetic study on daphniphyllum alka10ids.l~ Compound 34 was produced as a single stereoisomer in 87% yield, when the enolate of amide 30 was reacted with enoate 32 and the intermediate enolate trapped with iodide 33 (Scheme 8).Enantiomerically pure compounds were produced when the starting amide 31 was chiral (R = Me). PhCH20, PhCH207 (iii) 33 32 R O 30 R=H 31 R=Me Methyl homosecodaphniphyllate Scheme 8 An intramolecular Michael/aldol strategy has been developed by Stork et al., providing trans hydrindenone systems in a highly stereoselective fa~hi0n.l~ Various conditions were explored for the cyclization of systems such as 35a or 35b and it was found that high yields and stereoselectivities were obtained using zinc isopropoxide (Scheme 9). Esters such as 37 could also be cyclized efficiently and a chiral auxiliary could be incorporated to allow control of absolute stere~chemistry.'~(') 3.2 Double Michael addition reactions Over recent years the double Michael addition process has been developed as a powerful tool for stereocontrolled synthesis (Scheme 1 O).lh In this 35a X = H2 35b X=O H 36a X = H2 S O % d.e.36b X = O H 37 38 X = Me or OMe, W%O, >90% d.e. Scheme 9 process a potential Michael acceptor is converted into a Michael donor 39, usually by enolization. When this reacts as a nucleophile with a second Michael acceptor, it reverts to a Michael acceptor and at the same time converts what had been the acceptor into a nucleophile 40. Finally, a second Michael addition takes place to complete the cyclization process. The overall process is equivalent to a Diels-Alder reaction and indeed it is often difficult to determine which mechanism is taking place. Although the double Michael reaction comprises two consecutive steps, the new stereocentres are normally formed with a high degree of stereocontrol because the intermediate 40 is a highly ordered entity.Indeed it is sometimes the case that a double Michael process is more stereoselective than the equivalent Diels-Alder reaction. 39 40 41 Scheme 10 Bellamy17 and later Ban18 reported early double Michael additions and more comprehensive studies were subsequently reported. Important studies were carried out by LeelY and White and Reusch20 into reactions of dienolates, derived from cyclic enones such as 42, with Michael acceptors such as methyl vinyl ketone and methyl acrylate. Bicyclic products 44 were produced in high yield and with a high degree of stereocontrol, suggesting that a chelated intermediate 43 was involved (Scheme 11). 42 R', R2, R3 = H or Me yields 7040% Scheme 11 43 1 x+: R 44 390 Contemporary Organic SynthesisSeveral other reports have detailed bic yclo[ 2.2.210~ tane preparations involving double Michael reaction^.^'-^^ Chelation control has been used to explain the high diastereoselectivity of such reactions, as illustrated by the reaction of dienolate 45 with enoates to give 47, via 46 (Scheme 12).22(b) In order to achieve control of absolute stereochemistry, Spitzner et al.used chiral auxiliaries on the ester of enoate substrates but the best selectivity achieved was 64% d.e.23(d) The isolation of uncyclized intermediates from the reactions, which can be cyclized in a second stage, indicates that the double Michael reaction is a stepwise process.22(a) '4 LDA ~ + gMe Me02C OMe 45 oMe \ L;t\/ Me0 J 46 47 R = Me, 92% Scheme 12 Where the dienolate substrate already contains stereocentres there is a high degree of asymmetric induction during the reaction (Scheme 1 3).24-27 For example, reaction of 48 with racemic alkoxyenone 49 gave 50 in which four new chiral centres have been introduced, with good control of stereochemistry relative to the benzyl ether.2s Similarly, racemic 5 1 was converted into 52 which was used as an intermediate in a synthesis of ( f )-eriolanine.26 0 -8 OBn l l , \ 0 1 OBn AR O m A..A.. 0 II /fMe 0 I I Iil LDA 4 ; ! c o 2 M e M e O o . ' 5 3 1 , TMSO LI OMOM OTMS OMOM stereoisomer in over 80% yield. This has all the stereochemical information required for the key reserpine intermediate 57. In a very short sequence of steps, involving simultaneous Baeyer-Villiger oxidation of the ketone and stereospecific silane to alcohol interconversion, 55 was converted into 57 via 56.Scheme 14 Kobayashi and Yamada have carried out some interesting double Michael studies.2s When they reacted the 2 alkoxyenoate 59 with the enolate from 58,61 was obtained as a single diastereoisomer and a chelated transition state 60 was proposed to account for this selectivity (Scheme 15). The double Michael sequence was much more stereoselective than an equivalent Diels-Alder reaction, carried out on the silyl enol ether of 58, which gave a 1 : 1 mixture of diastereoisomers. The E-isomer of 59 also reacted much less selectively in double Michael reactions (3.5 : 1) than the 2-isomer. When HMPA was added to the reaction of the E-isomer of 59 there was an interesting reversal of the stereoselectivity.28(b) The facial selectivity of enoate 59 towards the lithium enolate here is interesting and should be compared to the selectivity observed when other lithium reagents are reacted with this type of enoate (see Section 4).\C02Me TMSO Q (=CO,M~ ""0% 58 OMOM 59 LOA-TkiF 52 *I Scheme 13 Perhaps the best illustration of the power of the double Michael strategy is Storks enantioselective synthesis of reserpine.27 This is probably the most effective and elegant route to the alkaloid to date (Scheme 14). Michael acceptors carrying the required methoxyl group at the C- 17 position would not undergo the double Michael cyclization so the silicon reagent 54 was designed for the purpose.It reacted with the enolate of 53 to give 55 as a single 0 &OM 60 OMOM 61 Scheme 15 Deslongchamps et al. have used stabilized enolates of 63 and 65 in double Michael reactions with activated enone 62 to prepare cis-decalins of the type 64,66, and 67.29 t-Butyl ester 63 gave 64 (R = H) with Leonard: Control of asymmetry through conjugate addition reactions 39 1excellent stereoselectivity, but where R is alkyl the stereochemistry at that position was not very well controlled. When sulfones or sulfonates were used the relative stereochemistry of the major product 6 6 or 67 was reversed (Scheme 16). I 62 C02tBu 83 C02Me & 62 X = SOPh H 64 66 & 0 W O (i) Cs&Od CHCI3 65 (ii)AVHg H E = COpMe 67 Scheme 16 Intramolecular double Michael additions have been investigated extensively by Ihara et al.They studied cyclizations of systems such as 68a-c in some detail and found that lithium amide bases in THF or hexane-Et20 gave the best results, with high diastereoselectivity for 7 0 a - ~ . ~ " The absence of cyclization with sodium and potassium bases, and the fact that hexane-Et20 was the best solvent, led them to suggest that a chelated intermediate 6 9 is involved. They found that cyclizations under Lewis acid catalysed conditions were less efficient and less stereoselective (Scheme 17). 68a-c L J / m TBSOTW Et3NI -78% N 0 0 71 72 (75%, 100% d.e.) MeO MeO - Ph la Scheme 18 74 (83%, 100% d.e.) Cyclization of the optically active ester 75 occurred via the predicted lithium-chelated intermediate to give 76 which has been converted into the terpene ( + )-ari~irene.~* Similarly, a highly stereoselective cyclization of 77 to 78 was the key reaction in an elegant synthesis of the aconitium alkaloid ati~ine.3~ A Lewis acid catalysed double Michael reaction of 80 was used as the key step in a synthesis of tylophorine. ?5 UHMDS 76 (92%.100% d.e.) Me0 77 78 (58%, 100% d.e.) 79 (atisine) Vl c R=Me,n=O E : p o / loIl W h , 100% d.e. A r l + Q J L o , R Ar )" 7Ob W0, 100% d.e. 0 w- 80 Ar = 3,4-C,H3(OMe), 7Oc 64%, 100% d.e. Scheme 17 R = phenylmenthyl OMe In contrast to the examples above, amides such as 71 and 73 did not cyclize under basic conditions, but were cyclized efficiently, in a highly stereoselective manner, under Lewis acid catalysis at low temperature.Since no intermediate silyl enol ethers could be detected, a double Michael mechanism rather than a Diels-Alder mechanism was suggested (Scheme 1 8).31 double Michael reactions in efficient and highly stereoselective approaches to several classes of natural products and some examples are given in Scheme 19. MeO ~ e o Ihara et al. have also used such intramolecular OMe OMe 82 (-)-Tylophorine ~W/O 8.8. 