An Enzymatic Platform for the Highly Enantioselective and Stereodivergent Construction of Cyclopropyl-δ-lactones.

Abstract

Abiological enzymes offers new opportunities for sustainable chemistry. Herein, we report the development of biological catalysts derived from sperm whale myoglobin that exploit a carbene transfer mechanism for the asymmetric synthesis of cyclopropane-fused-δ-lactones, which are key structural motifs found in many biologically active natural products. While hemin, wild-type myoglobin, and other hemoproteins are unable to catalyze this reaction, the myoglobin scaffold could be remodeled by protein engineering to permit the intramolecular cyclopropanation of a broad spectrum of homoallylic diazoacetate substrates in high yields and with up to 99 % enantiomeric excess. Via an alternate evolutionary trajectory, a stereodivergent biocatalyst was also obtained for affording mirror-image forms of the desired bicyclic products. In combination with whole-cell transformations, the myoglobin-based biocatalyst was used for the asymmetric construction of a cyclopropyl-δ-lactone scaffold at a gram scale, which could be further elaborated to furnish a variety of enantiopure trisubstituted cyclopropanes.