Total synthesis of four naturally occurring 2-azaanthraquinone antibiotics, 6-deoxy-8-methylbostrycoidin, 6-deoxybostrycoidin, 7-O-demethyl-6- deoxybostrycoidin and scorpinone

Article abstract of DOI:10.1016/j.tet.2005.01.035

A total synthesis of four natural 2-azaanthraquinones, 6-deoxy-8- methylbostrycoidin, 6-deoxybostrycoidin, 7-O-demethyl-6-deoxybostrycoidin and scorpinone was accomplished using an optimized procedure for 2-azaanthraquinone synthesis, involving a [4+2]-cycloaddition protocol, of a polyoxygenated diene with a suitably functionalized benzoquinone, acetonylation with pyridinium ylids, cyclisation with ammonia and O-demethylation with boron(III) bromide. 2-Azaanthraquinones are rarely found in nature and reveal interesting physiological properties.

Full text of DOI:10.1016/j.tet.2005.01.035

Tetrahedron 61 (2005) 2295–2300
Total synthesis of four naturally occurring 2-azaanthraquinone
antibiotics, 6-deoxy-8-methylbostrycoidin, 6-deoxybostrycoidin,
7-O-demethyl-6-deoxybostrycoidin and scorpinone
*
Tuyen Nguyen Van, Guido Verniest, Sven Claessens and Norbert De Kimpe
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Gent, Belgium
Received 4 November 2004; revised 11 January 2005; accepted 12 January 2005
Available online 2 February 2005
Abstract—A total synthesis of four natural 2-azaanthraquinones, 6-deoxy-8-methylbostrycoidin, 6-deoxybostrycoidin, 7-O-demethyl-6-
deoxybostrycoidin and scorpinone was accomplished using an optimized procedure for 2-azaanthraquinone synthesis, involving a [4C2]-
cycloaddition protocol, of a polyoxygenated diene with a suitably functionalized benzoquinone, acetonylation with pyridinium ylids,
cyclisation with ammonia and O-demethylation with boron(III) bromide. 2-Azaanthraquinones are rarely found in nature and reveal
interesting physiological properties.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
6-deoxy-8-methylbostrycoidin 5, were identified in the
mycelium of a Bispora-like tropical fungus and in the
cultures of the mycobionts of the lichen Haematomma sp.,
respectively.8,9 From a yellow strain mutant of Nectria
haematococca, grown in a medium enriched with asparagin
6-deoxybostrycoidin 610 and 7-O-demethyl-6-deoxybostry-
coidin 711 were isolated as intermediates in the bostrycoidin
biosynthesis.
Naturally occurring 2-azaanthraquinones are of special
interest due to their important physiological properties.1
Benz[g]isoquinoline-5,10-dione 1, the unsubstituted aza-
anthraquinone, has been isolated from Psychotricha
camponutans and Mitracarpus scaber, and exhibits growth
inhibition against multi-drug resistant pathogens, for
example, Staphylococcus aureus and Plasmodium
falciparum.1,2 This 2-azaanthraquinone 1 also revealed
antimalarial activity, and recently, in vivo and in vitro
trypanocidal activity against Trypanosoma congolense was
discovered (Fig. 1).2,3
Because of the physiological importance of 2-azaanthra-
quinones, several methods have been developed for their
synthesis. Most pathways deal with a Diels–Alder cycliza-
tion of appropriate building blocks, in which the nitrogen is
already incorporated.12–14 However, these methods suffer
from the disadvantage of low yield and poor regioselectivity
of the incorporation of the methoxy groups. The synthetic
pathway used by Watanabe et al. was based on a
condensation of C(4)-lithiated nicotinamide with a 2,3,5-
trimethoxybenzamide as the key reaction for the construc-
tion of the azaanthraquinones.14 The drawback of this
regiospecific method is the low yield due to its multistep
pathway, that is, condensation of aromatic rings, selective
methylation at the pyridine ring, reduction, ring closure,
oxidation and partial demethylation. Recently, we published
a straightforward synthesis of 2-azaanthraquinones via an
ammonia-induced cyclization of 2-acetonyl-3-bromo-
methyl-1,4-naphthoquinones.15 An optimized procedure
without the interference of side products, for example,
naphtho[2,3-c]pyran-5,10-diones, was now developed to
synthesize the natural product 6-deoxy-8-methylbostry-
coidin 5 for the first time and to result in an improved
Besides the unsubstituted 2-azaanthraquinone 1, also some
oxygenated derivatives, for example, bostrycoidin 2 and
analogues 3–8 as representative members, were found in
nature and showed interesting activities. Bostrycoidin 2 and
9-O-methylbostrycoidin 3, two metabolites of numerous
Fusarium species, showed antibiotic activity against the
tubercle bacil and GC bacteria, respectively.4,5 Tolypocla-
din 4, from the mycelium of Tolypocladium inflatum,
displayed metal-chelating properties.6 In addition, 2-aza-
anthraquinone derivatives interfere with the activity of
DNA topoisomerases and attract considerable attention in
cancer chemotherapy as intercalating DNA binding agents.7
Recently, two new 2-azaanthraquinones, scorpinone 8 and
Keywords: 2-Azaanthraquinone; Natural products; Naphthoquinone.
