Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Photoenzymatic enantioselective intermolecular radical hydroalkylation


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.

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.


  1. 1.

    Chen, K. & Arnold, F. H. Engineering new catalytic activities in enzymes. Nat. Catal. 3, 203–213 (2020).

    CAS  Article  Google Scholar 

  2. 2.

    Reetz, M. T. Laboratory evolution of stereoselective enzymes: a prolific source of catalysts for asymmetric reactions. Angew. Chem. Int. Ed. 50, 138–174 (2011).

    CAS  Article  Google Scholar 

  3. 3.

    Devine, P. N. et al. Extending the application of biocatalysis to meet the challenges of drug development. Nat. Rev. Chem. 2, 409–421 (2018).

    Article  Google Scholar 

  4. 4.

    Stephenson, C. R. J., Yoon, T. P. & MacMillan, D. W. C. (eds) Visible Light Photocatalysis in Organic Chemistry (Wiley-VCH, 2018).

  5. 5.

    Sandoval, B. A. & Hyster, T. K. Emerging strategies for expanding the toolbox of enzymes in biocatalysis. Curr. Opin. Chem. Biol. 55, 45–51 (2020).

    CAS  Article  Google Scholar 

  6. 6.

    Schmermund, L. et al. Photo-biocatalysis: biotransformations in the presence of light. ACS Catal. 9, 4115–4144 (2019).

    CAS  Article  Google Scholar 

  7. 7.

    Zimmerman, J. & Sibi, M. P. Enantioselective radical reactions. Top. Curr. Chem. 263, 107–162 (2006).

    CAS  Article  Google Scholar 

  8. 8.

    Lo, J. C., Gui, J., Yabe, Y., Pan, C.-M. & Baran, P. S. Functionalized olefin cross-coupling to construct carbon–carbon bonds. Nature 516, 343–348 (2014).

    ADS  CAS  Article  Google Scholar 

  9. 9.

    Studer, A. & Curran, D. P. Catalysis of radical reactions: a radical chemistry perspective. Angew. Chem. Int. Ed. 55, 58–102 (2016).

    CAS  Article  Google Scholar 

  10. 10.

    Huo, H., Harms, K. & Meggers, E. Catalytic, enantioselective addition of alkyl radicals to alkenes via visible-light-activated photoredox catalysis with a chiral rhodium complex. J. Am. Chem. Soc. 138, 6936–6939 (2016).

    CAS  Article  Google Scholar 

  11. 11.

    Capacci, A. G., Malinowski, J. T., McAlpine, N. J., Kuhne, J. & MacMillan, D. W. C. Direct, enantioselective α-alkylation of aldehydes using simple olefins. Nat. Chem. 9, 1073–1077 (2017).

    CAS  Article  Google Scholar 

  12. 12.

    Yegdaneh, A., Putchakarn, S., Yuenyongsawad, S., Ghannadi, A. & Plubrukarn, A. 3-Oxoabolene and 1-oxocurcuphenol, aromatic bisabolanes from the sponge Myrmekioderma sp. Nat. Prod. Commun. 8, 1355–1357 (2013).

    CAS  PubMed  Google Scholar 

  13. 13.

    Li, X.-D., Li, X.-M., Xu, G.-M., Zhang, P. & Wang, B.-G. Antimicrobial phenolic bisabolanes and related derivatives from Penicillium aculeatum SD-321, a deep sea sediment-derived fungus. J. Nat. Prod. 78, 844–849 (2015).

    CAS  Article  Google Scholar 

  14. 14.

    Liao, G. et al. The development of piperidinones as potent MDM2-P53 protein–protein interaction inhibitors for cancer therapy. Eur. J. Med. Chem. 159, 1–9 (2018).

    CAS  Article  Google Scholar 

  15. 15.

    Das, B., Shinde, D. B., Kanth, B. S., Kamle, A. & Kumar, C. G. Total synthesis of racemic and (R) and (S)-4-methoxyalkanoic acids and their antifungal activity. Eur. J. Med. Chem. 46, 3124–3129 (2011).

    CAS  Article  Google Scholar 

  16. 16.

    Alfaro Blasco, M. & Gröger, H. Enzymatic resolution of racemates with a ‘remote’ stereogenic center as an efficient tool in drug, flavor and vitamin synthesis. Bioorg. Med. Chem. 22, 5539–5546 (2014).

    CAS  Article  Google Scholar 

  17. 17.

    Gagnon, C. et al. Biocatalytic synthesis of planar chiral macrocycles. Science 367, 917–921 (2020).

