摘要:

Contemporary Organic Synthesis Editorial Board Professor G. Pattenden, FRS (Chairman), University of Nottingham Professor P. D. Bailey, Heriot- Watt University Dr S. E. Gibson (neC Thomas), Imperial College of Science, Technology, and Medicine Professor P. J. Kocienski, University of Southampton Professor C. J. Moody, Loughborough University of Technology Professor E. J. Thomas, University of Manchester International Advisory Board Professor E. J. Corey, Harvard University Professor S. Hanessian, Universitk de Montrkal Professor M. Julia, Universitk de Paris XI (Paris-Sud) Professor P. D. Magnus, University of 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, 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. 1995 subscription rate: EEA f165, USA $303, Canada El73 (plus GST), Rest of the World f173. Contemporary Organic Synthesis is published 6 times a year in February, April, June, August, October, 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, 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 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 (nee Thomas), Imperial College of Science, Technology, and Medicine Professor P. J. Kocienski, University of Southampton Professor C. J. Moody, Loughborough University of Technology Professor E. J. Thomas, University of Manchester International Advisory Board Professor E. J. Corey, Harvard University Professor S. Hanessian, Universiti de Montrial Professor M. Julia, Universiti de Paris XI (Paris-Sud) Professor P. D. Magnus, University of 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, 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 ZHN, England. 1995 subscription rate: EEA &165, USA $303, Canada El73 (plus GST), Rest of the World f173. Contemporary Organic Synthesis is published 6 times a year in February, April, June, August, October, 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, 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 in Great Britain by Unicus Graphics Ltd Printed in Great Britain by Whitstable Litho Ltd

ISSN:1350-4894    

DOI:10.1039/CO99502FX025

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/CO995020X027

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

ISSN 1350-4894 COGSE6 2 (6) 365-462 (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 6 CONTENTS ethylene lycol, \ PhMe. C8A &2 Et ** Et-DUPHOS H 7140% yield H Pd(PPh& Tf 1 Tf Dispiroketals: A new functional group for organic synthesis By Steven V. Ley, Robert Downham, Paul J. Edwards, Jean E. Innes and Martin Woods 365 Methods for the asymmetric preparation of amines By Anders Johansson Reviewing the literature published up to January 1995 393 Synthesis of thiols, sulfides, sulfoxides and sulfones By Christopher M. Rayner Reviewing the literature published between October 1993 and February 1995 409 Saturated and unsaturated hydrocarbons 441 By Richard I? C. Cousins Reviewing the literature published between September 1993 and December 1994Cumulative Contents of Volume 2 Number 1 1 Aromatic heterocycles as intermediates in natural product synthesis (up to the end of 1993) Michael Shipman 19 The hydrometallation, carbometallation, and metallometallation of heteroalkynes (up to August 1994) Sharon Casson and Philip Kocienski 35 Serotonin, sumatriptan, and the management of migraine Alexander Oxford 43 Stoichiometric organotransition metal complexes in organic synthesis ( 2 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 ( 2 January 1993 to 31 July 1994) T.Harrison and T. Laduwahetty 121 Hypervalent iodine in organic synthesis: a-functionalization of carbonyl compounds (up to February 2995) Om Prakash, Neena Saini, Madan I? Tanwar, and M. Moriarty Number 3 133 Saturated and unsaturated lactones ( 2 January 1993 to 31 July 1994) T. Laduwahetty 151 Aldehydes and ketones (July 1993 to September 1994) Patrick G. Steel 173 a-Cation equivalents of amino acids (up to the end of 2994) Patrick D. Bailey, Andrew N. Boa, and Joanne Clayson 189 Saturated oxygen heterocycles (1 April 1993 to 30 September 2994) Christopher J. Burns Number 4 209 Saturated nitrogen heterocycles (June 1993 to December 1994) Timothy Harrison 225 Synthesis and use of cyclic peroxides (January 1992 to January 1993) K.J. McCullough 251 Recent advances in organofluorine chemistry (January 1992 to April 1995) Jonathan M. Percy 269 Amines and amides (2994) Michael North Number 5 289 Synthetic developments in host-guest chemistry (1994) James Dowden, Jeremy D. Kilburn, and Paul Wright 315 Protecting groups (2994) Krzysztof Jarowicki and Philip Kocienski 337 Synthesis of aromatic heterocycles (Jub 1993 to February 1995) Thomas L. Gilchrist 357 Nitro and related compounds (December 1993 to May 1995) Graeme Robertson Number 6 365 Dispiroketals: A new functional group for organic synthesis Steven V. Ley, Robert Downham, Paul J. Edwards, Jean E. Innes and Martin Woods 393 Methods for the asymmetric preparation of amines (up to January 1995) Anders Johansson 409 Synthesis of thiols, sulfides, sulfoxides and sulfones (October 1993 to February 1995) Christopher M. Rayner 441 Saturated and unsaturated hydrocarbons (September 1993 to December 1994) Richard I? C. Cousins Articles that will appear in forthcoming issues include Stoichiometric applications of organotransition metal complexes in organic synthesis Timothy J. Donohoe Saturated and partially unsaturated carbocycles Christopher D. J. Boden and Gerald Pattenden The enediyne and dienediyne based antitumour antbiotics, Part I: Methodology and strategies for total synthesis and construction of bioactive analogues HervC Lhermitte and David S. Grierson Alcohols, ethers and phenols C. S. Hau, Ashley N. Jarvis and J. B. Sweeney The discovery of fluconazole K. Richardson Organic halides Stephen R Marsden

