NMR studies on the conformation of aromatic cyclodipeptides with two non-identical L-aromatic amino-acid residues in solution: cyclo-[L-5(MeO)Trp-L-Tyr(Me)]

Abstract

The conformation of aromatic cyclodipeptides in solution is governed mainly by the interaction between the aromatic groups and the diketopiperazine ring. As a result, the aromatic groups in these molecules are folded over the DKP ring. In the case of cyclodipeptides containing two non-identical L-aromatic amino-acid residues, only one residue can be folded over the DKP ring. Thus, it is possible to study the relative strength of the interaction existing between the DKP ring and the different aromatic groups, by determining the conformation of these molecules in solutions. ¹H NMR conformation studies of cyclo-[L-5(MeO)Trp-L-Tyr(Me)](2), and cyclo-[L-5(MeO)Trp-Gly](3) in DMSO and DMF solutions are reported here. [Compound (3) serves as a model compound for cyclodipeptide molecules where the indole moiety of the 5(MeO)Trp residue is folded over the DKP ring]. The conformation analysis of (2) could be completed only by careful analysis of the results of the chemical shifts, the spin–spin coupling constants, and the NOE measurements. It was shown that the fractional populations of the side chain of the Trp and Tyr residues of (2), among the folded (F) and extended-to-nitrogen (E_n) conformers are approximately: 0.6, 0.4 and 0.4, 0.6 respectively. This conclusion implies the existence of a fast conformational equilibria (above room temperature) for each of the two residues between the F and E_n conformers. The study indicates, further, the sensitivity of conformational analysis of cyclodipeptides in solutions in determining the relative strength of the interaction between aromatic moieties and the DKP ring.