Water → benzyl (5S)-N,N-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-6-nitro-D-norleucinate

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Reaction Steps

A solution of benzyl (2R,5E)-2-[bis(tert-butoxycarbonyl)amino]-6-nitrohex-5-enoate from Step B (34.0 g, 73.2 mmol), 2,3-difluorophenylboronic acid (28.9 g, 183 mmol) and water (4.62 mL, 256 mmol) in dioxane (240 mL) was degassed with argon for 15 min. To this solution was added sodium bicarbonate (3.08 g, 36.6 mmol), (S)-BINAP (1.28 g, 2.05 mmol) and acetylacetanotobis(ethylene)rhodium(I) (0.472 g, 1.83 mmol). The mixture was stirred at ambient temperature for 2 min then heated to 35° C. After 4 h, (S)-BINAP (255 mg, 0.41 mmol) and acetylacetanotobis(ethylene)rhodium(I) (94 mg, 0.36 mmol) were added. After an additional 2 h, the reaction was partitioned between CH2Cl2 and aqueous NaHCO3. The aqueous layer was extracted with another portion of CH2Cl2. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—95:5 to 40:60, to give the title compound. MS: m/z=379 (M-C10H15O4)

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