ISSN:1350-4894    

DOI:10.1039/CO99502FP029

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/CO99502BX031

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

Dispiroketals: A new functional group for organic synthesis STEVEN V. LEY," ROBERT DOWNHAM, PAUL J. EDWARDS, JEAN E. INNES and MARTIN WOODS Department of Chemist4 University of Cambridge, Lensfield Road, Cambridge, CB2 1EW UK 1 2 3 3.1 3.2 3.3 4 5 5.1 5.2 5.3 6 7 7.1 7.2 7.3 7.4 8 9 10 11 12 Introduction Vicinal diol protection Use of glyceraldehyde dispiroketals Preparation Reactions with carbon nucleophiles Miscellaneous reactions Preparation of chiral bis-dihydropyrans Enantioselective protection of vicinal diols Reaction with glycerol Reaction with other acyclic meso polyols Reaction with cyclic meso polyols Thermodynamic resolution of diols Protection of a-hydroxyacids and alkylation of the dispiroketal products Introduction Protection of (S)-lactic acid Alkylation reactions of a non-racemic equivalent of a lactic acid enolate A non-racemic equivalent of a glycolic acid enolate Preparation and use of dihydroxy dispiroketals as chiral auxiliaries Protection of vicinal diols in carbohydrates Use in oligosaccharide synthesis Summary and conclusions References 1 Introduction Occasionally in science observations are made which open up whole new areas of research.In 1991 we were fortunate enough to recognise one of these opportunities which has led us into some fascinating and useful new chemistry. The work centres on 1,8,13,16-tetraoxadispiro[5.0.5.4] hexadecanes, 'dispiroketals', as an easily decorated, well-defined and rigid skeletal motif which can be used for a wide range of synthetic applications (Figure 1). In addition to this appealing architecture, the benefits of the dispiroketal unit include its relatively low molecular weight, the potential for a wide range of substitution patterns, and its easy preparation.The key feature, however, is the control that can be achieved at the two spiro centres during dispiroketal formation owing to the operation of multiple Figure 1 anomeric effects',2 favouring the formation of a single diastereoisomeric product. been investigated the most convenient turns out to be the reaction of bis-dihydropyrans with vicinal diols. Preparation of the parent system 1, for example, is achieved in good yield by reaction of bis-dihydropyran 2 with ethylene glycol in refluxing toluene containing catalytic camphorsulfonic acid (CSA) (Scheme l).3 Although compound 2 and a limited range of similar derivatives had in fact been prepared previ~usly,~ they had not been utilized as reagents for organic synthesis.We find that the bis- dihydropyran 2 can be conveniently obtained in excellent yield by oxidative homocoupling of dihydropyran itself using tert-butyllithium to form the anion followed by treatment with catalytic PdC12(PPh3)2 and CuC12 in THF at 0 "C (Scheme 1). This reaction can be scaled up easily and we routinely run reactions on a 100 g scale. X-Ray crystal structure determination of 1 confirmed the identity of the product of this highly diastereoselective reaction; none of the alternative diastereoisomers 3 or 4, where anomeric Of the several routes to these molecules that have 2 1 Reagents: (i) Bu'Li (1 eq.), THF, followed by addition of Pdcl~(PPh~)~ (cat.), CuCI2 (1 eq.), 0 "C, 80%; (ii) Ethylene glycol (5 eq.), PhMe, CSA (cat.), reflux, 73%.Scheme 1 Ley, Downham, Edwards, lnnes and Woods: Dispiroketals: A new functional group for organic synthesis 3653 Figure 2 4 stabilization at the spiro centres is decreased, were observed in the reaction (Figure 2). Pure bis-dihydropyran 2 is a white and relatively stable crystalline solid. It is, however, sensitive to hydrolysis as would be expected of an enol ether and is best stored in the long term under an inert atmosphere at - 10 "C. It may also be stored in toluene solution containing trace amounts of galvinoxyl as a stabilizer for long periods of time at room temperature without noticeable decomposition. In the above preparation of 2 we relied upon an oxidative homocoupling reaction of 2-lithio dihydropyran anions. However, we can also prepare unsymmetrical dienes by heterocoupling reactions using vinyl stannanes and enol triflates.For example, the dienes 5 and 6 are obtained using Pd(TFP), to effect the coupling (Scheme 2). 5 6 8 Reagents: (i) Pd2(dba)3 (0.01 eq.), trifurylphosphine (0.04 eq.), LiCl (1 eq.), NMP, r.t., slow addition of triflate, 51%; (ii) ethylene glycol (10 eq.), CSA (cat.), PhMe, reflux, 75%; (iii) Pdp(dba), (0.01 eq.), trifurylphosphine (0.04 eq.), Licl (1 eq.), NMP, r.t., slow addition of triflate, 40%; (iv) ethylene glycol (10 eq.), CSA (cat.), PhMe, reflux, 10%. Scheme 2 The diene 5 was stable and reacts with ethylene glycol to give the corresponding dispiroketal7 in 75% yield.On the other hand 6 was unstable and reacts only poorly with ethylene glycol to afford the spiroketal 8 (Scheme 2). This review will encompass the applications of these dispiroketals in organic synthesis to date and discuss some new chemistry of these systems which has not been previously reported. 2 Vicinal diol protection There are a number of useful ways of achieving 1,2-diol protection' but there is a need for new methods which afford higher levels of selectivity or stability. Armed with the basic dispiroketal formation described above we considered the more general use of 2 as an agent for protecting vicinal diols as dispiroketals. Indeed we found that the bis- dihydropyran 2 reacted with glycerol 9 in toluene containing catalytic acid to give 15 as essentially the only product of the reaction.Pleasingly, other diols and dithiols 10-14 were equally successful and gave the corresponding dispiroketal ('dispoke') protected products 16 to 20 (Table 1). These results illustrate the potential of dispoke protection. Entry 1 shows that bis-dihydropyran reacts with glycerol to give a single diastereoisomer. This product has full anomeric control at the spiro centres, but the selectivity does not stop there; additionally, the hydroxymethylene side-chain has adopted an equatorial orientation. As with the control of the anomeric centres, this presumably reflects the thermodynamic control that is operating in the reaction giving the most stable product rather than the alternative, where the side-chain would be in the more congested axial position. Entries 1, 5 and 6 indicate that where the possibility of 1,2- and 1,3-protection patterns co- exist, the preference for six-membered ring formation enables dispoke to choose the former.Literature methods for the protection of the vicinal diol component in (S)-butane 1,2,4-triol 13 are less selective, giving for example a ratio of only 9 : 1 in favour of the 1,2 product when acetonide protection is employed." Once again dispoke protection gives, in almost quantitative yield, a single diastereoisomer. This result represents an example of chirality multiplication through the use of anomeric efsects since the starting material which contained one stereogenic centre has been transformed to a product which possesses three.When 1,3-diol protection is the only option, as with propane- 1,3-diol itself, we find that the corresponding dispoke adduct is formed but in only 15% yield,3 illustrating the instability of such a dispoke product. The natural extension of these favourable results was to try dispoke protection on carbohydrates and Entry 6 of Table 1 begins to explore this; we see that dispoke meets the challenge since the 1,2-diequatorial diol has reacted, to give a stable dispoke product, in preference to substitution on the normally more reactive primary hydroxy group. 366 Contemporary Organic SynthesisEntry Did Dispoke Product Yiild (%) Ref. OH 1 HO&OH 98 3 99 64 64 72 9 15 2 6 10 16 3 7 HO 11 17 H S L H 12 3 4 18 OH OH HO A J 5 8 13 19 $23 0 6 To& 64 9 14 20 This was clearly a major growth area in the project and the ensuing work is described later (see Sections 9 and 10).0 3 Use of glyceraldehyde dispiroketals 3.1 Preparation D-Glyceraldehyde, especially as its isopropylidine derivative 21 (Figure 3), is an important and widely used three-carbon chiral building block for organic synthesis. It does, however, suffer some limitations as it is prone to racemization, polymerization, and hydrate formation. Moreover, the stereocontrolled addition of carbon nucleophiles, especially methyl groups, to 21 is disappointing. While good selectivity can be achieved using principles of chelation control to afford syn products, a new method is required to achieve an anti stereochemical relationship. We therefore sought to assess the reactivity towards carbon nucleophiles of our dispiroketal derivative, 22 (shown in Figure 3, where the wedging on the pyran ring indicates enantiomeric enrichment) against that of [2,3]-O-isopropylidene D- glyceralde hyde, 21 .* 22 21 Figure 3 It was anticipated that 22 would be more configurationally stable than 21 owing to the locking of the aldehyde in an equatorial position.In addition 22 should be less prone to polymerization because of the bulk of the protecting group. We hoped that since 22 contains three stereogenic centres, compared with one in 21, improved facial selectivity might be observed during carbonyl group addition reactions. The preparation of 22 can be achieved by two routes. The first of these uses inexpensive mannitol as a starting material but involves an inelegant acylation step to facilitate purification (Scheme 3).This route is interesting because it demonstrates the use of the dithiadioxadispiroketal 18 (Table 1) to Ley, Downham, Edwards, Innes and Woods: Dispiroketals: A new functional group for organic synthesis 36718 = 19 Reagents: (i) Dithiadioxadispiroketall8, Met, NaHCO3, MeCN; (ii) AqO, pyr ; (iii) NaOMe, MeOH (40% over three steps); (iv) Na104, H20, Et20, 99%; (v) TsCl (1 eq.), pyr, 92%; (vi) KOBU' (1.2 eq.), DMSO, 83%; (vii) 03, PPh3, 92% Scheme 3 transfer the dispiro function to mannitol in the presence of methyl iodide under basic conditions. The second route utilized the dispoke-protected (S)- butane-1,2,4-triol derivative 19 discussed earlier. This was readily converted into 22 via tosylation, elimination, and ozonolysis (Scheme 3).As expected, the dispiroketal aldehyde 22 formed in this way was far less volatile than 21 and was very much more stable. Indeed samples have been stored at 4 "C for over one year without noticeable decomposition. Compound 22 does show a tendency to hydrate, but the process may be reversed by Dean-Stark removal of water with toluene prior to use in synthesis. 3.2 Reactions with carbon nucleophiles We then turned our attention to the addition of carbon nucleophiles to 22 to examine the selectivity for the preferential formation of the anti versus the syn product.' In Table 2 we compare the results obtained for additions to 22 with corresponding literature results for additions to 21. The results demonstrate the ability of dispoke protection to influence the stereochemistry of the product. Entries 1,3,4, and 6 show a consistent anti selectivity for methylation, which seems to be independent of reagent choice.The titanium reagent (Entry 7) gives excellent anti selectivity, comparable to that achieved with dibenzyl or benzyl-tert-butyldime t hylsilyl ethers of glyceraldehyde."~'2 Addition of vinyl magnesium bromide (Entry 8) gives good anti selectivity in contrast to previous reported work.13 Interestingly, ethynyl Grignard addition proceeds with opposite selectivity when glyceraldehyde is protected as the dispoke derivative 22 compared to isopropylidene glyceraldehyde 21 where a slight syn preference was 0b~erved.l~ It can be seen that the addition of most reagents to 22 leads to anti adducts as predicted by both Felkin's non-chelation controlled mode115>16 and the fl or a, p coordination models proposed for 21.'' In the dispoke derivative 22 the rigidly defined geometry of the dioxane ring is likely to negate the possibility of fl-coordination, due to greatly Table 2 Entry Reagent Lit.antilsyn Conditions (solvent, temp., Yield antilsyn time, method&h) (%)" Ratio Ratiob 1 2 3 4 5 6 7 8 9 10 11 12 MeLi MeLi MeMgCl MeMgBr MezCuLiMezS MeCuMgBrMe2S MeTi (OPi), CHz=CHMgBr (CH,==CH),Zn E t hyn ylMgBr AllylMgBr EtMgBr EtzO/THF, -78 "C, 22 h, A EtZOmF, 25 "C, 12 h, A THF, -78 "C, 24 h, A THF, -78 "C, 22 h, A Et20, -78 "C, 20 h, B EtzO, -78 "C, 20 h, B EtZO/C6H14, -40 "C, 20 h, B THF, -78 "C, 4 h, A THF, 25 "C, 48 h, A THF, -78 "C, 5 h, A THF, -78 "C, 18 h, A THF, -78 "C, 6 h, A 82 78 92 62 69 85 87 56 84 65 89 62 82 : 18' 67 : 33' 81 : 1Y 79 : 21" 12:88' 82: 18' 93 : 7c 91:9 67 : 33d 89: lld 68 : 32" 73 : 27" 60 : 40 - - 73 : 27 18:82 65 : 35 70 : 30 60 : 40f 44:56 60 : 40 - - ~~~~~~~~~ ~~ ~ "Yield corrected for unreacted starting material.bLiterature ratio obtained for addition to 2,3-0-isopropylidene-~- glyceraldehyde. 'Yield and ratio by gas chromatography of crude material. dYield of isolated product, ratio by high field NMR. "Yield of isolated product, ratio by gas chromatography on acetylated product. fVinyl magnesium chloride at 20-60 "C. method A: To a stirred solution of 22 (1 eq.), in the indicated solvent (Table 2), cooled to -78 "C, under argon, was added, dropwise, a solution of the organometallic reagent (10-20 eq.) and the resulting mixture was kept at - 78 "C for 5-24 h.The reaction was quenched at - 78 "C by addition of saturated aqueous ammonium chloride solution. Ether was added and the organic phase washed twice with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude compounds were purified by flash chromatography (eluent: etherlpetroleum ether, 1 : 1). hMethod B: To a stirred solution of the organometallic reagent (10-20 eq.) cooled to -78 "C under argon was added dropwise a solution of 22 (1 eq.), and the resulting mixture was stirred at -78 "C for 5-24 h. The isolation procedure was the same as that given above for Method A. 368 Contemporary Organic Synthesisincreased interatomic distances between the 4 Preparation of chiral bis-dihydropyrans carbonyl oxygen and the P-oxygen.Molecular modelling studies (MM2)18 indicate that although axially disposed 6 oxygen atoms could theoretically form a chelated complex this would involve considerable strain. This suggests that the anti selectivity shown by the aldehyde 22 is mainly due to the large steric bulk of the dispiroketal group. 3.3 Miscellaneous reactions During the above studies we observed reactions which have not been previously published but which might be of some general interest. For example, reduction of 22 with sodium borohydride yields the corresponding alcohol 15 (Figure 4, see also Table l).19 This alcohol is synthetically equivalent to solketal23 (isopropylidene glycerol) (Figure 4).However, whereas enantiopure solketal needs to be stored at low temperatures or used immediately, to prevent racemization through rapid acetonide migration, the spiroketal derivative 15 is stable (> 1 year) at room temperature. HO 15 Figure 4 HO)\rO O-f- 23 28 (PS,P'S)-DMDHP 29 (2R, 2'R)-DMDHP We also find that derivative 24 is stable and involatile whereas by contrast 25 is extremely volatile and difficult to handle (Figure 5). Compound 26 shows superior stability towards p-elimination over the corresponding compound 27 (Figure 6); it is readily obtained from 19 (Table 1) by oxidation with tetra-n-propylammonium perrut henate (TPAP) .*O 24 Figure 5 In order to develop the chemistry of dispiroketals further we reasoned that the introduction of substituents on the diene would give us the opportunity to use chirality to achieve further control.During formation of dispiroketals, such substituents should have a preference for the equatorial orientation in the product; if these substituted centres were homochiral, this preference for the equatorial position should constrain the chirality at the two dispiroketal anomeric centres, leading to formation of a single diastereoisomeric product. An additional advantage is that the appended side-chains may facilitate alternative methods for removal of the dispiroketal protection which must be accomplished after the desired synthetic manipulations have been achieved. We therefore devised synthetic routes to homochiral bis- dihydropyrans such as 28-34 (Figure 7).The shorthand notation which we use for these compounds relates to the configuration and substitution in the bis-dihydropyrans (DHPs). Thus for 28, 29, and 34, 'DMDHP' refers to dimethyl bis- dihydropyran. The diphenyl substitution in 30 and 31 is indicated by 'DP' and diallyl substitution, as in 32 and 33, by 'DA', etc. The phenyl group in 30 and 30 (2R, 2'R)-DPDHP 31 (2S, 2'S)-DPDHP 32 (2R, 2'R)-DADHP T o O-f- 25 33 (2S, 2'S)-DADHP 26 27 Figure 6 I I 34 (4S, 4'S)-DMDHP Figure 7 Ley, Downham, Edwards, Innes and Woods: Dispiroketals: A new functional group for organic synthesis 36931 was placed in this position to make possible later removal of the corresponding dispoke derivative by a hydrogenolysis or benzylic cleavage procedure. Likewise in 32 and 33 the ally1 functional group was chosen as a chiral controlling substituent which could also facilitate removal of the dispoke adduct by an ozonolysislP-elimination pathway (Section 9, Scheme 40).dihydropyrans have been developed. For example, compound 28 was synthesized starting from (S)- ethyl lactate as the initial source of chirality.2' This was converted into an intermediate phenylsulfonyl- tetrahydropyran 35 (Scheme 4) since we had shown previouslf2 that use of phenylsulfones of this type was an attractive way to stabilize anions at anomeric centres. Indeed anion formation and reaction with tributyltin chloride gave vinyl stannane 36 after spontaneous elimination of benzenesulfinic acid on warming. Transmetallation and oxidative cross- coupling produced the desired diene 28 (Scheme 4).Several routes to these homochiral bis- 28 36 35 Reagents: (i) TBSCI, Imidazole, 98%; (ii) DIBAL-H, DCM, -78 OC; (iii) 2-( 1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide, KHMDS, THF, 0 OC, 79% over two steps; (iv) HdP102, EtOAc, 98%; (v) TBAF, THF, 94%; (vi) PhSOeH, CaCI2, DCM, 89% (vii) Bu"Li, THF, -78 OC; then Bu3SnCI, -20 OC to r.t.; then DIPEA, CHCI3,70 OC, 75%; (viii) Bu"Li, THF, -78 OC; 6 molyo PdC12(MeCN)2, CuCI2, -78 to 0 OC; NH4CVNH3,W %. Scheme 4 The opposite enantiomer 29 was available by the The route to (2R, 2'R)-DPDHP23 30 starts from equivalent route starting from @)-methyl lactate. the known keto ester 37 (Scheme 5) which is obtained either by addition of phenylmagnesium bromide to glutaric anhydride" and subsequent esterification, or more conventionally by Friedel- Crafts acylation of benzene with glutaric anhydride,25 again followed by esterification.Asymmetric reduction of the prochiral carbonyl group in 37 was investigated using a variety of methods the best of which turned out to be the use of oxazaborolidines.26 Application of the catalytic system consisting of borane methyl sulfide and the oxazaborolidine 38 gave the hydroxyester 39 in 83% e.e., which upon lactonization gave 40. This was converted into the sulfone 41 by reduction with 37 Ph o S O z P h 42 40 Reagents: (i) 0.7 eq. BMS, 10 md% 38, THF, -15 OC; (ii) 10 mol% CSA, DCM, 90% over two steps; (iii) DIBAL-H, PhMe, -78 OC; (w) PhS02H, CaCI2, DCM, 7588% over two steps; (v) Bu"Li, THF, -78 OC; then Bu,SnCI, -78 OC to r.t.; then DIPEA, CHC13, 70 OC, 2 h, 72%; (vii Bunti, M F , -78 OC then PdCh(MeCN)2 (Cat.), CUCI~, -78 to 0 OC, NH&IMH3,60%.Scheme 5 DIBAL-H and treatment with benzenesulfinic acid in the presence of calcium chloride.27 This material was then transformed into diene 30 via the vinyl stannane 42 and oxidative homocoupling route previously established (Scheme 5). Based upon a statistical distribution of coupled products and having started from the 83% enantiomerically enriched compound 42, the e.e. of 30 was estimated to be 98%, assuming equal rates of coupling of R to R, S to S, and R to S. The optical enhancement in the formation of 30 is at the cost of formation of some meso product which is produced by coupling of the major @)-configured stannane with the minor epimeric (S)-configured material.The prohibitive cost of the enantiomer of the catalyst 38 required for the synthesis of the enantiomeric (2S, 2'S)-DPDHP 31 caused us to investigate an alternative. It was found that the oxazaborolidine 4328 gave satisfactory results, affording 44 with an e.e. of 87%, although some over-reduction to the diol45 was also observed. It was also found that the lactone 44 could be recrystallized to improve the e.e. to 99.1% as indicated by chiral phase GC analysis. This was converted into 31 following the usual strategy (Scheme 6).23 has been subsequently developed.29 Reduction of ketoester 37 with ( - )-B-chlorodiisopino- campheylborane ( - )-DIP-C1, a stoichiometric asymmetric reducing agent,30 saponification to assist purification, and reacidification with concommitant lact~nization~' affords 44 directly, in 88% yield with an e.e.of 89%. Chromatographic purification is avoided, as the product is then recrystallized to A second, shorter route to (2S, 2's)-DPDHP 31 370 Contemporary Organic Synthesis31 Reagents: (i) 0.7 eq. EMS, 10 mot% 43, THF, r.t., 1 h. (ii) CSA, DCM, 44 47%, 45 11%. (iii) reagents and conditions as Scheme 5. Scheme 6 enhance its optical purity as before. The lactone is then converted into its enol triflate by deprotonation with lithium hexamethyldisilazide and treatment with N-phenyltriflimide. To the crude product is added hexamethylditin, lithium chloride, and catalytic tetrakis(tripheny1phosphine) palladium(o), conditions employed by Kocienski to prepare vinyl stannanes from 8-la~tones.~~ However, by employing only 0.5 equivalents of hexamethylditin we then have, theoretically, a 1 : 1 mixture of vinyl stannane 46 and unreacted enol triflate, which undergoes a Stille-type coupling33 affording (2S, 2's)-DPDHP 31 directly. In practice, enol triflate formation is not quantitative, hence 31 is obtained in 58% yield along with 19% of vinyl stannane 46 (Scheme 7).Ph L C O , M e Ph= 37 46 31 Reagents: (i) (-)-DlP-Cl, THF, -15 OC; NaOH (aq.) then neutralise (conc. HCI); CSA (cat.), PhMe, 88%, 89% e.e.; (ii) LHMDS, DMPU, THF, -78 "C; then PhN(Tf)2, -78 to 0 "C; then 3 mot% Pd(PPh3)4, Me,Sn, (0.5 eq.), LiCl(6 eq.), reflux, 16 h, 31 58%, 46 19%. Scheme 7 The C2-symmetric allyl substituted bis- dihydropyrans 32 and 33 were accessed by a different process, involving a lipase resolution, since the asymmetric reduction methods described above are not applicable to systems where there is relatively little differentiation in the substitution of the prochiral substrates.The racemic allyl lactone 47, readily available from ~yclopentanone,~~ was hydrolysed in pH 7.2 buffer with Hog Liver Esterase (HLE) by pH stat-controlled addition of 2M sodium hydroxide to give lactone 48 and the corresponding hydroxy acid salt 49. The reaction was allowed to progress until hydrolysis was 60% complete. Extraction with ether afforded pure 48 while acidification of 49 and lactonisation gave the enantiomeric lactone 50 (Scheme 8). 0 0 0 47 48 49 50 Scheme 8 The lactones 48 and 50 obtained by this process were shown by chiral GC to have enantiomeric excesses of 90.3 and 51.2% respectively.The lactones were transformed into bis-dihydropyrans via what was by then our standard route, shown for diene 32 in Scheme 9.35 I (iii) 48 SnBu3 32 Reagents: (i) DIBAL-H. PhMe, -78 OC; (ii) PhS02H, CaCI2, DCM, r.t., 83% over two steps; (iii) Bu"Li, THF, -78 OC; then Bu3SnC1, -78 to -10 OC; then DIPEA, CHC13, 70 OC, 55%; (iv) Bu"Li, THF, -78 OC; then PdCIz(MeCN)2 (cat.), CuCI2, NH&VNH3,30-75%. Scheme 9 For the preparation of the C2-symmetric (4S, 4's)-DMDHP 34 we used another enzymatic procedure involving hydrolysis of meso diester 51 since this allows the preparation of material on a large-scale and in excellent optical purity. The process is outlined in Scheme 10. This route provides the lactone 52 in 92% e.e.Conversion into 34 using the previously established chemistry gave material with an e.e. greater than 99%, the homocoupling process again enhancing the e.e. of the bis-dihydropyran with respect to the starting stannane at the cost of the production of 7% of the meso diene.36 Ley, Downham, Edwards, Innes and Woods: Dispiroketals: A new functional group for organic synthesis 37151 52 I I 3 4 l Reagents: (i) PLE, phosphate buffer (10% MeOH), pH 7,O OC, 5 d, 90%; (ii) LiOH, MeOH, then LiBH4, THF, 67%; (iii) DIBAL-H, PhMe, -78 "C, then PhSOpH, CaCb, DCM, r.t., W/O; (iv) BffLi, THF, -78 OC, then Bu3SnCI, -78 to 0 OC, then DIPEA, CHC13, 70 OC, 70%; (v) BffLi, THF, -78 OC; then PdCh(MeCN)z, CUCI~, NH~CVNHB, 50%. Scheme 10 5 Enantioselective protection of vicinal diols The incorporation of chirality in the bis- dihydropyrans provides an additional control element over dispiroketal formation.We have made use of this in a new concept which accomplishes a simultaneous protection and enantioselective desymmetrization of meso polyols. 5.1 Reaction with glycerol Reaction of glycerol with the C2-symmetric homochiral bis-dihydropyran 28, in the presence of catalytic camphorsulfonic acid in refluxing toluene, proceeded with complete diastereoselectivity to give the dispiroketal 53 in excellent yield (Scheme ll)*2'(a) H0- OH + OHC HO 2) 53 s y i (iii) I kl I B n 0 2 $ 7 B n O T O H a OH 58 0 59 + 53 I Reagents: (i) CSA (cat.), PhMe, reflux, 96%; (ii) DCM, 4 A mol sieves, 30 min.; then PCC, E M , 61%; (iii) NaH, BnBr, TBAI, THF, 85%; (iv) glycerol, CSA (cat.), PhMe, reflux, 83%.Scheme 11 This enantioselective desymmetrization of glycerol is explained as follows. The absolute stereochemistry of the spiro centres (S,R) is controlled by a combination of multiple anomeric effects and the absolute configuration at the site of substitution of the methyl groups, which adopt a preferred equatorial orientation. Due to steric effects, the hydroxymethylene substituent on the dioxane ring also adopts an equatorial arrangement under thermodynamic control. These factors result in the exclusive formation of the glycerol dispoke derivative 53 with (S)-stereochemistry at the C-(2) position of the glycerol unit. The alternative diastereoisomers 54, 55 and 56 which could be theoretically formed and still possess full anomeric stabilization are not observed (Figure 8).54 ' 55 56 Figure 8 All these alternative products are obviously higher in energy relative to 53 owing to severe 1,3-interactions as a result of the axial substituents. The formation of compound 53 represents, therefore, an enantioselective vicinal diol protection of glycerol. Oxidation of 53 with pyridinium chlorochromate gives the enantiomerically pure aldehyde 57.21(a) isopropylidene glyceraldehyde 21 as discussed earlier (Section 3.1). We therefore have a process for the preparation of useful three-carbon homochiral building blocks from a symmetrical starting material in just two synthetic steps. Scheme 11 also shows the conversion of 53 into its corresponding benzyl ether 58.We find that treatment of 58 with neat glycerol and catalytic CSA gives (R)-1-0-benzyl glycerol 59 in 83% yield, together with the returned dispiroketal adduct of glycerol 53 as a single diastereomer in high Together these reactions constitute a very efficient recycling process. We believe this new method for the preparation of dissymmetric glycerol derivatives is potentially very useful, especially as the reaction appears to be general and is not restricted to glycerol (see Sections 5.2 and 5.3). Obviously should the enantiomeric materials be required for a particular synthesis the antipodal bis-dihydropyran 29 could be used in the above reactions; however, synthesis of 29 requires unnatural @)-methyl lactate. An alternative enantiocomplimentary process involves the use of the (4S,4'S)-dimethyl bis-dihydropyran 34 which is much more readily available than 29 (see Section 4, Scheme 10).The aldehyde 57 is synthetically equivalent to (R)- 372 Contemporary Organic SynthesisI I Ethylene glycol, CSA, 120 "C, 4 h Reagents: (i) PhMe, CSA (cat.), 110 "C, 15 h, 75%; (ii) NaH, BnBr, THF, 95%. Scheme 12 Reaction of 34 with glycerol in refluxing toluene with catalytic CSA gave selectively 60 (Scheme 12), again as a result of combined anomeric and steric The equatorial orientation of the hydroxymethylene substituent is the result of the thermodynamic conditions under which the reaction is run. Initially, a mixture of two isomers was formed, but after fifteen hours of reflux only a small amount (less than 5%) of the axial isomer still remained in the crude reaction mixture.A prolonged reaction time did not alter the ratio further. After purification by flash chromatography, 60 was isolated in 75% yield as a single diastereomer. Benzylation of 60 gave 61 which on treatment with neat ethylene glycol furnished (S)- l-O-benzyl glycerol 62, identical to an authentic sample, together with 63, in 60 and 87% yield respectively (Scheme 12). With the aim of devising a recycling process, compound 63 was heated in glycerol with catalytic CSA. As expected 60 was obtained diastereomerically pure in 88% yield, after purification by flash chromatography. This recycling process, going via the ethylene glycol adduct 63, was necessary as 61 reacted only very sluggishly with glycerol. 