First total synthesis of the bioactive anthraquinone kwanzoquinone C and related natural products by a Diels-Alder approach

Article abstract of DOI:10.1002/ejoc.200600634

The first total synthesis of the novel anticancer agent kwanzoquinone C (1), an anthraquinone glycoside which has been isolated from extracts of the roots of orange daylilies (Kaempfer) (Hemerocallis fulva) is reported. The strategy involves the preparati

Full text of DOI:10.1002/ejoc.200600634

FULL PAPER
DOI: 10.1002/ejoc.200600634
First Total Synthesis of the Bioactive Anthraquinone Kwanzoquinone C and
Related Natural Products by a Diels–Alder Approach
Lutz F. Tietze,*[a] Kersten M. Gericke,[a] and Carlos Güntner[b]
Dedicated to Professor Gyula Schneider on the occasion of his 75th birthday
Keywords: Anthraquinones / Antitumor agents / Cycloadditions / Glycosidation / Natural products
The first total synthesis of the novel anticancer agent kwan-
zoquinone C (1), an anthraquinone glycoside which has been
isolated from extracts of the roots of orange daylilies
(Kaempfer) (Hemerocallis fulva) is reported. The strategy in-
volves the preparation of the tetrasubstituted 1,3-butadiene 6
by an electrocyclic conrotatory ring opening of the cyclobut-
anone rac-11, which is obtained by a [2+2] cycloaddition.
Diels–Alder reaction of 6 with the juglone derivative 5 gives
the bis-benzyl-protected anthraquinone 4 after aromatiza-
tion. Finally, glycosidation of the phenolic hydroxy group
using 2,3,4,6-tetra-O-acetyl-α- -glucopyranosyl trichloroacet-
D
imidate followed by the cleavage of the benzyl ethers and
the solvolysis of the acetate groups yields the natural product
1. A related anthraquinone natural product 2 with antioxidat-
ive properties was obtained by using the 1,3-butadiene 17
and the juglone derivative 16 as substrates.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
Natural products are important lead structures for the
development of novel drugs especially in the field of anti-
cancer agents.[1] Quite a new compound from nature which
might be of interest for the chemotherapy of cancer is the
anthraquinone glucoside kwanzoquinone C (1), which has
been isolated in 2002 by Nair and co-workers[2] from the
extracts of Kaempfer roots (Hemerocallis fulva) together
with a series of other hydroxylated anthraquinones (Fig-
ure 1).
Plants from the familia Hemerocallis are known to be
applied in the traditional medicine in eastern Asia, e.g. as
a remedy for schistosomiasis.[3] Kwanzoquinone C, was
found to be the anthraquinone glycoside 1, which possesses
growth inhibition of four different tumor cells (GI50 = 3.8–
7.5 µg/mL).[4] It belongs to the class of hydroxylated
anthraquinones which are known to be widely represented
as pigments in the plant kingdom.[5] Moreover, these com-
pounds have a high medicinal value,[6] for instance in the
treatment of a human filarial parasite, Brugia malayi.[7] The
related anthraquinone 2, extracted from the medicinal plant
Aster tataricus, has been found to exert an inhibitory ac-
Figure 1. Structures of kwanzoquinone C (1), antioxidative anthra-
quinone 2 and macrosporin (3).
tivity on superoxide radical generation.[8] Furthermore,
macrosporin (3), being a metabolite of a fungal species,[9]
has been proven to exhibit antibacterial properties.[10]
Most general strategies for the synthesis of hydroxylated
anthraquinones employ Diels–Alder reactions using ketene
silyl acetals[11] or 3-methyl-1-trimethylsiloxy-1,3-butadi-
ene[12] and halogenated naphthoquinones as substrates. An-
other approach, which has recently been developed, is based
on a Friedel–Crafts acylation between phthalic anhydrides
and substituted benzenes.[7]
[a] Institut für Organische und Biomolekulare Chemie, Georg-
August-Universität,
Tammannstr. 2, 37077 Göttingen, Germany
Fax: +49-551-399-476
E-mail: ltietze@gwdg.de
Here we describe the synthesis of 1 and 2 using a cyclo-
addition of a naphthoquinone and a tetrasubstituted 1,3-
butadiene as key-step.
[b] MBM ScienceBridge GmbH, Georg-August-Universität
Göttingen,
Hans-Adolf-Krebs-Weg 1, 37077 Göttingen, Germany
4910
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4910–4915

Synthesis of Bioactive Kwanzoquinone C and a Related Anthraquinone
FULL PAPER
of rac-11 can be explained by the observation made by
Scheeren[17] that cyclobutanones of type rac-11 isomerize to
the trans diastereomer under basic conditions. The needed
butadiene 6 can then be obtained from rac-11 by an electro-
cyclic conrotatory ring opening of the corresponding TMS
enol ether.[17,18] The reaction was carried out by treatment
of rac-11 with TMSCl in the presence of Et3N to yield the
TMS enol ether, which without isolation was heated to
60 °C to give the butadiene 6. It was used for the next step
without purification because it is not stable neither during
chromatography nor distillation, in the latter case due to its
high boiling point.
Results and Discussion
1. Total Synthesis of Kwanzoquinone C
According to the retrosynthetic analysis of kwanzoqui-
none C (1) as shown in Scheme 1, the glycosidation should
be performed as one of the last steps, because the sensitivity
of aromatic glycosides is rather high. The approach there-
fore led to the protected anthraquinone 4, which should be
accessible by a Diels–Alder reaction followed by an aroma-
tization of the bromo-naphthoquinone 5 and the tetrasub-
stituted 1,3-butadiene 6.
