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

Black, Michael; Biegasiewicz, Kyle; Meichan, Andrew J.; Oblinsky, Daniel G.; Kudisch, Bryan; Scholes, Gregory; Hyster, Todd

doi:10.1038/s41557-019-0370-2

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

Journal Article · Tue Jun 25 00:00:00 EDT 2019 · Nature Chemistry (Online)

DOI:https://doi.org/10.1038/s41557-019-0370-2· OSTI ID:1574669

Black, Michael ^[1]; Biegasiewicz, Kyle ^[2]; Meichan, Andrew J. ^[2]; Oblinsky, Daniel G. ^[2]; Kudisch, Bryan ^[2]; Scholes, Gregory ^[2]; Hyster, Todd ^[2]

Princeton Univ., NJ (United States); Princeton University
Princeton Univ., NJ (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Energy Frontier Research Centers (EFRC) (United States). Bioinspired Light-Escalated Chemistry (BioLEC); Princeton Univ., NJ (United States)

Sponsoring Organization:: National Science Foundation (NSF); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: SC0019370

OSTI ID:: 1574669

Alternate ID(s):: OSTI ID: 1597287

Journal Information:: Nature Chemistry (Online), Journal Name: Nature Chemistry (Online) Journal Issue: 1 Vol. 12; ISSN 1755-4349

Publisher:: Nature ResearchCopyright Statement

Country of Publication:: United States

Language:: English

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