Total synthesis and biological evaluation of a C(10)/C(12)-phenylene-bridged analog of epothilone D.
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End, Nicole, Furet, Pascal, Vancampenhout, Nathalie, 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 |