Synthesis of homophthalates from allenic diesters: Conversion into viocristin and analogues, and application to 6-methylpretetramid

Article abstract of DOI:10.1071/CH99065

Oxy-substituted homophthalic anhydrides have been synthesized by cycloaddition of di- and tri-oxy butadienes to the allenic diester (1). By base-catalysed cycloaddition to appropriate benzoquinones they have afforded new syntheses of viocristin (19), isov

Full text of DOI:10.1071/CH99065

C S I R O P U B L I S H I N G
Australian Journal
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Volume 52, 1999
© CSIRO Australia 1999
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Aust. J. Chem., 1999, 52, 1013–1020
Synthesis of Homophthalates from Allenic Diesters:
Conversion into Viocristin and Analogues,
and Application to 6-Methylpretetramid*
Ece Caliskan,A Donald W. CameronA,B and Peter G. GriffithsA
A School of Chemistry, The University of Melbourne, Parkville, Vic. 3052.
B Author to whom correspondence should be addressed.
Oxy-substituted homophthalic anhydrides have been synthesized by cycloaddition of di- and tri-oxy butadienes to
the allenic diester (1). By base-catalysed cycloaddition to appropriate benzoquinones they have afforded new syn-
theses of viocristin (19), isoviocristin (20) and analogous 1,4-anthraquinones. Related chemistry has led to the
naphthalene (34) and the anhydride (35), intermediates in published syntheses of semivioxanthin and 6-methyl-
pretetramid respectively.
Homophthalic anhydrides undergo regiocontrolled
cycloaddition to benzoquinones to form 1,4-anthraquinones
(Scheme 1). This is effected by base-catalysed enolization of
the anhydride. The derived cycloadduct undergoes aromati-
zation, with loss of carbon dioxide and hydrogen chloride
cal importance. Tamura’s group pioneered this approach in
synthesizing anthracyclinones.1–3 Work here has subse-
quently used it in synthesizing 6-methylpretetramid.4
Aromatic synthesis of a homophthalic anhydride, substi-
tuted as in Scheme 1, typically involves a six-step sequence
from an appropriate phenol, proceeding through an indanone
that is subsequently ring-opened to a homophthalate.4 The
method is tedious and overall yields are limited, particularly
by the indanone formation, which involves concomitant
Fries rearrangement and alkylation chemistry.
under the reaction conditions.
9-Hydroxy-1,4-anthra-
quinones so obtained can then react as conventional
dienophiles, affording linear tetracyclic systems of biologi-
A potentially simpler approach to the homophthalate
system employs allenic diesters (1) as dienophiles. Earlier
workers have shown that treating them with simple buta-1,3-
dienes5 or with butadiene equivalents in the form of α-
pyrones6,7 led to homophthalate diesters. For the former
case, aromatization of the cycloadduct required a deliberate
dehydrogenation step, while α-pyrones required extended
heating to 150° to promote addition and decarboxylation. A
milder approach along parallel lines was briefly reported by
Danishefsky’s group,8 who synthesized the homophthalate
diester (2) by treatment of (1) with the reactive 1,1,3-trioxy
butadiene (3). The hypothetical cycloadduct (4) was not iso-
lated, rapidly aromatizing with loss of methanol on contact
with acid.
This paper extends Danishefsky’s chemistry8 to a wider
range of diene and dienophilic systems. Following conver-
sion of the resulting diesters into anhydrides, it then uses
Tamura’s chemistry1–3 to synthesize some naturally occur-
ring quinonoid and related products.
The allenic dienophile (1) reacted with the 1,3-dioxy
diene (5) in boiling benzene. Aromatization of the crude
product with hydrochloric acid in tetrahydrofuran then gave
the new homophthalate (6) (92%), whose 1H n.m.r. spectrum
* This paper is dedicated to Professors W. R. Jackson, J. T. Pinhey, R. W. Rickards, S. Sternhell and W. C. Taylor.
Manuscript received 27 May 1999 © CSIRO 1999 10.1071/CH99065
0004-9425/99/111013

1014
E. Caliskan, D. W. Cameron and P. G. Griffiths
was amenable to first-order analysis. Hydrolysis with
sodium hydroxide gave the diacid (7) (86%). On being
heated in acetyl chloride, this underwent anhydride forma-
a chelated hydroxy resonance at δ 14.89, while the aromatic
region showed a pair of meta-coupled doublets (δ 6.81, 7.29,
J 2.2 Hz) and a singlet at δ 7.95. The C-methyl and
quinonoid protons resonated as an allylically coupled
doublet and quartet (δ 2.21, 6.89 respectively, J 1.5 Hz),
while acetate and methoxy protons were observed as singlets
at δ 2.38 and 4.05 respectively. Deacetylation with methano-
lic sodium hydroxide then gave viocristin (19) (90%). Its
physical data were mostly consistent with values reported for
natural (19)9 and wholly so with those reported for a sample
of (19) derived by reductive cleavage of the dimeric metabo-
lite asperinineA.13 For 1H n.m.r. spectra in (D6)dimethyl sul-
foxide, both the synthetic and asperinine-derived materials
showed the same discrepancies relative to that reported for
natural (19) (Experimental). These seem accountable by
reassigning aromatic and quinonoid resonances quoted for
the natural material9 and by association with the chloroform
solvent used in the original recrystallization. No such dis-
1
tion and concomitant acetylation to give (8) (82%). Its H
n.m.r. spectrum showed acetate and methylene resonances at
δ 2.31 and 4.32 respectively, and infrared carbonyl maxima
at 1792 and 1739 cm–1.
In the same way, reaction of (1) with the 1,1-dioxy diene
(9) successively gave the isomeric aromatized diester (10)
(73%), the diacid (11) (74%) and the acetylated anhydride
(12) (89%).
The diester (2), prepared as in the literature,8 was simi-
larly hydrolysed to the diacid (13) (85%) and thence to the
acetylated anhydride (14) (85%). The regioisomeric diester
(15) (67%) was next generated by analogous cycloaddition
of (1) with the trioxy diene (16). In sequence, it gave the cor-
responding diacid (17) and the anhydride (18) (88%). This
anhydride was isolated without concomitant acetylation of
the α-hydroxy group by limiting the time of exposure to
1
crepancies were observed for H n.m.r. spectra in (D5)pyri-
1
acetyl chloride in the final step. Its H n.m.r. spectrum
dine.
showed a chelated hydroxy resonance at δ 10.60.
Despite possessing a free hydroxy group, the homoph-
thalic anhydride (18) was similarly convertible into iso-
viocristin (20). Initially it was assumed that the relevant
base-catalysed cycloaddition chemistry would require pro-
tection of hydroxy substituents, such as occurred automati-
cally in the acetate formation that generally accompanied
anhydride synthesis on heating with acetyl chloride.
However, following treatment of (18) with two equivalents
of sodium hydride at 0°, the derived enolate pleasingly was
found to undergo smooth addition/aromatization with (22) to
form isoviocristin (20) (80%) itself. Its spectroscopic data
showed good agreement with those reported for the natural
material.9
With access to the anhydrides (8), (12), (14) and (18) thus
easily effected, the last two have been applied to new syn-
theses of the microbial 1,4-anthraquinones viocristin (19),
isoviocristin (20) and hydroxyviocristin (21).9,10 This has
involved the general chemistry of Scheme 1. Previous syn-
theses of these compounds have employed quite different
chemistry, proceeding through intermediate 9,10-
anthraquinones.9,11
Treatment of (14) with sodium hydride at 0° generated the
corresponding enolate, which underwent cycloaddition to
the chloro quinone (22),12 forming viocristin acetate (23)
(78%) after aromatization. Its 1H n.m.r. spectrum contained

Homophthalates from Allenic Diesters
1015
These syntheses of viocristin (19) and isoviocristin (20)
automatically also constitute a synthesis of hydroxy-
viocristin (21), Anke and Laatsch having shown that either
(19) or (20) was convertible into the latter.9 Their procedure
entailed reductive dealkylation with hydrogen iodide fol-
lowed by oxidation of the intermediate anthrone. The same
overall outcome has now also been effected by direct hydrol-
ysis, involving brief contact of (20) with molten aluminium
chloride–sodium chloride. This gave (21) (86%), whose
physical data agreed with those reported for the natural com-
pound9 and that was identical with a sample synthesized here
earlier by a different procedure.11
lized homophthalic anhydrides themselves functioning as
dienes in cycloaddition to (1) was next examined, in order to
assess the resulting formation of ring-extended outcomes. A
target system (34) was explored, hypothetically derivable by
the action of enolized (18) on the diester (1). Compound
(34) has been reported as an advanced intermediate in a
synthesis17 of the antifungal agent semivioxanthin.
