The 12,13-diol cyclization approach for a truly stereocontrolled total synthesis of epothilone B and the synthesis of a conformationally restrained analogue

A highly convergent and stereocontrolled synthesis of epothilone B (1) has been developed. The epoxide moiety in 1 was generated by regioselective mes ylation and base treatment of the 12,13-diol 30 which was formed by a chela te Cram controlled Grignard addition of 14 and methyl ketone 13. Both fragm ents were synthesized from the chiral carbon pool precursors (S)-citronello l and (S)-lactic acid, respectively. A highly diastereoselective aldol addi ton of epoxy-aldehyde 7 and the known Southern hemisphere ketone 8 delivere d the full carbon skeleton, containing all the stereogenic centers of 1. Fu nctional group manipulation, macrolactonization and removal of two protecti ng groups then yielded 1. The spatial closeness of the C4-beta -methyl and C6-methyl group in the crystal structure of 1 inspired us to connect them t hrough a methylene bridge to give a cyclohexanone derivative. Thus, the Nor thern hemisphere aldehyde 7 was added to the enolate of the cyclohexanone 4 7 Further manipulations and macrolactonization delivered the conformational ly restrained epothilone derivative 42.