Highly Enantioselective Construction of Oxazolidinone Rings via Enzymatic C(sp3)–H Amination

Abstract

Oxazolidinones are important heterocycles widely utilized in medicinal chemistry for the synthesis of antifungals, antibacterials, and other bioactive compounds and in organic chemistry as chiral auxiliaries for asymmetric synthesis. Herein, we report a biocatalytic strategy for the synthesis of enantioenriched oxazolidinones through the intramolecular C(sp³)–H amination of carbamate derivatives using engineered myoglobin-based catalysts. This method is applicable to a diverse range of substrates with high functional group tolerance to provide enantioenriched oxazolidinones in good yields with high enantioselectivity. The synthetic utility of this methodology is further highlighted by the development of enantiodivergent biocatalysts for this transformation and through the preparative-scale synthesis of key oxazolidinone intermediates for the production of cholesterol-lowering drugs ezetimibe and CJ-15-161. An outer sphere mutation, Y146F, was found to be beneficial in favoring the productive C–H amination reaction over an unproductive reductive pathway commonly observed in hemeprotein-catalyzed nitrene transfer reactions. This study demonstrates a biocatalytic, enantiodivergent synthesis of oxazolidinones via C–H amination of carbamate derivatives, which offers an attractive strategy for the synthesis of these valuable intermediates for applications in medicinal chemistry, target-directed synthesis, and asymmetric synthesis.