Proton Transfer Shuttle Mediated Dormant–Active Balance for Accelerated and Controlled Polymerization of N ‐Carboxyanhydrides

ABSTRACT

Since its inception in 2003, the concept of “reversible deactivation” to control chain propagation has emerged as a promising, though still evolving, strategy for precise polypeptide synthesis. Beyond a simple polymerization method, this concept is expected to promote unique reaction pathways. Nevertheless, achieving both rapid and well‐controlled ring‐opening polymerization of N ‐carboxyanhydrides through the equilibrium between dormant and active species is rare and challenging. In this study, we report a proton transfer shuttle‐assisted strategy that accelerates chain growth via trifluoroacetic acid (TFA) /tetrabutylammonium acetate (TBAA) cooperative system. Central to this strategy is reversible acceptance and donation of proton, thereby shifting the dormant–active equilibrium without disrupting it. This modulation increases the proportion of active chain ends while maintaining control over rapid polymerization process. Moreover, cooperative TFA/TBAA catalysis has streamlined the synthesis of well‐defined polypeptides, which are amenable to further chemical modifications. Control experiments and density functional theory calculations provide insights into the origin of controllability and critical role of TFA/TBAA in regulating the reversible deactivation equilibrium. Consequently, this work establishes a robust and efficient approach for accelerated yet controlled preparation of polypeptides and generates fundamental insights that advance understanding and application of the “reversible deactivation” concept for precision polypeptide synthesis.