Facile synthesis of polypeptoids bearing bulky sidechains via urea accelerated ring-opening polymerization of α-amino acid N-substituted N-carboxyanhydrides

Abstract

Polypeptoids, as synthetic mimics of polypeptides, exhibit a variety of biological functions and excellent proteolytic stability. Polypeptoids can be synthesized by the ring-opening polymerization of α-amino acid N-substituted N-carboxyanhydrides (NNCAs); however, they suffer from the generally slow reactivity and poor stability of NNCAs, especially those with bulky substitutes. This long-standing challenge greatly limits the synthesis of polypeptoids with diverse structures. Herein, we found that commercially available 1,3-bis[3,5-bis(trifluoromethyl)phenyl]urea can greatly accelerate the primary amine-initiated ring-opening polymerization of NNCAs by activating the NNCA carbonyl via hydrogen bonding interactions. Urea-catalyzed NNCA polymerization is compatible with diverse NNCAs in preparing polypeptoids with variable polymer lengths and narrow dispersity and is especially suitable for inactive NNCAs bearing bulky N-substitutes, such as cyclohexyl-NNCA. This urea-catalyzed NNCA polymerization strategy will substantially increase the structural diversity and functional study of polypeptoids, implying wider and diverse applications of these polypeptide mimics.