Journal
NATURE CHEMISTRY
Volume 12, Issue 1, Pages 71-75Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41557-019-0370-2
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Funding
- NIHGMS [R01 GM127703]
- Searle Scholar Program [SSP2017-1741]
- Princeton Catalysis Initiate
- NSF [DGE-1656466]
- Postgraduate Scholarships Doctoral Program of NSERC
- BioLEC, an Energy Frontier Research Center - DOE, Office of Science, BES [DE-SC0019370]
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Flavin-dependent 'ene'-reductases (EREDs) are exquisite catalysts for effecting stereoselective reductions. Although these reactions typically proceed through a hydride transfer mechanism, we recently found that EREDs can also catalyse reductive dehalogenations and cyclizations via single electron transfer mechanisms. Here, we demonstrate that these enzymes can catalyse redox-neutral radical cyclizations to produce enantioenriched oxindoles from alpha-haloamides. This transformation is a C-C bond-forming reaction currently unknown in nature and one for which there are no catalytic asymmetric examples. Mechanistic studies indicate the reaction proceeds via the flavin semiquinone/quinone redox couple, where ground-state flavin semiquinone provides the electron for substrate reduction and flavin quinone oxidizes the vinylogous alpha-amido radical formed after cyclization. This mechanistic manifold was previously unknown for this enzyme family, highlighting the versatility of EREDs in asymmetric synthesis.
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