Accelerated Polypeptide Synthesis via N-Carboxyanhydride Ring Opening Polymerization in Continuous Flow

In nature, polypeptide-based materials are ubiquitous, yet their synthetic production is hampered by high cost, limited scalability, and often stringent reaction conditions. Herein an elegant approach is presented for N-carboxyanhydride ring opening polymerization (NCA ROP) of Nε-benzyloxycarbonyl-l-lysine (ZLL) and γ-benzyl-l-glutamate (BLG) NCA in continuous flow. The polymerization is initiated by primary amine initiators using N,N-dimethylformamide (DMF) as solvent. Carrying out the reaction in a silicon microflow reactor speeds up the rate of ROP (92% conversion in 40 min in flow as opposed to 6 h in batch) due to highly efficient permeation of CO₂ through the reactor tubing. The polymerization strategy provides a facile, scale-up friendly alternative to traditional batch mode polymerization and has the capability of streamlining NCA ROP.