Exploring Stereochemical Constraints and Chemical Reactivity of Vinylogous Amino acids in the Design of Foldamers

Abstract

The relationship between a well-defined structure and function of proteins inspire the creation of foldamers from non-natural building blocks. Among them, the most widely studied foldamers are constructed from β- and γ-amino acid subunits. The remarkable protein secondary structure mimetics displayed by these β- and γ-peptide oligomers have been exploited in designing inhibitors for various protein-protein interactions, antimicrobials and biomaterials. Previously, we have showed the utilization of naturally occurring E-vinylogous amino acids in the design of β-hairpins and β-sheet mimetics. In the present study, we investigated the utility of these conformationally constrained yet highly reactive α,β-unsaturated γ-amino acids to engineer the folding in polypeptides and as Michael acceptors to derive a variety of 3,4-disubstituted γ-amino acids. We showed that by selective insertion of E-vinylogous amino acids in the α-peptide sequence, it is possible to design novel miniature β-meander as well as helix-turn-helix type of motifs even in small peptide sequences. Further, utilizing E-vinylogous residues as Michael acceptors, we derived highly functionalizable β-nitromethyl γ-amino acids as well as thiostatines (β-sulfhydryl γ-amino acids). Besides their utility as templates in the design of 14- and 12-helical foldamers, we showed the multifaceted nature of alkyl nitro group on peptides by transforming it into various functional groups including amines, carboxylic acids, oximes, and 1,3-dipolar addition products. Further, as E-vinylogous amino acids preferred to adopt extended β-sheets type structures, we investigated whether Z-vinylogous amino acids can be used to design helical peptide foldamers with conjugated double bond in the helix backbone. Finally, in the course of our investigation on structural and chemical characterization of unsaturated γ-amino acids and peptides, we encountered a base mediated novel rearrangement transforming the vinylogous amides into γ-lactams through double bond migration. Overall, these basic results on vinylogous amino acids open wide opportunities to further explore them as building blocks for the foldamers design as well as templates to perform various organic reactions.