Asymmetric assembly of congested contiguous stereocenters via photobiocatalytic three-component radical coupling
- 1University of California, Santa Barbara, California; Howard Hughes Medical Institute, University of California, Santa Barbara.
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 alpha-iodoesters, alpha-iodoamides, alpha-iodoketones, and alpha-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.
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BibTeX
@misc{hu2026asymmetric,
title = {{Asymmetric assembly of congested contiguous stereocenters via photobiocatalytic three-component radical coupling}},
author = {Q. Hu and C.-X. Zheng and B. K. Mai and P. Liu and Y. Yang},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.25.754468},
url = {https://www.biorxiv.org/content/10.64898/2026.09.25.754468v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Asymmetric assembly of congested contiguous stereocenters via photobiocatalytic three-component radical coupling
AU - Q. Hu
AU - C.-X. Zheng
AU - B. K. Mai
AU - P. Liu
AU - Y. Yang
PY - 2026
DA - 2026/09/25
PB - bioRxiv
DO - 10.64898/2026.09.25.754468
UR - https://www.biorxiv.org/content/10.64898/2026.09.25.754468v1
AB - 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 alpha-iodoesters, alpha-iodoamides, alpha-iodoketones, and alpha-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.
ER -