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Synfacts 2025; 21(07): 725
DOI: 10.1055/a-2601-4678
Organo- and Biocatalysis

Photoredox- and Enzyme-Catalysis Enables Enantioselective Anti-Markovnikov Hydroarylations of Olefins

Contributor(s):
Benjamin List 
,
Lennart J. Brücher 
Mukherjee P, Alassad Z, Hyster T *. Princeton University, USA
Synergistic Photoenzymatic Anti-Markovnikov Hydroarylation of Olefins via Heteroaryl Radical Intermediates.

J. Am. Chem. Soc. 2025;
147: 14048-14053
DOI: 10.1021/jacs.5c01066
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Keywords

ene-reductase - photoredox - anti-Markovnikov hydroarylation - heteroarenes - olefins

Significance

Mukherjee, Alassad, and Hyster combined photoredox with flavoenzyme-catalysis and developed an enantioselective anti-Markovnikov hydroarylation of 1,1-disubstituted olefins. Using a ruthenium(II) photocatalyst and OYE 3 as flavoenzyme, the desired products are obtained in low to very high yields with enantioselectivities up to 99:1 er. With this transformation, the authors expanded the scope of radical photoenzymatic catalysis and provided access to pyridyl structures with adjacent stereocenters, essential structural motifs of several biologically active molecules.


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Comment

Based on mechanistic studies and the proposed mechanisms of related systems in literature (e. g., Nat. Chem. 2023, 15, 206), the following mechanistic proposal could explain the reaction. After blue light irradiation, the excited photocatalyst PC* reduces the aryl halide, and a heteroaryl radical is generated. The subsequent anti-Markovnikov addition furnishes an alkyl radical, which is reductively quenched via HAT from the reduced flavin cofactor FlHQ. The PC is regenerated after an electron transfer (ET) from the flavin semiquinone (FlSQ), and the flavin cofactor is regenerated with the glucose, GDH-105, NADP +  system.


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Publication History

Article published online:
23 June 2025

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