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Total Synthesis of Epothilones B and D: Stannane Equivalents for β-Keto Ester Dianions

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posted on 19.12.2008, 00:00 by Gary E. Keck, Robert L. Giles, Victor J. Cee, Carrie A. Wager, Tao Yu, Matthew B. Kraft
Studies leading to a total synthesis of epothilones B and D are described. The overall synthetic plan was based on late-stage fragment assembly of two segments representing C1−C9 and C10−C21 of the structure. The C1−C9 fragment was prepared by elaboration of commercially available (2R)-3-hydroxy-2-methylpropanoate at both ends of the three-carbon unit. Introduction of carbons 1−4 containing the gem-dimethyl unit was achieved in a convergent manner using a diastereoselective addition of a stannane equivalent of a β-keto ester dianion. An enantioselective addition of such a stannane equivalent for a β-keto ester dianion was also used to fashion one version of the C10−C21 subunit; however, the fragment assembly (using bimolecular esterification followed by ring-closing metathesis) with this subunit failed. Therefore, fragment assembly was achieved using a Wittig reaction; this was followed by macrolactonization to close the macrocycle. The C10−C21 subunit needed for this approach was prepared in an efficient manner using the Corey−Kim reaction as a key element. Other key reactions in the synthesis include a stereoselective SmI2 reduction of a β-hydroxy ketone and a critical opening of a valerolactone with aniline which required extensive investigation.