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Trifluoromethyl‐substituted cyclopropanes (CF₃‐CPAs) constitute an important class of compounds for drug discovery. While several methods have been developed for synthesis oftrans‐CF₃‐CPAs, stereoselective production of correspondingcis‐diastereomers remains a formidable challenge. We report a biocatalyst for diastereo‐ and enantio‐selective synthesis ofcis‐CF₃‐CPAs with activity on a variety of alkenes. We found that an engineered protoglobin fromAeropyrnum pernix(ApePgb) 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‐cisnear‐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 CF₃‐CPAs for drug discovery.

Trifluoromethyl‐substituted cyclopropanes (CF₃‐CPAs) constitute an important class of compounds for drug discovery. While several methods have been developed for synthesis oftrans‐CF₃‐CPAs, stereoselective production of correspondingcis‐diastereomers remains a formidable challenge. We report a biocatalyst for diastereo‐ and enantio‐selective synthesis ofcis‐CF₃‐CPAs with activity on a variety of alkenes. We found that an engineered protoglobin fromAeropyrnum pernix(ApePgb) 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‐cisnear‐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 CF₃‐CPAs for drug discovery.