Diisopropylamine → (1R,5R,6R)-6-fluoro-bicyclo[3.1.0]hex-2-ene-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester

Participants

Reaction Conditions

Reaction Steps

A 2.47 M hexane solution of butyl lithium in an amount of 28.8 mL was added to a solution of 7.83 g of diisopropylamine dissolved in 84 mL of tetrahydrofuran, which was cooled to 0° C. The solution was stirred for 15 minutes, followed by cooling to −62° C. Subsequently, a solution of 12.0 g of ethyl (1R,5R,6R)-6-fluoro-2-oxo-bicyclo[3.1.0]hexane-6-carboxylate dissolved in 40 mL of tetrahydrofuran was added dropwise thereto, while being maintained at −62 to −58° C. One hour later, a solution of 25.3 g of N-phenyl-bis(trifluoromethanesulfonimide) dissolved in 84 mL of tetrahydrofuran was added dropwise thereto over 15 minutes, while maintained at −62 to −60° C. The reaction solution was allowed to naturally warm to room temperature, and was further stirred for one hour. The reaction was quenched with a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with diethyl ether. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and was subsequently dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200 (produced by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=20:1). Immediately, the produced ethyl (1R,5R,6R)-6-fluoro-2-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hex-2-ene-6-carboxylate was dissolved in 195 mL of N,N-dimethylformamide, and 389 mg of palladium acetate, 910 mg of triphenylphosphine, and 12.5 g of benzyl alcohol were added thereto, followed by addition of 11.7 g of triethylamine. Subsequently, the mixture was stirred under a carbon monoxide atmosphere for 4.5 hours at room temperature. 1M hydrochloric acid was added to the reaction mixture, followed by extractions with diethyl ether twice. The organic layers were combined, and the combined organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200 (produced by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=10:1 to 1:1), thereby yielding 6.42 g of (1R,5R,6R)-6-fluoro-bicyclo[3.1.0]hex-2-ene-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester.

Provenance & Evidence