Selective Alkoxycarbonylation of A-Ring Precursors of Vitamin D Using Enzymes in Organic Solvents. Chemoenzymatic Synthesis of 1α,25-Dihydroxyvitamin D₃C-5 A-Ring Carbamate Derivatives¹

Abstract

A-Ring modification of 1alpha,25-dihydroxyvitamin D(3) [2, 1alpha,25-(OH)(2)-D(3)] is an important area of analog studies to investigate biological activity of vitamin D-related structures. An efficient synthesis of 1alpha,25-(OH)(2)-D(3) C-5 A-ring carbamate derivatives 19 and amino acid derivatives 21 was developed by applying a two-step chemoenzymatic strategy, involving the enzymatic synthesis of carbonates followed by reaction with amino derivatives. Accordingly, we began the studies of enzymatic alkoxycarbonylation of 1alpha,25-(OH)(2)-D(3) A-ring precursor 7. Candida antarctica lipase (CAL) was found to be the best catalyst in toluene. Regioselective alkoxycarbonylation occurred only at the C-5-(R) hydroxyl group. Good to excellent yields were achieved by chemical reaction of these carbonates with amino derivatives. The procedure provided convenient synthesis of carbamates 19 and 21 under mild reaction conditions.