1-Allkylated analogs of 1 alpha,25-(OH)(2)D-3 were synthesized to investigate the effect of the alkyl group on the A-ring conformation and the biological potency. The analogs were synthesized via two routes. In the first approach, alkylation of 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) adduct of 1-oxopro-vitamin D (4) was used as the key step to synthesize 1 beta-methyl-1 alpha,25-dihydroxyprovitamin D-3 (OH)(2)D-3 (16a) efficiently and stereoselectively. The photolysis of the provitamin D (16a), however, gave the desired previtamin D (17a) only as a minor product (<5%) and an unusual 1,10-bond cleavage product (18a) occurred in high yield (79%). As an alternative C(1)-epimeric pairs of 1-alkyl-1,25-(OH)(2)D-3 were synthesized conveniently from 25-hydroxy-1-oxoprevitamin D-3 (19) by reaction with an alkyllithium followed by thermal isomerization. In the alkylation, the alkyllithium attacked the ketone preferentially from the side of the 3 beta-hydroxyl group to afford the 1 beta-alkyl-1 alpha-hydroxy epimer in a 1.6-2.7 to 1 ratio over the 1 alpha-alkyl-1 beta-hydroxy isomer. Introduction of a 1 beta-methyl group to 1 alpha,25-(OH)(2)D-3, shifted the equilibrium between the two chair conformations of the A-ring preferentially to the side of the alpha-form (4:1) and reduced considerably the activity to bind to the VDR.
