Stereoselective synthesis of P-stereogenic nucleotide prodrugs and oligonucleotides

Phosphorus(V) stereocenters play a crucial role in the therapeutic strategies for severe diseases, including viral infections, chronic conditions, and rare genetic disorders. These diseases often involve gene-related pathologies or arise from genetic mutations that affect intracellular metabolic processes. ProTide and antisense oligonucleotide therapies are among the most effective strategies for treating such conditions, where the absolute configuration of the phosphorus center is directly linked to therapeutic efficacy. However, the development of stereodefined ProTides and PS-oligonucleotides remains a significant challenge due to the lack of efficient and scalable synthetic methodologies. This review highlights various approaches for achieving stereocontrolled synthesis of phosphorus-based ProTides and PS-oligonucleotides, including the use of stereopure precursors, chiral auxiliaries, asymmetric catalysis and enzymatic approaches. By advancing these strategies, researchers can improve the stereochemical precision of nucleotide-based therapeutics, ultimately enhancing their clinical potential. Moreover, this review examines the current methodologies utilized for the industrial-scale production of P-stereogenic ProTides and oligonucleotides.