Thiourea-Based Bifunctional Catalysts for Epoxide-Involved Ring-Opening Polymerization of α-Amino Acid N-Carboxyanhydrides

Thiourea-quaternary ammonium salt bifunctional catalysts with both electrophilic and nucleophilic centers were designed in this paper to initiate the ring-opening polymerization (ROP) of α-amino acid N-carboxyanhydrides (NCAs) for the efficient synthesis of polypeptides. We disclosed this kind of bifunctional catalyst for the efficient synthesis of polypeptides in the presence of propylene oxide (PO), which was judiciously added as an in situ activator for the efficient ROP of NCA. By MALDI-TOF MS and 1H NMR analysis, we identified the end groups of the polymer and clarified the ROP process in the presence of the bifunctional catalyst. We showed that the PO was initially ring-opened by the nucleophilic attack of a halogen ion; then, the newly formed alkoxide ions attacked the electrophilic carbonyl of NCA, providing the carbamate anion. After undergoing a decarboxylation of the carbamate anion, the nucleophilic attack of N to the carbonyl on an NCA ring occurred synergistically to complete the chain growth. The involved three steps formed the whole catalytic cycle. We also disclosed that the structural factors, including the electronic effect on electrophilic/nucleophilic centers, steric factors, and the coupling thermodynamics, have a strong relationship with catalyst performance. We believe the insightful structure–performance relationship will shed light on further metal-free catalyst design for artificial polypeptide synthesis.