A facile synthesis of asterriquinone D

Article abstract of DOI:10.1002/jhet.5570450544

(Chemical Equation Presented) Asterriquinone D was easily synthesized in three steps from 2,5-dichloro-1,4-benzoquinone. The reaction of benzoquinone with indole in the presence of Pd(OAc)₂, followed by oxidation with cerium (IV) ammonium nitrate (CAN) produced 3,6-dichloro-2,5-bis (3-indolyl)-1,4-benzoquinone. The methoxylation of the dichloride with NaOH in CH₃OH afforded asterriquinone D.

Full text of DOI:10.1002/jhet.5570450544

Sep-Oct 2008
1509
A Facile Synthesis of Asterriquinone D
Yasuhiro Tanoue*, Takashi Motoi, Yutaka Masuda and Norihisa Kai
Department of Food Science and Technology, National Fisheries
University, Nagatahonmachi, Shimonoseki 759-6595, Japan
E-mail: tanoue@fish-u.ac.jp
Kazunori Sakata and Mamoru Hashimoto
Department of Applied Chemistry, Faculty of Engineering, Kyushu Institute of Technology, Tobata-ku,
Kitakyushu 804-8550, Japan
Takeshi Nagai
Department of Food Science and Technology, Tokyo University of Agriculture, Abashiri,
Hokkaido 099-2493
Received January 18, 2008
NH
O
O
O
O
Cl
MeO
+
2
N
H
Cl
OMe
HN
Asterriquinone D was easily synthesized in three steps from 2,5-dichloro-1,4-benzoquinone. The
reaction of benzoquinone with indole in the presence of Pd(OAc)2, followed by oxidation with cerium (IV)
ammonium nitrate (CAN) produced 3,6-dichloro-2,5-bis (3-indolyl)-1,4-benzoquinone. The methoxylation
of the dichloride with NaOH in CH3OH afforded asterriquinone D.
J. Heterocyclic Chem., 45, 1509 (2008).
INTRODUCTION
NR2
O
O
R1O
Asterriquinone (1), which has a bis(indolyl)benzo-
quinone skeleton, has been isolated by Yamamoto et al.
[1] from Asperigillus terreus IFO 6123 as one of the
intracellular metabolic products. They have also reported
its antitumor activity [2] and other asterriquinones [3]
such as asterriquinone A-D. There are many reports on
other medicinal activities [4]. Didemethylasterriquinone,
another isomer of hinnuliquinone (3) [5] and cochliodinol
(4) [6], has similar properties.
OR1
R2N
1. Asterriquinone: R1=Me, R2= -C(CH3)2CH=CH2
2. Asterriquinone D: R1=Me, R2=H
R1
NH
O
R2
HO
The total synthesis of the natural product asterriquinone
B1 and demethylasterriquinone B1 has been accomplished
by Liu et al. [7], Tatsuta et al. [8], and Pirrung et al. [9].
Tetrahydroasterriquinone E has also been reported by
Harris et al. [10].
OH
R2
O
HN
R1
3. Hinnuliquinone: R1= -C(CH3)2CH=CH2, R2=H
4. Cochliodinol: R1=H, R2= -CH2CH=C(CH3)2
Asterriquinone D (2) has also been isolated by
Yamamoto et al. [3] and it has been reported that dide-
methylasterriquinone D is an attractive lead compound for
inhibitors of HIV-1 protease [11]. The compound 2 has
no dimethylallyl group; therefore, it is the fundamental
compound on the asterriquinone group. We now report a
convenient synthesis of asterriquinone D.
Figure 1
22 h produced the hydroquinones (7 and 8). Attempts to
separate 7 and 8 by column chromatography were
unsuccessful. The total ion chromatogram of the EI-MS of
the mixture products showed two peaks, and the
molecular ion peaks appeared at m/z 408 and 209,
respectively. On the other hand, the bands due to the NH
and OH stretching modes in the IR spectrum of the
products were observed at 3415 cm-1 and 3280 cm-1,
RESULTS AND DISCUSSION
The reaction of 2,5-dichloro-1,4-benzoquinone (5) [12]
with 3 equiv. of indole (6) in the presence of a palladium
(II) acetate catalyst in acetonitrile at room temperature for