5.2 Reaction with other acyclic meso polyols Several other acyclic polyols have been enantioselectively protected with chiral bis- dihydropyrans to give dissymmetric products.37 For example, the symmetrical disilylated pentol 64 (Scheme 13) reacts with (2S,2'S)-DMDHP 28 in refluxing chloroform containing CSA to give the dispiroketal 65 in 79% yield as the only isolated product.The dispiroketal is formed on only one of the enantiotopic diol pairs because only one has a chirality match with the diene, i.e., the product which is formed is the thermodynamically most stable one in which the methyl substituents and the two dioxolane side-chains are equatorial and the spirocentres are fully anomerically stabilized (Scheme 13). of ways. For example, deprotection with tetra-n- butylammonium fluoride followed by benzylation afforded 66 which upon treatment with trifluoroacetic acid then gave the polyol derivative 67 in enantiomerically pure form (Scheme 13). We have also found that the symmetrical mono- protected polyol 68 reacts with two equivalents of the dimethyl bis-dihydropyran 28 to give the bis- dispiroketal 69.In this compound we see that there The dispiroketal65 may be elaborated in a variety (ii), (iii) U O H OTBDPS % (0 + TBDPSO TBDPSO %$ J HO * B i p $ a TBDPSO 28 OH 64 65 Reagents: (i) CSA (cat.), CHC13, reflux, 79%; (ii) TBAF, 90%; (iii) NaH, BnBr, TBAI, DMF, 71%; (iv) 95% TFA, 63%. Scheme 13 L q , Downham, Edwards, Innes and Woods: Dispiroketals: A new functional group for organic synthesis 373HO HO OBI 68 0 % Ph R= Q y y 28 \ I 53 (R)-Mosher acid (S)-Mosher acid chbrlde Pivo HO.?? 71 Reagents: (i) CSA (cat.), CHC13, reflux, 67%; (ii) CSA (cat.), CHC13, glycerol, reflux, 70 75%, 53 97%; (iii) PVCI, pyr, DCM, -20 "C, 82%.Scheme 14 has been a good chirality match with one diol pair but that the other diol pair, which is relatively unhindered, also reacts. In order to accommodate the mismatched chirality the dioxane ring here must adopt a boat conformation meaning that this dispiroketal is less stable and can be selectively deprotected by adding glycerol and warming briefly to 61 "C in chloroform. This has the effect of removing the unstable spiroketal unit to give the dissymmetric diol70 together with the glycerol adduct 53 (Scheme 14). The diol70 can be selectively protected at the primary position by treatment with pivaloyl chloride at -20 "C to give the alcohol 71 in 82% yield.Application of the Mosher method has confirmed the stereochemistry of the secondary alcohol centre. 5.3 Reaction with cyclic meso polyols Following the success of the enantioselective discrimination and protection procedure for acylic polyols we sought to apply the procedure to cyclic meso polyols in an effort to prepare enantiomerically pure inositols. These are extremely important materials in many biologically interesting systems. The conventional way of obtaining these compounds involves optical resolution of myo- inositol derivatives which requires tedious chromatographic separation or recrystallization procedures with generally low overall efficiency.Hence the known symmetrical 2,5-dibenzoyl-myo- inositol 7238 was reacted with the C2-symmetric (2S,2'S)-dimethyl bis-dihydropyran 28 under 76 Reagents (i) CSA, CHCI,, reflux, 70%; (ii) 1% NaOH, MeOH/Et,O (9:1), 96%; (iii) NaH, BnBr, TBAI, DMF, 74%; ( i ) 95% TFA, 63%. Scheme 15 standard conditions to give the 3,4-protected dispoke adduct 73 (Scheme 15). This dispoke- protected compound 73 is fully anomerically stabilized with the oxygen substituents at the spiro centres adopting axial orientations. Regioselectivity is achieved via the use of the chiral bis-dihydropyran 28 which has the ability to protect one enantiotopic 374 Contemporary Organic Synthesispair of vicinal diols in the substrate 72 to give a 'matched' dispoke adduct, with the side-chain methyl substituents equatorial.Protection of the other enantiotopic vicinal diol pair would lead to a 'mismatched' adduct with axial methyl substituents if the structure possessed full anomeric stabilization, and this is therefore disfavoured. It is important to note that as the dibenzoyl inositol derivative 72 is a meso compound all the starting material is utilized in the step leading to the dissymmetric dispoke product 73. Debenzoylation was achieved with sodium hydroxide to give the tetrol74 in 96% yield. This compound 74 was then perbenzylated to give the fully protected dispoke adduct 75. The diol was unmasked by treatment of 75 with 95% trifluoroacetic acid/water to give tetrabenzylated myo-inositol76 in 63% yield39 (Scheme 15), which was identical to an authentic sample prepared by alternative methods.could be prepared by the same sequence of reactions using either the (4S,4'S)-DMDHP 34 or the (2S,2'S)-DPDHP 31 as the desymmetrizing agent. The sequence of reactions for 31 is shown in Scheme 16. The enantiomeric tetrabenzylated-myo-inositol 77 HO+ 72 Ph I occurs via a thermodynamically controlled enantioselective reaction forming diastereo- isomerically pure dispiroketals. of racemic 1,Zdiol with a chiral bis-dihydropyran such as 30 in the presence of CSA in boiling toluene. Initially, two products are formed, both with a fully anomerically stabilized dispoke core, but one with the side-chain equatorial and the other with it in axial orientation. On prolonged heating at 110 "C interconversion of the dispoke adducts is possible; deketalization of the less stable diol adduct followed by ketalization of the opposite diol enantiomer occurs, that is, thermodynamic equilibration takes place to favour the more stable, equatorially substituted, dispiroketal such as 78 which is formed in high yield (Scheme 17).The process involves reaction of two equivalents 30 (' 1 , K O , Ph Ph R -$- S + .Po R P h Ph (ii) Ph 1 Ph Ph 78 Reagents: (i) CSA, CHCI,, reflux, 52%; (ii) 1% NaOH, MeOH/Et,O (9:1), 99%; (iii) NaH, BnBr, TBAI, DMF, 98%; (iv) 95% TFA, 33%. Reagents: (i) Diol(2 aq.), PhMe, CSA (cat.), 110 "C, 1 h; (ii) 11 0 "C, 48 h. Scheme 16 Scheme 17 6 Thermodynamic resolution of diols Enantiopure 1 ,2-diols are useful building blocks for organic synthesis and their preparation on a large- scale is desirable.Even the brilliant enantioselective procedures of Sharpless and others suffer some limitations, particularly for terminal alkene oxidation. Resolution procedures can therefore be an effective way of accessing chiral materials, especially on a large scale. We have investigated the use of the C2-symmetric bis-dihydropyrans as a route to chiral vicinal diols in which resolution This thermodynamic resolution procedure has been applied to a number of structurally different 1,2-diols using (2R,2'R)-DPDHP 30, the enantiomeric bis-dihydropyran 31, and the (2S,2'S)- DMDHP 28 (Table 3). Theoretically, after reaction of exactly two equivalents of racemic diol with (2R,2'R) or (2S,2'S)-DPDHP 30 and 31, one diol enantiomer should be ketalized and the other enantiomer left unreacted.In practice, however, a small amount of bis-dihydropyran decomposition occurs during the Ley, Downham, Edwards, Innes and Woods: Dispiroketals: A new functional group for organic synthesis + R K O " 375Table 3 Diem Did Dispoke Addud YieM (%)' Bu KOH 30 + 93 Ph a::: 30 80 + Ph Ph 30 + 90 Ph & OH ?H * OH 91 30 + Ph H O T O H OH "'-OH OH 30 + 62 Ph BU K O " ?H BU&OH 31 + bh Ph a::: 82 31 + Ph E S H + 96 31 28 ' Yklds basal on bk-dihydropyranreaction which lowers the optical purity of the unprotected diol and the yield, through not the optical purity, of the dispoke adduct. It was found that when two equivalents of diol were used complete reaction took up to forty-eight hours. This rather long reaction time could be decreased by using more equivalents of diol, but it should be noted that use of excess diol is inefficient as it naturally leads to a lower enantiomeric excess of the residual unprotected diol.Liberation of the diol from the dispoke protected adducts can be achieved by treatment with lithium in liquid ammonia. For example, 79 gives the deprotected diol 80 in 76% yield (Scheme 18).40 Ph 79 80 Reagents: (i) Li, NHafl), Et20, 76%, 89% 8.8. by chiral g.c. Scheme 18 The fact that the optical purity of the released diol80 is only 89% e.e., as opposed to >98% for the starting bis-dihydropyran 31, indicates that partial racemization occurs during the extended reaction times needed for complete resolution, owing presumably to some benzylic cleavage and readdition. For this reason in any further study we would recommend the use of dimethyl bis- hydropyrans 28,29 or 34 which should not suffer from this problem.We have also developed deketalization via ketal exchange as an alternative to the lithium ammonia reduction procedure which could find wider application with more sensitive substrate^.^' Alternatively, the use of DADHPs 32 or 33 where the chiral controller substituents are ally1 groups can be used in these resolutions; removal is then effected by ozonolysis to give the aldehyde and treatment with base to give deprotection by a p-elimination me~hanism.~' 7 Protection of a-hydroxyacids and alkylation of the dispiroketal products 7.1 Introduction In an effort to devise a new way to prepare enantiopure a, a-disubstituted a-hydroxyacids we envisaged that dispiroketals could be used to form a non-racemic equivalent of an enolate of lactic acid in a similar way to Seebach's elegant acetal work.42 The formation of dispiroketals, however, brings further possibilities of using homochiral bis- dihydropyrans to prepare non-racemic enolate equivalents of prochiral a-hydroxy acids.We decided first of all to attempt the dispiroketalization of chiral a-hydroxyacids with simple bis- dihydropyran 2. On the basis of previous work with diols it was hoped that such a reaction with a homochiral substrate would give one major diastereomer, with the substituent on the hydroxyacid preferentially adopting an equatorial position (Scheme 19). This tendency would, in conjunction with maximization of anomeric stabilization, control the configuration at the spiroketal centres.Having stored the chiral information in the dispiroketal, the original stereogenic centre could be destroyed by deprotonation to give the enolate which could then undergo a diastereoselective reaction with an electrophile. Finally, deprotection would afford the product of a useful overall enantioselective transformation (Scheme 19). xl Scheme 19 This process has worked well and has allowed us to prepare a number of a-hydroxy acid derivatives, as described be lo^.^'(^)*^^ 7.2 Protection of (S)-lactic acid The best conditions for the reaction of @)-lactic acid with the bis-dihydropyran 2 to give 81 and minimize formation of 82 were found to be the use of toluene as solvent with dry HCl (used as a 1.0 M solution in ether) as an acid catalyst at room temperature or below.These conditions gave an 85% yield of a 12: 1 mixture of 81 to 82 (Scheme 20). 0 1 + 81 82 Reagents: (i) 2, 10 mol% HCI, PhMe, r.t., 48 h, 85%. Scheme 20 Ley, Downham, Edwards, Innes and Woods: Dispiroketals: A new functional group for organic synthesis 377The major isomer could be obtained pure by a single recrystallization from 40-60 petroleum ether and X-ray crystallography showed, as expected, an all-chair conformation with the methyl group equatorial and the maximum anomeric stabilization at the spirocentres, that is, 81. No crystal structure of the minor diastereoisomer could be obtained; however, its structure must represent a thermodynamically less stable compromise between an all-chair conformation having an unfavourable 1,3-diaxial interaction between the substituent and a carbon-oxygen bond, and a structure possessing a boat conformation of the 1,4-dioxane ring which relieves this steric interaction at the expense of eclipsing strain and reduced anomeric stabilization.racemize significantly under the conditions employed for dispiroketalization. The pure major diastereomer 81 was treated with a small excess of ethylene glycol and catalytic acid in methanol to afford the dispiroketal adduct 1 and methyl lactate (Scheme 21). It was demonstrated by gas chromatography on a Lipodex E chiral column that It was necessary to confirm that lactic acid did not Me+? 0 0 81 + Reagents: (i) Ethylene glycd (1.1 eq.), CSA, MeOH, reflux, 16 h. Scheme 21 this possessed the S-configuration, with no trace of @)-methyl lactate being detectable.This confirmed that 81 was of high enantiomeric excess and importantly that no racemization had occurred during deprotection. 7.3 Alkylation reactions of a non-racemic equivalent of a lactic acid enolate Deprotonation of 81 occurred readily on treatment with strong bases in THF at -78 "C. The enolate was then alkylated with a range of alkyl halides to give the corresponding diastereoisomeric products 83a-e and 84a-e (Scheme 22, Table 4). alkylation with benzyl or allyl bromide is highly What is noticeable from the table is that ma-e Ma-e ma, 84a R = benzyl 83b, 84b R = allyl 83c, 84c R = ethyl 83d, 84d R = n-propyl 830,846 R = iso-propyl Reagents: (i) Base (see table), -78 OC.Method A, LDA, THF/DMPU; method B, LDA BunLi, THF/DMPU; method C, KHMDS, THF/PhMe; (ii) Electrophile R-X, -78 O C to r.t. Scheme 22 Table 4 Entry Electrophile Product(s) Methoda Ratiob YBM(%) h 3 Ethyl iodide h h A >98:2 72 6 >98:2 86 A B 96:4 96:4 95 94 h A 77:23 73 83:17 79 C 92:8 67 04d h a See scheme 22 for details. See ref. 21 b, 43 for methods empbyed. 9% Starting materlal also recovered. 378 Contemporary Organic Synthesisstereoselective, to the extent that it is difficult to detect the minor diastereoisomers. With smaller electrophiles such as ethyl and n-propyl iodide the selectivity is slightly lower. Alkylation with secondary halides such as iso-propyl iodide gave lower yields of alkylated product, presumably due to competing elimination, with no improvement in diastereoselectivity despite its greater size.We found that use of N, N '-dimethylpropylene- urea (DMPU),44 when added to the lithium enolate, gave enhanced reactivity during the alkylation reactions. In the cases where more moderate selectivity was observed this could be improved by the use of potassium hexamethyldisilazide (KHMDS) instead of LDA (Entries 3 and 4, Table 4). When LDA was used as the base increased yields were achieved when the diisopropylamine generated in the enolate formation was further deprotonated with a second equivalent of n- butyllithium prior to electrophile additi~n.~' the enolate is as expected on steric grounds; the incoming electrophile approaches from the least hindered face such that there is no 1,3-interaction with the pseudoaxially disposed C-0 bond of the spiroketal.The slightly lower selectivity observed for less reactive alkyl halides probably reflects the operation of a later transition state where the enolate has developed some pyramidal character, which reduces the energy differences between the competing alkylation pathways. The observed facial preference for alkylation of We have also investigated the reaction of the lactate dispiroketal enolate with a limited range of carbonyl compounds. Once again excellent diastereoselectivity was observed and in most examples only one of the four possible diastereomers was produced (Scheme 23, Table 5). Only in the reaction with acetaldehyde (Entry 3), which we would expect to give the lowest level of stereoselectivity on account of the small size of the RL group, were two diastereoisomeric products 8% and 86 formed, in 93% and 4% yield respectively.In the reactions with aldehydes yields were consistently high, but reactions with ketones gave lower yields with significant quantities of starting material being recovered, although the very high facial selectivity of alkylation was maintained. As retro-aldol reactions can occur in sterically hindered systems we suspect that this may have been occurring with the ketones although the reactions were quenched at -78 "C prior to product isolation in an attempt to minimize this pathway. xl M e x l Reagents: (i) LDA, THF/DMPU, -78 OC; (ii) Bunti; (iii) RLRSC=O. Scheme 23 Table 5 Entry Electrophile Product(s) Ratio Yield (%) Recovered SM ("h) 1 Benzaldeh yde 85a 2 Acrdein 3 Acetaldehyde 4 Cyclopentanone 5 Acetophenone +4J 85b Me a - - 96 8 - 94 93:4* 93c 06 8 - 8 - ' No minor ditsterwisomer detectable.* Based on isolated amounts of Ek and 86. 'Yield of major diestereoisomer b5c. 35 29 46 56 Lq, Downham, Edwards, Innes and Woods: Dispiroketals: A new functional group for organic synthesis 379The large preference for one diastereomer in these aldol coupling reactions can be rationalized by consideration of the two chair-like six membered transition states (Figure 9). In both, the larger substituent of the carbonyl component RL is directed pseudoequatorially while the smaller group RS, i.e. hydrogen for aldehydes, is axial and placed Figure 9 major diastereoisomer minor diasterehsomer -only observed for RL=Me, Rs=H in the vicinity of the dioxane ring.The transition state which favours the formation of the major diastereoisomer is obviously much less sterically encumbered than that leading to the minor component. of the need to develop mild deprotections of these spiroketal products, ways to remove the spiroketal unit were investigated. For example, we found that the dialkylated adduct 83a reacted with ethylene glycol in the presence of camphorsulfonic acid to give the parent spiroketal 1 and the ester 87 (Scheme 24). This ester could be further converted into the methyl ester 88 by treatment with MeOH and sodium carbonate giving an overall yield of 80% for the two steps. Alternatively, a more convenient procedure could be used to afford methyl esters directly whereby the aldol product 85a was exposed to just 1.5 equivalents of ethylene glycol in methanol containing an acid catalyst to give 8947 in quantitative yield (Scheme 24).As part of their structure elucidation, and because 7.4 A non-racemic equivalent of a glycolic acid enolate Although the above methods work well for the production of alkylated chiral a-hydroxy acids the process is restricted by the availability of enantiopure hydroxy acids as starting materials from the chiral pool. For this reason we sought to devise a method which would lead to a non-racemic glycolic acid enolate which could give access to a much wider range of a,a-disubstituted derivatives. This has been achieved using chiral bis- dihydropyrans both as a protecting group and as a chirality directing motif during alkylations.Me 61 61 83a 88 R=Me 85a 1 89 Reagents: (i) Ethylene glycol (excess), CSA, 100 OC, 1 h; (ii) MeOH, Na,CO,, r.t., 48 h, 80% over 2 steps; (iii) Ethylene glycol (1.5 eq.), MeOH, CSA, reflux, 5 h, 100%. Scheme 24 Reactions of glycolic acid with (2S, 2's)-DMDHP 28 gave 90 as a single diastereoisomer in 75% yield (Scheme 25). The excellent control in the formation of the dispiroketal product is once again achieved as a result of the desire for methyl groups to adopt equatorial positions and the spiro centres to be fully anomerically stabilized. Compound 90 was then alkylated via its corresponding enolate, derived by treatment with LDA in THF, with methyl iodide to give 91 as a 10 : 1 mixture of diastereoisomers (Scheme 25).88 - 28 (ii), (iii) 1 Bn 91 I Reagents: (i) PPTS, THF, r.t., 72 h, 75%; (ii) IDA, MF, -78 OC; (iii) Mel, 73%: ( i ) LDA, THF/DMPU, -78 OC; (v) BnBr, 70%; (vi) ethylene glycol (3 eq.), MeOH, CSA, reflux, 5 d, 31%. Scheme 25 These diastereomers could be isolated or simply treated as a mixture with LDA followed by alkylation with benzyl bromide as a second electrophile to give 92 as a single diastereoisomer. 380 Contemporary Otganic SynthesisOn deprotection compound 92 afforded the methyl ester 88 which is identical to the previously obtained material (Scheme 25). Overall the process therefore constitutes a novel way of forming two new carbon- carbon bonds asymmetrically with control of the absolute stereochemistry from an achiral substrate such as glycolic acid.We believe this method has considerable promise for the asymmetric synthesis of unusually substituted a-hydroxy acids and compares favourably with, and is complementary to, existing literature procedure^.^^ Currently we are investigating routes that might allow similar alkylation studies with thioglycolic acid, glycine, and other amino acid derivatives. h h OH 2 93 Q4 Reagents: (i) Epoxidation or dihydroxylation; (ii) Ethylene glycol, CSA, PhMe, reflux. Scheme 26 Table 6 8 Preparation and use of dihydroxy dispiroketals as chiral auxiliaries Epoxidation conditions Overall yield 93 : 94 (%I Another aspect of the dispiroketal chemistry which we have exploited makes use of the rigid architecture in these molecules for asymmetric synthesis. There is a consistent need for new cheap, low molecular weight chiral auxiliaries and chiral ligands for catalysts for asymmetric synthesis which are available in both enantiomeric forms.auxiliaries could be obtained by decorating further the dispiroketals to give bifunctional molecules such as those illustrated by the general structure types I, I1 and I11 below (Figure 10). It was envisaged that a wide range of such I I1 111 : reactive function for : bulky shielding group, @ asymmetric reactions directing group or proton source flgure 10 To obtain such compounds we had to introduce oxygen at the 5- and 1Zpositions of the dispiroketal framework (dispiroketal numbering). Extensive experiments showed that bis-dihydropyran 2 reacted under a variety of epoxidizing and hydroxylating conditions with subsequent trapping by ethylene glycol under thermodynamic acidic conditions to give two diastereoisomeric diols 93 and 94 which are readily separable by column chromatography (Scheme 26, Table 6).48 Proof of the structure of these compounds was obtained by X-ray crystallographic methods.48 The majority of our early work has concentrated on the use of the enantiopure C2-symmetrical diol95 as a bifunctional auxiliary, obtained by classical resolution of the racemate 94 via dicamphanate ester formation. The dicamphanates were readily separated by flash chromatography and subsequent basic hydrolysis furnished enantiopure diols which could then be used for asymmetric synthesis.Dimethyl dioxirane, -78 "C 83 Dimethyl dioxirane, 0 "C 92 mCPBA, DCM, 0 "C 48 2: 1 1 : l 1:4 Dihydroxylation conditions Overall yield 93 : 94 (a) 0 .~ 0 4 . Bu'OH, H20, 46 1:3 K3Fe(CN)6, 0 "C The first class of reactions to which we applied our auxiliary was Diels-Alder cycl~additions.~~ For example, the enantiopure diol95 was converted into the diacrylate 96 (Scheme 27) and then reacted with cyclopentadiene in the presence of various Lewis acids to afford the corresponding Diels-Alder adducts 97 and 98 (Scheme 28 and Table 7). 95 96 Reagents: (i) KOBu', THF, 0 "C to rt.; (ii) Acrybyl chloride, -78 "C, 82%. Scheme 27 96 97orW Reagents: (i) Cyclopentadiene, Lewis acid, DCM, galvinoxyl (10 md%), -78 "C to r.t. Scheme 28 Ley? Downham, Edwards, Innes and Woods: Dispiroketals: A new functional group for organic synthesis 381Table 7 Entry Lewis acid Temp.("C) Time (hours) Ratio of 97 : 98 Endo : Ex0 Yield (%) 1 EtAlC1, - 78 1 2 Et2AlCl - 78 3 3 Alc13 - 78 23 4 ZnClz - 78 18 5 TiC14 0 3.5 6 SnC14 0 3.5 23.5 : 1 15.5 : 1 6.3: 1 2.6: 1 2.6: 1 1.4: 1 99 98 80 84 40 12 During these reactions only one equivalent of the Lewis acid is required to give complete turnover to product. The acrylate side-chains are oriented in an S-trans configuration in the transition states leading to the major product being the bis-endo adduct 97. Under the optimum conditions, using EtAlC12, the ratio of endo, endo isomer 97 to endo, a o isomer 98 was 23.5 : 1 in virtually quantitative chemical yield. Cleavage of the Diels-Alder adduct in 97 from the auxiliary either hydrolytically (NaOH, MeOH, H20 at reflux) or reductively (LiAlH4 in Et20) gave 99 or 100 respectively (both identical in all respects to the literature).In neither case was any epimerization observed and the auxiliary 95 could be separated and recovered readily in high yield (Scheme 29). Using the optimized conditions for the formation of the bis-endo adduct 97 with cyclopentadiene, compound 96 was reacted with several other dienes to give the corresponding Diels-Alder products (10la-c) (Scheme 30, Table 8). These Diels-Alder reactions represent a new opportunity for the use of dispiroketals, with the C2-symmetrical dihydroxylated dispiroketal diol95 acting as a chiral scaffold for acrylates in Lewis- HO &+ 99 Ho 100 95 95 Reagents: (i) NaOH, H,O:MeOH (1 :2), reflux, 96% for 99 and 92% for 95; (ii) LiAH,, Et20, -30 "C, 93% for 100 and 93% for 95.Scheme 29 Q6 97,101 a-c Reagents: (i) Diene, EtACI,, DCM, -78 "C to r.t. Scheme 30 Table 8 Entry Diene Temp. ("C) Time (hours) R Yield (%) 4 -78 to 0 1 0 0 -78 to 0 3 78 to r.t. 14 78 to 0 4 Me 96 89 83 82 382 Contemporay Organic Synthesisacid-catalysed cycloaddition processes. The C2- symmetry and the bifunctional format of this auxiliary maximizes its effectiveness in that it is able to react two substrates per auxiliary unit. After achieving successful asymmetric induction in Diels-Alder reactions we turned our attention to the use of 95 to influence the stereochemistry of conjugate additions of various cuprate reagents to unsaturated systems such as compounds 102a-c (Scheme 31).50 fijk OH 95 102a 102b 102c lO2a-c 70% 74% 94% Reagents: (i) KOBU', THF, 0 "C to r.t.; (ii) Acid chloride, -78 "C.Scheme 31 In order to determine the best reaction conditions for conjugate addition we centred our studies on the dicrotonate derivative 102a. This compound was reacted with a variety of butyl organocuprate reagents which included homo- and hetero-cuprates and copper-catalysed Grignard reagents (Scheme 32, Table 9). 