Studies towards a Novel Synthesis of Tubulysins: Highly Asymmetric Aza-Michael Reactions of 2-Enoylthiazoles with Metalated Chiral Oxazolidinones

Abstract

Herein we report the highly asymmetric aza-Michael ­reactions of α,β-enones (2-enoylthiazoles) with metalated chiral ­oxazolidinones under different reaction conditions and for different substituents at the β-position of the Michael acceptor. The reaction proceeds with complete diastereoselectivity to give exclusively one of the two diastereomers. The significance of the reaction is that no catalyst has been used; the steric requirements of the chiral Michael nucleophile drive the stereospecificity of the reaction and the reaction time is much less compared to the reported procedures. This methodology might be useful for an improved total synthesis of the highly cytotoxic peptides known as the tubulysins.

Key words

asymmetric - aza-Michael Reaction - diastereoselectivity - noncatalytic - oxazolidinone

References and Notes

• 1a Perlmutter P. Conjugate Addition Reactions in Organic Synthesis   Pergamon Press; Oxford: 1992. 
• 1b Rossiter BE. Swingle NM. Chem. Rev.  1992,  92:  771 
• 1c Tomioka K. Nagaoka Y. In Comprehensive Asymmetric Catalysis   Vol. 3:  Springer; Berlin: 1999.  Chap 31.1.
• 1d Modern Carbonyl Chemistry   Otera J. Wiley-VCH; Weinheim: 2000.  Chap. 12.
• 1e Sibi MP. Manyem S. Tetrahedron  2000,  56:  8033 
• 1f Krause N. Hoffmann-Röder A. Synthesis  2001,  171 
• 2a Cardillo G. Tomasini C. Chem. Soc. Rev.  1996,  25:  117 
• 2b Fustero S. Pina B. Salavert E. Navarro A. Ramirez de Arellano MC. Fuentes AS. J. Org. Chem.  2002,  67:  4667 
• 2c George GI. The Organic Chemistry of β-Lactams   Wiley-VCH; New York: 1993. 
• 2d Juaristi E. Lopez-Ruiz H. Curr. Med. Chem.  1999,  6:  983 
• 2e Seebach D. Matthews JL. Chem. Commun.  1997,  2015 
• 3a Kakumoto K. Kobayashi S. Sugiura M. Org. Lett.  2002,  4:  1319 
• 3b Xu L.-W. Li J.-W. Xia C.-G. Zhou S.-L. Hu X.-X. Synlett  2003,  2425 
• 3c Xu L.-W. Xia C.-G. Tetrahedron Lett.  2004,  45:  4507 
• 3d Nakama K. Seki S. Kanemasa S. Tetrahedron Lett.  2001,  42:  6719 
• 3e Nakama K. Seki S. Kanemasa S. Tetrahedron Lett.  2002,  43:  3891 
• 3f Volonterio A. Zanda M. Tetrahedron Lett.  2003,  44:  8549 
• 4a Matsunaga H. Sakamaki T. Nagaoka H. Yamada Y. Tetrahedron Lett.  1983,  24:  3009 
• 4b D’Angelo J. Maddaluno J. J. Am. Chem. Soc.  1986,  108:  8112 
• 4c Hawkins JM. Lewis TA. J. Org. Chem.  1992,  57:  2114 
• 4d Loh T.-P. Wei L.-L. Synlett  1998,  975 
• 4e Bull SD. Davies SG. Delgado-Ballester S. Fenton G. Kelly PM. Smith AD. Synlett  2000,  1257 
• 4f Sani M. Bruché L. Chiva G. Fustero S. Piera J. Volonterio A. Zanda M. Angew. Chem. Int. Ed.  2003,  42:  2060 
• 4g Fleck TJ. McWhorter WW. DeKam RN. Pearlman BA. J. Org. Chem.  2003,  68:  9612 
• 4h Lurain AE. Walsh PJ. J. Am. Chem. Soc.  2003,  125:  10677 
• 5a Enders D. Müller SF. Raabe G. Angew Chem. Int. Ed.  1999,  38:  195 ; Angew. Chem. 1999, 111, 2112
• 5b Enders D. Wallert S. Synlett  2002,  304 
• 5c Job A. Janeck CF. Bettray W. Peters R. Enders D. Tetrahedron  2002,  58:  2253 
• 5d Enders D. Wallert S. Runsink J. Synthesis  2003,  1856 
• 6 Doi H. Sakai T. Iguchi M. Yamada K. Tomioka K.
  J. Am. Chem. Soc.  2003,  125:  2886 
• 7 Luo-Ting Y. Huang J. Chang CY. Yang TK. Molecules  2006,  11:  641 ; and references cited therein
• 8a Urbach H. Henning R. Tetrahedron Lett.  1984,  25:  1143 
• 8b Yamada M. Nagashima N. Hasegawa J. Takahashi S. Tetrahedron Lett.  1998,  39:  9019 
• 8c Ferencic M. Gärtner P. Girreser U. Klinge M. Gaischin L. Mereiter K. Noe CR. Monatsh. Chem.  1999,  130:  769 
• 9 Kakumoto K. Kobayashi S. Sugiura M. Org. Lett.  2002,  4:  1319 
• 10 Bigotti S. Volenterio A. Zanda M. Synlett  2008,  958 
• 11 Sani M. Fossati G. Huguenot F. Zanda M. Angew. Chem. Int. Ed.  2007,  46:  3526 
• 12 For other aza-Michael reactions on 2-enoyl-thiazoles, see: Dondoni A. Marra A. Boscarato A. Chem. Eur. J.  1999,  5:  3562 
• 13 Hughes RA. Thompson SP. Alcaraz L. Moody CJ. J. Am. Chem. Soc.  2005,  127:  15644 
• 14 Turconi J. Lebeau L. Paris JM. Mioskowski C. Tetrahedron  2006,  62:  8109 

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Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no CCDC 718419. Copies of the data can be obtained, free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax:[phone]; or e-mail: [e-mail]].