K. Yang et al. / Bioorg. Med. Chem. 17 (2009) 3810–3817
3815
d6) d 0.926 (d, J = 6.60, 3H), 1.033 (d, J = 6.60, 3H), 3.193 (d, J = 4.20, 1H),
3.748–3.862 (m, 1H), 4.963 (d, J = 4.20, 1H), 7.591 (d, J = 8.70, 2H),
7.651 (d, J = 7.80, 1H), 8.182 (d, J = 8.70, 2H). Anal. Calcd for
C12H17N3O4: C, 53.92; H, 6.41; N, 15.72. Found: C, 53.89; H, 6.48; N, 15.91.
8.182 (d, J = 8.70, 2H). Anal. Calcd for C17H19N3O4: C, 62.00; H,
5.81; N, 12.76. Found: C, 62.13; H, 5.80; N, 12.65.
5.3.3.10. (2R,3S)-2-Amino-N-(2-chlorophenethyl)-3-hydroxy-3-
(4-nitrophenyl) propanamide (6j). White solid, yield 72.3%,
5.3.3.3. (2R,3S)-2-Amino-N-butyl-3-hydroxy-3-(4-nitrophenyl)-
propanamide (6c). White solid, yield 83%, mp = 88–89 °C,
mp = 140–142 °C, ½a D25
¼ þ25:2 (c 1, MeOH). ESI-MS m/z: 364.2
ꢀ
(M+H); 1H NMR (DMSO-d6) d 2.730 (t, J = 6.30, 1H), 3.220–3.391
(m, 2H), 3.398 (d, J = 3.9, 1H), 5.041 (d, J = 3.90, 1H), 7.226–7.260
(m, 3H), 7.400–7.432 (m, 1H), 7.601 (d, J = 8.70, 2H), 8.184 (t,
J = 5.70, 1H), 8.213 (d, J = 8.70,2H). Anal. Calcd for C17H18ClN3O4:
C, 56.13; H, 4.99; N, 11.55. Found: C, 56.52; H, 5.01; N, 11.54.
½
a 2D5
ꢀ
¼ þ24:2 (c 1, MeOH). ESI-MS m/z: 282.4 (M+H); 1H NMR
(DMSO-d6) d 0.786–0.835 (m, 3H), 1.082–1.204 (m, 2H), 1.242–
1.333 (m, 2H), 2.908–3.233 (m, 2H), 3.234 (d, J = 3.90, 1H), 4.982
(d, J = 3.90, 1H), 7.591 (d, J = 8.70, 2H), 7.854 (t, J = 6.00, 1H),
8.188 (d, J = 8.70, 2H). Anal. Calcd for C13H19N3O4: C, 55.50; H,
6.81; N, 14.94. Found: C, 55.31; H, 6.76; N, 14.83.
5.3.3.11. (2R,3S)-2-Amino-3-hydroxy-N-(4-hydroxyphenethyl)-
3-(4-nitrophenyl) propanamide (6k). White solid, yield 83%,
5.3.3.4. (2R,3S)-2-Amino-3-hydroxy-3-(4-nitrophenyl)-N-pentyl-
propanamide (6d). White solid, yield 83%, mp = 112–144 °C,
mp = 99–100 °C, ½a D25
¼ þ21:0 (c 1, MeOH). ESI-MS m/z: 346.3
ꢀ
(M+H); 1H NMR (DMSO-d6) d 2.538–2.563 (m, 2H), 3.145–3.164
(m, 2H), 3.188 (d, J = 3.90, 1H), 5.067 (d, J = 3.90, 1H), 6.657 (d,
J = 8.70, 2H), 6.953 (d, J = 8.70, 2H), 7.591 (d, J = 8.70, 2H), 7.988
(t, J = 6.00, 1H), 8.187 (d, J = 8.70, 2H). Anal. Calcd for
C17H19N3O5: C, 59.12; H, 5.55; N, 12.17. Found: C, 59.08; H, 5.57;
N, 12.46.
½
a 2D5
ꢀ
¼ þ26:8 (c 1, MeOH). ESI-MS m/z: 296.4 (M+H); 1H NMR
(DMSO-d6) d 0.795–0.842 (m, 3H), 1.098–1.319 (m, 6H), 2.908–
2.970 (m, 1H), 3.044–3.108 (m, 1H), 3.228 (d, J = 3.60, 1H), 4.968 (d,
J = 3.60, 1H), 7.597 (d, J = 8.70, 2H) 7.849 (t, J = 6.00, 1H.), 8.176 (d,
J = 8.70,2H). Anal. Calcd for C14H21N3O4: C, 56.94; H, 7.17; N, 14.23.
