摘要:

Contemporary Organic Synthesis Editorial Board Professor G. Pattenden, FRS (Chairman), University of Nottingham Professor P. D. Bailey, Heriot- Watt University Dr S. E. Gibson (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 X I (Paris-Sud) Professor P. D. Magnus, University of Texas at Austin Professor G. Mehta, University of Hyderabad Professor K. C. Nicolaou, The Scripps Research Institute and University of Professor R. Noyori, Nagoya University Professor L.E. Overman, University of California, 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 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 2165, USA $303, Canada 2173 (plus GST), Rest of the World 2173. 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 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, Haward University Professor S. Hanessian, Universiti 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, The Scripps Research Institute and University of Professor R. Noyori, Nagoya University Professor L. E. Overman, University of California, Iwine Professor L. F. Tietze, University of Gottingen California at San Diego, La Jolla Contemporary Organic Synthesis is a bimonthly journal which aims to review and provide perspective in all aspects of methodology, selectivity, and efficiency in contemporary synthesis.As well as covering all the principles and methods in functional group chemistry and interconversions, organometallic chemistry and asymmetric synthesis will feature prominently, so too will modern aspects of strategy and computer aided design, biotransformations, and protecting group protocols. Special methods and techniques, such as sonochemistry, FVP, electroorganic synthesis, and supported catalysis will be included as occasional articles, and the manner in which synthesis addresses problems and provides solutions in biology, medicine, agriculture, 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 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 2165, USA $303, Canada 2173 (plus GST), Rest of the World 2173. 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. 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/CO99502FX009

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

128 G. Handke and N. Krause, Tetrahedron Lett., 1993,34, 129 C. Darcel, S. Bartsch, C. Bruneau and P.H. Dixeuf, 130 T. Moriya, N. Miyaura and A. Suzuki, Synlett, 1994, 131 H. Bienaym6, Tetrahedron Lett., 1994,35,7387. 132 Y.S. Lee, K.H. Nam, S.H. Jung and H. Park, 133 P. Rochet, J-M. Vatkle and J. Go&, Synthesis, 1994, 134 H-F. Chow, X-P. Cao and M. Leung, J. Chem. SOC., 135 F. Toda, K. Tanaka and H. Nawata, J. Chem. SOC., 136 B.J.L. Royles and D.M. Smith, J. Chem. SOC., Perkin 137 V. Ratovelomanana, Y. Rollin, C. GCbkhenne, 6037. Synlett, 1994, 457. 149. Synthesis, 1994, 792. 795. Chem. Commun., 1994,2121. Perkin Trans. 1, 1994, 2043. Trans. 1, 1994, 355. C. Gosmini and J. Perichon, Tetrahedron Lett., 1994, 35, 4777. 138 D. Grandjean, P. Pale and J. Chuche, Tetrahedron Lett., 1994,35, 3529.139 K. Kusuda, K. Kawamura, Y. Ueno and T. Toru, Tetrahedron Lett., 1993, 34, 6587. 140 K. Miwa, T. Aoyama and T. Shioiri, Synlett, 1994, 107. 141 G.G. Melikyan, R.C. Combs, J. Lamirand, M. Khan and K.M. Nicholas, Tetrahedron Lett., 1994, 35, 363. 142 K. Iida and M. Hirama, J. Am. Chem. SOC., 1994,116, 10310. 143 M. Yoshimatsu, H. Yamada, H. Shimizu and T. Kataoka, J. Chem. SOC., Chem. Commun., 1994, 2107. Lett., 1993, 34, 5403. Tetrahedron Lett., 1994,35, 7615. 5975. 59, 6877. SOC., Chem. Commun., 1994, 1845. 1829. 4738. 713. 144 M. Alami, F. Ferri and G. Linstrumelle, Tetrahedron 145 T. Mandai, Y. Tsujiguchi, S. Matsuoka and J. Tsuji, 146 S. Ikeda and Y. Sato, J. Am. Chem. SOC., 1994, 116, 147 S. Ikeda, D.-M. Cui and Y. Sato, J. 0 ~ .Chem., 1994, 148 C. Darcel, C. Bruneau and P.H. Dixeuf, J. Chem. 149 K.K. Wang and Z. Wang, Tetrahedron Lett., 1994,35, 150 Z. Wang and K.K. Wang, J. 0%. Chem., 1994,59, 151 M.E. Maier and D. Langenbacher, Synlett, 1994, 152 J. Isihara, N. Kanoh, A. Fukuzawa and A. Murai, 153 K.K. Wang, Z. Wang and Y.G. Gu, Tetrahedron Lett., 154 H. Hopf and M. Theurig,Angew. Chem., Znt. Ed. 155 M. Moniatte, M. Eckhardt, K. Brickmann, Chem. Lett., 1994, 1563. 1993,34,8391. Engl., 1994,33, 1099. R. Bruckner and J. Suffert, Tetrahedron Lett., 1994, 35, 1965. Tetrahedron Lett., 1994, 35, 5689. Tetrahedron Lett., 1994, 35, 5645. 50,5335. 156 M. Yamaguchi, K. Omata and M. Hirama, 157 C. Meyer, I. Marek, J-F. Normant and N. Platzer, 158 D. Chemin and G. Linstrumelle, Tetrahedron, 1994, 159 S.A.Hitchcock, S.H. Boyer, M.Y. Chu-Moyer, S.H. Olson and S. J. Danishefsky, Angew. Chem., Znt. Ed. Engl., 1994, 33, 858. 160 T. Brandstetter and M.E. Maier, Tetrahedron, 1994, 50, 1435. 161 H. Audrain, T. Skrydstrup, G. Ulibarri, C. Riche, A. Chiaroni and D.S. Grierson, Tetrahedron, 1994, 50, 1469. K.M. Pham, D.M. Vyas and M.D. Wittman, Tetrahedron, 1994, 50, 1519. 482. 35, 37. 35, 2655. Tetrahedron Lett., 1994,35, 7997. R.A. Fairhurst, J. Chem. SOC., Chem. Commun., 1994, 1543. Danishefsky, Angew. Chem., Znt. Ed. Engl., 1994,33, 2477. 169 M.D. Shair, T. Yoon and S.J. Danishefsky, J. 0%. Chem., 1994,59,3755. 170 M.F. Braiia, M. Moran, M.J.P. de Vega and I. Pita- Romero, Tetrahedron Lett., 1994,35, 8655. 171 K. Toshima, K. Yanagawa, K. Ohta, T. Kano and M.Nakata, Tetrahedron Lett., 1994, 35, 1573. 172 P. Magnus, Tetrahedron, 1994,50, 1397. 173 D. Elbaum, T.B. Nguyen, W.L. Jorgensen and S.L. 162 J.F. Kadow, D.J. Cook, T.W. Doyle, D.R. Langley, 163 T. Nishikawa, S. Shibuya and M. Isobe, Synlett, 1994, 164 J.M. Nuss and M.M. Murphy, Tetrahedron Lett., 1994, 165 R.S. Huber and G.B. Jones, Tetrahedron Lett., 1994, 166 T. Nishikawa, M. Yoshikai, K. Obi and M. Isobe, 167 P. Magnus, D. Parry, T. Iliadis, S.A. Eisenbeis and 168 M.D. Shair, T. Yoon, T-C. Chou and S.J. Schreiber, Tetrahedron, 1994,50, 1503. Cousins: Saturated and unsaturated hydrocarbons 461128 G. Handke and N. Krause, Tetrahedron Lett., 1993,34, 129 C. Darcel, S. Bartsch, C. Bruneau and P.H. Dixeuf, 130 T. Moriya, N. Miyaura and A. Suzuki, Synlett, 1994, 131 H.Bienaym6, Tetrahedron Lett., 1994,35,7387. 132 Y.S. Lee, K.H. Nam, S.H. Jung and H. Park, 133 P. Rochet, J-M. Vatkle and J. Go&, Synthesis, 1994, 134 H-F. Chow, X-P. Cao and M. Leung, J. Chem. SOC., 135 F. Toda, K. Tanaka and H. Nawata, J. Chem. SOC., 136 B.J.L. Royles and D.M. Smith, J. Chem. SOC., Perkin 137 V. Ratovelomanana, Y. Rollin, C. GCbkhenne, 6037. Synlett, 1994, 457. 149. Synthesis, 1994, 792. 795. Chem. Commun., 1994,2121. Perkin Trans. 1, 1994, 2043. Trans. 1, 1994, 355. C. Gosmini and J. Perichon, Tetrahedron Lett., 1994, 35, 4777. 138 D. Grandjean, P. Pale and J. Chuche, Tetrahedron Lett., 1994,35, 3529. 139 K. Kusuda, K. Kawamura, Y. Ueno and T. Toru, Tetrahedron Lett., 1993, 34, 6587. 140 K. Miwa, T. Aoyama and T. Shioiri, Synlett, 1994, 107.141 G.G. Melikyan, R.C. Combs, J. Lamirand, M. Khan and K.M. Nicholas, Tetrahedron Lett., 1994, 35, 363. 142 K. Iida and M. Hirama, J. Am. Chem. SOC., 1994,116, 10310. 143 M. Yoshimatsu, H. Yamada, H. Shimizu and T. Kataoka, J. Chem. SOC., Chem. Commun., 1994, 2107. Lett., 1993, 34, 5403. Tetrahedron Lett., 1994,35, 7615. 5975. 59, 6877. SOC., Chem. Commun., 1994, 1845. 1829. 4738. 713. 144 M. Alami, F. Ferri and G. Linstrumelle, Tetrahedron 145 T. Mandai, Y. Tsujiguchi, S. Matsuoka and J. Tsuji, 146 S. Ikeda and Y. Sato, J. Am. Chem. SOC., 1994, 116, 147 S. Ikeda, D.-M. Cui and Y. Sato, J. 0 ~ . Chem., 1994, 148 C. Darcel, C. Bruneau and P.H. Dixeuf, J. Chem. 149 K.K. Wang and Z. Wang, Tetrahedron Lett., 1994,35, 150 Z. Wang and K.K. Wang, J. 0%. Chem., 1994,59, 151 M.E.Maier and D. Langenbacher, Synlett, 1994, 152 J. Isihara, N. Kanoh, A. Fukuzawa and A. Murai, 153 K.K. Wang, Z. Wang and Y.G. Gu, Tetrahedron Lett., 154 H. Hopf and M. Theurig,Angew. Chem., Znt. Ed. 155 M. Moniatte, M. Eckhardt, K. Brickmann, Chem. Lett., 1994, 1563. 1993,34,8391. Engl., 1994,33, 1099. R. Bruckner and J. Suffert, Tetrahedron Lett., 1994, 35, 1965. Tetrahedron Lett., 1994, 35, 5689. Tetrahedron Lett., 1994, 35, 5645. 50,5335. 156 M. Yamaguchi, K. Omata and M. Hirama, 157 C. Meyer, I. Marek, J-F. Normant and N. Platzer, 158 D. Chemin and G. Linstrumelle, Tetrahedron, 1994, 159 S.A. Hitchcock, S.H. Boyer, M.Y. Chu-Moyer, S.H. Olson and S. J. Danishefsky, Angew. Chem., Znt. Ed. Engl., 1994, 33, 858. 160 T. Brandstetter and M.E.Maier, Tetrahedron, 1994, 50, 1435. 161 H. Audrain, T. Skrydstrup, G. Ulibarri, C. Riche, A. Chiaroni and D.S. Grierson, Tetrahedron, 1994, 50, 1469. K.M. Pham, D.M. Vyas and M.D. Wittman, Tetrahedron, 1994, 50, 1519. 482. 35, 37. 35, 2655. Tetrahedron Lett., 1994,35, 7997. R.A. Fairhurst, J. Chem. SOC., Chem. Commun., 1994, 1543. Danishefsky, Angew. Chem., Znt. Ed. Engl., 1994,33, 2477. 169 M.D. Shair, T. Yoon and S.J. Danishefsky, J. 0%. Chem., 1994,59,3755. 170 M.F. Braiia, M. Moran, M.J.P. de Vega and I. Pita- Romero, Tetrahedron Lett., 1994,35, 8655. 171 K. Toshima, K. Yanagawa, K. Ohta, T. Kano and M. Nakata, Tetrahedron Lett., 1994, 35, 1573. 172 P. Magnus, Tetrahedron, 1994,50, 1397. 173 D. Elbaum, T.B. Nguyen, W.L. Jorgensen and S.L. 162 J.F. Kadow, D.J.Cook, T.W. Doyle, D.R. Langley, 163 T. Nishikawa, S. Shibuya and M. Isobe, Synlett, 1994, 164 J.M. Nuss and M.M. Murphy, Tetrahedron Lett., 1994, 165 R.S. Huber and G.B. Jones, Tetrahedron Lett., 1994, 166 T. Nishikawa, M. Yoshikai, K. Obi and M. Isobe, 167 P. Magnus, D. Parry, T. Iliadis, S.A. Eisenbeis and 168 M.D. Shair, T. Yoon, T-C. Chou and S.J. Schreiber, Tetrahedron, 1994,50, 1503. Cousins: Saturated and unsaturated hydrocarbons 461128 G. Handke and N. Krause, Tetrahedron Lett., 1993,34, 129 C. Darcel, S. Bartsch, C. Bruneau and P.H. Dixeuf, 130 T. Moriya, N. Miyaura and A. Suzuki, Synlett, 1994, 131 H. Bienaym6, Tetrahedron Lett., 1994,35,7387. 132 Y.S. Lee, K.H. Nam, S.H. Jung and H. Park, 133 P. Rochet, J-M. Vatkle and J. Go&, Synthesis, 1994, 134 H-F.Chow, X-P. Cao and M. Leung, J. Chem. SOC., 135 F. Toda, K. Tanaka and H. Nawata, J. Chem. SOC., 136 B.J.L. Royles and D.M. Smith, J. Chem. SOC., Perkin 137 V. Ratovelomanana, Y. Rollin, C. GCbkhenne, 6037. Synlett, 1994, 457. 149. Synthesis, 1994, 792. 795. Chem. Commun., 1994,2121. Perkin Trans. 1, 1994, 2043. Trans. 1, 1994, 355. C. Gosmini and J. Perichon, Tetrahedron Lett., 1994, 35, 4777. 138 D. Grandjean, P. Pale and J. Chuche, Tetrahedron Lett., 1994,35, 3529. 139 K. Kusuda, K. Kawamura, Y. Ueno and T. Toru, Tetrahedron Lett., 1993, 34, 6587. 140 K. Miwa, T. Aoyama and T. Shioiri, Synlett, 1994, 107. 141 G.G. Melikyan, R.C. Combs, J. Lamirand, M. Khan and K.M. Nicholas, Tetrahedron Lett., 1994, 35, 363. 142 K. Iida and M. Hirama, J. Am. Chem.SOC., 1994,116, 10310. 143 M. Yoshimatsu, H. Yamada, H. Shimizu and T. Kataoka, J. Chem. SOC., Chem. Commun., 1994, 2107. Lett., 1993, 34, 5403. Tetrahedron Lett., 1994,35, 7615. 5975. 59, 6877. SOC., Chem. Commun., 1994, 1845. 1829. 4738. 713. 144 M. Alami, F. Ferri and G. Linstrumelle, Tetrahedron 145 T. Mandai, Y. Tsujiguchi, S. Matsuoka and J. Tsuji, 146 S. Ikeda and Y. Sato, J. Am. Chem. SOC., 1994, 116, 147 S. Ikeda, D.-M. Cui and Y. Sato, J. 0 ~ . Chem., 1994, 148 C. Darcel, C. Bruneau and P.H. Dixeuf, J. Chem. 149 K.K. Wang and Z. Wang, Tetrahedron Lett., 1994,35, 150 Z. Wang and K.K. Wang, J. 0%. Chem., 1994,59, 151 M.E. Maier and D. Langenbacher, Synlett, 1994, 152 J. Isihara, N. Kanoh, A. Fukuzawa and A. Murai, 153 K.K. Wang, Z. Wang and Y.G. Gu, Tetrahedron Lett., 154 H.Hopf and M. Theurig,Angew. Chem., Znt. Ed. 155 M. Moniatte, M. Eckhardt, K. Brickmann, Chem. Lett., 1994, 1563. 1993,34,8391. Engl., 1994,33, 1099. R. Bruckner and J. Suffert, Tetrahedron Lett., 1994, 35, 1965. Tetrahedron Lett., 1994, 35, 5689. Tetrahedron Lett., 1994, 35, 5645. 50,5335. 156 M. Yamaguchi, K. Omata and M. Hirama, 157 C. Meyer, I. Marek, J-F. Normant and N. Platzer, 158 D. Chemin and G. Linstrumelle, Tetrahedron, 1994, 159 S.A. Hitchcock, S.H. Boyer, M.Y. Chu-Moyer, S.H. Olson and S. J. Danishefsky, Angew. Chem., Znt. Ed. Engl., 1994, 33, 858. 160 T. Brandstetter and M.E. Maier, Tetrahedron, 1994, 50, 1435. 161 H. Audrain, T. Skrydstrup, G. Ulibarri, C. Riche, A. Chiaroni and D.S. Grierson, Tetrahedron, 1994, 50, 1469. K.M. Pham, D.M.Vyas and M.D. Wittman, Tetrahedron, 1994, 50, 1519. 482. 35, 37. 35, 2655. Tetrahedron Lett., 1994,35, 7997. R.A. Fairhurst, J. Chem. SOC., Chem. Commun., 1994, 1543. Danishefsky, Angew. Chem., Znt. Ed. Engl., 1994,33, 2477. 169 M.D. Shair, T. Yoon and S.J. Danishefsky, J. 0%. Chem., 1994,59,3755. 170 M.F. Braiia, M. Moran, M.J.P. de Vega and I. Pita- Romero, Tetrahedron Lett., 1994,35, 8655. 171 K. Toshima, K. Yanagawa, K. Ohta, T. Kano and M. Nakata, Tetrahedron Lett., 1994, 35, 1573. 172 P. Magnus, Tetrahedron, 1994,50, 1397. 173 D. Elbaum, T.B. Nguyen, W.L. Jorgensen and S.L. 162 J.F. Kadow, D.J. Cook, T.W. Doyle, D.R. Langley, 163 T. Nishikawa, S. Shibuya and M. Isobe, Synlett, 1994, 164 J.M. Nuss and M.M. Murphy, Tetrahedron Lett., 1994, 165 R.S. Huber and G.B. Jones, Tetrahedron Lett., 1994, 166 T.Nishikawa, M. Yoshikai, K. Obi and M. Isobe, 167 P. Magnus, D. Parry, T. Iliadis, S.A. Eisenbeis and 168 M.D. Shair, T. Yoon, T-C. Chou and S.J. Schreiber, Tetrahedron, 1994,50, 1503. Cousins: Saturated and unsaturated hydrocarbons 461128 G. Handke and N. Krause, Tetrahedron Lett., 1993,34, 129 C. Darcel, S. Bartsch, C. Bruneau and P.H. Dixeuf, 130 T. Moriya, N. Miyaura and A. Suzuki, Synlett, 1994, 131 H. Bienaym6, Tetrahedron Lett., 1994,35,7387. 132 Y.S. Lee, K.H. Nam, S.H. Jung and H. Park, 133 P. Rochet, J-M. Vatkle and J. Go&, Synthesis, 1994, 134 H-F. Chow, X-P. Cao and M. Leung, J. Chem. SOC., 135 F. Toda, K. Tanaka and H. Nawata, J. Chem. SOC., 136 B.J.L. Royles and D.M. Smith, J. Chem. SOC., Perkin 137 V.Ratovelomanana, Y. Rollin, C. GCbkhenne, 6037. Synlett, 1994, 457. 149. Synthesis, 1994, 792. 795. Chem. Commun., 1994,2121. Perkin Trans. 1, 1994, 2043. Trans. 1, 1994, 355. C. Gosmini and J. Perichon, Tetrahedron Lett., 1994, 35, 4777. 138 D. Grandjean, P. Pale and J. Chuche, Tetrahedron Lett., 1994,35, 3529. 139 K. Kusuda, K. Kawamura, Y. Ueno and T. Toru, Tetrahedron Lett., 1993, 34, 6587. 140 K. Miwa, T. Aoyama and T. Shioiri, Synlett, 1994, 107. 141 G.G. Melikyan, R.C. Combs, J. Lamirand, M. Khan and K.M. Nicholas, Tetrahedron Lett., 1994, 35, 363. 142 K. Iida and M. Hirama, J. Am. Chem. SOC., 1994,116, 10310. 143 M. Yoshimatsu, H. Yamada, H. Shimizu and T. Kataoka, J. Chem. SOC., Chem. Commun., 1994, 2107. Lett., 1993, 34, 5403. Tetrahedron Lett., 1994,35, 7615.5975. 59, 6877. SOC., Chem. Commun., 1994, 1845. 1829. 4738. 713. 144 M. Alami, F. Ferri and G. Linstrumelle, Tetrahedron 145 T. Mandai, Y. Tsujiguchi, S. Matsuoka and J. Tsuji, 146 S. Ikeda and Y. Sato, J. Am. Chem. SOC., 1994, 116, 147 S. Ikeda, D.-M. Cui and Y. Sato, J. 0 ~ . Chem., 1994, 148 C. Darcel, C. Bruneau and P.H. Dixeuf, J. Chem. 149 K.K. Wang and Z. Wang, Tetrahedron Lett., 1994,35, 150 Z. Wang and K.K. Wang, J. 0%. Chem., 1994,59, 151 M.E. Maier and D. Langenbacher, Synlett, 1994, 152 J. Isihara, N. Kanoh, A. Fukuzawa and A. Murai, 153 K.K. Wang, Z. Wang and Y.G. Gu, Tetrahedron Lett., 154 H. Hopf and M. Theurig,Angew. Chem., Znt. Ed. 155 M. Moniatte, M. Eckhardt, K. Brickmann, Chem. Lett., 1994, 1563. 1993,34,8391. Engl., 1994,33, 1099.R. Bruckner and J. Suffert, Tetrahedron Lett., 1994, 35, 1965. Tetrahedron Lett., 1994, 35, 5689. Tetrahedron Lett., 1994, 35, 5645. 50,5335. 156 M. Yamaguchi, K. Omata and M. Hirama, 157 C. Meyer, I. Marek, J-F. Normant and N. Platzer, 158 D. Chemin and G. Linstrumelle, Tetrahedron, 1994, 159 S.A. Hitchcock, S.H. Boyer, M.Y. Chu-Moyer, S.H. Olson and S. J. Danishefsky, Angew. Chem., Znt. Ed. Engl., 1994, 33, 858. 160 T. Brandstetter and M.E. Maier, Tetrahedron, 1994, 50, 1435. 161 H. Audrain, T. Skrydstrup, G. Ulibarri, C. Riche, A. Chiaroni and D.S. Grierson, Tetrahedron, 1994, 50, 1469. K.M. Pham, D.M. Vyas and M.D. Wittman, Tetrahedron, 1994, 50, 1519. 482. 35, 37. 35, 2655. Tetrahedron Lett., 1994,35, 7997. R.A. Fairhurst, J. Chem. SOC., Chem. Commun., 1994, 1543.Danishefsky, Angew. Chem., Znt. Ed. Engl., 1994,33, 2477. 169 M.D. Shair, T. Yoon and S.J. Danishefsky, J. 0%. Chem., 1994,59,3755. 170 M.F. Braiia, M. Moran, M.J.P. de Vega and I. Pita- Romero, Tetrahedron Lett., 1994,35, 8655. 171 K. Toshima, K. Yanagawa, K. Ohta, T. Kano and M. Nakata, Tetrahedron Lett., 1994, 35, 1573. 172 P. Magnus, Tetrahedron, 1994,50, 1397. 173 D. Elbaum, T.B. Nguyen, W.L. Jorgensen and S.L. 162 J.F. Kadow, D.J. Cook, T.W. Doyle, D.R. Langley, 163 T. Nishikawa, S. Shibuya and M. Isobe, Synlett, 1994, 164 J.M. Nuss and M.M. Murphy, Tetrahedron Lett., 1994, 165 R.S. Huber and G.B. Jones, Tetrahedron Lett., 1994, 166 T. Nishikawa, M. Yoshikai, K. Obi and M. Isobe, 167 P. Magnus, D. Parry, T. Iliadis, S.A. Eisenbeis and 168 M.D.Shair, T. Yoon, T-C. Chou and S.J. Schreiber, Tetrahedron, 1994,50, 1503. Cousins: Saturated and unsaturated hydrocarbons 461 Contemporary Organic Synthesis Editorial Board Professor G. Pattenden, FRS (Chairman), University of Nottingham Professor P. D. Bailey, Heriot- Watt University Dr S. E. Gibson (ne'e Thomas), Imperial College of Science, Technology, and Medicine Professor P. J. Kocienski, University of Southampton Professor C. J. Moody, Loughborough University of Technology Professor E. J. Thomas, University of Manchester International Advisory Board Professor E. J. Corey, Haward University Professor S. Hanessian, Universiti de Montrial Professor M. Julia, Universiti de Paris X I (Paris-Sud) Professor P. D. Magnus, University of Texas at Austin Professor G.Mehta, University of Hyderabad Professor K. C. Nicolaou, The Scripps Research Institute and University of Professor R. Noyori, Nagoya University Professor L. E. Overman, University of California, Iwine Professor L. F. Tietze, University of Gottingen California at San Diego, La Jolla Contemporary Organic Synthesis is a bimonthly journal which aims to review and provide perspective in all aspects of methodology, selectivity and efficiency in contemporary synthesis. As well as covering all the principles and methods in functional group chemistry and interconversions, organometallic chemistry and asymmetric synthesis will feature prominently; so too will modern aspects of strategy and computer aided design, biotransformations and protecting group protocols.Special methods and techniques, such as sonochemistry, FVP, electroorganic synthesis and supported catalysis will be included as occasional articles, and the manner in which synthesis addresses problems and provides solutions in biology, medicine, agriculture, the environment and new materials, will also be encompassed. Contemporary Organic Synthesis aims to be proactive, drawing attention to new opportunities and new directions, providing timely information to the synthetic chemist who needs to keep abreast of developments in the field. Although the majority of articles are intended to be specially commissioned, the Society is always prepared to consider offers of articles for publication. In such cases a short synopsis, rather than the completed article, should be submitted to Dr S.R. Buxton, Managing Editor, Organic Publications, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF, UK. Members of The Royal Society of Chemistry may subscribe to Contemporary Organic Synthesis by placing their orders on the Annual Subscription renewal forms in the usual way. All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letchworth, Herts SG6 lHN, England. 1996 subscription rates: EEA &185, USA $350, Canada El90 (plus GST), Rest of the World E190. Contemporary Organic Synthesis is published 6 times a year in February, April, June, August, October and December. Airfreight and mailing in the USA by Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey, NJ 07001, USA and at additional mailing offices.Second class postage is paid at Rahway, NJ. USA Postmaster: Send address changes to Contemporary Organic Synthesis, c/o Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey 07001. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. + 0 The Royal Society of Chemistry, 1996 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording or otherwise, without the prior permission of the publishers. Typeset in Great Britain by Unicus Graphics Ltd 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 (ne'e Thomas), Imperial College of Science, Technology, and Medicine Professor P. J. Kocienski, University of Southampton Professor C. J. Moody, Loughborough University of Technology Professor E. J. Thomas, University of Manchester International Advisory Board Professor E. J. Corey, Haward University Professor S. Hanessian, Universiti de Montrial Professor M. Julia, Universiti de Paris X I (Paris-Sud) Professor P. D. Magnus, University of Texas at Austin Professor G. Mehta, University of Hyderabad Professor K. C.Nicolaou, The Scripps Research Institute and University of Professor R. Noyori, Nagoya University Professor L. E. Overman, University of California, Iwine Professor L. F. Tietze, University of Gottingen California at San Diego, La Jolla Contemporary Organic Synthesis is a bimonthly journal which aims to review and provide perspective in all aspects of methodology, selectivity and efficiency in contemporary synthesis. As well as covering all the principles and methods in functional group chemistry and interconversions, organometallic chemistry and asymmetric synthesis will feature prominently; so too will modern aspects of strategy and computer aided design, biotransformations and protecting group protocols. Special methods and techniques, such as sonochemistry, FVP, electroorganic synthesis and supported catalysis will be included as occasional articles, and the manner in which synthesis addresses problems and provides solutions in biology, medicine, agriculture, the environment and new materials, will also be encompassed.Contemporary Organic Synthesis aims to be proactive, drawing attention to new opportunities and new directions, providing timely information to the synthetic chemist who needs to keep abreast of developments in the field. Although the majority of articles are intended to be specially commissioned, the Society is always prepared to consider offers of articles for publication. In such cases a short synopsis, rather than the completed article, should be submitted to Dr S. R. Buxton, Managing Editor, Organic Publications, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF, UK.Members of The Royal Society of Chemistry may subscribe to Contemporary Organic Synthesis by placing their orders on the Annual Subscription renewal forms in the usual way. All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letchworth, Herts SG6 lHN, England. 1996 subscription rates: EEA &185, USA $350, Canada El90 (plus GST), Rest of the World E190. Contemporary Organic Synthesis is published 6 times a year in February, April, June, August, October and December. Airfreight and mailing in the USA by Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey, NJ 07001, USA and at additional mailing offices.Second class postage is paid at Rahway, NJ. USA Postmaster: Send address changes to Contemporary Organic Synthesis, c/o Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey 07001. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. + 0 The Royal Society of Chemistry, 1996 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording or otherwise, without the prior permission of the publishers. Typeset in Great Britain by Unicus Graphics Ltd 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 (ne'e Thomas), Imperial College of Science, Technology, and Medicine Professor P. J. Kocienski, University of Southampton Professor C. J. Moody, Loughborough University of Technology Professor E. J. Thomas, University of Manchester International Advisory Board Professor E. J. Corey, Haward University Professor S. Hanessian, Universiti de Montrial Professor M. Julia, Universiti de Paris X I (Paris-Sud) Professor P. D. Magnus, University of Texas at Austin Professor G. Mehta, University of Hyderabad Professor K. C. Nicolaou, The Scripps Research Institute and University of Professor R.Noyori, Nagoya University Professor L. E. Overman, University of California, Iwine Professor L. F. Tietze, University of Gottingen California at San Diego, La Jolla Contemporary Organic Synthesis is a bimonthly journal which aims to review and provide perspective in all aspects of methodology, selectivity and efficiency in contemporary synthesis. As well as covering all the principles and methods in functional group chemistry and interconversions, organometallic chemistry and asymmetric synthesis will feature prominently; so too will modern aspects of strategy and computer aided design, biotransformations and protecting group protocols. Special methods and techniques, such as sonochemistry, FVP, electroorganic synthesis and supported catalysis will be included as occasional articles, and the manner in which synthesis addresses problems and provides solutions in biology, medicine, agriculture, the environment and new materials, will also be encompassed. Contemporary Organic Synthesis aims to be proactive, drawing attention to new opportunities and new directions, providing timely information to the synthetic chemist who needs to keep abreast of developments in the field.Although the majority of articles are intended to be specially commissioned, the Society is always prepared to consider offers of articles for publication. In such cases a short synopsis, rather than the completed article, should be submitted to Dr S. R. Buxton, Managing Editor, Organic Publications, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF, UK.Members of The Royal Society of Chemistry may subscribe to Contemporary Organic Synthesis by placing their orders on the Annual Subscription renewal forms in the usual way. All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letchworth, Herts SG6 lHN, England. 1996 subscription rates: EEA &185, USA $350, Canada El90 (plus GST), Rest of the World E190. Contemporary Organic Synthesis is published 6 times a year in February, April, June, August, October and December. Airfreight and mailing in the USA by Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey, NJ 07001, USA and at additional mailing offices.Second class postage is paid at Rahway, NJ. USA Postmaster: Send address changes to Contemporary Organic Synthesis, c/o Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey 07001. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. + 0 The Royal Society of Chemistry, 1996 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording or otherwise, without the prior permission of the publishers. Typeset in Great Britain by Unicus Graphics Ltd 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 (ne'e Thomas), Imperial College of Science, Technology, and Medicine Professor P. J. Kocienski, University of Southampton Professor C. J. Moody, Loughborough University of Technology Professor E. J. Thomas, University of Manchester International Advisory Board Professor E. J. Corey, Haward University Professor S. Hanessian, Universiti de Montrial Professor M. Julia, Universiti de Paris X I (Paris-Sud) Professor P. D. Magnus, University of Texas at Austin Professor G. Mehta, University of Hyderabad Professor K. C. Nicolaou, The Scripps Research Institute and University of Professor R. Noyori, Nagoya University Professor L. E. Overman, University of California, Iwine Professor L.F. Tietze, University of Gottingen California at San Diego, La Jolla Contemporary Organic Synthesis is a bimonthly journal which aims to review and provide perspective in all aspects of methodology, selectivity and efficiency in contemporary synthesis. As well as covering all the principles and methods in functional group chemistry and interconversions, organometallic chemistry and asymmetric synthesis will feature prominently; so too will modern aspects of strategy and computer aided design, biotransformations and protecting group protocols. Special methods and techniques, such as sonochemistry, FVP, electroorganic synthesis and supported catalysis will be included as occasional articles, and the manner in which synthesis addresses problems and provides solutions in biology, medicine, agriculture, the environment and new materials, will also be encompassed.Contemporary Organic Synthesis aims to be proactive, drawing attention to new opportunities and new directions, providing timely information to the synthetic chemist who needs to keep abreast of developments in the field. Although the majority of articles are intended to be specially commissioned, the Society is always prepared to consider offers of articles for publication. In such cases a short synopsis, rather than the completed article, should be submitted to Dr S. R. Buxton, Managing Editor, Organic Publications, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF, UK. Members of The Royal Society of Chemistry may subscribe to Contemporary Organic Synthesis by placing their orders on the Annual Subscription renewal forms in the usual way. All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letchworth, Herts SG6 lHN, England. 1996 subscription rates: EEA &185, USA $350, Canada El90 (plus GST), Rest of the World E190. Contemporary Organic Synthesis is published 6 times a year in February, April, June, August, October and December. Airfreight and mailing in the USA by Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey, NJ 07001, USA and at additional mailing offices. Second class postage is paid at Rahway, NJ. USA Postmaster: Send address changes to Contemporary Organic Synthesis, c/o Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey 07001. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. + 0 The Royal Society of Chemistry, 1996 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording or otherwise, without the prior permission of the publishers. Typeset in Great Britain by Unicus Graphics Ltd Printed in Great Britain by Whitstable Litho Ltd

