Generalizing the Aromatic δ-Amino Acid Foldamer Helix

A series of aromatic oligoamide foldamer sequences containing different proportions of three δ-amino acids derived from quinoline, pyridine, and benzene and possessing varying flexibility, for example due to methylene bridges, were synthesized. Crystallographic structures of two key sequences and ¹H NMR data in water concur to show that a canonical aromatic helix fold prevails in almost all cases and that helix stability critically depends on the ratio between rigid and flexible units. Notwithstanding subtle variations of curvature, i. e. the numbers of units per turn, the aromatic δ-peptide helix is therefore shown to be general and tolerant of a great number of sp³ centers. We also demonstrate canonical helical folding upon alternating two monomers that do not promote folding when taken separately: folding occurs with two methylenes between every other unit, not with one methylene between every unit. These findings highlight that a fine-tuning of helix handedness inversion kinetics, curvature, and side chain positioning in aromatic δ-peptidic foldamers can be realized by systematically combining different yet compatible δ-amino acids.