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(R)-2-(tert-butoxycarbonyl)-3-phenylpropyl
methanesulfonate
5.1.6. (2S)-2-Amino-3-methyl-N-[(2R)-2-amino-3-phenyl-
(5.52 g yield 84.3%), which was of suitable purity to use directly
in next reaction.
propyl]propionamide hydrochl-oride (8c)
Yield: 72.45%, mp = 190–193.5 °C, ½a D25
ꢁ
+55.0° (c 1, MeOH). ESI-
MS m/z: 250.3 (M+H)+; 1H NMR (D2O) d 0.91–0.95 (J = 12, d, 6H),
2.12–2.17 (m, 1H), 1.65–1.73 (m, 1H), 2.80–2.88 (J1 = 6, J2 = 15,
dd, 1H), 2.97–3.04 (J1 = 6, J2 = 15, dd, 1H), 3.31–3.40 (J1 = 9,
J2 = 18, dd, 1H), 3.57–3.63 (J1 = 6, J2 = 15, dd, 1H), 3.60–3.63 (m,
1H), 3.71–3.73 (J = 6, d, 1H), 7.23–7.37 (m, 5H).
5.1.2. (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenyl-
propylamine (4)
A mixture of sulfonate 2 (10 g, 30 mmol) and NaN3 (3.95 g,
60 mmol) in anhydrous DMF (80 mL) was stirred at 60 °C for
10 h. The mixture was poured to the cold water and extracted with
ethyl acetate. The organic layer was washed with water and brine,
dried over Na2SO4 and concentrated in vacuum. The residue was
purified by flash column chromatography to give on silica gel
(Petroleum/EtOAc 10:1) to afford compound 3 (2R)-tert-butyl (2-
azidomethyl-1-benzylethyl) carbamate.
The azide 3 (4 g, 0.015 mol) was hydrogenated on Mg (1.08 g,
0.045 mol) in MeOH at ordinary pressure and 0 °C for 1 h. MeOH
was removed under reduced pressure and the residue was diluted
with water. The aqueous solution was extracted efficiently with
ether and the ether layer was washed with brine, dried over
Na2SO4 and concentrated in vacuum to give product 4 (2R)-2-
[(tert-butoxycarbonyl)amino]-3-phenyl-propylamine. ESI-MS m/z:
251.1 (M+H)+; 1H NMR (MeOD) d 1.41(s, 9H), 2.59–2.65 (J1 = 6,
J2 = 12, dd, 1H), 2.71–2.81 (m, 3H), 3.79 (m, 1H), 7.18–7.32 (m, 5H).
5.1.7. (2S)-2,6-Amino-N-[(2R)-2-amino-3-phenylpropyl]caproyl-
amide hydrochloride (8d)
Yield: 78.48%, mp = 221.4–223 °C, ½a D25
ꢁ
+61.6° (c 1, MeOH). ESI-
MS m/z: 280.3 (M+H)+; 1H NMR (D2O) d 1.36–1.41 (m, 2H), 1.59–
1.64 (m, 2H), 1.77–1.82 (m, 2H), 2.80–2.87 (J1 = 6, J2 = 15, dd, 1H),
2.87–2.90 (J = 9, t, 2H), 2.96–3.03 (J1 = 6, J2 = 15, dd, 1H), 3.34–
3.40 (m, 1H), 3.55–3.62 (J1 = 6, J2 = 15, dd, 1H), 3.62–3.68 (J1 = 6,
J2 = 15, dd, 1H), 3.89–3.93 (J1 = 12, t, 1H), 7.23–7.37 (m, 5H).
5.1.8. (2S)-2-Amino-4-methylthio-N-[(2R)-2-amino-3-phenyl-
propyl]butyramide hydrochloride (8e)
Yield: 72.41%, mp = 82–84.5 °C, ½a D25
ꢁ
+19.2° (c 1, MeOH). ESI-MS
m/z: 283.4 (M+H)+; 1H NMR (D2O) d 2.01 (s, 3H), 2.05–2.09 (m, 2H),
2.50–2.55 (J = 15, t, 2H), 2.80–2.87 (J1 = 6, J2 = 15, dd, 1H), 2.92–
3.00 (J1 = 6, J2 = 15, dd, 1H), 3.47–3.53 (m, 1H), 3.55–3.610 (J1 = 6,
J2 = 12, dd, 1H), 3.62–3.69 (J1 = 6, J2=12, dd, 1H), 3.62–3.66 (J = 12,
t, 1H), 7.22–7.37 (m, 5H).
