N-Methyldehydroamino acids promote a configuration cis of N-methylamide bond

Dehydroamino acids with a methylated N-terminal tertiary amide bond occur in natural small cyclic peptide toxins. To investigate their conformational preferences a systematic theoretical analysis was performed on N'-methylamides of N-acetyl-N-methyldehydroamino acids (Ac-Delta(Me)Xaa-NHMe, where Xaa = (Z)-Abu, (E)-Abu, Val, (Z)-Phe, and (E)-Phe) considering the configuration trans and cis of the tertiary amide bond. The phi, psi potential energy surfaces were calculated at the B3LYP/6-31+G**//HF/3-21G level with inclusion of the solvent (water) effect (SCRF method). The conformers localised were fully optimised at the B3LYP/6-31+G** in vacuo. The accessible areas of the potential energy surfaces; the number of conformers and the stabilising internal forces were compared for all the studied molecules. The main feature of the studied N-methyldehydroamino acids is their considerable tendency to adopt the configuration cis for the N-terminal tertiary amide bond. It results from the specific ability of these dehydroamino acids to be able to gain stability from the pi-electron conjugation between the C-alpha = C-beta double bond and the neighbouring C-terminal amide group. This stabilising force concomitant with the short N-H center dot center dot center dot N hydrogen bond makes the conformer cis C7(eq) (phi, psi similar to -105 degrees, 8 degrees) the lowest in energy. The data presented hereinto indicates that N-methyldehydroamino acids can potentially be new promoters of trans-cis isomerisation of the amide bond. (c) 2007 Elsevier B.V. All rights reserved.