2,2,6,6-Tetramethylpiperidine → (3aR,4S,6aS)-6a-(3-chloro-2,4-difluorophenyl)-4-((trityloxy)methyl)hexahydrofuro[3,4-c]isoxazole

Participants

Reaction Conditions

Reaction Steps

A stirred solution of 2,2,6,6-tetramethylpiperidine (1.31 mL, 7.78 mmol) in dry THF (20 mL) under nitrogen was cooled in an acetone/dry ice cooling bath. n-Butyl lithium (2.5 M in hexanes, 3.11 mL, 7.78 mmol) was added to this solution such that the internal temperature remained below −75° C. The pale yellow solution was stirred at this temperature for 15 minutes before the addition of a solution of 2-chloro-1,3-difluoro-benzene (0.86 mL, 7.78 mmol) in dry THF (2 mL). The solution was stirred for an additional 30 minutes at −78° C. before the addition of a solution of (3aR,4S)-4-((trityloxy)methyl)-3,3a,4,6-tetrahydrofuro[3,4-c]isoxazole (1.5 g, 3.89 mmol) in dry THF (12 mL). The reaction was stirred at −78° C. After 60 min, the reaction was quenched with saturated aqueous ammonium chloride and then removed from the cooling bath. The mixture was partitioned between EtOAc and water and the layers were separated. The aqueous layer was extracted with EtOAc (3×). The combined organic extracts were washed with brine (1×), then dried over (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (normal phase, 50 g, Biotage SNAP cartridge KP-Sil, 50 mL per min, gradient 5% to 20% to 30% EtOAc in n-hexane) to give the title compound (712 mg). 1H NMR (400 MHz, CDCl3) δ ppm: 3.23-3.35 (m, 2 H) 3.47 (dd, J=9.84, 6.42 Hz, 1 H) 3.86 (dd, J=8.31, 3.79 Hz, 1 H) 3.91 (dd, J=10.33, 1.90 Hz, 1 H) 4.08-4.20 (m, 2 H) 4.22-4.33 (m, 1 H) 6.92-7.00 (m, 1 H) 7.20-7.36 (m, 9 H) 7.41-7.48 (m, 6 H) 7.57-7.67 (m, 1 H).

Provenance & Evidence