Chemistry on Unnatural Amino acid Peptide Building Blocks and Bioinspired Peptide Synthesis

Abstract

Non-ribosomal E-vinylogous -amino acids and the thiazole δ-amino acids are widely present in many peptide natural products. Many of these peptide natural products display broad spectrum biological activities including anti-cancer and anti-microbial activities. We sought to investigate the chemical reactivity of conjugated double bonds in E-vinylogous amino acids and their incorporation into peptides. Utilizing E-vinylogous amino acids, we developed novel thiostatines as H-bond surrogates to staple the two anti-parallel β-sheets in the designed β-hairpin structures. Though there are numerous strategies existed for the stapling of -peptide helices, this is the first strategy that β-sheet or β-hairpin structures can be stapled through the backbone disulfide bonds of thiostatines. Further, the , β-unsaturated acids have been scarcely explored as Michael acceptors in the conjugate addition reactions due to their poor reactivity, however, here we proved that unsaturated acids can be used as Michael acceptors in the presence of HBTU and developed a new strategy for the HOBt substituted -amino acids and peptides. Inspired by the serendipity of S- to N-acetyl group migration in the synthesis of thiostatines and the involvement of acyl-CoA in various acylation reactions in biology led us to investigate the thioacids mediated peptides synthesis in the presence of metal salts. We discovered that peptides can be synthesized in methanol using thioacids in the presence of copper sulfate. In addition, we have also demonstrated the selective N-acylation of various aliphatic and aromatic amines using thioacetic acid and copper sulfate. Inspired by the versatile reactivity of sulfur, persulfide and thioacids, we have developed a new synthetic strategy for the synthesis of N-protected thioacids and showed their utility in peptide synthesis in the presence and absence of metal salts. Overall these results demonstrate that peptides can be synthesized without using standard coupling agents. In addition, these results also support the speculation of thioacids as possible precursors in the synthesis of polypeptides in the prebiotic era. Finally, we investigated the involvement of sulfur in thiazole amino acids in the solvent dependent intermolecular chalcogen-chalcogen interactions. On the basis of these investigations we divided this thesis into four chapters. The summary of these investigations are given in this synopsis and details are provided in the main chapters of the thesis.