1028 Reagents: (i) Butyl cuprate, Et20. Scheme 32 In order to achieve the highest facial selectivity in the addition it was necessary to incorporate Lewis acids into the medium. Under these conditions reaction occurred with high yield and high R-selectivity. In the absence of a Lewis acid stereofacial selectivity was reversed. Once the most effective reaction conditions had been found (a modified version of conditions developed by Yamamoto5') these were applied to a variety of different systems (Scheme 33, Table 10).Reagents: (i) R-Li, CubPBy, BF3"oEt2, ether. Scheme 33 In general the addition process proceeded with high yield and stereoselectivity. The addition of a phenyl organocuprate reagent (Entry 2), however, went with both reduced yield and selectivity; this was probably due to the low reactivity of this cuprate which necessitated an elevated reaction temperature. Additions of phenyldimethylsilyl ~ u p r a t e ~ ~ (Entries 3 and 5) to the dienoate system proceeded in high yield but with reduced stereofacial selectivity. The high chemical and optical yields achieved with this novel C2-symmetric bifunctional auxiliary in some of these Diels-Alder reactions and Michael additions are pleasing results per se; they also show the power of the dispiroketal framework as a chiral inductor.We are currently working on using the asymmetric unit more efficiently, as a chiral Table 9 Entry Butyl cuprate Temp. ("C) Time (hours) Yield (%) Config. e.e. (%) 1 BuCU. BF3.PBu3 - 60 16 2 BuCU.BF~*PBU~ - 45 16 3 Bu,CuCNLi,, ZnC1, - 60 16 4 BuMgC1, CuBr-DMS, ZnCI, - 60 16 5 Bu,CuCNLi, - 60 16 88 R 96 63 R 89 80 R 63 40 R 28 82 S 35 Table 10 ~ ~ ~~ ~ ~ ~ ~ ~ ~~~~~~~~ Entry R R' Temp. ("C) Time (hours) Yield (%) Config. e.e. (%) 1 Me Bu - 60 16 2 Me Ph - 40 36 3 Me SiMezPh - 70 12 4 Ph Me - 60 16 5 Ph SiMezPh - 60 16 6 Ph Bu - 60 16 7 Bu Me - 60 16 88 R 94 68" R 81 92b R 76 83 S 92 91b R 71 87 R 92 79 S 93 "Yield based on recovered starting material.bReaction carried out in 50 : 50 ether: THF. Ley, Downham, Edwards, Innes and Woods: Dispiroketals: A new functional group for organic synthesis 383modifier or as a basis for ligands to be used in asymmetric catalysis. 9 Protection of vicinal diols in carbohydrates We are witnessing a resurgence of interest in carbohydrates owing to their involvement in an increasing array of important biological events ranging from cell-cell and viral recognition to cellular signalling and adhesion properties. In order to advance this area of glycoscience it will be necessary to have ready access to materials to probe their various biological functions. Although traditional methods of synthesis and the rapidly developing biological methods are proving useful, new techniques are going to be crucial to achieve success in the future.protection makes it an excellent candidate for achieving selective protection in carbohydrates; dispiroketalization leads to highly-stabilized fused six-membered ring systems which favours protection of diequatorial vicinal diols over axial-equatorial or diaxial systems. In addition, the use of homochiral bis-dihydropyrans should afford further possibilities for control. Therefore it was anticipated that use of dispiroketals could bestow considerable strategic advantages in the synthesis of carbohydrates. In practice the reactions of bis-dihydropyrans with carbohydrates worked well and have led to a general method for the protection of diequatorial vicinal diols in a wide range of monosaccharide^.^^^^^ This result creates a new opportunity in selective carbohydrate protection; the protecting group pattern obtained in this way could normally only be achieved in a multistep protection/deprotection sequence.We find that bis-dihydropyran 2 reacts in toluene, or preferably boiling chloroform solution, in the presence of catalytic CSA, with the polyol to give diequatorial diol protection as the major outcome in all cases (Table ll).53(a) In order to fully characterize the products they were often acylated to aid NMR analysis. In a few cases some cis diol protection was noticed as a minor product when steric interactions were of lesser magnitude. At the C-1 carbon, 0-methyl, S-ethyl or 0-pentenyl groups are tolerated. From these data it was also noticed that the more lipophilic the groups at the anomeric centre, the higher were the yields of dispiroketals, reflecting the greater solubility of the compounds in CHC13.The use of more polar solvents such as DMF or acetonitrile failed to give any products probably due to competitive decomposition of the bis-dihydropyran. In a trial to assess the stability of dispiroketal-protected sugars, the galacto-derivatives 103 and 105 were shown to withstand benzylation and silylation to give 104 and 106 and then conversion back into 103 and 105 without loss of the protecting group (Scheme 34).9 Of particular note is that p-methoxybenzyl substituents can be removed even in the presence of the -SEt group using DDQ oxidation. Dispiroketal protection also has a significant effect on reactivity of the carbohydrate in Certain special properties associated with dispoke glycosylation reactions, which can be profitably harnessed in oligosaccharide coupling reactions. This key observation will be discussed in the next section.The regiocontrol in these reactions is as a result of the predictable stabilizing influence of multiple anomeric effects leading to the thermodynamically most stable isomers. regiocontrol is posed by gluco-derived carbohydrates owing to the presence of two 1,2-trans diequatorial diol relationships. The other problem which we encountered in the gluco-series was that of poor chemical yield. Reaction of methyl OI-D- glucopyranoside 107 under standard conditions gave two dispiroketals 108 and 109 (1 : 1.6) in only 39% yield (Scheme 35).53(b) We first addressed the issue of improving the yield.The low conversion of 107 was attributed to its low solubility in chloroform and the instability of bis-dihydropyran under prolonged reaction conditions. We have found three alternative ways of surmounting this problem. Firstly, ultrasound is effective in assisting the dissolution process. Secondly, use of DMF as a solvent, although previously shown to be disadvantageous due to the greater rate of decomposition of bis-dihydropyran 2 relative to the rate of the desired dispiroketalization reaction, was found to be effective in the presence of a milder acid catalyst, triphenylphosphine/ hydrogen bromide complex:4 under these conditions methyl a-D-glucopyranoside 107 gave the regioisomeric dispiroketals 108 and 109 in a greatly improved combined yield of 68%, again as a 2:3 mixture.Separation and NMR analysis was aided by diacylation to give derivatives 110 and 111, in 22% and 36% yield respectively from 107. Thirdly, selective protection of the primary hydroxy group of 107 as its tert-butyldiphenylsilyl (TBDPS) ether 112, with the aim of improving the solubility of the substrate, gave the two dispiroketals 113 and 114 in an excellent 82% yield (Scheme 36). A ratio of 1.4: 1 for the 2,3- to the 3,4-protected products was obtained. Thus, once again even with a large group at C-6 there was little regiocontrol in the protection rea~tion.’~(~) To overcome this regiochemical challenge we devised an original solution using the concepts of chirality recognition previously established for meso- polyols (Section 5).Thus, chiral bis-dihydropyrans such as 30 and 31 were used to discriminate between the enantiomeric pairs of trans-1,2 diols in llZ4l The process once again exploits the preference of substituents (phenyl groups) to adopt equatorial positions while maintaining maximum anomeric stabilization at the spiro centres to give the most thermodynamically stable product. Pleasingly, reaction of (2R,2’R) DPDHP 30 with D-glucopyranoside derivative 112 under the usual conditions gave the dipiroketal adduct 115 as a single diastereomer in 88% yield (Scheme 37). Complete regioselectivity was observed as a result of chirality ‘matching’ of the C-2, C-3 diol pair with However, an even greater challenge to 384 Contemporary Organic Synthesis~ ~~ Table 11 ~~~ Substrate Products Yield trans:& W) Entry 1 Fuco- R=H R = AC) 76 g:G OMe ?Me RO OQO OMe 2 Arabino- R = H 3 R=Ac R = H R = AC) 98 3:2 OMe 3 Rhamno- R=H R =Ac) R = H R = AJ 3:2 79 H$oO OMe 4 Lyxo- RO OMe R = H R = Ac) 62 H O 4 HO 5 Manno- SEt SEt R = H R = AJ a 36 6 Manno- OPent OPent R = H R = AJ 45 a ’ Other minor products were formed which w r e not readily identified.Ley, Downham, Edwards, Innes and Woods: Dispiroketals: A new functional group for organic synthesis 385(iii), ( i i ) 103 OMe 104 OMe Reagents: (i) TBSCI. pyr, 86%; (ii) NaH, BnBr, 83%; (iii) TBAF, THF, 100%; (iv) HP, PdlC, 91%; (v) TBSCI, TEA, DMAP, 56%; (vi) NaH, 4-MeOBnC1, 84%; (vii) lBAF, THF, 100%; (viii) DDQ then AcOHMzO.1ooOA. Scheme 34 107 RO RO OMe Reagents: (i) 2 (2.1 eq.), CSA (cat.), CHCb, A, 1.5 h then ethylene glycol, A, 0.5 h, 39% or 2 (2.1 eq.), Ph,P=HBr (cat.), DMF, 60 .C, 4 d, 68%; (ii) Ac20, pyr, 110 22%, 11 1 36%. Scheme 35 mDL=% HoOMe 112 3,4-isomer 2b-isomer 113 34% TBDPSO 114 48% Reagents: (i) CSA (cat.), 2 (1.5 eq.), CHCb, reflux. overnight, 82%. Scheme 36 that of the bis-dihydropyran leading to the most stable arrangement of the appended functionality. Mismatched products in this case would have led to severe steric crowding and placement of phenyl side-chains in axial positions. The presence of phenyl groups in the dispiroketal at these positions also facilitates deprotection of the sugar with, for example, hydrogenolysis (Na/NH3) or, in these monosaccharide examples and later derivatives, by treatment with FeC13.of the 3,4-diol pair in 112 using the enantiomeric (2S,2’S)-DPDHP 31 which was chosen to provide the correct chirality recognition leading to the matched product 116. Once again this reaction proceeded extremely well and afforded 116 in 75% yield as the only isolated product (Scheme 37). Next we examined the complementaty protection I 116 Ph I 3,4-Protected 1 producl only TBDPSO 115 kh 2,SProtected I pr~udonly I Reagents: (i) CSA (cat.), 31 (1.5 eq.), CHC13, reflux, overnight, 75%; (ii) CSA (cat.), 30 (1.5 eq.), CHC13, reflux, overnight, 88%. Scheme 37 What we have established, therefore, is a new concept in vicinal diol protection whereby not only will these methods select trans-1,2 diequatorial pairs but they will also recognise the chirality associated with these units.These new enabling procedures should therefore considerably enhance the protecting group strategies available for oligosaccharide research. We went on to explore further the scope of these reactions. In other experiments we have studied the use of different enantiopure bis-dihydropyrans such as (4S,4’S)-DMDHP 34 with the same glucopyranose derivative l12.53(c) In this case, while we still see the 3,4-‘matched’ products 117 as the major isomer (58%) some of the 2,3-‘mismatched’ dispiroketal 118 becomes significant (ll%), although the two are readily separable. 386 Contemporary Organic SynthesisFurther reaction of the major 3,4 adduct 117 with benzoyl chloride furnished the fully protected derivative 119.The dispiroketal was then removed under acidic conditions with 95% trifluoroacetic acid/water giving methyl-2-O-benzoyl-a-~- glucopyranoside 120 (Scheme 38). OTBDPS o%Me + OTBDPS OMe (iii) - 3,4 Protected 'Matched' HO OMe 120 119 Reagents: (i) CSA (cat.), 34 (1.5 eq.). CHCI,, reflux, overnight, 118 11% + 117 58%; (ii) BzCI, DMAP (cat.), pyr, CHCI,, r.t., 2 d, 57%; (iii) 95% TFA, 4 h, r.t., 54%. Scheme 38 Alternatively, reaction of the glucopyranose derivative 121 with (2S,2'S)-DMDHP 28 under the usual reaction conditions gave the 2,3-adduct 122 as the exclusive product (Scheme 39). OTBDPS HO H0&OSEt HO 121 + I I Exclusive 2.9 Protection TBDPSO 'uv I 'Matched' 1 HO b J Reagents: (i) CSA (cat.), 28 (1.72 eq.), CHCI,, reflux, overnight, 64%.Scheme 39 In another series of experiments we have shown that the diallyl substituted bis-dihydropyran 32 also exhibits exclusive matched diol recognition to give 123 upon reaction with 112 (Scheme 40).41 This is of particular interest because ally1 groups can be used to effect an alternative method of deprotection in a two step process involving oxidative cleavage and base-catalysed @-elimination. Thus, ozonolysis to 124 and treatment with DBU leads to recovery of 112. Use of the Schwesinger base55 in the elimination step at 0 "C in THF gives not only rapid @-elimination but also removal of the silyl protection to give 107 in good yield (Scheme 40). (OTBDPS & o y y B - t (OH 3 R _ _ 123 R=CHP 107 OMe J (ii) 124 R=O Reagents: (i) PPTS (cat.), 32 (1.16 eq.).CHC13, reflux, 2 d. 78%; (ii) 03, CH2CI2, -78 OC then Ph3P (1.4 eq.), 7 h, r.t.. 100%; (iii) DBU (1 eq.), PhMe, 80 OC, 21 h, 56%; (iv) P,-tert-odyl (1 eq.), 0 "C, THF, 2 h, 7%. Scheme 40 Protection 'Matched' Ley, Downham, Edwards, Innes and Woods: Dispiroketals: A new functional group for organic synthesis 387OTBDPS I HOE&SEt HO 1 25 I Ph Reagents: (i) CSA (cat.), 31 (1.5 eq.), CHCI,, reflux overnight, 76%; (ii) CSA (cat.), 30 (1.5 eq.), CHC13, reflux overnight, 82%. Scheme 41 Since fl-thioglucopyranosides represent an alternative and more versatile class of monosaccharide, useful in oligosaccharide synthesis, we have briefly examined the use of chiral bis dihydropyrans to achieve new regioselective protection of these substrates. Reaction of the thioethyl derivative 125 with (2R,2’R)-DPDHP 30 under standard spiroketalization conditions gave the 2,3-adduct 126 whereas upon reaction with the enantiomeric (2S,2‘S)-DPDHP 31 gave the corresponding 3,4-dispiroketal 127 (Scheme 41).Both of these reactions once again proceeded in excellent yield with complete sele~tivity.~’(~) not restricted to coupling with gluco-configured substrates. In fact the corresponding galacto derivative 128 reacts with 30 to give the 2,3-matched adduct 129 in 88% yield (Scheme 42). The reaction of these chiral bis-dihydropyrans are OMe 128 Ph TBDPSO *o+ OMe 129 Ph Reagents: (i) CSA (cat.), 30 (1.5 eq.), CHCI,, reflux, overnight, 88%. Scheme 42 On the other hand the reaction with manno- derivatives such as 130 was less selective. The reaction of 130 with 31 under standard conditions gave a separable mixture of dispoke adducts 131 and 132 in approximately equal amounts.These adducts arise from the protection of both the 2,3- and 3,4-vicinal diol moieties. The poor regioselectivity is disappointing but can be rationalized since both possess fully anomerically stabilized structures and have the phenyl substituents equatorial. The remaining steric interactions are obviously insufficient to discriminate between the formation of the two structures (Scheme 43). TBDPSO H%&$) OMe 130 c Yh + Ph OTBDPS h e 131 7 132 Ph 2,3 prdected product Not ‘mismatched‘ but Reagents: (i) CSA (cat.), 31 (1.8 eq.), CHC13, 37% and 132 43%. Scheme 43 3,4 protected ILZL 1 reflux, overnight, 131 In spite of this one disappointing result we believe this new method of regioselective control in monosaccharide vicinal diol protection is a powerful tool for rapid achievement of protection patterns in carbohydrates which previously have required tedious multi-step procedures using conventional chemistry.10 Use in oligosaccharide synthesis In the previous section we described the development of a new enabling methodology for regioselective protection of trans-diequatorial 1,Zdiols in monosaccharides. Our next step was to show that dispiroketals can also have an effect on the next level of carbohydrate architecture; dispiroketalization of sugar derivatives can have a 388 Contemporary Organic Synthesisdramatic and controlling effect on the rate of coupling reactions in oligosaccharide synthesis.effects that dispiroketalization might have on disaccharide formation. We therefore studied the coupling of the 2,3-dispiroketalized derivative of galactopyranoside 133, in which the spiroketal is neighbouring the free hydroxyl group at C-4, with the thioethyl perbenzoylated glucosyl donor 134. In the presence of N-iodosuccinimide (NIS) and triflic The dispiroketal protecting group in 135 was removed by treatment with aqueous trifluoroacetic acid to give 136. We have also placed the dispiroketal function in the glycosyl donor as in 137 and successfully achieved coupling with the C-6 alcohol of the glucopyranoside derivative 138 to give the disaccharide 139, again using NIS/triflic acid activation. Disaccharide 139 was formed in respectable yield and with a : = 4 : 1.This could also be selectively deprotected to 140 with TFA/ H20 as before (Scheme 44). group is compatible with glycosidic couplings whether present on the donor or the acceptor moiety. Importantly, we also note that the deprotection reaction proceeds without interfering with other protecting groups such as acetates or benzoates. Next we considered the important armed/ disarmed glycosylation concept introduced by Fraser-ReidS7 which has proven to be an extremely In the first experiments we investigated the steric disaccharide 135 was formed (Scheme 44).9 These results demonstrate that the dispiroketal ?Bz OBz B z O d BzO OH OMe effective strategy for the concise preparation of complex oligosaccharides. The process relies upon the fact that reactivity of the anomeric centre can be regulated by the substitution of the hydroxy groups in the glycosyl dono3* as ether^,^^(^) esters59 or cyclic acetaka For example, a donor having an ether protecting group at C-2 would be highly reactive, and can be chemoselectively coupled to an acceptor bearing a C-2 ester group which would be relatively deactivated.Further glycosylation of the resulting oligosaccharide could be accomplished by using a more powerful activator of the anomeric leaving group or via functional group interconversion. Although this approach is useful there remains an exciting opportunity to tune the glycosyl donor still further and thus release a greater potential for more complex coupling reactions. We envisaged that dispiroketalization, because of the constraining effects of the fused chair ring systems, would inhibit the formation of the intermediate flattened oxonium ion species prior to glycosidic coupling and therefore slow down, that is, tune the rate of the coupling reaction.This tuning process would provide a new range of differentially reactive coupling substrates which would increase chances of achieving rnuttiple saccharide coupling reactions. Accordingly, we find that the highly reactive glycosyl galacto-donor 141 couples with the dispiroketal-detuned galacto-acceptor 142 in the presence of iodonium collidine perchlorate (IDCP) to give the disaccharide 143 in a convincing 82% yield. This undergoes a further coupling with a third manno-acceptor 144 which is deactivated by benzoyl BzO ?Bz B z O - - Y o “ O Y 9 (+ 11% B) /OBZ BzO HO Reagents: (i) NIS, triflic acid, CICH2CH2CI/Et20, 53%; (ii) TFAM20 (19:1), 58%; (iii) NIS, triflic acid, CICH2CH2CI/Et20, 42%; (iv) TFAR120 (19:1), 59%.Scheme 44 HOA / 140 Lq, Downharn, Edwards, Innes and Woo&: Dispiroketals: A new functional group for organic synthesis 389substitution at C-2, with the use of a more vigorous activating agent NISDfOH, to give 145 (Scheme 45).61 implications for the assembly of large carbohydrate molecules. It should be noticed that although the product 145 is deactivated by ester substitution in the manno-ring it is in principle still capable of further coupling with yet another monosaccharide to give a tetrasaccharide. It is conceivable that these reactions could also be performed in one pot and if so this would greatly simplify oligosaccharide synthesis.In connection with other work we have further coupled the trisaccharide 145 with a complex inositol substituted glucosyl derivative 146 to give 147. This product was of interest in our work on the synthesis of the GPI anchor from Trypanosoma brucei (Scheme 46). To demonstrate the usefulness of these new coupling ideas we have demonstrated an extremely These observations have very important 142 - R\ -F? BnO Bn& Bib 141 SSEt rapid assembly of a tris-manno derivative. Thus, initial coupling is achieved between two thioethyl manno-derivatives 148 an 149. The benzyl protected compound 148 was chosen as the reactive glycosyl donor while 149, the coupling acceptor, was differentiated, detuned in its reactivity, by dispiroketalization. Coupling was effected in the presence of IDCP to give 150.The third manno derivative 151, which was fully deactivated by benzoylation at C-2, could then be coupled with 150 to afford 152 in the presence of NIS/triflic acid (Scheme 47).61 11 Summary and conclusions The concepts which we have delineated in the above discussion all harness the special control that can be achieved during the formation of two spiro centres owing to the four anomeric effects, especially when combined with the steric preference of a substituent OBn BnO / SEt SEt Reagents: (i) IDCP, ClCH2CHGVEt20, r.t., 82%; (ii) 144, NIS, triflic acid, CICH2CH2CVEt20, 0 oc, 57%. SEt Scheme 45 147 Reagents: (i) 145, NIS, triflic acid, CICH2CH2CVEt20, 0 O C , 24%.Scheme 46 390 Contemporary Organic SynthesisSEt 148 I 149 sEt / BnO BnO BzO BzO SEt SEt Reagents: (i) IDCP, CICH2CH2CVEt20, r.t., 56%; (ii) 151, NIS, triflic acid, CK=H2CH2CV Scheme 47 EtpO, 0 O C , 60%. to sit equatorially on a six-membered ring. These powerful principles have already led to the use of dispiroketals to achieve a surprisingly wide variety of synthetic objectives, as described in this review. We can anticipate many more such applications of these architecturally rigid motifs in the future as to date we have only exploited a small selection of the range of possible ring sizes and substitution patterns. 12 References 1 P. Deslongchamps, in ‘Stereoelectronic Effects in Organic Chemistry’, Pergamon Press, Oxford, 1983, pp. 4-53. Stereochemical Effects at Oxygen’, Springer-Verlag, Berlin, 1983.3 M. Woods, Ph.D. Thesis, University of London, 1992. 4 S. Ghosal, G.P. Luke and K.S. Kyler, J. 0%. Chem., 1987,52,4296. 5 T.W. Greene and P.G.M. Wuts, in ‘Protective Groups in Organic Synthesis’, Wiley, New York, 1991, Ch. 2. 6 G.H. Castle, unpublished observations. 7 J.E. Innes, unpublished observations. 8 S.V. Ley, M. Woods and A. Zanotti-Gerosa, Synthesis, 9 S.V. Ley, R. Leslie, P.D. Tiffen and M. Woods, 10 A.I. Meyers, J.P. Lawson, D.G. Walker and R.J. 11 M.T. Reetz and K. Kesseler, J. 0%. Chem., 1985, 50, 12 K. Mead and T.L. Macdonald, J. 0%. Chem., 1985, 50, 13 D.J. Walton, Can. J. Chem., 1967, 45, 2921. 14 D. Horton, J.B. Hughes and J.K. Thompson, J. 0%. 15 M. Cherest, H. Felkin and N. Prudent, Tetrahedron 16 N.T.Anh, Top. Cum Chem., 1980, 88, 145. 2 A.J. Kirby, in ‘The Anomeric Effect and Related 1992, 52. Tetrahedron Lett., 1992, 33, 4767. Linderman, J. 0%. Chem., 1986,51, 5111. 5434. 422. Chem., 1968,33,728. Lett., 1968, 9, 2199. 17 S. Pikul and J. Jurczak, Tetrahedron Lett., 1985,26, 18 Macromodel, the Batchmin program and the 4145. associated documentation are available from W.C. Still, Columbia University, New York. For details of the MM2 force field see: N.L. Allinger, J. Am. Chem. SOC., 1977,99, 8127. For details of MOPAC see: (a) M.J.S. Dewar, E.G. Zoebish, E.F. Healy and J.J.P. Stewart, J. Am. Chem. SOC., 1985, 107, 3209; (b) M. J.S. Dewar, J. Mol. Struct., 1983, 100, 41 and references therein. 19 M. Woods, unpublished observations. 20 S.V. Ley, J.Norman, W.P. Griffith and S.P. Marsden, Synthesis, 1994, 639. 21 (a) G.-J. Boons, D.A. Entwistle, S.V. Ley and M. Woods, Tetrahedron Lett., 1993, 34, 5649; (b) G.-J. Boons, R. Downham, K.-S. Kim, S.V. Ley and M. Woods, Tetrahedron, 1994,50,7157. 22 S.V. Ley, B. Lygo, F. Sternfeld and A. Wonnacott, Tetrahedron, 1986, 42, 4333. 23 D.A. Entwistle, Ph.D. Thesis, University of London, 1993. 24 R.C. Fuson, M.E. Davis, B.H. Davis, B.H. Wojick and J.A.V. Turck, J. Am. Chem. SOC., 1934, 56,235. 25 M. Julia and A. Rouault, Bull. Chim. SOC. Fr., 1959, 1833. 26 E.J. Corey, R.K. Bakshi and S. Shibata, J. Am. Chem. SOC., 1987, 109, 5551. 27 S.V. Ley, N.J. Anthony, A. Armstrong, M.G. Brasca, T. Clarke, D. Culshaw, C. Greek, P. Grice, A.B. Jones, B. Lygo, A. Madin, R.N. Sheppard, A.M.Z. Slawin and D.J. Williams, Tetrahedron, 1989, 45, 7161. 28 (a) G.J. Quallich and T.M. Woodall, Tetrahedron Lett., 1993, 34, 4145; (b) G.J. Quallich and T.M. Woodall, Synlett, 1993, 929. 29 R. Downham, unpublished observations. 30 (a) J. Chandrasekharan, P.V. Ramachandran and H.C. Brown, J. 0%. Chem., 1985, 50,5446; (b) R.K. Dhar, Aldrichimica Acta, 1994, 27, 43. 31 P. Simpson, D. Tschaen and T.R. Verhoeven, Synth. Commun., 1991,21, 1705. 32 C. Barber, K. Jarowicki and P. Kocienski, Synlett, 1991, 197. Ley, Downham, Edwards, Innes and Woods: Dispiroketals: A new functional group for organic synthesis 39133 W.J. Scott and J.K. Stille, J. Am. Chem. SOC., 1986, 34 N.B. Lorette and W.L. Howard, J. 0%. Chem., 1961, 35 G. Visentin, unpublished observations. 36 C. Genicot and S.V. Ley, Synthesis, 1994, 1275. 37 P.J. Edwards and S.V. Ley, Synlett, in press. 38 Y. Watanabe, M. Mitani, T. Morita and S. Ozaki, J. Chem. SOC., Chem. Commun., 1989,482. 39 P.J. Edwards, D.A. Entwistle, C. Genicot, K . 4 . Kim and S.V. Ley, Tetrahedron Lett., 1994,35, 7443. 40 P.J. Edwards, D.A. Entwistle, S.V. Ley, D. Owen and E. J. Perry, Tetrahedron: Asymmetry, 1994,5,553. 41 D.A. Entwistle, A.B. Hughes, S.V. Ley and G. Visentin, Tetrahedron Lett., 1994, 35, 777. 42 (a) D. Seebach, in ‘Modern Synthetic Methods 1986’, ed. R. Scheffold, Springer-Verlag, Berlin, 1986, pp. 125-257; (b) D. Seebach, R. Naef and G. Calderari, Tetrahedron, 1984,40, 1313. Tetrahedron Lett., 1994,35, 769. 1982, 65, 385. Acta, 1985, 68, 1373. Bull., 1972, 20, 1898. Chem., 1979,44,4294. Tetrahedron Lett., 1994,35,7447. S.V. Ley, Tetrahedron Lett., 1994,35, 7451. 108,3033. 26, 3112. 43 R. Downham, K . 4 . Kim, S.V. Ley and M. Woods, 44 T. Mukhopadhgay and D. Seebach, Helv. Chim. Acta., 45 T.H. Laube, J.D. Dunitz and D. Seebach, Helv. Chim. 46 M. Kobayashi, K. Koga and S. Yamada, Chem. Pharm. 47 C.H. Heathcock, M. C. Pirrung and J. E. Sohn, J. 0%. 48 B.C.B. Bezuidenhoudt, G.H. Castle and S.V. Ley, 49 B.C.B. Bezuidenhoudt, G.H. Castle, J.V. Geden and 50 G.H. Castle and S.V. Ley, Tetrahedron Lett., 1994,35, 7455. 51 Y. Yamamoto, Angew. Chem., In?. Ed. Engl., 1986, 25, 947. 52 I. Fleming and T.W. Newton, J. Chem. SOC., Perkin Trans. 1 , 1984, 1805. 53 (a) S.V. Ley, G.-J. Boons, R. Leslie, M. Woods and D.M. Hollinshead, Synthesis, 1993, 689; (b) A.B. Hughes, S.V. Ley, H.M. W. Priepke and M. Woods, Tetrahedron Lett., 1994, 35, 773; (c) P.J. Edwards, D.A. Entwistle, C. Genicot, S.V. Ley and G. Visentin, Tetrahedron: Asymmetry, 1994,5,2609. 54 V. Bolitt, C. Mioskowski, D.-S. Shin and J.R. Falck, Tetrahedron Lett., 1988, 29, 4583. 55 R. Schwesinger, Nachr. Chem. Tech. Lab., 1990,38, 1214. 56 G.H. Veeneman, S.H. van Leeuwen and J.H. van Boom, Tetrahedron Lett., 1990, 31, 1331. 57 (a) D.R. Mootoo, P. Konradsson, U. Udodong and B. Fraser-Reid, J. Am. Chem. SOC., 1988, 110, 5583; (b) B. Fraser-Reid, U.E. Udodong, Z. Wu, H. Ottoson, J.R. Merritt, C.S. Rao, C. Roberts and R. Madsen, Synlett, 1992,927. 58 H. Paulsen, Angew. Chem., 1982,94, 184. 59 G.H. Veeneman and J.H. van Boom, Tetrahedron Lett., 60 (a) B. Fraser-Reid, Z. Wu, C.W. Andrews and E. 1990,31, 275. Skowronski, J. Am. Chem. SOC., 1991, 113, 1434; (b) K. Toshima, Y. Nozaki and K. Tatsuta, Tetrahedron Lett., 1991,32, 6887; (c) G.H. Veeneman, Ph.D Thesis, Leiden, 1991, 103. Yeung, Tetrahedron Lett., 1993,34,8523, 61 G.-J. Boons, P. Grice, R. Leslie, S.V. Ley and L.L. 392 Contemporary Organic Synthesis

