Reaction Steps
A solution of (3aR,5R)-5-[(benzyloxy)methyl]-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (P1) (10.0 g, 40.4 mmol) in toluene (404 mL) was cooled down to −78° C. and then boron trifluoride-diethyl etherate (46.5%, 10.8 mL, 40.8 mmol) was added. The resulting solution was allowed to stir at the same temperature for 30 minutes, with fast stirring. After that time, 4-bromo-1-fluoro-2-iodobenzene (12.3 g, 40.8 mmol) was added to the reaction mixture, followed by the slow addition (temperature never varied more than 5° C.) of n-butyllithium (2.5 M in hexanes; 16.3 mL, 42.7 mmol). The resulting solution was allowed to stir at −78° C. for 90 minutes. At this time, a saturated aqueous solution of ammonium chloride (20 mL) was added to the reaction mixture at −78° C. The reaction mixture was warmed to room temperature and partitioned between ethyl acetate (400 mL) and water (800 mL). The organics were separated and the aqueous layer was extracted with additional ethyl acetate (3×200 mL). The combined organics were then washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to yield a clear oily residue. Purification via silica gel chromatography (Gradient: 10% to 70% ethyl acetate in heptane) afforded the product as an orange solid. Yield: 11.5 g, 27.1 mmol, 67%. 1H NMR (400 MHz, CD3OD) δ 8.01 (dd, J=6.9, 2.6 Hz, 1H), 7.47 (ddd, J=8.8, 4.4, 2.7 Hz, 1H), 7.38-7.28 (m, 4H), 7.07 (dd, J=11.6, 8.7 Hz, 1H), 4.58 (s, 2H), 4.10 (dd, J=11.6, 2.4 Hz, 1H), 3.82-3.78 (m, 2H), 3.72 (d, J=7.2 Hz, 1H), 3.61-3.55 (m, 2H), 3.52 (dd, J=8.8, 4.7 Hz, 1H), 3.16-3.10 (m, 1H), 1.86 (ddd, J=14.1, 7.0, 2.2 Hz, 1H), 1.59 (dtd, J=13.7, 11.8, 1.7 Hz, 1H).
