The crude product from Step G was dissolved in tetrahydrofuran (80 mL) and the solution was cooled in an ice bath. A slurry of 1,1'-carbonyldiimidazole (4.09 g, 25.2 mmol) in tetrahydrofuran (10 mL) was added over 10 min with additional tetrahydrofuran (3×5 mL) to complete the transfer. After 30 min, a solution of L-leucine N-phenylamide (5.60 g, 27.1 mmol) in tetrahydrofuran (10 mL) was added over 10 min with additional tetrahydrofuran (5 mL) to complete the transfer. The homogeneous solution was allowed to slowly warm to room temperature and stirred for 16 h. The mixture was concentrated on a rotary evaporator to remove most of the tetrahydrofuran and the residue was partitioned between ethyl acetate (150 mL) and 2N aqueous hydrochloric acid (75 mL). The ethyl acetate layer was washed with saturated aqueous sodium chloride (2×25 mL). The crystals which spontaneously formed in the organic layer were separated by filtration and partioned between chloroform (300 mL) and 2N aqueous hydrochloric acid, and the chlorform layer was washed with saturated aqueous sodium chloride (50 mL). The sodium chloride layer was extracted with chloroform (2×25 mL). The combined chlorform extracts were dried (magnesium sulfate), filtered, and evaporated. The residue was dissolved in boiling tetrahydrofuran (100 mL), allowed to cool to 25° C., evaporated to a mass of 40 g, and dissolved in ethyl acetate (150 mL). After 2 h at 25° C., the crystals were separated by filtration,washed with ethyl acetate (2×20 mL) and ether (20 mL), and dried under vacuum to give 6.17 g of almost colorless crystals. Evaporation of the mother liquor and recrystallization produced a second crop of 1.62 g (total yield 54% for steps F-H) of (2-(((4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butyl)hydroxyphosphinyl)methyl)-4-phenylbutanoyl)-L-leucine N-phenylamide.