ISSN:1350-4894    

DOI:10.1039/CO9950200365

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

Methods for the asymmetric preparation of amines ANDERS JOHANSSON Department of Organic Chemistry, Chalmers University of Technology, S-412 96 Goteborg, Sweden Reviewing the literature published up to January 1995 1 2 2.1 2.2 2.2.1 2.2.2 3 3.1 3.1.1 3.1.2 3.2 4 5 Introduction Reduction of the C=N bond Catalytic processes Non-catalytic processes Reductions with chiral reagents Reductions using internal chiral auxiliaries Alkylations Nucleophilic alkylations Alkylations using internal chiral auxiliaries Alkylations using external chiral auxiliaries Electrophilic alkylations Double bond manipulations References 1 Introduction In light of the development of asymmetric synthesis during the past twenty years, it may seem surprising that the asymmetric preparation of amines is still met with such difficulties and is so unpredictable.However, the problems associated with asymmetric aminations are several. One is the lack of an apparent prochiral functional group as a precursor. Another is the different behaviour of what at first glance seem to be quite similar nitrogen-containing prochiral compounds. Nevertheless, several promising methods have emerged. It is noteworthy that completely different approaches have become useful in the past few years, both when it comes to the choice of prochiral functional group and method to convert it into an amino group. Hence, in this review, I have tried to cover the literature within the field as broadly as possible, but I soon realized that a few limitations were necessary, and so decided to deal only with general methods in which a new chiral centre is created as the amine is produced. The methods covered are divided into three categories: reductions, alkylations, and additions to double bonds.Of these, additions to double bonds is the smallest category as cycloaddition reactions are not included. Furthermore, I have excluded asymmetric syntheses of amino acids, because I considered this a topic of its own. 2 Reduction of the C=N bond 2.1 Catalytic processes So far, all asymmetric catalytic processes for the reduction of C=N double bonds have been based on the use of transition metals. A majority of the reported catalytic systems consist of transition metals with a chiral diphosphine ligand.' A selection of ligands used in these C=N reductions are shown below.Some of the results obtained with these ligands are summarized in Table 1. (+)-DIOP (-)-NORPHOS Et-DUPHOS oh P k P PPh, (-)-BDPP (2s ,4S )-BPPM (+)-BIN AP NBD COD In an early example, the (+)-DIOP ligand together with [RhCl(C2H4)], and Ph2SiH2 was used for hydrosilylations of prochiral imines.2 The silyl amines were not isolated, but hydrolysed in situ to produce amines. In all cases, the yields are excellent. The highest selectivity reported (65% e.e.) is achieved with the imine la when the reaction is performed at around 0 "C. Raising the temperature to 60 "C results in a dramatic decrease in selectivity, as an e.e. of only about 27% is observed. In a later paper, the same catalytic system was used for the asymmetric reduction of enamine~.~ A modification, in which [Rh(COD)Cl], was used instead of [RhCl (C2H4)12, appeared several years later! In this study, five-membered cyclic imines 2 were Johansson: Methods for the asymmetric preparation of amines 393hydrosilylated but, contrary to the paper by Kagan et aZ.,2 the amines could not be isolated after hydrolysis.Instead, the silylamines were treated with trifluoroacetic anhydride to yield the trifluoroacetamide derivatives. The best result (64% e.e.) is obtained with an unsubstituted phenyl group at the 2-position, although bromine in thepara- position does not decrease the selectivity significantly. When the phenyl moiety contains a methoxy group in one or several positions, the optical yield is considerably lower. This observation is ascribed to intra- and inter-molecular coordination of the methoxy substituent to rhodium.Hydrosilylations of oximes with this catalyst system have also been studied, but substantially lower selectivities were observed (1.4-18.7% e.e.).5 I / I t a. Ar = Ph n Nb Ph b. Ar = 2-MeO-Ph c: Ar = 4-MeO-Ph d. Ar = 2-OH-Ph 8, Ar = 3-MeO-Ph 1 2 The (R)-( +)-cycphos ligand has been used together with [Rh(NBD)Cl], and KI for the reduction of aromatic imines la-d.6 Here, the presence of a methoxy substituent in thepara- position increases the e.e. Thus, imine l c can be hydrogenated to give an e.e of 91% and imine l a gives 71% e.e. For the ortho-substituted imine lb, the optical yield is somewhat lower and no asymmetric induction was observed with imine Id. The catalyst is not effective for the asymmetric hydrogenation of aliphatic imines.An interesting observation is that the selectivity is significantly lower without KI. A similar decrease in selectivity has been reported earlier,7 although the effect of halide was less dramatic. In a detailed structural study of ( - )-(S, S)-BDPP, Bakos and co-workers' reported a 73% e.e. in hydrogenations of la. In a later paper,' they examined the effect of sulfonation at the meta-position of one or several phenyl groups in the (-)-BDPP ligand. The sulfonated ligands were not purified, but used as a mixture. The compositions were determined with HPLC. When performing the hydrogenation with [Rh (NBD) Cl], and partly sulfonated (-)-BDPP, they were able to obtain high enantioselectivities of aromatic benzylamines la-c and l e (89-96% e.e.).In a comparative study," several chiral diphosphines were used together with [Ir(COD)Cl], (Scheme 1). The most effective ligands are those capable of forming a flexible six- or seven- membered metallacycle, e.g. BDPP, DIOP and BPPM. With these ligands, both reactivity and enantioselectivity are high. Quite contrary, 1,2-diphosphino compounds, such as NORPHOS, are considerably less efficient. Furthermore, a strong halogen effect is observed, as the halogen-free catalytic system [Ir(COD)2] BF@, S)-DIOP produces the (R)-amine with only 4% e.e. and only 30% conversion. Also, the two methyl substituents 3 (2S, 3S)-DIOP 70% 8.8. (2S, 4S)-BPPM 73% 8.8. (2S14S)-BDPP 84% 8.8. Scheme 1 in the ortho-positions of the phenyl group of 3 are important, presumably by hindering the rotation about the N-aryl bond.Another type of iridium-reagent, the dimeric [Ir(P-P)HI2I2, in which P-P is a diphosphine, has been investigated by Osborn et aZ." The reagent was investigated with (+)-DIOP, (-)-BDPP, (+)-BINAP and (-)-NORPHOS as chiral diphosphine ligands. Osborn's findings indicate dissociation of the dimeric catalyst to the monomer and an equilibrium between free imine and monomer and an imine/monomer complex. Moreover, by studying the hydrogenation of deuterated imine 3, they concluded that addition occurs almost exclusively (> 95%) to the C-N bond and not to the enamine tautomer. Of the substrates studied, the highest selectivity is observed in hydrogenation of 4 with (-)-BDPP as the ligand (80% e.e.). 4 5 Oppolzer and co-workers have reported the reduction of 5 with Ru2C14[(R)-( +)-BINAPI2, which proceeds with exclusive formation of one enantiomer.'* A very efficient rhodium-based catalyst has been reported by Burkl3>l4, who used a cationic rhodium complex together with the chiral 1,2-bis(phospholano)-benzene, Et-DuPHOS (Scheme 2).The hydrogenations are performed on N-benzoylhydrazones to yield hydrazines in 72-97% e.e. After the hydrogenation, the N-N bond is readily cleaved with Sm12 to produce amines in high yields without loss of optical purity. An interesting observation is that no hydrogenation takes place without the carbonyl functionality of the hydrazones present. This observation is ascribed to chelation of the N-benzoylhydrazone functionality to the cationic rhodium centre.Furthermore, the hydrogenations are highly chemoselective. For example, little or no reduction is observed for alkenes, alkynes, ketones, aldehydes, esters, nitriles, carbon- halogen bonds, nitro groups, or even imines in competition experiments. This is attributed to the aforementioned substrate chelation of the N-benzoyl hydrazone and the fact that N-benzoylhydrazine inhibits the reduction of aldehydes, alkenes and alkynes among others. 394 Contemporary Organic SynthesisR' = Ph, R2= Me R' = pMew6H4, R2= Me R' = pEtO&C&, R2 = Me R' = pNO2C6H4, R2 = Me R' = pBCsH4, R2 = Me R' = 2-Naphthyl, R2 = Me R' = Cy, R2= Me 95% 8.8. 88% 8.8. 96% e.8. 97% 8.8. 96% 8.8. 95% 8.8. 73% e.8. Scheme 2 Another excellent asymmetric hydrogenation catalyst based on titanium has been developed by Buchwald and co-worker~.~~-~~ The active catalyst is the titanium(n1)hydride 7, which is formed in situ by treating the chiral air stable ansa-titanocene 6'* with Bu"Li and phenylsilane (Scheme 3).The catalyst works extraordinarily well for the reduction of cyclic imines (97-98% e.e.). Though still respectable in several cases, the selectivity is generally lower (53-85% e.e.) when the substrate is an acyclic imine. The observed e.e.s correlate roughly with the antilsyn ratios of the investigated imines. For this observation the authors suggest that both the anti and syn isomers are reactive, giving rise to opposite enantiomers of the product amines." The catalyst has also been used for asymmetric hydrogenations of enamines.*' (i) Bu"Li - (ii) PhSiHI 7 -H Scheme 3 The last two mentioned methods are the subject of an excellent review by Bolm.21 2.2 Non-catalytic processes 2.2.1 Reductions with chiral reagents There are examples of asymmetric reductions of imines and oxime ethers using aluminium h ~ d r i d e s .~ ~ , ~ ~ However, the asymmetric induction is at best fair and, hence, these reagents have given way to boron-based reagents, in some cases combined with Lewis acids, such as ZrC14 or ZnC12/ AlC13. Hitherto, no reports have appeared in which boron reagents are used in a catalytic fashion, as is the case with carbonyl reduction^.^^ Chiral sodium triacyloxyborohydrides such as 8 and 9 can be prepared from NaBH4 and N-carboxyl derivatives of optically active a-amino acids. These reducing agents have proven useful for reductions of certain cyclic imines. Iwakuma et aZ.25,26 have described asymmetric reductions of imines 10a-d. In their study, several acyloxyborohydrides were investigated of which 8 in CH2C12 produces the highest optical yield (Scheme 4).In another in~estigation,~~ the amine 11, a precursor to the antibacterial agent (S)-( -)-ofloxacin,28 has been prepared in 95% e.e. from the corresponding imine using 9 as the reducing agent. Me0 Me0 W N LMeow~t-Me0 R 1084 R 70436% 8.8. 4 R = Me; b. R m ) ; ' 0 c, .Do"" OMe ; d, R w M e OMe 8 R=Bn 9 R=B& Scheme 4 11 A comparative study of several reducing agents efficient in asymmetric ketone reduction has been undertaken by Cho and C h ~ n . ~ ~ The asymmetric reducing characteristics of Itsuno's reagent 12,30 Corey's reagent 13,31 K-glucoride (Brown's reagent) 14,32 Sharpless' reagent 1533 and Mosher's reagent 16,34 were compared with propiophenone N- phenylimine 17 as the substrate (Scheme 5).Under the same conditions as those found most successful for ketone reductions. Itsuno's reagent is the most effective (87% e.e.), whereas 14 and 16 did not reduce the examined imine 17. Further reductions with Itsuno's reagent show that aromatic N-phenyl imines can be reduced with good to high selectivity (71-88% e.e.). Lower optical yields are observed for aromatic N-alkyl imines (ca. 50% e.e.) and for aliphatic N-phenyl imines the selectivity drops significantly. The cyclic imine 10a was inert to the reagent. investigated for several different i m i n e ~ .~ ~ . ~ ~ The e.e.s obtained range from 12 to 73% and it is notable that the only alkyl ketimine in the study, 19, The chiral dialkoxyborane 18 has been Johansson: Methods for the asymmetric preparation of amines 395Tablo 1 Asymmetric catalytic reductions of imines Catalyst Substrate 8.8. Ref. DIOP/(Rh(COD)CIk DIOP/[ Rh(COD)CIJz (R )-cycphos/ [ Rh( NBD)CIWI ( R )-cycphos/ [ Rh(NBD)Clk/KI (R )-cycphost [Rh(NBD)CIklKI (-)-BD PP/ [Rh(NBD)CI]2 (-)-BDPP+)/ [Rh(COD)Clk (-)-BDPP)I [ Rh(C0D)Clk (-)-BDPP+)/ [R h(COD)C1]2 (-)-BDPP+)/ [Rh(COD)Clk (-)-NORPHOS [I r(C0 D)C Ik (+)-DIOP/ [ Ir(COD),BF4YI- (+)-DIOP/ [Ir(COD)Cl]fl- (2S, 4 s )-BPPM/ [Ir(COD)Clk 65% 64% 31 % 33% 60% 79% 91% 71 % 0% 73% 96% 95% 89% 91% 27% 68% 70% 73% 1 3 3 3 3 5 5 5 5 7 8 8 8 8 9 9 9 9 Catalyst Substrate 8.8.Ref. (-)-BD PP/ [Ir(COD)Cl]d/l- (+)-D IOP/ [Ir(COD)C1]& (+)-DIOP/ [Ir(COD)ClkN (+)-DIOP/ [Ir(COD)Cl]fl/l- (-)-BDPP/ [Ir( p- P)H I212 (-)-BDPP/ [Ir( P- P)H I2k NORPHOW [Ir( P-P)H I2k DIOPI [Ir( P-P)H121, BINAPI [Ir(P-P)H1212 7 7 7 7 7 7 7 7 84% 66% 52% 1 6% WYO 80% 4w0 63% 22% 58% 76% 76% 98% 97% 98% 98% 85% 9 9 9 9 10 10 10 10 10 13,14 13,14 13,14 13,14 13,14 13,14 13,14 13,14c 12 Itsuno’s reagent 13 Corey’s reagent 14 K-glucoride 15 Sharpless’ reagent 16 Mosher’s reagent 12 (87% e.eJ 17 Scheme 5 was reduced to the (S)-amine with 71% e.e. No reaction takes place without the addition of MgBr2-OEt2. Oxime ethers are unreactive to these reaction conditions. A selection of asymmetric reductions of imines with chiral reagents are shown in Table 2.While the (E)- and (2)-isomers of an imine are in equilibrium with each other through inversion of the nitrogen, oxime ethers have distinct syn- and anti- isomers,37 as the energy barrier for inversion of the nitrogen is considerably higher. Although the oxygen of the oxime functionality offers an additional stereochemical control element through coordination to the reagent, one must also take into consideration the issue of performing the reduction on pure syn- or anti-isomer, as a mixture of these might decrease the optical yield substantially. Asymmetric reductions of oxime ethers have been reported by Itsuno and co-worker~.~~ Using Itsuno’s reagent 12, the anti-oxime ether 20a is reduced to 18 19 the corresponding amine with 99% e.e.In addition to Itsuno’s reagent 12, other chiral amino alcohols were used to prepare analogues of 12. All of the amino alcohols examined give a high degree of asymmetric induction. The study also includes the effect of various 0-substituents and suggests that both bulkier groups such as SiMe3, and more electron-withdrawing groups such as COMe, decrease the optical yields considerably. When the reaction is performed on the oxime 20b, no asymmetric induction at all is observed. The same type of chiral ligand has been used for reductions with hydride reagents.397‘@ The cfiiral amino alcohol 21 has been used as a ligand together with NaBH, and ZrC14 or ZnC1JAlCl3 (Scheme 6). The amino alcohol is inert to suspensions of NaBH4 in THF and, furthermore, no reduction of the oxime ethers take place under these conditions. Thus, the reducing species is thought to be a mixture of zirconium aminalkoxy borohydrides.It is also noteworthy that no amine is produced with Lewis acids such as CuCl,, ZnC1, or AlC13 alone, or ZnBr,. a, R=Me b , R = H HO 20 OR^ NaBH4/ Lewis acid 21 1 R2 D R’ Lewis acids: R‘ = Ph, R2 = R3 = Me R’ = Ph, R2 = Et, R3 =PhCH, R’ = Ph, R2= *= Me ZrC14 =I4 ZnC12/AICI3 Scheme 6 21 95% yield, 90% 8.8. 88% yield, 72% 8.8. 75% yield, 95% 8.8. Several other amino alcohols have been examined by Didier et uL41 The substrate studied, the oxime ether 20a, is reduced to the corresponding amine with BH3 and the chiral amino alcohols 22,23 and 24 [(-)-norephedrine1 with 95, 94.5 and 93.2% e.e. OH ?H 22 23 24 respectively. In some cases, the reduction of the oxime ether is not complete and a mixture of oxime ether, amine and hydroxylamine methyl ether is obtained.However, after elimination of the oxime ether, the hydroxylamine can be treated with an excess of BH3 to produce the amine without loss of optical purity. Itsuno and c o - ~ o r k e r s ~ ~ have also reported reductions with the polymer supported chiral alcohol 25 and borane, but here the selectivities are lower (6-67% e.e.). 25 A systematic investigation of reduction of syn- or anti-ketoxime ethers has been undertaken by Sakito, Yoneyoshi, and Suzukam0.4~ They examined the reduction of several oxime ethers with BH3 and Johansson: Methods for the asymmetric preparation of amines 397(-)-norephedrine, 24, and obtained either enantiomer of the amine depending on the syn- or anti-configuration of the oxime ether.The most spectacular example is shown in Scheme 7. Thus, the difference in bulkiness of the two R-groups attached to the prochiral carbon seems to be of little importance and, accordingly, oxime ethers in which this steric difference is small can be reduced with high enantioselectivity, as exemplified by the reduction of the oxime ether of octan-2-one (26; 80% e.e., Scheme 8). For a summary of asymmetric reductions of oxime ethers, see Table 3. BH3 I ( R )-24 anfi-oxime Me’O” - ( R 1-amine 92% 8.8. & synoxi me Scheme 7 26 ( R ) or (S), 80% 8.8. Scheme 8 In a different approach,44 the oximes were first converted into phosphinyl imines (Scheme 9). The introduction of the diphenylphosphinyl group enhances the electrophilicity of the imine carbon, thus making it more susceptible to nucleophilic attack.After the reduction, the phosphinyl moiety is easily removed. The reductions were performed on a number of substrates with Mosher’s reagent 16, (R)- or (S)-bi-2-naphthol/LiH4 (Noyori’s reagent),45 and K-glucoride 14 (Brown’s reagent) as reducing agents. The results are somewhat varying, but in some cases both high yields and high optical purities are obtained. The best results are shown in Scheme 9. 9 0 R’ = Me R2 = cyclohexyl R’ = Me: R2 = naphthyl Brown’s 95% yield 84% 8.8. { reagent 14 82% yield: 77% 8.8. lH+ Scheme 9 398 Contempora y Organic Synthesis 2.2.2 Reductions using internal chiral auxiliaries As a substrate bonded chiral auxiliary in C=N bond reductions, phenylethyl amine (27) is by far the most commonly employed.One reason is that it is easily removed with Pd/C to produce primary amines. Also, both enantiomers of 27 are commercially available. Using borane as the reducing agent, a 20 a-steroid is produced with 84% e.e. by reduction of the corresponding phenylethyl imine.46 Other applications of 27 as a chiral promoter include reductions of fluoroalkylated i m i n e ~ , ~ ~ the use of an NADH model as reducing agent,”’ and NaB& reductions of cyclic iminium ions.49 A number of imines derived from 27 have been studied in reductions with lithium aminoborohydrides. Reduction of the tert- butylmethylimine derivative proceeds with 92% d.e.50 Oxime ethers with chiral promoters derived from P-pinene or a-amino acids have been used in reductions with L i H 4 and BH3-SMe2.’l However, the degree of asymmetric induction is generally quite low.For example, the oxime ether 28 is reduced with 44% e.e. using LiAlH4. 27 28 3 Alkylations 3.1 Nucleophilic alkylations 3.1.1 Alkylations using internal chiral auxiliaries Yamamoto and co-workers have studied the addition of allylic metal compounds to aldimine 29,52,53 derived from l-(R)-phenylethylamine and 2-methylpropanal. With allyl-9-BBN’ the Cram They suggest that the reaction proceeds through transition state 30 (Figure l), in which the steric repulsions between the methyl group (and/or the phenyl group) and the other ligands on the metal are minimized. Further experimental data from Hoffmann and EichlerS3 indicatate that increased size of the ligands (L) leads to higher diastereoselectivity. With allylstannane, the selectivity depends strongly on the Lewis acid, as TiC14 gives a 82 : 18 and BF3 a 67 : 33 ratio in favour of the Cram isomer.All metals investigated give the Cram isomer as the major product. derivative 32, gives exclusively the Cram isomer in a syn :anti ratio of 75 : 25 (Scheme 11). Both enantiomers of the vicinal diamine 33 have been prepared by double addition of allylic Grignard reagents to dialdimines prepared from glyoxal and (R)- or (S)-phenylethylamine followed by removal is obtained in a 92: 8 ratio (Scheme 10). Addition of crotyl-9-BBN to the propanalTable 2 Non-catalytic asymmetric reductions of irnines Reducing agent Substrate e.e.Ref. 8 8 Me0 MomN WMe OMe 70% 9 95% 12 12 12 12 N/ph Ph 87% myo 71% 73% NnPh 46% PhAMe 12 25 25 26 29 29 29 29 29 Reducing agent Substrate e.e. Ref. 12 13 15 18 18 18 18 18 18 18 18 52% 78% 66Yo 73% 56% 65% 18% 65% 71 % 72% 36% 29 29 29 35,36 35,36 35,36 35,s 35,36 Table 3 Non-catalytic asymmetric reductions of oxime ethers ~~~ Reducing agent Substrate 8.8. Ref. 12 12 12 12 12 22INaBHJZrCI4 22/NaBH4/ZrCI4 22/NaBHJZrCI4 22/NaBH4/ZrCI4 22/NaBH4/ZrCI4 99% 81 % 91 % 62% 70% 66% 61% 6910 72% 92% 38 38 38 38 38 39,40 39,40 39,40 39,40 40 Reducing agent Substrate 8.8. Ref. BHB’TH F/ 22 BHs‘TH F/ 23 BHiTHF/ 24 BH3.W F/ 24 BHS.THF/ 24 BH3.M F/ 24 BHB.THF/ 24 BH3’TH F/ 24 BH3.THFI 24 N-OMe Ph A Me N.OBn NMOMe Ph4 95% 94.5% 93.2% 92% 90% 91% 92% 80% 86Yo 41 41 41 43 43 43 43 43 43 Johansson: Methods for the a.ymrnetric preparation of amines 399of the chiral auxiliary with Pd/C.55 The (R,R)- or (S, S)-diamines were produced in 6 : 1 ratios, respectively.It was not determined which enantiomer of phenethylamine gives which diamine, but in both cases only trace amounts of the meso- compound were detected. These findings are in accordance with those cited above. With this substrate, double chelation to the metal is suggested to take place, thus forming a bicyclic transition state (Figure 2). 29 ++J- NHR NHR Cram isomer anti-Cram isomer 92 a Addition of methylcopper and dimethyl cuprate to the aromatic aldimines 34 and 35 follow the same patterd6 (Cram : anti-Cram up to 90 : 10; Scheme 12), whereas the aliphatic aldimine 36 shows reversed selectivity (15 : 85).No reaction was observed with compound 37. Addition of allylic Grignard and copper reagents to 34 and 35 followed no general trend and the diastereoselectivity was found to be moderate.57 H H Starting Material (S,S) Cram : (R,S) anticram 34 90 10 35 73 27 36 15 85 37 ~KI reaction Scheme 10 Scheme 12 .L L 30 31 Figure 1 Interactions b e p e n the metal ligands and the chiral auxiliary 1 32 ++y NHR NHR Scheme 11 Me-,; ,Ph H7 Figure 2 55 Crarn-syn Cram-ant i 75 25 Allylic metal reagents based on Zd9 and Mg/Cd7 have been added with excellent diastereoselectivity to imines derived from (S)- valine (38, Scheme 13). The allylic metal species is suggested to add to a five-membered cyclic chelate between the imino ester and Al or Mg.The chiral auxiliary can be removed electrolytically in high yields. OMe eM*m 0 A 0 38 M = Ti, m = At _ _ R = Ph 95% d.e. M=Cu, m= Mg R=Ph 98% d.e. R = n-pentyl 98% d.e. M=Zn R = Ph 90% d.e. Scheme 13 Additions of aliphatic (Me, Et, Bu) organocerium reagents to allylic and prop-2-ynylic imines prepared from amine 39 and an aldehyde,@' provide secondary amines of high diastereoisomeric purity (86-98% d.e. Scheme 14). The auxiliary 39 can be removed without loss of diastereoisomeric purity, although the yields are not excellent. Turning away from imines, the SAMP-hydrazones 40 are very useful for highly asymmetric additions of organolithium6* and organocerium62 reagents to yield optically active hydrazines (Scheme 15). The hydrazines are prone to air oxidation and, hence, or (S, S)-enantiomer HZN NH2 (9 R1-33 400 Contemporary Organic SynthesisMe R'LUCeCb H2N R' Ph (S,S )-3e R2= Me 89% d.e.(S,S,S) R' = PhCEC R' = PhCEC R2= Et >98% d.e. (S,S,S ) R' = PhCiC R ~ = BU 92% d.e. (S,S,S) R' = Bu'CEC R2= Me >98% d.e. (S,S,S) R2= Me R ~ = BU 86% d.e. (S,S,S) 97% d.e. (S,S,S) Scheme 14 95 100 9 92 R' =Me p = P i , X = B r 5 R' = Et p=c-hex X=Br 0 (i) R2LVlHF, (ii) H20 8.8. of amine after reduction: R' = P f $=Et,X=Br 8 40 R' = Et I?- = Me, X = I 91 R' = But, R2=cyclohexyl R'= BU', R2= Bu" R1= Pt, R2 = ~ y ~ l ~ h e x y l 90% 93% 90% Scheme 16 (i) R2Li/CeC1JWlF, (ii) ClC02R d.e. of carbamates: (R3 = C02R) 0- OBn OH OBn YH OBn R' = PhCH2CH2, F?- = Me 96% R2MgxcR'yl!J? + RlVN$ 1 1 R Ph bh R' = PhCH2CH2, F?- = Ph 96% 92% H bh R' = (E )-CH3CH =CH, R2 = Me 42 Scheme 15 the yields are generally higher for the organocerium protocol, according to which the initially formed metallohydrazines are quenched with methyl or benzyl chloroformate before work-up to obtain the more stable carbamates.The N-N bond is readily cleaved with Raney-Ni without loss of optical purity. If desired, the auxiliary can be recycled. The chiral 1,3-oxazolidine 41, easily prepared in two steps from commercially available (+)-p~legone,~~ has been used by Pedrosa et aE. to prepare aminoalcohols of high diastereoisomeric purity through nucleophilic ring-opening with Grignard reagents.@ Thus, additions of phenyl and alkyl (Et, Pri, Pr", Me and cyclohexyl) Grignard reagents proceed with high diastereoisomeric discrimination (Scheme 16).When the nucleophile is a bromide-based Grignard reagent, the attack occurs from the nitrogen side of the heterocycle and, surprisingly, when the Grignard reagent is prepared from an alkyl iodide, the nucleophilic attack comes from the opposite side. A non-polar solvent such as hexane gives higher diastereoselectivity than diethyl ether. Removal of the chiral auxiliary is effected in a two-step procedure with high yields (the yield for each step is Additions of Grignard reagents to the nitrone 42 to yield hydroxylamines (Scheme 17) were found to 96-98%). 6 5 R' = 4-MeOPh, R2= Ph, X = Br 2 98 1 R'= Ph, I?-= Pr', X = CI R' = Ph, R2 = Bu', X = CI R' = n-pentyl, I?-= Me. X = Br 10 90 R' = n-pentyl, p = Bu'. X = CI 94 95 99 Scheme 17 I Favoured Disfavoured figure 3 Addition of Grignard reagents tgnitrone 42; chelated transition state model take place with high selectivity in most cases (60-96% d.e.).65 Notable exceptions are allyl- and (o-methoxypheny1)-magnesium bromides, which give high yields but low selectivity (56 and 59% d.e., respectively) and tert-butyl- and isopropyl- magnesium chlorides, where the yields remain low, but the selectivities are respectable (90 and 88% d.e., respectively). The stereochemical outcome was explained by invoking a chelated transition state model (Figure 3) which was supported by NMR investigations.Both steric and stereoelectronic Johansson: Methods for the asymmetric preparation of amines 401considerations predict nucleophilic attack from the same side. The hydroxylamines from the Grignard additions are converted into carbamates, reduced p-methoxyphenyl group can be oxidatively removed to produce a primary ami~~e.~' The N-p- methoxyphenyl imine of cinnamaldehyde shows with lithium in liquid ammonia, cleaved with periodic acid, and hydrolysed with aqueous hydrochloric acid to yield primary amines.derived sulfenimines 43 proceeds with high diastereoselectivity (98% d.e.).66 However, alkyl Grignard reagents show varying degrees of asymmetric induction (20-88% d.e.). Chiral oxime ethers 44, prepared from ephedrine and norephedrine, undergo 1,2-nucleophilic addition reactions with alkyllithium reagents with 64-88% d.e. The diastereoselectivity was found to mirror the synlanti ratio of the starting oxime ethers.67 Addition of ally1 magnesium bromide to camphor- 43 R = benzyl or neopentyl 44a X = NMe2, R = Me, Ps or Ph b X = N 3 .R=Pr' 3.1.2 Alkylations using external chiral auxiliaries Compound 45 has been used as an external chiral auxiliary in alkylations of N-(4-methoxyphenyl) imines with organolithium reagents.68 When organolithium reagents are added to N-p-methoxyphenyl-substituted imines in the presence of a stoichiometric amount of 45, asymmetric addition to the C=N bond is observed. The authors have also shown that it is possible to further enhance the enantioselectivity of the reaction by alkylsubstitution of the ortho-position of the N-p-methoxyphenyl moiety (Scheme The PhCH2 M e 2 4 45 H Y = H Y=Me R'= Ph, R2= Me 75Y0 8.8. 90% 8.8. R' = Ph, R2= BU 71% 8.8. 70% 8.8. R' = Ph, R2 = vinyl 77% 8.8.90% 8.8. R' = PhCH=CH, R2 = Me 40% 8.8. 90% 8.8. R' = 1 -Naph, R2 = Me 70% 8.8. 78% 8.8. R' = 2-Naph, R2= Me 74"/e.e. - R' = l-Naph, R2= Bu" 68%e.e. - lower enantioselectivity and, interestingly, exchange of the N-substituent to cyclohexyl results in 1,4-addition instead of 1,2-addition. When performing the reaction with catalytic amounts of the auxiliary 45, the asymmetric induction is lower.71 Several other chiral additives have been examined in enantioselective alkylations of N-(trimethylsilyl) benzaldehyde by Itsuno et al. (Scheme 19).72 The chiral dialcohol 46 gives up to 62% e.e. when butyllithium is used in the alkylation of N-(trimethylsilyl) benzaldehyde imine, although it is necessary to use four equivalents of the ligand. Surprisingly, the enantioselectivity is substantially lower in non-coordinating solvents such as hexane and toluene.V &ii Ph hexane 9.1% 8.8. diethylether 62% 8.8. tduene 7.2% 8.8. Fjh 46 Scheme 19 Denmark et al. have investigated the bis- isoxazoline 47 (Scheme 20).73 Without the ligand, little or no reaction takes place between methyllithium and 48 at -78 "C, whereas in the presence of 47 the addition is complete after 1 h. Using stoichiometric amounts of 47, the reaction selectivities are generally good (71-89% e.e.) for additions of methyllithium and vinyllithium to the examined imines. The enolizable imine 49 could be alkylated with a comparable level of enantio- selectivity, using a substoichiometric amount (0.2 eq.) of the bis-oxaline 47. Lesser selectivity is 47 50 N R'Li I 47 1 11 A R-H R' 'R' 48R=Ph 49 R = PhCH&H, 1.0 eq.47 0.2 eq. 47 R'Li = MeLi: 48 75% 8.8. 68% 8.8. RZi = MeLi: 49 91% 8.8. 02% 8.8. R U = CH2=CHLi: 49 89% 8.8. 82% 8.8. Scheme 18 Scheme 20 402 Contemporary Organic Synthesisobserved in additions of butyllithium (57% e.e.) and phenyllithium (30% e.e.), which is speculated to arise from weaker coordination of these lithium reagents to the ligand. With these reagents, the bidentate tertiary amine (-)-sparteine was found to be effective (butyllithium and phenyllithium added with 91 and 82% e.e., respectively). react with imines or silylimines in the presence of aminoalcohol promotors and, therefore, imine analogues have to be used together with these reagents. In one approach the N-(amidobenzyl) benzotriazoles (masked N-acylimines) 51 are used as substrates (Scheme 21).75 In the presence of (1 S, 2R)-( -)-N,N-dibutylnorephedrine (52), diethylzinc can be added with good selectivity (76% e.e.is the highest reported). The yields seem to drop as the selectivity goes up, though. In another approach, the N-diphenylphosphinoylimines 53 serve as electrophiles (Scheme 22).76 Hydrolysis of the initial products affords primary amines. The chiral auxiliary used in this study is the chiral aminoalcohol 54. Using diethylzinc, the alkylation proceeds with good selectivity (75-89% e.e.). Other alkyl groups, such as butyl and methyl, show about the same selectivity, but the yields are lower. When using 54 in catalytic amounts, a considerable drop in Unlike lithium reagents, alkylzinc reagents do not Scheme 21 51 Bu",N OH MeHPh 52 lEtzfi 0 PhA Et R = Me 46% yield, 76% 8.8. R = Pr' 80% yield, 41% 8.8.R = But 96% yield, oo/. 8.8. selectivity could be noted, although the enantiomeric mixture could be refined by crystallization. 3.2 Electrophilic alkylations The SAMP-hydrazones 55 (Scheme 23), previously mentioned in section 3.1.1, have also been used in diastereoselective electrophilic alkylati~ns.~~ When treated with lithium diisopropylamide and quenched with alkyl halides, these compounds provide a convenient route to P-chiral amines. After reduction of the C-N-bond and cleavage of the chiral 1-substituted pyrrolidine moiety with Raney-Ni/H2, the resulting amines are produced in 90-95% e.e. Another paper has dealt with the heterocycle 56 (Scheme 24).78 The carboxylic group in the a-position directs the incoming electrophile to the opposite face of the ring system.Thus, the dianion of 56 yields only one diastereoisomer when treated with methyl iodide or benzyl bromide. In contrast, reaction of dilithiated 56 with benzaldehyde afforded two diastereoisomers in a 1 : 1 mixture. However, this could be overcome by transmetallation of the dianion with MgBr,-etherate prior to addition of benzaldehyde: only one of four possible diastereoisomers was formed. The product LN OH MeHPh I I H30*, then OH- 54 1 ArYNH2 R Ar = Ph. R = Et Ar = 2-Naphthy1, R = Et Ar= Ph, R=Me Ar = Ph. R = Bun Ar = 4-MeC6H4, R = Et 90% e.e. 91% e.e. 85% e.e. (46% yield) 87% e.e. (56% yield) 90% e.e. Scheme 22 (iii) Catechoborane 55 R' = Me, R2 = n-pentyl R' = n-pentyl, R2 = Me R' = Me, R2= benzyl R' = benzyl, R2 = Me R' = Me.R2 = iso-hexyl R' = , R2= Me R' = phenyl, f# = Me R'T H f# A2 8.8. of amine after reduction: Scheme 23 Johansson: Methods for the asymmetric preparation of amines 403= Me1 oniy one diistereoisomer RX = BnBr Scheme 24 can be decarboxylated electrochemically. Meyers and co-workers have published several studies of chiral formamidines as vehicles for the production of optically active secondary a m i n e ~ . ~ ~ The strategy has been applied to the total syntheses of morphine," isoquinoline alkaloids" and ( + )-anisomycin.82 In another example, the same group has applied this strategy to the stereoselective alkylation of the formamidine 57 (Scheme 25).83 The anion of 57 is alkylated with 3-methoxybenzyl chloride and the formamidine part removed by treatment of the alkylation product with a mixture of hydrazine- ethanol-acetic acid.The e.e. of the resulting amine is 98%. The cyclic amine is then elaborated into the historically important alkaloid yohimbone 58. The N-benzyloxazolidinone 59 has also been used for asymmetric alkylations.84 Lithiation of 59 and subsequent treatment with an alkyl halide affords alkylation products with e.e.s between 75% and 99% (Scheme 26). Thereafter, the amine is liberated in three steps. In the same paper, electrophilic alkylations of the aminooxazoline 60 are described, but the diastereoselectivity is lower. The auxiliary has been employed for sequential asymmetric alkylations of i~oindoline.~~ 57 (i) Bu'Li.m -MeOBnCI I (ii) N&, WAC I h e several steps1 1 58 (-)-yohimbone Scheme 25 I 59 Ar = Ph RX- Me1 Ar = a-naphthyl RX = Me1 Ar = Ph RX = Bu"Br Ar= Ph RX = BnCl Ar = p -BnOC6H4 RX = BrCH2C02But Ar = Ph RX = EtI Scheme 26 B,ji up Ar "*' 99% d.e. 99% d.e. 99% d.e. 75"/0 d.e. 87% d.e. 93% d.e. 4 Double bond manipulations Diastereoselective 1,4-addition of amines to the furanone 61 has been shown to provide aminolactones (Scheme 27) which can be reduced to 2-amin0-1,4-diols.~~ The addition takes place anti to the menthoxy group and proceeds with high diastereoselectivity (more than 96% in all cases studied). Treatment of the adducts with lithium aluminium hydride affords (R)-2-amino-butane- 1,4-diols in good yields. 61 R' = H, R2= CeH& Scheme 27 Both cyclic and acyclic alkenes have been shown to react with the chiral chloronitroso sugar 62 as shown in Scheme 28.The resulting hydroxylamines can be reduced to allylic a m i n e ~ . ~ ~ The observed enantioselectivity is generally greater than 80%. 62 404 Contemporary Organic SynthesisScheme 30 X = OCOOEt 98 2 RpNH = bemylamine 80% 8.8. ( S ) 95 5 53% 8.8. ( S ) 88 12 X = OCOOEt 63% 8.8. (S) Asymmetric allylic amination has also been performed on substrates of the type 63 (Scheme 29).88 The chiral ferrocenylphosphine 64 is used together with Pd to form a chiral n-ally1 complex of 63, which is converted into an optically active allylic amine by nucleophilic attack by a benzylic amine. When the R-groups of 63 are phenyl, the reaction 63 R = Ph, X = OCOpEt R = Me, X = OP(0)Pb NuH = R = PS, X = OCOOEt NuH = E : Z 9 6 : 4 73% 8.8.23% 8.8. E : Z 100 : 0 97?40 8.8. G P P h 3 64 Scheme 29 X = OAC RdH = benzyhmine RzNH = (BOC)&JH proceeds with high enantioselectivity (85-98% e.e.) producing the (E)-isomer exclusively. With methyl groups, the enantioselectivity is somewhat lower and small amounts of the (2)-isomer can be detected [73% e.e., 4% (2)-isomer]. For other alkyl groups ( P i and P f ), the enantioselectivity is again higher (97 and 82% e.e., respectively) and essentially one geometrical isomer is formed. In a later paper,89 the authors describe the use of the (E)- and (Z)-isomers of 65 for the same operation (Scheme 30). The nucleophilic attack was found to be y-selective, leading to the SN2’ products.However, (2)- or @)-geometry around the double bond of 65 does not unambiguously lead to opposite configurations of the chiral carbon produced. Also, the degree of asymmetric induction varies, but is somewhat higher for the reactions performed on the w-. isomer. Acknowledgement Several people have read and commented on this manuscript. My gratitude goes especially to Dr Thomas Olsson, Magnus Eriksson, Dr Kaye Stern, and Professor Martin Nilsson for their advice and assistance during the preparation of this text. 5 References 1 For chiral auxiliary-based catalytic hydrogenations, see: (a) C.K. Miao, R. Sorcek and P.-J. Jones, Tetrahedron Lett., 1993,34, 2259; (b) R. Sreckumar and C.N. Pillai, Tetrahedron: Asymmetry, 1993,4,2095; (c) M.B. Eleveld, H.Hogeveen and E.P. Schudde, J. OR. Chem., 1986,51,3635; ( d ) A.W. Frahm and G. Knupp, Tetrahedron Lett., 1981, 22, 2633. Lett., 1973, 49, 4865. Chem., 1975,90,353. Wiegrebe,Angew. Chem., Int. Ed. Engl., 1985,24, 995. Organometallics, 1986, 5, 739. and J.P. Kutney, J. Chem. SOC., Chem. Commun., 1988, 1466. 2 N. Langlois, T.P. Dang and B.K. Kagan, Tetrahedron 3 N. Langlois, T.P. Dang and B.K. Kagan, J. Organomet. 4 R. Becker, H. Brunner, S. Mahboobi and W. 5 H. Brunner, R. Becker and S. Gauder, 6 G.-J. Kang, W.R. Cullen, M.D. Fryzuk, B.R. James Johansson: Methods for the asymmetric preparation of amines 4057 S. Vastag, J. Bakos, S. Toros, N.E. Takach, R.B. King, B. Heil and L. Marko, J. Mol. Catal., 1984,22,283. 8 J. Bakos, I. Tbth, B. Heil, G. Szalontai, L.Parkanyi and V. Fiilop, J. Organomet. Chem., 1989,370,263. 9 J. Bakos, A. Orosz, B. Heil, M. Laghmari, P. Lhoste and D. Sinou,J. Chem. SOC., Chem. Commun., 1991, 1684. 10 F. Spindler, P. Pugin and H.-U. Blaser, Angew. Chem., Int. Ed. Engl., 1990, 29, 558. 11 Y. Ng Cheong Chan and J. Osborn, J. Am. Chem. SOC., 1990,112,9400. 12 W. Oppolzer, M. Wills, C. Starkemann and G. Bernardinelli, Tetrahedron Lett., 1990,31, 4117. 13 (a) M.J. Burk, J. Am. Chem. SOC., 1991,113,8518; (b) M.J. Burk and J.E. Feaster, J. Am. Chem. SOC., 1992, 114, 6266; (c) M.J. Burk, J.P. Martinez, J.E. Feaster and N. Cosford, Tetrahedron, 1994,50,4399. hydrogenations of double bonds see M.J. Burk, J.E. Feaster, W.A. Nugent and R.L. Harlow, J. Am. Chem. SOC., 1993, 115, 10125. 15 C.A. Willoughby and S.L.Buchwald, J. Am. Chem. Soc., 1992, 114, 7562. 16 C.A. Willoughby and S.L. Buchwald, J. Org. Chem., 1993,58,7627. 17 In an earlier study, the same chiral moiety was used together with Zr for the enantioselective synthesis of allylic amines: R.B. Grossman, W.M. Davis and S.L. Buchwald, J. Am. Chem. SOC., 1991,113,2321. 18 F.R.W.P. Wild, J. Zsolnai, G. Huttner and H.H. Brintzinger, J. Organomet. Chem., 1982,232, 233. 19 C.A. Willoughby and S.L. Buchwald, J. Am. Chem. SOC., 1994, 116, 8952. 20 N.L. Lee and S.L. Buchwald, J. Am. Chem. SOC., 1994, 116,5985. 21 C. Bolm, Angew. Chem., Int. Ed. Engl., 1993,32, 232. 22 S.R. Landor, 0.0. Sonola and A.R. Tatchell, J. Chem. 23 S.R. Landor, Y.M. Chan, 0.0. Sonola and A.R. 24 See for example L. Delow and M. Srebnik, Chem.25 K. Yamada, M. Takeda and T. Iwakuma, Tetrahedron 26 K. Yamada, M. Takeda and T. Iwakuma, J. Chem. 27 S. Atarashi, H. Tsurumi, T. Fujiwara and I. Hayakawa, 28 K. Sato, Y. Matsura, M. Inoue, T. Une, H. Osada, H. 14 For the use of Et-DUPHOS in asymmetric SOC., Perkin Trans. I , 1978, 605. Tatchell, J. Chem. SOC., Perkin Trans. I , 1984, 493. Rev., 1993, 93, 763, or V. Singh, Synthesis, 1992,605. Lett., 1981, 22, 3869. SOC., Perkin Trans. I , 1983, 265. J. Heterocycl. Chem., 1991, 28, 329. Ogawa and S. Mitsuhashi, Antimicrob. Agents Chemother., 1982, 22, 548. 1990,3200. 29 B.T. Cho and Y.S. Chun, J. Chem. SOC., Perkin Trans. I , 30 See references 17-19. 31 E.J. Corey, R.K. Bakshi and S. Shibita, J. Am. Chem. SOC., 1987, 109, 5551. 32 H.C. Brown, B.T. Cho and W.S.Park, J. Org. Chem., 1988,53, 1231. 33 J.M. Hawkins and K.B. Sharpless, J. Org. Chem., 1984, 49, 386. 34 S. Yamaguchi and H. Mosher, J. 0%. Chem., 1973,38, 1870. 35 T. Kawate, M. Nakagawa, T. Kakikawa and T. Hino, Tetrahedron: Asymmetry, 1992,3,227. 36 M. Nakagawa, T. Kawate, T. Kakikawa, H. Yamada, T. Matsui and T. Hino, Tetrahedron, 1993,49, 1743. 37 G.J. Karabatsos and N. Hsi, Tetrahedron, 1967,23, 1079. 38 S. Itsuno, M. Nakano, K. Miyazaki, H. Masuda, K. Ito, A. Hirao and S. Nakahama, J. Chem. SOC., Perkin Trans. I , 1985,2039. 39 S. Itsuno, Y. Sakurai, K. Shimzu and K. Ito, J. Chem. SOC., Perkin Trans. I , 1989, 1548. 40 S. Itsuno, Y. Sakurai, K. Shimzu and K. Ito, J. Chem. SOC., Perkin Trans. I , 1990, 1859. 41 E. Didier, B. Loubinow, G.M. Ramos Tombo and G.Rihs, Tetrahedron, 1991,47,4941. 42 S. Itsuno, M. Nakano, K. Ito, A. Hirao, M. Owa, N. Kanda and S. Nakahama, J. Chem. SOC., Perkin Trans. I , 1985,2615. Tetrahedron Lett., 1988, 29, 223. Wambsgans, J. Org. Chem., 1987,52,704. J. Am. Chem. SOC., 1984,106,6709. 29, 2471. 2436. 6005. Lett., 1990,31, 797; (b) R.P. Polniaszek and C.R. Kaufman, J. Am. Chem. SOC., 1989,111,4859; (c) R.P. Polniaszek and J.A. McKee, Tetrahedron Lett., 1987, 28, 4511. 50 J.C. Fuller, C.M. Belisle, C.T. Goralski and B. Singaram, Tetrahedron Lett., 1994,35, 5389. 51 S. Itsuno, K. Tanaka and K. Ito, Chem. Lett., 1986, 1133. 52 Y. Yamamoto, T. Komatsu and K. Maruyama, J. Am. Chem. SOC., 1984, 106, 5031. 53 Y. Yamamoto, S. Ninshii, K. Maruyama, T. Komatsu and W. Ito, J. Am. Chem. SOC., 1986,108,7778.54 (a) D. Cram and F.A. Abd Elhafez, J. Am. Chem. SOC., 1952, 74, 5828; (b) M. Cherest, H. Felkin and N. Prudent, Tetrahedron Lett., 1968,2199. 55 W.L. Neumann, M.M. Rogic and T.J. Dunn, Tetrahedron Lett., 1991,32, 5865. 56 C. Boga, D. Savoia and A. Umani-Ronchi, Tetrahedron: Asymmetry, 1990,1,291. 57 A. Bocoum, C. Boga, D. Savoia and A. Umani-Ronchi, Tetrahedron Lett., 1991,32, 1367. 58 H. Tanaka, K. Inoue, U. Pokorski, M. Taniguchi and S. Torii, Tetrahedron Lett., 1990,31, 3023. 59 A. Bocoum, D. Savoia and A. Umani-Ronchi, J. Chem. SOC., Chem. Commun., 1993, 1542. 60 D. Enders and J. Schankat, Helv. Chim. Acta, 1993, 76, 402. 61 D. Enders, H. Schubert and C. Niibling, Angew. Chem., 1986, 98, 1118 or Angew. Chem., Int. Ed. Engl., 1986, 25, 1109. 62 (a) S.Denmark, T. Weber and D.W. Piotrowski, J. Am. Chem. SOC., 1987,109,2224; (b) D. Enders, J. Schankat and K. Klatt, Synlett, 1994, 795. 63 X.-H. He and E.L. Eliel, Tetrahedron, 1987,21,4979. 64 A. Alnerola, C. AndrCs and R. Pedrosa, Synlett, 1990, 763. 65 Z.-Y. Chang and R.M. Coates, J. 0%. Chem., 1990,55, 3475. 66 T.-K. Yang, R.-Y. Chen, D.-S. Lee, W.-S. Peng, Y.-Z. Jiang, A.-Q. Mi and T.-T. Jong, J, 0%. Chem., 1994, 59, 914. 814. Tetrahedron Lett., 1990,31, 6681. 43 Y. Sakito, Y. Yoneyoshi and G. Suzukamo, 44 R.O. Hutchins, A. Abdel-Magid, Y.P. Stercho and A. 45 R. Noyori, I. Tomino, Y. Tanimoto and M. Nishizawa, 46 G. Demailly and G. Solladie, Tetrahedron Lett., 1975, 47 W.H. Pirkle and J.R. Hauske, J. Org. Chem., 1977,42, 48 J.C.G. van Niel and U.K. Pandit, Tetrahedron, 1985,41, 49 (a) R.P. Polniaszek and L.W. Dillard, Tetrahedron 67 R.K. Dieter and R. Datar, Can. J. Chem., 1993, 71, 68 K. Tomioka, I. Inoue, M. Shindo and K. Koga, 406 Contemporary Organic Synthesis69 I. Inoue, M. Shindo, K. Koga and K. Tomioka, 70 ( a ) F.A. Davis and P.A. Mancinelli, J. 0%. Chem., Tetrahedron: Asymmetry, 1993,4, 1603. 1977,42, 398; ( b ) D.J. Hart, K. Kanai, D.G. Thomas and T.K. Yang, ibid., 1983,48, 289. 71 ( a ) K. Tomioka, I. Inoue, M. Shindo and K. Koga, Tetrahedron Lett., 1991,32, 3095; ( b ) I. Inoue, M. Shindo, K. Koga and K. Tomioka, Tetrahedron, 1994, 50, 4429. Chem. SOC., Perkin Trans. I , 1991, 1341. Am. Chem. SOC., 1994,116,8797. reagents see P. Beak and H. Du, J. Am. Chem. SOC., 1993,115,2516. Asymmetry, 1992,3,437. Chem. Commun., 1992,1097. 368. 1944. 72 S. Itsuno, H. Yanaka, C. Hachisuka and K. Ito, J. 73 S.E. Denmark, N. Nakajima and 0 . J . X . Nicaise, J. 74 For the use of (-))-sparteine and organolithium 75 A.R. Katritzky and P.A. Harris, Tetrahedron: 76 K. Soai, T. Hatanaka and T. Miyazawa, J, Chem. SOC., 77 D. Enders and H. Schubert, Angew. Chem., 1984,96, 78 I. Huber and D. Seebach, Helv. Chim. Acta, 1987, 70, 79 ( a ) A.I. Meyers, Aldrichimica Acta, 1985, 18,59; (b) A.I. Meyers, Lect. Heterocycl. Chem., 1984, 7, 75. 80 A.I. Meyers and T.R. Bailey, J. 0%. Chem., 1986, 51, 872. 81 A.I. Meyers, M. Bos and D. Dickman, Angew. Chem., Int. Ed. Engl., 1984, 23, 458. 82 A.I. Meyers and B. Dupre, Heterocycles, 1987, 25, 113. 83 A.I. Meyers, D.B. Miller and F.H. White, J. Am. Chem. 84 R.E. Gawley, K. Rein and S. Chemburkar, J. 0%. 85 R.E. Gawley, S.R. Chemburkar, A.L. Smith and T.V. 86 B.L. Feringa and B. de Lange, Tetrahedron Lett., 1988, 87 H. Braun, H. Felber, G. Kresse, A. Ritter, F.P. SOC., 1988, 110, 4778. Chem., 1989, 54, 3002. See also Chemtracts, 1989, 2, 46. Ankelkar, J. 0%. Chem., 1988, 53,5381. 29, 1303. Schmidtchen and A. Schenider, Tetrahedron, 1991,47, 3313. Miura and K. Yanagi, J. Am. Chem. SOC., 1989,111, 6301. Tetrahedron Lett., 1990, 31, 1743. 88 T. Hayashi, A. Yamamoto, Y. Ito, E. Nishioka, H. 89 H. Hayashi, K. Kishi, A. Yamamoto and Y. Ito, Johansson: Methods for the asymmetric preparation of amines 407

