Chemistry on unnatural amino acid peptide building blocks and bioinspired peptide synthesis

Abstract

Non ribosomal E vinylogous 61543 amino acids and the thiazole 948 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 946 sheets in the designed 946 hairpin structures Though there are numerous strategies existed for the stapling of 61537 peptide helices this is the first strategy that 946 sheet or 946 hairpin structures can be stapled through the backbone disulfide bonds of thiostatines Further the 61537 946 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 61543 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 su newline newline