Disappointingly, however, the combination of enolized (18)
with (1) under standard conditions could not be made to give
(34) in yield greater than 9%. The bulk of the reaction
mixture following workup, consisted of diacid (17) deriving
from hydrolysis of (18).
To illustrate further the regiocontrol available in the syn-
thesis of the 1,4-anthraquinones (19)–(21), attention then
turned to preparing their regioisomers (24)–(26) for the first
time. Thus the enolate of (14), on being made to react with
the isomeric chloro benzoquinone (27), gave first the acetate
(28) (76%) and then, following hydrolysis, the viocristin
isomer (24) (88%).
Similarly, the enolate of (18), generated with two equiva-
lents of sodium hydride, reacted with (27) to give the iso-
viocristin regioisomer (25) (75%). Brief exposure to an
aluminium chloride–sodium chloride melt then gave (26)
(88%).
1
The H n.m.r. spectra of the new compounds (24)–(26)
were very similar to those of their respective regioisomers
(19)–(21), as expected. The most notable difference between
the two groups was the small but consistent deshielding
(0.14–0.27 ppm) of the hydroxy substituent adjacent to the
carbonyl group, in the former series. This effect on the
chelated hydroxy resonance is qualitatively consistent with
those observed on simpler models,14 for which a still smaller
regiochemical difference was considered to be diagnostic.
Thus for 5-hydroxy-2-methyl-1,4-naphthoquinone the
hydroxy group resonated sharply at δ 11.93, whereas for the
8-hydroxy-2-methyl isomer it was observed at δ 12.01.
The final pair of 1,4-anthraquinones synthesized were the
dimethyl ethers (29) and (30). Treatment of the diester (15)
with methyl iodide/silver(I) oxide efficiently gave the appro-
priate homophthalate (31).15 As for parallel systems this also
efficiently gave the diacid (32)15 and then the anhydride
(33).16 Enolization of (33) and reaction with (22) afforded
1
The H n.m.r. spectrum of (34) showed two chelated
hydroxy resonances (δ 9.80, 14.26), while the aromatic
region appropriately contained a pair of meta-coupled dou-
blets (δ 6.55, 6.57, J 2.5 Hz) and a singlet at δ 6.95. Its low
yield could be attributed to incompatibility of the allenic
system (1) with the strongly basic reaction conditions. The
published alternative synthesis17 required six steps, consti-
tuting an overall yield of 6%.
The final aspect of this work has sought improved access
to the C-methyl homophthalic anhydride (35), a key inter-
mediate in our earlier synthesis of 6-methylpretetramid.4 In
that work, compound (35) was derived in six steps from
phenol. It was hoped that a better synthesis might result from
appropriate cycloaddition to the methyl-substituted allene
(36), assuming that such addition might favour the less sub-
stituted 3,4-double bond.
1
the 1,4-anthraquinone (29) (70%). Its H n.m.r. spectrum
contained a chelated hydroxy resonance (δ 14.92) and two
methoxy resonances at δ 3.95 and 4.02. It has been prepared
independently by selective methylation of viocristin (19).9
The enolate of (33) reacted similarly with the isomeric
benzoquinone (27) to give the isomeric 1,4-anthraquinone
(30) (72%). Its 1H n.m.r. spectrum was similar to that of (29)
except for the expected small deshielding (0.18 ppm) of its
chelated hydroxy resonance.
The syntheses so far described have been based on two
novel stages proceeding reliably: (i) cycloaddition to the
allenic diester (1), necessary for forming the homophthalate
system in the first place; and (ii) cycloaddition of derived
homophthalic anhydrides as enols. To this point, stage (i)
has involved conventional acyclic butadienes and stage (ii)
conventional quinonoid dienophiles. The possibility of eno-
The new allene (36) was synthesized by conventional
chemistry.18 Diethyl acetone-1,3-dicarboxylate (37) was
mono-C-methylated to give (38).19,20 Treatment with phos-
phorus pentachloride followed by boiling in methanolic acid
afforded the chloro diester (39) (85%). It was formed appar-

1016
E. Caliskan, D. W. Cameron and P. G. Griffiths
over magnesium sulfate prior to evaporation. Flash chromatography
was carried out using Merck Kieselgel No. 9385. In instances where
the silica had been acidified with oxalic acid (2% w/w), the separated
fractions were washed with water before drying and evaporation. All
solvents were of A.R. grade or were redistilled prior to use. Petrol
refers to the fraction boiling in the range 60–80° and light petrol refers
to the fraction boiling in the range 40–60°. Organic extracts were gen-
erally dried over magnesium sulfate before evaporation at reduced pres-
sure.
ently as a single geometrical isomer, whose configuration
1
was not established. Its H n.m.r. spectrum showed C-
methyl, two methoxy and methylene resonances at δ 2.05,
3.67, 3.70 and 3.90 respectively. On treatment with
trimethylamine at 0° it gave the desired allene (36) (88%).
The 1H n.m.r. spectrum of (36) contained a doublet
methyl resonance (δ 1.96, J 2.9 Hz) coupling to the olefinic
proton, which was observed as a corresponding quartet (δ
5.89). Significant long-range coupling has analogously been
observed for other allenic systems.21,22 There was also an
infrared absorption maximum at 1957 cm–1 consistent with
the allenic group.22
Methyl (5-Hydroxy-2-methoxycarbonylphenyl)acetate (6)
A solution of (5)24 (2.6 g) and allene (1)18 (2 g) in benzene (20 cm3)
was heated at reflux for 20 h. The solvent was evaporated and the
residue was dissolved in a solution of tetrahydrofuran (10 cm3) and con-
centrated hydrochloric acid (3 drops). The solution was stirred at room
temperature for 20 min and the resulting suspension was filtered to give
the diester (6) as a white solid (2.6 g, 92%). Recrystallization from
diethyl ether/light petrol afforded colourless needles, m.p. 110–112°
(Found: C, 58.7; H, 5.4. C11H12O5 requires C, 58.9; H, 5.4%). νmax 3319,
1710, 1608 cm–1. δ 3.75, 3.83, s, s, 2×OMe; 3.95, s, CH2; 6.24, s, OH;
6.61, d, J 2.6 Hz, H6; 6.67, dd, J 8.6, 2.6 Hz, H4; 7.92, d, J 8.6 Hz,
H3. m/z 224 (M, 15%), 193 (39), 192 (80), 165 (84), 164 (100), 149
(76), 135 (31).
Cycloaddition of diene (9) to the allene (36) proceeded in
boiling benzene followed by aromatization with acid. The
anticipated product (40) was not purified but was directly O-
methylated with methyl iodide/silver(I) oxide to give the
methoxy diester (41) (75%). As a dienophile, the allene (36)
was only marginally less reactive than its unsubstituted
counterpart (1) and it pleasingly underwent addition with
selectivity completely favouring the less substituted of its
two ene components, within the limits of detection.
1
(2-Carboxy-5-hydroxyphenyl)acetic Acid (7)
The H n.m.r. spectrum of (41) showed resonances con-
The diester (6) (1 g) was dissolved in 10% aqueous sodium hydrox-
ide (20 cm3) solution and heated to 80° for 30 min. The cooled solution
was acidified with concentrated hydrochloric acid to pH 1–2, diluted
with water (20 cm3) and extracted with diethyl ether (4×50 cm3). The
ethereal phase was dried and concentrated to yield the diacid (7) as a
white solid (750 mg, 86%), m.p. 194–197° (Found: M+•, 196.0365.
sistent with the three aromatic protons, together with com-
plementary doublet and quartet resonances (δ 1.47, 3.72
respectively, J 7.1 Hz) corresponding to the ethylidene
group, and a non-ester methoxy singlet at δ 3.65. Its mass
spectrum showed an appropriate molecular ion at m/z 252.
