cis‐trans Peptide‐Bond Isomerization in α ‐Methylproline Derivatives

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‐ α MePro‐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 1.24 kcal/mol (at 298 K) higher than the corresponding value for Boc‐ L ‐proline. These findings further illuminate the conformationally constraining properties of α ‐methyl‐ L ‐proline.