Protoglobin‐Catalyzed Formation of cis‐Trifluoromethyl‐Substituted Cyclopropanes by Carbene Transfer

Abstract Trifluoromethyl‐substituted cyclopropanes (CF 3 ‐CPAs) constitute an important class of compounds for drug discovery. While several methods have been developed for synthesis of trans ‐CF 3 ‐CPAs, stereoselective production of corresponding cis ‐diastereomers remains a formidable challenge. We report a biocatalyst for diastereo‐ and enantio‐selective synthesis of cis ‐CF 3 ‐CPAs with activity on a variety of alkenes. We found that an engineered protoglobin from Aeropyrnum pernix ( Ape Pgb) can catalyze this unusual reaction at preparative scale with low‐to‐excellent yield (6–55 %) and enantioselectivity (17–99 % ee), depending on the substrate. Computational studies revealed that the steric environment in the active site of the protoglobin forced iron‐carbenoid and substrates to adopt a pro‐ cis near‐attack conformation. This work demonstrates the capability of enzyme catalysts to tackle challenging chemistry problems and provides a powerful means to expand the structural diversity of CF 3 ‐CPAs for drug discovery.