Electronic substituent effect on the conformation of a phenylalanine-incorporated cyclic peptide.

The Phe-incorporated cyclic peptide [cyclo(-Phe 1 -oxazoline 2 -d-Val 3 -thiazole 4 -Ile 5 -oxazoline 6 -d-Val 7 -thiazole 8 -)] is in a conformational equilibrium between square and folded forms in solution. In the folded form, a CH⋯π interaction between the Phe 1 aromatic ring and the Oxz 2 methyl group is observed. We endeavored to control the local conformation and thus modulate the CH⋯π interaction and flexibility of the Phe 1 side chain by controlling the electronic substituent effects at the 4-position of the aromatic ring of the Phe 1 residue. The effect of the 4-substituent on the global conformation was indicated by the linear relationship between the conformational free energies (Δ G o ) determined through NMR-based quantification and the Hammett constants ( σ ). Electron-donating substituents, which had relatively strong CH⋯π interactions, promoted peptide folding by restraining the loss in entropy. Local control by the 4-substituent effects suggested that the Phe side chain exerts an entropic influence on the folding of these cyclic peptides.