* Corresponding author. Tel.: C32 9 264 59 51; fax: C32 9 264 62 43;
e-mail: norbert.dekimpe@UGent.be
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.035

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T. Nguyen Van et al. / Tetrahedron 61 (2005) 2295–2300
Figure 1.
synthesis of three natural 2-azaanthraquinone antibiotics,
6-deoxybostrycoidin 6, 7-O-demethyl-6-deoxybostrycoidin
7 and scorpinone 8.
synthesized by reacting o-cresol 12 with 3 equiv of bromine,
first at 30 8C with 2 equiv of bromine to give the aromatic
bromination, and afterwards at 120 8C with 1 equiv of
bromine to introduce the bromine at the benzylic position.18
The substitution reaction of 13 with phenoxide was carried
out in good yield without the need for protection of the
hydroxyl function of the brominated cresol 13. Formation of
byproducts was successfully suppressed by adding the
brominated cresol to a refluxing solution of phenol in
acetone in the presence of potassium carbonate (Scheme 2).
2. Results and discussion
The strategy for the synthetic pathway of the azaanthra-
quinones 5–8 consists of the synthesis of naphthoquinone 9
(LG, leaving group) which leads directly to the desired
2-azaanthraquinone system after treatment with ammonia
via an intramolecular substitution (Scheme 1). The idea
behind this approach was based on the hypothesis that
naturally occurring 2-azaanthraquinones originate in vivo
from the incorporation of ammonia into their
O-analogues.16 The naphthoquinone skeleton can be
synthesized by a cycloaddition of an appropriate electron-
rich and oxygenated diene 10 with the brominated
benzoquinone 11. In this strategy the choice of the leaving
group in naphthoquinone 9 is determining the outcome of
the cyclization reaction towards 5–8. Earlier experiments
showed that the use of a bromo atom as leaving group
resulted in a mixture of pyranonaphthoquinones and
2-azaanthraquinones when treating naphthoquinones,
analogous to 9, with ammonia. However, when phenoxide
was used as a leaving group, the reaction gave predominantly
rise to 2-azaanthraquinones with almost no side products.15,17
2,4-Dibromo-6-(phenoxymethyl)phenol 14 was oxidized by
reaction with CrO3 at room temperature to the benzo-
quinone 15, which served as a dienophile in the subsequent
regioselective cycloaddition. (1,3-Dimethoxy-1,3-butadien-
1-yloxy)trimethylsilane 10a was synthesized from methyl
acetoacetate, while the analoguous 1,3-dimethoxy-2-
methyl-1,3-butadien-1-yloxy)trimethylsilane 10b was
prepared from methyl 2-methylacetoacetate.19 These dienes
10a and 10b were subsequently reacted with benzoquinone
15 to yield the substituted naphthoquinones 16a–b in 62 and
55% yield, respectively. Dehydrobromination of the
intermediate occurred spontaneously when treated with
SiO2 (during column chromatography). The naphtho-
quinones 16a–b, bearing a free hydroxyl function, were
protected as methyl ethers 17a and 17b by reaction with
iodomethane and silver(I) oxide, prior to the introduction of
an acetonyl group.
