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

Abstract

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-Δ(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 ϕ, ψ 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 π-electron conjugation between the C α C β double bond and the neighbouring C-terminal amide group. This stabilising force concomitant with the short N H⋯N hydrogen bond makes the conformer cis C7 eq ( φ, ψ ∼ −105°, 8°) 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.