Conformational investigation of α,β‐dehydropeptides. IX. N‐Acetyl‐(E)‐α,β‐dehydrobutyrine N′‐methylamide: stereoelectronic properties from infrared and theoretical studies*

Abstract

: The Fourier transform infrared spectra of Ac‐(E)‐ΔAbu‐NHMe were analyzed to determine the predominant solution conformation (s) of this (E)‐α,β‐dehydropeptide‐related compound and the electron density perturbation in its amide groups. The measurements were performed in dichloromethane and acetonitrile in the region of mode vs (N–H), amide I, amide II and vs (Cα= Cβ). The equilibrium geometrical parameters, calculated by a method based on the density functional theory with the B3LYP functional and the 6–31G* basis set, were used to support spectroscopic interpretation and gain some deeper insight into the molecule. The experimental and theoretical data were compared with those of three previously described molecules: isomeric Ac‐(Z)‐ΔAbu‐NHMe, Ac‐ΔAla‐NHMe, which is deprived of any β‐substituent, and saturated species Ac‐Abu‐NHMe. The titled compound assumes two conformational states in equilibrium in the DCM solution. One conformer is extended almost fully and like Ac‐ΔAla‐NHMe is C5 hydrogen‐bonded. The other adopts a warped C5 structure similar to that of Ac‐(Z)‐ΔAbu‐NHMe. The C5 hydrogen bond, unlike the H‐bond in Ac‐ΔAla‐NHMe, is disrupted by acetonitrile. The resonance within the N‐terminal amide groups in either of the (E)‐ΔAbu conformers is not as well developed as the resonance in Ac‐Abu‐NHMe. However, these N‐terminal groups, compared with the other unsaturated compounds, constitute better resonance systems in each conformationally related couple: the C5 hydrogen‐bonded Ac‐(E)‐ΔAbu‐NHMe/Ac‐ΔAla‐NHMe and the warped C5 Ac‐(E)‐ΔAbu‐NHMe/Ac‐(Z)‐ΔAbu‐NHMe. The resonance within the C‐terminal groups of the latter couple apparently is similar, but less developed than the resonance in Ac‐Abu‐NHMe. The electron distribution within the C‐terminal group of the hydrogen‐bonded C5 (E)‐ΔAbu conformer apparently is determined mainly by the electron influx from the Cα= Cβ double bond.

The effect of β‐methylation on the conformation of α, β‐dehydrophenylalanine: a DFT study

“…For both residues the calculation in vacuo places the conformer C 7 as the lowest in energy. The solvent environment disfavours the conformers C 7 of both residues but to a much greater extent for non‐methylated ( Z )‐ΔPhe25 than for ( Z )‐Δ(βMe)Phe. For the latter, the conformers β, C 7 and α L differ in energy by less than 0.9 kcal/mol.…”

“…Comparison of the conformational map and minima calculated for 1 to that of the analogue without the β‐methyl group (Ac‐( E )‐ΔPhe‐NHMe25) (Table 1) shows that both residues have a tendency to adopt the extended conformer C 5 , which is stabilised mainly by the N 1 H 1 ···O 2 and N 2 H 2 ···π hydrogen bonds. In the case of the ( E )‐Δ(βMe)Phe derivative, however, the β‐methyl group imposes a steric effect on the torsion angle ϕ (127°), and the conformation C 5 is considerably distorted.…”

“…The Ramachandran diagram of Ac‐( E )‐ΔPhe‐NHMe shows the conformer β (ϕ, ψ = −43°, 123°). In polar environment, it becomes the global conformer of α,β‐dehydroamino acids, often adopted in the solid state25–27. The compound 1 does not have the conformer β.…”

“…Sixty‐nine residues were found to have counterpart conformation in the range of values of torsion angles ϕ from −39° up to −99° and ψϕ from −43° up to 3° with the average ϕ,ψ (−61°, −21°]. The conformer β (ϕ, ψ ∼ −62°, 148°) should also be taken into consideration22–24 and this conformation is probably preferred in solution25. According to the scarce literature data, ( E )‐ΔPhe adopts in its crystal state the conformation β (ϕ, ψ ∼ −42°, 124°) and α L (ϕ, ψ ∼ 51°, 49°)26, 27.…”

“…According to the scarce literature data, ( E )‐ΔPhe adopts in its crystal state the conformation β (ϕ, ψ ∼ −42°, 124°) and α L (ϕ, ψ ∼ 51°, 49°)26, 27. In solution, the extended conformer C 5 (ϕ, ψ ∼ −179°, 162°) can also be found25.…”