Scheme 2. Synthesis of the 1,3-butadiene 6; (a) Na, BnOH, THF,
room temp., 18 h, 73%; (b) SOCl2, DMF (cat.), CH2Cl2, reflux 4 h,
97%; (c) (E/Z) ethyl propenyl ether, Et3N, CH3CN, 60 °C, 105 min,
62%; (d) Et3N, TMSCl, 60 °C, 3 h.
Scheme 1. Retrosynthetic analysis of kwanzoquinone C (1).
The synthesis of the dienophile 5 was carried out accord-
ing to a known procedure starting with 1,5-dihydroxynaph-
With the building blocks 5 and 6 in hand, the cycload-
thalene (7) to give the desired compound within four steps dition was carried out in dichloromethane at low tempera-
and an overall yield of 68% (Scheme 1).[13] We anticipated ture to avoid the formation of the unwanted regioisomer
that the bromo substituent in 2 position in 5 is necessary to employing an excess of the diene 6 (Scheme 3). The cy-
assure the desired regioselectivity in the cycloaddition on cloadduct, which presumably has the structure as depicted
the one hand and on the other hand to guarantee a facile in 12, was formed smoothly, and after complete consump-
aromatization of C-ring by elimination of hydrogen bro- tion of the dienophile 5 the solvent was removed and the
mide. It was known that the bromine can act as a control crude product directly subjected to the aromatization pro-
element to allow a C–C bond formation between the elec- cedure. Unexpectedly, in the beginning this turned out to
tron-rich end of the diene and the unsubstituted carbon of be very problematic. Treatment of the cycloadduct 12 in
the quinone.[14] Furthermore, we decided to protect the phe- THF[19] or chloroform[20] with aqueous hydrogen chloride
nolic hydroxy group as benzyl ether because it exhibits a as well as the usage of acetic acid[21] or silica gel[22] in boil-
good stability against acidic condition, and it should be eas- ing toluene failed completely, furnishing only complex mix-
ily removable within the last steps without affecting the sen- tures of reaction products. Furthermore, we tried the appli-
sitive glycosidic bond.
cation of TBAF, again with a negative result. Finally, a very
For the Diels–Alder reaction with 5 we synthesized the short treatment with 1% TFA in methanol and a subse-
novel tetrasubstituted 1,3-butadiene 6 containing an ethoxy quent quenching with aqueous potassium carbonate led to
group at C-4. We assumed that the latter would act as a the desired anthraquinone 4 in 64% yield. The formation
leaving group during the aromatization step, and thus al- of 4 is assumed to proceed via an initial cleavage of the
lowing a selective construction of the C-ring moiety. For the TMS enol ether in the primarily obtained cycloadduct 12
preparation of 6 we used a method which we had already caused by the TFA followed by an elimination of hydrogen
established in our approach towards a total synthesis of bromide under basic conditions and the final elimination of
mensacarcin.[15] Starting from bromoacetic acid (8), in a ethoxide to give the thermodynamically favored aromatic
two-step procedure[16] the acid chloride 10 was obtained, C-ring.
which was treated with triethylamine to give the transient
For the following glycosidation we chose the trichlo-
ketene needed for the [2+2] cycloaddition with commer- roacetimidate method developed by Schmidt[23] because it
cially available (E/Z) ethyl propenyl ether (Scheme 2). The is best suitable for the formation of aryl β-glucosides with
reaction led to the cyclobutanone rac-11 as an almost single high selectivity using the acetyl-protected trichloroacetimid-
diastereoisomer in 62% yield. The stereoselective formation ate 13[24,25] as donor. The glycosidation was carried out in
Eur. J. Org. Chem. 2006, 4910–4915
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4911

L. F. Tietze, K. M. Gericke, C. Güntner
FULL PAPER
Scheme 3. Synthesis of kwanzoquinone C (1); (a) 1) CH2Cl2, –10 °C, 20 h, 2) 1% TFA, MeOH, room temp., 2 min, 3) 1  K2CO3, room
temp., 5 min, 64%; (b) cat. BF3·Et2O, CH2Cl2, –10 °C, 30 min, 94%; (c) 1) HCO2NH4, cat. Pd/C, THF/MeOH/H2O (3:1:0.25), room
temp., 30 min, 2) air, 5 min, 80%; (d) 1) NaOMe, MeOH, room temp., 1 h, 2) IR-120, 100%.
dichloromethane at –10 °C with BF3·OEt2 as catalyst and the tetrasubstituted diene 17, which we have already used
4-Å molecular sieves to afford the β-glycoside 14 within during our approach towards the total synthesis of mensa-
30 min in 94% yield with only traces of the α-anomer, carcin, led to 18 after a twofold elimination (Scheme 4).[15]
which could be removed by chromatography. At this stage This was achieved by treatment of the crude cycloaddition
the regioselectivity of the Diels–Alder reaction could be un- product with 2  HCl in refluxing THF. Because there is
ambiguously deduced from HMBC-1H NMR experiments no halogen atom present which could eliminate, both the
showing a clear correlation of one carbonyl group of the methoxy and ethoxy group are lost during this step to af-
anthraquinone system with two ortho-hydrogen atoms at ford the anthraquinone 18 in a very high yield of 92%. The
the aromatic rings as depicted in 14. The removal of the sequence was completed by deprotection of the methyl
benzyl protecting groups to give 15 was achieved under ether in 18 with hydrogen bromide in refluxing acetic acid
mild conditions using transfer-hydrogenolysis with ammo- to furnish the target compound 2 in a nearly quantitative
nium formate as hydrogen source in 80% yield. In contrast, yield of 96%.
the application of gaseous hydrogen led to an additional
reduction of the aromatic system with formation of an
anthracenediol. The latter side-reaction was also observed
to a small extent during the transfer-hydrogenolysis, if the
reaction was carried out for too long. However, the anthra-
cenediol can be reoxidized by bubbling air through the reac-
tion solution. Finally, the acetate protecting groups at the
glucose moiety in 15 were removed by solvolysis according
to Zemplén[26] using NaOMe in methanol. Kwanzoquinone
C (1) could be obtained by acidic work up with ion ex-
change resin IR-120 in quantitative yield and high purity.
