Analysis of the isomerization of diketopiperazine consisting of proline and aromatic amino acid residues using nuclear magnetic resonance

Abstract

Under different concentrations of the base potassium deuteroxide KOD, the progress of reactions, such as enolization, D-substitution, isomerization, and conformational changes of diketopiperazine cyclo(L-Pro-L-Xxx) and cyclo(D-Pro-L-Xxx) (Xxx = Phe, Tyr) in D₂O solution, was investigated by ¹H nuclear magnetic resonance (NMR). Cyclo(L-Pro-L-Xxx) is mostly isomerized to cyclo(D-Pro-L-Xxx) in D₂O solution, whereas cyclo(D-Pro-L-Xxx) is only slightly isomerized to cyclo(L-Pro-L-Xxx) even under stronger basic conditions. After adding a deuterated organic solvent (CD₃COCD₃, CD₃SOCD₃ or CD₃OD) to a D₂O solution of cyclo(L-Pro-L-Xxx), cyclo(D-Pro-L-Xxx), or increasing the temperature of the D₂O solution, CH-π interaction between H₉ and the benzene ring of cyclo (D-Pro-L-Xxx) was stronger than that between H_8α and the benzene ring of cyclo(L-Pro-L-Xxx).