Conformational investigation of ?,?-dehydropeptides.N-acetyl-(E)-dehydrophenylalanineN?-methylamide: conformational properties from infrared and theoretical studies, part XIV

Abstract

N-Acetyl-(E)-dehydrophenylalanine N'-methylamide [Ac-(E)-DeltaPhe-NHMe], one of a few representative (E)-alpha,beta-dehydroamino acids, was studied by FTIR in dichloromethane and acetonitrile. To support spectroscopic interpretations and to gain some deeper insight into the Ac-(E)-DeltaPhe-NHMe molecule, the Ramachandran potential energy surface was calculated by the B3LYP/6-31G*//HF/3-21G method and the conformers localized were fully optimized at the B3LYP/6-31 + G** level. The spectra and calculations were compared with those of the related molecules Ac-DeltaAla-NHMe and Ac-(Z)-DeltaPhe-NHMe. The title compound assumes two conformational states in equilibrium in dichloromethane solution with a predominance of the extended conformer E. The Ac-(E)-DeltaPhe-NHMe spectrum is like that of Ac-DeltaAla-NHMe, particularly in the region of bands AI and AII, and unlike that of Ac-(Z)-DeltaPhe-NHMe. The positions of bands AI and II together with the nu(s)(N1--H1) band proves that the conformers E of both DeltaAla and (E)-DeltaPhe compounds are stabilized by the quite strong C5 hydrogen bonds N1--H1...O2. The same conclusion is drawn from the Ramachandran diagrams. The conformers E of both compounds are placed in the global minima and the gaps in energy order between them and the second conformer are large. The conformers E of DeltaAla and (E)-DeltaPhe, apart from the N1--H1...O2 hydrogen bond, show the Cbeta--H...O1 interaction, and Ac-(E)-DeltaPhe-NHMe displays the NH/pi interaction with the N2--H2 projecting in the first carbon atom of the phenyl ring. The C5 hydrogen bond is stronger in (E)-DeltaPhe than that in the DeltaAla compound. This is in agreement with interactions found in the calculated structures and can be explained by the influence of the phenyl ring in position (E). In acetonitrile, the molecule of Ac-(E)-DeltaPhe-NHMe loses its C5 hydrogen bond and becomes unfolded, whereas that of Ac-DeltaAla-NHMe does not vary practically. Adopting conformation E in a non-polar solvent seems to be a general feature of the (E)-DeltaXaa residues.

Effects of Side-Chain Orientation on the Backbone Conformation of the Dehydrophenylalanine Residue. Theoretical and X-ray Study

“…Figure 4 shows the 3D-Ramachandran map for the 1a molecule calculated by DFT method in the gas phase. The shape of this surface is almost identical to those obtained earlier 29 at the B3LYP/6-31G*//HF/3-21G level, but in this case we localized additional, high energy helical conformers A (φ, ψ = À56°, À36°) and A* (φ, ψ = 56°, 36°). The PES of 1a calculated by the MP2 method reveals only three minima and their mirror images (including the helical ones) and predicts a visibly smaller difference in energy between the two lowest conformers, compared to the DFT results.…”

“…33À35 In solution, the extended conformer C 5 (φ, ψ ∼ À179°, 162°) can be also found. 29 N-Methylation is another structural modification of significant interest in the area of medicinal chemistry, because several compounds with good pharmacokinetic profiles are based on N-methylamino acid-containing substances. 36 N-Methylation is an important tool to modify lipophilicity, proteolytic stability, and bioavailability and to induce conformational rigidity to a peptide backbone.…”

Conformational properties of N-acetyl-N-methyl-alpha,beta-dehydroalanine N'-methylamide.

“…The conformers were designated by general short-hand letter notation (Zimmerman et al, 1977) by analogy with the designation of the dehydroam-ino acids studied previously (Siodłak et al, 2004a;2004b;Broda et al, 2005a;2005b).…”

“…As a result, the extended conformer E and the semi-extended is not adopted by ∆(Me)Ala as compared to non-N-methylated dehydroalanine, ∆Ala (E: φ, ψ = 180°, 169°; D: φ, ψ = 165°, 25°) and N'N'-dimethyldehydroalanine, ∆Ala-NMe (E: φ, ψ = 180°, 153°; D: φ, ψ = 177°, 48°) (Siodłak et al, 2004a). Instead, ∆(Me)Ala adopts the conformation E* (φ, ψ = 135°, 144°) that is typical of (Z)-∆Xaa (Thormann & Hofmann, 1998;Siodłak et al, 2004a;2004b) (but not for (E)-∆Xaa (Thormann & Hofmann, 1998;Broda et al, 1998Broda et al, , 2005a). The N-methylation of the amide bond seems not to influence either the conformer B (φ, ψ = -76°, 38°) or the conformer F (φ, ψ = -56°, 142°).…”

Association of model peptides and dehydropeptides: N-acetyl-L-butyrine and (Z)-dehydrobutyrine N',N'-dimethylamides.

“…In a weakly polar environment, Ac-(Z)-∆Abu-NMe 2 occurs mainly in the extended conformation E, stabilized by the hydrogen bond C 5 , and is accompanied by the conformers D and F in small amounts. The conformers were designated by general short-hand letter notation (Zimmerman et al, 1977) by analogy with the designation of the dehydroamino acids studied previously (Rzeszotarska, et al, 2002;Siodłak et al, 2003;2004a;2004b;2004c;Broda et al, 2005a;2005b;2005c). To study the association, as was the case for conformation, we also first used the FTIR measurements.…”