1
The H NMR and 13C spectra of the compound isolated
by Nair[2] and synthetic compound 1 are in a good agree-
ment in all respects, including chemical shifts as well as
coupling constant values.
Scheme 4. Synthesis of natural product (2); (a) 1) CH2Cl2, 0 °C,
3.5 h, 2) 2  HCl, THF, reflux, 20 h, 92%; (b) HBr, HOAc, 100–
110 °C, 2 h, 96 %.
In conclusion we have completed the first total synthesis
of the novel anticancer agent kwanzoquinone C (1) as well
2. Synthesis of the Anthraquinone 2
In addition to the synthesis of kwanzoquinone C (1) we as of the related natural anthraquinone 2, which shows anti-
also prepared the natural anthraquinone 2 employing a sim- oxidative properties. The newly developed tetrasubstituted
ilar procedure. Cycloaddition of O-methyl juglone (16) and dienes 6 and 17 are versatile substrates for the Diels–Alder
4912
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4910–4915

Synthesis of Bioactive Kwanzoquinone C and a Related Anthraquinone
FULL PAPER
2 H, 2-CH2), 4.66 (s, 2 H, CH2Ph), 7.30–7.41 ppm (m, 5 H, Ph-H)
cycloaddition with naphthoquinones to give highly substi-
tuted cycloadducts. Moreover, different aromatization pro-
cedures allowed us to control the substitution pattern at the
C-ring of the resulting anthraquinones.
ppm. 13C NMR (50.3 MHz, CDCl3): δ = 73.56, 74.79, 128.1, 128.4,
128.7, 136.1, 171.8 ppm. IR (film): ν = 3066, 3033, 2877, 1802,
˜
1651, 1455, 1413, 1263, 1212 cm–1. UV (CH3CN): λmax (lgε) =
257.0 (2.381), 251.5 (2.323), 263.0 nm (2.273). MS (EI, 70 eV): m/z
(%) = 184.1 (1) [M]+, 107.1 [M – C6H5]+, 91.1 (100) [C7H7]+.
HRMS (EI): calcd. for C9H9ClO2: 184.0291; confirmed. C9H9ClO2
(184.62): calcd. C 58.55, H 4.91; found C 58.27, H 4.76.
Experimental Section
General: All reactions were performed in flame-dried glassware un-
der argon. Solvents were dried and purified according to the
method defined by Perrin and Armarego.[27] Commercial reagents
were used without further purification. Thin-layer chromatography
(TLC) was carried out on precoated Alugram SIL G/UV254
(0.25 mm) plates from Macherey–Nagel & Co. Column chromatog-
raphy was carried out on Kieselgel 60 from Merck with particle
size 0.063–0.200 mm for normal pressure and 0.020–0.063 mm for
flash chromatography. Melting points were recorded with a Mettler
FP61 and are uncorrected. IR spectra were determined with a
Bruker Vektor 22, UV/Vis spectra with a Perkin–Elmer Lambda 2,
and mass spectra with a Varian MAT 311A, Varian MAT 731 for
EI-HRMS, and a Bioapex fourier transformation ion cyclotron res-
2-Benzyloxy-3-ethoxy-4-methylcyclobutanone (rac-11): Compound
10 (42.9 g, 0.232 mol) was added dropwise with vigorously stirring
to a solution of ethyl 1-(E/Z) propenyl ether (25.0 g, 0.290 mol)
and triethylamine (35.2 mL, 0.251 mol) in acetonitrile (85 mL) at
0 °C within 15 min. Then the reaction mixture was placed in a pre-
warmed oil bath at 65–75 °C and stirred for 105 min. The solvent
was removed under reduced pressure and the slurry suspended in
Et2O (150 mL), filtered through a sintered-glass-fritted funnel (po-
rosity 3). After removing the solvent in vacuo the crude product
was subjected to silica gel flash chromatography (pentane/EtOAc,
20:1). Concentration of the appropriate fractions afforded cyclobu-
tanone rac-11 (33.2 g, 61%) as a colorless oil. Rf = 0.38 (pentane/
1
EtOAc, 4:1). H NMR (300 MHz, CDCl3): δ = 1.21–1.27 (m, 6 H,
1
onance mass spectrometer for ESI-HRMS. H NMR spectra were
OCH2CH3, 4-CH3), 2.96 (dq, J = 7.2, 4.2 Hz, 1 H, 4-H), 3.60 (dq,
J = 7.0, 1.2 Hz, 2 H, OCHbHaCH3), 3.73 (dd, J = 6.6, 5.4 Hz, 1 H,
3-H), 4.66 (d, J = 11.9 Hz, 1 H, OCHHbPh), 4.67 (dd, J = 5.4,
4.2 Hz, 1 H, 2-H), 4.81 (d, J = 11.5 Hz, 1 H, OCHaHPh), 7.27–
7.40 ppm (m, 5 H, Ph-H) ppm. 13C NMR (50.3 MHz, CDCl3): δ =
11.60, 15.21, 51.79, 65.74, 72.49, 77.78, 90.69, 128.0, 128.1, 128.4,
137.0, 206.9 ppm. UV (CH3CN): λmax (lgε) = 192.5 (4.405), 242.0
recorded with a Varian UNITY-300 MHz and 13C NMR spectra
at 75 MHz. Spectra were taken at room temperature in deuteriated
solvents as indicated using the solvent peak as internal standard.
Elemental analysis was performed at the Mikroanalytisches Labor
des Institutes für Organische und Biomolekulare Chemie der Uni-
versität Göttingen.
