Synthesis of 2,3-dioxy-1,4-anthraquinones related to tetracenomycins C and X

Article abstract of DOI:10.1071/CH99181

The 2,3-dioxy-1,4-anthraquinones (6) and (7) have been synthesized from the 9,10-anthraquinone (19), through the anthrone (18). Quinones (6) and (7) respectively possess substituents appropriate for three of the four rings of tetracenomycins C (2) and X (

Full text of DOI:10.1071/CH99181

C S I R O P U B L I S H I N G
Australian Journal
of Chemistry
Volume 52, 1999
© CSIRO Australia 1999
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Aust. J. Chem., 1999, 52, 1173–1177
Synthesis of 2,3-Dioxy-1,4-anthraquinones
Related to Tetracenomycins C and X
Donald W. Cameron,A,B Peter G. GriffithsA,C and Andrew G. RichesA
A School of Chemistry, The University of Melbourne, Parkville, Vic. 3010.
B Author to whom correspondence should be addressed.
C Present address: Chiron Technologies Pty Ltd, Clayton, Vic. 3168.
The 2,3-dioxy-1,4-anthraquinones (6) and (7) have been synthesized from the 9,10-anthraquinone (19), through the
anthrone (18). Quinones (6) and (7) respectively possess substituents appropriate for three of the four rings of tetra-
cenomycins C (2) and X (3) but they did not show dienophilic properties towards the reactive diene (5). Interaction
with the diene was complicated by transsilylation, as was also observed for the model quinone (25).
Introduction
The tetracenomycin antibiotics comprise aromatic naph-
thacenequinones, like tetracenomycin A2 (1), together with a
closely related group where one ring is non-aromatic in con-
sequence of a pair of angular dioxy substituents. This latter
group, which includes tetracenomycins C (2)1 and X (3),2 is
biosynthesized from the former by oxidation and hydra-
tion.2,3 Tetracenomycin
C possesses significant anti-
leukaemic properties. Its entire biosynthetic gene cluster of
polyketide synthase enzymes from Streptomyces
glaucescens has been sequenced.4,5
Earlier work here described the first synthesis of tetra-
cenomycin A2 (1), by cycloaddition of the 1,4-anthraquinone
dienophile (4) to the 1,1,3-trioxy diene (5) followed by oxida-
tive aromatization. Other aromatic tetracenomycins were
obtained analogously.6 This paper describes the synthesis of
the new 2,3-dioxy-1,4-anthraquinones (6) and (7) to assess
their effectiveness as dienophiles analogous to (4), as a poten-
tial basis for approaching the angular dioxy system of (2) and
(3). This approach was encouraged by recent synthesis of the
model tricycle (8) through addition of diene (5) to 2,3-diace-
toxy naphthoquinone (9).7 Despite the yield of (8) being poor,
owing to competing Michael addition/elimination, it was con-
sidered that the large structural change from a simple
dienophile like (9) to the highly functionalized tricyclic
systems (6) and (7) warranted independent investigation.
Results and Discussion
At the beginning of this work there was no general method
for synthesizing 2,3-dioxy-1,4-anthraquinones. Initial experi-
ments sought to obtain the target system (6) through the 9,10-
anthraquinone (10). This would have paralleled efficient
synthesis of the 1,4-quinone (4) by deoxygenation of the 9,10-
quinone (11) with sodium borohydride. However, synthesis of
(10), by cycloaddition of diene (12) to the tautomeric diacetoxy
naphthazarin (13), could not be effected. The diacetate (13),
which was originally derived by treatment of the tetrol (14)8
with ketene,9 was more conveniently obtained by the action of
Manuscript received 16 December 1999
© CSIRO 1999
10.1071/CH99181 0004-9425/99/121173

1174
D. W. Cameron, P. G. Griffiths and A. G. Riches
acetic anhydride/pyridine in cold tetrahydrofuran. Alternative
acetylation of (14) catalysed by sulfuric acid gave the new tri-
acetate (15), another potentially tautomeric system through
acyl migration,10–13 which also was found to be unreactive
towards diene (12). Its 1H n.m.r. spectrum showed one chelated
hydroxy resonance (δ 11.97) and three acetate resonances (δ
2.39, 2.38, 2.37). Chlorination of (13) and (15), in an effort to
improve their dienophilicity, led only to decomposition.
