Intramolecular aldol-type condensation between side chains of naphthoquinones: Biomimetic synthesis of 1,6- and 1,8-dihydroxyanthraquinones

Article abstract of DOI:10.1039/b104789m

Intramolecular condensation of 2-(acetonyl)-3-acyljuglone derivatives under basic conditions gave 1,6- and/or 1,8-dihydroxyanthraquinones depending on the conditions employed. Treatment of 6-[(3-acetyl-5-methoxy-1,4-dioxo-1,4-dihydro-2-naphthyl)methyl]-2,2- dimethyl-4H-1,3-dioxin-4-one with K₂CO₃ in alcohol brought about the intramolecular Knoevenagel-type reaction to give 3-hydroxy-8-methoxy-1-methyl-9,10-dioxo-9,10-dihydro-anthracene-2- carboxylates in good yields, while the same naphthoquinone gave 4-hydroxy-5-methoxy-9,10-dioxo-9,10-dihydroanthracene-2-acetic acid in good yield by treatment with potassium bis(trimethylsilyl)amide (KHMDS). Chrysophanol, aloe-emodin, aloesaponarin I, and K1115A were prepared in good yields.

Full text of DOI:10.1039/b104789m

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Intramolecular aldol-type condensation between side chains
of naphthoquinones: biomimetic synthesis of 1,6- and
1,8-dihydroxyanthraquinones†
1
Hidemitsu Uno,*a Akane Masumoto,a Erina Honda,a Yumi Nagamachi,a Youtarou Yamaokaa
and Noboru Onob
a Advanced Instrumentation Center for Chemical Analysis, Ehime University, Bunkyo-cho 2-5,
Matsuyama 790-8577, Japan
b Department of Chemistry, Faculty of Science, Ehime University, Bunkyo-cho 2-5,
Matsuyama 790-8577, Japan
Received (in Cambridge, UK) 31st May 2001, Accepted 17th October 2001
First published as an Advance Article on the web 7th November 2001
Intramolecular condensation of 2-(acetonyl)-3-acyljuglone derivatives under basic conditions gave 1,6- and/or
1,8-dihydroxyanthraquinones depending on the conditions employed. Treatment of 6-[(3-acetyl-5-methoxy-
1,4-dioxo-1,4-dihydro-2-naphthyl)methyl]-2,2-dimethyl-4H-1,3-dioxin-4-one with K2CO3 in alcohol brought
about the intramolecular Knoevenagel-type reaction to give 3-hydroxy-8-methoxy-1-methyl-9,10-dioxo-
9,10-dihydro-anthracene-2-carboxylates in good yields, while the same naphthoquinone gave 4-hydroxy-
5-methoxy-9,10-dioxo-9,10-dihydroanthracene-2-acetic acid in good yield by treatment with potassium
bis(trimethylsilyl)amide (KHMDS). Chrysophanol, aloe-emodin, aloesaponarin I, and K1115A
were prepared in good yields.
Introduction
Among various kinds of naturally occurring quinones, dihy-
droxy- and trihydroxyanthraquinones are abundantly isolated
from different sources.1 These quinone skeletons are biologic-
ally synthesized from polyketides.2 For example, chrysophanol
(1), aloe-emodin (2), rhein (3), emodin (4), physcion (5), aloe-
saponarins (6 and 7), and laccaic acid D (9) are believed to be
biosynthesized from the common octaketide having an acetyl
group as a starting unit via different biosynthetic pathways, and
the key step forming the skeletons is an aldol-type reaction such
as a Knoevenagel or a Michael reaction (Scheme 1).2 During the
biosynthesis, the ending unit is variously modified and the oxy-
gen functionality is occasionally removed from the 9-position
of the octaketide. Contrary to the biosynthesis, most suc-
cessful syntheses of these quinones involve the Diels–Alder or
Friedel–Crafts reaction as a key construction step of the target
quinone skeletons,3 although some biomimetic syntheses of
naturally occurring quinones have been reported by Krohn’s,
Yamaguchi’s, Harris’, and one of author’s, groups.4 One of the
reasons for the different choice of routes between biological
and artificial syntheses may be due to the labile nature of
quinones under basic conditions.5 Neutral or acidic conditions
commonly employed in the Diels–Alder and Friedel–Crafts
reactions are thought to be suitable for reactions using pro-
tected quinones or the quinones themselves. Basic conditions
required for the aldol-type reactions would cause decom-
position of quinones or simple reduction to hydroquinones
mainly by the electron-transfer mechanism. We thought that
this disadvantage under the aldol-type conditions would be
overcome when the quinone side chains bearing carbonyl
groups at appropriate positions are intramolecularly con-
densed. In such cases, a proper choice of the conditions would
† Electronic supplementary information (ESI) available: preparation
and experimental details of acetonylquinones. See http://www.rsc.org/
suppdata/p1/b1/b104789m/
Scheme 1 Biosynthesis of widely distributed 9,10-anthraquinones with
hydroxy groups from an octaketide.
DOI: 10.1039/b104789m
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This journal is © The Royal Society of Chemistry 2001
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alter the reaction mode to provide various quinone homologues
starting from the common precursor quinones. In this paper, we
would like to report 1,6- and 1,8-dihydroxyanthraquinone
syntheses from common naphthoquinone precursors by the
suitable choice of conditions6 and the total synthesis of chryso-
phanol (1), aloe-emodin (2), aloesaponarins I (6) and II (7), and
K1115A (8).
ations of alkylated naphthoquinones were accomplished by the
reaction with an acetonylpyridinium reagent.12 The 2-acetonyl-
3-acetylnaphthoquinone 14 was prepared either in 40% yield
via acetonylation of 11 with 2-(trimethylsiloxy)propene to
give 13, followed by oxidation with cerium() ammonium
nitrate (CAN) or in 45% yield via 2-methylallylation of 11 with
trimethyl(2-methylprop-2-enyl)silane followed by sequential
oxidation with CAN and ozone (Scheme 3). The pivaloyloxy
derivative 15 was prepared in 58% yield. The detailed discussion
for the preparation of 14 and 15 is in the Experimental section.
Results and discussion
Our strategy
Our retro-synthesis of the dihydroxyanthraquinones 1, 2, 6,
and 7 is illustrated in Scheme 2. When the right-hand aromatic
Scheme 3 Preparation of acetonylnaphthoquinones 14 and 15. Details
are in the Experimental section.
For the synthesis of aloesaponarin I 6, an acetoacetate unit
was to be introduced to the quinone 11. 1-Methoxy-1,3-
bis(trimethylsiloxy)buta-1,3-diene13 seemed to be a promising
candidate. However, the reaction of 11 with the reagent resulted
in formation of a very complex mixture. 2,2-Dimethyl-4-methyl-
ene-6-trimethylsiloxy-4H-1,3-dioxine14 16 was next chosen as
the introducing reagent. The reaction of 11 and the dioxine
reagent 16 (1.7 molar ratio) was examined in an NMR tube
(Scheme 4). The signals due to the quinone 11 disappeared
within 1 h at Ϫ20 ЊC without any additive and new signals
assigned to adduct 17 by COSY were observed (the position of
a trimethylsilyl group could not be determined; 17 vs. 17Ј).
Conversion of the cyclohexadienone form 17 to the correspond-
ing phenolic form would be very slow due to the steric
encumbrance around the ring sp3 carbon.15 As the adduct 17
could not be isolated, the reaction mixture was treated with
Ac2O and pyridine to give a spiro compound 19a in 6% yield in
addition to hydroquinone diacetate 18a (70%). When the reac-
tion mixture was treated with tert-butyldimethylsilyl chloride
(TBDMSCl) and imidazole, mono-silyl ether 18b (35%), bis-silyl
ether 18c (16%), and spiro compounds (19b, 17%; 19c, trace)
were obtained. As both the spiro compounds 19b and 19c could
be converted to the quinone 20 by oxidation, the mixture from
the reaction of 11 with the dioxine reagent 16 was oxidized by
CAN after treatment with trimethylsilyl chloride (TMSCl) and
Et3N. The quinone compound 20 was obtained in 84% yield
from the starting quinone 11.
