Influence of Stereochemistry of the Preceding Acyl Residue on the cis/trans Ratio of the Proline Peptide Bond

Naturally occurring amino acids form predominantly trans peptide bonds, with the exception of proline whose ability to form cis peptide bonds and undergo cisltrans isomerization is well known [1]. The isomerization barrier of the acyl-Pro bond in proline containing molecules is lowered from ca 20 kcal/mol to ca 13 kcal/mol due to concomitant pyrrolidine puckering changes; additionally, the trans bond, involving a nitrogen atom of the pyrrolidine ring, is favored only slightly (ca 2 kcal/mol) over the cis bond [2]. Here we report the synthesis, X-ray structure analysis, and NMR conformational study of 1 and the corresponding diastereomer 2, providing evidence that the (2S)-2,6-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-carbonyl moiety constrains the acyl-Pro bond of 1 to trans.