Ground-State Electron Transfer as an Initiation Mechanism for Biocatalytic C-C Bond Forming Reactions

Haigen Fu, Heather Lam, Megan A. Emmanuel, Ji Hye Kim, Braddock A. Sandoval, Todd K. Hyster

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

The development of non-natural reaction mechanisms is an attractive strategy for expanding the synthetic capabilities of substrate promiscuous enzymes. Here, we report an "ene"-reductase catalyzed asymmetric hydroalkylation of olefins using α-bromoketones as radical precursors. Radical initiation occurs via ground-state electron transfer from the flavin cofactor located within the enzyme active site, an underrepresented mechanism in flavin biocatalysis. Four rounds of site saturation mutagenesis were used to access a variant of the "ene"-reductase nicotinamide-dependent cyclohexanone reductase (NCR) from Zymomonas mobiles capable of catalyzing a cyclization to furnish β-chiral cyclopentanones with high levels of enantioselectivity. Additionally, wild-type NCR can catalyze intermolecular couplings with precise stereochemical control over the radical termination step. This report highlights the utility for ground-state electron transfers to enable non-natural biocatalytic C-C bond forming reactions.

Original languageEnglish (US)
Pages (from-to)9622-9629
Number of pages8
JournalJournal of the American Chemical Society
Volume143
Issue number25
DOIs
StatePublished - Jun 30 2021

All Science Journal Classification (ASJC) codes

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

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