81 (9%, 100% d.e.) Scheme 19 392 Contemporary Organic SynthesisR R Using a phenylmenthyl ester as a chiral auxiliary, intermediate 8 1 was formed as a single stereoisomer and converted into tylophorine 82 in enantiomerically pure form.34 This group have also used double Michael reactions in approaches to steroid^,,^(^^^) triq~inanes,~~(~) and quinolizidine alkaloid^.^ A quite spectacular approach to seychellene involved a triple Michael reaction (Scheme 20).36 Hagiwara et al.reacted 83 and 84 together under Lewis acid conditions and obtained, in a single step, seychellene precursor 87 in 43% yield. The reaction presumably proceeds via intermediates 85 and 86. 03 1 8 4 CH&I, 43% ="I 0 seychellene 07 Scheme 20 0- - - I I i 4 Conjugate addition to acyclic a$-unsaturated systems bearing a chiral centre at the y-position 4.1 Reactions with ester and amide chiral auxiliaries Conjugate additions to cyclic a,#?-unsaturated systems bearing a chiral centre at the y-position are normally very predictable (see Section 3), but that is certainly not the case in acyclic systems, and indeed empirical results are quite c o n f u ~ i n g .~ ~ - ~ ~ Yamamoto et al. reported additions of a range of nucleophiles to a,#?-unsaturated systems of type 88a-e (Scheme 2 Addition of copper or copper-lithium reagents appeared to favour anti products from substrates with an E-alkene. Addition of copper-lithium reagents to Z-substrates or those with two electron-withdrawing groups generally favoured the syn product. Ally1 tin reagents generally reacted with the opposite selectivity as did monocopper reagents on Z-alkenes. A modified Felkin transition state (Figure 2a) with the large phenyl group perpendicular to the alkene and the methyl group on the 'inside' accounts for the formation of the anti product from the E-alkene. Yamamoto suggested that this mode of reaction was favoured for nucleophilic attack, whereas reagents that react via an electron- transfer mechanism would attack predominantly via the arrangement in Figure 2b, to give the syn product as the major isomer.Interestingly, when p-dinitrobenzene was added to some of the copper-lithium reactions the stereoselectivity was switched. Heathcock found that TMS-enol ethers react with the E-unsaturated methyl ketone 88e, in the presence of TiCl,, to give syn adducts in a highly selective manner. P h f l P h e Me Y Me Y Me Y a X=Y=CN Bu2CuLi 68% 9(68)+ : 91(32)* BuCu 72% 23(67)+: 77(33)* Bu,/AIBN/Bu~S~H 13% 82 : 18 e S n B U 3 52% 71 : 28 b X=Y=COPEt Bu&uLi 87% 8 : 92 Bu,CuLi.BF3 67% 32 : 68 e S n B u , 93% 96 : 4 BuCu.BF3 90% 74 : 26 c XzC02Et Bu~CULLBF~ 90% 70 : 30 BuCU.BF~ 82% 88 : 12 d X = H Bu&uLi.BF, 89% 30 : 70 Y=Co2Et BuCu.BF3 84% 74 : 26 e X = COMe TMSO 10 : 90 Y=H WT~CI, R Y=H * Figures in ( ) are for reactions with added pdinitrobenzene Scheme 21 Ph Me "Ph F- F phfl anti Me Y R Ph*X syn Me Y F phyy anti Me Y Nu' ngure 2 - Modified Felkin model Morokuma et al.40(a) and Bernardi et al. 40(b) have carried out molecular mechanics studies to try to account for the observed stereoselectivities of these reactions. They appear to agree that the modified Felkin model (Figure 2a) should be preferred for reactions of E-alkenes, but both groups have difficulty in accounting for the observed product ratios for the Z-alkenes and for the disubstituted alkenes. However, they agree that the 'inside' position of the methyl group is disfavoured and that reaction occurs via the arrangement in Figure 2b (leading to syn product) or that in Figure 2c (leading to anti product) and that the preference can be dependent upon the reagent, conditions, etc.the stereoselectivity preferences are even more For y-oxygenated a,#?-unsaturated systems, some of Leonard: Control of asymmetry through conjugate addition reactions 393difficult to interpret. In contrast, addition of organometallic reagents to cyclic enones bearing an alkoxide at the y-position is easy to rationalize. For example, cuprate-type reagents add from the opposite face to acetalized diol systems in both five-membered rings (e.g. 91)41(a) and six-membered rings (e.g. 92) (Scheme 22).41(b) In the case of alcohol 94, chelation of Grignard reagents produced high selectivity for addition syn to the hydroxyl, whereas cuprates reacted anti to the hydr~xyl.~l(~) The steric preference of cuprates was also illustrated by their selective attack from the same face as oxygen rather than sulfur with a hemithioacetal substitutent in the y-position.41(d) 91 0 Ph 0 OMOM MOMOCHzLV CuBr.Me& THF 91 (70%) 0 0' )r6 93 (93%) R-MgBr - -0 : R2CuLi.Me8 - -90 Scheme 22 Ph -100 -10 Some of the earliest investigations on conjugate additions of organometallic reagents to y-alkoxy a$-unsaturated sytems set the pattern that the stereoselectivity of such reactions is very difficult to rationalize (Scheme 23).Both N i c ~ l a o u ~ ~ and Ziegler43 investigated conjugate additions to carbohydrate derived ester 97. They found that most copper-lithium reagents reacted with high selectivity ( - 90% d.e.) in favour of the anti addition product (e.g.98). Roush also found that compounds 105a-c reacted with similar ~electivity.~~ However, it was surprising that allylic cuprates reacted with 97 to give syn products (e.g. 99) with high sele~tivity.4**~~ Unsaturated ester 103 also gave syn addition product 104 when reacted with a stabilized sulfoxide lithium reagent.45 The E / Z geometry of the alkenes appeared to have little influence over the outcome of these reactions. Roush proposed a modified Felkin transition state to account for the addition of vinyl cuprates to these systems, but suggested that allyl reagents might be an e~ception.4~(~) Ziegler et al. attempted to clarify the discrepancy by reacting 100 with allyl and butyl-lithium reagents.This substrate bears a chiral oxazoline unit which is also capable of directing an incoming organometallic reagent with predictable face 0 K 0 0Bn 0 Bu OMe 0 97 OMe I he \ 4 W T H F OMe 99 (81%. 86% d.e.) pKp oMe * K Ph k6 100 OMe [*. py bM* Ph 102 (90% d.e.) stereochemistry opposite to that predicted by Meyers' model 103 lo4 (79%. syn only) 105a-c 106a X = H, 90%. 90% d.e. b X = OMe, 30%. 82% d.e. c X = Me, 96%d.e. Scheme 23 selectivity (see Section 5 for examples of the use of this auxiliary). They found that butyl-lithium added with higher selectivity from the opposite face than Bu2CuLi addition to 97, with the facial selectivity predicted by Meyers' model for such oxazolines. It may have been that the oxazoline was simply overriding the effect of the y-alkoxide, but unlike cases of very similar simple 394 Contemporary Organic Synthesisoxazolines, allyl-lithium reagents again reacted with the opposite selectivity.Ziegler stated in 198 1, 'it is apparent that subtle effects are operative and no simple analysis of reactive transition state conformations of the substrates could have predicted a priori the eventual outcome of these reactions'. It is still difficult to rationalize these results and those described below. Cha and Lewis reported that the addition of Me,CuLi to a glyceraldehyde derived enone 107a gave the anti product with modest stereosele~tivity,~~ but a more extensive study by Leonard et al. has again highlighted some anomalies (Scheme 24).47 Both E- and 2-methyl ketones 107a and 107b gave the anti product as the major isomer when reacted with isopropenyl copper reagents, but the stereoselectivity was reversed with butyl reagents.It was surprising that both monocopper and most lithium reagents gave high yields of conjugate addition products, with the lithium reagents being highly syn selective. Lithium reagents also added in a conjugate manner to ester 107c and ketoester 107d, but again the stereoselectivity was puzzling. Most of the reactions were moderately syn selective, but lr" 0 1 a X = Me, Zalkene b X = Me, Ealkene c X = OEt, E-dkm d X = CH2C02Et, Edkene I I w O R butyl-lithium added to 107d with a slight preference for the anti-isomer and phenyl-lithium gave high anti selectivity. It was intriguing that phenyl-lithium gave only 1,2-addition with 107b and only conjugate addition with 107d.Addition of a silicon radical to ester 107c has