Scheme 2 Retro-synthesis of 1,8- and 1,6-dihydroxyanthraquinones
with an acetyl group as the starting octaketide unit.
part of the dihydroxyanthraquinones is cleaved between the
β,γ-carbons from the hydroxy group, the common skeleton of
2-acetonyl-3-acetyl-1,4-naphthoquinones 10 is obtained. These
quinones should be obtained from the reaction of acetyljuglone
derivative 117 with enol silyl ethers 12. This quinone 11 is con-
sidered as an equivalent of a hexaketide unit with an acetyl
starter.
Condensation between the side chain carbonyl groups
Preparation of quinones
Intramolecular aldol-type condensation reactions were exam-
ined using both quinone and hydroquinone derivatives (13–15)
(Scheme 5). Treatment of the dihydrofuran derivative 13
with potassium tert-butoxide in THF gave a mixture of chry-
sophanol 8-O-methyl ether (21a; 35%) and aloesaponarin II
8-O-methyl ether (22a; 4%). Similar treatment of the quinone
14 gave 21a (16%) and 22a (37%). When the reaction of 14
was carried out using KHMDS, an intractable mixture was
The highly electrophilic nature of 2-acylnaphthoquinones at
the 3-position was well exemplified by their reactions with
allylsilanes,4d,7 allylstannanes,7,8 enamines,9 ketene acetals,7,10
and 2-siloxyfuran,11 and various kinds of naturally occurring
quinones were successfully synthesized. Simple acetonylation
of the acylquinones, however, has not been employed for the
construction of higher quinone skeletons, though acetonyl-
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obtained. Treatment of the quinone bearing a pivaloyloxy
group, compound 15, with potassium tert-butoxide in THF
gave the quinone 21b as the sole product in 65% yield.
The preference observed in the reaction of 13, 14 and 15 is
rationalized as follows. In the case of 13, proton abstraction
from the phenolic hydroxy group would first occur to give a
6-membered cyclic potassium chelate and then base-induced
rearrangement to the corresponding acetonylhydroquinone
derivative would occur. In this intermediate, the methyl moiety
of the acetyl group would be directed to the neighbouring
acetonyl group. Therefore, attack from the methyl moiety to the
acetonyl carbonyl carbon would be favoured. On the other hand,
the carbonyl oxygen of the acetyl group would be directed
to the neighbouring acetonyl group in the quinone 14 due to
the dipole–dipole interaction between the quinone and acetyl
carbonyl groups. Therefore, attack from the methyl moiety to
the acetonyl carbonyl carbon would be disfavoured. In the case
of 15, the steric hindrance of the pivaloyloxy group would
thwart the proton abstraction from the acetonyl methylene, and
the intramolecular condensation reaction caused by the proton
abstraction from the acetyl group would be predominant to give
21b.
Next, we turned our attention to the preparation of aloe-
saponarin from the adducts 18 and 20. Deprotection of the
diacetate 18a under acidic conditions gave only 23 in low yield
(12%; Scheme 6), whereas the treatment of 18a with K2CO3 in
Scheme 4 Reaction of 11 with 16. Reagents and conditions: a) CH2Cl2,
below 0 ЊC; b) Ac2O, pyridine, rt; c) TBSCI, imidazole, DMF, rt; d) 18b,
18c, 19b, or 19c, CAN aq. MeCN, rt.
Scheme
Reagents and conditions: a) BF3ؒOEt2, MeOH, rt; b) KHMDS, THF,
Ϫ78 Њ rt; c) K2CO3, MeOH, rt; d) Et3N, THF, rt.
6
Intramolecular condensation of masked octaketides.
THF–MeOH gave an intractable mixture. Hydroquinone
mono-silyl ether 18b and quinone 20 were employed as the sub-
strate. When the quinone 20 was treated with KHMDS, a clean
intramolecular Michael-type reaction between the acetyl and
β-alkoxy α,β-unsaturated ester moieties occurred to give only
4-hydroxy-5-methoxy-9,10-dioxo-9,10-dihydroanthracene-2-
acetic acid 24 in 62% yield (Scheme 6). On the other hand, a
completely different condensation route was observed in the
reaction of the same quinone compound 20 with a weak base.
When the quinone 20 was treated with K2CO3 in methanol, an
intramolecular condensation between the acetyl and masked
β-keto ester moieties was observed to give only 3-hydroxy-
8-methoxy-1-methyl-9,10-dioxo-9,10-anthracene-2-carboxylate
25 in 70% yield. When the quinone 20 was treated with Et3N in
THF, a similar cyclization leading to 26 occurred in 94% yield.
Scheme 5 Intramolecular condensation. Reagents and conditions: a)
t-BuOK, THF, rt.
J. Chem. Soc., Perkin Trans. 1, 2001, 3189–3197
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The anthraquinone 26 was converted to aloesaponarin I 8-O-
methyl ether 25 under the same conditions as the transform-
ation of 20 to 25. The alteration of condensation route depends
on the steric bulkiness and basicity of the base employed. A
strong and bulky base such as KHMDS can only deprotonate
from the less-hindered acetyl moiety, while weak bases such
as an alkoxide and Et3N cannot deprotonate from the acetyl
moiety but from the most acidic methylene moiety (Scheme 7).
Scheme 8 Synthesis of crysophanol 1 aloe-emodin 2 and aloe-
saponarin I 6. Reagents and conditions: a) AlCl3, CH2Cl2, rt; b) NaOH,
aq. THF–MeOH, rt; c) BBr3, CH2Cl2, Ϫ78 ЊC
rt.
Scheme 7 Reaction pathways of 20.
A similar transformation to 1,6- and 1,8-dihydroxyanthra-
quinones was also achieved by employing the TBS ether 18b
as the substrate. Treatment of 18b with KHMDS in THF and
with K2CO3 in MeOH brought about the similar ring closures
followed by air oxidation to give the quinones 24 and 25. The
yields were slightly lower (50% and 56% yield, respectively)
than those from the quinone 20.
Conversion to naturally occurring 1,8- and 1,6-dihydroxy-
anthraquinones
Deprotection of the O-methyl group of 21a, 21b, and 25 with
AlCl3 or BBr3 gave chrysophanol 1, aloe-emodin ω-pivalate 27,
and aloesaponarin I 6 in 91, 84, and 69% yield (Scheme 8). The
physical and spectroscopic data of chrysophanol16 1 and aloe-
saponarin I17 6 were identical with those reported. The pivaloyl
group of 27 was hydrolyzed with NaOH to give aloe-emodin 2
in 39% yield.
Synthesis of K1115A
K1115A18 8 was thought to be biologically derived from an
octaketide bearing a butyryl group as the starting unit (Scheme
9). Therefore, we employed butyryljuglone derivative 28 as the
starting quinone. The reaction of 28 with the dioxine reagent 16
gave an adduct, which was treated successively with TMSCl–
Et3N and CAN to give quinone 29 in 90% yield. Treatment of
29 with K2CO3 in MeOH gave a mixture of 30a (62%) and 31
(6%). The latter compound 31 was derived from the intra-
molecular Michael-type reaction followed by decarboxylation.
The methyl ether of 30a was removed by treatment with BBr3 to
afford 32 in 87% yield. Since attempted saponification of the
methyl ester 32 to K1115A failed, the nucleophile in the reac-
tion of 29 was changed to p-methoxybenzyl alcohol (PMB
alcohol) and the PMB ester 30b was obtained in 72% yield.
Simultaneous deprotection of the methyl ether and PMB ester
of 30b was achieved by treatment with BBr3 at Ϫ78 ЊC to pro-
vide K1115A 8 in 59% yield. Identity of the synthetic and
authentic K1115A was confirmed by NMR investigation of the
mixed sample.
Scheme 9 Synthesis of K1115A 8. Reagents and conditions: a) 16,
CH2Cl2, Ϫ78 ЊC; TMSCl, Et3N, rt; CAN, MeCN; b) K2CO3, MeOH, rt;
c) K2CO3, 4-MeOC6H4CH2OH, rt; d) 30a, BBr3, CH2Cl2, Ϫ78 ЊC
rt;
e) 30b, BBr3, CH2Cl2, Ϫ78 ЊC
rt.
Conclusions
We have demonstrated that naturally occurring 1,6- and 1,8-
dihydroxy-9,10-anthraquinones are prepared via the intramole-
cular aldol-type condensation of common naphthoquinones
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bearingacylandacetonylgroups. Wehaveachievedthesyntheses
of chrysophanol, aloe-emodin, aloesaponarin, and K1115A, the
last of which is reported to show an inhibitory activity towards
activation protein I (AP-I).