For that reason 4,6-dibromo-2-(phenoxymethyl)phenol 14
was used as a starting material to synthesize 2-azaanthra-
quinones. The synthesis of 14 was accomplished by treating
bromomethylphenol 13 with an excess of phenol under
alkaline conditions. The latter brominated phenol 13 was
In this way, 6,8-dimethoxy-2-(phenoxymethyl)-1,4-
naphthoquinones 17a–b were reacted with N-(acetyl-
methyl)pyridinium ylide, formed in situ by reaction of
N-acetonylpyridinium chloride and triethylamine
Scheme 1.

T. Nguyen Van et al. / Tetrahedron 61 (2005) 2295–2300
2297
Scheme 2.
Scheme 3.

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T. Nguyen Van et al. / Tetrahedron 61 (2005) 2295–2300
(Scheme 3).20 The acetonylated products 18a–b were
treated with 10 equiv of ammonia resulting in a nucleophilic
addition across the carbonyl of the acetonyl moiety and
intramolecular substitution of the phenoxy group. The
cyclized product oxidized spontaneously and afforded
2-azaanthraquinone 19 in 72% yield (from 18a) and the
natural product scorpinone 8 in 81% (from 18b). No
naphtho[2,3-c]pyran-5,10-dione was formed as side
product, contrary to reactions of similar substrates with a
bromine instead of a phenoxy group as leaving group. To
obtain the recently discovered natural product 6-deoxy-8-
methylbostrycoidin 5, compound 19 was 9-O-demethylated
using boron(III) bromide in dichloromethane in 96% yield
in the final step (Scheme 3). In order to obtain the natural
product 6-deoxybostrycoidin 6, the natural product scorpi-
none 8 was selectively 9-O-demethylated by using 5 equiv
of boron(III) bromide and stirring for 2 h at room
temperature. A complete O-demethylation was obtained
by reacting 8 with boron(III) tribromide in dichloromethane
at room temperature for 48 h affording the natural product
7-O-demethyl-6-deoxybostrycoidin 7 in 86% yield.
impurities, 14 was purified by column chromatography with
5% ethyl acetate in hexane as eluent, yielding 3.7 g of white
crystals (71%), mp 68–69 8C. 1H NMR (CDCl3): d 5.12 (2H,
s, CH2), 6.10 (1H, s, OH), 6.98–7.03 (3H, m, 3!]CH),
7.26–7.35 (2H, m, 2!]CH), 7.50 (1H, d, JZ2.3 Hz,
]CH), 7.58 (1H, d, JZ2.3 Hz, ]CH). 13C NMR (CDCl3):
d 65.3 (CH2O), 110.9 (Cquat), 112.7 (Cquat), 114.7 (2!
]CH), 121.6 (]CH), 126.2 (Cquat), 129.6 (2!]CH),
130.6 (]CH), 133.5 (]CH), 149.2 (]C–O), 157.9 (]C–
O). IR (KBr) n 3408 (OH), 1598 (C]C), 1587 (C]C),
1497 (C]C), 1451 (C]C), 1245, 1222 cmK1. MS m/z (%)
355/7/9 (MKHC, 100). Anal. Calcd C13H10Br2O2: C
43.61%, H 2.82%; found: C 43.24%, H 2.93%.
3.1.2. 2-Bromo-6-(phenoxymethyl)benzo-1,4-quinone
(15). To a solution of 2,4-dibromo-6-(phenoxymethyl)-
phenol 14 (895 mg, 2.5 mmol) in 20 ml of HOAc:CH3CN/
4:1 was added CrO3 (250 mg, 2.5 mmol) in 2 ml of aqueous
HOAc (50%). The solution was stirred for 3 h at room
temperature and, after completion of the oxidation, the
mixture was poured in water and extracted with dichloro-
methane. Evaporation of the solvent in vacuo yielded
700 mg of crude benzoquinone 15, which was recrystallised
from hexane:EtOAc/70:30 (600 mg, 82%), mp 145–146 8C.