On hydrolysis it gave the diacid (42)23 (88%), which under-
went dehydration in boiling acetyl chloride to afford the
target anhydride (35)23 (76%). Its spectroscopic and other
physical data were indistinguishable from those for this com-
pound, independently obtained in our previous work.4 In
that latter synthesis the yield of (35) from phenol was 17%
overall, in six steps. The new approach afforded the same
anhydride in yield of 32% based on the acetonedicarboxylate
(38); or of 50% based on the allenic diester (36). To this can
be added considerable qualitative advantage in its mildness,
convenience and relative simplicity.
C9H8O5 requires M+•, 196.0372). νmax 3341, 1689, 1656 cm–1.
δ
[(D6)acetone] 3.99, s, CH2; 6.82, m, H4, H 6; 7.96, d, J 9.3 Hz, H3;
9.09, s, OH. m/z 196 (M, 5%), 178 (30), 152 (61), 150 (33), 135 (28),
134 (100), 121 (25), 106 (49), 105 (24), 78 (26), 77 (32).
6-Acetoxy-1H-2-benzopyran-1,3(4H)-dione (8)
Diacid (7) (200 mg) was dissolved in a mixture of acetone (5 cm3)
and acetyl chloride (15 cm3) and the solution was heated at reflux for 2
h. The solvent was removed by evaporation to give the anhydride (8),5
as a white solid (190 mg, 82%). Recrystallization from acetone/petrol
gave colourless needles, m.p. 155–157° (Found: C, 60.2; H, 3.7. Calc.
for C11H8O5: C, 60.0; H, 3.6%). νmax 1792, 1739 cm–1. δ [(D6)acetone]
2.31, s, OAc; 4.32, s, CH2; 7.27, d, J 2.2 Hz, H5; 7.30, dd, J 8.4, 2.2 Hz,
H7; 8.15, d, J 8.4 Hz, H8. m/z 220 (M, 23%), 178 (30), 134 (100), 106
(43), 77 (20).
Experimental
General
Methyl (3-Hydroxy-2-methoxycarbonylphenyl)acetate (10)
Melting points were determined on a Kofler hot-stage and are
uncorrected. Microanalyses were carried out by National Analytical
Laboratories, Melbourne, or Chemical and Microanalytical Services,
Geelong. Electronic spectra were recorded in chloroform unless other-
wise stated, by using a Varian Super Scan 3 spectrophotometer.
Infrared spectra were recorded with a Perkin–Elmer 983G 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 with a JEOL
JNM-GX400 spectrometer or a Varian Unity 300 spectrometer. The
solvent was (D)chloroform unless otherwise stated. High- and low-res-
olution mass spectra were recorded by using a V.G. Micromass 7070F
or a JEOL JSM-AX505H instrument at 70 eV. The mass of each ion is
given followed by its relative intensity. In general, only peaks greater
than 20% are quoted. Analytical and preparative thin-layer chromatog-
raphy (t.l.c.) were carried out on glass 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 with ethyl acetate or dichloromethane. Oxalic
acid was removed by washing the extracts with water and then drying
Diene (9)25 (3 g) and allene (1) (1.8 g) were made to react as for the
formation of (6). The acidified solution was stirred at room tempera-
ture for 20 min before being diluted with water (20 cm3) and extracted
into diethyl ether (2×50 cm3). The combined extracts were washed with
water, dried and concentrated. The oily residue was subjected to flash
chromatography, with diethyl ether/petrol (1: 4) as eluent, and the
major band gave the diester (10) (1.9 g, 73%) as a white solid.
Recrystallization from diethyl ether/light petrol gave colourless plates,
m.p. 54–56° (lit.26 53–55°). δ 3.69, 3.90, s, s, 2×OMe; 3.89, s, CH2;
6.72, d, J 8 Hz, H4; 6.97, d, J 8 Hz, H6; 7.37, t, J 8 Hz, H5; 11.21, s,
OH.
(2-Carboxy-3-hydroxyphenyl)acetic Acid (11)
The diester (10) (500 mg) was hydrolysed as for the formation of (7)
to give the diacid (11) (320 mg, 74%) as a white solid, m.p. 160–162°
(lit.26 161–163°) which was used in the next step without further purifi-
cation. δ [(D6)acetone] 4.01, s, CH2; 6.83, d, J 8 Hz, H4; 6.89, d, J 8
Hz, H6; 7.40, t, J 8 Hz, H5.

Homophthalates from Allenic Diesters
1017
8-Acetoxy-1H-2-benzopyran-1,3(4H)-dione (12)
8-Hydroxy-6-methoxy-1H-2-benzopyran-1,3(4H)-dione (18)
The diacid (11) (100 mg) was dissolved in a mixture of acetone (5
cm3) and acetyl chloride (10 cm3), and the solution was heated at reflux
for 2 h. Concentration of the mixture afforded the anhydride (12) (100
mg, 89%) as a white solid. Recrystallization from acetone/petrol gave
colourless needles, m.p. 151–154° (Found: C, 60.0; H, 3.7. C11H8O5
requires C, 60.0; H, 3.6%). νmax 1780, 1745, 1605 cm–1. δ [(D6)acetone]
2.31, s, Ac; 4.37, s, CH2; 7.22, d, J 8 Hz, H 7; 7.42, d, J 8 Hz, H5; 7.78,
t, J 8 Hz, H6. m/z 220 (M, 2%), 178 (100), 160 (35), 150 (63), 134 (28).
The diacid (17) (76 mg) was dissolved in a solution of acetyl chlo-
ride (10 cm3) and acetone (1 cm3) and the mixture was heated at reflux
for 1 h. Concentration of the solution afforded the anhydride (18) (62
mg, 88%) as a white solid. Recrystallization from acetone/petrol gave
colourless needles, m.p. 173–177° (Found: C, 57.9; H, 3.9. C10H8O5
requires C, 57.7; H, 3.9%). νmax 1784, 1696 cm–1. δ [(D6)acetone] 4.25,
s, CH2; 6.48, d, J 2.5 Hz, H 5 or H 7; 6.55, d, J 2.5 Hz, H 5 or H7; 10.60,
s, OH. m/z 208 (M, 10%), 207 (83), 189 (32), 180 (100), 164 (34), 151
(28), 78 (20), 69 (21).
Methyl (5-Hydroxy-3-methoxy-2-methoxycarbonylphenyl)acetate (2)
7-Acetoxy-10-hydroxy-5 methoxy-2-methyl-1,4-anthraquinone (23)
Diene (3)27 (2.2 g) and allene (1) (1.4 g) were made to react as for
the formation of (10). The crude product was subjected to flash chro-
matography, with diethyl ether as eluent, to give the diester (2) (1.7 g,
76%) as a white solid. Recrystallization from diethyl ether/petrol gave
colourless needles, m.p. 82–84° (lit.8 70–72°) (Found: C, 56.7; H, 5.6.
Calc. for C12H14O6: C, 56.7; H, 5.6%). νmax 3283, 1724, 1690 cm–1. δ
3.62, s, CH2; 3.70, 3.76, 3.85, s, s, s, 3×OMe; 5.86, br s, OH; 6.30, br s,
2×ArH. m/z 254 (M, 40%), 223 (48), 222 (31), 195 (84), 194 (100), 191
(23), 179 (82), 165 (20), 69 (21).
To a stirred suspension of sodium hydride (22 mg, 60% in paraffin oil)
in tetrahydrofuran (5 cm3) at 0° was added the anhydride (14) (57 mg).
The mixture was stirred for 20 min before being added dropwise to a solu-
tion of the benzoquinone (22)12 (42 mg) in tetrahydrofuran (5 cm3). The
resulting purple solution was stirred for a further 10 min at 0° and warmed
to room temperature over 30 min. The mixture was quenched with satu-
rated ammonium chloride solution (10 cm3) and extracted with ethyl
acetate (2×70 cm3). The combined organic extracts were washed with
water, dried and concentrated to a dark red residue which was subjected
to preparative t.l.c., with toluene/ethyl acetate (7 :3) as eluent. Removal
of the leading red band afforded the anthraquinone (23) (68 mg, 78%) and
recrystallization from dichloromethane/petrol gave red needles, m.p. dec.
