Single-conformation IR and UV spectroscopy of the prototypical capped γ-peptide Ac-γ4-Phe-NHMe (γ4F) was carried out under jet-cooled conditions in the gas phase in order to understand its innate conformational preferences in the absence of a solvent. We obtained conformer-specific IR and UV spectra and compared the results with calculations to make assignments and explore the differences between the γ2- and γ4-substituted molecules. We found four conformers of γ4F in our experiment. Three conformers form nine-membered hydrogen-bonded rings (C9) enclosed by an NH···OC H-bond but differing in their phenyl ring positions (a, g+, and g−). The fourth conformer forms a strained seven-membered hydrogen-bonded ring in which the amide groups lie in a nominally anti-parallel arrangement stacked on top of one another (labeled S7). This conformer is a close analogue of the amide-stacked conformer (S) found previously in γ2F, in which the Phe side chain is substituted at the γ2 position, Ac-γ2-Phe-NHMe (J. Am. Chem. Soc. 2009, 131, 14243–14245). IR population transfer spectroscopy was used to determine the fractional abundances of the γ4F conformers in the expansion. A combination of force field and density functional theory calculations is used to map out the conformational potential energy surfaces for γ4F and compare it with its γ2F counterpart. Based on this analysis, the phenyl ring prefers to take up structures that facilitate NH···π interactions in γ4F or avoid phenyl interactions with the CO group in γ2F. The disconnectivity graph for γ4F reveals separate basins associated with the C9 and amide-stacked conformational families, which are separated by a barrier of about 42 kJ/mol. The overall shape of the potential energy surface bears a resemblance to peptides and proteins that have a misfolding pathway that competes with the formation of the native structure.

The α/β-peptide 11/9-helix and the β-peptide 12/10-helix belong to “mixed” helices, in which two types of hydrogen bonds with opposite directionality alternate along the helical axis. cis-2-Aminocyclohaxanecarboxylic acid (cis-ACHC) is...

A series of nylon‐like oligomers was synthesized, which consisted of alternating cyclic 1,2‐diamine and 1,2‐dicarboxylic acid building blocks with a five‐membered ring constraint. The nylon 2 4 oligomers are symmetric and display helical structures similar to the β‐peptide 12‐helix with intramolecular 12‐membered ring hydrogen bonds. The cyclopentane moiety allows each building block to promote 12‐helical folding. In addition, a tartaric acid derivative with the acetonide moiety increases the solubility of oligomers in common organic solvents and promotes helical folding.

Anti‐β2,3‐amino acids are a class of acyclic β‐amino acids that usually stabilize β‐sheet‐like conformations of unnatural peptides. (2S,3R)‐3‐amino‐2‐ethylpentanoic acid (AEPA) is a diethyl‐substituted anti‐β2,3‐amino acid that can be regarded as an acyclic analog of cis‐2‐aminocyclohexanecarboxylic acid, which is known to promote the α/β‐peptide 11/9‐helix and the β‐peptide 12/10‐helix. We report that AEPA can be incorporated into the two unnatural peptide helices without disrupting helical folding. Crystal structure data reveal that the anti‐β2,3‐residue adopts unconventional gauche (+) conformation in those unnatural peptide helices.