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, Universiti de Montrkal Professor M. Julia, Universiti de Paris XI (Paris-Sud) Professor P. D. Magnus, University of Texas at Austin Professor G. Mehta, University of Hyderabad Professor K. C. Nicolaou, 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 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 th2 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 E 169 (plus GST ), Rest of the World E 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 Contemporary Organic Synthesis, Publications Expediting Inc. Second class postage is paid at Jamaica, New York 1143 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 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 Ltd

ISSN:1350-4894    

DOI:10.1039/CO99401FX013

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

ISSN 1350-4894 COGSE6 l ( 4 ) 219-316 (1994) Contemporary Organic Synthesis A journal of current developments in Organic Synthesis VOLUME 1 NUMBER4 CONTENTS wco2Et OH The role of zinc carbenoids in organic synthesis By W. B. Motherwell and C. J. Nutley Reviewing the literature published up to February 1994 Alcohols, phenols, and ethers By Joseph Sweeney Reviewing the literature published between July 1992 and July 1993 219 243 Synthetic developments in host-guest 259 chemistry By Jeremy D. Kilburn and Hitesh K. Pate1 Reviewing the literature published between July 1992 and December 1993 Synthetic approaches to butenolides By D. W. Knight Reviewing the literature published between 1976 and 1992 287Cumulative 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 31 August 1993) Graham J. Dawson and Jonathan M. J. Williams 95 1 13 125 Saturated nitrogen heterocycles (January 1992 to May 1993) John Steele Organic halides (1 July 1992 to 30 June 1993) P. L. Spargo 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. Cilchrist 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 Articles that will appear in forthcoming issues include Recent developments in asymmetric aldol methodology (up to the end of1993) Alison S. Franklin and Ian Paterson Main group organometallics in synthesis (July 1992 to December 1993) Martin Wills Synthesis of materials for molecular electronic applications (mid-1992 to December 1993) Martin C. Grossel and Simon C. Weston Control of asymmetry through conjugate addition reactions John Leonard

ISSN:1350-4894    

DOI:10.1039/CO99401FP015

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-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-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/CO99401BP017