recently been reported to take place with 82% d.e. on the Z-alkene and 40% d.e. on the E-alkene, but the configuration of the major adduct was not determined.48 additions to simple y-benzyloxy enoates 1 10a-c (Scheme 25).49 The E-enoate generally reacted with anti selectivity, whereas the diester was generally syn selective. The selectivity of the 2-alkene was variable and the ally1 reagent shows some inconsistency with the others, but not the dramatic change noticed for additions to 97. It was also found that t-butyldimethylsilyl ethers react with almost identical selectivities, indicating that chelation is not an important Yamamoto carried out an extensive study of cuprate OBn 0 1lOa-c ?Bn Etov+ O R 112a-c, syn Yield anti syn Reagent a X = H, 6alkene (CH2=CH)2C~Li 99% 72 : 28 (CH,-CH),CuLi.BF3 58% 96 : 4 O R (CH&H)~CUCNL~, 83% 72 : 28 1-, syn (CH2=CH)2C~CNLi2.BF3 66% 95 5 Reagent 1,4:1,2 Veld anti syn X = Me, Zalkene CH2(Me)CCu 1:O 80% 8 : 1 [C H2( Me)CI2CuLi l:o 60% 4 : 1 [CH2( Me)CkCuCNLi, l:o 73% 7 : 1 X = Me, €-alkene R"mQMe2CuLi CH2(Me)CCu [CH,(~V~~)C]~CUL~ BU"CU Bun2CuLi CH2(Me)CLi Bu"Li PhLi 1 :o 1 :o 1 :o 1 :o 1 :o 19:o 2.50 1:lO 56% 80% 60% 70% 50% 60% 76% 76% 4 : l 5 1 3 : l 1 : 1.5 1 : 3 1 : 3 6 1 : 15 2 : l X = OEt, Galkene (solvent -Et20) CH 2( Me)CLi 3:l 65% 1 : 5 Bu"Li 6 3 1 66% 1 : 6 MeLi 6:l 70% 1 : 6 X = CH2C0,Et, Galkene (solvent - THF) CH2(Me)Ch 251 82% 1 : 4 Bu"Li 3 1 66% 2 : 1 PhLi 1:0 61% 12 : 1 Scheme 24 MeCu.BF3 BuCu.BF3 [CH2=CHCH2],CuLi (CHFCH),CUL~ (CH2=CH)2CuLi.BF3 (CHPCH)~CUCNL~~ (CH2=CH)2C~CN Liz .BF3 b X = H, 2-alkene MeCu.BF:, BuCu.BF3 [CH2=CHCH2I2CuLi (CH2=CH)&uLi (CH2=CH)&uLi.BF3 (CH+?,H)2-C~CNLi2.BF3 c X = C02Et (CH&H)~-CUCNL~, MeCu.BF3 BuCu.BF3 [CH~=CHCH~]~CUL~ 60% 64% 99% 82% 63% 58% 64% 30% 56% 99% 91% 91 % 94% 96% 54% 52% 79% 69 : 31 92 : 8 42 : 58 >99 : 1 52 48 96 : 4 21 : 79 22 : 70 22 : 78 20 80 38 : 62 39 61 29 : 71 31 : 69 6 : 94 5 : 95 10 : 90 Scheme 25 Hanessian has shown that y-alkoxy enoates 113a-d react with Me,CuLi/TMS-C1 with consistently high anti selectivity (Scheme 26).However, the stereoselectivity was reduced slightly when the 8-doxy group was Leonard: Control of asymmetry through conjugate addition reactions 395replaced by a methyl group.When the same reaction conditions were applied to enolates bearing a nitrogen group in the y-position syn products were formed seiec tively . 11 4 a 4 , anti 7-96 pR2 anti syn 0 A2 Meo)fVW a R' = CH20SiPhBut, $ = BOM 14 : 1 Wn b R' = CHpOSiPhBu', I?- = MOM 11 : 1 c R' = CH20SiPhBu', F? = Me 10 : 1 2 : 1 d R' = CH3, R2 = BOM Scheme 26 It has also been shown that glyceraldehyde derived systems, for example 116, react with nitrogen and oxygen nucleophiles with a high degree of syn selectivity (Scheme 27).5' 0 116 O R 117a,b, syn PhCH20Na - 87%. 80% d.e. PhCH2NH2 - 87%, 80% d.e. Scheme 27 Bernardi and Scolastico have studied a range of conjugate additions on oxazolidine 1 18, and found generally high consistency for anti selectivity (with respect to oxygen).The stereochemistry at the y-position appears to be the controlling factor (Scheme 28).52 Ph Ph a Ph 119 anti 120 syn anti syn Me2CuLi 14 : 1 B&CuLi 11 : 1 [CH2=CH]2CuLi 10 : 1 [CH&H]2CH2C~Li 9 5 : 5 BnONa+ 9 5 : s Higher order cuprates ( R3CuLi2) have also been found to react in a highly stereoselective manner with y-hydroxy-a$-unsaturated sulfones 12 la-c (Scheme 29). Again the major isomer had an anti arrangement between the hydroxyl and the added alkyl 12la-c 122a-c a R' = Me, R2 = Me - 92%, 78% d.e. b R' = Bu". R2 = Me- 90%. 84% d.e. c R1 = Pr', R 2 = Bun- 91%, 82% d.e. Scheme 29 Roush originally suggested a modified Felkin m0de1,~~(~) with the small group (H) adopting the 'inside' position (Figure 3a), to account for the more common anti addition of cuprates to y-alkoxy-a, p-unsaturated systems.Other workers initially adopted this model and Leonard et al. suggested a chelated modification to account for the syn selectivity of lithium reagent^,^^(^) although the syn addition of ally1 cuprates could not be accounted for. Morokuma et al.40(a) and Bernardi et aZ.40(b) have attempted to account for the observed stereoselectivities through molecular mechanics studies, but their conclusions differ. Bernardi et al. suggested that a Felkin-type transition state (Figure 3b) accounts for the syn selectivity of lithium reagents and alkoxides, and that anti addition of certain cuprates may be caused by chelation. However, chelation of cuprates and not lithium reagents would appear to be unlikely, especially in the light of Yamamoto's results with silyl ethers.Nu' Nu' Nu' (b) Nu b i OR' Scheme 28 Figure 3 396 Contemporary Organic SynthesisMorokuma et al. suggested a transition state with the alkoxide in the inside position (Figure 3c) to account for the anti attack of most cuprates on trans-alkenes. Leonard et al. have also proposed a similar arrangement based on the lowest energy ground state conformation of 107a and again suggest that chelation of lithium reagents could lead to directed syn a d d i t i ~ n . ~ ~ ! ~ ) Yamamoto et al. suggested several models to account for the results in Scheme 25 .49(b) They concur that the model in Figure 3c could account for the anti attack of most cuprates on trans-alkenes, but suggest that some cuprates react preferentially via a n-complex, as in Figure 3d, leading to syn adducts.Overall, there is no universal model to account for the array of observed selectivities for additions of nucleophiles to y-alkoxy-a, B-unsaturated systems. There are several unusual anomalies and none of the models proposed so far are really satisfactory. Although not strictly related to the other reactions in this section, Evans has reported that efficient 1,3-asymetric induction can occur via conjugate addition directed by a hydroxyl at the &position on an acyclic chain.54 Some examples are shown in Scheme 30. The reaction process is simple and the structure of substrate 123 appears to be very general. A methyl group of either configuration at position R2 appears to have little effect on the outcome or stereoselectivity of the reaction and a range of other groups along the chain can also be tolerated.Ph I o*o - R’ U X i2 123a-d PhCHO ‘ 1246d R’ = Et, R2 = H, X = OMe R’ = Ps, R2 = H, X = OMe R’ = PhCH2CH2, Ff = H, X = OMe R’ = Pi, R2 = HI X = N(Me)OMe 79%, 9OW.e. 71%. W . e . 73%, 92oM.e. 71%. 90Yd.e. Scheme 30 5 Conjugate additions to a, @-unsaturated systems with chirality in the electron-withdrawing group 5.1 Conjugate additions to a, @-unsaturated esters and amides derived from chiral alcohols and chiral amines A variety of organometallic reagents add to a,B-unsaturated esters and amides in a conjugate manner. If the alcohol or amide from which the system is derived is a chiral unit there is potential for asymmetric induction.Hydrolysis would then release the original chiral auxiliary group as well as a chiral acid (Schemes 3 1 and 32). Esters generally have a practical advantage over amides in that they are easier to hydrolyse, and a wide range of chiral alcohols have therefore been investigated as auxiliaries. Addition of organo-copper-lithium reagents to esters is often an inefficient process but Oppolzer et alVs6 found that 0 It R2-Ma 0 R2 II I * ‘X-H + JJRl HO Lp- chiral or chiral alcohd mine HO chiral acid Scheme 31 monocopper reagents (RCu) with added F,B . OEt, and PBu, react with esters of phenylmenthol125a in a highly diastereoselective manner. Even when reactions of this sort give high levels of diastereoselectivity it is useful to be able to purdy the addition product to a single diastereoisomer before removal of the auxiliary, to provide the final product in enantiomerically pure form.For this reason the use of camphor auxiliaries has been examined because they are generally highly crystalline, allowing the initial addition product to be purified efficiently by simple cry~tallization.~~ Neopentyloxy esters 125b reacted with generally good facial selectivity with copper reagents and this auxiliary has been used successfully in several natural product ~yntheses.