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

Sreejith Shankar P.; Monica Sani; Giancarlo Terraneo; Matteo Zanda

doi:10.1055/s-0029-1216729

LETTER

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

Sreejith Shankar P.^a, Monica Sani^b,c, Giancarlo Terraneo^d, Matteo Zanda*^c,e
^a Dipartimento di Chimica, Materiali e Ingegneria Chimica ‘G. Natta’, Politecnico di Milano, Via Mancinelli 7, 20131 Milano, Italy
^b KemoTech s.r.l., Parco Scientifico e Tecnologico della Sardegna, Loc.Piscinamanna, 09010 Pula (CA), Italy
^c CNR - Istituto di Chimica del Riconoscimento Molecolare, Sezione ‘A. Quilico’, Via Mancinelli 7, 20131 Milano, Italy
Fax: +39(02)23993080; e-Mail: matteo.zanda@polimi.it;
^d NFMLab-Dipartimento di Chimica, Materiali e Ingegneria Chimica "G. Natta", Politecnico di Milano, Via Mancinelli 7, 20131 Milano, Italy
^e Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK

Abstract

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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

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References and Notes

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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:+44 (1223)336033; or e-mail: deposit@ccdc.cam.ac.uk].