Unnatural amino acids: synthesis and structure-property relationship studies

The conformations, tautomerization, and aggregation of different unnatural amino acids were examined in solution and in the gas phase. These properties were analyzed using H NMR spectroscopy, IR spectroscopy and computational chemistry techniques.

H NMR spectroscopy was used to quantify the substituent effects on the tautomerization of substituted N,N-dimethylamino acids in DMSO. The results show that the tautomeric equilibrium constant is shifted to the unionized tautomer with increased branching on the p-carbon of the amino acid. The results are explained in terms of the substituent steric and solvation effects on the conformation of the amino acids. Additionally, variable temperature H NMR spectroscopy illustrated that N,Ndimethylphenylglycine derivatives associate in aqueous solution due to hydrophobic and intermolecular hydrogen bonding interactions.

ab Initio calculations were utilized to examine the conformational potential energy surface (PES) of fiuorinated and N-alkyl substituted amino acids. For 2-fluoroglycine, 2,2-difluoroglycine, and 3,3,3-trifluoroalanine, the resuhs of the study show that for each amino acid conformation, the optimized geometry is highly dependent on the level of theory utilized. For instance, the amino group is planar at some, but not all, levels of theory. The anomeric effect and intramolecular hydrogen bonding interactions were shown to be important stabilizing factors of the gas phase conformations of these species. For N-alkyl substituted amino acids, the conformations of N-methylglycine and N,N-dimethylglycine have been examined and the results reveal the importance of hydrogen bonding interactions as a stabilizing element for each conformation. The tautomerization of N-methylglycine and N,N-dimethylglycine was also examined by ab initio methods and the results indicate that the "stretched out" conformation of N,N-dimethylglycine zwitterion is a minimum on the conformational PES in the gas phase. This is believed to be one of the first amino acid zwitterions predicted to be a real molecule in the gas phase.

A viable pathway for the synthesis of conformationally constrained P,P-alkyl substituted cysteine analogs was examined. The pathway has been described in the chemical Hterature, however the route has not been optimized to readily give the desired cysteine derivatives. This study examined this route in more detail.