Total synthesis of a novel isoquinolinone alkaloid marinamide and its methyl ester

Article abstract of DOI:10.3184/174751913X13662146264623

A naturally occurring isoquinolinone alkaloid marinamide and its methyl ester were synthesised from phthalic anhydride over eight steps in 46% and 52% overall yield. The key intermediate methyl 2-(1-benzyl-1H-pyrrole-2-carbonyl) benzoate was synthesised from the acid chloride of mono methyl phthalate and 1-benzyl-1H-pyrrole catalysed by Zinc oxide under solvent-free conditions at room temperature.

Full text of DOI:10.3184/174751913X13662146264623

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 291
MAY, 291–293
Total synthesis of a novel isoquinolinone alkaloid marinamide and its
methyl ester
Shuguang Zhang, Chengliang Feng, Jin Cai, Junqing Chen and Min Ji*
Institute of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu, 211189,
P. R. China
A naturally occurring isoquinolinone alkaloid marinamide and its methyl ester were synthesised from phthalic anhy-
dride over eight steps in 46% and 52% overall yield. The key intermediate methyl 2-(1-benzyl-1H-pyrrole-2-carbonyl)
benzoate was synthesised from the acid chloride of mono methyl phthalate and 1-benzyl-1H-pyrrole catalysed by
Zinc oxide under solvent-free conditions at room temperature.
Keywords: isoquinolinone, marinamide, methyl ester, total synthesis
The isoquinolinone pharmacophore has an important therapeu-
tic potential.1 Some isoquinolinone derivatives exhibit marked
biological effects such as antitumour, cytotoxic antibiotic and
cardiovascular activities.2–6
been reported. The development of an efficient synthesis of
marinamide and its methyl ester would be of significance. We
report an efficient approach (Scheme 1) to the synthesis of
marinamide and its methyl ester.
Marinamide(1), a novel isoquinolinone alkaloid and its
methyl ester (2) (Fig.1) were isolated from the metabolites of
a mixed fermentation of two mangrove endophytic fungi from
the South China Sea. They display significant antibacterial
activities against Escherichia coli, Pseudomonas pyocyanea,
and Staphylococcus aureus and exhibit significant antitumour
activities against HepG2, 95-D, MGC832 and Hela cells with
IC50 value of 2.52, 1.54, 0.013, 0.110 and 0.007, 0.0004, 0.091,
0.529 µg mL−1, respectively.7 To the best of our knowledge, the
total synthesis of marinamide and its methyl ester has not yet
As illustrated in Scheme 1, monoesterification of phthalic
anhydride with methanol afforded 3 in 98% yields8. Regiose-
lective Friedel–Crafts acylation of 1-benzyl-1H-pyrrole(8)
with 4 yielded the key intermediate 9 in 78% yield. Subse-
quently the hydrolysis of 9 with NaOH gave 10. The alkylation
of 10 with diethyl bromomalonate followed by treatment with
acetic acid and concentrated hydrochloric acid gave compound
11. Reaction of 11 with the appropriate amines followed by
methyl ester gave the compound 12. The deprotection of 12
with acid yielded the compound 2. Hydrolysis of 2 with 6N
hydrochloride acid produced marinamide 1.9
The synthesis of the key intermediate 9 involved a regiose-
lective Friedel–Crafts acylation of pyrrole. Initially, the
compound 9 was prepared using 1-benzyl-1H-pyrrole (8) with
4 in toluene catalysed by Zn based on the literature method.10
However, this method had some drawbacks including the use
of toxic solvents, low yields and long reaction time. In recent
years, progress in the field of solvent-free reactions has gained
significance because of their high efficiency, operational
simplicity and environmentally benign processes11. Hence
we adopted a solvent-free method to prepare 9. Traditional
Friedel–Crafts acylation catalysts, such as AlCl3, ZnCl2, and
FeCl3, showed little catalytic activity. Zinc oxide (ZnO) gave a
Fig. 1 Structures of marinamide (1) and its methyl ester (2).
Scheme 1 Synthesis of marinamide (1) and its methyl ester (2). Reagents and conditions: (a) methanol, reflux; (b) thionyl
chloride, reflux;(c) potassium hydroxide, THF, benzyl bromide; (d) zinc oxide, room temperature; (e) 50%NaOH, methanol;
(f) potassium carbonate, diethyl bromomalonate, room temperature; (g) concentrated hydrochloric acid, acetic acid, 120 °C;
(h) ammonia, methanol, hydrochloric acid,room temperatureand methanol, sulfuric acid; (i) trifluoroacetic acid, sulfuric acid,
anisole; (j) 6 N hydrochloric acid, acetonitrile, reflux.
