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s), 5.17 (2H, s), 5.53 (1H, br d, J = 7.5 Hz), 6.97–7.01 (3H, m), 7.20
(1H, dd, J = 8.6 and 7.7 Hz), 7.26–7.40 (15H, m). 31P NMR (CDCl3)
dP: 29.2. HRMS-FAB-glycerol (m/z): [M+H]+ calcd for C36H39NO9P,
660.2362; found 660.2359.
5.2.8. (2RS,RPSP)-Benzyl 2-benzyloxycarbonylamino-4-(diphen-
oxyphosphoryl)butanoate (7b)
This compound was prepared as described for 7a. Yield 60%, col-
orless oil. 1H NMR (CDCl3) dH: 1.94–2.25 (3H, m), 2.33–2.48 (1H,
m), 4.49–4.56 (1H, m), 5.10 (2H, s), 5.18 (2H, br s), 5.49 (1H, br
d, J = 7.8 Hz), 7.10–7.34 (20H, m). 31P NMR (CDCl3) dP: 24.5.
HRMS-FAB-NBA (m/z): [M+H]+ calcd for C31H31NO7P, 560.1838;
found 560.1837.
5.2.3. (2RS,RPSP)-Benzyl 2-benzyloxycarbonylamino-4-{[3-(eth-
oxycarbonylmethyl)phenoxy](methoxy)phosphoryl}butanoate
(6c)
Yield 55%, colorless oil: 1H NMR (CDCl3) dH: 1.23 (3H, t,
J = 6.9 Hz), 1.78–2.13 (3H, m), 2.18–2.36 (1H, m), 3.58 (2H, s),
3.73 (3H, d, J = 10.8 Hz), 4.13 (2H, q, J = 6.9 Hz), 4.44–4.51 (1H,
m), 5.10 (2H, s), 5.17 (2H, s), 5.62 (1H, br d, J = 4.5 Hz), 7.05–7.11
(3H, m), 7.25 (1H, dd, J = 8.0 and 8.0 Hz), 7.33 (10H, br s). 31P
NMR (CDCl3) dP: 29.4. Anal. calcd for C30H34NO9P: C, 61.74; H,
5.87; N, 2.40; found: C, 61.48; H, 6.00; N, 2.48. HRMS-FAB-glycerol
(m/z): [M+H]+ calcd for C30H35NO9P, 584.2049; found 584.2039.
5.3. General procedure for the synthesis of 2a–d, 2g, 3a, and 3b
The preparation of 2a is representative. Hydrogen gas was bub-
bled into a mixture of compound 6a (1.31 g, 2.07 mmol), water
(7 mL), and acetic acid (6 mL) in the presence of 5% palladium on
activated carton (0.20 g) for 4 h at room temperature. The catalyst
was removed by filtration and the concentrated filtrate was lyophi-
lized to afford 2a (0.59 g, 90%) as a colorless solid.
5.2.4. (2RS,RPSP)-Benzyl 2-benzyloxycarbonylamino-4-{[3-(car-
bamoylmethyl)phenoxy](methoxy)phosphoryl}butanoate (6d)
Yield 41%, colorless oil: 1H NMR (CDCl3) dH: 1.73–2.13 (3H, m),
2.18–2.34 (1H, m), 3.52 (2H, s), 3.75 (3H, d, J = 11.4 Hz), 4.43–4.50
(1H, m), 5.09 (2H, s), 5.17 (2H, s), 5.42–5.75 (3H, m), 7.06–7.11 (3H,
m), 7.26–7.34 (11H, m). 31P NMR (CDCl3) dP: 29.6, 29.7 (ratio = 1:1).
