STEREOSELECTIVE SYNTHESES OF (22R)-22-METHYL-1-ALPHA,25-DIHYDROXYVITAMIN-D3 AND (22S)-22-METHYL-1-ALPHA,25-DIHYDROXYVITAMIN-D3 - ACTIVE VITAMIN-D3 ANALOGS WITH RESTRICTED SIDE-CHAIN CONFORMATION

(22R)- and (22S)-22-methyl-1alpha,25-dihydroxyvitamin D3 (1b and 1c) were synthesized stereoselectively from 1alpha-hydroxylated C(22)-steroid 2. The two new vitamin D analogs, which have a side chain with restricted flexibility, were designed to allow the study of the stereochemical structure required to bind to the receptor of the active vitamin D3 (VDR). According to force-field calculations, the side chain of (22R)- and (22S)-methylated active vitamin D3 analogs (1b and 1c) adopts with more than 90% of the population gauche(+) and anti conformations, respectively, at the C(17-20-22-23) dihedral angle. Either the (22R)- or (22S)-methylated steroidal side chain was constructed with high stereoselectivity via a kinetically controlled conjugate addition of methylcopper reagent to (22E)- or (22Z)-22-en-24-ones (6 or 7), respectively, as a key step. The ability of the two analogs to bind to VDR was examined and only the (22S)-isomer (1c) showed significant activity. From the results, the side chain conformation best fitted to VDR was suggested to be the anti with respect to the C(17-20-22-23) dihedral angle.