Found: C, 56.92; H, 7.07; N, 14.29.
5.3.3.12. (2R,3S)-2-Amino-3-hydroxy-N-((S)-1-hydroxy-3-phe-
nylpropan-2-yl)-3-(4-nitrophenyl)propanamide (6l). White so-
5.3.3.5. (2R,3S)-2-Amino-N-cyclohexyl-3-hydroxy-3-(4-nitrophenyl)
propanamide (6e). White solid, yield 83%, mp = 127–129 °C,
lid, yield 80.3%, mp = 133–134 °C, ½a D25
¼ þ22:3 (c 1, MeOH). ESI-
ꢀ
½
a 2D5
ꢀ
¼ þ13:2 (c 1, MeOH). ESI-MS m/z: 308.5 (M+H); 1H NMR (DMSO-
MS m/z: 360.3 (M+H); 1H NMR (DMSO-d6) d 3.259–2.809 (m,
2H), 3.176–3.343 (m, 2H), 3.882 (d, J = 3.30, 1H), 5.047 (d,
J = 3.30, 1H), 7.151–7.176 (m, 3H), 7.223–7.272 (m, 2H), 7.593 (d,
J = 8.70, 2H), 7.901 (d, J = 8.70, 1H), 8.164 (d, J = 8.70, 2H). Anal.
Calcd for C18H21N3O5: C, 60.16; H, 5.89; N, 11.69. Found: C,
60.19; H, 5.88; N, 11.48.
d6) d 0.679–1.312 (m, 6H), 1.437–1.990 (m, 4H), 3.417 (d, J = 4.50, 1H),
3.393–4.064 (m, 1H), 4.988 (d, J = 4.50, 1H), 7.659 (d, J = 9.00, 1H),
8.238 (d, J = 9.00, 2H), 8.283 (d, J = 7.80, 1H). Anal. Calcd for
C15H21N3O4: C, 58.62; H, 6.89; N, 13.67. Found: C, 58.42; H, 6.40; N, 13.99.
5.3.3.6.
(2R,3S)-2-Amino-3-hydroxy-3-(4-nitrophenyl)-N-pro-
pylpropanamide (6f). White solid, yield 88%, mp = 125–127 °C,
5.3.3.13. (2R,3S)-2-Amino-N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-
3-hydroxy-3-(4-nitrophenyl) propanamide (6m). White solid,
½
a 2D5
ꢀ
¼ þ26:4 (c 1, MeOH). ESI-MS m/z: 316.3 [M+H]; 1H NMR
(DMSO-d6) d 3.355 (d, J = 3.90, 1H). 4.217 (dd, J = 5.70, J = 15.70,
1H), 4.326 (dd, J = 5.70, J = 15.70, 1H), 5.040 (d, J = 3.90, 1H),
7.181–7.285 (m, 5H), 7.618 (d, J = 8.70, 2H), 8.157 (d, J = 8.70,
2H), 8.442 (t, J = 5.70, 1H). Anal. Calcd for C16H17N3O4: C, 60.94;
H, 5.43; N, 13.33. Found: C, 60.44; H, 5.73; N, 12.97.
yield 85.9%, mp = 136–137 °C, ½a D25
¼ þ18:7 (c 1, MeOH). ESI-MS
ꢀ
m/z: 374.4 (M+H); 1H NMR (DMSO-d6) d 2.581 (t, J = 7.20, 2H),
3.171–3.214 (m, 2H), 3.236 (d, J = 3.30, 1H), 5.060 (d, J = 3.30,
1H), 5.961 (s, 2H), 6.622 (d, J = 7.80, 1H), 6.756–6.819 (m, 2H),
7.696 (d, J = 8.70, 2H), 7.998 (t, J = 5.40, 1H), 8.183 (d, J = 8.70 Hz,
2H). Anal. Calcd for C18H19N3O6: C, 57.90; H, 5.13; N, 11.25. Found:
C, 57.84; H, 5.11; N, 11.20.
5.3.3.7.
(2R,3S)-2-Amino-N-(4-fluorobenzyl)-3-hydroxy-3-(4-
nitrophenyl) propanamide (6g). White solid, yield 81.5%,
Compounds 8a and 8b were synthesized following the general
procedure as described bellow (preparation of 12a).
mp = 115–118 °C, ½a D25
¼ þ24:5 (c 1, MeOH). ESI-MS m/z: 334.3
ꢀ
(M+H); 1H NMR (DMSO-d6) d 3.327 (d, J = 3.60, 1H), 4.193 (dd,
J = 6.00, J = 15.00, 1H), 4.294 (dd, J = 6.00, J = 15.00, 1H), 5.053 (d,
J = 3.60, 1H), 7.052–7.111 (m, 2H), 7.187–7.235 (m, 2H) 7.593 (d,
J = 8.70, 2H), 8.155 (d, J = 8.70, 2H), 8.458 (t, J = 6.30,1H). Anal.