ISSN:1350-4894    

DOI:10.1039/CO995020X011

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

ISSN 1350-4894 COGSE6 2 (3) 133-208 (1995) Contemporary Organic Synthesis A journal of current developments in Organic Synthesis V O L U M E 2 N U M B E R 3 C O N T E N T S 91 N Bn2 I (i) NaHMDS (ii) W H O I NBn2 83%, >98:2 d.s. (i) NBS, CC14. hv (iii) RuCI,, NaI04 (ii) MeMgX, Et20 MeCN. H20 (iv) HCI. Et,P I H2N)J0" H 'Me " " ' c d OBn Me02C* I" OB." CSA, CH2CI2 25 "C. 76% OBn HO H Saturated and unsaturated lactones By T. Laduwahetty Reviewing the literature published between 1 January 1993 and 31 July 1994 Aldehydes and ketones By Patrick G. Steel Reviewing the literature published between July 1993 and September 1994 133 151 a-Cation equivalents of amino acids 173 By Patrick D. Bailey, Andrew N. Boa, and Joanne Clayson Reviewing the literature published up to the end of 1994 Saturated oxygen heterocycles By Christopher J.Burns Reviewing the literature published between 1 April 1993 and 30 September 1994 189Cumulative Contents of Volume 2 Number 1 1 19 35 43 Aromatic heterocycles as intermediates in natural product synthesis (up to the end of 1993) Michael Shipman The hydrometallation, carbometallation, and metallometallation of heteroalkynes (up to August 1994) Sharon Casson and Philip Kocienski Serotonin, sumatriptan, and the management of migraine Alexander Oxford Stoichiometric organotransition metal complexes in organic synthesis ( 1 September 1993 to 31 August 1994) Julian Blagg Number 2 65 Catalytic applications of transition metals in organic synthesis ( 1 September 1993 to 31 August 1994) Christopher G. Frost and Jonathan M.J. Williams 85 Organic halides ( 1 July 1993 to 30 June 1994) Peter L. Spargo 107 Carboxylic acids and esters ( 1 January 1993 to 31 July 1994) T. Harrison and T. Laduwahetty 121 Hypervalent iodine in organic synthesis: cx-functionalization of carbonyl compounds (up to February 1995) Om Prakash, Neena Saini, Madan F! Tanwar, and M. Moriarty Number 3 133 Saturated and unsaturated lactones ( 1 January 1993 to 31 July 1994) T. Laduwahetty 151 Aldehydes and ketones (Jury 1993 to September 1994) Patrick G. Steel 173 r-Cation equivalents of amino acids (up to the end of 1994) Patrick D. Bailey, Andrew N. Boa, and Joanne Clayson Saturated oxygen heterocycles ( 1 April 1993 to 30 September 1994) Christopher J. Burns 189 Articles that will appear in forthcoming issues include Ene-diynes D. Grierson Recent advances in organofiuorine chemistry Jonathan Percy Amines and amides Michael North Acylation and alkylation of aromatics and heteroaromatics H. Heaney Saturated and unsaturated hydrocarbons R. F! C. Cousins Saturated nitrogen heterocycles T. Harrison Nitro and related nitrogen based functional groups G. M. Robertson Imines and related nitrogen based functional groups G. M. Robertson Synthesis and use of cyclic peroxides K. McCullough Synthetic developments in host-guest chemistry Jeremy D. Kilburn

ISSN:1350-4894    

DOI:10.1039/CO99502FP013

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

EUCHEM Conference on Tycloadditions and Related Reactions: Theory and Practice” Vulcano Island, Italy, 21-24 June, 1995 Address for Correspondence: Prof. Mario Gattuso - Universith di Messina Dpt di Chimica Organica e Biologica - Salita Spemne 31, S. Agata 98166 MESSINA, Italy - FAX +39 90 392840EUCHEM Conference on Tycloadditions and Related Reactions: Theory and Practice” Vulcano Island, Italy, 21-24 June, 1995 Address for Correspondence: Prof. Mario Gattuso - Universith di Messina Dpt di Chimica Organica e Biologica - Salita Spemne 31, S. Agata 98166 MESSINA, Italy - FAX +39 90 392840

