Thiourea-Promoted Controllable Interlocked Polymerization in Cocrystals of <i>N</i> -Thiocarboxyanhydrides

Poly(amino acid)s, renowned for their biodegradability and structural versatility, are widely used in biomedical applications. While <i>N</i>-carboxyanhydride (NCA) ring-opening polymerization (ROP) has enabled polypeptide synthesis, challenges persist in controlling β-branched amino acid derivatives such as valine due to their low reactivity. Leveraging the superior hydrolytic stability of <i>N</i>-thiocarboxyanhydrides (NTAs), a thiourea-catalyzed ROP system was reported, which achieves rapid controlled polymerization under mild conditions. This strategy yields high-molecular-weight polyvaline (DP = 93, <i>D̵</i> < 1.1) while preserving chiral fidelity via interlocked polymerization in cocrystals (iPiC). The thiourea catalyst enhances polymerization rates in a p<i>K</i>_a-dependent manner with the best catalyst/initiator ratio around 1:1, which maintains zero-order kinetics. This work broadens the monomer choice in iPiC and advances the development of functional biomaterials by addressing longstanding limitations in polypeptide synthesis.