~’ Either enantiomer of the auxiliary is available and the mode of attack is indicated in Scheme 33, showing how isopropenyl copper reacted with 127 as the key step in a synthesis of California-red-scale pheromone 129. Ester dienolate 130 also reacted with good facial selectivity as a nucleophile in a conjugate addition to cyclopentenone. The enolate generated was reacted in situ with ally1 bromide to give 131 which was then used as a sesquiterpene precursor (Scheme 34).also reacted with high diastereoselectivity, but are considered to be more practical than those above because of their ease of preparation and high crystallinity. The mode of reaction of these esters is shown in Scheme 35, which illustrates a route to southern corn rootworm pheromone 134.58 Oppolzer et al. also developed the sultam auxiliary 12 5d for Diels-Alder reactions initially, but it has proved very useful for conjugate additions.5Y Although an amide bond connects the auxiliary, it is very easily cleaved with LiOH with complete recovery of the auxiliary.The auxiliary is also installed very easily, its derivatives are highly crystalline and hence it is one of the most practical of all the chiral auxiliaries that have been developed, for any purpose, to date. It was discovered that Grignard reagents add very effectively to the sultam enoates and that the stereoselectivity of addition is defined by a chelated transition state (Scheme 36). As well as simple conjugate additions, tandem addition-electrophile-trapping reactions have also been achieved with good stereoselectivity at both a- and /%positions. The outcome of the reaction depends on the original substituents present and on whether the intermediate magnesium enolates ( e.g. 136 or 138) are protonated or alkylated. Alkylation of 136 leads to 137, while protonation of 138 leads to 139.The enoates ( e g . 140) also undergo Sulfonamide esters 125c, and their enantiomers, Leonard: Control of asymmetry through conjugate addition reactions 397R2-Met *X R' Diastereoselecthre * *X addition 125a-I 126a-l Yield d.e. WS Auxiiiary(X+) R' V-Met Yield d.e. R 5 Auxiliary(>C) R' P-Met tran~Me PhCu.BF3 76% >99% R transMe Bu"Cu.BF, 75% >99% R transBu MeCu.BF, 96% 87% R a &: &Me PhCu.BF3 36% 24% R transBu MeCu.BF3 02% 94% R transMe CHFCHCU.BF, 85% 94% R transEt MeCu.BF, 85% 92% R transMe BU"Cu.BF, 89% 97% S transMe CH2=CHCu.BF3 80% 98% R t r a ~ B u MeCu.BF3 93% 97% R Me2PhSi Mecu.BF, 61% 86% Me2PhSi BuCu.BF3 61% 92% Me2PhSi PhCu.BF3 86% 94% transMe EtMgCl 85% 90% R 0 2 trans Me BU"MSCI 02% 84% R trans Me EtCu.BF3 90% 99% R transMe PhCu.BF3 97% 99% S NS02ph fmnSMe CH~=CHCU.BF~ 94% 99% s trans Me EtCu.BF3 84% 99% s transMe CH,=CHCu.BF, 81% 99% R %S02Ph transMe PhCu.BF, 94% 99% R Ar trans Me Bu,CuLi trans Me Ph,CuLi trans Ph Me,CuLi transPh mCuLi OH transPh Bu2CuLi 0 transPh MeMgBr.Cul trans Ph EtMgBr.Cul P-& \ / Me Me,,, N transMe EtMgBr trans Bu PhMgBr Ph'OH trans Ph EtMgBr 91% 88% R 96% 99% R 71% 84% s 84% 87% R 71% 58% 73% 48% s 38% 20% 58% 98Yo s 54% 99% R 47% 98% R transMe BuMgBr 29% 84% s trans Ph BuMgBr 49% 1Oo%S trans Ph EtMgBr 51% 88% S trans Me EtMgCl 75% 80% R transPh CH,=CHMgBr 90% 85% S transBu PhMgBr 77% 96% s trans Me Et2AICI 70% R tram Ph Et2AICI 78% s trans Ph Me2AK=I 84% s 0 AN %Ph Scheme 32 R'Cu.PBu3 8 127 -BU' 0 128 129 2s 0-But 130 O f l ,o ?p' 0 Scheme 34 ** 0 131 Scheme 33 RCU stereoselective conjugate reduction with lithium tri-s-butylborohydride and again the lithium enolate trapped with electrophiles selectively as shown.Helmchen et al. have developed 125e and 125f as useful camphor derived auxiliaries, which react to give 132 133 134 0 To+ d$ M:G intermediate 141 or 143 can either be protonated or - OR' _c / 0 (cylohex)2 0 products with opposite configuration at the newly formed centres."O Again their enoates react with high Scheme 35 398 Contemporary Organic Synthesis135 138 139 137, (82%. 82% j3d.e. 98% ud.e.) 139, (81%. 99% j3d.e. 9930 Ord.e.) R1 = Me, R2 = Bu, E = Me(l) R1 = Me. R2 = Et 143 144 142, (64%, 90% pd.e. 88% 0rd.e.) 144, (85%. 82% 0rsJ.e.) R1 = Bu, R2 = Me, E = Me(l) R1 = Et.R2 = Me Scheme 36 levels of selectivity with copper reagents.60(a,b) Recently 145 has been reacted with silylated ester enolates in the presence of a P40,, catalyst to provide chiral 2,3-disubstituted cyclopentanones 146 in good overall yield (Scheme 37).h0(C) OsiTBs C02Me 0 146 (8OV0 d.e.) Scheme 37 Fang et al. have reported that enoates, such as 125g, derived from quite simple diols can give high levels of diastereoselectivity when reacted with copper-lithium reagents:' Fuji et al. found that both copper-catalysed Grignard reagents and copper-lithium reagents react with reasonable diastereoselectivity with mono-enoates derived from binaphthol 1 25h.62 These two classes of reagent react with opposite face selectivity because of different internal chelation effects.Fleming et al. showed that several of the enoates in Scheme 32 react selectively with phenyldimethylsilyl copper-lithium, allowing the introduction of a chiral centre at sili~on.h~(~) More recently, Polomo et al. have shown that higher order silicon cuprates react with sultam derived enoates with a high degree of shown that amines react with enoates bearing chiral auxiliaries to give addition products with d.e.s. in the range of 75-95°/0.64 d'Angelo has also Mukaiyama and Iwasawa found that simple enamides 125, derived from ephedrine, add Grignard reagents in a conjugate manner with good diastereoselectivities.hS((") A chelated magnesium alkoxide is believed to be responsible for the high levels of stereoselectivity. More recently, Touet et al.found that derivatives of the very cheap chiral amine 2-aminobutanol are also very effective auxiliaries.hs(b.c) Mukaiyama also found that oxazepines 14 7, derived from ephedrine, undergo conjugate addition of Grignard reagents with very high facial selectivity, leading to chiral acids with high e.e. on hydrolysis (Scheme 38). The drawback with this technique is that the oxazepine is difficult to prepare and is destroyed on the final hydrolysis.66 147 (64-94%, up to 99% e.e.) Scheme 38 Soai et al. have investigated conjugate additions on several enamides bearing auxiliaries derived from proline and prolinol (e.g. 125 j)P7 They achieved fairly good d.e.s. with moderate yields using prolinol derivatives, but the stereoselectivities were not as good using derivatives of proline i t ~ e l f .~ ~ ( ~ ) In either case addition of tertiary amines improved the selectivities. Tomioka et al. achieved fairly good diastereoselectivity through conjugate Grignard additions to trityl prolinol derived enamides 125k.68 An interesting use of an 0-methyl prolinol auxiliary was reported by Schultz and Harrington.69 A Birch-type reduction of 149 gave enamide 150 which reacted with Grignard reagents, in the presence of ZnBr,, with good facial selectivity (Scheme 39). I I RMgW ZnBrflHF 149 OMe R = Me, 80%, 67% d.e. R = I ~ H ~ $ , ~ ~ $ o ~ & % Ph, 49%. 94% d.e. d.e. ep 151 OMe Scheme 39 Oxazolidinone derived enamides 125 I have recently been reacted with alkyl aluminium chlorides with moderate diastereosele~tivity,~~ and Cardilo et al.have chlorinated similar enamides, although the diastereoselectivity was Leonard: Control of asymmetry through conjugate addition reactions 3995.2 Chiral auxiliaries based on oxazolines and imines Meyers was one of the pioneers in the use of chiral auxiliaries for creating new chiral centres with high stereoselectivity. In particular, his group were one of the first to develop effective methods for obtaining products with high enantiomeric excess via conjugate addition reactions. In order to increase the rigidity of the transition state for the addition they used an oxazoline ring as an equivalent masked form of an acid. The oxazoline ring conveniently holds the chiral auxiliary and, after the conjugate addition, it is released by hydrolysis to unmask the acid unit, or by reduction to provide an aldehyde (Scheme 40).72*73 MeO; a MeO; Scheme 40 It was discovered that the stereochemistry of the conjugate addition was governed largely by the stereochemistry of the group a-to the nitrogen in the oxazoline.In early studies this was normally a chelating methoxymethyl group. It was found that organometallic reagents react with high selectivity from the face opposite the methoxymethyl group. This was attributed to that face being hindered by chelation, as shown in Figure 4(a). Figure 4 In more recent studies a bulky group in the same position proved to be equally effective in controlling the stereochemistry of addition to the same face (Figure 4(b).75 Some examples of conjugate additions that have been carried out are shown in Scheme 4 1.The absolute stereochemistry at the new chiral centre can be controlled by reversing the groups attached to the alkene and of the organometallic reagent. The intermediate enolate ion can also be methylated with a high degree of stereo~electivity.