Conformational investigation of α, β‐dehydropeptides. XI. Molecular and crystal structure of Ac‐( Z )‐ΔPhe‐NMe 2 as compared to those of related molecules

A series of three homologous dimethyldiamides Ac‐( Z )‐ΔPhe‐NMe 2 , Ac‐ L ‐Phe‐NMe 2 and Ac‐ DL ‐Phe‐NMe 2 have been synthesized and their structures determined from single‐crystal X‐ray diffraction data. To learn more about the conformational preferences of the compounds studied, the fully relaxed ϕ, ψ conformational energy maps on the free molecules of Ac‐ΔAla‐NMe 2 and Ac‐( Z )‐ΔPhe‐NMe 2 were obtained with the HF/3‐21G method and the calculated minima re‐optimized with the DFT/B3LYP/6‐31G ** method. The crystal state results have been compared with the literature data. The studied dimethyldiamide Ac‐ΔXaa‐NMe 2 combines the double bond in positions α, β and the C ‐terminal tertiary amide within one molecule. As the representative probe with ΔXaa = ΔAla, ( Z )‐ΔLeu and ( Z )‐ΔPhe shows, in the solid state they adopt the conservative conformation with ϕ, ψ∼ −45°, ∼130° and with a non‐planar tertiary amide bond, whatever the packing forces are. This conformation is located on the Ramachandran map in region H/F, which is of high‐energy for common amino acids, but not so readily accessible to them. The free molecule calculations on Ac‐ΔAla‐NMe 2 and Ac‐( Z )‐ΔPhe‐NMe 2 reveal that, in spite of dissimilar overall conformational profiles of these molecules, this structure is one of their low‐energy conformers and for Ac‐( Z )‐ΔPhe‐NMe 2 it constitutes the global minimum. So, the theoretical results corroborate those experimental results proving that this structure is robust enough to avoid conformational distortion due to packing forces. In contrast to Ac‐ΔXaa‐NMe 2 , the saturated Ac‐ L/DL ‐Xaa‐NMe 2 shows the constancy of the associative patterns but do not prefer any molecular structure in the solid state. Copyright © 2003 European Peptide Society and John Wiley & Sons, Ltd.