L. Su et al. / Bioorg. Med. Chem. 19 (2011) 900–906
905
dissolved in DCM (20 mL). This solution was then added to the
mixture of -glycine methyl ester hydrochloride (2.64 g, 21 mmol)
5.1.1.13. 6-Benzyloxycarbonylamino-2-[3-(1-carboxy-2-methyl-
propyl)-ureido]-hexanoic acid methyl ester (3c). Yield 52.3%,
oil; ESI-MS: m/z [M+H]+ 451.7; 1H NMR (600 MHz, CDCl3): d
7.36–7.30 (m, 5H), 5.45–5.39 (m, 2H), 5.26–5.24 (m, 1H), 5.14–
5.07 (m, 2H), 4.45–4.41 (m, 2H), 3.72 (s, 3H), 3.71 (s, 3H), 3.20–
3.14 (m, 2H), 1.80–1.30 (m, 7H), 0.93–0.85 (m, 6H).
L
and triethylamine (2.12 g, 21 mmol). The reaction mixture was
stirred at room temperature for 30 min and then the solvent was
removed under low pressure. The residue was taken up with ethyl
acetate (40 mL) and washed with 1 N HCl (10 mL) and brine
(20 mL). The organic phase was dried with MgSO4 and compound
3a was obtained as yellow oil and separated by silica gel column
chromatography (petroleum ether/ethyl acetate = 1:1) as white so-
lid (4.55 g), yield 53.2%, mp = 48–50 °C; ESI-MS: m/z [M+H]+ 409.2;
1H NMR (300 MHz, CDCl3): d 7.36–7.28 (m, 5H), 5.68 (br, 2H), 5.15
(s, 1H), 5.09 (s, 2H), 4.46 (s, 1H), 4.04–3.87 (m, 2H), 3.73 (s, 3H),
3.71 (s, 3H), 3.20–3.14 (m, 2H), 1.78–1.26 (m, 6H).
5.1.1.14. 6-Benzyloxycarbonylamino-2-[3-(1-carboxy-2-methyl-
propyl)-ureido]-hexanoic acid (4c). Yield 49.6%, mp = 70–73 °C;
ESI-MS: m/z [M+H]+ 423.4; 1H NMR (600 MHz, CDCl3+D2O): d
7.32–7.30 (m, 5H), 5.09 (s, 2H), 4.33–4.31 (m, 1H), 4.07–3.94 (m,
1H), 3.13–3.12 (m, 2H), 1.69–0.88 (m, 10H); 13C NMR (300 MHz,
DMSO-d6): d 172.4, 169.0, 157.2, 156.0, 137.3, 128.3, 127.7, 65.1,
51.4, 46.3, 33.0, 29.1, 23.5, 22.4, 14.2, 14.1.
5.1.1.8.
6-Benzyloxycarbonylamino-2-(3-carboxymethyl-ure-
5.1.1.15. 6-Benzyloxycarbonylamino-2-[3-(1-carboxy-3-methyl-
butyl)-ureido]-hexanoic acid methyl ester (3d). Yield 51.2%,
mp = 50–52 °C; ESI-MS: m/z [M+H]+ 465.5; 1H NMR (600 MHz,CDCl3):
d 7.36–7.30 (m, 5H), 5.32–5.30 (m, 1H), 5.15–5.12 (m, 2H), 5.10–5.07
(m, 2H), 4.47–4.44 (m, 2H), 3.72 (s, 3H), 3.69 (s, 3H), 3.20–3.16 (m,
2H), 1.81–1.35 (m, 9H), 0.92 (d, 6H).
ido)-hexanoic acid (4a). Compound 3a (4.09 g, 10 mmol) was
added to a solution of sodium hydroxide (0.80 g, 20 mmol) in
water (10 mL)and methanol (10 mL). The reaction mixture was
stirred at room temperature for 5 h and then methanol removed
under low pressure. The residue was acidified with 1 N HCl and ex-
tracted with ethyl acetate. The organic phase was washed with
brine and dried with MgSO4. After the solvent removed under
low pressure, Compound 4a was obtained as yellow oil and sepa-
rated by silica gel column chromatography (petrol ether/ethyl ace-
tate = 1:2) as white solid (1.25 g), yield 32.8%, mp = 111–113 °C;
ESI-MS: m/z [M+H]+ 381.4; 1H NMR (300 MHz, DMSO-d6): d
12.48 (s, 2H), 7.40–7.30 (m, 5H), 7.29–7.23 (m, 1H), 6.46 (s, 1H),
6.24 (s, 1H), 5.02 (s, 2H), 4.10–3.99 (m, 1H), 3.71 (s, 2H), 3.00–
2.94 (m, 2H), 1.99–1.24 (m, 6H); 13C NMR (300 MHz, DMSO-d6):
d 169.3, 169.0, 156.6, 156.0, 137.2, 128.3, 127.7, 65.1, 50.4, 42.4,
33.1, 29.2, 22.5.
