1α,25-Dihydroxyvitamin D₃ A-Ring Precursors:  Studies on Regioselective Enzymatic Alkoxycarbonylation Reactions of Their Stereoisomers. Chemoenzymatic Synthesis of A-Ring Synthon Carbamate Derivatives, Including Carbazates and Polyamino Carbamates

Abstract

The stereoisomers of 1α,25-dihydroxyvitamin D3 A-ring synthon 3a, named 3b−d, were subjected to a very comprehensive regioselective enzymatic study with Candida antarctica lipase (CAL). From this, it emerged that 3b, the enantiomer of the natural A-ring synthon, was a very good substrate for CAL in toluene, dioxane, or THF, showing in all cases conversions close to 100% and regioselectivities between 95% and 99% toward the C-5-(S) hydroxyl group. The best results for the regioselective enzymatic transformation of stereoisomer 3c were achieved with toluene at 30 °C or with THF at 60 °C. The regioselectivity displayed a preference toward the C-5-(S) hydroxyl group. The 1:10 ratio (3c:4) was mandatory so as to obtain an acceptable degree of conversion (in dioxane or THF). The A-ring synthon 3d has a surprising conduct, suffering C-5-(R) enzymatic alkoxycarbonylation, whereas in the acylation process with Chromobacterium viscosum lipase, it showed behavior opposite to that observed for 3a−c. In addition to the above, an efficient chemoenzymatic synthesis of A-ring synthon carbamate derivatives 15a,c−17a,c, including carbazates 15b−17b, and polyamino carbamates 15d−17d was accomplished by a two-step strategy, involving the regioselective enzymatic synthesis of carbonates 5, 7, and 10, followed by reaction with (poly)amino derivatives 14.

Sustainable routes to polyurethane precursors

“…91 Later, the same group showed the CAL catalyzed alkoxycarbonylation of 1α,25-dihydroxyvitamin D3 A-ring precursors with O-[(vinyloxy)carbonyl]oxime to obtain carbamate derivatives in quite good yields. 92 Furthermore, the first regioselective enzymatic alkoxycarbonylation of primary amines to carbamates of pyrimidine 3′,5′-diaminonucleoside derivatives applying CAL-B was described. 93 Diallyl or dibenzyl carbonates are adequate reagents in this alkoxycarbonylation reaction to obtain allyl and benzyl carbamate derivatives in yields between 63% and 72%.…”

2 Synthetic methods : Part (v) Enzyme methods

“…98 A remarkable temperature dependent regioselective acylation has been observed using CAL for the acylation of ethynylcyclohexendiols (Scheme 2). 99 While at 30 ЊC vinylcarbonates were predominant, at 60 ЊC oxime carbonates were the major products. Transesterification of mixed carbonates has also been used as a resolution strategy.…”

Preparative biotransformations

“…The study was extended to cover the regioselective formation of a required carbamate. 130 The diester 68 was obtained (44%, >99% ee) from the racemic diol together with recovered starting material (47%, 98% ee). 131 When the polyol 69 was used as a substrate for lipase PS-catalysed acetylation reactions employing vinyl acetate as the acylation agent at 45 ЊC, it was found that esterification occurred initially at C-9 then at C-4 and then at C-8.…”