Abstract
State-of-the-art non-natural photoenzymatic catalysis typically relies on either ultraviolet light activation or the formation of electron donor–acceptor complexes. Inspired by nature, herein we develop a biocatalytic scheme based on direct visible-light excitation of flavoprotein to achieve stereocontrolled intermolecular radical hydroarylation of alkenes with electron-rich arenes. Following visible-light activation, flavin-dependent ene-reductases—which naturally catalyse the two-electron reduction of activated alkenes—are repurposed to trigger single-electron oxidation of arenes and afford C(sp2)–C(sp3) bond-forming products in a redox-neutral and enantiodivergent fashion while both enantiomers are obtained with different enzymes. Experiments and computational simulations demonstrate that the reaction is initiated from the single-electron oxidation of substrate by the direct visible-light-excited flavoprotein, and explain the origin of enantioselectivity in this radical hydroarylation that is otherwise notoriously challenging to achieve by chemocatalysis. This work expands the repertoire of photoenzymatic catalysis and will stimulate the development of further biotransformations.
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Data availability
Data relating to the materials and methods, experimental procedures, mechanistic studies and computational calculations, HPLC spectra and NMR spectra are available in the Supplementary Information or from the authors on reasonable request. The atomic coordinates of the optimized computational models are available in the Supplementary Data. The configurations of molecular dynamics simulations have been deposited in GitHub (https://github.com/fpikachu96/OYE1-GluER). Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre under deposition no. CCDC 2226701 (3aa). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.
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Acknowledgements
We thank N. Jiao (Peking University), E. Meggers (Philipps University Marburg) and H. Zhao (UIUC) for insightful discussions. This work was supported by the National Key Research and Development Program of China (nos. 2022YFA0913000 to X.H., 2019YFA0405600 to L.Y. and 2019YFA0706900 to C.T.), the National Natural Science Foundation of China (nos. 22277053 to X.H., 22121001 to B.W. and 21927814 and 21825703 to C.T.), the Natural Science Foundation of Jiangsu Province (no. BK20220760 to X.H.) and the Youth Innovation Promotion Association CAS (no. 2022455 to L.Y.). A portion of this work was performed at Steady High Magnetic Field Facilities, High Magnetic Field Laboratory, CAS.
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B.Z. developed the reactions and performed the majority of synthetic experiments. Z.X., B.C. and F.S. assisted with synthetic experiments and mechanistic investigations. F.L. created mutations. J.F. and B.W. conducted computational studies. A.L. and L.Y. carried out EPR measurements and analysis under the supervision of C.T. Y.Z. performed X-ray crystal structure analysis. X.H., B.W. and C.T. wrote the paper with input from all authors. X.H. coordinated and conceived the project.
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Nature Catalysis thanks Jian Xu, Kai Chen, Wei Shu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Supplementary Figs. 1–37, Tables 1–17 and Methods.
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Atomic coordinates of the optimized computational models.
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Zhao, B., Feng, J., Yu, L. et al. Direct visible-light-excited flavoproteins for redox-neutral asymmetric radical hydroarylation. Nat Catal 6, 996–1004 (2023). https://doi.org/10.1038/s41929-023-01024-0
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DOI: https://doi.org/10.1038/s41929-023-01024-0
