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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 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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Fig. 1: Strategies and challenges in using ‘ene’-reductases for redox-neutral radical cyclizations.
Fig. 2: Studies to determine the mechanism of oxindole formation.

Data availability

Data are available in the Supplementary Information or from the corresponding author upon request.

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Acknowledgements

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.

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T.K.H. conceived and directed the project. T.K.H., M.J.B., A.J.M. and K.F.B. designed the experiments. M.J.B., A.J.M. and K.F.B. performed and analysed the experiments. D.G.O. performed the EPR measurements and B.K. and D.G.O. performed the time-correlated single photon counting) and transient absorption measurements. B.K., D.G.O. and G.D.S. analysed and interpreted the spectroscopy results. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Todd K. Hyster.

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Supplementary Information

Supplementary materials and methods, data and Figs. 1–25.

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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

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