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

The role of zinc carbenoids in organic synthesis W. B. MOTHERWELL AND C. J. NUTLEY Department of Chemistry, Christopher Ingold Laboratories, University College London, 20 Gordon Street, London, WCl H OAJ, UK Reviewing the literature published up to February 1994 1 1.1 1.2 2 2.1 2.1.1 2.1.1.1 2.1.2 2.1.3 2.1.4 2.2 2.2.1 2.2.2 2.2.3 2.2.4 3 3.1 3.2 3.3 4 5 6 Introduction Carbenes and carbenoids Organozinc reagents and their carbenoid connection Zinc carbenoids from carbonyl compounds The Clemmensen reduction Mechanistic studies Spectral studies on prototypical zinc carbenoids a ,/&Unsaturated ketones in the Clemmensen reduction Diketones in the Clemmensen reduction Practical advances in the Clemmensen reduction Controlled reductive deoxygenation of carbonyl compounds The demise of the proton Direct deoxygenation of carbonyl compounds to give alkenes Dicarbonyl coupling reactions Cyclopropanation reactions The Simmons-Smith reaction and Furukawa modification The Simmons-Smith reaction The Furukawa modification A synthetic overview Simmons-Smith reagents from the reduction of a zinc(rr) salt with a diazoalkane Conclusions References 1 Introduction 1.1 Carbenes and carbenoids The unique electronic structure of the free divalent carbene intermediate,' either in its singlet state or in its biradical like triplet state, has proven, over many years, to be a fascinating area of study for the synthetic organic chemist.Thus the singlet carbene may be viewed simultaneously either as an electron-deficient species, comparable to the carbonium ion, or as a carbanion delivering a pair of non-bonding electrons.The overall reactivity in terms of nucleophilic or electrophilic character is strongly dependent on the electron-withdrawing or -donating ability of the two groups which are attached to the carbene carbon atom. However, to those synthetic organic chemists interested in the selective manipulation of sensitive polyfunctional molecules, such intermediates have often been rejected as being rather indiscriminate and hyperactive in their behaviour. schizophrenic and over-aggressive tendencies of the less electron-rich free carbenes have been 'domesticated' through the introduction of an ever increasing range of carbenoids which can generally be considered as derived by complexation of the free carbene with a metal.2 The influence of the metal both in terms of structure, and as a control element in terms of reactivity, is of paramount importance.Furthermore, the nature of the ancillary ligands around the transition metal, and the selection of a cationic or a neutral complex, can also be used to great advantage as additional methods of attenuating reactivity. Many of these facets are encapsulated by the selected examples shown in Schemes 1-4. Thus structures may vary from the tetrahedral lithium chlorocarbenoids 1 (Scheme l a ) to those which possess a formal metal-carbon double bond 2. In terms of reactivity, there is an evident bifurcation between the behaviour of the early transition metal carbenoids or alkylidenes which undergo olefin metathesis (Scheme lb),4 and those which effectively mirror their free carbene counterparts in terms of insertion (Scheme 2),5 cyclopropanation (Scheme 3): and ylide formation and rearrangement reactions (Scheme 4).7 Fortunately, within the last thirty years, these Scheme l a 33% 0.w.ACS PhH, 1-2h EkP " H - 2 Scheme 1 b (+ - + H p q H H Scheme 2 Motherwell and Nutley: The role of zinc carbenoid in organic synthesh 219R' = (1 S,3S,4R)-menthyl 97% 8.8. 95% e.e. Y = R, halide, .... 4.5 : 1 M = Ti, Mo, Ta, Nb, V, Pd, Ni, Pt, Cu, ...... CN I RMLn + ZnXY Scheme 5 R \cl catalyst R=CMe20H Unfortunately, the intermediate species RZnY has frequently been referred to as an organozinc carbenoid, even when the carbenoid carbon is not I CN Scheme 3 N2yCO2E1 0 Scheme 4 A substantial number of extensive reviews dealing with the carbenoid behaviour of individual metals are currently available.8-10 In recent years, however, it has become apparent that the use of stoichiometric metal carbenoids is less attractive than the development of catalytic cycles, especially when the latter involve chiral ligands.In this respect, the use of rhodium and geminally substituted with zinc and a leaving group. The reactivity of these very versatile, but non-carbenoid, organozinc compounds, whose use in synthesis has increased dramatically in the past 15 years, is the subject of a recent very comprehensive review. These fundamental properties of the carbon-zinc bond are also of course germane to the generation and behaviour of organozinc carbenoids. To the vast majority of synthetic organic chemists, such reagents are still only commonly encountered in the Simmons-Smith cyclopropanation reaction13 and its variants, and recent developments in this area are highlighted in Section 3.The idea that a readily available carbonyl compound, rather than a gem dihalide, may be used as a direct precursor of an organozinc carbenoid, could still be somewhat foreign. The major portion of this review is accordingly devoted to this less frequently encountered area of organozinc carbenoid reactivity. copper carbenoids, invariably generated in situ from a-diazo carbonyl precursors, is proving to be the most popular choice at the present time. 2 Zinc carbenoids from carbonyl compounds 1.2 Organozinc reagents and their carbenoid connection The purpose of the present review is to highlight the current status of organozinc carbenoids within the above framework, both from the practical standpoint of their generation and synthetic utility, and also in terms of current mechanistic understanding.sinusoidal popularity of organozinc reagents for synthesis. Thus, although the reactivity of dialkylzinc reagents was studied for some thirty years after the first preparation of diethylzinc by Frankland in 1849,' by the turn of the century attention had turned to the more reactive Grignard reagents. The highly covalent character of the carbon-zinc bond which is responsible for the relative lack of reactivity of these organometallics is, however, the very reason for their current renaissance. With zinc possessing low-lying p orbitals, transmetallation with metallic salts is a facile process, as long as it is thermodynamically favoured.In this way, zinc can be used to convert a highly functionalized organic substrate into a stable In the wider context, it is interesting to reflect on the From the most simplistic viewpoint of electronic stocktaking, the conversion of a carbonyl compound to an organometallic carbenoid requires only the delivery of two electrons from a metal or metal complex M and the addition of two equivalents of an electrophilic reagent (E+Y-) in order to generate the classical reactivity pattern of a geminally substituted carbon atom possessing both the carbon-metal bond and a leaving group shown in 3 (Scheme 6). 5 3 1- 4 M = metal 220 organometallic, which can then be transmetallated to a more reactive organometallic (M = Cu, Pd, Ti, etc .), capable of reacting with an electrophile (Scheme 5).E-Y = eledrophilic reagent Scheme 6 Contemporary Organic SynthesisThe further evolution of this intermediate to other metallocarbenoid structures such as 4 and 5 is then a function of the leaving group ability of E,O, the nucleophilicity of Y-, and the nature of the metal M, in terms of wishing to sustain a carbon-metal double bond, or otherwise. The substitution of zinc as the metal and the proton as the ultimate electrophile in Scheme 6 immediately leads to the recognition of the Clemmensen reduction, and to the notion that some form of organozinc carbenoid should be involved in such reactions, even though further reduction steps are still required.As we shall see, however, considerable problems arise as soon as the timing of various electronic events is subject to scrutiny. It is therefore highly instructive in this section to discuss the behaviour and mechanisms involved in the Clemmensen reduction of various carbonyl substrates, since this provides valuable insight for the exploitation of other conceptually similar, but more controlled, methods of generating the same organozinc carbenoids. 2.1 The Clemmensen reduction The Clemmensen reduction of a carbonyl group to give, in the simplest cases, a methylene unit, is perhaps one of the most familiar reactions in organic chemistry (Scheme 7). Since its discovery by Clemmensen14 over 80 years ago, the original procedure employing amalgamated zinc and 40% aqueous hydrochloric acid, with an immiscible co-solvent, has undergone considerable modification.Commonly used procedures today are more suitable for use with compounds that were very labile under the original harsh conditions of Clemmensen's reaction. The reaction has been extensively reviewed.' Scheme 7 2.1.1 Mechanistic studies It is intriguing, however, that so long after its discovery, the mechanism of such an apparently simple transformation is still far from clear. Although free alcohols have been ruled out as intermediates, a unifying mechanism that explains the various reactivities of substrates such as diketones and a ,P-unsaturated ketones under Clemmensen conditions has yet to be found. Some of the earliest detailed work was carried out by Brewster and co-workers.lh In the first paper in this series, Brewster presented evidence that the mechanism involved direct metal intervention - i.e. formation of some metal-bound intermediate. He termed this process 'chemisorption' of the ketone on the metal surface (bonding via carbon or oxygen of the carbonyl group). Following on from this chemisorption theme, Brewster suggested that the zinc in the reduction acts essentially as an electron pump, and hence the mechanism demands the formation of partially reduced intermediates. Nakabaya~hi's'~ work also concluded that the mechanism was a stepwise process involving organozinc intermediates. As alcohols are not generally reduced under Clemmensen conditions, Brewster ruled free alcohols out as intermediates in the reduction.In Nakabayashi's studies, stopping the reduction of acetophenone or t-butyl phenyl ketone after five minutes, a complex product mixture was found, including saturated, unsaturated and rearranged hydrocarbons, alcohols and pinacol coupling-derived products. The hydrocarbon products were shown not to have arisen via alcohol intermediates - indeed when the alcohols isolated were separately subjected to the reaction conditions, no reduction was observed. He suggested that the major products of the reduction were derived from a carbocationic intermediate [Path (b)], and that there was a minor side reaction leading to the formation of the observed alcohol( s) [Path (a)] (Scheme 8). Furthermore, it was claimed that the pinacol coupling, which may occur at the one-electron reduction stage of a carbonyl compound, came about via a mechanism (termed as electrochemical) that shared no common intermediates with the Clemmensen reduction.0 II 0- I WO' OH R' I H a ' + I + Zn+CI R' R' Unsaturated R;( +-+ ~ 3 ( - rearranged zn+ zn- produds + zn+CI + Zn'CI o( zn Hpl + zn2+ Scheme 8 Nakabayashi found in kinetic studies that the chloride ion concentration had a considerable influence on the reaction, and rationalized this as due to chloride ions being involved in the rate determining step. As the zinc concentration in the amalgam is also important, and the yields of Clemmensen-type products fall with the concentration of zinc in the amalgam, it was concluded that the rate determining step involved attack of zinc and chloride ion on the carbonyl group (the first step in the mechanism shown in Scheme 8).However, as an added complication, at very low zinc concentrations in the amalgam, Nakabayashi found that the one-electron pinacol processes dominated, with an absence of 22 1 Motherwell and Nutley: The role of zinc carbenoids in organic synthesisClemmensen-type products. It was on the basis of this result that he concluded that the mechanisms of the pinacol process and the Clemmensen reduction were quite different. Indication that the mechanism of the Clemmensen reduction involved a carbenoid intermediate was, in fact, present in Clemmensen’s original work on the reaction. He noted that on the reduction of acetophenone at low acid concentration, styrene rather than ethylbenzene was obtained.With this result strongly suggesting a C-H insertion reaction of an intermediate carbenoid, this aspect of the reaction became the subject of further investigations by other workers.I8 The effect of acid concentration on the reduction of 11 different carbonyl compounds was examined, and the ratio of alkane to alkene found. Generalizing the results, the formation of alkenes is favoured over alkanes as the acid concentration falls. It was interesting to note that under all reaction conditions cyclohexanone gave exclusively cyclohexene, but that p-ethoxy- and p-methoxy-acetophenone gave exclusively the corresponding alkane, presumably due to electronic influences which facilitate further reduction of the carbenoid. When the derived alcohol corresponding to several of the ketones was subjected to the reaction conditions, different product distributions were obtained to those from the parent compound, strongly suggesting yet again that alcohols are not free intermediates in the reduction.In 1986, an elegant study by BurdonlY provided results further indicative of a carbenoid mechanism. Under the reduction conditions studied - zinc in 50% aqueous ethanol at 20°C - the chosen substrates, acetophenone, substituted acetophenones, and propiophenone, were found to give classic Clemmensen reduction products, and products formed via ‘carbenoid chemistry’. Cyclopropanes were formed, in the first instance by the trapping of alkenes formed in the reaction, and later by trapping alkenes added to the reaction mixture.The alkenes formed during the reaction are proposed to have been formed by a C-H insertion process, another classic carbene reaction. Deuterium labelling studies provided further backing for the intervention of a zinc carbenoid in the reduction. The product distribution from the reduction of 6 is shown in Scheme 9. HCI D 0 ArAc.3 ArACD3 + ArdD 6 7 (27%) 8 (29%) D D + ”>=<,” + Ar,& Ar Ar DaC H 9 (S2%) 10 (37%) Ar = p-CI-C6H4 + pinads (- 7%) Scheme 9 of two electrons and two protons to the carbenoid. Compound 8 results from the loss of D+ from the Thus, 7, the alkane product, occurs via the transfer carbenoid to give a vinyl zinc species, and hence for this substrate this is almost exclusively the route to the unsaturated products. Compound 9, the other olefinic product, results from a C-D insertion of the carbenoid (i.e.a 1,2-shift). The cyclopropane 10 results from the cyclopropanation of styrene formed during the reaction by further carbenoids. The high percentage yield of this species suggests that cyclopropanation by the carbenoid is a very facile process. These results allowed Burdon to propose the mechanism shown in Scheme 10. The route shown for the formation of the carbenoid 11 was only tentatively proposed by Burdon, although he did suggest that radical intermediate 12 could explain the pinacol type products obtained in the reaction (in direct opposition to Nakabayashi’s earlier conclusions on the mechanism of these two proces~es).l~(~) 0 Ar R 12 R=H,Me Ar zn Me Scheme 10 A recent series of papers by Rosnati and co-workers,20 has also examined the particular cases of mono- and diaryl-carbonyl compounds, in which sequential halide anion displacement may, not surprisingly, also intervene.From these studies it is clear that the tortuous path to the carbenoid is highly substrate and concentration dependent, and that competing pathways such as pinacolic coupling may well intervene when intermediates generated at the one-electron reduction level are particularly stable. 2.1.1.1 Spectral studies on prototypical zinc carbenoids The carbenoid mechanism that BurdonlY invoked for the Clemmensen reduction prompted the publication of a study on the isolation and characterization of the parent methylene zinc carbenoid, ZnCH,., A 1: 1 adduct was produced by co-deposition of zinc atoms with diazomethane and argon onto a rhodium-plated copper mirror at 12K.Under photolysis conditions (A > 400 nm), the adduct was converted to ZnCH,, whose structure was examined by Fourier Transform IR. The frequencies measured for the adduct, as well 222 Contemporary Organic Synthesisas for isotopically labelled species, agreed well with those calculated by a normal coordinate analysis. Later, ab initio quantum mechanical calculations22 showed that the species Billups and co-workers had isolated2* was a triplet carbene, and predicted that the singlet state species would lie only 49.6 kJmol- higher in energy. singlet and triplet carbenes, it was calculated that both the singlet 13 and triplet states 14 would have a pyramidal structure about carbon.The structure of the singlet state would be that preferred by the interaction of zinc with the empty p orbitals of carbenes with singlet ground states. Experimental data suggests a zinc-carbon bond distance of 1.93-1.96 A in the zinc carbenoid, which probably corresponds to a single bond (when compared to zinc-carbon bond distances measured for zinc carbynes), although the accuracy of calculations performed to date has not permitted confirmation of this. The estimated Mulliken charges for the zinc carbene of + 0.43 on Zn and - 0.66 on C indicate that the species has some ionic character. Considering the equilibrium geometries of the 2.1.2 a ,#LUnsaturated ketones in the Clemmensen reduction Whilst strong presumptive evidence for the intermediacy of an organozinc carbenoid may be found in the reactions of simple carbonyl compounds, the reduction of a ,P-unsaturated compounds under Clemmensen conditions presents a very different picture.Typical products include the saturated ketone and derived hydrocarbons, hydrocarbon dimers from radical couplings at the p-terminus induced at the one-electron reduction stage, similarly derived pinacol coupling products, and, perhaps most noticeably in a more general context, rearrangement products derived from cyclopropanol derivatives. Some of these reactions are illustrated below. in many ~tudies.'~(~) An example of such work is that of McKenna and co-worker~.~~ They examined the reduction of many different steroidal enones, amongst which were cholest-4-en-3-one 15, testosterone acetate 16, and androst-4-ene-3J7-dione 17.It is interesting to note that the reduction of the carbonyl group in the enone proceeds with shift of the alkene towards what was the carbonyl carbon. The isolated 17-ketone in androst-4-ene-3,17-dione remains untouched under the conditions employed (Scheme Steroidal enones have proved interesting substrates 11). In terms of the more often observed rearrangement process, Davis and Woodgate had proposed24 that the reduction of a$-unsaturated ketones under Clemmensen conditions proceeded via a cyclopropanol, which, depending upon its mode of ring-opening, could give two structurally isomeric saturated ketones. In their study, the authors also 0 a 15 A=CH.CBH17 16 A=CH.OAc 17 A=CO I Zn, AcOH 15' exclusive 16' - 1 : 1 17' exclusive Scheme 11 synthesized the cyclopropanol18 they believed to be an intermediate in the reduction of 4-methylpent-3-en-2-one 19 (Scheme 12). On acid-catalysed cleavage of this cyclopropanol, they formed the two isomeric ketones isolated from the reduction of the a $-unsaturated ketone, in the same ratio.0 Me%: Me 18 Scheme 12 In a very beautifully conceived study, Elphimoff-Felkin and Sarda examined the reductive behaviour of the two a $-unsaturated ketones 20 and 2 1, which could be expected to undergo reduction via rearrangement of the same cyclopropanol intermediates endo-22 and ex0-23.~~ The latter were not only isolated from the reactions as their acetates by carrying out the reactions in acetic anhydride, but also subjected to solvolytic proton-catalysed rearrangement to give the final product ketones 24 and 25.On the basis of the differing ratios of ketonic products formed from 20,21,22, and 23, it was concluded that direct reductive routes with skeletal preservation also exist in competition with the bicyclic cyclopropanol pathway (Scheme 13). In a very comprehensive study, a wide range of enones were subjected to the Clemmensen reduction, in anhydrous conditions [Zn( Hg), Et20-HC1, A C , ~ ] . ~ ~ For each enone, the product ratios were determined, Motherwell and Nutley: The role of zinc carbenoids in organic synthesis 223Ph Zn I HCI a, HCI & Ph 23 OH tioy 24 + Ph-& 21 Zn I HCI Y+ P h d 25 Scheme 13 but in all cases a cyclopropanol acetate was isolated, adding further weight to the evidence suggesting that such species are intermediates in the reduction.Their results also reinforced the idea that the configuration of the starting enone dictated the stereochemical outcome of the cyclopropanol formed and hence the regiochemical outcome of the reaction, and that an allylic anion was the key intermediate. This postulate arose partly due to the dismissal of radical intermediates, as the addition of a radical quench had no influence on the reaction. concluded that such competing pathways preclude access to a ,b-unsaturated organozinc carbenoids. By way of contrast, however, two isolated reports of 'carbene dimers' have been described, Schemes 14 From the above examples, it might well be and 15.15(c). 27 Zn, 3eq. HCI, wc-3 r.t. ph O 46% Scheme 14 Me Me + (isomers not Scheme 15 In both of these cases, neither double bond reduction nor skeletal rearrangement were observed, and, on the basis of later studies of dicarbonyl coupling using zinc and chlorotrimethylsilane (vide infra), it is highly probable that the carbenoid is in fact involved.the influence of the substrate structure is the determining factor in deciding which electronic pathway is to be followed under Clemmensen conditions for a ,#?-unsaturated carbonyl compounds. Nevertheless, in general terms it would appear that 2.1.3 Diketones in the Clemmensen reduction Diketones, particularly 1,3- and 1,4-diketones, are rarely found to give useful yields of the normal products expected from the Clemmensen reduction. Instead, they are frequently found to undergo intramolecular pinacol couplings at the one-electron reduction stage, with the products observed deriving from this pathway.This type of reaction has been reviewed,28 and numerous examples are available to show the generality of the reaction.2' The mechanism for dimedone, the first example studied in 1935 by Dey and Lin~tead,~" Scheme 16, is illustrative, and carbenoid chemistry has not been observed in these cases. Zn(Hg), HCI 0 Scheme 16 2.1.4 Practical advances in the Clemmensen reduction With the Clemmensen reduction classically being carried out using amalgamated zinc and 40% aqueous hydrochloric acid, with an immiscible co-solvent, typically toluene, the conditions are simply too harsh for many highly functionalized substrates to tolerate.Although the process was modified relatively early on to use organic solvents such as alcohols and acetic acid,ls((b) such a homogeneous system was found to favour the formation of pinacols. Perhaps the most significant advance was made by Yamamura and co-workers.3' They showed that by employing a large excess of activated zinc dust in diethyl ether saturated with hydrogen chloride at O'C, optimum results could be obtained in the reduction, with reactions typically complete in 1 hour. Surprisingly, little study seems to have been made of the effect of sonication on the reaction. Reeves and co-workers have published results on the reduction of ketones to the corresponding methylene compound 224 Contemporary Organic Synthesisusing zinc amalgam and hydroiodic acid in methanol, with sonication (5 hours).32 For the ketones selected, yields were high in most cases, with aromatic ketones generally giving better results than their aliphatic counterparts.It was found that amalgamation of the zinc was crucial to the reaction; without amalgamation, yields were found to be significantly lower. Finally, report of an electrochemical reduction of a diketone has been made that permitted the isolation of the labile cyclopropanediol as its dia~etate.~~ Triangular wave cyclic voltammetry was used on a hanging drop mercury electrode. With such electrochemical reductions being a powerful yet simple technique in organic synthesis, it is indeed surprising that these methods have not been exploited more, particularly using a zinc anode.2.2 Controlled reductive deoxygenation of carbonyl compounds 2.2.1 The demise of the proton Although convincing evidence has accumulated over the years for the intermediacy of a zinc carbenoid in the Clemmensen reduction, classic carbenoid reactivity is not routinely observed since the vigorous reaction conditions employed are also ideal for further protonations and two-electron reduction to the methylene group. In order to exploit the carbenoid's reactivity, reaction conditions are therefore required in which these later steps are effectively precluded. Two conceptually similar solutions, both involving replacement of the proton, have evolved. In the first of these, reported by Elphimoff-Felkin in 1969,34 the use of boron trifluoride etherate as a Lewis acid under Clemmensen-type reductive conditions allowed the carbenoid from benzaldehyde to be trapped by an alkene, to give cyclopropanes (Scheme 17). The yield of 7-phenylnorcarane 26 obtained was almost doubled (60%) by the use of the alkene as the reaction solvent.In the few examples studied, whilst yields were only F3B.OEt2 I zn (+ d) I ,I; 5 - Scheme 17 Zn, F3B.0Et, Et@, r.t. 2s 35%, endo : ex0 = 8:l PhAH F F moderate, a notable feature was that cyclic alkenes gave the more hindered endo isomer preferentially (vide infra Section 2.2.4). Our own independent approach began in 1973,j5 with a study of the behaviour of alicyclic ketones using chlorotrimethylsilane as a replacement for hydrogen chloride. This selection was made since the silicon electrophile is also capable of forming a very strong bond to oxygen.When viewed in this way, a mechanistic pathway for the formation of a heterogeneous organozinc carbenoid analogous to that proposed by BurdonLY (Section 2.1.1) for the Clemmensen reduction may be proposed (Scheme 18). R R MesiCI I R R Y Scheme 18 Alternatively, by analogy with the Simmons-Smith reaction, the carbenoid may be viewed as a tetrahedral chloro congener, arising from the series of electron-transfer steps indicated in Scheme 19. Me3SiCl I Scheme 19 Fortunately, further reduction of the organozinc carbenoid in the presence of silicon reagent to give a geminal disilane was not observed, presumably as a result of prohibitive steric interactions. The fate of the organozinc carbenoid in these cases was to undergo C-H insertion reactions (vide infra Section 2.2.2), and the case of cyclooctanone, which furnished not only cis-cyclooctene, but also bicyclo[3,3,0]octane as a result of transannular interaction (Scheme 20), was particularly indicative of carbenoid intermediacy.Motherwell and Nutley: The role of zinc carbenoids in organic synthesis 2250-0 +& li 2 : l 55% overall Scheme 20 Although the ratio of olefin to bicyclic hydrocarbon was different from that observed in the Bamford-Stevens reaction via the free carbene, this was not surprising since the metal might well be expected to have a considerable moderating influence. Following on from these original observations, a variety of useful reactions have been developed, based on the above methods and variants thereof. In the following sections, these have been conveniently grouped from a synthetic standpoint according to the fate of the carbenoid involved.2.2.2 Direct deoxygenation of carbonyl compounds to give alkenes The reaction of a variety of cyclic ketones with zinc and chlorotrimethylsilane offers a very simple 'one-pot' method for the conversion of this functional group to an alkene, without any need for prior formation of derivatives such as enol phosphonates, enamines, or tosylhydrazones.3s Trimethylsilylenol ethers are not intermediates in this reaction, and can in fact be recovered unchanged after exposure to zinc and chlorotrimethylsilane. As in the case of the Clemmensen reduction performed at very low acid concentrations, alkene formation most probably arises by insertion of the organozinc carbenoid into the neighbouring C-H bond.In chemoselective terms, the reaction conditions are very mild, and remote ester functionality and even alkyl bromides are tolerated, as shown by the examples in Scheme 2 1. 0 X x X = H 72% X=OAC 60% X = Br 48% Scheme 21 The behaviour of unsymmetrical ketones also reveals some features of interest (Scheme 22). Thus, for 2-methylcyclohexanone,35 although a relative series of migratory aptitudes for alkyl, hydrogen, and aryl substituents remains to be established, there is a preference for formation of the more substituted alkene. 0 Mebr 3 : l a1 % Me 7h TMSCI, 70% TMSCI, L! 61% Me. + *' 0 1 : 4 37% overall Scheme 22 A useful study by Hodge and Khan36 in the steroidal series revealed that, as in the Clemmensen reduction, an unhindered 3-01~0 steroid can react while carbonyl functionality in 6,7,12,17, and 20-0x0 steroids remain intact.The regioselectivity in the reactions is also noteworthy, with a preference for formation of the less strained A2-alkene from the trans-fused decalin moiety in 5 a -cholestan-3-one derivatives, presumably as a result of a relatively late transition state for the C-H insertion reaction. This notion is supported by the isolation of a mixture of A2- and A3-alkenes from the cis-fused methyl 3-oxo-5/?-cholanate derivative. 2.2.3 Dicarbonyl coupling reactions The first report of a dicarbonyl coupling reaction appeared in 1980, using a zinc-copper couple and dichlorodimethylsilane as the silicon ele~trophile.~~ The vast majority of the products from benzophenone, benzaldehyde, and cyclohexanone, shown in Scheme 23, were most readily rationalized by invoking pinacolic coupling followed by rearrangement. 226 Contemporary Organic SynthesisTable 1 Products derived from ketone reduction using zinc and diiododimethylsilane in dichloromethane38 Zn(Cu), Me2SiCI2 ph8H Et20.r.t.’ Ph 45% overall Scheme 23 However, the isolation of 2-phenylacetophenone was indicative of the intermediacy of stilbene epoxide, and led the authors to propose that oxirans could be formed by reaction of a derived organozinc carbenoid with the carbonyl partner. Support for the presence of such an intermediate was adduced from a trapping experiment using cyclohexene and benzaldehyde to give 7-phenylnorcarane in 1 5% yield.Clearly, however, the major products need not necessarily have been involved in this pathway. Curiously, in the same year, Ando and Ikeno38 found that it was only possible to achieve the reduction of ketones using zinc and diiododimethylsilane in dichloromethane. These authors stated that ‘dichlorodimethylsilane did not show any reaction with ketones’. Their results (Table 1) were also at variance with those of Smith and c o - ~ o r k e r s ~ ~ for the product( s) derived from cyclohexanone, and, with the exception of aromatic carbonyl compounds, their major products are most readily explicable in terms of an aldol condensation followed by dehydration and subsequent zinc reduction of the a ,P-unsaturated carbonyl compound (Table 1 ). Our own investigation^^^ in this area began in collaboration with the group of Banerjee, who had discovered that certain aryl and a ,P-unsaturated carbonyl compounds could be induced to undergo a McMurry-like dicarbonyl coupling under Clemmensen conditions (Section 2.1.2, Scheme 15).27 Although several coupling reactions could be achieved in a very high yield using the basic chlorotrimethylsilane - zinc system (Scheme 24), other substrates such as isophorone yielded complex mixtures which included one-electron induced dimerization at the softer #?-carbon atom.It soon became apparent that these reactions were not only highly substrate dependent, but also crucially ’influenced by the relative concentrations of substrate, reagents, and the presence or absence of small amounts of hydrogen chloride.The case of a-tetralone (Scheme 25), where the reaction could be channelled to unimolecular C-H insertion, to pinacolic coupling followed by dehydration, or to dicarbonyl coupling, is illustrative. A series of control experiments in the case of the formation of stilbene from benzaldehyde indicated Ketone oo 0 PhAMe 0 PhKPh Product 25% Ph Ph Ph J&yh 16% Me n Zn, TMSCI, THF 4 ° C * 1 5% Scheme 24 Motherwell and Nutley: The role of zinc carbenoids in organic synthesis 2270 20% Scheme 25 that neither benzpinacol nor its silylated derivative was a precursor of the alkene. As in the work of Smith,37 however, when trans-stilbene-oxide was subjected to the reaction conditions, alkene formation was observed, together with diphenylacetaldehyde, thereby implying that the epoxide was a viable intermediate. Interestingly, a sonochemical study of the coupling of aromatic and a ,#?-unsaturated carbonyl compounds in the presence of zinc and chlorotrimethylsilane,4” which was published shortly afterwards, indicated that pinacolic coupling was a dominant pathway under these conditions.Faced by the obvious problem of competing intermolecular reactions at the one-electron reduction level, it therefore became necessary to reduce the ‘longevity’ of these radical intermediates, and enhance the efficiency of carbenoid generation, in order to improve the yields in dicarbonyl coupling. Consideration of the overall stoichiometry of the reaction, which requires two silicon electrophiles to produce hexamethyldisiloxane as a leaving group, suggested the simple solution shown in Scheme 26.Zn (2e-) Me2Si SiMe2 CI CI 27 - A Me9 Scheme 26 Thus, selection of 1,2-bis( chlorodimethylsilyl)ethane 27 as a bis electrophile would permit intramolecular delivery of the second necessary silicon atom. The use of this reagent in the symmetrical dicarbonyl coupling reaction with aryl and a ,#?-unsaturated carbonyl compounds led to a significant improvement in yield.4 Some examples are shown in Table 2, and reveal several aspects worthy of comment. Table 2 Reaction of aromatic aldehydes and a, B-unsaturated carbonyl compounds with 1, 2-bis(chlorodimethylsilyl)ethane and zinc Substrate Product X Yiild ,x OMe 79% 6 8 \ / Me H 06% 69% / CI 26% X g 0 0 76% 72% 18% The best yields of stilbene derivatives are obtained from aromatic aldehydes possessing electron-releasing groups.This trend is also mirrored in the Clemmensen reduction of some substrates, and may well be a consequence of anchimeric assistance towards the departure of the cyclic siloxane (or water) as a leaving group, as implied in Scheme 27. DaH It -Zn*eZn-Zn Scheme 27 228 Contemporary Organic SynthesisExamination of the enone substrates reveals that the construction of oxygen sensitive s-trans-trienes which contain a highly hindered tetra-substituted central double bond is possible. As with cyclopropanation studies, however (Section 2.2.4), the generation of an a,/?-unsaturated organozinc carbenoid is very substrate dependent, as emphasized by the two cyclopentenone derivatives, of presumably similar redox potential, which behave in a very different fashion. from the attempted intramolecular dicarbonyl coupling of 28, to give three products 29 (31%), 30 (14%), and 31 (21%) (Scheme 28), without any indication for formation of a cyclopentanoid.The isolation of the dihydropyran 29 is most readily understood in terms of the carbonyl ylide shown, whose ring closure to the epoxide, necessary for deoxygenation to an alkene, is retarded by a combination of electronic effects and ring strain. In mechanistic terms, a very significant result came ph 30 L J Scheme 28 At the present time, the convoluted mechanistic pathway from carbonyl to organozinc carbenoid, and then via carbonyl oxide to epoxide followed by deoxygenation, has been restricted to symmetrical coupling and to aryl and a ,/?-unsaturated carbonyl substrates.A separate study of the epoxide deoxygenation step using chlorotrimethylsilane and zinc has also been carried the pathways for this transformation involves ring-opening to a siloxychlorohydrin followed by zinc induced elimination of hexamethyldisiloxane, as implied in Scheme 29. and reveals that one of inci 1 ct- Scheme 29 A limiting factor is that the chloride formed must be at least tertiary in order for further zinc-induced elimination to occur. Benzylic and allylic substrates which are formed in the observed dicarbonyl coupling are therefore particularly favoured. While a range of unsymmetrical couplings may be possible, it is nevertheless unlikely that this approach will replace the inherently more flexible and mechanistically simpler McMurry reaction.43 2.2.4 Cyclopropanation reactions The formation of cyclopropanes from alkenes and carbenes or metallocarbenoids is certainly a very useful synthetic operation.On a large scale, however, the necessity for preparing or handling all but the simplest of the most often used gem dihalo or diazo precursors, is not an attractive proposition. As we have seen (Section 2.2.1 ), the first observations of useful trapping of an organozinc carbenoid by an alkene were made by Elphimoff-Felkin and Sarda.34 At a later stage the same authors published a series of cyclopropanation reactions for a range of olefins with benzaldehyde, and for the same olefin, various para-substituted benzaldehyde~.~~ These, together with a selection of our own results45 for aromatic aldehydes using the zinc - 1,2-bis( chlorodimethylsilyl)ethane system (which, not surprisingly exhibit similar trends), are displayed in Table 3.Table 3 Cyclopropanes derived from aromatic aldehydes Substrate \ x Method OMe A OMe B Me A H A Alkene Product Yiild, Ratio (mdaexo) e 60%, 19:l 96%, 15:l a%, 7.51 75%, 8:l 43%, 5:1 60%, 4:l 43%, 4.51 CI B L 46%, 3:l Ar 20%, 1:l J 0:e &k 53%, 1:l Method A: Zn, F3B.0Et2 Method B: Zn, (CH2SiMe2C1)2 Once again, as in the dicarbonyl coupling reaction, yields are best for electron rich substrates, thereby lending additional credence to the idea that these participate most efficiently in carbenoid generation. The virtually quantitative yield in the trapping of the carbenoid from para-anisaldehyde in the presence of only two equivalents of cyclohexene, using the zinc and silicon electrophile system is particularly noteworthy.Motherwell and Nutley: The role of zinc carbenoih in organic synthesis 229Reactions with cis- and trans-but-2-ene lead to retention of the original alkene geometry, and there is a highly stereoselective tendency for formation of the more hindered isomer, which is particularly marked in the case of para-anisaldehyde, but apparently falls off as a function of decreasing electron-release from the aromatic ring. published by C a ~ e y ~ ~ in a study of cyclopropanation by stoichiometric tungsten alkylidenes (Scheme 30), and would also seem to be applicable in the case of zinc carbenoids. An elegant rationalization of these trends has been H &L” X _ _ Path (a) I cis trans Scheme 30 Thus, approach of the alkene to the metal carbenoid always occurs in such a way as to place any substituents on the alkene trans to, or away from, the metal.As the bulk of the substituent increases, this tendency increases, and Path (b), resulting in formation of the trans isomer, is favoured. However, in less sterically demanding cases, opportunities exist for additional electronic stabilization of the developing positive charge on the alkene, through electron-donation via the ips0 carbon of the aromatic ring, and Path (a), leading to the more hindered cis substituted cyclopropane, is then followed. This model also rationalizes the general observation that yields in the metallocarbenoid cyclopropanation of trans disubstituted alkenes always tend to be lower than in the case of their cis counterparts, as a result of increased demands in steric approach control.We were also intrigued to examine the behaviour of non-aromatic a,B-unsaturated organozinc carbenoids in cyclopropanation reacti0ns.4~ In this instance, of course, conventional wisdom relating both to the isolation of cyclopropanol acetates by Elphim~ff-Felkin,~~ and to the reductive ring contractions observed under Clemmensen conditions (Section 2.1.3) would argue that carbenoid reactivity should not be observable. range of carbenoids from both cyclic and acyclic enones and ends may be trapped. In the event, however, as shown in Table 4, a useful Table 4 Cydopropanes derived from alicyclic ketones and acyclic aldehydes Carbonyl Alkene Compound Product phw Ph phM5 Ph Ph Yield, Ratio (cis: trans) 53“/, all cis 55%, 20:l 59%, 11:l 44%, 1:l 1 !woo.1:l A curious prerequisite for successful generation and trapping of these vinylidene organozinc carbenoids is the presence of some degree of steric crowding around the #?-olefinic terminus of the enone or enal. Thus, attempted cyclopropanation reactions using ‘parent’ systems such as cyclohexenone, cyclopentenone, and cyclopenten- 1 -carboxaldehyde, were without success. From the stereochemical standpoint, the cis selective preference observed in the case of aromatic aldehydes also seems to be maintained in the cases of the isoprenoid enal and cyclohexenone substrates. It is, however, absent in the more planar cyclopentenones, suggesting perhaps again that the three-dimensional shape around the /3-terminus has a profound role in governing reactivity.230 Contemporary Organic Synthesis3 The Simmons-Smith reaction and Furukawa modification The Simmons-Smith reaction, first reported in 1958,13 involves the cyclopropanation of an alkene with a reagent prepared in situ from a zinc-copper couple and diiodomethane (Scheme 3 1). The reaction is stereospecific with respect to the geometry of the alkene, and unlike reactions involving free carbenes, is generally free from side reactions. + CH212 + Zn-Cu + Zn12 + CU Scheme 31 Since that time, it has become the most frequently used method for the preparation of simple cyclopropanes. The reaction has been reviewed very ~omprehensively,4~ and hence our intention is to present an overview of the more recent key synthetic modifications and applications of the reaction, as well as the methodological advances.Of these, the most significant variation lies in the use of diethyl zinc and diiodomethane in place of a zinc couple and diiodomethane (or substituted diiodides). First reported by F u r u k a ~ a , ~ ~ this adaptation will be considered in this section, as it is frequently used to provide a comparison with the Simmons-Smith reagent system. The other reagent system of importance involved the reaction of diazomethane with zinc iodide to give a cyclopropanating agent, and will be discussed in Section 4. 