1510
Y. Tanoue, T. Motoi, Y. Masuda, N. Kai, K.Sakata, M. Hashimoto and T. Nagai
Vol 45
Scheme 1
Pd(OAc)2
NH
NH
O
OH
OH
OH
in CH3CN
rt, 22 h
Cl
Cl
Cl
+
+
N
H
Cl
Cl
Cl
O
OH
HN
5
6
7
8
Ce(NH4)2(NO3)6
in CH3CN
NH
NH
O
O
O
Cl
Cl
+
Cl
Cl
rt, 20 min
O
HN
9
10
NaOH
NH
O
in CH3OH
MeO
9
OMe
2-4˚C, 1 h
O
HN
2
pellets. The melting points were obtained using a Yanaco MS-
S3 micro melting point apparatus (hot-plate type). For
preparative column chromatography, Wakogel C-200 silica gel
was employed. Thin-layer chromatography (TLC) was
accomplished on precoated plates of silica gel 60
F254+365(Merck). Indole and 2,5-dichloro-1,4-benzoquinone were
purchased from Tokyo Kasei Kogyo Co, Ltd. (Tokyo, Japan).
respectively. The structures of the hydroquinone (7 and 8)
were determined by these data.
The oxidation of the mixture (7 and 8) with 3 equiv. of
cerium (IV) ammonium nitrate (CAN) [13, 14] gave two
products, 3,6-dichloro-2,5-bis(3-indolyl)-1,4-benzo-
quinone (9) (23%) and 3,6-dichloro-2(3-indolyl)-1,4-
benzoquinone (10) (11%) [15]. The product mixture could
be separated by the difference in the solubility for
chloroform and the ratio of these products was about 2:1.
The 13C NMR spectrum of 9 shows only one (C=O)
signal, indicative of para regiochemistry. On the other
hand, the 13C NMR spectrum of 10 contains two (C=O)
signals, indicative of the asymmetric regiochemistry.
Asterriquinone D (2) was synthesized in 35% yield
from 9 by treatment with NaOH in CH3OH for 1 hour.
The compound was insoluble in most organic solvents [3].
Thus, 2 was prepared in three simple steps from the
commercially available 2,5-dichloro-1,4-benzoquinone.
The Reaction of 2,5-Dichloro-1,4-benzoquinone (5) with
Indole (6). To a solution of 5 (100 mg, 0.565 mmol) and 6 (199
mg, 3ꢀ 0.565 mmol) in acetonitrile (10 mL) was added
palladium (II) acetate (12.7 mg, 0.0565 mmol). The mixture was
stirred at room temperature for 22 h. After concentration under
reduced pressure, the residue was chromatographed on silica-gel
to give the mixture (123 mg) of 3,6-dichloro-2,5-bis(3-
indolyl)hydroquinone (7) and 3,6-dichloro-2(3-indolyl)hydro-
quinone (8). ir: NH, OH 3500-3100, 1433, 1179, 867, 805, 746
cm-1; EI-ms: m/z ( relative intensity) 408 (M+,100%), 410 (M+2,
66.0), 412(M+4, 12.7), 293 (M+, 100%), 295 (M+2, 61.4), 297
(M+4, 9.7).
Oxidation of Indolylhydroquinones (7 and 8) with CAN. A
solution of 7 and 8 (123 mg) in acetonitrile (8 mL) was cooled to
2-4°C. To the solution was added dropwise over 5 min a
solution of cerium (IV) ammonium nitrate (493 mg, 0.9 mmol)
in water (3 mL). After stirring for 20 min, the reaction mixture
was diluted with water and extracted with chloroform. The
chloroform solution was washed with brine, dried over
anhydrous sodium sulfate, and evaporated. To the residue was
added 1 mL of chloroform and the insoluble product was
filtered, and washed with 0.3 mL of chloroform to give 3,6-
dichloro-2,5-bis(3-indolyl)-1,4-benzoquinone (9) (48.2 mg). The
filtrate was concentrated and chromatographed by preparative
EXPERIMENTAL
1
The H NMR and 13C NMR spectra were obtained using a
JEOL JNM-A500 (500 MHz) spectrometer in dimethyl
sulfoxide-d6 at room temperature. Chemical shifts are given in
ppm relative to tetramethylsilane as the internal reference
standard. Mass spectra were performed using a JEOL JMS-SX
102A mass spectrometer. The infrared spectra were recorded
using a Shimadzu IR 470 spectrometer in potassium bromide

