摘要:

317 339 367 387 417 433 457 475 Recent developments in asymmetric aldol methodology Alison S. Franklin and Ian Paterson Reviewing the literature published up to the end of 1993 Main group organometallics in synthesis Martin Wills Reviewing the literature published between July 1992 and December 1993 Synthesis of materials for molecular electronic applications Martin C. Grossel and Simon C. Weston Reviewing the literature published between mid-1 992 and December 1993 Control of asymmetry through conjugate addition reactions John Leonard Reviewing the literature published up to the end of March 1994 The synthesis of natural p-lactam antibiotics Robert Southgate Reviewing the literature published up to February 1994 Saturated and partially unsaturated carbocycles Christopher D.J. Boden and Gerald Pattenden Reviewing the literature published between August 1992 and January 1994 Recent developments in the synthesis of medium-ring ethers Mark C. Elliott Reviewing the literature published between 1 October 1990 and 30 June 1994 Amines and amides Michael North Reviewing the literature published between July 1992 and December 1993 Contributors to Volume I Blagg, Julian, 125 Boa, A. N., 47 Boden, Christopher D. J., Burns, Christopher J., 23 Cousins, R. P. C., 173 Dawson, Graham J., 77 Elliott, Mark C., 457 Franklin, Alison S., 317 Gilchrist, Thomas L., 205 Gribble, Gordon W., 145 433 Grossel, Martin C., 367 Jenkins, P. R., 47 Kilburn, Jeremy D., 259 Knight, D.W., 287 Lawrence, N. J., 47 Leonard, John, 387 Mascal, Mark, 31 Motherwell, W.B., 219 North, Michael, 475 Nutley, C. J., 219 Patel, Hitesh K., 259 Paterson, Ian, 317 Pattenden, Gerald, 433 Raper, Christopher M., 191 Southgate, Robert, 417 Spargo, P. L., 113 Steel, Patrick G., 1 Steele, John, 95 Sweeney, Joseph, 243 Weston, Simon C., 367 Williams, Jonathan M. J., 77 Wills, Martin, 339Contemporary 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 Montrial Professor M. Julia, Universiti de Paris XI (Paris-Sud) Professor P. D. Magnus, University of Texas at Austin Professor G. Mehta, University of Hyderabad Professor K. C. Nicolaou, 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 the'majority of articles are intended to be specially commissioned, the Society is always prepared to consider offers of articles for publication.In such cases a short synopsis, rather than the completed article, should be submitted to the Senior Editor (Reviews), Books and Reviews Department, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF. Members of the Royal Society of Chemistry may subscribe to Contemporary Organic Synthesis by placing their orders on the Annual Subscription renewal forms in the usual way. All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letchworth, Herts SG6 lHN, England. 1994 subscription rate: EC &150, USA $282, Canada .€ 169 (plus GST ), Rest of the World &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 Ltd

ISSN:1350-4894    

DOI:10.1039/CO99401FX001

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

ISSN:1350-4894    

DOI:10.1039/CO99401BX003

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Saturated oxygen heterocycles CHRISTOPHER J. BURNS Pfizer Central Research, Sandwich, Kent CT13 9NJ Reviewing the literature published between January 1992 and March 1993 1 2 3 3.1 3.2 4 4.1 4.2 5 6 T hree-membered rings Four-membered rings Five-membered rings Tetrahydrofurans Dihydrofurans Six-membered rings Tetrahydropyrans Dihydropyrans Medium and large ring ethers References 1 Three-membered rings Significant progress has been made in the synthesis of chiral epoxides from unfunctionalized olefins. Kolb and Sharpless have shown that chiral vicinal diols, prepared by Sharpless' asymmetric dihydroxylation protoco1,l can be efficiently converted into chiral epoxides via a three-step one-pot procedure.2 Thus, the diol 1 yields the epoxide 4 via the intermediate acetoxy bromides 2 and 3 in 83% overall yield.In related work the protected chiral glyceraldehyde epoxide 6 was prepared from the chiral diol5 by mono-tosylation and subsequent base-promoted cy~lization.~ An analogous one-pot procedure has been reported by Rao and co-workers wherein treatment of the diol7 with a mixture of tosyl chloride and sodium hydride affords the enantiomerically pure epoxide 8 in 72% yield.4 5 6 7 8 Of numerous reports detailing the use of molecular oxygen as oxidant in epoxidations, the work of the group of Kaneda is particularly n~teworthy.~ They have shown that a combination of molecular oxygen and an aldehyde, particularly pivalaldehyde, efficiently epoxidizes olefins, as exemplified by the formation of the epoxide 10 from 2-methyl-1-pentene 9.Molecular oxygen has also been used in the synthesis of epoxy-alcohols directly from vinyl silanes.6 Thus, photo-oxygenation of the vinyl silane 11 followed by treatment with titanium tetra-isopropoxide gave the product 12 in 59% overall yield. Caubere and his co-workers have shown that a combination of hydrogen peroxide and sodium tungstate under phase transfer conditions is the method of choice for the epoxidation of olefins containing the sensitive methacrylate m~iety.~ Using this method the epoxide 14, for example, could be generated from ally1 methacrylate 13 in good yield. Cooke and Lindsay Smith have reported the use of polymer bound iron ( 111) tetra( 2,6-dichloro- pheny1)porphyrin (Fe'" TDCPP) as an efficient catalyst in the epoxidation of cyclooctene 15.8 The procedure Burns: Saturated oxygen heterocycles 23uses iodosylbenzene as the oxidant, with a catalyst turnover of 7900, giving the epoxide 16.15 16 2 Four-membered rings Saksena et al. have reported a much improved route to substituted oxetane-2-carboxylic acids.' Thus, they have demonstrated that ring contraction of a furanone bearing a mesylate at the three position can be affected in aqueous base, as shown in the preparation of the oxetane 18 from the glucose-derived lactone 17. The [2 + 21 photocycloaddition between a 2-substituted furan and an aldehyde generally gives a mixture of regioisomeric bicyclic oxetanes. Cartess and Halfhide have now shown, however, that 2-acetylfuran 19 undergoes highly regioselective [ 2 + 21 cycloadditions, with the reactions occurring on the more substituted furan double bond, as exemplified by the reaction of 19 with p-cyanobenzaldehyde 20 leading to the bicycle 2 1.l0 C H ~ O M ~ 18 19 H 21 a,B-Epoxy diazomethylketones have been shown to yield oxetanones on treatment with tin tetrachloride.' The reaction proceeds through a chlorohydrin intermediate 23 (which in certain instances can be isolated) as shown in the transformation of 22 to the product 24.r 1 22 L 23 J 0 24 3 Five-membered rings 3.1 Tetrahydrofurans Progress in the synthesis of natural and unnatural furanosides has been partly covered in a review (3 17 references) entitled 'AIDS-Driven Nucleoside Chemistry',12 while the applications of palladium (11) catalysis in tetrahydrofuran synthesis has been reviewed (54 references) by Hosokawa and Murahashi.13 The use of free-radical chemistry to gain access to substituted tetrahydrofurans continues to be an active area of research.For example, Dalla and Pale, have reported the first synthesis of spiroketals using a free-radical approach, wherein a 2-methylene tetrahydrofuran 25 is converted in two steps via the iodide 26 into the spirocycle 27 in good yield.I4 The addition of tributyltin hydride to carbohydrate derived propargyl ethers has been shown to be an efficient route into fused bicyclic ketals.15 The conversion of 28 into 29 is representative, though in some instances a mixture of E and 2 isomers of the vinyl stannane product results. 25 26 Bu3SnH 1 27 ACO e b 0 PhH 75% H Bu3SnH I BuBSn 28 29 A highly regioselective [ 3 + 41 annulation reaction for the synthesis of bridged cyclic ethers has been reported by Molander and Cameron.16 Thus, the bis(trimethylsily1) enol ether 30 adds to the diketones 3 1 under Lewis acid catalysis to give the product ethers 32 in fair to excellent yields. 32 Wender et al.have extended their work on [ 5 + 21 cycloaddition reactions and shown that the pyrylium salt 33 reacts with dimethyl acetylenedicarboxylate, in 24 Contemporary Organic Syntheskthe presence of base, to provide the cyclic ether 34.17 The aqueous Diels-Alder reaction between the arylfuran 35 and dimethyl acetylenedicarboxylate offers a highly efficient route to the cyclic ether 36 which has then been converted in several steps into the unusual antifungal agent 37.'* 33 73% 0 I CI 35 CI / CI 36 Iodoetherifications and related processes continue to offer efficient routes to tetrahydrofuran derivatives. Thus, Knight and his group have shown that E-homoallylic alcohols readily cyclize to trans- iodotetrahydrofurans in anhydrous acetonitrile, as exemplified by the formation of 39 from 38; the corresponding 2-homoallylic alcohols furnish the cis products.' Interestingly, the 2-hydroxyalkenoates 40 cyclize under identical conditions to give the hydroxytetrahydrofurans 42, presumably via the intermediate orthoester 4 1 .20 38 39 r 1 40 L 41 1 RH& C02Me 42 Beebe et al.have shown that the polymer-bound isoxazole 44 liberates the tetrahydrofuran 45 upon treatment with iodine monochloride, regenerating in the process the starting aldehyde 43.21 Treatment of y-silyloxyallenes 4 6 with N-iodosuccinimide has been shown to efficiently generate iodovinyl tetrahydrofuran derivatives 47, with the cis isomer predominating by greater than nine to one.22 0 TMSO II I p--- 43 44 N C y J - 1 45 Acetone > 8796 46 47 In a synthetic process related to iodoetherification, Mikami and Shimizu have shown that the bis-homoallylic silyl ether 48 undergoes an intramolecular cyclization on treatment with methyl glyoxylate and tin tetrachloride to provide the substituted tetrahydrofuran 49.23 Another interesting route to highly functionalized tetrahydrofurans, e.g.5 1, involves the treatment of the protected polyol benzyl ether 50 bearing a leaving group at the y-carbon with very mild acid.24 40 O x b ' O x 0 50 Kennedy and Tang have shown that treatment of 5-hydroxyalkenes with rhenium (WI) oxide is an efficient route to 2-hydro~ymethyl-tetrahydrofurans.~~ Thus, for example, the tetrahydrofuran 53 is formed in 86% yield from the hydroxyalkene 52, with oxidative cyclization occurring stereospecifically syn to the double bond.26 .. 53 88% 52 Burns: Saturated oxygen heterocycles 25A novel three component palladium catalysed process for the synthesis of 2-alkylidene-tetrahydrofurans has been reported by Luo and a~sociates.~~ The reaction presumably proceeds through the vinylpalladium intermediate 55, as shown for the synthesis of 56 from the hydroxy acetylene 54. 54 Ph 55 of the protected oxazine 62 with lithium diisopropylamide generates the dihydrofuran 63 in 63% yield.62 63 The tungsten 11 '-propynyl compound 64 has been shown to react with a range of aldehydes leading to the cyclized intermediates 65, which can then be demetallated in reasonable yields to provide the corresponding dihydrofurans 66.31 r 56 Clark has shown that copper acetylacetonate is the catalyst of choice for the conversion of the a-diazo ketone 57 into the trans-furanone 59, a reaction which appears to proceed through the metal-bound ylide 58.28 Crandall et al. have extended their earlier work on the epoxidation of allenes and demonstrated that the hydroxy-allene 60 can be converted into the hydroxyfuranone 6 1 on treatment with dimethyldioxirane.2Y \ 66 Ozaki and co-workers have demonstrated that the nickel (11) catalyst 68 can induce intramolecular free-radical cyclization reactions under electrochemical condition^;^^ the synthesis of the dihydrobenzofuran 69 from the ally1 ether 67 in 75% yield is representative of the procedure.0 60 61 3.2 Dihydrofurans Desai and co-workers have uncovered an interesting base-induced rearrangement reaction of 3,6-dihydro- 1,2-0xazines which provides an efficent route to 2-amin0-2,5-dihydrofurans.~~ Thus, treatment L 65 64 57 59 67 75% 69 4 Six-membered rings 4.1 Tetrahydropyrans A highly stereoselective route to cis-2,6-disubstituted tetrahydropyrans has been reported by Mandai and co-workers, whereby intramolecular addition of an hydroxyl to an a,#?-unsaturated sulfoxide proceeds under thermodynamic c0nditions.3~ The product sulfoxide 7 1 can then be converted into the corresponding alcohol, as shown in the overall transformation of 70 into the pyran 72.26 Contemporary Organic Synthesis70 n NaOAc 83% overall 72 Mark6 et al. have developed an efficient one-pot synthesis of tetrahydropyrans based on an intramolecular Sakurai reaction.34 Thus, reaction of the allylsilane 73 with ketones (or aldehydes) 74 leads to the pyrans 76 presumably via the oxonium cation 75. The isomeric 3-methylene-tetrahydropyrans can be prepared in a two-step, one-pot reaction sequence reported by Klumpp and his Addition of the ally1 Grignard reagent 77 to cyclopentene oxide 78 first affords the intermediate 79 which then undergoes palladium catalysed cyclization to the desired pyran 80. THF 77 7s 1 R b 76 H 80 4.2 Dihydropyrans The syntheses of dihydropyrans via hetero Diels-Alder reactions offers a rapid entry into this ring system. Dujardin, Molato, and Brown have undertaken a systematic investigation of the europium catalysed Diels-Alder reaction of the pyruvate 8 1 with numerous chiral enol ethers, and have shown that use of the chiral en01 ether 82 gives the best asymmetric induction (d.e.72%) affording the endo-product 83 in a highly endo selective reaction.36 Tietze and 81 8 3 0 Schneider have demonstrated that reaction of the en01 ether 84 with the heterodiene 85 can be controlled to give either the ex0 or endo product.37 Thus, the reaction catalysed by the strong Lewis acid tin tetrachloride gives the ex0 product 86 in 86% yield, whereas trimethylsilyl triflate as catalyst affords the corresponding endo adduct. Phenylboric acid has been shown to catalyse the hetero Diels-Alder reaction of citronellal88 with activated phenols.38 The reaction is presumed to proceed through a quinone methide intermediate such as 89, as shown in the synthesis of 90 from the phenol 87.0 a4 71% 87 6Et 86 89 The use of molybdenum carbene complexes in the synthesis of dihydropyrans has been reported by Harvey and Brown,39 as exemplified in the synthesis of the dihydropyran 93 via the intermediate 92, on thermolysis of the Fischer carbene complex 9 1. Bums: Saturated oxygen heterocycles 27r 1 91 L 92 J 1 ola 93 Tsai and his co-workers have reported a novel cyclization process using acylsilanes to generate 2-~ilyldihydropyrans.4~ Thus, simply heating the 6-bromo acylsilane 94 in N-methylpyrrolidine yields the dihydropyran 95 in 83% yield.0 I 95 5 Medium and large ring ethers Berger and Overman have reported a simple route to oxepenes bearing an halogenated side chain at the two position, via a Prins-type cyclization.4l The reaction yields only the czk-2,7-disubstituted oxepene, as a mixture of stereoisomers at the halogen bearing carbon, as shown for the synthesis of 97 from the mixed ketal96. Boeckman and his co-workers have described an elegant entry into seven- and eight-membered cyclic ethers based on an intramolecular retro-Claisen rearrangement of substituted cycl~propanes.~~ Thus, oxidation of the cyclopropane diols 98 with Dess-Martin reagent provided the desired products 99 in fair to excellent yield. 98 99 An interesting free-radical ring-expansion approach to oxepenes has been reported by Marples et al.whereby treatment of the thiocarbonylimidazolide 100 with tributyltin hydride gives the ring expanded product 102 via the oxiranyl radical 101.43 Moody et al. have shown that the intramolecular Wadsworth-Emmons reaction of the ketone phosphonate 103 affords the cyclic en01 ether 104 in 47% yieid.44 Ph 102 6 References 1 K.B. Sharpless, W. Amberg, Y.L. Bennani, G.A. Crkpho, J. Hartung, K.-S. Jeong, H.-L. Kwong, K. Morikawa, Z.M. Wang, D. Xu, and X.-L. Zhang, J. 0%. Chem., 1992,57, 2768. 2 H.C. Kolb and K.B. Sharpless, Tetrahedron, 1992,48, 10515. 3 R. Oi and K.B. Sharpless, Tetrahedron Lett., 1992,33, 2095. 4 V.S. Murthy, A.S. Gaitonde, and S.P. Rao, Synth. Commun., 1993,23,285. 5 K. Kaneda, S.Haruna, T. Imanaka, M. Hamamoto, Y. Nishiyama, and Y. Ishii, Tetrahedron Lett., 1992,33, 6827. 6 W. Adam and M. Richter, Tetrahedron Lett., 1992,33, 346 1. 7 Y. Fort, A. Olszewski-Ortar, and P. Caubere, Tetrahedron, 1992,48,5099. 8 P.R. Cooke and J.R. Lindsay Smith, Tetrahedron Lett., 1992,33,2737. 9 A.K. Saksena, A.K. Ganguly, V.M. Girijavallabhan, R.E. Pike, Y.-T. Chen, and M.S. Puar, Tetrahedron Lett., 1992, 33,7721. 10 H.A.J. Carless and A.F.E. Halfhide, J. Chem. Soc., Perkin Trans. I , 1992,1081. 11 L. Thijs, P.J.M. Cillissen, and B. Zwanenburg, Tetrahedron, 1992,48,9985. 12 D.M. Huryn and M. Okabe, Chem. Rev., 1992,92,1745. 13 T. Hosokawa and S.-I. Murahashi, Heterocycles, 1992, 14 V. Dalla and P. Pale, Tetrahedron Lett., 1992,33,7857. 15 N. Moufid, Y.Chapleur, and P. Mayon, J. Chem. Soc., 16 G.A. Molander and K.O. Cameron, J. Am. Chem. SOC., 17 P.A. Wender and J.L. Mascareiias, Tetrahedron Lett., 33,1079. Perkin Trans. 1, 1992,999. 1993,115,830. 1992,33,2115. 28 Contemporary Organic Synthesis18 A.K. Saksena, V.M. Girijavallabhan, Y.-T. Chen, E. Jao, R.E. Pike, J.A. Desai, D. Rane, and A.K. Ganguly, Heterocycles, 1993,35, 129. 19 S.B. Bedford, K.E. Bell, G. Fenton, C.J. Hayes, D.W. Knight, and D. Shaw, Tetrahedron Lett., 1992,33,6511. 20 F. Bennett, S.B. Bedford, K.E. Bell, G. Fenton, D.W. Knight, and D. Shaw, Tetrahedron Lett., 1992,33,6507. 21 X. Beebe, N.E. Schore, and M.J. Kurth, J. Am. Chem. SOC., 1992,114,10061. 22 R.D. Walkup, L. Guang, S.W. Kim, and Y.S. Kim, Tetrahedron Lett., 1992,33,3969.23 K. Mikami and M. Shimizu, Tetrahedron Lett., 1992,33, 6315. 24 H. Dehmlow, J. Mulzer, C. Seilz, A.R. Strecker, and A. Kohlmann, Tetrahedron Lett., 1992,33,3607. 25 R. Kennedy and S. Tang, Tetrahedron Lett., 1992,33, 3729. 26 R. Kennedy and S. Tang, Tetrahedron Lett., 1992,33, 5299. 27 F.-T. Luo, I. Schreuder, and R.-T. Wang, J. Org. Chem., 1992,57,2213. 28 J.S. Clark, Tetrahedron Lett., 1992,33,6193. 29 J.K. Crandall, D.J. Batal, F. Lin, T. Reix, G.S. Nadol and 30 M.C. Desai, J.L. Doty, L.M. Stephens, and K.E. Brighty, 31 M.-H. Cheng, G.-M.Yang, J.-F. Chow, G.-H. Lee, R.A. Ng, Tetrahedron, 1992,48,1427. Tetrahedron Lett., 1993,34,961. S.-M. Peng, and R.-A. Liu, J. Chem. SOC., Chem. Commun., 1992,934. 32 S. Ozaki, H. Matsushita, and H. Ohmori, J. Chem. SOC., Chem. Commun., 1992,1120. 33 T. Mandai, M. Ueda, K. Kashiwagi, M. Kawada, and J. Tsuji, Tetrahedron Lett., 1993,34, 11 1. 34 I.E. Mark6, A. Mekhalfia, D.J. Bayston, and H. Adams, J. 05. Chem., 1992,57,2211. 35 J. van der Louw, J.L. van der Baan, G.J.J. Out, F.J.J. de Kanter, F. Bickelhaupt, and G.W. Klumpp, Tetrahedron, 1992,48,9901. Asymmetry, 1993,4, 193. 36 G. Dujardin, S. Molato, and E. Brown, Tetrahedron: 37 L.F. Tietze and C. Schneider, Synlett., 1992,755. 38 W.S. Murphy, S.M. Tuladhar, and B. Duffy, J. Chem. SOC., 39 D.F. Harvey and M.F. Brown, J. Org. Chem., 1992,57, 40 Y.-M. Tsai, H.-C. Nieh, and C.-D. Cherng, J. Org. Chem., 41 D. Berger and L.E. Overman, Synlett, 1992,8 11. 42 R.K. Boeckman, M.D. Shair, J.R. Vargas, and L.A. Stolz, 43 D.A. Corser, B.A. Marples, and R.K. Dart, Synlett, 1992, 44 C.J. Moody, E.-R.H.B. Sie, and J.J. Kulagowski, Perkin Trans. 1, 1992,605. 5559. 1992,57,7010. J. Org. Chem., 1993,58,1295. 987. Tetrahedron, 1992,48, 3991. Burns: Saturated oxygen heterocycEes 29

ISSN:1350-4894    

DOI:10.1039/CO9940100023

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Contemporary Organic Synthesis Editorial Board Professor G. Pattenden, FRS (Chairman), University of Nottingham Professor P. D. Bailey, Heriot- Watt University Professor P. J. Kocienski, University of Southampton Professor C. J. Moody, Loughborough University of Technology Dr S. E. Thomas, Imperial College of Science, Technology, and Medicine Professor E. J. Thomas, University of Manchester International Advisory Board Professor E. J. Corey, Harvard University Professor S. Hanessian, Universite' de Montrkal Professor M. Julia, UniversitP de Paris X I (Paris-Sud) Professor P. D. Magnus, University of Texas at Austin Professor G. Mehta, University of Hyderabad Professor K. C. Nicolaou, The Scripps Research Institute and University of California at Sun Diego, La Jolla Professor R.Noyori, Nagoya University Professor L. E. Overman, University of California, Irvine Professor L. F. Tietze, University of Gottingen Contemporary Organic Synthesis is a bimonthly journal which aims to review and provide perspective in all aspects of methodology, selectivity, and efficiency in contemporary synthesis. As well as covering all the principles and methods in functional group chemistry and interconversions, organometallic chemistry and asymmetric synthesis will feature prominently, so too will modern aspects of strategy and computer aided design, biotransformations, and protecting group protocols. Special methods and techniques, such as sonochemistry, FVP, electroorganic synthesis, and supported catalysis will be included as occasional articles, and the manner in which synthesis addresses problems and provides solutions in biology, medicine, agriculture, the environment, and new materials, will also be encompassed. Contemporary Organic Synthesis aims to be proactive, drawing attention to new opportunities and new directions, providing timely information to the synthetic chemist who needs to keep abreast of developments in the field. Although the majority of articles are intended to be specially commissioned, the Society is always prepared to consider offers of articles for publication. In such cases a short synopsis, rather than the completed article, should be submitted to the Senior Editor (Reviews), Books and Reviews Department, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF.Members of the Royal Society of Chemistry may subscribe to Contemporary Organic Synthesis by placing their orders on the Annual Subscription renewal forms in the usual way. All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letchworth, Herts SG6 lHN, England. 1994 subscription rate: EC &150, USA $282, Canada &169 (plus GST), Rest of the World &161. Air freight and mailing in the USA by Publications Expediting Inc., 200 Meacham Avenue, Elmont 1103; USA Postmaster, send address changes to Contemporary Organic Synthesis, Publications Expediting Inc. Second class postage is paid at Jamaica, New York 11431. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe.0 The Royal Society of Chemistry, 1994 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording, or otherwise, without the prior permission of the publishers. Typeset by Unicus Graphics Ltd Printed in Great Britain by Whitstable Litho LtdContemporary Organic Synthesis Editorial Board Professor G. Pattenden, FRS (Chairman), University of Nottingham Professor P. D. Bailey, Heriot- Watt University Dr S. E. Gibson (nek Thomas), Imperial College of Science, Technology, and Medicine Professor P. J. Kocienski, University of Southampton Professor C. J.Moody, Loughborough University of Technology Professor E. J. Thomas, University of Manchester International Advisory Board Professor E. J. Corey, Harvard University Professor S. Hanessian, Universitk de Montrkal Professor M. Julia, Universitk de Paris XI (Paris-Sud) Professor P. D. Magnus, University of Taus at Austin Professor G. Mehta, University of Hyderabad Professor K. C. Nicolaou, The Scripps Research Institute and University of Professor R. Noyori, Nagoya University Professor L. E. Overman, University of California, Irvine Professor L. F. Tietze, University of Gottingen California at Sun Diego, La Jolla Contemporary Organic Synthesis is a bimonthly journal which aims to review and provide perspective in all aspects of methodology, selectivity, and efficiency in contemporary synthesis.As well as covering all the principles and methods in functional group chemistry and interconversions, organometallic chemistry and asymmetric synthesis will feature prominently, so too will modern aspects of strategy and computer aided design, biotransformations, and protecting group protocols. Special methods and techniques, such as sonochemistry, FVP, electroorganic synthesis, and supported catalysis will be included as occasional articles, and the manner in which synthesis addresses problems and provides solutions in biology, medicine, agriculture, and environment, and new materials, will also be encompassed. Contemporary Organic Synthesis aims to be proactive, drawing attention to new opportunities and new directions, providing timely information to the synthetic chemist who needs to keep abreast of developments in the field.Although the majority of articles are intended to be specially commissioned, the Society is always prepared to consider offers of articles for publication. In such cases a short synopsis, rather than the completed article, should be sdbmitted to the Senior Editor (Reviews), Books and Reviews Department, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF. Members of the Royal Society of Chemistry may subscribe to Contemporary Organic Synthesis by placing their orders on the Annual Subscription renewal forms in the usual way. All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letchworth, Herts SG6 lHN, England. 1995 subscription rate: EEA &165, USA $303, Canada El73 (plus GST), Rest of the World &173. Air freight and mailing in the USA by Publications Expediting Inc., 200 Meacham Avenue, Elmont 1103; USA Postmaster, send address changes to Contemporary Organic Synthesis, Publications Expediting Inc. Second class postage is paid at Jamaica, New York 11431. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. 0 The Royal Society of Chemistry, 1995 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording, or otherwise, without the prior permission of the publishers. Typeset by Unicus Graphics Ltd Printed in Great Britain by Whitstable Litho Ltd

