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

We report the effect of a minimal (i, i + 4) staple on the dynamic interconversion between right-handed (P) and left-handed (M) forms of an optically inactive α-helical peptide composed only of helicogenic achiral amino acids, such as 1-amino-cyclohexanecarboxylic acid (Ac₆c) and 4-aminopiperidine-4-carboxylic acid (Api) residues. The P/M interconversion rate of the peptide with a flexible hydrocarbon-based staple was estimated to be 0.41 s^-1 at 298 K through variable temperature ¹H NMR measurements in 1,1,2,2-tetrachloroethane-d₂. A combined analysis using ¹H 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 Ac₆c residues exhibit a stronger propensity for α-helical conformation over the 3₁₀-helix than α-aminoisobutyric acid (Aib) residues, with their influence being highly dependent on position and sequence within the oligopeptides.