A more effective approach to 1,4-anthraquinones (6) and
(7) was based on earlier work here, typified by formation of
the quinone (16) as the major product from treatment of 1,3-
dihydroxy-9-anthrone (17) with oxygen under alkaline con-
ditions (Scheme 1).14 Establishing whether such chemistry
could be applied to synthesizing the highly functionalized
1,4-quinones (6) and (7) required access to the new anthrone
(18). This was expected to be derivable by regioselective
reduction of the 9,10-anthraquinone (19). Protection of the
central oxygen of the pyrogallol system of (18) was incorpo-
rated to avoid unwanted formation of a 1,2-anthraquinone
during oxidation.14
Synthesis of the anthraquinone (19) paralleled the proce-
dure employed earlier for the corresponding ethyl ester.15
This entailed cycloaddition of the diene (12) to 2,6-dichloro-
1,4-benzoquinone (20), followed by aromatization and
acetylation to give the protected naphthoquinone (21). A
second cycloaddition involving the tetraoxy diene (22), fol-
lowed by aromatization and hydrolysis then gave (19)
1
(86%). Its H n.m.r. spectrum showed singlet resonances
appropriate to the α- and two β-hydroxy protons (δ 13.25,
11.65, 10.97), the two aromatic protons (δ 7.58, 7.17) and
the two methoxy groups (δ 3.86, 3.83).
Reduction of (19) with tin(II) chloride in
ethanol/hydrochloric acid gave the desired anthrone (18)
(82%). The expected regiochemistry was confirmed by
retention of a chelated hydroxy resonance (δ 13.60) in its 1H
n.m.r. spectrum, together with considerable shielding of the
two aromatic protons (δ 6.81, 6.40), whose signals were

Synthesis of 2,3-Dioxy-1,4-anthraquinones
1175
1H n.m.r. spectrum contained a sharp α-hydroxy resonance
(δ 11.47) and two acetate resonances (δ 2.40, 2.39) as well as
other signals supporting the assigned structure.
broadened through benzylic coupling with the new methyl-
ene protons (δ 4.24).
Treatment of this anthrone (18) with oxygen in dimethyl
sulfoxide containing methanolic sodium methoxide pleas-
ingly gave the 1,4-anthraquinone (23) (54%), accompanied
by minor reoxidation to its 9,10-isomer (19) (11%). The
former quinone showed characteristic long-wavelength elec-
tronic absorption (λmax 496 nm), together with strongly
deshielded hydroxy and aromatic resonances (δ 15.12, 7.87)
for the protons of the central ring. The course of oxidation
was base-dependent, sodium hydroxide favouring formation
of (19) and other bases (lithium diisopropylamide, sodium
hydride, potassium t-butoxide) giving sub-optimal ratios of
the two quinones. All oxidations were accompanied by for-
mation of polar, dark red by-products, which increased with
reaction time.
Reaction of the quinone (25) with an excess of diene (5)
1
at room temperature was monitored by H n.m.r. spec-
troscopy. After 7 h in (D6)benzene the quinone was con-
sumed, with formation of a single major product. Its
spectrum lacked an α-hydroxy resonance and, apart from an
appropriate overlapping resonance (δ 1.80) for the two
acetate groups, it showed aromatic (δ 7.47, 6.64) and C-
methyl (δ 1.72) signals different from those of (25). It was
inferred to be the trimethylsilyl ether (30) but it could not be
purified because of rapid desilylation and its spectrum
reverted to that of (25) on addition of trifluoroacetic acid to
the reaction solution.
After the mixture of (25) and (5) was heated at 50° for 4
days, the major component recoverable by chromatography,
again, was (25) (44%). The only identifiable new product
(18%) was a 3 : 1 mixture of regioisomers (31) and (32), cor-
responding to Michael addition/elimination; like (25), they
probably derived from hydrolysis of their O-silyl derivatives
during chromatography.
