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Diversity-oriented photobiocatalytic synthesis via stereoselective three-component radical coupling

12 August 2025

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In recent years, the field of synthetic chemistry has undergone a transformation centered on diversity-oriented synthesis (DOS). As a powerful strategy, DOS addresses both chemical and biological challenges by generating functional compound libraries that exhibit excellent skeletal, functional group, and stereochemical diversity. Among the various approaches, multicomponent reactions are particularly attractive because they rapidly assemble molecular complexity from readily available building blocks in a single operation. Enzymes can impose outstanding stereocontrol over challenging chemical reactions; however, beyond multi-domain mega-synthases such as non-ribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs), employing a single-domain enzyme or a set of closely related enzyme mutants for diversity-oriented synthesis remains a formidable challenge.

To overcome these challenges, Prof. Yang Yang’s team at the University of California, Santa Barbara, in collaboration with Prof. Peng Liu’s group at the University of Pittsburgh, published a paper in Science entitled “Diversity-oriented photobiocatalytic synthesis via stereoselective three-component radical coupling.” Using a cooperative photobiocatalytic strategy, they developed the first stereoselective, three-component, radical-mediated C–C coupling reaction reported in both organic chemistry and biochemistry. Under these catalytic conditions, a diverse library of multi-scaffold compounds bearing multiple stereocenters was efficiently assembled. The enzymatic platform integrates multiple asymmetric catalytic tactics—including remote stereocenter construction, stereodivergent catalysis, kinetic resolution, and parallel kinetic resolution—demonstrating the enzyme’s exceptional ability to exert both diastereo- and enantiocontrol over radical intermediates.

Figure 1. Diversity-oriented photobiocatalytic synthesis via pyridoxal decarboxylase-catalyzed three-component radical C-C coupling

Discovery and directed evolution of three-component coupling enzymes
At the outset of this study, the research team employed the PLP-dependent decarboxylase mutant UstD-L392G, pairing it with the photosensitizer Rose Bengal and irradiating the reaction with green light (520 nm) to initiate radical generation and transfer. Under these conditions, the cyclized product 5a featuring a skipped α,γ-stereochemical dyad and a γ-quaternary stereocenter was obtained in low yield (9 %) yet with high stereoselectivity (d.r. = 74 : 26, e.r. > 99 : 1) (Figure 2A). Subsequently, the team conducted four rounds of directed evolution, introducing mutations within the active site and nearby flexible loop regions to progressively improve both catalytic efficiency and stereocontrol. The final variant, UstDᴬᵂᴹᴹ, which carries four mutations (T391A, M393W, L392M, and S60M), elevated the yield of 5a to 77 % while maintaining an exceptionally high stereoselectivity of 98 : 2 (Figure 2B).

Figure 2. Diastereo- and enantioselective photobiocatalytic three-component radical coupling of organoboronates, methacrylonitrile and aspartic acid

Substrate scope of biocatalytic amidine synthesis
With this evolved biocatalyst, UstDᴬᵂᴹᴹ, they surveyed its substrate scope (Figure 3). Aromatic substituents (e.g., halogens, alkyl, methoxy), heteroaromatic rings (e.g., pyrazole, pyridine, thiophene), all coupled efficiently (Figure 3). Even unstabilized primary alkyl radicals and secondary alkyl radicals such as isopropyl and cyclopentyl were successfully converted to the desired products under the mild conditions, demonstrating the system’s exceptional adaptability to radical lifetimes and reaction rates.

Figure 3. Substrate scope for the stereoselective photobiocatalytic three-component radical C-C coupling using methacrylonitrile

Functional-Group Expansion: Biocatalytic Conversion of Other α,β-Unsaturated Substrates
Beyond methacrylonitrile, the researchers surveyed a range of additional α,β-unsaturated compounds as radical acceptors in the three-component radical coupling (Figure 4A). Substrates included acrylonitrile, methyl acrylate, and α-substituted acrylates such as methyl methacrylate and α-methylene-γ-lactone, delivering products ranging from non-cyclized amino esters (4b, 4c) to cyclic, non-natural γ-lactams (6a–6c). α,β-unsaturated aldehydes and ketones were also excellent radical acceptors, furnishing δ-oxo-α-amino acids that spontaneously underwent intramolecular amine–carbonyl condensation to form the corresponding cyclic imines 11 (Figure 4B). These imines were readily reduced by an imine reductase (IRED-110) to furnish structurally novel, polysubstituted, non-natural proline derivatives (7a, 7b) with outstanding diastereo- and enantiocontrol. Overall, the broad scope of radical acceptors and the excellent structural diversity of the resulting products demonstrated the potential of this photobiocatalytic three-component radical coupling in diversity-oriented synthesis.

Figure 4. Diversity-oriented photobiocatalytic synthesis using alternative radical precursors and multienzyme cascades

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References

[1]Zhang, Chen, Zhou, Jun, Xie, Pei-Pei, et al. Diversity-oriented photobiocatalytic synthesis via stereoselective three-component radical coupling. Science 2025, eadx2935.

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