Total Synthesis of 25-Hydroxy Vitamin D3Northern Portion, Involving Tandem Conjugate Additions

New approaches to 25-hydroxy vitamin D building blocks 7 and 8 have been developed. Tandem acid-catalyzed conjugate addition of ketene acetal 2d or 2c and acceptors 3 and then 11 yielded 5b (76% from 3 ) or 22 (64%), respectively, with the proper relative configuration on C20, C17, and C13 (steroid numbering, all compounds are racemic). The trans -hydrindan ring junction in 16 and 27 has been secured by chirality transfer in palladium-catalyzed hydrogenolysis of formates 15 and 26 . Treatment of 16 with N -bromoacetamide followed by NaOH yielded a mixture of 8β,9β- and 8α,9α-epoxides 18 in a ratio of ca. 2:1, which was tosylated and reduced with lithium aluminum hydride without separation. The required diol 20 and its isomer 21 were obtained. In a complementary approach, 27 was oxidized into 8α,9α-epoxide 29 with a new reagent composed of m -CPBA, KF, and 2,6-di- tert -butyl-4-methylphenol. Opening of the epoxide ring in 29 with thiophenoxide anion followed by oxidation afforded dihydroxy sulfone 31 . The latter was reduced via the respective dimesylate, and then the protective benzyloxy group was removed yielding 8 .