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 theseˆndings 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 diŠerent para-substituents, and demonstrated that the folded conformation likely arose from intramolecular CH/p interactions, based on the electronic eŠects of para-substituents on the benzyl group in 1 H 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 1 H 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 theˆrst time, and its metal-chelating ability with not only Fe(III) but also Mg(II) was conˆrmed 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.