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

Nucleoside analogues have seen significant advancements in treating viral infections and cancer through ProTide technology, leading to a series of FDA-approved drugs such as sofosbuvir, tenofovir alafenamide, and remdesivir. The stereochemical configuration at the phosphorus center of ProTides significantly influences their pharmacological properties, necessitating efficient stereoselective synthesis. Traditional methods using chiral auxiliaries or nonracemic phosphorylating agents are labor-intensive and inefficient, while recent organocatalytic approaches, despite their promise, still face limitations. Herein, we present a novel approach employing chiral metal complexes for the stereoselective assembly of P-stereogenic ProTides via asymmetric P–O bond formation. This approach leverages a chiral metal catalyst to activate the electrophilic phosphorylating reagent, facilitating a base-promoted nucleophilic replacement pathway. Our protocol, featuring mild reaction conditions and broad applicability, enables the highly stereoselective synthesis of previously inaccessible (S,R P) and (R,S P)-ProTide derivatives. The practical utility of this method is demonstrated through the preparation of pharmaceutically relevant ProTide targets and mechanistic studies were conducted to elucidate the reaction pathway, offering significant advancements for drug development and pharmaceutical research.