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

Abstract 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.