Rapid and Mild Synthesis of Amino Acid N‐Carboxy Anhydrides: Basic‐to‐Acidic Flash Switching in a Microflow Reactor

Polymerization of N‐carboxy anhydrides (NCAs) is the primary process used to prepare polypeptides. The synthesis of various pure NCAs is key to the efficient synthesis of polypeptides. The only practical method that can be used to synthesize NCAs requires harsh acidic conditions that make acid‐labile substrates unusable and results in an undesired ring opening of NCAs. Basic‐to‐acidic flash switching and subsequent flash dilution technology in a microflow reactor was used to demonstrate the synthesis of NCAs. It is both rapid (0.1 s) and mild (20 °C) and includes substrates containing acid‐labile functional groups. The basic‐to‐acidic flash switching enabled both an acceleration of the desired NCA formation and avoided the undesired ring opening of NCAs. The flash dilution precluded the undesired decomposition of acid‐labile functional groups. The developed process allowed the synthesis of various NCAs which cannot be readily synthesized using conventional batch methods. In a flash: Rapid (0.1 s) and mild (20 °C) synthesis of N‐carboxy anhydrides (NCAs) using basic‐to‐acidic flash switching and subsequent flash dilution was demonstrated. This process enabled the synthesis of acid‐labile NCAs, which are impossible to access using conventional batch conditions. The developed process requires simple phase separations and recrystallization to yield pure NCAs. This microflow approach could pave the way to on‐demand, on‐site NCA synthesis.