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Photoenzymatic enantioselective intermolecular radical hydroalkylation

Nature volume 584, pages 69–74 (2020)Cite this article

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Abstract

Enzymes are increasingly explored for use in asymmetric synthesis1,2,3, but their applications are generally limited by the reactions available to naturally occurring enzymes. Recently, interest in photocatalysis4 has spurred the discovery of novel reactivity from known enzymes5. However, so far photoinduced enzymatic catalysis6 has not been used for the cross-coupling of two molecules. For example, the intermolecular coupling of alkenes with α-halo carbonyl compounds through a visible-light-induced radical hydroalkylation, which could provide access to important γ-chiral carbonyl compounds, has not yet been achieved by enzymes. The major challenges are the inherent poor photoreactivity of enzymes and the difficulty in achieving stereochemical control of the remote prochiral radical intermediate7. Here we report a visible-light-induced intermolecular radical hydroalkylation of terminal alkenes that does not occur naturally, catalysed by an ‘ene’ reductase using readily available α-halo carbonyl compounds as reactants. This method provides an efficient approach to the synthesis of various carbonyl compounds bearing a γ-stereocentre with excellent yields and enantioselectivities (up to 99 per cent yield with 99 per cent enantiomeric excess), which otherwise are difficult to access using chemocatalysis. Mechanistic studies suggest that the formation of the complex of the substrates (α-halo carbonyl compounds) and the ‘ene’ reductase triggers the enantioselective photoinduced radical reaction. Our work further expands the reactivity repertoire of biocatalytic, synthetically useful asymmetric transformations by the merger of photocatalysis and enzyme catalysis.

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Fig. 1: Catalytic asymmetric radical hydroalkylation for C(sp3)−C(sp3) bond formation.
Fig. 2: Visible-light-induced enantioselective intermolecular radical hydroalkylation catalysed by ‘ene’ reductases.
Fig. 3: Proposed catalytic cycle.
Fig. 4: Mechanistic investigations.

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Data availability

All data are available in the main text or the Supplementary Information. The X-ray crystallographic coordinate for the structure of 3f reported in this article has been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition number CCDC 1989831.

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Acknowledgements

This work was supported by the US Department of Energy (DE-SC0018420). NMR data was collected in the Carl R. Woese Institute for Genomic Biology Core on a 600-MHz NMR funded by NIH grant number S10-RR028833. We thank T. Woods for assistance with X-ray diffraction studies and X. Guan for help with NMR analysis. X.H. acknowledges partial support from the Shen Postdoctoral Fellowship.

Author information

Author notes

  1. These authors contributed equally: Xiaoqiang Huang, Binju Wang

Authors and Affiliations

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

    Xiaoqiang Huang, Yajie Wang, Guangde Jiang & Huimin Zhao

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

    Xiaoqiang Huang, Yajie Wang, Guangde Jiang & Huimin Zhao

  3. State Key Laboratory of Physical Chemistry of Solid Surfaces, Xiamen University, Xiamen, China

    Binju Wang & Jianqiang Feng

  4. College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China

    Binju Wang & Jianqiang Feng

  5. Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, Xiamen, China

    Binju Wang & Jianqiang Feng

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

    Guangde Jiang & Huimin Zhao

Authors
  1. Xiaoqiang Huang
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Contributions

H.Z. coordinated the project. X.H. and H.Z. conceived the project and designed the experiments. X.H., Y.W. and G.J. performed the experiments. B.W. and J.F. carried out the computational studies. X.H, B.W. and H.Z. wrote the manuscript.

Corresponding author

Correspondence to Huimin Zhao.

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The authors declare no competing interests.

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Peer review information Nature thanks Frank Hollman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

This file contains Supplementary Figs. 1-19, Supplementary Tables 1-7, Supplementary Methods and Supplementary References.

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Huang, X., Wang, B., Wang, Y. et al. Photoenzymatic enantioselective intermolecular radical hydroalkylation. Nature 584, 69–74 (2020). https://doi.org/10.1038/s41586-020-2406-6

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