5.1.3. 2-[(tert-Butoxycarbonyl)amino]-N-[(2R)-2-[(tert-
butoxycarbonyl)amino]-3-phenylpropyl] acetamide (7a)
To a stirred solution of tert-butoxycarbonyl-2-amino-acetic
acid (1.54 g, 8.80 mmol) and N-methylmorpholine (1.05 mL,
9.60 mmol) in THF (15 mL) was added isobutyl chloroformate
(1.23 mL, 9.60 mmol) at ꢀ15 °C. The mixture was stirred for
30 min at the same temperature. A solution of compound 4
(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenyl-propylamine
(2.00 g, 8.00 mmol) in THF (20 mL) was added dropwise to the
reaction mixture. The stirring was continued for 1 h at ꢀ15 °C
and then remove the cooling bath. The reaction was continued
for 4 h and the mixture was filtrated. After filtration, the filtrate
was concentrated with a rotary evaporator. The residue was dis-
solved in EtOAc and washed with 5% NaHCO3, 10% citric acid,
and brine in turn. The EtOAc solution was dried over Na2SO4
and concentrated with a rotary evaporator to afford crude prod-
uct. The crude product was recrystallized by EtOAc to afford
pure title compound 7a. Yield: 67.54%, mp = 103–105 °C. ESI-
MS m/z: 408.3 (M+H); 1H NMR (DMSO-d6) d 1.22 (s, 9H), 1.38
(s, 9H), 2.58–2.61 (m, 1H), 2.67–2.74 (J1 = 5.4, J2 = 13.8, dd, 1H),
3.01–3.07 (m, 1H), 3.16–3.19 (m, 1H), 3.50–3.56 (m, 2H), 3.66–
3.68 (m, 1H) 7.17–7.27 (m, 5H).
5.1.9. (2S)-2-Amino-3-hydroxyl-N-[(2R)-2-amino-3-phenyl-
propyl]propionamide hydrochloride (8f)
Yield: 78.61%, mp = 111–114 °C, ½a D25
ꢁ
+19.5° (c 1, MeOH). ESI-
MS m/z: 238.4(M+H)+; 1H NMR (D2O) d 2.80–2.88 (J1 = 6, J2 = 13.5,
dd, 1H), 2.96–3.03 (J1 = 6, J2 = 12.6, dd, 1H), 3.47–3.49 (J = 6, d,
2H), 3.64–3.69 (m, 1H), 3.85–3.90 (m, 2H), 4.03–4.06 (J = 9, t,
1H), 7.23–7.37 (m, 5H).
5.1.10. (2S)-2,5-Amino-N-[(2R)-2-amino-3-phenylpropyl]-
valeramide hydrochloride (8g)
Yield: 68.73%, mp = 130–133.3 °C, ½a D25
ꢁ
+16.8° (c 1, MeOH). ESI-
MS m/z: 265.2 (M+H)+; 1H NMR (D2O) d 1.64–1.72 (m, 2H), 1.82–
1.88 (m, 2H), 2.81–2.88 (J1 = 6.6, J2 = 15, dd, 1H), 2.89–2.96 (J1 = 6,
J2 = 14.4, dd, 1H), 3.01–3.03 (m, 2H), 3.34–3.40 (m, 1H), 3.57–
3.63 (m, 2H), 3.93–3.99 (J = 15, t, 1H), 7.23–7.36 (m, 5H).
