Azole γ‐Peptides Helix Switching via Heterocycle Substitutions

ABSTRACT Precise control of peptide backbone folding through non‐covalent interactions remains a major challenge in foldamer design. In this work, we demonstrate that heteroatom substitutions program conformational switching in azole γ‐peptides by tuning intrinsic stereoelectronic effects within heterocyclic γ‐amino acids. Conformationally constrained thiazole‐ and oxazole‐based γ‐amino acids were designed to adopt conformations driven by either a C 9 or a C 7 intramolecular H‐bond depending on key 1,4‐X···O interactions (X = S or N). We previously showed that thiazole‐based oligomers form a well‐characterized canonical 9‐Helix. Here, permutation of the sulfur and nitrogen atoms within the heterocycle induces a stretched helical structure with alternating C 7 ‐turns and residues in extended conformations. This unusual topology arises from competition between seven‐membered intra‐residue H‐bonds and attractive S···N electrostatic‐chalcogen interactions. Reversing this effect through an S→O substitution affords oxazole‐derived oligomers that adopt a stable 7‐Helix stabilized by a continuous seven‐membered H‐bond network in solution. These findings show that simple heteroatom permutation or substitution allows control over heterocyclic γ‐peptide folding, thereby expanding opportunities for foldamer design in molecular recognition, catalysis, and biomedical applications.