ISSN:1350-4894    

DOI:10.1039/CO99502BX015

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

Saturated and unsaturated lactones T. LADUWAHETTY Merck Sharp and Dohme, Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR - Arq:x Reviewing the literature published between 1 January 1993 and 31 July 1994 1 Introduction 3 Macrolides Pyr, CHCI3 'H ...O (i) EtOH, reflux (ii) H,. (R)-BINAP-Run 2 /3-Lactones 0 4 Medium-ring lactones 5 &Lactones 6 Spirolactones 7 y-Lactones 8 But-2-enolides and tetronic acids OH 0 A r a O E 1 1 (9696%) 9 a-Methylene butyrolactones 10 References go eHg(= A r d s e OH 0 Ar\/ N- 3 (52430%; 95% e.e.) 2 (90%) but 10 References Hg(W3Me)Z Ar&se Ar\/ MeCN Scheme 1 1 Introduction This review surveys the literature relating to saturated and unsaturated lactones, and includes macrolides, tetronic acids, and a-methylene lactones.The chemistries associated with carboxylic acids and esters are covered in separate articles in Contemporary Organic Synthesis. 2 /?-Lactones Few lactonization methods are suitable for /3-lactone formation due to the inherent lability of this moiety. In fact, hitherto, no practical methods exist for the preparation of enantiopure B-lactones. Combining Noyori's efficient protocol for the synthesis of #?-hydroxy esters and a variant of the Corey/Nicolaou lactonization methodology, large-scale syntheses of /3-lactones such as 3 are now possible (Scheme 1 ).I It was found that cyclization of the 2-pyridylthiol ester 2 is superior to the benzenethiol analogue since the latter gives the cyclized product in only 60% yield, making chromatography necessary.The use of Masamune's mercury( 11) methanesulfonate catalyst together with the 2-pyridylthiol ester ensures that lactone formation occurs quickly ( 10 min.), without resorting to prolonged heating so that decomposition is avoided. It should be noted that only one of the six steps in the synthesis (the formation of 1) requires chromatography, thus making it a viable synthesis on multigram-scale, to obtain /3-substituted B-lactones of either absolute configuration. An interesting variation of the classical Reformatsky reaction involves treating the a-bromoester 4 with ketones in the presence of indium (Scheme 2).2 Aliphatic ketones (with the exception of acetone) and aromatic ketones are transformed into #?-lactones instead of the /3-hydroxy esters. It is noteworthy that even aromatic ketones give /3-lactones with zinc in DMF, instead of the traditional non-polar solvents used for the Reformatsky reaction. Formation of /3-lactones using this methodology is entirely restricted to the synthesis of a,a * ,/3,/3'-tetrasubstituted #I-lactones, since cyclization is facilitated by the gem-dialkyl effect.Polar solvents such as DMF also facilitate elimination of the intermediate metal alkoxide, hence favouring #I-lactone formation. r 1 M In 95 Zn 2 Scheme 2 5 (84%) 98 (76%) Ladu wahetty: Saturated and unsaturated lactones 133H0YC6H13 3 Macrolides A novel macrolactonization procedure involves the in situ generation of a conjugated ketene, viz. 6, from the l-butoxy-1,3-diyne 5.3 Addition of 5 to a refluxing benzene solution of triethylamine then gives the highly functionalized lactone 7 in 45% yield. The neutral reaction conditions make this strategy ideal for acid/base sensitive compounds such as 8 (Scheme 3).The ethoxy alkyne intermediates, which are readily available from the corresponding aldehydes, have not only been used to construct macrolides, but also five-, six-, and seven-membered ring lactones! PhS 5 Et3N, A benzene 1 L 7 (45%) 6 (i) Liz-OEt (ii) TBDMSCI (iii) deprotection I OTBDMS H e Y H 0 0 (49%) Scheme 3 1 , 1 , 1-Trifluoroethyl-o-hydroxy-carboxylates give macrolactones ( 16-membered or higher) in good yields5 under tin( IV ) catalysis (Scheme 4). The thermodynamic impetus for the formation of the lactone is the formation of R,SnOCH,CF,, which in turn dissociates to form the tin alkoxide 9 and trifluoroethanol which boils off under the reaction conditions.Smaller ring lactones (ten-membered and less) do not form due to competing dimerization. L 9 41 % Scheme 4 Large ring lactones can be synthesized by cyclizing hydroxy acids under Lewis acidic conditions via an activated anh~dride.6.~ This method can also be used for the synthesis of seven-membered lactones (Scheme 5). Hydrous zirconium( IV ) oxide8 modified with TMSCl and zeolites' has also been used to synthesize medium to large ring lactones. 0 0 5 mol% TiCI, + I d (92%) (R)-ricindeic acid lactone (n= 1-9) \ I n Scheme 5 Several macrolactonization methods involving acyl activation have proved to be unsuccessful for the synthesis of the macrolides 10 and 1 1.The presence of the 174-diene and the p, y-unsaturated ester functionality makes these pheromones unstable to heat, acid, and base. The use of the Steglich modification of the Mitsunobu cyclization, however, has enabled the efficient cyclization of the hydroxyacid precursors of 10 and 11 in very acceptable yields.'(' 10 (71%) 11 (68%) 134 Contemporary Organic SynthesisThermolysis of 1,2,4-trioxane derivatives is an attractive possibility to access large ring systems." The synthetic utility of this methodology (Scheme 6) is limited, however, since the rules governing ring-opening have yet to be fully understood. n = 4 25% n=12 - Scheme 6 4 Medium-ring lactones A useful method for the preparation of nine-membered unsaturated lactones involves using the Malherbe-Bellus variant of the Claisen rearrangement.I Thus 2-vinyltetrahydrofurans (12-14) (Scheme 7) react with dichloroketene, generated in situ, to give the trans-lactones ( 15- 17) in good yields. The reaction is stereospecific with regard to the stereochemistry of the initial alkene double bond. Thus a mixture of transfcis (85 : 15) 14 gives a mixture of 2-methyl conformers of 17 (85: 15). The tri-n-butyltinhydride mediated dechlorination of 14 results in the formation of the cis-lactone, indicating 18 to be the thermodynamically favoured product. Tetrahydrofuranyl trifluroacetic anhydrides undergo a similar ring-expansion, via an acyloxonium ion 19,13 to give functionalized ten-membered lactones. Attack of a nucleophile at the bridge-head carbon in 19 then gives the major product 20, whilst regioselective elimination leads to 2 1 (Scheme 8).R' 12 R'=H 15 R' =H,s% 13 R' = CH2OTBDMS 16 R' = CH,OTBDMS, 60% 14 R'=Me 17 R' =Me, 55% 1Bun3SnH R' b 18 Scheme 7 Laduwahetty: Saturated and unsaturated lactones n TiCI, 19 1 CI I OCOCF3 I 1 ; 85% 4 20 21 Scheme 8 While iodolactonizations, to form medium-ring lactones, are not favourable processes, due to gauche interactions in the transition state, replacing one of the carbons with an oxygen, as in 22, gives the seven-membered lactone product without resorting to high dilution ~0nditions.l~ e 0 - C O 2 H 22 I bis(simcd1idine)iodine-hexafluorophosphate 0 59% The methodology developed by Holmes et al. for the synthesis of medium-ring ethers has been extended to the corresponding lactones.lS Thus the homochiral diol24, which is readily available from the oxazolidinone 23, can be converted into a selenoxide 2 5, which then undergoes a stereoselective Claisen rearrangement to provide the eight-membered lactone 26.The seven-membered lactone 27 is also accessible using this methodology (Scheme 9). Medium-ring and macrocyclic acetylenic lactones can be accessed by treating bicyclic tosyl-hydrazones with N-bromosuccinimide (Scheme 1 0).l6 An interesting diastereoselective synthesis of medium-ring lactones 29 involves treating the trichloroacetate 28 with Cu(bpy)Cl (Scheme 1 l ) . 1 7 Although similar cyclizations of dichloroacetates have been reported previously, the dichloroacetate analogue of 28 did not cyclize. Simple alkenyl trichloroacetates (30,3 1 ) do cyclize to give eight- and nine-membered rings as well, although terminal substitution of the alkene reduces the rate of the reaction.Except in the cyclization of 28, dichloroacetates generally give higher yields than trichloroacetates in these cyclizations. 5 &Lactones Radical-mediated endocyclic cleavage of the tetrahydrofuranyl hydroxy ester 32 provides the keto 1350 OBn Dmannose - \ CHO - oiN+ LiBH4, q, OBn Bn 23 24 O X 0 l(0 PhSe-zE (ii) NaI04 26 (73%, > 95% e.e.) 25 ,%Ph 29 Scheme 9 n = 1,3,7 Scheme 10 O)TBDMS 27 (45%, > 95% e.8.) 0 n = 0,65% n = 1.3,7, -90% ester 33, which then cyclizes the corresponding d-lactone under basic conditions (Scheme 12).’* The corresponding tetrahydropyranyl analogue also undergoes exclusive endocyclic cleavage although re-cyclization to the seven-membered ring only occurs when constrained in a bicyclic system (Scheme 13).ci.s-4,5-disubstituted d-lactones involves the heterolytic cleavage of vicinal donor-acceptor substituted cyclobutanes (Scheme 14).” The 1,4-zwitterionic species produced from the cyclobutane under Lewis acidic conditions forms the (E)-enolate intermediate 34 which then reacts with aldehydes. The resulting hydroxy esters are cyclized under acidic conditions. The chelated chair transition state explains the formation of the cis-lactone 35 as the major product. The reactions with methyl ketones are less selective, although dehydration of the anti-hydroxy ester, in preference to the syn, during the lactonization conditions ensures that the cis-lactone emerges as the major product.The diastereoselectivity in the analogous reaction of a-monosubstituted cyclobutanes 36 with symmetrical ketones (Scheme 15) to provide cis-2,4-d-lactones is diminished. This is attributed to the fact that the chiral centre in the zwitterionic species 37 formed from 36 is A diastereoselective synthesis of - 02cc13 30 Scheme 11 0 0 + +OLi OR - q o 0 II 0 Q 33 (45%) Scheme 12 #? to the reaction centre and therefore less likely to influence the reaction. A novel cyclization strategy for the synthesis of homochiral2,4-disubstituted #?-keto- d-lactones (Scheme 16) involves treating the halo diester 38 with Zn and trimethylchlorosilane?O Simple trituration of the crude product with hexanes then gives 39 in 70% yield. The presence of TMSCl is crucial to the reaction as the lack of it produces large amounts of the diester 40 due to protonation of the zinc enolate.Since the proton source is the product lactone, TMSCl silylates the intermediate ketal until work-up. 136 Contemporary Organic Synthesis' U O R R OH I NaH R=(CH,), I Qco2. 65% Scheme 13 0 H13C6J0 40 38 (1:4, ether/TMSCI) 1'" 1 H20 0 C6H 13 OH 39 (70%) Scheme 16 The radical-mediated cyclization of 4 1 in the presence of Bu,SnH to produce the corresponding d-lactone is dramatically concentration dependent (Entries a and b).,' Under the concentrated conditions Tris( trimethylsilyl)silane, on the other hand, undergoes the desired exo-trig mode of cyclization to produce the d-lactone, independent of concentration.shown only the reduced product 42 is obtained. + 0 34 cat. pTsOH toluene, 90°C OHRs C02Et RS 35 cisltrans : 92 : 8 41 42 Concentration Bu",SnH (TMS),SiH (ratio d volume of entry a x loo 0% 82% entry b x lo00 92% 90% Scheme 14 solvent/gram substrate) Acyloxypalladation and subsequent room temperature elimination of palladium hydride under mild conditions constitutes an efficient synthesis of bicyclic p and y-lactones. Larock et a(." have improved upon the present methodology by employing Pd( OAc), in DMSO. A variety of ring systems, including fused, bridged bicyclic, and spirocyclic, involving the formation of five- and six-membered + 36 - UZM (i) T~(OP~~CI, (ii) H20, pTsOH TMSO P f 0 cisltrans : 65/35 pfYpf 0 37 Scheme 15 Laduwahetty: Saturated and unsaturated lactones rings are produced efficiently.Four-, seven- and twelve-membered rings, however, are not. The product composition in the Pd( OAc), catalysed reaction 43 -, 44/45 can be different from that obtained from iodolactonization or selenolactonization (Scheme 17). Even cyclization reactions involving different palladium catalysts can make a difference to the outcome of the reaction. Thus, Hegedus et al. have cyclized the alkenoic acid 46 to the 3-methyl coumarin 48 using PdC1,. The (Z)-phthalide 47 is the only 137product formed under the Larock conditions. It is likely that 47 is produced through a n-ally1 intermediate which undergoes an intramolecular displacement by the carboxylate group followed by subsequent double bond isomerization. n = I , 81% n = 2 , 68% 43 44 45 3 1 46 47 (71%) \% PdCI+?IkCN 48 (41%) Scheme 17 DDQ in aqueous acetone is an extremely mild method for the selective deprotection of an orthoester to a d-lactone23 even in the presence of an acetal (Scheme 18).This selectivity can be attributed to the orthoester being a more electron-rich species than the acetal, and hence forming a charge-transfer complex with the DDQ. The reaction of DDQ in benzene only effects the oxidation of the allylic hydroxyl group. 6 Spirolactones Sequential reaction of the metallocycle 49 with an epoxide and carbon dioxide provides a direct, one-step synthesis of spiro d-la~tones.~~ This approach can be used to prepare both bicyclic and tricyclic spiro- 6-lactones. Whilst good regioselectivity is observed with unsymmetrical epoxides, this methodology also provides a direct method for the synthesis of d-lactones with a p-quaternary centre.Radical cyclizations of 1,3-diones 50 or of /3-keto esters 51 and alkenes either directly25 or via a selenide26 intermediate provide novel routes to spiro lactones (Scheme 19). OMe ?Me ( - - - A 0 --0 0 : H I 99% yield 34% Scheme 18 63% (1:l mixture of diastereorners) 0 0 50 64% 0 0 0 0 (i) LDA, PhSeCl (ii) hv, C6H, 254 nM SePh 51 Scheme 19 64% 138 Contemporary Organic Synthesis7 y-Lactones A highly enantioselective reduction of bicyclic Osmium tetroxide mediated dihydroxylations of p-amino-( E)-crotylsilanes provide a route for the asymmetric synthesis of a-amino- y-lactones (Scheme 20).27 The diastereoselectivity arises from the approach of the osmium reagent anti-to the silyl group.Whereas the anti-diastereomer gives the 3'4-cis-lactone 52 in good yield and selectivity, the syn-diasteromer provides the 3,4-trans-lactone. Even basic amines are tolerated under the reaction conditions. d C 0 2 M e SiMe2Ph ,SiMe2Ph R, ,SiMqPh 0 H OH H OH 52 trans cis R=N3 15 1 05% R = NHCO~BU' 40 1 95% R = NMe2 23 1 54% Scheme 20 The xanthate 53 derived from a sugar cyclizes in the presence of Bu,SnH to give a mixture of bicyclic lactones in 47% yield.28 Although there clearly needs to be an improvement in terms of selectivity, this route is a simple and elegant method of obtaining these homochiral intermediates which are precursors in prostaglandin syntheses (Scheme 2 1 ). 03- I 6 steps - rq C02Me ] 1 23 20 : 57 Scheme 21 meso- 1,2-dicarboxylic anhydrides using Noyori's (R)-BINAL-H provides an efficient route into a variety of y-lactones.29 The lactones 55 and 57, which are used as building blocks in the synthesis of prostanoids, are obtained in good yield with 8349% enantiomeric excess. The fused lactone 59 which is a key intermediate in the synthesis of ( + )-biotin can be obtained from 58 in 95% e.e.after one recrystallization from benzene. The reaction is governed by the steric bulk on the concave and convex faces of the bicyclic system. Thus an increase in bulk on the convex face reduces enantioselectivity, whereas an increase in bulk on the concave face improves selectivity. The chirality of the product cannot be predicted u priori: for instance, ( R )-BINAL-H reduces the carbonyl attached to the group with the (R)-configuration in 56, whilst reducing the carbonyl attached to the carbon with the (S)-configuration in 54.But since both enantiomers of l,l,-bi-2-naphthol are commercially available, the lactone of desired configuration can be obtained. (R)-BI NAL-H 0 54 55 (99%) 56 57 (84%) 0 0 PhANKNAPh (R)-BINAL-H PhANKNAPh 58 59 (76%, 95% e.e.) Additions of silyl ketene acetals to lactones occur only under forcing conditions. Using tris( dimethyl-amido)sulfonium trimethyl silicate (TAST ) as catalyst, however, enables their smooth reaction at low temperature.,' The greater reactivity of ketones under forcing conditions is still observed with TAST (Scheme 22). Homochiral truns-3,4-disubstituted lactones can be synthesized from the thermodynamically stable truns-cyclobutanone 6 1,' which is in turn obtained by asymmetric deprotonation of 3-phenylcyclobutanone (Scheme 23).The direct alkylation of the enol silyl ether 60 was unsuccessful and the 2-alkylated products are obtained by sequential acylation, elimination, and hydrogenation. Vicinal donor-acceptor substituted cyclopropanes have been used as an innovative entry to 2,3,4-trisubstituted y-lactones. The cyclopropanes are obtained from the corresponding ketene acetal and the diazoacetic ester to give the trans-isomer of 62 as the Ladu wahetty: Saturated and unsaturated lactones 139R' + OSiMe HOMe TASF THF -25 "C - 63% Scheme 22 Me Me Ph '4, PhANXPh ti c 'n Ph' Phh -0 L\ OSiEt3 60 (92% e.e.) (i) C4H&H0 (ii) AqO, DBU 1 Scheme 23 major product.Reactions of 62 with symmetrical ketones under Lewis acid conditions provides the cis-2,3-disubstituted lactones with excellent selectivity and in high yield.32 This selectivity arises from the approach of the ketone anti-to the cationic substituent (Scheme 24). Shimada et al. have extended this reaction to the synthesis of cis-2,3-trans- 3,4-trisubstituted y-lactones by employing an aldehyde as the ele~trophile.~~ Reaction of 63 with 62 0 R' = Et 99 1 , 95% Scheme 24 cyclohexanaldehyde, for instance, gives the cis-trans product 64 with moderate selectivity (Scheme 25). A variety of aldehydes can be utilized, although selectivity increases with increasing bulkiness. Using ZrCl,, in which the metal-oxygen bond is longer, results in a higher trans-3,4 selectivity (85: 15).Optically active alcohols obtained by the well established reaction of chiral boron reagents with aldehydes can be converted into y-lactones in a two step procedure (Scheme 26).34 Taking advantage of the fact that aromatic esters are less likely to be reduced by borane than an alkyl ester, due to their lower basicity, the alkene 65 can be reacted with a borane reagent and oxidized in situ to obtain the lactone directly in good yield. The corresponding acetate protected alcohol only forms the lactone in 17% yield. For acid-sensitive lactones such as 66 thexylborane can be employed, thus avoiding the presence of HC1 in the oxidizing step, since the original conditions only gives 66 in 80% e.e. (Scheme 27). The selectivity of disiamylborane for terminal alkenes, on the other hand, can be taken into account for the synthesis of useful intermediates such as 67.butyrolactones, such as those present in ( - )-cis-whiskey lactone, can be achieved by the samarium diodide promoted fragmentation of 68 (Scheme 28).3s N-oxidations of b- y-unsaturated carboxylic acids3h followed by iodolactonizations provide a route to trans, trans-2,3,4-trisubstituted lactones (Scheme 29). The stereoselectivity of the reaction is governed by the transition state 69 and involves a 5-endu-tet type cyclization. The alternative transition state 70, where the electronegative substituent allows for maximum n-o* interaction, leads to electron withdrawal from the olefinic system, thus making it less reactive to the electrophile.The 4-hydroxy butenolide 71 may be readily converted into the menthyl ether 72, which is a useful homochiral synthon for conjugate addition reactions.37 The menthyl group can be removed later by reduction with NaBH, (Scheme 30). alkynoic acid 73 and a 2-alkynyl acetate in the Enantioselective syntheses of 3,4-disubstituted Allenol y-lactones can be synthesized from an 140 Contemporary Organic Synthesis63 Scheme 25 64 TCI, 2 10 61 27 ZrC14 4 4 81 11 R3 = cyclohexyl =/"i, ether, -lOO°C RCHO R > 99% e.e. 1PC2B- R Go R = Me. (i) BHflI.SMe2, CHfl12 (ii) CrO3, AcOH (iii) NaOH (iv) HCI - 0 -No2 78%. > 99% 8.e. 65 Scheme 26 0 II .o OAAr (i) thexylborane ~~~~ ' Ph R (N) HCI 66 ( W h , > 98% e.e.) 0 il I disiamylborane OCAr - \ 67 (a%, 98% e.e.) Scheme 27 OSiEt3 (+)-cawone ------ CO,Me CI 68 J SmI2 0 one diastereomer R = Me, 50% R = Bn, 70% Scheme 29 69 70 OMenth OMenth oeoH 120°C-130"C, (-)-men! hol 3 d' 7; +g 71 0 0 Q OMe OMe Scheme 30 OSiEt3 intramolecular nucleophilic attack of the carboxylate anion on the triple bond to generate 74 (Scheme 31).esters such as 75, followed by acid-catalysed fb ~~~~~ mo2& The addition of Me,A1 to a$-unsaturated sulfone 91 % Scheme 28 cyclization, provides a stereoselective route to cis-p- y-substituted lac tone^.^^ Lithium and magnesium reagents give mixtures of 1,2- and l,LC-adducts, whilst Bu,CuLi gives 1,4-addition without stereoselectivity. The coordination of the Me,Al to the MOM-ether prior to addition is the origin of the diastereoselectivity in this reaction. This methodology can be used to obtain homochiral lactones by enzymatic resolution of the alcohols obtained by condensing ( S)-( phenylsulfony1)-p-tolysulfinyl methane with an aldehyde (Scheme 32).The sulfoxide is then presence of Pd0.3* This methodology is an extension of an earlier report by the same research group, involving the coupling of alkynoic acids and 1-haloalkynes. The mechanism involves the generation of a a-allenyl palladium species which in turn activates the Ladu wahetty: Saturated and unsaturated lactones 141R' Ph02S e R 3 R2 - Pdo Ri + &C02H OAc R3 Pd(0Ac) 73 O O R 76 n (93 : 7) (30) : I OAC Scheme 33 R' = R2 = H, R3 = Ph, 50% R' = R2 = Me, R3 = Ph, 62% Scheme 31 Medl PhO2S MeO2C OMOM PM2sYYR - Me02C OMOM 75 1:1.6 mixture at a-position p o 4 Ph02S, 0 &CR R = Me, 82% Ph02S,,ioMe - + RCH2CH0 I (i) piperidine (ii) Lipase PS 1 FAG Ph02S d R + Ph02S+R (56%, > 98% e.e.) (41 %.> 95% e.e.) Scheme 32 eliminated and the resulting vinyl sulfone alkylated to provide the substrate for the addition of the organometallic reagent. Products with > 90% e.e. can be obtained in this manner. The addition of Me,A1 to the butenolide 76 results directly in the trans-lactone 77 as the major product. Et,AlCN, on the other hand, gives the cis-lactone 78 as the major product although with reduced selectivity (Scheme 33). This difference in stereoselectivity is attributed to the constraints imposed by the phenylsulfonyl group and its sensitivity to different reagents. The exploitation of molecular symmetry in synthesis has been extended to the halolactonization reaction by Kurth et al.(Scheme 34).,O The dienoic acids 79 and 80, prepared by an iterative Claisen rearrangement can be cyclized with I, to obtain the lactones 85 and 86 with excellent selectivity. The diastereoselectivities in the reactions of 79 and 80 arise from the fact that the nucleophilic carboxylate is confronted by two diastereoselective olefins which experience different ground-state conformations relative to the carboxylate. The conformational energy differences in the transition state favour cyclization towards the side where the carboxy and allylic substituents are anti; thus olefin selectivity can be anticipated when the C,-C,/C, - CBf differ in stereochemistry (8 1 versus 82). The C,-C, stereochemistry is determined by the face selectivity in the iodination (83 versus 84).The subtlety in these cyclizations can be illustrated (Scheme 34) by the dienoic acid 87, where both allylic substituents are syn and only differ from each other by a single methylene. The acid 87 cyclizes to give the lactone 88 with CY1 selectivity (22: 1) and excellent cis/trans selectivity. Having had success with the transition metal catalysed tandem cyclization/cycloaddition reactions of diazoketones, Padwa et al. have now explored the analogues reactions with diaz~esters.~' The ester 89 does not cyclize, possibly due to the reduced electrophilicity of the rhodium carbenoid. The presence of an additional stabilizing group, as in 90, however, promotes the cyclization, providing the lactone product in good yield.Conformational differences between the mono- and di-substituted carbenoids may also govern their reactivity. presence of potassium iodide and sodium persulfate (Scheme 35). Unlike the standard iodolactonization conditions which require substantial amounts of KI and I,, this new procedure, which is based on the in situ oxidation of iodide with persulfate, only requires a slight excess of KI.42 Cyclizations of the acids 9 1-93 using standard iodolactonization conditions always give lower yields and need longer reaction times than the KI/persulfate method. The successful iodolactonization of but-3-enoic acid to the corresponding @-lactone is particularly noteworthy. The acid-sensitive fused-ring lactones 94 and 95 can be synthesized efficiently from the cyclic enol ethers shown and the monomethyl ester of malonic acid using ceric ammonium nitrate in acetic acid.43 Addition of Cu( OAc), to the reaction mixtures, to oxidize any secondary radical intermediates to A variety of carboxylic acids afford y-lactones in the 142 Contemporary Organic Synthesis81 olefinselectivity [w vemm +I% 79 R=Me 80 R=Et - * [N~HCO, i2 / I 87 Scheme 34 65% * b: 0 & Et KI, sodium persulfate HO 91 I Et 92% (20 min.) 92 94% (20 min.) I HO 93 62% (50 rnin.) Scheme 35 carbocations, avoids large amounts of side-products that may otherwise be formed.Ultrasound further increases the yields in the reactions by ca. 10%. Simple olefins give low to moderate yields of lactones, although a variety of electron-rich olefins have been shown to work very efficiently.Mn( OAc),, on the other hand, is not suitable for the synthesis of acetals such as 95. 88 CyKy' 1 :22 cidtmns 12:l. 74% CAN, CU(OAC)~ 94 (84%) C0,Me Me0 MeO a0 95 (81%) Samarium iodide promoted cyclizations of acetals provide trans-2,4-disubstituted y-lactones in good yields (Scheme 36). Although similar to the analogous reactions with Bu,SnH, the samarium iodide conditions are milder and avoid the troublesome removal of tin residues. This methodology also paves the way to introduce functional groups through sequential intramolecular cyclization and electrophilic trapping. Preparations of chiral lactones from meso-diols can be accomplished in high yields and enantioselectivity with Norcardia corallina B-276.44 Using whole cell methods such as this is more economical since it avoids the need to recycle the expensive co-factors necessary for enzyme-based methods. Analogous to horse-liver alcohol dehydrogenase (HLD), the initial oxidation is of the pro-( S) hydroxymethylene (Scheme 37).In contrast to HLD, however, the whole cell system is selective only for diols. extremely useful method for obtaining optially pure ketones and lactones (Scheme 38).4s The whole cell methodology using Acinetobacter calcoaceticus (NCIMB 987) or Cuwularia lunata (NRRL 2380) has The bio-Baeyer-Villiger reaction promises to be an Laduwahetty: Saturated and unsaturated lactones 143R' X = Br, I 1H2CQ. R' 5249% tmndcis- 86:14- 94:6 1 PhSeCl L O B d Scheme 36 0 a::;:: - 50%. W h 8.8. 0 50%. > 90% 8.8.0 95%, 91% 8.8. Scheme 37 b Br L (+)-40% + Scheme 38 144 Contemporary Organic Synthesis some drawbacks, as the organisms are not readily available and the yields are rarely high due to overmetabolism. A recent development in the area is the use of an enzyme-based method using a monooxygenase from the micro-organism Pseudomonas putida. This monoxygenase is unusual in that it utilizes NADH as its co-factor. NADH is much easier to recycle compared to the more common NADPH, which makes the whole process much more economical. This enzyme can also be used together with a dehydrogenase to convert an alcohol into a lactone directly (Scheme 39). 0 0 80% 8.8. > 95% 8.8. 4 &hydrogene* mono-cacygena: +o OH 0 Scheme 39 A mild method for the synthesis of 5-ethenyl- y-lactones involves an initial Baylis-Hillman coupling to form the hydroxy ester 96, followed by cyclization (Scheme 40).4h t-butyl-acetate, in the presence of a Lewis acid such as The enolate generated from LHMDS and 96 H 0 0 0 Scheme 40Et2A1C1, reacts with ( R ) - or (S)-propylene oxide resulting in the formation of (S)-4-methylbutyrolactones with 98% e.e.(Scheme 4 1).47 98% 8.8. Scheme 41 Scheme 43 8 But-2-enolides and tetronic acids Annulated butenolides, viz. 98 and 99, can be formed in a regioselective manner from the same intermediate sulfoxide 97 by generating the corresponding sulfene under different condition^.^^ Under anhydrous Pummerer conditions a vinyl sulfide is formed which upon mercury-mediated hydrolysis forms the butenolide 98 exclusively (Scheme 42).In the presence of H,O, however, the thermally generated sulfene reacts via the hydrated aldehyde 100 to provide 99 as the sole product. Acfl, 110°C ?I Ph (d I p H 0 97 dioxane or I toluene, 98 L 100 Scheme 42 99 Bromolactonizations of a P, y-unsaturated carboxylic acid provides p-lactone 10 1 which when treated with AgNO, results in the generation of an exocyclic cation (Scheme 43). Ring expansions then provide a, y-disubstituted butenolides in good yield.jY ethanol to a-P-unsaturated carboxylic acids provides the sulfone 102, the dianion of which can be reacted with aldehydes and ketone^.^" The resulting The addition of sodium p-toluenesulfinate in 101 R' 1Bu"i-i 25% Ts OH 102 Scheme 44 hydroxyfulfone can then be converted into the butenolide in modest overall yield (Scheme 44).The reactivity of bicyclic tetronates has been explored by Bertucco et al. and interesting differences between the monocyclic- and bicyclic-tetronates have been found.52 Unlike the methyl tetronate 103, which is completely inert to 174-addition by nucleophiles, the bicyclic tetronate 104 reacts with even poor nucleophiles such as trifluoroacetate to provide the 174-adduct 105 in 95% yield. Some other nucleophiles give interesting ring-opened butenolides. The addition of TMSI to bicyclic tetronates, a reagent previously used by Pattenden et al. for the de-esterification of methyl tetronates, results in rapid formation of the corresponding silyl enolate 106. Further reaction with excess reagent then leads to the ring-opened iodide 107 which can be hydrolysed to the tetronate 108 (Scheme 45).The hydrolysis of the methyl tetronate itself with TMSI does not, of course, involve the initial 1,4-addition. MeO bo 1 03 104 105 (95%) Ladu wahetty: Saturated and unsaturated lactones 145c -. 106 TMSI, MeCN or Ac@, MgBr2 1 X ~ O H - X ~ O T M S 0 0 108 107 X = I, Br Scheme 45 The first example of a conjugate addition of a carbon nucleophile to a tetronate has also been reported by these same research workers (Scheme 46). The bicyclic tetronate 109 was found to react with dialkyl cuprates in the presence of TMSCI to give a mixture of the ring-opened and bicyclic products 110 and 11 1, which on exposure to DBU are converted into 1 1 1 exclusively. The substituted tetronate 1 12 reacts with dialkylcuprates even without TMSCI, with the strain relief in the bicyclic structure being the driving force for the reaction.Methyl tetronate is, once more, inert to these conditions. ($yo =Hop + I DBU 111 110 t 109 111 112 Scheme 46 R = Me, 75% R = Bu, 70% 4-Fluoroalkylbut-2-en-4-olides can be synthesized by reaction of 2-silyloxy furans with perfluoroalkyl peroxides (Scheme 47).s2 The mechanism involves the oxidation of the furan to a radical cation and the simultaneous reduction of the resulting peroxide to a radical anion which in turn dissociates to a perfluoroalkyl radical. Addition of the radical to the furan radical cation, followed by rearrangement then provides the butenolide. Due to the strong electron-withdrawing effect of the trifluoromethyl group the anion 113 can react with various acrylates under weakly basic conditions (Scheme 48).Defluorination, a common problem with perfluoroalkyl anions, does not occur due to delocalization into the ring. n R(=CF3, 63% = C2F2, 78% Scheme 47 F3C [ Me02C%o] 113 1 82% Scheme 48 The titanium-catalysed additions of enol silanes to squaric acid 114, and heating of the resulting a-hydroxy ketones in the presence of pyridine, results in the exclusive formation of the (2)-butenolide 1 17 in 64% yield (Scheme 49).s3 The mechanism of this reaction involves a thermally allowed electrocyclic ring-opening to give 1 15 which recyclizes to the CI MeO K: 114 +OSiMe3 R CI MeO % 0 tl A R 116 0 0 R Scheme 49 R 117 146 Contemporary Organic Synthesisbutenolide. The observed (Z)-geometry of the methylene is due to the H-bonded enol form in the intermediate 1 16.A concise synthesis of (2)-isomers of y-alkylidenebutenolides can be achieved under mild conditions by reaction of acetylenes with bromoalkenoic acids under Pd ~atalysis.'~ This reaction provides an interesting interplay between the in situ generated Pd" species, which catalyses the coupling of 118 and 119, and the Pd" species which assists in the cyclization. Prolonged reaction times result in a lower E/Z ratio. PdC12(Ph3P)Z, CUI C02H E3N, MeCN, r.t. * R+H + Br u 118 119 d R = Ph, 80% ZIE: 97:3 R = THPOCH,, 62% ZIE : 9713 Cycloaddition reactions between the nitrile oxides 120 and propene afford mixtures of isoxazolidines (55-68% yield).55 Conversion of the latter into their corresponding salts, followed by hydrogenolysis and elimination then provides a useful route to disubstituted butenolides (Scheme 50)." CO2Et 120 I TfOMe R PPBA 0 a M e Scheme 50 9 a-Methylene butyrolactones The electroreduction of a catalytic amount of ZnBr, in acetonitrile provides an active Zn species which reacts with 12 1 and aldehydes or ketones to provide a-methylene- y-butyrolactones in one step (Scheme 5 1 ).sh The reaction is, however, sensitive to the steric hindrance around the carbonyl group. The allylic carbanion equivalent 12 1 also reacts with aldehydes and ketones in the presence of SnCl, to provide a-methylene- y-butyrolactones (Scheme 5 1 ).57 The allyltrihalostannane intermediate in this sequence not only enhances the nucleophilicity of the anion, but also activates the carbonyl group towards nucleophilic attack. The resulting alkoxystannane 122 is reactive enough to form the lactone in situ.Due to the sensitivity of the organostannane to substitution around the carbonyl, diketones such as 123 can be utilized to give only the mono-alkylated product. =cBr CO2Et 121 + (i) Zn(CH3CN), (cat.), Zn rod (ii) H&+ R' EtO EtO <lr ____) SnCI2 qr - E t o B 1 2 B r R2 R' \' SnCI,Br 122 I 121 R g R' 0 &' R2 1 23 51% Scheme 51 Sodium dithionite initiated cyclizations of acyclic alkynoates give fluorinated a-alkylidine y-butyrolactones in good yield and selectivity (Scheme 52).s8 The reaction works best when R # H, although propynoates do give modest yields (44%). The reaction is initiated by the generation of a perfluoroalkyl radical by the dithionite which, due to its electrophilic nature, adds to the more electron-rich double bond.Cyclization to the triple bond is followed by iodine transfer to the vinyl radical. Good E/Z selectivities ( > 95:5) are obtained under the reaction conditions. This is due to the iodine transfer being slow, allowing the vinyl radical to invert to form the more stable ( E ) isomer. R 1 Scheme 52 A comprehensive study of the synthesis of iodoacetylenic esters and their radical mediated cyclization to ( E)-iodoalkylidine butyrolactones has been conducted by Weavers et aLS9 Whereas the exo-dig ring-closures of propargyl ethers and acetals have been successful, thereby making subsequent oxidation a necessity, the cyclization of the ester gives direct entry to the desired product.A variety of iodo esters have been synthesized by the iodonium ion Ladu wahetty: Saturated and unsaturated lactones 147mediated addition of a carboxylic acid to an alkene. Although several radical cyclization methods were attempted [ e.g. AIBN; Bu,SnH; Bu,SnCl, NaBH,; cobalt( I)] only one, the heating of a benzene solution of the iodoesters with dibenzoyl peroxide, proved 90% successful. A number of cyclic, bicyclic, and spirocyclic lactones were formed in modest (33%) to excellent yields (Scheme 53). With a few exceptions, Scheme 54 the cyclizations were stereospecific giving only the esters (E)-isomer. cyclized The to cyclopentyl give the more and stable cyclohexyl cis-ring iodo junction, g - Tz q regardless of the stereochemistry of the initial iodo ester.As expected, larger rings give significant proportions of the trans-isomer. SiMe, 0 CO2 Et 124 125 + 'O)+,H 0 B~;NF/ H 0 0 1 27 + H H 126 1 28 117a wo H O 33% Scheme 55 cis-lactones 125 and 126, whereas fluoride promoted cyclizations provide only the trans isomers 127 and 128. The five-membered ring is essential to allow for the folded conformation of 124 in order for the reaction to proceed. air-oxidation of vinyl phosphates, undergo Horner-Wadsworth-Emmons reactions to give ( E ) - or (Z)-a-methylene lactones depending on the conditions (Scheme 56)F4 The y-lactone gives exclusively the a-Phosphonolactones, which are prepared by 77% Ph - 0 / Scheme 53 Although direct photolysis of the iodoesters has proved unsuccessful, the (E)-alkylidine lactones can be photoisomerized to give E/Z mixtures, and the less accessible (2)-isomer can then be separated by chromatography.60 These lactones have the capacity to undergo nucleophilic displacement/elimination 75% KHMDS, / 18-Crown-6 reactions.The degree of stereospecificity is dependent R on the nucleophile.h' An interesting difference in OP(0Et)z outcome dimethylcuprate, is seen between where a the mixture reaction of isomers with lithium are O' 3 - [O] &n.,, KZc030 0 18crown-6 Y" obtained, and trifluoromethylcopper (Scheme 54) where the geometry of the reacting double bond is op Intramolecular cyclizations of o-formyl-a-trimethylsilylmethyl a,P-unsaturated esters 124 pave the way for carbocyclization, lactonization, and a-methylenation in one step, albeit in low yield (Scheme 55).63 The Lewis acid promoted cyclization of the (2)-isomer 124 gives only the 87% Scheme 56 148 Contemporary Organic Synthesis(25)-propylidine lactone with KHMDS in the presence of 18-crown-6, whilst giving a high proportion of the (2)-isomer with K,CO, and 18-crown-6.A survey of the examples cited, however, reveals that the conditions for ( E ) - or (2)-alkene formation vary with the structure of the starting phosphonolactone. 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 References G. 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Wallach, Tetrahedron Lett,, 1993,34,3129. J. Rojo, M. Garcia, and J.C. Carretero, Tetrahedron, 1993,49,9787. J. McKew, M.M. Olmstead, and M.J. Kurth, J. Org. Chem., 1994,59,3389. A. Padwa, D.C. Dean, D.J. Fairfax, and S.L. Xu, J. 0%. Chem., 1993,58,4646. A. Royer, R.C. Mebane, and A. Swafford, Synlett, 1993, 899. For the lactonization of alkenoic acids using ammonium persulfate see M. Tiecoo, L. Testaferri, and M. Tingoli, Tetrahedron, 1993,49,535 1. A. D'Aunibale and C. Trogolo, Tetrahedron Lett., 1994, 35,2083. S. Fukuzawa and T. Tsuchimoto, Synlett, 1993,803. H. Luna, K. Prasad, and 0. Repic, Tetrahedron: Asymmetry, 1994,5,303. S.M. Roberts and A. Willets, Chirality, 1993,334. P. Perlmutter and T. McCarthy, Aust. J. Chem., 1993,46, 253. S.K. Taylor, J.A. Fried, Y.N. Grassi, A.E. Marolewski, E.A. Pelton, T. Poel, D.S. Rezanka, and M.R. Whittaker, J. Org. Chem., 1993,58,7304. B.J. Jansen, C.T. Bouman, and A. de Groot, Tetrahedron Lett., 1994,35,2977. H.T. Black and J. Huang, Tetrahedron Lett., 1993,34, 141 1. P. Bonete, C. Najera, J. Org. Chem., 1994,58,3202. A. Bertucco, J. Brennen, M. Fachini, S. Kluge, P.J. Murphy, F. Pasutto, R. Signorini, and H.L. Williams, J. C'hem. SOC., Perkin Trans. I , 1993, 183 1. M. Yoshida, R. Imai, Y. Komatsu, Y. Morinaga, N. Kamigata, and M. Iyoda, ibid., 1993,50 1. M. Ohno, Y. Yamamoto, and S. Eguchi, Tetrahedron Lett., 1993,34,4807. X. Lu, X. Huang, and S. Ma, Tetrahedron Lett., 1993,34, 5963. Y. Rollin, S. Derien, E. Dunach, C. Gebenhenne, and J. Perichon, Tetrahedron, 1993,49,7723. G. Fouquet, A. Gabriel, B. Maillard, and M. Pereyre, Tetrahedron Lett., 1993,34, 7749. X. Lu, Z . Wang, and J. Ji, Tetrahedron Lett., 1994,35, 613. G. Haaima, M. Lynch, A. Routledge, and R.T. Weavers, Tetrahedron, 1993,49,4229. G. Haaima, L.R. Hanton, M. Lynch, S.D. Mawson, A. Routledge, and R. T. Weavers, Tetrahedron, 1994,50, 2161. G. Haaima, S.D. Mawson, A. Routledge, and R.T. Weavers, Tetrahedron, 1994,50,3557. S.D. Mawson and R.T. Weavers, Tetrahedron Lett., 1993, 34, 3139. C. Kuroda, S. Inoue, R. Takemura, and J.Y. Satoh, J. Chem. SOC., Perkin Trans. 1, 1994,52 1. K. Lee, J.A. Jackson, and D.F. Wiemer, J. Org. Chem., 1993,58,5967. Ladu wahetty: Saturated and unsaturated lactones 149