Calcd for C16H16FN3O4: C, 57.56; H, 4.84; N, 12.61. Found: C,
57.09; H, 4.82; N, 12.30.
5.3.3.14. 4-((2R,3S)-2-Amino-3-hydroxy-3-(4-nitrophenyl)prop-
anamido)butanoic acid (8a). White solid, yield 43.3%, mp = 141–
143 °C, ½a 2D5
ꢀ
¼ þ20:5 (c 1, MeOH). ESI-MS m/z: 312.3 (M+H); 1H
NMR (DMSO-d6) d 1.186–1.210 (m, 2H), 2.137 (t, J = 7.50, 2H),
2.996–3.020 (m, 2H), 3.581 (d, J = 5.10, 1H), 5.024 (d, J = 5.10,
1H), 7.649 (d, J = 8.70, 2H), 8.204 (d, J = 8.70, 2H), 8.292 (d,
J = 7.80, 1H). Anal. Calcd for C13H17N3O6: C, 50.16; H, 5.50; N,
13.50. Found: C, 50.12; H, 5.53; N, 13.60.
5.3.3.8. (2R,3S)-2-Amino-3-hydroxy-N-(4-methoxybenzyl)-3-(4-
nitrophenyl) propanamide (6h). White solid, yield 66.7%,
mp = 141–143 °C, ½a D25
¼ þ21:3 (c 1, MeOH). ESI-MS m/z: 346.3
ꢀ
(M+H); 1H NMR (DMSO-d6) d 3.330 (d, J = 3.30, 1H), 3.717 (s, 3H),
4.114 (dd, J = 6.30, J = 15.70, 1H), 4.225 (dd, J = 6.30, J = 15.70,
1H), 5.014 (d, J = 3.30, 1H), 7.061 (d, J = 8.70, 2H), 7.592 (d,
J = 8.70, 2H), 7.907 (d, J = 8.70, 2H), 8.147 (d, J = 8.70,2H), 8.325
(t, J = 6.30, 1H). Anal. Calcd for C17H19N3O5: C, 59.12; H, 5.55; N,
12.17. Found: C, 59.15; H, 5.61; N, 12.48.
5.3.3.15. 6-((2R,3S)-2-Amino-3-hydroxy-3-(4-nitrophenyl)prop-
anamido)hexanoic acid (8b). White solid, yield 43.3%, mp = 150–
153 °C, ½a 2D5
ꢀ
¼ þ25:6 (c 1, MeOH). ESI-MS m/z: 340.3 (M+H); 1H
NMR (DMSO-d6) d 1.066–1.165 (m, 2H), 1.214–1.430 (m, 4H),
2.134 (t, J = 7.50, 2H), 3.006–3.055 (m, 2H), 3.583 (d, J = 4.80, 1H),
5.028 (d, J = 4.80, 1H), 7.633 (d, J = 8.70, 2H), 8.204 (d,
J = 8.70,2H), 8.259 (d, J = 7.00,1H). Anal. Calcd for C15H21N3O6: C,
53.09; H, 6.24; N, 12.38. Found: C, 53.04; H, 6.28; N, 12.36.
5.3.3.9. (2R,3S)-2-Amino-3-hydroxy-3-(4-nitrophenyl)-N-phen-
ethylpropanamide (6i). White solid, yield 76%, mp = 126–128 °C,
½
a 2D5
ꢀ
¼ þ27:4 (c 1, MeOH). ESI-MS m/z: 330.3 (M+H); 1H NMR
5.3.3.16. (S)-2-((2R,3S)-2-Amino-3-hydroxy-3-(4-nitrophenyl)
propanamido)-4-methylpentanoic acid (10a). To a 150 mL solu-
(DMSO-d6) d 2.664 (t, J = 7.50, 2H), 3.246 (d, J = 3.60, 1H), 3.286–
3.349 (m, 2H), 5.059 (d, J = 3.60, 1H), 7.167–7.213 (m, 3H),
7.225–7.306 (m, 2H), 7.593 (d, J = 8.70, 2H), 8.037 (t, J = 5.70, 1H),
tion of compound 4 (3.26 g, 10 mmol),
L-leucine methyl ester
hydrochloride (1.81 g, 10 mmol), and HOBt (1.62 g, 12 mmol) in