Efficient Preparation of Polypeptides through Accelerated Polymerization of N-Carboxyanhydrides in Continuous Flow

The preparation of polypeptide materials in continuous flow reactors shows great potential with improved reproducibility and scalability. However, conventional polypeptide synthesis from the polymerization of N -carboxyanhydride (NCA) is conducted at relatively slow rates, requiring long tubing or ending up with low-molecular-weight polymers. Inspired by recent advances in accelerated NCA polymerization, we report the crown-ether-catalyzed, rapid synthesis of polypeptide materials in cosolvents in flow reactors. The incorporation of low-polarity dichloromethane and the use of catalysts enabled fast conversion of monomers in 30 min, yielding well-defined polypeptides (up to 30 kDa) through a 20-cm tubing reactor. Additionally, random or block copolypeptides were efficiently prepared by incorporating a second NCA monomer. We believe that this work highlights the accelerated polymerization design in flow polymerization processes, offering the continuous production of polypeptide materials.