[
C.-L. Feng et al. / Chinese Chemical Letters 24 (2013) 767–769
O
O
O
O
O
O
O
OH
O
e
b
d
a
O
O
O
O
+
O
N
Bn
7
Bn
Bn
N
N
O
OH
Cl
4
8
5
3
9
c
O
HClHN
+
O
g
11
N
H
6
O
f
O
O
O
O
O
j
NH
h
H2N
NH
N
H
O
NH
i
OH
O
OH
O
O
10
O
O
O
Bn
NH
NH
N
N Bn
1
13
12
2
Scheme 1. The synthesis of marinamide (1) and its methyl ester (2). Reagents and conditions: (a) methanol, reflux; (b) SOCl2, reflux; (c) KOH, DMSO, benzyl bromide, N2; (d)
Zn, toluene, r.t.; (e) 50% NaOH, methanol; (f) SOCl2, methanol; (g) HOBT, EDCI, THF; (h) DBU, methanol/THF; (i) TFA/H2SO4, anisole; (j) 6 mol/L HCl, CH3CN.
(m, 2H), 7.85–7.88 (m, 1H). 13C NMR (75 MHz, CDCl3):
d
51.26,
(cmÀ1):
n 3428, 3294, 3100, 3056, 3028, 2950, 2927, 1762, 1660,
51.98, 108.96, 122.58, 127.18, 128.13, 129.39, 129.39, 129.43,
129.43, 129.61, 129.67, 129.70, 130.64, 131.82, 132.01, 138.71,
1624, 1591, 1544, 1525, 1457, 1409, 1396, 1348, 1316, 1256, 1209,
1175, 1153, 1084, 1036, 1011, 968, 920, 876, 758, 752, 688; 1H
141.51, 166.60, 185.05. HRMS calcd. for
320.1287; found: 320.1289.
C
20H18NO3 [M+1]:
NMR (300 MHz, DMSO-d6): d 3.60 (s, 3H), 3.86 (d, 2H, J = 6.6 Hz),
5.65 (s, 2H), 6.14 (m, 1H), 6.34 (m, 1H), 7.37–7.18 (m, 7H), 7.59 (m,
2H), 7.70 (m, 1H), 8.87 (d, 1H, J = 6.6 Hz); 13C NMR (75 MHz,
2.2. Preparation of 2-(1H-pyrrole-2-carbonyl)benzoic acid (9)
DMSO-d6): d 41.65, 52.23, 52.64, 109.27, 124.86, 125.81, 127.34,
127.53, 128.43, 128.56, 128.61, 129.71, 129.96, 130.48, 131.91,
133.09, 134.28, 138.05, 139.64, 167.94, 169.95, 186.73; HRMS
calcd. for C22 H21N2O4 [M+1]: 377.1501; found: 377.1504.
The compound 8 (12 g) was dissolved in methanol (100 mL)
followed by the addition of a 50% NaOH solution (20 mL). The
mixture was stirred at room temperature for 1 h and neutralized
with hydrochloric acid. After methanol was evaporated under
reduced pressure, the residue was extracted with ethyl acetate (3Â
100 mL). After evaporation of the solvent, the solid was recrys-
tallized from dichloromethane/methanol to give the colorless
2.4. Preparation of 4-(1-benzyl-1H-pyrrol-2-yl)-1-oxo-1,2-dihydro-
isoquinoline-3-carboxylic acid methyl ester (13)
Compound 12 (0.38 g, 1 mmol) was dissolved in methanol
(10 mL) and THF (5 mL), and then 1,8-diazabicyclo[5.4.0]-7-
undecene (DBU, 0.3 g, 2 mmol) was added. The mixture was
heated under reflux for 12 h. The solvent was evaporated under
reduced pressure, and the residue was partitioned between ethyl
acetate and 1 mol/L hydrochloric acid, washed with aqueous
sodium bicarbonate, and brine. The solvent was evaporated under
reduced pressure, and the obtained residue was purified by silica
gel column chromatography to give 13 (0.3 g, 86% yield) as yellow
crystal 9 (9.6 g, 96% yield). Mp: 166–168 8C. IR (cmÀ1):
n 3414,
3004, 2952, 1721, 1631, 1524, 1461, 1403, 1383, 1329, 1287, 1254,
1123, 1088, 1060, 961, 917, 886, 875, 777, 752. 1H NMR (300 MHz,
DMSO-d6):
d
5.71 (s, 2H), 6.13 (m, 1H), 6.27 (m, 1H), 7.22–7.37 (m,
51.08, 108.90,
9H), 7.88 (m, 1H). 13C NMR (75 MHz, DMSO-d6):
d
122.15, 126.95, 127.09, 127.09, 127.78, 127.78, 129.35, 129.48,
130.02, 130.02, 130.38, 131.47, 131.47, 138.87, 141.87, 167.39, and
185.79. HRMS calcd. for C19H16NO3 [M+1]: 306.1131; found:
306.1130.
