Facile synthesis of avicequinone-B natural product

Article abstract of DOI:10.1081/SCC-120013719

An efficient synthesis of avicequinone-B (2) and furonaphthoquinone 4 has been carried out starting from 2-hydroxy-1,4-naphthoquinone (6) by CAN-mediated cycloaddition reaction.

Full text of DOI:10.1081/SCC-120013719

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FACILE SYNTHESIS OF AVICEQUINONE-B NATURAL
PRODUCT
a
a
a
a
b
Yong Rok Lee , Byung So Kim , Yong Ug Jung , Wha Soo Koh , Jin Soon Cha & Nam Woo
c
Kim
a
School of Chemical Engineering and Technology , Yeungnam University , Kyungsan,
7
12-749, Korea
b
Department of Chemistry , Yeungnam University , Kyungsan, 712-749, Korea
c
Kyungsan University , Kyungsan, 712-240, Korea
Published online: 16 Aug 2006.
To cite this article: Yong Rok Lee , Byung So Kim , Yong Ug Jung , Wha Soo Koh , Jin Soon Cha & Nam Woo Kim (2002)
FACILE SYNTHESIS OF AVICEQUINONE-B NATURAL PRODUCT, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 32:20, 3099-3105, DOI: 10.1081/SCC-120013719
To link to this article: http://dx.doi.org/10.1081/SCC-120013719
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 20, pp. 3099–3105, 2002
FACILE SYNTHESIS OF
AVICEQUINONE-B NATURAL PRODUCT
1
,
1
1
Yong Rok Lee, * Byung So Kim, Yong Ug Jung,
1
Wha Soo Koh, Jin Soon Cha, and NamWoo Kim
2
3
1
School of Chemical Engineering and Technology, and
2
Department of Chemistry, Yeungnam University,
Kyungsan 712-749, Korea
3
Kyungsan University, Kyungsan 712-240, Korea
ABSTRACT
An efficient synthesis of avicequinone-B (2) and furonaphtho-
quinone 4 has been carried out starting from 2-hydroxy-1,4-
naphthoquinone (6) by CAN-mediated cycloaddition reaction.
[
1]
Furonaphthoquinone derivatives are widely distributed in nature
and they have shown a variety of interesting biological activities such as
[2]
antileukemic activity, in vitro cytotoxicity against KB, K562, and P388
[4]
[3]
cells, and in vitro antiprotozoan activity against Trypanosoma cruzi.
They have been also used in traditional medicine as Pau d’Arco, Ipe
´
Roxo, Lapacho, and Taheebo for many years in North and South
America as anticancer, antifungal, antibacterial, and antiinflammatory
[5]
drugs.
*
Corresponding author. E-mail: yrlee@yu.ac.kr
099
3
DOI: 10.1081/SCC-120013719
Copyright & 2002 by Marcel Dekker, Inc.
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3
100
LEE ET AL.
Figure 1.
Very recently, new three naphthoquinones, avicequinone-A (1),
avicequinone-B (2), and avicequinone-C (3), have been isolated from
[
6]
the stem bark of Avicennia alba (Fig. 1). In addition, the furonaphtho-
quinones 4 and 5, isolated previously from Avicennia marina by Gillan
[
7]
[6]
et al., have been revised to furonaphthoquinones 2 and 3 by Ito et al.
Although the syntheses of these types of furonaphthoquinone
derivatives have been reported, simple and efficient approaches still
[8]
remain scarce. Before isolation from a natural source, synthesis of
[
9]
avicequinone-B (2) has already been reported by other groups. The
many steps and low yields in previous work have prompted a research
for better synthesis of furonaphthoquinone natural products. We describe
here a simple and efficient synthesis of avicequinone-B (2) and furo-
naphthoquinone 4.
We have recently reported on Ceric Ammonium Nitrate (CAN)-
[
mediated cycloaddition of 1,3-dicarbonyl compounds to several substrates.
10]
This method also seemed ideal for the synthesis of biologically active
furonaphthoquinone natural products. Our strategy was based on the
CAN-mediated oxidative cycloaddition of the commercially available
2
-hydroxy-1,4-naphthoquinone (6) to phenyl vinyl sulfide or ethyl vinyl ether.
Reaction of 6 with phenyl vinyl sulfide (2-fold excess) in the presence
ꢀ
of 2.2 equivalents of CAN at 0 C for 6 h in acetonitrile afforded the
dihydrofuronaphthoquinone 7 (42%) and 8 (51%) as a mixture of linear
and angular isomers (Sch. 1). The mixture was easily separated by
column chromatography and the two isomers were assigned by their
spectroscopic data and by comparison with reported data in the literature.
The methine proton of 7 appeared as a double doublet (J ¼ 10.0, 6.1 Hz)
[
11]