3.1 The Simmons-Smith reaction In their first report of the reaction,13 the authors obtained cyclopropanes in yields ranging from 10-70%, depending on the type of couple employed.They considered that the reactive intermediate, i.e. the cyclopropanating agent, was iodomethylzinc iodide, and that it would be displaced by the x-bond of an olefin to give a cyclopropane and zinc iodide. A full paper was later published on the reaction,"9 and was followed by two papers which sought to define the nature of the intermediate, and the optimum conditions for synthesis.so Studies indicated that di-iodomethane formed a 1 : 1 complex with zinc (from a zinc-copper couple), which existed as a colourless homogeneous solution, capable of forming cyclopropanes with alkenes.4Y It was proposed that this complex may best be represented as 32 or 33, and was also shown in the same study that the copper simply acted via activation of the zinc surface, and had no other role.H2C::f ZnI H2C - ZnI2 32 33 Mechanistically, it was suggested that the reaction proceeded by a one-step methylene transfer, where the quasi-trigonal methylene group of the active cyclopropanating agent 33 adds to the alkene, with essentially simultaneous formation of two bonds. This interpretation fitted well with the following experimental observations: (i) few side reactions are found, suggesting that free methylene is not an intermediate; and (ii) the reaction follows second-order kinetics, in accordance with a bimolecular process; and, cyclopropane formation is stereospecific. It was also shown that the iodomethylzinc iodide behaves as a weak electrophile, since alkene reactivity increased with alkyl substitution although, of course, at the price of a balanced steric pay-off.3.2 The Furukawa modification In many ways, the reagent generated by Furukawa's reagent. The major advantages of Furukawa's system are the following: (i) the reaction is homogeneous; (ii) reagent formation is rapid under mild conditions; (iii) it is suitable for the cyclopropanation of vinyl ethers and similar substrates that are prone to undergo polymerization under Simmons-Smith condition^;^ and (iv) the reaction is not restricted to methylene transfer, but may also be used with alkyl and phenyl carbenoidsS2 As with the Simmons-Smith reaction, cyclopropanes were found to form stereospecifically. The observed syn-selectivity was augmented with increased electron-donating ability of the substituents on the carbenoid.s3 It was also found that electron-donating substituents on the olefin increase both the yield and rate of reaction, strongly indicating that the cyclopropanating agent is electrophilic (and hence analogous to the Simmons-Smith reagent).s4 Reactions were found to give the highest yields when a hydrocarbon solvent was employed.Polar solvents, such as ethers, gave far lower yields.s1 Denmark has made an extensive study of the nature of the reagent generated by the Furukawa procedure.ss The research demonstrated that the highly reactive bis( ha1omethyl)zinc reagents generated are stabilized by coordination to ethers or acetone. The first X-ray crystallographic analysis of an (iodomethy1)zinc complex was also undertaken, and gave a strong indication as to the structural parameters of reagent stabilization by proximal oxygenated functionality.is very similar to the Simmons-Smith 3.3 A synthetic overview The Simmons-Smith reaction provides a route for the introduction of a methyl group to a molecule bearing an alkene unit suitable for cyclopropanation. Cleavage of such an introduced cyclopropane furnishes an angular methyl group. Conia and co-workers published some very elegant work on this theme.s6 In essence, by a three step sequence, it was possible to introduce an a -methyl group to a ketone. A silyl enol ether was generated from the desired ketone, and this cyclopropanated with zinc-silver couple and diiodomethane, using a pyridine work-up.The cyclopropane thus generated could then undergo either a standard deprotection sequence to yield the Motherwell and Nutley: The role of zinc carbenoitis in organic synthesis 23 1cyclopropanol, or hydrolysis to yield the a-monomethylated ketones (Scheme 32). The reaction sequence was found to work for cyclopentanones, cyclohexanones, cycloheptanones, and cyclooctanones, as well as aldehyde^.^^(^) In the case of unsymmetrical ketones, it was possible, through selection of the appropriate silyl enol ether, to orientate methylation to the a or a' position. In all cases, the yields were good. A, 350 "c tube 9 OSiMe3 OSiMe3 Initially, the influence of the solvent was examined. Dichloroethane was found to be the superior solvent for the reaction, giving 35 in a yield of 94%, while cat.HCI THF@A (ii) Pyridine Scheme 32 When 2-trimethylsiloxycycloalka- 1,3-dienes were examined,s6(bj it was found that monocyclopropanation occurred almost exclusively on the double bond bearing the trimethylsiloxy group (using 1.1 equivalents of diiodomethane). The 2-trimethylsiloxycycloalka- 1,3-dienes were prepared from the corresponding a $-unsaturated ketones. In the presence of 3 equivalents of diiodomethane, cyclopropanation of both double bonds occurred in 80-90% two cyclopropane rings was believed to be anti, since the second cyclopropanation reaction of the 3,4-alkene would be directed to occur on the same face as the siloxy group. Using the same methodology, Conia accessed cyclobutanones and cyclopentanones via the rearrangement (either acid-catalysed or thermal) of 1-siloxy- 1 -vinyl cyclopropanes, formed via the cyclopropanation of silyl enol ethers of cisoid or labile a -ethylenic ketones (Scheme 33).s6(cj The relative stereochemistry of the iduences which affect its reactivity.Recently, work was published comparing the regioselectivities of the mono-cyclopropanation of such substrates as limonene 34 and 4-vinylcyclohexene with the classic Simmons-Smith reagent (diiodomethane, zinc, and copper(r) chloride in diethyl ether), the modified Furukawa conditions (diiodomethane with diethyl zinc in toluene) and the Yamamoto conditionss7 (diiodomethane and triethylaluminium in toluene-dichl~romethane).~~ 34 The relative reactivity of dibromomethane, zinc, and copper( I) chloride in diethyl ether was also examined.Earlier results had suggested that CH,I,-Zn-Cu gave rise to an electrophilic cyclopropanating agent, which was sterically was known to provide a less sterically hindered reagent, especially in non-coordinating solvents. The final triethylaluminium based systemSY had been found to cyclopropanate exclusively at an alkene distant from a hydroxyl group, the opposite of the other two systems, although this facet of the systems's reactivity was not relevant in this particular study. Thus it was found that in the case of limonene 34, the Et,Zn-CH,I, system exhibited the lowest regioselectivity for mono-cyclopropanation, and was hence determined to have the lowest steric requirements of all the systems examined. CH,I,- or CH,Br,-Zn-Cu both gave similar regioselectivities, with an average of 3: 1 preference for the exocyclic disubstituted alkene.The regioselectivity of the Et,Al system was found to lie between the other two systems. These findings were confirmed with 4-vinylc yclo hexene. Denmark and co-workers made a comparison of (chloromethy1)- and (iodomethy1)zinc as cyclopropanation reagents in the modified Furukawa process,h* using the reaction shown in Scheme 34. whilst the Furukawa system 232 Contemporary Organic Synthesisthe stereochemical course of the reaction. The evident superiority of the chloromethylzinc reagent examined here over the more normal iodomethylzinc would suggest that this should become the reagent of choice for Furukawa modified Simmons-Smith c yclopropanations. The Simmons-Smith cyclopropanation of enol ethers has been found to give different results depending on the concentration of the reaction mixture."' Under dilute conditions ( - 0.5 M with respect to the substrate), it was found that cyclopropanation occurred exclusively, whereas under much higher concentrations, allylic ethers were generally found to be the exclusive product (Scheme 35).The allylic ether products were assumed to have formed via zinc iodide catalysed rearrangment of the initially formed cyclopropane. The isomerization step was also examined, although less successfully, using diiodomethane and diethylzinc. It was found that although the isomerization of the cyclopropane occurred, the resulting allyl ether then underwent rapid cyclopropanation itself.In general, the isomerization reaction proceeds more smoothly in less coordinating solvents. OMe MeQ OMe U EtzO, A U U Concentration Product Ratio Total Yield (%) -0.94 98 : 2 72 - 1.25M 83 : 17 59 -2.w 2 : 98 66 Scheme 35 In an early study, the carbenoid nature of the Simmons-Smith cyclopropanation reagent was shown by the ability of a modified reagent to undergo intramolecular C-H insertion reactiomh2 The reagents concerned were prepared from the reaction of 1,l -diiodopropane 36 or 1,l -diiodo-2-methylpropane 3 7 with a zinc-copper couple. After a short induction period, volatile products were found to form (Scheme 36), and were proposed to have arisen via the intermediacy of 38. The heterogeneity of the Simmons-Smith reaction would suggest that reactivity would be increased enormously by sonication.Repic and Vogt undertook such a study,63 and found that whereas the Simmons-Smith reaction normally requires prior activation of the zinc, i.e. formation of a couple (a capricious process), by sonicating the reaction, ordinary unactivated zinc is sufficiently reactive. They also found that it was possible to cyclopropanate alkenes with consistently higher yields than in the literature. It is surprising in view of these results that sonication of such reactions has not met with wider use. Lie Ken Jie and Lam later published on the influence of sonication in the cyclopropanation of unsaturated long chain keto esters, and the effect of changing the metal employed (zinc versus cadmium I = : 1 6 : 1 36 I + w + y 1 : 1 via 4 f i - X X R=H,Me = I or iodoalkyi R 38 Scheme 36 versus ~opper)."~ It was found that under sonication at 80-90°C in DME, copper metal and diiodomethane were able to effect alkene cyclopropanation.Interestingly, when 39 was sonicated in the presence of either cadmium or zinc and diiodomethane, furan formation was observed (Scheme 37). R' = Me(CH& R2 = (CH2)7C02M8 Scheme 37 zn: 46% Cd: 10% Sibille and co-workers examined what may be considered an electrochemical version of the Simmons-Smith reacti0n.6~ The optimized reaction conditions were found to be a 9:l dichloromethane : dimethylformamide solvent mixture, using a carbon fibre cathode and zinc anode. Zinc bromide was then generated in situ by the electrolysis of 1,2-dibromoethane, in the presence of the alkene, and then dibromoethane added to facilitate cyclopropanation.In this manner cyclopropanes were obtained in yields ranging from 8-75 per cent, with the best yields for allylic or unfunctionalized alkenes. Syn addition was observed in all cases. The authors suggested that the cyclopropanating agent formed in this process is a zinc carbenoid 'as proposed for the classical chemical reaction', on the basis of similarities in reactivity observed. The use of allyl thioetherP and a-oxoketene dithi~acetals~~ as substrates in the Simmons-Smith reaction has led to some interesting reactions. It was found that the cyclopropanation of cyclohexene was completely suppressed in the presence of an allyl or alkyl thioether using diiodomethane and either a zinc-copper couple, zinc-silver couple or copper powder."6 However, taking 3-methyl-l- phenylthio-2-butene, diethyl zinc, and diiodomethane, Motherwell and Nutley: The role of zinc carbenoids in organic synthesis 233234 a methylene homologation reaction is observed, which presumably proceeds via the formation of a sulfur ylide and a 2,3-sigmatropic rearrangement (Scheme 38).If a homoallylic sulfide is used, it can form an ylide capable of elimination to form dienes (Scheme 39). The goal of many of the more recent studies on the Simmons-Smith reaction has been to achieve an enantioselective cyclopropanation reaction. Nearly all strategies to date have involved the use of a chiral auxiliary, and in the majority of cases the auxiliary contains oxygenated functionality capable of 80% Scheme 38 + Ph'S'Me Scheme 39 The attempted cyclopropanation of a -0xoketene dithioacetals gave rise to a new route to 3,4-substituted and annelated thiophenes.6' In essence, under normal Simmons-Smith conditions, the carbenoid intermediate forms a sulfur ylide with a -0xoketene dithioacetal, which then reacts intramolecularly to yield a thiophene (Scheme 40).M& # / i J 1- coordinating to the incoming zinc carbenoid. Thus, a continuing theme in this section will be the directing effect of oxygenated substituents in the Simmons-Smith reaction. Charette has published some particularly elegant work recently, employing carbohydrates as a chiral auxiliary to achieve a highly stereoselective cyclopropanation of allylic alcohols.6* This methodology capitalizes on the fact that one of the oxygen atoms in the auxiliary (the free hydroxyl at the 2-position) proximal to the alkene undergoes direct attack by the reagent to facilitate prior coordination of the zinc.This anchoring of the reagent was found to give good diastereoselection and high yields of the cyclopropane (Scheme 4 1). A large excess of reagents is required, and the exact reagent ratios were found to be important. Brio\ R' R' BnO OH Yields > 97% Diastereoselectivities z- 50:l Scheme 41 Cleavage to the cyclopropylmethanol was achieved via the conversion of the product into the corresponding triflate, and then heating in DMF-water at 1 60°C, yielding the free cyclopropane (90%) via a Scheme 40 The reaction was found to be unaffected by the presence of additional alkene units, and in the examples examined, yields of the thiophenes ranged from 53-65%.In some cases, dethiomethylation of the resulting thiophene was possible using Raney nickel in methanol. It is thus possible that a whole range of ylide chemistry could be accessed via the zinc carbenoid formed in the Simmons-Smith reaction. One interesting aspect of this is that in the Simmons-Smith reaction a neighbouring oxygen (alcohol) serves to promote the rate of cyclopropanation, an effect considered to be due to coordination of the zinc via the oxygen. There have apparently been no similar examples of oxonium ylide chemistry, which reflects on the relative availability of the lone pairs of electrons in divalent sulfur and oxygen, and the rate of cyclopropanation versus ylide formation.novel fragmentation of the 2-hydroxyglucopyranoside. Preliminary results using the auxiliary with the opposite anomeric configuration indicate formation of the cyclopropane of opposite relative configuration with a good level of asymmetric induction (diastereoselection > 12:1, yield > 97%). later published results on the use of 1,2-trans-cyclohexanediol as the chiral auxiliary for the asymmetric cyclopropanation of allylic ethershY After optimization studies the auxiliary was found to give a high level of stereochemical induction ( > 20:l) if bis( chloromethy1)zinc was used instead of bis(iodomethy1)zinc. In this instance, in contrast to the sugar-based auxiliaries, only three equivalents of the reagent in toluene were necessary to maximize yields and diastereoselection.Furthermore, protection of the secondary alcohol was found to be detrimental to the diastereoselectivities, indicating the pivotal importance of zinc coordination to the free hydroxyl group on the Developing and simplifying this strategy, Charette Contemporary Organic Synthesisstereochemical outcome. A typical reaction, and the sequence for removal of the auxiliary, is shown in Scheme 42. ZnCu. CH212, 12 (cat.), Etg. A. l h 97%, ds 24:l Ph y i , THF, -78 oc C('T Ph 10 min. I Scheme 42 A considerable body of work has been published using homochiral ketals as auxiliaries in the cyclopropanation reaction. The first results in this area were published simultaneously by Yamarnoto7O and Mash.71 Yamamoto had employed an acetal of an a ,#?-unsaturated aldehyde, derived from diisopropyl tartrate, as the chiral auxiliary (since this substrate was found to give slightly higher enantiomeric excesses than that derived from diethyl tartrate).Cyclopropanation was then carried out using diethyl zinc and diiodomethane. Yields were high, as were the diastereomeric excesses (Scheme 43). -cYo2pr' I h C H O ,-* 'C02Pr' 63% (over 2 steps) Et2MH212 -20%. l h H -*co2pr' 90%, 94% d.e. Scheme 43 The acetal could be transformed to the aldehyde (p-TsOH-H,O) or to the ester (ozonolysis). The ready availability of both the (R,R)- and (S,S)-tartaric acid esters allows the synthesis of both enantiomers of cyclopropanes from a ,#?-unsaturated aldehydes. Yamamoto then used this methodology in the synthesis of (5 R ,6R)-5,6-methanoleukotriene In the same paper results were also presented on the use of acetals derived from (2R,4R)-2,4-pentanediol, which gave the corresponding (R,R)-cyclopropane in good to high yield (69-95%) and moderate diastereomeric excess (29-75%).The mechanism for the action of these auxiliaries was suggested to be via the coordination of the incoming cyclopropanating agent to the more exposed acetal oxygen on the auxiliary. Mash employed homochiral cycloalkenone ketals, prepared by the direct ketalization of the corresponding a ,#?-unsaturated ketones and aldehydes using 1,4-di- 0-benzyl-L-threitol as the diol c~mponent.~ These ketals were then cyclopropanated using zinc-copper couple, diiodomethane, and a crystal of iodine in refluxing diethyl ether.After a short reaction time ( - 1 h), yields were found to be in the range 90-98%, with, in the case of the cycloalkenone ketals, a good diastereomeric excess (Scheme 44). However, acyclic ketals derived from a,#?-unsaturated aldehydes were found to give very poor diastereoselection. &xx 'X X = CH20CH2Ph 99% 20:l dr Scheme 44 In a later paper the methodology was expanded successfully to synthesize tricyclo[m.n.l .O]-alkanones as well as bicyclo[m. 1 .O]-alkanones of the sort shown in Scheme 44.73 As with Yamamoto's method, both cyclopropane enantiomers could be accessed by using either the L- or D-forms of 1,4-di-O-benzyl-threitol, readily available from natural and unnatural tartaric acids. The ketal was readily hydrolysed in acidic methanol, and the auxiliary easily recovered.The stereochemistries of the cyclopropanes thus synthesized suggested that a common mode of reagent delivery is operative (Figure 1). The major drawback, however, with this method, was found to be that the diastereomers produced were neither crystalline nor chromatographically separable, and so it was not possible to obtain enantiomerically pure cyclopropyl ketones by this route. 0- "CH2" Figure 1 This work was later applied by Mash in the total synthesis of ( + )-modhephene, using a slightly modified auxiliary. The first steps in the synthesis involved an enantioselective cyclopropanation, which, on ring-opening of the cyclopropane, eventually furnished an angular methyl Motherwell and Nutley: The role of zinc carbenoids in organic synthesis 235Mash went on to examine other diols, which allowed more successful separation of the diastereomers produced, and all recent work has employed the diol ( S,S)-( - )-hydrobenzoin, giving the corresponding 2-cycloalken-1-one (S,S)-( - )-hydrobenzoin ketals.These were found to give good yields of the cyclopropane, and high diastereomeric ratios (Scheme 45).75 (iii) Etgn, CHd2 DCM phh- 0 0 I MeOH-HCI 0 Scheme 45 Phh,Ph + oG 90% 19:l dr An interesting study was also made on the influence on the diastereoselectivities of having strongly Lewis basic oxygenated appendages on the ketals 40.7h These were found to both lower yields and diastereoselectivity, and the results were in contrast to those of Yamamoto, shown in Scheme 43.70 Yamamoto had reported similar yields and diastereomeric excesses to Mash, who was employing either ether or alkyl appendages on the ketal, using diisopropyl tartrate as the chiral auxiliary, i.e.R = CO,Pri in 40. Mash discusses the mechanistic implications of the observed effects. Studies were also carried out on the effect of ring conformation on dia~tereoselectivity.~~ v 40 Tai and co-workers examined the use of 2,4-pentanediol or 2,6-dimethyl-3,5-heptanediol as an auxiliary. Early work employing 2,4-pentanediol gave moderate yields ( - 55%) and high diastereomeric excesses ( > 95%) (Scheme 46).7x The use of both the classic Simmons-Smith reagent, and the Furukawa modified procedure was examined. The chiral auxiliary was removed by PCC oxidation followed by treatment with potassium carbonate in methanol.major .=w 0 OH Using the more sterically congested chiral auxiliary 2,6-dimethyl-3,5-heptanediol, and cyclopropanating using diethylzinc and diiodomethane in diethyl ether at 20°C, yields were elevated up to 86%, with excellent diastereomeric excesses ( > 99.5°/0).79 The major drawback to this auxiliary appears to be that, as with the 2,4-pentanediol derivative, a two step deprotection protocol is necessary. In an interesting variant on the chiral auxiliary theme Fujisawa and co-workers found that they were able to take an allylic alcohol, form in situ a complex with diethyl zinc and ( + )-diethy1 tartrate (DET ) (other esters of R,R-tartaric acid were also examined), such that the tartrate moiety still had one free pendent hydroxyl group.On the addition of the second equivalent of diethyl zinc and diiodomethane, the cyclopropanating agent formed carried out a stereospecific methylene delivery by virtue of the transient auxiliary-substrate complex formed (Scheme 47).x" Although the results reported were variable, this approach to the enantioselective synthesis of cyclopropanes from allylic alcohols seems promising. L Scheme 47 Fujisawa's preliminary results in this area were extended by Ukaji and co-workers.81 Optically active silicon substituted cyclopropylmethyl alcohols were prepared by the reaction of y-trimethylsilyl substituted allylic alcohols with diethyl zinc, diiodomethane, and ( + )-DET (Scheme 48). The products were formed with a high diastereoselectivity (up to 92% e.e.), and in most cases in high yield. It was found that using dichloroethane as the reaction solvent lowered the selectivity compared with dichloromethane, and that 236 Scheme 46 Scheme 48 Contemporary Organic Synthesislowering the reaction temperature enhanced selectivity. It was assumed as before that the addition of the first equivalent of the diethyl zinc and ( + )-DET led to the formation of the zinc bridging intermediate 41.also been enantioselectively cyclopropanated in a catalytic fashion via the use of a C,-symmetric disulfonamide as a chiral ligand.82 Thus, a catalytic quantity of the disulfonamide 42 is reacted with diethyl zinc to generate what is assumed to be species 43. When diiodomethane is added, a chiral cyclopropanating agent is formed, giving excellent chemical yields, and good enantiomeric excesses (Scheme 49).The free hydroxyl group of the allylic alcohol was found to be very important, and when ether derivatives were subjected to these reaction conditions, racemic mixtures of cyclopropanes resulted. In a very exciting development, allylic alcohols have I-I EtpZn m situ " NHS02R _____c a H NHSOpR SO2R (yn N H I SO2 R 42 43 H 2eq. E t a c DCM-10% hexane -23 "C, 5h Ph H Ph H Quantitative yield e.e.02% Scheme 49 The authors suggested, in view of the experimental results, that the chiral Lewis acid zinc complex 43, formed a chiral complex of type 44 in the transition state, which must of course react even faster than the normal achiral reagent. Thus the oxygen atom of a zinc alkoxide and an iodine atom of iodomethylzinc coordinate to the zinc atom in 44, giving rise to a trinuclear complex.The enhanced reactivity observed by the authors could thus be attributed to the coordination of the zinc atom of 43 with an iodine atom of iodomethylzinc. 44 The asymmetric synthesis of cyclopropane carboxylic acid derivatives has been examined using an iron complex as the chiral auxiliary.x3 When [( q 5-C,H,)-Fe( Co)(PPh,)] was complexed with a Z-a $-unsaturated acyl ligand, and cyclopropanated using diethyl zinc and diiodomethane, in the presence of zinc chloride in toluene, the corresponding cyclopropanes were isolated in 9 1 O/O yield (Scheme 50). Stereoselectivity was found to increase with increasing size of the terminal alkene substituent. However, it was found that this method could not be used for the corresponding E- a ,B-unsaturated acyl ligands, as these appeared to require a nucleophilic me th y lene transfer reagent.3( b, 4eq. ZnClp 91%. 9:l Scheme 50 via the cyclopropanation of B-hydroxysulfoximines using a zinc-silver couple and diiodomethane, refluxing in diethyl ether for 72 h (Scheme 51).84 Optically active cyclopropyl ketones were accessed J A Scheme 51 The cyclopropanation was found to occur cis to the hydroxyl group of the allylic B-hydroxysulfoximine. As both the enantiomers of the P-hydroxysulfoximine can be accessed, it is possible to synthesize both cyclopropane enantiomers. Removal of the B-hydroxysulfoximine group is achieved simply by a thermal elimination. This technology has been applied to the synthesis of ( - ) and ( + )-thujopsene (Scheme 52).I (i) MeMgBr (ii) TsOH. PhH. reflux Et2O 0 . 72% 95% (-) -t hu jopsene Scheme 52 Motherwell and Nutley: The role of zinc carbenoids in organic synthesis 237Finally, in this section, some of the more recent uses of the Simmons-Smith reaction in natural product synthesis will be outlined. Cyclopropanes feature in many important synthetic targets, and their introduction has also been used to furnish angular methyl groups via a ring cleavage protocol. In the first total synthesis of the limonoid skeleton, Corey utilized a hydroxyl-directed Simmons-Smith reaction to stereospecifically generate a cyclopropane, which was then cleaved using lithium-liquid ammonia, to create the C/D angular methyl group (Scheme 53).85 Generally this group is difficult to introduce, and the Simmons-Smith methodology provides a useful entry.The same synthetic strategy for the introduction of the C/D angular methyl group was also applied in the synthesis of azadiradione, a tetracarbocyclic member of the limonoid family.86 PDC 3A sieves DCM, 23 “C 12h @P O c--- Li-NHs -78 “c. 15mn. ‘8 H 92% limonoid system Scheme 53 The first enantioselective total synthesis of 3/3,20-dihydroxyprotost-24-ene 45, a protostenediol of the protosterene system, again used a hydroxyl-directed cyclopropanation to furnish eventually an angular methyl group (Scheme 54).87 In this instance, however, the yield in the cyclopropanation step was only moderate (66%). The enantiospecific synthesis of ring system 46, characteristic of the crenulide diterpenes was recently published.88 In this instance, the cyclopropane moiety was introduced through reagent delivery from the least hindered face of the alkene, using diethyl zinc and diiodomethane to give a high yield (83%) to give the desired product (Scheme 55).As part of a strategy towards the linearly fused sesquiterpene hirsutene, Hudlicky and co-workers demonstrated the first example of an intramolecular Simmons-Smith reactionax9 The reaction examined is illustrated in Scheme 56. Although the yields of the cyclopropanes were relatively low, the authors suggested that this was due to the purity of the precursor, which had to be generated in situ due to its instability. n n 0- R‘ = Me, R2 = OH R’ =OH, R2= Me 0- HO 45 Reagents: (i) leq. Bu”ti; (ii) 15eq.ICHDI, Et20, 23 “C, 12h Scheme 54 04 ’0 0 OQ-* 0 46 Scheme 55 R=H,Me X = Y = Br, I / X=Br*Y=l Zn. DME / dR I R Scheme 56 238 Contemporary Organic Synthesis4 Simmons-Smith reagents from the reduction of a zinc(]]) salt with a diazoalkane This method for the generation of Simmons-Smith type reagents for the cyclopropanation of olefins was first reported by Wittig,Yo and has since received relatively little attention. The active cyclopropanating species is formed by the addition of diazomethane or aryldiazomethane to an ethereal suspension of a zinc (11) halide, Schemes 57 and 58, with the active species being either the ‘monomer’ 47 or ‘dimer’ 48. * ICH2.ZnI 47 4 2 Zn12 + CH2N2 Scheme 57 ICH2.ZnI + CH2N2 - ICHpZnCH21 48 Scheme 58 Wittig proceeded to publish a series of papers on this reaction,” where salt effects were examined, and the influence of other metals such as magnesium and lithium.It was possible to cyclopropanate alkenes with the reagent derived from diazomethane in moderate to good yields.Y1(a) Whilst cyclohexene could only be cyclopropanated in 30% yield, aromatic substituted alkenes such as styrene and 4-propenylanisole gave far higher yields, 85% and 80% respectively. In a variant of this dibenzoyloxy zinc and diazomethane, an effective methylene insertion occurred to give the benzoyloxymethyl zinc derivative 49. Characterization by IR suggested structure 50. This reagent could then be used to cyclopropanate alkenes in the presence of zinc( 11) halides (Scheme 59). it was found that taking * (PhCO&H2)2Zn - NP (PhC02)2Zn + CH2N2 49 I - ZnI, Scheme 59 Apart from Wittig, few groups have examined this reaction, and it is primarily of academic interest. ClossY2 published a detailed study on the influences on the decomposition of aryldiazomethanes with lithium and zinc halides (Scheme 60).In effect, by considering the carbenoid generated by this method as having a general formulation 5 1, the study examined the effect of the R (aryl only), M (metal), and X (leaving group). R M R X X 51 t R R2 .$ H Scheme 60 Zinc halide catalysis of the reaction (Scheme 60) was found to give excellent yields of cyclopropanes, with the syn isomer always predominating. The reaction also worked for catalytic quantities of zinc halide, although most results were for the use of stoic hiome tric quantities.For any one olefin and zinc halide, increasing electron-donating ability of the para-substituent on the aromatic ring of the aryldiazomethane led to a marked increase in the syn to anti ratio of the resulting cyclopropane, although this was surprisingly mirrored by a decrease in yield, in contrast to our own observation^.^^ It would seem likely that this yield reduction was in fact due to increased substrate instability, and not inefficiency of carbenoid formation per se. Interestingly, a systematic study of the variation of the zinc halide used revealed that the chloride ion caused the smallest syn to anti ratio and iodide the largest (with bromide in between). The influence of the zinc halides on the reaction was measured using kinetic studies on the relative rates of additions of the various reactive intermediates to different olefins.Over all substrates, the rate increases markedly chloride to bromide to iodide, with iodide being significantly faster. A substrate (olefin) dependency also became apparent from this study: the greater the degree of substitution around the olefin, the faster the addition; as a corollary to this, the greater the degree of substitution, the larger the rate difference across the series from chloride to bromide to iodide. The influences of both the anion of the zinc halide and the para substituent on the aromatic ring were assigned to electronic effects affecting the charge density ( i.e. electrophilic nature) of the carbenoid carbon in the transition state.However, for this explanation to be valid for the stereochemical outcome of the reactions, it assumes that charge transfer or dipolar interactions are responsible for the stereochemistry. Extending this principle, Goh and co-workersY3 examined the formation of dicarbenoid species from the reaction of 1,3-bis( diazomethy1)benzene with zinc halides. Best results were obtained using isobutylene, with the decomposition of the diazo compound being Motherwell and Nutley: The role of zinc carbenoids in organic synthesis 239carried out in the presence of zinc bromide at - 20°C in diethyl ether (Scheme 6 1). These reaction conditions gave a 62% yield of the dicyclopropane. In the absence of an alkene trap, the dicarbenoid was found to insert into the a-CH of diethyl ether (12%) and THF ( MY0), depending on the solvent employed for the reaction.Similar insertion reactions were also observed by Closs.92 Attempted addition of the dicarbenoid to a di-olefin (diallyl ether) failed to give any of the expected adduct. CHN2 I , Br Scheme 61 5 Conclusions Organozinc carbenoids seem to occupy a rather curious position in metallocarbenoid chemistry, and despite their historical pedigree both in terms of the Clemmensen reduction and the Simmons-Smith cyclopropanation, their recognition as a discrete and useful class of reagents in their own right has yet to be fully appreciated. The very position of zinc in the Periodic Table, where it is, to some extent, shunned by the transition metal cognoscenti, may well be responsible. The foregoing review has attempted to tie some of these disparate threads together, and to highlight that these reactive intermediates display all of the classical features of carbene and carbenoid reactivity in terms of insertion reactions, ylide formation, and cyclopropanation.Moreover, their generation from readily available carbonyl compounds under mild reductive conditions, without recourse to diazo or gem dihalo precursors is an added advantage, which will hopefully enable organozinc carbenoids to increasingly serve as useful reagents for organic synthesis. 6 References 1 W. Kirmse, ‘Carbene Chemistry’, Academic Press Inc., 2 E.O. Fischer and A. Massbol, Angew. Chem., Znt. Ed. 3 U. Burger and R. Huisgen, Tetrahedron Lett., 1970,35, 4 J.H. Wengrovius, R.R. Schrock, M.R.Churchill, J.R. London, 1971, p. 5. Engl., 1964,3,580. 3049. Mssert, and W.J. Youngs, J. Am. Chem. SOC., 1980,102, 4515. 5 D.F. Taber and R.E. Ruckle, Tetrahedron Lett., 1985,26, 3059. 6 H. Fntschi, U. Leutenegger, and A. Pfaltz, Helv. Chim. Acta, 1988,71,1553. 7 J.D. Rodgers, G.W. Caldwell, and A.D. Gauthier, Tetrahedron Lett., 1992,33,3273. 8 M. Brookhart and W.B. Studabaker, Chem. Rev., 1987, 87,411. 9 For a general review see P. Helquist in ‘Comprehensive Organic Chemistry’, ed. B.M. Trost and I. Fleming, Pergamon Press, Oxford, 1991, vol. 4.6, p. 951. 10 (a)M.P. Doyle,Acc. Chem. Res., l986,19,348;(b) idem., Chem. Rev., 1986,86,919. 11 (a) E. Frankland, Liebigs Ann. Chem., 1849,71,171; (b) idem., ibid., 1849,71,213. 12 P. Knochel and R.D. Singer, Chem.Rev., 1993,93,2217. 13 H.E. Simmons and R.D. Smith, J. Am. Chem. SOC., 1958, 80,5323. 14 (a)E. Clemmensen, Chem. Ber., 1913,46,1837; (b) idem., ibid., 1914,47,51; (c) idem., ibid., 1914,47,681. 15 (a) E.L. Martin, Org. React., Wiley, New York, 1942,1, 155; (b) D. Staschewski, Angew. Chem., 1959,71,726; (c) E. Vedejs, 0%. React., Wiley, New York, 1975,22, 401. 16 (a) J.H. Brewster, J. Am. Chem. SOC., 1954,76,6361; (b) idem., ibid., 1954,76,6364; ( c ) J.H. Brewster, J. Patterson, and D.A. Fidler, ibid., 1954,76,6368. (b) idem., ibid., 1960,82,3906; (c) idem., ibid., 1960, 82,3909. 18 G.A. Risinger, E.W. Mach, and K.W. Barnett, Chem. Znd., 1965,679. 19 J. Burdon and R.C. Price, J. Chem. Soc., Chem. Commun., 1986,893. 20 (a) M.L. Di Vona, B. Floris, L. Luchetti, and V.Rosnati, Tetrahedron Lett., 1990,31,6081; (b) M.L. Di Vona and V. Rosnati, J. Org. Chem., 1991,56,4269; (c) L. Luchetti and V. Rosnati, ibid, 1991,56,6836; (d) M.L. Di Vona and V. Rosnati, Gazz. Chim. Ztal., 1993,123,25. 21 S.-C. Chang, R.H. Hauge, Z.K. Kafafi, J.L. Margrave, and W.E. Billups, J. Chem. Soc., Chem. Commun., 1987, 1683. 22 T.P. Hamilton and H.F. Schaefer, 111, J. Chem, SOC., Chem. Commun., 199 1,62 1. 23 J. McKenna, J.K. Norymberski, and R.D. Stubbs, J. Chem. SOC., 1959,2503. 24 B.R. Davis and P.D. Woodgate, J. Chem. SOC. (C), 1966, 2006. 25 I. Elphimoff-Felkin and P. Sarda, Tetrahedron, 1975,31, 2781. 26 C.W. Jefford and A.F. Boschung, Helv. Chim. Acta, 1976,59,962. 27 A.K. Banerjee, J. Alvarez, G.M. Santana, and M.C. Carrasco, Tetrahedron, 1986,42,66 15.28 J.G. St. C. Buchanan and P.D. Woodgate, Quart. Rev., 1969,23,522. 29 See for example, (a) N.J. Cusack and B.R. Davis, Chem. Znd., 1964,1426; (b) E. Wenkert and E. Kariv, Chem. Commun., 1965,571; (c) N.J. Cusack and B.R. Davis, J. Org. Chem., 1965,30,2062; (d) K.M. Baker and B.R. Davis, Chem. Ind., 1966,768; (e) J.G. St. C. Buchanan andB.R. Davis,J. Chem. SOC. (C), 1967,1340. 17 (a) T. Nakabayashi, J. Am. Chem. Soc., 1960,82,3901; 30 A.N. Dey and R.P. Linstead, J. Chem. SOC., 1935,1063. 3 1 See for example, M. Toda, Y. Hirata, and S. Yamamura, Bull. Chem. SOC. Jpn., 1972,45,264. 32 W.P. Reeves, J.A. Murry, D.W. Willoughby, and WJ. Friedrich, Synth. Commun., 1988,18,1961. 33 T.J. Curphy, C.W. Amelotti,T.P. Layloff, R.L. McCartney, and J.H. Williams, J.Am. Chem. Soc., 1969, 69,28 17. 240 Contemporary Otganic Synthesis34 I. Elphimoff-Felkin and P. Sarda, Chem. Commun., 35 W.B. Motherwell, J. Chem. Soc., Chem. Commun., 1973, 36 P. Hodge and M.N. Khan, J. Chem. SOC. Perkin Trans. I , 37 C.L. Smith, J. Arnett, and J. Ezike, J. Chem. SOC., Chem. 38 W.Ando and M. Ikeno, Chem. Lett., 1980,1255. 39 A.K. Banerjee, M.C. Sulbaran de Carrasco, C.S.V. 1969,1065. 935. 1975,809. Commun., 1980,653. Frydrych-Houge, and W.B. Motherwell, J. Chem. SOC., Chem. Commun., 1986,1803. 40 J.-H. So, M.-K. Park, and P. Boudjouk, J. 0%. Chem., 1988,53,5871. 41 C.A.M. Afonso, W.B. Motherwell, D.M. OShea, and L.R. Roberts, Tetrahedron Lett., 1992,33,3899. 42 C.A.M. Afonso, W.B. Motherwell, and L.R. Roberts, Tetrahedron Lett., 1992,33,3367. 43 J.E.McMurray, Chem. Rev., 1989,89,1513. 44 I. Elphimoff-Felkin and P. Sarda, Tetrahedron, 1975,3 1, 2785. 45 W.B. Motherwell and L.R. Roberts, J. Chem. Soc., Chem. Commun., 1992,1582. 46 C.P. Casey, S.W. Polichnowski, A.J. Shusterman, and C.R. Jones,J.Am. Chem. Soc., 1979,101,7282. 47 H.E. Simmons, T.L. Cairns, S.A. Vladuchick, and C.M. Hoiness, Org. React., Wiley, New York, 1973,20, 1. 48 J. Furukawa, N. Kawabata, and J. Nishimura, Tetrahedron Lett., 1966, 3353. 49 H.E. Simmons and R.D. Smith, J. Am. Chem. SOC., 1959, 81,4256. 50 (a) E.P. Blanchard and H.E. Simmons, J. Am. Chem. Soc., 1964,86,1337; (b) H.E. Simmons, E.P. Blanchard, and R.D. Smith, ibid., 1964,86,1347. 5 1 J. Furukawa, N. Kawabata, and J. Nishimura, Tetrahedron, 1968,24,53. 52 J. Furukawa, N. Kawabata, and J. Nishimura, Tetralledron Lett., 1968,3 1,3495. 53 (a) J. Nishimura, J. Furukawa, and N. Kawabata, Bull. Chem. Soc. Jpn., 1970,43,2195; (b) J. Nishimura, J. Furukawa, N. Kawabata, and H. Koyama, Bull. Chem. SOC. Jpn., 1971,44,1127. 54 J. Nishimura, N. Kawabata, and J. Furukawa, Tetrahedron, 1969,25,2647. 55 (a) S.E. Denmark, J.P. Edwards, and S.R. Wilson, J. Am. Chem. SOC., 1991,113,723; (b) idem., ibid., 1992,114, 2594. 56 (a) J.M. Conia and C. Girard, Tetrahedron Lett., 1973, 29, 2767; (b) idem., ibid., 1974,37,3327; (c) C. Girard, P. Amice, J.P. Barnier, and J.M. Conia, ibid., 1974,37, 3329; (d) C. Girard and J.M. Conia, ibid., 1974,37, 3333. 57 K. Maruoka, Y. Fukutani, and H. Yamamoto, J. Org. Chem., 1985,50,4412. 58 E.C. Friedrich and F. Niyati-Shirkhodaee, J. Org. Chem., 1991,56,2202. 59 J. Nishimura, N. Kawabata, and J. Furukawa, Tetrahedron, 1969,25,2647. 60 S.E. Denmark and J.P. Edwards, J. Org. Chem., 1991,56, 6974. 61 I. Rhu, T. Aya, S. Otani, S. Murai, and N. Sonada, J. Organomet. Chem., 1987,32 1,279. 62 R.C. Neuman Jr., Tetrahedron Lett., 1964,37,245 1. 63 0. Repic and S. Vogt, Tetrahedron Lett., 1982,23,2729. 64 M.S.F. Lie Ken Jie and W.K. Lam, J. Chem. Soc., Chem. Commun., 1987,1460. 65 S. Durandetti, S. Sibille, and J. Pkrichon, J. Org. Chem., 66 Z . Kosarych and T. Cohen, Tetrahedron Lett., 1982,23, 67 (a) A. Thomas, G. Singh, H. Ila, and H. Junjappa, 1991,56,3255. 3019. Tetrahedron Lett., 1989,30,3093; (b) L. Bhat, A. Thomas, H. Ila, and H. Junjappa, Tetrahedron, 1992, 48,10377. 68 A.B. Charette, B. CbtC, and J.-F. Marcoux, J. Am. Chem. SOC., 1991,113,8166; A.B. Charette and B. C6t6, J. Org. Chem., 1993,58,933. 1993,34,7157. 1985,107,8254. 107,8256. Tetrahedron, 1986,42,6447. 679. 1988,29,2147. 69 A.B. Charette and J.-F. Marcoux, Tetrahedron Lett., 70 1. Arai, A. Mori and H. Yamamoto, J. Am. Chem. Soc., 71 E.A. Mash and K.A. Nelson, J. Am. Chem. Soc., 1985, 72 A. Mori, I. Arai, H. Yamamoto, H. Nakai, and Y. Arai, 73 E.A. Mash and K.A. Nelson, Tetrahedron, 1987,43, 74 E.A. Mash, S.K. Math, and C.J. Flann, Tetrahedron Lett., 75 E.A. Mash and D.S. Torok, J. 0%. Chem., 1989,54,250. 76 E.A. Mash, S.B. Hemperly, K.A. Nelson, P.C. Heidt, and S. Van Deusen, J. Org. Chem., 1990,55,2045. 77 E.A. Mash and S.B. Hemperly, J. Org. Chem., 1990,55, 2055. 78 T. Sugimura, T. Futagawa, and A. Tai, Tetrahedron Lett., 1988,29,5775. 79 T. Sugimura, M. Yoshikawa, T. Futagawa, and A. Tai, Tetrahedron, 1990,46,5955. 80 Y. Ukaji, M. Nishimura, and T. Fujisawa, Chem. Lett., 1992,61. 81 Y. Ukaji, K. Sada, and K. Inomata, Chem. Lett., 1993, 1227. 82 H. Takahashi, M. Yoshioka, M. Ohno, and S. Kobayashi, Tetrahedron Lett., 1992,33,2575. 83 (a) P.W. Ambler and S.G. Davies, Tetrahedron Lett., 1988,29,6979; (b) idem., ibid., 1988,29,6983. 84 C.R. Johnson and M.R. Barbachyn, J. Am. Chem Soc., 1982,104,4290. 85 E.J. Corey, J.G. Reid, A.G. Myers, and R.W. Hall, J. Am. Chem. SOC., 1987,109,918. 86 E.J. Corey and R.W. Hahl, Tetrahedron Lett., 1989,30, 3023. 87 E.J. Corey and S.C. Virgil, J. Am. Chem. Soc., 1990,112, 6429. 88 J. Ezquerra, W. He, and L.A. Paquette, Tetrahedron Lett., 1990,3 1,6979. 89 T. Hudlicky, B.C. Ranu, S.M. Naqui, and A. Srnak, J. Org. Chem., 1985,50,123. 90 G. Wittig and K. Schwarzenbach, Angew. Chem., 1958, 71,652. 91 (a) G. Wittig and K. Schwarzenbach, Leibigs Ann. Chem., 1961,650,l; (b) G. Wittig and F. Wingler, ibid., 1962, 656,18; (c) idem., Chem. Ber., 1964,97,2139; (d) idem., ibid., 1964,97,2 146; (e) G. Wittig and M. Jautelet, Leibigs Ann. Chem., 1967,702,24. 1969,34,25. 1976,29,1699. 92 S.H. Goh, L.E. Closs, and G.L. Closs, J. Org. Chem., 93 S.H. Goh, K.C. Chan, and H.L. Chong, Aust. J. Chem., Motherwell and Nutley: The role of zinc carbenoids in organic synthesis 24 1