Cleavage of the quinonoid methoxy group of (23) with
aluminium trichloride in boiling dichloromethane yielded
the tetrahydroxy quinone (24) (64%). Survival of the methyl
ester was indicated by an appropriate 1H n.m.r. resonance (δ
3.85). Similarly hindered ester groups in 9,10-
anthraquinones are known to be resistant to hydrolysis.15
Selective acetylation of the respective 1,4-anthraquinones
(24) and (23) was effected by boiling with acetic anhydride
in tetrahydrofuran, giving the target triacetate (6) and diac-
Their regiochemistry was assigned on the basis of the
expected greater deshielding of the α-hydroxy resonance of
(32) (δ 11.93) relative to (31) (δ 11.51), through conjugative
electron donation from the acetoxy group of the former, to the
chelated carbonyl.7 Crystallization of the isomeric mixture
1
etate (7). The H n.m.r. spectrum of the former product
showed three new acetate resonances (δ 2.43, 2.40, 2.32),
while retaining a chelated hydroxy resonance (δ 14.37). For
(7) the two acetate groups resonated at δ 2.41, 2.32 and the
hydroxy at δ 14.64.
1
gave pure (31), its H n.m.r. spectrum showing aromatic (δ
7.50, 7.06), olefinic (δ 5.12), methylene (δ 4.25), and other
signals consistent with the assigned structure. Its mass spec-
trum contained an appropriate molecular ion (m/z 374).
These observations militate against 2,3-dioxy-1,4-
anthraquinones serving as synthetic sources of tetraceno-
mycins C (2) or X (3). Apart from the problem of competing
Michael chemistry, their weak dienophilicity, even towards a
reactive 1,1-dioxy diene like (5), exceptionally allows
transsilylation of the regiocontrolling α-hydroxy group to
supervene. This stands to reduce dienophilicity still further
and compromise regiocontrol.
However, the two quinones (6) and (7) proved to be inef-
fective as dienophiles. When separately treated with diene
(5) in benzene, their orange solutions became yellow with
unexpected ease but nothing useful could be isolated from
1
them. Though complex, the H n.m.r. spectra of the crude
products conspicuously lacked any chelated hydroxy reso-
nance. This suggested that interaction with the diene was
complicated by transsilylation of this group, an outcome that
would not only reduce dienophilicity but would nullify the
important directive role the hydroxy group was expected to
play in any successful cycloaddition.
Experimental
To obtain a better perspective for assessing possible
transsilylation from diene (5) onto the α-hydroxy group of
(6) and (7), we sought a less highly functionalized model
system. Apart from possessing an α-hydroxy group, this was
to resemble the parent 2,3-diacetoxy naphthoquinone (9) as
closely as possible. This resulted in synthesis of the hydroxy
diacetate (25).
Access to (25) began with cycloaddition of the diene
(26)16 to 2,3-dimethoxy-1,4-benzoquinone (27)17 and oxida-
tive aromatization, initially affording the dimethoxy naph-
thoquinone (28). Its 1H n.m.r. spectrum was consistent with
the assigned structure, in particular containing two methoxy
resonances (δ 4.10, 4.09) and an α-hydroxyl (δ 11.85). On
demethylation with aluminium trichloride in boiling
dichloromethane it gave the sparingly soluble trihydroxy
quinone (29). The latter underwent selective acetylation with
acetic anhydride in boiling tetrahydrofuran to give (25). Its
General
Melting points were determined on a Kofler hot stage and are uncor-
rected. Microanalyses were carried out by National Analytical
Laboratories, Melbourne, or Chemical and Microanalytical Services,
Geelong. Electronic spectra were recorded in ethanol containing 1%
formic acid (v/v), unless otherwise stated, on a Varian Superscan 3
spectrophotometer. Infrared spectra were recorded on a Perkin Elmer
983-G grating spectrophotometer. Solids were recorded as potassium
bromide disks and liquids as films between sodium chloride plates.
