Ligand-Enabled Cu-Catalyzed Stereoselective Synthesis of P-Stereogenic ProTides

Abstract We present a copper-catalyzed, stereoselective phosphorylation of nucleosides with phosphoryl(V) chlorides, providing an efficient and straightforward approach to the synthesis of a series of nucleoside analogues that demonstrate significant promise in the treatment of viral infections and cancers. The stereochemical configurations at the phosphorus center in ProTides are known to have a profound impact on their pharmacological properties. However, the asymmetric construction of P–O bonds remains a major challenge in the synthesis of nucleoside-based therapeutics. In this study, we introduce a base-promoted nucleophilic substitution pathway that facilitates the highly stereoselective synthesis of previously inaccessible (S,R P) and (R,S P)-ProTide derivatives, offering a powerful strategy for the diversification of nucleoside drug candidates.