ISSN:1350-4894    

DOI:10.1039/CO9940100219

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Alcohols, phenols, and ethers JOSEPH SWEENEY School of Chemistry, The University, Cantock's Close, Bristol BS8 ITS, UK Reviewing the literature published between July 1992 and July 1993 1 1.1 1.2 1.3 1.4 1.5 2 3 Preparation of alcohols From carbonyl compounds via carbon-carbon bond formation By oxidation Reductive methods of alcohol synthesis Preparation of alcohols from epoxides Miscellaneous methods of alcohol synthesis Preparation of phenols and ethers References This review seeks to identlfy new synthetic methods for the preparation of alcohols, phenols, and ethers and covers only those articles describing novel techniques or interesting modifications to existing protocols. 1 Preparation of alcohols 1.1 From carbonyl compounds via carbon-carbon bond formation The chelation-controlled alkylation of B-keto- and /3-formyl-esters has been extended to encompass reactions of 2-alkyl-2-formylamides 1 (Scheme 1);l 1 I R2-M threo erythro R' R2-M threo: ervthro Me MeAICIz 97:3 EtAlCIz 9 6 ~ 4 Ph AlCIz 9 3 ~ 7 PhTiCl3 4:96 Pr' MeAIClz 9 9 : l Ph AlCI, 99: 1 Et Al CI2 99: 1 these substrates are of particular interest due to the possible peptidomimetic properties of the alkylated products.The scheme illustrates the general reaction: alkyl and aryl aluminium dichlorides delivered carbon ligands from the less hindered face in good yields, and with excellent selectivity. The use of phenyltitanium trichloride in the reaction was capricious; in some circumstances, a reversed selectivity was observed. In the reaction of electron-deficient o-formyl allenes with samarium di-iodide, an interesting divergence in regioselectivity was observed between homologues (Scheme 2).2 (66% yield) OH 6H 2 3 4 M e o 2 c ~ Bs :mzcv +Meo;:Q 1 1 OH OH CHO above 6 (15:1)82% 5 Scheme 2 Thus, when 1-( 2'-formylethy1)-1- methoxycarbonylallene 2 was treated with samarium( 11) iodide in tetrahydrofuran, a 2 : 1 mixture of endo- and exo-cyclopentenecarboxylates 3 and 4, respectively, was obtained.The exo-methylene compound 4 was a 2 : 1 mixture of diastereoisomers, and so the reaction had exhibited poor selectivity. However, when the higher homologue 5 was reacted under the same conditions, a highly selective 5-ex0 cyclization took place to give cis-2-hydroxy- 1 -methoxycarbonyl- 1- vinylcyclopentane 6 as the almost exclusive diasteroisomer. This 5-ex0 cyclization contrasts with previously reported 6-endo radical cyclizations of similar compound^.^ Chelation control, mediated by Sm3 + (Scheme 3) was suggested to explain the stereoselectivity since a parallel reaction using tributylstannane as radical agent gave a product of much lower diastereopurity ( - 5 : 1 ratio).Scheme 1 Sweeney: Alcohols, phenols, and ethers Scheme 3 243The previously reported conversion of allylic and benzylic mesylates to the corresponding allyl- and benzyl-lithiums4 has been extended to provide a new route to organolithium reagents (Scheme 4).5 Thus, primary and secondary dialkylsulfates 7, prepared by Sharpless's method," reacted with an excess of lithium powder, in the presence of a catalytic amount of naphthalene at low temperature, to give two equivalents of a primary or secondary organolithium reagent.These reacted with carbonyl compounds to give alcohols 8 in moderate to excellent yield. The reaction of cyclic sulfates under these conditions gave alkenes, via the intermediacy of 1 -1ithio-2-sulfonates. - 78 "C 8 R' R2 R3 Yield8(%) M e Ph H 52 Et Ph H 73 Et -(CH2)5- 41 P+ Ph H 40 Scheme 4 The halogen-metal exchange reaction of iodoimines 9 derived from trifluoroacetaldehyde provided a useful entry to umpoled species 10, which reacted with ketones in moderate yield and with aldehydes in better yield (Scheme 5).7 9 L J 10 Scheme 5 An unprecedented stereoselectivity was observed in the addition of organoiron (11) reagents to cyclohexanones (Scheme 6).8 It was proposed that the combination of organolithium and iron salts gave octahedral iron reagents, e.g.11, which delivered alkyl groups with high facial selectivity to substituted cyclohexanones, the nucleophile ending up in the equatorial position in the product. The authors proclaim that 'essentially complete stereocontrol in the formation of axial alcohols is possible for the first time'. The use of organomagnesium reagents led to lower selectivity. OH R axial equatorial 11 R' R2 'R-Fe' axial : equatorial But H 2MeLi,FeCI3 98:2 But H 3Meli,FeC13 99:l But H 4MeLi,FeCI3 98:2 But H 2 MeLi. Fe(acadP 99 : 1 .- H Me 3MeLi,F&I3 99:l Scheme 6 alkyl-zirconocene chlorides to aldehydes is subjected to a remarkable acceleration in rate in the presence of silver perchlorate." As an example, under normal conditions the reaction of the hexenylzirconium reagent 12 with 3-phenylpropionaldehyde gave a low yield of addition product.However, when silver perchlorate was added, yields were excellent (Scheme 7). Even 0.1 mol% perchlorate was sufficient to give good yields. The authors proposed the intermediacy of a cationic zirconium species 13 to explain their observations. The Grignard-type addition of alkenyl- and AgClOi Ph OH Ph 6 Bu 13 n0AgCI04 23% 1 md % AgCIO, 90% 0.1 mol% AgC10, 84% Scheme 7 A similar enhancement was observed in the reaction of alkylzirconocene chlorides with aldehydes, but two equivalents of the alkylzirconocene dichloride must be used along with a ten-fold increase in the level of perchlorate. For alkenylzirconium reagents, the reaction was complete in ten minutes; alkyl zirconium species typically required several hours to react. The authors proposed the cyclic mechanism shown in Scheme 8 to illustrate the importance of perchlorate to the reaction.A highly active form of copper(o), generated in situ from a copper( I ) cyanide/lithium chloride complex, reacted at very low temperature with 1,2-dichloropropene to generate the 1,2-dimetallated propene 14.10.1 This underwent sequential reaction with electrophiles to give homoallylic alcohols (Scheme 9) in moderate to good yields. 244 Contemporary Organic SynthesisL carbonyl activation Scheme 8 4 8, R’* R > 94% 14 El E2 Product Tiid(%) PhCHO bBr 88% Ph Scheme 9 There appears to be some restriction regarding the range of electrophiles which will react in the second alkylation step, and only active electrophiles, e.g.allylic halides, react efficiently. non-regioselectively with electrophiles.’ It has been reported that the addition of freshly fused zinc chloride to 15 allows for exclusive a-reactivity with carbonyl compounds (Scheme 1 O).’ The product chlorohydrins were exclusively syn-isomers when the carbonyl compounds were aromatic aldehydes. Epoxides were formed in high yield when desired. occurred, without the need for a catalyst, by reaction with allyltrichlorosilanes in N, N-dimethylformamide (Scheme 1 l ) . 1 4 The dimethylformamide was found to be essential for the reaction, presumably due to complexation between silicon and the amide. The well known15 propensity of a-monosubstituted allylic chromium reagents to undergo anti-selective addition reactions with aldehydes was overcome by the use of allylic phosphates to prepare the chromium reagents.16 This allowed for a stereodivergent alkylative protocol.The a-lithiated allylchloride 15 reacts The stereoselective allylation of aldehydes 15 5 2 4 % Scheme 10 OH I 024% Scheme 11 88-91 % A selective allylation of aldehydes was effected by use of 3-( tetrahydropyranyloxy )-propenylstannanes 16.17 The allylated products were obtained in moderate to good d.e. (Scheme 12), although the removal of the chiral auxilary hampered the overall efficacy of the process. YTBDMS /ObO,-OTBDMS fo’r..J RCHO 16 63-94% d.e. Scheme 12 Barrett et al. recently reported the use of 3-silylpropenylboranes for the efficient and enantioselective preparation of anti-alk-1-ene-3,4-diols.l8 The same group have now disclosed B-[ ( E )-( diphenylamino)prop-2-enyl]-diisopinocamph- eylboranes 17 as highly selective reagents for the synthesis of anti-2-( diphenylamino)-3-hydroxy- 1 -alkenes 20 (Scheme 1 3).19 Sweeney: Alcohols, phenols, and ethers 245Ph2N /\// BunLi TMEDA -10 "C 1 [Ph2NCHCHCH,Li ] I 17 R L NPh, 20 Scheme 13 I 20 Deprotonation of 3-( diphenylamino) propene, followed by reaction of the allyllithium species so formed with the methoxyboranes 18 and 19 derived from pinene, allowed in situ formation of both enantiomers of the (aminoally1)borane 17.Upon reaction with aldehydes at low temperature, anti-l,2-aminoalcohols 20 were then formed with uniformly excellent diasteroisomeric and enantiomeric excess.There was one exception to this rule: the acetonide of (S)-glyceraldehyde, when a mismatched substrate reacted with poor diastereoselectivity. glyoxalate-ene reactions continue. The previously reported work,2o utilizing homochiral BINOL-derived titanium dichloride 2 1 , described the reaction of mono-alkenes with methyl glyoxalate; the reaction of symmetrical bis-alkenes allows for a desymmetrizing reaction (Scheme 1 4).2 Developments in the area of asymmetric I I 0 + 0 HAC02Me I - Si- MS 4A, 21 22 (27%; 60% based on Si consumed) Scheme 14 In the products 22, high syn-selectivity was shown ( > 99% syn) and enantiomeric selectivity was excellent, but conversions were poor. The reaction may be used kinetically to resolve racemic allylic alcohols .The asymmetric variant of the glyoxalate-ene reaction has been extended to embrace the use of vinyl selenides and sulfides as the alkene components of the process (Scheme 1 5).22 The reaction exhibited good enantiocontrol when a variety of alkenes was used. With non-terminal alkenes, the reaction had poor to excellent diastereoselectivity, but the anti-diastereoisomers were obtained with high enantiopurity. syn-Diastereomers were produced with moderate to high e.e. uC02Me A + HKCO,Me 4AMS phs SPh 0 cat*. CH2C12 > 99% 8.8. -30°C 94% yield anti SYn Me 45 (99) 55 (78) Et 81 (99) 19 (84) Bun 91 (>99) 9 ( S O ) Bu' 95(>99) 5 ( S O ) Scheme 15 R anfie.e.(%) syne.e.(%) An interestingly selective preparation of homoallylic alcohols from hydroxyacetone relied on an unusual remote protecting group effect (Scheme 16).23 Thus the use of a protecting group, R in 23, which was predisposed to coordinate strongly to a cation favoured conformer c, and led to (Re)-face attack, producing isomer a.The authors proposed that the use of a less-coordinating or bulkier protecting group, such as a trialkylsilyl moiety, favoured conformer d in which the ring-oxygen atom coordinated the metal, thereby leading to (Si)-facial 246 Contemporary Organic Syntheskattack and the formation of isomer b. In these reactions, the group causing the effect was six atoms away from the reacting centre, an unusually distant influence. -0J OR 23 t OH \ + y + O & y + O - OR OR a b C d Scheme 18 R a : b Yield(%) Temp.Bn 93.7: 6.3 93 -20 "C Bn 97.6: 2.4 92 -55 "C+r.t. Ps3Si 7.2 : 92.8 90 -55 "C4r.t. pri3si 1 2 : ~ 88 -20 "C Scheme 16 A similarly distant stereocentre facilitated the highly enantioselective ring-opening of epoxides by a-silylbenzylic anions (Scheme 1 7).24 Chan and co-workers improved upon their previous report25 of enantioselective alkylation of proline-derived aminosilanes, and described the preparation of homochiral syn- 1,3-diols via the regiospecific ring-opening of disubstituted epoxides. Yields were good and stereocontrol complete. PhASi/- 0 I Scheme 17 1"'. H202 5340% all > 90% 8.8. The utility of chiral ligands as mediators of enantioselective addition reactions of carbonyl compounds has continued to attract interest. When propargyl ethers, obtained from propargylation of homochiral alcohols (norephedrine, prolinol, menthol, diacetone glucose, among others), were treated with potassium t-butoxide, homochiral alkoxyallenes were obtained (Scheme 1 8).26 R*OH = homochiral alcohol 24 1 NHCl 15 min.- r.t. 25 (66% e.e.) These ethers, when deprotonated and reacted with aldehydes, gave ( 1-hydroxyalky1)allenyl ethers 24 in good yield but with only moderate diastereoselectivity ( < 50435% d.e.). Acidic hydrolysis of 24 gave enantiomerically enriched (hydroxyalkyl) vinyl ketones, e.g. 25, which are useful synthetic intermediates for use in cycloaddition reactions. The utility of the previously reported work by Knochel on the novel preparation of polyfunctionalized dialkylzinc reagents27 was hampered by two drawbacks: firstly, a large excess (five equivalents) of diethylzinc had to be used to allow efficient reaction and, secondly, scale-up of the reactions was accompanied by incomplete conversion of starting material.An improved protocol has now been reported to overcome these serious limitations.28 When a functional alkyl iodide was treated with diethylzinc and a catalytic amount of a copper(1) salt (either CuI or CuCN were employed), a functionalized dialkylzinc was formed which reacted with a , p-unsaturated aldehydes in the presence of a homochiral catalyst (derived from trans- 1,2-diaminocyclohexane) to give functionalized secondary allylic alcohols 26 with moderate to excellent chemical yields and enantiomeric excesses (Scheme 19). Ti 26 (56-95%, -98% e.e.) R' R2 R3 Yield(%) e.e.(%) Me Me H 70 98 H Pr H 75 83 Me Et0,C H 78 80 Br Pr H 95 94 Br Me Me 68 68 Br Me H 77 80 Scheme 19 Sweeney: Alcohols, phenols, and ethers 247A two-fold increase in the rate of reaction was observed compared with the previous method, and only a 50% excess of diethylzinc was required to achieve > 95% conversion of starting material, in both small- and large-scale reactions.The authors noted that a-bromoaldehydes reacted to give products with higher e.e.’s than non-halogenated substrates, as noted before in enantioselective cycloaddition reactions,2Y due to more restricted conformations. by the naturally occurring diamine( - )-sparteine was first reported in the early 1970’s although the stereoselectivity of this pioneering work was poor (7-39% e.e.).30 The Reformatsky reaction of aryl methyl ketones with t-butylbromoacetate has since been found to be more selective when the reaction is carried out in the presence of N, N-diallylephedrine 28 (Scheme 20).3 The use of ( 1 S, 2R)-ephedrine gave (S)-2-hydroxyesters 27 with moderate enantioselectivity.An enantioselective Reformatsky reaction mediated THF PhMe 0 “C R’yMe + BrZnAC02Bu‘ 0 Ph Me H o X N v Scheme 20 2Qa. X= OMe b, X=H R Reaction T Sdvent A:B Ph 0°C THF 94:6 Ph reflux THF 5 : 95 Ph 23°C PhMe 88: 12 Ph 60°C PhMe 4:96 Me 23°C PhMe 87: 13 Me 60°C PhMe 5:95 Scheme 21 (Scheme 22).35 That this reaction proceeded through the (2-hydroxyalky1)enol ether was demonstrated when the preformed enol ethers 32, prepared via silylative ketal cleavage,36 were oxidized using the rhenium ( VII) oxidant; the same levels of diastereoselectivity were observed.28 27 x Y P h Ph 30 OH threo A OH threo B Ph 74 2-Naplh 75 F a 73 R 31 A Finally in this section, an extremely interesting example of a counter-intuitive effect of temperature upon selectivity has been observed during the reaction of chiral aldimines with dialkylzirconocenes (Scheme 2 1). Thus, when dibutylzirconocene was reacted with imines such as 29 in tetrahydrofuran or toluene, a zirconoaziridine 3032333 was generated. This metalloheterocycle reacted with aldehydes to yield exclusively threo- 1,2-aminoalcohols in good yield.34 The authors found that the facial selectivity could be completely reversed by increasing the temperature of the reaction; however, the reversal in selectivity was only possible when imines 29a, derived from phenylglycinol, were used.When simpler imines, such as 29b, underwent the reaction, selectivity was merely diminished and not reversed. 1.2 By oxidation ( S)-2-Hydroxycycloalkanones were prepared with virtually complete enantioselectivity via the rhenium-mediated oxidation of c ycloalkanone ketals 3 1 derived from homochiral 1,2- and 1,3-diols Scheme 22 Alkylations of dianions derived from N-9-phenylfluorenyl aspartic acid diesters 3337 have been employed in the stereodivergent preparation of (3R)- and (3S)-3-hydroxy aspartates (Scheme 23).38 Such specifically hydroxylated compounds are of significance in many biological systems and the preparation of both diastereoisomers of these compounds is feasible using MoOOPH oxidation.When no excess of HMPA was employed, the (2S,3R)-isomer 35 was produced in > 90% d.e.; when the phosphonamide was present, the ( 2S73S)-diastereoisomer 34 predominated (85% d.e.). The authors employed the fact that the enolate derived from 33 exists as a mixture of open and chelated forms, the chelate being favoured in poorly coordinating solvents. 248 Contemporary Organic SynthesisC02Me w2c/\I (9 LHMDS(3eq.) MF-HMPA 34 4- 35 & (ii)MoOOPH,-78% 11 : 1 ratio w 33 (i) LHMDS (3 eq.) (ii) MoOOPH (2 eq.) BuLi (1 eq.) \ - 78 "C \ THF .. 34 1 : 20 ratio 35 Scheme 23 Organolanthanides are the latest organotransition metal derivatives to be utilized as catalysts for olefin hydrob~ration.~~ A variety of lanthanide complexes mediate the reaction, a common feature to all of the catalysts being the use of polymethylated cyclopentadienyl ligands (Scheme 24).The mechanistic fulcrum of the process is the formation of a dicyclopentadienyl-lanthanide hydride 36 which adds regiospecifically across the alkene, producing an alkyl-lanthanide which is converted by a second equivalent of catechol borane into an alkyl boronate. * "<R3 ( I ) O o * B - H (2 9s.) benzene, 20 "C ' 0' R' R3 R2 R2 cat. (5 ml%) (11) H202 frequently pyrophoric and not easily handled. Singleton et a1?* employed a coupling reaction of commercially available reagents to allow a facile in situ preparation of vinyl-9-BBN, and reacted the dienophile with a variety of dienes to yield, after the usual peroxidative treatment, 1 -hydroxycyclohex-3-enes which had not previously been reported or whose previous syntheses were laboured.The regiocontrol in the cycloaddition reaction was high, usually > 90% in favour of the para-cycloadduct. 1 H202 # Scheme 25 81 % Transition-metal activation of alkenes has been used by Speckamp and Hiemstra in a novel synthetic approach to 1-amino-3-alken-2-01s (Scheme 26)?* Thus, carbamate-protected allylic amines were converted into hemi-aminals by reaction with glyoxalate hemi-acetals, and these were oxidatively cyclized under palladium catalysis to give oxazolidines in good yields. The oxazolidines were converted in a 6145% one-pot, four-step process (including an electrolytic decarboxylation) to aminoalkenols in excellent yield. However, where diasteroisomerism is possible, mixtures were generally obtained, although amines derived from cycloalkenes showed high cis-selectivity.-k $-H 36 Scheme 24 A useful application of, and improvement to, the recently disclosed40 use of vinyl boranes as dienophiles, has been reported (Scheme 25). The improvement in the methodology was in the preparation of the requisite vinyl borane, which is 68% (ii) BocNH + - OH Me0,c 91% 76% OH Reagents: (i) M~O&OM= ,4A MS, CH2C12, 11, 18h; (ii) Pd(OAc),, Scheme 26 (0.1 eq.) CU(OAC)~, (3 eq.) DMSO, 70 "C, 2h The development of asymmetric dihydroxylation (AD) reactions continues to result in improved methodology. The known asymmetry of the addition of alkylzincs in the presence of homochiral piperazines, such as 37, led to the de~elopment~~ of asymmetric Sweeney: Alcohols, phenols, and ethers 249cis-dihydroxylation of olefins employing dimers of 3 7 (Scheme 27).Thus, treatment of prochiral olefins with OsO, in the presence of stoichiometric amounts of 37a gave cis-diols in low chemical yield and with unsatisfactory e.e.'s. ph, )-l R-N+N-R Dh I I, 378, R=Me b, R=Pr' Ph 38 -04 38 * Ph% Ph OH Ph 81 %, 98% 8.8. Pl 0 40 (Schematic drawing d 38 + substrate) 39 Scheme 27 This result was rationalized by the authors as being due to energetically disfavoured coordination to osmium, caused by the severe distortion of the ligand necessary to achieve good bonding to the metal atom. To obviate this problem, the workers developed bis-piperazine 38, in which the dimeric structure allowed efficient formation of an osmium-ligand complex 39.Whether or not 39 is an accurate representation of the species involved in the reaction, the dihydroxylation of representative olefins in the presence of 38 proceeded in good chemical yield and with good to excellent enantiomeric excesses (see 40). As previously noted in such dihydroxylations, the best substrates for the reaction were trans-l,2-disubstituted alkenes in which at least one of the substituents is aromatic. The limiting feature of this work was the need for stoichiometric quantities of ligand. A similar drawback was present in the system offered by Hanessian et aZ.44 Thus, osmylation of trans-stilbene in the presence of homochiral trans-[ N, N'-di-( 3,3-dimethylbutyl)] cyclohexane- 1,2-diamine 4 1 at very low temperature was enantioselective (Scheme 28).Although in this reaction cis-substrates reacted poorly (as is usual), there were several which reacted with greater efficiency than in previously reported systems. Thus, fumarates react with high e.e. (96%) as do other previously unreactive AD substrates. The authors isolated a derivative 43 of the first product of the reaction, presumed to be osmate 42, and solved its structure by X-ray analysis. preparation and crystal structures of the cinchona alkaloids used in AD-mix reacti0ns.4~ The same group Sharpless has published full details of the Y + 43 Scheme 28 has also tackled the often referred to weakness of asymmetric dihydroxylations, viz. reaction of cis- 1,2-disubstituted substrates. They have maintained their search for improvement of reaction conditions and discovered that the use of indolinyl derivatives of dihydroquinidines vastly improved the enantioselectivity of the dihydroxylation of these difficult Whereas previous e.e.'s were poor, < 35%, the new ligands gave acceptable e.e.'s (Scheme 29).DHQD-IND 44 gave the products of p-attack as expected, and DHQ-IND gave the a-products, the difference in selectivity between the two systems being the most pronounced discovered to date. OH DHQD-IND* Ho PhmC0*Pr' Os04 PhHC02P+ 80% 8.8. Hq OH P t i i C 0 2 P + 72% 8.8. 44 Scheme 29 250 Contemporary Organic SynthesisThe AD-mix reaction of /3, y- and y, &unsaturated esters has been shown to be highly enantio~elective,~~ and has been used to synthesize all four isomers of di~parlure.~~ To accomplish highly selective hydroxylation of a , /3- and p, y-unsaturated amides, a modified AD-mix employing a five-fold increase in the ligand and potassium osmate was req~ired.~' When this new, improved mix was used, both a , /3- and /3, y-unsaturated amides reacted in good chemical yield and with high levels of enantioexcess (Scheme 30).The products of these reactions were easily dehydrated to give homochiral y-hydroxy-a, /3-unsaturated amides (Scheme 3 Sharpless has utilized this oxidation-elimination process to prepare ( + )-coriolic acid in four steps.5o C OH 0 0 R' = Et, z-0 , OMe, Me u Scheme 30 I N. / 0 &Lo, O H 0 (i) SOCIa Etd, 0 "C (ii) DBU, 0 "c + r.t. I &Lo/ 0 (+)- coriolic acid Scheme 31 2 81% 2 93% 8.0. Further work from the group has revealed an interesting nuance when the AD protocol is applied to enol etherss1 a-Hydroxyketones are produced in high enantiomeric purity, but the reaction of enol ethers derived from phenylbenzylketone gives the same absolute stereochemistry at the new chiral centre, regardless of enol ether geometry (Scheme 32).So, (Z)-enol ether 45 gives the (R)-hydroxyketone, as does the (E)-enol ether 46. These substrates were expected to give enantiomeric products. AD-mix B P h h p h MeO OH 45 (> 99% Z) 99% 8.0. P:? Ph OH 90% e.8. APmk $ PhJy 46 (> 99% E ) Scheme 32 The selective asymmetric dihydroxylation of dienes is a highly viable and valuable synthetic process (Scheme 33).52 Both conjugated and non-conjugated dienes react selectively, with the olefin of greater substitution reacting preferentially.When an electron-withdrawing substituent lies in conjugation with the diene, the olefin most distant from the substituent is hydroxylated. Trienes also react selectively. Corey has examined the origins of the high enantioselectivity in the AD reaction,53 and prepared monomeric derivatives of cinchona alkaloids, e.g. 47, for use in dihydroxylations. AD reactions using 47 were one-hundred-fold slower than the reactions in which dimeric alkaloids were employed. The Harvard workers used this evidence to support their suggestion that the bridged osmium complex 48 is the active ingredient of AD-mixes. Finally, a review dihydr~xylation.~~ has appeared covering asymmetric I OH 73%. 98% 8.0. 90% 8.8. 72% 8.8.3 : 1 - COzEt &C02Et OH 70%. 2 92% 8.8. CO2Et CO2Et - OH 93%, 95% 8.8. Scheme 33 Sweeney: Alcohols, phenols, and ethers 251n OMe 47 48 1.3 Reductive methods of alcohol synthesis Although not strictly speaking a reduction of carbonyl compounds, the unusual reactivity shown by borane towards tetrahydropyranyl ethers is a useful reductive method for the direct preparation of 5-h~droxyethers.~~ N, N-Methoxy-N-methyloxamides were reduced in excellent yield to 1,2-diols with borohydride.56 Simple dialkylamides were reduced to a-hydroxyamides. A new system for reduction of ketones, aldehydes, and acid halides used cadmium chloride and magnesium in watereS7 Simple carbonyl compounds were reduced to alcohols, while acid chlorides were reduced to aldehydes in good yield.Some epoxides were regioselectively, reductively cleaved. Buchwald previously reported the reduction of esters using titanocene as catalyst;58 a new 'second generation catalyst system' for ester hydrosilylation, employing (tetraisopropyloxy )-titanium as the transition metal component (Scheme 34), has been de~cribed.~~ (9, (ii) RCOZ Et L RCHZOH (2 70% yield) Reagents: (i) Et,SiH, Ti(OPi),, (5 mol. %), 55 OC Scheme 34 (ii) 1 N NaOH, THF, r.t. The authors claim several advantages for their system over the reagents available for such transformation: the catalyst is self-activating, the process requires no solvent, and the catalyst may be used and generated without the need for an inert atmosphere. 0-Benzyloximes have been reduced to the corresponding hydroxylamines using an excess of titanium tetraisopropoxide and diphenylsilane.6° Lithium aminoborohydrides have been reported as a new class of powerful reducing agents.They exhibit similar levels of reactivity to lithium aluminium hydride but they are non-pyrophoric and air-stable, and were prepared by reaction of borane-amine complexes with butyl lithium (Scheme 35).61 A range of amines may be used. R = Et, Pr, Pi, c-hept. c-pent, morphdino Scheme 35 Lithium pyrrolidinoborohydride is a highly useful reagent for the chemoselective 1,2-reduction of enones (Scheme 36).62 Scheme 36 61 : 39 94% Sodium diethylpiperidinohydroaluminate (prepared from commercially available sodium diethylaluminium dihydride) has also been prepared as a new selective reducing agent.63 Esters, N, N-dialkylamides and nitriles were reduced to aldehydes in excellent (GC) yield.(R)-( - )-2-( 2-isoindolinyl)butan-l-o149 has been used as an asymmetric mediator in reduction of benzophenones (Scheme 37).64 The products were obtained in up to 95% e.e., but the authors made no assignment of the absolute stereochemistry generated in the reaction. 0 OH Ar' AA? ArlAA? LiAIH4 r n N * OH 49 (2 eq.) -1 3 "C, Et@ Scheme 37 Biaryl ligands continued to be of utility in catalytic asymmetric reactions. To solve the difficulty associated with hydrogenation of ketones which do not contain another coordinating group, a combination of the cationic BINAP-derived iridium complex 50 and a mixed P,N-donor ligand 51 has been prepared.65 Thus, the hydrogenation at high pressure of bicyclic ketones proceeded with good e.e.(often 2 92%) (Scheme 38). The reduction of monocyclic ketones was less selective. When ligand 5 1 was omitted from reaction mixtures, lower enantioselectives were obtained. similarly catalysed the hydrogenation of phenyl glyoxalate and glyoxamides to mandelates and mandelamides."6 Yields were good and enantiopurities were excellent ( 2 93% e.e.). para-Cymene derivatives 5 2 of bisphenylphosphine 252 Contemporary Organic Synthesis0 OH L 84% 8.8. 90 "C autoclave 82% 8.8. L J 51 50 Scheme 38 Rhodium ( I ) complexes containing ( - )-sparteine ligands 53 have been used in the enantioselective hydrosilylation of prochiral ketones."' Enantioselectivities were uniformly low. An efficient Baker's-yeast-mediated reduction of 3-aryl-2,3-epoxy ketones has been reported (Scheme 39).68 The epoxide ring was cleaved stereospecifically by fermenting yeast after the carbonyl had been stereoselectively reduced.Only one of the eight diastereoisomeric triols possible was produced in the reaction. The authors investigated the mechanism and suggested that the carbonyl reduction was followed by a regiospecific epoxide ring-opening, caused by a hydrolytic moiety present in the yeast. Water then displaced the endogenous nucleophilic species to give the product. Oxazaborolidines continue to be of widespread interest. Corey has described a new process for the generation of 1,3,2-0xazaborolidines (Scheme 40).69 Previous methods of preparing these heterocyclic catalysts used the reaction of aminoalcohols with the borane-THF complex or substituted boronic acids, and such processes require long reaction times.Corey has devised bis( trifluoropropyl) alkylboronates 54 as more reactive alkylboronic acid equivalents, and the use of these species thereby speeds catalyst formation. The paper described a new synthesis of 54 and the procedures using 54 for in situ formation of oxazaborolidine catalysts. The enantiomeric excesses obtained using catalysts prepared by this new method equal those seen before.70 The addition of amines to Corey oxazaborolidine reductions has been found to have an influence upon the levels of enantiomeric excess (Scheme 4 Thus, when a series of ketones was reduced using Corey conditions, e.e.'s were up to 20% lower than when the reaction was performed in the presence of triethylamine.The reason for the improved selectivity was in the availability of more than one equivalent of hydride from the chiral intermediate 55. It was proposed that the product 56 arising from the via + 52 H p 53 (-) sparteine yeast OH I R (SR, SR, SR ) (9 Enz , Ph AR Enz-XH P h v R Scheme 39 (61%, R = Bu, Et) I 10 min., 23 "C 110 "C, 30 rnin. 0.07 TON Scheme 40 first hydride transfer then itself acted as a possible, less selective reducing agent. There would then be two distinct reductions, one of e.e. x% and one of y%; the observed e.e. in the alcohol product would then be [(x + y)/2]%. When triethylamine was added to the product, intermediate 56 was converted into 57, which could be isolated and fully characterized, thus preventing a second, less selective hydride transfer occurring.Sweeney: Alcohols, phenols, and ethers 2538.8 with Et3N (%) 99.1 8.8. without (%) 90 99.4 91 99.4 99.2 07 90 96 67 via : 55 57 (isolated when Rs = Me Scheme 41 RL= Ph) 56 y% 8.8. + Liotta has performed MNDO Hamiltonian calculations in an attempt to ascertain the origins of the enantioselectivity observed in oxazaborolidine ketone reduction.72 These calculations showed that the most favoured situation was that in which hydride transfer occurred via a chair transition state, with the oxazaborolidine and ketone substituent effects reinforcing each other. Four papers have appeared describing quantum chemical modelling of chiral catalysis by oxazab~rolidines.~~-~~ The first of these was concerned with the role of alkoxyboranes in CBS carbonyl reduction, the second discussed the relative stability of dimer homochiral oxazaborolidines, and the third and fourth described the effects controlling the coordination of borane to oxazaborolidines during reductive processes and the conformational constraints of the reduced species, respectively.A review of the uses of homochiral oxazaborolidines in asymmetric synthesis has appeared.77 Quallich and Woodall have introduced a new oxazaborolidine catalyst 58, available in both antipodes, which reduced arylalkylketones with high enantioselectivity. The sense of chiral induction was predictive (Scheme 42) and the selectivity was proposed to arise from the highly ordered transition state arising from n-stacking. Only arylalkylketones were reduced with high ~electivity.~~ 1.4 Preparation of alcohols from epoxides Two reports by Larock et al. have extended the palladium-catalysed heterocycle cleavage (Scheme 94% 8.8.58 (5 mot%) ? via : z-stacking Scheme 42 43).79,x0 Thus, palladium acetate in the presence of sodium formate, tetrabutylammonium chloride, and Hunig's base catalysed the cross-coupling of vinylic epoxides with aryl or vinyl halides to give allylic alcohols. This complemented the previous work on ring cleavage of unsaturated epoxides by aryl iodides.g1 The second report illustrated in Scheme 43 extended the previously described S,2' ring-opening of vinylic oxetanes by organometallic species in the presence of palladium; the new processg2 allows the replacement of organometallics by aryl iodides (two examples of aryl iodides), but a five-fold excess of vinyl oxetane was necessary to obtain even moderate yields.The process was again successful when 1 -( trifly1oxy)cyclohexene was used as the pro-nucleophile. Homoallylic alcohols were obtained in 11-70°/0 yields although many yields were moderate. R-I R-OH 2441% vo R = aryl or vinyiic- 5 eq. Reagents: 10% P~(OAC)~, 5 eq. Na02CH, Bu4NCI, Pi2NEt R2 - as above Ar I + R1& 0 R3 A w e * 1 1-70% 80 oc Scheme 43 An anti-Markovnikoff hydration of olefins may be efficiently carried out by a two-step epoxidation-reductive ring-opening process involving a photochemical ring-cleavage reaction (Scheme 44).83 Thus, when an epoxide was photolysed under nitrogen in a Rayonet apparatus, in the presence of sodium 254 Contemporary Organic Synthesisborohydride in acetonitrile-water solvent, a non-stereospecific but regiospecific reductive ring-opening occurred.83 The reaction proceeded via radical anions such as 59; NaBH, suppressed the formation of by-products arising from other radical reactions.96% ,OH 90% Scheme 44 The best method previously reported for the preparation of 2-substituted 3-butyn- 1-01s was that of S e e b a ~ h ~ ~ which used titanium acetylides to ring-open epoxides nucleophilically; a new method of accomplishing the preparation of such alkynols uses a reductive ring-opening of 1 -substituted 1-alkynyl-epoxides 60 (Scheme 45)F5 I h -20°C THF 60 61 80% R Yield Bu" 96% Ph 96.5% But 87% Scheme 45 Only DIBAL-H reacted regiospecifically to give products arising from nucleophilic hydride attack at the more hindered carbon.Even extremely hindered substrates (such as 6 1) reacted regioselectively. epoxides (Scheme 46).s6 Yields were moderate to good. High pressure was used to catalyse the hydrolysis oi 1.5 Miscellaneous methods of alcohol synthesis It is known that radical alkylation of carbon monoxide under high pressure gives aldehydes;87 when Kahne et mo I H@ 10kbar la50oc OH Hb HO 47% 44% Scheme 46 al. employed these conditions in an attempt to prepare analogues of carbohydrates seen in calichemycins, very poor yields of the hydroxymethylated product 62 were obtained.88 To circumvent this problem, the authors utilized an in situ generated germane instead of the stannane previously used.Under these conditions, a much better (though still low) yield of 62 was obtained. The authors claim their improvement represents a general method for direct introduction of a hydroxymethyl group via intermolecular trapping of CO (Scheme 47). 62 (37% 20 : 1 in favour of this isomer) Reagents: Ph3GeH(0.1eq.), AlBN ( O . l q . ) , NaBH3CN(2.9eq.), benzene-THF (50 :1), 1400 p.s.i. CO, 105 "C, 12 h Scheme 47 When Stevenson et al. attempted a Cr'I-mediated intramolecular alkylative cyclization of 63, the only product isolated was the reduced cyclopropyl alcohol 648y (Scheme 48). The reaction was general for a-monosubstituted acroleins but not generally useful for terminally substituted systems. The process was similar to the intramolecular addition of allylbromides to a, p-unsaturated aldehydes reported by Still.9o NICE%) 4 I I r.t.I I 63 Scheme 48 64 (72%) When 0,Se-ketals (prepared from the corresponding dibenzylketals and Et,AlSePh) 65 and 66 were treated with lithium naphthalenide, both isomers generated anion 67 via radical 68.y11y2 This anion then underwent a [ 1,2]-Wittig rearrangement to Sweeney: Alcohols, phenols, and ethers 255give an axial alcohol. This overall process offered an improved route to such axial alcohols (for instance, reaction of 4- t-butylc yclohexanone with benzylmagnesium bromide gave equal amounts of axial and equatorial product) (Scheme 49). 65 LiNap - 78 "C, THF, 56% OH 1 *Ph wph W O - P h 66 via O V P h - 68 67 inversion 1 OH WPh Scheme 49 2 Preparation of phenols and ethers Tricarbonyl( vinyl ketene)iron( 0) complexes 69 reacted with alkynes to give stable and isolable di- and tri-carbonyl iron(o) adducts 70 (Scheme 50).When these compounds were heated, phenols were produced in good yield.y3 R3 69 I A R3 P h G O H R' R2 5747% Scheme 50 256 Contemporary Organic Synthesis When toluene solutions of methoxybenzenes and crown ethers were reacted with potassium and then treated with isopropanol, a high-yielding demethylation reaction occurred (Scheme 5 1). The toluene radical anion was the reactive species; in the reaction of dimethoxybenzenes, the less hindered ether was demeth~lated.'~ 90% Reagents: toluene, K, dicyclo-hexano-18-crown-6 (2 eq.), NO, r.t. R n X d 4 7 -0 0- @nX23H47 + 1 p n c * 3 H 4 7 HO 0- -0 OH (major product) Scheme 51 Diarylethers may be prepared via the nucleophilic attack of phenolates oh chloroarene-metal n-comple~es.~~ After decomplexation, moderate to good yields of ethers were obtained (Scheme 52).y6 If dichlorinated arenes were used, the second chloride was also displaced by nucleophiles.+ + FeCp P O " ' c , NAC02Me X H 88% NaCH(C0&le)2 hv MeCN I 1 45% Scheme 52 Trifluoromethyl ethers may be prepared by a desulfurative fluorination of xanthates (Scheme 53).y7 Scheme 533 References 1 2 3 4 5 6 7 8 9 10 1 1 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 H. Fujii, M. Taniguchi, K. Oshima, and K. Utimoto, Tetrahedron Lett., 1992,33,4579. T. Gillmann, Tetrahedron Lett., 1993,34,607. J.K. 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Hatano, K. Kayoh, J. Kotabe, and T. Oishi, Tetrahedron Lett., 1992,33,5555. 95 A.J. Pearson, J.C. Park, and P.Y. Zhu, J. 0%. Chem., 1992,57,3583. 96 A.J. Pearson, H.S. Lee, and F. Gouzoules, J. Chem. SOC., Perkin Trans. I, 1990,225 1. 97 M. Kuroboshi, K. Suzuki, and T. Hiyama, Tetrahedron Lett., 1992,33,4173. 2 5 8 Contemporary Organic Synthesis

