The research group of Shang Ming at the Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University (www.shangchemlab.com) is dedicated to the efficient synthesis, structural modification, and application of chiral nucleotide molecules in nucleic acid drug development. Building on their previous work on copper-catalyzed asymmetric synthesis of nucleoside ProTide prodrugs (J. Am. Chem. Soc. 2024, *145*, 31339) and nucleic acid modification studies (Angew. Chem. Int. Ed. 2025, e202500744; Angew. Chem. Int. Ed. 2024, e202418806), the team has further designed and constructed a cost-effective copper-based chiral Lewis acid catalytic system. This system successfully enables the enantioselective desymmetrization of (thio)phosphoric dichlorides, allowing modular construction of P=O and P=S scaffolds containing diverse P–heteroatom bonds. The method provides an efficient and practical new strategy for the stereoselective synthesis of various phosphorus-centered chiral nucleotide molecules, including chiral thiodinucleotides.

Article abstract:

Chiral phosphorus(V) centers—particularly those bearing fully heteroatom-substituted frameworks—are key stereochemical motifs in pharmaceuticals, nucleic acid therapeutics, and functional materials. However, their stereoselective construction remains a long-standing challenge in synthetic chemistry. Here, we report a copper-catalyzed desymmetrization strategy enabled by rationally engineered PIM ligands that affords broad and modular access to structurally diverse P(V)-stereogenic compounds. By harnessing the tunable Lewis acidity and well-defined chiral environment of the catalyst—together with the distinct mechanistic features of chiral Lewis acid catalysis—this strategy overcomes the substrate scope limitations that have constrained traditional approaches. The method demonstrates broad functional group tolerance and delivers high levels of stereocontrol across seven distinct substitution patterns, including the efficient construction of chiral P═S motifs previously considered synthetically challenging. Importantly, the approach enables efficient late-stage derivatization of nucleosides and their analogs, thereby providing a general entry point to stereodefined P(V)-containing bioactive molecules. This work not only expands the utility of transition-metal Lewis acid catalysis in phosphorus chemistry, but also establishes a versatile framework for applications in drug discovery and nucleic acid-based therapeutics where precise stereochemical control is essential.