1716, 1700, 1660, 1587, 1475 and 1271 cmϪ1; m/z (rel. intensity)
286 (Mϩ, 1%), 245 (17), 244 (100), 243 (16), 229 (67) and 201
(18).
3-Acetyl-5-methoxy-2-[2-oxo-3-(pivaloyloxy)propyl]-
1,4-naphthoquinone 15
Experimental
For the experimental procedure, see the electronic supple-
mentary information.†
General details
Yellow crystals (Found: C, 65.0; H, 5.75. C21H22O7 requires
C, 65.3; H, 5.7%); Rf (40% EtOAc–hexane) 0.45; mp 120–
122 ЊC; δH 1.25 (9 H, s), 2.50 (3 H, s), 3.69 (2 H, s), 4.01 (3 H, s),
4.79 (2 H, s), 7.32 (1 H, d, J = 7.8), 7.69 (1 H, t, J = 7.8) and 7.72
(1 H, d, J = 7.8); δC 27.1, 31.7, 36.1, 38.7, 56.6, 68.0, 118.4,
119.1, 119.6, 133.4, 135.5, 136.8, 148.8, 159.9, 177.6, 182.4,
184.4, 199.3 and 202.1; νmax (KBr) 2976, 1750, 1728, 1708, 1664,
1640, 1584, 1272 and 1160 cmϪ1; m/z (rel. intensity) 388 (Mϩ ϩ
2, 4%), 386 (Mϩ, 3), 368 (17), 356 (25), 284 (25), 271 (94), 244
(57) and 143 (100).
Melting points are uncorrected. Unless otherwise specified,
NMR spectra were obtained with a JEOL GSX-270 or JNM-
400 spectrometer at ambient temperature using CDCl3 as
1
solvent and tetramethylsilane as internal standard for H and
13C. J-values are given in Hz. Mass spectra and high-resolution
mass spectra were measured with a Hitachi M80B spectrometer
under EI (20 eV) ionizing conditions. Column chromatography
and TLC analysis were carried out using Wakogel C-200 and
Kieselgel 60 F254 (Merck), respectively. Ether (Et2O) and THF
were freshly distilled from sodium diphenyl ketyl. Dichloro-
methane, benzene, toluene, diisopropylamine, and triethyl-
amine were distilled from CaH2 under an inert atmosphere and
stored over molecular sieves 4Å. Other commercially available
materials were used without further purification.
Reaction of 11 with 16
To a CDCl3 solution (0.5 mL) of 11 (20 mg, 0.087 mmol) in
an NMR sample tube was added 16 (32 mg) at Ϫ70 ЊC. This
mixture was immediately subjected to NMR measurements at
Ϫ20 ЊC. The structure of the adduct was elucidated by COSY.
6-[(3-Acetyl-5-methoxy-1-oxo-4-trimethylsiloxy-1,2-dihydro-2-
naphthyl)methyl]-2,2-dimethyl-4H-1,3-dioxin-4-one 17 showed
δH 0.22 (9 H, s), 1.39 (3 H, s), 1.59 (3 H, s), 1.91 (1 H, dd, J =
13.9 and 12.0), 2.25 (1 H, dd, J = 13.9 and 5.6), 2.34 (3 H, s),
3.93 (4 H, m), 4.12 (1 H, s), 7.20 (1 H, br d, J = 8.3), 7.42 (1 H,
br d, J = 7.3) and 7.51 (1 H, dd, J = 8.3 and 7.3).
Reaction of 11 with 2-(trimethylsiloxy)propene
To a solution of compound 117 (460 mg, 2.0 mmol) in dry
CH2Cl2 (40 mL) were added SnCl4 (1.0 mol LϪ1 in CH2Cl2,
2.2 mL) and 2-(trimethylsiloxy)propene (0.40 mL, 2.4 mmol)
at Ϫ78 ЊC. After the addition, the mixture was stirred for 1 h
at the same temperature. Ethyldiisopropylamine (0.418 mL,
2.4 mmol) was added and then the mixture was allowed to
warm to room temperature. After 1 h, the reaction was
quenched with water. The organic phase was separated and the
aqueous phase was extracted with dichloromethane. The com-
bined organic phase was washed successively with 5% HCl,
water and brine, dried over Na2SO4, and concentrated by a
rotary evaporator to give a crude product, which was purified
by silica gel chromatography (30–50% EtOAc–hexane) to give
290 mg (40%) of 4-acetyl-5-hydroxy-6-methoxy-2-methyl-
2-trimethylsiloxy-1,2-dihydronaphtho[1,2-b]furan 13 as pale
yellow crystals (Found: C, 63.6; H, 6.65. C19H24O5Si requires C,
63.3; H, 6.7%); mp 109–110 ЊC (yellow needles from CH2Cl2–
hexane); Rf (40% EtOAc–hexane) 0.65; δH 0.05 (9 H, s, SiMe3),
1.75 (3 H, s, 2-Me), 2.67 (3 H, s, COMe), 3.54 (2 H, br s, H3),
4.05 (3 H, s, OMe), 6.82 (1 H, d, J = 7.3, H7), 7.45 (1 H, m, H8),
7.47 (1 H, m, H9) and 11.81 (1 H, br s, OH); δC 1.4 (SiMe3), 29.1
(2-Me), 32.3 (COMe), 48.2 (C3), 56.2 (OMe), 105.4 (C7), 110.4
(C2), 114.9 (C5a), 115.0 (C9), 115.6 (C4), 118.3 (C3a), 125.2
(C9a), 128.9 (C9), 145.4 (C9b), 154.8 (C5), 158.1 (C6) and 201.4
(COMe); νmax (KBr) 3332, 1651, 1633, 1591, 1403, 1282, 1250
and 997 cmϪ1; m/z (rel. intensity) 360 (Mϩ, 100%), 318 (59), 270
(13) and 240 (11).
Work-up with acetylation. To a solution of 117 (230 mg, 1.0
mmol) in dry CH2Cl2 (30 mL) was added 16 (210 mg, 1.2 mmol)
at Ϫ78 ЊC. The mixture was stirred for 1 h at that temperature
and then warmed up to room temperature. After disappearance
of 11 (TLC), the solvent was removed. Pyridine (1 mL) and
acetic anhydride (1 mL) were added to the residue and the
resulting mixture was stirred overnight. The volatile material
was removed under reduced pressure (ca. 13 Pa). The residue
was chromatographed on silica gel (30–50% EtOAc–hexane) to
give 26 mg (6%) of 6-[(1,4-diacetoxy-3-acetyl-5-methoxy-
2-naphthyl)methyl]-2,2-dimethyl-4H-1,3-dioxin-4-one 18a and
294 mg (71%) of 5Ј-acetoxy-4Ј-acetyl-6Ј-methoxy-2,2-dimethyl-
spiro{1,3-dioxane-4,2Ј(3ЈH)-naphtho[1,2-b]furan}-6-one 19a.
18a: pale yellow crystals (Found: C, 63.1; H, 5.4. C24H24O9
requires C, 63.15; H, 5.3%); mp 132–133.5 ЊC; Rf (40% EtOAc–
hexane) 0.15; δH 1.60 (6 H, s), 2.36 (3 H, s), 2.47 (3 H, s), 2.56
(3 H, s), 3.63 (2 H, s), 3.93 (3 H, s), 5.15 (1 H, s), 6.92 (1 H, d,
J = 8.5), 7.27 (1 H, d, J = 8.5) and 7.50 (1 H, t, J = 8.5); δC 20.6,
20.8, 24.8, 31.2, 32.3, 56.2, 94.5, 107.0, 107.7, 114.4, 119.0,
120.4, 128.9, 130.0, 132.2, 141.8, 143.9, 155.8, 160.8, 168.0,
168.5, 169.0 and 202.1; νmax (KBr) 1763, 1748, 1735, 1700, 1377,
1275 and 1205 cmϪ1; m/z (rel. intensity) 372 (Mϩ Ϫ 2 CH ᎐C᎐O,
2᎐ ᎐
5%), 330 (22) and 270 (100). 19a: pale yellow crystals (Found:
C, 63.7; H, 5.45%. C22H22O8 requires C, 63.8; H, 5.35%); mp
121–123 ЊC; Rf (40% EtOAc–hexane) 0.4; δH 1.60 (3 H, s), 1.79
(3 H, s), 2.41 (3 H, s), 2.60 (3 H, s), 3.09 (1 H, d, J = 17.8), 3.20
(1 H, d, J = 17.8), 3.60 (1 H, d, J = 17.8), 3.63 (1 H, d, J = 17.8),
3.94 (3 H, s), 6.88 (1 H, dd, J = 7.1 and 1.5) and 7.40–7.45
(2 H, m); δC 21.2, 28.8, 29.9, 31.8, 38.8, 45.1, 56.2, 106.8,
107.3, 109.0, 114.2, 117.2, 118.8, 124.0, 126.4, 128.8, 140.9,
150.7, 156.3, 165.2, 169.9 and 198.9; νmax (KBr) 1768, 1751,
1681, 1394, 1363 and 1205 cmϪ1; m/z (rel. intensity) 414 (Mϩ,
2%), 356 (7), 312 (22), 270 (100) and 255 (38).
