Cis-trans peptide-bond isomerization in α-methylproline derivatives

Abstract

α-Methyl-L-proline is an α-substituted analog of proline that has been previously employed to constrain prolyl peptide bonds in a trans conformation. Here, we revisit the cis-trans prolyl peptide bond equilibrium in derivatives of α-methyl-L-proline, such as N-Boc-protected α-methyl-L-proline and the hexapeptide H-Ala-Tyr-αMePro-Tyr-Asp-Val- OH. In Boc-α-methyl-L-proline, we found that both cis and trans conformers were populated, whereas, in the short peptide, only the trans conformer was detected. The energy barrier for the cis-trans isomerization in Boc-α-methyl-L-proline was determined by line-shape analysis of NMR spectra obtained at different temperatures and found to be 1.24kcal/mol (at 298K) higher than the corresponding value for Boc-L-proline. These findings further illuminate the conformationally constraining properties of α-methyl-L-proline. Copyright © 2012 Verlag Helvetica Chimica Acta AG, Zürich, Switzerland.