Olefin Cyclopropanation via Carbene Transfer Catalyzed by Engineered Cytochrome P450 Enzymes

TLDR

Transition‑metal carbene, nitrene, and oxene transfer reactions are powerful tools for C=C and C‑H functionalization, yet no biological system performs the isoelectronic carbene transfer to olefins that is widely used in synthetic chemistry. We aim to develop engineered cytochrome P450(BM3) variants that catalyze diastereo‑ and enantioselective cyclopropanation of styrenes from diazoester reagents. These variants achieve the reaction via putative carbene transfer. This work highlights the capacity to adapt existing enzymes for the catalysis of synthetically important reactions not previously observed in nature.

Abstract

Transition metal-catalyzed transfers of carbenes, nitrenes, and oxenes are powerful methods for functionalizing C=C and C-H bonds. Nature has evolved a diverse toolbox for oxene transfers, as exemplified by the myriad monooxygenation reactions catalyzed by cytochrome P450 enzymes. The isoelectronic carbene transfer to olefins, a widely used C-C bond-forming reaction in organic synthesis, has no biological counterpart. Here we report engineered variants of cytochrome P450(BM3) that catalyze highly diastereo- and enantioselective cyclopropanation of styrenes from diazoester reagents via putative carbene transfer. This work highlights the capacity to adapt existing enzymes for the catalysis of synthetically important reactions not previously observed in nature.