ISSN:1350-4894    

DOI:10.1039/CO9950200393

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

Synthesis of thiols, sulfides, sulfoxides and sulfones CHRISTOPHER M. RAYNER School of Chemistiy, University of Leeds, Leeds LS2 9JI; UK Reviewing the literature published between October 1993 and February 1995 Continuing the coverage in Contemporary Organic Synthesis, 1994, 1, 191 1 2 2.1 2.2 2.3 2.4 2.5 2.6 3 3.1 3.1.1 3.1.2 3.1.3 3.2 3.2.1 3.2.2 3.2.3 4 4.1 4.2 4.2.1 4.2.2 4.2.3 5 6 Introduction Synthesis of thiols and sulfides Simple alkylthiols and dialkylsulfides Substituted thiols and sulfides Thiols and sulfides as mediators of asymmetric transformations Allyl, homoallyl and benzyl thiols and sulfides Vinyl, allenyl and alkynyl thiols and sulfides Aryl thiols and sulfides Synthesis of sulfoxides Oxidation of sulfides Non-stereoselective oxidation Stereoselective oxidation Enant ioselect ive oxidat ion Non-oxidative sulfoxide synthesis General methods for sulfoxide synthesis Functionalized sulfoxides Unsaturated sulfoxides Synthesis of sulfones Oxidation of sulfides and sulfoxides Non-oxidative sulfone synthesis General methods for sulfone synthesis Functionalized sulfones Unsaturated sulfones Conclusion References 1 Introduction This review continues from the previous one published in 1994,' and covers new methods for the synthesis of acyclic thiols, sulfides, sulfoxides and sulfones.Cyclic systems will be covered elsewhere. A similar format has been adopted to that of the previous review in that it is divided into three Sections: t hiols and sulfides; sulfoxides; and sulfones. Each section begins with synthetic routes to simple systems, and then goes on to consider methods leading to more complex, polyfunctional molecules.Considerable emphasis has been placed on stereo- and enantio-selective reactions, reflecting the current interest in this area. A number of new texts on organosulfur chemistry have appeared over the past year or so. There is a recent edition of Patai on the chemistry of sulfur- containing functional groups.' Along with the usual physical aspects of organosulfur compounds, it contains chapters on the carbon acidity, pyrolysis, and electrochemistry of organosulfur compounds, thiyl radicals, synthesis of isotopically labelled organosulfur compounds, soft metal ion promoted reactions, thiol-disulfide interchange, vinyl sulfides, high-coordinated sulfur compounds and biological activity of sulfoxides and sulfones.A more general text on sulfur reagents in organic synthesis has also been publi~hed.~ Recently, the first of a new series of books on the synthetic aspects of organosulfur chemistry has also appeared, this volume containing chapters on B-ketosulfoxides, homolytic processes at sulfur, thiiranium ions, 1,3-dithioacetals and t hioalde h y d e ~ . ~ 2 Synthesis of thiols and sulfides There has been a review of thiols as ~ynthons.~ The chemistry of thiols is included in a lengthy review on organosulfur chemistry.6 The manufacture, main uses, and potential developments of industrial sulfur compounds have also been re~iewed.~ 2.1 Simple alkylthiols and dialkylsulfides The reaction of alkyl halides with various nucleophilic sulfur species is one of the classic methods of thioether synthesis.A recent report utilizes a borohydride exchange resin with phenyldisulfide in MeOH to generate a nucleophilic phenylthiolate which reacts with primary alkyl bromides, iodides and epoxides to give the expected phenylthioethers.' Secondary alkyl halides are also successful but require the use of elevated temperatures. The main benefit of this procedure is that essentially pure product can be obtained simply by removing the resin by filtration. The use of freshly prepared Na2S-AI2O3 for the synthesis of macrocyclic thioethers by reaction with dihalides has also been reported and obviates the need for the high dilution conditions often required for such macrocy~lizations.~ Other related reactions utilize Cs2C03 in DMF'Oi1* or KOH" to generate thiolate nucleophiles from thiols or thiolacetates respectively, which react with dihalides to form macrocyclic thioethers.Rayner: Synthesis of thiols, sulfides, sulfoxides and sulfones 409Recently, thiosilane reagents have been developed to extend this methodology. The use of TMSCl and anhydrous Na2S can be used for the in situ generation of the equivalent of TMSSNa. This reacts with alkyl halides to give symmetrical dialkylsulfides in good overall yield (Scheme l ) . 1 3 RBr - [ Me,Si-S-Nd - Na,S + Me,SCI CH&,24h R2S R = alkyl 7643% yield Scheme 1 In a related procedure, the use of the more robust triisopropylsilyl group in place of trimethylsilyl allows interception of the initial monoalkylation product 1.This can be deprotected to give the thiolate which on aqueous work-up gives the thiol, or alternatively the intermediate thiolate can undergo further ablation as a useful route to unsymmetrical sulfides (Scheme 2).14-16 1 I .. t R' = Bn, R' = Bn, RlSR2 R2=PP, '' 73% yield 769'0 yield Scheme 2 Other silane-based H2S equivalents have also provided routes to thiols, notably triphenylsilylthiol, which adds to alkenes under free radical initiation to give selectively, after deprotection, the primary thiol (Scheme 3).17 (I) AlBN or hu SH R = alkyl. aryl R% + Ph3SiSH * R N -%yield Scheme 3 (ii) CF3C02H A novel route to unsymmetrical thioethers utilizes the reaction of sodium or potassium thiolates with alcohols and carbon monoxide at elevated pressure and temperature (Scheme 4).18 A series of equilibria allows generation of the formate 2 and thiolate, which undergo conventional nucleophilic coupling to give the thioether in good to excellent yield.0 R~OH + co + PSM = + R'OM M=Na.K HCO2M + R2SR1 80-90% yield Scheme 4 410 Contemporary Organic 0 2 Synthesis Also, alcohols can be directly converted into thiols using Lawessons's reagent (3) (Scheme 5).19 This is particularly successful for allylic and benzylic halides, with some dehydration often occurring as a side-reaction. /OH SH 1 toluene, 0.5 h, A a+& 72% yield 13% yield Scheme 5 Alcohols can also be converted into thioethers using a CsF catalysed displacement of mesylate by a thiophenylate, with inversion of stereochemical configuration (Scheme 6).20>21 No elimination products are formed using this method. 48% yield Scheme 6 The use of Mitsunobu chemistry with thiol- derived nucleophiles, followed by hydrolysis of intermediate thiolesters, also provides a convenient method of converting alcohols to thiols (Scheme 7).22T23 A similar transformation has been achieved using Zn(CS2NMe2)2 as the nucleophile in the Mitsunobu reaction (Scheme 8).24 88% yield NaOH, Hfl 100%.3 h 65% yield I F 3 c v S H f 'F Scheme 7 Me I Me EtO&N=NCO& (il) LiAIH4. E t D I RBr. DBU 60% yield Me M e F S R Scheme 8Thiolacetate intermediates can also be directly converted into disulfides by treatment with clay supported Fe (NO3), (Clayfen) (Scheme 9).25 The thiocyanates 4 can also be converted into disulfides by treatment with one equivalent of Sm12.26 Alternatively, if two equivalents are used, a nucleophilic samarium thiolate is generated which reacts with acid chlorides to produce thiolesters in good yield (Scheme 10).Scheme 9 68-8370 yield Scheme 13 The Lewis acid catalysed addition of thiols to ketones with in situ reduction of the thionium ion intermediate using Et,SiH has been applied to the synthesis of a number of chiral sulfides derived from camphor (Scheme 14)” A single diastereoisomeric sulfide is formed, resulting from attack of hydride at the less-hindered face of the thionium ion. 4037% yield Scheme 14 Scheme 10 The cleavage of disulfides to give thiols using reagents such as dithiothreitol has been extensively investigated (Scheme 11). This has led to a useful, coherent set of equilibrium constants for a variety of thiol-disulfide interchange reaction^.^'*^ + RSSR = “‘L! + 2RSH HO Scheme 11 Carboxylic acids have been converted into thiols via their N-hydroxy-2-thiopyrone esters, by photolytic decarboxylation in the presence of sulfur and reduction of the initial polysulfide products (Scheme 12).2R This is successful for a wide variety of primary, secondary and tertiary alkyl carboxylic acids in high yield.Thioethers can also be prepared by reduction of sulfoxides and sulfones. The use of Mg with HgC12 catalyst,31 SOC12/Si02,32 Me3SiSNa,13 and TeC14/Na133 have all recently been reported to reduce efficiently sulfoxides to the corresponding sulfides. Similarly, LiAlHfliCl, reduces sulfones to sulfides in reportedly better and more reproducible yields than s m ~ ~ .~ ~ Finally, some new thiol protecting group chemistry has been reported. The use of bromochloromethane and KOH allows introduction of the MOM protecting group to a thiol, avoiding carcinogenic MOMCl (Scheme 15).35 Selective protection of thiols in the presence of alcohols is possible using this system. RSH cI’Br R O S v o * M e 70-90% yield MeOH, KOH 25 “c. 3-5 h Scheme 15 S (i) ho, 0 “c RSH (ii) NaBHb MeOH. 25 “c 0 8848% yield Scheme 12 Enzymatic reduction of thioketones provides a novel route to enantiomerically enriched thiols. Unfortunately, alcohol biproducts are also formed during reaction, resulting from thioketone hydrolysis by water in the reaction medium and subsequent enzymatic reduction, however, both products are obtained in high enantiomeric excess (Scheme 13).29 The introduction of benzyl-type protecting groups (including solid support resins) onto thiols using benzylic alcohols and chlorides, and benzaldehydes, is also reported, and is particularly useful for amino acid based systems (Scheme 16).36 In the case of aldehydes, the initial cyclic thioaminal products 5 are reduced with Et3SiH under Lewis acidic conditions to give the required benzylthioethers.has also been introduced as a new method for the protection of the thiol group on cy~teine.~~ It is readily introduced in high yield, and can be deprotected under mild conditions (Scheme 17). The allyloxycarbonylaminomet hyl (allocam) group Rayner: Synthesis of thiols, suljides, sulfoxides and sulfones 41 1fH + aoMe H2N CO2H X = OH, CI H2N *COsH EW-IN*CO~H Scheme 16 0 CF3Cofi CHgI, r.t I 7045% yield 65-1 00% yield Scheme 17 The nucleophilic boroxazolidinone cysteine equivalent 6, soluble in organic media, has also been developed and has been shown to displace primary mesylates to form S-substituted cysteine derivatives which are precursors to potential renin inhibitors (Scheme 18).38 0 Scheme 18 412 Contemporary Organic Synthesis 2.2 Substituted thiols and sulfides The nucleophilic ring-opening of epoxides with thiol-derived nucleophiles is a well established route to /3-hydroxysulfides and thiols.Triphenylsilane thiol has been introduced as a solid H2S equivalent for this reaction (Scheme 19).39 If an epoxide is treated with Ph3SiSH in methanol then P-hydroxythiols can be isolated directly. Alternatively, if the reaction is carried out in THF then the intermediate 0- triphenylsilylether, formed by silyl transfer within the initial epoxide ring-opened product, can be obtained.In the presence of excess epoxide, the intermediate thiols can be made to react further to give symmetrical /?-dihydroxythioethers by using Cs2C03 as base. OSiPh3 Ph3SiSH + R MeOHorTHF) NEt3 R K S H OrRI\/SH .. 4047% yield cs,co, 2k6H13&o) +Ph3SiSH Scheme 19 A number of other reagent systems have also been reported to catalyse the nucleophilic ring- opening of epoxides with thiols, including tetrabutylammonium fluoride (TBAF) (Scheme 20),40 titanium tetraisopropoxide (Scheme 21)41 and sodium borohydride, used in situ after Sharpless asymmetric epoxidation and is superior to the corresponding titanium-catalysed process (Scheme 22).4* PhSH, TBAF (cat.) Ph 64% yield 23% yield Scheme 20 Scheme 22 (i) C6HI3SH.NaBH4, P h H J (ii) NaOH (aq.) H0-sc6H13 HO 75% yieldA new synthesis of P-hydroxythioethers from carbonyl compounds using SmIz and an a-chlorosulfide has been reported (Scheme 23).43 Yields are moderate to good, and the reaction is successful with aromatic and aliphatic aldehydes and ketones. .. R3 = Me, Ph Scheme 23 The selective heteroatom directed chlorohydroxylation of an allylthioether allows access to chlorohydrins which, on treatment with base, give 2,3-epoxysulfides (Scheme 24).44 Related systems, prepared in a homochiral form via Sharpleis asymmetric epoxidation can be used as sources of reactive thiiranium ions which react regiospecifically with nucleophiles at C-( l), to generate l-substituted 3-hydroxy-2-thioethers in moderate to excellent yield and with full control of absolute and relative stereochemistry (Scheme 25).45 LipdCI, (1 Om~l%) RSe R S L C I DMF, HzO I NaOH.H90 = Phv 73-79% yield R S A o Scheme 24 Bdays (ii) K2C03, MeOH 1 53-81% yield Scheme 25 8 PPL, pH 72.0 'C 8 85% yield, 96% e.e. OAc OAc OAc OH 7 86% 8.8. Scheme 26 The asymmetric dihydroxylation of unsaturated sulfides provides an attractive route to the synthesis of optically active dihydroxy sulfides, with good to excellent enantiomeric excesses being achievable (Scheme 27), and with only minor traces of S-oxidation observed in a few cases.47 OH R' = Ph, Bn R2 = H, Ph, alkyl n =1,2 OH 6647% yield 6148% 8.8.Scheme 27 High levels of stereocontrol have been obtained in the addition of organometallic reagents to a-phenylthioaldehydes (Scheme 28).* Addition of MeTiC13 gave the highest syn :anti ratios, whereas Grignard and organolithium reagents gave significantly lower stereoselectivity. The product /3-hydroxy sulfides are obtained in good yield. Scheme 28 The nucleophilic opening of thiiranes has also been used for the synthesis of substituted thiol derivatives. The epoxide 8, obtained via Sharpless epoxidation, is converted into the thiirane using OR OR S H2NKNH2 MeOH. 5 d '< OH 67%yie# OH An alternative approach to optically active &%epoxy sulfides relies on the lipase hydrolysis of the prochiral diacetate 7 (Scheme 26).46 The initial product is converted, in a further eight steps, into the phenyl glycidyl sulfide which has potential as a new chiral building block for the synthesis of tertiary alcohols.Scheme 29 YR QR OH OH 9 : 1 60% yield Rayner: Synthesis of thiols, sulfides, sulfoxides and sulfones 413thiourea. Subsequent treatment with allylmagnesium bromide results in regioselective ring-opening of the thiirane (Scheme 29).49 The initial unsaturated thiol products were too unstable to be isolated cleanly, and were therefore isolated as their benzoate thioesters, which also served to protect the thiol groups in a subsequent osmylation reaction. The nucleophilic ring-opening of aziridines by thiols provides a route to 6-amino sulfides, and has been used in the synthesis of unusual amino acids.Thus treatment of aziridine 9, again obtained via Sharpless asymmetric epoxidation, with a thiol in the presence of BFJOEt, gives the protected a-methylcysteine in good yield (Scheme 30).50 c A F.rB.OEt9. CHoCh H Me 78% ykid Scheme 30 An alternative approach for the synthesis of optically active 6-amino sulfides is nucleophilic ring- opening of prochiral N-acyl aziridines by thiols in the presence of a chiral zinc-based Lewis acid (Scheme 31). The complex formed by reacting diethylzinc with L-( + )-diisopropyl tartrate (DIPT) catalyses such a reaction with up to 88% e.e.51 Use of less than stoichiometric quantities of catalyst is also successful but gives significantly lower enantioselectivities. COAr i) ZnEtp, L-(+)-DIPT RSH, CH&, 0 "C ii) HZO 63-0846 yield d' 12438% e.e.Scheme 31 Recently, the use of enantiopure thiosulfonium salts has led to a method for synthesis of optically active 6-amidosulfides. Addition of a homochiral thiosulfonium salt to trans-hex-3-ene forms a thiiranium ion which reacts with acetonitrile to give the acetamide after aqueous hydrolysis, in a Ritter type reaction. Enantioselectivities are moderate to Scheme 32 414 Contemporary Organic Synthesis (ii) H,O, NaHCO, NHAc I SMe good, but side-reactions are observed under reaction conditions favouring high e.e.s (Scheme 32).30,52 New methods for the synthesis of a-sulfenyl carbonyl compounds have been reported. Sulfonium salts derived from formaldehyde dithioacetals react with aromatic aldehydes under basic conditions to give 2-aryl-2-thioalkyl acetaldehydes in good yield (Scheme 33).53 The reaction proceeds by initial formation and subsequent rearrangement of the epoxide 10 under the reaction conditions.The products are reported to be in equilibrium with their enol tautomers. I Me-C+/\ ""*,c/\ I O H C Y ""3 0 Y 61434% yield Scheme 33 The electrolysis of alkenylsulfides, in the presence of thiols and oxygen, provides an alternative route to a-(pheny1thio)carbonyl compounds via an electroinitiated radical reaction, with net 1,2-transposition of the carbonyl group (Scheme 34).54 A similar oxygenation of alkynes also provides a route to this class of compounds. RYcHo PhSH. MeCN. 0 2 SPh 5247% yield PhSH, MeCN, 02. - e- (cat.) I 6680% yield R-H xR PhSH, - e-(cat.) MeCN. 02 PhSJR 6641% yield Scheme 34 Optically active a-sulfenyl aldehydes can be prepared from enantiopure a-sulfenyl dithioacetals (Scheme 35).55 Hydrolysis of the dithioacetal functionality gives a-sulfenyl aldehydes which can be isolated in an optically active form in good yield but racemize on attempted purification by column chromatography on silica gel.Ph Me 82% yield I PhI(CF&O& 75% yield J Scheme 35 An attractive alternative route to a-sulfenyl aldehydes utilizes an Evan's oxazolidinone chiral auxiliary to control stereochemistry during sulfenylation of an enolate anion (Scheme 36).56 The product is then best converted into the aldehyde by reduction (LiBH4) to the alcohol and oxidation with the Dess-Martin periodinane.Other procedures resulted in significant racemization. 0 0 R A N K , (i)LDA.-78"c R$,,,lo # SPh (ii) PhSSPh, -78 "c.3 h \ ~ - 9 % yield Ph (I S4% d.e. Ph (i) LiBH4 H@ (ii) Dess-Marlin periodinane 9042% yield I VCHO SPh Scheme 36 The addition of thiols to a, P-unsaturated carbonyl compounds provides a route to P-sulfenyl carbonyl compounds. Recent developments in this area include the use of ytterbium or samarium metals which react with disulfides in the presence of catalytic benzophenone to generate lanthanoid thiolates, which in turn react with enones to give Michael adducts in good yield (Scheme 37).57 TBAF has also been reported to catalyse the addition of thiols to P-alkyl-a, B-unsaturated trifluoromethyl ketones, giving exclusive 1,4-addition in good yield (Scheme 38).58 Phase transfer catalysis has also been shown to promote similar reactions between polysulfide anions and a, P-unsaturated carbonyl compound^.^^ Scheme 38 Related processes have also been used to prepare optically active P-sulfenyl carbonyl compounds.These include the Lewis acid catalysed conjugate addition of thiols to camphorsultam derivatives,60 and also the corresponding base-catalysed process (Scheme 39).61 0 EtSH. Bu"L1 x, qh M F , -78 "c+f.t. * 'SEt II 98% yield 19:l seledivity (I) LIOH, THF, H& (iii) CH2N2. Et20 (ii) H30' 1 91 % yield 0 ,Ye <SEt Scheme 39 An interesting alternative method of asymmetric induction involves the enantioselective Michael addition of thiols to a, P-unsaturated ketones as their inclusion crystals with optically active hosts such as 11 (Scheme 40).62 The reaction occurs in the solid state and is catalysed by ultrasound.Very good e.e.s are obtained with pyridyl thiols, but no enantioselectivity is observed with simple thiophenols, even though the reaction occurs in quantitative yield, implying that the pyridine nitrogen plays a crucial role in the stereocontrol. ultrasound SPY 51% yield I ~ 0 ~ 0 e . e . I:I inclusion crystal -I THF, HMPA Yb(orSm) + 1.5RSSR PhpCO (at.) Scheme 37 0 R = Me, 58% yield Scheme 40 Other methods of synthesizing optically active p-sulfenyl carbonyl compounds include asymmetric hydrogenation of unsaturated carbovlic acids using a ruthenium catalyst modified with a chiral BINAP ligand (Scheme 41).63 High enantioselectivities can be obtained, with the enantiofacial selectivity being Rayner: Synthesis of thiols, suljides, sulfoxides and sulfones 415RU(OAC)~, H2 (1 50 bar) D (S )-(-)-BINAP C6H12,lOO “C >95% yield Up to 84% e.e.But’ ‘&02H Scheme 41 reversed if the reaction is carried out in trifluoroethanol rather than cyclohexane (up to 64% e.e.) Baker’s yeast reduction of /?-thioketoesters gives the corresponding /?-mercaptoester with low to very high enantiomeric excess (Scheme 42).29 A serious limitation on this reaction is that significant amounts of fl-hydroxyesters are also produced, resulting from reduction of a B-ketoester formed in situ by hydrolysis of the thioketone in aqueous media. R = H, Me. Et 1-93% 8.8. Scheme 42 The preparation of isotopically labelled B-chlorosulfides shows interesting scrambling properties depending on the synthetic route used (Scheme 43).64 If a deuterium labelled /?-hydroxy sulfide is treated with thionyl chloride then complete scrambling of the carbon atoms is observed, probably due to participation by the sulfur atom.If, however, a labelled chlorohydrin is used, and the alcohol converted into the thioether using a disulfide and tributyl phosphine, then no scrambling of the label is observed. D D L S P h - CI HO 1 : 1 Scheme 43 New methods for the preparation of fluorinated sulfides have also been reported. The selective anodic monofluorination of fluoroalkyl and alkyl sulfides provides access to a-fluorosulfides in good yield (Scheme 44).6s Alcohols are converted into trifluoromethyl sulfides by treatment with bis- (diethy1amido)chlorophosphite followed by trifluoromethyl disulfide (Scheme 45).66*67 c NEt,MF, MeCN F -2e-,4* 5 1 4 % yield Scheme 44 CF3SSCF3 5 min.. -set20 “c W 5 % yield I R = Bn, CH2C02Et, CHMeCOZEt Scheme 45 Finally, in a synthesis of dysoxysulfone 12, a sulfenylsulfonate is reacted with a thiolate to form a complex polysulfide by disulfide bond formation (Scheme 46).68 The final product, 12, is an active component of a tea made from the leaves of Dysoxylum richii, which, according to a wise old native, when prepared by boiling the plant with water in a bully beef (or salmon) tin, is capable of relieving all pains in the head, arms, legs, or body! 0, KMnO,, Zn(OAc), 57% yidd MgSO4, Me2CO I Scheme 46 2.3 Thiols and sulfides as mediators of asymmetric transformations There have been a number of reports of the use of functionalized homochiral thiols and thioethers for controlling asymmetric induction in new enantioselective processes.The asymmetric reactions of high symmetry chiral organosulfur reagents has been reviewed.69 Whilst it is beyond the scope of this review to discuss these in any detail, the potential importance of this area warrants brief discussion of the use and efficiencies of these compounds. New synthetic routes to these compounds are included in the appropriate section. The /?-aminothiol derivatives 13,70 14,71 and 15,72 and the thioether 1673 have been shown to promote asymmetric addition of organozinc reagents to aldehydes. All are capable of excellent asymmetric induction. The thiols 1774 and 1t17’ are both efficient ligands for enantioselective Michael addition to a, /?-unsaturated ketones.Moderate to good 416 Contemporary Organic Synthesisenantioselectivities can be achieved with either ligand. Related systems, such as 19, have been used in asymmetric palladium-catalysed allylic substitution reactions with up to 96% e.e.76777 Sulfides tethered to oxazolines, e.g. 20, also give high selectivity in similar reactions.77 13 14 15 Me Me+ ' X ! h €1-N OH H \ R 16 17 Me/ 19, n =o, 1,2 20 18 The homochiral sulfides (21-23)30 and 2452 have been investigated as asymmetric sulfenylating agents when converted into the corresponding thiosulfonium salts. Highest enantioselectivities are reported with (24, Scheme 32). The related ligand 25 has been used in asymmetric hydroformylation reactions, and gives up to 20% e.e.78 introduced as a new chiral resolving agent, and has been used to resolve racemic binaphth01.~~ The application of the new, camphor-derived chiral auxiliary 27 for the synthesis of optically active Neomenthylthioacetic acid chloride (26) has been 21 R = Ph, 1-Naphthyl, 2-Naphthyl 22 23 24 25 26 Me-Me Me MeC V 27 28 R = Me, Bn, P i primary amines via the corresponding sulfinimines has been reported,80 and sulfide 28, prepared from ( + )-isopinocampheol, has been used for asymmetric epoxidation of carbonyl compounds via the corresponding sulfur ylide with up to 43% e.e.24 2.4 Allyl, homoallyl and benzyl thiols and sulfides The Pdo catalysed allylation of thiols using allylic carbonates and aromatic thiols provides a route to allyl and cinnamyl aryl sulfides in moderate to excellent yield (Scheme 47).'l The products of a-substitution predominate; however, y-substitution is observed in some cases.PhSH, Pdp(dba)o f R 6oco2Me dppb, THF, 50°C * -SPh 44-089" yield Scheme 47 An interesting route to allyl sulfides is by loss of C 0 2 from a substituted P-lactone. The substrates are prepared by Michael addition of a thiol to an exocyclic a, P-unsaturated P-lactone. High trans selectivity can be obtained in the reaction (up to ~ 9 5 5 ) and this stereochemistry is retained in the allyl sulfides after extrusion of C02 (Scheme 4Q8* SR2 SR2 Scheme 48 The ,migration of a phenylthio group of a P-hydroxy sulfide can in some cases lead to formation of allylic sulfides by elimination of a proton in a thiiranium ion intermediate (Scheme 49).83 In the case of the acetamide 29 the allyl sulfide is obtained in high yield; however, other reaction pathways can be dominant if subtle structural modifications are made.t SPh 91% yield Scheme 49 Rayner: Synthesis of thiols, sulJides, sulfoxides and sulfones 417Homoallyl thiols can be obtained in an optically active form by stereospecific [2,3]-thia-Wittig rearrangement of S-ally1 a-lithiated sulfides (Scheme 50).84 The a-lithio sulfides are generated in situ by tin-lithium exchange, and were found to be sufficiently configurationally stable to allow stereospecific rearrangement with inversion at the carbanionic centre. In less favourable cases (S-benzyl thioethers) much lower stereoselectivity was observed probably due to some loss of configuration at the carbanionic centre prior to rearrangement.In a related reaction, high 1,2-asymmetric induction was observed in a [2,3]-thia-Wittig rearrangement giving the homoallyl thiol product as a single isomer (Scheme 51).85 (i) LIHMDS, M F , (ii) TBDMSCI. -78 "C -78 to 20 "C Scheme 50 + OBn i) NaOEt, EtOH, r.t. c E ' B " g s n ~ I 88% yield 1"." Ph Bm 89% yield Bu3SnAF v OBn Bu"LI, -78 "C >8% yield 1 PH + OBn Scheme 51 Unsymmetrical benzylic disulfides have been synthesized via the corresponding Bunte salts derived from benzylic bromides and chlorides (Scheme 52).86 The Bunte salts are synthesized in the usual manner using thiosulfate in DMSO, and subsequent treatment with thiolate generates the unsymmetrical disulfide. DMSO y Y X = Br, CI Y = H, NOz, Br, OMe, Me, OCOAr Y 10^ s's, 51 -75% yieM Scheme 52 418 Contemporaly Oqanic Synthesis A new method of preparing benzyl methyl thioethers involves the 'superelectrophilic' methylthiomethylation of aromatics rings with a chloromethyl methyl sulfide:AlC13 (1 : 2) reagent (Scheme 53).87 Predominant para-disubstitution is observed in the products (up to 93:7).The highly electrophilic complex 30 is believed to be the active species-in the reaction, requiring Lewis acid for formation. two equivalents of 30 I X =\?$, F, Me, Et 76-94% yield Scheme 53 Finally, an unusual rearrangement leads to ortho- thiomethylation of arylacetic acid derivatives (Scheme 54).88 The ester precursors are readily prepared from an arylacetic acid and an a-chlorosulfide in the presence of NEt3. Subsequent formation of the ketene acetal by deprotonation and 0-silylation followed by warming to 20 "C or above results in formation of the ortho-thiomethylated arylacetic acid derivatives in good yield.The precise mechanism of this process is unclear at present. Scheme 54 2.5 Vinyl, allenyl and alkynyl thiols and sulfides The palladium(0)-catalysed thioboration of terminal alkynes with 9-( alky1thio)-BBN derivatives provides a route to vinyl sulfides (Scheme 55).89 Protonolysis of the initial thioboration product using MeOH provides the terminal 2-(alkyl- or phenylthio) alkene with high regioselectivity. The reaction is successful for a wide variety of substrates. With more hindered thiols (eg. But) a more reactive form of palladium, generated from Pd(dba)2 and Ph2[2,4,6-(Me0)3C6H2]P is required for good yields.The palladium-catalysed regioselective addition of thiophenol to conjugated enynes also results in formation of the terminal 2-(thiophenyl)-1,3-dienes (Scheme 56).90 3 'R+H + 2 ~ - ~ - ~ (I) Pd(PPhd4 (at.) THF, 50 "c, 24 h. styrene (ii) MeOH 60-869/. yield 'RY ~ ' = v a r i M s sR2 R2 = alkyl, phenyl Scheme 55 R dPh oxone MeOH. 0 "C 6047% yield I MCPBA, 65-78% yield CHZCIZ I R Scheme 56 A very powerful one-pot method for vinyl sulfide synthesis is via catalytic hydroboration/cross- coupling of thioalkynes. Treatment of a thioalkyne with catechol borane in the presence of a Pdo catalyst regioselectively gives the terminal 1-(alkyl- or phenylthio) alkene (Scheme 57)?l The intermediate borane can be further utilized in a cross-coupling reaction to give a trisubstituted alkene with full control of double bond geometry.PdClddppf) C&, r.t. 1 4 R3$ SR2 3MNaOH,A SR2 H 7140% yield H Scheme 57 Conjugated (E,E)- 1 -phenylt hiobuta- 1,3-dienes have been synthesized via a trimethylsilylalkyne using a Ni"-based cross-coupling between Grignard reagents and (E)- 1-chloro-2-phenylthioethene (Scheme 58).92 The initial coupling product, after desilylation, undergoes regio- and stereo-specific hydrozirconation. Work-up using N- bromosuccinimide (NBS) gives the vinyl bromide, which can undergo further cross-coupling if required. Reaction of aromatic thiolates with vinyl bromides in the presence of a Pdo catalyst also allows access to vinyl aryl sulfides (Scheme 59).14715 Me,Si+MgBr phs PhS4CI NiClAdppe).THF 70% yield (i) W, MeOH (ii) CpzZr(CI)H (iii) NBS 1 60% yield PhS- Br Scheme 58 a i)CsF,DMF *a Scheme 59 The regioselective allylation of enol silyl ethers with y-heterosubstituted vinyl thionium ions provides a route to l-(phenylthio)-alk-l-en-5-ones. The reactive thionium ion intermediates are generated under Lewis acid conditions from the corresponding dimethoxy- or bis-(pheny1thio)acetals (Scheme 60).93 y-Hydroxy-a, fi-unsaturated sulfides have been prepared by base-induced elimination in a 2,3-epoxysulfide. Although high yields are obtained, E : Z ratios can be low (Scheme 61).94 R r X = OMe, SPh OSiMe3 I6 W S P h 67432% yield Scheme 60 B n O w S P h OH 8u"Li (3 eq.) THF, -78 "c, 30 min. I 81% yield B n o v s p h OH OH 3:2 EZ Scheme 61 Rayner: Synthesis of thiols, suljides, suIfoxides and suIfones 419A number of routes to carbonyl-substituted vinyl thioethers have been reported.These include the oxidative chlorination of a-(phenylthio) amides to give (2)-3-chloro-2-phenylthio acrylamides (Scheme 62),95 the Vilsmaier reaction of dithioketals for the synthesis of /3-(alkylthio)ethylenic aldehydes (Scheme monoacetal of a /3-ketoaldehyde, or an a, /3-unsaturated ketone and oxidation, for the synthesis of /3-(alkyl- or ary1thio)-a, /3-unsaturated ketones (Scheme 64).97 and addition of thiols to the NCS (2.2 eq.) NHR CCl4.A P h S q Mi3 57-80% yield Scheme 62 Buns SBu" SBU" R2 bH Scheme 66 sulfides (Scheme 67).'" Alkynyl sulfides have been synthesized either using phenylsulfenyl halides and terminal alkynes in the presence of CuI which avoids the use of the HMPA required for previously reported procedures (Scheme 68),"' or by using Ni" or Pd" catalysed coupling of phenylthioethynyl magnesium bromide with allylic halides (Scheme 69).'02 Scheme 67 Scheme 63 Rs>o (0 PhSH.NEt3 (ii) NCS. NEt3 73% yield =ko Bu'SH. CF&O&I 85% yield Scheme 64 Trifluoromethyl vinyl sulfides can be prepared by a Wittig reaction on thioltrifluoroacetates. High (2)-selectivity is observed, and both stabilized and non-stabilized ylides can be used (Scheme 65).98 Ph3P=CH R2 F3C 8,, 2 h. r.t. * SR' phenyl, CO2Et 4045% yield F3c Scheme 65 A novel synthesis of enethiols by the retro-Diels- Alder reaction of dihydroanthracene derivatives has been reported (Scheme 66).w The reaction is stereospecific in appropriate systems, consistent with the concerted nature of the reaction.The ethene derivative (R' = R2 = H) is unstable and polymerizes at room temperature, however, more substituted systems are stable in solution. by base-catalysed isomerization of prop-2-ynylic A number of allenic sulfides have been prepared R+H PhSCl R-sph CuI. DMF 3846% yield Scheme 68 Br NClddppe) THF. r.t 14-8296 yield - PhS-MgBr c PhS = Scheme 69 2.6 Aryl thiols and sulfides A new method for the synthesis of aryl thiols and sulfides utilizes the Pdo-catalysed coupling of aromatic halides with the potassium salt of triisopropylsilylthiol (Scheme 70). l4?l5 The initial products can be further transformed into the corresponding thiols or aryl alkyl thioethers (Scheme 2), or aryl vinyl thioethers (Scheme 59).2-arylthio-cyclohexanones provides a novel route to The brominative aromatization of 2-alkylthio- and Br Scheme 70 420 Contemporary Organic Synthesisortho-(hydroxyaryl) thioethers (Scheme 71).'03 Mechanistic studies on SNAr reactions of thiolate anions with ortho-halonitrobenzenes have also been reported, and have shown that the efficiencies of the reactions with the chloro-, bromo- and fluoro- nitrobenzenes are greater than those with the corresponding iodonitrobenzenes.'04~105 use for asymmetric synthesis (Section 2.3). The aromatic thiol precursors are almost invariably prepared by a Newman-Kwart rearrangement of an 0-thiocarbamate, obtained by acylation of the corresponding phenol. An elegant example of this is the formation of the phenolthiophenol (+)-31 which is an effective catalyst for Michael additions using organocuprate reagents.Selective mono- acylation is achieved by use of the stannylene acetal intermediate (Scheme 73).'07 Protection of the remaining phenol as its carbamate, thermolysis, and hydrolysis gives (&)-31 in three steps from binaphthol. The Newman-Kwart rearrangement has been used for the synthesis of a number of related systems, including 321°8 and 25.78~109~1'0 Br20rNBS SR 7m2%yiekl SR Scheme 71 The thiocyanation of phenols using phenyliodine dichloride and lead (11) thiocyanate proceeds with high para-selectivity (Scheme 72).'06 The active species in the reaction, generated in situ, is believed to be phenyliodine bis(thi0cyanate).32 PhIClp 0-C + 6147% yield OH 0. Scheme 72 There has been considerable recent interest in the synthesis of axially chiral binaphthyl thiol and sulfide derivatives, mainly because of their potential 31 Scheme 73 (ii) HCI, dkxane 7540% yield (ii) 250 "c, 5 h (iIi) KOH, MeOH 75% yield New methods for the optical resolution of such binaphthyl systems have also been reported. These include formation and chromatographic separation of diastereomeric dithioacetals derived from glucose (Scheme 74),"' an esterase resolution of a dipentanoate thioester (Scheme 75)112 and by asymmetric oxidation (Scheme 84).'13 3 Synthesis of sulfoxides 3.1 Oxidation of sulfides The preparation of sulfoxides by oxidation of the corresponding sulfides continues to be an important area of research.This section is divided into three parts. The first is concerned with new methods of oxidation where the problem of chirality at sulfur is not addressed. The second part is concerned with diastereoselective processes, whereas the final part concentrates on new methods for the enantioselective oxidation of sulfides to sulfoxides. 3.1.1 Non-s tereoselec t ive oxidation A number of new reagent systems have been developed for the simple oxidation of sulfides to sulfoxides. These include the following: the oxaziridinium salt 34, derived from dihydroisoquinoline, which can also be used catalytically with similar efficiency using oxone as reoxidant for the iminium ~ a l t , " ~ the peduoro-cis- 2,3-dialkyloxaziridine 35 at -40 "C (the volatile imine biproduct is easily rem~ved),"~ salts between selenoxides and sulfonic acids,' dimethyldioxirane (DMDO), generated in situ using Rayner: Synthesis of thiols, sulfides, sulfoxides and sulfones 421(hr) LIAIH,.Et@, 97% Nld 33 Scheme 74 Cholesterol ester- pH 72, sodium taurocholate~ Et@, phosphate buffer I + 33 30% yield, 98% 8.8. 