5.1.11. (2S)-2-Amino-N-[(2R)-2-amino-3-phenylpropyl]-
propionamide hydrochloride (8h)
Yield: 67.54%, mp = 161–163.5 °C, ½a D25
ꢁ
+28.4° (c 1, MeOH). ESI-
MS m/z: 222.4(M+H)+; 1H NMR (D2O) d 1.42–1.46 (J = 12, d, 3H),
2.82–2.89 (J1 = 6, J2 = 14.4, dd, 1H), 2.96–3.03 (J1 = 5.4, J2 = 15, dd,
1H), 3.41–3.50 (m, 2H), 3.64–3.71 (m, 1H), 4.01–4.08 (m, 1H),
7.24–7.39 (m, 5H).
5.1.4. 2-Amino-N-[(2R)-2-amino-3-phenylpropyl] acetamide
hydrochloride (8a)
Compound 7a (0.8 g, 1.96 mmol) was dissolved in 20 mL HCl–
EtOAc (3 mol/L). After 30 min, the solvent was filtrated and the
precipitate was washed with EtOAc to get 0.32 g of compound 8a
5.1.12. N-[(2R)-2-Amino-3-phenylpropyl]-L-glutamamide
hydrochloride (8i)
as a white solid. Yield: 78.66%, mp = 195.5–197.8 °C, ½a D25
ꢁ
+26.8°
(c 1, MeOH). ESI-MS m/z: 208.3 (M+H)+; 1H NMR (D2O) d 2.81–
2.89 (J1 = 6, J2 = 15, dd, 1H), 2.94–3.01 (J1 = 6, J2 = 15, dd, 1H),
3.38–3.48 (J1 = 4.5, J2 = 15, dd, 1H), 3.49–3.56 (J1 = 4.5, J2 = 15, dd,
1H), 3.62–3.73 (m, 1H), 3.80 (s, 2H), 7.23–7.37 (m, 5H).
Yield: 70.53%, mp = 167–171 °C, ½a D25
ꢁ
+24.6° (c 1, MeOH). ESI-
MS m/z: 279.4 (M+H)+; +H NMR (D2O) d 1.98–2.07 (m, 2H), 2.35–
2.40 (J = 15, t, 2H), 2.83–2.89 (J1 = 6.3, J2 = 14.1, dd, 1H), 2.96–3.03
(J1 = 6, J2 = 14.7, dd, 1H), 3.38–3.45 (J1 = 4.8, J2 = 14.4, dd, 1H),
3.54–3.61 (J1 = 4.5, J2 = 14.7, dd, 1H), 3.63–3.67 (J = 12, t, 1H),
3.95–3.99 (m, 1H), 7.24–7.38 (m, 5H).
5.1.5. (2S)-2-Amino-4-methyl-N-[(2R)-2-amino-3-phenyl-
propyl]valeramide hydrochloride (8b)
Yield: 75.46%, mp = 165.5–168 °C, ½a D25
ꢁ
+53.8° (c 1, MeOH). ESI-
5.1.13. (2S)-2-Amino-3-thiol-N-[(2R)-2-amino-3-phenyl-
MS m/z: 264.0 (M+H)+; 1H NMR (D2O) d 0.86–0.87 (J = 3d, 6H),1.52–
1.63 (m, 2H), 1.65–1.73 (m, 1H), 2.81–2.88 (J1 = 6, J2 = 15, dd, 1H),
2.94–3.01 (J1 = 6, J2 = 15, dd, 1H), 3.36–3.43 (J1 = 6, J2 = 15, dd,
1H), 3.49–3.56 (J1 = 6, J2 = 15, dd, 1H), 3.64–3.74 (m, 1H), 3.92–
3.94 (J = 6, t, 1H), 7.22–7.36 (m, 5H).
propyl]propionamide hydrochloride (8j)
Yield: 61.28%, mp = 156–158 °C, ½a D25
ꢁ
+30.3° (c 1, MeOH). ESI-
2.83–2.89 (J1 = 5.4,
MS m/z: 254.3(M+H)+; 1H NMR (D2O)
d
J2 = 13.2, dd, 1H), 2.92–2.99 (J1 = 5.1, J2 = 12.6, dd, 1H), 3.08–3.15
(J1 = 6, J2 = 13.5, dd, 1H), 3.27–3.32 (J1 = 5.7, J2 = 12.6, dd, 1H),