Novel chiral precursors of 6-s-cis locked 1α,25-dihydroxyvitamin D3 analogues through selective enzymatic acylation

The syntheses of selectively modified chiral A-ring precursors for the preparation of 17,25-dihydroxyvitamin D-3 analogues by regioselective enzymatic acylation are described. Candida antarctica lipase B (CAL-B) catalyzes the acylation of 1alpha,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 (3S,5R)-configuration, it catalyzes acylation at the C-5 hydroxyl group for substrates which possess (3R,5S)-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 (3S,5S)-6 and the C-3 hydroxyl group of (3R,5R)-7. CAL-B also exhibits high selectivity towards the acylation of the C-3 hydroxyl in 19-nor-A-ring precursors with (3R,5R)-configuration. (C) 2002 Elsevier Science Ltd. All rights reserved.