Proton nuclear magnetic resonance (1H n.m.r.) spectra were recorded at
399.65 MHz on a JEOL JNM-GX400 spectrometer. The solvent was
(D)chloroform unless otherwise stated. High- and low-resolution mass
spectra were recorded by using a V.G. Micromass 7070F instrument or
a JEOL JMS-AX505H mass spectrometer at 70 eV, unless otherwise
stated. In general, only peaks greater than 20% are quoted. Analytical
and preparative thin-layer chromatography (t.l.c.) were carried out on
glass plates coated with a layer of silica gel [Merck Kieselgel 60 GF254
or Merck Kieselgel 60 GF254 containing 2% oxalic acid (oxalated
silica)]. The separated components were extracted from the silica by
using ethyl acetate or dichloromethane. Oxalic acid was removed by

1176
D. W. Cameron, P. G. Griffiths and A. G. Riches
ric acid (85 cm3) was added carefully. The mixture was then boiled for
30 min. An equal volume of hot water was added slowly and the
mixture was allowed to cool. The pale brown needles which precipi-
tated were filtered off and washed with water to give the anthrone (18)
(1.27 g, 82%). An analytical sample was recrystallized from ethyl
acetate/petrol as buff needles, m.p. 125-129° (dec.) (Found: C, 62.8; H,
4.6. C18H16O7 requires C, 62.8; H, 4.7%). λmax (logε) 210, 277, 323 nm
(4.62, 4.15, 4.46). νmax 3555, 3489, 1665, 1620, 1565 cm–1. δ
[(CD3)2SO] 13.60, s, 8-OH; 11.03, 10.33, s, s, 2×β-OH; 6.81, s, H4;
6.40, s, H5; 4.24, s, CH2; 3.86 3.83, s, s, 2×OMe; 2.57, s, ArMe. m/z
345 (M+1, 20%), 344 (M, 100), 313 (21), 312 (74), 297 (54), 294 (33).
washing the extracts with water and then drying over magnesium
sulfate prior to evaporation. Flash chromatography was carried out
using Merck Kieselgel No. 9385. All solvents were of A.R. grade or
were redistilled prior to use. Petrol refers to the hydrocarbon fraction
boiling in the range 60–80°. All diene preparations and reactions were
performed under dry nitrogen in flame-dried glassware. Acid-sensitive
cycloadditions were performed in glassware which had been previously
washed with aqueous ammonia solution followed by distilled water.
Organic extracts were generally dried over magnesium sulfate before
evaporation at reduced pressure.
2,3-Diacetoxy-5,8-dihydroxy-1,4-naphthoquinone (13)
Oxidation of Anthrone (18)
Prepared according to the literature, quinone (14) had m.p. >267°
(dec.) (lit.8 265°). δ [(CD3)2SO] 12.12, s, 5-OH, 8-OH; 10.52, br s, 2-
OH, 3-OH; 7.25, s, 2×ArH. To a solution of this quinone (14) (105 mg)
in tetrahydrofuran (3 cm3) was added acetic anhydride (1 cm3) and the
mixture was cooled in an ice/salt bath. Pyridine (2 drops) was added
and the mixture was stirred for 10 min. Ice-cold 1 M hydrochloric acid
(20 cm3) was then added and the mixture was stirred vigorously for 15
min and extracted into ethyl acetate (2×50 cm3). The extract was
washed with water (100 cm3), brine (100 cm3), and then dried and evap-
orated. The residue was subjected to preparative t.l.c. on oxalated silica,
with ether/petrol (1 : 1) as eluent. The major red band gave the di-
acetoxy naphthoquinone (13) (69 mg, 50%) as red bars from
dichloromethane, m.p. 151–163° (lit.9 158–60°). δ 12.07, s, 2×OH;
7.29, s, 2×ArH; 2.40, s, 2×OAc. m/z 306 (M, 4%), 222 (100), 194 (65),
165 (21), 108 (27).
A solution of anthrone (18) (255 mg) in dimethyl sulfoxide (50 cm3)
was purged with nitrogen for 5 min before addition of sodium methox-
ide in methanol (10% w/v, 2 cm3). The stream of nitrogen was contin-
ued for 3.5 min, after which a strong stream of oxygen was passed
through the solution for a further 3.5 min. The mixture was then quickly
poured into 1 M hydrochloric acid (300 cm3) and extracted with ethyl
acetate (2×100 cm3). The extract was washed with water (300 cm3),
brine (300 cm3), and then dried and evaporated. The residue was sub-
jected to column chromatography, with an acetone/toluene/acetic acid
(10: 89: 1 → 30: 69: 1) solvent gradient as eluent.
The more mobile, yellow fraction gave the anthraquinone (19) (31
mg, 11%), identical to material described previously.
The less mobile, orange-red fraction gave methyl 3,6,9-trihydroxy-
7-methoxy-1-methyl-5,8-dioxo-5,8-dihydroanthracene-2-carboxylate
(23) (145 mg, 54%) as red needles from ethyl acetate, m.p. 258–267°
(dec.) (Found: C, 60.7; H, 3.9. C18H14O8 requires C, 60.3; H, 3.9%).
λmax (logε) 231, 248, 329, 434, 496 nm (4.44, 4.44, 4.25, 3.61, 3.66).
