New Carbene Donor for Biocatalysis: Stereodivergent Synthesis of Pyridyl Cyclopropanes via Enzymatic Activation of Pyridyltriazoles

Hemoproteins have recently emerged as powerful biocatalysts for new-to-nature carbene transfer reactions. Despite this progress, these strategies have remained largely limited to diazo-based carbene precursor reagents. Here, we report the development of a biocatalytic strategy for the stereoselective construction of pyridine-functionalized cyclopropanes via hemoprotein-mediated activation of pyridyl triazoles (PyTz) as stable and readily accessible carbene sources. This method enables the asymmetric cyclopropanation of a variety of olefins, including electronrich and electrodeficient ones, with high activity, high stereoselectivity, and enantiodivergent selectivity, providing access mono- and diaryl-cyclopropanes that incorporate a pyridine moiety, and thus two structural motifs of high value in medicinal chemistry. Mechanistic studies reveal a multifaceted role of 7-halogen substitution in the pyridyltriazole reagent toward favoring multiple catalytic steps in the transformation. This work provides a first example of asymmetric olefin cyclopropanation with pyridotriazoles, paving the way to the exploitation of these attractive and versatile reagents for enzyme-catalyzed carbene-mediated reactions.