ISSN:1350-4894    

DOI:10.1039/CO9950200133

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

Aldehydes and ketones PATRICK G. STEEL Department of Chemistiy, Science Laboratories, South Road, Durham, DH1 3LE, UK Reviewing the literature published between July 1993 and September 1994 1 1.1 1.2 1.3 2 3 4 5 5.1 5.2 5.3 6 6.1 6.2 7 Synthesis of saturated aldehydes and ketones Redox methods Umpolung methods General methods Synthesis of aromatic aldehydes and ketones Synthesis of cyclic ketones Protection and deprotection strategies Synthesis of functionalized aldehydes and ketones Unsaturated aldehydes and ketones a-Heteroatom substituted aldehydes and ketones Dicarbonyl compounds Reactions of aldehydes and ketones The aldol reaction and other enolate additions Conjugate addition reactions References 1 Synthesis of saturated aldehydes and ketones 1.1 Redox methods Oxidation of alcohols provides the simplest route to aldehydes and ketones and this remains an area of much activity.The use of tetrapropylammonium perruthenate (TPAP) has become well established and a review of oxidations with this reagent has appeared.' Despite the well established use of Cr"' based oxidants, developments in this area continue to appear. Quinolium fluorochromate, C9H7NH[FCr03], has been reported as a more soluble (in non-aqueous solvents), less acidic, but equally effective alternative to the corresponding pyridine based reagents2 Magnesium chlorochromate, which is very simple to prepare in either hydrated or anhydrous form, has been noted although there does not appear to be a significant advantage associated with its use.3 Simplified procedures also continue to be of interest; including those based on supported reagents4 and the use of sub-stoichiometric amounts of the chromium salt together with a co-oxidant, e.g.sodium percarbonate.' A similar strategy has been employed with a variety of other transition metal species. t-Butylhydroperoxide (TBHP) has been employed with reagents based on iron,6 c o ~ p e r , ~ and osmium.8 Interestingly, the last combination is selective for the oxidation of allylic alcohols; neither alkene dihydroxylation nor saturated alcohol oxidation is observed. Cobalt Schiff base complexes together with either ethyl- 2-oxocyclopentanecarboxylate9~a) or 2-methylpr0panal'(~) efficiently mediate the conversion of alcohols into the corresponding carbonyl compounds. With the former co-reactant allylic and benzylic hydrocarbons are also converted into the corresponding ketones. Similar catalytic systems for the aerobic oxidation of alcohols have been developed using ruthenium complexes together with a cobalt salt as oxygen activator." These latter systems have a significant safety advantage in that they operate at sufficiently low partial pressures of oxygen to render air a viable working atmosphere.Related catalysts have also been employed to activate manganese dioxide for the oxidation of saturated alcohols." directly into the corresponding carbonyl compound in a heterogeneous process using silver or sodium perbromate. l2 The isomeric a-hydroxysilanes also undergo oxidative desilylation to afford aldehydes in good yields upon treatment with chromic acid in DMS0.13 to primary alcohols on reaction with tri~hloromelamine.~~ Unlike other N-halo oxidants the formation of a-haloketones is not a problem although with this reagent diols tend to afford lactones.Similar selectivity is achieved with HOF.MeCN and in this case the oxidation of primarylsecondary diol combination occurs smoothly to afford the hydroxyketone with competing lactone formation not being a pr0b1em.l~ The relatively low temperatures counterbalance the high acidity of the medium so that acid labile substrates can be oxidized with few problems. allylic methylene units to aldehydes and enones respectively can be achieved using perfluorobenzeneselenic acid or the related N-oxidopyridineselenic anhydride.16 The latter reagent is the more active but is unstable and must be prepared in situ.Both can be used catalytically in conjugation with a co-oxidant, TBHP or PhI(OAc), respectively, and in this respect provide a convenient alternative to the use of SeO,. Alkane and allylic hydrocarbon oxidation remains an area of much activity.I7 Many of these procedures suffer Primary and benzylic silyl ethers can be converted Secondary alcohols can be oxidized in preference The efficient oxidation of primary alcohols and Steel: Aldehydes and ketones 151from both modest selectivities and/or low conversions. Further evidence for heteroatom mediated regiocontrol in the Wacker oxidation has been forthcoming18 whilst methyl ketones may be selectively prepared without contamination by chlorinated by-products in a modified version of the electrochemically mediated Wacker process." a-Chiral aldehydes, derived from amino-acids, can be prepared in high yields with minimal racemization through the lithium tri-t- butoxyaluminium hydride reduction of the mixed anhydride prepared in situ from pivaloyl chloride?' In certain cases e.g.arginal, the use of the analogous phenyl ester can provide some advantages. Although less soluble, in other solvents, the use of the corresponding sodium reagent in diglyme results in superior yields of aldehydes with a wider range of substrates.21 Thionaphthol esters may be efficiently reduced to the aldehyde in a free- radical process using cyclohexa-l,4-diene as the hydrogen atom source.2z for the conjugate reduction of enones. Both limonenez3 and ammonium f ~ r m a t e ~ ~ prove to be acceptable hydrogen atom sources.Similar high selectivity can be achieved on hydrosilylation and recent developments in this area allow for the formation of bulky silyl enol ethers, e.g. triphenylsilyl or triis~propylsilyl.~~ Sodium hydrogen telluridez6 and purified nickel b ~ r i d e ~ ~ also show chemoselectivity for the carbon-carbon double bond, although with the latter reagent isolated alkenes may be competitively reduced. Transfer hydrogenation provides a facile method 1.2 Umpolung methods Protected cyanohydrins continue to find application as umpolung reagents in synthesis. Van Rozendaal et al. have shown that saturated aldehydes may be activated in this manner with the resulting lithioanion adding efficiently, in a 1,2 fashion, to a range of vinyl and aryl ketones.z8 Functionality may also be incorporated, providing routes to a-ket~esters.'~ adds efficiently, in a one-pot process, to two equivalents of a variety of terminal epoxides, affording the symmetrical ketone masked as the dithiane 3, Scheme l.30 The key step is this process is the [1,4] Brook rearrangement of the initially formed alkoxide 2.benzotriazol-1-ylmethoxymethane (4) with butyl lithium behaves as a classical acylanion equivalent undergoing alkylation and acylation to afford, after acidic methanolysis, the protected aldehyde or a-ketoaldehyde re~pectively.~' a,P-Unsaturated acylanion equivalents are obtained by treatment of acrolein and crotonaldehyde acetals with the Schlosser base ( LICKOR).32 The direct formation of acyl-lithiums from carbon monoxide has been extended to allow the preparation of aryl ketones.However, unlike their aliphatic counterparts, the yields obtained render this of little preparative Upon metallation, 2-trimethylsilyldithiane (1) The anion obtained from treatment of n sYs I SiMe, 1 (i) BuLi, THF (ii) 2eq. I O R (iii) NaF THF-H20 1 I\ HO I I OH R 3 (4149%) (i) Rx, THF (ii) pTsOH, MeOH 4 1 R<OMe OMe 4042% Scheme 1 ~tility.~' Acyl samarium34 and titanium35 species have been implicated in the coupling of acid chlorides with carbonyl compounds mediated by SmI, and TiC13 respectively. Finally, acyl units may be added in a conjugate fashion to enones in a free radical process initiated by treatment of aldehydes with di-t-butylh~ponitrite.~~ 1.3 General methods Although addition of an organometal to lithium carboxylates provides a simple entry to ketones, over-reaction is frequently a problem.This can be circumvented through the use of the corresponding organocerium reagent.37 In this case improvements are observed in both the yield and rate of reaction. The synthesis of lactols from lactones is similarly enhanced. A high yield for the ketone has also been obtained in the sonochemical Barbier reaction of lithium ben~oate.'~ In this process alkylchlorides are the most efficient substrates with the less reactive bromo and iodoalkanes affording significant amounts of the diketone, presumably via a Wurtz- type coupling mechanism. Similar selectivity has been obtained using other activated carboxylic acid units, including N-(N-acyl-N- methy1amino)cycloimminium salts 539 and P-lactam~.~' Upon treatment with SmI, and an FelI1 catalyst, iodopropyl esters undergo an intramolecular nucleophilic acylation reaction to produce b-hydroxyketones with almost complete retention of configuration.Similarly, the corresponding m-iodoesters afford cyclic ketones4* 1 5 2 Contemporary Organic SynthesisSamarium iodide also promotes the combination of ketenes delineated with the allylic scope halides. and limitations Recent reports of this have strategy 5 - MeCHN2 ($"+p+ $ in which significant asymmetry can be observed in the final protonation step, Scheme 2 (see also Section 6.1).42 Acid chlorides may also be employed in nucleophilic acylation although more recent 20%EtOH,Et20 91% 43 : 43 : 14 developments have employed Friedel-Crafts type M%AI 81% 54 : 32 : 14 MAD 87% 94 : 3 : 3 condition^.^^ In this latter process, using substituted alkenes, some regioselectivity can be observed which depends upon the nature of the Lewis acid employed, Scheme 3.43(c) I M P y o R 5 0 3&79%, 29-97% e.e.Scheme 2 Scheme 3 Ketones may be converted in moderate to good yield into the branched homologous aldehyde on reaction with lithiotrimethylsilyldiazomethane.44 Diazoalkanes also undergo Lewis acid catalysed insertion reactions with aldehydes and ketones.45 These reactions can occur with high regio- and chemo-selectivity to afford the substituted ketones in good yield, Scheme 4. Carbene insertion has also been postulated in an efficient chromium-mediated homologation of aldehydes to methyl ketone^.^^ Alkenes are converted into the homologous aldehyde in the hydroformylation process.This important area has continued to receive much attention. The principal areas of concern have been Scheme 4 regiochemistry and enantioselectivity. High ratios of branched to linear aldehydes have been achieved with ligands based on aminophosphine diph~sphinites,~' dipho~phites:~ and phosphineph~sphinates.~' These last ligands, based on the binaphthyl system, have also afforded good levels of asymmetry for both 1,Zdisubstituted and monosubstituted alkenes. The regiochemistry of hydroformylation of substituted alkenes appears less dependent on the presence or nature of added ligands and excellent regioselectivities for both linear and branched aldehydes have been rep~rted.~' Epoxides may replace alkenes as substrates, producing ~-silylo~yaldehydes.~~ Further reactions of this product can contaminate this process but are inhibited through the use of Rh-amine catalysts. Finally, utilizing triethylorthoformate as the hydroformylation solvent together with a catalytic amount of p-TsOH leads directly to the diethylacetal in good yield.53 In a related process t-butylstyrene may be polymerized under an atmosphere of CO in the presence of a bis(oxazo1ine) palladium catalyst to form a polyketone of high isotacticity and high optical rotation.54 This represents the first example of good asymmetric induction in such a process.Similar polyketones may also be accessed through the use of free radical polymerization of a-cyclopropyltrimethylsilylenol ethers.55 Palladium-mediated catalysis is also involved in the synthesis of P-arylketones from allylic alcohols via the Heck reaction.56 The presence of a base is essential and although triphenylphosphine affords the best yields the rate is adversely affected.Consequently, the use of potassium acetate is advocated to provide optimum results. In contrast, the related ruthenium-catalysed rearrangement of allylic alcohols to saturated ketones occurs at a much faster rate in the absence of added base when the dimeric ruthenium complex 6 (Figure 1) is employed.57 The isomeric enol ethers undergo regioselective substitution to afford a-arylated ketones, albeit in moderate yields. The regiochemistry can also be affected by other factors. For example, in the presence of Cp(COD)RuCl, alkynes react with allylic alcohols to afford y, &unsaturated ketones whereas the corresponding Steel: Aldehydes and ketones 153Ph Phqy:-H-$ Ph Ru' Ru OC'' A A k 0 Ph co co Ph H.'h/ Me 6 7 Figure 1 diphosphine complex (Ph3P)2CpRuC1 leads to the P, y-unsaturated product. In this process, with the exception of propargylic alcohols which exclusively result in linear product, isomeric mixtures of linear and branched enones arise.58 Alkenes and alkynes react with the cationic zirconium q2-( iminoacy1)complex 7 to form, after hydrolysis, ketones and @)-enones re~pectively.~~ Hydroboration of alkynyl halides offers entry to P, y-unsaturated ketones6' whilst terminal alkynes may be converted into the homologous aldehyde in moderate overall yield via the corresponding propargylic thioether.61 Developments in aldehyde synthesis have resulted in enhanced procedures being reported for the Vilsmeyer-Haack formylation of organomercurials62 and the x-oxidation of sulfones utilizing Me3SiOOBut as the oxidant.63 Aldehydes may be converted into ketones directly through classical dithiane chemistry; naphthalene- 1,8-dithiol has been introduced for this purpose.Photochemical regeneration of the carbonyl compound occurs very efficiently after oxidation to the monosulfoxide.64 Similar overall transformations can be achieved for aliphatic aldehydes on treatment with a boron lid.^^ achieved using a designed antibody.66 The anionic version of this rearrangement is known to proceed at a much higher rate and this has been carried out in tandem with the [2,3] Wittig rearrangement. Since the anionic oxy-Cope rearrangement is stereoconvergent, favouring the (E)-olefin, isomer purification after the [2,3] Wittig rearrangement is not required.67 Tandem rearrangements are also involved in the synthesis of y, &unsaturated aldehydes from allylmethallyl ammonium salts via a base-induced isomerization-aza-Claisen rearrangement sequence.68 The rearrangement of epoxides continue to provide good routes to carbonyl compounds.Treatment of aliphatic terminal epoxides with the complex iron reagent, Me4FeLi2, or an alkyl lithium in the presence of catalytic FeCl, affords the methyl ketone, presumably by way of the en01ate.~~ In contrast, treatment of all terminal epoxides with 2.5 equivalents of lithium tetramethylpiperidide leads to exclusive formation of the aldeh~de.~' Alkenylepoxysilanes undergo radical-induced rearrangements to afford, initially, the a-silylaldehyde which on heating tautomerizes to the isomeric silylenol ether.71 Under acid-catalysed conditions the regiochemistry of the epoxide Catalysis of the oxy-Cope rearrangement has been rearrangement is similarly dependent on the nature of the initiator.72 For example, trisubstituted epoxides are converted into aldehydes on treatment with methyl-bis(4-bromo-2,6-di-t- buty1phenoxide)aluminium (MABR) whilst the use of antimonylpentafluoride affords ketones, Scheme 5 .7 w (&Bu - (&Bu + QBu CHO 0 MABR, CHZCI,, -20°C' 1 h 73% ( 0 : loo) SbF,, PhMe, -78"C, 2 h 79% (85 1 6) Scheme 5 a, P-Epoxyalcohols undergo pinacol-type migration with high ~electivity.~~ Since the starting materials are accessible in enantiomerically pure form through the Sharpless epoxidation this can provide an entry to all four possible aldol isomers 8-11, Scheme 6.74 Similar rearrangements are also observed in the reaction of y-functionalized allylstannanes with aldehydes.75 The regiochemistry is controlled by the alkene substituent with the particular pathway followed being very aldehyde dependent.In general these reagents function as either homoenolate 12, a,P-dianionic ketone 13, or vinyl carbene 14 equivalents, Scheme 7. True pinacol-pinacolone rearrangements can be efficiently catalysed by aminium salts.76 as homoenolate equivalent^.^^ The synthesis of substituted ketones by oxidative free radical Alkoxycyclopropanes continue to find application 1 a 9 P r v O H 10 11 -75%.85-97% 8.e. (i) TBHP, Ti(OPr')4, (-)DIPT; (ii) TBHP, Ti(OPr')4, (+)DIPT; (iii) TBSOTf, Pr'2NEt Scheme 6 154 Contemporary Organic Synthesisr OLAI X = CI, LA = ZnBr,, R = Ph 0% 6% 45% X = OTf, LA = ZnBr,, R = Ph 0% 0% 48% X = OTf, LA= ZnBr,, R = C6HI3 0% 53% 0% 12 13 Scheme 7 alkylation of silyl enol ethers remains an active area with a variety of electrophiles being employed, including i d o e ~ t e r s , ~ ~ organostannane~,~~ selenides,80 chromium complexes,81 and allylsiianes.82 2 Synthesis of aromatic aldehydes and ketones The principal development in aromatic acylation chemistry has involved the use of lanthanide triflates as recyclable catalysts for activated aromatic species.Further studies in this area have revealed that the equivalent scandium complexes are more effective catalysts.83 An alternative to the traditional Lewis acid catalysed procedures utilizes zeolites and this, being heterogeneous, provides further simplifications in the work-up With substituted aromatics, regioselectivity remains a challenge. In a study of the acylation of 2-methoxynaphthalene, Nomura and co-workers have demonstrated that a degree of control can be achieved by varying the strength and stoichiometry of the Lewis acid.85 Site selective ortho formylation of phenol can be achieved via the magnesium phenoxide. Traditionally this has required the use of stoichiometric HMPA although recent reports have suggested that either triethylamine or methanol are equally effective.86 A method for the synthesis of meta acylated phenols has been Treatment of pyridylhalides with activated zinc and an acid chloride provide a very direct method for acylation of aromatic species resistant to Friedel-Crafts methodology.88 Alternatively, although limited in regiochemistry, 4-pyridyldiethylacetals may be directly metallated and the resultant anion alkylated.After hydrolysis this provides the corresponding 4-acylpyridine in excellent overall yield.89 The alternative acylation strategy employing an aryl acyl electrophile has also been explored. Thioesters have found significant use and a survey of the optimum conditions for coupling with a range of cuprates has been reported.” Acylsilanes react with the radical anion generated from reaction of diarylketones with ytterbium to afford diarylmethyl ketones in good to moderate yields.” Symmetrical diarylketones can be obtained through the electrochemical reduction of aroyl chlorides,92 whilst unsymmetrical products are accessed through the palladium-catalysed carbonylative coupling of an aryl boronic acid and an aryl halide.93 Although complete chemoselectivity cannot be obtained, the highest ratios of ketone to biaryl products are gained using potassium carbonate/anisole as the base/solvent combination.Replacing the boronic acid with sodium formate leads to good yields of the aryl aldehyde whereas the use of other formate salts promote reduction.94 Transmetallation of an aryl lithium with triethylboron generates a tetravalent borate complex which can efficiently undergo palladium-catalysed carbonylation with a variety of alkyl halides.95 Oxidation remains a valuable method for the preparation of arylketones.Selective oxidation of polyhydroxymethylphenols can be achieved with Mn02 through careful control of the reaction conditions.”6 A simplified procedure for benzylic alcohol oxidation is obtained when the reagent is supported on clay in the absence of Activated benzylic alcohols, ethers, and amines are oxidized to the corresponding aldehyde on treatment with CAN98 whilst a-hydroxyesters are converted into the corresponding ketone in an electrochemically mediated ~xidation.~” The presence of arylalkyl substituents complicates the process through competing bromination.Diketones can similarly be prepared. Further developments in the Crvl-catalysed TBHP oxidations of benzylic alcohols have been reported.’” Although not synthetically viable the same catalytic system also causes oxidation of stilbenes to a complex mixture of ketones, diketones, epoxides, and acids. Interest in other benzylic hydrocarbon oxidations continues with methods utilizing potassium permanganate in conjunction with alumina,lol calixerenes or 1 8 - c r o ~ n - 6 ~ ~ ~ being noted. Diarylmethanes can be converted into the corresponding ketone in good yield using NBS although alkyl substituents are prone to suffer competing (po1y)bromination. lo3 Arylmethyl groups may be efficiently converted into the aldehyde, under mild conditions, through a sequence involving oxidative cleavage of the corresponding enamine.lo4 Oxidative photochemical cleavage of alkenes can be achieved in the presence of 1,4-dimethoxybenzene.lo5 Finally, an unusual carbon-carbon bond cleavage, to give indanones, occurs on reaction of 1-hydroxymethylindanes with either PDC or PCC.‘06 Similar conversions of Steel: Aldehydes and ketones 1551 - hydroxymet hyltetralins to tetralones also occur and both are believed to proceed via oxidation of the intermediate enol. 3 Synthesis of cyclic ketones Intramolecular enolate condensations provide the simplest entry to cyclic ketones and enhancements in the synthetic efficiency of these processes continues to attract attention. The 'one-pot' synthesis of 3-alkenyl-2-cyclohexenones 16 and, to a lesser extent, cyclopentenones can be achieved via the cyclocondensation of dimethyl(lithiomethy1)phosphonate 15 with either dimethylglutarate or dimethylsuccinate, respectively, followed by trapping with an appropriate aldehyde, Scheme 8.lo7 Similar multiple carbon-carbon bond- forming synthesis of cyclic ketones can be achieved through the tandem double Michael addition/ Dieckmann cyclization of active methylene compounds with methylacrylate promoted by disodium iron-tetracarbonyl.lo8 The 'one-pot' tandem Robinson annulation-decarboxylation of cyclic P-ketoesters may be achieved under neutral conditions although both high temperatures and the use of HMPA are required."' Tandem Cope rearrangements can be utilized to generate a variety of polycyclic ketones and full details of this approach have appeared.' lo Spirocyclic methylenecyclopentanones are accessed in a single step from bis acetylenic alcohols in a tandem oxy- Cope catalysed by t-butylcatechol under conditions of photo-assisted single-electron transfer.' ' Similar methylenecyclopentanones are available through the rearrangements of alkoxyallenes,'12 arylallenylketones,' l3 alkynylcyclobutanols, ' I 4 and chromium carbene complexes.1 l5 : (Me0)2PCH2Li 15 Me02Cw:02Me n = 2,3 PO(OMe), 1 RCHO 0 q R 16 (671%) Scheme 8 Cyclopentenones can be efficiently accessed from bulky silylenol ethers and terminal alkynes under the influence of a SnC1,-Bu3N promoter.'16 A greater variety of alkynes may be employed with this procedure than with the related oxyallylcation [3 + 21 cycloaddition.Similar products can also be obtained with high diastereoselectivity through the reaction of P-thioenoylsilanes with ketone en01ates.l'~ The corresponding /3-trialkylsilylenoylsilanes do not cyclize efficiently. Enantiomerically pure 5,5-disubstituted cyclopentenones 18 can be prepared from the bicyclic lactam 17, Scheme 9,11' whilst the related thiolactams 19 can provide access to homochiral 4,4-disubstituted cyclohe~enones.'~~ Similar products have been prepared using chiral sulfoxides as the initial source of asymmetry'2o whilst Takano et al. have outlines methods for the production of 2,5-cyclohexadienone synthons in either enantiomeric form.'21 . . 17 (I) Re2CH& 0 18 U R2 = H, Ref. 1 18(a) Scheme 9 Cyclopentenones may also be accessed through the Pauson-Khand reaction and this remains an active area of study.A simplified procedure which enables the in situ preparation of the alkyne- dicobalthexacarbonyl complex has been published. 122 New catalysts and ligands which enable both faster reactions and higher substrate loadings continue to be deve10ped.l~~ Similar accelerations are found when employing methylenecy~lopropanes.'~~ Substrate induced stereoselectivity is also a topic of this respect, a range of chiral auxiliaries'26 have been employed with the major advance being asymmetric induction in the intermolecular Pauson- Khand r e a ~ t i 0 n . l ~ ~ Iron carbonyls have been known to promote similar alkyne-alkene couplings, albeit requiring high CO pressures and/or high temperatures.In contrast the related alkyne-allene process proceeds under ambient conditions. 128 Cyclopentenones can also be prepared through the cobalt octacarbonyl induced rearrangement of alkynylcyclopropanols.129 This conversion can now be achieved catalytically, with good regioselectivity being observed with substituted cyclopropanes. Cyclopentenones may also be realised on photolysis of cyclopropylcarbyne and, in 156 Contemporary Organic Synthesismolybdenum complexes although the yields are only moderate. 130 A number of other cyclocarbonylative routes to cyclic ketones have been reported."' In this respect carbon monoxide has found use as a one-carbon component in the Heck reaction, Scheme Intramolecular trapping of the intermediate acylpalladium species with enolates can now occur through either oxygen or carbon to yield lactones or ketones respectively.Selectivity is usually controlled by ring size with five- and six- membered ring formation being favoured, Scheme 11. When all other factors are equal oxygen- trapping is f a ~ 0 u r e d . l ~ ~ 0 11 H 75% Scheme 10 0 77% 0 90% Scheme 11 Radical mediated synthesis of cyclic ketones continues to be a fertile area. Dowd and co-workers have illustrated the use of a-chlorocyclobutanones as precursors to ring-enlarged ketones via tandem intramolecular radical acylation/ring expansion sequences. 142 Polycyclic ketones are also accessible through tandem radical macrocyclization- transannular ring closure protocols and further reports have appeared to this may be directly employed in similar radical macrocyclizations through the treatment of (wiodoalky1)acrylates with tris( t ri trime t hylsily1)silane under an atmosphere of carbon m0no~ide.l~~ Radical mediated fragmentations of tertiary alkoxides have also been utilized in the synthesis of macrocyclic ketone^.'^' Fragmentation and ring expansion strategies continue to provide a large number of routes to functionalized cyclic For example, treatment of the silyloxycyclopropane 20, readily accessible from cyclopentenone by conjugate additiodenol cyclopropanation, provides a general route to ring-expanded, 4-substituted cyclohexenones, 147 Scheme 12; whilst a-vinyl cyclic ketones 23 are readily accessed from the cyclic alkene (21) via fragmentation of the alkoxycyclopropane 22 in a cyclopropylcarbinyl/ homoallylic ketone rearrangement, Scheme 13.148 Finally, direct cyclization can provide entry to cyclic ketones. The intramolecular McMurry Acyl radicals wTMS&! (i) RMgX. CuI, HMPA, TMSCI (ii) CH212, Et2Zn 0 0 The concurrent generation of two chiral centres can now be achieved with both high diastereoselectivity and high enantioselectivity in rhodium-catalysed intramolecular hydroacylation reaction^.'^^ A full report on the scope and limitations of such an approach to 3-substituted cyclopentanones has been p~b1ished.l~~ Cyclopentanones are frequently the major product from the rhodium-catalysed decomposition of diazoketones. Much work has been reported on the effect of both substrate and ligand structure on the selectivity and stereochemistry of this process.136 The carbene need not arise from a diazoalkane. For example, cyclopentenones are obtained by C-H insertion of the alkylidene carbene generated by Michael addition to P-ketoethynyl(pheny1)iodonium t r i f l a t e ~ ' ~ ~ whilst P-ketosulfoxonium ylids may be employed in the synthesis of cyclic a~aket0nes.I~~ Similar cyclic azaketones have also been prepared through dioxirane oxidation of allenylto~ylamides~'~ and the electrochemical oxidation of N-carbamoyl piperidines. I4O Related oxygen heterocycles can be prepared in moderate to good overall yields via the Claisen rearrangement of 2-vinyl-4-methylene dioxolanes. 14' Scheme 12 k 20 (40-93%) (i) FeC13, DMF, 0°C (ii) NaOAc, MeOH 1 0 R 45-71% (i) NaOMe, MeOH (ii) DIBAL 1 21 R R 23 22 Scheme 13 Steel: Aldehydes and ketones 157olefination may be achieved using a,P-unsaturated esters to provide entry to macrocyclic en one^.'^^ Silylenol ethers may be trapped by a suitably positioned cobalt-stabilized propargylic cation'50 whilst P-ketoesters provide an excellent terminating group for the Lewis acid mediated cyclization of acetals 24 to afford 2-carboxyal~lcyclohexenones 25 in good yield, Scheme 14.151 CO2Et OEt TiCI,, Et3N.CHzC12 r.t 4 h - R MeO*OMe 24 Scheme 14 25 (70-94%) 4 Protection and deprotection strategies Conditions have been sought that enable the formation of cyclic acetals under milder conditions. In this respect the known reaction of ketones with ethylene epoxide has been re-examined and conditions optimized (0.1 equivalents F3B.0Et2, -78°C) for a range of substrate^.'