Nature Catalysis, Published online: 05 August 2026; doi:10.1038/s41929-026-01557-0 Existing methodologies for the stereocontrolled synthesis of phosphorothioate oligonucleotides and cyclic dinucleotides generally rely on chiral auxiliaries and are not catalytic. This study reports a catalytic asymmetric P(V)-based strategy, enabled by a C2-symmetric multifunctional chiral bis(amidine) organocatalyst, for the stereoselective synthesis of these classes of compounds.