(1.955), 279.5 (1.999), 312.5 nm (1.694). IR (film): ν (cm–1) = 3065,
˜
Synthesis of Kwanzoquinone C (1)
3033, 2975, 2874, 1781, 1703, 1497, 1455, 1376, 1356, 1311,
1210 cm–1. MS (EI, 70 eV): m/z (%) = 234.2 (1) [M]+, 107.1 (8)
[M – C6H5], 91.1 (100) [C7H7]+. HRMS (EI): calcd. for C14H18O3:
234.1256; confirmed.
Benzyloxyacetic Acid (9): Benzyl alcohol (250 mL) was treated with
small portions of sodium (57.5 g, 2.50 mol) with mechanical stir-
ring at 20 °C . After the gas evolution had ceased the mixture was
heated to 100–120 °C until the conversion of the sodium metal was
completed. The solution was cooled to 20 °C, diluted with THF
(800 mL) and then bromoacetic acid (8, 70 g, 0.50 mol) in THF
(200 mL) was added dropwise within 30 min. After being stirred
for 12 h the thick, white suspension was dissolved by addition of
H2O (1.2 L). After phase separation, the aqueous layer was washed
with Et2O (5×400 mL), and acidified at 0 °C with a 5  HCl solu-
tion to pH 1–2. The aqueous layer was extracted with Et2O
(3×400 mL) and the combined organic layers were washed success-
ively with H2O (500 mL) and brine (500 mL). After drying
(MgSO4), filtration and concentration under reduced pressure, the
crude product was distilled in vacuo over a 10-cm Vigreux column
to afford benzyloxyacetic acid (9, 64.2 g, 77%) as a colorless, vi-
[(1Z,3E)-1-Benzyloxy-4-ethoxy-3-methylbuta-1,3-dien-2-yloxy]tri-
methylsilane (6): TMSCl (2.80 mL, 21.9 mmol) was added dropwise
to a solution of cyclobutanone 10 (3.41 g, 14.6 mmol) and triethyl-
amine (6.15 mL 43.8 mmol) in acetonitrile (11 mL) at 20 °C. Then
the mixture was placed in a prewarmed oil bath at 65–75 °C and
stirred for 4 h (TLC control). After removing the solvent under
reduced pressure, the slurry was suspended in Et2O (100 mL), and
filtered through a sintered-glass-fritted funnel (porosity 3). Re-
moval of the solvent in vacuo afforded the crude product 6 as
slightly reddish oil, which was used directly for the next step
(4.31 g).
1,8-Bis(benzyloxy)-2-hydroxy-3-methylanthraquinone (4): Diene 6
(4.31 g, ca. 14.1 mmol) was added dropwise to a solution of naph-
thoquinone 5 (1.10 g, 3.21 mmol) in CH2Cl2 (50 mL) at –10 °C
with stirring over 10 min. Stirring was continued for 20 h at –10 °C,
and the reaction mixture was concentrated under reduced pressure.
The residue was treated at 20 °C with 1 % TFA in methanol
(60 mL) and stirred for 2 min, then 1  aqueous K2CO3 solution
(15 mL) was added (color change from yellow to deep red, one
must strictly keep to the reaction time). After stirring for 5 min the
mixture was poured into ice-cold 1  HCl solution (200 mL). The
yellow precipitate was filtered, washed with pentane (100 mL), and
then subjected to silica gel chromatography (CH2Cl2 + 1% acidic
1
cious liquid. B.p. 141 °C (0.2 Torr). H NMR (300 MHz, CDCl3):
δ = 4.15 (s, 2 H, 2-CH2), 4.65 (s, 2 H, CH2Ph), 7.27–7.43 (m, 5 H,
Ph-H), 9.89 (br. s, 1 H, CO2H) ppm. 13C NMR (50.3 MHz,
CDCl3): δ = 66.48, 73.41, 128.1, 128.2, 128.6, 136.5, 175.6 ppm.
IR (film): ν = 3033, 2918, 1731, 1497, 1455, 1429, 1208 cm–1. UV
˜
(CH3CN): λmax (lgε) = 206.0 (3.906), 251.5 (2.091), 257.0 (2.215),
263.0 nm (2.095). MS (EI, 70 eV): m/z (%) = 166.1 (5) [M]+, 91.1
(100) [C7H7]+. C9H10O3 (166.17): calcd. C 65.05, H 6.07; found C
65.28, H 5.85.
Benzyloxyacetyl Chloride (10): Thionyl chloride (274 mL, 3.76 mol)
was added dropwise to a solution of benzyloxyacetic acid (9, 104 g,
0.626 mol) and a cat. amount of DMF (0.1 mL) in CH2Cl2 acid). Concentration of the appropriate fractions afforded the
(500 mL) at 0 °C over 30 min. After being heated under reflux for
4 h the solvent and the excess of thionyl chloride was removed un-
der reduced pressure. The residue was distilled in vacuo in a 10-cm
Vigreux column to give 10 (104 g, 90%) as a pale yellow liquid.