^^ A mild, high yielding, room temperature method for the synthesis of dioxanes proceeds from the cyclic orthoester 26.153 Selectivity is another ongoing issue and the functionalized dioxolanes 27,28 have been advocated as protecting groups which may be selectively cleaved under conditions in which 'normal' cyclic acetals are ~ t a b 1 e .I ~ ~ However, the non-specific creation of an additional chiral centre during formation can result in analytical or synthetic complications. Selective protection of one of the carbonyl groups derived from alkene ozonolysis can be achieved as the ozonide 29 by in situ reaction with methyl pyruvate. Regeneration of the aldehyde is achieved under mild, reductive conditions whilst conversion into the corresponding carboxylic acid occurs on treatment with triethylamine, Scheme Similar to the related rhodium species,156 the ruthenium catalyst [ Ru( MeCN),(triphos)] (OTf), is reported to be an effective promoter for selective ace t alizat ions and t ransace t alizat ions.l5 Not ably, acyclic acetals are cleaved more rapidly than their cyclic counterparts. Similar observations have been recorded using a SmC13-AcC1 combination which is an enhanced modification of the previously noted SmCl3-TMSC1 reagent system.158 The SnC12 mediated acetal cleavage process can be accelerated by the addition of certain aromatic hydrocarbons, including naphthalene and C60.159 n-Acceptors such as DDQ have long been known to promote the <SiMe, K OEt 26 27 83% aa% Scheme 15 Protic conditions can be avoided through the use of 5M LiC104 in ether162 or by the use of various anhydrous heterogeneous catalysts.163 The latter group of reagents have been shown to be particularly effective for relatively unreactive carbonyl compounds such as diary1 ketones.Vinyl oxathioacetals, difficult to prepare directly, can be prepared from the corresponding dimethylacetal by sequential treatment with Me$- TMSOTf followed by a lithium thi01ate.I~~ The cyclic counterparts, oxathiolanes, have synthetic utility since it is possible to achieve the selective deprotection of ketones in the presence of aldehydes under conditions in which dithiolanes are ~ t a b 1 e . l ~ ~ In contrast to the acetal, gem-diacetates can be employed as acid-stable carbonyl protecting groups. However, the reported methods for cleavage provide only moderate yields. A recent report suggests the use of aromatic alkoxides for this purpose which enables the unmasked aldehyde to be realized in near quantitative yields.166 Ketones and aldehydes can also be masked as oximes, hydrazones, and related species. Considerable effort has been applied to developing methods for revealing the parent carbonyl group.Many of these are oxidative in nature and include hydrogen peroxide/TS-1 zeolite,167 sodium hypochlorite,168 dimet hylsulfoxide-TMSC1, 69 zinc bi~muthate,'~~ cupric ~hloride,'~' d i ~ x i r a n e , ' ~ ~ iodosylbenzenediacet at e,173 and tetrabutylammonium pero~ydisulfate.'~~ The principal advantage of most of these 'new' methods is that they proceed under neutral or near neutral conditions which enable other functional groups to be tolerated. hydrolysis of acetals and dithioacetals and additional reports to this effect continue to appear.16' A survey of a number of these species has indicated that whilst DDQ, TCNQF4, and TCNE are effective promoters both TCNQ and chloranil are not.'61 treatment of carbonyl compounds with a dithiol.5 Synthesis of functionalized aldehydes and ketones 5.1 Unsaturated aldehydes and ketones Variations on the selective oxidation of allylic alcohols achieved using palladium catalysts continue to appear.17s Competing epoxidation can complicate Dithioacetals are readily formed on acid-mediated 1 5 8 Contemporary Organic Synthesisthe use of dioxiranes for this purpose and the factors which control the selectivity have been de1ir1eated.l~~ When the alcohol is subject to steric crowding good selectivity may be attained with a TBHP-VO( a ~ a c ) ~ combination.177 In the presence of acetic anhydride and pyridine photo-oxygenation of vinyl silanes affords a-trimethylsilylenones in moderate to good yields. Similar products may be obtained from the equivalent vinyl stannane although in this case isolation of the intermediate peroxide is required.'78 Both protocols appear to be prone to producing regioisomeric mixtures. Treatment of ozonides with a preheated solution of diiodomethane and diethylamine affords the corresponding a-methylene aldehyde in good ~ i e 1 d s . l ~ ~ The parent aldehyde also reacts under the same conditions.Aldol-dehydration strategies continue to provide efficient routes to unsaturated carbonyl compounds. 180 Aldehydes combine with bromomethylketones in a samarium triodide mediated reaction,"' and enol formates in the presence of various transition metal complexes, to afford enones in a high yielding one-pot processes. 182 Similarly, P-(trimethylsily1)silylenol ethers react with aldehydes but not ketones in a mild non-basic reaction to afford predominantly the (E)-enol in good yield.lS3 In an interesting sequence, aldehydes react with t-butyldimethylsilyl dibromomethyl lithium (30) to afford a-bromo- a-silyketones 31. Without isolation, treatment with butyl-lithium affords the silylenolate which combines, in a Peterson-type reaction, with a second aldehyde to provide the desired enone, Scheme 16.lS4 The nature of the solvent is critical since if THF is employed 1,3 diols result whilst without HMPA the final elimination can be inefficient.OLi ButMe2SiyBr2 Li Et20 [ R 1 q i r R 1 9 ] 31 30 I (ii) BusLi (iii) R%HO (iv) HMPA 0 R' b R 2 53-59% Scheme 16 Ketones may be converted into enones with transposition of the carbonyl group through the cerium-mediated addition of Grignard reagents to enaminoketones. Although similar conversions have been recorded using alkyl-lithiums these do not show the selectivity observed in this modification which results in the incoming nucleophile being predominantly trans to the new carbonyl group. This is attributed to cerium chelation with addition then occurring anti to the N-methyl group, Scheme 17.'85 Related carbonyl transpositions have been observed in the reaction of P-acyldithioacetals,'86 the Vilsmeyer formylation of dithioacetal~,'~~ and the R' (i) R2MgX.CeCb (ii) 1% AcOH I 6545% Scheme 17 Rupe reaction of cyclic- 1 -alkynols.' 88 Lewis acid mediated rearrangements of silylated alkynyl- 1,4-diols provide an efficient entry to a-~ilylallenones~~~ whilst the related epoxyalkynols afford mixtures of allenals and [3]-cummulenals.'90 In extensions to previously reported strategies, aldehydes may be homologated to the dienals through condensation with the silylated unsaturated imine 32191 whilst aromatic aldehydes are converted into the trienone on reaction with the pyrylium- derived Wittig reagent 33.192 Trienones have also been prepared through the Heck reaction of P-iodovinylacet als with tertiary allylic alcohols,193 the Lewis acid promoted reaction of dienylalcohols with P-bromosilylenol and by dimethyldioxirane oxidation of furans with in situ trapping of the dicarbonyl compound with a Wittig reagent."' Dienones may be accessed through the Claisen rearrangement of propargylic P-ketothioenol or through the triphenylphosphine- mediated rearrangement of acetylenic ketones.197 Cross-conjugated dienones are obtained by the reaction of bis-ylids 35, readily accessible, in good yield, through sequential alkylation and decarboxylation of (triphenyl- phosphorany1idene)ethenone 34, Scheme 18. 198 32 33 HX, H20, Bu'OH 90°C J 0 R' 35 Scheme 10 Steel: Aldehydes and ketones 159Both 2,4- and 2,5-cyclohexadienones can be prepared through the reactions of the q2-phenol- osmium complex 36 Scheme 19.Whilst selectivity is observed it appears to be highly dependent on the particular combination of substrate, reagents, and conditions employed. Although attractive, this strategy is limited by the moderate yields obtained and also by scale since it currently requires the use of stoichiometric quantities of osmium. 199 Enantiomerically enriched cyclic enones and dienones can be efficiently obtained through the catalytic asymmetric Heck reaction and this conversion has been discussed in some Substituted cyclic enones are produced in the tandem Michael reaction/aldol condensation between 2-acyldithianes and a second enone. Although mixtures of products can arise, some selectivity is observed depending upon the nature of the alkyl substituents, Scheme 20.20’ 36 0 A Pr‘2NEt, Zn(OTf)2, MeCN, 25°C ( 5 : 85) Pr‘,NEt, Zn(OTf),, MeOH, -25°C (100 : 0) Scheme 19 0 n n R’ =R2=Me 78% ( 5-8 : R’ = R2 = C2H5 96% ( 1 : 7.7) Scheme 20 A strategy for the synthesis of a-H- p,P-disubstituted cyclic enones, which complements earlier routes to a,P disubstituted analogues, has been outlined although this modified procedure is not viable for cyclopentenones.202 These can be obtained via the oxidation of fu1venes203 and furans and this latter subject has been comprehensively reviewed.204 Furans have also been employed as end groups in a tandem radical cyclization-fragmentation approach to P-(cyclopenteny1)-alkenones, Scheme Acylation of vinylanions provides a valuable method for the synthesis of enones.Full details of the palladium-catalysed acylations of bis stannyl ethenes have been reported.206 In a variation on this theme the vinylstannane acetal37 has been 21.205 18U3SnH 0 1240% Bu3SnT0Et EtO 37 38 tl 39 40 (79-95%) Scheme 21 introduced as a P-formylvinyl anion equivalent.207 Acylation of the vinyl copper species generated by transmetallation of the ketene dithioacetal38 affords the functionalized enones 39 and 40.208 The stereochemistry of this process is controlled by the bulk of the activating electron-withdrawing group in the P-position. Iron tricarbonyl diene complexes are well known to produce the (2)-dienone on Friedel-Crafts acyclation. Unusually the @)-isomer results when monoethyl oxalylchloride is employed as the ele~trophile.~’~ q3-Allyl iron tricarbonyl complexes undergo carbonylative insertion reactions to afford, in good yields, either ap- or Py-enones depending on the reaction conditions, Scheme 22.210 Scheme 22 Finally, P-oxophosphorus ylids 41, readily available through simple ylid acylation,21 couple with a-ketoacids to generate P, y,P’-trioxo-ylids 42 which on flash vacuum pyrolysis provide 1,4 diketoacetylenes 43 in modest to excellent yields (Scheme 23).212 5.2 a-Heteroatom substituted aldehydes and ketones Enolate oxidation remains the simplest method for the preparation of a-oxycarbonyl compounds.Recent developments have included the use of 160 Contemporary Organic Synthesis42 f.v.p. I 500°C 43 (23-70%) Scheme 23 cobalt-catalysed procedures for the mild non-acidic oxidation of enol acetates and silyl enol ether^."^ Employing MCPBA as the oxidant, good diastereoselectivities are obtained with enol ethers derived from trans-cycloalkanediols.Interestingly, the opposite stereochemical outcome is obtained depending on the nature of the second alcohol group of the chiral auxiliary, Scheme 24.214 0 cIln 0 -0'. OTMS C02Me 1.2eq. MCPBA, NaHCO, (R = TMS) 2eq. MCPBA, Li&03 60%, > 99% d.e. (R = H) I 94%, 03% d.e. Scheme 24 Titanium affords advantages over other counter-ions (rates, yields, and diastereoselectivities) in the dimethyldioxirane-mediated enolate oxidation. Furthermore, significant asymmetry ( 2 63% e.e.) can be obtained through the use of chiral titanium l i g a n d ~ .~ ' ~ The same oxidant can also convert 1,2-diols into a-ketols with chiral starting materials reacting with little degradation of stereochemical purity. No overoxidation or bond cleavage is observed although with unsymmetrical s, s-diols regiochemical mixtures Allenes may be directly converted into ketols through the use of peracetic acid/catalytic OsC13217 or TBHP/catalytic Os04.218 High regiochemical control is observed. For example, terminal allenes are converted into hydroxymethyl ketones with no evidence for the alternative a-hydroxyaldehyde. Although asymmetry can be obtained with chiral additives the level of induction is low. High enantiomeric excesses are obtained in the dihydroxylation of en one^.^'" Acylation of a-carbamoyloxylithium 44 proceeds with complete conservation of asymmetry and either retention or inversion of stereochemistry depending upon the electrophile employed, Scheme 25.220 The corresponding alkoxystannane undergoes palladium- mediated acylations with retention of configuration and similar conversions are possible with the corresponding a-aminostannanes.221 Optimum yields are obtained with arylchlorides.The a-stannylacetal 45 is readily transmetallated to the organolithium derivative and as such reacts as a formyl anion equivalent with a wide range of electrophiles, including aldehydes and ketones.222 0 I I 0 I I Pt',NCq Me Pi2NCq Me MeCOfle E Me, OCNPi, PhALi -78°C- Ph%* 0 44 0 OEt OEt Bu,Sri-( 45 Scheme 25 a-Hydroxyacetals can be obtained on oxidation of aldehydes with thianthrenium tetrafluor~borate.~~~ These masked a-hydroyaldehydes may be converted into the isomeric alkoxyketone through an acid-mediated pinacol-pinacolone rearrangement The two-step conversion of aldehydes and ketones into the homologous trialkylsilyloxyaldehyde can be achieved in excellent yield via cyanohydrin formation.225 The nitrile to aldehyde reduction can be achieved with no loss of stereochemical purity, although vinylic aldehydes undergo a double bond migration to afford masked dicarbonyl compounds.The samarium iodide promoted synthesis of ketols from isonitriles and carbonyl compounds has been reviewed.226 This reagent also moderates the formation of a, P-dihydroxy ketones from a-dicarbonyl compounds and aldehydes in what is effectively a crossed aldol reaction.Carbonyl hydrates are equally effective substrates and the reaction may be carried out in aqueous media although in this case the diastereoselectivity is enantiomerically pure form through the use of chiral oxazolines,228 oxazolidinone~,~~~ and hydra zone^.^" The latter methodology has also been employed to synthesize quaternary thiocarbonyl compounds as single enantiomers. Homochiral a-silylketones may similarly be prepared.231 These latter species are also accessible via the inverse Brook rearrangement of P-lithiosilylenol and the condensation of acyl silanes with sulfur y l i d ~ . ~ ~ ~ Thiomethyl sulfonium ylids react with aromatic aldehydes to afford the homologous a-alkylthi~aldehydes.~"~ This conversion presumably proceeds via the corresponding thioalkyl epoxide.The corresponding sulfoxy-epoxide may be selectively converted into either the z-thioketone or t h i o e n ~ n e . ~ ~ ~ Dithiane oxides are efficiently acylated a-Thioaldehydes have been prepared in Steel: Aldehydes and ketones 161by acylimidazoles although two equivalents of base are required since the product 2-acyldithiane is considerably more acidic than the starting material. Addition of an alkylhalide can provide a ‘one-pot’ route to quaternary acyldithaine oxides of high diastereomeric purity.236 Similarly good diastereoselectivities are obtained in the further reaction of these species with diazodicarboxylates to afford masked p-arnino-a-diketone~.~’~ synthesized by the in situ Claisen rearrangement of the N-vinyl-0-imminylhydroxylamines 46, generated by 0-alkylation of nitrones with imidoylhalides, Scheme 26.238 Similarly, coupling of diazocarbonyl compounds with tertiary amines affords a transient ammonium ylid which undergoes an in situ Stevens rearrangement to give N,N-dialkylated a-aminoketones and esters in moderate to good yield.239 Imidoylhalides may also be metallated and combined with aldehyde to afford hydoxyimines.These tautomerize on heating to generate a-aminoketones in moderate to good overall yield.240 Finally, nitrogen nucleophiles have continued to find applications with a variety of electrophiles, including a-chloroepoxides, a-no~yloxyketones,~~~ and alkyl bismuthonium salts a-Aminoketones, but not aldehydes, can be (47).242 R’CH;! )co R2 NMe (i) MeNHOH (ii) PhKCI. Et3N I although regioisomeric mixtures arise from internal olefins unless an additional controlling element, e.g.allylic alcohol, is present.245 Ketones, on reaction with an 12-CAN combination, afford a, a’-diiodoketone~~~~ whilst the same reagent system converts enones into P-alkoxy-a-iodo- a-Iodoenones are obtained from l-alkynol~~~* whilst a-chloroenones can be prepared, in a ‘one-pot’ procedure, through the reaction of silylenol ethers with an in situ generated dichl~rocarbene.~~~ The corresponding a-chloro- and a-fluoro-enals are simply accessed via formylation of the corresponding a-halosulfoxide followed by thermoly~is.~~~ molecules has become an area of much activity. Electrophilic fluorination of P-dicarbonyl compounds remains the most direct entry methods and can provide strategies for the synthesis of secondary and tertiary a-fluoro, x , a-difluoro, and a-fluoro-a, P-unsaturated ketones.251 Enantiomerically pure a-fluoroketones may be generated through the fluoride ion opening of a-silyl-ab-epoxymesylates prepared through the Sharpless epoxidation procedure.252 Similarly nucleophilic-opening of perfluoroalkylenol ether epoxides leads to a-substituted alkyl perfluoroalkyl ketones.‘53 Perfluoroalkyl ketones are important synthetic intermediates and a number of strategies for their preparation have been reported,254 including the Friedel-Crafts perfluoroacetylation of alkenes2” and the Claisen rearrangement of perfluoroalkylvinyl ethers.256 The introduction of fluorine into organic 46 -71 % Scheme 26 These last reagents also combine with a multitude of other nucleophiles.With halide salts this can provide a simple, efficient entry to a-halomethylketones. The same products can also be obtained from the reaction of vinyl chlorides with NXS (X = Cl, Br, I) and these substrates have been proposed as being more convenient to handle then the corresponding enol ether as well as providing a cleaner reaction with little competing p~lyhalogenation.~~~ Polybromination of silyldienol ethers can be avoided through the use of phenyltrimethylammonium tribromide as the bromide source.244 The photo-oxygenation of alkenes to a-chloroketones occurs in enhanced yields using CuC12 rather than FeC1,. Terminal alkenes afford a-chloromethylketones selectively 5.3 Dicarbonyl compounds Polycarbonyl compounds are simply accessed through the C-acylation of enolates.Both N- acyla~iridines~’~ and the bismuthonium salt 47258 have proved to be particularly useful for this task. Although Darzens condensations can complicate the direct alkylation of a-haloketones, these difficulties can be circumvented through the use of the corresponding tin enolate and employing a-halo- imines as the e l e ~ t r o p h i l e . ~ ~ ~ Branched triketones are efficiently generated through the reaction of P-diketone copper chelates with ketene.260 The initial diketones can be accessed through the reaction of aP-acetylenic ketones with benzaldoximate.261 Imidoyl stannanes have previously been acylated in low yields and a recent report suggests that improved efficiency is obtained with bulkier nitrogen substituents, e.g. the N- 2,6-xylyl species.262 The a-hydroxyalkylimine generated by reaction of a-iminoalkylsamariumdiiodide with carbonyl compounds may be directly oxidized to the a - d i k e t ~ n e .~ ~ ~ This and other oxidations of a-heterosubstituted ketones provide a relatively facile entry to functionalized dicarbonyl compounds. a-Chloroketones can be converted into the monoprotected diketone via oxidation with NBS followed by silver-promoted methanolysis. The 16 2 Contemporary Organic Synthesisintermediate a-chloro-a-bromo-ketones are also useful precursors to a-amin~acetals.~~~ into the a-diketone on treatment with carb~nyldiimidazole~~~ or into the triketone by oxidation with various TEMPO derivatives.266 Triketones can also be prepared through the known oxidation of diazoalkanes with dimethyldi~xirane.~~~ Copper-catalysed oxidative cleavage of a-alkylated cyclic P-diketones provides routes to unsymmetrical a-diketones268 whilst symmetrical products are obtained in the cobalt-mediated coupling of aldehydes.269 Both symmetric and unsymmetric benzils are prepared via the palladium chloride mediated oxidation of diphenylethyne~.~~' This affords several advantages over existing oxidative protocols, notably the toleration of aqueous conditions and increased chemoselectivity in relation to competing alkene oxidation.a, P-Dihydroxyketones are efficiently converted 6 Reactions of aldehydes and ketones 6.1 The aldol reaction and other enolate additions The a-alkylation of ketones remains an area of intense activity.Normally achieved through the use of lithium enolates the process can suffer from polyalkylation and with unsymmetrical ketones from poor regioselectivity. Improvements in both these areas, notably selective monoalkylation, have been realized through the use of the corresponding manganese reagents.271 Alternatively, good regiocontrol in the alkylation step can be obtained through the use of the silylenol ether. Alkylation of these is limited to SN1 active electrophiles although Jefford and co-workers have previously demonstrated that the use of silver trifluoroacetate enables primary halides to be alkylated. Recent reports have indicated that steric bulk in the /?-position is no hindrance to this process and that good yields can be achieved with stoichiometric amounts of a primary alkyl halide.272 The a,a-dialkylatedketones 49 can be obtained in a one- pot process through the use of the tin enolate 48 derived from diketene and bis(tributyltin)oxide, Scheme 27.Both a-halo-aldehydes and -ketones are efficiently alkylated by this species with no competing aldol reaction, although simple aldehydes do undergo a tandem aldol dehydration process to afford enones in respectable yields.273 Increased efficiency in alkylations using acyclic epoxides is observed on addition of yttrium triflate to the reaction mixture. The use of related chiral ytterbium complexes afforded low but measurable levels of a~yrnmetry.~'~ Asymmetric alkylation has been achieved with a number of chiral auxiliaries with varying degrees of success.Most of these reports have focused on cyclic ketones275 although acyclic chiral 173-diketones have been prepared by asymmetric y-alkylation of the corresponding enaminone 50, Scheme 28.276 Related aldol products 52 can be obtained from diketene in the presence of the non- covalently bound chiral Schiff base additive 51.277 Bu,SnO YYoSnBu3 0 48 RX HMPA 1 -coz ___) 41 OSnBu3 IE+ R 49 E = RX, RCHO, 3041% Scheme 27 0 HN Ph*R3 ( i ) 2.w. MeLi, HMPA-THF 0 HN F ' h M (ii) R3X,-1000C R' R2 R' R2 50 75-95%, 27-98% d.e. (i) Ti(OPi),Sl~ mop+ 52 + bo (iii) ii) H30+ PrbH R (69430%, 6741% d.e.) Ph OH odNANANMe2 H Me 51 53 H ph**dph O w 54 55 Scheme 28 The use of such chiral additives was pioneered by the Seebach group and an account of the early work in this area has been More recently this has been extended to a catalytic asymmetric process utilizing the polyamine 53 as the source of Related to this subject is that of enantioselective deprotonation of ketones and protonation of Steel: Aldehydes and ketones 163enolates and work in this area continues to appear.280 Most of the proton sources are based on amino alcohols although the use of the chiral imide 54 derived from Kemp's triacid results in ketones of ~ 9 7 % e.e.281 Enantiopure ketones can also be obtained by resolution through enzymic processes282 or by formation of a chiral acetal.Eliel's hydroxythiol reagent 55 has been shown to be singularly effective in this latter approach.283 Determination of enantiopurity of the product ketone can be rapidly and efficiently achieved through the use of (R,R)- or (S,S)- 1,2-diphenylethane diamine.284 The aldol reaction continues to see developments.A particularly active area is the design of new promoters for the Mukaiyama aldol reaction. In this respect an in situ preparation of trimethylsilylfluorosulfonate, a cheaper alternative to the commonly employed TMSOTf, has been reported.285 Bismuth trichloride has been used in a 'one-pot' tandem aldol-halogenation reaction although isolation of the intermediate aldol is possible and provides higher overall yields.286 Tri~(perfluoropheny1)boron~~~ has been developed as an air-stable water tolerant Lewis acid although this has been superseded by the lanthanide triflates.288 Recent results in this area indicate that recycling of the catalyst is more efficient if a mixed solvent system (water-ethanol-toluene) is employed.289 As with Friedel-Crafts acylations (Section 2),83 the corresponding scandium reagents are not only considerably more effective promoters but are also capable of selectively activating aldehydes in preference to a ~ e t a l s .~ ~ ' In the presence of an amine base these lanthanide triflates can efficiently promote the crossed aldol although the scope of these condensations are limited by the low basicity of the catalyst. Enhanced reactivities are possible using the corresponding tris( hexame t hyldisilazide) .292 An alternative ene-type mode of reactivity of silylenol ethers has been developed. This mechanistic pathway is favoured by bulky silyl groups and non-polar solvents.As a consequence of the ene mechanism high syn diastereoselectivity is observed regardless of the enol ether geometry whilst through the use of a BINOL-TiC12 complex very high enantioselectivities may be obtained.293 Asymmetry may also be incorporated into the aldol reaction through the use of chiral enolates, notably those based on boron, and results in this area continue to appear.294 Chelation is frequently invoked to account for high ~tereoselectivity.~~~ However, the reaction of sodium enolates of a-amino ketones proceeds with a much higher kinetic diastereoselectivity than the equivalent lithium species. The open transition state 56, based on electrostatic control, is postulated (Scheme 29) to account for this Finally, a titanium-mediated aldol reaction has been employed, as the key step, in a total synthesis of rapamycin to generate the 31-membered macrocyclic ring, albeit with low diastereo~electivity.~~~ - 70 *pi NBn2 83%, > 98:2 d.s.(d. LDA 91%, 88:12) Scheme 29 6.2 Conjugate addition reactions Conjugate addition reactions to enones and enols can suffer from competitive 1,2-addition. Complexation with bulky aluminium Lewis acids can inhibit this unwanted pathway and with substituted enones the addition of organolithiums results in the complementary stereochemical outcome to that obtained using copper reagents, Scheme 30.298 Allylbarium reagents show exclusive 1,4 reactivity with, unusually, a preference for a-attack of the allyl This is an attractive option since allyl cuprates are unstable and tandem alkylation is not feasible with most soft allyl metal units.High levels of 1,4-addition is also obtained with alkyl alanes and titanates in the presence of nickel or copper catalyst^.^^ The reaction of alanes with a,P-unsaturated acetals to afford the P-substituted aldehyde is well documented and a similar transformation has how been achieved employing a zirconene catalyst. In this recent development the aldehyde is obtained masked as the corresponding enol ether.301 0 0 0 Me2CuLi 86% (42 : 58) MeLi/(2,6-Ph2C6H30)3AI 73% (94 : 6) Scheme 30 The Mukaiyama-Michael reaction proceeds with high 1,4-selectivity and may be promoted by both P4010302 and also photochemically in the presence of copper(1) salts.303 A variety of other reagents undergo selective conjugate addition including aryl ~tibines,~'~ ~ i l a n e s , ~ ' ~ and tellurides,306 both of these last two can be achieved with moderate to good enantioselectivity and it is in this area of stereocontrolled Michael additions that there has been the greatest activity.As synthons for acrylaldehydes Fischer carbene complexes are exceptionally active Michael acceptors for reactions with ketone enolates but not silyl enol ethers. An extended transition state 58 is proposed to account for the high syn selectivity observed (Scheme 31). This can be optimized through the use of the 164 Contemporary Organic Synthesis57 R’ u 58 I 81-84%, 86-> 99% d.e. Scheme 31 imidazolidone complex 57”’ whereas the use of the phenylmenthol as a chiral auxiliary provides very high levels of asymmetric Differences have emerged in the use of lithium and titanium enolates in conjugate additions to chiral enones.With ketone enolates the use of titanium species affords advantages in terms of yields and selectivities. However, with ester enolates, although both are equally effective, different stereochemical outcomes are obtained, Scheme 32, and this has been rationalized in terms A + P h d B d base 1 -78”C, THF LHMDS-Ti(OPr‘), 69% (95 5) LHMDS 50% (80 20) P h k B u t 0 + minor isomers Ph [MI = Li 80% (8 : 1 : 0.8) = Ti(opi)4Li iooo/o (1 : 5.2 : 0.5) Scheme 32 of a chelated conjugate addition and a cycloaddition mechanism respectively.309 The major aspect of this chemistry has focused on chiral reagent mediated strategies with a further emphasis on the development of methods for the catalytic asymmetric conjugate addition.Copper- based reagents remain the most common with the highest enantioselectivities being recorded with sulfur-nitrogen based ligands.”’” Similar levels of asymmetric induction can be achieved in the nickel amine catalysed conjugate addition of dialkylzinc~.”~ However, despite these successes it does appear that all these reagents are very substrate specific and that a truly general method remains to be discovered.312 A variety of P-ketoester derivatives undergo highly enantioselective selective conjugate additions catalysed by a variety of species, including rhodium ferrocenyl phosphine complexes and lanthanide alko~ides.”~ Using a chiral titanium oxide catalyst the Mukaiyama-Michael reaction has now been rendered both catalytic and asymmetric although with only moderate selectivities when acyclic enones are employed.”‘“ mediated Michael additions are possible using the sterically hindered chiral P-ketosulfoxide 59 as a chiral a~xiliary.”~ Lastly, asymmetric intermolecular radical 59 7 References 1 S.V.Ley, J. 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ISSN:1350-4894    

