Precision Synthesis of Polypeptides via Living Anionic Ring-Opening Polymerization of N-Carboxyanhydrides by Tri-thiourea Catalysts

The chemistry of alpha-amino acid N-carboxyanhydrides (NCAs) has a history of over 100 years, but precise and efficient ring-opening polymerization methods for NCAs remain highly needed to facilitate the studies of polypeptides-that is, mimics of natural proteins -in various disciplines. Moreover, the universally accepted NCA polymerization mechanisms are largely limited to the amine and the activated monomer mechanisms, and the anionic ring-opening polymerization of NCAs has so far not been invoked. Herein, we show an unprecedented anion-binding catalytic system combining tripodal tri-thiourea with sodium thiophenolate that enables the fast and selective anionic ring-opening polymerization of NCAs. This method leads to the precision construction of various polypeptides with living polymerization behavior and is evidenced by narrow molecular weight distributions (Mw/Mn < 1.2), chain extension experiments, and minimal activated monomer pathway. Calculations and experimental results elucidate a living anionic polymerization mechanism, and high selectivities for monomer propagation relative to other deleterious side reactions, such as the activated monomer pathway, are attributed to the enhanced stabilization of the propagating carbamate anion, which is enforced by an intramolecular hydrogen bond within the tri-thiourea structure.

Automated summary

This article introduces an unprecedented anion-binding catalytic system for the fast and selective anionic ring-opening polymerization of NCAs. The method leads to the precise construction of various polypeptides with narrow molecular weight distributions and living polymerization behavior, demonstrating high selectivities for monomer propagation.