Total Synthesis of Epothilone B, Epothilone D, and cis- and trans-9,10-Dehydroepothilone D

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• 作者：James D. White ; Rich G. Carter ; Kurt F. Sundermann ; and Markus Wartmann
• 刊名：Journal of the American Chemical Society
• 出版年：2001
• 出版时间：June 13, 2001
• 年：2001
• 卷：123
• 期：23
• 页码：5407 - 5413
• 全文大小：110K
• 年卷期：v.123,no.23(June 13, 2001)
• ISSN：1520-5126

文摘

The phosphonium salt 35, representing one of the two principal subunits of the epothilones, wasprepared from propargyl alcohol via heptenone 22. A Wittig reaction of the phosphorane from 35 with aldehyde33, obtained from aldol condensation of ketone 27 with aldehyde 28, afforded 37. Seco acid 42 derived from37 underwent lactonization to give cis-9,10-dehydroepothilone D (43) which was selectively reduced withdiimide to yield epothilone D (4) and, after epoxidation, epothilone B (2). An alternative route to epothiloneD employed alkyne 39, obtained from 33, in a Castro-Stephens reaction with allylic bromide 34 to furnishenyne 40. The latter was semi-hydrogenated to provide 37. Alkyne 46, prepared from alcohol 45, was convertedto trans-vinylstannane 47 which, in a Stille coupling with allylic chloride 50, gave 51. Seco acid 52 derivedfrom 51 underwent lactonization to give trans-9,10-dehydroepothilone D (54). Bioassay data comparing theantiproliferative activity and tubulin polymerization of 43 and 54 with epothilone B (2), epothilone D (4), andpaclitaxel (7) showed that the synthetic analogues were less potent than their natural counterparts, althoughboth retain full antiproliferative activity against a paclitaxel-resistant cell line. No significant difference inpotency was noted between cis analogue 43 and its trans isomer 54.