1H NMR (CDCl3): d 4.92 (1H, d, JZ2.0 Hz, CHaHbO), 4.96
(1H, d, JZ2.0 Hz, CHaHbO), 6.94–7.05 (4H, m, 4!]CH),
7.26–7.35 (3H, m, 3!]CH). 13C NMR (CDCl3): d 63.5
(CH2), 114.6 (2!]CH), 121.9 (]CH), 129.7 (2!]CH),
132.0 (]CH), 137.1, 138.2 and 144.0 (2!Cquat, 1!]CH),
157.4 (Cquat), 178.9 and 184.4 (2!C]O). IR (KBr) n 1674
(C]O), 1660 (C]O), 1634 (C]C), 1599 (C]C), 1498
(C]C), 1293, 1250 cmK1. MS m/z (%) 293/5 (MKHC,
100). Anal. Calcd C13H7BrO3: C 53.27%, H 3.09%; found:
C 53.41%, H 3.21%.
In conclusion, using an optimized synthetic approach via
dioxygenated 2-phenoxymethyl naphthoquinones, 2-aza-
anthraquinones were synthesized by cyclization of
2-phenoxymethyl-3-acetonylnaphthoquinones
with
ammonia. This reaction pathway resulted in the first
straightforward synthesis of the natural product 6-deoxy-
8-methylbostrycoidin 5 and an optimized procedure for the
natural products scorpinone 8, 6-deoxybostrycoidin 6 and
7-O-demethyl-6-deoxybostrycoidin 7.
3. Experimental
3.1. General methods
3.1.3.
naphthoquinone (16a). To a solution of 2-bromo-6-
(phenoxymethyl)benzo-1,4-quinone 15 (450 mg,
8-Hydroxy-6-methoxy-2-(phenoxymethyl)-
1H NMR spectra (270 MHz) and 13C NMR spectra
(68 MHz) were run with a Jeol JNM-EX 270 NMR
spectrometer. Peak assignments were performed with the
aid of the DEPT technique, 2D-COSY spectra and
HETCOR spectra. IR assignments were obtained from a
Perkin Elmer Spectrum One spectrophotometer. Mass
spectra were measured with an Agilent 1100 Series mass
spectrometer (detector VL, 70 eV, ES 4000 V). Melting
points were measured with a Buchi B-540 apparatus. The
elemental analysis was performed on a Perkin Elmer 2400
Elemental Analyzer. Flash chromatography was carried out
on a glass column with ACROS silica gel (particle size
0.035–0.07 mm, pore diameter ca. 6 nm). All solvents and
reagents were obtained from commercial suppliers and were
used without further purification.
1.54 mmol) in 20 ml of dry toluene at K78 8C was added
dropwise a solution of vinyl ketene acetal 10a17 (513 mg,
2.54 mmol) in 5 ml of toluene. The reaction was kept at this
temperature for 30 min. Then, the resulting mixture was
allowed to warm to room temperature and was stirred for
3 h. After the reaction mixture was filtered through silica
gel, the filtrate was concentrated in vacuo and the resulting
Diels–Alder adduct was recrystallized from ethanol to give
300 mg of the pure product 16a (62%), mp 151–152 8C. 1H
NMR (CDCl3): d 3.90 (3H, s, CH3O), 5.05 (2H, d, JZ
2.3 Hz, CH2), 6.64 (1H, d, JZ2.3 Hz, H-5), 7.00 (1H, s,
H-3), 7.03–7.07 (2H, m, 2!]CH), 7.08 (1H, t, JZ2.3 Hz,
C3–H), 7.17 (1H, d, JZ2.3 Hz, H-7), 7.21–7.36 (2H, m, 2!
]CH), 12.10 (1H, s, OH). 13C NMR (CDCl3): d 53.1
(CH3O), 63.2 (CH2), 106.7 (C-7), 108.0 (C-5), 114.7 (2!
]CH), 116.5 (C-9quat), 121.7 (]CH), 129.7 (2!]CH),
132.6 (C-10quat), 134.1 (C-3), 146.8 (C-2), 157.7 (]C–O),,
164.5 (]C–O), 166.4 (]C–O), 183.8 and 187.6 (2!
C]O). IR (KBr) n 1640 (C]O), 1620 (C]O), 1609
(C]C), 1588, 1388, 1311, 1241 cmK1. MS m/z 497 (100),
311 (MCHC, 50). Anal Calcd C18H14O5: C 69.67%, H
5.55%; found: C 69.55%, H 5.42%.
