Catalysis

Asymmetric C-Alkylation of Nitroalkanes via Enzymatic Photoredox Catalysis

Authors

Abstract

Tertiary nitroalkanes and the corresponding α-tertiary amines represent important motifs in bioactive molecules and natural prod-ucts. The C-alkylation of secondary nitroalkanes with electrophiles is a straightforward strategy for constructing tertiary nitroal-kanes, however, controlling the stereoselectivity of this type of reaction remains challenging. Here we report a highly chemo- and stereoselective C-alkylation of nitroalkanes with alkyl halides catalyzed by an engineered flavin-dependent ‘ene’-reductase (ERED). Directed evolution of the old yellow enzyme from Geobacillus kaustophilus provided a triple mutant, GkOYE-G7, capable of synthesizing tertiary nitroalkanes with high yield and enantioselectivity. Mechanistic studies indicate that the excitation of an enzyme-templated charge-transfer complex formed between the substrates and cofactor is responsible for radical initiation. Moreover, a single-enzyme two-mechanism cascade reaction was developed to prepare tertiary nitroalkanes from simple nitroal-kenes, highlighting the potential to use one enzyme for two mechanistically distinct reactions.

Content

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Supplementary material

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Supplemental Information
Experimental procedures, characterization data, NMR spectra, HPLC traces, and X-ray crystallographic data.