~~ Tomioka et al. carried out similar studies to those of Meyers, using imines instead of oxazolines, but the 9' 152 153 Awiliary(X') R' t - M e t X Yield d.e. Fvs Ma-, Me EtLi OH s Me Bu"Li OH 0 Ph Etti OH Bun PhLi H 0 Cyclohexyl PhLi H 0 Ph BU"Li H Ma-, (I) &4i. Me1 ph4L~l 0 (ii) H30' D 152a 40% 92% R 38% 91% R 44% W O s 73% 99% R 66% 97% R 53% 97% s 60% 96% R 53% 96% R r3re 154 Scheme 41 X R' R2 R3-Met Yield d.e. WS Pr' Me H PhMgBr 49% 65% R But Me H PhMgBr 42% 91% R 56% 95% s But Ph H EtMgBr But -(CH&- PhLi 8% 82% But -(CH&- CHpCHLi 36% 71% But -(CH2),- PhLi 5% 49% But -(CH& CHFCHLi 310/0 69% Scheme 42 e.e.s were generally somewhat lower (Scheme 42).7s(c) Again, a chelated transition state was proposed to account for the high levels of stereoselectivity.They also found that the intermediate enolates could be alkylated in situ with good stereochemical control? An example of one such trapping reaction is shown in Scheme 43, which was part of a synthesis of ( + )-ivalin. (+)-ivalin, 95Vo 8.8. Scheme 43 400 Contemporary Organic SynthesisMeyers et al. found that the chiral oxazoline activated certain aromatic and heteroaromatic rings towards nucleophilic attack and led to induced chirality at the chiral centre formed by the n~cleophile.~~ Some examples of nucleophilic additions to 3-substituted pyridines are shown in Scheme 44.Alexakis et al. have extended this methodology, using an alternative heterocyclic auxiliary and used it in approaches to indole alkaloids.78 W-Met Yield d.e. WS Meti 79% 88% S PhLi 94% 84% S PhLi 82% 82% BU”M~CI gwo 90% s Scheme 44 An oxazoline substituent activates naphthalene rings towards nucleophilic addition of lithium reagents, and it was found that such additions can be highly stereoselective with respect to chiral centres in the oxazoline. The anion formed on addition of the lithium reagent is an effective nucleophile and can be trapped by a range of electrophiles. If the intermediate anion is simply protonated the oxazoline ends up trans to the nucleophile, whereas trapping with electrophiles leads to a cis relationship between the nucleophile and the oxazoline ring.Scheme 45 shows some representative examples of this type of reaction.79 This methodology has been used in several natural product syntheses.80 A neat example of how it has been exploited is illustrated by the synthesis of podophyllotoxin, as outlined in Scheme 46.80(a) It was also found that similar additions to naphthalenes could be carried out using t-butyl substituted imines, rather than oxazolines, as the chiral activating agent.81 A useful approach to chiral biaryls involves nucleophilic substitution of a methoxyl group ortho to an oxazoline ring (Scheme 47).74,82 Diastereoselectivity of the reactions is usually high and is normally governed by the reaction proceeding through the transition state with minimum interaction between the substituents on the nucleophilic ring and the oxazoline substituents.An example is the reaction between Grignard reagent 167 and oxazoline 168 which gives 169 with 87% d.e. An exception to this mode of stereocontrol occurs where there is an alkoxide group on the nucleophilic ring which can chelate with the magnesium in the transition state complex. This results in the opposite stereochemistry at the new chiral centre, as illustrated by the reaction between Grignard reagent 170 and oxazoline 168.74 Highly substituted aromatic systems are tolerated in the coupling process and several approaches to natural products have been based on this methodology.82 An example was the coupling between Grignard reagent 0YN 161 162 163 Auxiliary Naphth.R3Li E Yiild d.e. Prod MeO-, 1- MeLi H+ 42% 70% 163 1- BLTLi H+ 73% 88% 163 a P h Z J Phti H’ @Yo Toyo 163 1- BU”ti PhS(SPh) 99% 94% 164 0 1- Bu”ti Me(I) 97% 88% 164 1- Bu”Li Me02C(CI) 42% 70% 164 1- CHFCHLi Me(I) 80% 60Y0 164 2- Bu”Li Me(I) 85% 96% 164 4 *- PhLi Me(I) 89% 80% 164 1- Bu”Li Me(I) 99% 98% 164 2- PhLi Me(I) 81% 90% I64 0 1- CHFCHLi Me(I) 94% 98% 164 b Scheme 45 \OMe -0- N t O M e MeO OMe OMe 166 (75V0, 86% d.e.) OMe (-)podophyllotoxin Scheme 46 172 and oxazoline 173 which provided steganone precursor 174 as an 88 : 12 mixture with its diastereoisomer.82(b) a, B-Unsaturated chiral a c e t a l ~ , ~ ~ and chiral oxazolidine~,~~ can be reacted with nucleophiles in conjugate ( SN2‘) fashion, with induction of chirality at the newly formed chiral centres.These reactions are related to those covered in this section, but will not be described in this review. Leonard: Control of asymmetry through conjugate addition reactions 40 1qMe 167 MgBr ,Ph OMe 09- &N 168 "1 OMe 169 (a%, 87% d.e. [S]) a OMe .. ** 175b 178 (S) 179 (S) MgBr Ph 172 Me0 8 OMe OMe 174 (85%, 65% d.e.) 173 MeO (-) -st eganone Me0 OMe Scheme 47 1 EtTi(0Pr')a 6TYo 90% R 1 CHpCHMgBr/ZnBr2 75% 99% R 1 PhMgCVZnBr2 70% 92% R 2 M~LVTCYOP~')~ 83% 9 6 ~ ~ R 2 PhLi/TiCI(OP& 58% 93% R Scheme 48 ZnBr,, leads to reaction via chelated intermediate 175a which is hindered on the lower face and therefore reacts to provide ( R )-addition products 176( R ) selectively. The sulfoxide unit is easily removed by A1-Hg reduction, providing 177 or 179.A range of nucleophiles have been used in these additions and the intermediate a-enolate can be reacted with electrophiles, ether in situ or during a subsequent step.xh(h) The methodology has been used in several neat steroid syntheses, including the route to esterone methyl ether outlined in Scheme 49.86(c) Wallace et al. synthesized chromones with the tolysulfinyl group in the 3-position and found that copper-lithium reagents add to them, leading to 2-alkyl chroman-4-ones with high e.e.x7 5.3 Conjugate addition to a , p-unsaturated systems bearing a chiral sulfoxide at the a-position Although a chiral auxiliary at the a-position can provide effective chiral induction during conjugate additions, removal of the auxiliary might be difficult.(it) NaHlMel (57%) a , B-Unsaturated sulfoxides themselves do not react with nucleophiles in a conjugate manner, but Posner et Me0 780 (iv) BCHSH-CM~;~ (7194) (iii) M&uLI 1 al. have shown that the sulfoxide is an excellent chiral auxiliary in the a-position of Q , /3-unsaturated ketones.85-8h It was discovered that, depending on reaction conditions, one sulfoxide stereoisomer 175 could direct nucleophiles to either face of cyclic a , B-unsaturated systems. The ground state conformations of the (S)-sulfoxides 175 (five and six-membered rings) are similar to 175b (Scheme 48). lower face and the products will be 178( S). On the other hand, the addition of chelating agents, such as &r# \ Me0 \ Me0 Nucleophiles will attack this conformation from the (-)-esterone methyl ether 181 Scheme 49 402 Contemporary Organic SynthesisAnother example of a chiral auxiliary in the a-position has recently been reported by Yamamoto et al.They found that prolinol methyl ether derivatives, such as 182, reacted with copper-lithium reagents in a highly diastereoselective manner. The chiral auxiliary was eliminated during the reaction to leave a potentially useful a-methylene group 183 (Scheme 50). Acyclic systems reacted with somewhat lower selectivity.88 B 0 ,-OMe I1 n R&uLU LiBr wNa -go-o”c/THF * n R9CuLi Yield e.e. 183 1 82 ~~~ ~ 0 Et2CuLi 70% 84Y0 1 Me2CuLi 81Y0 95% 1 Bu2CuLi 81% 95% 2 Me2CuLi 87% 96Y0 2 Bu~CUL 91% 98Yo Scheme 50 6 Conjugate additions where the asymmetry is introduced via chiral centres covalently bonded within the nucleophile Some time ago Mukaiyama et al.developed ephedrine derivative 184 as a chiral malonate analogue. They added it to simple enones such as cyclopentenone, from which they obtained cyclopentanone-3-acetic acid, via 185, with a moderate e.e. (Scheme 51).5(a),89 0 43% yield 4445% 8.8. 