This is an unedited manuscript that has been accepted for publication. Nature Research are providing this early version of the manuscript as a service to our authors and readers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

Photoenzymatic enantioselective intermolecular radical hydroalkylation


Enzymes are increasingly explored for asymmetric synthesis1–3, but their applications are generally limited by the reactions available to naturally occurring enzymes. Recently, interest in photocatalysis4 has spurred the discovery of new reactivity from known enzymes5. However, so far photo-induced enzymatic catalysis6 has not been used for cross-coupling of two molecules. For example, 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 stereochemical control of the remote prochiral radical intermediate7. Here we show a new-to-nature, visible-light-induced ene-reductase catalysed intermolecular radical hydroalkylation of terminal alkenes with readily available α-halo carbonyl compounds. This method provides an efficient approach to various carbonyl compounds bearing a γ-stereocentre with excellent yields and enantioselectivities (up to 99% yield, 99% enantiomeric excess), which otherwise are difficult to access by chemocatalysis. Mechanistic studies suggest that the substrates/ene-reductase complex formation at the enzyme active site triggers the enantioselective photo-induced 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.

Author information



Corresponding author

Correspondence to Huimin Zhao.

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 (2020).

Download citation


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.