Exploring helix structures of γ‐peptides based on 2‐(aminomethyl)cyclopentanecarboxylic acid

Conformational search and density functional theory calculations were performed to explore the preferences of helical structures for chiro‐specific oligo‐γ‐peptides of 2‐(aminomethyl)cyclopentanecarboxylic acid (γAmc 5 ) with a cyclopentyl constraint on the C α –C β bond in solution. The dimer and tetramer of γAmc 5 ( 1 ) with homochiral (1 S , 2 S ) configurations exhibited a strong preference for the 9‐membered helix foldamer in solution, except for the tetramer in water. However, the oligomers of γAmc 5 ( 1 ) longer than tetramer preferentially adopted a right‐handed ( P )‐2.6 14 ‐helix (H 1 ‐14) as the peptide sequence becomes longer and as solvent polarity increases. The high stabilities for H 1 ‐14 foldamers of γAmc 5 ( 1 ) in solution were ascribed to the favored solvation free energies. The calculated mean backbone torsion angles for H 1 ‐14 helix foldamers of γAmc 5 ( 1 ) were similar to those calculated for oligomers of other γ‐residues with cyclopentane or cyclohexane rings. However, the substitution of cyclopentane constraints on the C α −C β bond of the γAmc 5 ( 1 ) residue resulted in different conformational preferences and/or handedness of helix foldamers. In particular, the pyrrolidine‐substituted analogs of the H 1 ‐14 foldamers of γAmc 5 ( 1 ) with adjacent amine diads substituted at a proximal distance are expected to be potential catalysts for the crossed aldol condensation in nonpolar and polar solvents.