Stabilization of optically inactive α-helices of peptidic foldamers through sequence control and , + 4 stapling.

We report the effect of a minimal (, + 4) staple on the dynamic interconversion between right-handed () and left-handed () forms of an optically inactive α-helical peptide composed only of helicogenic achiral amino acids, such as 1-amino-cyclohexanecarboxylic acid (Acc) and 4-aminopiperidine-4-carboxylic acid (Api) residues. The / interconversion rate of the peptide with a flexible hydrocarbon-based staple was estimated to be 0.41 s at 298 K through variable temperature H NMR measurements in 1,1,2,2-tetrachloroethane-. A combined analysis using H NMR spectroscopy, single-crystal X-ray crystallography, and density functional theory (DFT) calculations revealed that the present flexible stapling does not effectively constrain the conformational freedom of the helical peptide. DFT calculations revealed that Acc residues exhibit a stronger propensity for α-helical conformation over the 3-helix than α-aminoisobutyric acid (Aib) residues, with their influence being highly dependent on position and sequence within the oligopeptides.