anthraquinone 4 (920 mg, 64%) as a pale yellow solid. Rf = 0.31
(pentane/EtOAc, 4:1). M.p. 194 °C. 1H NMR (300 MHz, CDCl3):
δ = 2.33 (d, J = 0.6 Hz, 3 H, Ar-CH3), 5.14 (s, 2 H, OCH2Ph), 5.29
(s, 2 H, OCH2Ph), 6.58 (s, 1 H, OH), 7.26–7.43 (m, 7 H, 2×p-Ph-
H, 4×m-Ph-H, 7-H), 7.49–7.65 (m, 5 H, 4×o-Ph-H, 6-H), 7.86–
1
B.p. 85–87 °C (0.5 Torr). H NMR (300 MHz, CDCl3): δ = 4.42 (s,
Eur. J. Org. Chem. 2006, 4910–4915
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4913

L. F. Tietze, K. M. Gericke, C. Güntner
7.91 (m, 2 H, 4-H, 5-H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = CHCl3). 1H NMR (300 MHz, CDCl3): δ = 2.03 [s, 3 H, OC(O)
FULL PAPER
15.97, 71.38, 77.23, 119.7, 119.9, 124.3, 125.7, 125.8, 126.8, 127.7,
128.5, 128.7, 128.8, 128.8, 130.1, 134.0, 135.4, 136.5, 136.7, 144.3,
CH3], 2.05 [s, 3 H, OC(O)CH3], 2.07 [s, 3 H, OC(O)CH3], 2.18 [s,
3 H, OC(O)CH3], 2.39 (s, 3 H, Ar-CH3), 3.76 (mc, 1 H, 5Ј-H), 4.16
(dd, J = 12.3, 2.2 Hz, 1 H, 6Ј-Hb), 4.23 (dd, J = 12.1, 4.5 Hz, 1 H,
6Ј-Ha), 5.20 (mc, 1 H, 4Ј-H), 5.32–5.44 (m, 3 H, 1Ј-H, 2Ј-H, 3Ј-H),
7.25 (dd, J = 8.4, 1.1 Hz, 1 H, 7-H), 7.56 (s, 1 H, 4-H), 7.66 (t, J
153.9, 158.6, 182.5, 182.5. IR (KBr): ν = 3434, 2898, 1677, 1591,
˜
1496, 1470, 1454, 1377, 1312, 1258 cm–1. UV (CH3CN): λmax (lgε)
= 268.5 (4.433), 367.0 (3.915), 538.5 nm (2.763). MS
(EI, 70 eV): m/z (%) = 922.9 (100) [2×M + Na]+, 473.1 (54) [M + = 7.8 Hz, 1 H, 6-H), 7.74 (dd, J = 7.5, 1.5 Hz, 1 H, 5-H), 11.85,
Na]+. HRMS (ESI): calcd. for C29H22O5 + H+: 451.15400; found
451.15421; calcd. for C29H22O5 + Na+: 473.13594; found
473.13616. C29H22O5 (450.48): calcd. C 77.32, H 4.92; found
C 77.05, H 5.11.
12.24 (s, 2 H, 2×OH) ppm. 13C NMR (75.5 MHz, CDCl3): δ =
17.72, 20.54, 20.58, 20.77, 61.46, 68.29, 71.38, 71.84, 72.49, 100.4,
115.0, 115.6, 120.0, 122.4, 124.4, 128.6, 133.3, 137.3, 143.1, 147.1,
154.6, 162.3, 169.4, 169.7, 170.2, 170.4, 180.8, 192.5 ppm. IR
(KBr): ν = 2961, 1755, 1674, 1626, 1474, 1452, 1371, 1294, 1234,
˜
1,8-Bis(benzyloxy)-3-methyl-2-(2,3,4,6-tetra-O-acetyl-β-D-glucopyr-
1160 cm–1. UV (CH3CN): λmax (lgε) = 200.0 (4.373), 226.0 (4.482),
259.5 (4.432), 290.0 (3.994), 427.0 (4.028), 558.0 nm (2.742). MS
(ESI): m/z (%) = 1222.8 (100) [2×M + Na]+, 623.1 (21) [M + Na]+.
HRMS (ESI): calcd. for C29H28O14 + H+: 618.18173; found:
618.18157; calcd. for C29H28O14 + Na+: 623.13713; found:
623.13693.
anosyloxy)anthraquinone (14): A solution of the anthraquinone 4
(450 mg, 1.00 mmol) and freshly activated 4-Å molecular sieves
(3 g) in CH2Cl2 (60 mL) was treated at –10 °C with a solution of
the trichloroacetimidate 13 (985 mg, 2.00 mmol) in CH2Cl2
(12 mL). After being stirred for 30 min BF3·OEt2 (25.0 µL,
0.200 mmol) in CH2Cl2 (3 mL) was added dropwise at –10 °C. The
mixture was stirred for another 30 min at the same temperature
after which the reaction was quenched by slow addition of MeOH
(50 mL). The solution was filtered and the residue washed carefully
with CH2Cl2 and MeOH. The combined organic phases were
washed with half-concentrated NaHCO3 solution (200 mL) and
brine (200 mL), dried (MgSO4), filtered, and concentrated in
