A method for stabilizing the cis prolyl peptide bond: influence of an unusual n→π∗ interaction in 1,3-oxazine and 1,3-thiazine containing peptidomimetics

The cis/trans isomer ratios of the Xaa-Pyr (Pyr = pyrrolidine) 3° amide bonds are significantly high (∼90% cis) in the novel peptidomimetics where Pyr contains 1,3-oxazine (Oxa) or 1,3-thiazine (Thi) at its 2 position. We find that an unusual n→πi−1∗ interaction, selectively stabilizes the cis conformer and the n)(n repulsion destabilizes the trans conformer of these molecules. Both these electronic effects oppose the steric effects in the 3° amide bond. The structural requirements for manifestation of these electronic effects are determined.