Catalytic asymmetric formal synthesis of beraprost

The first catalytic asymmetric synthesis of the key intermediate for beraprost has been achieved through an enantioselective intramolecular oxa-Michael reaction of an α,β-unsaturated amide mediated by a newly developed benzothiadiazine catalyst. The Weinreb amide moiety and bromo substituent of the Michael adduct were utilized for the C–C bond formations to construct the scaffold. All four contiguous stereocenters of the tricyclic core were controlled via Rh-catalyzed stereoselective C–H insertion and the subsequent reduction from the convex face.

The reaction mixture was filtered through a pad of Celite and the filtrate was evaporated under reduced pressure. The resulting mixture was extracted with EtOAc three times, and the combined organic layers were washed with brine, dried over Na 2 SO 4 , and concentrated under reduced pressure to give the crude allyl ether, which was used for the next reaction without further purification.
The crude ether (11.0 g) was dissolved in hexane (130 mL), and Et 2 AlCl (1.0 M in hexane, 53 mL, 53 mmol) was added at room temperature. After being stirred at the same temperature for 3.5 h, the reaction mixture was cooled to 0 °C and quenched by careful addition of 2N HCl (35 mL). The aqueous phase was then separated and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na 2 SO 4 , and concentrated under reduced pressure to afford 2-allyl-6-bromophenol (11, 12.7 g), which was directly subject to the next ozonolysis. A crude solution of 11 in MeOH (150 mL) was cooled to -78 °C, and O 3 gas was bubbled through the solution at -78 °C until the starting material had disappeared.
The reaction was quenched with Me 2 S (5.6 mL, 75.7 mmol), slowly warmed to room temperature before the addition of water (60 mL). The resulting mixture was stirred for 1 h and concentrated under reduced S5 pressure. The residue was diluted with EtOAc and washed with water. The organic layer was dried over Na 2 SO 4 and concentrated in vacuo to give the crude aldehyde as a mixture with the corresponding lactol, which seemed to be unstable on silica gel [3].

benzofuran-1-carboxylate (15)
To a crude of 14 (758.0 mg, 2.40 mmol) in CH 2 Cl 2 (20 mL) was added Rh 2 (OAc) 4 (10.6 mg, 1.0 mol %), and the resulting mixture was stirred at ambient temperature for 15 min, when TLC indicated the reaction S8 was complete. MeOH (10 mL) was then added, and NaBH 4 (271.9 mg, 7.19 mmol) was added portionwise -40 °C. The mixture was stirred at -40 °C for 2 h and at the ambient temperature for additional 2 h, before being quenched with saturated aqueous NH 4 Cl solution (20 mL). The organic materials were extracted with EtOAc three times, and the combined organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , and evaporated to give the crude residue, which was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (7/1) to afford 15 (

Acetal 16
To a solution of 15 (513.5 mg, 1.77 mmol) in Et 2 O (17 mL) was added LiBH 4 (115.6 mg, 5.31 mol), and the resulting mixture was stirred at ambient temperature for 9 h. The reaction was quenched with 1 N aqueous HCl solution (10 mL), and the organic materials were extracted with EtOAc three times. The combined extracts were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , and evaporated to afford the crude diol (367.9 mg), which was then dissolved in THF (16 mL). To this solution were added 1,1-diethoxyethane (2.5 mL, 17.6 mmol) and p-TsOHH 2 O (31.8 mg, 10 mol%), and the reaction mixture was stirred at 60 °C for 3 h before being quenched with saturated aqueous NaHCO 3 solution (15 mL

Bromide 17
To the solution of 16 (40.0 mg, 0.162 mmol) and NBS (34.7 mg, 0.195 mmol) in CCl 4 (2.5 mL) was added azobisisobutyronitrile (AIBN, 3.2 mg, 0.0195 mmol) at room temperature, and the mixture was heated under reflux for 3 h. The crude mixture was filtered through a pad of Celite, and the filtrate was concentrated to give the crude, which was then purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (10/1) to afford 17 (

1-carboxylate (21)
To a solution of 20 (376.0 mg, 0.986 mmol) in CH 2 Cl 2 (10 mL) was added Rh 2 (OAc) 4 (4.4 mg, 1.0 mol%), and the resulting mixture was stirred at ambient temperature for 15 min, when TLC indicated the reaction was complete. MeOH (5.0 mL) was added, and NaBH 4 (111.9 mg, 2.96 mmol) was added portionwise at -S11 mL). The organic materials were extracted with EtOAc three times, and the combined organic layer was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduce pressure to afford the crude residue, which was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (6/1) to afford 21 (

Acetal (22)
To a solution of 21 (467.7 mg, 1.32 mmol) in Et 2 O (10 mL) was added LiBH 4 (86.03 mg, 3.95 mol), and the resulting mixture was stirred at ambient temperature for 15 h. The reaction was quenched with 1 N aqueous HCl solution (20 mL), and the organic materials were extracted with EtOAc three times. The combined extracts were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure to afford the crude diol, which was then dissolved in THF (10 mL). To this solution, were added 1,1-diethoxyethane (1.5 mL, 10.5 mmol) and p-TsOHH 2 O (25.2 mg, 10 mol %), and the reaction mixture was stirred at 60 °C for 3 h, before being quenched with saturated aqueous NaHCO 3 solution (10 mL). The product was extracted with EtOAc three times, and the combined extracts were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , and evaporated to give the resulting crude residue, which was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (8/1) to afford 22  4, 131.8, 130.2, 123.0, 122.0, 102.9, 99.6, 84.4, 79.4, 70.6, 48.1, 46.0, 37.7, 20.6

Ester 23
To a solution of the acetal 22 (76.7 mg, 0.246 mmol) in THF (2.5 mL) was added TMEDA (0.04 mL 0.32 mmol) at -78 °C, and the reaction mixture was stirred for 10 minutes. To this solution was added a

S37
Cartesian coordinates and total energies for all the calculated structures