Enzymatic synthesis of four stereoisomers of 3-substituted-4-hydroxypiperidines by carbonyl reductase-catalyzed reduction†

Abstract

Chiral 3-substituted-4-hydroxypiperidines are highly valuable in pharmaceutical applications due to their diverse and potent biological activities. Biocatalytic ketone reduction by carbonyl reductases represents a promising approach for synthesizing these compounds. In this study, two structurally similar yet stereoselectively distinct carbonyl reductases, HeCR and DbCR, were identified. Both enzymes exhibited exceptional catalytic performance, with >99% enantiomeric excess (ee) and >99% conversion rate in the reduction of tert-butyl 4-oxo-3-phenylpiperidine-1-carboxylate (1a). We found that 1a exhibits a relatively low rate of racemization under the mild reaction conditions. Subsequently, analogs of 1a were synthesized and reduced with high enantioselectivity (ee > 99%) using HeCR and DbCR. Carbonyl reductases demonstrated excellent catalytic activity and stereoselectivity in the synthesis of 3-substituted-4-hydroxypiperidines with dual chiral centers, underscoring their potential for pharmaceutical applications.