>208° (lit.9 dec. 210°). δ 2.21, d, J 1.5 Hz, Me; 2.38, s, Ac; 4.05, s, OMe;
6.81, d, J 2.2 Hz, H6; 6.89, q, J 1.5 Hz, H 3; 7.29, d, J 2.2 Hz, H8; 7.95,
s, H9; 14.89, s, OH.
(2-Carboxy-5-hydroxy-3-methoxyphenyl)acetic Acid (13)
Diester (2) (240 mg) was heated to 60–70° in 10% aqueous sodium
hydroxide solution (20 cm3) for 1 h. The cooled solution was acidified
to pH 1–2 with concentrated hydrochloric acid, diluted with water (25
cm3) and extracted with ethyl acetate (4×20 cm3). The combined
extracts were dried and concentrated to give the diacid (13) (183 mg,
85%) as a white solid, m.p. 184–185° (Found: M+•, 226.0488.
C10H10O6 requires M+•, 226.0477). νmax 3083, 1712, 1665, 1604 cm–1.
δ [(D6)acetone] 3.71, s, CH2; 3.84, s, OMe; 6.45, d, J 2.2 Hz, H 4 or H 6;
6.49, d, J 2.2 Hz, H4 or H 6; 9.00, br s, OH. m/z 226 (M, 8%), 208
(M– H2O, 14), 182 (100), 180 (20), 164 (65), 138 (20), 137 (83), 121
(22), 107 (23), 69 (23), 64 (21), 58 (37).
Viocristin (7,10-Dihydroxy-5-methoxy-2-methyl-
1,4-anthraquinone) (19)
The anthraquinone (23) (24 mg) was dissolved in a solution of
sodium hydroxide in methanol (15 cm3, 0.1 M) and the dark mixture was
stirred at room temperature for 30 min. The solution was acidified to
pH 1–2 with concentrated hydrochloric acid, diluted with water (10
cm3) and extracted with ethyl acetate (3×40 cm3). The combined
extracts were washed with water, dried and concentrated. The purple
residue was subjected to preparative t.l.c., with toluene/ethyl acetate
(7: 3) as eluent. Removal of the leading purple band gave viocristin
(19) (29 mg, 90%). Sublimation (210°/10–4 mbar) gave violet micro-
crystals which decomposed without melting below 300° (Found: M+•,
284.0693. C16H12O5 requires M+•, 284.0685). λmax (log ε) (EtOH) 249,
280sh, 337, 495, 524, 564sh nm (4.20, 4.65, 3.68, 3.81, 3.85, 3.61). νmax
3392, 1662, 1617, 1589, 1511, 1440, 1407, 1362, 1213, 1168, 1108
cm–1. δ [(D6)dimethyl sulfoxide] 2.08, br s, Me; 3.89, s, OMe; 6.70, br
s, H6; 6.96, br s, H3; 6.98, br s, H8; 7.74, s, H9; 10.73, s, 7-OH; 14.89,
s, 10-OH. δ [(D5)pyridine] 2.07, d, J 1.5 Hz, Me; 3.92, s, OMe; 6.87, q,
J 1.5 Hz, H3; 7.01, d, J 2 Hz, H6; 7.26, d, J 2 Hz, H8; 8.10, s, H 9. m/z
284 (100%), 266 (18), 255 (23), 238 (35), 210 (16).
6-Acetoxy-8-methoxy-1H-2-benzopyran-1,3(4H)-dione (14)
To a solution of the diacid (13) (100 mg) in acetone (4 cm3) was
added acetyl chloride (10 cm3) and the mixture was heated at reflux for
10 h. The cooled solution was concentrated to give the anhydride (14)
(88 mg, 85%) as a white solid. Recrystallization from acetone/petrol
afforded colourless needles, m.p. 134–136° (Found: C, 57.2; H, 3.8.
C12H10O6 requires C, 57.6; H, 4.0%). νmax 1786, 1750 cm–1.
δ [(D6)acetone] 2.29, s, Ac; 3.94, s, OMe; 4.22, s, CH2; 6.81, d, J 2 Hz,
H7; 6.95, d, J 2 Hz, H 5. m/z 250 (M, 10%), 208 (32), 164 (100), 121
(15), 106 (13).
Methyl (3-Hydroxy-5-methoxy-2-methoxycarbonylphenyl)acetate (15)
For naturally derived viocristin (19),9 m.p. dec. >300°. λmax (logε)
(EtOH) 253, 280sh, 340, 497, 517, 527 nm (4.59, 4.62, 3.74, 3.91, 3.91,
3.90). νmax 1667, 1639, 1590, 1510, 1437, 1399, 1366, 1210, 1163,
1107, 1048 cm–1. δ [(D6)dimethyl sulfoxide] 2.10, d, J 1 Hz, 2-Me; 3.94,
s, OMe; 6.70, m, H3; 6.96, 7.26, (br s, br s, H 6, H8); 7.72, s, H9;
14.89, s, 10-OH. δ [(D5)pyridine] 2.08, s, Me; 4.00, s, OMe; 6.87, 7.00,
br s, br s H3, H6; 8.08, s, H9. m/z 284 (M, 100%), 266 (20, M– H2O),
255 (25, M –CHO), 238 (30). Comparison with parallel data cited for
natural isoviocristin (20)9 and for the related 1,4-anthraquinones syn-
thesized herein suggests that, for the original spectrum9 [in
(D6)dimethyl sulfoxide], the cited δ values for H3 and H6 should be
interchanged. At 300 MHz the former resonance nearly overlaps that
for H 8; in the original spectrum, run at 100 MHz, the cited δ value for
H8 (7.26) may possibly derive from chloroform solvent used in the
original recrystallization.
Diene (16)28 (920 mg) and allene (1) (600 mg) were made to react as
for the formation of (10). The crude product was subjected to flash
chromatography, with diethyl ether/petrol (1: 1) as eluent, and the
major band afforded the diester (15) (650 mg, 67%) as a white solid.
Recrystallization from diethyl ether/light petrol gave colourless
needles, m.p. 79–81° (Found: C, 56.7; H, 5.7. C12H14O6 requires C,
56.7; H, 5.6%). νmax 3441, 1728, 1686 cm–1. δ 3.69, 3.82, 3.86, s, s, s,
3×OMe; 3.83, s, CH2; 6.29, d, J 2.5 Hz, H 4; 6.43, d, J 2.5 Hz, H 6;
11.66, s, OH. m/z 254 (M, 44%), 223 (23), 222 (55), 195 (46), 194 (99),
190 (34), 179 (100), 135 (40).
(2-Carboxy-3-hydroxy-5-methoxyphenyl)acetic Acid (17)
The diester (15) (220 mg) was hydrolysed as for the formation of (7)
to give the diacid (17) (190 mg, 97%). Recrystallization from
dichloromethane/petrol gave colourless microneedles, m.p. 160–163°
(Found: C, 53.0; H, 4.7. C10H10O6 requires C, 53.1; H, 4.5%). νmax
2988, 1683 cm–1. δ [(D6)acetone] 3.84, s, OMe; 3.95, s, CH2; 6.40, d, J
2.5 Hz, H 4 or H 6; 6.43, d, J 2.5 Hz, H 4 or H6; 10.60, s, OH. m/z 226
(M, 13%), 208 (72), 190 (34), 183 (91), 180 (100), 164 (36), 151 (27),
137 (78), 107 (24), 69 (25).
For (19) derived from reductive cleavage of asperinine A,13 m.p.
>300°. λmax (logε) (EtOH) 253, 281sh, 340, 487, 417 (sic), 530 nm. νmax
3400, 1665, 1635, 1615, 1590, 1518 cm–1. δ [(D6)dimethyl sulfoxide]
2.08, d, J 1.5 Hz, Me; 3.91, s, OMe; 6.70, d, J 2 Hz, H 6; 6.97, m, H3;
6.98, d, J 2 Hz, H8; 7.74, s, H 9; 10.75, s, 7-OH; 14.90, s, 10-OH. m/z
284 (M), 266, 255, 238, 210.