ISSN:1350-4894    

DOI:10.1039/CO9940100243

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Synthetic developments in host-guest chemistry JEREMY D. KILBURN and HITESH K. PATEL Department of Chemistry, University of Southampton, Southampton, SO9 5NH, UK Reviewing the literature published between July 1992 and December 1993 1 2 2.1 2.2 2.3 2.4 2.5 3 3.1 3.1.1 3.1.2 3.1.3 3.2 3.3 3.4 3.5 4 4.1 4.2 4.3 5 5.1 5.2 6 7 Introduction Crown ethers, cryptands, spherands, and podands Crown ethers Azacrown ethers and related compounds Cryptands Spherands Podands Calixarenes Calk[ 41 arenes Modifications to the lower rim Modifications to the upper rim Other modifications Calix[S]arenes Calix [6] arenes Calk[ 81 arenes Double calixarenes Cyclophanes All-carbon cyclophanes Heteroatom-containing c yclophanes Cage-type cyclophanes Cleft receptors and molecular bowls Cleft receptors Molecular bowls and other receptors Self-assembling receptors References 1 Introduction The discovery, by Pedersen in 1967,’ of dibenzo- 18-crown-6, and its ability to form stable complexes with alkali and alkaline-earth metals, effectively marks the beginning of synthetic host-guest chemistry.Since then research in this area has expanded dramatically, reflecting the important contribution that the study of artificial receptors can make to our understanding of molecular recognition phenomena in general, and pointing the way forward to the design and synthesis of supramolecular materials with tailored properties. Not surprisingly, much of the interest in this area focuses on the recognition properties of the receptors, a subject which is frequently reviewed in the literature.2 However, before the properties of a new receptor can be investigated, the receptor must, of course, be synthesized.The importance of efficient synthesis in this area cannot be overstated if sufficient material is to be obtained for study, in a realistic time-span. Receptor synthesis is often far from trivial, particularly for the synthesis of large macrocyclic compounds, and can rival natural product synthesis in complexity and elegance. The purpose of this article, therefore, is to review developments in host-guest chemistry, over the period July 1992 to December 1993, with the emphasis on the synthetic aspects. The review is divided into sections using conventional categorization of the type of receptor concerned, but because, increasingly, receptors are being prepared with features of more than one structural type, these categorizations become somewhat arbitrary! 2 Crown ethers, cryptands, spherands, and podands 2.1 Crown ethers More than 25 years after Pedersen’s original discovery of dibenzo-18-crown-6, work continues to modify the many useful properties of crown ethers, by altering the various structural parameters.Consequently new syntheses of crown ethers are continually being published and re~iewed.~ Because of its small size and high free energy of hydration, the lithium cation is difficult to bind selectively. A novel synthesis of highly substituted 14-crown-4 derivatives 3 (Scheme l), from tertiary and neopentyl alcohols, gave gram quantities of these materials which showed high selectivity for Li+ owing to the cylindrical cavity formed by the tertiary alkyl ~ubstituents.~ R = Et (76%) ” Me ti) NaH.dioxane ., . 4 (ii9 Ha Rh-A&03 benzene 3 (43-74%) 2 (6643%) Scheme 1 Kilburn and Patel: Synthetic developments in host-guest chemistry 259Previous syntheses of such compounds were low yielding, probably because of the low nucleophilicity and hij$ basicity of the tertiary alkoxides used in the syntheses. In this new work, reductive ring-opening of bis acetals 1 avoided the use of a Williamson ether synthesis, and gave the intermediate diols 2 in good yield. These were then condensed with methallyl dichloride at 2O0-25O0C in a stainless-steel bomb. Chiral crown ethers are of considerable interest because of their ability to differentiate between enantiomers of racemic substrates and because they can be used as chiral reagents or catalysts for a number of transformations.The stereospecific synthesis of (R, R, R, R, R, R)-hexaphenyl- 18-crown-6 6, and related crown ethers, has been reported by Stoddart (Scheme 2 ).5 PhJ-0" OH PhY 0 'OTs 5 Scheme 2 Starting from (R,R)-hydrobenzoin, the diol4 and ditosylate 5 were prepared and condensed together using sodium hydride in the presence of caesium carbonate. These new crown ethers showed some ability to catalyse an asymmetric Michael addition between methyl phenylacetate and methyl acrylate. The synthesis of chiral crown ethers derived from D-mannitol," and from various phenyl-substituted cyclohexane- 1,2-diols, have also been described.' A number of crown ether variants have been reported recently.Thus, Parker and co-workers have converted the tetraaza crown ethers 7 and 8 into macrocyclic thioureas, by reaction with carbon disulfide followed by treatment with HCl (Scheme 3).8 The thiourea macrocycles were, in turn, transformed into macrocyclic ureas by treatment with mercuric acetate. 7 n = O 8 n = l Scheme 3 Related macrocyclic ureas have also been synthesized, by transesterification of urea diester 9 with ethylene glycol (Scheme 4).y 9 Scheme 4 13% + mo O 3 NUoo 24% Macrocycles containing two thiophene rings have been prepared by a double Mannich reaction between bis( thieny1)ethers 10, formaldehyde, and either N , N'-dimethylethylenediamine or piperazine, in acetic acid (Scheme 5).'O This reaction gave the macrocycles in good yields when the linking group between the thiophenes contained sulfur or oxygen atoms, rather than straight alkyl chains.Internal templating, by heteroatom stabilization of the iminium species generated in the Mannich reaction, is postulated to explain the better yields. 0-x-0 (-jo-x-ol-) -aNnN> 10 u 42-62% Scheme 5 A novel crown ether incorporating a 2,2'-bithiophene has been prepared, as a possible precursor for a conducting polymer by reaction of dibromide 1 1 with suitable dialkoxides (Scheme 6).' fBr n = 0-4 (1 0-53%) Scheme 6 2.2 Azacrowns and related compounds Polyazamacrocycles and azacrowns have been popular because of their utility as ligands for a range of metal ions, and have found use in a number of contexts, including the removal of toxic metal ions from the 260 Contemporary Organic Synthesisbody, the transport of radioisotopes into cancer cells for radiotherapy, and as phase-transfer catalysts.An excellent review on methodology for the synthesis of azacrown macrocycles and cryptands has been published by Bradshaw et a1.I2 tetraazamacrocycles, with 28- to 44-membered rings, has been de~cribed,'~ and involves the use of o-chloroalkyl p-toluenesulfonates with the different leaving group abilities of the chloro and sulfonyl groups being used to advantage (Scheme 7). A general procedure for the synthesis of large 12 13 14 (2542%) Scheme 7 Thus bistoluenesulfonamides 12 are alkylated with o-chloroalkyl p-toluenesulfonates (at 60°C), using NaH as base, to give the dichlorides 13 which are then added, without any purification, to a further equivalent of the dianion of 12 at a higher temperature ( 1 20°C), giving macrocycles 14 in 2545% yield.While the use of anions derived from toluenesulfonamides is a common approach in polyazamacrocycle synthesis, the ultimate removal of the tosylate group is often not trivial. A recent report describes the use of trifluoromethanesulfonyl derivatives of linear tetra-amines in macrocyclizations, with subsequent deprotection using sodium in liquid ammonia (Scheme S).l H H n20, H H H2N .q N -cr," vnNH2 - Tf HN .q N vmN wnNHTf Etd. CYCh 5 7 4 % yield over 2 steps (except m = n = p = 2.5%) n = 2,3 m = 2,3,4 p = 2,3,4 Scheme 8 Schiff base formation is another popular method for assembling polyazamacrocycles, and 26-membered macrocycles containing 3,5-disubstituted pyrazoles, which form dinuclear complexes with zinc cations, have been prepared by condensation of pyrazole dialdehyde 15 with diamine 16 and hydrogenation of the resulting Schiff base (Scheme 9).15 An unusual multidentate macrocycle containing 173,4-oxadiazole, imine, and phenol functionality has been preparedI6 by dehydration of bis( acy1)hydrazine 17 followed by Claisen rearrangement, isomerization of the ally1 groups, and ozonolysis.Cyclization with O H C ~ C H O + N ~ ~ ~ N H ~ N-N, 15 16 X=O X=NH \""" X = 0 (66% overall) X = NH (30% overall) Scheme 9 1,2-diaminobenzene gave the macrocycle 18 in 74% yield. Similarly, condensation with 1,2-diaminoethane gave the corresponding macrocycle in 82% yield (Scheme 10).dCI NH2NH2H20* da-&J 0- ,/ (iii) KOBU'. (iv) 03 OHC CHO OH N-N OH 15% overall 1.2 benzene dmine \ 18 (74%) Scheme 10 A related macrocycle has been prepared by condensation of the partially neutralized diamine 19 with diketopyridine 20 templated by Pb( ClO,), (Scheme 1 l)." A route to tetrazole-containing macrocycles has also been reported.lx a bisquinazoline annelation and reductive ring enlargement (Scheme 12)." Thus, readily available dianthranilide 2 1 was condensed with 2-azidobenzoyl chlorides, followed by a Staudinger reaction/aza-Wittig sequence to give bisquinazolines 22. Reductive ring enlargement of 22 with 20 molar equivalents of H,B.THF gave macrocycles 23 in 41-52% yield. A novel route to benzopolyazamacrocycles involves Kilburn and Patel: Synthetic developments in host-guest chemistry 261Me 19 20 D KOH (1 eq.) MeOH Me 54Y0 as dilead complex Scheme 11 R2 R' $-- d o 21 EbN.10 ml% DMAP toluene. -71% - (ii) PBu3, toluene 7640% R' o d "N I I - e y 23 R1=R2=H (52%) R' = R2 = OMe (41Y0) R' = CI, R2 = H (45%) R' Q R' R2 22 Scheme 12 Azamacrocycles are useful building blocks for larger structures since the nitrogen atoms can be readily functionalized. A simple strategy for the synthesis and purification of unsymmetrical N, N'-bis-substituted diaza- 18-crown-6 has been reported, in which the purification of the highly polar intermediates was achieved by column chromatography, eluting first with acetone, and then with acetone/triethylamine.20 The synthesis of a range of amide and amide-ester N-functionalized polyazamacrocycles has been described by Parker2' while N-benzyloxycarbonylaziridine has been used as an efficient alkylating reagent for azacrowns in the preparation of 2-aminoethyl-armed lariat ethers (Scheme 1 3).22 The use of an N-carbamoylaziridine, as opposed to the previously reported N-tosylaziridine, again allows a much easier deprotection to release the free aminoethyl crown ether derivative.\-0 0-J W \-0 OJ W 0 86VO II R = PhAOKNHCH2CH2 R = H2NCH2CH2 xdc Scheme 13 The attachment of spirobenzopyrans and spironaphthoxazins to azacrowns gave multifunctional receptors,23 which rearranged to the coloured merocyanines in the presence of suitable alkali-metal cations, while attachment of 6-phenanthridinyl units led to new fluoroion~phores.~~ Attachment of bis[( pyrazo1e)ethyllamino units to azacrowns produced compounds capable of the simultaneous binding of copper and alkali-metal cations, and unusual redox properties were reported for these complexe~?~ The synthesis and redox properties of ferrocene-azacrown derivatives is described in detail in a full paper by Gokel.26 Azacrowns with indene and cyclopentadiene side-arms have also been prepared and were designed to bind alkali-metal cations and transition metals sim~ltaneously.~~ Although these azacrown derivatives could be synthesized by alkylation of the parent azacrown, they could also be prepared by the alternative strategy of condensing a suitable amine with a diiodide directly (Scheme 14).This method is, in principle, more economic than alkylation of the parent azacrown in situations where the parent azacrown is not readily available, and has itself to be synthesized.R = D C H 2 55% k 10% Scheme 14 Bifunctional chelating agents (BCAs) are used for the chelation of radioisotopes, and possess extra functionality to allow them to be linked to monoclonal antibodies for use in radiotherapy. A novel synthesis of such a BCA began with the readily available orthoamide 24 (Scheme 15).28 Monoalkylation and 262 Contemporary Organic Synthesishydrolysis gave the monoalkylated t r i b e , which was further derivatized with bromoacetic acid to give the ligand 2 5. NO2 24 (i) H&, reflux (ii) 6N HCI, reflux 1 25 (9Vo overall) Scheme 15 The synthesis of a related BCA began with the condensation of tetra-amine 26 with diethyl aminomalonate hydrochloride, to give 27 in 34% yield Scheme 16).2y Reduction with H3B .THF, reductive amination with 4-nitrobenzaldehyde, alkylation, and hydrolysis gave the desired ligand 28.reflux, COpH COpH NH2 (li) OHCCeH4NO2 NaBH3CN (iii) ErCH2COd KOH I 28 27 (34%) NO2 Scheme 16 2.3 Cryptands Syntheses of cryptands often require several steps, but a number of recent reports have described short routes to these important compounds. Bradshaw et al. started from diethanolamine which they condensed with dichlorides 29, to give tetrols 30 in 90% yield (Scheme 1 7).30 Ring-closure with a variety of aromatic or aliphatic dichlorides, dibromides, or ditosylates gave the cryptands 31 in yields of 20-55%. The same group has published an improved procedure for the synthesis of aliphatic cryptands which involves simply condensing diamines 32 with ditosylates 33 (using sodium carbonate in refluxing acetonitrile) over six days (Scheme 1 8).31 After work-up and chromatography the cryptands were obtained in yields of 36-50%. HOnNnOH H + C l q O p C l 29 n =2,3 31 n = 2.3 (20-55%) Scheme 17 H2N*O*NH2 32 n = 1,2,3 + r t \ / f 7 / 7 TsO 0 m 0 OTs 30 33 m = 1,2 3=0% Scheme 18 Short syntheses of rather different cryptands have been reported by B h a r a d ~ a j .~ ~ Thus tris( 2-aminoethy1)amine and trialdehyde 34 were condensed, in the presence of caesium cations as a template, and reduced to give cryptand 35 in 70% yield (Scheme 19). Similarly, the tripodal trialdehyde \t 11) NaEH4 36 (350/) Scheme 19 Kilbum and Patel: Synthetic developments in host-guest chemistry 26334 can be reductively aminated with 1,2-diaminobenzene, in the presence of caesium chloride, to give the product 36 in 35% yield (Scheme 19).33 A full paper has described in detail the synthesis of a number of macrobicyclic and macrotricyclic polyether ligands such as 4 1 (Scheme 20).34 Typically, condensation of diamine 37 with ditosylate 38, under weakly basic conditions, gave the crown ether derivative 39, which was further reacted with methallyl dichloride, using lithium hydride as base, and converted into diol40.Cyclization of diol40 with glycol ditosylates then gave the macrotricycles. CH&N 37 38 39 (66%) I J L I I (I) LiH,CI CI (lii) H& NaOH (ii) B d 6 1 41 n = 1 (30%) n = 2 (20%) 40 (2540%) oH Scheme 20 A series of benzene-bridged macropolycyclic polyethers has also been reported; the syntheses involve the condensation of tri- or tetra-tosylates, such as 42, with a trio1 or a tetrol respectively, using potassium dissolved in t-butyl alcohol as base (Scheme 2 I ).35 TsO 42 OH %OH OH OH K.Bu'OH dioxane 9% Scheme 21 2.4 Spherands The requirement that a receptor should be preorganized in order to maximize the resulting binding energy upon complexation is firmly established, largely as a result of Cram's seminal work in this area.36 In further work aimed at investigating the role of preorganization in the complexation of metal cations, Cram has reported the synthesis of a new spherand incorporating five anisyl units and one CH,OCH, unit to compare with previously reported variations on this theme.37 The synthesis began with a two-fold aryl-aryl coupling of 4-dibenzylfuranyl magnesium bromide with a diiodo anisole, followed by dimetallation and treatment with methyl-chloroformate, to give the diester 43 (Scheme 22).The diester was converted into chloroalcohol44 and then cyclized, using NaH, in a reaction which appeared to be templated by Na+ . A number of related spherands were also prepared. I - 0 - But (ii) BuLi (iii) CIC02Me 43 OH CI 65% Scheme 22 Cram has also reported on the synthesis of a series of saddle-shaped hosts based on fused dibenzofuran units.38 In one such synthesis, benzofuran was converted into the diboronic acid 45 and into the bromo alcohol 46 (Scheme 23). A Suzuki coupling of these two, conversion into the corresponding dichloride, and cyclization with TsNH, gave the new macrocycle.2.5 Podands The requirement for preorganization has meant that receptor design tends to concentrate on macrocyclic structures. However, in the last few years Still has described the synthesis and binding properties of a number of non-macrocyclic podand ionophores of general structure 47 (Scheme 24), which by careful choice of the position of various alkyl substituents, can 264 Contemporary Organic SynthesisScheme 23 47 ;::"2 x=s x = S o p ,*A A,, X H . # Scheme 24 be locked into just one, or at most just a few, low energy conformations, and thus can be preorganized for highly selective binding. prepared, with benzyloxy substituents to lock the conformation around the central inter-ring bond.39 Thus, tetrol48, derived from D-mannitol, was coupled to acetal50, which was obtained from ( + )-P-citrocellene, to give podand 5 1 as a mixture of diastereoisomers which could be equilibrated to pure 5 1 with further acid treatment (Scheme 25).The related thiopodand 52 was similarly prepared as a single stereoisomer by treatment of dithiol49 with acetal50 in the presence of catalytic F,B.OEt,. Oxidation then gave tne sulfoxide podand 53. These new podands bind various chiral ammonium ions enantioselectively, but, for instance, podand 53 is less enantioselective and less ionophoric than the analogous alkyl-substituted podand 47 (X = SO,). In recent work a related podand has been R OH OBn 50 OMe Reagents: when R =OH (i) cat. CSA, MF; (ii) TsOH, CH2Cb when R = SH (i) F3B.OEtp Scheme 25 Still has also sought to enhance the binding properties of these podands by adding suitable functional groups.Thus, the previously described tetrol45 was converted into the bis( cyanohydrin)ether 55 and then partially hydrolysed, alkylated, and epimerized under basic conditions, to give the equatorial-equatorial bis (dialkylamide) podand 56 (Scheme 26):O The binding of alkali metal cations (Li+, Na+, K + ) by 56 was significantly enhanced compared with the parent podand 47 (X = CH,) and approached that of macrocyclic crown ethers. Binding by the corresponding equatorial-axial isomer was approximately one order of magnitude lower and the axial-axial isomer showed a further drop in binding ability. 54 55 Ist- R = Bn R = Me Scheme 26 56 The same tetrol54 was taken through a series of steps to the diketone 57 which was then transformed to substituted podands 58,59, and 60 (Scheme 27).41 Acetamide 58 proved to be markedly more selective for the binding of a-amino acid methyl esters compared with the parent podand 47 (X = CH,) or acetoxy podand 59.Hexacyclic podands 62 and 63 have also been synthesized (Scheme 28), again from tetrol54 and acetal50 (see Scheme 25).42 These receptors align six oxygens in the same arrangement found in the crystal structure of potassium 18-crown-6 complex, and indeed were found to bind alkali metal cations with binding constants and selectivities closely matching those of dicyclohexyll8-crown-6. However, they showed lower enantioselectivities for the binding of amino acid derivatives as compared with the corresponding tetracyclic podands 47, which may be Kilburn and Patel: Synthetic developments in host-guest chemistry 2650 54 R (ii).(iii) for 59 R 58 R=NHAc 59 R=OAc 60 R=OH (ii) Li, NH3-THF; (iii) AqO, Et3N, CH2C12; (iv) K2CO3. MeOH (b) c Reagents:(i) NH20Me.HCI, EtOHpyreidine; Scheme 27 54 61 (86%) J 50 62 x = 0 (75”/0) 63 X = S (85%) Scheme 28 due to the gross conformation of 62 and 63 which is close to achiral D,, symmetry. In a further paper in this series, the work has been taken full circle with the synthesis of the novel 18-crown-6 derivatives 65 and 66 (Scheme 29).43 These were prepared by coupling either tetrol54 (prepared from L-tartrate), or the derived thio-analogue 6 1, with bisacetal64 (prepared from D-tartrate).In the preparation of 65 a mixture of diastereoisomers resulted, but could be equilibrated to the desired diequatorial isomer using p-TsOH. These Me0 )-OMe Me0 64 Scheme 29 65 X = 0 (40%) 66 X = S (40’16) macrocycles have only one available conformation-again matching that of the potassium 18-crown-6 complex-and consequently 65 bound K+ and Na+ more tightly than 18-crown-6 itself. In related work, Paquette and co-workers have synthesized di- and tri-spirocyclic tetrahydrofurans such as 68 using the acid-catalysed rearrangement of alcohols, such as 67, as the key step (Scheme 30).44 The syn-syn triether 68 was the most effective receptor for alkali-metal cations. (iii)-(vi) c-- + diastereomer (88% total yield over two steps) 68 + diastereomer Reagents: (i) pu THF, -78OC; (ii) Dow~x-~OX, CH2C12, r.t.; (iii) CH2=CHCH&lgBr; (iv) H3B.THF; (v) H202, HO-; (vi) TsOH, toluene, heat Scheme 30 3 Calixarenes Calixarenes are cavity-shaped cyclic molecules made up of phenol units linked via alkylidene Despite their attractive architecture, the host-guest chemistry of underivatized calixarenes has not been extensively developed, partly because calix[4]arene, in particular, has a rather small cavity.Calixarenes are, however, readily amenable to chemical modification on both the upper and lower rim, leading to molecules with selective binding properties. The easy accessibility of calix[4]arenes has made this member of the series increasingly popular as a building block or platform for assembling more elaborate structures with ligating side-arms.A timely review has been published which discusses many recent aspects of calixarene chemistry.46 a 3.1 Calix[4]arenes 3.1.1 Modifications to the lower rim The free hydroxyl groups in calix[4]arenes form strong intramolecular hydrogen bonds which favour the cone conformation. In tetra 0-alkylated calixarenes, without such interactions, the cone conformation is no longer necessarily favoured. NaH has frequently been used as a base in the alkylation of calixarenes, but alkali-metal carbonates, M,C03 (M = Na, K, Cs), when used as the base, can profoundly affect the conformer distribution of the resulting 0-alkylated calixarenes, through metal template effects. Shinkai and co-workers have carried 266 Contemporary Organic Synthesisout a systematic study involving the synthesis and classification of the many possible isomers which can be generated by partial or complete 0-alkylation of calix[4]arenes, using a variety of synthetic methods, including the metal template method and the stepwise synthesis 1nethod.4~ The lower ring of p-t-butylcalix[4]arene has been tetraalkylated to give a calix[4]arene tetraester containing anthracene moieties.48 High Li + selectivity was found for these receptors which can be detected by the marked changes in the receptor's fluorescence spectrum upon complexation. Beer has selectively introduced substituents at the 1,3-distal hydroxy groups of calix[4]arenes and prepared 1,3-bis-pyridyl and 1,3-bis-alkylthioether calix[4]arenes designed to coordinate transition metal cations.49 Adapting Reinhoudt's method50 for the selective attachment of substituents at 1'3-distal hydroxy groups, alkylation of calix[4]arene 69, with 2 equivalents of bromide 70, using 1 equivalent of K2C0,, in refluxing CH,CN, gave the 1,3-functionalized calix[4]arene 71 in 72% yield.The diol7 1 was then converted into the corresponding dibromide, which was condensed with 1,l O-diaza- 1 8-crown-6 7 2 to give the calixarene-cryptand 73 (Scheme 31). The syntheses of related 1,3-bipyridyl and 1,3-dialkylthioether calixarenes are also reported, along with the results of metal binding studies for these new receptors. BU' 69 'OH / HO 71 (72%) (I) MeS0,CI (ii) NaBr, DMF 0 HO OH 0 \ I 73 (40%) Scheme 31 Crown ethers have been similarly attached to the lower rim of calixarenes by the reaction of the 1,3-bis-( acid chloride) derivative 74 of p-t-butylcalix[4]arene with various diamines, including diaza- 15-crown-5 and diaza-18-crown-6 (Scheme 32).51 has functionalized the remaining hydroxyls on the lower rim to prepare a calix[4]arene, in the cone Starting with a 1,3-bispropoxycaiix[4]arene, Shinkai COCl Cloc' 74 Scheme 32 L o - 0 2 75 (52%) conformation, with an ionophoric site near a hydrogen-bonding receptor site in the form of an amidopyridine unit.52 Using an identical synthetic strategy, calix[4]arenes bearing diamidopyridine units at the lower rim have been ~ynthesized,~~ and this has allowed the simultaneous binding of Na + and simple flavin guests to be monitored by fluorescence spectroscopy.A series of calix[4]arenes containing transition-metal Lewis acid binding-sites, in combination with amide NH groups, have been prepared, and these represent the first examples of calix[4]arene anion receptors.54 The receptor was prepared by the condensation of the distal-( 1,3) bis-( hydroxyacid chloride) 74 and 2 moles of 4-aminopyridine.The resulting transition-metal complexes all formed 1 : 1 solution complexes with chloride and bromide anions. From 1,3-distal hydroxy-protected calix[4]arenes, mono- and di-phosphites have been prepared via the deprotonation of one or two phenol moieties and reaction with diphenylchlor~phosphine.~~ Using Et3N as the base afforded exclusively monophosphites, whereas the stronger base LiNPr; was required to introduce the second Ph2P group.selective coupling of 3,5-dinitrobenzyl chloride, and related aromatic units, to the distal-( 1,3) positions of p-t-butylcalixarene, followed by reduction to the tetraamine 76 and coupling with bis-( acid chlorides), to give 'doubly-spanned' calixarenes such as 77 (Scheme 33).56 More complex architectures have been produced by f Et3N. high dilution f Scheme 33 77 (72%) Calix[4]arenes with proximal-( 1,2) substitution have received less attention than the distal-( 1,3) regioisomers, but Reinhoudt and co-workers have found that subtle changes in the functionality, and their regioselective positioning on these calixarenes, has considerable influence on the binding selectivity for Kilbum and Patel: Synthetic developments in host-guest chemistry 267alkali-metal cati0ns.5~ A general method for the preparation of proximal-( 1,2) func tionalized calix[4]arenes has been developed and used 4.2 equivalents of NaH and 2.2 equivalents of alkylating agent in DMF.57 Further functionalization to give bis-proximally functionalized calix[4]arenes was best achieved using Cs,CO, as the base.3.1.2 Modifications to the upper rim Beer has prepared a redox-responsive calix[4]arene ditopic anion receptor, which contains two cobalticinium moieties.s* The receptor, which recognizes the adipate dicarboxylate dianion, was readily prepared from the reduction of the known dinitro-derivative using Raney nickel and hydrazine hydrate (Scheme 34). Condensation of the resulting diamine with dichloroacetyl cobaltacinium chloride 78 in DMF/CH,CN, and treating the residue with sodium hexafluorophosphate, gave receptor 79 in 6 1% yield.0 O Q 0, H' ~d Me -m 21% overall 79 Reagents: (i) HN03, AcOH; (ii) Raney Ni, NH2NH2; (iii) chloroacetyl Scheme 34 cobaltacinium chloride (78); (iv) NaPF6 Similarly, carefully controlled nitration of calix[4]arene 80 gives the diametrically substituted dinitrocalix[4]arene which was further derivatized to give calix[4]arene 81 (Scheme 35) in a rigid cone conformation, containing self-complementary a-pyridone moieties.5y These compounds were found 80 to form hydrogen-bonded aggregates in CDCl, solution, which could be denatured by the formation of a complex with urea derivatives. The same calix[4]arene has been used as a platform for the synthesis of a closely related receptor capable of recognizing phenobarbital >* provides an alternative method for derivatizing calixarenes.Reaction of a series of calix[4]arenes with a large excess of chlorosulfonic acid generally gave t e t r a s ( chlorosulfonyl) calixarenes in good yields, but the amide-substituted calix[4]arene 82 gave calixE4larene 83, having just two S0,CI groups appended to the upper rim (Scheme 36):' Chlorosulfonylation of the upper rim of a calixarene C102$ SO2CI 82 R = CH2CONMe2 83 R = CH2CONMe2 (42 O h ) Scheme 36 A novel fluorogenic calix[4]arene, functionalized at the upper ring with a benzothiazole chromophore, has been prepared via a Claisen rearrangement as the key step (Scheme 37)."* Thus, calix[4]arene 84 was selectively trialkylated using Me,SO, with BaO and Ba( OH), .8H20 in DMF, and the remaining free hydroxyl group was alkylated with ally1 bromide. Refluxing in N, N-dimethylaniline brought about the Claisen rearrangement, and treatment with KOBu' gave the disubstituted alkene 85, which was ozonolysed to the corresponding aldehyde and then condensed with o-aminothiophenol in acetic acid to give the fluorogenic calixarene 86. ' 81 Reagents: (i) acetylnitrate, CH2C12; (ii) Raney Ni, NH2NH2; 86 (58%) 85 (59%) Reagents: (i) Mefi04, BaO, Ba(OH)2.8H20, DMF; (ii) CH2=CHCH2Br, NaH, THE (iii) N,Ndimethylaniiine, reflux; (iv) KOBU', THF; (v) 0 3 , CHC13; (vi) eamhothophend, AcOH 268 Scheme 35 Scheme 37 Contemporaly Organic SynthesisShinkai has prepared calix[n]arenes (n = 4 and 6) modified with L-cysteines. These are water soluble, particularly at acidic and basic pH.63 The chloromethyl groups on the upper rim of calixarene 87 were converted into mercaptomethyl groups by treatment with thiourea, followed by alkaline hydrolysis (Scheme 38).f f SH in good yield (8 l0/o), and a Suzuki-type cross-coupling reaction between the bromide and appropriate boronic acids, catalysed by Pd( OAC)~ .2P( 0-tol),, gave the biphenyl derivatives 9 1 in reasonable yields (Scheme 39). R I Br eCHh ('I H2N.C=S*NH2 pzh @-A 4-Rw,B(OH)2, 2M Nag&, @ CH 4 CH n (ii) H#JCH2CH$lHa O M toluene, Pdo OEt OMe HO- OEt 87 n = 4,6 HCI.H2N C02H Y P C H k OMe 88 n = 4 (54%) n = 6 (46%) (ii) HCI. dioxane u 89 /I = 4 (38%) /I = 6 (32%) Scheme 38 The L-cysteine units were attached under anaerobic conditions, to avoid oxidation of 88 to unwanted disulfide products, and finally removal of the t-Boc groups gave water-soluble calixarenes 89 in moderate overall yields.These calixarenes were found to bind hydrophobic guests most effectively at pH 5-6. A water-soluble calixarene has also been prepared by the tetrasulfonylation of a tetraacid calixarene leading to a tetracarboxylate tetrasulfonated cali~[4]arene.~~ The conformation of a calix[4]arene has been locked by cross-linking the upper rim with catechol, resorcinol, or salycilic acid.65 The cross-linked calixarenes were synthesized by reaction of calix[4]arene with catechol (or resorcinol) in refluxing acetone in the presence of M2C03 (M = Na, K, Cs). The conformer distribution (cone, 172-alternate, or 1,3-alternate) was significantly affected by the metal cation present in the base.For example, the presence of Na+ or K' favoured the formation of 1,3-alternate, whereas Cs+ ions favour the formation of a proximal cross-link. In an attempt to develop a new class of extended chromogenic calixarenes, Suzuki cross-couplings have been utilized to prepare upper rim functionalized cone conformers of donor-acceptor phenylcalix[4]arene.h6 To stabilize the cone conformation of the chromogenic calix[4]arene derivatives, in which all the chromophores are essentially oriented in the same direction, ethyl substituents on the phenolic oxygens were introduced using the conditions described by Reinh0udt.6~ Bromination of calix[4]arene tetraethyl ether with N-bromosuccinimide afforded bromide 90 90 Scheme 39 91 R=CHO,CN, SMe (15-72%) 3.1.3 Other modifications Calixquinones are of interest because of their potential as redox systems and as participants in the formation of charge-transfer complexes.Calix[4]quinones are readily accessible by the direct oxidation of p-t-butylcalix[4]arene as mono-, di-, tri-, or tetraquinones-depending upon the number of free phenolic groups in the calixarene. Gutsche has published a comprehensive study on 1,2-carbonyl additions and 1,4-conjugate additions with such calix[4]quinones to give a range of chiral calixarenes.68 The oxidation of dialkyloxycalix[4]arenes with Ti( NO,), .3H,O has been reported to give calix[4]arenediquinones, which are more flexible than the unoxidized parent calixarenes and can assume two partial cone conformations.69 Biali has reported a method for the mild oxidation of calix[4]arenes using trimethylphenylammonium tribromide and a saturated solution of NaHCO,, to yield the chiral mono( spirodienone) 92 .70 Derivatization of this intermediate with diisopropyl chloroformate and LDA gave the bisphosphate ester 93, which on treatment with potassium in liquid ammonia resulted in the reduction of the spirodienone moiety, and reductive cleavage of the phosphate groups, to afford didehydroxylated calixarene 94 (Scheme 40).A new series of homoazacalixarenes has been described in which one or more of the methylene bridges of a calixarene are substituted by a dimethyleneaza bridge.71 It is suggested that the cyclizations, for example, of bishydroxyphenol95 with benzylamine in refluxing toluene to give the azacalixarenes such as 96 (Scheme 4 1 ), proceeded under the influence of a template effect provided by hydrogen-bonding between the hydroxyl groups and the nitrogen lone-pairs.reported for a macrotricyclic receptor related to calix[4]arenes in which two of the methylene bridges are substituted by dimethyleneoxa bridges.72 The two phenolic functions of 97 were linked with ditosylate 98, and the resulting diol99 was coupled with the corresponding dibromide 100. The final Williamson Similarly, a simple regioselective synthesis has been Kilbum and Patel: Synthetic developments in host-guest chemistry 269The larger cavity of 101, compared with an unmodified calix[4]arene, allows the complexation of several quaternary ammonium ions in chloroform solution.3.2 Calix[S]arenes A monodeoxycalix[ 51arene has been synthesized by stepwise methods.73 The treatment of diol 102 with phenol 103 (R = Me) under acidic conditions (conc. HCl in hot dioxane solution) gave the monodeoxycalix[5]arene 105 in low yield (7%), along with the previously described monodeoxycalix[4]arene 104,74 while reaction of 102 with 103 (R=But), under similar acidic conditions, gave only the monodeoxycalix[4]arene 104 in 29% yield (Scheme 43). An improved yield for the preparation of calk[ 51arene 105 (25%) was obtained by condensing 102 directly with diol 106. NOE experiments, along with crystal structures, suggested that these molecules adopt a partial cone structure in solution. But at But But \ I 94 (45%) Scheme 40 PH OH I Me Me Me &) OH OH OH Ph Me Me Me >N OH N, benz ylamine, 102 + c.HCI. Me- ? - -Me XYHX A \ dbxane Me Me HO OH OH 95 Ph/ 96 (37%) A Scheme 41 104 105 (n = 1) (n = 2) R=Me 15% 7% 103 R = Me, ’Bu R=BU‘ 29% reaction was carried out by slow addition of 99 and 100 to a suspension of excess powdered KOH in dioxane, to give the modified calix[4]arene 10 1 in 42% yield and as a single geometric isomer (Scheme 42). c. HCI. fi + 102 - dbxane 105 (25%) OH bH AH b H 106 Scheme 43 The first examples of calkcrown compounds derived from calix[5]arenes have also been reported.75 Alkylation of p-t-butylcalix[ Slarene with oligoethylene glycol-ditosylates in the presence of CsF affords 1,3-bridged calk[5]arenes in 51-72’/0 yield. These calixarenes were further modified by the alkylation of the remaining hydroxyl groups.99 R=OH(39%) 5:ne L- 100 R = Br (69%) But But I I 3.3 Calix [6] arenes Compared with calix[4]arenes7 much less is known about the chemistry of the more flexible calix[6]arenes, although in recent years the synthesis of several hexafunctionalized derivatives, and their corresponding complexing abilities with neutral molecules and cations, have been de~cribed.