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

作者：Siqiang Fang, Zanjiao Liu, Fan Wang, Tianli Wang · 发表于：Accounts of Chemical Research · 年份：2025 · DOI：10.1021/acs.accounts.5c00257 · 被引用次数：25 · 研究领域：Chemical Synthesis and Analysis、Synthesis and Catalytic Reactions、Asymmetric Synthesis and Catalysis

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-...