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Photoenzymatic enantioselective intermolecular radical hydroamination

Nature Catalysis volume 6, pages 687–694 (2023)Cite this article

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Abstract

Since the discovery of Hofmann–Löffler–Freytag reaction more than 130 years ago, both the structure and reactivity of nitrogen-centred radicals have been widely studied. Nevertheless, catalytic enantioselective intermolecular radical hydroamination remains a challenge due to the existence of side reactions, the short lifetime of nitrogen-centred radicals and lack of understanding of the fundamental catalytic steps. In the laboratory, nitrogen-centred radicals are produced with radical initiators, photocatalysts or electrocatalysts. In contrast, their generation and reaction are unknown in nature. Here we report a pure biocatalytic system for the photoenzymatic production of nitrogen-centred radicals and enantioselective intermolecular radical hydroaminations by successfully repurposing an ene-reductase through directed evolution. These reactions progress efficiently at room temperature under visible light without any external photocatalysts and exhibit excellent enantioselectivities. A detailed mechanistic study reveals that the enantioselectivity originates from the radical-addition step while the reactivity originates from the ultrafast photoinduced electron transfer from reduced flavin mononucleotide to nitrogen-containing substrates.

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Fig. 1: Catalytic enantioselective intermolecular radical hydroaminations.
Fig. 2: Reaction development.
Fig. 3: Substrate scope.
Fig. 4: Mechanistic studies.

Data availability

All data are available in the main text, the Supplementary information or from the authors on reasonable request.

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Acknowledgements

We thank the Core Facilities at the Carl R. Woese Institute for Genomic Biology, at which the majority of the experiments in this project were performed. We thank the School of Chemical Sciences NMR Laboratory for performing NMR experiments at varying temperatures. We thank X. Li (OSU), M. Li (UIUC) and G. Jiang (UIUC) for helpful discussions. We thank T. Yu (UIUC) for designing the primers. This work was funded by the DOE Center for Advanced Bioenergy and Bioproducts Innovation (US Department of Energy, Office of Science, Office of Biological and Environmental Research under award no. DE-SC0018420 to H.Z.), the National Natural Science Foundation of China (award no. 22122305 to B.W.) and the National Institute of Health (grant no. GM144047 to D.Z.). NMR data were collected at the Carl R. Woese Institute for Genomic Biology Core on a 600 MHz NMR funded by the National Institute of Health (grant no. S10-RR028833 to H.Z.). Any opinions, findings, and conclusions or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the US Department of Energy.

Author information

Author notes

  1. These authors contributed equally: Zhengyi Zhang, Jianqiang Feng.

Authors and Affiliations

  1. DOE Center for Advanced Bioenergy and Bioproducts Innovation, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Zhengyi Zhang, Wesley Harrison & Huimin Zhao

  2. Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Zhengyi Zhang, Haiyang Cui, Wesley Harrison & Huimin Zhao

  3. Carl Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Zhengyi Zhang, Haiyang Cui, Wesley Harrison & Huimin Zhao

  4. State Key Laboratory of Physical Chemistry of Solid Surfaces and Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, P. R. China

    Jianqiang Feng & Binju Wang

  5. Department of Physics, The Ohio State University, Columbus, OH, USA

    Chao Yang & Dongping Zhong

  6. NSF Molecule Maker Lab Institute, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Haiyang Cui & Huimin Zhao

  7. Department of Chemistry and Biochemistry, Programs of Biophysics, Chemical Physics and Biochemistry, The Ohio State University, Columbus, OH, USA

    Dongping Zhong

Authors
  1. Zhengyi Zhang
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Contributions

H.Z. coordinated the project. Z.Z. and H.Z. conceived the project and designed the experiments. Z.Z. performed most of the experiments. J.F. and B.W. performed computational studies. C.Y. and D.Z. performed optical studies. H.C. designed the mutants. W.H. contributed to scope investigation. Z.Z., B.W, C.Y. and H.Z. wrote the manuscript with input from all authors.

Corresponding authors

Correspondence to Dongping Zhong, Binju Wang or Huimin Zhao.

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The authors declare no competing interests.

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Peer review information

Nature Catalysis thanks Debabrata Maiti, Marc Garcia-Borràs, Nicholas Turner, and Frank Hollmann for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–23, Tables 1–8, Methods and references.

Reporting Summary

Supplementary Data 1

Atomic coordinates of the optimized computational models.

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Zhang, Z., Feng, J., Yang, C. et al. Photoenzymatic enantioselective intermolecular radical hydroamination. Nat Catal 6, 687–694 (2023). https://doi.org/10.1038/s41929-023-00994-5

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