* Correspondent. E-mail: jimin@seu.edu.cn

292 JOURNAL OF CHEMICAL RESEARCH 2013
132.01, 138.71, 141.51, 166.60, 185.05; HRMS ([M+H]+): m/z calcd
for C20 H18 N O3: 320.1287; found: 320.1289.
significant rate increase, affording 78% yields of 9. Further
optimisation showed that ZnO, solvent-free conditions and
room temperature were the most efficient reaction conditions.
Therefore, the key intermediate 9 was synthesised using 8 with
4 catalysed by ZnO in solvent-free conditions at room
temperature. Initially, we planned to adopt another program
for the synthesis of the two compounds (Scheme 2). However
alkylation of the key intermediate 6 with diethyl bromomalo-
nate under basic conditions gave the compound 7, rather than
13 and this approach was abandoned.
In conclusion, we have synthesised the natural isoquinoli-
none marinamide and its methyl ester in good yields for the
first time. Our synthetic approach to marinamide is flexible
and can be used to synthesise a variety of analogues for
antitumour testing.
2-(1-Benzyl-1H-pyrrole-2-carbonyl)benzoic acid (10): Compound
9 (12 g, 37.6 mmol) was dissolved in methanol (100 mL) and then
50% NaOH solution (20 mL) was added. The mixture was stirred at
room temperature for 1 h and then the solvent was neutralised by
treatment with hydrochloric acid. After the methanol was evaporated
under reduced pressure, the residue was extracted with ethyl acetate
(3×50 mL). After evaporation of the solvent, the solid was crystallised
with dichloromethane/methanol to the colourless crystals of 10 (9.6 g,
96% yield); m.p. 166–168 °C. IR(cm−1): 3414, 3004, 2952, 1721,
1631, 1524, 1461, 1403, 1383, 1329, 1287, 1254, 1123, 1088, 1060,
961, 917, 886, 875, 777, 752; 1HNMR (300 MHz, DMSO-d6) δ 5.71
(s, 2H), 6.13 (m, 1H), 6.27 (m, 1H), 7.22–7.37 (m, 9H), 7.88 (m, 1H);
13C NMR (75 MHz, DMSO-d6) δ 51.08, 108.90, 122.15, 126.95,
127.09, 127.78, 129.35, 129.35, 129.48, 129.48, 129.48, 130.02,
130.38, 130.38, 131.47, 138.87, 141.87, 167.39, 185.79; HRMS
([M+H]+): m/z calcd for C19H16NO3: 306.1131; found: 306.1130.
4-(1-Benzyl-1H-pyrrol-2-yl)-1-oxo-1H-isochromene-3-carboxylicacid
(11): Potassium carbonate (1.4 g, 10 mmol) was added to a solution of
compound 10 (3.1 g, 10 mmol) in acetone (100 mL) and the mixture
was stirred at room temperature for 10 min. Then diethyl bromomalo-
nate (3.6 g, 15 mmol) and DMF (2 mL) were added, and the mixture
was stirred at room temperature for 20 h. The reaction mixture was
concentrated under reduced pressure, and ethyl acetate (50 mL) and
water (50 mL) were then added to the residue. The mixture was stirred
at room temperature for 30 min. The organic layer was separated and
washed with water (50 mL) and brine (50 mL), dried over anhydrous
sodium sulfate and concentrated under reduced pressure. A mixture of
acetic acid (20 mL) and concentrated hydrochloric acid (20 mL) was
added to the residue, and the mixture was stirred at 120 °C for 15 h.
After cooling, the reaction mixture was concentrated under reduced
pressure. The residue was dissolved in ethyl acetate (100 mL),
washed with water (50 mL) and brine (50 mL), dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The residue
was crystallised from dichloromethane and collected by filtration to
give yellow crystals of 11 (2.48 g, 73% yield); m.p. 215–217 °C. IR
(cm−1): 3356, 2925, 2907, 1748, 1668, 1485, 1462, 1431, 1268, 891,
871, 771; 1H NMR (300 MHz, CDCl3) δ 5.04 (m, 2H), 6.04 (m, 1H),
6.23 (m, 1H), 6.94–7.13 (m, 7H), 7.58 (m, 2H), 8.17 (m, 1H), 12.67
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 51.04, 107.92, 110.16, 121.63,
123.64, 125.46, 126.02, 126.74, 126.74, 128.58, 128.92, 129.42,
129.42, 130.24, 130.40, 131.09, 131.28, 131.42, 133.87, 150.67,
164.78; HRMS ([M+H]+): m/z calcd for C21H16NO4: 346.1079; found:
346.1081.