    ADS  CAS  Article  Google Scholar 

  18. 18.

    Huffman, M. A. et al. Design of an in vitro biocatalytic cascade for the manufacture of islatravir. Science 366, 1255–1259 (2019).

    ADS  CAS  Article  Google Scholar 

  19. 19.

    Toogood, H. S. & Scrutton, N. S. Discovery, characterisation, engineering and applications of ene-reductases for industrial biocatalysis. ACS Catal. 8, 3532–3549 (2018).

    CAS  Article  Google Scholar 

  20. 20.

    Zultanski, S. L. & Fu, G. C. Catalytic asymmetric γ-alkylation of carbonyl compounds via stereoconvergent Suzuki cross-couplings. J. Am. Chem. Soc. 133, 15362–15364 (2011).

    CAS  Article  Google Scholar 

  21. 21.

    Emmanuel, M. A., Greenberg, N. R., Oblinsky, D. G. & Hyster, T. K. Accessing non-natural reactivity by irradiating nicotinamide-dependent enzymes with light. Nature 540, 414–417 (2016).

    ADS  CAS  Article  Google Scholar 

  22. 22.

    Biegasiewicz, K. F., Cooper, S. J., Emmanuel, M. A., Miller, D. C. & Hyster, T. K. Catalytic promiscuity enabled by photoredox catalysis in nicotinamide-dependent oxidoreductases. Nat. Chem. 10, 770–775 (2018).

    CAS  Article  Google Scholar 

  23. 23.

    Litman, Z. C., Wang, Y., Zhao, H. & Hartwig, J. F. Cooperative asymmetric reactions combining photocatalysis and enzymatic catalysis. Nature 560, 355–359 (2018).

    ADS  CAS  Article  Google Scholar 

  24. 24.

    Biegasiewicz, K. F. et al. Photoexcitation of flavoenzymes enables a stereoselective radical cyclization. Science 364, 1166–1169 (2019).

    ADS  CAS  Article  Google Scholar 

  25. 25.

    Black, M. J. et al. Asymmetric redox-neutral radical cyclization catalysed by flavin-dependent ‘ene’-reductases. Nat. Chem. 12, 71–75 (2020).

    ADS  Article  Google Scholar 

  26. 26.

    Sorigué, D. et al. An algal photoenzyme converts fatty acids to hydrocarbons. Science 357, 903–907 (2017).

    ADS  Article  Google Scholar 

  27. 27.

    Xu, J. et al. Light-driven kinetic resolution of α-functionalized carboxylic acids enabled by an engineered fatty acid photodecarboxylase. Angew. Chem. Int. Ed. 58, 8474–8478 (2019).

    CAS  Article  Google Scholar 

  28. 28.

    Brimioulle, R., Lenhart, D., Maturi, M. M. & Bach, T. Enantioselective catalysis of photochemical reactions. Angew. Chem. Int. Ed. 54, 3872–3890 (2015).

    CAS  Article  Google Scholar 

  29. 29.

    Rudroff, F. et al. Opportunities and challenges for combining chemo- and biocatalysis. Nat. Catal. 1, 12–22 (2018).

    Article  Google Scholar 

  30. 30.

    Sandoval, B. A., Meichan, A. J. & Hyster, T. K. Enantioselective hydrogen atom transfer: discovery of catalytic promiscuity in flavin-dependent ‘ene’-reductases. J. Am. Chem. Soc. 139, 11313–11316 (2017).

    CAS  Article  Google Scholar 

  31. 31.

    Doyle, A. G. & Jacobsen, E. N. Small-molecule H-bond donors in asymmetric catalysis. Chem. Rev. 107, 5713–5743 (2007).

    CAS  Article  Google Scholar 

  32. 32.

    Crisenza, G. E. M., Mazzarella, D. & Melchiorre, P. Synthetic methods driven by the photoactivity of electron donor–acceptor complexes. J. Am. Chem. Soc. 142, 5461–5476 (2020).

    CAS  Article  Google Scholar 

  33. 33.

    Beckwith, A. L. J. & Bowry, V. W. Kinetics of reactions of cyclopropylcarbinyl radicals and alkoxycarbonyl radicals containing stabilizing substituents: implications for their use as radical clocks. J. Am. Chem. Soc. 116, 2710–2716 (1994).

    CAS  Article  Google Scholar 

Download references


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




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.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Huang, X., Wang, B., Wang, Y. et al. Photoenzymatic enantioselective intermolecular radical hydroalkylation. Nature 584, 69–74 (2020).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing