Total synthesis of the proposed structure of astakolactin

The first total synthesis of the proposed structure of astakolactin, a sesterterpene metabolite isolated from the marine sponge Cacospongia scalaris, has been achieved, mainly featuring Johnson–Claisen rearrangement, asymmetric Mukaiyama aldol reaction and MNBA-mediated lactonization.

The mixture was extracted with diethyl ether and dried over Na 2 SO 4 . After evaporation of the solvent, the crude product was purified by preparative TLC on silica gel (chloroform/methanol/formic acid = 9/1/1) to afford the seco-acid 2 (25 mg, 97%). To a solution of MNBA (14 mg, 0.04 mol) and DMAP (23 mg, 0.19 mmol) in dichloromethane (25 mL) at room temperature was slowly added a solution of the seco-acid 2 (13 mg, 0.03 mol) in dichloromethane (6.2 mL) with a mechanically driven syringe over a 12 h period. After cooling to 0 °C, saturated aqueous sodium hydrogencarbonate was added. The mixture was extracted with dichloromethane, and the organic layer was washed with brine and water, dried over sodium sulfate. After evaporation of the solvent, the crude product was purified by thin layer chromatography on silica gel (hexane/ethyl acetate = 2/1) to afford 1 (9 mg, 71%).
General procedure for the synthesis of 1 using Yamaguchi lactonization. To a solution of 2 (5.5 mg, 13 mol) and Et 3 N (2 L, 14 mol) in THF (0.5 mL) was added 2,4,6-trichlorobenzoyl chloride (3.2 mg, 13 mol) in THF (0.5 mL) at room temperature. After stirring for 2 h, the mixture was added to a solution of DMAP (9.5 mg, 78 mol) in dichloromethane (4.0 mL) with a mechanically driven syringe over a 12 h period. After cooling to 0 °C, saturated aqueous sodium hydrogencarbonate was added.
After evaporation of the solvent, the crude product was purified by preparative TLC on silica gel

Preparation of alcohol 13
Alcohol 13 was prepared from (E,E)-farnesol according to the literature 2 with modification as shown below.
To a solution of the crude product obtained in methanol (45 mL) at 0 °C was added a 6 M aqueous solution of KOH (3.7 mL, 22.2 mmol). The mixture was stirred for 1.5 h at room temperature, and then quenched with water. The mixture was extracted with dichloromethane and dried over Na 2 SO 4 .
After a stirring for 2 h, diethyl ether was added. The organic layer was separated and washed with saturated aqueous sodium hydrogencarbonate and water, and dried over anhydrous Na 2 SO 4 . After evaporation of the solvent, the crude product was obtained, which was used in the next step without further purification.
To a solution of the crude product obtained in ethanol (42 mL) at 0 °C was added NaBH 4 (1.2 g, 31.3 mmol). After a stirring for 1.5 h, the reaction mixture was quenched by addition of saturated aqueous NH 4 Cl and extracted with diethyl ether. The organic layer was separated and dried over Na 2 SO 4 . After evaporation of the solvent, the crude product was purified by column chromatography on silica gel (hexane/ethyl acetate = 5/1) to afford the title compound

3-(Bromomethyl)furan:
In a similar mannar as described before, 3 to a solution of furan-3-ylmethanol (0.43 mL, 5.0 mmol) in 5 mL of THF at 0 °C was added 0.25 mL of phosphorous tribromide (PBr 3 ) (7.46 M in hexane). After a stirring for 1 h at 0 °C, the reaction mixture was purified by flash column chromatography on silica gel (hexane/ethyl acetate = 10/1) to afford the desired bromide (0.75 g, 93%), which was instantly used in the next reaction.