ISSN:1350-4894    

DOI:10.1039/CO99401FX025

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

ISSN 1350-4894 COGSE6 1-1-1-36 (1994) Contemporary Organic Synthesis A journal of current developments in Organic Synthesis VOLUME 1 INDEXES ... 111 Contents of Volume 1 1-1 Index of authors cited 1-23 Subject indexContemporary Organic Synthesis Editorial Board Professor G. Pattenden, FRS (Chairman), University of Nottingham Professor P. D. Bailey, Heriot- Watt University Dr S . E. Gibson (net Thomas), Imperial College of Science, Technology, and Medicine Professor P. J. Kocienski, University of Southampton Professor C. J. Moody, Loughborough University of Technology Professor E. J. Thomas, University of Manchester International Advisory Board Professor E. J. Corey, Harvard University Professor S . Hanessian, Universiti de Montrial Professor M. Julia, Universiti de Paris XI (Paris-Sud) Professor P.D. Magnus, University of Taus at Austin Professor G. Mehta, University of Hyderabad Professor K. C. Nicolaou, The Scripps Research Institute and University of Professor R. Noyori, Nagoya University Professor L. E. Overman, University of California, Irvine Professor L. F. Tietze, University of Gottingen California at Sun Diego, La Jolla Contemporary Organic Synthesis is a bimonthly journal which aims to review and provide perspective in all aspects of methodology, selectivity, and efficiency in contemporary synthesis. As well as covering all the principles and methods in functional group chemistry and interconversions, organometallic chemistry and asymmetric synthesis will feature prominently, so too will modem aspects of strategy and computer aided design, biotransformations, and protecting group protocols.Special methods and techniques, such as sonochemistry, FVP, electroorganic synthesis, and supported catalysis will be included as occasional articles, and the manner in which synthesis addresses problems and provides solutions in biology, medicine, agriculture, the environment, and new materials, will also be encompassed. Contemporary Organic Synthesis aims to be proactive, drawing attention to new opportunities and new directions, providing timely information to the synthetic chemist who needs to keep abreast of developments in the field. Although the majority of articles are intended to be specially commissioned, the Society is always prepared to consider offers of articles for publication.In such cases a short synopsis, rather than the completed article, should be submitted to the Senior Editor (Reviews), Books and Reviews Department, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF. Members of the Royal Society of Chemistry may subscribe to Contemporary Organic Synthesis by placing their orders on the Annual Subscription renewal forms in the usual way. All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letchworth, Herts SG6 lHN, England. 1995 subscription rate: EEA f165, USA $303, Canada f173 (plus GST), Rest of the World &173. Air freight and mailing in the USA by Publications Expediting Inc., 200 Meacham Avenue, Elmont 1103; USA Postmaster, send address changes to Contemporary Organic Synthesis, Publications Expediting Inc.Second class postage is paid at Jamaica, New York 11431. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. 0 The Royal Society of Chemistry, 1995 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording, or otherwise, without the prior permission of the publishers. Typeset by Unicus Graphics Ltd Printed in Great Britain by Whitstable Litho LtdISSN 1350-4894 COGSE6 1-1-1-36 (1994) Contemporary Organic Synthesis A journal of current developments in Organic Synthesis VOLUME 1 1 23 31 47 77 95 113 125 145 173 191 205 219 243 259 287 Aldehydes and ketones Patrick G.Steel Reviewing the literature published between July 1992 and June 1993 Saturated oxygen heterocycles Christopher J. Burns Reviewing the literature published between January 1992 and March 1993 Noncovalent design principles and the new synthesis Mark Mascal Recent progress in the synthesis of taxanes A. N. Boa, I? R. Jenkins, and N. J. Lawrence Reviewing the literature published between January 1991 and July 1993 Catalytic applications of transition metals in organic synthesis Graham J. Dawson and Jonathan M. J. Williams Reviewing the literature published between 1 July 1992 and 31 August 1993 Saturated nitrogen heterocycles John Steele Reviewing the literature published between January 1992 and May 1993 Organic halides I? L.Spargo Reviewing the literature published between 1 July 1992 and 30 June 1993 Stoichiometric applications of organotransition metal complexes in organic synthesis Julian Blagg Reviewing the literature published between 1 July 1992 and 31 August 1993 Recent developments in indole ring synthesis-methodology and applications Gordon W. Gribble Reviewing the literature published between 1990 and 1993 Saturated and unsaturated hydrocarbons R. I? C. Cousins Reviewing the literature published between 1 July 1992 and 1 September 1993 Thiols, sulfides, sulfoxides, and sulfones Christopher M. Rayner Reviewing the literature published between July 1992 and September 1993 Synthesis of five-membered aromatic heterocycles Thomas L.Gilchrist Reviewing the literature published between July 1992 and June 1993 The role of zinc carbenoids in organic synthesis W. B. Motherwell and C. J. Nutley Reviewing the literature published up to February 1994 Alcohols, phenols, and ethers Joseph Sweeney Reviewing the literature published between July 1992 and July 1993 Synthetic developments in host-guest chemistry Jeremy D. Kilburn and Hitesh K. Pate1 Reviewing the literature published between July 1992 and December 1993 Synthetic approaches to butenolides D. W. Knight Reviewing the literature published between 1976 and 1992317 339 367 387 417 433 457 475 Recent developments in asymmetric aldol methodology Alison S. Franklin and Ian Paterson Reviewing the literature published up to the end of 1993 Main group organometallics in synthesis Martin Wills Reviewing the literature published between July 1992 and December 1993 Synthesis of materials for molecular electronic applications Martin C.Grossel and Simon C. Weston Reviewing the literature published between mid-1 992 and December 1993 Control of asymmetry through conjugate addition reactions John Leonard Reviewing the literature published up to the end of March 1994 The synthesis of natural p-lactam antibiotics Robert Southgate Reviewing the literature published up to February 1994 Saturated and partially unsaturated carbocycles Christopher D. J. Boden and Gerald Pattenden Reviewing the literature published between August 1992 and January 1994 Recent developments in the synthesis of medium-ring ethers Mark C. Elliott Reviewing the literature published between 1 October 1990 and 30 June 1994 Amines and amides Michael North Reviewing the literature published between July 1992 and December 1993 Contributors to Volume I Blagg, Julian, 125 Boa, A. N., 47 Boden, Christopher D. J., Burns, Christopher J., 23 Cousins, R. P. C., 173 Dawson, Graham J., 77 Elliott, Mark C., 457 Franklin, Alison S., 317 Gilchrist, Thomas L., 205 Gribble, Gordon W., 145 433 Grossel, Martin C., 367 Jenkins, P. R., 47 Kilburn, Jeremy D., 259 Knight, D.W., 287 Lawrence, N. J., 47 Leonard, John, 387 Mascal, Mark, 31 Motherwell, W. B., 219 North, Michael, 475 Nutley, C. J., 219 Patel, Hitesh K., 259 Paterson, Ian, 317 Pattenden, Gerald, 433 Raper, Christopher M., 191 Southgate, Robert, 417 Spargo, P. L., 113 Steel, Patrick G., 1 Steele, John, 95 Sweeney, Joseph, 243 Weston, Simon C., 367 Williams, Jonathan M. J., 77 Wills, Martin, 339

