Asymmetric C-Alkylation of Nitroalkanes via Enzymatic Photoredox Catalysis

Haigen Fu, Tianzhang Qiao, Jose M. Carceller, Samantha N. MacMillan, Todd K. Hyster

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Tertiary nitroalkanes and the corresponding α-tertiary amines represent important motifs in bioactive molecules and natural products. The C-alkylation of secondary nitroalkanes with electrophiles is a straightforward strategy for constructing tertiary nitroalkanes; 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 in 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 nitroalkenes, highlighting the potential to use one enzyme for two mechanistically distinct reactions.

Original languageEnglish (US)
Pages (from-to)787-793
Number of pages7
JournalJournal of the American Chemical Society
Volume145
Issue number2
DOIs
StatePublished - Jan 18 2023
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • Biochemistry
  • Catalysis
  • Colloid and Surface Chemistry

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