1018
E. Caliskan, D. W. Cameron and P. G. Griffiths
Isoviocristin (5,10-Dihydroxy-7-methoxy-2-methyl-
6-Acetoxy-9-hydroxy-8-methoxy-2-methyl-1,4-anthraquinone (28)
1,4-anthraquinone) (20)
To a suspension of sodium hydride (13 mg, 60% in paraffin oil) in
tetrahydrofuran (5 cm3) was added the anhydride (14) (44 mg) and the
mixture was stirred for 15 min at 0° before being added dropwise to a
solution of the benzoquinone (27)29 (35 mg) in tetrahydrofuran (5 cm3).
Stirring was continued at 0° for 10 min and the mixture was warmed to
room temperature over 30 min before being quenched with saturated
ammonium chloride solution (20 cm3). It was then extracted with ethyl
acetate (3×50 cm3), and the extract was washed with water, dried and
concentrated. The dark residue was subjected to preparative t.l.c., with
chloroform as eluent, and the leading red band was removed to afford
the anthraquinone (28) (53 mg, 76%) as a red solid. Recrystallization
from dichloromethane/petrol gave red needles, m.p. dec. >215° (Found:
M+•, 326.0781. C18H14O6 requires M+•, 326.0790). λmax (logε) 263sh,
325, 347sh, 485, 508, 548sh nm (4.11, 3.71, 3.46, 4.05, 4.07, 3.78). νmax
3450, 1750, 1656, 1610 cm–1. δ 2.24, d, J 1.6 Hz, Me; 2.38, s, OAc;
4.05, s, OMe; 6.81, d, J 2 Hz, H 7; 6.84, q, J 1.6 Hz, H 3; 7.91, s, H10;
15.06, s, OH. (The signal for H5 was evidently obscured by a residual
chloroform peak at δ 7.26.) δ (C6D6) 1.63, d, J 1.5 Hz, Me; 1.78, s, OAc;
3.32, s, OMe; 6.30, q, J 1.5 Hz, H 3; 6.51, d, J 2 Hz, H7; 6.97, d, J 2
Hz, H 5; 7.97, s, H 10; 15.34, s, OH. m/z 326 (M, 53%), 284 (100), 83
(28), 81 (42), 71 (21), 69 (85), 56 (39), 54 (40).
To a suspension of sodium hydride (15 mg, 60% in paraffin oil) in
tetrahydrofuran (7 cm3) was added the anhydride (18) (30 mg) and the
mixture was stirred at 0° for 15 min before being added dropwise to a
solution of the benzoquinone (22)12 (22 mg) in tetrahydrofuran.
Stirring was continued for 10 min at 0° and the mixture was warmed to
room temperature over 40 min before being quenched with saturated
ammonium chloride solution (30 cm3). The suspension was extracted
with dichloromethane (3×50 cm3), and the extract was washed with
water, dried and concentrated. The dark residue was subjected to
preparative t.l.c., with toluene/ethyl acetate (7: 3) as eluent, and
removal of the leading purple band afforded isoviocristin (20) as a dark
solid (36 mg, 80%). Recrystallization from dichloromethane/petrol
gave microcrystals which decomposed without melting below 199°.
λmax (logε) 256, 282, 293, 306sh, 339, 506, 535, 572 nm (4.77, 3.94,
3.94, 3.77, 3.68, 3.94, 3.96, 3.77). νmax 3403, 1658, 1618, 1577, 1502,
1460, 1425, 1374, 1359, 1293, 1226, 1154, 1085, 1032, 1002, 893, 839,
701 cm–1. δ 2.20, d, J 1.4 Hz, Me; 3.92, s, OMe; 6.65, d, J 2.2 Hz, H 6;
6.84, d, J 2.2 Hz, H8; 6.90, q, J 1.4 Hz, H 3; 7.85, s, H 9; 10.28, s, 5-
OH; 15.98, s, 10-OH. m/z 284 (M, 100%), 227 (27), 213 (41), 188 (24),
185 (24), 139 (59), 127 (32), 117 (20), 102 (25), 99 (22), 89 (37), 88
(21), 87 (22), 77 (23), 75 (27), 74 (21), 69 (21), 62 (39), 61 (22), 56
(28), 53 (32).
6,9-Dihydroxy-8-methoxy-2-methyl-1,4-anthraquinone (24)
For naturally derived isoviocristin (20),9 m.p. 198°. λmax (logε) 258,
282, 294, 306sh, 341, 507, 535, 572sh nm (4.77, 4.00, 3.99, 3.84, 3.73,
3.99, 4.02, 3.79). νmax 1667, 1623, 1582, 1504, 1464, 1429, 1376, 1359,
1292, 1227, 1156, 1086, 1034, 999, 891, 840, 700 cm–1. δ 2.21, d, J 1.5
Hz, Me; 3.95, s, OMe; 6.67, 6.86, (d, d, J 2.3, 2.3 Hz, H 6, H8); 6.91,
q, J 1.5 Hz, H 3; 7.86, s, H 9; 10.32, s, 5-OH; 16.02, s, 10-OH.
The anthraquinone (28) (17 mg) was hydrolysed and the crude
product chromatographed, as for the formation of (19), to afford the
dihydroxy anthraquinone (24) (15 mg, 88%) as a dark solid.
Sublimation (210°/10–4 mbar) gave violet microcrystals, m.p. dec.
>238o (Found: M+•, 284.0673. C16H12O5 requires M+•, 284.0685). λmax
(logε) (EtOH) 252, 288sh, 301sh, 339, 490, 521, 563sh nm (4.64, 3.81,
3.66, 3.64, 3.79, 3.87, 3.67). νmax 3420, 1629, 1596 cm–1.
δ [(D6)dimethyl sulfoxide] 2.13, br s, Me; 3.90, s, OMe; 6.69, d, J 1.9
Hz, H 7; 6.90, br s, H 3; 6.96, d, J 1.9 Hz, H 5; 7.70, s, H10; 10.78,
br s, 6-OH; 15.06, s, 9-OH. m/z 284 (M, 26%), 266 (M–H2O, 6), 149
(47), 97 (28), 85 (29), 83 (41), 71 (46), 69 (49), 56 (100).
Hydroxyviocristin (5,7,10-Trihydroxy-2-methyl-
1,4-anthraquinone) (21)
The anthraquinone (20) (20 mg) was added to a melt of anhydrous
aluminium trichloride (2 g) and sodium chloride (0.5 g) at 140°. The
mixture was quickly heated to 180°, stirred for 2 min, cooled for 1 min,
and then poured into ice (200 cm3) containing concentrated hydrochlo-
ric acid (10 cm3). The purple mixture was stirred for 1 h with gentle
heating before being extracted with dichloromethane (3×30 cm3). The
combined organic extracts were washed with water (2×20 cm3), dried
and concentrated to give a dark residue which was subjected to prepar-
ative t.l.c., with toluene/ethyl acetate (9: 1) as eluent. The leading
purple band was removed to afford hydroxyviocristin (21) (16 mg,
86%) as a sparingly soluble dark solid which decomposed without
melting below 250°. Attempted recrystallization or sublimation
resulted in decomposition. It was indistinguishable from authentic
material11 in chromatographic behaviour, and electronic, i.r., and n.m.r.
spectra. λmax [MeOH containing Me2SO (5%) and HCO2H (1%)] (logε)
288sh, 338, 503sh, 530, 572sh nm (3.97, 3.78, 3.81, 3.83, 3.67). νmax
1647, 1610, 1588, 1443, 1400, 1369, 1155, 1087, 878, 669 cm–1.
δ [(D6)acetone] 2.16, d, J 1.2 Hz, Me; 6.60, d, J 2.2 Hz, H 6; 6.99, d, J
2.2 Hz, H 8; 7.03, br s, H 3; 7.78, s, H 9; 9.71, br s, 7-OH; 10.40, s, 5-
OH; 16.19, s, 10-OH. m/z 270 (M, 100%), 255 (9), 242 (15), 241 (8),
227 (5), 155 (5), 109 (10), 97 (6), 83 (10).
8,9-Dihydroxy-6-methoxy-2-methyl-1,4-anthraquinone (25)
To a suspension of sodium hydride (29 mg, 60% in paraffin oil) in
tetrahydrofuran (10 cm3) was added the anhydride (18) (77 mg) and the
whole was stirred at 0° for 20 min before being added dropwise to a
solution of the benzoquinone (27) (57 mg) in tetrahydrofuran (10 cm3).