Anal. calcd for C28H31N2O8P: C, 60.65; H, 5.63; N, 5.05; found: C,
60.50; H, 5.78; N, 5.06. HRMS-FAB-NBA (m/z): [M+H]+ calcd for
5.3.1. (2RS,RPSP)-2-Amino-4-[(3-carboxyphenoxy)(methoxy)
phosphoryl]butanoic acid (2a)
Yield 90%, colorless solid: 1H NMR (D2O) dH: 2.12–2.40 (4H, m),
3.88 (3H, d, J = 11.1 Hz), 3.89 (1H, br s), 7.46 (1H, br d, J = 8.0 Hz),
7.55 (1H, dd, J = 8.0 and 8.0 Hz), 7.77 (1H, br s), 7.89 (1H, br d,
J = 8.0 Hz). 31P NMR (D2O) dP: 32.6. HRMS-FAB-glycerol (m/z): [M
+H]+ calcd for C12H17NO7P, 318.0743; found 318.0755.
C28H32N2O8P, 555.1896; found 555.1898.
5.3.2. (2RS,RPSP)-2-Amino-4-{[3-(2-carboxyethyl)phenoxy](met-
hoxy)phosphoryl}butanoic acid (2b)
5.2.5. (2RS,RPSP)-Benzyl 2-benzyloxycarbonylamino-4-[(3-nitro-
phenoxy)(methoxy)phosphoryl]butanoate (6e)
Yield 87%, colorless solid: 1H NMR (D2O) dH: 2.10–2.30 (4H, m),
2.68 (2H, t, J = 7.2 Hz), 2.93 (2H, t, J = 7.2 Hz), 3.82 (1H, br s), 3.84
(3H, d, J = 11.4 Hz), 7.07 (1H, d, J = 7.5 Hz), 7.09 (1H, s), 7.17 (1H,
d, J = 7.5 Hz), 7.36 (1H, dd, J = 7.5 and 7.5 Hz). 31P NMR (D2O) dP:
32.5. HRMS-FAB-glycerol (m/z): [M+H]+ calcd for C14H21NO7P,
346.1056; found 346.1059.
Yield 44%, pale yellow oil. 1H NMR (CDCl3) dH: 1.81–2.17 (3H,
m), 2.22–2.39 (1H, m), 3.77 (3H, d, J = 11.1 Hz), 4.48–4.54 (1H,
m), 5.11 (2H, s), 5.19 (2H, s), 5.49 (1H, br d, J = 7.8 Hz), 7.30–7.39
(10H, m), 7.46–7.56 (2H, m), 8.01–8.06 (2H, m). 31P NMR (CDCl3)
dP: 30.4. HRMS-FAB-NBA (m/z): [M+H]+ calcd for C26H28N2O9P,
543.1532; found 543.1523.
5.3.3. (2RS,RPSP)-2-Amino-4-{[3-(ethoxycarbonylmethyl)phen-
oxy](methoxy)phosphoryl}butanoic acid (2c)
5.2.6. (2RS,RPSP)-Benzyl 2-benzyloxycarbonylamino-4-{[4-(ben-
zyloxycarbonyl)phenoxy](methoxy)phosphoryl}butanoate (6g)
Yield 48%, colorless oil: 1H NMR (CDCl3) dH: 1.78–2.13 (3H, m),
2.22–2.35 (1H, m), 3.74 (3H, d, J = 11.1 Hz), 4.45–4.52 (1H, m), 5.08
(1H, d, J = 11.1 Hz), 5.12 (1H, d, J = 11.1 Hz), 5.15 (1H, d,
J = 12.9 Hz), 5.19 (1H, d, J = 12.9 Hz), 5.35 (2H, s), 5.47 (1H, br d,
J = 7.2 Hz), 7.21 (2H, d, J = 8.7 Hz), 7.28–7.45 (15H, m), 8.04 (2H,
d, J = 8.7 Hz). 31P NMR (CDCl3) dP: 29.5. Anal. calcd for C34H34NO9-
P: C, 64.65; H, 5.43; N, 2.22; found: C, 64.72; H, 5.54; N, 2.22.
HRMS-FAB-NBA (m/z): [M+H]+ calcd for C34H35NO9P, 632.2049;
found 632.2057.