Experimental
All reagents were purchased from commercial sources and used with-
out further purification. Melting points were determined on a RY-1 hot
stage microscope and are uncorrected. IR spectra were determined as
1
KBr pellets on a Thermo Nicolet 6700 spectrophotometer. H NMR
and 13C NMR spectra were recorded on Bruker Avance DPX-300
MHz/500 MHz instruments in CDCl3 or DMSO, chemical shifts (δ)
are given in part per million(ppm) relative to TMS as an internal
standard. The HRMS spectra were obtained on a Thermo Finnigan
spectrometer, model MAT 95XP. All reactions were monitored by
TLC on silica gel GF-254 glass plates (E.Merck) and viewed under
UV light at 254 nm.
Methyl 2-(1-benzyl-1H-pyrrole-2-carbonyl) benzoate (9): 2-(Meth-
oxycarbonyl)benzoic acid (12.6 g, 70 mmol) was dissolved in dry
dichloromethane (100 mL) and then thionyl chloride (12.5 g, 105 mmol)
was added and the mixture was heated under reflux for 45 min. The
solvent was evaporated under reduced pressure, toluene (50 mL) was
added and the mixture was re-concentrated. The residue which
was obtained was dropped into the mixtures of 1-benzyl-1H-pyrrole 8
(7.5 g, 50 mmol) and ZnO powder (1.6 g, 20 mmol). The mixture was
stirred at room temperature. After completion of the reaction as indi-
cated by TLC, the solid mass was then eluted with dichloromethane
(100 mL) and washed with saturated sodium bicarbonate(2×100 mL)
and then dried over anhydrous sodium sulfate. Evaporation of the
solvent followed by purification on silica gel gave a colourless
liquid 9 (12 g, 78% yield). IR(cm−1): 2950, 2921,1721, 1630, 1457,
1
1397, 1323, 1331, 1263, 1122, 1078, 1030, 913, 871, 714; H NMR
(300 MHz, DMSO-d6) δ 3.38 (s, 3H), 5.70 (s, 2H), 6.18 (dd, 1H,
J = 2.52 Hz, 4.05Hz), 6.33 (dd, 1H, J = 1.71 Hz, 4.05 Hz), 7.23–7.46
(m, 7H), 7.60–7.66 (m, 2H), 7.85–7.88 (m, 1H); 13C NMR (75 MHz,
DMSO-d6) δ 51.26, 51.98, 108.96, 122.58, 127.18, 128.13, 129.39,
129.43, 129.43, 129.61, 129.70, 129.70, 131.82, 131.82, 132.01,
4-(1-Benzyl-1H-pyrrol-2-yl)-1-oxo-1,2-dihydroisoquinoline-3-carboxylic
acid (12): An ammonia/methanol solution (20 mL) was added to
a solution of compound 11 (1.7 g, 50 mmol) in methanol (30 mL)
and the mixture was stirred at room temperature for 24 h. The
reaction mixture was concentrated under reduced pressure, and 1 N
Scheme 2 Reagents and conditions: (a) Znic oxide, rt; (b) 50%NaOH, methanol; (c) potassium carbonate, diethyl bromomalonate,
room temperature.

JOURNAL OF CHEMICAL RESEARCH 2013 293
hydrochloric acid (20 mL) was added to the residue. The mixture was
extracted with ethyl acetate (3×50 mL). The organic layer was dried
and concentrated under reduced pressure and 4N hydrochloric acid
(30 mL) was added to the resultant oily substance. The mixture was
stirred at room temperature for 2 h. The reaction mixture was concen-
trated under reduced pressure. The resultant yellow powder was
washed with water (2×50 mL), and dried under reduced pressure to
give a yellow powder which was dissolved in a mixture of methanol
(20 mL) and concentrated sulfuric acid (2 mL), and refluxed for 20 h.
The reaction mixture was concentrated under reduced pressure,
and the residue was neutralized with aqueous potassium carbonate
solution and extracted with dichloromethane (3×50 mL). The organic
layer was washed with water (50 mL) and brine (50 mL), dried over
anhydrous sodium sulfate, and concentrated under reduced pressure
to give yellow powder 12 (1.72 g, 96% yield); m.p.182–183 °C. IR
(cm−1): 3433, 3169, 3109, 3049, 2948, 2917, 1737, 1655, 1602, 1495,
1463, 1431, 1336, 1294, 1249, 1230, 1154, 1124, 1067, 873, 751,724,
3H), 7.88 (m, 1H), 9.76 (s, 1H), 11.79 (s, 1H), 14.95 (s, 1H); 13C NMR
(75 MHz, DMSO-d6) δ 106.48, 109.17, 113.56, 120.18, 121.96,
122.54, 123.31, 123.48, 125.46, 134.34, 136.78, 146.72, 167.56,
178.34; HRMS ([M+H]+): m/z calcd for C14H11N2O3: 255.0770; found:
255.0773.
