Conformational analysis of homochiral and heterochiral diprolines as β- turn-forming peptidomimetics: Unsubstituted and substituted models

The effect of replacing one of the proline residues in either unsubstituted homochiral or heterochiral diproline segments with either a 2- or a 3-substituted prolyl residue on the allowed conformation of the diproline template has been examined. In heterochiral (L-D) diprolines, placement of a 2-methyl-n-proline residue in the i + 2 position and placement of either a cis- or trans-3-methyl-L-proline residue in the i + 1 position results in substituted diproline peptides that adopt the same type II β- turn conformation as that identified experimentally for the unsubstituted diproline peptides. In contrast, placement of a cis-3-methyl-D-proline residue in the i + 1 position of a homochiral (D-D) diproline peptide seems to promote a different conformation than that seen in the unsubstituted case, whereas the trans-3-methyl-D-proline residue seems to provide a stabilizing influence for the predicted type VI' β-turn. The demonstrated ability of certain substituted diproline templates to adopt predictable conformations coupled with the development of asymmetric synthetic routes to both 2- and 3- substituted prolyl residues capable of mimicking a variety of side chains should make these templates useful tools in designing specific turn mimics of biologically active molecules.