(2S,4S)-benzyl 2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (220 mg, 0.27 mmol) was dissolved in DCM (5 mL), MeOH (0.4 mL) and cooled to 0° C. HBr (33% in AcOH, 1 mL) was added dropwise. After stirring for 1 hr, the mixture was concentrated under reduced pressure, coevaporating with PhMe. The crude residue was treated with (R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (68 mg, 0.27 mmol), COMU (129 mg, 0.27 mmol) and DMF (5 mL), then DIPEA (0.24 mL, 1.35 mmol) was added dropwise. After 1 h, the mixture was diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 40% MeOH/EtOAc) to afford methyl (S)-1-((2S,4S)-2-(5-(4′-(2-((2S,4S)-1-((R)-(tert-butoxycarbonylamino)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methylthio)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (179 mg, 73%).
