Reaction Steps
Hoveyda-Grubbs 2nd generation catalyst (22 mg, 0.035 mmol) was added to a stirred solution of (S)-1-{(S)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-[(S)-2-((2R,3R)-3-methoxy-2-methyl-hept-6-enoylamino)-3-methyl-butyrylamino]-prop ionyl}-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(3-vinyl-phenyl)-ethyl]-amide (276 mg, 0.35 mmol) in 1,2-dichloroethane (135 mL) and the reaction mixture was heated at 80° C. under nitrogen for 3 hours. The reaction mixture was cooled to room temperature, silica gel was added and the reaction mixture was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:1 to neat ethyl acetate to afford (E)-2R,5S,11S,14S,17R,18R)-11-[3-(tert-butyl-dimethyl-silanyloxy)-benzyl]-14-isopropyl-18-methoxy-2,17-dimethyl-3,9,12,15,28-pentaaza-tricyclo[21.3.1.1*5,9*]octacosa-1(27),21,23,25-tetraene-4,10,13,16-tetraone (59 mg, 22%) as a gum. LCMS (m/z) 762 [M+H], Tr=5.01 min. A solution of (E)-(2R,5S,11S,14S,17R,18R)-11-[3-(tert-butyl-dimethyl-silanyloxy)-benzyl]-14-isopropyl-18-methoxy-2,17-dimethyl-3,9,12,15,28-penta-azaricyclo[21.3.1.1*5,9*]octacosa-1(27),21,23,25-tetraene-4,10,13,16-tetraone (59 mg, 0.077 mmol) in tetrahydrofuran (5 mL) was stirred at 0° C. under nitrogen. A solution of tetra-N-butylammonium fluoride (1 M in tetrahydrofuran, 0.12 mL, 0.123 mmol) was added and the reaction mixture was stirred at 0° C. for 10 minutes. Silica gel was added and the solvent was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:3 to neat ethyl acetate. The residue was triturated with ether and the resulting solid was collected, washed with ether and dried to afford the title compound (30 mg, 60%) as a white solid. 1H NMR (300 MHz, CD3CN) δ0.94 (d, J=6.7 Hz, 3H), 0.95 (d, J=6.7 Hz, 3H), 1.30 (d, J=7.1 Hz, 3H), 1.45 (d, J=6.9 Hz, 3H), 1.55-2.20 (m, 9H), 2.62-2.68 (m, 2H), 2.81-2.98 (m, 2H), 3.26-3.38 (m, 2H), 3.45 (s, 3H), 3.96 (d, J=12.2 Hz, 1H), 4.17 (t, J=8.0 Hz, 1H), 4.34-4.39 (m, 1H), 4.80-4.90 (m, 1H), 5.50-5.56 (m, 1H), 5.85 (d, J=15.8 Hz, 1H), 6.01-6.08 (m, 1H), 6.66-6.69 (m, 1H), 6.86-7.30 (m, 10H), 8.15-8.25 (br s, 1H). LCMS (m/z) 648 [M+H], Tr=4.30 min.
