Synthesis of compound 6
To a solution of Boc-Cys-OMe (0.88g, 3.74 mmol) in DMF (30 mL) at 0 °C was added K2CO3 (0.51 g, 3.74 mmol) and MeI (0.23 mL, 3.74 mmol) warmed to room temperature and stirred for 20 h. The reaction was diluted with a 9:1 water/NH4Cl (2 M aq. Solu.) and extracted with EtOAc (×2). The organic extracts were washed with 5 % brine, dried over Na2SO4 and concentrated. Dissolved in MeOH (10 mL) and added to a 2 N methanolic-HCl solution and stirred at room temperature for 3 h. The mixture was concentrated and the solid was washed with MTBE (50 mL ×3) to afford (S)-methyl 2-amino-3-(methylthio)propanoate hydrochloride) as a clear light yellow oil (0.62 g, 90 %). Dissolved in MeOH (8 mL) and cooled to -78 °C, added 2,2,2,4?-trifluoroacetophenone (0.60 g, 3.35 mmol) and MeOK (0.47 g, 6.70 mmol). The reaction was slowly warm to room temperature whilst stirring for 20 h – solution A. To a solution of NaBH4 (0.51 g, 13.4 mmol) in DME (10 mL) at 0 °C was added a 2 M solution of ZnCl2 in Et2O (8.03 mL). The mixture was allowed to age for 20 h –solution B. Solution A was cooled to -40 °C, diluted with MeCN (28 mL) and slowly added solution B over 20 min, then stirred at -40 °C for 2.5 h. The reaction was quenched with acetone (40 mL) over 20 min and then warmed to room temperature. The mixture was poured into an ice/water mix (250 mL), the pH was adjusted to 5 with 1 N HCl and extracted with EtOAc (200 mL ×3). The organic extracts were washed with brine (400 mL), dried over Na2SO4 and concentrated. Dissolved in DMF (15 mL), added 1-amino-1-cyclopropanecarbonitrile hydrochloride (0.39 g, 3.35 mmol), HBTU (1.59 g, 4.20 mmol) and NMM (0.54 mL, 4.00 mmol) and stirred at room temperature for 20 h. Diluted the reaction with water (120 mL) and extracted with EtOAc (100 mL ×2). The combined organic extracts were washed with 5 % brine (120 mL ×2) and brine (140 mL), dried over Na2SO4 and concentrated. The residue was purified by column chromatography (40 g column) using 0 to 75 % EtOAc in hexanes to afford (S)-N-(1-cyanocyclopropyl)-3-(methylthio)-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)propanoate as a clear colourless oil (0.36 g, 29 %). To a solution of (S)-N-(1-cyanocyclopropyl)-3-(methylthio)-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)propanoate (0.34 g, 0.91 mmol) in EtOAc (8.78 mL) was added NaTg•2H2O (3.56 mg, 0.01 mmol) and TBAH (15.6 mg, 0.05 mmol) followed by addition of H2O2 (30 % w/w in water, 0.23 mL). The reaction was stirred at room temperature for 3 h. Diluted the reaction mixture with EtOAc (70 mL) and washed with a solution of 2 M Na2S2O3 (100 mL ×2) and brine (100 mL), dried over Na2SO4 and concentrated to afford (S)-N-(1-cyanocyclopropyl)-3-(methylsulfonyl)-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino) propanoate (compound 6) as a white powder (0.29 g, 79 %); 1H-NMR (400 MHz, d
6
-DMSO) ? 9.05 (s, 1H), 7.45 (dd, J = 8.0, 6.0 Hz, 2H), 7.25 (dd, J = 8.0, 6.0 Hz, 2H), 4.37 (quintet, J = 8.0 Hz, 1H), 3.74-3.66 (m, 1H), 3.54-3.46 (m, 2H), 3.17 (dd, J = 16.0, 4.0 Hz, 1H), 3.12 (s, 3H), 1.42-1.33 (m, 2H), 1.05-0.98 (m, 1H), 0.79-0.74 (m, 1H); LC-MS 98 %, m/z = 408.12 [M + H].