Pyrrolo [1,2-b]isoquinoline-5,10-dione (7): Potassium carbonate
(0.14 g, 1 mmol) was added to a solution of compound 6 (0.22 g,
1mmol) in acetone (20 mL) and the mixture was stirred at room
temperature for 10 min. Diethyl bromomalonate (0.36 g, 1.5 mmol)
and DMF (0.1 mL) was added and the mixture was stirred at room
temperature for 20 h. The reaction mixture was concentrated under
reduced pressure, and ethyl acetate (20 mL) and water (20 mL) were
added to the residue. The mixture was stirred at room temperature
for 30 min. The organic layer was separated and washed with water
(50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and
then concentrated under reduced pressure to give yellow powder
7(0.185 g, 94% yield); m.p.119–120 °C. IR (cm−1): 3297, 3129, 1714,
1659, 1595, 1554, 1440, 1410, 1335, 1310, 1295, 1213, 1179, 1139,
1
579; H NMR(300 MHz, CDCl3) δ 3.57 (s, 3H), 4.88 (m, 2H), 6.02
1
(m, 1H), 6.19 (m, 1H), 6.93–7.16 (m, 7H), 7.62 (m, 2H), 8.24 (d, 1H,
J = 7.26 Hz), 11.43 (s, 1H); 13C NMR (75 MHz, CDCl3) δ: 52.64,
53.51, 112.83, 113.11, 117.69, 126.80, 127.81, 128.06, 128.30,
128.47, 128.76, 128.76, 128.76, 129.61, 130.06, 130.06, 133.36,
134.53, 137.38, 137.38, 160.94, 161.17; HRMS ([M+H]+): m/z calcd
for C22H19N2O3: 359.1396; found: 359.1398.
1065, 1014, 972, 867, 797, 757, 711, 602, 586; H NMR(300 MHz,
CDCl3) δ 6.51 (m,1H), 7.33 (m,1H), 7.74–7.83 (m, 3H), 8.26–8.36
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 109.99, 118.57, 125.99,
127.88, 129.49, 129.50, 130.86, 131.45, 131.81, 141.04, 167.59,
184.79; HRMS ([M+H]+): m/z calcd for C12H8NO2: 198.0555; found:
198.0559.
Methyl ester of marinamide (2): A solution of compound 12
(0.36 g, 1 mmol), trifluoroacetic acid (1.5 mL), methoxybenzene
(0.5 mL) and concentrated sulfuric acid (0.2 mL) was heated at 90 °C
for 30 min. The reaction mixture was dissolved in ice-water and
extracted with dichloromethane (3×50 mL) and washed with saturated
sodium bicarbonate (2×30 mL). The organic layer was dried with
anhydrous sodium sulfate, and concentrated under reduced pressure to
give yellow solid followed by purification on silica gel to give pure
product 2 (0.18 g, 67% yield); m.p. > 300 °C, (lit.12 m.p. > 300 °C).
IR(cm−1): 3425, 3169, 3112, 3049, 2951, 2920, 1737, 1655, 1602,
1496, 1464, 1452, 1432, 1336, 1294, 1271, 1249, 1232, 1155, 1125,
1068, 963, 892, 771, 724, 695, 645, 580; 1H NMR (300 MHz, CDCl3)
δ 3.54 (s, 3H), 6.11 (m, 1H), 6.25 (m, 1H), 7.06 (m, 1H), 7.41–7.58
(m, 3H), 7.89 (m, 1H), 12.01 (s, 1H), 13.45 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 52.17, 108.54, 110.67, 112.48, 116.98, 122.23,
122.45, 123.61, 124.50, 124.63, 131.44, 140.07, 141.14, 167.45,
172.28; HRMS ([M+H]+): m/z calcd for C15H13N2O3: 269.0926; found:
269.0931.
Marinamide (1): 6N Hydrochloric acid (25 mL) was added to a
solution of methyl ester of marinamide (0.1 g, 0.37 mmol) in acetoni-
trile (10 mL) and the mixture was refluxed for 20 h. The reaction
mixture was extracted with ethyl acetate (3×50 mL). The organic layer
was washed with water (20 mL) and brine (20 mL), dried over anhy-
drous sodium sulfate, and concentrated under reduced pressure to give
a yellow powder of 1 (0.085 g, 89% yield); m.p. > 300 °C, (lit.12 m.p.
> 300 °C). IR(cm−1): 3428, 3168, 3116, 3049, 2952, 2918, 1737, 1655,
1602, 1496, 1464, 1452, 1432, 1336, 1294, 1271, 1249, 1231, 1155,
1125, 1068, 963, 874, 771, 724, 695, 645, 580; 1H NMR (300 MHz,
DMSO-d6) δ 6.18 (m, 1H), 6.23 (m, 1H), 6.98 (m, 1H), 7.35–7.56 (m,
We are grateful to the National Basic Research Program of
China (No. 2011CB933503) for financial support.
Received 22 January 2013; accepted 14 March 2013
Paper 1301741 doi: 10.3184/174751913X13662146264623
Published online: 15 May 2013
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