Synthetic polypeptides, as mimics of natural analogues, is a unique family of bio-inspired biomaterials with broad biomedical applications including controlled drug release, gene delivery, tissue engineering, and regenerative medicine. Ring-opening polymerization (ROP) of α-amino acid N-carboxyanhydrides (NCAs) initiated by different amines and amines derivatives is considered to be the most common method for polypeptide synthesis. However, in the ROP of NCAs, the normal amine mechanism (NAM) and activated monomer mechanism (AMM), often compete with each other, which complicates the overall polymerization process, making it challenging to produce well-defined (co)polypeptides.

In this contribution, we show that 1,3-bis(2-hydroxyhexafluoroisopropyl)benzene (1,3-Bis-HFAB), a small fluorinated alcohol, without the assistance of a Lewis base cocatalyst, can catalyze a fast and selective ROP of α-amino acid N-carboxyanhydride (NCA), resulting in well-defined polypeptides. Different from the bicomponent-bifunctional catalytic process of fluorinated alchohol/(−)-sparteine system for ROP of cyclic esters, the 1,3-Bis-HFAB catalyst doesn’t require a Lewis base cocatalyst, and it is defined as a monocomponent-multifunctional catalytic process for ROP of NCA. During polymerization, 1,3-Bis-HFAB can form multiple dynamic hydrogen bondings with initiator, monomer and propagating polymer chain-end, moving between them. These cooperative hydrogen-bonding interactions activate the monomer and simultaneously protect the overactive initiator/polymer chain from side reactions, offering high reaction rates and selectivity in the polymerization. This finding not only represents a nonconventional catalysis methodology of fluorinated alcohols but also provides a pathway for polypeptides synthesis, fulfilling metal free, high activity, and high selectivity. Other merits of this strategy are: (1) the 1,3-Bis-HFAB catalyst and the aminoalcohol initiator used in this study are all commercially available organic chemicals, (2) the catalyst can be easily removed from final polypeptide after polymerization, which provides a facile way to get clean polypeptides for researchers who focus on the functions and applications of polypeptides but have backgrounds other than organic chemistry.