[Development of Novel Functional Molecules Based on the Molecular Structure Characteristics of Diketopiperazines]

Abstract

This article focuses on our investigation of the molecular structure characteristics of diketopiperazines (DKPs), and application of these findings to the development of novel functional molecules. DKPs bearing a benzyl moiety are known to adopt a folded conformation, in which the benzyl moiety is folded over the DKP ring. In order to investigate the driving force behind the folded conformation, we synthesized DKPs bearing a benzyl moiety with different para-substituents, and demonstrated that the folded conformation likely arose from intramolecular CH/π interactions, based on the electronic effects of para-substituents on the benzyl group in ¹H NMR spectroscopy. On the other hand, N4-methylation of DKPs bearing a benzyl moiety was found to change their folded conformation to an extended conformation, based on single crystal X-ray crystallography and ¹H NMR spectroscopy analysis. Next, we attempted to synthesize both hydroxamate-type siderophores containing the DKP ring: rhodotorulic acid and erythrochelin. Facile synthesis of rhodotorulic acid and its N,N'-dimethylated derivative was achieved by microwave-assisted cyclization of the corresponding dipeptide precursors. Interestingly, N,N'-dimethylated rhodotorulic acid was found to be more soluble in various organic solvents than rhodotorulic acid. Moreover, erythrochelin was synthesized for the first time, and its metal-chelating ability with not only Fe(III) but also Mg(II) was confirmed based on electrospray ionization mass spectrometry (ESI-MS) analysis. Finally, we synthesized DKPs bearing a primary amino group, and found that they could catalyze the asymmetric aldol reaction between hydroxyacetone and p-nitrobenzaldehyde.

Keywords: CH/π interaction; N-methylation; conformation; diketopiperazine; organocatalyst; siderophore.