Water-Insensitive Synthesis of Poly-β-Peptides with Defined Architecture

Biocompatible and proteolysis-resistant poly-beta-peptides have broad applications and are dominantly synthesized via the harsh and water-sensitive ring-opening polymerization of beta-lactams in a glovebox or using a Schlenk line, catalyzed by the strong base LiN(SiMe3)(2). We have developed a controllable and water-insensitive ring-opening polymerization of beta-amino acid N-thiocarboxyanhydrides (beta-NTAs) that can be operated in open vessels to prepare poly-beta-peptides in high yields, with diverse functional groups, variable chain length, narrow dispersity and defined architecture. These merits imply wide applications of beta-NTA polymerization and resulting poly-beta-peptides, which is validated by the finding of a HDP-mimicking poly-beta-peptide with potent antimicrobial activities. The living beta-NTA polymerization enables the controllable synthesis of random, block copolymers and easy tuning of both terminal groups of polypeptides, which facilitated the unravelling of the antibacterial mechanism using the fluorophore-labelled poly-beta-peptide.