N-((1S)-1-{[((1S)-3-Hydroxy-2-oxo-1-{[(3S)-2-oxopyrrolidin-3-yl]methyl}propyl)amino]carbonyl}-3-methylbutyl)-4-methoxy-1H-indole-2-carboxamide (4)
A solution of 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 (488 mg, 0.99 mmol) and benzoylformic acid (195 mg, 1.3 mmol) in DMF (6.5 mL) was placed under an atmosphere of N2. This clear pale yellow solution was treated with cesium fluoride (350 mg, 2.3 mmol) followed by heating to 65 °C. After 4 h, the now yellow suspension was cooled to RT, diluted with ethyl acetate (60 mL), washed three times with water (30 mL) and once with brine (30 mL), dried over MgSO4, filtered, and concentrated to give (3S)-3-({N-[(4-methoxy-1H-indol-2-yl)carbonyl]-l-leucyl}amino)-2-oxo-4-[(3S)-2-oxopyrrolidin-3-yl]butyl oxo(phenyl)acetate as a crude yellow foam. MS (ESI+) for C32H36N4O8m/z 605.2 (M + H)+. A solution of the crude (3S)-3-({N-[(4-methoxy-1H-indol-2-yl)carbonyl]-l-leucyl}amino)-2-oxo-4-[(3S)-2-oxopyrrolidin-3-yl]butyl oxo(phenyl)acetate in methanol (40 mL) was placed under an atmosphere of N2 and treated with potassium carbonate (7 mg, 0.05 mmol) with vigorous stirring. After 1 h, the volatiles were removed in vacuo (bath < 30 °C) to give a crude yellow glass. This material was purified by Biotage MPLC (25 M column, 6% methanol/chloroform) to afford 346 mg (73%) of the title compound as an off-white solid. 1H NMR (DMSO-d6) δ 11.56 (s, 1H), 8.44 (d, J = 8 Hz, 1H), 8.39 (d, J = 8 Hz, 1H), 7.61 (s, 1H), 7.35 (s, 1H), 7.08 (t, J = 8 Hz, 1H), 6.99 (d, J = 8 Hz, 1H), 6.49 (d, J = 8 Hz, 1H), 5.04 (t, J = 8 Hz, 1H), 4.46 (m, 2H), 4.25 (dd, J = 8, 20 Hz, 1H), 4.13 (dd, J = 8, 20 Hz, 1H), 3.87 (s, 3H), 3.10 (m, 2H), 2.28 (m, 1H), 2.08 (m, 1H), 1.92 (m, 1H), 1.70–1.53 (m, 5H), 0.93 (d, J = 8 Hz, 3H), 0.89 (d, J = 8 Hz, 3H); MS (ESI+) for C24H32N4O6m/z 473.2 (M + H)+.