3.1.1. 2,4-Dibromo-6-(phenoxymethyl)phenol (14). A
solution of 2,4-dibromo-6-(bromomethyl)phenol 1315 (5 g,
14.5 mmol) in 50 ml of acetone was added dropwise to a
refluxing mixture of phenol (13.6 g, 0.145 mol) and
potassium carbonate (20 g, 0.145 mol) in 100 ml of acetone.
After reflux overnight, the solvent was evaporated and the
residue was redissolved in dichloromethane. After washing
with water, the organic layer was dried over MgSO4, filtered
and evaporated in vacuo. Residual phenol was distilled off at
high vacuum (0.5 mmHg, at 70 8C). To remove some minor
3.1.4. 8-Hydroxy-6-methoxy-7-methyl-2-(phenoxy-
methyl)naphthoquinone (16b). Mp 188–189 8C (55%).

T. Nguyen Van et al. / Tetrahedron 61 (2005) 2295–2300
2299
1
1H NMR (CDCl3): d 2.18 (3H, s, CH3), 3.99 (3H, s, CH3O),
5.07 (2H, d, JZ2.0 Hz, CH2O), 6.99–7.06 (3H, m, 3!
]CH), 7.07 (1H, t, JZ2 Hz, ]CH), 7.21–7.36 (3H, m, 3!
]CH), 12.21 (1H, s, OH). 13C NMR (CDCl3): d 8.1 (CH3),
53.4 (CH3O), 63.2 (CH2), 102.5 (C-5), 109.7 (Cquat), 114.6
(2!]CH), 120.3 (Cquat), 121.7 (]CH), 129.0 (Cquat),
129.7 (2!]CH), 133.9 (C-3), 146.4 (C-2), 157.7 (]C–O),
161.3 (]C–O), 163.5 (]C–O), 184.2 and 188.2 (2!
C]O). IR (KBr) n 1661 (C]O), 1638 (C]O), 1609
(83%), mp 146–147 8C. H NMR (CDCl3): d 2.26 (3H, s,
CH3), 3.91 (3H, s, CH3O), 3.92 (2H, s, CH2C]O), 3.96
(3H, s, CH3O), 5.08 (2H, s, CH2O), 6.73 (1H, d, JZ2.3 Hz,
H-5), 6.90–6.98 (3H, m, 3!]CH), 7.22 (1H, d, JZ2.3 Hz,
H-7), 7.24–7.30 (2H, m, 2!]CH). 13C NMR (CDCl3): d
30.1 (CH3C]O), 41.2 (CH2C]O), 55.8 (CH3O), 56.4
(CH3O), 61.3 (CH2O), 103.2 (C-7), 104.3 (CH-5), 114.2
(Cquat), 114.5 (2!]CH), 121.3 (]CH), 129.5 (2!]CH),
132.3 (Cquat), 135.5 (C-3), 141.4 (C-2), 158.0, 161.9 and
164.6 (3!]C–O), 181.4 and 184.6 (2!C]O), 203.3
(CH3C]O). IR (KBr) n 1715 (C]O), 1663 (C]O), 1654
(C]O), 1597, 1556, 1354, 1334, 1273, 1164 cmK1. MS m/z
381 (MCHC, 100). Anal. Calcd C22H20O6: C 69.46%, H
5.30%; found: C 69.52% H 5.42%.
(C]C), 1598 (C]C), 1497 (C]C), 1323, 1248, 1120 cmK1
MS m/z (%) 323 (MKHC, 35), 309 (MKCH3, 100).
.
3.1.5.