~~ In order to make calk [6]arenes available as molecular building KOH, dbxane 99 +loo - 101 (42%) Scheme 42 270 Contemporary Organic Synthesisblocks, several approaches have been investigated for the selective functionalization of these molecules, and two recent papers have described the selective benzylation and aroylation of p-t-b~tylcalix[6]arene.~~ Modest regioselectivity in the methylation of calix[6]arenes on the lower rim can be achieved, the conditions for which have been described in detail?8 Thus, for example, the 1,3,5-trimethylated compound was produced in 72% yield using 3 equivalents of potassium carbonate and 4 equivalents of methyl iodide, under 2 atmospheres of pressure.The same research group have also substituted the lower rim of p-t-butylcalix[6]arene with phosphate and thiophosphate groups, resulting in a restriction in the conformational freedom of the calk[ 6]arene.79 An extensive study of the base-catalysed alkylation of p-t-butylcalix[ 61 arene with 2-( chloromethy1)-pyridine in DMF, has led to the isolation and identification of 10 of the 12 possible pyridinium homologues of lower-rim-substituted cali~[6]arenes.~~~~~ The identity of the base, and the molar ratios of the reactants used, played a major role in determining the product distribution. Conformationally restricted calix[6]arenes have also been synthesized by transannularly bridging across the 1,4-position with several dihalides, using KOSiMe, as base .s A spherand-type calix[6]arene has been prepared by condensation of biphenyl derivative 107 with f~rmaldehyde.~, Using NaOH as base gave the trimeric structure 108 in 52% yield, whereas the use of CsOH gave the tetrameric compound 109 in 66% yield (Scheme 44).The use of KOH gave a mixture of the two compounds and these results provide clear evidence of a metal templating effect. (HCHO), , MOH xylene. reflux. 15h 108 109 JyQ!j (n = 1) (n =2) NaOH 52% trace KOH 32% 29% CSOH 4% 66% Scheme 44 3.4 Calix[8]arenes Early attempts at the selective functionalization of the lower rim of calix[8]arene led to mixtures of regioisomers or structurally undefined di-, tetra-, and hexa-substituted derivatives.However, Neri has recently reported the synthesis of the first partially substitued calix[8]arenes 110 (Scheme 45) with defined having a 1,3,5,7-tetrasubstitution pattern and C4 symmetry. The compounds were prepared in 20-41% yields by the treatment of calix[8]arene with various benzyl bromides (8 equivalents) and K,CO, ( 16 equivalents) in THF/DMF ( 1 O : l v/v). BU' But But 110 R = 4-XC6H4CH2; X = H, But, Me, NOp, CN Scheme 45 Kovalev and co-workers have prepared p-l-adamantylcalix[8]arenes 1 1 1 in good yield (72%) by refluxing under N, an o-xylene solution of 4-( 1 -adamantyl)phenol, paraformaldehyde, and KOH in the ratio 45 : 85 : 1 (Scheme 46).85 No other cyclic oligomers were found in the reaction mixture and 11 1 was further derivatized with various acylating or alkylating groups.(HCHO)n, KOH, OH Scheme 46 111 (72%) 3.5 Double calixarenes The ease with which calix[4]arenes can be selectively derivatized had led to the synthesis of various double calixarenes, possessing large and well-defined molecular cavities. Progress in this area has been reviewed recently.86 The biscalix[4]arene cage molecule 114 was prepared in 12% yield from 1 12 and 1 13, under high-dilution conditions in THF, using NaH as the base (Scheme 47).87 The synthesis of a receptor possessing two divergent hydrophobic cavities was achieved by fusing two p-t-butylcalix[4]arene units in cone conformation using silicon atoms.88 The reaction of p-t-butylcalix[4]arene with SiCl, in THF, in the Kilburn and Patel: Synthetic developments in host-guest chemistry 271MebMeb OMedMe 113 Scheme 47 114 (12%) presence of NaH, at room temperature, afforded the double calixarene 11 5 in 52% yield (Scheme 48).This multicavitand has been shown to form specific interactions with iodine. Bu' Bubu' ' (ii)SiCl, (1.254 HO HO OH OH 116 (36%) 117 (76%) Scheme 48 Similarly, the synthesis and structural investigation of a non-centrosymmetric 'koiland' (hollow molecular unit), composed of two p-t-butylcalix [4] arenes fused by both silicon and titanium atoms has been reported.89 Treatment of p-t-butylcalix[4]arene with 2 equivalents of NaH in THF followed by reaction with SiC14 afforded the mono-fused calixarene 116 in 36% yield.Since all four unreacted hydroxyl groups in 116 are disposed face-to-face, another atom requiring tetrahedral coordination can be accommodated and treatment of 116 with TiC14 in dichloromethane produced the heterobinuclear calixarene 1 17 in an almost instantaneous reaction, and in good yield (76%) (Scheme 48). Finally, the condensation of dipyrryl methane and calix[4]arene-173-dialdehyde 1 18, under dilute conditions, and in the presence of a catalytic amount of trifluoroacetic acid, gave a double porphyrin linked by two calix[4]arene units (Scheme 49).'O The low yield of 0.4% was higher than the statistical yield ( - 0.01%) predicted for the random combination of 12 reactive centres located on 6 distinct molecules. (i) H30+, CH2C12 (ii) DW I 118 0.4% Scheme 49 4 Cyclophanes Cyclophanes are broadly defined as 'bridged aromatic compounds7 and as such most host-guest systems, including many crown ethers, cryptands, and spherands, can be termed cyclophanes, while calixarenes are simply meta-cyclophanes." For the purposes of this review, the section on cyclophanes is intended to cover those compounds which do not fit into the earlier categories and for which the main structural feature are the aromatic units.4.1 All-carbon cyclophanes In spite of the extensive studies on cyclophanes, only a few [ 1 n ] orthocyclophanes that contain more than three aromatic rings have been reported.Recently the first syntheses of [ 14] and [ 15] orthocyclophanes have been described.Y2 Thus, dibromide 119 was lithiated with Bu"Li and coupled with dialdehydes 120, to give cyclic diols, which were oxidized with PCC to give the corresponding diketones 12 1 (Scheme 50). Palladium-catalysed reduction of 12 1 in EtOH/HCl afforded the deoxygenated cyclophanes 122 in good yield. Alternatively, reduction of the diketones with Zn(Hg)/HCl or with TiClJLiAlH, gave the bicyclic coupled products 123 which could be hydrogenated to give the same monocyclic cyclophanes 12 2. 272 Contemporary Organic SynthesisXI: 119 (9 BPLI 8 0 \ H,, Pdo - 121 = l (23%) m = 2 (30%) Ha Pdo EtOH. HCI I 8 0 \ 123 = 1 (81%) 122 m = 1 (8OVo) m = 2 (94%) = 2 (93%) Scheme 50 [( 2.1)J Metacyclophanes have been prepared by condensation of the bisarylethane unit 124 with formaldehyde (Scheme 5 l).93 This synthesis is very similar to the preparation of 109 and 110 described earlier, and product distribution was similarly affected by the templating effect of the base used in the reaction.D M - Na, K. CS I But I But 124 Scheme 51 n = 3 (2944%) n = 4 (2248%) Vogtle has prepared a series of molecules ('tolanophanes'), such as 127, which contain two acetylene units, by Wittig cyclization reactions of 125 with dialdehyde 126, using lithium ethoxide as the base, followed by oxidation of the alkene units to alkynes (Scheme 52).94 p p PPh3Br BrPh3P (i) LiOEt (ii) Br, (iii) KOBU' - 127 4.2 Heteroatom-containing cyclophanes A simple method for the synthesis of tetraaza[ 3.3.3.31paracyclophanes has been de~cribed.'~ Thus, alkylation of N-substituted trifluoroacetamides 128 with the corresponding bis( bromomethyl) benzenes 129, followed by removal of the trifluoroacetyl group and N-methylation of the resultant amines, gave the cyclophanes 130 and 13 1 in yields of 21% and 5% respectively (Scheme 53).An identical route was used to prepare the corresponding tetraaza[34]metacyclophane along with diaza [ 3 Jmetacyclophane. CHzNHTf fBr I 130 R = Me, n = 1 (21%) 131 R=Me,n =3 (5%) rile Reagents: (i) NaH, DMF, 100OC; (ii) NaBH,, EtOH; (iii) CH20, NaH2P03, H 2 0 , dioxane Scheme 53 Murakami has coupled L-valine methyl ester to the tetrakis( carboxynicotinoyl) derivative of 130, followed by quarternization of the pyridine moiety to give 132 (Scheme 53), a water-soluble analogue of 130.96 Similarly, tetraazaparacyclophane 133 has been coupled with Na-9-t-butoxycarbony1-~-aspartic acid benzyl ester in the presence of DCC, followed by removal of the protecting groups, to give the water-soluble derivative 134 (Scheme 54), which exhibits marked pH-dependent binding of various organic guest^.'^ R R /N--(CH2)n-N )=\ 133, R=H NHp Scheme 54 Mehta has constructed some unusual cyclophanes by a one-pot reaction between a 1 : 3 mixture of triquinane dione 135 and dianilines 1 36.98 Cyclization is carried out in glacial acetic acid to give cyclophanes 137 in - 15% yield, with a simultaneous rearrangement of the triquinane system (Scheme 55).Kilburn und Patel: Synthetic developments in host-guest chemistry 273H H (JQ +H2NyJ&NH2 H H 0 0 135 136 n = 1.2 30%.8h 1 -"' 137 n = 1 (15%) n = 2 (15%) Scheme 55 2,l l-diaza[3.3]cyclophanes such as 139 and 140 have been prepared by condensation of p-toluenesulfonamide with dibromide 138 and subsequent functional group manipulation.99 These cyclophanes were used to construct tube-shaped molecules such as 14 1, albeit in low yield (Scheme 56). A series of four-fold functionalized EQCRCO~E~ TosNHNa+ * TosN DMF Br Br 138 units, using a three-fold acetylene dimerization reaction, to produce compounds with novel solvatochromic and halochromic properties. lo3 This chemistry has also been used in the synthesis of a four-fold bridged macrocyclic compound 143 (Scheme 57).'04 The tetraalkyne 142 underwent an oxidative cyclodimerization in pyridine, containing 120 equiv.of CuCl and 16 equiv. CuCl,, to afford macrocycles 143 in 9.2% yield. II P H H 142 Cucl(1M eq.) CuClz (16 eq.) pyrMine 25%,7d I R AAR R = CO2Et (20-26%) 139 R=CH2Br E 140 R=CHpSH 143 (9.2%) Scheme 57 141 (3.4%) Scheme 56 Much larger dithiacyclophanes have also been prepared in good yields by condensation of dichlorides with xylenedithiols, and m-terphenyldithiol, using high dilution conditions,*00 and a biscatechol-derived tetrahydroxycyclophane has been prepared via the condensation of a suitable diamine and a bis-( acid chloride).1017102 With its large cavity and endo-acidic functional groups, this receptor proved to be an ideal hydrogen bond receptor for piperazine-type guests in organic solution. 4.3 Cage-type cyclophanes Vogtle has described the synthesis of a number of cage-type cyclophanes by bridging triphenylmethane Cyclophanes such as 146, containing phenanthroline units, have been synthesized in a one-step cyclization procedure utilizing diol 144 and an appropriate tribromide, such as 145, in DMF at 70°C with Cs,CO, as the base (Scheme 58).lo5 The rigid endo-preorganization of the nitrogen donors allows three 2,9-disubstituted 1,l O-phenanthrolines to be complexed within the large cavity.Vogtle has also reported the synthesis of related cage structures containing azobenzene units.lo6 synthesis of receptor 148, in 23% yield, by slow addition of an equimolar solution of 1,3,5-tris( bromomethy1)benzene and dimethyl methylenedisalicylate 147 to a suspension of caesium carbonate in refluxing acetone (Scheme 59).lo7 Hydrolysis of 148 afforded a water-soluble hexacarboxylate macrocycle, which, for instance, bound to acetylcholine with a higher affinity than previously reported tetracarboxylate receptors.Using a similar strategy, Lehn has described the 274 Contemporary Organic SynthesisDMF preorganization of the building blocks and their intermediates, the reduction proceeded without the application of high dilution conditions, to give 149 in overall 39% yield. ( KiIburn and Patel: Synthetic developments in host-guest chemistry dhN J 275A bicyclic cyclophane 158, with a molecular bowl structure, based on an aryl benzyl ether framework has been prepared.' l o The synthesis began with the construction of the central bridge, followed by stepwise cyclization.Thus, treatment of orcinol with the benzyl bromide 154 and hydrolysis, under dilute alkaline conditions, gave 155, with the exclusive monodeprotection of each resorcinol unit (Scheme 62). 155 (41%) (ii) NaOH, MeOH-THF 156 157 (38%) \ acetone Scheme 62 158 (43%) Me I Me -Me MA 159 (18%) Scheme 63 0 161 KOH, benzene-EtOH 160 The reaction of 155 with dibromide 156, under moderate dilution conditions, followed by further hydrolysis gave 157. The oxacyclophane 158 was obtained in 43% yield by coupling 157 with 156 using K,CO,/KI in acetone. Masci has reported the synthesis of macrocyclic and macropolycyclic ethers which are formally derived from the calix[4]arene family with the CH, groups replaced by CH20CH2 groups."' The key step involves the reaction of suitable diols or tetrols with polybromides to give monocyclic, bicyclic, and tricyclic ether derivatives, as exemplified by the synthesis of 159 in 18% yield (Scheme 63).A similar strategy has been used for the construction of a series of functionalized cyclophanes with cage structures, by the coupling of tetrathiol 160 with two equivalents of various dibromides, or with tetrabromide 161 (Scheme 64).' l 2 Under high dilution conditions, in the presence of KOH in benzene-ethanol, 162 was prepared in 35% yield. Scheme 64 162 (35%) 276 Contemporary Organic SyntheskCram has previously synthesized some remarkable globe-shaped hemicarcerands (highly sophisticated cyclophanes!) by linking two rigid bowl-like units, but previously the linking units were hydrolytically unstable.In more recent work the bowls have been linked by a i d e bonds using 1,3-phenylenediamine,' l 3 and by ether bonds using dibromo-o-xylene.' l 4 In the latter case the reaction is templated by dimethylacetamide, one molecule of which is encapsulated in the resulting cage, giving a yield of 20-25% for the reaction (Scheme 65). 20-25% Scheme 65 5 Cleft receptors and molecular bowls The receptors described in Sections 1-4 of this review have been classified as crown ethers or cyclophanes (including calixarenes), but a large range of other receptors are constantly being reported (some of which are also, strictly speaking, cyclophanes!). Broadly speaking these receptors are designed to arrange hydrogen-bonding functionality in suitable alignment to allow optimal interaction with chosen guests, although other binding interactions may also play an important role in the binding event.Such an arrangement of hydrogen bonds can be achieved using molecular clefts or macrocyclic structures with convergent functionality. 5.1 Cleft receptors As remarked earlier, the requirement for preorganization to allow strong binding has meant that much receptor chemistry has concentrated on producing macrocyclic structures which are conformationally constrained. However, a number of groups have shown that molecular clefts with convergent functional groups can provide highly selective artificial receptors. Rebek has amply demonstrated this with the study of a range of receptors based largely upon the rigid architecture provided by Kemp's triacid derivatives.This work has recently been extended with the preparation of molecular clefts containing an adenine receptor portion and a metal binding site.115 Thus, bromination of 3,6-dinitrocarbazole and an Ullmann coupling with 3 (5)-isopropylpyrazole gave dinitro-compound 163, which was reduced to the corresponding diamine and coupled with acid chloride 164 to give receptor 165 (Scheme 66). Cup. NMP. heat 163 (iii) Fe / HCI I BnO 164 pyridine. heat BNO ,OBn 165 Scheme 66 A similar route was used to prepare a water-soluble receptor 166, which bound to adenosine and 9-ethyladenosine in water. These clefts are prepared in short and highly modular syntheses, and with the inclusion of a metal-binding site, it is suggested that development of enzyme-like behaviour may be possible.Kilburn and Patel: Synthetic developments in host-guest chemistry 277278 -OH I A Pr Pr BU' But I Pr 167 Vogtle has prepared [ 2.2]metacyclophanes such as 17 1 , which provided a cleft with potentially two convergent carboxylic acid groups.' l 7 The cleft cyclophane 17 1 was synthesized (Scheme 67) from dithia[3.3]metacyclophane 168, which was prepared in a few steps from 2'6-dimethylaniline and 5-t-butyl- 1,3-dimethylbenzene. Oxidation of 168 led to the corresponding sulfone, and subsequent vacuum pyrolysis afforded the metacyclophane 169. Palladium-catalysed ethynylation and silyl cleavage with K,CO, gave 170, which was directly coupled using CuI and Et,N in 26% yield.Hydrolysis of the methyl groups afforded the desired cleft 17 1 , which was found to bind to pyrimidine and purine bases, with a preference for 2,6-diaminopurine over adenine or 2-aminopurine. Zimmerman has previously described the synthesis and binding properties of 'molecular tweezers' which also provide hydrogen bonding and aromatic stacking interactions for the binding of the adenine skeleton.' lx Hashimoto has reported the synthesis of a water-soluble version of Zimmerman's tweezer, via coupling of these tweezers to a dextran polymer using a reductive amination.' l9 These modified tweezers are readily purified by gel filtration column chromatography and show high affinity for adenosine in an aqueous buffer. Con temporary Organic Synthesis Br 168 166 A similar strategy has been used for the synthesis of a 'scorpion-like' receptor 167 which binds adenosine derivatives by a combination of Watson-Crick and Hoogsteen base-pairing, further hydrogen-bonding interactions, and stacking interactions on both faces of the aromatic guest.116 171 Reagents: (i) H202, AcOH, C6H6; (ii) pyrolysis; (iii) MeGiCSH, (Ph3P)2PdC12, Cul, Et3N, 26%; (iv) K2C03, MeOH, 90%; (v) CuI, EtaN, 58%; (vi) LII, pyridine, reflux, 27Y0 Scheme 67 cyclu Bis-intercalands, such as 172, containing two 8-amino-6-phenanthridinyl moieties, have been prepared by an intramolecular oxidative coupling of N, N-dipropargyl-bis-phenanthridines using copper (11) acetate (Scheme 68).120 These clefts showed an + NO2 6' Cocl 172 (60%) benzene rdlux __c HN pyridine 60°C. 3 d C02Et Scheme 68increase of the emission intensity in their fluorescence spectra compared with their acyclic bis-phenanthridine counterparts.Glycoluril units have been used as building blocks for the development of 'molecular clip' receptors such as 175, which bind aromatic guests by means of hydrogen bonding as well as n-n interactions. Crown ether derivatives also bind alkali salts and ammonium salts. Improved procedures for the synthesis of these molecules have been described in detail, with the most versatile method being the Lewis acid catalysed reaction of the tetrachloride 173 with appropriate benzene or naphthalene derivatives.121 For instance, 173 was refluxed with 2,7-dihydroxynaphthalene, and SnCl, as catalyst, in 1,2-dichloroethane, to give 174 in 64% yield, and then alkylated with dimethyl sulfate to give 175 (Scheme 69). Compound 175 was an efficient receptor for aromatic guests, such as 1,4-dicyanobenzene, and binding occurred by an induced-fit mechanism.b Phi- Ph (10 P h w Ph C1-NKN-cl HNyNH CH&L, 0 0 173 + 174 R=OH (64%) Me804 175 R = OMe (94%) Z D M S O Scheme 69 Schrnidtchen has recently described an open-chain bis-guanidinium host 179 which bound dicarboxylate anions in competitive solvents such as methanol, despite the apparent lack of preorganization of binding sites.122 Starting from the chiral guanidinium 176, mild acid hydrolysis selectively removed the t-butyldimethylsilyl protecting group to give alcohol 177, which was converted into the chloride 178 and coupled with 2,7-dihydroxynaphthalene to give 179 in yields of - 70% (Scheme 70).In related work, Diederich has used clefts formed by functionalized homochiral9,9'-spirobifluorenes for the enantioselective complexation of dicarboxylic acids of N-protected derivatives of L-aspartic and L-glutamic acids, in chloroform.123 serve as a convenient binding site for carboxylic acid functionality. In an extension of this work, acylamino acid carboxylates have been Hamilton has previously shown that amidopyridines ,-OSiPh2Bu' OSiPhpBu' OSiPbBu' R I I HN I 176 R = OSiMepBu' 177 R=OH E 178 R=CI O m 0 179 (70%) Scheme 70 recognized using receptors such as 180 (Scheme 7 1 ), which was derived from 6-methyl-2-aminopyridine. * 24 Further work has led to the development of bis-ureas and bis-thioureas for the complexation of dicarboxylates in polar solvents,125 while the synthesis of 18 1, by coupling N-Cbz L-serine to ( 1 R, 2R)-trans- 1,2-diaminocyclohexane, provided a receptor which showed a particularly large association constant for the complexation of tetrabutylammonium acetate, due to the multiple hydrogen bonding contacts available.' 26 180 <OH 0 181 Scheme 71 Rebek has also used convergent ureas as binding sites for carboxylate functionality and has described a neutral receptor 183, which was prepared from xanthenedicarboxylic acid 182 via a Curtius rearrangement, followed by hydrogenolysis of the resulting carbamate, and coupling with the appropriate isocyanate (Scheme 72).127 182 183 Reagents: (i) DPPA, EtBN BnOH, toluene 80 "C; (ii) Hp, Pd-C,EtOH; (iii) VNCO Me Scheme 72 Kilburn and Patel: Synthetic developments in host-guest chemistry 279Caballero has prepared receptor 186 by desulfurization of episulfide 184, and subsequent derivatization, to give the tetrasubstituted alkene 185.A photochemical cyclization, in toluene, with iodine oxidant, then gave the 9,lO-diphenylphenanthrene skeleton (Scheme 73). These rigid receptors form strong complexes with malonic acid derivatives in chloroform, via a four-point hydrogen bonding array. I 28 Koo 184 (75%) Scheme 74 (i) NaOH-EtOH (ii) MeSGH. P206 (iii) EtOH-H+ (iv) ACOCl Q2N t 0 187 R=H(45%) R = Me (39%) 0 0 186 (72%) Reagents: (i) PbP; (ii) Fe-AcOH; (iii) Et20CC(C4HB)2COCI Scheme 73 (iv) NaOWEtOH; (v) pdyphosphoric acid A related receptor 187 has been prepared, starting from 4-bromo-5-nitrodimethylisophthalate and potassium nitrophenolate (Scheme 74).12' The introduction of the dinitrotoluic residue provided strong aromatic interactions, as well as hydrogen-bonding interactions, for the binding of suitable aromatic acid and amide guests.The Fischer cyclization of appropriate 8-quinolinylhydrazones has been employed for the preparation of a series of cavity-shaped hosts containing a central pyridine ring, appended on either the 2,6- or 3,5-positions by two pyrido[3,2-g]indole subunit^.^^".'^^ Pyridyl diketones were treated with 8-hydrazinoquinoline to form the intermediate hydrazones, which cyclized directly to the desired host systems 188 when heated with polyphosphoric acid (PPA) at 100°C (Scheme 75). These receptors showed high affinity €or imidazolidone and barbital guests.NHNH~ 0 (ii)pdyphosphoric * acid. 100% 188 n = 1,2.3 Scheme 75 Reinhoudt has previously demonstrated that metalloreceptors containing an immobilized uranyl cation can be used as receptors for neutral and anionic guests. More recently, the binapthyl metallocleft 190 has been synthesized by the reaction of aldehyde 189 with 1 ,2-diaminobenzene7 and subsequent addition of UO,( OAc),.2HZO, which afforded the hydrated complex 190, in 38% yield (Scheme 76).13, These metalloclefts, containing the immobilized Lewis acidic uranyl cation, are excellent receptors for complexing neutral molecules, as nucleophilic groups (C=O, S=O) can coordinate to the uranyl cation, in addition to the available hydrogen-bonding and aromatic interactions.Simple modifications to the clefts have led to the recognition of anions with a high selectivity being shown for dihydrogen ph0~phate.l~~ These clefts have also been converted into macrocyclic structures containing a 2,6-diaminopyridine unit, in addition to the metallocleft for the recognition of barbiturates.' 34 280 Contemporary Organic Synthesis189 Scheme 76 190 5.2 Molecular bowls and other receptors Still has previously described a novel C, symmetric receptor 194 (R = H), which binds to a variety of peptides and glycosides, displaying high selectivity for both the functionality and stereochemistry of the guest. An improved synthesis for this class of receptor has now been reported,’35 beginning with O-allyl-N-Boc-tyrosine methyl ester 19 1, which was readily converted in two steps into amide 192 (Scheme 77).Deprotonation of 192 with sodium hexamethyldisilylazide in THF at - 78°C led to rapid migration of one of the t-Boc groups, giving a t-Boc-stabilized amide anion which was alkylated with 1.2 equiv. of 3,5-bis(bromomethyl)benzoate to give 193 in 82% yield. Bromide 193 was then used to triply alkylate trimercaptobenzene, and the synthesis was completed with a triple macrolactamization, using an activated tris( pentafluorophenyl ester), which proceeded in 78% yield. A closely related receptor has been prepared containing additional methylene groups built into the apolar base of the binding cavity, and additional binding studies and molecular modelling calculations have been carried out to test the effect of the increased conformational flexibility on binding selectivity.’ 36 An efficient synthetic sequence has been described by Sanders for the preparation of a porphyrin-cyclocholate molecular bowl 197.13’ Cholic acid was the starting point of the preparation of aldehyde 195, which was converted, under Lindsey conditions, into a benzyl-protected tetrasteroidal porphyrin in 46% yield (Scheme 78).Metallation of the porphyrin ring followed by hydrogenation of the benzyl esters afforded the corresponding tetraacid. Tetramacrolactonization to give 196 was achieved in 18% yield using Yamaguchi conditions. Removal of the trifluoroacetyl protecting groups and metallation gave the final product 197. Davis has also used the readily available steroid cholic acid in the synthesis of cholophanes.Full papers now describe much of the synthetic work in detail, including the use of an arylmanganese reagent to introduce a 38-( p-aminomethy1)phenyl unit into the structure, and the use of a novel ‘benzostabase’ N-protection methodology.’ 389 39 Using similar 0 k 191 193 (82%) R’ .H Reagents: (i) MeOH, NH3, r.t, 2 days; (ii) -0, pr‘pNEt, 4-DMAP; (iii) NaN(Tl~ls)~, THF, -78 “C; (iv) tetra-n-butylammonium iodide and methyl 3,5-bis(bramomethyl)beeoate; (v) benzene-l,3,5-trithiol, pi2NEt; (vi) TFA, anisole, CH2Cl,; (vi) -0, pr‘pNEt, K2C03; (vii) UOH, M F , EtOH, H20; (viii) C6F50H, EDC, THF; (ix) TFA, anisole, CH2Ch; (x) P(’2NEt, THF Scheme 77 methodology, a new cholophane framework has been prepared, with exocyclic fun~tionality.’~~ The synthesis involved condensation of ketone 198 with malononitrile, followed by equatorial-selective addition of an aryl cuprate to give 199, which was then converted into the cholophane 200 (Scheme 79).Kilburn and Patel: Synthetic developments in host-guest chemistry 2810 I1 R'd CHO 195 Reagents: (i) pyrrole, F3B.0Et2, CH2C12; (ii) tetrachbroquinone; (iii) Z~(OAC)~; (iv) H2. Pd, C; (v) 2,6-dichlorobenzoyl chloride, Et3N, 4A sieves: (vi) DMAP, toluene, 100°C Scheme 78 Still has reported the remarkable synthesis of the polycyclic receptor 202, which displays similar enantioselectivities to the C3 symmetric hosts 194 for the complexation of N-acylated and Boc-protected peptides.141 Dimerization of oligomer 201, derived from trimesic acid 204 and (R, R)-diaminocyclohexane 203, gave the host 202 (Scheme 80).Direct treatment of free diamine 203 with the triacid chloride of trimesic acid 204, gave receptor 202 in 13% yield in one step! The receptor forms 1 : 1 complexes with certain peptides (eg. N-Ac-L-Val-NHBu' is particularly well bound) and can even interact with peptides containing as many as three residues, as is the case for complexation with N-Boc-Gly-Val-Gly-NHBn. 0% W - ' O A c 198 -wBu' NC CN 200 Reagents: (i) CH2(CN)2, NH40Ac, AcOH, benzene; (ii) Bu'OCH2C~H&lgBr, CUCN, THF; (iii) CF3CO&l, CH2Ch, 5OoC; (iv) NH3 (a@, Et20; (v) CH3S02CI, Pr'*NEt, THF; (vi) (Me2N)&NH2*N3-, CHC13; (vii) PhaP, THF, MeOH, H20; (viii) LDH; (ix) aq HCI; (x) [(EtO)ZP(O)CN, DECP], CHCI3-DMF. KHS04,3% Scheme 79 6 Self-assembling receptors The rapid success of chemists in preparing artificial receptors has led to the new area of 'self-assembly' in which non-covalent interactions between individual molecules are used to allow the spontaneous assembly of complex supramolecular architectures such as catenanes, rotaxanes, and helices.14* While self-assembly is not the subject of this review, it is exciting to find that examples of self-assembling receptors are appearing in the literature. Thus, compound 206 has been synthesized by condensing two molecules of diphenyl glycoluril with durene tetrabromide 205 using KOH in hot DMSO (Scheme 8 1).143 The lactam functionalities of 206 provide self-complementary hydrogen bonding groups, so that two molecules dimerize to form a closed-shell, three-dimensional surface through a network of hydrogen bonds, in a structure reminiscent of a tennis ball.More recently this dimer has been reported to encapsulate small hydrophobic guests, such as methane, ethane, and ethylene in a chloroform s01ution.l~~ self-associate strongly in CCl,, forming molecules with short cylindrical shapes.145 Starting from the readily available ketone 207, the free hydroxy groups were esterified with dodecanoic acid, followed by a Beckman ring-expansion to afford lactam 208 Triamide cyclocholates such as 209 also 282 Contemporary Organic Synthesis,NHBoc a COPR CO, R 201 R=CeFs \ 0 ( i ) TFA (ii) Pi2NEt, THF I 0 O H 202 (39%) (y' HO2CVCO2H 'NH2 203 Scheme 80 + 0 Br Bi 205 Scheme 81 hO,H 204 H PhH KOH, DMSO heat 206 (33%) (Scheme 82).Selective hydrolysis of the terminal ester protecting groups, and then macrolactonization, under modified Yamaguchi conditions, afforded the cyclotrimer 209 in 34% yield. Cram has also prepared molecules with large common surfaces which are capable of forming d i m e r ~ . ' ~ ~ Structure 2 12 (Scheme 83), when rotated through 90" about an axis perpendicular to the page, and then turned over and placed on top of 2 12, forms a complex containing a large contact surface area with the four methyl groups on each half unit inserted into four cavities provided by the other. The absence of OACllH23 208 (50%) 209 (34%) Reagents: (i) dodecanoic acid, 2,6dichlorobentoyl chloride, DMAP; (ii) NH20H.HCI, NaOAc: (iii) pTsCI, pyridine; (iv) aq NaOH: (v) 2,6-dichlorobenzoyl chloride, DMAP, 4A sieves, CH&b I Scheme 82 21 0 + 21 1 212 (41%) Scheme 83 Kilburn and Patel: Synthetic developments in host-guest chemistry 283hydrogen bonds, ion pairs, or metal ligation sites leaves dipole-dipole, Van der Waals, and hydrophobic attraction as the major driving forces for complexation.The synthesis of molecules such as 2 12 involved the condensation of aromatic dihalides, such as 2 10, with the octol2 11 (for which an improved synthesis is described). Each reaction between dihalides and the octol involved the making and breaking of eight bonds, producing four new nine-membered rings. Remarkably high yields were obtained (50-86%) in this step of the synthesis. hydrophobic binding site 2 16, with polar solubilizing functionality provided by connecting the aromatic rings with phosphonium f~nctionality.’~’ The self-assembly of this receptor occurred on addition of 4,4’-( hydroxyphosphinylidene ) bis-L-phenylalanine (PBP) 2 15 to an equimolar solution of a metal such as Co2 + , in the presence of NaOH.The PBP was prepared in 4 steps by the conversion of protected iodophenylalanine 2 13 into protected PBP 2 14, in 5 9% yield, using a palladium-catalysed coupling (Scheme 84). These receptors were able to transport pyrene from an isooctane layer across an aqueous phase. Schwabacher has designed a new class of 21 3 J 214 R’=Me$=E3oct 215 R’ = H*+Cr, R2= H / . -0 216 M2Ph Scheme 84 Current progress in host-guest chemistry, and in the more general area of supramolecular chemistry, is extremely rapid, as evidenced by the amount of new and varied chemistry reported in this review-which is far from comprehensive-and the frequent publication of articles dealing with the less synthetic aspects of this area of research.Molecules with ever more complex architectures are being designed and synthesized, and the incorporation of ideas of self-assembly and templatingI4* will continue to provide new avenues for the synthetic chemist to explore. 7 References 1 C. J. Pedersen, J. Am. Chem. SOC., 1967,89,2495. 2 Three very recent review articles are: D. R. Smith, Chem. Ind., 1994,14; M. Mascal, Contemp. 0%. Synth., 1994,1,31; T. H. Webb and C. S. Wilcox, Chem. SOC. 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SOC., 1992,114,9671. 134 A. R. van Doorn, D. J. Rushton, W. F. van Straaten-Nijenhuis, W. Verboom, and D. N. Reinhoudt, Red. Trav. Chim. Pay-Bas, 1992,111,42 1. 135 S. D. Erickson, J. A. Simon, and W. C. Still, J. 05. Chem., 1993,58,1305. 136 S . S. Yoon, T. M. Georgiadis, and W. C. Still, Tetrahedron Lett., 1993,34,6697. 137 L. G. Mackay, R. P. Bonar-Law, and J. K. M. Sanders, J. Chem. SOC., Perkin Trans. 1, 1993, 1377. 138 R. P. Bonar-Law and A. P. Davis, Tetrahedron, 1993, 49,9829. 139 R. P. Bonar-Law, A. P. Davis, and B. J. Dorgan, Tetrahedron, 1993,49,9855. 140 A. P. Davis and M. G. Orchard, J. Chem. SOC., Perkin Trans. I , 1993,919. 141 S. S. Yoon and W. C. Still, J. Am. Chem. SOC., 1993, 115,823. 142 See: J.-M. Lehn, Angew. Chem., Int. Ed. Engl., 1993, 32,69; G. Whitesides, Science, 1991,254, 1312. 143 R. Wyler, J. de Mendoza, and J. Rebek, Jr., Angew Chem., Int. Ed. Engl., 1993,32, 1699. 144 N. Branda, R. Wyler, and J. Rebek, Jr., Science, 1994, 263,1267. 145 R. P. Bonar-Law and J. K. M. Sanders, Tetrahedron Lett., 1993,34,1677. 146 D. J. Cram, H.-J. Choi, J. A. Bryant, and C. B. Knobler, J. Am. Chem. SOC., 1992,114,7748. 147 A. W. Schwabacher, J. Lee, and H. Lei, J. Am. Chem. SOC., 1992,114,7597. 148 The role of templates in the synthesis of macromolecules has not been discussed specifically in this review, but is increasingly being applied to receptor synthesis. For a recent account and leading references, see: S. Anderson, H. L. Anderson, and J. K. M. Sanders, Acc. Chem. Res., 1993,26,469. 130 V. Hegde, C.-Y. Hung, P. Madhukar, R. Cunningham, 286 Contemporary Organic Synthesis