2-Acetonyl-3-acetyl-5-methyl-1,4-naphthoquinone 14
To a solution of 13 (184 mg, 0.51 mmol) in acetonitrile (13 mL)
was added a solution of CAN (0.84 g, 1.53 mmol) in water
(6 mL). After 10 min brine and CHCl3 were added. The organic
phase was separated and the aqueous phase was extracted with
CHCl3. The combined organic phase was washed with brine,
dried over MgSO4, and concentrated by a rotary evaporator to
give 144 mg (100%) of 14. An analytically pure sample was
obtained by recrystallization from CH2Cl2–ether–hexane. 14:
yellow needles (Found: C, 66.75; H, 5.05. C16H14O5 requires C,
67.1; H, 4.9%); mp 117–119 ЊC (from CH2Cl2–hexane); Rf (40%
EtOAc–hexane) 0.3; δH 2.30 (3 H, s), 2.51 (3 H, s), 3.75 (2 H, s),
4.03 (3 H, s), 7.34 (1 H, dd, J = 7.8 and 2.0) and 7.73 (2 H, m);
δC 30.5, 31.6, 40.3, 56.5, 116.3, 118.3, 119.1, 119.6, 133.5, 135.4,
137.6, 148.3, 159.8, 182.6, 184.6, 202.3 and 202.9; νmax (KBr)
Work-up with silylation. To a solution of 117 (230 mg,
1.0 mmol) in dry CH2Cl2 (30 mL) was added 16 (360 mg,
1.7 mmol) at Ϫ78 ЊC. The mixture was stirred for 1 h at that
temperature and then warmed up to room temperature. After
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disappearance of 11 (TLC, within 1 h), the solvent was removed
on a rotary evaporator to give a crude material. To the crude
material in DMF (3 mL) were added TBDMSCl (226 mg,
1.5 mmol) and imidazole (225 mg, 3.3 mmol). The mixture was
stirred overnight at room temperature, the reaction was
quenched with water, and the mixture was extracted with ether.
The ethereal phase was washed successively with water and
brine, dried over Na2SO4, and concentrated on a rotary evapor-
ator to give a residue, which was dissolved in MeCN (16
mL) and 50% HF (1.8 mL, 60 mmol) was added. After being
stirred for 20 h, the mixture was quenched with saturated
aq. NaHCO3 (10 mL) and ether. The organic phase was separ-
ated and the aqueous phase was extracted with ether. The com-
bined ethereal phase was washed successively with saturated
aq. NaHCO3 and brine, dried over Na2SO4, and concentrated
by rotary evaporator. The residue was chromatographed on
silica gel (30–50% EtOAc–hexane) to give 171 mg (35%) of
6-[(3-acetyl-1-tert-butyldimethylsiloxy-4-hydroxy-5-methoxy-2-
naphthyl)methyl]-2,2-dimethyl-4H-1,3-dioxin-4-one 18b, 95
mg (16%) of 6-{[3-acetyl-1,4-bis(tert-butyldimethylsiloxy)-5-
methoxy-2-naphthyl]methyl}-2,2-dimethyl-4H-1,3-dioxin-4-one
18c, 62 mg (17%) of 4Ј-acetyl-5Ј-hydroxy-6Ј-methoxy-2,2-
dimethylspiro{1,3-dioxane-4,2Ј(3ЈH)-naphtho[1,2-b]furan}-6-
one 19b, and trace amounts of 4Ј-acetyl-5Ј-tert-butyl-
dimethylsiloxy-6Ј-methoxy-2,2-dimethylspiro{1,3-dioxane-4,2Ј-
(3ЈH)-naphtho[1,2-b]furan}-6-one 19c. 18b: pale yellow needles
(Found: C, 64.0; H, 6.8. C26H34O7Si requires C, 64.2; H, 7.0%);
mp 121–123 ЊC (from CH2Cl2–hexane); Rf (40% EtOAc–
hexane) 0.59; δH 0.11 (6 H, s), 1.05 (9 H, s), 1.63 (6 H, s), 2.59
(3 H, s), 3.77 (2 H, s), 4.05 (3 H, s), 4.81 (1 H, s), 6.85 (1 H, d,
J = 7.9), 7.36 (1 H, dd, J = 8.5 and 7.9), 7.62 (1 H, d, J = 8.5) and
9.60 (1 H, s, OH); δC Ϫ3.3, 18.6, 25.0, 26.0, 30.9, 32.4, 56.4,
93.5, 105.6, 106.5, 114.9, 117.4, 117.7, 123.3, 126.6, 130.8,
142.4, 148.1, 156.5, 161.3, 171.0 and 204.4; νmax (KBr) 3342,
1720, 1687, 1637 and 1384 cmϪ1; m/z (rel. intensity) 486 (Mϩ,
4%), 428 (29) and 386 (100). 18c: pale yellow needles (Found: C,
63.7; H, 7.8. C32H48O7Si2 requires C, 64.0; H, 8.05%); mp 116.5–
117.5 ЊC (from CH2Cl2–hexane); Rf (40% EtOAc–hexane) 0.73;
δH Ϫ0.09 (6 H, s), 0.15 (6 H, s), 0.99 (9 H, s), 1.05 (9 H, s), 1.62
(6 H, s), 2.57 (3 H, s), 3.76 (2 H, s), 3.91 (3 H, s), 4.75 (1 H, s),
6.83 (1 H, d, J = 7.7), 7.38 (1 H, dd, J = 8.4 and 7.7) and 7.60 (1
H, d, J = 8.6); δC Ϫ4.2, Ϫ3.2, 18.5, 18.7, 20.0, 26.1, 26.3, 30.9,
33.0, 55.2, 93.5, 106.2, 106.6, 115.9, 116.4, 120.1, 126.8, 130.5,
131.2, 144.7, 145.4, 156.9, 161.3, 171.0 and 205.1; νmax (KBr)
1720, 1691, 1631, 1570, 1376 and 1294 cmϪ1; m/z (rel. intensity)
600 (Mϩ, 3%), 542 (18), 485 (100) and 426 (73). 19b: yellow
needles (Found: C, 64.2; H, 5.4. C20H20O7 requires C, 64.5;
H, 5.4%); mp 169.5–172.5 (from CH2Cl2–hexane); Rf (40%
EtOAc–hexane) 0.4; δH 1.58 (3 H, s), 1.77 (3 H, s), 2.70 (3 H, s),
3.08 (1 H, d, J = 18.5), 3.17 (1 H, d, J = 18.5), 3.61 (1 H, d, J =
18.1), 3.72 (1 H, d, J = 18.1), 4.09 (3 H, s), 6.86 (1 H, m), 7.44 (2
H, m) and 11.08 (1 H, s); δC 28.8, 30.0, 32.7, 38.8, 46.5, 56.4,
105.7, 106.7, 108.2, 114.8, 115.0, 116.3, 118.3, 124.9, 129.2,
145.0, 154.4, 157.8, 165.6 and 200.4; νmax (KBr) 3294, 1741,
1653, 1637, 1400, 1286 and 1014 cmϪ1. 19c: pale yellow, waxy
crystals (Found: C, 63.9; H, 7.1. C26H34O7Si requires C, 64.2; H,
7.0%); Rf (40% EtOAc–hexane) 0.75; δH Ϫ0.11 (3 H, s), Ϫ0.09
(3 H, s), 1.09 (9 H, s), 1.60 (3 H, s), 1.80 (3 H, s), 2.65 (3 H, s),
3.07 (1 H, d, J = 17.4), 3.20 (1 H, d, J = 17.4), 3.51 (1 H, d, J =
18.1), 3.55 (1 H, d, J = 18.1), 3.92 (3 H, s), 6.82 (1 H, m) and
7.41 (2 H, m); δC Ϫ4.7, Ϫ4.5, 18.4, 26.4, 28.8, 29.9, 31.7, 39.0,
45.0, 55.2, 106.0, 106.7, 108.6, 113.6, 117.1, 120.1, 124.2, 126.2,
128.3, 147.2, 147.6, 157.7, 165.5 and 202.7; νmax (KBr) 1763,
1680, 1631, 1570, 1514, 1394 and 1267 cmϪ1; m/z (rel. intensity)
486 (Mϩ, 2%), 384 (10), 327 (100), 312 (22) and 297 (17).
