Highly Enantioselective Synthesis of Halogenated Cyclopropanes via Enzyme‐Catalyzed Carbene Transfer

Abstract

Halogenated cyclopropanes are highly desirable building blocks for both agrochemical and medicinal chemistry due to their unique structural features and ability to interact with biological targets through halogen bonds. However, methods for the highly diastereo‐ and enantioselective synthesis of these molecules are underdeveloped. Herein, we report the development of a new biocatalytic strategy to efficiently synthesize enantioenriched halogenated cyclopropanes through the enzymatic cyclopropanation of chloro‐ and bromo‐substituted olefins in the presence of diazoacetonitrile using engineered myoglobin‐based catalysts. This method tolerates a wide range of chloro‐ and bromo‐containing olefins at both α‐ and β‐positions with high yields (up to 75%) and excellent diastereo‐ and enantioselectivity (up to 99% de and ee). These transformations provide access to enantioenriched halogenated cyclopropanes that are challenging to prepare using existing methods, highlighting the value of engineered carbene transfer biocatalysts toward the asymmetric synthesis of enantiopure halogenated cyclopropane building blocks for applications in medicinal chemistry, agrochemicals, and target‐directed synthesis.