Synthesis of Dodecagalloyl-α-D-Xylose

The synthetic routes of the α12G are illustrated in Scheme 1. A detailed description of synthesis is in the Supplementary Materials. The intermediate 5 was prepared in a four-step reaction starting from gallic acid. Gallic acid was esterified under sulfuric acid/methanol to afford methyl 3,4,5-trihydroxybenzoate (1). The adjacent two phenol groups were protected with α,α-dichlorodiphenylmethane to obtain intermediate 2. The remaining free phenol group was then reacted with allyl bromide to give the fully protected monogalloyl motif 3. The methyl ester was saponified to produce compound 4. The carboxylic compound was reacted with oxalyl chloride to give acyl chloride 5, which was submitted to the next step within a short time. The digallic acid 11 was prepared in a six-step process starting from compound 5. Compound 5 was reacted with tert-butoxide to provide the tert-butyl ester 6. The allyl group was then deprotected with tetrakis(triphenylphosphine)palladium and aniline to afford compound 7. A coupling reaction between 7 and 4 under mild, non-acidic Steglich conditions gave the digalloyl motif 8. The compound was then submitted to palladium-catalyzed cleavage of allyl ether, giving compound 9. The free phenol group was protected with benzyl bromide to provide compound 10. The removal of the tert-butyl ester protecting group in the presence of a high concentration of formic acid afforded fully protected digallic acid 11. To synthesize tetragalloyl-α-D-xylose 12, α-D-(+)-xylose was acylated with acyl chloride 5 using pyridine as the base. After removing the allyl protecting groups from the four galloyl moieties, the installation of intermediate 11 was performed under Steglich conditions, providing the fully protected dodecagalloyl-α-D-xylose 14. Finally, the simultaneous removal of both diphenylmethylene ketals and benzyl groups under hydrogenolytic conditions in tetrahydrofuran at room temperature yielded the desired dodecagalloyl-α-D-xylose (α12G).