Highly Stereoselective Olefin Cyclopropanation via Enzyme-Catalyzed Reductive Activation of gem -Dibromoalkanes

Abstract Engineered hemoproteins have emerged as powerful biocatalysts for asymmetric, new-to-nature carbene transfer reactions. Despite significant advances in biocatalytic cyclopropanation reactions, these transformations have been largely limited to diazo-based carbene precursors with electron-deficient substituents. Herein, we report a biocatalytic strategy for stereoselective cyclopropanation of olefins using gem-dibromoalkanes as carbene precursors. This method enables the asymmetric cyclopropanation of vinylarenes bearing both electron-donating and electron-withdrawing groups to afford trans-1,2-diarylcyclopropanes in up to >99% yield and with high diastereo- and enantiodivergent selectivity (>99:1 d.r.; up to >99% ee). This strategy could be further applied to the construction of a variety of three-dimensional, sp3-rich spirocyclic scaffolds via cyclopropanation of exocyclic olefins, and it could be extended to σ-bond carbene insertions. Mechanistic studies support the formation of an α-halo radical intermediate via either a chemical or an enzyme-mediated reduction of benzylic gem-dibromides as a key step for generation of the reactive heme-carbenoid species implicated in carbene transfer. This work expands the scope of biocatalytic carbene transfer reactions, and it paves the way to the exploitation of gem-dibromoalkanes and other non-diazo carbene precursors in enzyme-catalyzed new-to-nature transformations.