Asymmetric Redox-Neutral Radical Cyclization Catalyzed by Flavin-Dependent ‘Ene’-Reductases
Abstract
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 α-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 suggest the reaction proceeds via the flavin semiquinone/quinone redox couple, where ground-state flavin semiquinone offers the electron for substrate reduction and flavin quinone oxidizes the vinylogous α-amido radical formed after cyclization. This mechanistic manifold was previously unknown for this enzyme family, highlighting the versatility of EREDs in asymmetric synthesis.
- Authors:
-
- Princeton Univ., NJ (United States)
- Publication Date:
- Research Org.:
- Energy Frontier Research Centers (EFRC) (United States). Bioinspired Light-Escalated Chemistry (BioLEC); Princeton Univ., NJ (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); National Science Foundation (NSF)
- OSTI Identifier:
- 1574669
- Alternate Identifier(s):
- OSTI ID: 1597287
- Grant/Contract Number:
- SC0019370; DGE-1656466
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Chemistry (Online)
- Additional Journal Information:
- Journal Name: Nature Chemistry (Online); Journal Volume: 12; Journal Issue: 1; Related Information: 10.26434/chemrxiv.8307629.v1; Journal ID: ISSN 1755-4349
- Publisher:
- Nature Research
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Citation Formats
Black, Michael, Biegasiewicz, Kyle, Meichan, Andrew J., Oblinsky, Daniel G., Kudisch, Bryan, Scholes, Gregory, and Hyster, Todd. Asymmetric Redox-Neutral Radical Cyclization Catalyzed by Flavin-Dependent ‘Ene’-Reductases. United States: N. p., 2019.
Web. doi:10.1038/s41557-019-0370-2.
Black, Michael, Biegasiewicz, Kyle, Meichan, Andrew J., Oblinsky, Daniel G., Kudisch, Bryan, Scholes, Gregory, & Hyster, Todd. Asymmetric Redox-Neutral Radical Cyclization Catalyzed by Flavin-Dependent ‘Ene’-Reductases. United States. https://doi.org/10.1038/s41557-019-0370-2
Black, Michael, Biegasiewicz, Kyle, Meichan, Andrew J., Oblinsky, Daniel G., Kudisch, Bryan, Scholes, Gregory, and Hyster, Todd. Tue .
"Asymmetric Redox-Neutral Radical Cyclization Catalyzed by Flavin-Dependent ‘Ene’-Reductases". United States. https://doi.org/10.1038/s41557-019-0370-2. https://www.osti.gov/servlets/purl/1574669.
@article{osti_1574669,
title = {Asymmetric Redox-Neutral Radical Cyclization Catalyzed by Flavin-Dependent ‘Ene’-Reductases},
author = {Black, Michael and Biegasiewicz, Kyle and Meichan, Andrew J. and Oblinsky, Daniel G. and Kudisch, Bryan and Scholes, Gregory and Hyster, Todd},
abstractNote = {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 α-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 suggest the reaction proceeds via the flavin semiquinone/quinone redox couple, where ground-state flavin semiquinone offers the electron for substrate reduction and flavin quinone oxidizes the vinylogous α-amido radical formed after cyclization. This mechanistic manifold was previously unknown for this enzyme family, highlighting the versatility of EREDs in asymmetric synthesis.},
doi = {10.1038/s41557-019-0370-2},
journal = {Nature Chemistry (Online)},
number = 1,
volume = 12,
place = {United States},
year = {Tue Jun 25 00:00:00 EDT 2019},
month = {Tue Jun 25 00:00:00 EDT 2019}
}
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