5.1.1.16. 6-Benzyloxycarbonylamino-2-[3-(1-carboxy-3-methyl-
butyl)-ureido]-hexanoic acid (4d). Yield 44.6%, mp = 60–63 °C;
ESI-MS: m/z [M+H]+ 437.4; 1H NMR (300 MHz, DMSO-d6): d 8.91
(s, 2H), 7.53–7.30 (m, 5H), 6.24 (m, 3H), 5.06 (s, 2H), 4.11–4.00
(m, 2H), 3.13–3.12 (m, 2H), 2.27–1.28 (m, 9H), 0.93 (d, 6H,
J = 8.4 Hz); 13C NMR (300 MHz, DMSO-d6): d 170.8, 170.3, 156.2,
156.0, 137.2, 128.3, 127.7, 65.1, 51.4, 49.9, 40.3, 36.2, 29.9, 23.1,
23.0, 21.4.
5.1.1.17.
{5-Hydroxycarbamoyl-5-[3-(1-hydroxycarbamoyl-3-
methyl-butyl)-ureido]-pentyl}-carbamic acid benzyl ester
(5d). Yield 63.5%, mp = 144–146 °C; ESI-MS: m/z [M+H]+ 467.5;
1H NMR (300 MHz, DMSO-d6): d 10.64 (s, 1H), 10.58 (s, 1H), 8.81
(s, 1H), 8.79 (s, 1H), 7.39–7.28 (m, 5H), 7.23 (s, 1H), 6.21 (s, 1H),
6.18 (s, 1H), 5.00 (s, 2H), 4.06–3.92 (m, 2H), 2.96–2.93 (m, 2H),
1.50–1.15 (m, 9H), 0.87–0.82 (m, 6H); 13C NMR (300 MHz,
DMSO-d6): d 169.3, 169.0, 156.6, 156.0, 137.2, 128.3, 127.7, 65.1,
50.5, 49.0, 42.4, 33.1, 29.1, 22.7, 22.5, 22.3.
5.1.1.9. [5-Hydroxycarbamoyl-5-(3-hydroxycarbamoylmethy-
ureido)-pentyl]-carbamic acid benzyl ester (5a). Yield 29.8%,
mp = 72–75 °C; ESI-MS: m/z [M+H]+ 411.4; 1H NMR (300 MHz,
DMSO-d6): d 10.61 (s, 1H), 10.50 (s, 1H), 7.39–7.28 (m, 5H), 7.24
(s, 1H), 6.39 (s, 1H), 6.25 (s, 1H), 5.02 (s, 2H), 4.08–4.06 (m, 1H),
3.89 (s, 2H), 2.96–2.94 (m, 2H), 1.36–1.15 (m, 6H); 13C NMR
(300 MHz, DMSO-d6): d 172.4, 169.0, 157.2, 156.0, 137.2, 128.3,
127.7, 65.1, 50.4, 41.3, 33.1, 29.1, 22.4.
5.1.1.18. 6-Benzyloxycarbonylamino-2-[3-(1-carboxy-2-methyl-
butyl)-ureido]-hexanoic acid methyl ester (3e). Yield 50.3%,
mp = 50–52 °C; ESI-MS: m/z [M+H]+ 465.5; 1H NMR (300 MHz,
DMSO-d6): d 7.71–7.30 (m, 5H), 7.24 (t, 1H, J = 5.4 Hz), 6.39 (t,
2H, 4.5 Hz), 5.00 (s, 2H), 4.12–4.06 (m, 2H), 3.61 (s, 3H), 3, 60 (s,
3H), 3.01–2.94 (m, 2H), 1.71–0.82 (m, 15H).
5.1.1.10.