TMSCl (1.27 mL, 10 mmol) and Et3N (2.78 mL, 20 mmol) were
added and the mixture was stirred for 2 h. The reaction was
quenched with saturated aq. NaHCO3. The organic phase was
separated and the aqueous phase was extracted with CHCl3.
The combined organic phase was washed successively with
water and brine, dried over Na2SO4, and concentrated by rotary
evaporator. The residue was dissolved in MeCN (20 mL) and a
solution of CAN (1.64 g, 3 mmol) in water (10 mL) was added
at room temperature. After 10 min, the mixture was extracted
with CHCl3. The organic extract was washed with brine, dried
over Na2SO4, and concentrated by rotary evaporator to give
crude
6-[(3-acetyl-5-methoxy-1,4-dioxo-1,4-dihydro-2-naph-
thyl)methyl]-2,2-dimethyl-4H-1,3-dioxin-4-one 20. Chromato-
graphy on silica gel (30–50% EtOAc–hexane) gave 314 mg (84%)
of pure 20 as yellow crystals (Found: C, 64.2; H, 4.7. C20H18O7
requires C, 64.9; H, 4.9%); mp 130 ЊC (decomp.); Rf (40%
EtOAc–hexane) 0.25; δH 1.65 (6 H, s), 2.51 (3 H, s), 3.49 (2 H,
s), 4.04 (3 H, s), 5.31 (1 H, s), 7.37 (1 H, m) and 7.76 (2 H, m);
δC 24.9, 30.4, 31.8, 56.6, 94.9, 107.0, 113.3, 118.5, 118.9, 119.7,
135.8, 136.2, 149.0, 159.9, 160.5, 166.7, 182.2, 183.9 and 200.9;
νmax (KBr) 1728, 1699, 1658, 1639, 1630, 1585, 1390, 1261 and
1203 cmϪ1
.
Intramolecular condensation of 13
To a solution of 13 (89 mg, 0.25 mmol) in dry THF (5 mL) was
added t-BuOK (1.0 M; 0.62 mL, 0.62 mmol) in THF at 0 ЊC.
After the cooling bath had been removed the mixture was
stirred for 14 h at room temperature. The reaction mixture
was quenched with saturated aq. NH4Cl. The aqueous phase
was extracted with EtOAc. The combined extract was washed
successively with water and brine, dried over MgSO4, and
concentrated by rotary evaporator. The residue was purified by
silica gel chromatography (30–50% EtOAc–hexane) to give
23 mg (35%) of 1-hydroxy-8-methoxy-3-methyl-9,10-anthra-
quinone (chrysophanol 8-O-methyl ether; 21a) and 2 mg (4%)
of 3-hydroxy-8-methoxy-1-methyl-9,10-anthraquinone (aloe-
saponarin II 8-O-methyl ether; 22a). 21a: yellow crystals, mp
195–197 ЊC (lit., 197 ЊC,16a 198 ЊC,19 196–197 ЊC20); Rf (40%
EtOAc–hexane) 0.45; δH 2.43 (3 H, s), 4.06 (3 H, s), 7.07 (1 H, d,
J = 1.0), 7.33 (1 H, d, J = 8.1), 7.58 (1 H, d, J = 1.0), 7.73 (1 H, t,
J = 8.1), 7.94 (1 H, d, J = 8.1) and 12.89 (1 H, s, OH); δC 22.0,
56.6, 114.9, 118.1, 120.0, 120.1, 120.8, 124.6, 132.4, 135.6,
135.8, 147.6, 160.8, 162.7, 182.9 and 188.5; νmax (KBr) 3409,
1637, 1583, 1446, 1301, 1274 and 1246 cmϪ1; m/z (rel. intensity)
268 (Mϩ, 100%), 250 (43), 239 (20), 222 (49) and 181 (22). 22a:
yellow crystals; mp 218–220 ЊC; Rf (30% EtOAc–hexane) 0.2;
δH (DMSO-d6; 50 ЊC) 2.94 (3 H, s), 3.93 (3 H, s), 7.01 (1 H, d,
J = 2.6), 7.37 (1 H, d, J = 2.6), 7.52 (1 H, dd, J = 8.3 and 2.5),
7.72 (2 H, m) and 10.7 (1 H, br, OH); νmax (KBr) 3465, 1662,
1646, 1604, 1585, 1568, 1458, 1342 and 1247.
Intramolecular condensation of 14
The reaction was carried out according to the procedure
described above by using 111 mg of 14. Chromatographic
purification (silica gel) gave 17 mg (16%) of 21a and 39 mg
(37%) of 22a.
Intramolecular condensation of 15
The reaction was performed according to the procedure
described above by using 50 mg (0.13 mmol) of 15. Chromato-
graphic purification (silica gel) gave 31 mg (65%) of 21b as
yellow crystals (Found: C, 68.4; H, 5.5. C21H20O6 requires C,
68.5; H, 5.5%), mp 163–165 ЊC; Rf (40% EtOAc–hexane) 0.35;
δH 1.28 (9 H, s), 4.09 (3 H, s), 5.17 (2 H, s), 7.25 (1 H, d, J = 2.0),
7.38 (1 H, dd, J = 8.3 and 1.5), 7.71 (1 H, d, J = 2.0), 7.77 (1 H,
dd, J = 8.3 and 7.8), 7.98 (1 H, dd, J = 7.8 and 1.5) and 12.98
(1 H, s, OH); δC 27.1, 38.8, 56.6, 64.6, 116.3, 116.9, 118.1, 120.1,
120.5, 122.1, 132.8, 135.5, 135.8, 145.3, 160.8, 162.7, 177.9,
Oxidative work-up. To a solution of compound 11 (464 mg,
2.0 mmol) in dry CH2Cl2 (20 mL) was added 16 (730 mg,
3.4 mmol) at Ϫ78 ЊC and then the cooling bath was removed.
After the mixture had been stirred for 1 h at room temperature,
3194
J. Chem. Soc., Perkin Trans. 1, 2001, 3189–3197

View Article Online
182.3 and 188.3; νmax (KBr) 3432, 2920, 1724, 1676, 1632, 1584,
1284 and 1166 cmϪ1; m/z (rel. intensity) 368 (Mϩ, 100%), 284
(98), 267 (20) and 239 (30).
νmax (KBr) 3572, 3459, 1712, 1670, 1587, 1336 and 1240 cmϪ1
;
m/z (rel. intensity) 326 (Mϩ, 100%), 311 (54), 294 (17), 276 (47)
and 220 (23).
Treatment of 20 with Et3N in THF
Treatment of 18a with acid in MeOH
To a solution of 20 (180 mg, 0.49 mmol) in dry THF (10 mL)
was added Et3N (0.68 mL, 4.9 mmol) at room temperature. The
solution was stirred overnight and then water was added. The
mixture was extracted with CHCl3, and the extract was washed
with brine, dried over Na2SO4, and concentrated. The residue
was chromatographed on silica gel (30–50% EtOAc–hexane) to
give 163 mg (94%) of 7-methoxy-2,2,5-trimethyl-4H-anthra-
[2,3-d][1,3]dioxin-4,6,11-trione 26 as yellow needles (Found: C,
67.8; H, 4.6. C20H16O6 requires C, 68.2; H, 4.6%); mp 222–225
ЊC; Rf (40% EtOAc–hexane) 0.4; δH 1.74 (6 H, s, 2-Me), 3.10
(3 H, s, 5-Me), 4.01 (3 H, s, 7-OMe), 7.32 (1 H, d, J = 8.1, H10),
7.63 (1 H, s, H12), 7.64 (1 H, t, J = 8.1, H9) and 7.78 (1 H, d, J =
8.1, H8); δC 19.2 (5-Me), 25.7 (2-Me), 56.6 (7-OMe), 105.8 (C2),
113.5 (C12), 118.0, 118.5, 119.0, 124.6, 130.8, 134.1, 134.4,
138.8, 148.6, 159.0, 159.0, 159.4, 182.9 (CO) and 184.1 (CO);
νmax (KBr) 1738, 1672, 1595, 1585, 1323 and 1221 cmϪ1; m/z
(rel. intensity) 352 (Mϩ, 73%), 294 (100), 276 (82), 248 (20) and
220 (40).
