Catalytic and Crystallization Strategies for Phosphorus Stereocontrol in ProTide Synthesis

Phosphorus stereochemistry affects the activation and manufacture of phosphoramidate and phosphonamidate nucleotide prodrugs, including sofosbuvir, tenofovir alafenamide and remdesivir. This critical narrative review compares static separation, enzymatic kinetic resolution, crystallization-induced dynamic resolution, asymmetric phosphorylation, catalytic desymmetrization and auxiliary-mediated transfer by identifying the interconverting molecular pool, the recovered product and the yield denominator. The 50% ceiling applies to recovery of one component from an equimolar, non-interconverting mixture; it does not directly limit nucleoside-based yield or describe atom economy. Representative remdesivir procedures illustrate how reagent stoichiometry, isolation and deprotection change the apparent advantage of a stereoselective coupling. Catalyst design is examined alongside mechanistic evidence, substrate scope and process requirements. Current phosphotriesterase resolutions recover unhydrolyzed activated precursor. An illustrative kinetic model shows that symmetric epimerization can reduce survivor purity, whereas sufficiently biased exchange can improve transient recovery. Both exchange rates and equilibrium bias must therefore be assessed at a specified purity; peak recovery alone is insufficient. Product-forming capture, selective withdrawal and hydrolysate reactivation provide alternative research directions, each requiring an experimentally closed phosphorus balance. These distinctions support route selection and define testable objectives for productive biocatalytic stereoconvergence.