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

Thiourea-quaternary ammonium salt bifunctional catalystswith bothelectrophilic and nucleophilic centers were designed in this paperto initiate the ring-opening polymerization (ROP) of & alpha;-aminoacid N-carboxyanhydrides (NCAs) for the efficientsynthesis of polypeptides. We disclosed this kind of bifunctionalcatalyst for the efficient synthesis of polypeptides in the presenceof propylene oxide (PO), which was judiciously added as an in situ activator for the efficient ROP of NCA. By MALDI-TOFMS and H-1 NMR analysis, we identified the end groups ofthe polymer and clarified the ROP process in the presence of the bifunctionalcatalyst. We showed that the PO was initially ring-opened by the nucleophilicattack of a halogen ion; then, the newly formed alkoxide ions attackedthe electrophilic carbonyl of NCA, providing the carbamate anion.After undergoing a decarboxylation of the carbamate anion, the nucleophilicattack of N to the carbonyl on an NCA ring occurred synergisticallyto complete the chain growth. The involved three steps formed thewhole 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 relationshipwith catalyst performance. We believe the insightful structure-performancerelationship will shed light on further metal-free catalyst designfor artificial polypeptide synthesis.

Automated summary

In this paper, thiourea-quaternary ammonium salt bifunctional catalysts with both electrophilic and nucleophilic centers were designed for the efficient synthesis of polypeptides through ring-opening polymerization (ROP) of α-amino acid N-carboxyanhydrides (NCAs). We demonstrated the use of propylene oxide (PO) as an in situ activator for the efficient ROP of NCA in the presence of this bifunctional catalyst. The catalytic cycle involves three steps, including the initial nucleophilic attack of PO, the electrophilic attack of NCA, and the nucleophilic attack of N to complete chain growth. The structural factors and coupling thermodynamics were found to strongly influence the catalyst performance.