Reaction Steps
THF (2 mL) was added to cerium(III) chloride (0.130 g, 0.527 mmol). The suspension was warmed to about 50° C. for about 30 min then cooled to about −78° C. A solution of methylmagnesium bromide (3.0 M solution in Et2O, 0.165 mL, 0.495 mmol) and THF (2 mL) was added dropwise and the reaction mixture was stirred for about 15 min. A solution of rac-(4aS,12bR,E)-2-benzylidene-12b-ethyl-9-(4-fluorophenyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3 (2H)-one (53, R1=4-Fluorophenyl, R2=Ethyl) (0.100 g, 0.215 mmol) and THF (2 mL) was added dropwise via syringe and the reaction was stirred at about −78° C. for about 1 h. Methylmagnesium bromide (3.0 M solution in Et2O, 0.16 mL, 0.48 mmol) was added. After about 1 h, methylmagnesium bromide (3.0 M solution in Et2O, 0.1 mL, 0.3 mmol) was added. After about 1 h, the reaction was quenched with MeOH (1 mL) maintaining an internal temperature of less than about −60° C. Sat. aq. NH4Cl (2 mL), water (2 mL), and EtOAc (20 mL) were added and the mixture was allowed to warm to rt. EtOAc (50 mL) and water (20 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (25 g) using a gradient of 0-10% EtOAc in heptane. The product fractions were combined and concentrated under reduced pressure to give rac-(3R,4aS,12bR,E)-2-benzylidene-12b-ethyl-9-(4-fluorophenyl)-3-methyl-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (54, R1=4-Fluorophenyl, R2=Ethyl, R3=Methyl) (0.057 g. 55% yield); LC/MS, method 3, Rt=3.16 min.; MS m/z: 481 (M+H)+. 1H NMR (400 MHz, DMSO) δ 7.76-7.70 (m, 2H), 7.64 (s, 1H), 7.62-7.55 (m, 2H), 7.46 (s, 1H), 7.43-7.35 (m, 5H), 6.86 (s, 1H), 6.80 (s, 1H), 4.57 (s, 1H), 3.63-3.53 (m, 1H), 3.06-2.86 (m, 2H), 2.36-1.99 (m, 4H), 1.81-1.61 (m, 2H), 1.61-1.42 (m, 3H), 1.39 (s, 3H), 1.30-1.22 (m, 1H), 0.51 (t, J=7.3 Hz, 3H).