186 Scheme 51 More recently, Brown et al. utilized 184 in an interesting example of a thermodynamically controlled asymmetric Michael addition reaction. Under the reaction conditions cyclopentadienone dimer 187 reacted in its monomeric form, leading to adduct 189 as the dominant product (60% isolated) after equilibration. Enantiomerically pure Michael adduct 189 was then converted into cyclopentenone 190 which was used as a synthon for various monoterpenoids and indole alkaloids (Scheme 52).90 A number of proline derived nucleophiles have been used successfully to induce chirality during conjugate additions.Seebach et al. reacted enamines of prolinol derivatives, such as 191, with reactive Michael acceptors and obtained products with a high level of diastereoselectivity (Scheme 53).7 HO Me02C 188 187 L 4 + ‘ I Me C02Me $-O’-Ph 189 (sOo/o yield (>70% d.e.)) 190 0 Scheme 52 n OM( 0 Ar ___t 193 (55-76% yield, 191 192 82-95% e:e.) Scheme 53 Enders et al. have developed highly diastereoselective conjugate addition reactions using lithium anions of SAMP and RAMP hydrazones ( e g 194). The hydrazones are usually cleaved by ozonolysis to give the equivalent ketone with high enantiomeric purity.” Some examples of simple conjugate addition are shown in Scheme 54, together with a more recent example of conjugate addition followed by internal trapping of the initially formed enolate, leading to cyclopentanes 197 of high enantiomeric purity.91(d) Similarly, enamines 19 8 were prepared from 1,3-dicarbonyl compounds and their anions also reacted with high facial selectivity in conjugate additions.92 This methodology allowed some chiral dihydropyridines and dihydropyridones to be synthesized, and an example is shown in Scheme 54.201 (derived from aldehydes R,CHO) as chiral acyl anions equivalents. These reacted with enoates in a conjugate manner with very high diastereoselectivity, and ketones 203 were obtained with high e.e., after hydrolysis of intermediate 202 (Scheme 55).93 Another example of a proline derived auxiliary was developed by Yamaguchi et al.They prepared amides (e.g. 204) from amino alcohols and found that their lithium dianions 205 reacted with enoates. Two new chiral centres are created during the reaction with high selectivity. After hydrolysis of the auxiliary chiral amino alcohol, chiral acids 207 were obtained with high optical purity ( - 80%) and with a high level of dia~tereoselectivity.’~ When the dianion of prolinol derivative 204 was reacted with diester 208 cyclopentanone 209 was obtained and converted into alcohol 210. This was then converted into ( - )-isodehydroiridodiol with an e.e. of 79% (Scheme 56). Enders has also used lithium anions of cyanoamines Leonard: Control of asymmetry through conjugate addition reactions 403(I) LDN M F cN,N R3 MeO-' R' &C02Me k 195 194 R2 Examples: R' R~ Yield 8.8.H Me Me 58% ~96% H Bn Ph 38X >%YO Et Me Me 45% >92% Ph Me Me 45% >%YO Bu Pr Ph MYo >%Yo 'R a c o 2 M e I A2 1% 2 equ. LDA 204 205 OLi 207,84% yield 75% d.e., 7910 8.e. o n 206 C N X N MeO-" 197 (43-78Or6 yield >95% e.e.) 6; 204 2 eq. LDA he (I) NaBH4 I (in H'I H20 209 HO 1 (ii)CHzNZ E E (i) BuLV M F ( " ) A r p C o f " c N - N , M e o d ' d A r 4 steps - R R R R 1 98 199 (-)-isodehydroiridodiol 21 0 (39% overall) 79% e.8. " " - ' i 5 0 - Scheme 56 R ( 5 w v o overall R -98% e.e.) Scheme 54 201 Examples: 202 Scheme 55 Corey et ~ 1 . ~ ~ reacted E-enolates, such as 2 11, derived from phenylmethanol esters with enoates. E-Enoates reacted quite selectively, favouring syn adduct 2 12, whereas 2-enoates reacted with very little selectivity (Scheme 57).Haynes et al?6(b) found that anions from chiral phosphine oxides react in a highly diastereoselective manner with cyclopentenones. For example, the OLi n.2 CH3 -COAL 21 1 \ 212 (75% yieM, 71% d.e.) low diastereoseledivity Scheme 57 lithium anion of 2 13 reacted with methyl 2-methylcyclopentenone, and the enolate 2 14 which was formed was trapped to give 2 15. After hydrogenation of the alkene aldol, cyclization gave the hydrindenone 2 16 (Scheme 58). Hua et al. carried out similar reactions using phophine oxides derived from ephedrine.Y6(b) When amides bearing oxazolidinone chiral auxiliaries 2 17 are converted into titanium 'ate' enolates, they react as nucleophiles in conjugate addition reactions with simple a, p-unsaturated systems giving products 2 18 with a high degree of stereocontrol (Scheme 59).However, Evans et al. found that more complex enones, such as cyclohexenone, react with low stereosele~tivity.~~ Conjugate addition reactions of enamines derived from chiral amines have been studied for some time."(c),y8 For example, Lewis acid catalysed reaction of proline derived enamine 19 1, Scheme 53. d'Angelo 404 Contemporary Organic SynthesisThe outcome of these reactions is highly predictable, in terms of both stereochemistry and regiochemistry. Enamines 221 and 222 can be formed by tautomerism of imine 220 and the conformations shown for 221 and 222 are the ones that are highly favoured over any of the alternatives.In what appears to be a kinetically controlled process enamine 222 reacts with the electrophile selectively and regioisomer 223 is normally produced with high selectivity. It has been demonstrated that the preferred mechanism for this type of reaction is one in which the proton is delivered to the a-position of the Michael acceptor by intramolecular transfer from the enamine nitrogen atorn.l0* It is therefore suggested that the process is concerted, involving a cyclic transition state. Clearly, enamine 22 1 cannot react via a concerted cyclic transition state and so its products are disfavoured. A chair-like cyclic transition state is proposed on the basis of molecular modelling studies and an enamine X-ray structure and this accounts for the high degree of stereocontrol at the new chiral centre.d'Angelo et al. have found that this type of process is tolerant to a wide variety of enamines and Michael acceptors. They explored the effects of using chiral amines other than a-methyl benzylamine as auxiliaries. Amines without an aromatic substitutent gave much lower enantioselectivity, but the reactions were virtually unaffected by electron-donating7 electron-withdrawing, or bulky substituents in the aromatic ring of the auxiliary.lO' successfully in these reactions and a selection are shown in Figure 5 . In general, reactants with a substituent at the P-position are quite ~ n r e a c t i v e . ' ~ ~ - ' ~ ~ Other reagents which did not react successfully were methyl propiolate, nitroethene, and methyl methacry late.A wide range of Michael acceptors have been used * L 0 ph* ( i ) BuLYTHF *Pq0 21 3 *4BF 214 0 215 21 6 Scheme 58 21 7 21 8 R ~ E W G R' Yield d.e. Me CH,=CHCOEt CH,CH,COEt 88% 98% Me CH2=CHC02Me CH2CH2C02Me 78% 78% CH(Me), CH,=CHCN CH7CH7CN 80% >99% Me CHP=CHCN CH2CH2CN 99% 9670 CH2CH2C02Me CH2zCHCN CH2CH2CN 80% >99% Scheme 59 and Guingant have developed a powerful series of reaction sequences involving conjugate additions of chiral enamines to achiral Michael acceptors and they have reviewed these recently.99 In these reactions racemic ketones 2 19 are converted into chiral Michael adducts 224 via chiral imines 220 (Scheme 60). 0 0 Ph- Me COZR qCozR C02R S02Ph alk 21 9 224, high e.e. 223 I kinetically controlled reaction via a cyclic chair-like transition state Figure 5 Examples which indicate the scope of these conjugate addition reactions are presented in Schemes 61 and 62. Simple cyclic ketones, such as 225 and 229, bearing an alkyl group at the a-position react with most Michael acceptors, via their chiral enamines, to provide adducts such as, 227 and 23 1 in high yield and with high e.e.99,102 Ketone 227 has been used in a synthesis of ( + )-aspidospermine and ketone 23 1 has been used to prepare vallesamidine intermediate 232.' l 5 The tolerance of the process to other substituents at the a-position of the ketone has been explored. An acetate side chain, as in 233, does not influence the reaction adversely106-108 but aromatic substituents reduced the reactivity of the chiral imine. The high Ph Me HXN,H EWG 4;" .... 