Reaction Steps
n-Butyllithium (2.5 M solution in hexanes, 11.3 mL, 28.3 mmol) was added in a drop-wise manner to a solution of 1-fluoro-2-iodobenzene (3.30 mL, 28.3 mmol) in a mixture of tetrahydrofuran (26 mL) and toluene (116 mL) at −78° C., and the reaction mixture was stirred at this temperature for 30 minutes. In a separate flask, a solution of (3aR,5R)-5-[(benzyloxy)methyl]-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (P1) (3.50 g, 14.2 mmol) in toluene (116 mL) was cooled to −78° C. and treated with boron trifluoride diethyl etherate (3.49 mL, 28.3 mmol); this mixture was also allowed to stir at −78° C. for 30 minutes, and then added via cannula over three to four minutes to the aryllithium solution. The reaction mixture was stirred at −78° C. for approximately 30 minutes and was then quenched with saturated aqueous ammonium chloride solution. The mixture was extracted three times with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 20% ethyl acetate in heptane) provided the product as a yellow oil. Yield: 4.39 g, 12.8 mmol, 90%. The stereochemical outcome of this reaction (cis ring fusion) was established via single crystal X-ray analysis of intermediate C17 (see data below). LCMS m/z 344.5 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.50-1.61 (m, 1H), 1.82-1.90 (m, 1H), 3.10-3.18 (m, 1H), 3.50 (dd, half of ABX pattern, J=10.3, 4.1 Hz, 1H), 3.55-3.60 (m, 2H), 3.72 (br d, J=7.2 Hz, 1H), 3.85-3.93 (m, 2H), 4.20 (dd, J=12.7, 1.8 Hz, 1H), 4.61 (AB quartet, JAB=12.1 Hz, ΔνAB=22.5 Hz, 2H), 7.04 (ddd, J=12.1, 8.2, 1.2 Hz, 1H), 7.17 (ddd, J=7.8, 7.4, 1.4 Hz, 1H), 7.26-7.40 (m, 6H), 7.95 (ddd, J=8.1, 8.0, 1.8 Hz, 1H).
