Synthesis and studies of polypeptide materials: Enantioselective polymerization of gamma-benzyl glutamate-N-carboxyanhydride and synthesis of optically active poly(beta-peptides)

A class of zero-valent transition metal complexes have been developed by Deming et al for the controlled polymerization of α-aminoacid-N-carboxyanhydrides (α-NCAs). This discovery provided a superior starting point for the development of enantioselective polymerizations of racemic α-NCAs. Bidentate chiral ligands were synthesized and tested for their abilities to induce enantioselective polymerization of γ-benzyl-glutamate NCA (Glu NCA) when they were coordinated to zero-valent nickel complexes. When optically active 2-pyridinyl oxazoline ligands were mixed with bis(1,5-cyclooctadiene)nickel in THF, chiral nickel complexes were formed that selectively polymerized one enantiomer of Glu NCA over the other. The highest selectivity was observed with the nickel complex of (S)-4-tert-butyl-2-pyridinyl oxazoline, which gave a ratio of enantiomeric polymerization rate constants (k_D/k_L) of 5.2. It was found that subtle modification of this ligand by incorporation of additional substituents had a substantial impact on initiator enantioselectivities.; In separate efforts, methodology was developed for the general synthesis of optically active β-aminoacid-N-carboxyanhydrides (β-NCAs) via cyclization of N_β-Boc- or N_β-Cbz-β-amino acids using phosphorus tribromide. The β-NCA molecules could be polymerized in good yields using strong bases or transition metal complexes to give optically active poly(β-peptides) bearing proteinogenic side chains. The resulting poly(β-peptides), which have moderate molecular weights, adopt stable helical conformations in solution. Poly(β-homoglutamate and poly(β-homolysine), the side-chain deprotected polymers, were found to display pH dependent helix-coil conformation transitions in aqueous solution, similar to their α-analogs.; A novel method for poly(β-aspartate) synthesis was developed via the polymerization of L-aspartate alkyl ester β lactams using metal-amido complexes. Poly(β-aspartates) bearing short ethylene glycol side chains were obtained with controlled molecular weights and narrow molecular weight distributions when Sc(N(TMS)₂)₃ was used as initiator for the β-lactam polymerizations. Polymer chain lengths could be controlled by both stoichiometry and monomer conversion, characteristic of a living polymerization system. Di- and tri-block copoly(β-peptides) with desired chain lengths were also synthesized using this method. It was found that these techniques were generally applicable for the synthesis of poly(β-peptides), bearing other proteinogetic side chains.; Synthesis and studies of polypeptide materials were extended to unexplored areas by incorporation of both α- and β-amino acid residues into single polymer chains. Two sequence specific polypeptides bearing alternating β-α, or β-α-α amino acid residues were synthesized. Both polymers were found to adopt unprecedented stable conformations in solution.