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Stereospecific radical coupling with a non-natural photodecarboxylase

Melchiorre, Paolo
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Nature ( 2024 ) Cite this article

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Photoenzymes are light-powered biocatalysts that typically rely on the excitation of cofactors or unnatural amino acids for their catalytic activities 1,2 . A notable natural example is the fatty acid photodecarboxylase (FAP), which uses light energy to convert aliphatic carboxylic acids to achiral hydrocarbons 3 . Here, we report a way to design a non-natural photodecarboxylase based on the excitation of enzyme-bound catalytic intermediates, instead of relying on cofactor excitation 4 . Iminium ions 5 , transiently generated from enals within the active site of an engineered class I aldolase 6 , can absorb violet light and function as single-electron oxidants. Activation of chiral carboxylic acids, followed by decarboxylation, generates two radicals that undergo stereospecific cross-coupling, yielding products with two stereocenters. Using the appropriate enantiopure chiral substrate, the desired diastereoisomeric product is selectively obtained with complete enantiocontrol. This finding underscores the active site's ability to transfer stereochemical information from the chiral radical precursor into the product, effectively addressing the longstanding problem of rapid racemization of chiral radicals. The resulting ‘memory of chirality’ scenario 7 is a rarity in enantioselective radical chemistry.

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Author notes

  1. These authors contributed equally: Vasilis Tseliou, Laura Kqiku

Authors and Affiliations

  1. ICIQ, Institute of Chemical Research of Catalonia, the Barcelona Institute of Science and Technology, Avenida Països Catalans, 16 – 43007, Tarragona, Spain

    Vasilis Tseliou, Laura Kqiku, Martin Berger & Florian Schiel

  2. Department of Chemical and Pharmaceutical Biology, University of Groningen, Groningen Research Institute of Pharmacy, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands

    Hangyu Zhou & Gerrit J. Poelarends

  3. University of Bologna, Department of Industrial Chemistry ‘Toso Montanari’, via Piero Gobetti 85 – 40129, Bologna, Italy

    Paolo Melchiorre

Authors

  1. Vasilis Tseliou

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  2. Laura Kqiku

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  3. Martin Berger

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  4. Florian Schiel

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  5. Hangyu Zhou

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  6. Gerrit J. Poelarends

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  7. Paolo Melchiorre

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Corresponding author

Correspondence to Paolo Melchiorre .

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Tseliou, V., Kqiku, L., Berger, M. et al. Stereospecific radical coupling with a non-natural photodecarboxylase. Nature (2024). https://doi.org/10.1038/s41586-024-08004-9

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  • DOI : https://doi.org/10.1038/s41586-024-08004-9

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