ISSN:1350-4894    

DOI:10.1039/CO99401FP027

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Noncovalent design principles and the new synthesis MARK MASCAL Department of Chemistry, Universiw of Nottingham, University Park, Nottingham NG7 2RD 1 1.1 2 2.1 2.2 2.3 2.4 2.5 2.6 2.7 3 4 Introduction Supermolecules and information The design principles Simple coulombic interactions Hydrogen bonding Noncovalent interactions involving n-systems only Noncovalent interactions involving heteroatoms Noncovalent interactions involving transition metals Solvophobic interactions Topological bonding and incarceration Conclusion References and notes 1 Introduction Like most disciplines, organic chemistry has evolved through several phases. From a predominantly physical-chemical basis in the earlier part of the twentieth century emerged, when the technology made it possible, a stage of hard-fought, target-oriented synthetic chemistry, which has continued into the present with a strong emphasis on methodology and stereoselectivity. A new genre of experimentalist co- evolved in the late 1960’s with a keen interest in what has today become known as supramolecular Chemistry.This branch of science, although nominally organic with respect to the chemical species involved, defined aims which set it apart from mainstream chemistry. This review will examine these aims and look at how synthesis has undergone a conceptual revolution, no longer only addressing the making of covalent bonds to create molecules, but also noncovalent bonds to create ‘supermolecules’. To appreciate why molecular assemblies have emerged as ‘synthetic’ targets, the collective behaviour of species at the molecular level will briefly be considered, followed then by a survey of the principles applied to the generation of such assemblies. 1.1 Supermolecules and information Supramolecular chemistry is the chemistry of the noncovalent bond.’ Conceptually, it can be loosely divided into two categories, which may be termed host-guest chemistry and self-assembly.In host-guest systems, species combine in a small integer ratio (most often one to one) where one component, the ‘host’, is perceived to spatially accommodate (or include) the ‘guest’, while self-assembly describes the building up of noncovalent arrays of defined geometry by specifically ‘engineered’ molecular components. There is, unsurprisingly, a degree of overlap between these two areas and certain cases will defy categorization.A classic example of host-guest chemistry is the complex between 18-crown-6 and ammonium ion (Figure 1 ). Self-assembly can be illustrated by the spontaneous organization of mixtures of barbituric acid and triaminopyrimidine derivatives into a supramolecular ‘rosette’ (Figure 2). Figure 1 Crystal structure of the 18-crown-6/ammonium ion inclusion complex.? The role of supramolecular science in the life process cannot be overstated. Nucleic acid transcription and translation, enzymatic function, antibody specificity, virus assembly and action, lipid biomembranes, and the mechanical strength of structural protein/mineral composites serve as an inspiration: if nature uses the noncovalent organization of molecules to drive the very life process itself, can we not apply the same principle to our own (less ambitious) aims? Mascal: Noncovalent design principles and the new synthesis 31Figure 2 Crystal structure of the assembly generated from 5,5-diethylbarbituric acid and 2-amino-4,6-di( 4-t- but ylphen yl )aminopyrimidine.3 Collective behaviour in molecular systems involves the coherence of vast numbers of degrees of freedom.The spontaneous organization seen in systems under (certain) conditions of equilibrium, where intermolecular forces dominate kinetic energy, can be superimposed on nonequilibrium conditions in the bulk material to generate order on a grand scale. The intermolecular forces (see below), which operate over a range of a few angstroms, are the design principles of supramolecular chemistry since they can be catalogued as a repertory for the design of self-assembling systems.They are quite simply the energetic currency for payment of entropy. The far-from-equilibrium physics of matter, on the other hand, which describes a subtle balance between extensive (macroscopic) order and chaos, is the next frontier of the supramolecular scienti~t.~ covalent bonds (e.g. 20 kJ mol- for a typical hydrogen bond versus 350 kJ mol- for a C-C single bond) and are easily disrupted. Thus the mean lifetime of a hydrogen bond in solution is in the order of 10- lo of a second, whereas covalent bonds are, in the absence of external influence, long lived if not permanent. And yet it is the relative weakness of the noncovalent bond which makes it ideally suited to the chemistry of living organisms, where the processes involved in motion and perception require events on the molecular level much faster than the making and breaking of covalent bonds.In terms of economy of energy, the encoding of genetic information by means of reversible noncovalent assembly is far more efficient than if, for example, the unwinding of DNA and the readout of messenger RNA were of a covalent nature. Despite the fleeting lifetime of the isolated noncovalent bond, many higher order structures are capable of discrete existence on the same time scale as covalent species due to the large Intermolecular forces are much weaker than number and (often) cooperative nature of the interactions involved. Recognition-directed organization in simpler systems is also observable by freezing out the interactions in the solid state.Finally, recognition, or the capacity to distinguish one spatial relationship from another, requires the presence of information. There are two fundamental types of complementarity by which information is expressed at the molecular level: steric and functional. The shape of a subunit and thus its steric requirements in the context of an assembly derives from its primary covalent structure, over which the synthetic chemist exercises a degree of control. Although not a noncovalent force in itself, steric complementarity is important in achieving an optimal geometry and interface for weak interactions, leading to a maximum gain in enthalpy on association and, in the case of multiple interactions, cooperativity. Functional complementarity refers to the reciprocal functionality with which subunits enter into noncovalent bonding relationships with partner subunits. Thus, one begins with an idea, the desire to express a certain geometrical motif on the molecular scale.To do this, one will require a species which possesses the functional and steric information to unambiguously describe such a structure. Hence programming is the first step of a process which further consists of realization (synthesis), recognition, and finally organization to the desired supermolecule ( i. e. supramolecular synthesis). 2 The design principles 2.1 Simple coulombic interactions Although they will be discussed under several headings, all intermolecular forces are fundamentally electrostatic in character. Those, however, which are 32 Contemporary Organic Synthesisnot associated with specific functionalities are referred to as van der Waals forces, and include the mutual attraction between any combination of point charges, permanent dipoles, and induced dipoles.The bonding between species with formal charges, often called ion pairs or salt bridges, is the most significant of these interactions. Opposite charges in a vacuum attract each other with a potential energy which varies inversely with the distance that separates them. Thus the bond energy between sodium and chloride ions in an ionic lattice can be calculated at 494 kJ mol- I . In solution, however, the relative permittivity of the medium diminishes this interaction.For example, in water the attraction is about two orders of magnitude weaker or ca. 5 kJ mol- 1.5 Because the relationship is non-directional, at least three points of contact would be necessary to fix components in 3-d space. Alternatively, control can be achieved in combination with other constraints. Carboxypeptidase A for example binds substrates (such as glycyltyrosine in Figure 3) by both ion pairing and coordination to Zn2 + at the active site. Hydrogen bonding is often found coupled with ionic interactions wherever these involve NH or OH functions, and this is discussed further in section 2.2. Figure 3 The guanidinium function of an arginine residue of carboxypeptidase A (right) interacts with the carboxyl terminus of the dipeptide Gly-Try (left) in the crystal structure of the complex.The ions are separated by about 2.9 A.h The description of mixed ion, dipole and induced dipole interactions is more complex than for purely ionic forces, and potential energy abruptly drops off as the interaction becomes less defined, as is demonstrated by the greater inverse power dependence on increasing separation (Table 1). As a result the interaction potential may be only slightly above the average thermal energy of the molecules, and so these forces are only of utility as design principles when they operate en rnasse and/or in combination with other types of bonding. Dipole-dipole interactions would be expected to influence spatial relationships in molecular crystals, especially in the absence of more pronounced interactions.Crystals themselves can be considered supramolecular assemblies of a sort, and much work has been devoted to crystal engineering, whose ultimate objective is to favour ‘topochemical’ reactions leading to ordered material^.^ The outcome of a crystallization is, however, non-trivial to predict and as much a matter of efficient lattice packing as optimizing electrostatic interactions. For example, recent work demonstrated no correlation between the magnitude of the dipole and the relative molecular orientations in noncentrosymmetric crystals, or indeed even the population of centrosymmetric versus non-centrosymmetric space groups.X The attainment of the liquid crystalline state is a manifestation of a non-isotropic distribution of van der Waals forces.Rod or disk shaped molecules (Figure 4) adhere more weakly to each other along their short contact axes (x and z rods, y for disks) than their long contact axes ( y for rods, x and z for disks), allowing transition to non-isotropic states (‘mesophases’) of varying degrees of order as thermal energy overcomes intermolecular forces. Thus, moderating the magnitude of weak interactions with respect to direction by synthetic design literally makes possible the creation of ordered states of matter. The generation of macroscopic order will again be taken up in Section 2.6. Y “9Fl nn VUV I Figure 4 Cylindrical and discotic molecular shapes which undergo transitions to liquid crystalline phases. The final entry in Table 1, repulsion, is related to the second type of complementarity by which molecular information is communicated, i.e.steric. The extremely disfavourable energetics involved in co-occupying the same space make this an important ~ ~ _ _ _ _ _ ~ ~ _ _ _ _ ___ ~~ ~~ Table 1 Dependence of separation ( Y ) on the potential energy ( V ) of van der Waals forces Interaction n in L‘K Y - ” Remarks Ion-ion Ion-dipole Dipole-dipole (parallel) Dipole-dipole (free rotation) Dipole-induced dipole Induced dipole-induced dipole Repulsion 1 2 3 6 6 6 9-15 Idealized point charges Dependence on dipole moment p Dependence on orientation 6 ‘Keesom’ force ‘Deb ye’ force ‘London’ force n = 12 standard value Mascal: Noncovalent design principles and the new synthesis 33Figure 5 Crystal structure of the assembly generated from 5,5-diethylbarbituric acid and 5-butyl-2,4,6-triaminopyrimid consideration in component design.Indeed, Whitesides used this principle to drive the formation of the cyclic hexamer in Figure 2 .3 Because of the functional symmetry of the barbituric acid and triaminopyrimi- dine components, their association may lead to the formation of either a cyclic or zig-zag chain motif. Under normal circumstances the chain is observed (Figure 5),9 but in the example in Figure 2 the steric bulk of the substituents on the nitrogen atoms disfavours the chain and leads to the observation of the 'rosette', where the p-t-butylphenyl substituents point out towards the corners of a hexagon instead of being lined up in rows. 2.2 Hydrogen bonding The hydrogen bond is not only one of the strongest intermolecular forces (bond energies up to 30 kJ mol- l, depending on the medium) but has the added advantage of being directional and therefore has immediate appeal as a design principle.Hydrogen bonding is the attraction between a hydrogen attached to an electronegative atom (A) and a second species (B) bearing a lone pair, as shown below. where A = O,N,F,S,C B = O,N,F,S,X It is chiefly electrostatic in nature but rigorous descriptions include a number of higher order energy terms. Although halogens, sulfur, and even acidic protons on carbon may participate in hydrogen bonding, for practical purposes A and B are either oxygen or nitrogen. To maximize the interaction, the geometrical requirement is that the A-H-B angle be near 180" and that the hydrogen approximately align itself with an unshared pair of the donor atom B.'O This is observed by sp2- more than sp3-hybridized B, where the proton resides in the lone-pair plane but not necessarily on the lone-pair axis.A simple example which illustrates this is the H-bonding between water molecules in ice, the crystal structure of which (Figure 6) clearly shows the hydrogens directed towards the neighbouring oxygen atoms. The 0-0 distance is 2.7 A, which is less than the sum of the van der Waals radii of the oxygen atoms themselves. Such geometric constraints constitute a high degree of information, Figure 6 Cyclic hexamer extracted from the unit cell of ice 11." which has been applied in numerous instances to the design of supramolecular species. The quality of hydrogen bonds can vary, and the aptitude of A as a hydrogen bonding donor and of B as a hydrogen bonding acceptor has been estimated using a number of techniques.Table 2 gives values of H-bond donor acidity ( G I y ) and acceptor basicity (py) for several species after Abraharn.l2 There is some correlation between these properties and the Br~nsted acidity and basicity of HA and B, but the relationship has its limitations. For example, sulfoxides and phosphine oxides, though nonbasic, are among the best acceptors. As the donor and acceptor ability increase, the distance between A and B decreases and the proton is more evenly shared. Cases where the proton is approximately equidistant between A and B are known, and this interaction is called 'very strong hydrogen bonding', with bond energies calculated in excess of 50 kJ mol-'.13 As is shown in Figure 7, this typically involves a negatively charged acceptor B.Likewise, exceptionally weak hydrogen bonds have also been characterized. In particular, examples of well defined C-H-0 and C-H--N relationships where the proton is consistently found in the plane of the heteroatom lone pair have been described, and these are also known to influence solid state structure.14 Such interactions apparently operate even beyond the accepted van der Waals limit for C-H-0 contact (ca. 3.4 A). As mentioned above, hydrogen bonding may be reinforced by ionic interactions. Benzamidinium 34 Contemporary Organic SynthesisTable 2 Some values of the solute hydrogen bond acidity and basicity parameters a: and by.” Solute (CCI,) Solute (CCI, 1 ,@’ Alkanes Alkenes RSH PhSH CH,C12 RC = CH CHCI, PhNH, ROH CH,CONHCH, FCH,CH,OH 4-nitro-P hNH RCO,H F,CCH,OH PhC0,H PhOH 4-fluoro-P hOH 3-fluoro-PhOH 4-16 tro-PhC0,H FCH,CO,H 4-ni tro-PhOH F,CCO,H RNH, CH,NO, HZO t-C4F90H 0.00 0.00 0.00 0.00 0.12 0.12 0.13 0.13 0.20 0.26 0.32-0.33 0.35 0.38 0.40 0.42 0.54 0.57 0.59 0.60 0.63 0.68 0.68 0.77 0.82 0.86 0.95 Alkanes Alkenes PhCl RCl, RBr, RI Alkynes PhOH C,H, Me,C,H3 RNO, R,S PhNH2 RCHO RCN RzO RCOZR ROH RCOR Pyrimidine Pyridine HCONR, Me,SO HMPA H,O R3N (RO),PO R,PO 0.00 0.07 0.09 0.14 0.1 5-0.1 8 0.20 0.20 0.22 0.25 0.29 0.38 0.38 0.40 0.44 0.45 0.45 0.48 0.53 0.6 1 0.62 0.66 0.77 0.78 0.98 1 .oo 0.45-0.49 pyruvate (Figure 8) is an example of a hydrogen bonded ion pair.Whereas simple hydrogen bonds are easily disrupted in the presence of competing donors or acceptors, H-bonding ‘salts’ associate strongly even in dimethylsulfoxide and water.17 Since the medium of assembly is a primary concern, the effectiveness of the interaction under the required conditions must be taken into account. The expression, but not the quality of information is circumstance-dependent, either in a fundamental sense, such as in solvophobic forces (Section 2.6) or due to competition. In the case of multiple hydrogen bonding, there are yet additional design considerations. If the acidic proton is designated ‘ + ’, interaction with the lone pair donor (‘ - ’) as above defines the hydrogen bond. However, secondary electrostatic relationships between donors and acceptors in such close proximity Figure 8 X-ray crystal structure of benzamidinium pyruvate.I have a considerable influence on the overall energetics of association. This is demonstrated by comparing K,,,,, for the triply hydrogen bonded complexes 1 + 2,3 + 4, and 5 + 6 below (Figure 9).l9 These experimental values are consistent with Jorgensen’s theoretical analysis of such systems, in which secondary interactions between diagonally situated partial charges were found to be energetically worth about one-third of the primary H-bond.20 information in partners 1 + 2 and 5 + 6 from either direction, as discussed above for the barbituric acid/triaminopyrimidine systems. Partners 3 and 4, on the other hand, only recognize each other as shown, and thus may be considered to possess a higher degree of information than the other pairs.Finally, yet another advantage of hydrogen bonding as a design principle is that its presence can be demonstrated spectroscopically. Indeed, the case for simple H-bonding host-guest interactions is often advanced on the basis of shifts in the proton NMR and infrared spectra. In the NMR, deshelding of A-H is experienced proportional to the extent of association, which can be evaluated by titrating one component into the other and plotting concentration versus Ad.21 In the infrared, the A-H stretching band moves to lower wavenumbers with an accompanying increase in breadth and intensity. Likewise, the degree of H- bonding can be estimated by the magnitude of these effects. A correlation of A-B distance with the A-H stretching frequency gives good curves where the Av/ Ar slope is about 1850 crn-’/Afor the N-H-N hydrogen bond and between 1500 and 12000 cm-I/A for O-H--0.22 The 0-H stretch may drop from its normal range of 3500-3600 down to less than 1000 cm- I in some cases.An AH--B stretch also appears in the far infrared between 250-100 cm-’. Interestingly, symmetry operations allow reading the Figure 7 Left: trifluoroacetic acid-trifluoroacetate cocrystal; the hydrogen is precisely equidistant between the oxygens (0-0 distance only 2.42 A).’5 Rtght: hydrogen maleate anion; 0-0 distance 2.44 A, with the proton 1.16 A from the carboxyl oxygen and 1.29 A from the carboxylate oxygen.’, Mascal: Noncovalent design principles and the new synthesis 35Figure 9 Association constants and partial charge distribution for complexes 1 + 2 , 3 + 4, and 5 + 6.''\*" 2.3 Noncovalent interactions involving n-systems only Two major types of molecular association, face-to-face and edge-to-face aromatic interactions, will now be considered together under the same heading.This is not because the nature of the interactions are necessarily comparable but rather that it is convenient in terms of design principles. Face-to-face aromatic n interactions were observed even before the concept of aromaticity was ~nderstood.~~ It was known that when x-deficient aromatics such as picric acid or trinitrobenzene encountered x-excessive or x-neutral species a stable, highly coloured 1 : 1 complex formed which could be recrystallized or even chromatographed.These were known as 'charge transfer complexes' and were convenient derivatives for characterizing aromatic hydrocarbons in the days before modern spectroscopy. X-Ray crystallography reveals that the components of such complexes normally lie in parallel, alternating planes with a spatial interval of 3.2 to 3.5 A. The relative orientation within the plane of the complementary x systems is, however, difficult to predict and varies widely between perfect superimposition and minimal overlap. A recent study proposed a model for these interactions and established a set of rules for the geometrical and electronic requirements, in which off set face-to-face and centred edge-to-face geometries were favoured.24 The crystal structure of the complex between 1,3,5- trinitrobenzene and 1,3,5-triaminobenzene is shown in Figure 10 from a perspective normal to the plane.In this example, alternate rings are spaced between 3.24 and 3.29 A apart, which is less than the sum of the van der Waals radii (3.4 A), and the overlap is 29%. The magnitude of electron donor-acceptor ('EDA') interactions loosely correlates with the ionization potential of the donor and the electron affinity of the acceptor. For example, the enthalpies of complexation of chloranil (tetrachlorobenzoquinone) with benzene and hexamethylbenzene are about 7 and 22 kJ mol- re~pectively.~~ Even where no apparent electronic complementarity exists, aromatic 'stacking' may still be observed, especially among polycyclic and expanded aromatic systems (Figure 11).Under these circumstances an attraction of the n cloud of one Figure 10 The 1,3,5-trinitrobenzene/ 1,3,5-triarninobenzene EDA complex.26 Figure 11 Stacking interactions in porphine. The aromatic planes are 3.4 A apart.27 system to the 0 framework of another is implicated, rather than a n-x* intera~tion.~~ An example of the application of aromatic EDA relationships to directed self-assembly can be seen in Section 2.7. association is only brought about by excitation of one of the two partners.28 These are referred to as eximers and their geometry is presumed to be analogous to ground state complexes. A classic example is that of pyrene, whose fluorescence spectrum undergoes marked changes with increasing concentration due to the presence of a pyrene-pyrene" EDA complex.Simple olefins with an electronic bias interact with complementary species in a similar way. Figure 12 shows how tetracyanoethylene stacks with hexamethylbenzene. As above, the interplane Complexes of this type are also known where 36 Contemporaly Organic Synthesisseparation (3.35 A) is less than the van der Waals distance, indicating the operation of cohesive forces. Complexes are observed likewise between aromatic rings and acid anhydrides, simple carbonyl compounds, sulfur dioxide, sulfur trioxide, and sulfur haloxides. Weak but measurable interactions even exist between noble gas atoms and aromatic donors.2y routinely observed in proteins and has a significant influence on tertiary structure.34 As above, the geometry of the association is well defined, whch makes it worth consideration as a design principle.Interacting aromatic residues on peptide chains are shown by X-ray crystallography to have centre to centre distances at an average of 5.5 A and a dihedral angle between the aromatic planes which tends to the perpendicular. The energies involved are in the order of 5 kJ mol-I, which is somewhat less than that of most hydrogen bonding and EDA complexes. Figure 14 shows the relationship between two phenyl rings in carp parvalbumin, where Phe 66 and Phe 85 are fixed in planes inclined 88” to each other and have a centre to centre distance of 5.44 A. This type of interaction is also relevant to the organization of acetylene molecules in the solid state, where the hydrogens are directed towards the centres of triple bonds of neighbouring molecule^.^^ Figure 12 The tetracyanoethylene-hexamethylbenzene EDA complex.30 In extreme cases a redox reaction occurs to give a radical cation-anion salt, the components of which formally reside in ‘fractional’ oxidation states. The classic example of this is the tetracyanoquinodimethane-tetrathiafulvalene co-crystal (Figure 13), which was the first example of a now extensive family of ‘organic metals’.31 Unlike the previous examples, in these materials the components are organized into segregated stacks of donors and acceptors, and indeed this is a prerequisite for conductivity.Despite the presence of like charges, the interplane spacing is approximately that of the van der Waals radii. Figure 13 Stacking arrangement in the tetracyanoquinodimethane-tetrathiafulvalene ~o-crystal.~~ Edge-to-face aromatic complexes involve the attraction of a proton of one aromatic molecule to the electron rich centre of a second.It emerges as the dominant motif in crystals of simple aromatics, and benzene itself crystallizes with just such ‘herringbone’ packing.33 This type of noncovalent relationshlp is also Figure 14 Detail from the crystal structure of carp parvalbumin.36 2.4 Noncovalent interactions involving heteroatoms In this section Lewis acid-base chemistry will be considered from the perspective of the noncovalent assembly. As with the above design principles, self- organization based on intermolecular heteroatom- heteroatom links has been described, and thus it is worth examining the nature of the association from a fundamental standpoint. Ths familiar interaction is brought about by the affinity of vacant orbitals for nonbonded electron pairs.The essential character of the bond is seen in the classic borane-ammonia complex (Figure 15a). Geometrically, it is as if the two species were covalently linked, but the boron-nitrogen distance is greater than that of the analogous covalent bond (1.60 versus 1.45 A) and the dissociation energy is 123 kJ mol-1,37 less than half that of the C-C bond of ethane, with which H,N-BH, is formally isoelectronic. Combinations of lesser donors and acceptors naturally form weaker complexes. Although boranes and alanes with their outer shell sextets are the classic nonmetal Lewis acids, elements capable of expanding their valences show similar behaviour.Typical of these are the group V nonmetals ( e g . in Figure 15b), sulfur, and the halogens. Among the best characterized molecular complexes between heteroatoms are those involving halogen acceptor^.^* These are sometimes referred to as ‘face- Mascal: Noncovalent design principles and the new synthesis 37Figure 15 (a) (left); crystal structure of the H,N-BH, complex;3H (b) (right); crystal structure of PF,-~yridine.~~ The P-N distance is 1.89 8, (typical covalent bond length 1.70 A). Figure 16 X-ray structure of the bromine-dioxane molecular complex! ' centred' donor-acceptor complexes and were first examined in detail by Hassel, who was awarded the 1969 Nobel Prize for this work. The interaction bears remarkable similarity to the hydrogen bond ( c j Section 2.2): where X = CI,Br,l B = N,O,Se,S,X- In hydrogen bonding the magnitude of the interaction is related to the Br0nsted acidity of A-H.Face-centred bonding has an analogous correlation with the Lewis acidity of X, and thus likewise on the nature of A as a potential 'leaving group'. As with the hydrogen bond, most of what is known about this intermolecular relationship comes from looking at X-ray crystal structures. Those of the bromine-dioxane, cyanuric chloride, and diselenane-diiodoacetylene complexes (Figures 16- 18) are given below as representative examples. As is seen, the A-X-B angle does not stray far from 180", and the intermolecular contacts are substantially closer than the sum of the van der Waals radii.Compare, for example, the Br-0 distance of 2.71 8, in Figure 16 with the 3.35 8, van der Waals contact. A slight elongation of the Br-Br axis (2.3 1 versus 2.28 in the gas phase) is also observed. With nitrogen-halogen and selenium-halogen adducts, van der Waals violations of greater than one Angstrom are common, malung the link not much longer than the sum of the covalent radii and thus comparable to classic Lewis acid-base complexes. In examining the literature the following generalizations about relative donor and acceptor strengths can be made: donors: sp3N, sp2N > sp30 > sp20 - spN Se>S acceptors: I, > Br, > Cl, > X-spC > X-sp2C > X-sp3C Despite the similarity to hydrogen bonding, both in geometry and association energy (estimates as high as 50 ld mol-1)44 this particular type of interaction has Figure 17 The self-complementary cyanuric chloride molecule in the crystal, featuring six linear N.-Cl contacts (2 x 3.100 and 4 X 3.1 13 A, vdW= 3.30 A).The interplane spacing is 3.26 rarely been exploited as a supramolecular design principle. One potential problem is the chemical reactivity of the species involved, particularly the molecular halogens. Indeed, preliminary charge transfer complexation is thought to mediate several types of reactions.45 Consider for instance the complex in Figure 19, which resembles a frozen transition state of an N-halogenation reaction. association observed between halogens and aromatic donors. In this case, the halogen occupies the sixfold symmetry axis of the aromatic ring and thus interacts equally with each ring atom.Figures 20 and 2 1 show X-ray crystal structures of the bromine-benzene and carbon tetrabromide-xylene complexes, respectively. Likewise, multiple bonds may serve as donors. The crystal structure of diiodoacetylene is remarkably like that of acetylene itself, with the participation of a perpendicular triple-bond.-I interaction in place of the triple-bond.-H hydrogen bond.47 Under certain circumstances other types of bonding involving heteroatoms are observed, most of whch Related to the above is the weak molecular 38 Contemporary Organic SynthesisFigure 18 X-ray structure of the diiodoacetylene-diselenane molecular complex, with Se-s.1 distance 3.34 A (vdW= 4.10 A).43 Figure 19 Crystal structure of the trimethylmine-I, complex.46 The distances are N.**I2.27 A (vdW 3.65, covalent 2.15), 1-1 2.83 A (2.70 in 12).2.05 A, but considerably less than the closest nonbonded sulfur-sulfur contact in S8 (3.32 A) (Figure 23). Although these of the weaker noncovalent associations generally serve to bring molecules into each other's vicinity, it is obvious that their nature is much less specific than, for example, the hydrogen bond. Despite this, they have been discussed in the literature in terms of 'topochemical control' and directed reactivity in crystals, and as such can be considered design principles for the solid state. Figure 20 The benzene-bromine molecular complex.4x The distance from each bromine atom to the adjacent benzene plane is 3.36 A (vdW 3.65 A).An analogous crystalline complex is formed with chlorine.4y Figure 22 Oxygen-carbon interaction (2.73 A) in crystalline a l l ~ x a n . ~ ' Figure 2 1 Crystal structure of carbon tetrabromide/ ~ylene.