CAL-B-Catalyzed Alkoxycarbonylation of A-Ring Stereoisomeric Synthons of 1α,25-Dihydroxyvitamin D3 and 1α,25-Dihydroxy-19-nor-previtamin D3: A Comparative Study. First Regioselective Chemoenzymatic Synthesis of 19-nor-A-Ring Carbonates
2001-05-17T00:00:00Z (GMT) by
A comparative study of alkoxycarbonylation processes of both 19-nor-A-ring and A-ring stereoisomers of 1α,25-dihydroxyvitamin D3 analogues catalyzed by Candida antarctica lipase B (CAL-B) has been described. The presence of the methyl group in the A-ring at C-2, as in 3−6, has a determining role in the regioselectivity of the biocatalysis, mainly allowing the hydroxyl group at C-5 position to react. For the 19-nor-A-ring stereoisomers 7−10, which lack the C-2 methyl group, the configurations at C-3 and C-5 have a high influence in the selectivity exhibited by CAL-B. Thus, each couple of enantiomers showed opposing regioselectivities depending on the C-3 configuration. When C-3 possesses an (S)-configuration, enzymatic alkoxycarbonylations took place at the C-5-(R) or C-5-(S) hydroxyl groups. However, if the chiral centers at C-3 are (R), CAL-B alkoxycarbonylated the C-3-(R) hydroxyl group independently of the configuration at C-5. The corresponding carbonates are useful A-ring precursors of 1α,25-dihydroxyvitamin D3 analogues, selectively modified at the C-1 or C-3 positions. In addition, an improved synthesis of cis A-ring synthons 5 and 6 is described using a Mitsunobu methodology.