Novel chiral precursors of 6- s- cis locked 1α,25-dihydroxyvitamin D 3 analogues through selective enzymatic acylation

Abstract

The syntheses of selectively modified chiral A-ring precursors for the preparation of 1α,25-dihydroxyvitamin D 3 analogues by regioselective enzymatic acylation are described. Candida antarctica lipase B (CAL-B) catalyzes the acylation of 1α,25-dihydroxy-19- nor-previtamin D 3 trans A-ring precursors 4 and 5 with high selectivity. The opposing regioselectivities observed for each pair of enantiomers is noteworthy: whereas CAL-B acylates the C-3 hydroxyl groups for derivatives of (3 S,5 R)-configuration, it catalyzes acylation at the C-5 hydroxyl group for substrates which possess (3 R,5 S)-stereochemistry. In relation to stereoisomer 4b, Chromobacterium viscosum lipase (CVL) showed opposite behavior to CAL-B, catalyzing acylation at the C-5 hydroxyl group with acceptable selectivity. In the enzymatic acylation of cis A-ring synthons 6 and 7, CVL gave total selectivity for acylation of the C-5 hydroxyl group of (3 S,5 S)- 6 and the C-3 hydroxyl group of (3 R,5 R)- 7. CAL-B also exhibits high selectivity towards the acylation of the C-3 hydroxyl in 19- nor-A-ring precursors with (3 R,5 R)-configuration.