powders. Mp: 182–183 8C; IR (cmÀ1):
n 3433, 3169, 3109, 3049,
2948, 2917, 1737, 1655, 1602, 1495, 1463, 1431, 1336, 1294, 1249,
1230, 1154, 1124, 1067, 873, 751,724, 579. 1H NMR (300 MHz,
2.3. Preparation of [2-(1-benzyl-1H-pyrrole-2-
carbonyl)benzoylamino]acetic acid methyl ester (12)
CDCl3):
7.16 (m, 7H), 7.62 (m, 2H), 8.24 (d, 1H, J = 7.26 Hz), 11.43 (s, 1H).
13C NMR (75 MHz, CDCl3):
52.64, 53.51, 112.83, 113.11, 117.69,
126.80, 127.81, 127.81, 128.06, 128.06, 128.30, 128.47, 128.76,
129.61, 129.61, 130.06, 130.06, 133.36, 134.53, 137.38, 160.94,
161.17. HRMS calcd. for C22H19N2O3 [M+1]: 359.1396; found:
359.1405.
d 3.57 (s, 3H), 4.88 (m, 2H), 6.02 (m, 1H), 6.19 (m, 1H), 6.93–
N-Hydroxybenzotrizole (HOBT) (1.6 g, 12 mmol) and com-
pound 9 (3.5 g, 10 mmol) were dissolved in anhydrous THF
(50 mL). Then, 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide
hydrochloride (EDCI) (1.91 g, 10 mmol) was added, and the
solution was stirred for 30 min. This solution was transferred to
d
a
solution of glycine methyl ester hydrochloride 11 (1.5 g,
12 mmol) and triethylamine (1.6 g, 16 mmol) in THF (60 mL) that
had been prepared. The reaction was allowed to stir overnight at
room temperature. Then the reaction was diluted with water
(200 mL) and extracted with ethyl acetate (200 mL). The organic
layer was washed with water (100 mL), a solution of saturated
sodium bicarbonate (100 mL), 1 mol/L hydrochloric acid (100 mL),
and finally water again (100 mL). After evaporation of the solvent,
the crude product was crystallized from dichloromethane to give
the colorless crystal 12 (3.4 g, 90% yield). Mp 187–189 8C; IR
2.5. Preparation of methyl ester of marinamide (2)
A solution of 13 (0.36 g, 1 mmol), trifluoroacetic acid (1.5 mL),
methoxybenzene (0.5 mL) and concentrated sulfuric acid (0.1 mL)
was heated at 90 8C for 30 min. The reaction mixture was dissolved
in ice water and extracted with dichloromethane (3Â 50 mL) and
washed with saturated sodium bicarbonate (2Â 30 mL). The
organic layer was dried over anhydrous sodium sulfate, and
concentrated under reduced pressure to give a yellow solid