4.2. Preparation of 6-Shogaol, 8-Shogaol, 10-Shogaol, 6-Paradol, 8-Paradol and 10-Paradol

Dry tetrahydrofuran (THF) was added to a flask with zingerone (1.0 equiv.) under inert atmosphere. The reaction was cooled to −78 °C; potassium tertiary butoxide (tBuOK, 2.5 equiv.) was added in a single portion, and the mixture was kept stirring for 1 h. For the preparation of each target compound, the corresponding aldehyde starting material (1.2 equiv.) was added slowly to the reaction mixture. The reaction was kept stirring for another 2 h and finally quenched by water. After extracting the mixture with dichloromethane, the organic part was evaporated under vacuum. The residue was purified by column chromatography using n-hexane/ethyl acetate (4:1) to afford the corresponding racemic gingerol. The synthesized gingerol racemate (1.0 equiv.) was dissolved in dry benzene followed by the addition of p-toluenesulfonic acid (0.4 equiv.). The mixture was refluxed for 1 h, then quenched by water. After extracting the mixture with dichloromethane, the organic layer was dried under vacuum. The residue was purified by column chromatography using n-hexane/ethyl acetate (4:1) as the solvent system to afford the corresponding shogaol.

For the synthesis of the three paradol derivatives, 6-, 8- or 10-shogaol (100.0 mg) was dissolved in 5 mL ethyl acetate. To this solution, 10% palladium on carbon (Pd/C, 82.0 mg) was added, and the mixture was degassed with hydrogen. The reaction was stirred under hydrogen atmosphere (1 atm) at room temperature for 12 h. After the reaction completion, the solution was filtered through a short pad of silica gel and washed with dichloromethane. The organic solvent was evaporated under vacuum, and the residue was purified by column chromatography eluted with n-hexane/ethyl acetate (4:1) to afford the corresponding paradol. The yield, purity, nuclear magnetic resonance data, ¹H NMR and ¹C NMR data for 6-shogaol, 8-shogaol, 10-shogaol, 6-paradol, 8-paradol and 10-paradol can be found in the Supplementary Materials.