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AVICEQUINONE-B NATURAL PRODUCT
3101
Scheme 1.
Scheme 2.
at ꢀ 6.26 and that of 8 as a double doublet (J ¼ 9.8, 6.1 Hz) at ꢀ 6.35. The
clear assignments come from the IR carbonyl absorptions at 1678 and
1
ꢁ
1
645 cm for the carbonyl groups in 7 and at 1698 and 1655 cm in 8.
ꢁ1
The conversion of compound 7 to the natural product was begun by
elimination of the phenyl sulfide group. Treatment of 7 and 8 with mCPBA
in dichloromethane at room temperature for 12 h resulted in avicequinone-B
(2) (85%) and furonaphthoquinone 4 (82%), respectively. The spectroscopic
properties of our synthetic material 2 and 4 agreed well with those reported
[6]
in the literature.
In order to extend the utility of this oxidative cycloaddition, an
additional reaction was investigated with ethyl vinyl ether. Treatment of
6 with ethyl vinyl ether (5-fold excess) in the presence of 2.2 equivalents
ꢀ
of CAN at 0 C for 6 h in acetonitrile gave dihydrofuronaphthoquinone
9 (54%) as a single compound, without the isolation required of the expected
angular regioisomer (Sch. 2). The dihydrofuronaphthoquinone 9 was easily

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102
LEE ET AL.
converted to avicequinone-B (2) by treatment of p-TsOH in refluxing
benzene (87%).
In conclusion, a new route to the biologically active furonaphtho-
quinones 2 and 4 has been developed from the readily available 2-hydroxy-
1,4-naphthoquinone (6) and phenyl vinyl sulfide or ethyl vinyl ether.
EXPERIMENTAL
All experiments were carried out under a nitrogen atmosphere.
Merck precoated silica gel plates (Art. 5554) with fluorescent indicator
were used for analytical TLC. Flash column chromatography was per-
formed using silica gel 9385 (Merck). Melting points were determined
in capillary tubes on a Fisher-Johns apparatus and are uncorrected.
1
H NMR spectra were recorded on a Bruker Model ARX (300 MHz)
spectrometer. IR spectra were recorded on a Jasco FTIR 5300 spectro-
photometer.
2
-Phenylsulfanyl-2,3-dihydronaphtho[2,3-b]furan-4,9-dione (7) and
-Phenylsulfanyl-2,3-dihydronaphtho[1,2-b]furan-4,5-dione (8)
2
To a solution of 2-hydroxy-1,4-naphthoquinone (6) (174 mg, 1 mmol)
and phenyl vinyl sulfide (272 mg, 2 mmol) in acetonitrile (20 mL) was added
ꢀ
CAN (1.21 g, 2.2 mmol) at 0 C and the reaction mixture was stirred under
nitrogen for 6 h. The mixture was diluted with water and extracted
with ethyl acetate (3 ꢂ 30 mL). The combined organic extracts were
washed with brine, dried (MgSO ), and evaporated under reduced pressure
4
to give the residue. The residue was purified by flash column chromatogra-
phy on silica gel (n-hexane/ethyl acetate ¼ 5 : 1) to give 7 (130 mg, 42%) and
ꢀ
1
(157mg, 51%) as a mixture. 7: m.p. 151–152 C; H NMR (300 MHz,
8
CDCl ) ꢀ 8.15–8.02 (2H, m), 7.73–7.64 (2H, m), 7.59–7.57 (2H, m),
3
7
.34–7.31 (3H, m), 6.26 (1H, dd, J ¼ 10.0, 6.1 Hz), 3.63 (1H, dd, J ¼ 18.2,
0.0 Hz), 3.18 (1H, dd, J ¼ 18.2, 6.1 Hz); IR (KBr) 3059, 2955, 1678, 1645,
1
1
ꢁ
1
593, 1485, 1391, 1289, 1173, 1092, 999, 897, 789 cm . 8: m.p. 148–149 C;
ꢀ
1
H NMR (300 MHz, CDCl ) ꢀ 8.07(1H, d, J ¼ 7.5 Hz), 7.67–7.65 (2H, m),
3
7
.59–7.55 (3H, m), 7.35–7.33 (3H, m), 6.35 (1H, dd, J ¼ 9.8, 6.1 Hz),
.56 (1H, dd, J ¼ 16.7, 9.8 Hz), 3.11 (1H, dd, J ¼ 16.7, 6.1 Hz); IR (KBr)
057, 2954, 1698, 1655, 1589, 1489, 1352, 1277, 1142, 1080, 999, 862,
3
3
7
ꢁ1
50 cm
.

