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 (γAmc₅) with a cyclopentyl constraint on the C^α-C^β bond in solution. The dimer and tetramer of γAmc₅ (1) with homochiral (1S, 2S) configurations exhibited a strong preference for the 9-membered helix foldamer in solution, except for the tetramer in water. However, the oligomers of γAmc₅ (1) longer than tetramer preferentially adopted a right-handed (P)-2.6₁₄-helix (H₁-14) as the peptide sequence becomes longer and as solvent polarity increases. The high stabilities for H₁-14 foldamers of γAmc₅ (1) in solution were ascribed to the favored solvation free energies. The calculated mean backbone torsion angles for H₁-14 helix foldamers of γAmc₅ (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 γAmc₅ (1) residue resulted in different conformational preferences and/or handedness of helix foldamers. In particular, the pyrrolidine-substituted analogs of the H₁-14 foldamers of γAmc₅ (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.