UCLA

Polyethylene glycol (PEG) is a polymer that has been widely utilized in the pharmaceutical industry. PEG has been found to cause health risks in recent years, especially after its incorporation in COVID-19 vaccine formulations. Consequently, there is an impetus to explore other polymers that could serve as safer alternatives to PEG, such as polypeptides and polypeptoids. This dissertation develops and investigates the mechanism of transition metal-mediated polymerization of N-alkyl amino acid N-carboxyanhydrides (NNCAs) to advance the preparation of polypept(o)id-based biomaterials. Chapter 2 demonstrates the potential of polypept(o)ide (polypeptide, polypeptoid, or statistical peptide-peptoid copolymers) based biomaterials. To prepare safe and effective lipid nanoparticle (LNP) carriers that do not contain PEG, synthetic methods were developed for polypept(o)ide-lipids that could substitute PEG-lipids in LNP formulations. These polypept(o)ide-lipids, which made use of poly(L-methionine sulfoxide) as the hydrophilic component, provide the advantages of being biodegradable and nontoxic. Both lipid tail length and polypeptide chain length could be easily adjusted. Chapter 3 elucidates the initiation requirements for transition metal-mediated NNCA polymerization. Zerovalent Ni and Co initiators were found to be able to initiate living polymerization of sarcosine NNCA. Pro NNCA, a sterically hindered NNCA, can be polymerized with particular metallacycle and ligand combinations. Contrary to what has been previously published, an N-H group on N-carboxyanhydride (NCA) monomers is not required for metallacycle-mediated polymerizations. New divalent metallacycle structures were synthesized and initiated living polymerization of NNCAs and NCAs. Chapter 4 investigates the propagation mechanism behind transition metal-mediated NNCA polymerization. It was hypothesized that these polymerizations proceed via reversible hydrogen (H) transfer reactions from ?-C-H bonds that NNCAs possess. Transition metal-mediated statistical copolymerizations of NNCAs with isotopically labeled N-D NCAs and NMR experiments on oligomerizations using N-D NCAs were conducted, but H/D transfer was not observed. Weak organic acids enhanced the rate of transition metal-mediated NCA polymerizations, but no H/D transfer was observed when deuterated acid was added. Based on these mechanistic studies, the carbon bound to the metal in these metallacyclic initiators is not protonated off and chain propagation more likely proceeds through a different process.