vacuo. The crude product was subjected to silica gel flash
chromatography (CH2Cl2/EtOAc, 20:1 Ǟ 10:1), and after concen-
tration of the appropriate fractions the glycoside 14 (733 mg, 94%)
was obtained as a pale yellow solid. Rf = 0.42 (pentane/
EtOAc, 3:2). M.p. 203 °C. [α]2D0 = +26.7 (c = 1.0 in CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 1.90, 1.93, 1.98, 2.00 [s, 12 H,
4×C(O)CH3], 2.35 (s, 3 H, Ar-CH3), 3.55 (mc, 1 H, H-5Ј), 3.83 (dd,
J = 12.3, 2.2 Hz, 1 H, 6Ј-Hb), 4.14 (dd, J = 12.1, 4.5 Hz, 1 H, 6Ј-
Ha), 5.01–5.21 (m, 4 H, 4Ј-H, 5Ј-H, OCH2Ph), 5.23 (s, 2 H,
OCH2Ph), 5.31 (br. t, J = 8.8 Hz, 1 H, 2Ј-H), 5.67 (d, J = 7.9 Hz,
1 H, 1Ј-H), 7.26–7.39 (m, 7 H, 2×p-Ph-H, 4×m-Ph-H, 7-H), 7.53–
7.64 (m, 5 H, 4×o-Ph-H, 6-H), 7.81 (d, J = 6.9 Hz, 1 H, 5-H), 7.85
(s, 1 H, 4-H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 17.40, 20.46,
20.94, 20.56, 61.11, 68.04, 70.89, 71.86, 71.90, 72.88, 76.05, 99.46,
119.4, 119.4, 124.3, 125.1, 126.7, 127.7, 128.2, 128.2, 128.4, 128.5,
128.7, 129.9, 134.0, 134.9, 136.2, 136.3, 140.0, 150.0, 152.7, 158.2,
2-(β-D-Glucopyranosyloxy)-1,8-dihydroxy-3-methylanthraquinone
(Kwanzoquinone C, 1): A solution of glycoside 15 (175 mg,
0.241 mmol) in MeOH (75 mL) was treated at 20 °C with NaOMe
(182 µL, 0.966 mmol, 5.3  solution in MeOH). After being stirred
for 1 h Amberlite® IR-120 was added to the red solution until the
color changed to yellow. Then the solution was filtered and the
residue was washed carefully with CH2Cl2 and MeOH. Concentra-
tion of the combined organic phases furnished pure kwanzoqui-
none C (1, 104 mg, 100 %) as yellow solid. Rf = 0.28 (CH2Cl2/
1
MeOH, 10:1 + 1% HOAc). H NMR (300 MHz, [D6]DMSO): δ =
2.40 (s, 3 H, Ar-CH3), 3.10–3.38 (m, 4 H, 5Ј-H, 4Ј-H, 3Ј-H, 2Ј-H),
3.45 (br. d, J = 11.0 Hz, 1 H, 6Ј-Hb), 3.64 (br. d, J = 11.3 Hz, 1 H,
6Ј-Ha), 4.35 (br. s, 1 H, OH), 4.94 (br. s, 1 H, OH), 5.08 (d, J =
7.4 Hz, 1 H, 1Ј-H and br. s, 1 H, OH), 5.45 (br. s, 1 H, OH), 7.28
(br. d, J = 8.4 Hz, 1 H, 7-H), 7.50 (s, 1 H, 4-H), 7.59 (br. d, J =
7.2 Hz, 1 H, 5-H), 7.72 (br. t, J = 8.1 Hz, 1 H, 6-H), 11.90, 11.97
(br. s, 2 H, 1-OH, 8-OH) ppm. 13C NMR (75.5 MHz, [D6]DMSO):
δ = 17.57, 60.81, 69.76, 74.20, 76.35, 77.30, 103.0, 115.2, 115.8,
119.0, 121.5, 124.0, 127.8, 133.0, 137.2, 141.5, 148.0, 153.9, 161.2,
180.5, 191.4 ppm. IR (KBr): ν = 3529, 3442, 2923, 1672, 1624,
˜
1570, 1473, 1420, 1377, 1262, 1213, 1163, 1060, 1036, 934, 888,
837, 785, 770, 749, 647, 567, 428 cm–1. UV (MeOH): λmax (lgε) =
226.5 (4.451), 259.0 (4.430), 290.0 (4.010), 428.0 nm (4.039). MS
(ESI): m/z (%) = 886.9 (100) [2×M + Na]+, 455.1 (5) [M + Na]+.
HRMS (ESI): calcd. for C21H20O10 + H+: 455.09487; found:
455.09491; calcd. for 2 × C21H20O10 + Na+: 887.20051; found:
887.20052.
169.4, 169.4, 170.1, 170.3, 182.2, 182.9 ppm. IR (KBr): ν = 2946,
˜
1754, 1673, 1586, 1499, 1456, 1372, 1332, 1283, 1242 cm–1. UV
(CH3CN): λmax (lgε) = 260.5 (4.447), 367.5 nm (3.723). MS (ESI):
m/z (%) = 1582.6 (83) [2 × M + Na]+, 803.2 (100) [M + Na]+.
HRMS (ESI): calcd. for C43H40O14 + H+: 781.24908; found:
781.24913; calcd. for C43H40O14 + Na+: 803.23103; found:
803.23095.
