Reaction Steps
To an iced slurry of (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(isopropylthio)pyrrolidine-2-carboxylic acid (28 mg, 0.050 mmol), (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide, pTSA, 0.68H2O (23.03 mg, 0.056 mmol), and HATU (28.5 mg, 0.075 mmol) in DCM (1 mL) was added N,N-Diisopropylethylamine (0.035 mL, 0.202 mmol). The formed light brown solution was stirred at room temperature overnight. Diluted with EtOAc, washed it with 5% citric acid, and brine, dried over MgSO4, filtered, evaporated. The formed residue was purified by prep-HPLC to afford the desired product tert-butyl (S)-1-((2S,4R)-4-(biphenyl-4-yl)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-(isopropylthio)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (23 mg, 59% yield) as a white solid. 1H NMR (500 MHz, MeOD) ppm 1.03-1.07 (m, 3H), 1.09-1.12 (m, 11H), 1.21-1.28 (m, 4H), 1.40-1.51 (m, 2H), 1.52 (s, 9H), 1.87 (dd, J=7.93, 5.49 Hz, 1H), 2.20 (q, J=8.85 Hz, 1H), 2.30 (t, J=11.60 Hz, 1H), 2.54-2.62 (m, 1H), 2.81 (dd, J=12.05, 6.26 Hz, 1H), 2.90-2.98 (m, 1H), 3.87 (dd, J=10.99, 6.41 Hz, 1H), 3.97 (d, J=0.99 Hz, 1H), 4.51 (d, J=9.77 Hz, 1H), 5.08-5.19 (m, 2H), 5.29 (d, J=17.09 Hz, 1H), 5.69-5.81 (m, 1H), 7.37 (t, J=7.32 Hz, 1H), 7.46 (t, J=7.78 Hz, 2H), 7.60 (dd, J=10.68, 7.93 Hz, 4H), 7.71 (d, J=8.55 Hz, 2H). LC-MS (retention time: 3.42 min, method B), MS m/z 767 (M+H).
