Reaction Steps
A 2.50 M solution of n-butyllithium in hexane (197 mL, 0.493 mol, 1.90 equiv.) was added dropwise to a solution containing 1-bromo-2,3-difluorobenzene (95.1 g, 0.493 mol, 1.90 equiv.) in THF/toluene (100 mL/1000 mL) under a nitrogen atmosphere at −75 to −69° C. After 10 min, boron trifluoride-diethyl etherate complex (62.5 mL, 0.493 mol) was added dropwise while maintaining temperature below −71° C. A previously prepared solution of (3aR*,4S*)-4-((trityloxy)methyl)-3,3a,4,6-tetrahydrofuro[3,4-c]isoxazole (100 g, 0.259 mol, 1.0 equiv.) in THF (400 mL) was added while maintaining the temperature below −70° C. After stirring at the −75° C. for 1.5 h, saturated aq. NH4Cl (300 mL) and water (100 mL) were slowly added (over 5 min) to the reaction solution. 2-methoxy-2-methylpropane (300 mL) was added and the reaction was allowed to warm up to 0° C. The organic phase was isolated and washed with 27% aq NaCl solution (200 mL). The organic layer concentrated under reduced pressure and recrystallised from THF (200 mL)/isopropyl alcohol (700 mL). Title compound (87.5 g) was isolated. 1H NMR (500 MHz, DMSO) δ ppm 7.42-7.33 (m, 8H), 7.31 (t, J=7.6 Hz, 6H), 7.28-7.21 (m, 3H), 7.20-7.12 (m, 1H), 6.39 (s, 1H), 4.13 (d, J=8.2 Hz, 1H), 4.03 (s, 1H), 3.97 (s, 1H), 3.89 (d, J=9.2 Hz, 1H), 3.81-3.70 (m, 1H), 3.36-3.29 (m, 1H), 3.26 (dd, J=10.1, 6.0 Hz, 1H), 3.15 (dd, J=10.0, 3.5 Hz, 1H); 13C NMR (125 MHz, DMSO) δ ppm 150.74 (dd, JCF=246.4, 14.4 Hz), 148.66 (dd, JCF=248.3, 13.5 Hz), 144.09, 130.58, 128.67, 128.32, 127.48, 124.75, 124.45, 117.18 (d, JCF=17.0 Hz), 86.57, 84.91, 78.16, 76.81, 64.82, 56.46.