νmax 3297br, 1728, 1648, 1581 cm–1. δ [(CD3)2SO] 15.12, s, 9-OH;
11.18, 11.07, s, br s, 2×β-OH; 7.87, s, H 10; 7.32, s, H4; 3.90, 3.85, s,
s, 2×OMe; 2.71, s, ArMe. m/z 358 (M, 55%), 327 (25), 326 (100).
2,3,5-Triacetoxy-8-hydroxy-1,4-naphthoquinone (15)
To a solution of quinone (14) (112 mg) in tetrahydrofuran (7 cm3)
was added acetic anhydride (1 cm3) and the mixture was cooled in an
ice/salt bath. Sulfuric acid (1 drop) was added and the mixture was
stirred for 10 min. Ice-cold water was added and the mixture was stirred
vigorously for 20 min and then extracted with dichloromethane (2×20
cm3). The extract was washed with water (50 cm3), brine (50 cm3), and
then dried and evaporated. The residue was subjected to preparative
t.l.c on oxalated silica, with ethyl acetate/petrol (2: 5) as eluent. The
major band gave the triacetoxy naphthoquinone (15) (78 mg, 44%) as
yellow needles from ethyl acetate/petrol, m.p. 153–155° (Found: C,
55.0; H, 3.2. C16H12O9 requires C, 55.2; H, 3.5%). λmax (logε) (CHCl3)
274, 433 nm (4.07, 3.64). νmax 1789, 1677, 1644 cm–1. δ 11.97, s, OH;
7.32, ABq, J 9.1 Hz, H 6, H 7; 2.39, 2.38, 2.37, s, s, s, 3×OAc. m/z (20
eV) 222 (100), 194 (35).
Methyl 3,6,7,9-Tetrahydroxy-1-methyl-5,8-dioxo-5,8-dihydro-
anthracene-2-carboxylate (24)
To a solution of the quinone (23) (9 mg) in dichloromethane
(25 cm3) under nitrogen was added aluminium trichloride (100 mg) and
the mixture was stirred vigorously for 24 h. Aqueous oxalic acid solu-
tion (5% w/v, 150 cm3) was added and stirring was continued for a
further 1 h. The mixture was then extracted with ethyl acetate (2×150
cm3) and the combined extracts were washed with water (150 cm3),
brine (150 cm3), and then dried and evaporated. The residue was sub-
jected to preparative t.l.c. on oxalated silica, with toluene/acetone (7 : 2)
as eluent. The mobile orange band gave the tetrahydroxy
anthraquinone (24) (6 mg, 64%) as red needles, m.p. >180° (dec.)
(Found: C, 59.2; H, 3.4. C17H12O8 requires C, 59.3; H, 3.5%). λmax
(logε) 234, 244, 286, 329sh, 404, 435, 490 nm (4.40, 4.40, 4.44, 4.14,
3.86, 3.69, 3.69). νmax 3337br, 1714, 1666, 1648, 1630sh, 1577 cm–1. δ
[(CD3)2SO] 14.76, s, 9-OH; 11.14, 10.33, br s, br s, 2×β-OH; 7.81, s,
H10; 7.30, s, H 4; 3.85, s, CO2Me; 2.72, s, ArMe. m/z 344 (M, 54%),
313 (25), 312 (100), 256 (24), 115 (20).
Methyl 3,6,8-Trihydroxy-7-methoxy-1-methyl-9,10-dioxo-9,10-
dihydroanthracene-2-carboxylate (19)
To a solution of the naphthoquinone (21)18 (470 mg), prepared as for
the corresponding ethyl ester,15 in dry tetrahydrofuran (2 cm3) was
added freshly prepared diene (22) (1.20 g) and the mixture was stirred
at room temperature for 3 days. The temperature was raised to 50° and
the mixture was stirred for a further 24 h. Ethanol (20 cm3) and sodium
acetate (1 g) were then added and the mixture was boiled for 15 min.