Yield 86%, colorless solid: dH: 1.23 (3H, t, J = 7.2 Hz), 2.09–2.33
(4H, m), 3.75 (2H, s), 3.82 (1H, br s), 3.84 (3H, d, J = 11.1 Hz),
4.16 (2H, q, J = 7.2 Hz), 7.15–7.21 (3H, m), 7.41 (1H, dd, J = 8.0
and 8.0 Hz). 31P NMR (D2O) dP: 32.7. HRMS-FAB-glycerol (m/z):
[M+H]+ calcd for C15H23NO7P, 360.1212; found 360.1212.
5.3.4. (2RS,RPSP)-2-Amino-4-{[3-(carbamoylmethyl)phenoxy]
(methoxy)phosphoryl}butanoic acid (2d)
Yield 98%, colorless solid: 1H NMR (D2O) dH: 2.11–2.34 (4H, m),
3.67 (2H, s), 3.85 (1H, br s), 3.88 (3H, d, J = 11.4 Hz), 7.18–7.26 (3H,
m), 7.45 (1H, dd, J = 7.8 and 7.8 Hz). 31P NMR (D2O) dP: 32.7. HRMS-
FAB-glycerol (m/z): [M+[M+H]+ calcd for C13H20N2O6P, 331.1059;
found 331.1051.
5.2.7. (2RS,RPSP)-Benzyl 2-benzyloxycarbonylamino-4-{bis[3-
(benzyloxycarbonylmethyl)phenoxy]phosphoryl}butanoate
(7a)
To an ice cold solution of compound 5 (prepared from 10.6 mmol
of racemic Z-APBA-OBn as described above) and benzyl 3-hydrox-
yphenylacetate (4.74 g, 19.6 mmol) in anhydrous dichloromethane
(40 mL) was added triethylamine (4.0 mL, 28.7 mmol) dropwise
and the mixture was stirred for 18 h at room temperature. To the
reaction mixture was added silica gel (50 mL) and the volatile com-
pounds were evaporated. The residue was subjected to silica gel
flash column chromatography (hexane/ethyl acetate = 3:2) to give
the title compound (6.42 g, 71%) as a pale yellow oil. 1H NMR (CDCl3)
dH: 1.94–2.22 (3H, m), 2.31–2.47 (1H, m), 3.61 (4H, s), 4.47–4.54 (1H,
m), 5.10 (6H, s), 5.17 (2H, s), 5.56 (1H, br d, J = 8.1 Hz), 7.03–7.08 (6H,
m), 7.22 (2H, dd, J = 8.1 and 8.1 Hz), 7.26–7.37 (20H, m). 31P NMR
(CDCl3) dP: 24.6. Anal Calcd for C49H46NO11P: C, 68.76; H, 5.42; N,
1.64. Found: C, 68.57; H, 5.53; N, 1.64.
5.3.5. (2RS,RPSP)-2-Amino-4-{[3-nitrophenoxy](methoxy)phos-
phoryl}butanoic acid (2e)
To compound 2e (1.09 g, 2.01 mmol) dissolved in nitromethane
(10 mL) were added anisole (1.30 g, 12.0 mmol) and aluminum
chloride (0.80 g, 6.00 mmol) successively, and the mixture was
stirred for 3 h at ambient temperature. When the reaction was
complete, water (20 mL) was added and the mixture was washed
with diethyl ether (3 ꢁ 50 mL). The mixture was passed through
the silica gel column (eluted with MeOH) and the red fraction
was collected. The fractions were evaporated and purified by
ODS column (30–60% MeOH/H2O, eluted at 60% MeOH).
Lyophilization gave 2e as colorless solid. Yield 0.40 g (63%). 1H
NMR (D2O) dH: 2.17–2.42 (4H, m), 3.86 (1H, br s), 3.88 (3H, d,
J = 12.0 Hz), 7.62–7.68 (2H, m), 8.04–8.14 (2H, m). 31P NMR (D2O)