~" The Br-Ar distance is 3.53 A. would have escaped notice but for X-ray crystallography. Carbonyl compounds for example sometimes show a perpendicular oxygen-carbon contact as illustrated in Figure 22 for alloxan. Remarkably, this interaction dominates hydrogen bonding, which is absent despite four carbonyl and two N-H functions present in each molecule. Weak intermolecular halogen-halogen and chalcogen-chalcogen bonding has also been recognized in a number of both organic and inorganic crystals through close interatomic contacts. Such interactions are, however, much more pronounced when they occur intramolecularly.Thus, in 2-nitrobenzenesulfenyl chloride the sulfur-oxygen distance is 2.38 A (van der Waals 3.20 A) and in tetrasulfurtetranitride the sulfur-sulfur distance is 2.58 A; not as short as the covalent bond length of Figure 23 Close S-S contacts in tetra~ulfurtetranitride~, (left) and S - 0 contact in 2-nitrobenzenesulfenyl chloride.53 2.5 Noncovalent interactions involving transition metals Based on our present definition of self-assembly we must, strictly speaking, include metal-ligand complexes under the heading of supramolecular species since the coordinate bond is not covalent. Yet for obvious reasons we need to restrict the context to cases where particular feats of organization are achieved or specific purposes are served, examples of which will now be considered.The way in which we approach ths subject depends on the role of the metal. Is it part of the fabric of the self-assembled species, or does it simply serve to bridge organic subunits of interest? In the former context we imagine the metal participating as the guest in a host-guest system or in the backbone of a Muscul: Noncovalent design principles and the new synthesis 39metallopolymer; in the latter as a template to a covalent reaction, where the metal is ultimately to be dispensed with, or purely in its capacity as a design principle akin to hydrogen bonding. If the metal is regarded as such, its presence or indeed absence in the final product may be inconsequential, but all the same, the assembly does not stick together of its own accord and the presence of a third party fundamentally differentiates this from other design principles.Consider, for example, bis( acety1acetonato)platinum ( 1 1 ) ~ ~ and compare it with the benzoic acid dimer (Figure 24).ss theory. The common octahedral and tetrahedral stereochemistries are exemplified by tris( 1,3- diaminopropane)cobalt ( 111) chloride56 and tetrakis( pyridine)copper ( I ) per~hlorate,~~ respectively (Figure 25), while square planar was represented by bis( acety1acetonato)platinum (11) in Figure 24. Five- coordinate trigonal bipyramidal and square pyramidal complexes are also known but the energy difference between these configurations is small and the two may even undergo rapid interconversion, thus limiting their use as design principles.Coordination states higher than six are also possible, but limitations involving configurational flux also apply. An example of an eight-coordinate complex is the dodecahedral [tetrakis( catecho1ato)gadolinium ( I I I ) ] ~ - anion (Figure 26). Figure 24 Noncovalent docking of two organic molecules by coordination to a metal (top) and hydrogen bonding (bottom). Although our requirements vary from case to case, the ideal design principle would make possible the spontaneous assembly from subunits of any given when we want them to be permanent and yet reversible Figure 26 Crystal structure of the dodecahedral molecular construct, with links which are permanent ~terakis~catecho~ato)~ado1inium(11r)15 - anion*58 if dissociation is desired.The metal-ligand bond actually approaches this ideal in many respects: generally speaking, it is the strongest of the noncovalent interactions, with bond energies commonly on the same order as those of covalent bonds. The thermodynamic stability of metal Olefins and aromatic n-systems also interact with metals to give defined assemblies, such as the silver ion/l,5-hexadiene complex in Figure 27 and the methylcyclooctatetraene dianionluranium sandwich compound in Figure 28. complexes thus allows for directed assembly under a wider range of conditions than, for example, hydrogen bonds, and yet such complexes are kinetically labile to certain influences ( e g . acid, light, ligand exchange). Further, not only is the geometry of the interaction predictable, but with transition metals the presence of d-electrons provides a choice of symmetries about the metal centre as dictated by ligand field Figure 27 Crystal structure of 2Ag*3C,H,,,.5’ Figure 25 Octahedral and tetrahedral ligand organization about the transition metals cobalt(rrr) and copper(r), respectively. 40 Contemporary Organic SynthesisFigure 28 Views of U"'(MeC,H,2 -)z from the top (left) and edge on (right).60 Since we are only concerned with introducing metal-ligand chemistry conceptually as a design principle, theoretical discussions and classification of the common stereochemistries of transition metal complexes are deferred to other sources.h1 Finally, the adsorption of alkane thiols and sulfides onto the surfaces of elemental gold, silver, and copper has recently been applied to the generation of molecular arrays with long-range order.62 Highly stable, structurally coherent, close-packed monolayers analogous to the intensively investigated Langmuir-Blodgett films result when solutions of the substrate are exposed to the clean metal surfaces.Including end groups on the alkyl chain makes possible the spontaneous organization of (comparatively) vast self-assembled functional surfaces, which are relevant to studies in electrochemistry, catalysis, corrosion, lubrication, adhesion, and sensor technology. Clearly, the noncovalent relationship between the components and the metal is not convergent in the same sense as for the above-described complexes, where a single metal ion gathers the ligands to itself.Rather, subunit-subunit intercohesion results from the mutual attraction to a continuous lattice of occupation sites in addition to multiple van der Waals interactions in the nearly crystalline 'organic phase'. For this reason, structurally well-defined monolayer formation is really only successful for H,C(CH,),SH where n 2 10. This organizational phenomenon also manifests itself in solvophobic interactions (Section 2.6). 2.6 Solvophobic interactions The remaining noncovalent relationship to be considered is the behaviour of domains of philicity. The concept of solvophobicity, where a chemical species finds itself in an environment where no mechanism exists for enthalpic gain, is in itself within the realm of supramolecular science. The species concerned may migrate into less hostile surroundings, for example the bulk phase which it departed, or, given the possibility, take refuge in the cavity of a receptor thus becoming the guest in an inclusion complex.Figure 29 gives an example of inclusion based principally on solvophobic circumstances. Thermodynamically, a balance between entropy and enthalpy of interaction leads to an expression of chemical potential where a cost of approximately 3 kJ mol- per CH, group of an alkyl chain is required to send a hydrocarbon molecule into water.63 This accounts for their remarkably low miscibility, for example 9.5 f 1.3 g n-hexane per 1 O6 g H20.64 The situation, however, becomes interesting when larger molecules associate with a relatively small number of partners to form stable, definable superstructures. Such species exhibit domain oriented behuviour.Amphiphilic surfactant molecules are the classic example. They possess large hydrophobic surfaces capped by highly hydrophilic head groups ('domains'), and to minimize the water-lipid interface, while maximizing the lipid-lipid (Section 2.1) and headgroup-water (Section 2.2) interfaces, they self- organize in aqueous media into what can only be described as spectacular examples of macromolecular architecture. Figure 29 Inclusion of durene in 1,6,20,25- tetraaza( 6.1.6.1 )paracyclophane.4HCLh5 In the simplest case, the introduction of a fatty acid to the surface of water results in monolayer formation ( c j Section 2.5). The vast body of literature on monolayers stretching from the days of Langmuir to the present is witness to the interest in molecular order and its applications.Langmuir-Blodgett monolayers6h are prepared as shown in Figure 30 by compressing surfactant films until closest packing is achieved. The monolayer is then usually transferred from the water to a glass surface, thereby depositing what is essentially a crystal one molecule thick. By redipping the slide, multilayers of precise composition can be prepared. Muscal: Noncovulent design principles and the new synthesis 41Figure 30 Schematic of the preparation of a condensed Langmuir-Blodgett monolayer using a film balance. When agitated in an aqueous medium, amphiphiles will take up and organize against water to form a supramolecular aggregate known as a micelle. The basic concept of the micelle is presented in Figure 3 1, although it should be borne in mind that they are highly fluid and have been shown to possess a rather unexpected degree of disorder.67 The optimal shape for a simple micelle is elliptical, but in ranges of higher viscoelasticity, rod-like assemblies are observed.68 In cases where the surfactant tail is of about the same volume as the head group, the aggregates no longer tend to the convex, and biZayer formation occurs.The components of a bilayer are commonly referred to as lipids, and lipid membranes close upon themselves under certain conditions to give spherical liposomes, true giants of supramolecular construction (Figure 32). Synthetic liposomes range in diameter between 200 and 1 000 000 A depending on the method of preparation, and may be either simple or compound (i.e.interleaved).6y The enclosed aqueous compartment, which houses the machinery of cells in living organisms, is ideal for studies of membrane permeability and can also be used as a vehicle for drug de1ive1-y.~~ Along these lines, Ringsdorf has employed modified lipids with unsaturations in the tail, headgroup, or even counter-ion in the preparation of liposomes which can be stabilized by polymerization, giving what are essentially little plastic capsules.71 This is an excellent example of using supramolecular preorganization to template the synthesis of a macromolecule which would be inaccessible by non- directed processes. The hydrophobic effect is also a major contributor to the tertiary structure of proteins, which analogously take on a globular form with charged groups at the surface and hydrophobic residues mainly on the inside. A great deal of work has been done on the prediction of higher order structure in polypeptides from the primary amino acid sequence based on an understanding of the attractive interactions and hydr~phobicity.~ hydrophobic forces are non-specific and tend to Although clearly a powerful organizing influence, Figure 32 Representation of a liposome.operate collectively, as do van der Waals interactions. In terms of design principle repertory, solvophobicity is the key to the complexation of neutral guests in water soluble hosts such as cyclophanes and cyclodextrins. The organization of amphiphiles into expansive molecular assemblies has been extended to the preparation of functional ( e.g. electroactive) films and model membranes, the templated synthesis of macromolecules, the understanding of crystallization processes, and the controlled nucleation of mineral growth in approaches to the fabrication of bioceramics .’ 2.7 Topological bonding and incarceration Like the concept of steric complementarity, topological bonding and incarceration are design principles without being noncovalent interactions.In the former, two or more species, which do not necessarily show mutual affinity, are confined to each other’s company by being physically intertwined. In the latter and as the name suggests, a guest species is retained not by attractive forces but rather total envelopment. Escape may only be possible under fierce conditions or even by destruction of the host. Catenanes are topological isomers of cyclic compounds.As illustrated schematically in Figure 33, two interpenetrating rings give a simple [ 21-catenane, whilst four distinct isomeric [ 31-catenanes are possible. The most elementary catenane, in theory, is the C,,-C,, hydrocarbon, which is just feasible with the rings at maximum aperture. However, no alkyl chain has yet been threaded through a ring smaller than Figure 3 1 Representations of elliptical (right) and cylindrical rod-like (left) micelles. 42 Contemporary Organic SynthesisC,, .74 Schdl, who recorded most of the early developments in catenane chemistry, has reported the only example of the isolation and characterization of an all hydrocarbon catenane, C,,-C,, ?5 Catenanes also occur naturally in the form of interlocked deoxyribonucleic acid rings, dramatic examples of which have been observed in v ~ v o .~ ~ 00 000 a b C d e Figure 33 (a) [2]-Catenane; (b)-(e) the isomeric [3]- catenanes. Structures (d) and (e) are chiral. Rotaxanes are a related species, the concept of which is presented graphically in Figure 34. Cases where the chain cannot withdraw from the ring without the breaking of a covalent bond are analogous to catenanes and true topological isomers of their components. Imaginative combinations of rings (hydrocarbons, crown ethers, cyclodextrins, cyclophanes), chains (arene, ether, amine, polymer) and stoppers (triphenylmethyl, porphines, trialkylsilyl, transition metal complexes) have been employed.n P Figure 34 Schematic representation of a rotaxane. Both statistical and directed synthetic approaches to topologically linked compounds have been registered, and the field has seen a recent flurry in the efforts of Sauvage and Stoddart, who have applied directed self- assembly to the problem. S a ~ v a g e ~ ~ templated his catenane/rotaxane synthesis by metal-ligand bonding, while Stoddart7, made use of aromatic EDA interactions (Figure 35). Hydrogen bonding has also been used.79 A general scarcity of organic compounds which form entirely closed cavities means that examples of molecular incarceration are uncommon. The advent of the fullerenes has perhaps generated an awareness of the possibility of absolute incarceration of any species from the size of a proton up to the 7 A cavity of C,o.However, it is the work of Cram which makes addressing this subject something more than an afterthought. Carcerands (Figure 36) is the name given by Cram to a family of compounds conceptualized Do- doT - 0 W Z Figure 36 The hemicarcerand within which the reaction sequence leading up to cyclobutadiene took place. Expulsion of the product led to dimerization and rearrangement to cyclooctatetraene. Figure 35 Crystal structures of Stoddart's catenane (left) and rotaxane (right), the syntheses of which were templated by aromatic EDA interactions between complementary hydroquinone and bipyridinium dication recognition units in the component^.'^ Mascal: Noncovalent design principles and the new synthesis 4344 wholly to the purpose of incarceration.*’ These molecules with rugby ball-shaped interiors trap guests by capture during synthesis or by the thermally assisted ingression of small species through the ‘portals’ of carcerands lacking one link between the two shells (hemicarcerands).The crowning accomplishment of this work has been the inclusion of a-pyrone and its conversion into cyclobutadiene,sl which is stable at room temperature in the interior of the hemicarcerand, which Cram has likened to a new phase of matter. non-associating guest is a rather more common phenomenon, but is observable only as long as the host system remains associated. A case already mentioned is compartmentalization within liposomes (Section 2.6). Another example is molecules which can accomodate guests in their crystal lattices, such as hydroquinone, urea, and water.The inclusion networks generated by such species are referred to as clathrates,82 over 1000 of which have been characterized by X-ray crystallography. These have been compared structurally to zeolites with their regular array of channels. Examples of hydrate and thiourea clathrates are given in Figure 37. The supramolecular containment of a 3 Conclusion The purpose of this review has been to catalog, in simple terms, the means at the disposal of the chemist for the design and synthesis of molecular assemblies. The analogy to the design of ‘atomic assemblies’ by synthesis in the traditional sense suggests itself. A number of practical applications of supramolecular chemistry have already emerged,85 and ever more ingenious work is continuously being published.Be that as it may, the accomplishments of three thousand million years of evolution will not be duplicated too soon, and the development of supramolecular devices to rival nature’s will only become possible in principle through an in-depth understanding of the information-structure-function relationship. To exemplify this let us briefly consider the tobacco mosaic virus. The viral particle assembles itself from its subunits without assistance or instruction from any external agent. This is solely the consequence of the information intrinsic to these subunits by virtue of their morphology and functionality. Thus information gave rise to recognition and hence self-assembly. But if we now assume that this virus never existed, we can assert that we could have created it if we had had the necessary information, i.e.that the combination of a particular 6 kilobase strand of RNA with 2 130 protein subunits 15 8 specific residues in length would result in a device which not only has a function, but belongs to a family of species which occupies the borderline between the animate and inanimate. The same case might be made for any functional biomolecule. It may, however, be pointed out that even if the information required for the synthesis of such supramolecular devices were to become available to us, the state of the art of synthesis would be yet another hurdle to making the components of assemblies of high complexity. For example, although the protein subunit of tobacco mosaic virus is currently withm the capabilities of the synthetic chemist, the RNA core may not be, the longest synthetic gene to date containing some 1000 bases.86 However, as synthetic methodology advances, the emphasis in the development of chemistry will be increasingly on information and its application to the design of task-specific devices, as inspired by nature.It is no longer only discovery and efect but also function which the synthetic chemist may exercise with his art. In the drive towards the ultimate goal of function, an interesting turn of events has taken place. It has recently been remarkedX7 that chemists, who for years have been using (for the most part) unnatural means to access natural products, now turn to means reminiscent of natural processes to access completely unnatural products.Figure 37 Left, trimethylammonium ion in (part) of its ice cage,x3 the ‘bonds’ between the oxygens representing H-bonding axes; right, cross-section of two cells of the thiourea-adamantane clathrate.x4 Contemporary Organic Synthesis4 References and notes 1 J.-M.Lehn, PureAppl. Chem., 1978,50,871. 2 D.A. Pears, J.F. Stoddart, M.E. Fakley, B.L. Allwood, and D.J. Williams, Acta Crystallogr. Sect. C, 1988,44,1426. 3 J.A. Zerkowski, C.T. Seto, and G.M. Whitesides, J. Am. Chem. SOC., 1992,114,5473. 4 G. Nicolis in ‘The New Physics’, ed. P. Davies, Cambridge University Press, Cambridge, 1989, pp. 316-347. 5 H.-J. Schneider, T. Schiestel, and P. Zimmermann, J. Am. 6 D.W. Christianson and W.N. Lipscomb, Proc.Natl. Acad. 7 G.M.J. Schmidt, Pure Appl. Chem., 1971,27,647; Chem. SOC., 1992,114,7698. Sci. USA, 1986,83,7568. L. Addadi, Z. Berkovitch-Yellin, I. Weissbuch, J. van Mil, L.J.W. Shimon, M. Lahav, and L. Leiserowitz, Angew. Chem. Znt. Ed. Engl., 1985,24,466; J.D. Wright, ‘Molecular Crystals’, Cambridge University Press, Cambridge, 1987, pp. 108-130; S.K. Kearsley in ‘Organic Solid State Chemistry’, ed. G.R. Desiraju, Elsevier, Amsterdam, 1987, pp. 69- 1 13; F. Toda in ‘Topics in Current Chemistry’, ed. E. Weber, Springer- Verlag, Berlin, vol. 149,1988, pp. 211-238; G.R. Desiraju, ‘Crystal Engineering. The Design of Organic Solids’, Elsevier, Amsterdam, 1989. 8 J.K. Whitesell, R.E. Davis, L.L. Saunders, R.J. Wilson, and J.P.Feagins, J. Am. Chem. SOC., 1991,113,3267.9 J.-M. Lehn, M. Mascal, A. DeCian, and J. Fischer, J. Chem. SOC., Chem. Commun., 1990,479. 10 See R. Taylor and 0. Kennard, Acc. Chem. Res., 1984, 17,320. A dramatic violation of this is found in crystalline urea, in which the oxygen atom accepts four hydrogen bonds: P, Vaughan and J. Donohue, Acta Crystallogr., 1952,5,530. 11 B. Kamb, W.C. Hamilton, S.J. la Placa, and A. Prakash, J. Chem. Phys., 1971,55,1934. 12 M.H.Abraham, Chem. SOC. Rev., 1993,22,73. 13 J. Emsley, Chem. SOC. Rev., 1980,9,91. 14 R. Taylor and 0. Kennard, J. Am. Chem. Soc., 1982, 104,5063; J.A.R.P. Sarma and G.R. Desiraju, Acc. Chem. Res., 1986,19,222; G.R. Desiraju and B.N. Murty, Chem. Phys. Lett., 1987,139,360;D.S. Reddy, B.S. Goud, K. Panneerseluam, and G.R. Desiraju, J. Chem. SOC., Chem.Commun., 1993,663. 15 A.L. MacDonald, J.C. Speakman, and D. Hadzi, J. Chem. SOC. Perkin Trans. 2,1972,825. 16 L. Golic, I. Leban, S. Detoni, B. Orel, and D. Hadzi, J. Cryst. Spectrosc., 1985,15,215. 17 For examples of synthetic receptors and a discussion of the interaction see E. Fan, S.A. Van Arman, S. Kincaid, and A.D. Hamilton, J. Am. Chem. SOC., 1993,115,369. 18 B. Kratochvil, J. Ondracek, J. Krechl, and J. Hasek, Acta Crystallogr., Sect. C, 1987,43,2 182. 19 T.J. Murray and S.C. Zimmerman, J. Am. Chem. SOC., 1992,114,4010. 20 J. Pranata, S.G. Wierschke, and W.L. Jorgensen, J. Am. Chem. SOC., 1991,113,2810. 2 1 For a concise discussion of the use of NMR for quantifying host-guest interactions see C.S. Wilcox in ‘Frontiers in Supramolecular Organic Chemistry and Photochemistry’, ed.H.-J. Schneider and H. Durr, VCH, Weinheim, 1991,pp. 123-143. 22 A. Novak in ‘Structure and Bonding’, ed. J.D. Dunitz, et al., Springer-Verlag, Berlin, 1974, vol. 18, pp. 177-2 16. 23 J. Fritzsche, J. Prakt. Chem., 1858,73,288. 24 C.A. Hunter and J.K.M. Sanders, J. Am. Chem. SOC., 25 G. Briegleb, ‘Elektronen-Donator-Acceptor-Komplexe’, 1990,112,5525. Springer-Verlag, Berlin, 196 1. 26 F. Iwasaki and Y. Saito, Acta Crystallogr., Sect. B, 1970, 26,251. 27 B.M.L. Chen and A.Tulinsky, J. Am. Chem. Soc., 1972, 94,4144. 28 For a review of the formation and chemistry of excited complexes see RS. Davidson, Adv. Phys. 0%. Chem., 1983,19,1. R. Knochenmuss and S. Leutwyler, J. Chem. Phys., 1990, 92,4686 and references therein; H.J. Neusser and E.W. Schlag, Angew.Chem., Znt. Ed. Engl., 1992,31,263. 30 E. Maverick, K.N. Trueblood, and D.A. Bekoe, Acta Crystallogr., Sect. B, 1978,34,2777. 3 1 For a review including metallomacrocycles see T.J. Marks, Angew. Chem., Znt. Ed. Engl., 1990,29,857. 32 A. Filhol, G. Bravic, J. Gaultier, D. Chasseau, and C. Vettier,Acta Crystallogr., Sect. B, 1981,37,1225. 33 G.R. Desiraju and A. Gavezzotti, J. Chem. SOC., Chem. Commun., 1989,621. 34 S.K. Burley and G.A. Petsko, Science, 1985,229,23; S.K. Burley and G.A. Petsko, J. Am. Chem. SOC., 1986, 29 S. Leutwyler, J. Chem. Phys., 1984,81,5480; 108,7995. 35 R.K. McMullan, A. Kvick, and P. Popelier, Acta 36 V.D. Kumar, L. Lee, and B.F.P. Edwards, Biochemistry, 37 Calculation: S.D. Peyerimhoff and R.J. Buenker, J. Chem. 38 D.R.Alston, J.F. Stoddart, J.B. Wolstenholme, B.L. Crystallogr., Sect. B, 1992,48,726. 1990,29,1404. Phys., 1968,49,3 12. Allwood, and D.J. Williams, Tetrahedron, 1985,41, 2923. 39 W.S. Sheldrick, J. Chem. SOC., Dalton Trans., 1974,1402. 40 0. Hassel and C. Ramming, Quart. Rev. Chem. SOC., 1962,16,1; H.A. Bent, Chem. Rev., 1968,68,587. 41 0. Hassel and J. Hvoslef, Acta Chem. Scand., 1954,8, 873. 42 R.A. Pascal, Jr., and D.M. Ho, Tetrahedron Lett., 1992, 33,4707; K. Xu, D.M. Ho, and R. Pascal, Jr., submitted for publication. 1966,20,2601. 1962,13,107. Chemistry’, ed. S.G. Cohen, A. Streitwieser, Jr., and R.W. Taft, Wiley, New York, 1965, vol. 3, pp. 8 1 - 163. 43 0. Holmesland and C. Rramming, Acta Chem. Scand., 44 R.S. Mulliken and W.B. Person, Ann. Rev. Phys. Chem., 45 E.M.Kosower in ‘Progress in Physical Organic 46 K.O. Strsmme,Acta Chem. Scand., 1959,13,268. 47 J.D. Dunitz, H. Gehrer, and D. Britton, Acta Crystallogr., Sect. B, 1972,28,1989. 48 0. Hassel and K.O. Strramme, Acta Chem. Scand., 1958, 12,1146. 49 0. Hassel and K.O. Stramme, Acta Chem. Scand., 1959, 13,1781. 50 F.J. Strieter and D.H. Templeton, J. Chem. Phys., 1962, 37,161. 5 1 R.K. McMullan, B.M. Craven, and S. Swaminathan, Am. Cryst. Assoc., Ser. 2,1983, 11,36. 52 M.L. deLucia and P. Coppens, Znorg. Chem., 1978,17, 2336. 53 A. Kucsman, I. Kapovits, M. Czugler, L. Parkanyi, and A.Kalman, J. MoI. Struct., 1989,198,339. 54 M. Katoh, K. Miki, Y. Kai, N. Tanaka, and N. Kasai, Bull. Chem. SOC. Jpn., 1981,54,611. 55 R. Feld, M.S. Lehmann, K.W. Muir, and J.C. Speakman, 2.Kristallogr., 1981,157,215. 56 R. Nagao, F. Marumo, and Y. Saito, Acta Crystallogr., Sect. B, 1973,29,2438. 57 K. Nilsson and A. Oskarsson, Acta Chem. Scand. A , 1982,36,605. Mascal: Noncovalent design principles and the new synthesis 4558 G.E. Freeman and K.N. Raymond, Inorg. Chem., 1985, 24,1410. 59 I.W. Bassi and G. Fagherazzi, J. Organornet. Chem., 1968,13,535. 60 T.R Boussie, D.C. Eisenberg, J. Rigsbee, A. Streitwieser, and A. Zalkin, Organometallics, 1991,10,1922. 6 1 For example: F.A. Cotton and G. Wilkinson, ‘Advanced Inorganic Chemistry’, Wiley, New York, 5th ed., 1988; N.N. Greenwood and A. Earnshaw, ‘Chemistry of the Elements’, Pergamon Press, Oxford, 1984. 62 R.G. Nuzzo and D.L. AUara, J. Am. Chem. SOC., 1983, 105,4481; C.D. Bain, E.B.Troughton, Y.-T. Tao, J. Evall, G.M. Whitesides, and R.G. Nuzzo, J. Am. Chem. SOC., 1989,111,321; C.D. Bain and G. Whitesides, Angew. Chem., Int. Ed. Engl., 1989,28,506. 63 C. Tanford, Science, 1978,200,1012. See also A. Ben-Naim, ‘Hydrophobic Interactions’, Plenum, New York, 1980; H.-J. Schneider, Angew. Chem., Int. Ed. Engl., 1991,30,1417. 64 C. McAuliffe, J. Phys. Chem., 1966,70,1267. 65 K. Odashima, A. Itai, Y. Iitaka, and K. Koga, J. Am. 66 I. Langmuir, Trans. Furuduy Soc., 1920,15,62; K.B. Chem. SOC., 1980,102,2504. Blodgett, J. Am. Chem. SOC., 1935,57,1007; G.L. Gaines, ‘Insoluble Monolayers at Liquid-Gas Interfaces’, Wiley-Interscience, New York, 1966. 1086. Engl., 1988,27,902. Micelles and Biological Membranes’, Wiley-Interscience, New York, 2nd ed., 1980; ‘Liposomes: From Physical Structure to Therapeutic Applications’, ed.G.C. Knight, Elsevier, Amsterdam, 198 1 ; J.H. Fender, ‘Membrane Mimetic Chemistry: Characterizations and Applications of Micelles, Microemulsions, Monolayers, Bilayers, Vesicles, Host-Guest Systems and Polyions’, Wiley, New York, 1982; V. Degiorgio, M. Corti, ‘Physics of Amphiphiles-Micelles, Vesicles, and Microemulsions’, North-Holland Publishing, New York, 1983; ‘Liposomes’, ed. M.J. Ostro, Dekker, New York, 1983; ‘Liposome Technology’ ed. G. Gregoriadis, CRC Press, Boca Raton, 1984; T. Kunitake, Angew. Chem., Int. Ed. Engl., 1992,31,709. Biomaterials’, Academic Press, New York, 1980; T.K. Lee, T.D. Sokoloski, and G.P. Royer, Science, 1981,213, 333; G. Gregoriadis, ‘Liposomes as Drug Carriers: Recent Trends and Progress’, Wiley, New York, 1988.71 L. Gros, H. Ringsdorf, and H. Schupp, Angew. Chem., Int. Ed. Engl., 1981,20,305; H. Ringsdorf, B. Schlarb, and J. Venzmer,Angew. Chem., Int. Ed. Engl., 1988,27, 113. 67 EM. Menger, Angew. Chem., Int. Ed. Engl., 1991,30, 68 H. Hoffhann and G. Ebert, Angew. Chem., Int. Ed. 69 C. Tanford, ‘The Hydrophobic Effect: Formation of 70 J. Heller and R.W. Blake, ‘Controlled Release of 72 T.E. Creighton, ‘Proteins: Structure and Molecular Properties’, W.H. Freeman Co., New York, 1984; R. Jaenicke, Angew. Chem., Int. Ed. Engl., 1984,23, 395; G. Schneider and P. Wrede, Angew. Chem., Int. Ed. Engl., 1993,32,1141. Calvert, K. Kendall, G.L. Messing, J. Blackwell, P.C. Rieke, D.H. Thompson, A.P. Wheeler, A. Veis, and A.I. Caplan, Science, 1992,255,1098. 74 I.T. Harrison, J. Chem. SOC., Perkin Trans. I, 1974,301. 75 G. Shill, N. Schweickert, H. Fritz, and W. Vetter, Angew. Chem., Int. Ed. Engl., 1983,22,889. 76 J.C. Wang, Acc. Chem. Res., 1973,6,252. 77 For an overview of Sauvage’s strategy and molecular 73 A.H. Heuer, D.J. Fink,V.J. Laraia, J.L. Arias,P.D. knots in general, see: C.O. Dietrich-Buchecker and J.-P, Sauvage, Chem. Rev., 1987,87,795; J.-C. Chambron, C. Dietrich-Buchecker, and J.-P. Sauvage in ‘Topics in Current Chemistry’, ed. E. Weber, Springer-Verlag, Berlin, vol. 1 6 5 , 1 9 9 3 , ~ ~ . 131-162. M. Delgado, M.T. Gandolfi, T.T. Goodnow, A.E. Kaifer, D. Philp, M. Pietraszkiewicz, L. Prodi, M.V. Reddington, A.M.Z. Slawin, N. Spencer, J.F. Stoddart, C. Vincent, and D.J. Williams, J.Am. Chem. SOC., 1992,114,193. 79 Remarkably, identical approaches were published independently by: C.A. Hunter, J. Am. Chem. SOC., 1992, 114,5303; and F. Vogtle, S. Meier, and R. HOSS, Angew. Chem., Int. Ed. Engl., 1992,31,1619. G.W. Kallemeyn,J. Am. Chem. SOC., 1985,107,2575; M.E. Tanner, C.B. Knobler, and D.J. Cram, J. Am. Chem. SOC., 1990,112,1659; H.J. Choi,D.J. Cram, C.B. Knobler, and E.F. Maverick, Pure Appl. Chem., 1993, 65,539. 81 D.J. Cram, M.E. Tanner, and R. Thomas, Angew. Chem., Int. Ed. Engl., 1991,30,1024. 82 ‘Molecular Inclusion and Molecular Recognition-Clathrates I and 11’: ‘Topics in Current Chemistry ’, ed. E. Weber, Springer-Verlag, Berlin, vol. 140,1987, vol. 149,1988. 47,263. Crystullogr., Sect. C, 1989,45,257. any save those accomplishments which served to exemplify the design principle under consideration. 86 J.W. Engels and E. Uhlmann, Angew. Chem., Int. Ed. Engl., 1989,28,716. 87 J.F. Stoddart, Izatt-Christensen Lecture, 18th International Symposium on Macrocyclic Chemistry, University of Twente, Enschede, The Netherlands. 78 P.L. Anelli, P.R. Ashton, R. Ballardini, V. Balzani, 80 D.J. Cram, S. Karbach, Y.H. Kim, L. Baczynskyj, and 83 D. Mootz and D. Staben, Z. Nuturforsch., Teil B, 1992, 84 R. Gopal, B.E. Robertson, and J.S. Rutherford, Actu 85 It was regrettably outside the remit of this review to detail 46 Contemporary Organic Synthesk

