Synthesis of the tetracyclic core of Illicium sesquiterpenes using an organocatalyzed asymmetric Robinson annulation

Summary An enantioselective synthesis of the core framework of neurotrophic Illicium majucin-type sesquiterpenes is described here. This strategy is based on an organocatalyzed asymmetric Robinson annulation and provides an efficient approach for a diversity-oriented synthesis of Illicium natural products that holds remarkable therapeutic potential for neurodegenerative diseases.

S3 14: To a vigorous stirred solution of 8 [1,2] (10.0 g, 52.6 mmol) in glacial AcOH (20 mL), was added at room temperature a solution of ethane -1,2-dithiol (5.45 g, 57.8 mmol) and p-TsOH (1.71 g, 15.8 mmol) in glacial AcOH (40 mL). The mixture was stirred for 2 h and was quenched by water (100 mL). The solid was separated by filtration and washed with water (50 mL), with 10% aqueous solution of NaHCO 3 solution (50 mL), and with water (50 mL), and dried under reduced pressure. The crude product was then dissolved in EtOAc, rotavaped on silica and purified by a plug of silica (hexane/EtOAc = 100:5) to afford 14 as white crystals (12 g 4, 142.3, 132.8, 126.5, 118.8, 64.9, 51.1, 40.9, 39.9, 38.5, 37.8, 36.5, 26.6 PIFA (23.2 g, 54.0 mmol) was then added in small portions. Upon complete addition, the reaction was stirred at rt for an additional 15 minutes before Na 2 SO 3 (4.5 g, 36 mmol) was added. The reaction was stirred for 15 minutes and quenched by water (100 mL) and the excess solvent was removed under reduced pressure. The residue was extracted with CH 2 Cl 2 (3 × 100 mL) and the combined organic extracts were washed with brine and dried over Na 2 SO 4 . The solvent was then removed under reduced pressure and the crude product was purified by flash column chromatography (silica, hexane/EtOAc = 10:1) to afford enone 10 as 9:1 diastereomeric mixture at C-1 (4.5 g, 66% 3 steps  3, 172.3, 147.2, 136.4, 129.2, 116.5, 61.7, 58.8, 49.8, 47.6, 39.4, 36.8, 36.5, 35.7, 20.1, 13.9, 13 and water (4.5 mL). The reaction mixture was allowed to warm up to room temperature and stirred for an additional 15 minutes before anhydrous MgSO 4 was added and the mixture diluted with ether (30 mL). The mixture was stirred for 15 minutes before filtration through Celite ® and washed thoroughly with ether (200 mL). The solvent was then removed under reduce pressure and the crude diol was used in the next step directly.

S9
The crude diol was dissolved in DCM (30 mL) and was cooled to 0 °C. Imidazole (0.74 g, 10.8 mmol) was added followed by the addition of TBSCl (0.90 g, 6.0 mmol).
After 30 min, this reaction was quenched with saturated NH 4 Cl solution (200 mL), extracted with DCM (3 × 50 mL), washed with brine and dried over Na 2 SO 4 , then concentrated under reduced pressure. The crude mono-TBS-ether was used in the next step directly. The crude mono-TBS-ether was dissolved in dry DMSO (30 mL), IBX (4.6 g, 16.3 mmol) was added, and this reaction was heated to 80 °C for 1 h. Upon completion, the reaction was cooled to rt, water (50 mL) was added, the reaction was filtered through Celite ® , and the filtrates were extracted with EtOAc (3 × 50 mL). The combined organic extracts were then washed with brine, dried over Na 2 SO 4 , and concentrated under reduced pressure. The obtained residue was purified by silica flash column chromatography (hexanes/EtOAc = 100:1 to 20:1) to afford 19 as a yellow oil  150.9, 136.9, 127.1, 116.2, 69.3, 54.9, 49.4, 48.0, 39.3, 37.1, 36.1, 34.4, 26.1, 21.1, 21.5, 13.3, −5.5 to afford epoxide as a white solid. The product was used without future purification.
Epoxide obtained above (~0.7 g, 2.66 mmol) was dissolved in 1,4-dioxane (30 mL) and water (10 mL). To this solution 2,6-lutidine (0.63 mL, 5.4 mmol) and OsO 4 (0.17 mL, 4% solution in H 2 O, 27 µmol) were added, and then NaIO 4 (2.3 g, 10.8 mmol) was added portionwise at 0 °C. This reaction was then warmed up to rt and stirred overnight. The reaction was diluted with water (60 mL) and extracted with CH 2 Cl 2 (3 × 50 mL). The organic phase was dried over Na 2 SO 4 and concentrated under reduced pressure to afford the aldehyde as a white solid, which was clean enough to be used for the next reaction.
To a solution of the aldehyde obtained above (~0.7 g, 2.66 mmol) in acetone (20 mL) was added Jones reagent (2.3 mL, 6.2 mmol, 2.67 M) dropwise at 0 °C, and this reaction was stirred at 0 °C for 30 min. Ethanol (10 mL) was carefully added dropwise to quench this reaction, followed by dropwise addition of the saturated NaHCO 3 solution (10 mL).
The mixture was stirred for 5 min before filtration through Celite ® , and the filter cake was then washed thoroughly with EtOAc (100 mL). The combined organic extracts were dried over Na 2 SO 4 and concentrated under reduced pressure. The crude residue was purified by column chromatography (hexanes/CH 2 Cl 2 = 1:1 to 1:3 to 100% CH 2 Cl 2 , then