Sep-Oct 2008
A Facile Synthesis of Asterriquinone D
1511
TLC (silica gel; CHCl3:EtOH = 5:1) to give 9 (5 mg) and 3,6-
dichloro-2-(3-indolyl)-1,4-benzoquinone (10) (18.6 mg).
(33.0). HRMS (EI): calcd for C24H18N2O4 M+ 398.1267, found
398.1295.
9; mp 282 – 284°C; ir: NH 3370, C=O 1654, 1557, 1421,
1251, 1209, 1114, 743 cm-1; 1H nmr (DMSO-d6): ꢀ 7.11 (m, 2H,
5'-H), 7.19 (m, 2H, 6'-H), 7.42 (d, 2H, 7'-H, J = 8.3 Hz), 7.50 (d,
2H, 4'-H, J = 8.3 Hz), 7.73 (d, 2H, 2'-H, J = 2.5 Hz), 11.80 (d,
2H, NH, J = 2.5 Hz); 13C nmr (DMSO-d6) : ꢀ 105.96, 112.04,
119.72, 121.32, 121.65, 125.47, 130.63, 135.80, 135.84, 138.30,
177.48 (C=O); FAB-ms : m/z (relative intensity) 408 ([M+2H]+,
28%), 307 (81), 289 (41). HRMS (FAB): calcd for
C22H12Cl2N2O2 [M+2H]+ 408.0432, found 408.0458.
Acknowledgement. We are grateful to the Center for
Instrumental Analysis, Kyushu Institute of Technology, for mass
spectra and NMR spectra.
REFERENCES AND NOTES
[1] Yamamoto, Y.; Nishimura, K.; Kiriyama, N. Chem. Pharm.
Bull. 1976, 24, 1853.
[2] Yamamoto, Y.; Kiriyama, N.; Shimizu, S.; Koshimura, S.
Gann, 1976, 67, 623.
[3] Arai, K.; Masuda, K.; Kiriyama, N.; Nitta, K.; Yamamoto,
Y.; Shimizu, S. Chem. Pharm. Bull. 1981, 29, 961. The melting point
and the elemental analysis of asterriquinone D have been reported, but
the NMR and MS spectral data have not been described.
[4] For example, Alvi, K. A.; Pu, H.; Luche, M.; Rice, A.; App,
H.; McMahon, G.; Dare, H.; Margolis, B. J. Antibiot, 1999, 52, 215.
[5] Thomson, R. H. Naturally Occurring Quinones III, Chapman
& Hall, London, 1987, p105.
[6] Hörcher, U.; Schwennen, E.; Frank, B. Liebigs Ann. Chem.,
1986, 1765.
[7] Liu, K.; Wood, H. B.; Jones, A. B. Tetrahedron Lett. 1999,
40, 5119.
[8] Tatsuta, K.; Mukai, H.; Mitsumoto, K. J. Antibiot. 2001, 54,
105.
[9] Pirrung, M. C.; Li, Z.; Park, K.; Zhu, J. J. Org. Chem. 2002,
67, 7919.
[10] Harris, Jr. G. D.; Nguyen, A.; App, H.; Hirth, P.; McMahon,
G.; Tang, C. Org. Lett. 1999, 1, 431.
[11] Fredenhagen, A,; Petersen, F.; Tintelnot-Blomley, M.; Rosel,
J.; Mett, H.; Hug, P. J. Antibiot, 1997, 50, 395.
[12] Willis et al. (Chem. Commun. 2007, 4764) have recently
reported the reaction of 5 with 1-(1,1-dimethylallyl)indole in the
presence of HCl, followed by oxidation with DDQ.
[13] Jacob, III. P.; Callery, P. S.; Shulgin, A. T.; Castagnoli, Jr. N.
J. Org. Chem. 1976, 41, 3627.
[14] Tanoue, Y.; Terada, A. Bull. Chem. Soc. Jpn. 1988, 61, 2039.
[15] Pirrung et al. (J. Org. Chem. 2002, 67, 8374) have reported
the NMR spectral data in CDCl3 solvent.
10; mp 166 – 168°C (lit. [15] 124 – 125°C) ; ir: NH 3390,
C=O 1673, C=O 1650, 1560, 1421, 1270, 1248, 1010, 881, 748,
1
596 cm-1; H nmr (DMSO-d6): ꢀ 7.07 (m, 1H, 5'-H), 7.16 (m,
1H, 6'-H), 7.33 (d, 1H, 7'-H, J = 7.5 Hz), 7.47 (d, 1H, 4'-H, J =
8.0 Hz), 7.53 (s, 1H, 5-H), 7.65 (d, 1H, 2'-H, J = 3.0 Hz), 11.88
13
(s, 1H, NH); C nmr (DMSO-d6): ꢀ 105.39, 111.64, 119.34,
120.86, 121.29, 124.88, 130.27, 132.66, 135.04, 135.40, 138.28,
142.51, 176.75 (C=O), 177.43 (C=O); FAB-ms: m/z (relative
intensity) 293 ([M+2H]+, 71%), 232 (8), 192 (22), 79 (100).
HRMS (FAB): calcd for C14H7Cl2NO2 [M+2H]+ 293.0010, found
292.9997.
Synthesis of Asterriquinone D (2). A solution of the
indolylbenzoquinone (9) (22.1 mg, 0.054 mmol) in methanol (30
mL) was cooled to 2-4°C. To the solution was added finely
crushed sodium hydroxide (4.3 mg). After stirring for 1 h, the
reaction mixture was evaporated under reduced pressure and the
residue was chromatographed by preparative TLC (silica gel;
CHCl3:EtOH = 10:1) to give 2 (7.5 mg, 35%). Mp > 300°C (lit.
[3] > 300°C); ir: NH 3330, C=O 1638, 1581, 1506, 1421, 1278,
1
1253, 1236, 1124, 1043, 737 cm-1; H nmr (DMSO-d6) : ꢀ 3.75
(s, 6H, OCH3), 7.05 (m, 2H, 5'-H), 7.14 (m, 2H, 6'-H), 7.43 (d,
2H, 7'-H, J = 8.0Hz), 7.46 (d, 2H, 4'-H, J = 8.0 Hz), 7.59 (d, 2H,
2'-H, J = 2.5 Hz), 11.62 (s, 2H, NH); 13C nmr (DMSO-d6): ꢀ
60.06 (OCH3), 104.08 (3'-C), 111.63(7'-C), 119.29, 120.83.
121.21, 122.81, 126.50 (8'-C), 128.68 (2'-C), 135.75 (9'-C),
153.22 (3-C), 183.13 (1-C); EI-ms: m/z (relative intensity) 398
(M+, 100%), 355 (57.9), 327 (27.3), 256 (27.7), 128 (33.2), 44