Moisture-Tolerant and Operationally Simple Synthesis of Synthetic Polypeptides and Polypeptoids by Ring-Opening Polymerization of N-Thiocarboxyanhydrides

Abstract

This work aims to develop a new synthetic strategy for synthesizing advanced functional This work aims to develop a new synthetic strategy for synthesizing advanced functional pseudo-peptidic polymers. Pseudo-peptidic polymers mimic poly(glycine) backbone with substituents on either the α-carbon or the nitrogen, appealing properties for various biomedical applications. One of the critical challenges in pseudo-peptidic polymers research is the synthesis of functional pseudo-peptidic polymers under mild conditions. We developed a system based on ring-opening polymerization (ROP) of N-Thiocarboxyanhydrides (NTAs) initiated by primary amines to synthesize polypeptides with a wide range of controlled molecular weights under mild conditions. Additionally, this method provides telechelic pseudo-peptidic polymers that have an amino terminus. Due to NTAs’ high hydrolytic and thermal stability, the system serves as an excellent alternative to the traditional ROP (N-carboxyanhydrides (NCA). Chapter 1 discusses the fundamental knowledge and the history of synthesis routes toward polypeptides. Chapter 2 will focus on why termination events are suppressed in the interfacial ROP compared to the homogenous solution polymerization, thus allowing for controlled polymerizations of α-amino acid-derived NTA in non-polar solution using a primary amine. In Chapter 3, I developed the first system to prepare polypeptides with controlled molecular weight via primary amine-initiated ROP of NTAs under mild conditions without requiring the exclusion of moisture with the assistance of a weak organic acid. The reaction does not require rigorous exclusion of moisture compared to conventional NCA polymerization. This method permits the synthesis of polypeptides with a broad molecular weight range (3.2– 57 kg/mol) and narrow molecular weight distribution (Ð < 1.08). The weak acid is proposed to promote the loss of carbonyl sulfide, thus circumventing termination by isocyanate formation typically seen in the polar medium. Chapter 4 focuses on developing zwitterionic ring-opening polymerization of Me-NNTAs with TMG. PNMG with a broad molecular weight range (1.2– 42.8 kg/mol) and narrow molecular weight distribution (Ð < 1.12) can be readily prepared with this system. TMG-mediated ROP of Me-NNTA is proposed to propagate by a macrozwitterionic species.