ISSN:1350-4894    

DOI:10.1039/CO9940100259

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Synthetic approaches to butenolides D. W. KNIGHT Chemistry Department, University Park, Nottingham, NG7 2RD, UK Reviewing the literature published between 1976 and 1992 1 2 3 4 4.1 4.2 4.3 4.4 4.5 5 5.1 5.2 5.2.1 5.2.2 6 7 8 9 10 11 Introduction a-Substituted butenolides #?-Substituted butenolides y-Substituted butenolides Simple derivatives Methods using carbanions From maleic anhydride/furan Diels-Alder adduc t s From furans Other methods Hydroxy- and alkoxy-substituted butenolides a-Hydroxy- and alkoxy-butenolides y-Hydroxy- and alkoxy-butenolides From furans Other methods Butenolides substituted with alkoxycarbonyl groups Y lidenebutenolides Ring-fused butenolides S piro-butenolides Multi-substituted butenolides References 1 Introduction Butenolides occupy a literally central position between butyrolactone and furan structures, both in terms of synthetic chemistry and biosynthesis.These compounds also form an important and diverse group of natural products in their own right, encompassing both fatty acid and terpenoidal biosynthetic origins, and they display a wide range of biological activities. Very simple examples include the buttercup metabolite protoanemonin, the butter flavour component bovolide, and the related component of mushroom flavour, long-chain butenolides represented by acarenoic acid and methyl lichensterinate, and the highly unsaturated ylidenebutenolide lissoclinolide. However, the bulk of natural butenolides are terpenoid in origin. These range from the simple monoterpenoid mintlactones to numerous sesquiterpenes, representing most of the major biosynthetic classes and exemplified by confertifolin, aristolactone, and furodysinin lactone.Other examples include the paniculides and the highly oxidized metabolites freelingyne and the piscicidal vallapin. protoanemonin . HT 0 mushroom component C02Me n-c’3H27* 0 methyl lichensterinate mintlactones aristolactone -+ 0 bovolide acarenoic acid OH 0 lissoclindide confertifolin Wo f urodysinin hctone paniculide A freelingyne Me0 vallapin Knight: Synthetic approaches to butenolides 287Butenolide diterpenes are represented amongst the labdanes and the related jolkinolide E, while sesterterpene representatives include the PLA, inhibitor manoalide and the unusual and cytotoxic carotenoid metabolite luffariolide A. Digitoxin and related cardenolides are perhaps the most widely known members of the butenolide family.Two final and unique examples are the seed germination stimulant strigol and members of the securinine alkaloids, such as 4-epiphyllanthine. labdadienolide A jolkinolide E manoalide Qo luff aridide A digitoxin referred to as indicated in formula 1. The literature has been surveyed from 1976, the year of publication of the last extensive review of this topic,' up to 1992 inclusively. An attempt has been made to be reasonably comprehensive, but complete coverage is not claimed. The material has been arranged primarily on the basis of structural types, in order to facilitate access. Thus, monosubstituted and polysubstituted examples are grouped in separate sections. Clearly, in many cases, the same methodology can be applied to syntheses of members of the different groups.Where this has been reported, every effort has been made to provide cross references; the imagination of the reader will be required when this is not the case. Applications of many of the methods to natural product synthesis have been included in order to emphasize the utility of the strategy concerned. The parent butenolide 1, which is commercially available, can be prepared by Baeyer-Villiger oxidation of furan-2-carbo~aldehyde,~ using hydrogen peroxide/formic acid or from furan itself, in 62-7 1% yield by treatment with bromine in acetic acid/acetic anh~dride.~ 2 a-Substituted butenolides A neat method for the conversion of the parent butenolide 1 into the a-substituted homologues 3 consists of sequential Michael addition of thiophenolate and aldol condensation of the resulting enolate to give intermediates 2 ,4 Conventional oxidative elimination of sulfur completes the sequence, which unfortunately fails when ketones are used as electrophiles.The isomeric enolate 4 can be generated from the corresponding a,a-bis-( pheny1thio)- butyrolactone by treatment with ethylmagnesium bromide; similar condensation and elimination steps then lead to the same a-substituted butenolides 3.5 1 2 I 4 3 In general, a-alkoxy- and silyloxy-furans react with .-..& N , . ' the exception other a-position is the stannyl of the triflate furan 5 , n u c l e ~ s . ~ ~ - ~ ~ which reacts An largely at the /?-position of the furan, thus providing a non-anionic route to the a-hydroxyalkyl-butenolides 3.6 R-0 electrophiles, usually under the influence of a Lewis acid, to give y-substituted butenolides by reaction at &g&o - OH Stflgol 4-epiphyllanthine For the purpose of this review, the term 'butenolide' specifically refers to the conjugated or A*-butenolides; other, more systematic, names include but-2-en-4-olides and 2( 5H)-furanones.The - 3 a O S m T f substituent positions in butenolide structures are 5 288 Contemporary Organic SynthesisAn alternative strategy, which allows the indirect generation of an anionic centre at the a position of a butenolide, begins with the easily prepared Diels-Alder adduct 6, which can be readily converted into the monoester 7. Enolization and alkylation under standard conditions, lactonization, and finally a retro-Diels-Alder reaction delivers the monosubstituted butenolides 8.7 Limiting factors are the restriction to allylic and benzylic halides as electrophiles, as is usual with ester enolates, and in some cases the high temperature [200-280"C] required in the last step.This idea has been employed el~ewhere,~'-~~> 233, 234 as the adduct 6 and relatives thereof also effectively prevent competition from Michael additions which could interfere in reactions between butenolides themselves and nucleophiles. Another way of generating a /3-carbanion in a butenolide precursor involves the use of a diaminophosphate group to direct deprotonation to the 6-position of a furan, rather than to the much more usual a'-site.The resulting anion 9 reacts with aldehydes, ketones, and benzylic bromides, but not with other alkylating agents, to provide the butenolides 8, together with some of the deconjugated isomers, in ca. 50% yield, following brief exposure to formic acid.8 0 6 7 (if LDA-RX (i9 200-280 "c 'I 9 8 The fact that A2-butenolides contain an endocyclic, conjugated double bond suggests that alkene positional isomerization should provide a number of approaches to them. The above examples6> * already attest to the ease of isomerization of A3-butenolides; a-alkylidenebutyrolactones similarly are useful as precursors to A2-butenolides. For example, the a-allenylbutyrolactones 10 are converted into butenolides 11 upon exposure to dicobalt octacarbonyl, by a formal [ 1.33-hydride shift;Y of more general use is the finding that many rhodium( I ) hydride complexes, of the type which are well known to induce alkene migrations, readily catalyse the isomerization of aklylidene lactones 12 into the butenolides 13,33.35.171,172+202,227 in generally good yields.'" R 10 11 An alternative way of achieving this type of isomerization, and at the same time incorporating an additional functional group, is to employ an ene reaction; for example, by using 2-phenyltriazoline- 3,5-dione as the enophile, the alkylidene lactones 12 can be converted into the butenolides 14, in generally excellent yields.' Using this strategy, the ancistrofuran precursor 16 has been prepared by cyclization of the initial ene product 15.A rather elegant alternative to this method features cation-driven cyclizations of the dienoate 17 [X = PhSe, Br, or 0 (from peracid)]; the natural compound itself is accessed by a related but stepwise process.' 15 H 16 axx+ /J C02Me 17 In general, a-silylfurans are converted into butenolides when oxidized by buffered per acid^'^ and using the hydroxyalkyl functions in the furans ( 18; n = 1 or 2) to direct metallation to the adjacent a-position, regioselective introduction of a trimethylsilyl group can be achieved; subsequent peracid oxidation then leads to the synthetically useful butenolides 19.13 into y-hydroxybutenolides by singlet oxygen.' 1 6 , ' l 7 B Y i a 19 20 The isomeric hydroxyalkyl lactones 20" can be obtained via the same strategy, after first blocking the more reactive a-position by using a phenylthio group.One use of this type of silylated furan is as a precursor to the Grignard reagent 2 1 .I4 Coupling the latter with alkyl iodides, using dilithium tetrachlorocuprate as the catalyst, followed by oxidation constitutes an alternative route to the a-substituted butenolides 13. The corresponding B-substituted butenolides can be similarly obtained. Knight: Synthetic approaches to butenolides 28921 An extra degree of synthetic flexibility is offered by the a-stannylbutenolide 22, prepared from the corresponding phenylthiobutenolide by a desulfurylative-stannylation reaction, which undergoes smooth palladium( 0)-catalysed couplings with aryl iodides and presumably many related Stille-type coupling reactions.' SnBu3 CXo 22 3 b-Substituted butenolides The /%isomer 23 of the foregoing stannylbutenolide 22 similarly provides a wide range of opportunities for the preparation of B-substituted butenolide~.'~ CO2Et Eto40 - ____c OEt 26 27 OEt 1, t 28 is found in the fungus Psathyrella scobinacea, and an E/Z mixture of which has been isolated from Senecio cZeveZandii.20 However, these reports suggest that a better route to the salt 30 is from 3,3-dimethylacrylic acid, as outlined below.205 SnBu3 I 23 29 30 31 E-Scobinolide Formally, the 'inverse' approach to this method of producing B-substituted butenolides 25 features palladium( 0)-catalysed coupling reactions between dialkylzincs and the B-bromobutenolide 24.16 Such butenolides can also be obtained from the bromide 24 by an alternative, if somewhat capricious combination of Michael addition and elimination reactions, usually using lithium dialkylcuprates as the nuc1eophiles.l Br R 24 25 A more convoluted approach to this type of butenolide begins with the keto-ester 26, which is first alkylated using an allylic chloride then saponified and finally decarboxylated and homologated to the unsaturated esters 27 by a Wadsworth-Emmons condensation. Acid-catalysed ring closure and borohydride reduction of the resulting y-ethoxybutenolides (Section 5.2) completes this synthesis of butenolides 28, which are useful precursors of the furanoterpenes perillene and dendrolasin.18 diacetoxyacetone, was the key step in a preparation of B-hydroxymethylbutenolide 29." (See also reference 14.) This compound occurs naturally as a metabolite of Siphonodon australe and is also useful as a precursor of the phosphonium salt 30 [ cf.reference 1951. One application of the latter is in a non-stereoselective synthesis of Scobinolide 3 1, which A similar olefination reaction, but of A different approach to the unsaturated esters 27 in general features a Peterson olefination as the key step.21 Another example of the way in which a Wadsworth-Emmons reaction can be employed in this area is illustrated in the synthesis of (S)-manoalide diol33b .22 Starting from 2-deoxy-~-ribose, the butenolide 32 was prepared to form the alkene linkage, as in the foregoing examples. A second Wadsworth-Emmons condensation was then used to obtain the central trisubstituted olefinic bond; the synthesis' 17, l8 was completed by selectively reducing the carboxylate function of ester 33a by mixed anhydride formation and treatment with sodium borohydride.32 0 33a; R=C02Bn b; R=CHzOH 290 Contemporary Organic Synthesis/I-Substituted butenolides, e.g. 35, can also be prepared by PDC oxidations of TMS cyanohydrins derived from #?,/?-disubstituted-a,/3-unsaturated aldehydes, e.g. 34.23 Yields are variable (40-75%) and the method is rather limited in that mixtures are obtained when both positions y- to the aldehyde carry hydrogens and are thus open to oxidation. This method has been used to prepare the labdadienolide 36 starting from manool, but the isolated yield from the oxidation step was only 16°h.24 Ar 34 35 36 Esters corresponding to the aldehydes 34 can be oxidized to butenolides using the allylic oxidant selenium dioxide; yields are increased by adding a little perchloric acid which apparently increases the reactivity of the oxidant by protonation of the Se = 0 bond.25 The method is limited to substituents lacking an a-photon (aryl; tert-alkyl).An alternative access to /I-arylbutenolides 35 is provided by an application of the Heck reaction in which aryl iodides are coupled with the unsaturated ester 37 under solid-liquid phase transfer conditions using palladium( 11) chloride as the catalyst.26 Yields are in the range of 48-71%; extensions of the method to more highly substituted examples have not been reported. 37 This approach has been applied to the elaboration of the /I-substituted butenolide unit in the cardenolides 39 by coupling between an enol triflate 38, derived from a steroidal 17-one, and the ester 37, followed by lactonization induced by an acidic ion exchange resin.27 Completion of the synthesis involves a regiospecific hydrogenation using conventional conditions to give the final product 40.The /?-substituted butenolide function present in the cardenolides has been prepared in a number of different ways involving construction of the lactone ring using anionic chemistry. For example, a Reformatsky reaction has been used to obtain the hydroxyester 4 1 from the corresponding a -met hylthio ketone; subsequent acid- and base-treatments lead to the desired products 40.28 A more extended but nevertheless efficient approach also begins with a steroidal 17-one, Knoevenagel condensation of which with ethyl cyanoacetate followed by borohydride reduction leads to the cyan0 alcohol 42.Alcohol protection, Dibal-H reduction, and treatment with cyanide then affords the protected cyanohydrin 43. Brief exposure to acid gives the corresponding /I-hydroxybutyrolactone and thence the butenolide 40, following chlorination and thermal elimination.29 38 37 Pd(OAC), ByN. PPh3 - then H30+ 42 39 H2 Pd-C,EtOAc I The Bestmann ketenylidene phosphorane method155 has been used in a much shorter approach to the 17-hydroxy-cardenolides 45 from the hydroxy ketones 44.30 This procedure was also found to be the best of a number of alternatives for the elaboration of the butenolide function in the insect antifeedant ajugarin IV 46.31 Ph#=C=C=O 44 45 46 Other Wittig-based methods leading to /I-substituted butenolides 48 include an intramolecular version in which the likely intermediate 47 in the Bestmann method is prepared in stepwise manner by ester formation between an a-bromo-acid and an a-bromoketone followed by quaternization Knight: Synthetic approaches to butenolides 291and elimination of hydrogen bromide.32 Overall yields are generally high in both models and in cardenolide synthesis, but the methodology is not appropriate for the elaboration of ring-fused butenolides, starting with cyclic a-bromoketones.tXPPh3 47 49 48 The phosphorane 49, derived from maleic anhydride, undergoes smooth Wittig reactions with aldehydes; subsequent selective reduction of the ester function using sodium diethylaluminium hydride leads to the corresponding p-alkylidenebutyrolactones, isomerization'" of which completes the sequence.33 During a synthesis of digitoxigenin, the butenolide function was introduced by a palladium-induced rearrangement of the allylic epoxide 50, with concomitant ~yclization.~~ Oxidative elimination of the sulfenyl function from the resulting butyrolactone 5 1 then completed the sequence.A contribution to butenolide synthesis from the burgeoning area of radical chemistry is the finding that the acetylenic mixed acetals 52 undergo smooth cyclization when treated with tributyltin radicals;35 the resulting acetals 53 are readily converted into examples of the butenolides 48, following oxidation and isomerization.'O* 35 52 53 A tandem version starting with the acetal54 can be used for the preparation of the cardenolide fragment 55.Sequential alkylation of the sulfone dianion 5641,206,225 by an alkyl halide and iodoacetate leads to the hydroxy-acids 57 and thence to the butenolides 48.36 The method can also be used to prepare y-substituted butenolides. 54 55 ArS02 KR-48 0- -0 c02- 56 57 A more direct but unfortunately less efficient approach to the lactones 48, developed during synthesis of the insect antifeedant ajugarin 1, ( cf reference 3 1 ) features Michael addition236, 245 of a sulfone 58 to the acetylenic ester 59.37 Overall yields are - 45% after completion of the route by lactonization and reductive removal of the sulfur function. 59 The potentially useful alkynyl butenolide 6 1 is available from an unusual reaction in which the ester 60 is subjected to gas-phase pyrolysis; the mechanism probably consists of a tandem ene/[ 1.51-hydride shift sequence.38 60 550 "c 61 4 y-Substituted butenolides 4.1 Simple derivatives A number of approaches to enantiomers of the simplest y-substituted butenolide, Angelicalactone 64 [( S)-enantiomer shown], have been developed which may be more generally useful.For example, the tetronic acid 62 is available in two steps from ethyl L-lactate; reduction of the alkene function1o5, 258 using the borane-ammonia complex and dehydration of the resulting, largely trans-hydroxy-butyrolactone 63 completes the sequence.39 OH OH 62 63 64 292 Contemporary Organic SynthesisOther precursors include y-hydroxymethyl-butenolide derivatives (see below)40 and the hydroxy-sulfone 65, obtained by yeast reduction of the corresponding keto-sulfone.4'.In contrast to the related #?-hydroxy-esters, the derived Frater-type diani0ns~~7 225 do not couple to ally1 bromide with any significant degree of stereoselectivity. Conversion of the separable epimers 66 into lactone 64 then proceeds along conventional lines. The ( + )-( S)-enantiomer 64 has also been prepared from ( L )-tartaric acid by a relatively lengthy route.42 Similarly, a number of routes are available for the elaboration of the useful (S)-hydroxymethyl butenolide 67. Starting with 66 67 ( R )-isopropylideneglyceraldehyde derived from D-mannitol, the necessary homologation can be achieved either by condensation with lithi~acetate~~ or through a cis-selective Wittig reaction.44 The latter route appears to be the more practical.Alternatives include overall oxidative removal of the two secondary functions from the D-ribono- 1,4-lactone derivative 68 by an apparently unprecedented elimination to give a mixture of the acetoxy and bromo derivatives 6945 and the more conventional deoxygenations of D-ribono- 1 $-lactone by pyrolysis of a derived cyclic orth~formate.~'*~~ OAc 68 69 These reports also outline approaches to ( - )-umbelactone206-208 and to lactone 67, starting from the corresponding butyrola~tone,~~ and to the natural butenolide glycoside ranunculin 70, by coupling lactone 6 7 to glucopyranosyl bromide.47 Further methods for effecting this type of bis-deoxygenation, but of ascorbic acid derivatives have been detailed;48 using these methods, useful y-substituted butenolides such as either enantiomer of the epoxides 7 1 can be prepared.49 70 71 Almost inevitably, butenolide 67 has also been prepared by a route which utilizes an asymmetric Sharpless epoxidation as the source of chirality.5o Thus, the epoxy-alcohol72 so obtained reacts with cyanide via a prior Payne rearrangement to give the homologue 73 and thence the target, as its O-benzyl ether.72 73 Closely similar chemistry has been used to obtain the y, y-disubstituted butenolides 74.51 Various methods for preparing the derivatives (75; X = OR, Br, SPh, NR,) have also been described, starting either with the hydroxymethyl lactone 6752 or by condensation of an appropriate epoxide with the dianion of phenylselenoacetic acid.53. 57 74 75 Almost complete stereocontrol is observed in condensations between y-hydroxy-butenofides and chiral N-acetyl thiazolidine thiones, leading to the useful butenolides 76.54 a R 76 4.2 Methods using carbanions Formation of the 2,3-bond using carbanion chemistry is the least common of the three possibilities described in this section.An intramolecular version features cyclization of the readily prepared sulfinyl carbonates 77 using LDA as the base, followed by pyrolytic elimination of the sulfur function, leading to generally excellent yields of the butenolides 78.55 Alternatively, the chloroacrylate 79, available in three steps from propargyl alcohol, reacts sequentially with two equivalents of a Grignard reagent and then lithium metal to give the intermediate vinyl carbanion 80, carboxylation of which leads to the y, y-disubstituted butenolides 8 1 .56 79 80 81 Methods involving formation of the 3,4 bond constitute some of the most generally applicable and useful approaches to butenolides.For example, Knight: Synthetic approaches to butenolides 293condensations between the dianion 82 and an epoxide, which can be homochiral as shown, followed by lactonization [DCC-DMAP] and a facile oxidative elimination of the selenide group lead to the lactones 83 in 70-75% overall yields.57 The analogous sulfur version of this approach was reported some ten years previously and continues to find application^.^^ The same chiral butenolides can also be accessed by yeast reductions of the chloro-keto esters 84; optical purities can be e~cellent.~~ 0 C02Me - u 82 83 84 A rather different way in which the homochiral butenolides 86 can be constructed from an epoxide starts with the epoxy-sulfone 85, also prepared using yeast reduction (but of the corresponding keto-sulfone) to generate the chiral centre,41, 206 and consists of sequential copper-catalysed attack by a Grignard reagent and homologation using i~doacetate,~ as shown.60 A weakness in this approach is the poor returns from the last two steps. 85 86 The sulfoxide analogues 87 of the first formed intermediates in the foregoing method can be generated by reduction of the corresponding keto-sulfoxides.61 Either epimer at the secondary alcohol position can be obtained, depending on the reducing agent and the final products 86 have enantiomeric enrichments in excess of 90%; however, similarly poor yields are obtained in the later, closely related homologation and elimination steps.A rather more efficient sulfur-based procedure is to subject the hydroxy-sulfoxides 87 to a Pummerer rearrangement and then homologate the resulting hydroxy-aldehydes using nucleophilic acetate.62 A sulfoxide rearrangement is also featured in an approach to the disubstituted butenolides 90 by condensations of the aldehydes 88 with sulfinylacetate which lead to the unsaturated esters 89.h3 The sequence is completed by Michael addition of thiophenolate, which allows formation of the corresponding butyrolactone, and elimination. ?- ,S 'Ar a7 88 89 I I 90 A very different approach to the chiral butenolides 83 features attack of a Grignard reagent onto the C,-symmetric imide 91, derived from tartrate, followed by stereoselective borohydride reduction and acidification to give the dihydroxy lactones 92 and finally reductive removal of the two hydroxyl groups (triiodoimidazole, P h,P, Zn); final enantiomeric enrichments can be 2 98°/0.64 Of the many possibilities for constructing a butenolide 78, by formation of the 4,5 bond, perhaps the simplest approach is by condensation of an aldehyde 93 with the acetylide 94, followed by Lindlar hydrogenation.Although conceptually straightforward, the experimental details require close attenti0n.6~ Reduction of 1 -trimethylsilylpropargylic alcohols using Bu'MgBr-Cp,TiCl,( cat.) leads smoothly to the dianionic intermediate 95; subsequent carboxylation and desilylation (TBAF ) provides an alternative.66 The availability of chiral, non-racemic starting alcohols means this approach should be well suited to the asymmetric preparation of y-substituted butenolides 83.R-0 + L i \ _L 78 CO2Et 93 94 +YSiMe3 - - ent -83 BrMgO MgBr 95 The /3-lithio acrolein derivative 96 represents a more reactive example of the same principle; the resulting /3-bromobutenolides 97, obtained following mild acidic hydrolysis and manganese dioxide oxidation, can be debrominated using tin hydride to give the final products 90.",'06 The related dianionic species 98 condenses smoothly with aldehydes leading to /3-sulfonyl butenolides 99; removal of the sulfur function is not described>* 96 97 98 99 A widely used method for preparing butenolides 90 involves condensations between a three carbon unit 294 Contemporary Organic Synthesis100, having a (masked) carboxylic acid function [XI at the distal position, and an aldehyde or ketone, followed by lactonization and oxidative elimination of the sulfur group.- - 90 \X 100 Examples of this include the acid derivative itself 101,6y the 0rthoester102,~~ the related amide dianion 103,71 the ally1 sulfone 104,72 the sulfoxide analogues 10573 and 106,74 and the tris-sulfenyl-propene 107.753 *06 Overall yields using the sulfones 102 and 103 are generally high. 104 PhS L i t PhS SPh 107 ' 3 O M e OMe 102 Lisa 105 R--20 PhS02 108 PhFO2 103 PhSO Li>R 106 Eto2c-o 109 Attempts to achieve asymmetric induction using analogues of the sulfone 103 derived from ( R )-a-methylbenzylamine were not successful but at least the chiral ligand could be used to allow separation of the resulting diastereomers.Much the same is true of the generally less useful chiral sulfoxides 105 and derivatives of sulfoxides 106 where asymmetry is incorporated either at sulfur or the carbonyl position. can be homologated by enolization and reaction with an electrophile. For example, such intermediates derived from y-sulfonyl-butenolides react with allylic or benzylic halides, but not saturated alkyl halides, to give the lactones cleanly removed using tin hydride. Similarly, the lithium enolate of angelica lactone 64 reacts with ethyl acrylate to give the ester 109.77 Unfortunately, in examples both of other electrophiles and isomeric methyl-substituted butenolides, mixtures of products arising from attack at the a- and y-positions are usually obtained.The 'reverse' disconnection is also possible. Thus, ethoxybutenolides (Section 5.2) react with two equivalents of an alkyl lithium in tetrahydrofuran to give the disubstituted butenolides 8 1, after Jones oxidation of the resulting lactol. In favourable circumstances, preformed butenolides The sulfonyl group can be y-Substituted butenolides 78 can be similarly prepared from the corresponding y- hydroxybuten~lide.~~ 4.3 From maleic anhydride/furan Diels-Alder adducts Generally excellent yields of the y, y-disubstituted butenolides 8 1 can be secured by reaction between the half-ester 1 1 1, obtained by methanolysis of the Diels-Alder adduct 110, and an excess of a Grignard reagent followed by cycloreversion at 150 - 1 80"C.7y 0 110 11 1 Prior methanolysis is not necessary as it was later found that the initial anhydride 1 1 077 233, 234 reacts equally well with Grignard reagents.s0 Secondary Grignard reagents tend to add only once, leading to y-monosubstituted butenolides.81 As the dimethyl ester derived from the anhydride 1 10 is a meso-isomer, it is amenable to resolution by selective hydrolysis using porcine liver esterase [PLE]; subsequent regioselective reduction of the resulting half-ester (cf 11 1) affords the chiral butyrolactone 112.Sequential reduction to the corresponding lactol using Dibal-H, reaction with an organometallic nucleophile, Jones oxidation, and cycloreversion gives the chiral y-substituted butenolides 113 in good overall yield and with generally excellent enantiomeric enrichments .8 * 0 112 113 4.4 From furans Homologations of simple butenolides by enolization are not in general particularly productive.76, 77 A much more effective tactic is to begin with a 2-oxyfuran derivative 114 as these often react smoothly and regiospecifically with electrophiles to give good yields of the y-substituted butenolides 11 5 , although a-selective exceptions are known.6 Lewis acids usually feature as catalysts in such reactions and an appropriate choice is important.Illustrative of the method is the rearrangement of the acyloxyfurans 1 16 to the butenolides 1 17 (40-65'74 upon exposure to boron trifluoride etherate.83 114 115 Knight: Synthetic approaches to butenolides 295More generally useful is the finding that the acetyloxyfuran 1 18, produced by anodic oxidation of furan itself, undergoes efficient condensations with aldehydes in the presence of titanium( IV ) chloride to give the y-substituted butenolides 1 19.84 116 117 118 119 In contrast, a similar condensation with acetyl chloride leads to the ylidenebutenolide 120.The corresponding 2-silyloxyfuran 12 1 reacts similarly with orthoesters to give good yields of the acetals 122 and with diethyl acetals to give the corresponding ethers 123.85 OAc 120 EtO OEt OEt 121 122 123 More extensive studies of the synthetic potential of furan 12 1 have revealed that alkylations by allylic halides are best performed using silver trifluoroacetate as the trigger, neatly illustrated by a total synthesis of the natural butenolide freelignite 1 24,*6 but that reactions with aldehydes are best catalysed by triethylsilyl t ~ i f l a t e .~ ~ By a judicious choice of condition~,'~' the latter condensations can be highly stereoselective, leading to either the erythro or the threo (shown) isomers 125, and can be used to obtain y- C-glycosylated butenolides by highly stereoselective condensations with sugar-derived aldehydes or imines.88 Subsequent results suggest that silver triflate is one of the best reagents for effecting alkylations by primary alkyl iodides.*' Being relatively soft nucleophiles, these intermediates are good participants in Michael additions. An example is the preparation of the butenolide 128, an early intermediate in an approach to the mitomycins, by the addition of furan 127 to the enone 126; however, the transformation may not involve a simple Michael addition, but rather a Diels-Alder cycloaddition followed by an acid-catalysed rearrangement.'O Nonetheless, an example of such a Michael addition has been reported in the reaction of 2-methoxyfuran with a cyclic enone, induced by trimethylsilyl iodide?' fl 0 1 24 Ph 125 + 126 127 Ph 128 A variety of furans 129 carrying heteroatomic substituents in an a-position can be oxidized, using hydrogen peroxide or various peracids, to the corresponding butenolides 130.These include borates [ 129; X = B (OMe),],'* selenides ( 129; X = SePh),93 and silanes (129; X = SiMe3).13* 1 4 y 0 4 Often some, or all, of the initial product is the A3-butenolide and so an additional isomerization step is required to reach the final product 130.129 130 A different way in which a furan can be converted into a butenolide is by low temperature photo-oxygenation which leads to the cis-enediones 131; further oxidation with PCC in the presence of trimethylsilyl cyanide leads to the y-cyan0 butenolides 132.95 131 132 Diols 133 which correspond to the foregoing diones, are regioselectively oxidized to y-substituted butenolides 130 by treatment with Fetizon's reagent.Y6 133 4.5 Other methods A somewhat inefficient addition of mercury( 11) chloride to propargylic alcohols leads to the vinyl mercurals 134; a subsequent palladium-catalysed carbonylation step236-243 leading to the chlorobutenolides 135 is, 296 Contemporary Organic Synthesishowever, very efficient.97 Closely related tellurium chemistry can be used to prepare the parent butenolides 90 directly, although only in moderate overall yieldsg8 dianion 14 1, which condenses with aldehydes, leading to the a-methoxy-butenolides 142.Io6 As is often, but not always, the case with this type of chemistry, the rapidity and simplicity compensate for the rather poor yields.67,75, 133,139,16l,170,208-210 134 135 141 142 Chiral y-substituted butenolides 83 can be obtained by acid-catalysed ring closure of chiral 2,3-allenylcarboxylic acids; a limitation with this method is the availability of the starting materials.99 The a-fluoro-butenolides 136 can be obtained by a related process.lo0 136 An overall 5-endo-trig cyclization of methyl 2,3-allenecarboxylates to give the bromobutenolides ( 137; X = Br) can be effected in essentially quantitative yield by using molecular bromine.101 Such cyclizations can also be carried out using many of the other electrophiles usually associatedywith this type of reaction, to give the lactones ( 137; X = HgOAc, I, PhS, PhSe) in variable yields.lo2 This type of cy~lization,~~~? 204, 232 in this case induced by acid, may well be the last step in the formation of the diary1 butenolides 139 from the hydroxy-butenolide 138, using Friedel-Crafts conditions followed by thermolysis in DMF.lo3 Simple y-aryl butenolides can be obtained directly from y-hydroxy-butenolide, but only in moderate yields.lo4 x CI R* Ho*c’ (ii) (I) Ar-H.125 ‘c.AK&- DMF “a: Ar 0 0 137 138 139 During the development of iterative approaches to polypropionates, some potentially useful butenolide chemistry has been exploited, such as the preparation of the y-substituted butenolide 140 from the corresponding tetronic acid by reduction and subsequent eliminati~n.~’. 258 The report also contains some useful preparations of alkoxy-substituted butenolides, the topic of the next section.Ios 140 5 Hydroxy- and alkoxy-substituted butenolides 5.1 a-Hydroxy- and alkoxy-butenolides Direct lithiation of a-methoxyacrylic acid (or derived secondary amides) using t-butyl lithium gives the The related dianion 143 gives rather better returns of the corresponding a-benzyloxy-butenolides; this method was the most successful of a number tried for the synthesis and hence structural proof of the natural acetylamino-butenolide Leptosphaerin 144, carried out by White and his colleagues.1o7 Another dianionic species, the oxazolidinedione 145, is useful as a general precursor to the a-hydroxy- butenolides 147, following condensation with an a-chloro-ketone and hydrolysis of the intermediate 146.1°8 The latter is presumably formed by base-triggered rearrangement of the initial Darzens product.0 145 146 R’ I R2eoH 0 147 An alternative approach to a-methoxy-butenolides 149 is by acid-catalysed cyclization of the acetylacetone derivatives 148; the mechanism appears to involve a [ 1.3)-hydride shift.Io9 A double carbonylation of styrene, using dicobalt octacarbonyl as the catalyst under phase transfer conditions, leads to the a-hydroxy-butenolide 150 in 65% yield; further studies are needed to fully define the utility of this reaction.A more general approach to this type of /?-substituted hydroxy-butenolide 152 consists of condensation of the a-oxodiesters 15 1 with formaldehyde, palladium( 0)-catalysed cleavage of the ally1 esters, and decarboxylation. Knight: Synthetic approaches to butenolides 297298 9' R' 148 149 kOH 150 R a Pd" &OH HCOflH, \' 0 151 152 No discussion of P-hydroxy- or alkoxy-butenolides is given here as these are the tetronic acids and derivatives, a separate class of compound which is beyond the scope of this review. 