DOI:10.1039/CO9950200151

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

@-Cation equivalents of amino acids PATRICK D. BAILEY, JOANNE CLAYSON, Department of' Clicwiistly, Heriot- Watt University, Riccurton, Eclinhurgh, EH I4 4AS, UK and ANDREW N. BOA Scliool o f C'licwiistly, Uriivcrsity of Leeits, Leeds LS2 YJ7: UK Reviewing the literature published up to the end of I994 1 2 2.1 2.2 2.3 2.4 2.5 3 3. I 3.1.1 3. I . 1.1 3.1.1.2 3.1. I .3 3. I . I .4 3.1.2 3.1.2.1 3. I .2.2 3.1.3 3.1.3.1 3.1.3.2 3.1.4 3.1.4. I 3.1.4.2 3. I .4.3 3. I .4.4 3.2 3.3 3.3.1 3.3.2 3.3.3 3.3.4 4 5 Introduction Methods for preparing x-substituted x-amino acid derivatives Bromination of glycine derivatives Direct routes to other x-substituted glycine derivatives Routes that do not start from the glycyl skeleton Interconversion of x-substituents Direct routes to the imines x-Substituted glycines in synthesis Reactions with carbon nucleophiles Grignard and related organometallic nucleophiles Grignard reagents Cuprates Alkyl zincs and alkyl lithiums Tributyl t in acetylides Enolate nucleophiles Stabilized anions Silyl enol ethers Allylsilanes and allylstannanes Ally1 silanes Ally1 stannanes Other carbon nucleophiles Al kyl boranes FriedelLCrafts reactions Alkyl nitronates Enamines Dicls-Alder reactions 0 t her reactions Radical reactions Reductions Witt ig-type reactions Reaction with diazomethane Conclusion References RN=CHCO-Y 1 Introduction Synthetic equivalents of amino acid cx-cation synthons have enormous potential in the synthesis of a wide range of amino acids, peptides, and many other nitrogen-containing compounds.The synthetic equivalents are the wsubstituted amino acid derivatives 1 and the imines/iminium ions 2/3.1 2 3 Glycine derivatives I possessing an additional heteroatom at the x-position are not only of value as synthetic intermediates, but they are also important compounds in their own right: They are amino acid derivatives that might be incorporated into biologically active peptides, to generate new analogues with enhanced medicinal proper t i e s . Some x-hetero-substituted x-amino acids are natural products, e.g. bicyclomycin 4 and aranotin 5 . The poly-functionalized rx-carbon possesses unusual chemical properties that can be studied and exploited. Many peptide analogues have been prepared in which residues have been modified by the incorporation of hetcroatom groups into the side- chains.In contrast, there are relatively few examples of such modification at the x-positions of peptides. This is almost certainly because of the inherent instability of the corresponding free x-amino acid, in which the nitrogen lone pair displaces the hetero- atom leaving group (Scheme I ) . When the nitrogen lone pair is not fully available to displace X (e.g. R2 0 Y - + Y x- 1 3 X = F, CI, Br, SR, OR, OCOR Y = OR, NHR R' and/or R2 = electron-withdrawing groups such as MeCO, PhCO, BubCO, PhCH20C0, phthaloyl. Scheme 1 Bailq, Boa, and Clayson: a-Cation equivalents of amino acids 173when R1 or R2 exert a -M effect), the a-substituted a-amino acid derivatives can be moderately stable. However, in most cases the nitrogen lone pair can still assist in the displacement of X, either through the anomeric effect or by generating imine/iminium ion intermediates.HO In nucleophilic displacement reactions of X from compounds such as 1, it is often unclear whether the reaction is accelerated simply by the anomeric effect displacement of X occurs before attack by the nucleophile. Whichever mechanism does operate, the enhanced electrophilic reactivity of a-substituted them to be exploited very successfully in further synthetic transformations. intermediates, it is difficult to obtain or exploit the 5 from the nitrogen lone pair, or whether full 4 BocHNY co2Bu' BocHN -C02But NBSi cc14ip peptides affects their medicinal potential, and allows hv, A Br Whether they are the ultimate target or synthetic Scheme 2 chirality that most a-substituted a-amino acids should possess - again, the reversible formation of imines is the culprit, usually causing racemization at the a-centre.The stability of an a-substituted a-amino acid is also affected by the leaving group ability of X. Although this can be influenced strongly by the reaction conditions, the following order of reactivity is a useful guide: F <OR < SR < C1< Br (R = alkyl or acyl; where R = H, the derivatives are usually unstable). Looking at this approximate order of reactivity, it is perhaps not surprising that the more stable derivatives are often targets in their own right, whilst the relatively reactive a-bromo derivatives have dominated work on the use of a-substituted a-amino acids as synthetic intermediates.a-cation equivalents began in the mid-l970s, but significant developments have taken place over the past 5-10 years which have really opened up their potential in synthesis.' This article gives an overview of the field, and includes references up to the end of 1994. Although this review primarily concerns a-substituted glycine derivatives, other a-substituted amino acids are discussed wherever this is appropriate. Throughout this review, a-substituents refer to heteruaturn groups on the a-carbon (ie. substituent X in 1). Work on compounds that were effectively glycine 2 Methods for preparing a-substituted a-amino acid derivatives 2.1 Bromination of glycine derivatives This is the commonest route to a-substituted amino acids, and is normally carried out under free radical conditions using N-bromosuccinimide. It gives easy access to a-bromoglycine derivatives, for use either directly, or after conversion into other a-substituted analogues.One of the earliest research groups to develop this chemistry was that of Steglich,*~~ for which the following transformation is illustrative (Scheme 2). Other simple, protected glycine derivatives have also been brominated using this method and a wide range of N-protecting groups is compatible with the transformation; for example, ben~oyl,*-~ acetyl,2,3 bromoace tyI2-? or c hloroace tyl ,s,f' t rifl uoroace tyl, 2.3 trichloroethoxycarbonyl,2.' and the benzophenone imir~e,~ and also Boc as illustrated in Scheme 2.2.3.8- I2 The carboxyl function is invariably protected as an ester, from the simple (m)ethy12-5,7 and t-buty12.3-' ' to the chiral menthyl" and 8-phenylmenthyl groups."-' ' Williams has shown that the diketopiperazine derivative of cyclo- glycylglycine 6 is brominated under free radical conditions to produce the diastereoisomerically pure racemic syn dibromide derivative 7 (Scheme 3).13 Selective bromination at the glycine a-position is also possible in cyclu-glycylvaline, and further asymmetric transformations are possible under the stereocontrol of the isopropyl group.I4 9 P R 6 Scheme 3 R 7 As time has progressed, it has become apparent that the a-bromination of quite complex glycine derivatives can be highly regioselective. The extensive investigations of Easton have shown that glycine derivatives are brominated at significantly faster rates than other residues.Initial work showed that in the case of N-benzoyl valine derivati~esl~,'~ the amido-carboxy substituted radical (a-radical) was considerably more stable than the tertiary radical produced at the p-centre, but that subsequent hydrogen abstraction by this radical led to mixtures of products being isolated. Lidert and Gronowits also reported mixtures of products from the bromination of the alanine derivative 8 (Scheme 174 Contemporary Organic Synthesishe Md 'Br 6H2Br 0 Scheme 4 4a), but, in contrast, Seebach et a1.l' reported regiospecific bromination of a cyclic oxazolidinone derivative of alanine, (Scheme 4b). Easton has put forward evidence15-17 that the intermediate a-centered radical produced by H- atom abstraction is planar, and therefore there are significant non-bonding interactions between the amino acid side-chain and the carbonyl group of the N-acyl function, and this explains the preferential reactivity of glycine derivatives (no side-chain) over those of other amino acids.He proposed that cyclic amino acid derivatives should be brominated selectively at the a-centre and this was duly illustrated with the pyroglutamate derivative 9 (Scheme 5). Scheme 5 The observed preferential cr-bromination of N- benzoyl glycine derivatives means that selective a-functionalization of the glycyl moiety can be achieved in the presence of other residues, for example in di- and tri-peptides. l9 Interestingly, reactivity can be further modified if the N-terminal residue is N-phthaloylated.20'21 This protecting group prevents a-bromination of the N-terminal residue and directs functionalization away from the phthaloylated residue (Scheme 6).is again demonstrated in the work of Williams, which (most unusually) leads to stereochemically pure a-bromoglycine derivatives (Scheme 7).22,2" The formation of the bromoglycine derivative 10 was essentially quantitative and, although NMR data were broad and relatively uninformative, single crystal X-ray diffraction studies led to an unambiguous structural assignment. It is interesting that neither of the benzylic positions underwent bromination, and that 100% asymmetric induction was observed. In further transformations, the displacement of bromide was found to take place with overall retention of stereochemistry, thereby giving access to optically active amino acid derivatives - see Section 3.The site-specificity of the free radical bromination NBS (I q.), CCl4, hv, A 1 H PhthNyNVCo2Me 0 NBS (1 eq.), CCI,, hv, A I H P h t h N y N Y C o 2 M e 0 Br NBS (1 q.), CCI,, hv, A i 0 Br * YBr NBS (1 eq.), PhthN x C02Me PhthN C02Me CCI4, hv, A Scheme 6 P h q NBS, CC14, Boc' NJo hv,A w Boc' ! Br 10 Scheme 7 There are very few examples of acyclic cx-bromoglycine derivatives that are predominantly one stereoisomer. However, the ( - )-8-phenylmenthyl ester of Boc-glycine 11 undergoes r-bromination with high diastereoselectivity when the reaction is carried out in reluxing CCl,;" this is perhaps the thermodynamic product, since room temperature reaction conditions lead to a mixture of stereoisomers.' I As in Williams' procedure, further transformations Bailq, Boa, and Clayson: a-Cation equivalents of amino acids 175proceed with overall retention of stereochemistry.For example, treatment with tributyltin deuteride, proceeding via a planar radical intermediate, produces the a-deuteroglycine derivative 12 in which the auxiliary has controlled the formation of the new chiral centre (Scheme 8).8 BocO Ph 11 cc'41 hv* * 1 BOCO 12 Scheme 8 Although the free radical procedures dominate the a-functionalization of glycine derivatives, Belok~n'~~'" has shown how x-brornination of a glycine derivative can be achieved using bromine and base catalysis. Thus, the homochiral Ni"-Schiff base complex 13 derived from (S)-o-(N-benzyl- prolyl) aminobenzophenone and glycine reacts with bromine to produce a 2: 1 mixture of the x-bromo derivative stereoisomers 14/15; these can be separated by chromatography (Scheme 9).derivatives is an efficient, and often chemoselective process, that readily gives access to a-bromoglycine derivatives. With suitable auxiliaries, this bromination can be stereospecific, but it is invariably the auxiliary that controls the stereochemistry of further transformations. Hence, the direct a-bromination of glycine 2.2 Direct routes to other a-substituted glycine derivatives There are surprisingly few routes to a-substituted glycine derivatives (other than a-bromo) for which the glycine skeleton is intact in the starting material. There are, however, examples in which it is inferred that an a-bromo intermediate is trapped in situ by a suitable nucleophile (see Section 2.4).It would seem 13 14 15 2 1 Scheme 9 that free radical halogenation of glycine derivatives is not a viable method of a-chlorination; in general, a-chloroglycines are obtained by either quenching a glycine enol/enolate with a source of 'Cl+', or by replacing an a-hydroxy by an a-chloro group (see Section 2.4 for examples of the latter). Williams23 has made a chloro analogue of the chiral glycine cation equivalent shown in Scheme 7 by treatment of an oxazinone with t-butyl hypochlorite (Scheme lo), and again the trans- product 16 is formed under the control of the auxiliary. Cl 16 Scheme 10 It is important to note that on treatment with t- butyl hypochlorite and base, glycine derivatives27p3o (and those of other amino acids,29p31 including f i - l a ~ t a m s ~ ~ ~ ~ ~ ) possessing a free NH do not produce a-chloro derivatives as in the case reported above. In these examples N-chlorination is observed, but subsequent treatment with a suitable base (Scheme 11)27,28 gives the same intermediate imine that an a-chloroglycine derivative would have generated.The bis-lactim ether methodology developed by Schollkopf for the asymmetric synthesis of amino acids usually employs the a-anion of a chiral glycine derivative (eg. the anion of 17), but he has extended the scope of this chemistry to a glycine a-cation equivalent via the a-chloro derivative 18 (Scheme 12).34,35 Interestingly, the cis-chloro compound 18 is produced in this enolate reaction: the authors propose that the lithium cation co-ordinates anti- to the isopropyl group, so directing the chloro group 176 Contemporary Organic SynthesisBU'OCI ZHN-CO,Me - ?-CO2Me CI M ~ O H OMe MN*CO,Me [ i!NeCO2Me] Scheme 11 OMe 17 OMe 18 Scheme 12 syn- to the isopropyl group.Nevertheless, whether by a straight SN2 mode or via elimination to an iminium ion, subsequent displacement of the chloride gives anti-products (see Section 3.1). The use of a-unsaturated glycine derivatives is also possible. Thus, an a-hydroxy glycine hydantoin can be prepared by borohydride reduction of triketoimidazolidine (Scheme 13), treatment of which with thionyl chloride then gives the useful a-chloro derivative 19.36 HNKNH O w o - LiBH4 " O H 0 HNyNH - SOCI, "'2-4" HNyNH 0 0 0 19 Scheme 13 A further example which exploits unsaturation, but yields a-haloalanine derivatives, is the addition of HX or X2 to protected dehydroalanine (Scheme 14).37-39 C02H h X ~ N H A ~ X C02H CI MeOH I 0 Me0 MeOH BzHN NAC02Me - H 57% (81% on consumed starting material) Scheme 15 0 of dipeptides good regiocontrol can be achieved (Scheme 15).41 Finally, degradative procedures have been reported, though these are probably of limited practical value.Methods falling into this category include electrochemical decarb~xylation~~-~" (Scheme 16) and chemical oxidative cleavage of serine and threonine ~ i d e - c h a i n s ~ ~ - ~ ~ (Scheme 17). NHAc NHAc HOzCAC02Et -f&+ MeOACOzEt Scheme 16 Scheme 17 2.3 Routes that do not start from the glycyl skeleton Most routes to a-hetero-substituted amino acid derivatives start with the amino acid skeleton intact.Of the routes to such compounds in which this is not the case, synthetic work has been dominated by the reaction of amides with glyoxylic acid or ester (Scheme 18). X = CI or Br 0 0 0 OH RlANH2 i- HKC02RZ - R'KNACOzR2 H Scheme 14 Electrochemical methods perhaps have limited appeal to many synthetic organic chemists, but they can be used very successfully for the direct a-derivatization of protected amino acids.40 In cases R' = MeO, PhCH201 Phi R2 = MeI Et Scheme 18 Bail?, Boa, and Clayson: @-Cation equivalents of amino acids 177This approach has been extensively studied by B e n - I ~ h a i , ~ ~ - ~ ~ and developed subsequently by many research This tactic is an excellent general way of gaining access to substituted glycine derivatives, because of the ease with which the a-hydroxy function can be further derivatized (see Section 2.4).Amides are usually insufficiently nucleophilic to react with carbonyl electrophiles; it would seem that unhindered primary amides and highly electron-deficient aldehydes are prerequisites for the reaction to be successful. Glyoxylate esters are rather unstable, and the use of the hemiacetal,62 although probably proceeding via the same aldehyde intermediate, is a useful practical alternative (Scheme 19). Alternatively, the equilibrium can be influenced by the use of TMS-triflate, forming a-silyloxy a-amino acids, and this approach has been used to generate a-oxygenated derivatives of amino acids other than glycine (i.e.a-alkyl-a-amino Me 1 Me +#yC02M. ZHN*CONH2 + OH I 0 OH ___c ZHN MeO*co2Me Scheme 19 A similar approach to the method described above is particularly effective when fluorine is the desired a-heteroatom, since its poor leaving group ability confers exceptional stability on a-fluoroglycine derivatives. Takeuchi et aZ.64,65 have employed ethyl bromofluoroacetate as a key starting material; reaction with nitrogen nucleophiles [eg. phthalimide, azide, KN(Boc),] can be controlled to give only displacement of bromide, allowing rapid access to a-fluoroglycine derivatives (Scheme 20). Using chiral esters of bromofluoroacetate, it has been possible to generate separable (and stable) diastereoisomers, which have found applications as chiral shift reagents, but the free amine (even in protonated form) has proved too unstable for detection or i s o l a t i ~ n .~ ~ . ~ ~ 0 In an alternative approach to a-fluoroglycine derivatives, Bailey et aZ.66 have used chlorotrifluoroethene and (S)-a-methylbenzylamine to generate a-chlorofluoro- and a-fluoroiodo- ethanamide derivatives (e.g. 20). In these cases, not only are the diastereoisomers separable, but single crystal structure determinations have allowed assignment of the absolute stereochemistry at the a-centre. Subsequent displacement with nitrogen nucleophiles occurs with 85-100% inversion of stereochemistry, giving a range of protected a-fluoroglycine derivatives (Scheme 21). In the case of 21, standard peptide cleavage conditions result in the isolation of an a-fluorobetaine, the only reported example of a 'free' a-fluorinated a-amino acid.67 0 phTNJJ@ H 0 Me 0 PhAN% NMe3+ H F 21 16M HCI, reflux, 48 h -0% NMe3+ F Scheme 21 2.4 Interconversion of a-substituents Either through the anomeric effect, or via an imine/ iminium ion intermediate, interconversion of heteroatoms a-to nitrogen is an easy process, even when the nitrogen is protected.Some of the major transformations are illustrated in Table 1. N3yC02Et F BOe2NYc02Et F \ F Scheme 20 I 78 Contemporay Organic Synthesis 2.5 Direct routes to the imines RN=CHCO-Y Given that a-substituted glycines are usually in equilibrium with the corresponding imine, and that the imine is often the reactive component in subsequent transformations, it is pertinent to consider synthetic methods that lead directly to the imine.Perhaps the most obvious method is theTable 1 Interconversion of x-heteroatom substituted glycine derivatives Br Br Br Br Br Br Br Br CI CI CI CI CI CI SR SR SR SCOR OH OH OH OR OCOR OCOR OR OAr SR SAr OCOR SCOR P(O)(OR), NR, OR SR SH SCOR SC(S)OEt P(O)tOR), OR Br CI OR CI OR SR CI OR SR 15-17, 19-21,24,84,90 24 13, 37, 48, 90, 121 23, 121 7, 90 5, 38 3, 48, 12.5 7, 24 39 37,38 38 5 , 38 I22 48,61 s 0 48 48, so 39 36, so, S7-60,62 50,61 50 so, 61 7 7, 48, 90 direct condensation of glyoxylic acid or its ester with an amine (Scheme 22). Imine formation is reversible, and these highly electrophilic imines can be formed only if water is explicitly removed (e.g. azeotroping conditions or dehydrating agents).68 Scheme 22 In contrast, amides react with glyoxylate to give the hydrated product - i.e. the a-hydroxy glycine derivatives (Scheme 18).50061 When N-acyl-imines are required, a Wittig variation is a neat way to overcome this problem (Scheme 23).69 PPh3 I1 "COR' R' = Me, OBu', OCH2Ph, OCH2CC13 + PhH, A 702R2 CHO R2 = Me, Et "COR1 Scheme 23 If the tosyl rather than the carbonyl electron- withdrawing group is required on nitrogen, then these compounds are readily accessed using the procedure of Steglich,2,3 Alb~echt,~".~' or Holmes7' (Scheme 24).Scheme 24 Finally, imines of glycine are being increasingly exploited as 1,3-dipole~,~"-~~ by virtue of the equilibrium illustrated in Scheme 25. However, we will not discuss this valuable chemistry further in this review, as it is dominated by reactions implied by the mesomeric tautomer 22 rather than by 23 (formally an iminium ion 3).RkHO H2N-C02R1 - R2&NAC02R1 1 23 22 Scheme 25 3 a-Substituted glycines in synthesis The use of a-glycine cations in synthesis has been reviewed by Williams,' and the versatility of this chemistry is summarized in the next section of this review - reactions with carbon nucleophiles, aza- Diels-Alder cycloadditions, radical chemistry, reductions, Wittig chemistry, and dipolar cycloadditions all feature in this rich area of chemistry. It is worth re-stating the observation that the chemistry of a-substituted a-amino acid derivatives appears to take place via imine/iminium ion intermediates (Scheme 26). Scheme 26 It is not clear whether it is the completely free imine that is always involved, or whether it is an extremely powerful anomeric effect in some cases.Nevertheless, asymmetric variations of these reactions have proved extremely important for the synthesis of optically active compounds. The two main types of reaction with wsubstituted glycine derivatives are: Attack by carbon nucleophiles, to give a-alkyl Diels-Alder reactions, to give pipecolic acid a-amino acid derivatives. derivatives. Bailq, Boa, and Clayson: a-Cation equivalents of amino acids 179Some additional reactions are discussed in a final section of this review (reductions, eliminations, free radical reactions). 3.1 Reactions with carbon nucleophiles 3.1 .I Grignard and related organometallic nucleophiles 3.1.1.1 Grignard reagents a-Bromo- and Y-chloro-glycine derivatives react with Grignard reagents to give a-substituted a-amino Two mole equivalents of reagent are needed; one to trigger elimination of HX, the second to add to the resulting imine at the a-carbon, so giving the new amino acid derivative (Scheme 27).This method has also been used successfully with alkenyl Grignards'"."" to give a-vinyl glycine derivatives. If the Grignard reagent to be employed is valuable, a tertiary amine can be used to form the acyl imir~e,~" before addition of just one equivalent of the Grignard reagent. acids. 1 0 . 1 1.58.76.79 BocHNYco2But R 31 -91 Yo Scheme 27 With the 8-phenylmenthyl esters of a-halo glycines"." the chiral group controls the face selectivity of the addition of the Grignard reagent to the acyl-imine, giving diastereoisomeric excesses of 51-98% in the products (Scheme 28).Careful acid hydrolysis" of the esters then gives the optically active amino acids, or reduction" yields the amino alcohols 24, which can be re-oxidized to the amino acids 25. --"*Me H2N 9 O H (i) NBS, CCI,, h H R 25 (ii) RMgX, Et,O R = Me, Pi, Bu', Ph (i) RuC13, NaIO,, MeCN, Hfl I (ii) HCI, Etfl H R 24 Scheme 28 3.1.1.2 Cuprates In an analogous fashion to the organomagnesium nucleophiles, the a-halo glycine derivatives also react with higher order mixed prate^.^^^^^^^^^^" Williams has shown that the homochiral Ex-bromo- oxazinone 26 can be treated with Lewis acid to produce the intermediate iminium species, to which the cuprate reagent adds from the least-hindered face (Scheme 29).22.23 An extensive study of solvent and Lewis acid condition^^^ showed that hard Lewis acids and non-polar solvents favour an SN2 mode (giving syn products) and soft Lewis acids and polar solvents lead to an elimination-addition mode (favouring anti-products).Br 26 I zN"0 BU Scheme 29 3.1.1.3 Alkyl zincs and alkyl lithiums Examples of displacement reactions of whetero substituted glycines with alkyl lithiums are rare. In one case,24 decomposition is reported; however, butyl-, phenyl-, and methyl-lithium add to N - acylimino malonates in good yields.'.3 Reactions of x-bromo glycines with alkyl zinc halides are also known,12-24,S(I although yields are generally poor. 3.1.1.4 Tributyltin acetylides Tin a ~ e t y l i d e s " ~ - ~ ~ may be used to generate a-alkynyl amino acid derivatives (Scheme 30).Subsequent deprotection via hydrogenation can be used to generate x-alkyl amino acids 27"' whereas dissolving metals"' cause reduction of the triple bond to the trans-alkene 28. This methodology gives an attractive approach to a-vinyl amino acids to augment methods using Grignards,'" cuprates,'" or am i doal ky 1 at ion of a1 ke nes .s3 3.1.2 Enolate nucleophiles 3.1.2.1 Stabilized anions x-Halo-glycine derivatives have been treated with a range of sodium and potassium enolates, especially those of maIonic dieSterS.",24..~4,3(,.'7,(,2.S3.S4 Such reactions have been used to make the non-natural amino acid 1)-carboxyaspartic acid and its I80 Contemporary Organic SynthesisBoc' br ZnCI, CC14 RCECSnBu3 - ... 5: 10 H2, PdCI2, EtOH, 20 / psi.[:a, NH3, EtOH 27 28 Scheme 30 3.1.2.2 Silyl enol ethers x-Bromo-glycines react in the presence of Lewis acids and silyl enol ethers to produce P-keto amino O'Donnell"l has also performed this type of reaction with other x-hetero substituted glycines ( e g a-methoxy and rx-acetoxy glycines). Yet again, if Williams' oxazinone template is employed as the a-bromo glycine derivative, impressive diastereoisomeric excesses are obtained in the final product (Scheme 34). 3-22,2-3 acids. 13.22.23.7') *oSiMe2Bu: OEt ZnC12, Z' \C02Et br 26 (i) NaCH(CO&')Z, (ii) 6M HCI. A Y C O , M e THF, -10°C Scheme 34 z-N 0 CI 3.1.3 Allylsilanes and allylstannanes Scheme 31 3.1.3.1 Allyl silanes derivatives. This transformation has also been achieved with an x-haloglycine containing dipeptide (Scheme 31)."2."3 sodium etiolate of malonic dialkyl esters has been reported using Pd( PPh3)4 catalysis (Scheme 32)."5 Other enolates react in a similar fashion," as do the enols of 1,3-dicarbonyl compounds under acidic conditions (Scheme 33).55,7') The coupling of x-acetoxy glycines with the Ph&=N C02R * x NaC H(CO,R), OAc Pd(PPh3)4 (at.), MeCN, 25°C R02C C02R Ph2C=NY C02R R = Me, CH2Ph Scheme 32 Allyl silanes react with x-hetero substituted glycines in the presence of Lewis acids to produce a-ally1 tin(iv) chloride (with a-chloroglycines) or boron trifluoridc etherate (with x-methoxy glycines) generates an intermediate iminium species which reacts with allylsilanes to give the x-ally1 amino acids in good to excellent yield (Scheme 35).Speckamp Speckamp has shown how amino acids. 2 2.7.3 .85.8(1 M e 0 4 NHC02Me X = CI or OMe 0 (i) SnC14 or F3B.OEt2 (ii) P h v S i M e 3 I 5 Ph NHC02Me 0 0 R3 73% Isomer ratio 44 : 56 Scheme 35 R, ), H AC02R2 When R3 R3 = OMe = Br then then H+ NEt3, - [ R1'N+C02p] Scheme 33 has extended this chemistry to give access to x-allyl- derivative." This use of protected x-chloroglycines has been further developed into an asymmetric R4 RS] alanine derivatives, via the a-trimethylsilyloxy R 4 y R 5 version using the N-menthyl chiral auxiliary."" 0 RIKN H co2R2 3.1.3.2 Allylstannanes -92% yield Like allyl silanes, allyl stannanes react with x-bromo glycine derivatives to give ;g,S-unsaturated (x-allyl) amino acids, but evidence for the mechanism of Bailq, Boa, and Clayson: a-Cation equivalents of amino acids 181these reactions indicates that they proceed via radical pathways (see Section 3.3.1).".90 Easton has exploited this chemistry via the N,N'-diacetyl diketopiperazine of glycylvaline (the absence of NH- protons being essential); after introduction of bromine at the x position of glycine displacement by allylstannane is controlled by the isopropyl group ( c .j Schiillkopf chemistry).14 3.1.4 Other carbon nucleophiles 3.1.4.1 Alkyl boranes O'Donnell has shown" that x-acetoxy glycine derivatives can react with alkyl boranes to give x-alkylated amino acids. This method can be used to generate quite sterically crowded amino acids such as x-cyclohexyl (90%) and x-t-butyl (57%) glycines in good yield (Scheme 36). Ph2CZN-CH -CO2Et * Ph&=N-CH-C02Et I I OAC R Me3C 0-K+ THF, 0°C Scheme 36 3.1.4.2 Friedel-Crafts reactions x-Heteroatom substituted glycines can be used successfully in Friedel-Crafts type reacti"ns23.5 I .sh.Xh.c)2 such as anisoles, indoles, and furans.Both x-halo- 23.5 1 .v2 and x-alkoxy-lhydroxy-' '.''M' glycines have been employed. Tin tetrachloride is the preferred Lewis acid for x-chloro glycines and Schiillkopfs bis-lactim ether methodology can be used to with electron-rich aromatics generate optically active a-aryl amino acids (Scheme 37)."* Ben-Ishai" has also shown that x-methoxy glycine derivatives react in a related fashion with alkenes under acid catalysis to produce ix-vinyl amino acids. 3.1.4.3 Alkyl nitronates N-Benzoyl x-bromo glycine methyl ester reacts with two equivalents of alkyl nitronates in a similar elimination/addition sequence to that for Grignard reagents.[I3 The {)-nitro functionalized amino acids 29 can then be modified in a range of interesting and useful ways (Scheme 38). (i) Bu"L1, THF (ii) C13CCC13 c Me0 R' R2 R3 R4 (a) OEt H OEt H (b) OMe OMe H OMe (c) H OMe H H (d) OMe H H H Scheme 37 Br ~ R'R2CHN02, * PhCONOCO2Me I PhCONHAC02Me base R' I? (i) HZ, Pd-c Y O 2 (ii) HSnBu, P j a H PhCONH C02Me 29 NaN02, HCI, CuCl / R2+ci PhCONH *C02Me R2q,NH2 R' PhCONHAC02Me Scheme 38 182 Contemporaly Organic Synthesis3.1.4.4 Enamines Steglich's group has reported the reaction of N- benzoyl a-bromo glycine menthyl and 8-phenylmenthyl esters with enamine~.'"."~ The reaction with simple enamines proceeds with high diastereoselectivity, favouring anti-products, but with poor enantioselectivity (27-67%).Adding a second auxiliary to the enamine produces excellent diastereo- and enantio-selectivity (d.e. and e x . > 99%) (Scheme 39). 0 Br (ii) (i) a Et3N or b , -100°C flro2R (iii) aq. citric acid THF PhKNAC02R H a b Scheme 39 3.2 Diels-Alder reactions A Despite the obvious appeal of directly accessing the piperidine ring system via aza-Diels-Alder chemistry, imines have found only limited use as dienophile partners in 4 7 ~ + 27~ cycloadditions."5."" Extensive work by Grieco and others has indicated that imines derived from methanal will usually add to reactive dienes in aqueous solution, but that more hindered imines, less reactive dienes, or non- aqueous solvents often render the reaction useless.c)7- '03 One problem with imine dienophiles is the ease with which alternative reactions can often com pe t e with cy cl oadd i t ion.However, strongly electron-deficient imines are more effective dienophiles, and imines of the type R'N=CHC02R7 are therefore potential 2n-partners in Diels-Alder chemistry. Moreover, their inability to tautomerize to the enamine reduces some of the potential side-reactions. This chemistry is particularly attractive because pipecolic acid derivatives can be accessed directly and they are a common structural unit in a wide range of important natural products (Scheme 40). A' X Scheme 40 Accordingly, there are several examples of r-hetero-substituted glycine derivatives for which, under suitable conditions, the corresponding imine can be trapped by a reactive diene."4-10" Non- aqueous acidic conditions are the norm, to prevent hydrolysis of the iminium dienophile.Nevertheless, the range of dienes has been very limited and it has been generally believed that aza- Diels-Alder reactions with less activated dienes require a second electron-withdrawing group on the imine; to this end, N-acyl"" (R'CON=CHCO2R2) and N-tosy]'"'-I I 2 (TsN=CHC02R2) derivatives have been used with considerable success. However, Bailey et al. found that N-alkyl imines of the type R'N=CHCO,Et are effective dienophiles with a range of dienes provided that the solvent is carefully chosen - DMF yields the best results, with an equivalent of TFA (forming the electron-deficient iminium ion) and catalytic water being essential additives; yields are typically around 50% with acyclic dienes and display excellent regio- and diastereo-control (Scheme 41)."8 TFWDMWH20 ( a t .) CH2Ph 'i (one regioisorner) CH2Ph \TFA/DMF/H,O (Cat.) kH2Ph V V Z " I CHO kH2Ph (one regioisomer: cis : rrans = 13 : 1) Scheme 41 In the chiral version of this reaction, using N- r-methylbenzyl as a chiral auxiliary, high asymmetric induction is observed for the 2-substituted dienes, and moreover the minor diastereoisomer can be removed by chromatography. Thus, after removal of the auxiliary, homochiral pipecolic acids derivatives can be formed.' conditions, Stella et af. j 5 . ' '" have also demonstrated the success of this auxiliary in this type of reaction. In a further development, asymmetric induction of >9S% can now be achieved using the double chiral auxiliary [ (R)-N-r-methylbenzyl and 8-phenylmenthyl ester], and the use of trifluoroethanol as solvent enhances the yield and reproducibility of the cycloaddition.' '' In general, the trapping of the imines derived from rx-hetero-substituted glycine derivatives is often possible using reactive dienes, but more reliable procedures use preformed imines in which additional electron-withdrawing groups (acyl/tosyl) are present, or in which careful choice of conditions l 4 Using slightly different Bailey, Boa, and Clayson: a-Cation equivalents of amino acids 183favours the cycloadduct over alternative reactions.This constitutes a short, general, and efficient route to pipecolic acid derivatives.3.3 Other reactions 3.3.1 Radical reactions %-Substituted glycine derivatives undergo a wide range of free radical reactions.".""'~"'.' '',I I" x-Bromo substituents can be replaced with hydrogen, or more usefully deuterium, using tributyltin hydride or deuteride.8.S4.')0 With thc 8-phenylmenthyl esters of a-bromo glycine,." the reaction proceeds to give the deuterated product in 60-70% yield with diastereoisomeric excesses greater than 90%.".1'0 A similar deuteration procedure has been used to generate ct-deutero glycine containing dipeptides (Scheme 42).s4 Bu3SnD H Bz/'$N COzMe - D H Br Scheme 42 cx-Substituted glycine derivatives also react with allyl tin c o m p o ~ n d s ~ ~ ~ ' ~ ~ ~ ~ ' ~ (with AIBN as initiator) to give the x-ally1 glycine derivatives in good yield (see Section 3.1.3.2).x-Benzoyloxy and x-methoxy substituents with allyl tributyl tin"" undergo a similar reaction giving x-ally1 glycine in 47 and 31% yield, respectively (Scheme 43). Isomers of the glycine dimer 30 are also detected in this reaction, indicating a free radical mechanism. This dimer can be generated as the major product"' by using N - benzoyl x-bromo glycine methyl ester and hexabutyl di-tin under rigorously dry conditions. In the presence of water the ether 31 can be isolated,"".' '' and this discovery prompted Easton to make a wide range of cross-linked peptides using x-bromo glycines and amino acids such as serine, lysine, and cysteine, though not via radical pathways. ' "' Routes H H I A, AIBN O K Ph 0 S Scheme 43 H BzNNhCOZMe H Bz H N ACOzMe 30 31 to glycine a-thio-ethers have also been developed by Easton, by the reaction of a-bromo glycine derivatives with Bu3SnH in the presence of RSSR or ArSSAr.12' Speckamp has accessed the related Me02C-NH-CH[SC(S)OEt]-C02Et using standard SN2 chemistry, and has utilized this dithiocarbonate in some elegant free radical reactions with alkenes.122 3.3.2 Reductions Heterogeneous reductions of homochiral a-bromo glycine derivatives can be performed using palladium-catalysed hydrogenat ion. 12391 24 The a-bromo oxazinone of Williams has been reduced in the presence of both D2 and T2 to produce optically active a - d e ~ t e r o l ~ ~ and ~x-tritiol~~ glycine for labelling experiments. The optical activity and label incorporation were excellent in both cases (Scheme 44).Reduction of a-bromo glycine derivatives is also possible using Bu3SnH, as discussed in Section 3.3.1. H D 8490% atm.D 7742% e.e. 02, PdC12 D20, THF Ph-(il. A 40h. 25°C 0.78 Ci / mmol Scheme 44 3.3.3 Wittig-type reactions %-Halo glycine derivatives react with trialkylphosphites in an Arbuzov-type reaction to yield phosph~nates.~.~.".~",'I' In fact, the Horner- Wadsworth-Emmons reagent Z-NH- CH[P(O)(OMe),]-CO,Et is now commercially available; treatment of this with base, to form the ylid, followed by addition of an aldehyde gives a,/Mehydro amino acids via a short and flexible route."" When this method was applied to his oxazinone template, Williams showed'15 that a single geometric isomer of the alkene 32 was produced (Scheme 45).This could be converted with high diastereoselectivity into the cyclopropyl amino acid derivative 33, in which the auxiliary controlled the face of addition of the cyclopropanating reagent. Another route to a,P-dehydroamino acids is by elimination from a-bromo substituted amino acids residues other than glycine (e.g. alanine in Scheme 46).18 The N-chlorination of protected amino acids with t-butyl hypochlorite has already been described (see Section 2.2),27-31 and, if these are derivatives of amino acids other than g l ~ c i n e , ~ ~ - ~ ' the action of base first converts the N-chloro compound into the imine, which then isomerizes to the a,P-dehydro amino acid. 184 Contemporary Organic SynthesisI Br 10 (i) NaH,THF (ii) CH3CH0 I Ph(Et#)+SO(Me) BF,; ph phG? NaH.DMSO B O C ’ Y O Boc’Ny% Me Me 32 33 Li’, NH,, EtOH 1 Scheme 45 Scheme 46 3.3.4 Reaction with diazomethane When N-acyl a-chloroglycine methyl ester is reacted with diazomethane, the imine is initially formed, which then reacts with excess diazomethane in a [3 + 21 cycloaddition to give the N-acyl triazoline 34.54 Upon warming, N2 is extruded to give the aziridine 35 (Scheme 47), further demonstrating the versatility of glycine a-cation equivalents. 35 \ C02Me Scheme 47 ’R 34 4 Conclusions With a range of reliable routes both to a-substituted glycine derivatives and to imino esters, synthetic equivalents of the glycine a-cation synthon are readily accessible. Moreover, their chemistry is more diverse and versatile than might have been imagined 10 years ago, and they can be converted into a wide range of compound classes with (perhaps unexpected) site-selectivity and stereo-control.If the chemistry of a-substituted a-amino acids can be harnessed successfully then such reactions allow access to a wide range of amino acids, N- heterocycles, and peptides with modified backbones. The use of a-substituted peptides for further functionalization is exemplified by the work of Steglich using a-~hloro-,’~’ a, a-dichloro-,’28 and a-acet~xy-glycine’~~ derivatives, whilst Ramage”” has indicated the future potential in this area by his use of a-methoxy-glycine derivatives in solid-phase peptide synthesis. 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ISSN:1350-4894    

