Asymmetric assembly of congested contiguous stereocenters via photobiocatalytic three-component radical coupling
Year: 2026
Type: preprint
Abstract: Despite rapid advances in new-to-nature biocatalysis, trimolecular enzymatic reactions that generate previously inaccessible molecular entities, particularly those bearing well-defined, congested stereochemical dyads, remain exceedingly rare. Here, we report a novel diastereo- and enantioselective photobiocatalytic three-component radical coupling unknown in both organic chemistry and enzymology, enabled by cooperative catalysis employing an evolved pyridoxal biocatalyst and a transition-metal photosensitizer. Directed evolution using high-throughput photobiocatalysis furnished two threonine aldolase variants, enabling the stereoselective assembly of contiguous tri- and tetrasubstituted stereocenters as well as vicinal tetrasubstituted stereocenters, which were long regarded as a challenging goal for stereoselective radical chemistry and asymmetric catalysis. Furthermore, a variety of radical precursors, including α-iodoesters, α-iodoamides, α-iodoketones, and α-iodonitriles, could be transformed into structurally diverse, densely substituted non-canonical amino acid derivatives via C-H functionalization with excellent stereocontrol. Leveraging the broad substrate compatibility of engineered pyridoxal biocatalysts, combinatorial biocatalysis was achieved by simultaneously varying all three coupling partners, delivering products with a 98% success rate. Collectively, this diversity-generating multicomponent photobiocatalytic radical coupling afforded a powerful strategy for addressing long-standing challenges in asymmetric catalysis while enabling access to valuable stereochemically complex small molecules with applications in medicinal chemistry.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Integrated Computational and Mechanistic Investigation on New Reactivity and Selectivity in Emerging Enzymatic Reactions, G1370689234, G3456468379, G3663069421, Track 1: ACCESS Resource Allocations Marketplace and Platform Services (RAMPS), G4010157413, G4533910268, G4723750406, G5011508902, G5070620238, MRI: Acquisition of Cutting-Edge GPU and MPI Nodes for the Interdisciplinary Pitt Center for Research Computing, G7218924412, G7916508619, Pyridoxal Radical Biocatalysis for the Stereoselective Production of Non-Canonical Amino Acids
OpenAlex ID: W7214594867