ISSN:1350-4894    

DOI:10.1039/CO9940100031

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Recent progress in the synthesis of taxanes A.N. BOA," P.R. JENKINS," and N.J. LAWRENCEb "Department of Chemistry, The University, Leicester LEI 7RH Department of Chemistry, UMIST, PO Box 88, Manchester M60 1 QD Reviewing the literature published between January 1991 and July 1993. Reference to earlier synthetic work is included where this provides additional perspective 1 2 2.1 2.2 2.3 2.4 3 4 4.1 4.2 4.3 4.4 4.5 4.6 5 Introduction Approaches to the total synthesis of taxanes From A-ring precursors From c-ring precursors From A-ring and c-ring precursors Syntheses starting from the Wieland-Miescher ketone Semi-syntheses of taxanes Syntheses of the C-13 side chain of taxol Phenylglycidate synthon method The Staudinger synthesis of p-lactams Lithiobenzylamine synthon method Enzymic syntheses Aldol reaction approaches A chiral pool approach References 1 Introduction The highly complex tetracyclic diterpene taxol 1, first described by Wall and co-workers in 1971,' is proving to be of great potential in the successful treatment of many types of cancer.* Taxol's unique antimitotic action3 and remarkable efficacy as an anti-cancer drug has stimulated great biochemical attention.BzNH 0 OH BzO 1 Nevertheless the true potential of taxol will only be realized when it is more readily available. The problems associated with its isolation from the bark of the Pacific yew tree Taxus brevifolia, have been reported at length." Total5 and semi-synthesis4 are just two of the many proposed solutions7 to increase the supply of taxol without endangering the yew tree.The former approach has proved extremely arduous and, to date: no successful total synthesis of taxol has been published. Nevertheless as a challenging target, taxol has stimulated many elegant synthetic approaches, including the development of new methods that, in addition, have led to the synthesis of many analogues. We have divided this review into two sections, namely (if approaches to the total synthesis of taxanes, and (ii) semi-synthesis of taxanes. We have further divided the first section, somewhat loosely, into three parts. The first part (2.1) describes linear approaches that sequentially build the taxane ring from an A-ring precursor (so-called left to right approach) whereas the second part (2.2) details approaches that construct the taxane ring from a c-ring precursor (the right to left approach).The third part (2.3) of the first section includes approaches to taxanes that construct the B-ring, as the final step. from precursors that contain both the A and c-rings. These approaches are summarized diagrammatically in Figure 1. ~ + A B C Figure 1 Disconnective approaches towards the synthesis of taxanes. 2 Approaches to the total synthesis of taxanes 2.1 From A-ring precursors Pattenden Pattenden and HitchcockY have synthesized a compound with the tricyclic ring system common to Boa, Jenkins, and Lawrence: Recent progress in the synthesis of taxanes 47+OAC 79% (1) + -=YH 0 0 k H 2 OH 4 a R = - b R = H 5 6 3a R = Br 1 (v9 bR=l- c R = H Reagents: (i) BF,.OEt,, - 78°C; (ii) 3 eq. CH,CHMgBr; (iii) cat.tetra (n-propy1)ammonium perruthenate, N-methylmorpholine oxide; (iv) 25eq (€)-Bu,SnCH=CH(CH,),Br, Bu"Li, - 75°C; (v) BaMnO,; (vi) Nal, MeCOEt; (vii) Bu,SnH, cat. AIBN, PhH, A Scheme 1 molecules of the taxane group using a powerful tandem radical macrocyclization-transannulation sequence (Scheme 1 ). In this sequence, the functionalized A-hg 2 containing the unsaturation and methyl substitution of the taxane skeleton was obtained from the Diels-Alder reaction between 2,4-dimethyl- 3- (ace t oxy me t hy 1 )-pent a- 2,4-diene and ac r olein, and was then modified to give the radical precursor 3b as depicted. Upon treatment with tributyltin hydride and a,a'-azoisobutyronitrile (AIBN) the iodo trienedione 3b gave the two separable C-1 epimers 5 and 6 of the taxane ring system in a 3 : 1 ratio (25% yield) along with the reduced product 3c (30%).A second product of reduction 4 b (20%) was isolated, resulting from quenching of the intermediate radical 4a produced after the initial and impressive 12-endo radical macrocyclization step. This ring closure fixes the eventual C-1 ratio of epimers 5 and 6 and is most likely controlled by the conformation of the trienedione 3b before cyclization. The 6-ex0 trig (transannular) cyclization of 4a to 5 and 6 led to the desired trans fused BC ring junction, in accord with the predictions made using the Beckwith transition state model. Oishi and Ohtsuka ABC ring structure 12. However, as it stood this approach seemed limited since synthesis of the mesylate 9 was rather lengthy (7-9,23 steps and 6% overall yield), and the Michael addition of nitromethane anion used in the synthesis of 8 was poor yielding.The chances of overall success in this strategy have recently been greatly increased, however, by a much improved, shorter synthesis (Scheme 3).12 Thus, the monobenzylated 1,5-pentanedio113 was converted in five steps into the diene 14, which reacted in a highly stereoselective Diels-Alder reaction with maleic anhydride to give 15 as a single isomer. Direct reduction of 15 with sodium borohydride under various conditions led to mixtures of the isomeric lactones 17 and 18, with the undesired isomer 18 predominating in most cases. Exclusive conversion of 15 to 17 could be achieved via the iodoacid 16, using a hydrolysis-iodolactonization-reduction sequence.Alkylation of the lactone 17 with LDA and methyl iodide next gave 19 in good yield. The lactone 19 was then converted into mesylate-acid 20 in which the two pendant groups in the A-ring have the cis relationship necessary for subsequent macrocyclization. The acid 20 was converted into the AB structure 1 l b following much the same sequence summarized in Scheme 3. Alkylation of the acid 20 was not effected immediately, that is to give 9, but was left until after Oishi and Ohtsuka have developed methodology for the formation of the AB ring system in the taxanes using a strategy based on transannular acylation of sulfone stabilized anion intermediates. Previous reports'O from formation of the marocyclic lacte-sulfide ring. This methylation was stereospecific, leading to a single isomer of 10 with undetermined relative configuration.their research group had shown that the mesylate 9 can be made from a-ionone 7 as briefly depicted in Scheme 2. Macrocyclization of 9 with 0-( methy1amino)thiophenol next gave the 12-membered lactam sulfide 10, which upon oxidation to the corresponding sulfone and treatment with lithium diisopropylamide (LDA) gave the ring- contracted bicyclic structure 1 la. Reductive cleavage of the sulfone group in 1 l a then gave the AB ring system 1 l b which has been converted" to the tricyclic Fetizon Fetizon has investigated several strategies for the synthesis of taxanes. The first strategy13 involved coupling of A and c ring fragments, but the subsequent attempted closure to form the B ring was unsuccessful.This work has been reviewed el~ewhere.~ In their most recent reportI4 Fetizon and co-workers have shown that the a-fenchol derived enols 2 1 and 22 undergo photocycloaddition with vinyl acetate to give the 48 Contemporary Organic Synthesk0 <-*- 7 30% --- 21 % 8 v*H OMS 9 H 0 12 Reagents: (i) (COCI),, PhH; (ii) (a) 2'-cyanoethyi(2-methylamino)phenyl sulfide; (b) K,CO,, NaBH,, DMF; (iii) NalO,; (iv) LDA, THF; (v) Na-Hg, Na,HPO, Scheme 2 HO-OBn 13 14 I 15 16 17 18 Reagents: (i) PCC, DCM; (ii) EtO,CC(=PPh,)Me, PhMe; (iii) LiAIH,, Et,O; (iv) PCC, DCM; (v) Ph,PMel, BuLi, THF; (vi) maleic anhydride, PhMe, A; (vii) 0.5M NaHCO, then I,, KI; (viii) (a) THF-B(OMe),, BH,.Me,S, (b) Zn-AcOH; (ix) LDA, Mel; (x) (a) DIBAL-H, PhMe, (b) NH,NH,, NaOH, diethyiene glycol, (c) Ac,O, pyridine; (xi) (a) H, Raney-Ni, EtOH, (b) 3,4-dihydro-2H-pyran, H +, (c) LiAIH,, (d) MsCI, (e) Jones' oxidation Scheme 3 cyclobutanes 23a,b and 24a,b as a mixture of separable isomers (Scheme 4).The boron trifluoride etherate mediated retroaldol reactions of either 23a or 24a then gave the bicyclic diketone 25a; likewise 24b led to the epimeric diketone 25b. The 0-methoxy isomer 23b on the other hand failed to undergo a retroaldol reaction and was recovered unchanged from the reaction mixture. The products 25 represent contracted AB ring systems in which the A ring is lacking a methylene group. The products 25a,b have been modified to give the new diketone 26, and the authors now hope to eventually attach the taxane c ring to 26 via an annulation procedure.Fetizon and his co-workers describe the photochemical cycloaddition route with more complex vinyl acetate derivatives. Thus, the known vinyl acetate 28 was first reacted photochemically with the enol In a subsequent reportt5 of an AB ring synthesis, Boa, Jenkins, and Lawrence: Recent progress in the synthesis of taxanes 49RO 21 R=Me 22R=H 0 H RO '' OAc + a:b 1 :2.6 23a + 23b (R = Me) a:b1:1 24a + 24b (R=H) 23. (85%) 1 24b (80%) (10 ;: (g; 26 25a R = H, R' = OAc 25b R = OAC, W = H Reagents: (i) CH,=CHOAc, hv, DCM (for 21) or MeOH (for 22) (ii) BF,.0Et2, DCM, 0°C; (iii) (CH,OH),, PPTS, PhH, A, 48 h; (iv) NaOMe, MeOH, O"C, 2 h; (v) PDC, DCM, 24 h Scheme 4 tautomer of dimedone 27, leading to cyclobutanol29 (Scheme 5), which was not isolated but instead underwent a spontaneous retroaldol reaction to give the diketone 30.The reaction leading to 30 was found to be regio- and stereo-specific. After various functional group interconversions the triketone 3 1 was next produced. Upon treatment of 3 1 with a range of bases ( e.g. sodium methoxide, potassium-t-butoxide, LDA, and sodium hydride) the dehydrated-cyclized product 32 was then formed. However, treatment of 3 1 with bromomagnesium diisopropylamide (BMDA ) gave the tertiary alcohol 33 in 50% yield. This proved to be very stable under acidic and basic conditions and its structure was determined by X-ray analysis. Fetizon and co-workers have recently reported16 another approach to the taxane AB ring system using a Norrish type I1 photo-fragmentation strategy (Scheme 6).The Diels-Alder cycloaddition of benzoquinone 34 to the diene 35 gave the bicyclic compound 36 as a single regio- and stereo-isomer. This enedione was next reduced to the dione 37, giving a mixture of epimers at C-9. Further reduction of the C-7 ketone in this mixture with lithium t-butoxy aluminium hydride led to the ketoalcohols 38 and 39 which were easily separated by chromatography. The structure of 38 was proven by X-ray crystallography. Treatment of 38 with the non-nucleophilic base sodium hexamethyldisilazide (NaHMDS) produced the hemiacetal4 la, via the lactone 40. Subsequent methylation of 4 l a gave the acetal4 l b in overall 56% yield from 34. Irradiation of 4 1 b resulted in homolysis of the C-4-C- 12 bond, followed by selective hydrogen migration from C-3 to give the aldehyde 42.Molecular models showed that, for steric reasons, the homolysis of the C-1-C-12 bond in 4 l b cannot be followed by a concerted H-migration from either C-1 or C-7. Unfortunately, the reaction was severely hampered by the appearance of [2 + 21 cycloaddition by-products quite soon after the start of photolysis. The reaction was monitored by TLC and stopped when these by- products built up, typically after only 12% conversion (69% yield based on consumed starting material) to 42. The starting material could be recovered easily using chromatrography. The aldehyde function in 42 was reduced to a methyl group, so giving the interesting acetal43. application of the Haller-Bauer reaction (sodium amide in toluene) to fragment the acetal4 1 b resulted in direct formation of the lactam 45.After formation of the expected product amide 44, the strongly basic conditions presumably promoted a ring closure reaction to the acetal functional group in 44, followed by a reduction of the resulting C-5 ketone. No further elaboration of 45 has been reported, but hydrolysis of the lactam, followed by reduction of the carboxylic acid function to a methyl group could give access to some interesting aza-analogues of the taxane AB ring sy s tem . In an earlier publi~ation,'~ Fetizon et al. showed that '0 27 r o Ac 29 32 Reagents: (i) hv, MeOH, 0°C; (ii) (CH,OH),, PPTS, PhH; (iii) MeONa, MeOH; (iv) PDC, DCM; (v) PPTS, H,O-acetone (1 :9); (vi) BrMgNPr:, THF, -78°C Scheme 5 50 Contemporary Organic Synthesis35 34 36 37 38 39 tviil 6996 (12.5%Conversion) I r 42 R = CHOJ 43 R = CH3 41aR = H 56% from 34 bR=MeJ@') 45 40 44 Reagents: (i) PhH, A, 72 h; (ii) Zn, AcOH,))))), ; (iii) lithium t-butoxyaluminium hydride; (iv) chromatography; (v) NaHMDS; (vi) (MeO)-,CH, p-TsOH; (vii) hv, 12254 nm, MeOH, 0°C; (viii) (a) LiAIH,, (b) MsCI, (c) lithium triethylborohydride; (ix) NaNH,, PhMe Scheme 6 Cha Cha has reported'* a synthesis of the taxane AB ring system based on an initial [4 + 31 diene-oxyallyl cation cycloaddition reaction (Scheme 7).Treatment of 3-chloro-2-pyrrolidinocyclohexene and spiro [2.4] hepta-4,Gdiene with AgBF, yielded, after basic hydrolysis to the ketone, the cycloadduct 46. The stereochemical assignment of this compound was based upon the known preference of oxyallyl cations to react in an endo mode.Reduction of the ketone functionality in 46 with lithium aluminium hydride occurred stereospecifically to give the corresponding endo alcohol which was next protected as its triisopropylsilyl (TIPS) ether. The alkene 47 was then treated with dichlorocarbene generated from ethyl trichloroacetate and sodium methoxide. This reaction gave the ring expanded product 48; which was modified, after the introduction of a methyl substituent using an SN2' substitution, to give the ketone 49. Initially, Cha et al. had hoped that this ketone would undergo a Baeyer-Villiger oxidation in order to gain access to the taxane AB skeleton, but unfortunately both of the ketones 49 and 46 proved resistant to this oxidation.This problem was circumvented by using a Beckman reaction. Thus, treatment of the ketone 49 with hydroxylamine hydrochloride led to a 3 : 2 mixture of oximes, which underwent Beckman rearrangement upon treatment with tosyl chloride in pyridine to give the regioisomeric lactams 50a,b (3 : 2 also). After conversion of 50a,b into the imidates 51a,b treatment with trifluoroacetic acid (TFA) and rn-chloroperbenzoic acid (m-CPBA) then gave the isomeric nitro esters 52a,b, but these were isolated in disappointingly low yields ( 18%). Cha et al. hope eventually to extend this approach to give access to the ABC ring system in the taxanes by using the bicyclo oxyallyl cation synthon 53 derived from the optically active Wieland-Miescher ketone. Fallis FallislY has recently reported an intramolecular Diels-Alder synthesis of the taxane ring system using a suitably functionalized A ring compound.The Diels-Alder precursor 58 was constructed from the aldehyde 54 as shown in Scheme 8. Addition of the diene fragment to the aldehyde 54 was achieved using l-lithio-1,3-butadiene, and led to the diene 55 as the major isomer in 74% yield after hydroxyl group protection. The relative stereochemistry in 55 was determined from an X-ray crystallographic structure determination of the derivative 56. The diene 55 was then taken through to the Diels-Alder precursor 58 via compound 57. It is interesting to note that oxidation of the acetylenic alcohol function in the desilylated derivative of 57 only gave moderate yields in a generally efficient synthesis, and attempts to improve this step by variation of the oxidant were unsuccessful.Boa, Jenkins, and Lawrence: Recent progress in the synthesis of taxanes 518 + 0 46 CI * N A0 i-l 5Oa 47 CI + 0 50b v 48 CI + 49 O H i A2 52a R' = C02Me, R2 = NO2 b R' = N02, R2 = C02Me 51 a I 51b OMe Reagents: (i) AgBF,, DCM; (ii) NaOH, MeOH, A; (iii) LiAIH,, Et,O, 0°C; (iv) TIPSOTf, DCM, 2,6-lutidine; (v) CCI,CO,Et, NaOMe, 0°C; (vi) Me,CuLi, Et,O; (vii) TBAF, THF, 0°C; (viii) PDC, DCM, 0°C; (ix) CIH.H,NOH, MeOH, py, 80°C; (x) TsCI, py, r.t.-80°C; (xi) Me,O.BF,, DCM; (xi) mCPBA, TFA, DCM Scheme 7 H 53 (+)-Wieland Miescher Ketone Microwave assisted Diels-Alder cyclization of 58 gave the tricyclic taxane ring structure, and the major adduct 59 arose from the endo transition state 60; here the non-bonded interactions are minimized due to alignment of the dienophile on the opposite face of the diene to the 0-methoxymethyl substituent.An attempted Lewis acid mediated cyclization of 58 proved unsuccessful due to the migration of the cyclohexene double bond into conjugation with the acetylenic ketone. The authors hope that a C- 1 3 carbonyl function, as found in natural taxanes, will suppress this tendency and lead to better yields in the Diels-Alder cycloaddition. Indeed the low yields of 55 57 58 (vii) 3540% I 59 Reagents: (i) (€)-Bu,SnCH==CH-CH-CH,, Bu"Li, THF, - 78°C; (ii) MOM-CI, DIPEA, DCM; (iii) DIBAL-H; (iv) HC = CTMS, Bu"Li, - 78°C; (v) Scheme 8 KOH, MeOH, DCM; (vi) Dess-Martin oxidation; (vii) 005 M in PhMe, microwave, 1 mol% hydroquinone 52 Contemporary Organic Synthesisthe thermal Diels-Alder reaction were also due to this double bond migration and large amounts of uncyclized products were recovered.for introducing the C- 13 ketone by allylic oxidation, and the authors also report that the C-1 hydroxyl function can be introduced via the corresponding C-2 enolate, in accordance with the results of other researchers. Previous studies provided Fallis et al. with a method Wmg Wang's approach20 to the taxanes also involves the construction of the c-ring by a Diels-Alder reaction, but in an intermolecular sense. The A-ring is derived from the mono protected ketone 6 1 (Scheme 9) which was first subjected to the Shapiro reaction followed by trapping with dimethylformamide and hydrolysis to produce the ketoaldehyde 62.Acetal formation and subsequent addition of a substituted diene fragment next gave the alcohol 63 which was then subjected to a protection, functional group interconversion sequence to give the aldehyde 64. Zinc mediated intramolecular cyclization with 64 next provided the AB-rhg fragment 65 which was finally converted into the taxoid 66 by an intermolecular Diels-Alder reaction with dimethyl acetylenedicarboxylate. Sakan Sakan's approach to the taxanes is similar to that described by Fallis, where a functionalized A-ring is cyclized to create the B and c rings together. In 1983 Sakan and Craven2' reported a synthesis of the diene 67 and showed that the thermal Diels-Alder reaction gave the trans fused ketone 68 (7O%), whereas the Lewis acid catalysed cyclization gave the corresponding cis fused product 69 (85%) (Scheme 10).This observation was unusual, as catalysis of Diels-Alder reactions normally enhances stereoselectivity, but does not reverse it! The outcome is presumably a result of endo attack in the Lewis acid mediated reaction giving 69, and ex0 attack in the thermal reaction giving 68. Subsequent to this initial observation the stereodirecting effects of alkyl substituents on the diene and dienophile components in 67 were investigated on model systems,22 and this strategy has now been extended to the taxane system.23 69 Reagents: (i) PhH, 160°C; (ii) MefilCI, PhH, r.t. Scheme 10 The aldehyde 71 was prepared from the enone 70, as previously reported, and was next converted to the diene-enones 67 and 72-74 by standard methods (Scheme 1 1).These compounds were then cyclized under both Lewis acid and thermal conditions, and the ratio of isomers determined. The results are summarized in Table 1. In the nomenclature used by Sakan et al. the four possible stereoisomers are designated either cis or trans depending on the relative stereochemistry of the B-c ring junction, and a or B depending on the C-1 -C-3 relative configuration. Thus 68 is the a-trans isomer (the relative configuration in naturally occurring taxanes) and 69 is the a-czk isomer. Where possible the relative configurations were elucidated by X-ray crystal structures; otherwise comparison of NMR spectra or H Me0 H (vii)-(ix) MEMO &r 62 63 64 61 BzO (xii) M Ehr 66 65 TBDPS Reagents: (i) p-TsNHNH,; (ii) 4 eq., BuLi; (iii) DMF; (iv) HCI, H,O; (v) p-TsOH, MeOH; (vi) Br x , ZnCu; (vii) MEMCI, PrLNEt; Scheme 9 (viii) Bu,NF; (ix) CBr,, Ph,P then silica gel; (x) Zn-Cu; (xi) PhCOCI, pyridine; (xii) Me0,C-C C - CO,Me, A Boa, Jenkins, and Lawrence: Recent progress in the synthesis of taxanes 5338.1% 11 steps I CO2Et 70 H 71 t l$f$ 67 R' = R2 = Me (8.8% from 71) 72 R' = Me, R2 = H (13.5%) 73 R' = H, R2 = Me (12.0%) 74 R' = R2 = H (10.3%) \ I R' Scheme 11 chemical correlation methods were used.The authors found that under thermal cyclization conditions a methyl substituent on the diene ( R2 = Me) increases selectivity for the a- over 8-isomers, and approximately doubles the a-trans: a-cis ratio. A methyl substituent on the dienophile (R2 = Me) decreases the a /8 ratio by 40%, but the selectivity for a-trans over a-ck increases significantly (ca.five-fold). In the Lewis acid catalysed reaction only the a-cis isomer was formed in all cases, with the exception of 73 where a minor product, tentatively assigned as the s-cis isomer, was isolated. The preference of the a stereochemistry at C-3 appears to be a unique feature of this carbon skeleton, and Smith and Houk are currently investigating the molecular mechanics of this system. Table 1 67 thermal 72 thermal 73 thermal 74 thermal catalyzed catalyzed catalyzed catalyzed 70 0 36 0 38 0 17 0 0 85 49 97 27 80 64 97 0 0 15 0 12 0 19 0 0 0 0 0 13.5 1 5(h) 0 0 (")Values are in absolute percentage yield (b)Structural assignment is tentative Blechert Blechert has investigated a photochemical [2 + 21 cycloaddition-retroaldol route to form the eight- membered B ring in the taxanes (Scheme 12).Earlier be built via the key dienone 75 and dione 76 intermediates. The ally1 carbonate derivative 77 underwent a stereospecific [2 + 21 cycloaddition with cyclohexene leading to cyclobutane 78. When the had shown how the tricyclic ABC skeleton could analogue of 7 7 lacking the C- 13 ketal protection was subjected to these reaction conditions Blechert found that the reaction occurred without stereoselectivity at the crucial C-8 centre. Another inconvenience was that using 1-methylcyclohexene, with the aim of incorporating the angular c-ring methyl group, gave the wrong regiosiomer, which would have led to a methyl group at C-3 instead of C-8.Blechert is reportedly investigating an alternative route to by-pass this particular p r ~ b l e m . ~ ~ . ~ ~ After deprotecting the tertiary alcohol and ketone functions in 78, followed by stereoselective reduction of the latter, treatment with potassium t-butoxide gave the retroaldol product (4 80) and the ABC tricyclic taxane skeleton. This sequence also effected complete epimerization at C-3 to give the thermodynamically favoured trans B/C ring junction. Blechert had found that if the C- 13 ketal was left in place, enolization occurred towards C- 1, C-9, and C-1 1 and not C-3. Alternatively, selective reduction of the C-10 carbonyl function allowed epimerization at C- 1 as a consequence of altered conformational preferences.through to the cinnamate ester 80 using the same retroaldol-epimerization sequence. Recently27 Blechert had taken the cyclobutanol79 75 CO2H C02Me (Vii) 85% I - 76 78 79 OH 0 .