The mixture was stirred at 0° for 10 min and warmed to room temper-
ature over 40 min. The dark suspension was quenched with saturated
ammonium chloride solution (15 cm3) and extracted with chloroform
(3×50 cm3). The combined organic extracts were washed with water
(2×20 cm3), dried and concentrated. The purple residue was subjected
to flash chromatography (on silica containing 2% oxalic acid), with
toluene/ethyl acetate (7 : 3) as eluent. Removal of the leading purple
band afforded the anthraquinone (25) as a dark solid (78 mg, 75%).
Recrystallization from dichloromethane/petrol gave microcrystals
which decomposed without melting below 215° (Found: C, 67.8; H,
4.2. C16H12O5 requires C, 67.5; H, 4.5%). λmax (logε) 256, 280, 290,
304sh, 334, 497, 527, 567sh nm (4.86, 4.11, 4.11, 3.92, 3.75, 4.07, 4.13,
3.94). νmax 3377, 1695, 1648 cm–1. δ 2.24, br s, Me; 3.93, s, OMe; 6.67,
d, J 2.3 Hz, H 7; 6.79, br s, H3; 6.86, d, J 2.3 Hz, H 5; 7.84, s, H10;
10.16, s, 8-OH; 16.25, s, 9-OH. m/z 284 (M, 100%), 188 (20), 139 (20),
266 (21), 255 (30), 238 (40), 149 (42).
For naturally derived hydroxyviocristin (21),9 m.p. 250°. λmax
(CHCl3/MeOH) (logε) 257, 282, 295, 307sh, 342, 515sh, 535, 572 nm
(4.70, 4.01, 3.98, 3.81, 3.64, 4.00, 4.03, 3.84). νmax 1664, 1630, 1597,
1445, 1383, 1367, 1227, 1159, 1089, 1028, 990, 887, 833, 728, 699
cm–1. δ [(D)chloroform/(D6)acetone] 2.22, d, J 1.5 Hz, Me; 6.68, d, J
2.5 Hz, H 6; 6.92, d, J 2.5 Hz, H 8; 6.94, m, H 3; 7.84, s, H 9; 9.04,
10.46, 16.16, s, s, s, 3×OH. m/z 270 (M, 98%), 255 (23), 242 (10), 241
(12), 227 (38), 155 (27), 109 (31), 97 (45), 95 (40), 83 (51), 81 (54), 42
(100), 41 (85).
6,8,9-Trihydroxy-2-methyl-1,4-anthraquinone (26)
The anthraquinone (25) (12 mg) was added to a melt of anhydrous
aluminium trichloride (1 g) and sodium chloride (0.3 g) at 140°. The
mixture was quickly heated to 180°, stirred for 2 min, air-cooled for 1
min, then poured into ice (100 cm3) containing concentrated hydrochlo-
ric acid (5 cm3). The purple suspension was stirred with gentle heating
for 70 min before being extracted with dichloromethane (3×20 cm3).
The combined organic extracts were washed with water, dried and con-
centrated to leave a dark residue which was subjected to preparative
t.l.c., with toluene/ethyl acetate (9: 1) as eluent. The major purple band
For a sample of (21) independently derived from previous work
here:11 m.p. dec. 280°. λmax [MeOH containing Me2SO (5%) and
HCO2H (1%)] (log ε) 279sh, 338, 503sh, 530, 577sh nm (4.00, 3.98,
3.69, 3.93, 3.69). νmax 3360br, 1655sh, 1620, 1585, 1510sh cm–1.
δ [(D6)acetone] 2.16, br s, Me; 6.60, d, J 2.2 Hz, H 6; 6.99, d, J 2.2 Hz,
H8; 7.03, br s, H 3; 7.78, s, H 9; 9.72, br s, 7-OH; 10.40, s, 5-OH; 16.18,
s, 10-OH.

Homophthalates from Allenic Diesters
1019
3.92, 4.07, 4.12, 3.90). νmax 1690, 1678 cm–1. δ 2.23, br s, Me; 3.95,
4.03, s, s, 2×OMe; 6.64, d, J 2 Hz, H 7; 6.80, br s, H3; 6.86, d, J 2 Hz,
H5; 7.85, s, H10; 15.10, s, OH. m/z 298 (M, 100%), 280 (22), 269 (20),
252 (25), 180 (21).
was removed to afford the trihydroxy anthraquinone (26) as a dark solid
(6.3 mg, 88%), m.p. dec. >290° (Found: M+•, 270.0530. C15H10O5
requires M+•, 270.0528). λmax [MeOH containing Me2SO (5%) and
HCO2H (1%)] (log ε) 290, 335, 494sh, 525, 565sh nm (3.80, 3.67, 3.77,
3.86, 3.68). νmax 3374, 1695, 1647, 1610 cm–1. δ [(D6)acetone] 2.20, d,
J 1.7 Hz, Me; 6.61, d, J 2 Hz, H 7; 6.85, m, H 3; 7.00, d, J 2 Hz, H 5;
7.73, s, H 10; 9.65, br s, 6-OH; 10.17, s, 8-OH; 16.33, s, 9-OH. m/z 271
(M+1, 23%), 270 (M, 100), 242 (11), 213 (7), 174 (12), 97 (14), 56 (29).
Methyl (4,5-Dihydroxy-7-methoxy-3-methoxycarbonylnaphthalen-
2-yl)acetate (34)
To a suspension of sodium hydride (24 mg, 60% in paraffin oil) in
tetrahydrofuran (10 cm3) was added anhydride (18) (60 mg) and the
mixture was stirred at 0° for 10 min. The suspension was added to a
solution of the allene (1) (54 mg) in tetrahydrofuran (5 cm3) and the
whole was stirred at 0° for 20 min and at room temperature for 2 h. A
solution of 10% aqueous hydrochloric acid (2 cm3) was added and stir-
ring was continued for 30 min before the mixture was diluted with
water (20 cm3) and extracted with dichloromethane (2×20 cm3). The
combined organic extracts were dried and concentrated to give an oily
residue which was subjected to preparative t.l.c., with diethyl ether as
eluent. Isolation of the major band (RF 0.8) afforded the diester (34)
(8 mg, 9%) as colourless needles, m.p. 161–163° (lit.17 162.0–162.5°).
δ 3.70, 3.88, 3.92, s, s, s, 3×OMe; 3.91, s, CH2; 6.55, d, J 2.5 Hz, H6 or
H8; 6.57, d, J 2.5 Hz, H6 or H8; 6.95, s, H 1; 9.80, s, 5-OH; 14.26, s,
4-OH. m/z 320 (M, 20%), 288 (32), 256 (100), 229 (10), 200 (10).
Methyl (3,5-Dimethoxy-2-methoxycarbonylphenyl)acetate (31)
To a solution of diester (15) (250 mg) in dichloromethane (20 cm3)
was added silver(I) oxide (2.5 g) and methyl iodide (1 cm3). The
mixture was stirred at room temperature in the absence of light for 24
h. The suspension was filtered and the solid was washed with
dichloromethane (2×10 cm3). The filtrate and washings were concen-
trated to give a pale yellow solid which was recrystallized from diethyl
ether/petrol to give the diester (31)15 (250 mg, 95%) as colourless
needles, m.p. 50–52° (Found: C, 58.4; H, 6.1. Calc. for C13H16O6: C,
58.2; H, 6.0%). νmax 1727, 1699 cm–1. δ 3.67, s, CH2; 3.68, 3.82, 3.83,
3.86, s, s, s, s, 4×OMe; 6.40, d, J 2.3 Hz, H 4 or H 6; 6.41, d, J 2.3 Hz,
H4 or H 6. m/z 268 (M, 37%), 237 (41), 236 (24), 209 (74), 208 (100),
193 (86).
Diethyl 3-Oxopentanedioate Magnesium Complex19
(2-Carboxy-3,5-dimethoxyphenyl)acetic Acid (32)
The diester (31) (103 mg) was dissolved in 10% aqueous sodium
hydroxide solution (20 cm3) and heated to 80° for 30 min. The cooled
solution was acidified to pH 1–2 with concentrated hydrochloric acid,
diluted with water (30 cm3) and extracted with ethyl acetate (4×50 cm3).
