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Total synthesis and biological evaluation of a C(10)/C(12)-phenylene-bridged analog of epothilone D.

End, Nicole and Furet, Pascal and Vancampenhout, Nathalie and Wartmann, Markus and Altmann, Karl-Heinz (2004) Total synthesis and biological evaluation of a C(10)/C(12)-phenylene-bridged analog of epothilone D. Chemistry & Biodiversity, 1 (11). pp. 1771-1784. ISSN 1612-1880

Abstract

The total synthesis of compound 8, a conformationally constrained analog of epothilone D (2), has been achieved through a convergent strategy based on three key fragments comprising C(1)-C(6) (26), C(7)-C(12) (16), and C(13)-O(16) (19) of the macrocyclic framework. Construction of the C(12)-C(13) bond involved Pd(0)-mediated B-alkyl Suzuki coupling between aryl bromide 16 and olefin 19, and proceeded in excellent yield, while formation of the C(6)-C(7) bond through aldol reaction was somewhat less efficient. Surprisingly, macrolactonization was rather low-yielding and gave protected 8 only in 39% yield. Although 8 had been suggested by pharmacophore modeling to adopt a conformation similar to the bioactive conformation of epothilone B, the compound was devoid of any significant antiproliferative activity.

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Date Deposited: 14 Dec 2009 13:58
Last Modified: 31 Jan 2013 01:14
URI: https://oak.novartis.com/id/eprint/549

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