Reaction Steps
A solution of (S)-1-{(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-[3-(tert-butyl-dimethylsilanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid hex-5-enyl ester in anhydrous dichloromethane (12 mL) was cooled to 0° C. before adding trimethylsilyl trifluoromethanesulfonate (242 μL, 1.088 mmol). The reaction mixture was stirred at 0° C. under a nitrogen atmosphere for 3.5 hours, then N,N-diisopropylethylamine (480 μL, 2.903 mmol) was added. The reaction mixture was evaporated to give the crude amine as a colourless gum. A solution of (2S,3S)-3-methoxy-2-methyl-hept-6-enoic acid in anhydrous N,N-dimethylformamide (6 mL) was cooled to 0° C., before adding 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (276 mg, 0.726 mmol) and N,N-diisopropylethylamine (480 μL, 2.903 mmol). It was stirred at 0° C. for 20 minutes before adding a solution of the crude amine in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for 16 hours then diluted with brine (20 mL) and extracted with ethyl acetate (3×15 mL). The extract was further washed with brine (2×15 mL) then dried over anhydrous sodium sulfate and evaporated to give a brown oil. The oil was purified by silica gel chromatography using ethyl acetate/iso-hexanes 1:1, then ethyl acetate/iso-hexanes 7:3 to give the title compound (187 mg, 35%) as a white solid. 1H NMR (300 MHz, CDCl3) δ0.19 (s, 6H), 0.83-1.00 (m, 7H), 0.98 (s, 9H), 1.16 (d, J=7.1 Hz, 3H), 1.20-1.30 (m, 3H), 1.36-1.55 (m, 3H), 1.58-1.72 (m, 3H), 1.73-1.90 (m, 2H), 2.03-2.24 (m, 4H), 2.41-2.55 (m, 1H), 2.65-3.00 (m, 3H), 3.31-3.44 (m, 1H), 3.39 (s, 3H), 3.57 (d, J=11.4 Hz, 1H), 4.05-4.19 (m, 2H), 4.25-4.40 (m, 2H), 4.92-5.10 (m, 4H), 5.65-5.90 (m, 3H), 6.41-6.57 (m, 2H), 6.65 (s, 1H), 6.69 (d, J=8.0 Hz, 1H), 6.81 (d, J=6.9 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H). LCMS (m/z) 743.46 [M+H] Tr=5.97 min.