The combined extracts were dried and concentrated to give diacid (32)
(76 mg, 83%) as a white solid. Recrystallization from acetone/petrol
gave colourless cubes, m.p. 175–178° (lit.15 172–173°). δ [(D6)acetone]
3.77, s, CH2; 3.84, 3.87, s, s, 2×OMe; 6.55, d, J 2.5 Hz, H 4 or H6; 6.58,
d, J 2.5 Hz, H 4 or H 6.
To a solution of diethyl acetone-1,3-dicarboxylate (37) (20 g) and
triethylamine (10 g) in dry benzene (80 cm3) was added anhydrous
magnesium dichloride (4.8 g) and the mixture was heated at reflux for
90 min. The cooled suspension was concentrated and the residue was
dissolved in dry diethyl ether (50 cm3). The resulting precipitate was
filtered off and the solid was washed with diethyl ether. The filtrate and
washings were concentrated to give the magnesium complex19 (20 g,
95%) as a pale yellow viscous oil. δ 1.21, t, J 7 Hz, 2×CH2Me; 3.10, s,
CH2CO2Et; 4.08, q, J 7 Hz, 2×CH2Me; 4.72, s, CH.
6,8-Dimethoxy-1H-2-benzopyran-1,3(4H)-dione (33)
Diethyl 2-Methyl-3-oxopentanedioate (38)
A solution of diacid (32) (200 mg) in acetyl chloride (10 cm3) was
heated at reflux for 30 min. The cooled solution was concentrated to
give the anhydride (33) (161 mg, 87%) as a pale yellow solid.
Recrystallization from acetone/petrol afforded colourless micronee-
dles, m.p. 166–167° (lit.16 167–168°). δ [(D6)acetone] 3.92, 3.93, s, s,
2×OMe; 4.15, s, CH2; 6.60, d, J 2.4 Hz, H 5 or H 7; 6.63, d, J 2.4 Hz,
H5 or H 7.
To a solution of the foregoing magnesium complex (21.4 g) in
tetrahydrofuran (50 cm3) at 0° was added sodium hydride (4.2 g, 60%
in paraffin oil) and the suspension was stirred at room temperature for
30 min. A solution of methyl iodide (6.6 cm3) in tetrahydrofuran (10
cm3) was added dropwise to the suspension and stirring was continued
for 22 h in the absence of light. The mixture was quenched slowly with
5% aqueous hydrochloric acid (40 cm3) and then acidified to pH 1–2
with concentrated hydrochloric acid. The suspension was extracted
with diethyl ether (3×50 cm3) and the combined organic extracts were
washed with water (100 cm3), dried and concentrated. Distillation
yielded the diester (38) (19.5 g, 90%) as a colourless oil, b.p. 100°/0.05
mmHg (lit.20 108–110°/1 mmHg). δ 1.23, t, J 7 Hz, 2×CH2Me; 1.32, d,
J 7 Hz, 2-Me; 3.53, 3.60, ABq, J 16 Hz, 4CHAHB; 3.68, q, J 7 Hz, H2;
4.15, q, J 7 Hz, 2×CH2Me.
10-Hydroxy-5,7-dimethoxy-2-methyl-1,4-anthraquinone (29)
To a suspension of sodium hydride (10 mg, 60% in paraffin oil) in
tetrahydrofuran (10 cm3) was added anhydride (33) (28 mg) and the
mixture was stirred at 0° for 10 min before being added dropwise to a
solution of the benzoquinone (22) (20 mg) in tetrahydrofuran (7 cm3).
Stirring was continued at 0° for 30 min and the mixture was warmed to
room temperature over 20 min. The suspension was then quenched
with saturated ammonium chloride solution (20 cm3) and extracted with
dichloromethane (2×20 cm3). The combined extracts were washed with
water, dried and concentrated to give a red residue which was subjected
to flash chromatography (on silica containing 2% oxalic acid), with
toluene/ethyl acetate (7: 3) as eluent. The leading red band was
removed to afford the anthraquinone (29) (26 mg, 70%) as a dark red
Dimethyl 3-Chloro-2-methylpent-2-enedioate (39)
To a stirred solution of the diester (38) (19.3 g), under nitrogen, was
added slowly, over 30 min, ground phosphorus pentachloride (20.6 g)
and the mixture was warmed to 40° and stirred for a further 30 min. The
red solution was cooled, poured onto ice (100 cm3) and stirred for 15
min. The suspension was extracted with dichloromethane (3×50 cm3)
and the combined organic extracts were dried and concentrated. The
residue was dissolved in a solution of anhydrous methanol (100 cm3)
and concentrated sulfuric acid (7 cm3) and the mixture was heated at
reflux for 18 h. The excess methanol was distilled off and the yellow
residue was cooled to room temperature before being extracted with
diethyl ether (5×40 cm3). The combined extracts were washed succes-
sively with aqueous saturated sodium hydrogen carbonate solution (50
cm3) and saturated sodium chloride solution (50 cm3), then dried and
concentrated. Distillation yielded the methyl diester (39) (15.7 g, 85%)
as a colourless oil, b.p. 60–70°/0.05 mmHg (Found: C, 46.8; H, 5.5.
C8H11ClO4 requires C, 46.5; H, 5.4%). νmax 1742, 1712 cm–1. δ 2.05, s,
2-Me; 3.67, 3.70, s, s, 2×OMe; 3.90, s, CH2. m/z 208 (M[37Cl], 20%),
206 (M[35Cl], 50), 174 (25), 144 (25), 146 (75), 59 (100).
solid.
Recrystallization from dichloromethane/petrol gave red
microneedles, m.p. dec. >225° (lit.9 224°). δ 2.19, d, J 2 Hz, Me; 3.95,
4.02, s, s, 2×OMe; 6.63, d, J 2.2 Hz, H 6; 6.84, br s, H3 and H8; 7.87,
s, H 9; 14.92, s, OH.
9-Hydroxy-6,8-dimethoxy-2-methyl-1,4-anthraquinone (30)
Sodium hydride (19 mg, 60% in paraffin oil), anhydride (33) (70
mg) and the benzoquinone (27) (49 mg) were made to react as for the
formation of (29). After chromatography the major red band was
removed to give the anthraquinone (30) (67 mg, 72%) as a red solid.
Recrystallization from dichloromethane/petrol afforded microneedles,
m.p. dec. >208° (Found: M+•, 298.0838. C17H14O5 requires M+•,
298.0841). λmax (logε) 286, 300, 331, 488, 516, 552sh nm (3.98, 3.99,

1020
E. Caliskan, D. W. Cameron and P. G. Griffiths
Dimethyl 2-Methylpenta-2,3-dienedioate (36)
Award (to E.C.). We thank the Research School of
Chemistry, A.N.U., for a Visiting Fellowship (to D.W.C.),
during which part of this paper was written.
To a stirred solution of the foregoing ester (39) (4.2 g) in tetrahy-
drofuran (20 cm3) at 0° was added dropwise triethylamine (3.2 cm3) and
the mixture was stirred at 0–5° for 18 h. The resulting suspension was
filtered and washed with anhydrous diethyl ether (3×20 cm3). The com-
bined filtrate and washings were washed with aqueous hydrochloric
acid (3×15 cm3, 0.1 M) and saturated sodium chloride solution (20 cm3).
The ethereal layer was dried and concentrated to give an oily residue
which was distilled to yield the pentadienedioate (36) (3 g, 88%) as a
colourless oil, b.p. 60–63°/0.1 mmHg (Found: C, 56.6; H, 6.1.
C8H10O4 requires C, 56.5; H, 5.9%). νmax 1957, 1727, 1630 cm–1.
δ 1.96, d, J 2.9 Hz, 2-Me; 3.75, s, 2×OMe; 5.89, q, J 2.9 Hz, H 4. m/z
170 (M, 24%), 156 (20), 142 (32), 83 (55), 58 (100), 51 (24), 50 (20).
References
1
Tamura, Y., Sasho, M., Akai, S., Akimori, W., and Kita, Y.,
Tetrahedron, 1984, 40, 4539.
2
Tamura, Y., Sasho, M., Nakagawa, K., Tsugoshi, T., and Kita, Y., J.