5.2 y-Hydroxy- and alkoxy-butenolides 5.2.1 From furans Photo-oxygenation of furan derivatives is one of the most popular ways of preparing y-hydroxy- butenolides.For example, such a reaction of the furfurals 153 l 2 or the corresponding furoic acids' l 3 leads to the lactones 154 in - 70% yields.' l 2 Rose bengal immobilized on Sephadex A25 is an especially useful sensitizer in these cases. Similarly, furfuryl alcohol can be converted into the parent y-hydroxy-butenolide in 97% yield.'12 153 154 Other unsaturated functions can be tolerated and when the oxidations are carried out in methanol, y-methoxybutenolides are produced, as illustrated by the conversion of furan 155 into the lactone 156.114 155 156 Problems of regioselectivity arise when 3-substituted or unsymmetrical 3,4-disubstituted furans are subjected to this type of oxidation; however, various carbonyl functions can act as effective control elements.' l 5 Undoubtedly, the major recent advance in this area has been the discovery that an a-trimethylsilyl group, when incorporated into the furan (e.g.157),'3314794 Contemporary Organic Synthesis facilitates each step of the sequence, especially the now regiospecific collapse of the intermediate endoperoxide, leading to the final producs 158.'16 (See also reference 123). This means that such silylfurans can serve as masked y-hydroxy-butenolides during a synthetic sequence; the final step of a total synthesis of manoalide 159 as well as of (E)-neomanoalide was just such a sequence.' l7 159 However, in some cases, it will no doubt be troublesome to incorporate the silicon function regioselectively. It is therefore interesting that a method has been developed for the regiospecific photo-oxygenation of 3-alkylfurans 160 to the lactones 16 1 .I l 8 The key is to induce decomposition of the intermediate endoperoxide using a highly hindered base which will only abstract the less sterically encumbered proton.This tactic has been successfully applied to syntheses of furodysinin lactone 162 and to relatives of manoalide 1 59.22 1 62 A number of other oxidative methods have also been used to convert furan derivatives into y-hydroxy-butenolides. These include treatment of the bromofurfuryl alcohols 163 with pyridinium chlorochromate (PCC), resulting in the formation of the y-hydroxy-butenolides 164 in 60-75% yields;' l9 Jones oxidation of the p-D-ribofuranosyl derivate 165 to give the C-nucleoside precursor 166 in 93% yield;'*O and oxidation of trimethylsilyloxyfurans 12 1 to y-acy10xy-l~~ and -sulfonyloxy-butenolides by treatment with iodosobenzene and the appropriate acid.'OH OH 1 63 164 BzO OBz BzO OBz 1 65 166 A rather different way in which such furans can be transformed into y-hydroxy-butenolides 164 is to use a version of the Lewis acid catalysed condensation reaction 1 14 -+ 11 5,85-89 but starting with the bis-( sily1oxy)furan 167, derived from a succinic anhydride.' 22 164 T E 4 OSi - I 167 A rather different approach to the hydroxy-butenolides 158 starts from the furan oxidation product 168 and involves sequential ozonolysis and Wittig homologation, leading to the dienes 169. Subsequent, rather brutal, acidolysis then gives the final products 158 in - 60% overall yields, along with the corresponding (E)-aldehyd~-acid.'~~ MeOQ OMe 168 5.2.2 Other methods COPE1 Me0 OMe 169 5m HCI dioxan 100 "c, 2h 1 158 Carbonylations of terminal alkynes which use dicobalt octacarbonyl as the catalyst in the presence of iodomethane to yield the y-hydroxy-butenolides 170 are best carried out using solid-liquid phase transfer conditions124 rather than those originally r e ~ 0 r t e d .l ~ ~ Attempts to use other alkylating agents have only been partially successful. Symmetrical alkynes can similarly be converted into the alkoxy-butenolides 17 1, but using a rhodium carbonyl ~ a t a l y s t ~ ~ ~ , ~ ~ * in the presence of an alcohol, R20H.126 R' R20 --&: 1 70 171 Methods for introducing the y-hydroxy-butenolide function into the naturally occurring germination stimulant strigol 172 all rely on enolate alkylation by the sodium salt of y-bromo-a-methyl-b~tenolide,~~~ the potassium salt in the presence of HMPA,128 or improvements of these.129 172 A variety of other heterosubstituted butenolides can be obtained from the parent y-hydroxy- or alkoxy-butenolides.Lewis acid catalysed exchange of the latter with ethanethiol leads to the thiol derivative 1 73130 whereas a Michael addition-elimination sequence can be used to prepare the p-amino- or thio-derivatives ( 174; X = R'N or S ) from the corresponding halobutenolides.' 31 A useful enolate can be generated from the thiol derivative 173, which reacts with differing regioselectivities depending upon the electrophile used.Thus, reactions with aldehydes give the a-substituted homologues 175 whereas additions to Michael acceptors lead to the y-substituted butenolides 1 76.132 RX OH '"q E t s e R 0 0 0 173 1 74 175 0 176 The natural y-hydroxy-butenolide lepichlorin 17 7 has been prepared by a route which features /3-lithioacrylate chemistry.133 As outlined above,lo6 such methodology while usually very brief is often rather ineffecient; this example is no exception. " H T 177 As both y-hydroxy- and y-alkyloxy-butenolides are readily reduced to the corresponding y-unsubstituted analogues using, for example, sodium borohydride, the foregoing methods could all in principle be of use in the preparation of butenolides in general. 6 Butenolides substituted with alkoxycarbonyl groups Starting from butyrolactone 178, the a-methoxycarbonyl butenolide 179 is best prepared Knight: Synthetic approaches to butenolides 299by sequential condensations with dimethyl carbonate and the relatively more reactive thiophenylation reagent S-phenyl benzenesulfonothioate, PhSSO,Ph, followed by oxidative elimination of the sulfur group.134 Alternatively, the ylidenemalonates 180 undergo smooth elimination of bromomethane upon thermolysis in xylene to provide y, y-disubstituted homologues of lactone 179.135 178 179 180 A more convoluted approach begins with addition of malonte to the allenic sulfoxides 18 1; subsequent [ 2.31-sigmatropic rearrangement of the resulting adduct 182 leads to the hydroxy diesters 183 and thence, upon lactonization and isomerization, to a-methoxycarbonyl butenolides.' 36 181 182 183 P-Alkoxycarbonyl butenolides 184 are readily obtained in general by starting with a P-keto-ester which is alkylated using an a-bromo-acid; subsequent dehydrative cyclization and isomerization completes this a ~ p r 0 a c h .l ~ ~ A natural product containing this structural feature is methyl lichensterinate 185; a synthesis has as a key step the Lewis acid catalysed condensation of methyl a-ketopalmitate with (diethylamino)propyne'91-'93 to give the amide 186. The synthesis is completed by allylic bromination and bicarbonate induced cyclization.' 3x The fumarate derived vinyl anions [ 187; R = NR2, OR' or SR']l''h condense with aldehydes to give /I-methoxycarbonyl butenolides directly in 30-83% yields.'39 184 185 Me02C C02Me M.'CH2h2+ Li+R CONE12 C02Me 186 187 7 Ylidenebutenolides The simplest member of this group, the naturally occurring protanemonin 188, can be obtained from 5-hydroxymethylfurfural by sequential photo-oxygenation, borohydride reduction,18 and deh~drati0n.l~~ The y-substituted butenolides 189 are easily prepared by tin( IV) chloride-catalysed condensations of the a-silyloxyfuran 12 1 with aldehydes;87 dehydration brought about by treatment with tosic acid in hot benzene leads to the ylidenebutenolides 190 in excellent overall ~ie1ds.l~~ OH 188 189 1 90 Ylidenebutenolides 190 can also be obtained in ca.70% yields from the alkoxyfurans ( 19 1; R = Me) by treatment with zinc bromide142 or from the corresponding methyl ethers using trimethylsilyl iodide.143 The latter method has been used to prepare bovolide 192, a butter flavour component.R% OR 191 1 92 As an alternative to the foregoing Lewis acid induced preparation of lactones 189, the related furans (191; R = But) can be obtained from the corresponding lithiofuran and an aldehyde or ketone; conversion to butenolides 190, in 44-81% overall yields, simply requires treatment with tosic acid in aqueous tetrah~dr0furan.l~~ a-Stannylfurans can be oxidized, via an intermediate y-acetoxybutenolide,121 to butenolides 190 using lead(1v ) acetate.145 In extreme cases, no substituents are necessary on the furan ring to facilitate oxidation; the tertiary carbinols 193 are converted directly into the corresponding ylidenebutenolides using PDC in DMF.14h Yields are only high, however, when both chain substituents are aryl groups.Related hydroxyalkylfurans can also be oxidized using phenylselenenyl chloride, apparently by a rather convoluted mechanism.147 193 Dehydrobromination is another way of generating an ylidenebutenolide, as in the case of the potentially useful bromo derivative 194; the intermediate butenolide was prepared by starting with an effectively 5-endo-trig bromolactonization9Y-102. lh4, 204, 232 of the corresponding 2,3-allenyl ester.14x 300 Contemporary Organic Synthesis194 Phosphonium salts derived from butenolides offer an alternative but often non-stereoselective entry into ylidenebutenolides. An example is the preparation of the retinoic acid analogue 196, using the ylide derived from the salt 195.14’ 195 196 The lactone double bond can also be prepared via an intramolecular Wittig reaction.Thus, addition of an enolizable a-diketone to the salt 198, followed by cyclization, leads to the useful ‘~emi-protected~~~’ ylidenebutenolides 197 in respectable yields.15o OEt P h $ y o E * R3 OEt 6Et 197 198 In the reverse sense, to the use of ylides from salt 195, ylidenebutenolides 199 are available from condensations between stabilized phosphorylides and maleic anhydrides. In the case of ( 199; R = OBu‘), the corresponding, relatively unstable, carboxylic acid can be obtained by treatment with mineral acid,151 while the thiolates ( 199; R = MeS), obtained in the same manner, can be desulfurized, using Raney nickel, to give the lactones 190 as isomeric mixtures.152 In examples of unsymmetrical anhydrides, attack usually occurs regioselectively to give the isomers 200.’53 ‘m R 0 2 C q R 0 0 1 99 200 A rather lengthy route to ylidenebutenolides 190 has, as a key intermediate, the phosphonate 201, obtained by a [ 1.31-dipolar addition reaction.Subsequent N-0 bond cleavage, hydrolysis, and olefination leads to the esters 202 and thence to the final products (after borohydride reduction, cyclization, and dehydration).’ 54 0 N-0 0 OH 201 202 190 A further application of Bestmann’s ketenylidene phosphorane chemi~try~~-~* is in the direct formation of cyclic and acyclic butenolides 205 by condensations between enolizable 1,2-diones 203 and the phosphorane 204.155 Usually, good to excellent yields are obtained. 203 204 -0 205 A Wadsworth-Emmons homologation is a key step in the preparation of the epoxy-ester 206, the penultimate precursor of ( f )-8,9-dehydroasterolide 207.156 Related lithio-sulfone chemistry has proven suitable for the elaboration of the carotenoid-based ylidenebutenolides 208 (R = polyene chain) in which the vital alkene functions are generated by facile elimination of benzenesulfinic acid.157 206 207 “0- 208 The rather labile ylidenebutenolide 209 and related, ring-fused, structures are available from condensations between morpholine enamines and ketomalonates followed by cyclization of the resulting alcohols.158 Such products are often useful as Michael acceptors.Michael reactions are especially important for the preparation of examples of ring-fused butenolides in general, including ylidenebutenolides. Particularly useful in this respect is the P-vinylbutenolide 2 1 0,178 which condenses smoothly with /3-dicarbonyls to give, for example, the tricyclic system 2 1 1, following dehydration.’ 59 Another useful aspect of this type of product is that the corresponding sulfoxides readily rearrange to the transposed alcohols 212.A total synthesis of the phytoalexin lettucenin A featured as a central, but somewhat inefficient, step the radical-mediated rearrangement of the dibromomethyl dienone 213 to the hydroazulene 214, a ring expansion method developed some time ago by Barton’s group. 160 the synthesis of ylidenebutenolides by condensations of the weakly nucleophilic anion 2 15 with acid chlorides to give the lactones 216.161 Once again,lo6 yields are only moderate but the method is rapid and relatively simple.13-Lithioacrylate chemistrylo6 can also be applied to Knight: Synthetic approaches to butenolides 301302 \ kSPh 21 0 +co2Et 209 QSPh 0 21 1 (0 MCPBA (ii) NaHC03 I qH 0 0 21 2 Br \ Bu3SnH AIBN - I + Qio I 21 3 21 4 I C02Me 21 5 o--& 0 21 6 0 Cyclizations of acetylenic or allenic acids also constitute important approaches to ylidenebutenolides. For example, exposure of the enynoic acids 2 17 to mercuric oxide in hot DMF gives good yields of the corresponding lactones 2 21 7 21 8 Direct thermolysis in o-dichlorobenzene can also be used to effect such cyclizations when the substrates are ylidenemalonic acids.163 Ylidenebutenolides can be prepared from 3,4-allenecarboxylic acids by 5-exo-trig-iodolactonization,””02. ,04, 232 presumably followed by in situ e1iminati0n.l~~ The diary1 butenolides 220 can be obtained from the dienoic acids 2 19, prepared from an a-bromocinnamaldehyde and an arylacetic acid, by treatment with base.16s Contemporary Organic Synthesis __._c .-- I Br A? 0-6 0 21 9 220 A synthetic equivalent of the putative anion 22 1 is the dianion 222; following reaction with an electrophile (E), the resulting acid is subjected to iodolactonization and separate elimination steps to give the final products 223.166 These products could be useful as Michael acceptors in further syntheses.221 222 223 A final route to butenolides 190 is by reactions between trichloroacetic acid and 1 -alkenes, mediated by RuCl,(PPh,),; the initial products are a , a-dichlorobutyrolactones. 167 8 Ring-fused butenolides Cation-mediated cyclization of geranylphenyl sulfone leads to the cyclohexanol224; subsequent carboxylation, lactonization, and elimination completes this straightforward approach to the actinidiolide derivative 225.1b8 = p o S02Ph 224 225 Acid catalysis also plays a key role in a synthesis of 8,9-deoxyalliacol B 227 from the hydroxy-acid 226.169 More general approaches to ring-fused butenolides include a further application of /3-lithioacrylamide chemistrylo6 in which the vinyl anion 228 is condensed with carbonyls to give the adducts 229 directly,”O and a radical cyclization in which treatment of the acetylene 230 with the usual tributyltin hydride/AIBN combination leads to the butenolides 232 following oxidation and isomerization, for which rhodium trichloridelO is a particularly suitable catalyst,171 of the initially formed tetrahydrofuran 23 1.172 Both methods are generally efficient throughout, at least with these relatively simple examples.p C02H H30+* p OH OH 226 227 228 229230 231 232 An initial model established the viability of a novel approach to annulated butenolides and furans by intramolecular Diels-Alder cyclization of an acetylenic oxazole (e.g. 233) which leads to the furan 234, following expulsion of acetonitrile from the initial cycloadduct. In this particular example, acid-catalysed hydrolysis also results in rearrangement to the butenolide 235.174 233 234 lHi 0-d0 K 235 The potential of this methodology is demonstrated in syntheses of the norsecurinine precursor 237 from the initial cycloadduct 236, this time without rearrangement, and of the precursor 238 to paniculide A 239.175 As is often the case, the synthesis was completed only after some of the more obvious options failed.OMe 0 'Oki + I 'obi+ I 236 237 238 239 A key step in a different approach to the more highly oxygenated paniculides B and C relies on hydroxide-directed attack of dilithioacetate onto the epoxy alcohol 240, to give the butyrolactone 241.176 Subsequent, established chemistry then leads to the known precursor 24 2 MOMO MOMO 240 241 &i + / \ 242 The highly electrophilic Michael butenolide 2 has also been used as a precursor to the Paniculides 239 by condensation with the malonaldehyde 243 followed by rearrangementls9 of the initial adduct 244 to the later intermediate 245.'78 SPh DMSO Me02C OH Me02C DMF 243 244 OH M e O p C 245 The same idea, but using the alternative Michael acceptor 247, has been used to obtain the furoventalene precursor 248 from the malonaldehyde derivative 246.17y Similarly, the useful sesquiterpene precursors 249 have been prepared from /l-vinylbutenolide itself and Q -e t hoxy c arbon y lc y clo hexanone s .8o C02Me I 246 247 248 249 '0 Knight: Synthetic approaches to butenolides 303Generally, the foregoing Michael chemistry is not especially efficient, but relatively advanced precursors are produced from two much simpler reactants. A different type of Michael addition using the y-methylenebutenolide 250 as the acceptor has been used to prepare the elemane and eudesmane precursor 251.18' c02Me 250 TiCI, m o OH C02Me 251 A simple approach to annulated butenolides 253 is by Wadsworth-Emmons homologation of the corresponding epoxy-ketone 252;' 56 however, only the (2)-isomer of the intermediate mixture of alkenes cyclizes to the lactone.182 252 253 Less ambiguous is the intramolecular version exemplified in the conversion of the phosphonate 254 into jolkinolide E 255.183 The precursors 254 are best obtained from the corresponding a-hydroxyketones using a mixed anhydride formed from a phosphonoacetic acid and TFAA,lg4 although an alternative approach starts with a methyl vinyl ketone function; sequential oxidation by manganese( 111) acetate in the presence of chloroacetic acid leads to the key hydroxyketone derivatives.185 0 0 254 255 Sulfur chemistry plays a key role in a number of approaches to annulated butenolides.An unusual route to annulated butenolides (e.g. 257) features a vinylogous Pummerer rearrangement of a sulfinyl ester (e.g 256); extensions to more highly substituted systems could suffer from problems of regioselec tivity.186 q i i h A. H30+ Dioxan C02Me 256 257 A more general approach begins with the preparation of an a-thiomethylene ketone 258 which is homologated using phenylthiomethyl lithium. Pummerer rearrangement of the sulfoxide derived from the resulting thiomethyl aldehyde 259 leads to the corresponding furan 260 and thence to the butenolide 26 1 following slow acid hydr01ysis.l~~ Applications of this methodology include preparations of isodrimenin 262 and the coloratadienolide 263.BUS p - oBph 258 259 I1 t 261 260 0 0 %-? -0 262 263 An alternative method for the homologation of thiomethylene ketones 258 is to use dimethylsulfonium methylide; the resulting thiolactols are then easily converted into the corresponding furans (e.g. euryfuran, 264). Treatment of the latter with bromine in methanol leads largely to drimenin, while photo-oxygenation' occurs regioselectively to give valdiviolide 265 (R = OH).18s 264 Photo-oxygenation is the key step in a related approach to confertifolin 265 (R = H) from the diene 266; unfortunately, the yield is only 20°/~.189 The Diels-Alder adduct 267 is also a useful precursor to both Isodrimenin 262 and fragrolide 268.190 (diethylamino)propyne, catalysed by magnesium bromide, is a useful method for the preparation of unsaturated amides, which can be used as precursors to b~ten0lides.l~~ When 2,3-epoxycycloalkanones are the starting materials, the resulting amides (e.g.269) can be readily converted into a variety of butenolides The condensation of ketones with 270-272."' 304 Contemporary Organic Synthesisrp R 265 266 & O 2 k @ 0 0 267 268 270 I 269 272 271 I ,,e methodology has been useb to synthesize ( + )-eremophilenolide 2731q2 and can be extended to include the conversion of a-silyloxyketones (e.g. 274) into annulated butenolides 275.1q3 273 274 275 A somewhat related route has been used to obtain the mintlactone isomers 278 by sequential deconjugative methylation of the unsaturated ester 2 76, epoxidation, and base-induced rearrangement of the resulting epoxy ester 277.1q4 276 (I) LDA, Me1 (ii) MCPBA 277 LDA, HMPA 1 278 During the early stages of a total synthesis of marasmic acid, the ring system 280 was established by an intramolecular Diels-Alder reaction of the B-alkenylbutenolide 2 79, followed by base-catalysed i~omerization.'~~ The precursor was prepared using the phosphonate 28 1, which will be of value in other syntheses as well as complementing the corresponding Wittig method using salt 30.1q.20 279 O= P(OEt)2 ko 0 281 AcO 280 A much more unusual Diels-Alder cyclization in which a phenyl group acts as the diene has been used to obtain the annulated butenolides 283 by heating the allenic esters 282 in xylene.lY6 A2 282 ;12 283 A photochemical [2 + 21 cycloaddition between cyclobutene- 1 -carboxylic acid and ( + )-isopiperitenone is a key feature of a neat synthesis of the isoaristolactone isomer 286.Reduction of the initial photoadduct 284 leads to the lactone 285 which undergoes a thermal electrocyclic ring-opening to give the final product in 26% overall yield.197 Knight: Synthetic approaches to butenolides 305I I _ . NaCNBH- r-w 284 285 0 Q 286 ( k )-arktolactone itself (290) has been obtained by a clever application of a [ 2.31-Wittig rearrangement in which the cyclic ether 287 is converted into the cyclic enyne 288. Subsequent Mitsunobu inversion, alkyne reduction using Red-Al, and trapping of the resulting vinylalane using N-iodosuccinimide leads to the penultimate precursor 289, ~arbonylation~~~ of which completes the synthesis.lY8 287 288 290 289 Thus, authentic isoaristolactone differs from aristolactone 290 in the configuration of the alkene function; the latter can be transformed into the former by exposure to dilute acid.lY7 Routes to spiro-butenolides are detailed below; lower homologues can serve as precursors to ring-fused butenolides as in the Lewis acid catalysed rearrangement of the spiro-B-lactones 291 to the a-chlorobutenolides 292 .IY9 291 292 9 Spiro-butenolides Clearly, many of the foregoing methods could be adapted to the elaboration of spiro-butenolides; the following are approaches specifically designed to produce this type of lactone.The useful lithio-propynoate 946s condenses smoothly with cycloalkanones to provide the adducts 293; a subsequent Michael addition/trapping sequence leads to the spiro-lactones ( e g 294) in good yields .200 293 294 Unsubstituted spiro-butenolides can be similarly prepared from cycloalkenones by reaction with the dianion of 3-phenylsulfinyl-propionic acid followed by elimination, but not in especially good overall yields.*"l Radical cycli~ations~~~ 72, 227, 228 can also be used to access such butenolides, as illustrated by a synthesis of ( k )-andirolactone 297 from the mixed acetal295; Jones oxidation of the intermediate acetal296, obtained in ca.70% yield, and isomerization'O by silica gel completes the sequence.202 295 296 297 Essentially the same cyclization can be carried out using the corresponding bromo ester, mediated either phot~chemically~~~ or by tin h~dride/AIBN.~~~ An isolated example (298 + 299) indicates that iodocyclizations of allenecarboxamidesYY-102~ 14*9 1643 232 could be a useful route to functionalized spiro-buten~lides.~~~ 298 299 10 Multi-substituted butenolides As is the case in the foregoing section, many of the methods outlined above could be extended to include examples of polysubstituted butenolides.The following are procedures which have largely only been or can only be applied to such targets. Some synthetically useful bromobutenolides can be prepared by allylic bromination of the corresponding methylbutenolides; these include the y-bromo 306 Contemporary Organic Synthesisderivative 300 and the a-methyl isomer, together with the bromomethyl derivatives 301 and 3O2,l9y2O the Aldol reactions between a lithio- or O-silyl-enolate and an a-keto-acetal lead to the adducts 312; latter being best prepared from methyl ~enecioate.~~~ The yeast reduction product 303,41 obtained, essentially optically pure, successfully undergoes sequential, but non-stereoselective, a l k y l a t i ~ n s ~ ~ , ~ ~ by iodomethane and sodium iodoacetate to give ( R )-umbelactone 304,46 following lactonization and elimination, in 30% overall yield.206 Other approaches to the latter, as the racemate, include acid-induced rearrangement of the corresponding epo~y-enoate,~~~ and a relatively efficient condensation of the p-lithioacrylate 305 (R' = H; R2 = Me)lo6 with benzyloxyethanal.208 I f Br BfQ 0 Y p 0 Qo 300 30 1 302 303 304 305 Approaches based on the intermediacy of the corresponding /3-bromo dianion 306 followed by Michael addition/elimination to introduce the P-methyl substituent are less attractive due to the poor yields obtained in the last step.The foregoing is but a single example of a much more general approach in which dianions 305 are reacted with aldehydes or ketones to give polysubstituted butenolides 307 in 40-60% isolated yields.209 The related B-lithioamide 308 is similarly useful in butenolide synthesis;lo6 perhaps surprisingly, this intermediate is generated directly from the parent amide using lithium tetramethylpiperidide (LTMP) without competition from deprotonation at the a-site of the furan.210 306 307 308 A different way to construct an a,y-disubstituted butenolide 31 1 has the chlorosulfone 309 as the starting material.Michael additions of lithiostannane and condensation with an aldehyde, R2CH0, leads, after elimination, to the vinylstannane 310, carboxylation of which, by tin-lithium exchange,239 completes the sequence.21 309 31 0 31 1 subsequent acid-cat alysed reorganization provides another approach to the butenolides 3 1 1. Both steps proceed in - 70% yield.212 A related but slightly less efficient route has the alkylation of an acid enolate using an a-chloro acetal as the key step.213 31 2 Related to this are condensations between the dianion derived from the bis-sulfenyl species 3 13 and ketones; methanolysis aided by silver nitrate completes this efficient preparation of the potentially useful butenolides 3 14.214 31 3 31 4 Formation of the butenolide alkene linkage by an aldol-type condensation has been further exploited in a synthesis of the hydroxyethyl butenolide 3 15 from 2-deoxy-~-ribose,~'~ and in a preparation of the a-thiobutenolides 3 16 from an a-acetoxy aldehyde and the lithium enolate of ethyl phenylthioacetate.2 l6 31 5 31 6 Intramolecular variants are also useful, as in the synthesis of the a-arylbutenolides 3 18 from the esters 3 17, the latter being available from the corresponding arylacetic acid by esterification using an a-halo ketone.21 A similar intramolecular aldol condensation provides the useful phosphonates 3 19 from the corresponding propionates.218 31 7 31 8 31 9 Palladium (0)-induced cyclizations of the a-mercurio esters 320 lead to good yields of the butenolides 32 1; unfortunately, a stoichiometric quantity of the palladium reagent Li2PdC14 is required.219 A similar disconnection, but featuring an intramolecular Michael addition, can be used to obtain the butenolide precursors 322.220 Knight: Synthetic approaches to butenolides 307320 321 322 Another viable method for formation of the alkene bond in a butenolide is by reactions between an a-seleno- or a-sulfenyl-carboxylate enolate (e.g.82) and an e p o ~ i d e . ~ ~ + ~ ~ This method can be extended to include most types of substituted butenolides, starting from the initial adducts 323.221 For example, simple oxidative elimination of sulfur provides a , y-disubstituted butenolides whereas, when R2 = H, Pummerer rearrangement of the derived sulfoxide leads to the useful Michael acceptor 324, allowing the preparation of both /3,y-326 and a,#?, y-substituted analogues.R2 R'Tph "'-QSPh 0 323 324 More highly substituted homologues of the a-sulfenyl butenolides 324 can be obtained by intramolecular Wadsworth-Emmons condensations.222 Closely related to this is the extremely efficient Lewis acid catalysed thioalkylation of ketene bis-( trimethylsilyl)acetals.223 The sulfmyl analogues of a-sulfenyl butenolides 324 have also been prepared but by a rather different sequence which proceeds by way of a vinyl sulfoxide.224 A reverse way to construct the same bond is by homologation of the a-phenylthioketone anions 325 using iod~acetate;~~~ 41, 206 subsequent borohydride reduction and, again, oxidative elimination of the thiol group completes this efficient approach to B,y-substituted butenolides 326.22s phsf-o R2ao R' R2 325 326 Manganese( 111) acetate can be used to induce the addition of a variety of esters to unactivated alkenes; when a-chloro esters are used, a-halobutyrolactones are obtained and thence butenolides following elimination from the corresponding iodolactone.226 Unfortunately, the yields are not spectacular, especially from the initial addition (33-53%).What are now regarded as more standard radical processes are generally more productive. For example, the usual combination of tributyltin hydride and AIBN is highly suited to the transformation of the a-bromo-esters 327 into the /3-methylene-lactones 328,2039 227 which can easily be isomerized'" to the corresponding butenolides. Under similar conditions, the acetals 329 cyclize to give the alternative butenolide precursors 330.228 Anodic oxidation of the /3, y-unsaturated esters 33 1 is effective as a route to the polysubstituted butenolides 332 only when the /3-substituent is an aryl group.22Y 329 330 Ar A: 331 332 Bromolactonization of the readily available vinylmalonates 333 leads smoothly to the #?-bromobutyrolactones 334; degradation to the corresponding a , y-disubstituted butenolides 3 1 1 occurs slowly upon exposure to sodium iodide in hot 3-pentan0ne.~~" The method has been exemplified by a preparation of the natural butenolide acarenoic acid 335.A detailed study has been performed on related eliminations from a-bromobutyrolactones.23 Cyclizationyy-'02~ 1649 204 of the phenyl substituted allene carboxylic acids 336 requires only an acid catalyst to give good yields of the butenolides 337 although with hydrogen bromide the potentially useful /3-bromo derivatives 338 are obtained.232 336 337 338 A combination of methods7.7y-81 for homologation of the Diels-Alder adduct 6 represents an efficient approach to the trisubstituted butenolides 339233 and also, to the chiral y-methyl derivatives 340.234 308 Contemporary Organic Synthesis0 6 339 H*QR 0 340 The dimethyl derivative 340 (R= Me) is a component of mushroom flavour while the butyl analogue is one of the volatile Streptomyces lactones. A general approach to these, as racemates rac-340, features homologation of the methylene dioxane 34 1 by sequential deprotonation, using BusLi, and reaction with acetaldehyde and an alkyl halide to give the alcohols 342.235 Overall, this sequence can be summarized by the hypothetical dianion 343.341 342 -Y- '0 343 As already described, various acetylenes are the starting materials in many viable approaches to butenolides. A further example is a very simple route to disubstituted butenolides 345 by the addition of Grignard reagents to propargylic alcohols 344, followed by carb~xylation.~~~ Y1 9' 344 345 An attractive alternative consists of hydride reduction of a secondary propargylic alcohol 346 and iodination of the resulting vinylalane which leads to the (2)-iodo-alcohols 347 and thence to the a, y-disubstituted butenolides 3 1 1 lY8 following palladium( 0)-cataly sed ~arbonylation.~~~ 346 347 Propargylic alcohols can also be converted into butenolides 3 1 1 by regioselective hydrozirconation and carbonylation in 50-70% overall yields,238 or by formation of an intermediate vinylstannane.21 ' 9 239 Reaction between a disubstituted alkyne 348, an acid chloride, and NaCo( CO), followed by acidolysis of the resulting cobalt complex leads directly to the butenolides 349.240 Regioselection is clearly a problem with unsymmetrical alkynes although both phenyl and t-butyl groups are placed largely in the a-position of the final butenolide when in competition with methyl substituents in the acetylenic substrate.348 v 349 A remarkable triple carbonylation occurs in the conversion of the epoxy alcohol 350 into the butenolide 35 1 under phase transfer conditions.241 Unfortunately, a similar yield ( - 35%) of the product of single carbonylation 352 is obtained.HO 350 1 351 352 A neat way to exploit the power of palladium( 0)-catalysed carbonylation reactions is in the conversion of the vinyl triflates 353 into a,@-disubstituted butenolides 354.242 An especially attractive feature is that the triflates 353 are derived from the corresponding B-keto esters in two steps. 353 354 The vinyl manganese species 355, formed by sequential insertion of carbon monoxide and a 1-alkyne into an alkylmanganese pentacarbonyl complex, are similarly The same overall transformation can be carried out using an acylpentacarbonyl chromate and a l-alk~ne.~~, A significant feature of many of these methods, especially the latter, is the non-acidic nature of the required conditions.*lmR2 0 Mn(CO), 355 Knight: Synthetic approaches to butenolides 309Michael additions of Grignard reagents or lithium divinylcuprates to the ynoates 356, (cf reference 37) obtained using lithiopropynoate 94,(j5 constitutes a general approach to the B, y-disubstituted butenolides 357,245 while palladium-catalysed a-arylation of these intermediates gives variable yields (32-93%) of the a-arylbutenolides 3 1 1 ( R1 = Ar).246 356 357 A direct conversion of internal alkynes into a,B-disubstituted butenolides using the water gas shift reaction will probably only be useful for the elaboration of symmetrically substituted species.247 More highly substituted analogues can be prepared by a related method in which the carbonylation126 is carried out in the presence of a 1-alkene and with similar limitations.248 The foregoing drawbacks also apply to a very simple method for the conversion of aldehydes (RCH,CHO) into a,P-disubstituted butenolides 345 ( R1 = R2) by exposure to carbon monoxide in sulfuric acid; the first step is presumably an aldol conden~ation.~~' The readily available ketene dithioacetals 358 can be epoxidized using dimethylsulfonium methylide188 leading, after rearrangement, to the potentially useful and partly protected150 forms, 359, of the corresponding a,P-disubstituted butenolides 360.250 Mild acid treatment of the intermediates 359 generates the corresponding f ~ r a n ' * ~ which can be alkylated at the remaining free a-position, allowing the preparation of a$, y-trisubstituted homologues.R2 F2 358 359 360 Epoxides also feature in other routes to butenolides. For example, exposure of the diepoxy-ester 361 to HCl or HBr in DMF leads to the dihalo-butenolides 362251 while a related acid-catalysed rearrangement of the /3-lactams 363 results in formation of the aminomethyl-lactones 364.252 R2 F2 361 362 R' R' $%Nph R 2 q N H P h 0 363 364 1,l -Disubstituted alkenes 365 participate in reactions with a-oxocarboxylic acids 366 under (Lewis) acidic conditions, leading eventually to a , y, y-trisubstituted butenolides 367 in moderate yields which are somewhat offset by the simplicity of the method.253 R' R2 R' +o H02C k + R' PqR2 367 Baeyer-Villiger oxidation is effective for the conversion of the cyclobutenones 368 into the corresponding butenolides 369.254 The enones 368 are obtained from cycloadditions of alkynes to keteniminium salts derived from tertiary amides.368 369 Although somewhat limited in its scope, a mechanistically interesting butenolide synthesis is the conversion of diphenylcyclopropenone 370 into the a,B-diphenyl butenolides 37 1 by condensation with the sodium salt of an a~etoacetate.~~~ Pt qrn M=J* Y - O Me02C 370 371 Similar reactions with sodiomalonate lead to ylidenebutenolides. A useful but again somewhat restricted photochemical rearrangement is illustrated by the transformation of the a , y, y-trisubstituted butenolide 372 into the corresponding a$, y-isomer 373.256 At At P h q p h - hv ph%ph 372 373 Finally, two methods which approach butenolides from opposite ends of the oxidation scale: the silyl enol ether 374 can be converted into the butenolide 375 in an example of a more general reaction whereby unsaturation can be introduced into such 310 Contemporary Organic Synthesisintermediates by treatment with an ally1 carbonate and a palladium catalyst, while sequential hydrogenat ion and dehydration3Y! lo5 of the tetronic acid 376 is an efficient way to obtain the butenolide 377.258 374 375 ?H (i) Raney Ni (ii) TsCl Et3N OSiMe3 OMW 376 377 The tetronic acid was prepared using an intramolecular Grignard reaction; however, discussion of this class of hydroxy-butenolides is beyond the scope of this present review! 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 References Y.S.Rao, Chem. 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ISSN:1350-4894    

DOI:10.1039/CO9940100287

出版商:RSC    

年代:1994

数据来源: RSC