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Pure Appl. Chem., 2007, Vol. 79, No. 2, pp. 173-180

Natural products with taxol-like anti-tumor activity: Synthetic approaches to eleutherobin and dictyostatin

Cesare Gennari, Damiano Castoldi and Ofer Sharon

Dipartimento di Chimica Organica e Industriale, Centro di Eccellenza C.I.S.I., Università degli Studi di Milano, Istituto di Scienze e Tecnologie Molecolari (ISTM) del CNR, Via G. Venezian 21, 20133 Milano, Italy

Abstract: Eleutherobin and dictyostatin are antimitotic compounds which exert their cytotoxic activity by a taxol-like mode of action, i.e., hypernucleating tubulin assembly and interfering with the dynamic instability of the cytoskeleton during mitosis. A formal total synthesis of eleutherobin was accomplished by accessing a key intermediate reported by Danishefsky and coworkers in their 1998 synthesis of the natural product. The key step of our strategy, used for obtaining the [8.4.0] fused bicyclic ring system, is a ring-closing metathesis (RCM) reaction of a densely functionalized diene under forcing conditions, using Grubbs' second-generation catalyst. Synthetic approaches to dictyostatin are also described, and in particular the preparation of the C15-C23 fragment of the macrolide, containing 5 of its 11 stereocenters.