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

Abstract

The Phe-incorporated cyclic peptide [cyclo(-Phe¹-oxazoline²-D-Val³-thiazole⁴-Ile⁵-oxazoline⁶-D-Val⁷-thiazole⁸-)] is in a conformational equilibrium between square and folded forms in solution. In the folded form, a CH⋯π interaction between the Phe¹ aromatic ring and the Oxz² methyl group is observed. We endeavored to control the local conformation and thus modulate the CH⋯π interaction and flexibility of the Phe¹ side chain by controlling the electronic substituent effects at the 4-position of the aromatic ring of the Phe¹ residue. The effect of the 4-substituent on the global conformation was indicated by the linear relationship between the conformational free energies (ΔG^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.