Open AccessGround-State Electron Transfer as an Initiation Mechanism for Biocatalytic C–C Bond Forming Reactions
Author(s) -
Haigen Fu,
Heather Lam,
Megan A. Emmanuel,
Ji Hye Kim,
Braddock A. Sandoval,
Todd K. Hyster
Publication year - 2021
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.1c04334
Subject(s) - chemistry , flavin group , electron transfer , cofactor , stereochemistry , biocatalysis , reductase , active site , cyclohexanone , combinatorial chemistry , substrate (aquarium) , catalysis , reaction mechanism , enzyme , photochemistry , organic chemistry , oceanography , geology
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.