Synthesis of (S)-(+)-Mevalonolactone and Mevalonate Analogues

Tetrahydropyran (R/S)-1, a vinylidene analogue of mevalonolactone, was prepared by addition of excess allyl Grignard to 4-acetoxy-2-butanone, iodoetherification of the resultant diol 5, and DBN-mediated dehydrohalogenation. Sharpless asymmetric epoxidation of 3-methylhexa-2, 5-dien-1-ol (9) gave epoxide 10 that was reduced to diol 11 (>95% ee) by LiAlH₄. Annulation and elimination of HI as described for 5 furnished (S)-1. Ozonolysis of (S)-1 yielded (S)-mevalonolactone (2), whereas bromomethoxylation and controlled hydrolysis led to 3, a reactive analogue of (S)-mevalonic acid. Analogue 4, a nonionizable lipophilic version of (<S)-mevalonic acid, was generated upon exposure of (S)-1 or 2 to excess Tebbe-Grubbs reagent.