Concentrated hydrochloric acid (10 cm3) was added and boiling was
continued for 15 min. The mixture was cooled, diluted with water (200
cm3) and extracted with ethyl acetate (3×100 cm3). The extract was
washed with water (2×100 cm3), brine (100 cm3), and then dried and
evaporated. The residue was crystallized from ethyl acetate to give the
anthraquinone (19) (451 mg, 86%) as orange needles, m.p. 254–260°
(Found: C, 60.0; H, 3.9. C18H14O8 requires C, 60.3; H, 3.9%). λmax
(logε) 283, 346, 416 nm (4.64, 3.72, 3.80). νmax 3324, 1711, 1649,
1622, 1575 cm–1. δ [(CD3)2SO] 13.25, s, 8-OH; 11.65, 10.97, br s, br s,
2×β-OH; 7.58, s, H 4; 7.17, s, H5; 3.86, 3.83, s, s, 2×OMe; 2.59, s,
ArMe. m/z 358 (M, 67%), 326 (49), 311 (28), 309 (21), 308 (100), 283
(38), 280 (21), 250 (37), 227 (24).
Methyl 3,6,7-Triacetoxy-9-hydroxy-1-methyl-5,8-dioxo-5,8-dihydro-
anthracene-2-carboxylate (6)
To a solution of the quinone (24) (40 mg) in tetrahydrofuran (8 cm3)
was added acetic anhydride (1 cm3) and the mixture was boiled for 5 h.
The solvent was evaporated and the mixture was subjected to prepara-
tive t.l.c. on oxalated silica, with ethyl acetate/toluene (1: 9) as eluent.
The mobile orange band gave the triacetoxy anthraquinone (6) (21 mg,
38%) as orange-red crystals from dichloromethane/petrol, m.p.
209–212° (Found: C, 58.8; H, 3.8. C23H18O11 requires C, 58.7; H,
3.9%). λmax (logε) (CHCl3) 250, 284, 494 nm (4.77, 4.16, 3.99). νmax
1791, 1772, 1719, 1670, 1600, 1648, 1605 cm–1. δ 14.37, s, 9-OH; 8.03,
s, H10; 7.65, s, H4; 3.98, s, CO2Me; 2.92, s, ArMe; 2.43, 2.40, 2.32, s,
s, s, 3×OAc. δ (C6D6) 14.83, s, 9-OH; 7.73, s, H10; 7.05, s, H 4; 3.49,
s, CO2Me; 2.80, s, ArMe; 1.84, 1.83, 1.78, s, s, s, 3×OAc. m/z 470 (M,
1%), 469 (M –1, 4), 386 (21), 345 (36), 344 (100), 313 (31), 312 (82),
283 (32), 256 (25), 199 (25), 198 (22), 171 (22), 143 (23), 115 (41).
Methyl 3,6,8-Trihydroxy-7-methoxy-1-methyl-9-oxo-9,10-dihydro-
anthracene-2-carboxylate (18)
Quinone (19) (1.60 g) was dissolved in boiling acetic acid (300 cm3)
and a hot solution of tin(II) chloride (34 g) in concentrated hydrochlo-

Synthesis of 2,3-Dioxy-1,4-anthraquinones
1177
Methyl 3,6-Diacetoxy-9-hydroxy-7-methoxy-1-methyl-5,8-dioxo-5,8-
dihydroanthracene-2-carboxylate (7)
perature for 24 h. The temperature was raised to 50° and stirring was
continued for a further 24 h. More diene (385 mg) was added and the
mixture was stirred at 50° for another 48 h, then evaporated and sub-
jected to preparative t.l.c., with ethyl acetate/petrol (2 : 5) as eluent. The
more mobile yellow band gave starting quinone (14 mg, 44%). The less
mobile yellow band gave a 3: 1 mixture of Michael adducts (31) and
(32) (7 mg, 18%). Recrystallization of this material from ethyl
acetate/petrol afforded methyl 4-(3´-acetoxy-5´-hydroxy-7´-methyl-
1´,4´-dioxo-1´,4´-dihydronaphthalen-2´-yl)-3-methoxybut-2-enoate
(31) as yellow needles, m.p. 183–190° (Found: M+•, 374.1007.
C19H18O8 requires M+•, 374.1002). λmax (logε) (CHCl3) 241, 276sh, 427
nm (4.35, 4.13, 3.73). νmax 1772, 1701, 1670, 1619 cm–1. δ 11.51, s, 5´-
OH; 7.50, d, J 1.3 Hz, H8´; 7.05, br s, H6´; 5.12, s, H 2; 4.25, s, CH2;
3.72, 3.55, s, s, 2×OMe; 2.43, br s, ArMe; 2.31, s, OAc. m/z 374 (M,
38%), 332 (43), 301 (32), 300 (56), 273 (100), 272 (32).