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AVICEQUINONE-B NATURAL PRODUCT
Avicequinone-B (2)
3103
Reaction of 7 with mCPBA: To a solution of 7 (154 mg, 0.5 mmol) in
dichloromethane (5 mL) was added mCPBA (148 mg, 70%, 0.6 mmol) at
room temperature and the reaction mixture was stirred under nitrogen for
12 h. Saturated aqueous NaHCO solution was added, and the aqueous
3
layer was extracted with dichloromethane (3 ꢂ 30 mL). The combined
organic extracts were washed with brine, dried (MgSO ), and evaporated
4
under reduced pressure to give the residue. The residue was purified by flash
column chromatography on silica gel (n-hexane/ethyl acetate ¼ 5 : 1) to give
ꢀ
1
2
(84 mg, 85%) as a solid: m.p. 218–220 C; H NMR (300 MHz, CDCl ) ꢀ
3
8
.25–8.19 (2H, m), 7.80–7.75 (2H, m), 7.78 (1H, d, J ¼ 1.6 Hz), 7.01 (1H, d,
J ¼ 1.8 Hz); IR (KBr) 3111, 1684, 1585, 1555, 1475, 1365, 1207, 951, 777,
ꢁ
1
13 cm .
7
Naphtho[1,2-b]furan-4,5-dione (4)
To a solution of 8 (154 mg, 0.5 mmol) in dichloromethane (5 mL)
was added mCPBA (148 mg, 70%, 0.6 mmol) at room temperature and
the reaction mixture was stirred under nitrogen for 12 h. The mixture was
diluted with saturated NaHCO3 solution and extracted with dichloro-
methane (3 ꢂ 30 mL). The combined organic extracts were washed with
brine, dried (MgSO ), and evaporated under reduced pressure to give
4
the residue. The residue was purified by flash column chromatography on
silica gel (n-hexane/ethyl acetate ¼ 5 : 1) to give 4 (81 mg, 82%) as a solid:
ꢀ
1
m.p. 213–215 C; H NMR (300 MHz, CDCl ) ꢀ 8.09 (1H, d, J ¼ 7.9 Hz),
3
7
.73–7.62 (2H, m), 7.49 (1H, d, J ¼ 2.0 Hz), 7.45 (1H, m), 6.86 (1H, d,
J ¼ 2.0 Hz); IR (KBr) 3153, 1676, 1581, 1562, 1487, 1363, 1219, 945, 775,
ꢁ
1
15 cm .
7
2
-Ethoxy-2,3-dihydronaphtho[2,3-b]furan-4,9-dione (9)
To a solution of 2-hydroxy-1,4-naphthoquinone (6) (174 mg, 1 mmol)
and ethyl vinyl ether (360 mg, 5 mmol) in acetonitrile (20 mL) was added
ꢀ
CAN (1.21 g, 2.2 mmol) at 0 C and the reaction mixture was stirred under
nitrogen for 6 h. The mixture was diluted with water and extracted with
ethyl acetate (3 ꢂ 30 mL). The combined organic extracts were washed
with brine, dried (MgSO ), and evaporated under reduced pressure to
4
give the residue. The residue was purified by flash column chromatography
on silica gel (n-hexane/ethyl acetate ¼ 5 : 1) to give 9 (119 mg, 54%) as a

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104
LEE ET AL.
ꢀ
1
solid: m.p. 117–118 C; H NMR (300 MHz, CDCl ) ꢀ 8.08–8.02 (2H, m),
3
7
3
.73–7.64 (2H, m), 5.95 (1H, dd, J ¼ 7.2, 3.2 Hz), 4.04 (1H, m), 3.72 (1H, m),
.30 (1H, dd, J ¼ 18.2, 7.3 Hz), 3.05 (1H, dd, J ¼ 18.2, 3.2 Hz), 1.25 (3H, t,
J ¼ 7.1 Hz); IR (KBr) 3111, 2974, 1726, 1686, 1655, 1628, 1597, 1445, 1375,
ꢁ
1
101, 951, 855, 791, 743 cm .
1
Avicequinone-B (2)
Reaction of 9 with p-TsOH: The mixture of 9 (100 mg, 0.4 mmol) and
p-TsOH (30 mg) in dry benzene (10 mL) was heated at reflux for 4 h. The
mixture was treated with saturated NaHCO solution and extracted with
3
ether (3 ꢂ 30 mL). The combined organic extracts were washed with brine,
dried (MgSO ), and evaporated under reduced pressure to give the residue.
4
The residue was purified by flash column chromatography on silica gel
(
n-hexane/ethyl acetate ¼ 5 : 1) to give 2 (71 mg, 87%).
ACKNOWLEDGMENT
The author wishes to acknowledge the financial support of the Korea
Research Foundation made in the program year of 1998. Dr. Ronald
Tepper in discussion of this work is greatly appreciated.
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Received in the UK June 27, 2001

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