Triethylamine → 3-{2(s)-Biphenyl-4-yl-3-cyclopentyl-propionyl}-4(s)-isopropyl-oxazolidin-2-one

Beteiligte Stoffe

Reaktionsbedingungen

Reaktionsschritte

A solution of 2-biphenyl-4-yl-3-cyclopentylpropionic acid (prepared in Example 1A, 1.12 g, 3.80 mmol) in dry tetrahydrofuran (36 mL) under nitrogen was cooled to −78° C. and then treated with triethylamine (606 mL, 4.35 mmol). The reaction mixture was stirred at −78° C. for 15 min and then treated dropwise with trimethylacetyl chloride (491 mL, 3.98 mmol). The resulting reaction mixture was stirred at −78° C. for 15 min, at which time, the cooling bath was removed, and the reaction mixture was allowed to warm to 25° C. where it was stirred for 45 min. At this time, the reaction mixture was cooled back to −78° C. for the addition of the chiral auxiliary. Into a separate reaction flask, a solution of (4S)-(−)-4-isopropyl-2-oxazolidinone (467.9 mg, 3.62 mmol) in dry tetrahydrofuran (18 mL) under nitrogen was cooled to −78° C. and then treated with a 2.5M solution of n-butyllithium in hexanes (1.6 mL, 3.80 mmol). After complete addition of the n-butyllithium, the reaction mixture was allowed to warm to 25° C. where it was stirred for 1 h. This cloudy white solution was then added dropwise by syringe to the previously cooled (−78° C.) pivalate solution. The resulting reaction mixture was stirred at −78° C. for 1 h and then allowed to gradually warm to 25° C. The reaction mixture was stirred at 25° C. for 15 h. The resulting reaction mixture was quenched with a saturated aqueous sodium bisulfite solution and concentrated in vacuo to remove tetrahydrofuran. The resulting aqueous residue was diluted with ethyl acetate (150 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 19/1 to 17/3 hexanes/ethyl acetate gradient elution) afforded the higher Rf product 3-{2(S)-biphenyl-4-yl-3-cyclopentyl-propionyl}-4(S)-isopropyl-oxazolidin-2-one (679.2 mg, 92%) as a yellow oil: EI-HRMS m/e calcd for C26H31NO3 (M+) 405.2304, found 405.2310; and the lower Rf product 3-{2(R)-biphenyl-4-yl-3-cyclopentyl-propionyl}-4(S)-isopropyl-oxazolidin-2-one (127.4 mg, 17%) as a yellow oil: EI-HRMS m/e calcd for C26H31NO3 (M+) 405.2304, found 405.2313.

Herkunft & Nachweise