A Robust, Open-Flask, Moisture-Tolerant, and Scalable Route to Unprotected α/β-Amino Acid N-Carboxyanhydrides

Synthetic polypeptides, commonly prepared by the ring-opening polymerization (ROP) of amino acid N-carboxyanhydrides (NCA), are a family of biomimetic materials with vast biomedical applications. A great hurdle in the pro-duction of synthetic polypeptides is the synthesis of NCA, which requires ultra-dry solvents, Schlenk line/gloveboxes, and the protection of sidechain functional groups. Herein, we report a robust and scalable new method for the production of unpro-tected NCA monomers in air and under moisture. The method employs propylene oxide or epichlorohydrin as an inexpensive and ultra-fast scavenger of hydrogen chloride to prevent NCA from acid-catalyzed decomposition under moist conditions. The broad scope and outstanding functional group tolerance of the method are demonstrated by the successful synthesis of more than 30 different NCAs, including many otherwise inaccessible compounds with reactive functional groups (e.g. hy-droxyl, thiol, and carboxylic acid), at high yield and up to ten-gram scale. The scope of the method can be further extended to various α-hydroxyl acid O-carboxyanhydrides (OCA) and β-amino acid NCAs (βNCA). Given these merits, our strategy holds great potential for revolutionizing the synthesis of NCA and polypeptides, and dramatically expanding the industrial application of synthetic polypeptides