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Photoenzymatic enantioselective intermolecular radical hydroalkylation

Abstract

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.

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Correspondence to Huimin Zhao.

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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 (2020). https://doi.org/10.1038/s41586-020-2406-6

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