1. Chromium trioxide (11 g, 110 mmol) was slowly added to acetic anhydride (100 mL) at 0 °C and stirred until the solution was orange in color. Subsequently, raw material (1S,3aS,4aR,4bR,6aR,11aR,11bR,13aS)-1-(furan-3-yl)-4b,7,7,11a,13a-pentamethyl-6,6a,7,11a,11b,12,13,13a-octahydroxepino[4',3':3,4]benzo[1,2-f]oxirane[2, 3-d]isochromene-3,5,9(1H,3aH,4bH)-trione (45 g, 99.1 mmol) and the reaction temperature was raised to 60°C for 3 hours. The progress of the reaction was monitored by TLC (PE:EA = 2:1). Upon completion of the reaction, the reaction solution was concentrated and the concentrate was separated with ethyl acetate (200 mL) and water (200 mL). The organic phase was dried with magnesium sulfate and concentrated.
2. The resulting intermediate 2 (46.0 g, 98.2 mmol) was dissolved in tetrahydrofuran (200 mL) and methanol (20 mL). Sodium borohydride (6.0 g, 150 mmol) was added slowly at 0 °C and the reaction was monitored by TLC (PE:EA = 1:1) until completion. The reaction solution was concentrated and extracted with ethyl acetate (200 mL) and the organic phase was washed sequentially with saturated sodium bicarbonate (100 mL), water (100 mL) and saturated brine (100 mL). After drying, it was concentrated and purified by fast silica gel column, the eluent was petroleum ether (PE):ethyl acetate (EA) = 1:1 to obtain Intermediate 3 (33.0 g, 70.2 mmol).
3. Intermediate 3 (33.0 g, 70.2 mmol) was dissolved in tetrahydrofuran (100 mL) and a methanol (100 mL) solution of lithium hydroxide (2.4 g, 100 mmol) was added. The reaction was stirred for 3 h at room temperature and monitored by TLC (PE:EA = 1:1). After completion of the reaction, the pH was adjusted to 5-6 and extracted with ethyl acetate (2 x 100 mL). The organic phases were combined, dried over magnesium sulfate and concentrated to give crude intermediate 4 (24.0 g, 71% yield).
4. Intermediate 4 (24.0 g, 49.2 mmol) was mixed with DE (10.5 g, 60.0 mmol) and triphenylphosphine (15.7 g, 60.0 mmol) in anhydrous tetrahydrofuran (300 mL) under nitrogen protection and stirred for 16 hours at room temperature. The reaction was monitored by TLC (PE:EA = 1:1). After completion of the reaction, it was washed with saturated brine (3 x 50 mL). The organic phase was dried and concentrated and purified by fast silica gel column with eluent of petroleum ether (PE):ethyl acetate (EA) = 2:1 to give Intermediate 5 (18.0 g, 78% yield).
5. Intermediate 5 (18.0 g, 38.3 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL) and borane tetrahydrofuran solution (50 mL, 1 M THF solution, 50 mmol) was added slowly and dropwise. After stirring for 16 h, H2O2 (50 mL) and saturated sodium bicarbonate solution (50 mL) were added and the reaction was continued for 2 h at room temperature. The reaction solution was separated and the aqueous phase was extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, dried and concentrated, and then purified by fast silica gel column with the eluent of petroleum ether (PE):ethyl acetate (EA) = 4:1 to give Intermediate 6 (11.0 g, 58% yield).
6. Intermediate 6 (11.0 g, 22.5 mmol), DE (5.9 g, 33.8 mmol) and triphenylphosphine (8.9 g, 33 mmol) were dissolved in anhydrous tetrahydrofuran (300 mL) under nitrogen and reduced pressure and stirred for 16 h at room temperature. The reaction was monitored by TLC (PE:EA = 1:1). After completion of the reaction, it was washed with saturated brine (3 x 50 mL). The organic phase was dried and recrystallized by ethanol to give the final product citracin (8.0 g, 76% yield).
