An alternative route to Nα-methylamino acid derivatives: Synthesis and conformation of some Nα-acetyl-Nα-methylamino acid methylamides

Abstract

The methylation of tert-butyl- or isopropyl- esters of Nα-4-toluenesulfonyl-amino acids by dimethylsulfate in aqueous alkaline solution in the presence of a detergent gives the corresponding Nα-methylderivatives. Using this synthetic route the Nα-acetylderivatives of MeAla, MeLeu, MeOrn and MePhe methylamides have been prepared and the solution conformation of these dipeptide units has been investigated. 1H and 13C NMR spectra show that, while in dimethylsulfoxide the tertiary amide group is mostly in cis-conformation, in protic solvents the equilibrium is shifted towards trans-conformation. Circular dichroism spectra reveal some specific features (e.g. high band intensities in protic solvents) which cannot be explained solely on the basis of the increased rigidity caused by the Nα-methyl group. We tried to explain these effects supposing that the tertiary amide group is deviated from the planar arrangement (due to the interaction between the methyl groups, a substituent on Cα and a solvent molecule attached to the oxygen atom) and contributes to the observed circular dichroism as the inherently chiral chromophore.