6-Benzyloxycarbonylamino-2-[3-(1-carboxy-ethyl)-
ureido]-hexanoic acid methyl ester (3b). Yield 53.2%, mp = 50–
52 °C; ESI-MS: m/z [M+H]+ 423.2; 1H NMR (600 MHz,CDCl3): d
7.36–7.30 (m, 5H), 5.24 (br, 2H), 5.13–5.08 (m, 2H), 5.04 (br, 1H),
4.48–4.44 (m, 2H), 3.73 (s, 3H), 3.71 (s, 3H), 3.21–3.17 (m, 2H),
1.81–1.36 (m, 9H).
5.1.1.19. 6-Benzyloxycarbonylamino-2-[3-(1-carboxy-2-methyl-
butyl)-ureido]-hexanoic acid (4e). Yield 44.6%, mp = 65–67 °C;
ESI-MS: m/z [M+H]+ 437.4; 1H NMR (300 MHz, DMSO-d6): d
12.67 (s, 2H), 7.39–7.30 (m, 5H), 7.28–7.23 (m, 1H), 6.34–6.25
(m, 2H), 5.00 (s, 2H), 4.08–4.03 (m, 2H), 3.52–3.42 (m, 2H), 1.39–
0.88 (m, 15H); 13C NMR (300 MHz, DMSO-d6): d 170.2, 169.9,
156.6, 156.0, 137.3, 128.3, 127.6, 65.1, 55.9, 51.3, 36.4, 31.0, 28.7,
23.0, 14.7, 11.5.
5.1.1.11.
6-Benzyloxycarbonylamino-2-[3-(1-carboxy-ethyl)-
ureido]-hexanoic acid (4b). Yield 32.8%, mp = 110–112 °C; ESI-
MS: m/z [M+H]+ 395.4; 1H NMR (600 MHz, DMSO-d6): d 12.50 (s,
2H), 7.38–7.23 (m, 5H), 6.36–6.28 (m, 3H), 5.02 (s, 2H), 4.10–4.02
(m, 2H), 3.35 (s, 2H), 1.64–0.85 (m, 9H); 13C NMR (300 MHz,
DMSO-d6): d 170.2, 166.9, 157.0, 156.0, 137.3, 128.3, 127.6, 65.1,
52.1, 47.9, 32.0, 29.1, 22.4, 14.0.
5.1.1.20.
{5-Hydroxycarbamoyl-5-[3-(1-hydroxycarbamoyl-2-
5.1.1.12.
{5-Hydroxycarbamoyl-5-[3-(1-hydroxycarbamoyl-
methyl-butyl)-ureido]-pentyl}-carbamic acid benzyl ester
(5e). Yield 44.8%, mp = 75–77 °C; ESI-MS: m/z [M+H]+ 467.5; 1H
NMR (300 MHz, DMSO-d6): d 10.63 (s, 1H), 10.59 (s, 1H), 8.85 (s,
1H), 8.81 (s, 1H), 7.39–7.30 (m, 5H), 7.24–7.23 (m, 1H), 6.30–6.22
(m, 2H), 5.00 (s, 2H), 4.06–3.79 (m, 2H), 2.95 (s, 2H), 1.91–1.17
(m, 9H), 0.92–0.71 (m, 6H); 13C NMR (300 MHz, DMSO-d6): d
169.0, 168.4, 156.8, 156.0, 137.2, 128.3, 127.7, 65.1, 54.8, 50.5,
37.5, 33.1, 29.2, 22.5, 15.2, 11.1.
ethy)-ureido]-pentyl}-carbamic acid benzyl ester (5b). Yield
40.0%, mp = 75–77 °C; ESI-MS: m/z [M+H]+ 425.4; 1H NMR
(300 MHz, DMSO-d6): d 10.68 (s, 1H), 10.60 (s, 1H), 8.90 (s, 1H),
8.76 (s, 1H), 7.48–7.28 (m, 5H), 6.30–6.25 (m, 3H), 5.00 (s, 2H),
4.12–4.06 (m, 2H), 3.29 (s, 2H), 1.66–0.95 (m, 9H); 13C NMR
(400 MHz, DMSO-d6): d 172.4, 169.0, 157.2, 156.0, 137.3, 128.3,
127.7, 65.1, 51.4, 46.3, 33.0, 29.1, 22.4, 18.3.