N-((1S)-1-{[((1S)-3-Chloro-2-oxo-1-{[(3S)-2-oxopyrrolidin-3-yl]methyl}propyl)amino]carbonyl}-3-methylbutyl)-4-methoxy-1H-indole-2-carboxamide (12)
A solution of 29, N2-(tert-butoxycarbonyl)-N1-((1S)-3-chloro-2-oxo-1-{[(3S)-2-oxopyrrolidin-3-yl]methyl}propyl)-l-leucinamide (244 mg, 0.59 mmol) in 1,4-dioxane (1.0 mL) was placed under an atmosphere of N2. This clear colorless solution was treated with a solution of 4 M hydrochloric acid in 1,4-dioxane with no observable change. The reaction gradually became opaque with the formation of a gummy precipitate. After 2 h, the volatiles were removed in vacuo, diluted with 1:1 ethanol/1,4-dioxane, concentrated, and high-vacuum-dried to give N1-((1S)-3-chloro-2-oxo-1-{[(3S)-2-oxopyrrolidin-3-yl]methyl}propyl)-l-leucinamide hydrochloride as an off-white solid. 1H NMR (DMSO-d6) δ 9.18 (d, J = 8 Hz, 1H), 8.40 (bs, 3H), 7.69 (s, 1H), 4.68 (s, 2H), 4.49 (m, 1H), 3.81 (m, 1H), 3.15 (m, 2H), 2.37 (m, 1H), 2.17 (m, 1H), 1.92 (m, 1H), 1.67 (m, 3H), 1.55 (m, 2H), 0.92 (d, J = 4 Hz, 3H), 0.88 (d, J = 4 Hz, 3H); MS (ESI+) for C14H24ClN3O3m/z 318.1 (M + H)+.
A solution of the crude hydrochloride salt and 4-methoxy-1H-indole-2-carboxylic acid (123 mg, 0.64 mmol) in DMF (2.5 mL) was placed under an atmosphere of N2 and cooled to 0 °C. This pale yellow solution was successively treated with HATU (245 mg, 0.64 mmol) and N-methylmorpholine (0.14 mL, 1.29 mmol) turning a brighter color. After 30 min, the reaction was quenched with 1:1 ice/sat NaHCO3 (25 mL) and extracted three times with ethyl acetate (20 mL). The combined organics were washed once with brine (30 mL), dried over MgSO4, filtered, and concentrated to give a yellow syrup. This material was purified by LC (30 g 230–400 SiO2, 4% methanol/chloroform) to afford 167 mg (58%) of the title compound as an off-white solid. 1H NMR (DMSO-d6) δ 11.59 (s, 1H), 8.62 (d, J = 8 Hz, 1H), 8.44 (d, J = 4 Hz, 1H), 7.65 (s, 1H), 7.38 (s, 1H), 7.10 (t, J = 8 Hz, 1H), 7.02 (d, J = 8 Hz, 1H), 6.51 (d, J = 8 Hz, 1H), 4.60 (d, J = 16 Hz, 1H), 4.58 (d, J = 16 Hz, 1H), 4.46 (m, 2H), 3.89 (s, 3H), 3.11 (m, 2H), 2.29 (m, 1H), 2.11 (m, 1H), 1.99 (m, 1H), 1.76–1.54 (m, 5H), 0.95 (d, J = 8 Hz, 3H), 0.9 (d, J = 8 Hz, 3H); MS (ESI+) for C24H31ClN4O5m/z 491.1 (M + H)+; HRMS (ESI+) calcd for C24H31ClN4O5+H1 491.2056, found 491.2058.