Synthesis of 1,7-Dihydroxy-6-methylanthraquinone (2)
1,8-Dihydroxy-3-methyl-2-(2,3,4,6-tetra-O-acetyl-β-
yloxy)anthraquinone (15): A solution of the glucoside 14 (300 mg,
0.384 mmol) and Pd/C (10 mol-%, 41 mg, 38.4 µmol) in THF/
D
-glucopyranos-
7-Hydroxy-1-methoxy-6-methylanthraquinone (18): A solution of
the naphthoquinone 16 (1.00 g, 5.31 mmol) in CH2Cl2 (60 mL) was
treated at 0 °C dropwise within 10 min with diene 17 (3.66 g,
MeOH (3:1, 20 mL) was treated at 20 °C dropwise with a 25%ic 15.9 mmol). After being stirred for 3.5 h at 20 °C the reaction mix-
aqueous solution of HCO2NH4 (3.88 mL, 15.4 mmol). After being
stirred for 30 min the dark red mixture was filtered through a plug
of Celite® and saturated aqueous NH4Cl solution (10 mL) was
added to the filtrate. Then air was bubbled through the solution
until the color had changed to yellow; H2O (50 mL) was added
and the mixture extracted with CH2Cl2 (3×30 mL). The combined
ture was concentrated in vacuo. The residue was dissolved in THF
(100 mL), 2  HCl (30 mL) was added and the mixture was heated
under reflux for 20 h. Afterwards, the solution was poured on ice
and the yellow precipitate was filtered off. The residue was washed
with ice-cold EtOAc (3×30 mL) and dried in vacuo to furnish the
pure anthraquinone 18 (1.31 g, 92%) as a pale yellow solid. Rf =
organic layers were dried (MgSO4), filtered, and concentrated un- 0.28 (pentane/EtOAc, 1:1); m.p. Ͼ300 °C. IR (KBr): ν = 3306,
˜
der reduced pressure. The resulting crude product was subjected to
silica gel flash chromatography (CH2 Cl2 /EtOAc, 20:1,
+ 2% HOAc) and after concentration of the appropriate fractions
the glycoside 15 (185 mg, 80%) was obtained as a red-brown, glass-
like solid. Rf = 0.47 (pentane/EtOAc, 3:2). [α]2D0 = –58.3 (c = 1.0 in
2943, 2839, 1662, 1599, 1581, 1511, 1470, 1446, 1350, 1312, 1278,
1240 cm–1. UV (CH3CN): λmax (lgε) = 212.5 (4.457), 269.5 (4.559),
364.5 nm (3.897). 1H NMR (300 MHz, [D6]DMSO): δ = 2.24 (s,
3 H, Ar-CH3), 3.92 (s, 3 H, OCH3), 7.45 (s, 1 H, 8-H), 7.50 (dd, J
= 7.2, 2.0 Hz, 1 H, 2-H), 7.71–7.81 (m, 2 H, 3-H, 4-H), 7.83 (s, 1 H,
4914
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4910–4915

Synthesis of Bioactive Kwanzoquinone C and a Related Anthraquinone
FULL PAPER
5-H), 10.9 (br. s, 1 H, 7-OH) ppm. 13C NMR (75.5 MHz, [D6]-
DMSO): δ = 15.88, 56.23, 111.1, 118.4, 118.7, 120.7, 123.9, 129.1,
130.8, 134.8, 135.1, 135.2, 159.8, 161.4, 181.1, 181.3 ppm. MS (EI,
70 eV): m/z (%) = 268.2 (100) [M]+, 239.2 (31). HRMS (EI): calcd.
for C16H12O4: 268.0736; confirmed. C16H12O4 (268.26): calcd.
C 71.64, H 4.51; found C 71.41, H 4.44.
[8] T. B. Ng, F. Liu, Y. Lu, C. H. K. Cheng, Z. Wang, Compd.
Biochem. Physiol., Part C: Toxicol. Endocrinol. 2003, 136, 109–
115.
[9] a) R. Suemitsu, M. Nakajima, M. Hiura, Agric. Biol. Chem.
1961, 25, 100–102; b) R. Suemitsu, K. Ohnishi, S. Yanagawase,
K. Yamamoto, Y. Yamada, Phytochemistry 1989, 28, 1621–
1622.
[10] U. Höller, J. B. Gloer, D. T. Wicklow, J. Nat. Prod. 2002, 65,
1,7-Dihydroxy-6-methylanthraquinone (2): A suspension of the
anthraquinone 18 (200 mg, 0.746 mmol) in HOAc (20 mL) was
treated with a 30% solution of HBr in HOAc (15 mL). After being
stirred for 1.5 h at 100 °C additional HBr solution (5 mL) was
added and the reaction mixture was stirred for another 30 min.
Afterwards, the solution was poured on ice and the yellow precipi-
tate was filtered off. The residue was washed with ice-cold EtOAc
(3×10 mL) and dried in vacuo to furnish the pure anthraquinone
2 (182 mg, 96%) as a yellow solid. Rf = 0.34 (pentane/EtOAc, 4:1);
876–882.
[11] a) J. Banville, P. Brassard, J. Chem. Soc., Perkin Trans. 1 1976,
1852–1856; b) J. Savard, P. Brassard, Tetrahedron 1984, 40,
3455–3464; c) V. Guay, P. Brassard, Tetrahedron 1984, 40,
5039–5039; d) B. Simoneau, J. Savard, P. Brassard, J. Org.
Chem. 1985, 50, 5433–5434; e) D. W. Cameron, G. I. Feutrill,
G. B. Gamble, J. Stavrakis, Tetrahedron Lett. 1986, 27, 4999–
5002; f) B. Simoneau, P. Brassard, Tetrahedron 1988, 44, 1015–
1022; g) L. Boisvert, P. Brassard, J. Org. Chem. 1988, 53, 4052–
4059; h) D. W. Cameron, A. G. Riches, Aust. J. Chem. 1997,
50, 409–424.
m.p. Ͼ300 °C. IR (KBr): ν = 3299, 1652, 1638, 1572, 1463, 1430,
˜
1358, 1344, 1306, 1249 cm–1. UV (CH3CN): λmax (lg ε) = 211.5
(4.393), 273.5 (4.547), 382.0 nm (3.847). 1H NMR (300 MHz, [D6]-
DMSO): δ = 2.20 (s, 3 H, Ar-CH3), 7.21 (dd, J = 7.2, 1.0 Hz, 1 H,
2-H), 7.40 (s, 1 H, C-8), 7.53 (dd, J = 7.6, 0.8 Hz, 1 H, 4-H), 7.67
(t, J = 8.0 Hz, 1 H, 3-H), 7.74 (s, 1 H, 5-H), 10.9 (br. s, 1 H, 7-
OH), 12.4 ppm (br. s, 1 H, 1-OH) ppm. 13C NMR (75.5 MHz, [D6]-
DMSO): δ = 16.07, 111.0, 115.6, 118.5, 123.2, 124.8, 129.7, 132.4,
132.4, 133.2, 136.7, 161.2, 180.3, 188.1 ppm. MS (EI, 70 eV): 254.0
(100) [M]+, 226.1 (19) [M – CO]+. HRMS (ESI): calcd. for
C15H10O4 + H+: 255.06519; found: 255.06535. C15H10O4 (254.24):
C 70.86, H 3.96; found: C 70.59, H 4.14.
[12] a) K. Krohn, Tetrahedron Lett. 1980, 21, 3557–3560; b) K.
