Binol as a Bioisosteres for Hairpin and Parallel β-pleated Sheet Mimetic Foldamer

In this study, the efficient design and synthesis of a novel peptide bioisosteres for selective folding into a hairpin-like structure has been reported. The peptide mimetic comprises β-alanine, L-leucine, α-amino isobutyric acid, m-nitro cinnamic acid has been synthesized via solution-phase coupling methods. A hairpin conformation and extended β-pleated parallel sheet assembly have been characterized in solution as well as in solid state. The key to this success was the use of β-alanine as a flexible amino acid that can accommodate a wide range of dihedral angles proximal to the binol core. In its solid state, the molecule adopts a hairpin conformation with two perpendicular naphthalene rings. The centrally located binol segment act as bioisosteres and nucleates a chain reversal in the hairpin conformation. Two intramolecular cross-strand hydrogen bonds stabilize the hairpin. Moreover, the intermolecular NH…O═C hydrogen bonds connect the hairpins into an infinitely extended parallel β-sheet. The structure is also stabilized by face to edge π-stacking interactions. This peptide bioisosteres represents a promising tool for foldamer design.