DOI:10.1039/CO9950200173

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

Saturated oxygen heterocycles CHRISTOPHER J. BURNS Pfirer Central Research, Sandwich, Kent CT13 9NJ, UK Reviewing the literature published between 1 April 1993 and 30 September 1994 1 2 3 4 4. I 4.2 5 5.1 5.2 6 Introduction Expoxides Oxetanes Five-membered rings Tetrahydrofurans Di hy d rof ur ans Six-membered rings Tetrahydropyrans Dihydropyrans References 1 Introduction This review covers the literature on small ring, i.e. 3+6 membered, ethers only. The literature on medium-ring ethers has recently been covered elsewhere in the journal (M. Elliott, Contemporary Organic Synthesis, 1994, 457j, and a separate review of oxygen heterocycles accommodating additional heteroatoms will be published in a future issue of COS. 2 Epoxides Studies of enantioselective epoxidations of unfunctionalized olefins continues to be an extremely active area of research. Jacobsen and his research group have shown that trisubstituted olefins such as 1 can be epoxidized in high yield and with excellent enantioselectivity using commercial bleach, the manganese complex 2, and catalytic 4-phenylpyridine N-oxide.' Under essentially identical conditions, the cis double bond of conjugated cis,truns-dienes (such as 3) is epoxidized with high regioselectivity, giving the trans-epoxide 4 in good yield and enantioselectivity.' Interestingly, simple trans-epoxides can be obtained in high optical purity from cis-olefins by addition of the quinine-derived salt 6 to the epoxidation reaction. For example, epoxidation of cis-[,'-methyl styrene ( 5 j under these conditions furnished predominantly the trans-epoxide 7.3 Katsuki and co-workers have also examined the use of manganese salen complexes in the epoxidations of alkene~.~ For example, the manganese complex 9 catalyses the epoxidation of But 6 : ' f : b B u l Ph Bu' Bu' 2 NaOCI, PhCsHaNO, CH2CI2 * Ph Ph Ph 1 97% 92% 8.8.3 81%- 4 (87%e.e.) Ph Me * P h y ? M e 0 NaOCI, PhCl Ld 5 7 (81%e.e.) L N + 4 6 the chromene derivative 8 with iodosylbenzene, giving the epoxide 10 in good yield and in high optical purity.s By analysis of the results obtained for the epoxidation of a range of cis-olefins using numerous manganese complexes, Katsuki et al. suggest that cis-olefins approach the manganese 0x0 intermediate 11 along the axis depicted in Figure 1." The use of N-methyl imidazole in conjunction with a manganese complex such as 2 or 9, allows for the use of hydrogen peroxide' or molecular oxygen" as oxidants.Dhal and co-workers have reported the use of a related polymer bound manganese salen complex 13 for the epoxidations of alkenes." Use of this catalyst and iodosylbenzene as oxidant generates the epoxide 14 from indene 12 in 5 1 % yield. There have been a number of publications over the review period concerning the asymmetric synthesis of epoxides by biotransformation; a review containing 64 references has also been published. lo Hager, Jacobsen, and co-workers have shown that Burns: Saturated oxygen heterocycles 189AcHN 02Nm a PhIO, MeCN 78% 9 1 AcHN 02Nyy)J 10 (96% e.e.) R' 11 Figure 1 12 0 13 PhIO, MeCN. r.t. 51% 14 chloroperoxidase (CPO) effectively catalyses the epoxidation of aliphatic cis-olefins, as in the formation of the cis-epoxide 16 from 2-cis-heptene 15.' Veschambre and his research group have examined a range of microbial techniques for the stereospecific reduction of halo ketones, which on treatment with base give optically pure epoxides;12 *- CPO, H202 acetone 78% \.pH5 citrate buffer 0 16 (96%e.e.) 15 -w (i) Montierella isabellina (ii) NaH, benzene 60% 0 17 18 (e.e. > 98%) this procedure is illustrated for the synthesis of cis- 2,3-epoxyoctane 18 from the bromohydrin 17." The differentially protected epoxy diester 21 has been prepared by Crout and his colleagues also employing an enzymatic appr0a~h.I~ Thus, selective hydrolysis of the tartrate derived diester 19 with a-chymotrypsin, followed by some functional group manipulation first afforded the silyl protected chiral diester 20 which on treatment with fluoride anion then generated the enantiomerically pure epoxide 21.Koch, Reymond, and Lerner have raised catalytic antibodies to the hapten 22, and have shown that one of these efficiently catalyses the epoxidation of alkenes such as 23 with hydrogen peroxide/acetonitrile as oxidant. I s The epoxide formed has greater than 98% e.e. OH OTBDMS 19 20 1 BU~NF Et02C A C0,Bu' 21 (e.e. 2 98%) link CONH 0 22 0 23 Other new methods for the synthesis of chiral epoxides include the conversion of chiral trichloromethyl carbinols into terminal epoxides. l 6 Thus, reduction of the trichloromethyl ketone 24 with catecholborane in the presence of oxazaborolidine 25 first leads to the chiral carbinol 26 which, after bis-dechlorination with in situ generated tributyltin hydride, is subjected to base- induced ring closure producing the chiral epoxide 27 in high enantioselectivity.Chan et al. have demonstrated that alkenylsilanols 28 can be epoxidized enantioselectively using the Sharpless procedure, and after protodesilylation terminal epoxides 29 of high optical purity are obtained." 0 OH 24 catecholborane $:h Bun 25 26 (i) Bu,SnCI, NaCNBH3 AIBN, EtOH, A l(ii) Na%&.O 27 (96% e.e.) 190 Contempora y OGanic Synthesis29 (8595% e.e.) Agganval and his co-workers have shown that predominantly trans-epoxides can be obtained from the reaction of aldehydes and sulfur ylides generated by decomposition of a diazo compound in the presence of a sulfide;'" the starting sulfide is regenerated and the process operates as a catalytic cycle.The mechanism shown in Scheme 1 presumably operates, and use of a chiral sulfide such as 32 leads to moderate asymmetric induction. Aggarwal and his group have also shown that the reaction between aldehydes and chiral sulfur ylides (obtained from the treatment of diastereomeric sulfonium salts such as 33 with strong base) also lead to chiral epoxides, though again the e.e.'s are moderate.'" Yamamoto and his group have shown that decomposition of diazoalkanes in the presence of an aldehyde by the bulky aluminium catalyst ATPH (35) is an efficient route to epoxides, as exemplified by the transformation of 34 into 36." 0 R' g s + p' R3 31 Scheme 1 32 33 U C H O \ 34 36 Considerable work continues to be published on novel uses of dioxiranes as epoxidizing reagents.Thus, reaction of the chromanones 37 with dimethyl dioxirane affords the interesting spiro-epoxides 38 in moderate yield,*' while epoxidation of chalcones proceeds in excellent yield.22 Very interesting results have been obtained with the epoxidations of benzofuran derivatives 39, which lead to an equilibrium mixture of the epoxide 40 and quinone methide 41,23 which in turn can be transformed into other products, such as the benzopyran 42 by Diels- Alder reaction with ethyl vinyl ether.'4 The unstable benzoxetes 43 can also be obtained from the mixture of 40 and 41 though on warming, or over time, this reverts to the starting mixture of epoxide and quinone methide." o&pR 0 O H 37 WR 0 o o H 38 39 41 43 42 The diastereoselectivity of dioxirane epoxidations has been examined in a number of different substrates.Adam and his research group have demonstrated that epoxidations of certain allylic alcohols with dimethyl dioxirane lead preferentially to the anti-product, as in the epoxidation of 44 to give the epoxides 45 and 46.*" Substantial quantities of enone, resulting from oxidation of the alcohol moiety, can also be formed particularly if the reaction is performed at higher temperatures. Kurihara et al. have improved the diastereoselectivity in the epoxidation of the cyclohexenol 47 by using a more bulky dioxirane than dimethyl dioxirane (such as 50), or alternatively by protecting the hydroxyl with a silyl ether.27 Armstrong and co-workers have shown that the dimethyl dioxirane epoxidation of the cyclohexene ketone 51 leads to a 1 : l mixture of the syn-epoxide 52 and the diol 53 (presumably arising from facile ring-opening of the anti-epoxide), while in contrast mCPBA gives only the syn-epoxide 52.2" An oxygen labelling experiment indicates that in the latter case the diastereoselectivity arises through ketone-assisted delivery of the peracid, rather than in situ dioxirane formation from the ketone moiety.Bums: Saturated oxygen heterocycles 19144 ><%, acetone 0:: b + 45 46 >95 : 5 47 48 49 51 52 53 Albeck and Persky have devised an efficient route to peptide allylamines 54, and have shown that epoxidation with mCPBA leads to predominantly the threo-diastereoisomer Similar results have been obtained by Romeo and Rich who have also shown that the minor eiythro-diastereomer undergoes preferential decomposition under the acidic epoxidation conditions, thereby enhancing the diastereomeric excess.3o 55 The erythro-epoxides can be synthesized via an alternative route starting from halo ketones 56.3' Thus, reduction with sodium borohydride first affords the erythro halohydrin 57, which on treatment with base gives the desired epoxide 58.Similar compounds have been prepared by Barluenga and his colleagues, again using a ring- closure of preformed hal~hydrins.~~ A related procedure has also been used for the diastereoselective synthesis of disubstituted epichlorohydrins involving the conversion of the ketone 59, via the lithium alkoxide 60, into the epoxide 61.33 NaOMe, MeOH 6888% overall J R CbzN "lul, 58 L 59 60 120°C Me.0 ,Ph H %I 61 An intermediate lithium alkoxide also features in the synthesis of oxiranyl pyridines reported by Florio and T r ~ i s i . ~ ~ In this procedure the 2-chloromethylpyridine 62 is lithiated and reacted with a ketone, such as cyclohexanone, and the intermediate alkoxide formed them undergoes cyclization to give the desired epoxide, as illustrated for the synthesis of the spiro-epoxide 64. A related route to vinyl epoxides 66, involving the addition of the allyl zinc reagent derived from allyl chloride 65 to ketones, has also been reported.35 62 (ii) 64 OH (i) LDA,ZnClz THF, -78°C @VCl CI 65 0 fii) K, R R KOEt I EtOH, 61-73% 5240% t 66 Iodovinyl epoxides have been prepared from treatment of a-allenic alcohols with iodine, followed I92 Contemporaiy Urganic Synthesisby base-induced epoxide formation.36 For example, iodination of 67 gave the intermediate diiodide 68, which on treatment with sodium hexamethyldisilazide then generates the epoxide 69 predominantly as the trans-isomer shown.NaN(TMS)2 THF, 0°C 93% overall 1 A p”--~ H I 69 Of numerous reports detailing the use of molecular oxygen as oxidant, the work of Mukaiyama and his group is particularly noteworthy. In recent work they have demonstrated that acid-sensitive epoxides can be prepared via oxygenations of olefins in the presence of a cobalt cataly~t.”~ Propionaldehyde diethyl acetal, which is also added to the reaction mixture, acting as a reductant, is converted into ethyl propionate and ethanol, the reaction therefore occurs under neutral conditions; the synthesis of the epoxide 71 from the olefin 70 is typical.I 71 OEt 76% 70 Singlet molecular oxygen has been used in the epoxy-hydroxylation of allylic alcohols catalysed by titanium tetraisopr~poxide.’~ Thus, conversion of the allylic alcohol 72 into the hydroxy epoxides 75 and 76 is achieved in one-pot via the hydroperoxides 73 and 74, and with very high diastereo~electivity.”~ A similar procedure beginning with vinyl stannanes 77 leads to the stannyl epoxides 79 through the intermediacy of the corresponding hydroperoxide 78.40 OH ‘02, TPP, hv CCb, O”C, 4 h 72 77 R=H,alkyl 78 T~(oP~’), 2445% overall 1 79 3 Oxetanes The photocycloaddition of olefins and carbonyl compounds (Paterno-Buchi reaction) continues to be the main method of choice for the synthesis of oxetanes.Bach has demonstrated that /)-alkylsubstituted silyl enol ethers undergo remarkably regio- and stereo-selective additions to aryl aldehydes, e.g. formation of the oxetane 82 from benzaldehyde (80) and the enol ether 81.4’ Ciufolini and co-workers have examined the Paterno-Buchi reaction of henzoquinones and olefins, and have shown that alkylidenecyclohexanes 84 react with para-benzoquinone (83) in good yield to give the regioisomeric oxetanes 85 and 86 in the ratio shown.4’ Interestingly, with smaller ring alkylidenes the regioisomeric preference is reversed, whereas acyclic olefins react with little regioselectivi ty.43 0 OTMS PhH 82 (91% d.s.) 80 81 4 0 83 + X R 84 = CH2, NTs = alkyl hv PhH 60-90% ___c X f$ R 0 +R5j 85 86 >7 1 The reactions between chloranil (87) and a,/)-unsaturated carbonyl compounds have also been investigated and proceed in good yield, generating tra~s-oxetanes.~~ For example, irradiation of a benzene solution of chloranil with ethyl cinnamate isomers 88 leads to the oxetane 89 in excellent yield.Bums: Saturated oxygen heterocycles 1930 0 87 88 I C0,Et 89 The research groups of both R a ~ a l ~ ~ and Gleiter46 have examined the use of oxetane 91, derived from the Paterno-Buchi reaction of the norbornene 90, in synthesis. Thus, Rawal and Dufour have transformed the simple norbornene 90 (X = H2) into the diquinane 92 in only four while Gleiter and Sigwart have prepared 'stellatriene' 93 in three steps from the oxetane 91 (x = C H ~ ) .~ ~ 91 92 93 Craig and Munasinghe have synthesized keto- oxetanes via intramolecular trapping of an oxonium ion.47 The reaction proceeds with high stereoselectivity, as shown for the synthesis of 95 from the sugar-derived silyl enol ether 94. This work has also been extended to the synthesis of the analogous tetrahydrof~rans.~~ W O V 94 95 4 Five-membered rings 4.1 Tetra hydro fur an s The synthesis of substituted tetrahydrofurans via free radical chemistry continues to be an active area of research. Rai and Collum have demonstrated that the radical cyclization of the ether 96 to the tetrahydrofuran 98 proceeds under aqueous conditions via in situ reduction of the tin species 97 with sodium borohydride in the presence of the initiator 4,4'-azobis(4-cyanovaleric acid) (ACVA).49 Udding et al.have introduced the copper(1) catalyst 100 for chlorine-transfer radical cyclizations, as shown for the synthesis of the diastereomers 101 from 99.50 A chromium species, generated from chromium(r1) acetate and various reducing agents such as LiAlH4, has also been used for the generation of carbon-centred free-radicals in tetrahydrofuran synthesis.51 c NaBH,, HS, KOH ACVA 90°C 6% I Me' 98 Br 96 101 Burke and Jung have demonstrated that treatment of the alkyne 102 with thiophenol under radical conditions leads to the tetrahydrofuran diastereomers 104 presumably through the intermediacy of the alkoxymethyl radical 103." Rawal and co-workers have reported on the generation and use of simple alkoxymethyl radicals in tetrahydrofuran synthesis, e.g.in the synthesis of the spirocycles 106 and 107 from the selenide 105.53 102 103 178% CgPh CO,Bu' 104 (2 : 1 trans : cis) G 105 Bu",SnH, AIBN PhH, A 95Y0 1 a--- 4.3 + =a- 1 106 1 07 A review containing 90 references on synthetic routes to 2,5-disubstituted tetrahydrofurans has been p~blished.'~ Walkup and Kim have prepared I94 Contemporary Organic Synthesisthe 2,5-disubstituted tetrahydrofuran lower portion of the panamycin group of macrolides via the cyclization of y-silyl~xyallenes.~' Thus, treatment of the chiral allene 108 with mercury(I1) triflate, and subsequent carbonylation of the intermediate organomercurial gave the tetrahydrofuran 109, predominantly as the cis-diastereomer shown.In a related process y-oxoallenes have been shown to cyclize solely under the palladium-catalysis conditions of the carbonylation; for example, the formation of the furanoside 111 from the allene 1 1 0 . ~ ~ OTMS M * ~ O + - . = j 1 08 (i) Hg(OCOCF&, CH2C12 I (ii) CO, MeOH. PdCI2, CuC12 I A0 57% Me0 I 109 (90% d.e.) MeoYo MeOH, PdCIz, CO(1 CUCI~, atm.) c %OMe 110 111 OEt 442 Furanosides can also be prepared by a catalytic oxidation procedure of homoallylic alcohols.57 In this process substituted homoallylic alcohols 112 are oxidized by molecular oxygen, catalysed by the in situ prepared palladium complex 113, to the products 114. hR1 R2 112 R' = a!@[, ptwnyl R2 = alkyl Pd(N02)CI(MeCN)2 113 cUcl2, R~OH 02,55"C, 2 h 56-10090 R2 114 R3 = Pi, Bu' A number of research groups have reported on the synthesis of 2-hydroxymethyl substituted tetrahydrofurans via an intramolecular epoxide-ring opening process.For example, Ley and co-workers have prepared the tetrahydrofuran portion of the antibiotic tetronasin via epoxide ring-opening of the chiral epoxide 115 following desilylation of the protected secondary hydroxyl, giving the tetrahydrofuran 116 as one diastereomer in excellent yield. In a synthesis of (+)-tuberine, Taber et al. have used the intramolecular ring-opening of an epoxide to form the tetrahydrofuran portion of this natural product." Thus, Sharpless asymmetric dihydroxylation of the olefin 117 afforded, in one step, the chiral tetrahydrofuran 118 in good yield. Similarly, Panek, Garbaccio, and Jain have demonstrated that epoxidations of the bis- homoallylic alcohols 119 generate the tetrahydrofurans 121 with excellent diastereoselectivity, via the intermediacy of the epoxide 120.60 H N Br ADmb Q acetone 65% - BU'OH-HpO 117 118 R 9 OH Or* dPBA [+] VO(acac12 Me26iPh 20-81 TBHP Yo Me2!%Ph 119 120 I PhMe2Si ,R n 121 Interestingly, cyclopropanation of the isomeric alkenes 122, followed by treatment of the derived cyclopropanes 123 with catalytic acid generates the related tetrahydrofurans 124 with excellent diastereoseIectivity.'* Corey has also used an intramolecular cyclopropane ring-opening in a biomimetic synthesis of 12-desoxy-glycinoeclepin (127), wherein exposure of the cyclopropane 125 to excess boron trifluoride etherate gives the bridged tetrahydrofuran 126.6' R R Me2SiPh 67-8196 Me2SiPh 122 123 CH$& 1 r.t.pTSA 7446% PhMe&i TR 124 OH j A biomimetic approach to the polyether antibiotic etheromycin has been reported by Paterson and his group, whereby an acid induced cascade reaction of the diepoxide 128 led to the bis-tetrahydrofuran 129 in moderate yield.62 Mukai et al. have reported a B q p y O H OTBS Bun;imF- B m i . ; ; 115 116 Burns: Saturated oxygen heterocycles 195*'OH 126 ;ir9y' CO2H 127 synthesis of 3-hydroxytetrahydrofurans using an epoxide ring-opening pro~ess.~' In this reaction exposure of the epoxides 130 to catalytic boron trifluoride etherate generates the tetrahydrofurans 131 in good yield and with excellent diastereoselectivity; cis-epoxides are transformed into cis-tetrahydrofurans, while the trans-isomers give the trans products. Interestingly, complexation of the acetylene in 130 with COz(CO), prior to tetrahydrofuran formation reverses the stereoselect ivi ty.1 28 aq. HCI THF, 28"C, 30% 1 OBZ 0 OPMB OH 129 R FaB.OEt2 CH2C12 44-9846 R R = SiMe3, Br, Ph 1 30 131 Iodocyclizations also continue to be an attractive route to functionalized tetrahydrofurans. Knight and his research group have prepared annulated tetrahydrofurans via this route, and have shown that the reaction is highly stereoselective, as shown for the synthesis of the cis-tetrahydrofuran 133 from the cis-olefin 132.- Alteration of the electron- withdrawing effect of the nitrogen protecting group in the aminoalkenes 134 has a profound effect on the stereoselectivity of the iodocyclized products; the electron-withdrawing substituents force the reaction to run under electronic control giving predominantly cis-products 135, as opposed to trans- products 136 which arise through steric control.65 U + 1 35 136 NaHC03, Hfl ,34 Etfl or EtOAc 0°C R=SO&Fa 93 7 R = COPh 30 70 Stereoselective iodocyclizations have been used in a number of natural product syntheses over the review period, such as in the synthesis of the C1,-CZz subunit of ionomycinp6 the synthesis of m ~ s c a r i n e , ~ ~ and in the synthesis of the tetrahydrofuran portion of the marine natural product halichondrin B.68 In this latter work, the secondary triethylsilyl ether of 137 is cleaved in the cyclization reaction to give after acid treatment predominantly the tetrahydrofuran isomer 138 shown.TBDPSO 137 (i) 12, NaHCO3 (ii) IN HCI I PMB OH H d 138 A number of publications concerning syntheses of annulated tetrahydrofurans have appeared recently. Thus, Koreeda and co-workers have reported a highly efficient synthesis of the tetrahydrofuran 140 from the aldehyde 139 in a formal synthesis of aflatoxin B2."" Similar compounds have been prepared by a photolytic route, as shown in the preparation of the acetals 142 from the cyclobutanone 141." 