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 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 α-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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T.K.H. acknowledges NIHGMS (R01 GM127703), the Searle Scholar Program (SSP-2017-1741) and the Princeton Catalysis Initiate for Support. B.K. acknowledges the NSF for a Graduate Research Fellowship (DGE-1656466). D.G.O. acknowledges support from the Postgraduate Scholarships Doctoral Program of NSERC. Work by B.K., D.G.O. and G.D.S. was supported BioLEC, an Energy Frontier Research Center funded by DOE, Office of Science, BES under award no. DE-SC0019370.
The authors declare no competing interests.
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Black, M.J., Biegasiewicz, K.F., Meichan, A.J. et al. Asymmetric redox-neutral radical cyclization catalysed by flavin-dependent ‘ene’-reductases. Nat. Chem. 12, 71–75 (2020). https://doi.org/10.1038/s41557-019-0370-2
Journal of the American Chemical Society (2019)