To a solution of the quinone (23) (29 mg) in tetrahydrofuran (3 cm3)
was added acetic anhydride (0.5 cm3) and the mixture was boiled for 8.5
h. The solvent was evaporated and the solid was crystallized from
dichloromethane/petrol to give the diacetoxy anthraquinone (7) (9 mg,
23%) as orange needles, m.p. 210–213° (Found: C, 59.7; H, 4.0.
C22H18O10 requires C, 59.7; H, 4.1%). λmax (logε) (CHCl3) 245, 287,
477 nm (4.59, 4.50, 4.00). νmax 1771, 1726, 1657, 1600, 1565 cm–1. δ
14.64, s, 9-OH; 7.98, s, H10; 7.61, s, H 4; 4.23, 3.96, s, s, 2×OMe; 2.41,
2.32, s, s, 2×OAc. m/z 442 (M, 1%), 441 (M–H, 3), 399 (26), 357 (64),
343 (26), 326 (29), 325 (100).
5-Hydroxy-2,3-dimethoxy-7-methyl-1,4-naphthoquinone (28)
To a solution of 2,3-dimethoxy-1,4-benzoquinone (27)17 (1.37 g) in
benzene (10 cm3) was added diene (26)16 (2.26 g) and the mixture was
stirred at room temperature for 2 h. The solvent was then evaporated
and the residue was dissolved in tetrahydrofuran (10 cm3) and concen-
trated hydrochloric acid (5 cm3). The mixture was stirred in air for 5 h,
poured into water (100 cm3) and extracted with ethyl acetate (2×75
cm3). The extract was washed with water (100 cm3), brine (100 cm3),
and then dried and evaporated. The residue was subjected to flash chro-
matography in ethyl acetate/petrol (1: 1) to give the naphthoquinone
(28) (0.98 g, 49%) as orange needles from ethyl acetate/petrol, m.p.
139–140°(Found: C, 62.8; H, 5.0. C13H12O5 requires C, 62.9; H, 4.9%).
λmax (logε) (CHCl3) 253, 296, 421 nm (4.14, 4.10, 3.63). νmax 1673,
1625, 1606 cm–1. δ 11.85, s, OH; 7.63, d, J 1.2 Hz, H 8; 7.02, br s, H 6;
4.10, 4.09, s, s, 2×OMe; 2.40, s, ArMe. m/z 248 (M, 95%), 233 (100),
219 (23), 203 (58), 177 (33), 135 (35), 134 (62), 106 (51), 77 (25).
1
The H n.m.r. spectrum of an unrecrystallized sample of the less
mobile band showed additional, minor resonances attributed to methyl
4-(3´-acetoxy-8´-hydroxy-6´-methyl-1´,4´-dioxo-1´,4´-dihydronaph-
thalen-2´-yl)-3-methoxybut-2-enoate (32). δ 11.93, s, 8´-OH; 7.46, d, J
1.3 Hz, H 5´; 7.08, br s, H 7´; 5.13, s, H2; 4.26, s, CH2; 3.72, 3.56, s, s,
2×OMe; 2.42, br s, ArMe; 2.31, s, OAc.
Acknowledgments
We acknowledge the financial support of the Australian
Research Council and an Australian Postgraduate Research
Award (to A.G.R.). Early experiments leading to quinone
(28) were carried out by Mr A. K. Endress.
2,3,5-Trihydroxy-7-methyl-1,4-naphthoquinone (29)
To a solution of the quinone (28) (103 mg) in dry dichloromethane
(25 cm3) was added aluminium trichloride (0.5 g) and the mixture was
stirred vigorously at reflux for 20 h. Aqueous oxalic acid solution (5%
w/v; 50 cm3) was then added and stirring was continued for a further 30
min, after which time the purple colour was discharged and an orange
precipitate had formed. The mixture was poured into water (100 cm3)
and extracted into ethyl acetate (2×75 cm3). The extract was washed
with water (150 cm3), brine (150 cm3), and then dried and evaporated to
give the trihydroxy naphthoquinone (29) (92 mg, 100%) as a red solid,
m.p. >220° (subl.) (Found: M+•, 220.0374. C11H8O5 requires M+•,
220.0372). λmax (logε) 237sh, 260, 297, 402, 445 nm (3.98, 4.24, 4.04,
3.66, 3.45). νmax 3299br, 1674, 1648, 1615 cm–1. δ [(CD3)2SO] 11.73, br
s, 5-OH; 10.23, br s, 2-OH, 3-OH; 7.29, d, J 1.2 Hz, H 8; 7.05, br s, H 6;
2.35, s, ArMe. m/z 220 (M, 59%), 192 (100), 118 (20).
