Synthesis of Analogues of Cercidin, an Antimicrobial Compound of Cercidiphyllum japonicum: Glycosylation of Methyl Gallate with Ulosyl Bromides

Background: Plant materials of Cercidophyllum japonicum, a tree native in East Asia, have long been used in Asian traditional medicine, owing to their antiinflammatory, antioxidative, antifungal, antimicrobial, and hair growth promoting activities. Pharmacologically interesting ingredients include a biphenyl phytoalexin, a galloylflavonol glycoside, anomeric tannins and flavonoids, and phenolic glycosides. Of the latter, cercidin 1 has antimicrobial activity and contains a glycosidic tricyclic structure with a central 1,4-dioxan ring which is also a key structural component of the antibiotic spectinomycin 2 and the cardenolide gomphoside 3. To date, no total synthesis of cercidin 1 has been reported and therefore its stereochemistry is still unknown. Methods: Reaction processes and products were detected on thin-layer chromatography (TLC). Preparative chromatographic separations were carried out on columns with Merck silica gel 60 (15-40 µm) as well as Merck precoated silica gel plates 60 F254, 20 × 20 cm, 0.25 mm. Structures were elucidated by NMR spectra, which were measured on a Bruker 300, 500 and 700 MHz spectrometer at 300 K. Mass spectra were run on a Varian MAT 311 and Bruker Impact II spectrometer. Results: We synthesized the tricyclic pyran-dioxan-benzene ring framework of 1 for the first time, thereby generating novel cercidin analogues. The configuration and conformation of these phenolic glycosides, 13 to 19 as well as 24, 28 and 29 were proven on the basis of ¹H and ¹³C NMR data. Conclusion: These novel cercidin analogues will enable future structure-activity-relationship studies and thus may contribute to the development of novel cercidin-based antibiotics.