6-s-cis locked analogues of the steroid hormone 1α,25-dihydroxyvitamin D3.: Synthesis of novel A-ring stereoisomeric 1,25-dihydroxy-3-epi-19-nor-previtamin D3 derivatives

Efficient syntheses of A-ring synthons 24 and 32 are described from hydroxy ester 16, which is easily available on a preparative scale from (-)-quinic acid. Key features of the syntheses were (a) the ability to selectively perform desilylations in the presence of p-nitrobenzoate esters and (b) the excellent yield and complete stereospecificity with which the configuration of alcohols 16, 18, and 26 could be inverted under Mitsunobu conditions. Thus, A-ring synthons 24 and 32 were both prepared in 35-38% yield (eight steps) from the common precursor 16. The coupling of A-ring synthons 24 and 32 with the appropriate CD-ring/side chain fragment 7 provides access to novel 6-s-cis locked analogues of steroid hormone 1 alpha,25-dihydroxyvitamin D-3: 1 alpha,25-dihydroxy-3-epi-19-nor-previtamin D-3 (37) and 1 beta,25-dihydroxy-3-epi-19-nor-previtamin D-3 (38), which are unable to undergo rearrangement to the respective vitamin D form by virtue of the absence of the C-19 methyl group. Compounds 37 and 38 can be used as tools for studying the genomic and nongenomic mechanisms of action of the previtamin form of the hormone 1 alpha,25-dihydroxyvitamin D-3.