6,8-Dimethoxy-2-(phenoxymethyl)naphtho-
quinone (17a). To a solution of naphthoquinone 16a
(256 mg, 0.83 mmol) in 10 ml of chloroform was added
iodomethane (1.17 g, 8.3 mmol) and silver(I) oxide (2.02 g,
8.3 mmol). The mixture was refluxed for 3 h, under
protection from light by covering the flask with aluminum
foil. After cooling, the reaction mixture was filtered over
celite and evaporated in vacuo to give 240 mg of the pure
naphthoquinone 17a. The resulting product was pure and
was used without further purification (90%), mp 176–
177 8C. 1H NMR (CDCl3): d 3.91 (3H, s, CH3O), 3.94 (3H,
s, CH3O), 5.01 (2H, d, JZ2.0 Hz, CH2), 6.68 (1H, d, JZ
2.3 Hz, H-5), 6.94 (1H, s, H-3), 6.97–6.98 (2H, m, 2!
]CH), 6.99 (1H, t, JZ2.0 Hz, C3-H), 7.19 (1H, d, JZ
2.3 Hz, H-7), 7.26–7.32 (2H, m, 2!]CH). 13C NMR
(CDCl3): d 56.3 and 56.7 (2!CH3O), 64.2 (CH2), 103.5
(CH-7), 104.4 (CH-5), 115.0 (2!]CH), 121.8 (]CH),
130.0 (2!]CH), 131.5 (C-3), 132.8 (Cquat), 136.3 (Cquat),
148.5 (C-2), 158.2, 162.4 and 165.2 (3!]C–O), 182.9 and
185.0 (2!C]O). IR (KBr) n 1651 (C]O), 1633 (C]O),
1597, 1458, 1331, 1251, 1159 cmK1. MS m/z 325 (MCHC,
100). Anal. Calcd C19H16O5: C 70.36%, H 4.79%; found: C
70.22%, H 5.18%.
3.1.8. 2-Acetonyl-5,7-dimethoxy-6-methyl-3-(phenoxy-
methyl)naphthoquinone (18b). Mp 162–163 8C (77%).
1H NMR (CDCl3): d 2.22 (3H, s, CH3), 2.29 (3H, s, CH3),
3.83 (3H, s, CH3O), 3.92 (2H, s, CH2C]O), 3.96 (3H, s,
CH3O), 5.08 (2H, s, CH2O), 6.91–7.00 (3H, m, 3!]CH),
7.25–7.31 (2H, m, 2!]CH), 7.38 (1H, s, C5–H). 13C NMR
(CDCl3): d 9.0 (CH3), 30.2 (CH3C]O), 41.2 (CH2C]O),
56.1 (CH3O), 61.0 and 61.2 (CH2O and CH3O), 104.3 (CH-
5), 114.5 (2!]CH), 118.1 (Cquat), 121.4 (]CH), 128.5
(Cquat), 129.5 (2!]CH), 132.4 (Cquat), 142.0 (Cquat), 143.0
(Cquat), 158.0, 159.6 and 162.5 (3!]C–O), 181.8 and
184.6 (2!C]O), 203.5 (CH3C]O). IR (KBr) n 1696
(C]O), 1670 (C]O), 1626, 1580, 1334, 1222, 1143 cmK1
.
MS m/z (%) (MCHC,100), 301 (MKC6H5O, 75). Anal.
Calcd C23H22O6: C 70.04%, H 5.62%; found: C 70.20%, H
5.48%.
3.1.9. 7,9-Dimethoxy-3-methylbenzo[g]isoquinoline-
5,10-dione (8, scorpinone). To a solution of 3-acetonyl-
5,7-dimethoxy-2-(phenoxymethyl)naphthoquinone 18a
(100 mg, 0.26 mmol) in 10 ml of ethanol was added
dropwise a 25% aqueous solution of ammonia (0.43 ml,
5.2 mmol). The solution was protected from light and stirred
at room temperature for 4 h in an open flask, allowing
contact with air. After evaporation of the solvent, the
residue was dissolved in CH2Cl2, washed with water, dried
(MgSO4) and evaporated. After recrystallization from
ethanol 60 mg of 2-azaanthraquinone 8 was obtained
(81%), mp 213–214 8C (lit. mp 195 8C).1 Spectroscopic
data (1H NMR, 13C NMR, IR, MS) were in accordance with
those reported in literature.1,8
3.1.6. 6,8-Dimethoxy-7-methyl-2-(phenoxymethyl)-
naphthoquinone (17b). Mp 151–153 8C (93%). H NMR
1
(CDCl3): d 2.23 (3H, s, CH3), 3.85 (3H, s, CH3O), 3.99 (3H,
s, CH3O), 5.07 (2H, d, JZ2.0 Hz, CH2), 6.98–7.06 (3H, m,
3!]CH), 7.07 (1H, t, JZ2.0 Hz, C3-H), 7.26–7.41 (3H,
m, 3!]CH). 13C NMR (CDCl3): d 9.4 (CH3), 56.5 and
61.4 (2!CH3O), 64.2 (CH2), 104.6 (CH-5), 115.0 (2!