47% yield, 98% e.e. Scheme 75 34 35 36 acetone and oxone in water (particularly good for large-~cale),'~~~'~~ TBHP with or without H2SO4 catalyst,'" H20z and MeCN at 0 "C (via peroxyimidic acid intermediate 36),lZ1 TiC13/H202 in MeOH/H20,1z~~ethylrhenium t r i ~ x i d e / H ~ O ~ , ~ ~ ~ MnOJTMSCl, Mn02/HC1,125 nitric acid catalysed by FeBr3,lZ6 Fe"', Ni" or Co" P-ketoester complexes in the presence of a branched aldehyde and 02,1273128 NaBr02/3H20 in the presence of an H+ exchanged metallophthalocyanine and iodosylbenzene (accelerated by ultrasound)131 and photooxidation using tetranitr~methane'~~ or O2 and 1,4-dimethoxynaphthalene as sensiti~er.'~~ Finally, oxidation of p-nitrobenzylthioethers and p- nitrobenzenethioethers using NaI04 catalysed by an iodosylbenzene and TsOH catalyst,lN + antibody raised against hapten 37 has been reported, and shows considerable promise for the future.134 H02C' 37 3.1.2 Stereoselective oxidation There have been a limited number of studies on the diastereoselective oxidation of sulfides to sulfoxides, where the stereochemical configuration at sulfur is at least partly determined by pre-existing chiral centres in the substrate. The oxidation of a range of a-methylbenzyl sulfides with Bu'OCl, followed by aqueous base hydrolysis proceeds to give the sulfoxides with good to excellent diastereoselectivity for a range of systems, the best being a-methylbenzyl phenyl sulfides (Scheme 76).135 One of the advantages of using DMDO as oxidant is that it can be used at low temperatures (-78 "C).This can allow a high degree of diastereo- and chemo-selectivity to be achieved, as demonstrated by the oxidation of the chiral disulfide (38, Scheme 77).'36 up to >98% d.e. Scheme 76 422 Conternporaly Organic SynthesisNHR 9-0 VHR I -78 "C, A CH,CI, -no s+-s s-s high yield 8 38 0- R = pBr-C6H4S02 Up to 18: 1 diastereoselectivity Scheme 77 Finally, some of the established asymmetric oxidation systems have been used to achieve what is in effect a diastereoselective oxidation.The use of modified Sharpless asymmetric epoxidation conditions gives a very high diastereoselectivity for the oxidation of hydroxythioethers, although yields can be modest (Scheme 78).'37 R > P h S N TBHP, TI(oP~),, CH2C12, (+)-DET -20 "C ) 32% yield, 98% d.e. Me0 HO H d Scheme 78 Similar reaction conditions also give high diastereoselectivity in the preparation of novel 6-sulfinyl tetrahydromevinic acids (Scheme 79).138 The opposite diastereomer of similar diastereomeric excess can be prepared by oxidation using the dichlorooxaziridine 39. Conditions 1 I 1 0 &" 6- Ti(OPi),, (+)-DET, // cumene hydroperoxide 82 : 18, 87% yield s o 0 2 CH2C12. -20 "C 26 : 74, 100% yield 39 oxaziridine 39 Scheme 79 3.13 Enantioselective oxidation The enantioselective oxidation of sulfides to sulfoxides continues to be a popular and important area of organosulfur chemistry and has been the subject of a number of revie~s.'~~~''''' There are four main methods used for asymmetric sulfur oxidation. These are systems based on modified Sharpless asymmetric epoxidation conditions further developed by Kagan and Modena; chiral oxaziridines developed by Davis; the (sa1en)manganese (111) complexes of Jacobsen and Katsuki; and enzymatic oxidation procedures.Some of these are now well established and so the basic procedures for these will not be discussed in any detail, but relevant references are included in the previous review of this series.' However, important improvements on these methods and examples of applications will be included here.It is important to be aware of an intriguing recent report which describes how the optically activity of sulfoxides can be further enriched by preparative-scale flash chromatography on an achiral stationary phase.'41 For example, (R)- methylp-tolyl sulfoxide of 86% e.e., on chromatography, has an e.e. of 99% e.e. in the first sulfoxide-containing fraction off the column, but this decreases to 63% in the last fraction. The titanium-based procedure of Kagan (e.g. Scheme 81) has recently been adapted to be carried out using a catalytic heterogeneous system, using solid supports such as Al2O3, Si02, Zr02 and montmorrilonite. High enantiomeric excesses could be achieved, and a system using montmorrilonite K10 gave optimum r e s u l t ~ .' ~ ~ , ' ~ ~ The Kagan oxidation has also been used for the multi-kilogram scale asymmetric synthesis of the biologically active sulfoxide RP73163 (40, Scheme By judicious choice of substrate structure and reaction conditions very high enantiomeric excess and good chemical yields were achieved. Interestingly, the optimized reaction utilizes anhydrous conditions, rather than including the one equivalent of water which is often required for optimum enantioselectivity with a titanium: tartrate ratio of 1 : 2. More conventional Kagan conditions have been used for the enantioselective oxidation of organometallic complexes containing thioether groups, including chromium tricarbonyl complexes (Scheme 81),97.'45,146 and ferrocenyl sulfides (Scheme 82).147 The enantioselective oxidation conditions developed by Modena employ the use of four equivalents of tartrate relative to titanium, under anhydrous conditions.These have been used to synthesize C2-symmetrical bis-methylsulfinyl- benzenes by double asymmetric oxidation (Scheme 83).'48 Very high chemical and optical yields can be obtained for the ortho, meta and para-disubstituted systems. This oxidation protocol has also been used in a kinetic resolution of [ 1,l'-binaphthylenel- 2,2'-bi~-methylthioether (Scheme 84).'13 High enantioselectivity has been achieved with respect to Rayner: Synthesis of thiols, suljides, sulfoxides and sulfones 423Med Med Scheme 80 R' Scheme 81 Me 40, RP 73163 both sulfoxide and binaphthyl chirality. A mixture of products is formed, however, this can be simplified greatly by Pummerer rearrangement of the sulfoxide functionalities.In total, there is a net 81% recovery of resolved products [40% (S)-binaphthyl and 41% (R)-binaphthyl] based on racemic starting material. A related titanium-based oxidation procedure utilizes a chiral binaphthol ligand rather than tartrate esters. This system is capable of very high enantioselectivities, and has the added advantages that commercial 70% TBHP (aqueous) can be used as oxidant at room temperature, and with just 2.5 mol% catalyst (Scheme 85).149 The presence of > 1 equivalent of water was crucial for high enantio- selectivity, and to maintain catalyst activity. The enantioselectivities can be amplified by kinetic resolution during further oxidation of the sulfoxide to the s ~ l f o n e .' ~ ~ * ' ~ ~ Scheme 82 Scheme 83 -'-Me TI(OPh4 (1 9.). L-(+)-DET (4 9.)- , s+e cwnene hydroperoxide (1.8 eq.) Scheme 85 0- 32%, 98% e.8. 8%, 98% 8.e. 13%, 60% e.e. 41%. >98%e.e. Scheme 84 424 Contemporary Organic SynthesisThe oxaziridines developed by Davis have been used for the asymmetric chemical oxidation of 2-(trimethylsily1)ethyl sulfides. A variety of oxidation protocols were investigated, but the oxaziridine 41 was found to be the best reagent for these particular substrates (Scheme 86).151 A recently developed modification of the use of oxaziridine-type methodology involves the use of the well established imine precursors, hydrogen peroxide and DBU (Scheme 87).'52 However, under these conditions, the reactive intermediate is likely to be the peroxyaminal42 generated in situ, rather than an oxaziridine.D 0 CCI,, up to 80% e.e. R = aryl, c.C,H,, , But Scheme 86 and biomimetic oxidation of aromatic sulfides and sulfoxides has been r e ~ 0 r t e d . I ~ ~ The Helminthosporium species NRRL 4671 oxidizes p - alkyl benzyl sulfides and phenyl alkyl sulfides to the corresponding sulfoxides to give predominantly the (S)-sulfoxide enanti~rner.'~~,~'~ Good yields and high enantiomeric excesses can be achieved in some cases. The same species has been used for the preparation of (R)-sulforaphane 44, a significant component in the anticarcinogenic action of broccoli (Scheme 89).15' S MdS-N I Herninthospodum sp. NRRL 4671 I 45% yield, 86% 6.6. Scheme 89 Different strains of the bacterium Pseudomonas (1 eq.) f Hm~NHs02R3 putida can give opposite enantioselectivity for ROS,Me S.'R R2 asymmetric oxidation of aryl alkyl thi~ethers.''~ The UV4 strain gives predominantly the (R)-sulfoxide ( ~ 9 8 % e.e.) whereas the NCIMB 8859 strain gives the @)-isomer (76-91% e.e.). Chemical yields H202 (4 t!q.)RI@, & R' 'Me 42 R = &yl, CH&'% -20 OC* 48 -100% yield 2042% c.6. Scheme 87 There has been a recent report on the oxidation of aryl methyl sulfides using the (salen) manganese (111) complex 43 with iodosylbenzene reoxidant (Scheme 88).153 Good yields and moderate to excellent enantioselectivities are obtained. A patent for these types of system has also recently been p~blished."~ 43 (0.01 eq.) A 4040% 8.8. H- QH - --Ph Ph Scheme 88 There has been considerable progress on the biochemical asymmetric oxidation of sulfides to sulfoxides.A study on the mechanism of enzymatic decrease dramatically as the alkyl group becomes larger. Camphor-grown P putida NCIMB 10007 is also reported to catalyse the stereospecific oxidation of aryl alkyl sulfides to give the (S)-su1foxides.l6' The structure of the sulfide substrate again significantly influences the yield and enantioselectivity of the reaction. molecular engineering to improve the efficiency and selectivity of biochemical oxidations. Native horseradish peroxidase (HRP) oxidizes alkyl aryl sulfides with low to moderate enantioselectivities. If the phenylalanine-41 residue of HRP is mutated to a leucine residue then the enantioselectivity and rate of the oxidation improve dramatically (Table 1),l6' Finally, microperoxidase-11, a very simple 11 residue peroxidase with an iron-protoporphyrin covalently linked via a thioether, catalyses the enantioselective oxidation of alkyl aryl sulfides by H2O2 to give predominantly the (S)-sulfoxides in 3550% yield and 16-25% e.e.162 An exciting new development is the use of ~ ~~ Table 1 : Oxidation of thioethers using native HRP & F41 L HRP Substrate Native HRP (./,e.e.) F41 L HRP (%e.e.) PhO sx Et 35 94 Ph0'- 7 94 P-Naphthyl +Ae 69 99 Rayner: Synthesis of thiols, suljides, sulfoxides and sulfones 4253.2 Non-oxidative sulfoxide synthesis 3.2.1 General methods for sulfoxide synthesis The thio-Arbuzov reaction has been reported to be an efficient method for the preparation of unsymmetrical aryl sulfoxides from arenesulfenate esters and a variety of benzyl bromides (Scheme 90).163 Scheme 90 One of the most powerful methods of synthesizing optically active sulfoxides is by the use of a resolved sulfinate ester and an organometallic nucleophile, usually a Grignard or organolithium reagent. This was originally developed by Andersen, many years ago, who used menthyl sulfinate esters. Unfortunately, this procedure was unsuccessful for the synthesis of dialkyl sulfoxides because of problems accessing the required resolved alkyl sulfinate esters. Recently, alternative procedures to alleviate this problem have been developed, such as the use of sulfinate esters derived from diacetone-D- glucose (DAG).'@,165 These were discussed in the previous review,' but have now been further adapted for the synthesis of optically pure tert-butyl sulfoxides (Scheme 91).'66 The required sulfinate esters are readily prepared by treatment of DAG with tert-butyl sulfinyl chloride in the presence of either pyridine or triethylamine, which give diastereoisomeric sulfinate esters of good d.e., which can be further enhanced by recrystallization.Treatment of the individual diastereoisomers with Grignard reagents results in clean inversion of stereochemical configuration at sulfur (not retention as had previously been reported) and formation of the tert-butyl sulfoxides in high enantiomeric excess. Other chiral sulfinate esters have also been reported. Treatment of resolved trans-2-phenyl- cyclohexanol with thionyl chloride followed by dimethyl zinc gives a methane sulfinate ester with high diastereoselectivity (Scheme 92).'67 This reacts with Grignard reagents with inversion of configuration at sulfur to give methyl alkyl sulfoxides of high enantiomeric purity.This approach has been used in a synthesis of (I?)- sulforaphane 44 (cf. Scheme 89). 07% yield 82% d-e. 44 Scheme 92 In an extension of the original Andersen procedure, menthyl sulfinate esters have been developed for the synthesis of optically active aryl and alkyl2-methoxynaphthalene-1-sulfoxides (Scheme 93).'68,169 The diastereoisomeric menthyl sulfinate reagents are separable by recrystallization, and react with Grignard reagents with inversion of stereochemical configuration at sulfur. Use of an excess of the Grignard reagent results in cleavage of the methyl ether to give the naphthol derivative directly.o, S ,,'R R = alkyl, a@ Scheme 93 Z S n B u , 1 0- AIBN, conditions 0- 1 r SYn anti Conditions lduene, - 70 "C benzene, 10 "C 9 o : l O Scheme 94 0- RMsX 0- Scheme 91 426 Contemporary Organic SynthesisMe X X (i) LiCA (2 eq.) 'Q,J" (i) (ii) LiHMDS, MaOCO$Ae THF, -78 OC * 'Q,,..e 6- 0 A 80% yield 0- w S + W O H - C i S n 0 0 0 I 0- 0 n = 1,85% yield n = 2,96% yield (i)L/ \LO@ (i) Base, THF. -78 "C 7147% yield Me DL+ NHBoc (ii) R2C02Me R' =CI BOC CO2Et I Q++ 0- 0 70% yield Scheme 95 Recently, the use of a-sulfinyl radicals has been developed for the synthesis of sulfoxides, in some cases with considerable stereocontrol. Generation of an a-sulfinyl radical from the selenosulfinyl acetal using AIBN initiation, and allylation gives the product with high syn-selectivity, but low yield (Scheme 94).'70-'74 Higher yields can be obtained if the reaction is carried out higher temperatures, however, diastereoselectivity is reduced somewhat.3.2.2 Functionalized sulfoxides Sulfoxides containing a P-carbonyl group are readily prepared by reaction of an a-lithiosulfoxide with a carboxylic acid derivative (Scheme 9 9 , including carbonate^,'^^ anhydride^,'^^ and N-Boc a m i d e ~ . ' ~ ~ N Me2 Br Scheme 96 Scheme 97 P-Arnido-a-bromo sulfoxides undergo allylation via a-sulfinyl radicals with excellent stereoselectivity and in high yield (Scheme 96).'74 The corresponding esters are also successful in this reaction. P-Amido sulfoxides and related systems are also known to undergo efficient asymmetric Pummerer rearrangement, with good chirality transfer from sulfoxide to the S,O-acetal (Scheme 97).'80,181 A novel approach to the synthesis of optically active sulfoxides with a P-carbonyl group utilizes the enzymatic hydrolysis of prochiral sulfinyl dicarboxylates with pig liver esterase (PLE), which gives predominantly the (S)-sulfoxide, or a-chymotrypsin, which gives the (R)-sulfoxide (Scheme 98).182 The reactions of P-keto sulfoxides with nucleophiles provide routes to P-hydroxy sulfoxides, often with considerable stereocontrol. These reactions are now well established, and have been recently reviewed.'837184 Considerable work on stereochemical assignment in these systems has also been carried The stereoselective reduction of P-keto sulfoxides has been applied to the synthesis of a number of natural product^,'^^"^^ including ( + )-nonactic acid (Scheme 99),'" various ~ u g a r s ' ~ ~ > ' ~ ~ and ( - )-cladospolide A (Scheme It has also been used for the synthesis of optically active allylic alcohols via a recoverable sulfoxide chiral auxiliary (Scheme 101).19' Reduction can also give very high stereoselectivities in more substituted systems (Scheme 102).'767'92 Nucleophiles other than hydride can also be added stereoselectively to P-keto sulfoxides.These include cyanide (Scheme 103)19' and trimethyl- aluminium (Scheme 104).'94 In the case of the latter, a significant increase in the yield and stereoselectivity of the process is observed if the reaction is carried out in the presence of ZnC12.High stereoselectivity is also observed in the addition of diazomethane to fluorinated P-keto sulfoxides, forming the epoxides in poor to excellent yields (Scheme 1O5).lg5 The addition of Grignard reagents to 2-formyl- 3-sulfinyl furans can also occur with high diastereoselectivity, particularly if the reaction is Rayner: Synthesis of thiols, sulfides, sulfoxides and sulfones 427?- 0 ~ u-chymotrypsin 0 0- 0 plg liver esterase (PLE) 0- 0 p~ 7.5 M e 0 L&AoMe NaOH-KHPO4 pH 7.2 buffer -- MeO L ' + & O H NaOH-KHp04 buffer 63% yield, 02% 8.6. 709& yield, 79% e.e. M e 0 L ' A O H Scheme 98 (+)-Nonadic acid Scheme 99 -FTd-p 0 0 DibalH, THF,-78 "c 04% yield, >05% d.e. 'ToCp Wf' 1 OH 0 Scheme 100 carried out in the presence of ZnBrz (Scheme 106).196 Another synthetic approach to P-hydroxy sulfoxides utilizes the reaction of metallated sulfoxides with aldehydes. Chiral 2-(trimethylsilyl) ethyl sulfoxides can be prepared in an optically active form (Scheme 86),151 and can be deprotonated using LDA and react with aldehydes conditions: DibalH. THF, -78 "C 94 : 6.73% yield DibalH, ZnBrz, -78 "C <2 : 98,80% yield Scheme 101 to give P-hydroxy sulfoxides. Chemical yields are high, and stereoselectivities relative to the alcohol chiral centre are poor; however, there is almost total stereocontrol for bond formation adjacent to the sulfoxide (Scheme 107).197 Related alkylations have also been reported for a-flu~r~~~lfoxide~.'~~~~~ P-Amino sulfoxides can be prepared by Michael addition of amine nucleophiles to unsaturated sulfoxides.This has recently been demonstrated for amino acid derived systems, which give a moderate 428 Contemporary Organic Synthesis66% overall yield (i) LDA, THF, -78 "c, 1 h 0) RCHO, -78 "c, 5 min. R = Ph, 90% yield, 69 : 31 R = n-CSHO, 92% yield, 50 : 50 R = pr', 83% yield, 53 : 47 Scheme 102 Scheme 107 EtdCN PTd -78 "c ~ T o l Scheme 103 0 0- Ph k " T o C p I amditions ' HO Me y- + Ph ToI-p Ph Td-p conditions: AMe3 76:24, Whyield AIMe3 + ZnCI2 90 : 10, 70% yield Scheme 104 RF = CF2H, CFZCI, CF3, CF2CF3 Scheme 105 4' p PhMgBr, ZnBq, -10 "c 0 OH Scheme 106 yield of the conjugate addition product (Scheme 108) .200-202 Related systems have also been prepared by the addition of a-lithio sulfoxides to imine electrophiles. COPH 0 Scheme 108 Scheme 109 For example, N-acyl imines give reasonable yields but only very low diastereoselectivities (Scheme 109).203 The addition of sulfoxide anions to nitrones has also been reported (Scheme l10).'69y2M Good yields and excellent diastereoselectivities can be obtained, however, in the second example, if the reaction is carried out in the absence of the quinidine auxiliary, only low stereoselectivity is observed (64:36).3.23 Unsaturated sulfoxides A transition state model for the n-facial selection for electrophilic addition to a, P-unsaturated sulfoxides has been proposed which is consistent with a number of experimental observations, and will be of use in predicting stereoselectivity for related reactions.205 2-(mesyloxy)vinyl sulfoxides with malonate nucleophiles provides a route to 2-malonylvinyl sulfoxides (Scheme 111).2M A wide variety of The addition-elimination reaction of 2-halo- and Rayner: Synthesis of thioks, suljides, sulfoxides and sulfones 429THF. -78 "c M% 0- Scheme 110 malonate derivatives can be synthesized using this methodology, and importantly, the double bond geometry of the precursor is retained in the substitution product.A Horner-Wittig reaction has been exploited for the synthesis of 1-chlorovinyl sulfoxides (Scheme l12).207 Excellent (Z)-selectivity is observed in most cases. 0- n- 1 U LCH(COgt)2 I fs'Tdp NaH,MF, 12 h X 5&08% yield EtO2C COpEt I LCH(COgt)2 '. ToCp I I (st X = Br, I, OMS 0- 0- I 1 RCH(COgt)2 Bu"Li, THF, 12 h -6ooc-H.t -73% yield EtO& COpEt Scheme 11 1 Scheme 112 Diastereomerically pure 2,3-epoxy sulfoxides undergo a facile elimination reaction to give homochiral y-hydroxy-a, P-unsaturated sulfoxides when treated with base (Scheme 113).2087209 The opposite diastereoisomeric series can be accessed from the related 2,3-dihydroxy sulfoxides, by elimination of the corresponding cyclic sulfites using DBU.01, P-unsaturated sulfoxides is by the enzymatic kinetic resolution by ester hydrolysis of (2)- P-methoxycarbonyl-a, P-unsaturated sulfoxides using A novel approach to optically active A n- NaOH, H20, r.t. A 72% yield 0- U Scheme 113 a-chymotrypsin phosphate buffer, Bu'OMe 58% conversion 39% yield 41% yield 91% 8.8 65% 8.8. Scheme 114 a-chymotrypsin (Scheme 114).210 High enantiomeric excesses of either the ester or acid can be achieved depending on the % conversion during the hydrolysis reaction. The [2,3]-sigmatropic rearrangement of P-phenylsulfonyl prop-2-ynylic sulfenates has been applied as a method for the preparation of 1 -( phenylsulfinyl)-4-(phenylsulfonyl)-buta- 1,3-dienes (Scheme 115).211 Prop-2-ynylic alcohols are sulfenylated using phenyl sulfenyl chloride.Subsequent [2,3]-sigmatropic rearrangement occurs in situ to give an allenyl sulfoxide, which on treatment with base isomerizes to the dienyl sulfoxide. accessed by the palladium-catalysed coupling of P-halovinyl sulfoxides with an alkyne (Scheme Enantiomerically pure enynyl sulfoxides can be 430 Contemporary Organic Synthesis'S02Ph SOpPh 62% yield oxone 97% yield B"" // SO2Ph Scheme 115 11Q212 A variety of functional groups can be tolerated in the reaction including alcohols and triethylsilyl ethers.Retention of double bond geometry is observed in the coupling reaction, however, for the synthesis of (2)-enynyl systems, an acetylenic stannane is required for efficient reaction. The (E)-enyne products can be selectively hydrogenated to give (lE, 3Z)-l-sulfinyl dienes; the corresponding (Z)-isomers are not reduced cleanly. (3E)-ZSulfinyl dienes have been prepared by selective oxidation of the corresponding sulfides (Scheme 56).90197 0- I Br 0- I cTo'-p R-H Pd(PPh& - Cul, DBU 8447% yield CeH, 1.t. Hz, AhCI(PPh3)S C,H, r.t. , 63-84%yield R-SnBu3 Pd(MeCN)&I, DMF, r.t. 7447% yield 0- I CToLp 0- I Scheme 116 Alkenyl and dienyl sulfoxides have been the subject of considerable investigation as dienes, dienophiles, and dipolarophiles in cycloaddition reactions.Whilst it is beyond the scope of this chapter to discuss such reactions in any detail, a brief discussion of the kinds of system which have been reported will be included. Syntheses of many of these compounds have been reported previously; any important new synthetic routes have been discussed above. The use of camphor-derived a, P-unsaturated sulfoxides and other chiral sulfinylethenes as dienophiles in asymmetric Diels-Alder reactions, and their use in natural product synthesis, has been r e v i e ~ e d . ~ ~ ~ ? ~ ' ~ The a, P-unsaturated sulfoxides 462'5 and 472'6 have been reported to act as dienophiles in a Diels-Alder ~ycloaddition.~~'-~'~ A number of dienyl sulfoxides have also been investigated as Diels-Alder dienes, including simple l-s~lfinyl-48~~~ and 2-sulfinyl-dienes 49,221F222 and the more complex systems 50223 and 51.224 Chiral vinyl sulfoxides such as 52 have also been investigated as dipolarophiles.225 46 47 49 50 51 P T O ' ' s , y - F 0- OMe 52 4 Synthesis of sulfones An excellent text on the use of sulfones in organic synthesis has been published. It contains detailed sections on many aspects of sulfone synthesis and is highly recommended.226 4.1 Oxidation of sulfides and sulfoxides New methods for the oxidation of simple sulfides and sulfoxides to sulfones have been reported, many of which can also be used for sulfoxide synthesis, but under harsher reaction conditions or with more equivalents give the sulfone.These include dimethyl dioxirane (DMDO) generated in situ using oxone and acetone,"' trifluoromethyl methyl di~xirane,~'~ oxaziridinium salts 34 derived from dihydroiso- q~inoline;"~ H202 and MeCN at room temperature (via peroxyimidic acid intermediate 36);'*l the perfluoro-cis-2,3-dialkyloxaziridine 35 at - 20 "C (the volatile imine biproduct is easily removed);' l5 HOF/MeCN generated in situ from F2, H20, and MeCN;228 NaI04 with RuC1?JH20 catalyst (particularly good for highly unreactive sulfides);229 and N-methyl morpholine N-oxide with Pr,"N/Ru04 (TPAP) catalyst .230 There has also recently been reported a nice example of chemoselective sulfur oxidation in the Rayner: Synthesis of thiols, sulfides, sulfoxides and sulfones 43 1synthesis of dysoxysulfone (12, Scheme 46).Using 0 2 KMn04 and Z ~ ( O A C ) ~ the bis-sulfone 12 can be M * y S-pTOl [(But2PH)PdPButJ2 H2 (1 atm.), THF, r.t. Ph 93% yield ph isolated in 57% yield by selective oxidation of the two external thioether groups.68 Scheme 120 4.2 Non-oxidative sulfone synthesis 4.2.1 General methods for sulfone synthesis New methods for the synthesis of sulfones using methods other than oxidation have been reported. It has been shown that bis-sulfones undergo a stereospecific alkylation when treated with secondary alcohols under Mitsunobu conditions (Scheme 117).231 The reaction is successful with a wide variety of substrates and has been used in the enantioselective synthesis of the pheromone of the lesser tea tortrix.71 % yield Scheme 117 S02Ph The first examples of episulfone substitution reactions via a-sulfonyl carbanion intermediates have been reported (Scheme 118).2329u3 So far the range of electrophiles which can be used in the reaction are severely limited, but high yields can be obtained in some cases. A route to diary1 sulfones involving coupling between sulfonyl chlorides and arylstannanes has been reported (Scheme 119).234 Moderate to good yields can be obtained with high regioselectivity in the coupling reaction. by hydrogenation of the corresponding a, P-unsaturated sulfones (Scheme 120).235 In this case the catalyst used, [(Bu:PH)PdPBui],, needs to be pretreated with oxygen to generate the active catalyst. Finally, aryl alkyl sulfones have been synthesized 1 4.2.2 Functionalized sulfones The reaction of or-sulfonyl anions with carboxylic acid derivatives provides a route to fi-keto sulfones.Recent examples of this reaction are the use of P-lactams (Scheme 121)236 and tartaric acid derivatives (Scheme 122)237 as electrophiles. Alternatively, P-keto sulfones have been synthesized by reacting imines with sulfonyl chlorides (Scheme 123).238 In this case the reactive electrophile is a sulfene generated in situ from the sulfonyl chloride and base, and the initial imine product is hydrolysed by aqueous acid to give the desired P-keto sulfone. co& NHC02Bn PhSO&Hs Bu'LI THF. -78 "C 0 f l c o @ l 84%yield Scheme 121 0 0 Scheme 122 (i) NE$, THF. 24 h (ii) 3N HCI Ph /LCF-Ph NR O2 LDA(3eq.) k 3 S i 2 A k3sicI (excess) Me3Si Scheme 123 -78 "C, 2 h 35-779b yield 85% yield Scheme 118 The addition of sulfinate anions to a, P-unsaturated carboxylic acids generates the Michael adducts in moderate to good yield, which can act as fi-acyl vinyl anion equivalents.These can then be further functionalized by double deprotonation and treatment with a range of electrophiles to give the substituted /3-sulfonyl carboxylic acids (Scheme 124).239 Alternatively, a-sulfonyl anions can be accessed by reductive lithiation of bis-phenyl sulfones using lithium \ PhCI, I30 "c, 48 h 4245%yield +R1/- 0 2 \ / R2 Scheme 119 naphthalenide (Scheme 125).240-"3 432 Contemporary Organic SynthesisBu"Li (2 eq.) THF, -78 'C 1 E* = D20, Me,SiCI, RX. RCOCl Scheme 124 R' W2Ph Li Naphthalenlde R2 kS02Ph THF. -78 "c R2 E, = H20, RX, RCHO 68-97% yield Scheme 125 A new route to P-hydroxy sulfones has been reported which uses the sulfone-directed rhodium- catalysed hydroboration-oxidation of ally1 sulfones.The Markownikoff product is obtained preferentially with high regioselectivity (Scheme 126).'" P-Hydroxy sulfones have also been prepared by oxidation of a-sulfonyl carbanions with lithium tert-butyl peroxide, the carbonyl compound being generated in situ by loss of sulfinate (Scheme 127).245 alcohol has an enantiomeric excess of 90-95%. If the reaction is allowed to progress to 65% conversion then, after conventional hydrolysis, the enantiomeric alcohol can be obtained of ~ 9 7 % e.e. The product alcohols can then be readily converted into the phenylthioethers, which undergo regioselective lithiation a-to the sulfone and subsequent alkylation, with high stereoselectivity. &OH llpase P30 H@.phosphate buffer b 2 P h THF. 0.1N NaOH. r.t. 0 I D 90-95% 8.8. (at 35% conversion) (i) LDA, (ii) RX THF. -78 "c -79% yield I >97% 8.8. (at 65% conversion) I >12:1 diastereoseledivity Scheme 128 a-Lithio sulfones have also been reacted with enantiomerically pure N-tosyl aziridines to form y-amino sulfones, which can be further substituted by in situ lithiation and reaction with aldehydes to give the P-hydroxy sulfone in good overall yield (Scheme 129).247 5448% yield >85: 15 ( i ) Bu"Li, MF, TMEDA, -78 "c Scheme 126 .R2 R'-S02 (i) Bu"Li (2 eq.), M F (ii) TBHP (1 eq.), - 7 W a "C 7044% yield I Scheme 127 fl-Alkyl-y-hydroxy sulfones can be obtained in an optically active form by enzymatic hydrolysis of the corresponding chloroacetate esters using lipase P30 (Scheme 128).246 At 35% conversion the hydrolysed OR 0 NHTs (ii) n / ~ ' ,-78 "c+ r.t.N' TS 0 2 (iii) Bu"Li, -78 "C PhO"Me (iq R~CHO (v) AcOH. THF,-78 "C+ r.t. Scheme 129 The conjugate addition of organocopper reagents to (E)-y-hydroxy-a, P-unsaturated sulfones proceeds in excellent yield and with high anti selectivity (Scheme 130).248 Interestingly, if the alcohol group PhO2S dR R2&ULi* E t s , r.t. * PhO2S 4 1 R2 8!5-@2%Vleld 50-88%-d.8. R' = Me, Bun, Pr' I? = Me, Bu" Scheme 130 Rayner: Synthesis of thiols, sulfides, suvoxides and sulfones 433in the substrate is protected as the acetate ester, or the MOM or tea-butyldimethylsilyl ethers, then SN2' allylic displacement is observed with cuprate reagents .Other highly stereoselective conjugate addition reactions to a, /?-unsaturated sulfones have also been reported. In the system shown in Scheme 131, if the free alcohol is used then attack of the Grignard reagent occurs from the top face, however, if the trimethylsilyl ether is used with methyl lithium as the nucleophile, then the opposite stereoselectivity is observed.249 8:l diastereoselectivity 4.2.3 Unsaturated sulfones a,/?-Unsaturated sulfones can be prepared by the oxidation of the corresponding unsaturated sulfides (Scheme 56)w397 and sulfoxides (Scheme 115).'11 A convenient and economical synthesis of phenyl vinyl sulfone has been published, from simple precursors and in high overall yield (Scheme 133).254 An interesting synthesis of vinyl sulfones from 1,3-dithiolane tetraoxides has also been reported, and provides a direct route to vinyl sulfones from carbonyl compounds by thiolane formation, oxidation, and elimination of SO2 (Scheme 134).255 The well known extrusion of SOz from sulfolenes has also been exploited in the preparation of dienyl sulfones, which undergo in situ intramolecular cycloaddition in this case (Scheme 135).256 C IC H&H&I b-Yi;i - _Ph-s/\\ - (i) MeMgBr, M F !rL, 72% 1 PhSH NaOH, PTC - P h S N C ' (ii) NEt3, THF.quant. O2 .'OH 96:4 diastereoselectiviiy Scheme 131 In an interesting approach to the synthesis of homochiral syn-2-amino alcohol derivatives, (E)- y-hydroxy-a, /?-unsaturated sulfones are treated with trichloroacetylisocyanate to give an imide which undergoes stereoselective intramolecular addition of the nitrogen to the unsaturated sulfone, and partial hydrolysis, to give a cyclic urethane (Scheme 132).=' After benzylation, these systems can be further functionalized by lithiation and subsequent alkylation in good to excellent yield.The lithiation and subsequent alkylation of related /?-amino sulfones has also been r e p ~ r t e d , ' ~ ~ , ~ ~ ' as has the intermolecular addition of hydroxylamine to a, P-unsaturated sulfones, leading to formation of /?-hydroxylamino s ~ l f o n e s . ~ ~ ~ ~ " ~ 0 0 HN lo (i) BnBr, K&Q, THF. A #'qR (i9 Bu"Li, THF, -78 "c c (iii) E+ Ph02S- L 5948% yield E+ = RX, RCHO, RCOCI, MeS02SMe Scheme 132 8744% yield Scheme 133 EK)H Ph*R Scheme 134 X S02Ph &* 0 2 X = H, SPh, SiMe3 Scheme 135 X SOzPh 5" X S02Ph G 7 T q - J (E)-y-Hydroxy-a, /?-unsaturated sulfones have been prepared in an optically active form, by the base-induced elimination of 2,3-epoxy sulfones (Scheme 136).2089257 The optically active precursors were prepared via the Sharpless asymmetric epoxidation.?H R*S02Ph .-0 DBU, CH$& r.t. RaSOzPh 83%yield Scheme 136 Vinyl triflones (trifluoromethyl sulfones), which are known to be excellent substrates for Michael addition, have been prepared by a Peterson-type olefination. Treatment of trimethylsilyl methyl iodide with two equivalents of tert-butyl lithium followed by sequential condensation with the triflone anhydride and an aldehyde gives the alkene directly (Scheme 137).258 434 Contemporary Organic Synthesis0 2 ( i ) MeLi, LiBr THF, -78 "c 5644% yield (ii) Ei 35-8090 yield Scheme 137 Alkenyl stannanes can be coupled with sulfonyl chlorides with Pdo catalysis to selectively give (E)- a, P-unsaturated sulfones, irrespective of the initial alkene geometry (Scheme 138).259 These systems can be further substituted by lithiation a-to the sulfone and alkylation with a range of electrophiles.0, t 0 2 p T o l y y o E t E EtO E' = D20, RCOCI, RCHO, M~+$iil Scheme 138 (E)-P-iodo-a, P-unsaturated sulfones have been prepared by photolytic addition of iodine to alkynes in the presence of sodium benzenesulfinate (Scheme 139).260 (2)-1,Zbis(phenylsulfonyl) alkenes can also be prepared using sodium benzenesulfinate by substitution of the appropriate vinyl iodonium tetrafluoroborates (Scheme 140).2617262 PhS02Na, 1% hv SO2Ph Horn\ NaOAc, 4842% EtOAc, yield H@ - H O 4 n=1,2 I Scheme 139 R BF4- PhSOaa THF, 0 "C R R ItPh Wim%yield PhO2S S02Ph Scheme 140 Lithium enolates of dioxanones add to P-bromo- a, P-unsaturated sulfones to give the substitution product with retention of double bond geometry, and high stereoselectivity (Scheme 141).263 The reaction works best with (E)-isomers although (2)- isomers can also be used but are less reactive.Allyl sulfones can also be used as precursors to vinyl sulfones, via a protiodesilylation route (Scheme 142).264-266 The allyl sulfone precursors are lithiated and regiospecifically silylated a-to the sulfone. Treatment with strong acid results in protio- desilylation with clean allylic rearrangement to give the @)-vinyl sulfone selectively.(i) LHMDS, M F , -78 OC o*o o*o (ii) B,&SOph, -78 "C, 24 h 65% yield 'S02Ph Scheme 141 Ph02S -;;;;2 Scheme 142 A review on the chemistry of 3-heteroatom substituted allyl sulfones has been Optically active allyl sulfones have been prepared by reaction of an allyl acetate with sodium p-toluene sulfinate in the presence of Pdo modified with the chiral ligand 53 (Scheme 143).267 Enantiomeric excesses of up to 93% can be achieved with this methodology. 53 NaS02Tol-p 'y Pd(PPh&.53* R*R THF. r.t. Tol-p 02s. OAc R = Me, 4043% yield, up to 59V0 8.8. R = Ph, 87-98% yieM, up to 93% e.e. Scheme 143 Allyl sulfones have also been prepared by the addition of organocopper reagents to allenic sulfones.The products can also be further functionalized by lithiation and regiospecific alkylation, although direct alkylation of the initial cuprate adduct is not very efficient (Scheme Other alkylations of allyl sulfones have also been reported.269 Allenic sulfones can be accessed from 2,3-bis- (phenylsulfonyl)-buta-1,3-diene by Michael addition of an enolate and subsequent elimination of sulfinate (Scheme 145).2707271 If silylenol ethers and TBAF are used rather than lithium enolates then no elimination is observed and instead the intermediates undergo a 1,3-sulfonyl shift to give the observed allyl sulfone product .265926692707271 Rayner: Synthesis of thiols, sulfides, sulfoxides and sulfones 435Scheme 144 Ph THF. -20 “c S02Ph 60% yield Ptf Scheme 145 Ph TBAF, THF Chiral allenic sulfones have been prepared by asymmetric selenoxide elimination in an ally1 sulfone (Scheme 146).272 The selenoxide substrates are best prepared by asymmetric oxidation of the corresponding vinyl selenide using the Kagan oxidation protocol (cf.Scheme 81). Enantiomeric excesses of up to 42% were achieved. N E ~ cw BU’OK I R Ti(OP&, (+)-DET 4 TBHP, H$ (1 eq.) 85% yield up to 42% e.e. CHZCIa 0 “c H “* H pToD2S‘ Scheme 146 Finally, two new routes to acetylenic sulfones have been published. The first involves the reaction of bis-trimethylsilylacetylene with a sulfonyl chloride under Lewis acidic conditions (Scheme 147).273 Selective mono-sulfonation is possible, the remaining trimethylsilyl group being removed on column chromatography.The second new method of acetylenic sulfone synthesis utilizes the reaction of a wide range of acetylenic iodonium triflates with sodium salts of aromatic sulfinates (Scheme 148)?74 The reaction proceeds via initial addition of sulfinate to the triple bond to form an iodonium ylide which subsequently rearranges to give the acetylenic sulfone. 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Chem., 1993,58,5235. 440 Contemporary Organic Synthesis

