(alphaMe)Nva: steroselective synteses and preferred conformations of selected model peptides

Using different stereoselective chemical and chemoenzymatic approaches we synthesized the chiral, C-alpha-methylated alpha -amino acid L-(alpha Me)Nva with a short, linear side-chain. A set of terminally protected model peptides to the pentamer level containing either (alpha Me)Nva or Nva in combination with Ala and/or Aib was prepared using solution methods and characterized fully. Two (alpha Me)Nva peptides were also synthesized using side-chain hydrogenation of the corresponding C-alpha-methyl, C-alpha-allylglycine (Mag) peptides. A detailed solution and crystal-state conformational analysis based on FT-IR absorption, H-1 NMR and X-ray diffraction techniques allowed us to define that: (i) (aMe)Nva is an effective p-turn and 3(10)-helix former; and (ii) the relationship between (alpha Me)Nva chirality and the screw sense of the turn/helix formed is that typical of protein amino acids, i.e. L-(alpha Me)Nva induces the preferential formation of right-handed folded structures. In more general terms, this study reinforced previous conclusions that peptides based on alpha -amino acids with a C-alpha-methyl substituent and a C-alpha-linear alkyl substituent are characterized by a strong tendency to fold into turn and helical structures.