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

Abstract

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 Cα–Cβ 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 Cα−Cβ 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.