ISSN:1350-4894    

DOI:10.1039/CO9950200409

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

Saturated and unsaturated hydrocarbons RICHARD P. C. COUSINS Glam Wellcome Medicines Research Centre, Gunnels Wood Road, Stevenage, Heqordshire SGl 2m UK Reviewing the literature published between September 1993 and December 1994 Continuing the coverage in Contemporary Organic Synthesis, 1994, 1, 173 1 2 3 4 4.1 4.2 5 6 7 8 9 10 11 Introduction Saturated hydrocarbons Olefinic hydrocarbons Stereoselective simultaneous formation of sp3 and sp2 centres Claisen rearrangements Wittig rearrangements Conjugated dienes Non-conjugated dienes Polyenes Allenes Alkynes Enynes References 1 Introduction This review covers new methods for the synthesis of saturated and unsaturated hydrocarbons, with the emphasis being placed on practical and stereoselective methodologies. 2 Saturated hydrocarbons The development of radical deoxygenations, dehalogenations, and deaminations continues, with methods using dialkyl phosphates and hypophosphorus acid as hydrogen sources' along with a new approach using N-phenyl- thioxocarbamate derivatives applied to sugars and nucleosides (Scheme 1)233 being reported. The direct S Scheme 1 Cousins: Saturated and unsaturated hydrocarbons reductions of alcohols to alkanes using borohydride can be accomplished after initial phosphonium anhydride a~tivation,~ whilst selective deoxygenations of secondary allylic alcohols and acetates using triethylsilane in the presence of ethereal lithium perchlorate leave esters, isolated olefins, ketals, and tertiary alcohols unaffected (Scheme Z).5 Scheme 2 In an alternative approach to direct one-step deoxygenations of primary and secondary alcohols, constant current electrolysis of a mixture of alcohol, a phosphine, and tetraethylammonium bromide is found to give moderate yields of the corresponding alkane.6 Samarium iodide has been applied to a number of different structural classes to effect reductive transformations such as a-deoxygenations of unprotected aldonola~tones,~ deoxygenations of T ~ x o ~ ~ ~ ~ ~ ~ and hydrodehalogenations of alkyl halides." Other hydrodehalogenation methodologies which have been reported include the use of borohydride exchange resin with nickel acetate," the application of tri-n-butyltinhydride in aqueous media,12 the use of palladium mounted on poly(N- vinyl-2-pyrrolidine) with atmospheric pressure hydrogen in the presence of a base,13 and the utilization of aminoborohydride at room temperature in tetrahydr~furan.'~ and aldehydes can be affected with hydrogen in the presence of in situ generated nickel boride,15 whilst sodium hydrogen telluride is found to be effective in 1,4-reductions on a range of substrates (Scheme 3).16 The hydrogenation of a, P-unsaturated sulfones and phosphonates has been achieved with the activated binuclear palladium complex [ (But2PH) PdPBut2] in The 1,4-hydrogenation of a,P-unsaturated ketones NaHTe tc"" n n Scheme 3 441moderate to good yields," and the asymmetric hydrogenation of unfunctionalized trisubstituted olefins has been realized, in good yield and with high stereocontrol, through the use of a chiral C2- symmetric titanocene catalyst.l8 A simple, two-step reductive geminal dialkylation of a-unbranched aliphatic aldehydes via the corresponding geminal dihalide, using higher-order dialkyl-lithium cyanocuprates proceeds in good yield (Scheme 4).19 The carbozincation of alkenyllithiums leads to a-chloro-triorganozincates, which can then be monoalkylated selectively via an intramolecular nucleophilic substitution process in good yield in a one-pot reaction (Scheme 5).20 1 2 ,OAc Br Zn.CrCb _/c2Hs C7H,5CH0 + C2HsC C7HlC tt 56% -- ( E :z, 91 :9) Scheme 6 I 0 I 65% Scheme 4 (i) EtMgBr (ii) I2 I Hept "XI, 60% Scheme 5 3 Olefinic hydrocarbons A study of the Wittig ethylidenations of a number of different ketonic substrates has demonstrated that reagents 1 and 2 are always (E)-selective, and these reagents have overcome some of the difficulties in the use of Wittig olefination procedures leading to trisubstituted double bonds2' @)-Selective alkylidenations of aldehydes using reagents derived from a-acetoxy bromides, zinc, and CrC13 are reported to proceed in moderate yields with variable selectivity (Scheme 6).22 The stereoselectivity of the Peterson olefination procedure has been shown to be influenced by the choice of base and the silyl group in the synthesis of the anti-bacterial BRL49467, where a highly (E)- selective protocol is required (Scheme 7).23 The methylenation of carbonyl compounds using a CH212, zinc, and TiC14 system can be accelerated considerably with the addition of catalytic PbC12, as I ! N, 0 4 Y w - g g L o OH (E:Z, 13:l) Scheme 7 it promotes the formation of the reactive geminal dizinc intermediate CH2(ZnI)2.24 The asymmetric preparation of allylic alcohols can be achieved by the addition of the vinyl anion equivalent 3 to aldehydes, followed by fluoride-initiated desilylsulfinylation or thermal desulfinylation (Scheme 8).25 Scheme 8 442 Contemporary Organic SynthesisA number of methodologies for the stereoselective synthesis of trisubstituted olefins have been reported.Thus, reacting silyl nucleophiles with (2-phenylthiocyclobutyl)methyl benzoates or methyl ethers generates olefins in moderate yields with a high stereoselectivity (Scheme 9);26 stereodefined trisubstituted alkenes can be prepared using a 1,Zmetalate rearrangement starting with phenylthioacetylene (Scheme and di- and tri- substituted alkenes are obtained in moderate yields using the reactions of vinyl radicals with electron deficient alkenes (Scheme 11).28 Scheme 9 58% Scheme 10 PhS OMe TiC&(OP+) 81% R = n4llH23 Scheme 12 THF Et Scheme 13 BuaLi -70°C to r.t.n-C4HQ ' \ n-C4HQ 76% + I Scheme 11 85% Scheme 14 BU' 4 SO2Ph Bu3SnH <SO2ph respectively, via the stereoselective addition to the terminal olefinic group of these lithiated species Reported procedures for the synthesis of (2)- 66% (Scheme 14).31,32 ( E :z, 96:4) alkenes include the simple use of atmospheric hydrogenations of alkynes in the presence of a metallic nickel catalyst and modifier^;^^ treatment of substituted 1,2-dithietane-l,l-dioxides, prepared In a new, and general, stereoselective, high yielding protocol, easily prepared phosphorus heterocycles have been used to synthesize P-keto phosphonoamidates, which after keto group reduction to the corresponding alcohol and cyclo- elimination generate trisubstituted olefins in high stereopurity (Scheme lZ).29 Stereoselectively alkylated olefins can be prepared by the reaction of organolithium reagents with epoxides at low temperature followed by elimination (Scheme 13).30 Treatment of tantalum-alkyne complexes with lithium alkoxy olefins or lithioimines afforded trisubstituted olefins and (E)-allylic amines from the reaction of allenic sulfinates with-vinyl magnesium bromide, with lithium cyanide (Scheme 15);34 and the cross-coupling reaction of (2)-vinylic tellurides with Grignard reagents mediated by lower order cyano cuprates (Scheme 16).35 5,6-Disubstituted norbornenes have been prepared from palladium-catalysed cross-coupling reactions, and shown to undergo a retro Diels- Alder reaction to generate (Z)-olefins in good yield (Scheme 17).36 Polyfunctional di-substituted alkenes can be readily obtained by a cross-coupling reaction between (E)- or (2)-alkenyl iodides and alkyl copper zinc reagents (RCu(CN)ZnI) with complete Cousins: Saturated and unsaturated hydrocarbons 443Br- Et o -Tdyl-F-Ph TMP, NBS o -TolylrnPh Ph' 'Ph 7996 * Me \ b E t (E:Z 20:80) Scheme 19 Me Me LCN.90% t (E:Z,14:86) Scheme 15 OnN--/=\TB(n-C4HO) + W I CuCN OZN? 75% Scheme 16 Ph+Br + + Bu3SnCHpCH2 IPd 69% 71 % Scheme 17 retention of the configuration (Scheme 18).37 Styrenes have been smoothly prepared at room temperature from the highly selective cross- metathesis of terminal olefins using molybdenum ~atalysis.~' NC(CH2)3C~(CN)ZnI + 1- \ CO*Et 65% Scheme 18 (E)- and (Z)-Stilbenes were prepared using a Ramberg-Backlund type reaction of phosphonium salts with N-bromosuccinimide and 2,2,6,6- tet rame t hylpiperidine with moderate selectivity (Scheme whilst (E)-stilbenes were obtained with a high degree of stereoselectivity from the reaction of (a-1ithiobenzyl)phosphine oxides with aldehydes (Scheme 20).40 Scheme 20 A modification of the Julia olefination procedure whereby p-hydroxy or acetoxy sulfones are treated with Sm1,-HMPA has been reported, but only with moderate ~tereocontrol.~~ Symmetrical alkenes have been obtained from lithiated sulfones in the presence of catalytic amount of an iron salt with moderate stereocontrol, whilst disulfones give rise to cyclic alkenes (Scheme 21).42 Lithiated tertiary- butyl alkyl sulfones eliminate easily in the presence of Pd(acac), to generate the corresponding olefin (Scheme 22).43 R = C10H21 Scheme 21 ( E :Z, 84:16) Scheme 22 Vicinal dibromides have been debrominated reductively with Sm12 to afford (E)-alkenes4 and the application of microwave irradiation to vicinal sulfonyloxy groups in pyranosides has been found to considerably increase the rate of reaction for generating unsaturated products.45 Desulfurizations of thiiranes with triethylborane and tributyl tin hydride at low temperature afford alkenes in good yield (Scheme 23).46 Terminal olefins can be obtained in good yield from the simple reactions of benzylic, allylic, propargylic, and primary halides or mesylates with 444 Contemporary Organic SynthesisS 4 Stereoselective simultaneous formation of sp3 and Ptl- OSiMepBu' sp2 centres 122 Bu3SnH Ph- \ OSiMepBu' (E:Z, 6.6:l) Scheme 23 dimethylsulfonium methylide, whilst unactivated secondary halideslmesylates proved unreactive (Scheme 24).47 The reactions of excess dimethylsulfonium methylide with terminal, allylic, or benzylic epoxides was found to lead to the corresponding one-carbon homologated allylic alcohols in good yields (Scheme 25).48 4.1 Claisen rearrangements A useful protocol for preventing abnormal aromatic Claisen rearrangement products from forming has been reported and uses 1,1,1,3,3,3,-hexamethyl- disilazane or N,O-bis(trimethylsily1)acetamide to efficiently trap the normal products as their silyl ethers.@ Methodologies for the stereoselective preparation of silyl ketene acetals of a-siloxy esters, P-hydroxy esters, and a-amino esters have been reported and applied to the Ireland ester enolate Claisen rearrangement of allyl glycolates (Scheme 26).65 Scheme 24 Me&-H2 (2eq.) HO B n o T O 89% Scheme 25 Procedures for the preparation of functionalized olefins which have been reported include protocols for the dichloromethylenation of lac tone^,^^ the conversion of carbonyl compounds into vinyl iodides, 1, 1-diiodoalkenes, and 3,3-difluoropropene derivative^,^'-^^ a simple preparation of conjugated nitro olefins from /I-nitro a l c o h o l ~ ~ ~ the generation of vinyl triflates from terminal alkyne~,'~ and the synthesis of vinyl triflones from aldehydes using a Peterson olefination pr~cedure.~~ The preparations of synthetically useful vinyl stannanes can be achieved: (i) using chromium-mediated additions of Bu3SnCHBr2 to aldehydes to afford (E)-alkenyl ~tannanes;~~ (ii) through the use of organocopper coupling chemistry to furnish 2-tributylstannyl- l - a l k e n e ~ ; ~ ~ (iii) via the Pdo-catalysed syn- stannylstannylations and syn -silylst annat ions of 1 -alkoxy- 1 -alkynes and p henylthio- 1 -alkyne~;~~ (iv) via the Pdo-catalysed hydrostannation of disubstituted propargyl alcohols;59 and finally (v) in the preparation of (E)-2-methyl- 1 -alkenyl t rime t hyls t annanes from terminal acetylenes.6o Procedures for the synthesis of vinyl silanes include the hydrosilylations of alk-1-ynes, to afford selectively either (E)- or (2)-vinyl silanes using rhodium catalysis,61 the conversion of a molybdenum carbene complex into (E)- or @)-vinyl silanes by the addition of organolithiums or Grignard reagents,62 and the preparation of 1,l-bis(trimethylsily1)alkenes from the addition of (trimethyl~i1yl)~CBr~ to aldehydes using chromium ~hemistry.~~ I 1 I I A - LTMP, TMSCl 93% 96:4 B - LHMDS, then TBDMSCI 85% 3:97 Scheme 26 The utility of the [3,3]-Claisen sigmatropic rearrangement has been demonstrated with a number of different substrates, including the rearrangement of the cyclic keteneacetal4 in the synthesis of carbacyclin (Scheme 27),66 in the conversion of allyl N-phenylimidates, via N-silyl ketene N,O-acetals, into y,S-unsaturated anilides (Scheme 28),67 in the preparation of (E)-olefin C7H15 C 7 H l S a 160"C,H+c 93% o+:o ? 4 Scheme 27 NPh Me Scheme 28 NHPh NH the 98.1:1.9 Cousins: Saturated and unsaturated hydrocarbons 445dipeptide isosteres with high stereoselectivity (Scheme 29),68 in the synthesis of a-allyl-/?-amino acids in good yields (Scheme 30),69 for the introduction of allylic side-chains onto peptides using Pdo catalysis and ZnCl,! (Scheme 31),70 and as the key sequential steps in the preparation of the antiviral ( - )-rei~wigin.~' Scheme 29 (i) LDA, TMSCI, -78% (ii) reflux 177% rNHk 92:8 Scheme 30 (i) LDA, ZnCb.Pdo (ii) CHzN2 54% (1:l) Scheme 31 The Claisen rearrangement has also found application in the regioselective and stereocontrolled 2-C and 3-C allylation of L-ascorbic acid,72 in the preparation of the (-)-yellow-scale- pheromone via a ring expansion of an eight- membered cyclic thionocarbonate prepared in a one-pot, four step reaction sequence (Scheme 32)," as the key part of the stereoselective synthesis of the trisubstituted @)-olefins from N-disubstituted dimethylammonium salts (Scheme 33)T and finally in the synthesis y, &unsaturated perfluor~ketones.~~ 61 % Scheme 32 Scheme 33 ha-Claisen rearrangements have been applied in the synthesis of (-)-isoiridomyrmecin 5 with very high stereoselectivity (Scheme 34).76 They have also been used on carboxamides of isomerically pure (E)- and (2)-crotylamines (with unfortunately little stereo~ontrol),~~ and on substrates generated from the acid-catalysed Michael additions of allylamines to acetylene carboxylates, where Lewis acids are also found to give satisfactory results, and the overall strategy can be applied to ring expansion reactions (Scheme 35).78 4.2 Wittig rearrangements An enantioselective ester enolate [2,3]-Wittig rearrangement has been realized using chiral boron bis-sulfonamides to control stereoselectivity (e.e.up to 96%) with high threo preference but in only moderate yields (Scheme 36).79 Good asymmetric 446 Contemporary Organic SynthesisI (i) LHMDS, -78% (ii) 100°C 0 H # b o H : Scheme 34 Et ~TBDMS d.e. = 92% Scheme 35 C02Me + H0."C02Me 83:17 Scheme 36 control has also been obtained in the [2,3]-Wittig rearrangement of chiral allyloxy-acetaldehyde hydrazones undertaken in the synthesis of y, 6-unsaturated-a- hydroxyalde hydes and cyanohydrins (Scheme 37)" with a number of different substrates, such as the propargylic ether 6 with good stereocontrol in an asymmetric synthesis of Stork's prostaglandin intermediate 7 (Scheme 38),8' and on prop-2-ynyl ethers 8, where stereocontrol is realized by the use of the silicon groups favouring the required transition state in a general approach to leukotrienes (Scheme 39).82 rearrangement reaction has been shown to The [2,3]-Wittig rearrangement has been applied A one-pot tandem [2,3]-Wittig anionic oxy-Cope OTBS (or$, 3:l) 7 Scheme 38 SiMes 8 QH 80% BULi, -78°C OH I Scheme 39 transform very rapidly (45 minutes at room temperature) bis-allylic ethers to 6, &-unsaturated aldehydes with good selectivity (Scheme 40).83 The [2,3]-sigmatropic rearrangement of P-phenyl- sulfonylpropargylic sulfenates provides a method for preparing 1,4-bis(phenylsulfonyl) 1,3-b~tadienes,~~ whilst repeated alternate additions of a diazonium salt and tetrafluoroboric acid at low temperature enables the conversion of ally1 4-methoxy- phenylsulfides into sulfonium ylides which Cousins: Saturated and unsaturated hydrocarbons 447Scheme 40 Scheme 44 p-silyl sulfone derivative 9 to generate 2-alkyl substituted 1,3-dienes in a straightforward coupling reaction, with either a nucleophile or an aldehyde, followed by an elimination procedure (Scheme 45).89 then undergo [2,3]-Wittig rearrangement in high yield and good stereoselectivity (Scheme 41).85 A study of the aza-Wittig rearrangement of vinylaziridines has provided an interesting approach to tetrahydropyridines (Scheme 42).86 (i) BuLi T s A c I (ii) ICHfiiMg * Me3Si' 9 I Scheme 45 A range of substituted buta-1,3-dienes can be prepared from 1,4-dichlorobut-2-yne via a hydroboration strategy (Scheme 46),% or by the regioselective palladium-catalysed cross-coupling of 2,3-butadienyl carbonates with 9-alkyl- 9-borobicyclo[ 3.3.llnonanes, 1 -alkenylboronic acids, or arylboronic acids (Scheme 47) .91 no* 06% EtO LPJC BF4- R = 4-MeOCeH4 Scheme 41 Scheme 46 I1 Scheme 42 5 Conjugated dienes A facile elimination of allylic alcohols via the corresponding mesylates has been reported to provide a two step method for the preparation of terminal 1,3-dienes (Scheme 43).87 The coupling of 2-bromomethyl-l,4-dibromo-2-butene with various aldehydes and ketones allows a simple entry to isoprenylated alcohols (Scheme 44),88 and 2-(chloromethyl)-3-tosylpropene can be used via its i\ OH 64% Scheme 43 Scheme 47 2-Phenylsulfinyl or 2-phenylsulfonyl 1,3-dienes can be prepared stereoselectively in good yields using a Pd-catalysed addition reaction of thiophenol to conjugated enynes with a terminal alkyne followed by oxidation (Scheme 48)92 and l-substituted- 1-ethoq dienes are obtained from the coupling reaction of l,l-diethoqbut-2-ene with a range of carbonyl electrophiles using the mixed metal base LICKOR (Scheme 49).93 448 Contemporary Organic SynthesisSPh S4Ph Scheme 48 BuYi, Bu'OK (2eq.) '&OEt 302coMe / Scheme 49 The selective preparation of protected (E,E)- and (E,Z)-hepta-2,4-dien-l-o1 has been reported using a Horner-Wittig elimination of easily separated syn- and anti-P-acetoxy triphenylphosphine A simple methodology for the preparation of conjugated (E,E)-dienes has been reported and uses a sequential coupling reaction between Grignard reagents in the presence of NiC12(dppe) and readily available (E,E)-l-bromo-4-phenylthio-1,3-butadiene (Scheme An enyne metathesis reaction involving the use of a ruthenium catalyst allowed the preparation of five-, six-, and seven-membered heterocycles containing the 1,3-diene moiety in good yields (Scheme 51).96 PhS-Br + NiC12(dppe) (i) 2-thienyl MgBr 51% (ii) 4-pentenyl MgBr I Scheme 50 Scheme 51 Palladium-catalysed Stille cross-coupling procedures using vinyl stannanes leading to 1,3-dienes on the side-chains of a-amino acids, and 1,3-diene derivatives of 3-iodobut-3-enoic acid have been reported (Scheme 52).97,98 The utility of the w S n M e 3 wco2" I NHAc + , MeSi \ SiMe3 Scheme 52 SnMe3 i Tf Tf ''H \ H (+)-pawarnine Scheme 53 Stille cross-coupling has been demonstrated in a total synthesis of ( + )-papuamine (Scheme 53).99 synthesis of dienyltrialkylstannanes, such as the simple, two-step preparation of (E)- 1,3-butadienyl( tributy1)stannane from 3-sulfolene (Scheme 54),'O0 the use of 1,2-metalate rearrangements of 5-lithio-2,3-dihydrofurans with a suitable cyanocuprate (Scheme 55),"' the high yielding direct stereoselective stannylcupration of enynes with terminal alkynes (Scheme 56),*02 and the stereo- and regio-controlled Pd-catalysed hydrostannylation of enynes (Scheme 57).'03 A number of reports have dealt with the Scheme 54 Cousins: Saturated and unsaturated hydrocarbons 44911 Scheme 55 Scheme 59 Pd(PPhd4, NaOH I&% SiMe3 (€,ZI€,€ = 933 97:3 Scheme 56 6 Non-conjugated dienes The application of the Stille cross-coupling reaction has been reported to allow the easy introduction of 1,4-diene systems into the side-chains of a-amino acids containing a vinyl iodide (Scheme 60)y whilst the Pd-cat alysed cross-coupling of an allyl organozinc with 3-iodobut-2-enoic acid allows facile generation of a 1,4-diene moiety (Scheme 61).98 C02Me Pd', Bu3SnH, PhH, r.t.~ BuaSn R /A 80% R = G:2 Scheme 57 &SUBU3 + NHAc The stereocontrolled preparation of 2-substituted 1;; l-iodo-1,3-dienes has been achieved by the addition of methylmagnesium tributyltin to 6-phenylhex- 3-enyne, followed by alkylation with an appropriate electrophile and conversion of the resulting stannyldiene by reaction with iodine (Scheme 58).'04 vCozEt NHAc Scheme 60 Ph - ZnBr + I uoH Ph Ph &OH 65% overall Scheme 61 Scheme 58 A general stereoselective synthesis of the novel silyl-l,3-butadienes, 10 and 11, has been reported, and these compounds will no doubt find use in a number of applications such as intra- and inter- molecular cycloadditions.'" with the organoborane 12 with retention of stereochemistry in a palladium-catalysed reaction under basic conditions to generate trans-dienyl silanes (Scheme 59).lo6 Finally, vinyl bromides have been shown to couple A one-pot palladium-catalysed reaction between terminal acetylenes, allyl bromide, and organostannanes has allowed elaboration of 1-substituted 1,4-pentadienes in moderate yields, but better overall yields can be realized in two separate steps (Scheme 62).'07 20% Scheme 62 450 Contemporary Organic SynthesisPreparations of (E-l-alkeny1)ethylzinc reagents from the corresponding (2)-trialkenylboranes have been utilized in the cross-coupling reactions of zinc reagents with allylic halides to provide 1,4-dienes, regio- and stereo-selectively in the absence of a transition metal catalyst (Scheme 63).'08 Scheme 63 7 Polyenes Methodology for controlling the thermal electrocyclic ring-opening reactions of 4-alkyl- 2-cyclobutene- l-carbaldehydes have been reported and allows the easy stereoselective preparation of (2,E)- or (E,E)-dienals at low temperature which can then be further elaborated to stereodefined trienes (Scheme 64).'09 The isomerizations of enyne esters to (E,E,E)-trienes in good yields using a simple trip henylp hosp hine - p henol catalysed protocol have been reported (Scheme 65)."' (9 Swem oxidatbn * kCHO OH (ii) EhN.-78 to 20°C 92% Scheme 64 3 c 0 2 m e 6TBS Scheme 65 A simple one-pot stereospecific preparation of unsymmetrical (2)- or (E)-enediynes from (2)- or (E)-172-dichloroethylene and l-alkynes has been reported, using sequential palladium-catalysed coupling reactions (Scheme 66);"' pure (Z,Z,Z)- or (Z,E,Z)-conjugated trienes may then be Scheme 66 subsequently produced through the use of zinc reduction.In a similar approach the palladium- copper coupling reaction between (E)-l-chloro- 1,3-butadiene and l-alkynes, followed by stereoselective zinc reduction, furnishes trienes with high stereo purity (Scheme 67).l12 PdCIZ(PhCN)2 CUI. 85% Zn(Cu/Ag) + W c ! i H l l CSHl1 Scheme 67 The allylzirconations of alkynes has afforded intermediates which can be reacted with ally1 chloride in the presence of copper salts to give stereodefined nonconjugated 174,7-trienes in good yield (Scheme 68).'13 The use of sodium amalgam induced reductive eliminations of allylic dibenzoates has been exemplified in a synthesis of leukotriene B4 (Scheme 69).'14 CUCl BU- 79% Scheme 68 OTPS 0 OTPS oms OTBS Scheme 69 Cousins: Saturated and unsaturated hydrocarbons 45 1Nitriles have been reacted with pentadienyl lithium to yield metalated 1-substituted trienamines which upon careful workup produce l-aminohexa- 1,3,5-trienes with fairly good stereocontrol (Scheme 70).'15 w' (i) Bu"Li (ii) R-CN R = 2-pyridyl Scheme 70 A new approach to retinoids involving the addition of organometallic reagents to a variety of pyrylium tetrafluroborate salts has allowed the preparation of (2,E)- or (E,E)-dienals in a stereocontrolled manner (Scheme 71),'16 and in an extension of this approach to polyenes a direct route to trienals has been described whereby aldehydes are homologated by six carbon atoms by reaction with the 2-substituted 2H-pyran-based Wittig reagent 13 in good yields (Scheme 72).'17 Scheme 71 R = 3-pyridyl Scheme 72 In an alternative synthesis of retinal the key step involved a Pd-catalysed rearrangement of the mixed propargylic-dienyl carbonate 14 to an allenyl aldehyde followed by subsequent reconjugation (Scheme 73)."* HBr, 0°C. 57% 1 Scheme 73 A variety of symmetrical carotenoids have been synthesized by first using a chromium assisted iodomethylenation of a diketone followed by a silver- assisted Heck reaction with good stereocontrol (Scheme 74).*19 The iodoacetal 15 can be coupled to tertiary allylic alcohols using Heck chemistry, and subsequently hydrolysed and dehydrated to provide substituted trienals regioselectively (Scheme 75).I2O R' I R Scheme 74 Palladium-mediated coupling reactions of zinc bromide derivatives (generated from the enyne 16) with unactivated vinyl iodides have allowed facile preparations of polyenes with high stereocontrol (Scheme 76).121 452 Contemporary Organic SynthesisScheme 75 Scheme 76 In a new triply convergent synthesis of leukotriene B4, a stereocontrolled coupling reaction, ring-opening process, and elimination reaction involving the propargylic arsonium salt 17 and the furanose 18 affords an intermediate polyene in good yield, which is then further elaborated to the final product (Scheme 77).'22 TsO %OH 18 Scheme 77 8 Allenes A number of new approaches to aryl allenes have been published, including a simple conversion from benzopyrans using an anionic cleavage reaction (Scheme 78),'23 and the palladium-catalysed coupling reactions of stannyl allenes with either aryl iodides or aryl triflates in the presence of a copper co-catalyst (Scheme 79).'247'25 Scheme 78 Scheme 79 The regioselective preparation of allenyl stannanes has been achieved using a reductive coupling reaction of propargylic bromides with tributylstannyl chloride in the presence of magnesium metal and lead bromide (Scheme A novel [3,3]-sigmatropic rearrangement of cyclic thionocarbonates has been used to prepare medium- ring heterocyclic allenes in moderate yield (Scheme 81).'27 BuaSn - - <"" Bu3SnCI.MglPbBr, THF L e i Br 66% M8 Scheme 80 A number of approaches towards allenes have utilized functionalized alkynes and these include: the 1,6-addition of organocuprates to chiral eneynes, leading to allenes with moderate diastereoselectivity;'28 the hydrogenolysis of alkynyl cyclic carbonates to a-allenyl alcohols with triethylammonium formate and a palladium(o) catalyst in the presence of chelating diphosphines (Scheme 82);'29 and the cross-coupling reactions of organoboranes with propargylic carbonates with palladium catalysis to afford tetrasubstituted allenes (Scheme 83).13' Cousins: Saturated and unsaturated hydrocarbons 453S L J OSiMezBu' k< SrnIdMPA 78% OH 6lHP TBDMSO(CH2)dgBr CUI, P(OEt)3 ACQ h * * k .a O T B D M S Scheme 85 Scheme 81 -0Ph ~ T H P THPO Me Me H W d , NEt3, Pd'. Ph2P(CH&PPhs l 7 ~ t H Me HO Me Scheme 82 A range of chiral alcohols have been converted into propargylic ethers which were then isomerized under base catalysis to generate optically active allenic A simple procedure involving 1,4-elimination from l-acetoxy-4-trimethylsilylbut-2-ynes using tetrabutylammonium fluoride has enabled the preparation of alkyl and aryl substituted 1,2,3-butatrienes (Scheme 86),'% whilst the reduction of tetraalkylhexapentaenes with Zn- ZnClz affords 1,2,4,5diallenyl systems efficiently (Scheme 87).'35 SiMe3 I TBAF ~ ", c=c=c=c, A Ph' H &Ac - (t1.2) Scheme 86 Scheme 87 Scheme 83 Propargylic mixed carbonates have been rearranged into allenic carbonyls compounds using palladium catalysis (Scheme 84),131 and the allenic moiety of enprostil has been introduced via a propargylic acetate using a Grignard reagent in the presence of a copper catalyst (Scheme 85).13* Me Scheme 84 9 Alkynes The procedure for converting aryl methyl ketones into aryl ethynyl products using phosphoryl chloride and DMF has been extended to diphenyldiynes (Scheme 88),136 and the dehydrobromination of 1,l-dibromoethylenes under mild conditions using DMSO and DBU has allowed the preparation of 1-bromoarylalkynes in excellent yields (Scheme 89).13' A modification of the McKelvie-Corey procedure for converting 1,l-dibromoalkenes into 1-bromoalkynes using NaHMDS for the elimination reaction, has led to a series of epoxy, cyclopropyl, and alkyl derivatives in good yields (Scheme 90)."* 454 Contemporary Organic Synthesis0 Kn Cl Scheme 88 15 i!°F\ Br Br \\ Scheme 89 Siie3 f3:a.73:27 ToLoLH yN€cpc OH I I 8.8. >99% R = n-C~H11 Scheme 91 R = p--l OSiMepBu' Scheme 90 The chiral synthon 19 has been used to prepare a series of optically active propargylic alcohols from the reaction of the derived a-vinyl anion with aldehydes followed by the /I-elimination of the sulfinyl and trimethylsilyl groups or by the thermal elimination of the sulfinyl group (Scheme 91).'39 and aldehydes by reaction with lithium trimethylsilyldiazomethane generates the corresponding homologous disubstituted and terminal alkynes respectively in moderate to good yields (Scheme 92).140 Both cyclic and acyclic 1,5-diynes have been prepared using intra- and inter-molecular coupling react ions of Co2( C0)6-complexed propargyl radicals, in reasonable yields and with moderate diastereo~electivity.'~~ The preparation of a nine- membered cyclic 1,5-diene has been achieved through the cerium-assisted coupling reaction of a lithium acetylide with an aldehyde, affording a single diastereoi~omer.'~~ The (Colvin) rearrangement of aryl alkyl ketones 10 Enynes (2)-Enynes and (2)-enediynes are reported to be easily generated by the dehydration of propargylic I Me3SC(LI)Nz o.-""" 6296 Scheme 92 alcohols with polyphosphoric acid trimethylsilyl ester (PPSE) (Scheme 93).'43 A straightforward procedure for coupling terminal alkynes to viny halides using Pdo catalysis in the presence of piperidine or pyrrolidine has furnished enynes i good yield (Scheme 94),'@ whilst a palladium- 1 catalysed elimination from propargylic carbonates produced conjugated enynes using mild and neutral conditions (Scheme 95).145 H' (Z:E ,100:O) Scheme 93 Cousins: Saturated and unsaturated hydrocarbons 455Scheme 94 Scheme 95 The palladium-copper catalysed coupling reaction of terminal acetylenes with a-amino acids containing vinyl iodide side-chains has been shown to readily introduce enyne groups (Scheme 96).97 The zinc bromide derivatives of preformed (2)- or (E)- 1-stannyl-4-trimethylsilyl- 1-buten-3-ynes have been used in palladium-catalysed coupling reactions with a range of unactivated vinyl iodides and proceed in good yield with stereoretention, to afford terminal conjugated dienyne systems (Scheme 97).'*l -C02Et C02M PdCIdPPh&, CUI I X A c #OH 62% jOHNHAc Ph &Me &, + Bu-H + Ph+SnBu3 Ph p-c Scheme 98 Scheme 99 Scheme 96 straightforward sequence of reactions starting with bromoboration of a terminal alkyne and subsequent allenic zinc chlorides has led to acyclic enyne-allenes or enediynes with tri- or tetra-substituted double bonds with a high degree of stereocontrol (Scheme + Bn2N-1 Pdo coupling with acetylenic zinc chlorides and SiMe3 Pd(PPh& SiMe3 1w-1497150 B u 2 N d Scheme 97 A three-component one-pot reaction involving a terminal acetylene, a 1-alkynyl stannane, and either an enone or an ally1 chloride, using a nickel catalyst generated from Ni (acac)2, afforded regio- and stereo-defined enynes and 3,6-dien-l-ynes respectively in good yields (Scheme 98).146,147 catalysed coupling reaction of alkynyl cyclic carbonates with terminal alkynes (Scheme 99).14" A R Conjugated alkynyl a-allenols have been obtained readily in good yields from the palladium-copper 78% Scheme 100 456 Contemporary Organic SynthesisAn intramolecular Nicholas reaction on a dicobaltohexacarbonyl-complexed propargylic silylenol ether has enabled the preparation of the reactive bicyclic [7.4. llenediyne, and the surprisingly stable bicyclic enyne-allene 20 (Scheme lOl).’” OTBS 5% TCId.DABC0 1 + 20 Scheme 101 The isomerization of (2)- to (E)-enynes using trifluoromethane sulfonic acid at room temperature was found to be more readily accomplished when the acetylene group is protected as the dicobaltohexacarbonyl complex.’52 The readily prepared y-silylallenylborane 21 can be used to prepare enynes and enediynes with high geometric purity by reaction with simple alkyl and acetylenic aldehydes respectively, followed by an elimination step using Peterson olefination procedures to define the stereochemistries of the alkene bonds (Scheme 102).1’~ Me3sk*< fi) RCHO I \ KH 6 7 9 2 % / / 21 R = n-C5HI1 R = n-C5H Scheme 102 Symmetric dienediynes have been prepared using a nickel-catalysed coupling reaction of 2,3-dichloro- 1,3-butadiene with terminal acetylenes (Scheme 103)’54 and conjugated dienynes are obtained with good regioselectivity from the monocoupling of (Z)-conjugated bis(eno1triflates) and trimethylsilylacetylene using palladium catalysis.”’ The coupling of unactivated allenes and 1-alkynes can be achieved using a rhodium-based catalyst with a high regio- and stereo-selectivity, leading to endo- (E)-enynes in good yields (Scheme 104).’56 Scheme 103 ’n-C5H11 Scheme 104 Carbocyclization of 178-bis-trimethylsilyloctadiyne has been accomplished using a propargylic organozinc derivative to provide stereocontrolled 1,4-enyne cyclopentanes with an exocyclic double bond ready for further elaboration (Scheme 105).’” Palladium-catalysed sequential coupling reactions of (E)- and (2)-dichloroethenes with 1-alkynes afford (2)- and (E)-enediynes bearing different substituents on the alkyne groups (Scheme 106).15’ L SiMe3 (iii) H30+ $+SiMe3 89% Me0 Scheme 105 50% L O H Scheme 106 A large number of biologically active molecules containing the enediyne group have been isolated and a number of different synthetic strategies have been developed to prepare these interesting molecules.A convergent total synthesis of calicheamicin y l l has been rep~rted,”~ and studies directed at calicheamicin and esperamicin type chromophores and aglycones include: the synthesis of an oxabicyclo[7.2.llenediyne via a Nozaki reaction using CrC1, and catalytic NiC1, to generate a single diastereoisomer (Scheme 107),16’ the use of a [2,3]-Wittig rearrangement to generate 1,5-diynes which are further elaborated to generate enediyne systems;’61 the use of straightforward cyclizations mediated by LiN(TMS)2 (Scheme 108),16, or initiated by caesium fluoride (Scheme 109);’63 and Cousins: Saturated and unsaturated hydrocarbons 4570 Qoa CrCIa NiC12 44% Scheme 107 € 3 d M e 2 S 8 CHo 67% LiN(TMS)2 \ G t)H Scheme 108 CsF, 18-C-6 CHO 40% 1- SiMe3 - \ + OSiMe3 Scheme 109 the utilization of the Norrish Type I1 photochemical reaction in the highly efficient preparation of acyclic and cyclic enediynes (Scheme 110).'@ Scheme 11 0 In an attempt to circumvent the use of the expensive (2)-dichloroethene and palladium catalysts, the direct self-coupling of trimethylsilyl propargylic bromide has been achieved using strong lithium bases with concommitant elimination to prepare acyclic (2)-enediynes (Scheme lll).16' (Z:€,2:1) Scheme 11 1 Studies directed towards the synthesis of dynemicin-type compounds include: constructing the enediyne unit from a terminal acetylene derivative, generated from the addition of a magnesium acetylide in a 1,4-asymmetric induction and subsequently elaborated for a caesium fluoride mediated cyclization;'66 the use of a dicobaltohexacarbonyl propargylic alcohol in a cyclization reaction with a bridgehead enolate mediated by trifluoromethylsulfonic anhydride (Scheme l12);'67 palladium-mediated cross-coupling of the diiodoacetylene derivative 22 with (2)- distannylethylenes (Scheme 113),'68,'69 and acetylene anion addition to a conjugated aldehyde (Scheme 114).l7' OMe Ad = 1 -adamantyl 0 OMe Scheme 112 I I ATBS I Scheme 11 3 458 Contemporary Organic Synthesisf i Scheme 114 Other studies published in this area have included the preparation of monocyclic dienediyne systems related to the neocarzinostatin chromophore starting from D-xylitol and using an aldol cyclization as the key step (Scheme 115);17' a description of the general strategies using dicobaltohexacarbonyl complexed acetylenes for the synthesis of enediyne antitumour agents;172 and the synthesis of enetetraynes using palladium-mediated coupling reactions starting with (Z)-dich~oroethylene~.'~~ Scheme 115 11 References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 D.H.R.Barton, D.O. 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ISSN:1350-4894    

DOI:10.1039/CO9950200441

出版商:RSC    

年代:1995

数据来源: RSC