Catalytic and Crystallization Strategies for Phosphorus Stereocontrol in ProTide Synthesis
- 1Chemical Pharmaceutical Research Institute, Taizhou Vocational & Technology College, Taizhou 318000, China
- 2Zhejiang Hisun Pharmaceutical Co., Ltd., Taizhou 318000, China
Abstract
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.
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BibTeX
@article{ran2026catalytic,
title = {{Catalytic and Crystallization Strategies for Phosphorus Stereocontrol in ProTide Synthesis}},
author = {Yan Ran and Zhenhong Zhou},
journal = {Catalysts},
year = {2026},
month = oct,
doi = {10.3390/catal16110970},
url = {https://www.mdpi.com/2073-4344/16/11/970},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Catalytic and Crystallization Strategies for Phosphorus Stereocontrol in ProTide Synthesis
AU - Yan Ran
AU - Zhenhong Zhou
PY - 2026
DA - 2026/10/30
JO - Catalysts
DO - 10.3390/catal16110970
UR - https://www.mdpi.com/2073-4344/16/11/970
AB - 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.
SN - 2073-4344
ER -