221 220 * Concerted conjugate addition-protonation not possible 222 Scheme 60 405 Leonard: Control of asymmetry through conjugate addition reactionsPh Me \I 225 226 227 (Wh, 88% e.e.) / 228 (+)-aspidospermine 0 233 234 @SOzPh 1 U 235 (74%, QO%e.e.) 0 231 (70%, 90% e.e.) J/ N/\ vallesamidine intermediate Ph Me 236 237 230 (75%, 90% e.e.) 239 240 241 (Wh, 95% e.e.) 242 (-)-vertindide Scheme 61 efficiency of the process is retained when an oxygen substituent is attached at the a-position. For example, benzyl ether 238 was obtained with an e.e. of 98% from 236,"' and 241 was obtained with an e.e. of 95% from tetrahydrofuranone 239.' l 2 Tetrahydrofuranone 24 1 has been used in the synthesis of several natural products, including the tetronic acid ( - )-vertinolide 242.Chiral enamines formed from 1,3-dicarbonyl compounds were found to be less reactive towards Michael additions, but reactions were often successful at high pressures or in the presence of a Lewis acid cata1y~t.I~~ For example, nitrile 244 was obtained from 243 in 85% yield (90% e.e.) using ZnC1, as a catalyst."' Some very useful compounds have been synthesized by modified Robinson annulation procedures. The 2,6-dimethyl imine 245 reacted with lower stereoselectivity than normal, providing annulation product 246 with a 73% e.e. However, after three recrystallizations enantiomerically pure material was obtained and converted into ( + )-octalin 247.Io3 Robinson annulations with bicyclic imines such as 248 were highly productive, leading to potential steroid/terpenoid precursors, e.g.249 with an e.e. of 92°/0.10y~ Intramolecular Michael addition reactions were also successful, provided there are 3-5 atoms between the imine group and the electrophilic a1kene.l'' The interesting spiro ketone 252 was formed with an e.e. of > 90'/0,''~ and Hirai et al. have prepared the yohimbine/heteroyohimbine alkaloid precursor 255 with an e.e. of 90°h.114 d'Angelo et al. have utilized a-methyl benzylamine as a cheap source of chirality and developed a simple, efficient conjugate addition procedure which is a significant addition to the methodology available for asymmetric synthesis. methodology for introducing chirality at a primary amine centre. They discovered that chiral lithium amides derived from a-methyl benzylamine, for example 257, react with prochiral enoates with very high diastereoselectivity at the newly generated amine chiral centre (Scheme 63).Since both the original Davies et al. have developed a simple and effective 406 Contemporary Organic Synthesis243 244 (85%, 90% e.e.) THF/-78% (il) Me1 0 N q M e - b H Ph 245 (i) Me phx .Bn UgBr i -&-a 0 I I 246 (Sl%, 73% e.e.) 247 (+ )-octalin Me--& 249 (71%, 92% e.e.) 250 252 (>9O%e.e.) Ph 240 Scheme 62 Me PhAfk, R1 AORz 256 MF/ -78 OC Bn Bn Bn 255 (Wh, 90% e.e.) Ph 253 254 Examples: R1 R2 Yield d.e.(258) Me Me 69% 93% Me tBu 47% >95% Ph tBu 92% 95% rzBnOCfiHIMe 78% >99% Ph 260 Ph 264 261 Me (l)phAbB" b THF/ -78% 261 Scheme 63 Me (i) PhAC8"_ NR2' 0 (ii) H20 THF/ -78 "c Ph A&"' 8 Ph'N' Bn 0 (iii) LON THF/ Mei tie R1 =OR2 258 Ph d O B u ' 267 (74%, 94%d.e.) 260 R1 E C 0 2 H 259 Ph Ph W O t B u OH 262 (86%.92'3'4.0.) 1( + NHCOPh Ph+'" 263 OH I OBu' OH 265 (63%, 91% d.0.) 268 (73%. 9OYd.e.) 269 ('' (y,: 270,6!5-70% 271 >95%d.e. I t NR2' y 4 2 (y25Bd&f02H 272 (>98%d.e.) 273 Leonard: Control of asymmetry through conjugate addition reactions 407groups attached to the nitrogen are benzylic they can easily be removed by simple hydrogenation, and the overall process is therefore equivalent to enantioselective conjugate addition of ammonia to the prochiral enoate.' 18-123 Although the chirality of the 'auxiliary' group is destroyed during the process, a-methylbenzylamine is a very cheap reagent which is available in either enantiomeric form.From a practical point of view, the hydrocarbon by-products from the hydrogenolysis are volatile and therefore easily removed. An early application of this procedure was the synthesis of (S)-p-tyrosine (259, R1= p-OHC,H,) from 2 56 ( R1 = p-OHC,H,, R2 = Me).' The initial conjugate addition of the lithium amide generates an ester enolate. When the enolate from addition of 257 to enoate 260 was trapped using chiral oxaziridine 261, aminoalcohol262 was formed in a highly diastereoselective manner. The enantiomer of the taxol side chain 263 was then prepared from 262 via a few simple steps, including Mitsunobu inversion of the hydroxyl group."' When the homologous enoate 264 was subjected to the same addition-oxidation sequence as 260, the selectivity between anti and anti hydroxylamine isomers was very poor, caused by an enantiomeric mismatch of reagents.Thus, when the opposite enantiomer of the lithium amide was incorporated into the sequence, anti aminoalcohol 265 was obtained with 9 1% diastereoselectivity.120 When the intermediate lithium enolates formed after conjugate addition were alkylated with methyl iodide, the syn :anti relative stereochemistry was disappointing (about 30% d.e.). However, when the reaction was quenched with water and the product re-enolized with LDA, then alkylated amine 267 was obtained with high anti selectivity. 21 Interestingly, it was later found that the enolates from magnesium amide addition were alkylated with high selectivity, but in that case syn amine 268 was obtained from 260.122 Lithium amides added to cyclic enoates 269 ( n = 1 or 2) in a highly stereocontrolled manner.The initial product, after conjugate addition and enolate quenching with a bulky proton source, had the amine and ester groups cis to one another and this allowed the antifungal antibiotic cis-peritacin 271 ( n = 1) to be prepared efficiently. However, the ester group in 270 could be inverted by treatment with base giving access to the trans compound 272.123 7 Conjugate additions of achiral nucleophiles to achiral a, p-unsaturated systems in the presence of chiral ligands or other chiral mediators Enantioselective reactions of achiral substrates in the presence of chiral additives is a very attractive prospect, especially if the chiral additive can be used as a catalyst.This is an area of study that has attracted a good deal of attention in recent years. Many of the studies carried out so far have been quite similar and enantioselectivities have often been quite low. Recent review^'*^(^) have covered the literature up to 1992 in some detail and this review will therefore highlight processes that proceed with high enantioselectivity and novel methods that have been reported recently. Certain processes of the type covered in this section proceed with very high enantioselectivity, but they are normally substrate specific, rather than general processes. 7.1 Modification of cuprate and magnesium reagents An array of chiral alcohols and amines have been incorporated with cuprate reagents as non-transferable ligands. The most common substrates used to test such reagents have been chalcone-type enones and simple carbocyclic enones.Scheme 64 shows selected examples these reactions. Most of the early studies gave low e . e - ~ . , ' ~ ~ but Mukaiyama achieved an e.e. of 66°/0,125 which was later improved to 88% by Leyendecker ' 26 for Me,MgCuBr addition to chalcone in the presence of N-methyl prolinol276. Leyendecker also found that other proline derivatives, such as 277 were good chiral mediators for cuprate additions to chalcone.126(c) One of the main breakthroughs was made by C ~ r e y , ' ~ ~ using amino alcohols 278a and 278b to achieve reasonable levels of e.e. for cuprate additions to cyclic enones. It also became clear that the purity of the lithium reagent used and all other experimental variables, such as counter-ions, solvent, temperature, etc., were critical for achieving high enantio~electivity.'~~, 128, 129(b) Corey suggested the transition state model shown in Figure 6 to account for the observed enantioselectivity.Rossiter et al. screened a range of chiral amine ligands for cuprate additions to cycloalkenones and found that 282 (S-MAPP) was particularly effective.13' The products from reactions of cycloheptenone had the highest e.e. and asymmetric amplification was recognized in the proce~s.'