Bioinspired Chiral Peptide–Phosphonium Salt Catalysis: From Enzymes to Cationic Small-Molecule Enzyme Mimics

Enzymes exemplify nature's catalytic mastery through precise stereochemical control and remarkable rate enhancements, yet their synthetic application remains limited by inherent vulnerabilities: thermal instability, narrow substrate tolerance, and complex engineering requirements. These challenges drive our pursuit of modular organocatalysts that emulate enzymatic cooperativity while combining ease of synthesis, versatility, and high tunability, termed "bioinspired organic small-molecule enzymes".In this Account, we detail the creation of peptide-phosphonium salt (PPS) catalysts that marry conformationally ordered peptide scaffolds with phase-transfer-active phosphonium cations. This design strategically combines (1) programmable peptide secondary structures (α-helices/β-sheets) for spatial control of hydrogen-bonding networks, (2) tunable phosphonium centers (electronic/steric modulation via aryl/alkyl substituents) for electrostatic activation, and (3) modular architecture enabling three-dimensional optimization (peptide sequences, cation substituents, and counterions). Such integration permits systematic enhancement of stereoselectivity and catalytic efficiency across diverse reaction manifolds under ambient conditions.The PPS platform has revolutionized challenging asymmetric annulation reactions. Our initial breakthrough in aza-Darzens reactions (formal [2 + 1]) established a general method for synthesizing sterically hindered enantioenriched aziridines, overcoming long-standing stereochemical challenges through synergistic substrate preorganization by peptide hydrogen bonding and charge stabilization by phosphonium ion-pairing interactions. Subsequent expansion to a variety of cycloadditions, including [2 + 2], [3 + 2], [4 + 2], and formal [4 + 3]/[5 + 1]/[5 + 2]/[6 + 1]/[6 + 2], etc. delivered structurally diverse chiral N-heterocycles, while pioneering the first catalytic asymmetric Atherton-Todd reaction enabled the stereodivergent synthesis of P-chiral compounds, significantly expanding the toolbox for phosphorus stereochemistry. Beyond single-molecule catalysis, PPS catalysts exhibit excellent adaptability in relay and cooperative catalysis systems. A bifunctional PPS/Lewis base relay catalysis system achieved efficient axial chirality induction in biaryl phosphates, while metal-cooperative platforms enabled stereocontrolled synthesis of strained medium rings, including seven- to nine-membered systems, through synergistic weak-bonding and metal catalysis. These advances underscore PPS catalysts as versatile platforms surpassing enzymatic systems in construction of structurally diverse chiral molecules.This Account not only summarizes our progress in PPS catalyst development and applications but also highlights the mechanistic insights, providing design principles for next-generation enzyme mimics. By emulating nature's strategy, we envision expanding PPS catalysis to address unmet challenges in asymmetric synthesis, from enzymatic-level stereochemical editing to the sustainable manufacturing of chiral substances.