Enhancing Reaction Kinetics and Structural Control in N ‐Carboxyanhydride (NCA) Polypeptide Synthesis by Structurally Tuned Azamacrocyclic Ligands

Rapid and controlled synthesis of polypeptides remains a challenge due to trade‐offs between reaction rate, precision and practicality. We present a new class of compounds that enable fast and controlled Ring‐Opening Polymerization (ROP) of N ‐carboxyanhydrides (NCAs) under ambient, open‐vessel conditions. N ‐heterocyclic azamacrocycles allow for polymerization of γ‐benzyl‐ L ‐glutamate (BLG), sarcosine (SAR), and ε ‐benzyloxycarbonyl‐ L ‐lysine N ‐carboxyanhydride (ZLYS) with dispersities as low as Đ ≈1.1 for both low and high targeted degrees of polymerization (DP T ∼20 to 1000). Degree of methylation of the macrocycle modulates their final role in ROP‐NCA: the fully N ‐methylated azamacrocycle N 14 Me 3 acts predominantly as an external rate‐enhancing catalyst under the tested external nucleophile conditions, while partially methylated N 14 Me 1 analogue exhibits dual initiator‐catalyst (IniCat) behavior. Kinetic studies and DFT calculations support cooperative participation of the azamacrocyclic scaffold and identify plausible accelerated amine mechanism via monomer activation (AAMMA)‐related pathways involving secondary‐sphere stabilization of reactive species. The combined results indicate a dynamically evolving system in which the relative contributions of individual interactions may depend on monomer structure, reaction environment and chain growth, highlighting azamacrocycles as tunable platforms for facile precision polypeptide synthesis.