Ligand-Enabled\nCu-Catalyzed Stereoselective Synthesis\nof P‑Stereogenic ProTides

Nucleoside\nanalogues have seen significant advancements in treating\nviral infections and cancer through ProTide technology, leading to\na series of FDA-approved drugs such as sofosbuvir, tenofovir alafenamide,\nand remdesivir. The stereochemical configuration at the phosphorus\ncenter of ProTides significantly influences their pharmacological\nproperties, necessitating efficient stereoselective synthesis. Traditional\nmethods using chiral auxiliaries or nonracemic phosphorylating agents\nare labor-intensive and inefficient, while recent organocatalytic\napproaches, despite their promise, still face limitations. Herein,\nwe present a novel approach employing chiral metal complexes for the\nstereoselective assembly of P-stereogenic ProTides via asymmetric\nP–O bond formation. This approach leverages a chiral metal\ncatalyst to activate the electrophilic phosphorylating reagent, facilitating\na base-promoted nucleophilic replacement pathway. Our protocol, featuring\nmild reaction conditions and broad applicability, enables the highly\nstereoselective synthesis of previously inaccessible (<i>S</i>,<i>R</i><sub>P</sub>) and (<i>R</i>,<i>S</i><sub>P</sub>)-ProTide derivatives. The practical utility\nof this method is demonstrated through the preparation of pharmaceutically\nrelevant ProTide targets and mechanistic studies were conducted to\nelucidate the reaction pathway, offering significant advancements\nfor drug development and pharmaceutical research.