196 Contemporary Organic SynthesisSEMO CHO SEMO OTBDMS a q . ~ ~ THF, r.t. MeO MeO 139 140 Me 56% Me 141 142 Overman and his group have prepared the annulated tetrahydrofuran 144 with high diastereoselectivity via methanolysis of the unsaturated lactone 143 in a synthesis of the marine natural product kumausallene 145.'' 0 & .,/OBz H 143 H H 144 145 Mikami and co-workers have prepared the furofuran-containing natural product neopaulownin 148 via a stereoselective ene reaction of the ether 146 to give the trans-tetrahydrofuran 147, which was then converted into the natural product 148 through regioselective olefin epoxidation, reductive double bond cleavage, and acid-catalysed epoxide ring- opening." The related natural product asarinin has been prepared by Takano and co-worker~.'~ In this work they found that treatment of the dioxepin 149 with a Lewis acid, followed by a reductant, gave the diastereomers 150 and 151, the ratio being dramatically affected by the choice of reagents.been reported by Hojo et al. wherein an in situ generated carbonyl ylide reacts with activated double bonds.74 Thus, treatment of the trimethylsilylmethyl ether 152 with fluoride ion, in the presence of dimethyl fumarate generated the tetrahydrofurans 154 as essentially a 1 : 1 mixture of diastereomers at the two position, presumably through the intermediacy of the ylide 153.A cycloaddition approach to tetrahydrofurans has 146 147 (i) mCPBA (ii) 0% then NaBH, (iii) pTSA, 30% overall 148 &pc5H11 149 (i) Lewisacid (ii) reductant, 2745% 0 150 151 (PSO),TiCI,-NaBH, 30 : 1 lBSOTf-NaBH4 1 : 25 152 153 (81%) ~M-.cri""e Ar 154 Bums: Saturated oxygen heterocycles 197An alternative [3 + 21 cycloaddition approach to tetrahydrofurans has also been p ~ b l i s h e d . ~ ~ In this process, tin tetrachloride promoted addition of an ally1 silane such as 156 to the a-keto ester 155 gives the intermediate 157 which, after a 1,241icon shift, affords the tetrahydrofuran 158 in excellent yield and high diastereoselectivity.Functionalized allylsilanes have been used in an alternative synthesis of tetra hydro fur an^.^^ In this work, the oxocarbenium ions 161, formed by the reaction between the allylsilanes 159 and the acetals 160, undergo an intramolecular Sakurai reaction to generate the all-cis tetrahydrofurans 162 in moderate to excellent yield. YsiMe2Ph 156 SnCI, P h G o E t 0 CH&12. 82% r.t 155 157 Em&-- Ph - 0 ’SiMe2Ph 158 R2 ‘o+ I R’-R2 = alkyl 14143% R2P 162 Bridged tetrahydrofurans have been prepared via the intermediacy of oxonium ylides as shown for the synthesis of the compounds 165 and 166.77 In this reaction, the ether oxygen adds to the rhodium carbenoid generated from the diazo compound 163 and rhodium acetate, giving the oxonium ylide 164, which then undergoes a Stevens [ 1,2]-shift leading to the product tetrahydrofurans in the ratio shown.tetrahydrofurans such as 168 can be obtained from sugar-derived 1’- and ii-lactones bearing ring triflates by treatment with acidic lactone 167 was converted into the tetrahydrofuran 168 in 93% yield, with clean inversion occurring at the carbon bearing the triflate moiety. A similar base-induced rearrangement has also been reported for the synthesis of analogues of m~scarine.’~ Finally, highly functionalized chiral Thus, the L 163 1 165 166 15-19 : 1 OH 167 168 4.2 Dihydrofurans The dihydrobenzofuran 170, which is an intermediate in a formal synthesis of (+)-morphine, has been formed in one step from the bicycle 169 via a tandem intramolecular Heck insertion/ heterocyclization reaction disclosed by Overman and Hong.80 MeO P OH / 169 170 This report follows an earlier total synthesis of both antipodes of morphine by Overman’s group where the dihydrofuran 173 was constructed in a separate step after Heck-cyclization of 171, via ring-opening of an in situ prepared epoxide derived from 172, as depicted in Scheme 2.8’ In work also directed towards the synthesis of morphine, Parker and Fokas have reported that the aryl bromide 174 undergoes free-radical cascade cyclization to produce the tetracycle 175 exclusively as the diastereomer shown.82 Grubbs and his research group have continued their work on the use of transition metal complexes 198 Contemporary Oiganic Synthesis2,3-Dihydrofurans have been prepared via a different route, also through the intermediacy of carbene complexes, in a novel cyclization of homopropargylic alcohols.85 Thus, treatment of the homopropargyllic alcohol derivative 182 with molybdenum hexacarbonyl and trimethylamine N- oxide (TMNO) in ether and triethylamine as solvents generates the dihydrofuran 183 in 52% yield.An in situ generated free-carbene has also been used in the synthesis of 2,3-dihydrof~rans.~~ In this work, lithium trimethylsilyldiazomethane 185 reacts with P-trimethylsilyoxyketones 184 to generate 2,3-dihydrofurans 187, presumably through the intermediacy of the carbene 186.Me0 6Bn 171 1 e, PhMe, 120°C. 60% 10% Pd(OCOCF&oh3P)2 goMe OBn DBS-N f d d 3 172 - Mo(CO)s, TMNO EtsN, Et20 20 "C (0 FsB.OEt2. EtSH, 79% , CSA, CH2Cl2, 0°C (ii) OZN -Q"OsH 60% NO2 182 52% 183 DBS= $ overall 1 84 R' ,R* = altcyl R3 = alkyl, aryl 186 I DBS-N OH 1 73 TMS R3 187 Scheme 2 There have been numerous reports over the review period concerning the use of furan as the diene in Diels-Alder reactions, generating bridged dihydrofuran products for use in natural product synthesis. Corey and Loh report that the H H oxazaborolidene 189 is an effective catalyst for the enantioselective reaction of furan with 2-bromo- or ____t Bu3SnH Me0 0 AIBN, 140°C *'C02Me C02Me 6% 174 1 75 2-chloro-acrolein 188.87 The products 190 are in ring-closing metathesis reactions.Thus, they report that the ruthenium carbene 177 smoothly converts the acyclic diene 176 into the dihydrofuran 178 at room temperature,x3 and that the molybdenum carbene 180 catalyses the metathesis of enol ethers such as 179, leading to dihydrofurans such as 181.84 formed in greater than 98% yield, with excellent stereoselectivity (exolendo = 99/1), and high enantioselectivity. 0 =(" CHO + / \ JOTPh (yPh CHS12, -78°C > 98% 84% 190 X = Br 92% 8.8. X = CI 90% 8.8. 188 X = CI, Br 1 76 178 The Diels-Alder reaction between furan and the chiral cephalosporin triflate 191 generated the RO Ro:Mo+ ! Ph bridged dihydrofuran 193, presumably through in situ formation of the cyclic allene 192.88 179 pentane, r.t., 81% 181 the Diels-Alder reaction across the 3,4 position.Pha P h J o L R 5 CMe(CF& 180 c o Ph Interestingly, the corresponding sulfide undergoes Burns: Saturated oxygen heterocycles 1990- PtCHZCONH 0 COPPMB 191 192 I 0- C02PMB 193 De Meijere and his group have studied the Diels- Alder reaction between substituted furans and the cyclopropylidene 194 as part of a programme directed toward the synthesis of the sesquiterpene illudin M.'" For example, reaction of 194 with the furan 195 occurs with complete regioselectivity, to generate the ex0 and endo adducts 196 and 197 respectively in the ratio shown. 194 195 neat 20°C. 76% 1 e 2 M e + l o . Q"'" 196 197 1-5 1 An approach to the dihydrobenzofuran natural product r-viniferin which proceeds via a [5 + 21 cycloaddition has been reported by Engler et al."" In this work polarized, nucleophilic stilbenes such as 198 react with benzoquinones 199 in the presence of stannic chloride to give, via the carbocation intermediate 200, the trans product 201.Marshall and Pinney have disclosed a stereoselective synthesis of 2,5-dihydrofurans involving cyclization of a stereoselectively formed allenyl carbinol.'" The allenyl carbinols, such as 203, were formed with high stereoselectivity by SN2' addition of lithium dimethyl cuprate to chiral propargylic epoxides such as 202, and after selective silylation underwent smooth cyclization to 0 199 R=H,Me SnCI,, CH&12, -78°C Cl, 1 200 R = H 73% R=Me 82% I 201 dihydrofurans, as shown for the preparation of 204. Hydride, as opposed to cuprate addition has been used in the synthesis of the furan-containing macrocycles found in natural products of the pseudopterane family."* HO ;c" Me2CuU Hk > ___t THF 75% MOMOF" OMOM OH 202 203 d.e.> 95% (i) TBDMSCI, NEtS CH2Cb, 90% (ii) AgNO,, H@/acetone, 86% OTBDMS I \ 204 The manganic acetate promoted addition of P-diketones to enynes usually produces a mixture of furan and dihydrofuran products depending on substitution on the enyne. Melikyan et al. have now shown that the triple bond of enynes can be protected with the dicobalt hexacarbonyl group, thus forcing the reaction to occur exclusively at the alkene, as depicted for the synthesis of the dihydrofuran 207 from the complexed enyne 205 and the P-ketoester 206."-? Mellor and Mohammed have used manganic acetate promoted additions of P-diketones to enol ethers to generate spirocyclic corn pound^"^ and annulated dihydr~furans.'~ In this latter work, annulated dihydrofurans related to the aflatoxins have been prepared: for example, reaction of the dihydrofuran 208 with dimedone (209) produces the dihydrofuran 210.200 Contemporary Organic Synthesis0 205 206 (i) 4 eq. Mn(OAc)3, AcOH, 30°C 1 (ii) (NH4L$l(N0,)6 0 Mn(OAc)3 AcOH, 60°C 0 40% 208 209 21 0 An entirely different approach to the dihydrofuran ring of annulated dihydrofurans, employing an oxaza-Cope rearrangement has been reported by Civitello and Rapoport.'" In this work (Scheme 3) the chiral oxime 211 undergoes the acid-catalysed oxaza-Cope rearrangement to give the lactam 212, which can be converted into the dihydrofuran 213 by treatment with methanolic HCI.The annulated systems 214 and 215 are obtained in the ratio shown by debenzoylation and intramolecular acetal formation. OTs J: TsO 21 1 C02Me OBz &: MeOH HCI so TsO 0 TsO 21 3 (i) K&05MeOH (ii) HCI J 67% overall 212 + TsO TsO ' 0 'H 214 21 5 (1.6 1) Scheme 3 Trost and Shi have reported a synthesis of the natural product solamin 218 using a Ramberg- Backlund reaction of the in situ generated a-chlorosulfone derived from 216 to produce the dihydrofuran 217.'7 216 (i) Bu'OK, Bu'OH, CCI,, r.t., 65% (ii) TsOH, H@. EtOH, r.t.. 95% HO-. C12H23 A. HO 1 21 8 Finally, a base-induced rearrangement of 3-methylenetetrahydrofurans has been shown to be an efficient method for the preparation of fused 2,5-dihydrof~rans.'~ For example, treatment of the methylene tetrahydrofuran 219 with potassium t- butoxide in DMSO affords the product dihydrofuran 220 in good yield.&-& I 60-80 "C I 219 220 5 Six-membered rings 5.1 Tetrahydropyrans Of the numerous methods available for the synthesis of tetrahydropyrans, electrophile induced ring closure processes continue to be one of the favourite routes to this ring system. For example, while cyclization of the spirocyclic oxindole derivative 221 could not be effected under iodo- or bromo-etherification conditions, recourse was made to an intramolecular oxymercuration reaction which, after organomercurial reduction, gave the complex tetrahydropyran 222, an advanced intermediate in the synthesis of gelsemine."" In other work directed towards the synthesis of gelsemine Johnson and co-workers have formed the tetrahydropyran derivative 224 by treatment of the tricycle 223 with silver acetate and iodine.'"" Construction of the c-ring in forskolin has been examined by Welzel and his group, who have shown that while treatment of 225 with N-phenylseleno- Bums: Saturated oxygen heterocycles 201221 NMe2 I (ii) NaBH,, NaOH.CH2C12, EtOH 48% overall J 222 phthalimide gives the anti-product 226, treatment with mercury triflate leads to 227, the product of syn-addi t ion. 0- OH AgOAc, I2 .____L AcOH 0 AcO 223 224 (p '*, H 0 225 The dioxadecalin 231 has been prepared from the sugar-derived epoxide 230 via an acid-induced epoxide-ring opening, as part of the total synthesis of hemibrevetoxin B. been employed in the synthesis of related dioxadecalin ring systems.t043tos 6-endo Ring-closure has also been shown to operate in the epoxide ring- opening of cobalt-complexed propargylic epoxides. ' O 6For example, complexation of the trans- propargylic epoxide 232, followed by treatment with boron trifluoride etherate, gave almost exclusively the cis-tetrahydropyran 233. Similar approaches have 230 M e 0 2 C d OBn H H H 231 (i) CO~(CO)~, CH&I,, r.t. tii) F3B.0Et2, CH2CI2, -78°C 96% ph' 232 233 Intramolecular hetero-Michael addition has also been used for the preparation of tetrahydropyrans as shown for the preparation of the dioxadecalin 235 from the a,/?-unsaturated ester 234.1°7 A fluoride ion induced Michael addition has been used as the ring-forming step in an asymmetric synthesis of the cholesterol biosynthesis inhibitor decarestrictine L, as shown in the transformation of the acyclic ketone 236 into the tetrahydropyran 237.1°8 NaH THF, -36°C ZQWe HgOTf _____c 226 227 A number of research groups have used intramolecular epoxide-ring opening reactions to form complex tetrahydropyrans in the synthesis of natural products. Thus, Roush and Marron have prepared the tetrahydropyran 229 from the epoxide 228 via fluoride ion induced desilylation, as part of a programme directed toward the synthesis of the mycalamide family of antibiotics.lo' OTBDPS L_ I MeCN 9WO OH C>Me 228 229 234 235 p O M 60°C 11% 236 O A 237 An alternative route to this ring substitution has been reported by Clark and Whitlock who have demonstrated that copper-catalysed decomposition of the diazoketone 238 affords the tetrahydropyrans 239 and 240 in the ratio shown."'" The use of 202 Contemporary Organic SynthesisY l copper hexafluoroacetylacetonate in this process had been shown in previous work to promote insertion of the in situ formed copper carbenoid into the allyl ether oxygen in preference to CH- MeAICI,, 246 -78OC - n=m CH2C12 insertion.' lo 245 63% 247 238 CU(CF&OCHCOCF& CHS12, A, 6890 I --- + -*-ate H H 239 240 77 23 PhMe/pentane.-100"C, 70-8596 OH R , XI\\ NaHiDMSO- : - THF V ' C I 7 H 5 % 249 (-98% e.e.) R = alkyl 250 (8598% e.e.) As part of an investigation into tetraene cyclizations, Takacs and Chandramouli have shown 5.2 Dihydropyrans that treatment of the tetraene 241 with catalytic palladium( 1 1 ) leads to the olefinic tetrahydropyran 242 in good yield.' ' ' Palladium catalysis has also been used in a highly stereoselective preparation of spirocyclic tetrahydropyrans from dienes, eg.in the transformation of the diene 243 into the tetrahydropyran 244. ' " E : F 3 \ \ 24 1 Pd(OAc)z, PPh3 THF, 65"C, 82% 1 Et02C E t 0 2 G \/.*-A 242 0 Li&03 HOAclacetone 243 81 % 244 Lactols have been shown to undergo an intermolecular ene reaction generating trans- 2,6-disubstituted tetrahydropyrans with high stereoseleetivity.' I Thus, exposure of the lactol ether 245 to methyl aluminium dichloride followed by addition of the olefin 246 gave the truns product 247 in good yield. cis-2,3-Disubstituted tetrahydropyrans 250 have been prepared in high optical purity from the chlorohydrins 249, themselves prepared in high optical purity by the reaction between chiral allyl boronates 248 and aldehydes.' l 4 There have been numerous reports over the review period concerning the synthesis of dihydropyrans via hetero Diels-Alder reactions, and a review containing 1 1 1 references concerned with the asymmetric variant of this reaction has been published.' I s Yamamoto and his research group have shown that in situ prepared borane complexes derived from tartaric acid (such as 252) catalyse the reaction of oxygenated butadienes such as 251 with benzaldehyde to give pyrones, e.g. 253, in high optical purity after treatment with acid.' I 6 Motoyama and Mikami have demonstrated that the boron complex 256 also catalyses the Diels-Alder reaction of siloxydiene 254 and methyl glyoxylate (255), giving the pyrone 257, again after acid treatment of the adduct, in good yield and in high optical purity.'" OMe 251 + 252 c MeCH2CN, -78°C PhCHo (ii) CF3CO&l, 950/.0 QPh 253 (97% e.e.) A stereoselective synthesis of precursors to the natural products robustadial A and B has been published, which employs a regioselective hetero Diels-Alder reaction. ' '' Thus, Knoevenagel condensation of the 1,3-dione 258 and the aldehyde 259, in the presence of (S)-P-pinene (261) affords the spirocyclic product 262, presumably through the intermediate 260. Tietze and his co-workers have used a similar approach in the synthesis of the tricycles 265 from the reaction of aldehydes 263 and the dione 264, the trans products always being formed as the major isomer.'" Burns: Saturated oxygen heterocycles 203p” acrolein, 269) and ao-methylene compounds such as 270.12’ TMSO 258 PhMe, -78°C .‘C02Me 254 + 0 (ii) CF3CO$i,69% 0 II HKC02Me 255 To Me0& 0 258 KOAc + ____e 3A sieves HOAc 259 257 (94% e.e.) Ma2cY 260 IB 1 261 (80% overall) 262 263 264 R = alkyl 265 The highly stereoselective hetero Diels-Alder reactions of sulfonyl-a, P-unsaturated alkenes have been published by Wada et aZ.120 They have shown that various Lewis acids catalyse the reaction of a,B-unsaturated alkenes 266 with ethyl vinyl ether 267, as shown for the synthesis of 268.0 R \ 4 S O 2 P h R = alkyl 268 Spirocyclic dihydropyrans, such as 271, have been formed with high stereoselectivity by the Lewis acid catalysed reaction of a, P-unsaturated aldehydes (e.g.271 Samarium diiodide has also been shown to catalyse hetero Diels-Alder reactions,’22 and recent work by Grieco and Moher has demonstrated that lithium perchlorate in diethyl ether promotes the reaction between amino aldehydes and oxygenated dienes. 123 For example, reaction of the aldehyde 272 and the diene 273 leads to the pyrone after acid treatment, predominantly as the threo isomer 274 shown. Synthesis of the dihydropyrans 277 and 278 has been achieved in excellent yield by hetero Diels- Alder reaction in water between the diene 275 and glyoxylic acid 276.124 4 C H O HNBoc ( i ) 0.5MLc104, Etg, r.t. 74% 272 + OMe (ii) HCI (aq.) 0 HNBoc AOTBDMS 273 274 + 100°C -100% C02H 277 278 64 36 A number of significant publications concerning alternative routes to dihydropyrans and related systems have also been published recently.Paterson and Smith have prepared the chiral pyrone 280 from the alcohol 279 by a Lewis acid promoted Michael addition-elimination procedure125 as part of a total synthesis of the marine macrolide (-)-preswinholide An efficient synthesis of trans-3-hydroxyflavanones 282 from a base- promoted ring closure of the epoxides 281 has been reported, the epoxides themselves coming from dimethyl dioxirane epoxidation of the corresponding olefins. 127 Mark6 and Bayston have reported on the use of the intramolecular silyl-modified Sakurai reaction in the synthesis of 3,4-dihydro~yrans.’~” Thus, a trimethylsilyl triflate induced reaction between the 204 Contemporary Organic SynthesisBzoTc' 0 279 TMSOTf P&NEI CH2C12 -78"C+20"C 61 % BzoT 0 0 281 R = alkyl, alkoxy, chloro Bu4NOH CH&I+i20.r.t. I 0 282 280 olefin 283 and the aldehyde 284 generates the dihydropyran 285 solely as the cis isomer, in excellent yield. T M S T A TMSO 283 + dH TMSOTf -78°C +20°C 87% c CH$b CP 285 284 Hoveyda and co-workers have reported a very useful kinetic resolution of 3,4-dihydropyrans using a zirconium-mediated carbomagnesation process. '29 For example, when the racemic pyran 286 is treated with ethylmagnesium bromide and the chiral zirconium complex ( EBTHI)ZrCI2, recovered starting material of exceptionally high optical purity (287) is obtained when the reaction is stopped after 60% conversion. om 286 (R)-(EBTHI)ZrCI, EtMgCI, THF I om 287 (> 99% e.e.) 2,3-Dihydropyrans have been prepared from sugar derived lactones via Grignard additions to the lactone carbonyl groups and subsequent dehydration of the hemiketals so formed, e.g.the preparation of 289 from the lactone 288.130 A two-step route to 6-chiral-2,3-dihydropyrans has been reported by Jacobs and Gopalan, also involving dehydration of an intermediate hemiketal.l3I For example, deprotonation of the chiral sulfone 290 generated the lacto1291 (as a mixture of diastereomers), which was then dehydrated to give the dihydropyran 292 in good yield. (i) PhMgBr, THF OBn CH2C12, r.t. 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ISSN:1350-4894    

DOI:10.1039/CO9950200189

出版商:RSC    

年代:1995

数据来源: RSC