Asymmetric assembly of congested contiguous stereocenters via photobiocatalytic three-component radical coupling
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,…
In a groundbreaking development, scientists have unveiled a groundbreaking photobiocatalytic three-component radical coupling method that enables the asymmetric assembly of densely substituted, congested stereocenters. This novel approach, combining the power of evolved pyridoxal biocatalysts and transition-metal photosensitizers, marks a significant leap forward in biocatalysis and asymmetric catalysis.
By harnessing high-throughput directed evolution techniques, researchers have successfully engineered two distinct threonine aldolase variants. These biocatalysts have proven instrumental in facilitating the stereoselective synthesis of tri- and tetrasubstituted stereocenters, as well as vicinal tetrasubstituted stereocenters, which have long presented formidable challenges in the field of radical chemistry.
The versatility of this method is further demonstrated by its ability to transform a wide array of radical precursors, including alpha-iodoesters, alpha-iodoamides, alpha-iodoketones, and alpha-iodonitriles, into structurally diverse non-canonical amino acid derivatives. The incorporation of C-H functionalization in this process ensures exceptional stereocontrol, allowing for the efficient assembly of complex molecular structures.
The researchers' innovative approach to combinatorial biocatalysis sets this method apart from previous techniques. By simultaneously varying all three coupling partners, the system achieves a remarkable 98% success rate in generating products with diverse stereochemical configurations. This achievement represents a significant step forward in the quest to overcome long-standing obstacles in asymmetric catalysis.
The implications of this discovery are far-reaching, particularly in the realm of medicinal chemistry. The ability to access a vast array of stereochemically complex small molecules opens up new avenues for the development of novel drugs and therapeutics. By providing a powerful strategy for addressing longstanding challenges in asymmetric catalysis, this novel photobiocatalytic radical coupling method promises to revolutionize the field and unlock new possibilities for the synthesis of valuable molecules.
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