The example of Protease inhibiting succinic acid derivatives

A solution of 3(S)-(dibenzylamino)-2(R)-hydroxy-4-phenylbutanenitrile [50.82 g, 143 mmol] described by M. T. Reetz et al., Tetrahedron Lett., 29, 3295 (1988)] in anhydrous Et2 O (250 mL) was added dropwise over a period of 2 h to a stirred, cooled (0°) mixture of LiAlH4 (8.10 g, 213 mmol) and anhydrous Et2 O (500 mL). The mixture was allowed to warm to room temperature while being stirred for 4.5 h. The mixture was cooled again to 0°. EtOAc (100 mL) was added slowly over 15 min. Stirring was continued for 15 min at 0°. A cold (0°) solution of 2N NaOH (250 mL) was added dropwise to the reaction mixture giving a white suspension/emulsion. The cloudy organic supernatant was separated and the remainder of the suspension/emulsion was passed through a 45 μm filter. The filtrate was extracted with EtOAc and the extract was combined with the first organic phase. After drying over NaCl/Na2 SO4, the solution was concentrated to a volume of ca 100 mL and allowed to stand at 5° for 18 h. The precipitated material was separated, triturated with hexane (300 mL), collected by filtration, and dried under reduced pressure to give the title compound as a white solid (34 g, 66% yield). Mp: 72°-76°. [α]D24 -1.9° (c=1, MeOH). [α]Hg36524 -24.0° (c=1, MeOH). 1 H NMR (CDCl3, 400 MHz) δ 2.68 (dd, J=12.6, 7.6, 7.2 Hz, 1H), 2.81 (dd, J=12.6, 3.8, 3.5 Hz, 1H), 2.86-3.00 (m, 2H), 3.08 (dd, J=14.1, 7.6, 7.3 Hz, 1H), 3.59 (d, J=13.7 Hz, 2H), 3.69 (m, 1H), 3.71 (d, J=13.7 Hz, 2H), 7.16-7.35 (m, 15H). FAB-MS (m/z): 361 (M+H)+.

A solution of 1-amino-3(S)-(dibenzylamino)-4-phenyl-2(R)-butanol (5.00 g, 13.9 mmol; described in example 2), 4-(1-ethylpropylamino)-2(R)-tert-butyl-4-oxobutanoic acid (3.70 g, 15.2 mmol; described in example 1), TBTU (5.30 g, 16.5 mmol) and N-methylmorpholine (6 mL, 54.5 mmol) in acetonitrile (60 mL) was stirred 18 h at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc. The solution was washed with 1N aqueous ammonia (4×) and brine (2×). After drying over a mixture of decolorizing charcoal and Na2 SO4, the solvent was removed under reduced pressure. The residue was purified by flash chromatography using 8:2 hexanes/EtOAc (8:2) followed by hexanes/EtOAc (1:1) as eluants. After combining the appropriate fractions and removing the solvent, the resulting yellow residue was triturated with hexanes and dried under reduced pressure to give the title compound as a white solid (4.43 g, 55% yield). Mp: 110°-112° . [α]D24 +6° (c=1, MeOH). 1 H NMR (CDCl3, 400 MHz) δ 0.82 (s, 9H), 0.86 (t, J=7.3 Hz, 3H), 0.88 (t, J=7.3 Hz, 3H), 1.23-1.38 (m, 2H), 1.43-1.58 (m, 2H), 1.95 (dd, J=11.6, 3.2, 2.9 Hz, 1H), 2.26 (dd, J=13.7, 2.9 Hz, 1H), 2.40 (dd, J=13.4, 11.8 Hz, 1H), 2.93 (m, 1H), 3.02 (m, 1H), 3.18 (dd, J=14.0, 4.1 Hz, 1H), 3.33 (dt, J=14.6, 4.7 Hz, 1H), 3.42 (d, J=13.4 Hz, 2H), 3.58 (broad s, 1H), 3.70 (d, J=13.4 Hz, 2H), 3.70-3.81 (m, 3H), 5.00 (broad t, J=5.5 Hz, 1H), 5.20 (d, J=9.2 Hz, 1H), 7.15 (d, J=7.0 Hz, 3H), 7.20-7.37 (m, 12H). FAB-MS (m/z): 586 (M+H)+.