Krohn, Liebigs Ann. Chem. 1981, 12, 2285–2297; c) K. Krohn,
M. Klimars, H.-J. Koehle, E. Ebeling, Tetrahedron 1984, 40,
3677–3694; d) K. Krohn, S. Bernhard, U. Floerke, N. Hayat,
J. Org. Chem. 2000, 65, 3218–3222.
[13] a) J. Becher, O. A. Matthews, M. B. Nielsen, F. M. Raymo, J. F.
Stoddart, Synlett 1999, 3, 330–332; b) M. E. Jung, J. A. Hag-
enah, J. Org. Chem. 1983, 48, 5359–5361; c) M. E. Jung, J. A.
Hagenah, J. Org. Chem. 1987, 52, 1889–1902; d) J. R.
Grunwell, A. Karipidis, C. T. Wigal, S. W. Heinzman, J. Par-
low, J. A. Surso, L. Clayton, F. J. Fleitz, M. Daffner, J. E. Ste-
vens, J. Org. Chem. 1991, 56, 91–95; e) M. A. Brimble, T. J.
Brenstrum, J. Chem. Soc., Perkin Trans. 1 2001, 14, 1612–1623.
[14] J. R. Grunwell, A. Karipides, C. T. Wigal, S. W. Heinzman, J.
Parlow, J. A. Surso, L. Clayton, F. J. Fleitz, M. Daffner, J. E.
Stevens, J. Org. Chem. 1991, 56, 91–95.
Acknowledgments
[15] L. F. Tietze, C. Güntner, K. M. Gericke, I. Schuberth, G. Bun-
koczi, Eur. J. Org. Chem. 2005, 2459–2467.
[16] Y. Yamashita, S. Saito, H. Ishitani, S. Kobayashi, J. Am. Chem.
Soc. 2003, 125, 3793–3798.
[17] R. W. Aben, H. W. Scheeren, J. Chem. Soc., Perkin Trans. 1
1979, 3132–3138.
[18] a) J. Stadlwieser, Synthesis 1985, 490; b) W. D. Wulff, W. E.
Bauta, R. W. Kaesler, P. J. Lankford, R. A. Miller, C. K. Mur-
ray, D. C. Yang, J. Am. Chem. Soc. 1990, 112, 3642–3659.
[19] A. Echavarren, P. Prados, F. Farina, Tetrahedron 1984, 40,
4561–4568.
The authors are grateful to the Deutsche Forschungsgemeinschaft
(SFB 416) and the Fonds der Chemischen Industrie for supporting
this work. We are also indebted to the BASF AG, the Bayer AG,
the Degussa AG and the Wacker-Chemie GmbH for generous gifts
of chemicals.
[1] a) Biodiversity and drug discovery – a symbiotic relation-
ship:G. A. Cordell, Phytochemistry 2000, 55, 463–480; b) S.
Grabley, I. Sattler: Modern Methods of Drug Discovery, Bir-
khäuser Verlag, Schwitzerland, 2003.
[20] B. Beagley, A. D. M. Curtis, R. Pritchard, R. Stoodley, J.
Chem. Soc., Perkin Trans. 1 1992, 1981–1991.
[2] R. H. Cichewicz, K.-C. Lim, J. H. McKerrow, M. G. Nair, Tet-
rahedron 2002, 58, 8597–8606.
[3] a) S.-H. Shiao, B.-R. Shao, Y.-X. He, Y.-Q. Yang, H. Z. Yang,
Y.-C. Chang, Acta Pharm. Sin. 1962, 9, 218–224; b) S.-H.
Shiao, B.-R. Shao, S.-Y. Tseng, C. Chen, Y.-C. Chang, L.-S.
Huang, Acta Pharm. Sin. 1962, 9, 208–217.
[4] a) R. H. Cichewicz, Y. Zhang, N. P. Seeram, M. G. Nair, Life
Sci. 2004, 74, 1791–1799; b) R. H. Cichewicz, N. P. Seeram,
M. G. Nair, Y. Zhang, PCT Int. Appl. 2003, WO 2003089576,
60 pp..
[21] A. Echevarren, P. Prados, F. Farina, J. Chem. Res. Miniprint
1986, 10, 3137–3161.
[22] Y. Horiguchi, A. Toeda, K. Tomoda, H. Suzuki, T. Sano,
Chem. Pharm. Bull. 1998, 46, 1356–1363.
[23] a) R. R. Schmidt, Angew. Chem. 1986, 98, 213–236; Angew.
Chem. Int. Ed. Engl. 1986, 25, 212–235; b) R. R. Schmidt, Pure
Appl. Chem. 1988, 61, 1257–1270.
[24] W. Dullenkopf, J. C. Castro-Palomino, L. Manzoni, R. R.
Schmidt, Carbohydr. Res. 1996, 296, 135–147.
[25] P. Zimmermann, R. Bommer, T. Bär, R. R. Schmidt, J. Car-
bohydr. Chem. 1988, 7, 435–452.
[26] G. Zemplén, Ber. Dtsch. Chem. Ges. 1927, 60, 1555.
[27] D. D. Perrin, W. L. F. Armarego, Purification of Laboratory
Chemicals, 3rd ed., Pentagon Press, Oxford, 1988.
Received: July 21, 2006
[5] R. H. Thomson, Naturally occurring Quinones; Academic
Press, London, 1971, 367–535.
[6] C. Y. Tai, B. H. Chen, J. Agric. Food Chem. 2000, 48, 5962–
5968.
[7] M. R. Dhananjeyan, Y. P. Milev, M. A. Kron, M. G. Nair, J.
Med. Chem. 2005, 48, 2822–2830.
Published Online: August 22, 2006
Eur. J. Org. Chem. 2006, 4910–4915
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4915