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Merging photoredox with metalloenzymatic catalysis for enantioselective decarboxylative C(sp3)‒N3 and C(sp3)‒SCN bond formation

Nature Catalysis volume 7, pages 1394–1403 (2024)Cite this article

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Abstract

The scope of nature’s catalytic abilities has been expanded by recent advancements in biocatalysis to include synthetic transformations with no biological equivalent. However, these newly introduced catalytic functions represent only a small fraction of reactions utilized in synthetic catalysis. Here we present a biocatalytic platform that combines photoredox and metalloenzymatic catalysis for enantioselective radical transformations. Under green light irradiation, the eosin Y photocatalyst enables 4-hydroxyphenylpyruvate dioxygenases to catalyse enantioselective decarboxylative azidation and thiocyanation of N-hydroxyphthalimide esters. The final optimized variant obtained through directed evolution can afford diverse chiral organic azide and thiocyanate compounds with up to 77% yield, 385 total turnovers and 94% enantiomeric excess. Mechanistic studies show that the eosin Y catalyst mediates the generation of both C(sp3) radical and Fe(III)‒N3/Fe(III)‒NCS intermediate, leading to efficient enantioselective C‒N3 and C‒SCN bond formation in the enzyme active site. These findings establish an adaptable biocatalytic platform for introducing abiological metallophotoredox catalysis into biology.

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Fig. 1: The design of a photobiocatalytic platform for decarboxylative functionalization.
Fig. 2: Initial activity discovery and directed evolution.
Fig. 3: Substrate scope of photobiocatalytic decarboxylative azidation and thiocyanation.
Fig. 4: Mechanistic studies.

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All data required to assess the conclusions of this study are included in the Article and its Supplementary Information or can be obtained from the authors upon reasonable request.

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Acknowledgements

Financial support was provided by the Johns Hopkins University (to X.H.) and by National Institutes of Health (NIH) GM R01-125924 (to Y.G.). This work was also supported by the Generalitat de Catalunya AGAUR 2021SGR00623 project (to M.G.-B.), the Spanish MICINN (Ministerio de Ciencia e Innovación) PID2022-141676NB-I00 and TED2021-130173B-C42 projects, RYC 2020-028628-I grant (to M.G.-B) and the Spanish MIU (Ministerio de Universidades) pre-doctoral fellowship FPU18/02380 (to J.S.). Part of the computational resources used were funded by the European Research Council (ERC) under the European Union’s ERC-StG-2015 (grant agreement no. 679001), as well as by FEDER (Fondo Europeo de Desarrollo Regional) and Spanish MINECO (Ministerio de Economía, Comercio y Empresa) through projects CTQ2014-54306-P, CTQ2015-69363-P and MPCUdG2016/096.

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Author notes

  1. These authors contributed equally: Jinyan Rui, Xinpeng Mu.

Authors and Affiliations

  1. Department of Chemistry, Johns Hopkins University, Baltimore, MD, USA

    Jinyan Rui, Xinpeng Mu & Xiongyi Huang

  2. Institut de Química Computacional i Catàlisi, Departament de Química, Universitat de Girona, Girona, Spain

    Jordi Soler & Marc Garcia-Borràs

  3. Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA, USA

    Jared C. Paris & Yisong Guo

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  1. Jinyan Rui
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Contributions

X.H. and J.R. conceived the project and designed the experiments. J.R. performed initial screening and directed evolution experiments and results analysis. X.M. and J.R. performed substrate scope study. Y.G. and J.C.P. conducted the electron paramagnetic resonance studies. M.G.-B. directed the computational modelling studies. J.S. performed density functional theory calculations and MD simulation studies under the guidance of M.G.-B. X.H. and J.R. wrote the manuscript with input from all other authors, M.G.-B. wrote the computational section.

Corresponding authors

Correspondence to Yisong Guo, Marc Garcia-Borràs or Xiongyi Huang.

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Competing interests

A provisional patent application covering radical C–N3 and C‒SCN bond formation has been filed through the Johns Hopkins University with X.H. and J.R. as inventors (PCT/US2023/022431). The other authors declare no competing interests.

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Nature Catalysis thanks Qi Wu, Wei Yu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

Supplementary Methods, Tables 1–6, Figs. 1–11 and Notes 1–13.

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Supplementary Data 1

Coordinates from MD simulations.

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Rui, J., Mu, X., Soler, J. et al. Merging photoredox with metalloenzymatic catalysis for enantioselective decarboxylative C(sp3)‒N3 and C(sp3)‒SCN bond formation. Nat Catal 7, 1394–1403 (2024). https://doi.org/10.1038/s41929-024-01257-7

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