Stereospecific radical coupling with a non-natural photodecarboxylase

Vasilis Tseliou, Laura Kqiku, Martin Berger, Florian Schiel, Hangyu Zhou, Gerrit J. Poelarends and Paolo Melchiorre ()
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Vasilis Tseliou: The Barcelona Institute of Science and Technology
Laura Kqiku: The Barcelona Institute of Science and Technology
Martin Berger: The Barcelona Institute of Science and Technology
Florian Schiel: The Barcelona Institute of Science and Technology
Hangyu Zhou: Groningen Research Institute of Pharmacy, University of Groningen
Gerrit J. Poelarends: Groningen Research Institute of Pharmacy, University of Groningen
Paolo Melchiorre: University of Bologna

Nature, 2024, vol. 634, issue 8035, 848-854

Abstract: Abstract Photoenzymes are light-powered biocatalysts that typically rely on the excitation of cofactors or unnatural amino acids for their catalytic activities1,2. A notable natural example is the fatty acid photodecarboxylase, which uses light energy to convert aliphatic carboxylic acids to achiral hydrocarbons3. Here we report a method for the design of a non-natural photodecarboxylase based on the excitation of enzyme-bound catalytic intermediates, rather than reliance on cofactor excitation4. Iminium ions5, transiently generated from enals within the active site of an engineered class I aldolase6, 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 stereocentres. Using the appropriate enantiopure chiral substrate, the desired diastereoisomeric product is selectively obtained with complete enantiocontrol. This finding underscores the ability of the active site to transfer stereochemical information from the chiral radical precursor into the product, effectively addressing the long-standing problem of rapid racemization of chiral radicals. The resulting ‘memory of chirality’ scenario7 is a rarity in enantioselective radical chemistry.

Date: 2024
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DOI: 10.1038/s41586-024-08004-9

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