Org. Chem., 1984, 49, 473.
3
Tamura, Y., Sasho, M., Akai, S., Kishimoto, H., Sekihachi, J.-I., and
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Methyl 2-(3Ј-Methoxy-2Ј-methoxycarbonylphenyl)propanoate (41)
4
Cameron, D. W., and de Bruyn, P. J., Tetrahedron Lett., 1993, 34,
To a solution of the allene (36) (400 mg) in benzene (2 cm3) was
added diene (9) (670 mg) and the mixture was heated at reflux for 20 h.
The cooled solution was concentrated and the residue was dissolved in
tetrahydrofuran (1 cm3). Concentrated hydrochloric acid (2 drops) was
added and the solution was stirred at room temperature for 20 min
before being extracted with diethyl ether (2×20 cm3). The ethereal
layer was washed with water, dried and concentrated to give an oily
residue which was dissolved in dichloromethane (5 cm3). Silver(I)
oxide (2 g) and methyl iodide (1 cm3) were added to the solution and
the whole was stirred for 20 h in the absence of light. The suspension
was filtered and the solid was washed with dichloromethane (2×20
cm3). The filtrate and washings were concentrated and the residue was
subjected to preparative t.l.c., with diethyl ether as eluent. The leading
band was removed to afford the diester (41) (443 mg, 75%) as a white
solid, m.p. 35–36° (Found: C, 62.0; H, 6.3. C13H16O5 requires C, 61.9;
H, 6.4%). νmax 1727 cm–1. δ 1.47, d, J 7.1 Hz, CMe; 3.65, s, OMe; 3.72,
q, J 7.1 Hz, H2; 3.82, 3.92, s, s, 2×CO2Me; 6.84, d, J 8.1 Hz, H6Ј or
H4Ј; 6.95, d, J 8.1 Hz, H6Ј or H 4Ј; 7.34, t, J 8.1 Hz, H 5Ј. m/z 252 (M,
73%), 177 (21), 161 (20), 91 (20), 69 (22), 57 (100), 56 (20).
4689.
5
Kozikowski, A. P., and Schmiesing, R., Synth. Commun., 1978, 8,
363.
6
Jung, M. E., Node, M., Pfluger, R. W., Lyster, M. A., and Lowe, J.
A., J. Org. Chem., 1982, 47, 1150.
7
Tamura, Y., Fukata, F., Tsugoshi, T., Sasho, M., Nakajima, Y., and
Kita, Y., Chem. Pharm. Bull., 1984, 32, 3259.
8
Danishefsky, S., Yan, C.-F., Singh, R. K., Gammill, R. B., McCurry,
P. M., Fritsch, N., and Clardy, J., J. Am. Chem. Soc., 1979, 101,
7001.
9
Anke, H., and Laatsch, H., Liebigs Ann. Chem., 1982, 2189.
10
Anke, H., Kolthoum, I., Zahner, H., and Laatsch, H., Arch.
Microbiol., 1980, 126, 223; Anke, H., Kolthoum, I., and Laatsch,
H., Arch. Microbiol., 1980, 126, 231.
11
Cameron, D. W., Edmonds, J. S., and Raverty, W. D., Aust. J.
Chem., 1976, 29, 1535.
12
13
14
15
16
Andrews, K. J. M., Marrian, D. H., and Maxwell, D. R., J. Chem.
Soc., 1956, 1844.
Arai, K., Aoki, Y., and Yamamoto, Y., Chem. Pharm. Bull., 1989,
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2-(2Ј-Carboxy-3Ј-methoxyphenyl)propanoic Acid (42)
Lillie, T. J., and Musgrave, O. C., J. Chem. Soc., Perkin Trans. 1,
1977, 355.
A solution of diester (41) (100 mg) in aqueous sodium hydroxide
solution (20 cm3, 0.1 M) was heated at 80° for 1 h. The cooled solution
was acidified with concentrated hydrochloric acid to pH 1–2 and
diluted with water (20 cm3) before being extracted with diethyl ether
(100 cm3). The ethereal phase was filtered while hot (charcoal), dried
and concentrated to yield the diacid (42) (75 mg, 88%) as a white solid,
m.p. 178–180° (lit.23 180–182°). It was undepressed in admixture with
authentic material4 and was indistinguishable from it in chromato-
graphic behaviour. δ [(D6)acetone] 1.41, d, J 7.1 Hz, CMe; 3.83, s,
OMe; 3.86, q, J 7.1 Hz, H2; 6.97, d, J 8 Hz, H 4Ј or H 6Ј; 6.99, d, J 8
Hz, H 4Ј or H 6Ј; 7.37, t, J 8 Hz, H 5Ј.
Hardegger, E., Rieder, W., Walser, A., and Kugler, F., Helv. Chim.
Acta, 1966, 49, 1283.
Matsuda, F., Kawasaki, M., Ohsaki, M., Yamada, K., and
Terashima, S., Tetrahedron, 1988, 44, 5745; Henderson, G. B., and
Hill, R. A., J. Chem. Soc., Perkin Trans. 1, 1982, 1111.
Yamaguchi, M., Okuma, T., Nakamura, S., and Minami, T., J.
Chem. Soc., Perkin Trans. 1, 1990, 183.
17
18
19
20
21
Bryson, T. A., and Dolak, T. M., Org. Synth., 1977, 57, 62.
Yamato, M., and Kusunoki, Y., Chem. Pharm. Bull., 1981, 29, 1214.
Yamato, M., and Kusunoki, Y., Chem. Pharm. Bull., 1981, 29, 2832.
Nader, F. W., Brecht, A., and Kreisz, S., Chem. Ber., 1986, 119,
1196.
8-Methoxy-4-methyl-1H-2-benzopyran-1,3(4H)-dione (35)
22
23
24
25
Pover, K. A., and Scheinmann, F., J. Chem. Soc., Perkin Trans. 1,
1980, 2339.
The diacid (42) (100 mg) in a sublimation apparatus was dissolved
in acetyl chloride (5 cm3) and acetone (1 cm3) with heating. Heating
was continued until all the solvent evaporated to leave a viscous
residue. Sublimation (100°/0.01 mmHg) afforded the anhydride (35)
(70 mg, 76%) as white microneedles, m.p. 90–92° (lit.23 90–92°). νmax
1785, 1745, 1600, 1480 cm–1. δ [(D6)acetone] 1.66, d, J 7 Hz, CMe;
3.96, s, OMe; 4.21, q, J 7 Hz, CHMe; 7.12, d, J 8 Hz, H5 or H7; 7.16,
d, J 8 Hz, H 5 or H 7; 7.70, t, J 8 Hz, H 6.
Tokoroyama, T., Nishikawa, T., Ando, K., Nomura, N., and Kuboto,
T., Nippon Kagaku Kaishi, 1974, 136.
Danishefsky, S., and Kitahara, T., J. Am. Chem. Soc., 1974, 96,
7807.
Grunwell, J. R., Karipides, A., Wigal, C. T., Heinzman, S. W.,
Parlow, J., Surso, J. A., Clayton, L., Fleitz, F. J., Daffner, M., and
Stevens, J. E., J. Org. Chem., 1991, 56, 91.
For (35) derived from phenol:4 m.p. 90–92°. νmax 1787, 1743, 1594,
1478 cm–1. δ [(D6)acetone] 1.66, d, J 7 Hz, Me; 3.96, s, OMe; 4.21, q,
J 7 Hz, CHMe; 7.16, apparent t, J 7 Hz, 2×ArH; 7.73, apparent t, J 7.7
Hz, 1×ArH.
26
27
Wagatsuma, S., Higuchi, S., Ito, H., Nakano, T., Naoi, Y., Sakai, K.,
Matsui, T., Takahashi, Y., Nishi, A., and Sano, S., Org. Prep.
Proced. Int., 1973, 5, 65.
Banville, J., and Brassard, P., J. Chem. Soc., Perkin Trans. 1, 1976,
1852.
Acknowledgments
We acknowledge the financial support of the Australian
Research Council and an Australian Postgraduate Research
28
29
Savard, J., and Brassard, P., Tetrahedron, 1984, 40, 3455.
Cason, J., Allen, C. F., and Goodwin, S., J. Org. Chem., 1948, 13,
403.