New synthetic strategies to vitamin D analogues modified at the side chain and D ring. Synthesis of 1α,25-dihydroxy-16-ene-vitamin D3 and C-20 analogues

Article abstract of DOI:10.1021/jo982393e

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.