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Asymmetric Redox-Neutral Radical Cyclization Catalyzed by Flavin-Dependent ‘Ene’-Reductases

preprint
submitted on 21.06.2019 and posted on 24.06.2019 by Michael Black, Kyle F. Biegasiewicz, Andrew J. Meichan, Daniel G. Oblinsky, bryan kudish, Gregory Scholes, Todd Hyster

Flavin-dependent ‘ene’-reductases (EREDs) are exquisite catalysts for effecting stereoselective reductions. While these reactions typically proceed through a hydride transfer mechanism, we recently found that EREDs can also catalyze reductive dehalogenations and cyclizations via single electron transfer mechanisms. Here we demonstrate that these enzymes can catalyze redox-neutral radical cyclizations to produce enantioenriched oxindoles from a-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 a-amido radical formed after cyclization. This mechanistic manifold was previously unknown for this enzyme family, highlighting the versatility of EREDs in asymmetric synthesis.

Funding

NIGMS R01 GM127703 (TKH)

Searle Scholar Award (TKH)

NSF Graduate Research Fellowship (BK)

NSERC Postgraduate Scholarships Doctoral Program (DGO)

Office of Basic Energy Sciences of the US Department of Energy Grant No. DE-SC0019370 (GDS)

History

Email Address of Submitting Author

thyster@princeton.edu

Institution

Princeton University

Country

USA

ORCID For Submitting Author

0000-0003-3560-355X

Declaration of Conflict of Interest

No conflicts of interest

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