New Synthetic Strategies to Vitamin D Analogues Modified at the Side Chain and D Ring. Synthesis of 1alpha,25-Dihydroxy-16-ene-vitamin D(3) and C-20 Analogues(1).

Two efficient synthetic routes to 1α,25-dihydroxy-16-ene-vitamin D3 (4a) and their C-20 analogues (3 and 4) have been developed. Key features common to both routes A and B are the introduction of side chains functionalized at C20 (17, 21, 19, and 25). In route A the CD side chain fragments 5 and 6 are prepared by SN2‘ syn displacement of allylic carbamates 8 and 9 (X = OCONHPh) by Li2Cu3R5. The triene unit is then constructed by assembling the latter fragments with the A-ring fragment using the Wittig−Horner method (average yield of vitamin D analogue 35%, 11−13 steps from ketone 11). In route B, the SN2‘ syn displacement of the carbamate moiety by Li2Cu3R5 is carried out on intermediates 12 and 13, both of which bear the vitamin D triene unit (average yield of vitamin D analogue 27%, 13−15 steps from ketone 11). The latter route is particularly attractive as an approach to diverse C-20 vitamin D analogues for biological screening.