Reaction Steps
Tert-butyl (1S,2S,5R,9S)-2-(4-hydroxyphenyl)bicyclo[3.3.1]nonan-9-ylcarbamate 80A (40.5 mg, 0.11 mmol) in DMF (1 ml) was treated with NaH (12 mg, 0.3 mmol). After stirring at ambient temperature for 5 minutes, compound 2C (63 mg, 0.1 mmol) was added and stirring was continued for 1.5 hours. HCl (4N HCl in dioxane) (2.5 ml, 10 mmol) was added and the mixture was stirred overnight at room temperature and then at 60° C. for 6 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was slurried with 1N HCl, filtered, rinsed with water, slurried in Et2O, filtered and rinsed with additional Et2O. The solid was purified by column chromatography on silica gel using a gradient of 0 to 5% MeOH in CH2Cl2. The solid was dissolved in dioxane (2 ml), treated with NaOH (4N aqueous) (0.25 mL, 1 mmol) and stirred overnight at rt. The reaction mixture was acidified with 1N HCl to induce precipitation of the product. The solid was filtered, rinsed with water, slurried in Et2O, filtered and rinsed with additional Et2O. The solid was purified by HPLC (Preparative reverse phase HPLC was performed on an automated Gilson HPLC system, using a SymmetryPrep Shield RP18 prep cartridge, 250 mm×21.20 mm i.d., 10 um, and a flow rate of 25 mL/min; λ=214, 245 nm; mobile phase A, 0.1% TFA in H2O; mobile phase B, CH3CN; linear gradient 20-90% of B in 40 min) to provide the title compound 80 in 7% yield as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.85 (1H, s), 12.50 (1H, s), 8.03 (1H, d), 7.97 (2H, d), 7.97 (1H, d), 7.47 (2H, m), 7.37 (2H, m), 7.13 (2H, d), 6.88 (2H, m), 4.83 (2H, s), 3.95 (2H, t), 3.72 (2H, t), 3.17 (2H, m), 3.02 (2H, m), 2.19 (2H, m), 1.98 (5H, m), 1.80 (5H, m), 1.59 (2H, m), 1.40 (3H, m). MS (ESI(+)) m/e 708 (M+H).
