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Title: Asymmetric redox-neutral radical cyclization catalysed 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:
 [1];  [1];  [1]; ORCiD logo [1];  [1];  [1]; ORCiD logo [1]
  1. Princeton Univ., NJ (United States)
Publication Date:
Research Org.:
Princeton Univ., NJ (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Science Foundation (NSF)
OSTI Identifier:
1597287
Grant/Contract Number:  
[SC0019370; DGE-1656466]
Resource Type:
Accepted Manuscript
Journal Name:
Nature Chemistry
Additional Journal Information:
[ Journal Volume: 12; Journal Issue: 1]; Journal ID: ISSN 1755-4330
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Black, Michael J., Biegasiewicz, Kyle F., Meichan, Andrew J., Oblinsky, Daniel G., Kudisch, Bryan, Scholes, Gregory D., and Hyster, Todd K. Asymmetric redox-neutral radical cyclization catalysed by flavin-dependent ‘ene’-reductases. United States: N. p., 2019. Web. doi:10.1038/s41557-019-0370-2.
Black, Michael J., Biegasiewicz, Kyle F., Meichan, Andrew J., Oblinsky, Daniel G., Kudisch, Bryan, Scholes, Gregory D., & Hyster, Todd K. Asymmetric redox-neutral radical cyclization catalysed by flavin-dependent ‘ene’-reductases. United States. doi:10.1038/s41557-019-0370-2.
Black, Michael J., Biegasiewicz, Kyle F., Meichan, Andrew J., Oblinsky, Daniel G., Kudisch, Bryan, Scholes, Gregory D., and Hyster, Todd K. Mon . "Asymmetric redox-neutral radical cyclization catalysed by flavin-dependent ‘ene’-reductases". United States. doi:10.1038/s41557-019-0370-2.
@article{osti_1597287,
title = {Asymmetric redox-neutral radical cyclization catalysed by flavin-dependent ‘ene’-reductases},
author = {Black, Michael J. and Biegasiewicz, Kyle F. and Meichan, Andrew J. and Oblinsky, Daniel G. and Kudisch, Bryan and Scholes, Gregory D. and Hyster, Todd K.},
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},
number = [1],
volume = [12],
place = {United States},
year = {2019},
month = {12}
}

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