Abstract
Photoenzymatic catalysts are attractive for stereoselective radical reactions because the transformation occurs within tunable enzyme active sites. When using flavoproteins for non-natural photoenzymatic reactions, reductive mechanisms are often used for radical initiation. Oxidative mechanisms for radical formation would enable abundant functional groups, such as amines and carboxylic acids, to serve as radical precursors. However, excited state flavin is short-lived in many proteins because of rapid quenching by the protein scaffold. Here we report that adding an exogenous Ru(bpy)32+ cofactor to flavin-dependent ‘ene’-reductases enables the redox-neutral decarboxylative coupling of amino acids with vinylpyridines with high yield and enantioselectivity. Additionally, stereo-complementary enzymes are found to provide access to both enantiomers of the product. Mechanistic studies indicate that Ru(bpy)32+ binds to the protein, helping to localize radical formation to the enzyme’s active site. This work expands the types of transformation that can be rendered asymmetric using photoenzymatic catalysis and provides an intriguing mechanism of radical initiation.
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Data availability
The data that support the findings in this study are available within the paper and its Supplementary Information or from the corresponding author upon reasonable request.
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Acknowledgements
We thank the S. Lin, P. Milner, A. Musser and R. A. Cerione groups for use of their equipment and the D. Collum group for use of their computational resources. S.-Z.S. thanks Z. Lu (S. Lin group) for helping with electrochemical measurements and W. Fu (SJTU) for examining the electrostatic map of OYE3. S.-Z.S. thanks H. Fu and Y. Ye for discussion. The research reported here was supported by the National Science Foundation CHE-2135973. C.G.P. acknowledges the NSF-GFRP for support. This work made use of the Cornell University NMR Facility, which is supported, in part, by the NSF though MRI Award CHE-1531632.
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T.K.H. conceived and directed the project. S.-Z.S. and T.K.H. designed the experiments. S.-Z.S. and B.T.N. performed experiments and analysed the results. T.Q. conducted DFT experiments. D.B. and A.J.M. conducted and analysed time-resolved fluorescence spectroscopy. C.G.P helped with revisions of the manuscript. The manuscript was prepared with feedback from all the authors.
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Sun, SZ., Nicholls, B.T., Bain, D. et al. Enantioselective decarboxylative alkylation using synergistic photoenzymatic catalysis. Nat Catal 7, 35–42 (2024). https://doi.org/10.1038/s41929-023-01065-5
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DOI: https://doi.org/10.1038/s41929-023-01065-5