References
1
Weber, W. H., Zähner, H., Siebers, J., Schröder, K., and Zeeck, A.,
Arch. Mikrobiol., 1979, 121, 111.
Anderson, M. G., Khoo, C. K. Y., and Rickards, R. W., J. Antibiot.,
2
1989, 42, 640.
3
Udvarnoki, G., Wagner, C., Machinek, R., and Rohr, J., Angew.
Chem., Int. Ed. Engl., 1995, 34, 565.
McDaniel, R., Hutchinson, C. R., and Khosla, C., J. Am. Chem. Soc.,
4
1995, 117, 6805.
5
Shen, B., Summers, R. G., Wendt-Pienkowski, E., and Hutchinson,
C. R., J. Am. Chem. Soc., 1995, 117, 6811.
Cameron, D. W., and de Bruyn, P. J., Tetrahedron Lett., 1992, 33,
6
5593.
7
Cameron, D. W., and Riches, A.G., Aust. J. Chem., 1999, 52, 1165.
Huot, R., and Brassard, P., Can. J. Chem., 1974, 52, 838.
Singh, I., Ogata, R. T., Moore, R. E., Chang, C. W. J., and Scheuer,
2,3-Diacetoxy-5-hydroxy-7-methyl-1,4-naphthoquinone (25)
8
To a solution of the quinone (29) (63 mg) in tetrahydrofuran (7 cm3)
was added acetic anhydride and the solution was boiled for 3 h. It was
then evaporated and subjected to preparative t.l.c., with ethyl
acetate/petrol (2 : 5) as eluent, to give the diacetoxy naphthoquinone
(25) (28 mg, 32%) as yellow needles from ethyl acetate/petrol, m.p.
148–149° (Found: C, 59.1; H, 3.7. C15H12O7 requires C, 59.2; H, 4.0%).
λmax (logε) (CHCl3) 251, 257sh, 278, 432 nm (3.86, 3.85, 3.93, 3.49).
νmax 1782, 1675, 1656sh, 1635 cm–1. δ 11.47, s, 5-OH; 7.49, br d, J
1.3 Hz, H8; 7.09, br s, H6; 2.43, br s, ArMe; 2.40, 2.39, s, s, 2×OAc. δ
(C6D6) 11.72, s, 5-OH; 7.17, d, J 1.4 Hz, H 8; 6.55, br s, H 6; 1.79, 1.78,
s, s, 2×OAc; 1.63, br s, ArMe. m/z 304 (M, 4%), 262 (24), 220 (100),
192 (53).
9
P. J., Tetrahedron, 1968, 24, 6023.
Kelly, T. R., Ananthasubramanian, L., Borah, K., Gillard, J. W.,
10
Goerner, R. N., King, P. F., Lyding, J. M., Tsang, W.-G., and Vaya,
J., Tetrahedron, 1984, 40, 4569.
Calder, I. C., Cameron, D. W., and Sidell, M. D., J. Chem. Soc.,
11
Chem Commun., 1971, 360.
Brockmann, H., and Zeeck, A., Chem. Ber., 1968, 101, 4221.
Farina, F., and Vega, J. C., Tetrahedron Lett., 1972, 1655.
Cameron, D. W., Edmonds, J. S., and Raverty, W. D., Aust. J. Chem.,
12
13
14
1976, 29, 1535.
15
Cameron, D. W., Conn, C., and Feutrill, G. I., Aust. J. Chem., 1981,
34, 1945.
Reaction of Diene (5) with Quinone (25)
To a solution of the naphthoquinone (25) (32 mg) in benzene (1 cm3)
was added diene (5) (109 mg) and the mixture was stirred at room tem-
16
Savard, J., and Brassard, P., Tetrahedron, 1984, 40, 3455.
Matsumoto, M., and Kobayashi, H., J. Org. Chem., 1985, 50, 1766.
Cameron, D. W., and Høyer, T. J. M., unpublished data.
17
18