@ H 0 Ph 81 Ph 80 Reagents: (i) KCN, NH,CI; (ii) HOCH,CH,OH, TsOH; (iii) KOH, H,O,; (iv) DCC; (v) LiMe,Cu; (vi) CH,N,; (vii) KH; (viii) CICO,CH,CH=CH,, NaHCO,; (ix) cyclohexene, hv; (x) Pd(PPh,),, morpholine; (xi) HCI, H,O, THF; (xii) lithium selectride, - 70°C; (xiii) ButOK, Bu'OH; (xiv) cinnamic acid, dicyclohexylcarbodiimide; (xv) NaBH,, citric acid, CH,OH, 3 min.; (xvi) OsO,, N-methylmorpholine-Noxide Scheme 12 54 Contemporary Organic Synthesiscis-Dihydroxylation of the double bond in 80 gave a 1 : 1 mixture of separable diastereoisomers of 8 1. Both isomers were subjected to ,an in vitro tubulin test.The less polar of this pair was shown to inhibit the depolymerization of tubulin. This result is important as it is the first synthetic taxane with action analogous to taxol. More recent work by Blechert26 has focused on the intermediate 78, as a compound to modify in order to introduce oxygen functionalhation at C-9 in the wring. Thus, deprotection and dehydration of 78 (Scheme 13) first gave the dehydro derivative 82. Various functional group interconversions followed by ozonolysis of the double bond then gave the C- 10 epimers 83 and 84, the first taxanes with three oxygen functionalities in the wring. 0 0 70 82 / (iiir/ (vii) I retroaldol methods to form the wring. Kraus, however, has instead employed a fragmentation of the ring system via a bridgehead carbocation.28 The known keto-ester 85 was prepared as a mixture of diastereoisomers, and was allylated to give the derivative 86 (Scheme 14).This step was unexpectedly difficult and low yielding (35%), but the product was isolated as a single isomer with the alkylation assumed to have occurred from the em face. Wacker oxidation and cyclization of 86 next gave the bridgehead alcohol 87 which, after bromination, fragmented in the presence of silver tetrafluoroborate to give the AB model compound 88. 0s 0 H e-co2M* 6 86 (iO,(iiO 55% 1 0 Reagents: (i) K,CO,, MeOH; (ii) H,O+; (iii) LiAIH,, THF -20"-0°C; 84 (iv) (a) MnO,, DCM, (b) LiAIH,; (v) Ac,O, DMAP, Et,N; (vi) 0, DCM, MeOH then DMS; (vii) NaBH,, MeOH; (viii) NaBH,/CeCI,, MeOH Scheme 13 Kraus The approach to the taxane AB ring system adopted by Kraus et al. involves a similar strategy to that of Blechert and by Fetizon.The common link is the [2 + 21 photocyloaddition of a cyclohexane- 1,3-dione enol leading to a [6.4] ring system. The other researchers, as mentioned above, then investigated 0 ij 88 a7 Reagents: (i) 2.2 eq. LDA, ally1 bromide; (ii) PdCI,, 0,; (iii) NaOMe, Scheme 14 0°C; (iv) PBr,; (v) 1.2 eq. AgBF,, 5: 1 MeCN/H,O, 0°C An alternative synthesis was investigated in the light of the poor yields for the conversion of 85 into 86. Thus the enol ether 89 was elaborated as depicted in Scheme 15, eventually yielding the tertiary alcohol 90. The subsequent bromination and fragmentation of this compound has not yet been reported. 89 ,o, 0 H 59 OH 90 Reagents: (i) hv, PhH, 72 h; (ii) LDA, TMS-CI; (iii) Pd(OAc),; (iv) ButOK, Ph,P=CHCOCH,CO,Et, THF, r.t.; (v) 1 1O"C, aq.THF Scheme 15 Boa, Jenkins, and Lawrence: Recent progress in the synthes& of taxanes 55Ghosh In 1990 Ghosh et al. reported29 a Diels-Alder fragmentation sequence in their strategy for making the taxane carbon skeleton. Full details of this work30 have now appeared. The unsaturated anhydride 9 1 first underwent a Diels-Alder reaction with cyclopentadiene leading to an adduct which was then modified to give the diester 92 (Scheme 16). COrrMe o w 0 91 (i)-(iii) 91% 5- C02Me 92 CO&e Cp2Me i/- 97 Reagents: (i) cyciopentadiene, THF, AICi,; (ii) NaHCO, EtOH, H,O, A; (iii) CH,N,, Et,O; (iv) Na, NH,(I), - 55°C; (v) BH, THF, 0°C then NaOH, H,O,; (vi) acetone, Jones reagent; (vii) Et,OBF,, CH,CI,, N,CHCO,Et, 0°C; (viii) cyclopentadiene, PhMe, A Scheme 16 Unfortunately, Ghosh et al.found that the analogous reaction with 5,5-disubstituted cyclopentadienes failed to produce any of the expected adducts, and so prevented direct entry to analogues with the functionalization needed to introduce the C- 15 (taxane numbering) geminal dimethyl group of the taxane skeleton. He is currently addressing this problem in a number of ways.31 Reductive cleavage of the strained tricyclic 1,2-diester 92 with sodium in liquid ammonia led to the ring expanded diester 93. The double bond in 93 was then modified by a hydroboration-oxidation sequence to give the ketone 94, which then underwent a ring expansion when treated with ethyl diazoacetate, giving the AB analogue 95.Following a similar strategy, the aromatic c-ring tricyclic model 97 was made from the anhydride 96; unfortunately the yield of the key C-C bond cleavage was a disappointing 33%. Recently Ghosh has reported two alternative protocols to replace the sodium-liquid ammonia reductive cleavage step 92-93, again making use of the strain in polycylic systems to help the fragmentation. The first3* method is shown in Scheme 17. The diester 92 was first fully reduced and the resulting diol was then protected as the dimesylate 98. Treatment of 98 with zinc and sodium iodide in hexamethylphosphoramide (HMPA) next gave the ring expanded triene 99. Normally this reductive protocol would reduce the rnesyloxy function in 98 to a methyl group, but in the strained polycyclic compound 98 an intermediate carbanion at one of these centres triggered the fragmentation to give 99, in favourable competition with the reduction.In contrast, with the less strained dimesylate 100 the doubly reduced product 101 was isolated from a mixture of products, and no compounds arising from ring cleavage were detected. In a similar fashion the aromatic dimesylate 102 was converted into the diene 103 in 64% yield (qf 33% for the sodium/liquid ammonia mediated fragmentation). Ruthenium tetroxide oxidation of 103 then gave the diketone 104, so showing the synthetic potential of this protocol. CHrrOMs CH20Ms nr R Reagents: (i) LiAIH,, THF, r.t.; (ii) CH,SO,CI, NEt,, DMAP, DCM, 0°C; (iii) Nai, Zn, HMPA, A; (iv) BH,-THF, 0°C then NaOH, H,O,; (v) Jones oxidation, (CH,),CO; (vi) CH,N,, Et,O; (vii) RuCI,.nH,O, CCI,, MeCN, H,O, r.t.Scheme 17 The second alternative cleavage procedure used by Ghosh involved a radical fragmentati~n.~~ Thus, the anhydride 105 was first reduced to the lactone 106 with sodium borohydride (Scheme 18), and 106 was next converted into the chloro ester 107 using thionyl chloride in methanol. Treatment of this chloro ester with tributyltin hydride and catalytic AIBN then initiated a smooth fragmentation to produce the diene 56 Contemporary Organic Synthesis108 in good yield, with only a trace of the directly reduced product detectable in the 'H NMR spectrum. Conversely with the 'strain free' chloro ester 109, the reduced product 110 predominated. Reduction of the benzo analogue 11 1 under these conditions, gave only 25% of the fragmented product 113 and 31% of the reduced product 1 12 even though the tertiary benzylic radical formed after C-C bond cleavage in this case was expected to be more stable than the corresponding debenzo system.Ghosh has speculated that replacement of the hydrogen atoms at C-3 and C-4 with sp2 carbons in the benzo analogue 11 1 reduces the non-bonded interactions with the hydrogen atoms at C- 10 and so decreases the likelihood of strain- assisted fragmentation. Ghosh has successfully applied many useful protocols and with suitably functionalized precursors a range of interesting ABC taxane compounds should be accessible in the near future. (I) 65% HO 11 4 (-)-Bpatchculene oxide 115 117 116 Reagents: (i) BF,.OEt,; (ii) (Pr'O),Ti, Bu'OOH then Me,S Scheme 19 @& 'H 0 4) C02Me CHpCI 118 119 J steps kO2Me 107 @'R "C02Me Reagent: (i) (Pr'O),Ti Scheme 20 CO&le 2.2 From c-ring precursors "Left to Righr c+AK 111 R=CI 112 R = H (31%) 113 Reagents: (i) NaBH,, THF, 0°C; (ii) SOCI,, MeOH, A; (iii) Bu,SnH, Scheme 18 AIBN, PhH, A Shea The Diels-Alder approach to c-aromatic taxoid structures developed by Shea is an example of a Type II Diels-Alder reaction that he and his colleagues had previously developed in a series of elegant studies.38 The key step is the intramolecular Diels-Alder reaction of the triene 12 1 which gives the c-aromatic taxoid 122 under both thermal and Lewis acid conditions.Shea discovered that the product was produced as two atropisomers, endo 123 and ex0 124, and that the ratio depended upon the conditions used.A strong kinetic preference for the endo isomer 123 was observed when the reaction 12 1 -+ 122 was carried out in the presence Of A Q 3 ' The phenomenon of atropisomerism in taxoid structures has been studied in detail by Shea,4O and the results obtained used by all other workers synthesizing c-aromatic taxoid structures. More recent publications from Shea et aZ.4' demonstrate developments in converting c-aromatic compounds into structures with a non-aromatic c-ring Holton No review of taxane systems would be complete without mention of the elegant work of Holton. The key steps in the Holton route were first illustrated by the rearrangement of ( - )-p-patchoulene oxide 114 into the tertiary alcohol 115 (Scheme 19).Subsequent epoxidation and fragmentation of 1 15 via the intermediate 116 then gave the AB-rhg system of the taxane structure 1 1 7.343 35 This result was then extended to produce the functionalized epoxide 118 (Scheme 20).36 Fragmentation of 1 18 next led to the intermediate 1 19 which was then elaborated to the unnatural enantiomer of taxusin 120. At the time of writing this review Holton's approach is the most advanced taxane synthesis. He has recently written an excellent behind-the-scenes account of his 57 Boa, Jenkins, and Lawrence: Recent progress in the synthesis of taxanes121 122 * ex0 124 endo 1 23 (Scheme 2 1). Thus, the dianion of the aromatic acid 125 was alkylated with the chlorodiene 126 to provide the aromatic diene 127 after esterification.Reduction of the ester 127 to the corresponding aldehyde, followed by addition of vinylmagnesium bromide and oxidation next produced the enone 128. A Lewis acid catalysed intramolecular Diels-Alder reaction then gave the c-aromatic taxoid structure 129 as the single endo product 130. The reduction of 130, with DIBAlH, occurred with acceptable stereocontrol to give a 1 : 3.9 mixture of alcohols from which the stereoisomer 131 was isolated in 71% yield. Methylation of the alcohol 13 1 followed by lithium- halogen exchange and reaction with carbon dioxide next provided the acid 132. Reduction of the aromatic c-ring in 132 followed by esterification and hydrogenation then yielded the ester 133. The major step of reduction of the aromatic c-ring has therefore been taken, and clearly further work on this strategy is underway.Jenkins Concurrent with the work of Shea, Jenkins and his group have also investigated the c --* ABC Diels-Alder approach to taxanes. The main difference between the two approaches is that Shea et al. use an aromatic c-ring precursor which is reduced after cyclization while in the Jenkins route the c-ring precursor is alicyclic. The route of Jenkins et al. is illustrated in Scheme 2242 and it starts from the trimethylsilyl enol ether 134, a compound prepared by the Robinson annulation of 2-methylcyclohexanone and methylvinyl ketone. Ozonolysis of 134 and treatment with diazomethane next gave the ester aldehyde 135. Addition of vinylmagnesium bromide to 135 followed by protection of the resulting allylic alcohol then led to the ester 136.Reduction of the ester group in 136 to an aldehyde with DIBAlH followed by addition of trimethylsilylmethylmagnesium chloride next produced the sensitive alcohol 137. Oxidation of 137 to the corresponding ketone, using a very short reaction time to avoid desilylation, followed by addition of vinylmagnesium bromide and Peterson elimination then provided the key triene 138. Diels-Alder reaction was not possible without the presence of an electron-withdrawing group in the dienophile; hence the silyl protecting group in 138 was removed and the resulting alcohol was oxidized to give the enone 139. The intramolecular Diels-Alder reaction with 139 occurred readily with diethylaluminium chloride to produce the tricyclic taxoid structure 140 as a single diastereoisomer. The relative stereochemistry of the three asymmetric centres in the tricycle 140 was shown to be the same as the corresponding centres in the natural taxanes by X-ray crystallography, which also proved that the eight-membered ring was in the boat-chair conformation 14 1.This is the conformation observed in the X-ray crystal structure of a wide range of taxane derivatives. This Diels-Alder route to the taxanes has been adapted to produce an alkylated taxoid structure as shown in Scheme 23.43 Thus, addition of 2-propenylmagnesium bromide to the aldehyde 142 followed by a Collins oxidation first provided the enone 143. The selenoacetal of acetone was next lithiated and the resulting anion ( LiCMe2SePh)44 was then added to the enone 143; subsequent elimination of PhSeOH finally gave the triene 144.Deprotection and oxidation of 144, to produce the enone 145, was + q (igl ~ $.nQ “ib; * 0 / Me02C H02C Br 0 Br Br 127 128 126 125 133 132 endo 131 130 129 Reagents: (i) LDA, -78°C then the chloride; (ii) CH,N,; (iii) DIBAL, C,H,, 0°C; (iv) PCC; (v) CH,CHMgBr; (vi) BaMnO,; (vii) Et,AICI; (viii) DIBAL, CH,CI,, C,H,, - 78°C; (ix), NaH, Me1 then Bu‘Li followed by CO,; (x) Li, NH,, EtOH, THF, - 78°C then CH,N, followed by H,, PtO, Scheme 21 58 Contemporary Organic Synthesis134 135 bTBS 136 OTBS 138 0 139 om 142 0 145 0 om 144 146 Reagents: (i) CH,C(Me) MgBr; (ii) Collins oxidation; (iii) Me,C(SePh)Li; (iv) SOCI,, Et,N; (v) HF, H,O, CH,CN; (vi) BF,.OEt, H3C LJp=(=Jp 0 0 Scheme 23 141 140 Reagents: (i) 0,, Me,S; (ii) CH,N,; (iii) CH,=CHMgBr; (iv) TBDMSOTf, 2,glutidine; (v) DIBAL; (vi) TMSCH,MgCI; (vii) Collins oxidation; (viii) CH,-CHMgBr; (ix) NaOAc, HOAc; (x) HF, H,O, CH,CN; (xi) Et,AICI Scheme 22 148 147 followed by intramolecular Diels-Alder reaction, using BF,.OEt, as a catalyst, to give the alkylated taxoid 146. The product 146 was not crystalline, and so the relative stereochemistry was determined by NOE studies and comparison with the spectra of the unalkylated model compound 14 1. The preference for the formation of the eight-membered ring in 146 in the boat-chair conformation is reflected in the transition state of 147 -* 148 for the Diels-Alder reaction. The products 141 and 148 correspond to the endo isomers observed in the Lewis acid catalysed Diels-Alder cyclization to c-aromatic taxoid structures presented by Shea et al.taxanes by using a chiral pool derived c-ring. Thus, the readily available protected glucose methyl ketone 149 (Scheme 24) was first subjected to a Robinson annulation to produce the tricyclic enone 1 5045-the first reported example of the application of this annulation reaction to the synthesis of annulated sugars. Reduction of the ketone group in 150 with L-Selectride" next provided the allylic alcohol 15 1, the structure of which was determined by X-ray crystallography. The formation of a trans ring junction between the carbocyclic ring and the sugar was achieved using the Stork silylmethylene radical cy~lization~~ as illustrated in 15 1 -, 152 4 1 53.47 The ring junction between the carbocyclic ring and the sugar ring had now been established with the correct absolute configurations.The next task was to cleave Jenkins et al. have extended their approach to the methoxyacetal group in 153 to leave the highly substituted cyclohexane, the future cring.48 The siloxane ring in 153 proved to be unstable to subsequent reactions, and so it was cleaved oxidatively and then protected to yield the bis-silyl ether 154. Reaction between 154 and N-bromosuccinimide caused fragmentation of the benzylidene ring to give the bromoester 1 55.49 A second fragmentation, following the Vasella protocol, was achieved on heating the bromoester 155 with zinc leading to the aldehyde 156. Reduction and protection of the aldehyde 156 next gave the olefin 157 which was treated with ozone to produce the aldehyde 158.The aim of Jenkins et al. is to construct diene and dienophile components onto the aldehyde 158, and then to use the intramolecular Diels-Alder reaction to produce the A and B rings of the taxoid structure. Yadav An interesting variation on the Diels-Alder approach to the taxanes has been published by Yadav et al. (Scheme 25).50 The diol 159 was alkylated selectively with the bromodiene 160 to give the ether 161. Swern oxidation of 16 1, followed by epimerization and addition of vinylmagnesium bromide next gave the alcohol 162. A further Swern oxidation led to the trienone 163, which underwent an intramolecular, Lewis acid catalysed Diels-Alder reaction to produce Boa, Jenkins? and Lawrence: Recent progress in the synthesis of taxanes 59159 Me' h e 153 OTBPS OTBPS 157 158 Reagents: (i) Lithium tetramethylpiperidine, Et,O, O"C, 1 h; (ii) 3-(trimethylsilyl) but-3-en-2-one, - 78°C -, r.t., 1 h; (iii) KOH (03 mot equiv.), MeOH, 80"C, 6 h; (iv) L-Selectride; (v) CISiMe,CH,Br, Et,N; (vi) Bu,SnH, azoisobutyronitrile (AIBN); (vii) H,02, KF; (viii) t-butyldiphenylsilyl chloride, CH,CI,, imidazole, r.t., 72 h; (ix) NBS, BaCO,, CCI,, reflux 3 h; (x) Zn, Pr'OH, reflux, 5 h; (xi) NaBH,, Pr'OH, 60"C, 15 min.; (xii) Et,SiCI, CH,CI,, imidazole, 15 h; (xiii) 0,, CH,CI,, - 78°C then dimethyl sulfide Scheme 24 the tricyclic ether 164.Reduction of the ketone group in 164 and protection of the resulting alcohol then gave the ether 165 which underwent Wittig rearrangement, using BuLi at - 78"C, to produce the 2 ob+e$J the publication m-ring fragment of the 168 conversion by S.F.Martin of the diene et aL5I 167 in into K*- K* / \ tricyclic compound 166. 160 OH OH 159 161 Oxy-Cope routes (i,Mlem The story of the oxy-Cope route to taxanes starts with 1982. 0 OH &OH KH * a0 167 168 Paque tte The oxy-Cope rearrangement is a key step in Paquette's route to the taxanes. Recent progress on this work is illustrated in Scheme 26. The enantiomerically pure ketone 169 is first reacted with the optically enriched cerium reagent 170 to give the alcohol 17 1. [ 3,3] Sigmatropic rearrangement of 17 1 occurred via an endo chair transition state, leading to the 'carbonyl down' atropisomer 172. Deprotection of 172 and oxidation next produced the ketone 173 which was then equilibrated with sodium methoxide to give a 1 : 1 mixture of ketones with the cis and trans ring junctions, 173 and 174 respectively.Separation and recycling the cis ketone 173 gave the trans isomer 174 in 80% yield. Hydroxylation of 174 next provided a 163 162 I; 164 om 1 0 OTBS 166 Reagents: (i) NaH; (ii) (COCI),, Me,SO, Et,N, -78°C; (iii) NaOMe, MeOH; (iv) H,C=CHMgBr, THF; (v) Et,AICI, CH,CI?j. (vi) NaBH,, EtOH; (vii) TBDMS-CI, imidazole, DMF; (viii) BuLi, THF, -78°C Scheme 25 60 Contemporary Organic Synthesis0' 177 Reagents: (i) THF, - 78°C; (ii) KH, 18crown-6; (iii) Bu,NF then PDC; (iv) NaOMe, MeOH, separate and recycle; (v) OsO,, NaHSO,, pyridine, Scheme 26 water; (vi) CH,SO,CI, pyridine; (vii) EtfilCI O H & 0 90% (9 -& TBSOH OTBS 178 179 < \ ) < I I + 186 single diol 175 which was mesylated selectively to yield the secondary mesylate 176.The second step in this route towards the taxanes is the Et,AlCl catalysed 1 ,Zmigration of the C , bridge in the mesylate 176 to produce the functionalized tricyclo [9.3.1.0.378] pentadecane 177.52 The alternative depiction 178 gives a representation that is easier to compare with the other taxanes covered in this review. Further transformations of the B and c rings of the triketone 178 are outlined in Scheme 27.53 The three carbonyl groups in 178 are differentiated by first converting the A and c-ring ketones into silyl enol ethers to produce the bis-silyl ether 179. Steric factors dictate that the c-ring silyl enol ether is more reactive to hydroxylation, which leads to the diol 180.Protection of 180 followed by low temperature reduction with DIBAlH in hexane provides the /?-alcohol 18 1, whereas reduction in benzene at 8°C led to the a-alcohol 182. Dehydration of alcohols 181 and 182 gave the olefins 183 and 184 respectively, which finally produced the respective diacetates 185 and 186. Clearly this approach is very close to synthesizing some taxane natural products. The main problem to be faced is the introduction of the bridgehead double bond into the A-ring. Once this task has been achieved the route has great potential. 2.3 From A-ring and c-ring precursors Kuwajima The key step in the approach to taxanes highhghted by Kuwajima et al. is the formation of the 9- 10 Reagents: (i) TBSOTf, Et,N; (ii) Me,CO,; (iii) MOMCI, PrLEtN; (iv) DIBAL, hexane, - 78°C to - 10°C; (v) DIBAL, benzene, 8°C; (vi) Burgess reagent, benzene, 2545°C; (vii) [C,H,C(CF,),O],SPh,, benzene, 25°C; (viii) OsO,, CH,CI, then NaHSO, pyridine followed by Ac,O, pyridine, DMAP Scheme 27 Boa, Jenkins, and Lawrence: Recent progress in the synthesis of taxanes 61carbon-carbon bond by an intramolecular Lewis acid catalysed cyclization of a dienol silyl ether and an a~etal.~, In the unsubstituted case, 187, the cyclized product 190 was obtained in 74% yield.Despite the fact that a 1 : 1 mixture of E and 2 thioethers 188 was used, conditions were varied until a single stereoisomer of 19 1 was obtained. Similarly, a mixture of the vinyl ethers 189 was converted into one product, the bis-methyl ether 192.In all cases NOE studies showed that the endo product was obtained. 187X=H 188 X = SPh EiZ= 1 :I 189 X = OMe EiZ= 1:4.6 TBDMSO OMe lTiCt4 x, p e 190X=H 74% 191 X = SPh 80% 192 X = OMe 84% H Further progress in this approach is directed towards the introduction of oxygen at C-2 and the synthesis of compounds with a non-aromatic c-ring. Extensive studies on the first problem,55 were based on an efficient synthesis of the A-ring synthon 197 (Scheme 28). Addition of the lithiated THP-propargyl ether 194 to propionaldehyde first produced the alcohol 195. Lindlar hydrogenation of 195 and Swern oxidation next gave the a$-unsaturated ketone 196. Michael addition of lithiated ethyl isobutyrate to 196 then led to the ketoester 197.Dieckmann-like cyclization of 197 next gave the 1,3-diketone 198 which was subjected to a sequence of acetylation, deprotection, and oxidation leading to the key intermediate 193 in 43% overall yield for the eight-step synthesis. 