To a solution of diacetate 18a in MeOH (10 mL)–CH2Cl2
(10 mL) was added BF3ؒOEt2 (0.24 mL, 0.24 mmol) at room
temperature. The mixture was stirred overnight. As some start-
ing material remained (TLC), conc. H2SO4 (10 drops) was
added and the mixture was warmed to 50 ЊC. After disappear-
ance of the starting material (TLC), the reaction was quenched
with saturated aq. NaHCO3. The mixture was extracted
with EtOAc, and the extract was washed with brine, dried
over Na2SO4, and concentrated on a rotary evaporator. The
residue was purified by silica gel chromatography (30–50%
EtOAc–hexane) to give 8 mg (12%) of methyl 4-acetyl-5-
hydroxy-6-methoxynaphtho[1,2-b]furan-2-acetate 23 as colour-
less crystals (HRMS Found: Mϩ, 328.0943. C18H16O6 requires
M, 328.0946); mp 159–161 ЊC (needles from CH2Cl2–hexane);
Rf (50% EtOAc–hexane) 0.4; δH 2.79 (3 H, s), 3.77 (3 H, s), 3.92
(2 H, s), 4.09 (3 H, s), 6.88 (1 H, d, J = 7.5), 7.01 (1 H, s), 7.56
(1 H, dd, J = 8.5 and 7.5), 7.78 (1 H, d, J = 8.5) and 13.52 (1 H,
br s); δC 31.9, 34.4, 52.4, 56.3, 105.6, 105.7, 107.4, 109.9, 113.0,
122.2, 126.6, 130.6, 144.0, 150.6, 159.0, 160.5, 169.2 and 201.4;
νmax (KBr) 3311, 1730, 1647, 1633, 1589, 1389, 1244, 1214 and
1029 cmϪ1; m/z (rel. intensity) 328 (Mϩ, 100%), 313 (49), 269
(43) and 239 (14).
Conversion of 26 to 25
To a solution of 26 (163 mg, 0.46 mmol) in THF (5 mL) were
added MeOH (20 mL) and K2CO3 (640 mg, 4.6 mmol) at room
temperature. The suspension was stirred for 30 min and then
aq. NH4Cl was added. The mixture was extracted with EtOAc,
and the extract was washed with brine, dried over Na2SO4, and
concentrated. The residue was chromatographed on silica gel to
give 128 mg (85%) of 25.
Treatment of 20 with KHMDS in THF
To a solution of 20 (230 mg, 0.6 mmol) in dry THF (10 mL)
was added KHMDS (4.46 mL, 2.23 mmol; 0.5 M in toluene) at
Ϫ78 ЊC. After the addition, the mixture was allowed to warm
to room temperature and was stirred for 1 h. The reaction was
quenched by acidification with 5% HCl. The mixture was
extracted with EtOAc, and the extract was washed with brine,
dried over Na2SO4, and concentrated. The residue was tritur-
ated with CH2Cl2–ether–hexane. Filtration gave 118 mg (63%)
of 4-hydroxy-5-methoxy-9,10-dioxo-9,10-dihydroanthracene-2-
acetic acid 24 as a yellow powder (Found: C, 61.7; H, 4.5.
C17H12O6ؒH2O requires C, 61.8; H, 4.3%); mp 234–237 ЊC; Rf
(40% EtOAc–hexane) 0.5; δH (DMSO-d6) 3.75 (2 H, s), 3.99
(3 H, s), 7.25 (1 H, s), 7.59 (1 H, s), 7.60 (1 H, d, J = 6.8), 7.83
(2 H, m), 12.35 (1 H, br, OH) and 12.77 (1 H, br, OH); δC
(DMSO-d6) 40.3, 56.3, 115.2, 119.0, 119.2, 119.3, 119.8, 124.4,
131.9, 134.7, 135.8, 143.7, 160.4, 161.1, 170.9, 181.8 and 187.3;
Treatment of 18b with KHMDS in THF
The reaction of 18b (97 mg, 0.2 mmol) was performed accord-
ing to the procedure described above to give 31 mg (50%) of 24.
Treatment of 18b with K2CO3 in MeOH
The reaction of 18b (97 mg, 0.2 mmol) was carried out accord-
ing to the procedure described above to give 36 mg (56%) of 25.
1,8-Dihydroxy-3-methyl-9,10-anthraquinone (chrysophanol; 1)
To a solution of compound 21a (44 mg, 0.16 mmol) in dry
CH2Cl2 (5 mL) was added AlCl3 (0.8 mmol) at 0 ЊC. After the
addition, the mixture was allowed to warm to room temper-
ature. After disappearance of the starting compound 21a, the
reaction was quenched with 1 M HCl. The mixture was
extracted with CHCl3, and the organic phase was washed with
brine, dried over Na2SO4, and concentrated by rotary evapor-
ator. The residue was purified by silica gel chromatography (30–
50% EtOAc–hexane) to give 37 mg (91%) of chrysophanol 1 as
yellow crystals, mp 192.5–193.3 ЊC (lit., 195–196 ЊC,16a 194–
195 ЊC19), Rf (30% EtOAc–hexane) 0.45; δH 2.46 (3 H, s), 7.10
(1 H, s), 7.28 (1 H, d, J = 8.8), 7.66 (1 H, s), 7.66 (1 H, dd, J = 8.8
and 7.4), 7.82 (1 H, d, J = 7.4), 12.00 (1 H, s) and 12.11 (1 H, s);
νmax (KBr) 3255, 3050, 1676, 1628, 1606, 1475, 1452, 1373 and
1268 cmϪ1; m/z (rel. intensity) 254 (Mϩ, 100%), 226 (9), 197 (9)
and 152 (8).
νmax (KBr) 3438, 1716, 1670, 1635, 1585, 1282 and 1226 cmϪ1
;
m/z (rel. intensity) 312 (Mϩ, 73%), 294 (21), 268 (100), 250 (49),
222 (61) and 181 (28).
Treatment of 20 with K2CO3 in MeOH
To a solution of 20 (314 mg, 0.85 mmol) in dry MeOH (10 mL)
was added K2CO3 (1.17 mg) at room temperature. The sus-
pension was stirred overnight and then 5% HCl was added to
neutralize. The mixture was extracted with EtOAc, and the
extract was washed with brine, dried over Na2SO4, and concen-
trated. The residue was chromatographed on silica gel (50%
EtOAc–hexane) to give 193 mg (70%) of methyl 3-hydroxy-
8-methoxy-1-methyl-9,10-dioxo-9,10-dihydroanthracene-2-
carboxylate (aloesaponarin I 8-O-methyl ether; 25) as yel-
low crystals (Found: Mϩ, 326.0786. C18H14O6 requires M,
326.0790); mp 200–201 ЊC; Rf (50% EtOAc–hexane) 0.55; δH
2.88 (3 H, s, 1-Me), 4.03 (3 H, s, 8-OMe), 4.05 (3 H, s, CO2Me),
7.33 (1 H, d, J = 8.3, H7), 7.65 (1 H, dd, J = 8.3 and 7.3, H6), 7.67
(1 H, s, H4), 7.83 (1 H, d, J = 7.3, H5) and 10.53 (1 H, br s, OH);
δC 20.6 (1-Me), 52.8 (CO2Me), 56.6 (8-OMe), 113.4 (C4), 118.5
(C7), 119.1 (C5), 121.8 (C2 or C9a), 124.8 (C8a), 128.1 (C9a or
C2), 133.8 (C6), 134.8 (C10a), 137.5 (C4a), 144.9 (C1), 159.5
(C8), 161.8 (C3), 170.4 (CO2), 183.3 (C10) and 184.3 (C9);
1,8-Dihydroxy-3-(pivaloyloxymethyl)-9,10-anthraquinone 27
To a solution of compound 21b (736 mg, 2.0 mmol) in dry
CH2Cl2 (10 mL) was added AlCl3 (6 mmol). After the addition,
the mixture was stirred overnight at room temperature. The
reaction was quenched with water (10 mL) and conc. HCl
(1.2 mL). The organic phase was separated and the aqueous
phase was extracted with CH2Cl2. The combined organic phase
was washed with brine, dried over Na2SO4, and concentrated.