]CH), 118.6 (Cquat), 121.9 (]CH), 128.5 (Cquat), 130.0
(2!]CH), 132.0 (C-3), 133.2 (Cquat), 147.8 (C-2), 158.2,
160.4 and 163.1 (3!]C–O), 183.3 and 185.0 (2!C]O). IR
(KBr) n 1657 (C]O), 1634 (C]O), 1583, 1497, 1323, 1243,
1128 cmK1. MS m/z (%) 339 (MCHC, 100). Anal. Calcd
C20H18O5: C 70.99%, H 5.36%; found: C 70.63%, H 5.54%.
3.1.10. 7,9-Dimethoxy-3,8-dimethylbenzo[g]isoquino-
line-5,10-dione (19). Mp 186–187 8C (72%). 1H NMR
(CDCl3): d 2.29 (3H, s, CH3), 2.77 (3H, s, CH3C]N), 3.93
(3H, s, CH3O), 4.05 (3H, s, CH3O), 7.60 (1H, s, ]CH), 7.84
(1H, s, CH–C]N), 9.43 (1H, s, HC]N). 13C NMR
(CDCl3): d 9.3 (CH3), 25.1 (CH3C]N), 56.2 and 61.3
(2!CH3O), 104.7 (HC-5), 117.5 (HC–C]N), 119.5, 125.2,
130.0, 133.9 and 137.7 (5!Cquat), 149.6 (HC]N), 160.3,
162.9 and 164.4 (3!Cquat), 180.8 and 183.2 (2!C]O). IR
(KBr) n 1674 (C]O), 1661 (C]O), 1579, 1319, 1229,
1127 cmK1. MS m/z (%) 298 (MCHC, 100). Anal. Calcd
C17H15NO4: C 68.68%, H 5.09%, N 4.71%; found: C
68.88%, H 4.96%, N 5.01%.
3.1.7. 2-Acetonyl-5,8-dimethoxy-3-(phenoxymethyl)-
naphthoquinone (18a). To a solution of naphthoquinone
17a (220 mg, 0.68 mmol) and acetonylpyridinium chloride
(174 mg, 1.02 mmol) in 10 ml acetonitrile was added
dropwise a solution of triethylamine (82 mg, 1.02 mmol)
in 2 ml of acetonitrile. The resulting mixture was stirred for
3 h at room temperature under a nitrogen atmosphere and
protected from light. After evaporation of the solvent, 5 ml
of aq 2 M HCl was added and extracted with ethyl acetate.
The combined organic phases were washed with saturated
NaHCO3, dried (MgSO4) and evaporated in vacuo.
Purification by flash chromatography with 30% EtOAc in
hexane as eluent yielded 200 mg of naphthoquinone 18a
3.1.11. 6-Deoxy-8-methylbostrycoidin (6). To a solution of
2-azaanthraquinone 19 (120 mg, 0.4 mmol) in 10 ml of dry

2300
T. Nguyen Van et al. / Tetrahedron 61 (2005) 2295–2300
dichloromethane was added dropwise boron(III) bromide
(301 mg, 1.2 mmol) under a nitrogen atmosphere at
K78 8C. After 30 min, the reaction was quenched with
water and poured into 5 ml of 2 M NaOH. 1 M HCl was
added in portions until the colour of the reaction mixture
turned yellow. The resulting solution was extracted with
dichloromethane, dried (MgSO4) and evaporated. 6-Deoxy-
8-methylbostrycoidin 6 was obtained as a pure product in
almost quantitative yield (108 mg, 96%), mp 150–151 8C
(decomposed, lit. mp9 149–153 8C). Spectroscopic data (1H
NMR, 13C, IR, MS) were in accordance with those reported
in literature.9
Acknowledgements
The authors are indebted to the Janssen Research
Foundation (Beerse, Belgium) and the IWT (Flemish
Institute for the promotion of Scientific-Technological
Research in Industry) for financial support.
References and notes
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