Bioinspired Peptide-Phosphonium Salt Catalysis Unlocks Asymmetric Desymmetrization of Phosphoryl Acids: Programmable Synthesis of P(V)-Stereogenic Molecules.

Enantioselective desymmetrization of prochiral phosphorus(V) compounds represents a pivotal strategy for constructing P(V)-stereogenic skeletons, yet existing methods face limitations in structural diversification and metal-free catalytic systems. Here we disclose that a bioinspired peptide-phosphonium salt (PPS) catalytic system successfully enables precise desymmetrization of phosphinic acids through synergistic ion-pairing and hydrogen-bonding interactions. This strategy affords multifunctional platform molecules bearing P(V)-stereocenters with excellent enantiocontrol and broad compatibility (43 examples, up to 92% yield, up to >99% ee) at very low catalyst loading (1 mol%). Furthermore, the P(V)-chiral building blocks undergo stereospecific derivatization to access structurally diverse phosphinates (27 examples, up to 75% yield, up to >99% ee) and tertiary phosphine oxides (10 examples). Mechanistic studies reveal that the stereochemical origin is from a semi-enclosed chiral cavity, where dynamic electrostatic and hydrogen-bonding interactions synergistically orchestrate the stereodetermining transition state. The two-stage desymmetrization-derivatization process establishes a versatile platform for modular synthesis of valuable P(V)-stereogenic pharmaceuticals and functional molecules.