194 OMP 195 OMP 196 OHC Hgo 193 Reagents: (i) H,, Pd, BaSO,; (ii) (CF,CO),O, DMSO; (iii) (CH,),CLiCO,Et; (iv) Bu'OK; (v) (CH,CO),O, Et,N; (vi), pTsOH, MeOH The substituted phenyllithium 199 was now added to the aldehyde 193 in the presence of CeCl,, and a 3 : 1 ratio of Cram to anti-Cram products was obtained. This mixture was separated and converted into the four products 200-203 as illustrated (Scheme 29); the vinyl ethers 201 and 203 were obtained as a mixture of E and Z isomers as in previous cases. The stereochemistry of the C-2 silyloxy group plays a crucial role in the cyclizations of compounds 200-203. Cyclization of 201 (Scheme 30) at - 78°C with TiCl, gave the endo product 204; on separate treatment of 204 with TiCl, at 0°C epimerization at C-10 produced the endo isomer 205.An unfavourable steric interaction involving the silyloxy group at C-2 causes 203 (Scheme 31) to cyclize via an ex0 transition state leading to the product 206. OMe I 200 X = H 201 X = OMe 193 + Meox - + Y 202X=H 203 X = OMe Reagents: (i) CeCI,; (ii) pyrrolidine, Bu'Me,SiCl, Et,N, separation; (iii) Et,SiCI, Et,N; (iv) Me,SiCH,Li, Bu'OK, for 200 and 202; Me,Si CH (OMe) Li, Bu'OK for 202 and 203 Scheme 29 Isomerization of 206 ex0 to endo was achieved by deprotection and heating; epimerization to the desired isomer 207 was realized on acetylation of the OH at C-2 and treatment with TiC1,.205 endo Reagents: (i) TiCI,, - 78°C; (ii) TiCI,, WC, 30 min. Scheme 30 62 Scheme 28 Contemporary Organic Synthesis203 206 ex0 0 * OAC OMe 207 Reagents: (i) NBu,F; (ii) heat, 30 min.; (iii) Ac,O, Et,N; (iv) TiCI,, Scheme 31 - 45T, 45 min. Two recent publication^^^^^^ have given further details of these cyclization and isomerhation reactions, and studies on the synthesis of a non-aromatic c-ring have been reviewed.5g The precursor 208 has been synthesized and cyclized to the tricyclic compound 209, whose stereochemistry was confirmed by X-ray crystallography. The objective now is to introduce the c-ring methyl group via conjugate addition and to further elaborate the structure to that of taxusin 120.TIPS0 0 =t@? H 0 208 209 120 Taxusin Frejd Frejd's approach to the taxane is a convergent strategy in which separate A and cring fragments are first synthesized, then coupled to give an A[B]C structure; a final cyclization to form the B ring completes the tricyclic structure. In a recent report5' Frejd used an enzymic resolution in the synthesis of an optically active c-ring unit. The racemic acetoxy enone 2 10 was converted into the enantiopure alcohol 2 1 1 ( > 99% e.e.) using an enzymic resolution/chemical hydrolysis sequence (Scheme 32). Elaboration of enone 2 11 next gave the silyl enol ether 2 12, a homochiral taxane c-ring analogue. The enol ether 2 12 was coupled successfully to the cyclohexane carboxaldehyde derived acetal2 13 giving the axially substituted product 2 14, which had the incorrect relative configuration at C-2 (C-3 in the eventual taxane skeleton).It is hoped that this can be altered at a later stage. Progressing to a functionalized cyclohexane carboxyaldehyde acetal ( A-ring fragment) in place of 2 13, Frejd naturally chose the acetal2 16, a derivative of compound 2 15 and an optically active A-ring unit synthesized from L-arabinose. Unfortunately, attempts to form the coupled product 2 17 have till now met with failure. 21 0 21 1 I II oms 0 21 3 I 212 0 .+o 03 21 5 21 6 I HO 214 OH 21 7 Reagents: (i) PLE; (ii) Na,CO,, MeOH; (iii) TBDPSCI, imidazole; (iv) CH,=CHMgBr, CuBr.Me,S; then TMSCI, TMEDA; (v) TiCI,, -75°C Scheme 32 The sequence from L-arabinose to 2 18 was somewhat arduous (23 steps), and is considered too lengthy to be of practical use.Nevertheless full details have just been reported,6O and another publication has revealed details of a much improved synthesis of the diol215:' outlined in Scheme 33. The ene reaction between the allylic ether 2 19 and ethyl glyoxylate 220a yielded none of the desired allylic alcohol when the reaction was catalysed by the chiral Lewis acid derived from (S)-1,1 '-binaphthalene-2,2'-diol and C1,Ti(OPri),. The reaction of 219 and the phenylmenthyl ester 220b using SnC1, as Lewis acid was successful though, and this auxiliary controlled reaction gave yields of the allylic alcohol 22 1 in excess of 90% with diasteroisomeric excesses greater than 95%. The protected alcohol 222 was homologated by a Claisen ester condensation.Subsequent nickel catalysed coupling of a silyl Grignard reagent and an Boa, Jenkins, and Lawrence: Recent progress in the synthesis of taxanes 6321 s b R = 8-phenylmenthyl (v)*(vi) 21 8 6296 4 PMBO PMBO - 215 - COpEt 78% TMS TMS 223 Reagents: (i) SnCI,, DCM, -78°C; (ii) 1M NaOH, THF, MeOH; (iii) DBU, Et8r. PhH, A; (iv) TBSCI, imidazole, DCM; (v) LiHMDS-EtOAc, TMEDA, THF; (vi) ButOK, CIP0,Eh. THF; (vii) TMSCH,MgCI, Ni(acac),, EQO; (viii) DDQ DCM, H,O, 0°C; (ix) ButO,H, TiOPr',, (-)-diethy1 tartrate; (x) BF,.OEt, Scheme 33 22s 32:l ais:Erans OHC 227 0 0 228 230 229 Reagents: (i), Bu'OK, Bu'OH, Mel; (ii) H, 10% Pd-C; (iii) BF,.OE%, DCM; (iv) HO(CH,),OH, p-TsOH. PhH, A; (v) DMSO. (COCI),, Et3N, DCM; (vi) TMSOTf, collidine, DCM; (vii) 0,.DCM, pyridine, - 78°C then PPh,; (viii) CH,N, Et,O; (ix) 1 N HCI, THF, r.t., (x) Sml,, THF-MeOH, - 25°C; (xi) NalO,, THF, MeOH Scheme 34 enol phosphate gave, after deprotection, the allylsilane 223, a precursor to the diol215. The stage is now set for coupling the A and c-rings. Arseniy adas Arseniyadas62 has used the derivative 224 of the known lower analogue of the Wieland-Miescher ketone as a precursor in his synthesis of an A-ring equivalent (Scheme 34). The homochiral compound 224 was modified, as depicted, in a highly efficient, stereoselective process. The cis ring junction in 225 was introduced by catalytic hydrogenation, and only a small percentage of the undesired trans isomer was detected. Another interesting point to note in this sequence is the conversion of the silyl enol ether 226 into both the acyloin 227 and the required ester- aldehyde 228 products.The by-product 227 was produced in sigdicant amounts (23%), but could easily be converted into the desired product 228 by periodate cleavage and esteacation, so conveniently increasing the yield of the required compound. Conversion of the aldehyde-ketone 229 into bicyclic ketone 230 by a samarium diiodide-mediated reductive coupling followed by oxidation occurred stereospecifically as a consequence of the cis ring junction in the hydrindanone 225, and this importantly fixed the absolute configuration of the C-1 centre. The authors aim to couple this A-ring fragment, 230, to a c-ring equivalent using enolate chemistry, and then complete the B-ring to form a complete taxane skeleton (Scheme 35).64 Contemporary Organic Synthesis230 0 0 R' I' Scheme 35 Wendec A very efficient synthesis of a c-aromatic taxane structure has been published by Wender.63 The key steps of (i) rearrangement to give a quaternary centre in the A-ring precursor and (ii) an hydroxy epoxide fragmentation to produce the B-ring, are related to the Holton synthesis. The starting material for the Wender route (Scheme 36) is pinene which is available in both enantiomeric forms and contains ten of the twenty carbon atoms of the taxol skeleton. Pinene was first subjected to air oxidation to give verbenone 23 1; deprotonation followed by alkylation next produced the enone 232. Irradiation of 232 achieved the crucial rearrangement to the ketone 233.The stereochemistry of the cyclization of ketone 233 is determined by its bicyclic structure, and leads to a single alcohol 234. Epoxidation of 234 at C-1 led to a single epoxide 235, which fragmented to the taxoid 236. Oxidation of 236 Q to the carbonyl group occurred under basic conditions and reduction of the resulting hydroxyketone 237 led to the c-aromatic taxoid 238 in enantiomerically pure form. The efficiency of this route shows great potential for further elaboration to taxol and related compounds. Clearly the key question is whether the c-aromatic ring can be fashioned into the functionalized c-ring of taxol. Nicolaou Nicolaou has reported an enantioselective synthesis of the fully functionalized A-ring of tax01,~~ together with the synthesis of the c- and D-rings in racemic form.65 The diene 239 (Scheme 37) was first prepared from the appropriate ester,"6 and then subjected to thermal Diels-Alder reaction with 2-chloroacrylonitrile.The adduct 240 was next treated with base to introduce the carbonyl group which was then converted into the ketal24 1 after reacetylation of the alcohol. Regioselective allylic oxidation of 24 1 with Se02 was followed by pyridinium chlorochromate (PCC) oxidation to produce the enone 242, which with the oxazaborolidine procedure developed by core^^^ gave the corresponding allylic alcohol 243 in greater than 98% e.e. Removal of the ketal group in 243 and protection of the alcohol function then gave the fully functionalized taxol A-ring 244 in essentially optically pure form. Nicolaou's synthesis of the taxane c, D-rings is yet again based on the Diels-Alder reaction (Scheme 38).The dienophile is the unsaturated ester-alcohol 245, the diene is 3-hydroxy-2-pyrone 246, and the reaction is made intramolecular using phenylboronic acid. The presumed intermediate 247, where the two components are temporarily tethered together, undergoes regioselective cyclization to give 248 as an initial product which rearranges under the reaction conditions to the lactone 249. Rearrangement back to a bicyclo[2.2.2] lactone 250 occurred under the influence of potassium hydride during the benzylation of 249. Both the ester and the lactone groups in 250 were reduced with Red-A1 to give the trio1 25 1. Acetal formation, hydroboration, and acetylation of both the primary and the secondary alcohols in 25 1 next produced the triply protected diacetate 252.Reorganization of these protecting groups by acetal removal, silylation, and acetate hydrolysis then gave the diol253 which was converted into the mesylate 254. The crucial oxetane ring forming reaction proceeded well, and a final desilyation yielded the fully functionalized, racemic taxol c, D-ring fragment 255. 238 237 236 Reagents: (i) Bu'OK; (ii) hv; (iii) Bu'Li, TMEDA; (iv) (a) Ti(OPr'),, Bu'OOH; (b) DABCO, heat; (v) Bu'Me,SiCI, imidazole; (vi) KOBu', 0,, 60°C; Scheme 36 (vii) Na, EtOH Boa, Jenkins, and Lawrence: Recent progress in the synthesis of taxanes 65A ring c and 0 rings x 2Y' CN (i) - 85% CN Cl 0d 240 241 243 242 (vii), (viii) 244 Reagents: (i) 135"C, 96 h, 85%; (ii) KOH, Bu'OH; (iii) Ac,O, DMAP; (iv) HOCH,CH,OH, CSA; (v) SeO,, then PCC; (vi) (R)-oxazaborolidine, catecholborane; (vii) TsOH, acetone, H,O; (viii) Bu'Me,SiOTf, 2,6-lutidine Scheme 37 Having completed effective routes to both A and c-ring units Nicolaou has now joined a functionalized A-ring fragment to a simplified c-ring component (Scheme 39).68 The ketone 256 was converted into the vinyl lithium 257 using the Shapiro reaction, and the aldehyde 258 was then added to produce the alcohol 259.A 2 : 1 mixture of diastereoisomers of 259 was formed from which the required alcohol 259 was separated by chromotography. Vanadium catalysed epoxidation of the allylic alcohol 259 next led to the epoxide 260 which was then reduced to the diol26 1 with LiAlH4.Protection of the diol26 1 leading to the acetonide 262 was followed by a sequence of selective deprotections and oxidations to form the di-aldehyde 263. McMurry coupling of 263 gave the diol264 as a 1 : 1 mixture of diastereoisomers which was then oxidized to the enediol265 with MnO,. 2.4 Syntheses starting from the Wieland-Miescher ketone Danishefsky The Wieland-Miescher ketone 266 is an important commercially available, enantiomerically pure, starting material. The c and D-rings in the taxanes have been prepared from the Wieland-Miescher ketone as shown in Scheme 40.69 The alcohol 267 was prepared by the method of Heathc~ck,~~ and protection followed by stereoselective hydroboration and oxidation produced the ketone 268. Conversion of 268 to the corresponding enol triflate was followed by a palladium-catalysed carbonylation reaction in the 245 246 L EtO2C.. $JH 249 (ii) 80% J h EtO2C 250 247 \ TBDMSO OSMDBT (vii)-(ix) 4 86% OH OAc 253 (x) 80% J TBDMSO OSMDBT L..M 252 HO OH (xi), (xii) 86% 254 255 Reagents: (i) PhB(OH),, 90°C.48 h then 2,2-dirnethylpropane-1,3-diol; (ii) KH, PhCH,Br; (iii) Red-Al; (iv) 2,2-dimethoxypropane, CSA; (v) BH,.THF then H,O, NaOH; (vi) Ac,O, DMAP; (vii) CSA, MeOH; (viii) Bu'Me,SiOTf, 2,6-lutidine; (ix) NaOMe, MeOH; (x) MeSO,CI, DMAP; (xi) NaH, 45", 12 h; (xii) Bu,NF Scheme 38 presence of methanol to give the ester 269. Reduction of 269 to the allylic alcohol, then hydroxylation to the olefin led to the trio1 270 as the major product. Formation of the D-ring from 270 was achieved by the selective silylation of the primary alcohol group and then conversion into the secondary triflate.Heating the triflate with ethylene glycol caused desilylation and cyclization to the oxetane which was then hydrolysed to the ketone 27 1. Deprotonation of 2 7 1 with LDA followed by reaction with trimethylsilyl chloride gave the corresponding trimethylsilyl enol ether, which was treated with Pd( OAc), according to the method of Ito7I giving rise to the enone 272. Formation of a 66 Contemporary Organic Synthesis256 257 258 137% MEMO, ,OBn MEMO, ,OBn - 0J-J OH HC 261 * 264 263 265 Reagents: (i) 2,4,6-triisopropylbenzenesuIfonyI hydrazine; (ii) BuLi, THF, -78°C then 0°C; (iii) Bu'OOH, VO(acac),; (iv) LiAIH,; (v) 2,2-dimethoxypropane, camphor sulfonic acid; (vi) H,, Pd/C; (vii) Ac,O, 4-DMAP; (viii) TiCI,; (ix) K,CO,, MeOH; (x) tetrapropylammonium perruthenate, 4-methylmorpholine-N-oxide; (xi) TiCI,-(DME),.,, Zn-Cu; (xii) MnO, Scheme 39 trimethylsilyloxy diene from 272 followed by ozonolysis finally gave the dialdehyde 273; alternatively the enone 272 was hydroxylated to give the hydroxyketone 274.have reported the synthesis of other taxane intermediates containing the ring.^^ Thus, reaction between 2-methylpentane-3-one 275 and acryloyl chloride was carried out by a known procedure to first give the ketone 276.73 Conversion of 276 into the enol triflate 2 77 and reaction with vinyltributylstannane, with Pdo catalysis, followed by the hydroboration next produced the alcohol 278. Silylation of the alcohol In a separate publication the Sloan-Kettering group 278, and regioselective allylic oxidation with chromium trioxide- 3,5 -dimet hylp yrazole then gave the A-ring synthon 279.The enone 280 was prepared by Swern oxidation of the alcohol 278 followed by addition of 2-propenylmagnesium bromide and a second Swern oxidation. Regioselective Diels-Alder reaction of the enone 280 with the Danishefsky diene next yielded the taxol A , c-ring synthon 28 1. Finally, the enolate from 280 was hydroxylated with the Davis ~xaziridine,~~ and the product was oxidized to the diketone 282 which led to the ~ , c - r i n g synthon 283. Clearly the Sloan-Kettering group are now poised to combine the work described in Schemes 40 and 4 1. Watt The Wieland-Miescher ketone 266 has also been used in an A-ring synthesis (Scheme 42).75 Protection of the a,#?-unsaturated carbonyl group in 266 with 1,2- ethanedithiol gave a thioacetal and, despite the fact that the saturated carbonyl group is hindered, addition of t-butyldimethylsilyl cyanide proceeded stereoselectively to produce the protected cyanohydrin 284.Selective removal of the thioacetal group in 284 occurred with Tl(NO,), leading to the enone 285. The a-acetoxy ketone corresponding to 286 was prepared by the reaction of 285 with Pb( OAc), and this reacted with methanol and potassium carbonate to give the a-hydroxy ketone 286. Periodate cleavage of 286, followed by treatment with diazomethane then yielded the ester aldehyde 287. Finally, decarbonylation with Wilkinson's catalyst provided the A-ring synthon 288.3 Semi-syntheses of taxanes This approach to taxanes has, to date, been the most successful way of making taxol and biologically active analogues. Potential starting materials for semi- synthesis must be easy to obtain, renewable, and require as little elaboration as possible.76 10-Deacetylbaccatin 111 289, first described as a degradation product of taxol,' and isolated from needles of the widely distributed Taxus baccata (ca. 1 g/kg dry leaves)77 nicely meets these criteria. Synthetic routes to taxanes utilizing 289 have been developed to exploit the differing reactivity of the free hydroxyl groups; 7-OH > 1 0-OH % 13-OH (the low nucleophilicity of the 13-OH, is due to H-bonding to the C-4 acetyl C = 0 group and is also on the endo-convex face). Sharpless ~xyamination~~ of 290-obtained by sequential protection of 289 and formation of the C- 13 cinnamate-gave a mixture of regio- and stereo-isomers with little control (Scheme 43).The reaction was later improved7Y by the addition of dihydroquinine p-chlorobenzoate and although regiocontrol was again poor the required (2'R, 3's) stereoisomer 29 1 was now the major product (d.e. - 60%). This isomer was converted into taxol by removal of the t-butyl amido group, followed by benzoylation and removal of the trichloroethoxycarbonyl group. Although the poor control in the oxyamination reaction renders the Boa, Jenkins, and Lawrence: Recent progress in the synthesis of taxanes 670 d OTBS e o @- oT, 266 267 268 0 do (viii) c--- 66% 'OH HO 272 \OH 270 273 274 KHMDS, THF, - 78°C then PhNTf,; (vi) Pd (OAc),, PPh,, CO, MeOH; (vii) DIBAL, - 78°C; (viii) 5 mol% OsO,, NMMO; (ix) TMSCI, pyridine, - 78°C then Tf,O - 78°C --L r.t.followed by ethyleneglycol, 40"C, 12 h; (x) collidinium tosylate, acetone, H,O; (xi) 2 equiv. LDA, -78°C then TMSCI; (xii) Pd(OAc), then MeOH, K,CO,; (xiii) TBSCI, imidazole; (xiv) LDA, THF, -78°C then TMSCI then 0,, CH,CI,, - 78°C then Ph,P; (xv) TMSCI, pyridine; (xvi) KHMDS, THF, - 78°C then 2-(phenylsulfonyl)-3-phenyloxaziridine then H,O Reagents: (i) steps reference 70; (ii) TBSOTf, 2,g-lutidine; (iii) BH,-THF then H,O, NaOH; (iv) tetrapropylammonium perruthenate; (v) Scheme 40 C P 0 275 276 , 277 266 284 c- 75% 70% TBDMSO TBDMSO 288 287 286 Reagents: (i) HSCH,CH,SH, p-TsOH then TBSCN, Znl,; (ii) TI (NO,),, MeOH, H,O; (iii) Pb(OAc),; (iv) K,CO,, MeOH; (v) NalO,, H,O, Bu'OH; (vi) CH,N,; (vii) RhCI(PPh,),, 80°C Scheme 42 279 approach impractical it has nevertheless given access to many analoguesso including RP 56976 and taxotere,81 which has similar pharmacological activity to taxol.A more direct approach to taxol was first described by the research groups of Potier and Greene,82 involving the esterification of 7-triethylsilylbaccatin I11 292 with the taxol side-chain acid, Scheme 44. The use of a large excess of the protected acid 293 (6 eq.), 1,3-dicyclohexylcarbodiirnide (DCC), and N,N-dimethyl-4-aminopyridine (DMAP) to effect the esterification was followed by deprotection of the silyl and ethylethoxy protecting groups to give taxol(36% from 10-DAB 111).Other acyl-activated side chain equivalents have been used in attempts to overcome the problems associated with the low reactivity of the 281 Po 283 O b J w 282 O d Reagents: (i) steps, reference 73; (ii) KHMDS, PhNTf,; (iii) Bu,SnCH=CH,, cat. Pd (PPh,),; (iv) 9-BBN; (v) TBDMSCI, Et,N, DMAP; (vi) Cr03-3,5-DMP; (vii) Swern oxidation; (viii) BrMgC(Me)=CH,; (ix) Danishefsky diene, 125"C, then HCI, H,O; (x) KHMDS, F. Davis oxaziridine; (xi) Danishefsky diene, 80°C, then HCI, H,O Scheme 41 68 Contemporary Organic Synthesis289 1 0-Deacetyl baccatin 111 290 AgNcg, Os04 :kmNNacl n I 291 (I) TMSl (ii) PnCOCl (iii) WAcOH 4 Tax011 Scheme 43 C- 13 OH (epimerization of the 2' centre, and generally low yield~)-Ojima~~ and Holtons4 have independently used the P-lactam derivatives 294 to directly couple with 7-TES-10-DAB I11 292.OjimaS5 has further reported a significant improvement to the P-lactam method that avoids large excesses of the p-lactam. A near quantitative coupling can be achieved by sequential treatment of the 7,lO-ditroc- 10- deacetylbaccatin I11 (troc = 2,2,2- trichloroethoxylcarbonyl) with sodium hexamethyldisilazide (2.5 equiv.) and the lactam 294, providing an efficient route to taxotkre. Holtons6 has developed another method that utilizes the oxazinone 295 as the acyl equivalent. It is interesting to note that Swindell has also invoked intermediate oxazinone derivatives as coupling agents.87 4 Syntheses of the C-13 side chain of taxol The C-13 side chain in taxol, the (2'R,3'S)-3'- phenylisoserine unit, presents an interesting and manageable sub-target for asymmetric syntheses, and has consequently seen many elegant approaches.In addition, since the binding of taxol to microtubulesS7 is particularly sensitive to changes in the structure of the side-chain, many active analogues of taxol have been made by semi-synthesis. 4.1 Phenylglycidate synthon method In their first synthesis Greene8* (Scheme 45) and his group started with methyl phenylglycidate 296a which HO- 292 (7-Triethylsilyl)-l O-deacetybaccatin 111 1 (i) AcCI, PY (ii) 283,294 or 285 Taxol BzNH 0 Ph 4 0 H 6eq. OR 36% to taxol 293 Ph -OR 92% to tax01 294 phT?J;H 4eq. Ph 69% to taxol 295 Scheme 44 was made by way of Sharpless epoxidation of cis-cinnamyl alcohol, followed by oxidation and esterification. The amine group was next introduced stepwise following ring-opening of the epoxide with trimethylsilyl a i d e {to give a hydroxy azide which was esterified to give the benzoate 297), and reduction of the azide.The azide reduction was accompanied by 0 -, N migration of the benzoyl group, a procedure followed subsequently by other workers, to give the desired product 298. 0 (i) Bu'OOH. Ti(OPr'), L-(+)-DET, (65%. 80% e.e.1 Ph (ii) RuCS. Nal04; H+ * PhACO,R CH&2 (a%) - - . . 296a R = Me bR=Et (i) MeSiNs ZGI2 (90%) (ii) PhCOCI, NEts DMAP (94%) 1 N3 0 =OM* ~ H2 lO%Pd/C 89% 298 Scheme 45 297 Greene's second and improvedsY synthesis (Scheme 46) is essentially a refinement of the synthesis of 296a. Asymmetric Sharpless dihydroxylation of methyl cinnamate, using dihydroquinidine 4-chlorobenzoate first gave the diol299; a new Sharpless procedureg0 gives 299 (ethyl ester) with even higher selectivity (97% e.e.).The diol299 was next tosylated selectively 69 Boa, Jenkins, and Lawrence: Recent progress in the synthesis of taxanesto give the 2-tosylate 300 where the high selectivity is thought to be a consequence of strong C-3-OH to ester hydrogen bonding. The epoxide 296a was then obtained from 300 by treatment with potassium carbonate and elaborated to 293 and the taxotkre methyl ester side-chain as described before. 