~l(~) A study of the amplification led to the suggestion that the reactive form of the reagent is a dimer and that the meso form of the reagent does not react. Tanaka et al. screened a range of camphor-derived aminoalcohols as chiral ligands for methyl cuprate addition to enone 289.They found that 283 was the best reagent and only 0.33 equivalents were used with CuI and MeLi to give a 76% yield of muscone 290 with 96% e.e. (Scheme 45),13* Lippard et al. found that the Cur complex of 284 acts as a chiral catalyst for Grignard additions to cyclohexenone. The e.e. was dependent on reaction conditions and they found that the addition of HMPA and trialkylsiyl chlorides was advantageous, with a highest e.e. of 7 8 Y 0 . l ~ ~ ligands 285a and 285b to mediate alkyl copper additions to cyclohexenone.'34 They found that addition of several equivalents of LiBr to the reactions led to improved e.e.s. range of proline derived diphenylphosphines in enantioselective conjugate additions of copper reagents to chalcone and cycl~hexenones.'~~ t-Butyl ester 286 was the most effective ligand investigated Alexakis et al.have achieved high e.e. levels using Quite recently, Tomioka et al. have evaluated a 408 Contemporary Organic SynthesisExamples d chiral additives used with clprate reagents Bu', Ph 284a Ar=Ph 284b Ar = Naphth. 285a R=Me 285 R=Pr' 286 chid additive 287 Ref. Additive R1 F? R3-Met Yield 8.8. WS 125 276 Ph Ph MeGuMgBr 88% 68% S 126b 276 Ph Ph Me2CuMgBr 80% 88% S 126c 277 Me Me BuSuLi 37% 68% R 128 279 Ph Ph MeCu.BF3 96% 87% R 135 286 Ph Ph MeCuLi 79% 84% S chiral additive 288 Ref. Additive n R' R2-Met Yield 8.e. HS 127 278a 1 H Et2CuLi 68% 77% R 127 278e 1 H Bu2CuLi 60% 72% R 127 278a 2 H Et2CuLi 90% 92% R 127 278a 2 H Bu2CuLi 90% 89% R 127 278b 2 H MepCuLi 60V0 90% R 128 279 1 H Ph2CuLi 90% 50% R 129 280a 1 H Me2CuLi 45% 77T0 S 129a 280a 2 H Me2CuLi i7Vo 41% S 129b 281 2 H Bu2CuLi 63Y0 63% R 130 280b 1 Me (CH2=CHMe)2C~Li 88% 88% R 131 282 1 H MepCuLi 40% 32% R 131 282 1 H Bu2CuLi 51% 45% S 131 282 2 H Me2CuLi 57% 58% S 131 282 2 H Bu2CuLi 92% 83% S 131 282 3 H Me2CuLi 60% 97% S 131 282 3 H Bu2CuLi 63% 96% S 131 282 4 H Me2CuLi 48% 67% 131 282 4 H Bu2CuLi 50% 86% 133 284a 2 H Bu&lgCVCul 97% 78% S 134 285b 2 H MeCu 75% 26% R 134 2BSb 2 H EtC u 81% 95% R 134 285b 3 H BuCu 82% 95% R 134 286 1 H EtCu 90% 94% R 134 286 1 H BuCu 9 9 O h 95% R 134 286 2 H MeCu 66Oh 92% R 134 286 2 H EtCu 89% 91% R 134 286 2 H BuCu 97% 90% R Scheme 64 H H Figure 6 289 290 (76'Y0, 96%e.e.) Scheme 65 and induced high levels of enantioselectivity, although reaction conditions were critical and three equivalents of the ligand were normally required.7.2 Modification of organozinc reagents Jansen and Feringa carried out conjugate additions using chiral zinc complexes in conjunction with Grignard reagents, but the enantioselectivities of such reactions were generally very low.13h The same workers, and several other group^,'^^-^^^ have used dialkyl zinc reagents, with catalytic quantities of ligands 291-296, together with Ni(acac),. High enantioselectivities have been achieved with these reagents (Scheme 66), but the reactions conditions are quite critical and it was found that certain achiral amine additives (e.g. 2,2'-bipyridine) led to enhanced enantioselectivity. 7.3 Modification of 1,3-dicarbonyIs and other activated nucleophiles Some time ago Wynberg showed that cinchona alkaloids act as chiral catalysts for conjugate additions of certain activated nucleophiles, for example 297 was reacted with MVK in the presence of 1% quinine to give 298 in 99% yield with 76% e.e.(Scheme 67).14, It was also found that quaternary ammonium salts derived from cinchona alkaloids can act as chiral phase transfer catalysts in similar proce~ses.~~*~ 143 This Leonard: Control of asymmetry through conjugate addition reactions 409Examples of chiral additives used with organozinc reagents PhAOH 291 "u"3 PhAOH 292 294 NHR , 293 AUt * R2 F?*Zn/ Ni(acac)* Chiral additive 287 288 R1 ~ ~~~~ Ref. Additive R' R2 Md%katl R3-Met Yield 9.8. WS 137a 137c 137d 137d 137d 137d 138a 138a 139 137d 140 141 291 291 292 292 292 292 293 293 294 292 295 296 Scheme 66 Ph Ph Ph Ph Ph CPha Ph CPh3 Ph But Me Ph Ph Ph Ph Me Ph Ph Ph Me Ph Ph Ph Ph 0.5 0.5 0.25 1 0.25 1 20% 20% 10 7 75% 6% 63% 82% 81% 80% 96% 94% 02% 72% 34% 02% 75% 72% 76% 2% 80% 91% 74% %Yo 90% 62% 75% 85% R R R R R R R R - 297 298 (76%e.e.) 299 (100%.60% e.e.) Scheme 67 particular process appears to be unusually well suited to this type of catalysis and chiral cobalt complexes have also proved to be effective.'44 Moderate enantioselectivities ( - 60%) have also been achieved for additions of thiols to cyclic enones and for addition of cyclic a-nitroketones to methyl vinyl ketone.145 The catalysts can be polymer supported and Sera et al. found that although enantioselectivities generally fall when the reactions are carried out at high pressure, addition of nitromethane to chalcone was only possible at high pressure and proceeded to give 299 with 61% e.e.146 quaternary ammonium salts catalysed the enantioselective conjugate addition of diester 300 to Loupy and Zaparucha found that various 302 (51%.82% e.e.) Br- Me 301 ' ' Scheme 68 cha1~0ne.l~~ The best catalyst was 30 1 which led to 302 with 82% e.e. (Scheme 68). Several important new organometallic catalysts for conjugate additions have been reported recently. Ito et al. found that the ferrocene compound 304 ('TRAP') catalysed the enantioselective addition of a-cyanoesters to enones, leading to 1,5-dicarbonyls 303 with high e.e.s (Scheme 69).148 0.1-1MoW Rh(CO)(PPh)s 'TRAP benzene - ~~ R' R2 Yield 8.8.WS \ Me Me 99Yo 72% R Me Et 95% 81% R Me Pr' 97% 86% R Me But 95% 81% R Me' TRAP Et Pr' 98% 85% R Ph Pr' 95% 83% R H Pr' 88% 87% R kppb (S,S)-(R,R> Scheme 69 Yamaguchi et al. explored the use of simple proline salts as catalysts for malonate-type additions and found that rubidium salt 305 was very effective. They found that cyclic enones reacted preferentially from the Re face, whereas acyclic enones reacted from the Si face, with enantioselectivities of up to 77% e.e. (Scheme 70).149 Very high enantioselectivities for a range of reactions were reported by Sasai et al. using 306 4 Scheme 70 ~ ~~~~ Me Me 71% 76% S Ph Et 79% 53% S 307 (87'% yield, 49% 8.8. ( R ) ) 4 10 Contemporary Organic SynthesisBINO-rare earth bimetallic complexes as catalysts.' Several catalyst systems were investigated and the best of them gave uniformly high e.e.s over a range of reactions, as shown in Scheme 7 1.This appears to be the most effective generally applicable catalyst for enantioselective malonate additions reported to date. n b 10 mol% cat. n 4c02Bn C02Bn Cat. = L~(o'PI)~ ~ H F / S-BINOL lequ. n R1 $ Yield e.e. WS 1 H Bn 96% 929'0 S 1 Me Bn 97% !%"/a S 2 H Bn 94% 92% S 2 Me Bn 83% 8790 S 2 H Me 100% 75% S 2 H Et 97yo 78% S 309 (86%. 62% e.e. Scheme 71 7.4 Other miscellaneous reactions Tomioka et al. investigated conjugate addition reactions of simple lithium reagents mediated by chiral ethers 310 and 311 (Scheme 72). Thioacetal312 was prepared from the lithium dithiane anion with an e.e. of 67% using 310,'"(") Using diether 31 1, simple Me0 Ph NMe2 31 1 312 (3W0, 67V0 e.e.) FHO 31 3 (82%.94% e.e.) I,N46H11 FHO (i) 31 1, Ph-LV toluene (ii) H30' R l / y P h c 314 R2 Scheme 72 R' R2 Yield 8.8. H Me 48% 79% H BU 58Yo 99% -(CH2)3- 6lY0 96% -(CHp),- 59% 98% lithium reagents reacted with conjugated imines, leading to 3 13 and 3 14 with very high e.e.s. Yura and Mukaiyama et al. used proline derived diamines as catalysts in a number of enantioselective processes (Scheme 73). Addition of aryl thiols to cyclohexenone proceeded with enantioselectivities of up to 88% e.e. in the presence of 2 mol% 315.152(a) The more simple bidentate bases 3 16a and 3 16b catalysed enolate and enethiolate conjugated additions, leading to 317 with an e.e. of up to 93%, and 318 with an e.e. Of Up to 70°/o.'s2(b3c) o n 317 (80-93% e.e.) 0 s (N STMS Ph 0 Ph AMe MeSkMeSk MeS h Me 3161 Sn(OTt), Scheme 73 - 31 8 (26-70"/0 e.e.) Kobayashi et al.used binaphthol derivative 32 1 to catalyse the addition of thioester enolates to 3 19 leading to products 320 with up to 90% e.e. (Scheme 74). I s 3 OTMS 31 9 320 R' F? 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ISSN:1350-4894    

DOI:10.1039/CO9940100387

出版商:RSC    

年代:1994

数据来源: RSC