Total synthesis of epothilones B and D: Stannane equivalents for β-keto ester dianions

Article abstract of DOI:10.1021/jo802215v

(Chemical Equation Presented) 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-C ₉ and C₁₀-C₂₁ of the structure. The C ₁-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 SmI ₂ reduction of a β-hydroxy ketone and a critical opening of a valerolactone with aniline which required extensive investigation.