Base-Mediated Molecular Rearrangement in Alpha-Beta Unsaturated Gamma Amino Acids

Abstract

Proteins are large biomolecules which performs considerable function in all living organisms. Various structures adopted by protein via folding phenomenon make them specific to their functions. Recent studies in foldamer chemistry shows that the folding phenomenon exists not only in proteins but also in peptides. These studies also gave a wide scope to search significant structures that can be formed by peptides containing non-natural amino acids. The existence of different biologically active peptide natural products where non-natural amino acids like γ-amino acids are present also states its significance. Several studies on non-natural amino acids and their utility on designing various secondary structures are done in our lab. The study on conformational properties and chemical reactivity of α,β-unsaturated γ-amino acids (dehydro γ-amino acid) which was previously conducted shown that double bond on dehydro γ-amino acid in a peptide got migrated on treatment with a base. By exploiting the migration reaction, a method of direct transformation of non-helical α, γ-hybrid peptides composed of alternating α- and E-vinylogous amino acids into 12-helical structures has been observed.1 This base-mediated chemical rearrangement has also been used to turn N‑protected α,β unsaturated γ‑amino amides into γ‑lactams.2 These transformations are carried out by the strong base KOtBu, which makes it challenging to utilize in the presence of chiral amino acids. We wanted to see if mild bases like NaOH could be used to convert N‑protected α,β unsaturated γ‑amino amides into γ‑lactams. In this study, we examined whether the double bonds can migrate in the presence of NaOH by subjecting various types unsaturated amino acid esters and terminal amides. Among the various amino acids tested, we found that the double bond migration was observed case of dehydro γ-Phenylglycine. Further various peptides composed of dg- γ-Phenylglycine and chiral amino acids were synthesized and double bond migration was studied using base NaOH without affecting the chiral integrity of the molecule. Similar type of NaOH mediated double bond migration was not observed in the peptides consists of other unsaturated amino acids. Overall, the results obtained in this project revealed that α,β-unsaturated γ-amino acids cannot used for the alkaline hydrolysis. In addition, it has been proved all unsaturated amino acids are not same and the acidity of gamma-H play a crucial role in the double bond migration in unsaturated amino acids. The conformational studies of all synthesized peptides are in progress.