0 P h q O M e OH 299 dOMe (i) DCQB. NMNO, oso, (cat.) Ph 51% TsCI, Et3N t U O M e 91% Ph K&%. H#. DMF 296a Scheme 46 6TS 300 Commergon et al. have also made the ethyl ester 296b using Evans chiral-enolate chemistry (Scheme 4 7).91 Reaction of the boron enolate of the bromoacetyl30 1 with benzaldehyde first gave the bromoalcohol302, and formation of the epoxide and concomitant removal of the auxiliary then gave the ester 29613.OH 0 0 P h v N A O FNl0 (ii) (i) Et3N, PhCHO BUaBOTf Br w. 5870 Br ,w- / 'Ph *' .Ph 30 1 302 EtOLi 81% I 0 PhAC02Et 296b Scheme 47 JacobsenV2 has reported a similar approach to 306 starting from the epoxide derived from ethyl cis-cinnamate (Scheme 48). The catalytic epoxidation of ethyl cis-cinnamate with 6 mol% ( salen)MnllT complex93 303 and commercial bleach gave rise to the epoxide 29613 in excellent (95-97%) e.e. A modified procedure whereby the epoxide 296b was treated with ethanolic ammonia to give the amide 304 followed by hydrolysis with barium hydroxide then gave the acid PhmC02Et NaOCl -b (R,R) 303 (6 mol%) 305 without epimerization.Generation of the side- chain 306 from 305 was effected by simple treatment with benzoyl chloride. 4.2 The Staudinger synthesis of #blactams A chiral-pool approach to the C- 13 side-chain in taxol is described by Farina and shown in Scheme 49.94 Thus, a highly selective Staudinger reaction between the L-threonine derived imine 307 and acetoxyacetyl chloride first led to the cis p-lactam 308 (PI%, 84% d.e.). This P-lactam was subsequently converted into the #I-lactam 309, by removal of the silyl group, elimination of water, and ozonolysis to give the corresponding mixed oxalic acid derivative, which was simply hydrolysed to the required p-lactam 310. Georg et aL9' have also described a chiral-pool Staudinger reaction (Scheme 50) in which the galactose imine 3 1 1 and the acid chloride 3 12 gave a 2 : 3 mixture of the diastereoisomeric P-lactams 313.Hydrolysis of both the monosaccharide and the p-lactam groups in 313, followed by benzoylation then led to the amide 3 14. Removal of the hydroxyl protecting group in 314 gave the unnatural (2'S,3'R) enantiomer 315. A more detailed study has shown that this poor selectivity is observed with other galactose imines.'6 Aco(hc' Ad,. ,Ph 0 p h l l ?SiPh20But NEt3 ?SiPh20But 74%. d.9.U% - 0 Gp N-P C02Me C02Me 307 308 (I) TBAF (ii) MsCI. NEb I (iii) 0, HO, ,Ph Ad., ,Ph NaHC03 0 f i H 66~frorn * 308 0 J $ O 31 0 C02Me 309 Scheme 49 HoltonY7 has used the p-lactam 3 16 to make taxol from 7-triethylsilyl- 1 O-deacetylbaccatin I11 as described earlier (Scheme 5 1).He made the lactam using the Staudinger reaction between a-acyloxy acetyl chloride and the imine 31 7 as the key step to 0 NH3. EtOH b PhAC02Et 100% 296b 56%,95-97?4 e.e. PhCONH 0 : II 306 (74%) 304 65% &OH 305 (92%) Scheme 48 70 Contemporary Organic SynthesisAcO OAc Ad-!&&N-Ph OAc 31 1 (i) PMPOCH,COCI 312, NEb 1 Ph 313 (4:6,75”!0) bh \ PhCONH 0 PhCONH 0 (NHl)&e(N03)6 phvo Me OPMP Ph+&Me * OH 315 (95%) 314 (84%) Scheme 50 0 NEt3 68% OMe 31 7 318 (45% e.e. 98%) EEO,. ,Ph HO, ,Ph (i) H2C=CHOEt, pTsOH ph (ii) MeLi; BzCl 0 0 31 6 Scheme 51 319 (92oJo) give the p-lactam 3 18, which was converted into 3 16 using standard transformations. The alcohol 3 19 was obtained enantiomerically pure by resolution of its 2-methoxy-2-( trifluoromethyl)phenylacetic ester.Ojirna’sg8 strategy, shown in Scheme 52 is also based on the use of P-lactams, made by a highly selective ester enolate-imine condensation. Thus, deprotonation of the triisopropylsilyl protected ester 320 with lithium diisopropylamide followed by condensation with the imine 32 1 gave exclusively the cis B-lactam 322 (97%). The lactam 322 was then converted into the hydrochloric salt of 305 by treatment with HCl. Palomo99 has made the related P-lactam derivative 324 by cis-selective reduction of 323 (Scheme 53).loo Protection of the hydroxyl group in 323 and N-dearylation led to the P-lactam 324 which by standard treatment gave the ester 298. 4.3 Lithiobenzylamine syn thon method Two approaches that introduce the 3’ carbon in the C- 13 side chain of taxanes, from benzylamine have been developed.Thus, Greene et aZ.lol amongst their many reports have described an alternative synthesis of the side chain of taxotkre (Scheme 54). In this approach dilithiation of BOC-benzylamine with s-butyllithium first gives the dianion 325 which adds to 320 322 321 (97%) ~ G N H C I 305 Scheme 52 323 324 (70%) 298 Scheme 53 acrolein to produce the hydroxycarbamate 326 with reasonable selectivity (syn:anti 6 : 1). The syn preference observed here is consistent with a chelated transition state of the type 327. Protection of the 2’ OH in the syn alcohol 326 as its (trichloroethoxy )methyl ether, followed by oxidative cleavage and resolution using ( + )-ephedrine finally gave the protected taxotkre side-chain 328.r t i 1 325 HNBOC (i) BrAOACCls (70%) HYBOC , 326 (syn :antiB:l) 328 ?OC Scheme 54 Davies et aZ.lo2 have reported a strategy towards 333 involving conjugate addition of the homochiral lithio ( R )-( a-methylbenzy1)benzylamide 329 to t-butyl cinnamate followed by hydroxylation of the intermediate enolate with ( + )-( camphorsulfony1)oxaziridine 330 leading to the anti hydroxy arnine 33 1 with excellent selectivity (92% d-e.). When 33 1 was subjected to hydrogenolysis followed by methanolysis and benzoylation the anti hydroxy amide 332 was produced which could be converted into the corresponding syn (2’S,3’R) isomer 333 (the enantiomer of 298) via Mitsunobu inversion (Scheme 55). Since ( S)-( a-methylbenzy1)benzylamide is readily available, this method will also produce the taxol side chain with the natural (2‘R,3’S) configuration.Boa, Jenkins, and Lawrence: Recent progress in the synthesis of taxanes 7172 Ph (i) Ph 0 . .. - (f7)-329 Ph v OH (ii) &y 86% (92% d.e.) 331 $,\ 0 0 0 (+)-330 (i) H2 (7 atm.). PdK: (ii) HCI. MeOH (iii) PhCOCI, NEt3 I PhCONH (i) Diethyl azodicarboxylate. PhCONH PPha phv OMe (iii) ii) HCI NaHC4 P h v O M e 6H 333 Scheme 55 Ph V 0 E t OH 332 (92%) + P h v O E t Ph VOEt 0 334 (35%, e.e. >98%) 4.4 Enzymic syntheses The first example of an enzyme-assisted taxol side-chain synthesis came from the group of H0nig,lo3 in which the racemic butyryl ester ( f )-334, obtained from ( f )-ethyl cis-P-phenylglycidate, was resolved by selective hydrolysis of the (2'S,3'R) isomer with Pseudornonas fluorescens, leaving the required (2'R,3'S) ester 334 unreacted (e.e.> 98%). transesterification of methyl trans-p-phenylglycidate ( k )-335 has been described by Chen.lo4 The best result was obtained with Mucor miehei lipase MAP- 10 An enzymatic resolution involving lipase-mediated Muwr meihei MAP- 10 lipase Ph 0 - \L1, kobutanol C02Me using isobutanol as the acyl acceptor. The ( - )-methyl ester 335 (42%,95% e.e.) and the ( + )-isobutyl ether 336 (43%, 95% e-e.) could be separated by chromatography or fractional distillation. Interestingly, both 335 and 336 can be converted into the azide 337 in 40% and 38% yields respectively. The route from 335, illustrated in Scheme 56, involves epoxide ring-opening by bromide ion and subsequent displacement with sodium wide with overall retention of configuration at the 3 ' position; the same sequence from ( + )-336 results in both the 3' and 2' positions being inverted leading to 337.Sihlo5 has reported a comprehensive study of the lipase-mediated kinetic resolution of P-lactam derivatives. For example, the racemic B-lactam ( k )-338 gives ( + )-338 in high yield, with impressive stereoselection, on treatment with immobilized lipase P-30 (from Pseudornonas cepacia). AcO, ,Ph -m 0 * N K P h 0 (f)-338 Pseudomonas Cq0ack-i (P-30 J 50%.48h J A d , ,Ph 'I7 0 * N K P h 0 (+)-338 (45% e.e.98%) HO Ph 0 0 43% e.e. 99.5% 4.5 Aldol reaction approaches Hanoaka et aZ.lo6 have used an asymmetric aldol reaction between the homochiral chromium complex 339 of o-trimethylsilyl benzaldehyde and the titanium enolate of 340 (Scheme 57).The reaction is highly anti selective yielding only the alcohol 34 1; interestingly reaction of the corresponding lithium enolate was syn selective (syn: anti 4 : 1). Sequential decomplexation of the chromium from 34 1, followed by deprotection of the silyl group and Mtsunobu 0 + PhP8kO2E3ui (*)-335 (-)-Xi5 (42%, 95% e.e.) (+)-336 (43%, 95% e.e.) PhCONH 0 (ij Et2NH#r, Et#l N3 0 -------+ Ph40Me (ib NaN3 * P h d O M e (-)-335 OH 0 (ii) (i) EtCl NaN3 PhCONH 0 SOCI, NAO Php'k02Bui (lv) (iii) MeOH, H,. PdlC Na2C& * Ph+Otvle - P6 C02Me (+)-336 OH Scheme 56 Contemporary Organic Synthesisdisplacement of the hydroxyl group then led to the aide 342. Reduction of 342 with wet triphenylphosphine, followed by benzylation, thallium ( 111) assisted thioester-to-ester interconversion, and deprotection of the benzyl ether finally completed the synthesis of 298.added to vinylmagnesium bromide to give predominantly the syn aUylic alcohol 348 where the selectivity is explained by chelation controlled addition to 350. The alcohol 348 was then protected and the alkene group oxidized to give the required acid 349. 339 341 93% (anti :syn 935) 1 (i) hv, E W (ii) TBAF-HF (6!5%) (iii) HN3. DEAD, Pph, PhCONH 0 . . 298 342 Scheme 57 Yamamoto and his colleaguesio7 have described an efficient enolate-imine condensation involving the imine 343 and the Z-enolate 344, catdysed by the phenylborate (S)-345, leading to the (2'R,3'S) amino alcohol 346 (syn: anti 99 : 1; syn 98% d.e.).The observed selectivity is only slightly reduced if instead the enantiomer (R)-345 is used (syn: anti 94 : 6; syn 94% d.e.). Removal of the a-methylbenzylamine group in 346, followed by selective hydrogenolysis, and Schotten-Baumann benzoylation then produced 306 (Scheme 58). OMe 306(68%) 346 (>9OY0, syn :anti99:1; d.e. 98?/o) (S)-345 Scheme 58 4.6 A chiral pool approach Greene et allo8 have reported a synthesis of 349 starting from (S)-phenylglycine (Scheme 59). Thus, the protected amino aldehyde intermediate 347 was . . 347 (74%) (i) H&=CHMgBr 349 Scheme 59 5 References 1 M.C. Wani, H.L. Taylor, M.E. Wall, P. Coggon, and A.T. McPhail, J. Am. Chem. SOC., 1971,93,2325. 2 WJ. Slichenmyer and D.D. Van Hoff, Anti-Cancer Drugs, 1991,2,519; E.K.Rowinsky and R.C. Donehower, J. Natl. Cancer Inst., 1991,83,1778; F.A. Holmes, R.S. Walters, R.L. Theriault, A.D. Forman, L.K. Newton, M.N. Raber, A.U. Buzdar, D.K. Frye, and G.N. Hortobagyi, J. Natl. CancerInst., 1991,83,1797. 277,665; S.B. Horwitz, Trends Pharm. Sci., 1992,13, 134. 4 S. Borman, Chern. Eng. News, 1991,69,11. 5 S. Blechert and D. Guinard in The Alkaloids, ed. A. Brossi, Academic Press, 1990,39,195; L.A. Paquette in 'Stud. Nat. Proc. Chem'., 1992,ll [Stereoselective synthesis pt. (G)], 3; see also Ref. 8. 6 An overview of semi-synthesis is included in Kingston's review of the chemistry of taxol, D.G.I. Kingston, Pharmac. Ther., 1991,52,1. 3 P.B. Schiff, J. Fant, and S.B. Horwitz, Nature, 1979, 7 S.M. Edgington, Biotechnology, 1991,933.8 For a comprehensive review of approaches towards the total synthesis of taxanes published up to 1990 see: C.S. Swindell, Org. Prep. Proc. Znt., 199 1,4,465. 9 S.A. Hitchcock and G. Pattenden, Tetrahedron Lett., 1992,33,4843. 10 (a) Y. Ohtsuka and T. Oishi, Chem. Pharm. Bull., 1988, 36,4722; (b) Y. Ohtsuka and T. Oishi, Tetrahedron Lett., 1986,27,203. 11 Y. Ohtsuka and T. Oishi, in 'Studies in Natural Products Chemistry', ed. Atta-ur-Rahman, Vol. 3 [Stereoselective Synthesis (Pt B)], p. 73,1989, Elsevier, Amsterdam. 12 Y. Ohtsuka and T. Oishi, Chem. Pharm. Bull., 1991,39, 1359. 13 R. Andriamilisoa, M. Fetizon, I. Hanna, C. Pascard, and T. Prange, Tetrahedron, 1984,40,4285. Boa, Jenkins, and Lawrence: Recent progress in the synthesis of taxanes 7314 M.Benchikh le-Hocine, D. Do Khac, and M. Fetizon, 15 M. Benchikh le-Hocine, D. Do Khac, M. Fetizon, and T. 16 M. Benchikh le-Hocine, D. Do. Khac, M. Fetizon, F. Synth. Commun., 1992,22,245. Prange, Synth. Commun., 1992,22,1871. Guir, Y. Guo, and T. Prange, Tetrahedron Lett., 1992, 33,1443. Fetizon, A. Neuman, and T. Prange, Acta Crystallogr., Sect. C., 1991,47,2109. 18 J. Oh, J.-R. Choi, and J.K. Cha, J. 0%. Chem., 1992,57, 6664. 19 Y.-F. Lu and A.G. Fallis, Tetrahedron Lett., 1993,34, 3367. 20 Z. Wang, S.E. Warder, H. Perrier, E.L. Grimm, M.A. Bernstein, and R.G. Ball, J. 0%. Chem., 1993,58, 2931. 105,3732; (b) B.M. Craven and K. Sakan, Acta Crystallogr., Sect. C, 1983,39, 1556. 22 K. Sakan and D.A. Smith, Tetrahedron Lett., 1984,25, 2081. 23 K. Sakan, D.A.Smith, S.A. Babirad, F.R. Fronczek, and K.N.Houk, J. Org. Chem., 1991,56,2311. 24 (a) H. Neh, A. Kuhling, and S. Blechert, Helv. Chim. Acta, 1989,72,101; (b) H. Neh, S. Blechert, W. Schnick, and M. Jansen, Angew. Chem., Int. Ed. Engl., 1984,23,905. 27,2845. 1992,48,6953. Ed. Engl., 1991,30,412. 17 F. Guir, D. Do Khac, M. Benchikh le-Hocine, M. 21 (a) K. Sakan and B.M. Craven, J. Am. Chem. SOC., 1983, 25 R. Kaczmarek and S. Blechert, Tetrahedron Lett., 1986, 26 S . Blechert, R. Muller, and M. Beitzel, Tetrahedron, 27 S. Blechert and A. Kleine-Klausing, Angew. Chem., Int. 28 G.A. Kraus and D. Zheng, Synlett, 1993,7 1. 29 G. Saha, A. Battacharya, S.S. Roy, and S. Ghosh, Tetrahedron Lett., 1990,31,1483. 30 G. Saha, A. Karpha, S.S. Roy, and S. Ghosh, J. Chem. SOC., Perkin Trans. I , 1992,1587.3 1 (a) G. Saha and S. Ghosh, Synth. Commun., 1991,21, 2129; (b) S. Ghosh, G. Saha, G. Mostafa, and S. Ray, J. 0%. Chem., 1992,57,7344. Tetrahedron Lett., 1992,33,2363. 2987. 32 S. Ghosh, A. Karpha, G. Saha, and D. Patra, 33 S. Sarkar and S. Ghosh, Tetrahedron Lett., 1993,34, 34 R.A.Holton, J. Am. Chem. SOC., 1984,106,5731. 35 R.A. Holton and R.M. Kennedy, Tetrahedron Lett., 36 R.A. Holton, R.R. Juo, H.B. Kim, A.D. Williams, S. 1984,25,4455. Harusawa, R.E. Lowenthal, and S. Yogai, J. Am. Chem. SOC., 1988,110,6558. 37 R.A. Holton in ‘Strategies and Tactics in Organic Synthesis’, Academic Press Inc., 1991,3,165. 38 K.J. Shea and S. Wise, J. Am. Chem. SOC., 1978,100, 6519. 39 K.J. Shea and P.D. Davis, Angew. Chem., Znt. Ed. Engl., 1983,22,419.40 K.J. Shea and J.W. Gilman, Tetrahedron Lett., 1983,24, 657; 1984,24,2451; J. Am. Chem. Soc., 1985,107, 4791; KJ. Shea and S.T. Sakata, Tetrahedron Lett., 1992,33,426 1. 41 R.W. Jackson, R.G. Higby, and KJ. Shea, Tetrahedron Lett., 1992,33,4695; R.W. Jackson, R.G. Higby, J.W. Gilman, and KJ. Shea, Tetrahedron, 1992,48,70 13. 42 P.A. Brown, P.R. Jenkins, J. Fawcett, and D.R. Russeli, J. Chem. SOC., Chem. Commun., 1984,253; P.A. Brown and P.R. Jenkins, J. Chem. SOC., Perkin Trans. I , 1986, 1303. 43 R.V. Bonnert and P.R. Jenkins, J. Chem. SOC., Chem. Commun., 1987,1540: J. Chem. SOC., Perkin Trans. 1, 1989,413. 44 D. Van Ende, W. Dumont, and A. Krief, Angew, Chem., Int. Ed. Engl., 1975,14,700; A. Krief, Tetrahedron, 1980,36,2632. 45 R.V. Bonnert and P.R.Jenkins, J. Chem. SOC., Chem. Commun., 1987,6; R.V. Bonnert, J. Howarth, P.R. Jenkins, and NJ. Lawrence, J. Chem. SOC., Perkin Trans. I , 1991,1225. 46 G. Stork and MJ. Sofia, J. Am. Chem. SOC., 1986,108, 6826. 47 R.V. Bonnert, MJ. Davies, J. Howarth, and P.R. Jenkins, J. Chem. SOC., Chern. Commun., 1990,148; R.V. Bonnert, M.J. Davies, J. Howarth, P.R. Jenkins, and N.J. Lawrence, J. Chem. SOC., Perkin Trans. 1,1992,27. 48 A.N. Boa, J. Clark, P.R. Jenkins, and N.J. Lawrence, J. Chem. SOC., Chem. Commun., 1993,15 1. 49 S. Hanessian and N.R. Plessas, J. 0%. Chem., 1969,34, 1035. 50 J.S. Yadav and R. Ravishankar, Tetrahedron Lett., 1991, 32,2629; J.S. Yadav, Pure App. Chem., 1993,65,1349, 51 S.F. Martin, J.B. White, and R. Wagner, J. 0%. Chem., 1982,47,3190; V.M. Lynch, J.-M.Assercq, A.F. Martin, and B.E. Davis, Acta Crystallogr. Sect. C., 1990, 46,2472; ibid., 1991,47,468. Hickey, and R.D. Rogers, Helv. Chim. Acta, 1992,75, 1755; L.A. Paquette, K.D. Combrink, S.W. Elmore, and M. Zhao, ibid., 1992,75,1772; S.W. Elmore, K.D. Combrink, and L.A. Paquette, Tetrahedron Lett., 199 1, 32,6679; L.A. Paquette, M. Zhao, and D. Friedrich, ibid., 1992,33,7311. 53 L.A. Paquette and M. Zhao, J. Am. Chem. SOC., 1993, 115,354. 54 T. Furukawa, K. Morihira, Y. Horiguchi, and I. Kuwajima, Tetrahedron, 1992,48,6975. 55 M. Seto, K. Morihira, S. Katagiri, T. Furukawa, Y. Horiguchi, and I. Kuwajima, Chem. Lett., 1993,133. 56 Y. Kataoka, Y. Nakamura, K. Morihira, H. Arai, Y. Horiguchi, and I. Kuwajima, Tetrahedron Lett., 1992, 33,6979. 57 K. Morihira, M.Seto, T. Furukawa, Y. Horiguchi, and I. Kuwajima, Tetrahedron Lett., 1993,34,345. 58 I. Kuwajima in ‘Organic Synthesis in Japan’, ed. R. Noyori, 1992, Tokyo Kagaku Dozin, Tokyo, page 205. 59 M. Polla and T. Frejd, Tetrahedron, 1991,47,5883. 60 (a) L. Pettersson, T. Frejd, and G. Magnusson, 52 L.A. Paquette, S.W. Elmore, K.D. Combrink, E.R. Tetrahedron Lett., 1987,28,2753; (b) L. Pettersson, G. Magnusson, and T. Frejd, Acta Chem. Scand., 1993,47, 196. 61 M. Polla and T. Frejd, Tetrahedron, 1993,49,2701. 62 S. Arseniyadas, D.V. Yashunsky, R. Pereira de Freitas, M. Munoz Dorado, E. Toromanoff, and P. Potier, Tetrahedron Lett., 1993,34,1137. 63 P.A. Wender and T.P. Mucciaro, J. Am. Chem. SOC., 1992,114,5878. 64 K.C. Nicolaou, C.-K. Hwang, EJ. Sorensen, and C.F.Clairborne, J. Chem. SOC., Chem. Commun., 1992, 1117. 65 K.C. Nicolaou, J.J. Liu, C.-K. Hwang, W.-M. Dai, and R.K. Guy, J. Chem. SOC., Chem. Commun., 1992,1118. 66 I. Alkonyi and D. Szabo, Chem. Ber., 1967,100,2773. 67 E.J. Corey and R.K. Bakshi, Tetrahedron Lett., 1990, 31,611; EJ. Corey, R.K. Bakshi, and S. Shibata, J. Am. Chem. SOC., 1987,109,5551. 68 K.C. Nicolaou, Z. Yang, EJ. Sorensen, and M. Nakada, J. Chem. SOC., Chem. Commun., 1993,1024. 69 T.V. Magee, W.G. Bornmann, R.C.A. Isaacs, and S.J. Danishefsky, J. Org. Chem., 1992,57,3274. 74 Contemporary Organic Synthesis70 C.H. Heathcock and R. Ratcliffe, J. Am. Chem. SOC., 1971,93,1746. 71 Y. Ito, T. Hirao, and T. Saegusa, J. Org. Chem., 1978, 72 Y. Queneau, W.J. Krol, W.G. Bornmann, and S. J. Danishefsky, J.0%. Chem., 1992,57,4043. 73 J. Detering and H.-D. Martin, Angew. Chem., Znt. Ed. Engl., 1988,27,695; J.R. Hargreaves,P.W.Hickmott, and B.J. Hopkins, J. Chem. SOC., C 1968,2559. 74 L.C. Vishwakarama, O.D. Stringer, and F.A. Davis, Org. Synth., 1987,88,203. 75 M. Golinski, S. Vasuden, R. Floresca, C.P. Brock, and D.S. Watt, Tetrahedron Lett., 1993,34,55; M. Golinski, C.P. Brock, and D.S. Watt, J. 0%. Chem., 1993,58, 159. 76 For recent reviews listing natural taxanes see D.G.I. Kingston, A.A. Molinero, and J.M. Rimoldi, in ‘Progress in the Chemistry of Organic Natural Products’. ed. by W. Herz, G.W. Kirby, and C. Tamm, 1993, Springer-Verlag, New York, 59, pp. 1-188. 77 G. Chauviere, D. Guinard, F, Picot, V. Senilh, and P. Potier, C. R. Acad. Sci. Ser. 2,1981,293,501. 78 F. Gueritte-Voegelein, B. David, D. Guinard, V. Sknilh, and P. Potier, Tetrahedron, 1986,42,4451; M. Colin, D. Guenard, F. Gueritte-Voegelein, and P. Potier, Eur. Pat. Appl. EP 253739A1,20 Jan., 1988; V. Sinilh, F. Guiritte, D. Guinard, M. Colin, and P. Potier, C. R. Acad. Sci. Ser. 2, 1984,299,1039. Gueritte-Voegelein, and P. Potier, Tetrahedron, 1989, 45,4177. Goff, L. Mangatal, and P. Potier, J. Med. Chem., 1991, 34,992. 8 1 D. Guenard, F. Guiritte-Voegelein, and P. Potier, Ace. Chem. Res., 1993,26,160. 82 J.N. Denis, A. E. Greene, D. Guenard, F. Gueritte-Voegelein, L. Mangatal, and P. Potier, J. Am. Chem. SOC., 1988,110,591 7; M. Colin, D. Guenard, F. Gueritte-Voegelein, and P. Potier, Eur. Pat. Appl. EP 253738A1,20 Jan., 1988; J.-N. Denis,A. Greene, D. Guinard, and F. Guiritte-Voegelein, Eur. Pat. Appl. EP 336840A1,5 April, 1989. 83 I. Ojima, I. Habus, M. Zhao, G. I. Georg, and L.R. Jayasinghe, J. Org. Chem., 1991,56,1681. 84 R.A. Holton, Eur. Pat. Appl. EP 40097 1Al,30 May, 1990, Chem. Abstr., 114, P164568q. 85 I. Ojima, C.M. Sun, M. Zucco, Y.H. Park, 0. Ducios, and S. Kuduk, Tetrahedron Lett., 1993,34,4149. 86 R.A. Holton, US Patent Appl. US 5 015 744, Nov. 14, 1989; R.A. Holton, Eur, Pat. Appl., EP 428376A1, 13 Nov, 1990, Chem. Abstr., 1 15, P 1 148 17v. 87 C.S. Swindell, N.E. Krauss, S.B. Horwitz, and I. Ringel, J. Med. Chem., 1991,34,1176. 43,1011. 79 L. Mangatal, M.T. Adeline, D. Guinard, F. 80 F. Guiritte-Voegelein, D. Guinard, F. Lavelle, M.-T. Le 88 J.N. Denis,A.E. Greene, A.A. Serra, and M.-J. Luche, J. Org. Chem., 1986,5 1,46; Analogues: A. Chatterjee, J.S. Williamson, J.K. Zjawiony, and J.R. Peterson, Biorg. Med. Chem. Lett., 1992,2,91. 89 J.N. Denis, A. Correa, and A.E. Greene, J. Org. Chem., 1990,55,1957. 90 K.B. Sharpless, W. Amberg, Y.L. Bennani, G.A. Crispino, J. Hartung, K.-S. Jeong, H.-L. Kwong, K. Morikawa, Z.-M. Wang, D. Xu, and X.-L. Zhang, J. 0%. Chem., 1992,57,2768. 91 A. CommerCon, D. Bizard, F. Bernard, and J.D. Bourzat, Tetrahedron Lett., 1992,33,5185. 92 L. Deng and E.N. Jacobsen, J. Org. Chem., 1992,57, 4320. 93 E.N. Jacobsen, W. Zhang, A.R. Muci, J.R. Ecker, and L. Deng,J. Am. Chem. SOC., 1991,113,7063. 94 V. Farina, S.I. Hauck, and D.G. Walker, Synlett., 1992, 761. 95 G.I. Georg, P.M. Mashava, E. Akgun, and M.W. Milstead, Tetrahedron Lett., 1991,32,3151. In this paper the diastereoselectivity was incorrectly judged to be 100 : 0-see corrigendum, Tetrahedron Lett., 1992, 33,1524. 96 G.I. Georg, E. Akgiin, P.M. Mashava, M.W. Milstead, H. Ping, Z. Wu, and D. Vander Velde, Tetrahedron Lett., 1992,33,2111. 97 R.A. Holton, EP 90305845.1, May 1990; Chem Abstr., 114, P164568q. 98 I. Ojima, I. Habus, M. Zucco, Y.H. Park, C.M. Sun, and T. Brigaud, Tetrahedron, 1992,48,6985; Analogues: G.I. Georg, Z.S. Cheruvallath, R.H. Himes, and M.R. Mejillano, Biorg. Med. Chem. Lett., 1992,2,295. 99 C. Palomo, A. Arrieta, F.P. Cossio, J.M. Aizpurua, A. Mielgo, and N. Aurrekoetxea, Tetrahedron Lett., 1990, 31,6429. Rubiales, and C. Palomo, Tetrahedron Lett., 1988,28, 3133. 101 A. Correa, J.N. Denis, M.-J. Luche, and A.E. Greene, J. 0%. Chem., 1993,58,255. 102 M.E. Bunnage, S.G. Davies, and C.J. Goodwin, J. Chem. SOC., Perkin Trans. 1, 1993, 1375. 103 H. Honig, P. Seufer-Wasserthal, and H. Weber, Tetrahedron, 1990,46,3841. 104 D.-M. Gou, Y.-C. Liu, and C.-S. Chen, J. 0%. Chem., 1993,58,1287. 105 R. Breiva, J.Z. Crich, and CJ. Sih, J. Org. Chem., 1993, 58,1068. 106 C. Mukai, I.J. Kim, and M. Hanoaka, Tetrahedron Asymmetry, 1992,3,1007. 107 K. Hattori, M. Miyata, and H. Yamamoto, J. Am. Chem. SOC., 1993,115,1151. 108 J.N. Denis, A. Correa, and A.E. Greene, J. Org. Chem., 1991,56,6939. 100 F.P. Cossio, C. Lbpez, M. Oiarbide, D. Aparicio, G. Boa, Jenkins, and Lawrence: Recent progress in the synthesis of taxanes 75

ISSN:1350-4894    

DOI:10.1039/CO9940100047

出版商:RSC    

年代:1994

数据来源: RSC