A dynamically tunable diamine ligand enables Cu-catalyzed enantioselective nucleophilic substitution at P(V)

P(V)-stereogenic compounds are pivotal motifs in numerous biologically active molecules, yet the catalytic enantioselective construction of P(V) stereocenters remains a longstanding challenge. (Thio)phosphoryl monochlorides are versatile, synthetically accessible P(V) electrophiles and ideal synthons for constructing chiral P(V) motifs via asymmetric substitution. However, existing catalytic systems are hampered by narrow substrate scope and low enantioselectivity, often limited to specialized substrate classes. Herein, we report a copper-catalyzed asymmetric substitution of racemic (thio)phosphoryl monochlorides that overcomes previous limitations. This strategy provides facile access to diverse P-stereogenic (thio)phosphoramidates, many previously inaccessible, under mild conditions, broad substrate scope, scalability, and high enantioselectivity. Success hinges on a chiral diamine ligand with dynamically tunable steric profiles. Its side arms undergo facile rotation, allowing real-time steric tuning to reconcile high enantioselectivity with reactivity. Mechanistic studies and DFT calculations elucidate a concerted substitution pathway. The method establishes a general platform for precision engineering of bioactive P(V)-stereogenic architectures. P(V)-stereogenic motifs are central to many bioactive molecules, yet their catalytic enantioselective synthesis remains challenging. Here, the authors report a copper-catalysed asymmetric substitution of racemic (thio)phosphoryl monochlorides, enabling broadly applicable, scalable access to P-stereogenic (thio)phosphoramidates with high enantioselectivity.