J. Chem. Soc., Perkin Trans. 1, 2001, 3189–3197
3195

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The residue was purified by silica gel chromatography (30–50%
EtOAc–hexane) to give 592 mg (84%) of 27 as yellow crystals
(Found: C, 67.8; H, 5.15. C20H18O6 requires C, 67.8; H, 5.1%);
mp 164–166 ЊC (needles from CH2Cl2–hexane); Rf (CH2Cl2)
0.65; δH 1.29 (9 H, s), 5.19 (2 H, s), 7.25 (1 H, d, J = 1.7), 7.31
(1 H, dd, J = 8.3 and 1.0), 7.69 (1 H, dd, J = 8.3 and 7.8), 7.77
(1 H, d, J = 1.7), 7.84 (1 H, dd, J = 7.8 and 1.0), 12.05 (1 H, s)
and 12.07 (1 H, s); δC 27.2, 38.9, 64.5, 115.2, 115.8, 118.2, 120.1,
122.0, 124.8, 133.5, 133.9, 137.3, 147.0, 162.6, 162.8, 177.9,
181.5 and 192.7; νmax (KBr) 3452, 3220, 3080, 2972, 1730,
1676, 1622, 1456, 1440, 1278, 1168, 1154 and 772 cmϪ1; m/z
(rel. intensity) 354 (Mϩ, 84%), 270 (100), 254 (40), 253 (50) and
225 (56).
Intramolecular cyclization of 29 with K2CO3 in MeOH
The reaction of 29 (360 mg, 0.9 mmol) with K2CO3 (1.2 g) in
MeOH (30 mL) was carried according to the usual procedure as
described for the reaction of 20 with K2CO3 and methanal to
give compound 25. Silica gel chromatography (30–50% EtOAc–
hexane) gave 197 mg (62%) of methyl 3-hydroxy-8-methoxy-
9,10-dioxo-1-propyl-9,10-dihydroanthracene-2-carboxylate 30a
and 16 mg (6%) of 2-ethyl-1-hydroxy-8-methoxy-3-methyl-
9,10-anthraquinone 31. 30a: yellow crystals (Found: C, 67.5; H,
5.1. C20H18O6 requires C, 67.8; H, 5.1%), mp 190–194 ЊC; Rf
(CHCl3–MeOH–AcOH = 92 : 5 : 3) 0.3; δH 1.06 (3 H, t, J = 7.3),
1.72 (2 H, m), 3.29 (2 H, m), 4.01 (3 H, s), 4.03 (3 H, s), 7.31
(1 H, dd, J = 8.3 and 1.0), 7.63 (1 H, dd, J = 8.3 and 7.8), 7.67
(1 H, s), 7.77 (1 H, dd, J = 7.8 and 1.0) and 10.12 (1 H, br); δC
14.6, 25.1, 33.6, 53.0, 56.6, 113.7, 118.2, 118.9, 121.4, 125.0,
127.4, 133.8, 134.6, 137.7, 149.1, 159.2, 161.7, 170.4, 183.6 and
1,8-Dihydroxy-3-(hydroxymethyl)-9,10-anthraquinone (aloe-
emodin; 2)
184.4; νmax (KBr) 3400, 1741, 1662, 1579, 1240 and 1215 cmϪ1
;
To a solution of t-BuOK (954 mg, 8.5 mmol) in dry ether (17
mL) was added water (0.04 mL) at 0 ЊC. After 5 min, a solu-
tion of 27 (354 mg, 1.0 mmol) dry THF (4 mL)–dry CH2Cl2
(10 mL) was added and then the cooling bath was removed.
After 12 h, trifluoroacetic acid (10 mL) was added. After 1 h,
the reaction was quenched with water (20 mL). The organic
phase was separated and the aqueous phase was extracted
with CHCl3. The combined organic phase was washed with
brine, dried over MgSO4, and concentrated by rotary evapor-
ator. The residue was purified by silica gel chromatography
(30% EtOAc–hexane) to give 106 mg (39%) of 2 as yellow
crystals, mp 215–217 ЊC (lit., 222–223 ЊC,21 220 ЊC22); Rf (30%
EtOAc–hexane) 0.3; δH (DMSO-d6) 4.63 (2 H, d, J = 5.4), 5.59
(1 H, t, J = 5.4, OH), 7.28 (1 H, br s), 7.37 (1 H, d, J = 7.3),
7.68 (1 H, br s), 7.70 (1 H, d, J = 7.3), 7.80 (1 H, t, J = 7.3),
11.89 (1 H, s, OH) and 11.96 (1 H, s, OH); δC 62.0, 114.4,
115.9, 117.1, 119.3, 120.6, 124.4, 133.1, 133.3, 137.3, 153.7,
161.3, 161.6, 181.4 and 191.6; νmax (KBr) 3404, 1676, 1628,
m/z (rel. intensity) 354 (Mϩ, 89%), 339 (78), 337 (21), 321 (20),
307 (100), 305 (39) and 279 (24). 31: yellow crystals (HRMS
Found: Mϩ, 296.1068. C18H16O4 requires M, 296.1049), mp
185–188 ЊC; Rf (CHCl3–MeOH–AcOH = 92 : 5 : 3) 0.65; δH 1.17
(3 H, t, J = 7.5), 2.43 (3 H, s), 2.79 (2 H, q, J = 7.5), 4.07 (3 H, s),
7.34 (1 H, dd, J = 8.3 and 1.0), 7.58 (1 H, s), 7.72 (1 H, dd,
J = 8.3 and 7.8), 7.96 (1 H, dd, J = 7.8 and 1.0) and 13.33 (1 H,
s, OH); νmax (KBr) 3444, 1672, 1631, 1585 and 1274 cmϪ1; m/z
(rel. intensity) 296 (Mϩ, 100%), 281 (79), 278 (28), 263 (15) and
251 (12).
Intramolecular cyclization of 29 with K2CO3 in p-methoxybenzyl
alcohol
To a solution of compound 29 (50 mg, 0.13 mmol) in dry THF
(0.5 mL) were added p-methoxybenzyl (PMB) alcohol (0.1 mL)
and K2CO3 (174 mg, 1.3 mmol) at room temperature. After
being stirred for 24 h, the reaction mixture was quenched with
saturated aq. NH4Cl. The mixture was extracted with EtOAc,
and the organic phase was washed successively with water and
brine, dried over Na2SO4, and concentrated by rotary evapor-
ator. The residue was purified by silica gel chromatography (30–
50% EtOAc–hexane) to give 42 mg (72%) of p-methoxybenzyl
3-hydroxy-8-methoxy-9,10-dioxo-1-propyl-9,10-dihydroanthra-
cene-2-carboxylate 30b as yellow crystals (Found: C, 70.2;
H, 5.4. C27H24O7 requires C, 70.4; H, 5.25%); mp 171–172 ЊC; Rf
(40% EtOAc–hexane) 0.3; δH 0.84 (3 H, t, J = 7.0), 1.59 (2 H, m),
3.24 (2 H, m), 3.82 (3 H, s), 3.98 (3 H, s), 5.39 (2 H, s), 6.92 (2 H,
m), 7.28 (1 H, d, J = 8.3), 7.40 (2 H, m), 7.60 (1 H, dd, J = 8.3
and 7.8), 7.65 (1 H, s), 7.77 (1 H, d, J = 7.8) and 10.14 (1 H, br,
OH); δC 14.3, 25.2, 33.3, 55.3, 56.6, 68.3, 113.8, 114.2, 118.2,
118.9, 121.1, 125.2, 126.4, 127.5, 131.0, 133.7, 134.7, 137.8,
149.3, 159.2, 160.2, 161.9, 169.8, 183.6 and 184.4; νmax (KBr)
3529, 3434, 1718, 1691, 1670, 1649, 1577, 1513, 1425, 1330,
1240 and 1213 cmϪ1; m/z (rel. intensity) 460 (Mϩ, 5%), 339 (21),
228 (19), 197 (11) and 121 (100).
1572, 1456 and 1288 cmϪ1
.
Methyl 3,8-dihydroxy-1-methyl-9,10-dioxo-9,10-dihydro-
anthracene-2-carboxylate (aloesaponarin I; 6)
To a solution of 25 (14 mg, 0.04 mmol) in dry CH2Cl2 (5 mL)
was added a 1 mol LϪ1 solution of BBr3 in CH2Cl2 (0.45 mL,
0.45 mmol) at Ϫ78 ЊC. After disappearance of 25 (ca. 1 h),
saturated aq. NH4Cl was added (pH ca. 2). The mixture was
extracted with EtOAc, and the extract was washed with brine,
dried over Na2SO4, and concentrated. The residual solid was
triturated with ether–hexane to afford 10 mg (69%) of 6 as
yellow powdery crystals, mp 204–206 ЊC [lit., 199–203 ЊC
(decomp.),17a 206.5–207 ЊC,17b 202.5–207 ЊC17c]; Rf (40%
EtOAc–hexane) 0.45; δH 2.99 (3 H, s), 4.06 (3 H, s), 7.30
(1 H, dd, J = 8.3 and 1.0), 7.62 (1 H, dd, J = 8.3 and 7.8), 7.76
(1 H, dd, J = 7.8 and 1.0), 7.78 (1 H, s), 10.45 (1 H, br) and
12.92 (1 H, s); νmax (KBr) 3318, 1728, 1668, 1631, 1579,
1367 and 1215 cmϪ1; m/z (rel. intensity) 312 (Mϩ, 70%),
297 (13), 280 (100), 252 (17), 224 (26), 196 (10) and 168 (19).
Methyl 3,8-dihydroxy-9,10-dioxo-1-propyl-9,10-dihydro-
anthracene-2-carboxylate 32
6-[(3-Butanoyl-5-methoxy-1,4-dioxo-1,4-dihydro-2-naphthyl)-
methyl]-2,2-dimethyl-4H-1,3-dioxin-4-one 29
The reaction of 30a (177 mg, 0.5 mmol) was carried out accord-
ing to the procedure described for the preparation of chryso-
phanol 1 except that BBr3 was used instead of AlCl3 to give 115
mg (87%) of 32 as orange crystals (Found: C, 65.3; H, 4.8.
C19H16O6ؒ0.5H2O requires C, 65.3; H, 4.9%); mp 190–193.5 ЊC;
Rf (40% EtOAc–hexane) 0.45; δH (DMSO-d6) 1.00 (3 H, t, J =
7.3), 1.60 (2 H, m), 3.03 (2 H, m), 3.89 (3 H, s), 7.32 (1 H, dd,
J = 8.3 and 1.5), 7.63 (1 H, dd, J = 7.3 and 1.5), 7.66 (1 H, s),
7.71 (1 H, dd, J = 8.3 and 7.3), 11.42 (1 H, br) and 12.74 (1 H,
br); δC (DMSO-d6; 80 ЊC) 13.9, 23.1, 33.8, 51.8, 112.1, 116.6,
117.9, 121.8, 124.0, 129.4, 132.1, 135.6, 136.9, 145.4, 158.7,
161.2, 166.6, 181.5 and 188.7; νmax (KBr) 3388, 1720, 1660,
1630, 1577, 1467, 1243, 1214 and 1080 cmϪ1; m/z (rel. intensity)
340 (Mϩ, 57%), 325 (13), 307 (22), 290 (100) and 265 (20).
The reaction of 287 (258 mg, 1.0 mmol) with 16 (322 mg,
1.5 mmol) was carried out according to the procedure described
for the preparation of 20 to give 318 mg (90%) of 29 as yellow
crystals (Found: C, 66.1; H, 5.8. C22H22O7 requires C, 66.3; H,
5.6%); mp 90–92 ЊC; Rf (40% EtOAc–hexane) 0.25; δH 0.99
(3 H, t, J = 7.3), 1.65 (6 H, s), 1.74 (2 H, sextet, J = 7.3), 2.75
(2 H, t, J = 7.3), 3.42 (2H, s), 4.03 (3 H, s), 5.30 (1 H, s), 7.74
(1 H, m) and 7.76 (2 H, m); δC 13.6, 16.4, 24.9, 30.7, 46.1,
56.6, 94.8, 107.0, 118.5, 118.9, 119.6, 133.3, 135.8, 136.1,
149.3, 159.9, 160.6, 166.8, 182.4, 184.0 and 203.3; νmax (KBr)
1729, 1698, 1664, 1657, 1632, 1585, 1280 and 1261 cmϪ1
;
m/z (rel. intensity) 298 (Mϩ Ϫ 100, 52%), 281 (14), 255 (100)
and 240 (20).
3196
J. Chem. Soc., Perkin Trans. 1, 2001, 3189–3197

View Article Online
107, 7760; (e) T. M. Harris, A. D. Webb and C. M. Harris, J. Am.
3,8-Dihydroxy-9,10-dioxo-1-propyl-9,10-dihydroanthracene-
2-carboxylic acid (K1115A; 8)
Chem. Soc., 1976, 98, 6065.
5 The Chemistry of the Quinonoid Compounds, ed. S. Patai, Wiley,
London, 1974.
6 For the preliminary communication, see H. Uno, Y. Nagamachi,
E. Honda, A. Masumoto and N. Ono, Chem. Lett., 2000, 1014.
7 H. Uno, J. Org. Chem., 1986, 51, 350.
8 Y. Naruta, H. Uno and K. Maruyama, J. Chem. Soc., Chem.
Commun., 1981, 1277; Y. Naruta, Y. Nishigaichi and K. Maruyama,
J. Org. Chem., 1988, 53, 1192.
9 K. Kobayashi, M. Uchida, S. Watanabe, A. Takanohashi, M.
Tanmatsu, O. Morikawa and H. Konishi, Tetrahedron Lett., 2000,
41, 2381.
An identical reaction of 30b (40 mg, 0.09 mmol) was carried out
as above to give 17 mg (59%) of 8 as orange crystals; mp 243–
245 ЊC (lit.,18 255–258 ЊC); Rf (CHCl3–MeOH–CH3CO2H = 94 :
5 : 1) 0.4; δH (DMSO-d6) 1.02 (3 H, t, J = 7.3), 1.61 (2 H, m),
3.08 (2 H, m), 7.36 (1 H, dd, J = 8.3 and 1.0), 7.63 (1 H, s), 7.65
(1 H, dd, J = 7.6 and 1.5), 7.74 (1 H, dd, J = 8.3 and 7.6), 11.8
(1 H, br, OH), 12.91 (1 H, s, OH) and 13.4 (1 H, br, OH);
νmax (KBr) 3388, 1736, 1707, 1670, 1631, 1582, 1468, 1363,
1321, 1270, 1234 and 1215 cmϪ1; MS m/z (rel. intensity) 326
(Mϩ, 48%), 293 (22), 290 (100) and 265 (19).
10 K. Krohn, N. Böker, A. Gauhier, G. Schäfer and F. Werner, J. Prakt.
Chem., 1996, 338, 349.
11 M. A. Brimble, L. J. Duncalf and D. Neville, J. Chem. Soc., Perkin
Trans. 1, 1998, 4165 and references cited therein.
12 (a) B. Kesteleyn and N. D. Kimpe, J. Org. Chem., 2000, 65, 640;
(b) B. Kesteleyn, L. V. Puyvelde and N. D. Kimpe, J. Org. Chem.,
1999, 64, 438.
13 T.-H. Chan and P. Brownbridge, J. Chem. Soc., Chem. Commun.,
1979, 578.
14 B. L. Pagenkopf, J. Krüger, A. Stojanovic and E. M. Carreira,
Angew. Chem., Int. Ed., 1998, 37, 3124; Y. Kim, R. A. Singer and
E. M. Carreira, Angew. Chem., Int. Ed., 1998, 37, 1261; R. A. Singer
and E. M. Carreira, J. Am. Chem. Soc., 1995, 117, 12360.
15 In the reaction of acetylquinone with allylic stannanes, similar
cyclohexadienone derivatives were isolated by recrystallization. See
the supplementary material of ref. 7.
Acknowledgements
Financial support from the Grant-in-Aid for Scientific
Research (12640521) from the Ministry of Education, Science,
Sports and Culture are greatly acknowledged. We also thank
Dr Masaki Goto (Eisai Co. Ltd.) for the gift of natural
K1115A.
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