Efficient method for the synthesis of tectorigenin

Article abstract of DOI:10.1080/00397910701796725

Tectorigenin, isolated from the rhizomes of Belamcanda chinensis, shows a wide variety of biological activities. The interest in its biological activities has been matched by a corresponding interest in its synthesis. We herein reported a convenient synth

Full text of DOI:10.1080/00397910701796725

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Efficient Method for the Synthesis of
Tectorigenin
Zhu‐Ping Xiao a b , Huan‐Qiu Li a , Jia‐Yu Xue a , Lei Shi a & Hai‐Liang Zhu a
a Institute of Functional Biomolecules, State Key Laboratory of
Pharmaceutical Biotechnology, Nanjing University , Nanjing, China
b Department of Chemistry , Shangrao Normal College , Shangrao, China
Published online: 27 Feb 2008.
To cite this article: Zhu‐Ping Xiao , Huan‐Qiu Li , Jia‐Yu Xue , Lei Shi & Hai‐Liang Zhu (2008) Efficient
Method for the Synthesis of Tectorigenin, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:4, 525-529, DOI: 10.1080/00397910701796725
To link to this article: http://dx.doi.org/10.1080/00397910701796725
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Synthetic Communicationsw, 38: 525–529, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701796725
Efficient Method for the Synthesis
of Tectorigenin
Zhu-Ping Xiao,1,2 Huan-Qiu Li,1 Jia-Yu Xue,1 Lei Shi,1
and Hai-Liang Zhu1
1Institute of Functional Biomolecules, State Key Laboratory
of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China
2Department of Chemistry, Shangrao Normal College, Shangrao, China
Abstract: Tectorigenin, isolated from the rhizomes of Belamcanda chinensis, shows a
wide variety of biological activities. The interest in its biological activities has been
matched by a corresponding interest in its synthesis. We herein reported a convenient
synthesis of tectorigenin in good yield. The starting material, 2,4,6-trihydroxyanisole,
gave the intermediate 2,4,40,6-tetrahydroxy-3-methoxydeoxybenzoin by a Hoesch
reaction with 4-hydroxyphenylacetonitrile. The intermediate was then reacted with
methanesulfonyl chloride to produce a mixture of tectorigenin and C-tectorigenin.
Purification of tectorigenin was unnecessary at this stage as C-tectorigenin in the
mixture was isomerized to tectorigenin by refluxing in n-BuOH in the presence of
K2CO3.
Keywords: isoflavones, isomerization, synthesis, tectorigenin
Tectorigenin (4), one of the derivatives of 5,7-dihydroxy-6-methoxyisofl-
avone, was isolated from the rhizomes of Belamcanda chinensis. It is well
known that 4 shows a wide variety of biological activities such as antioxida-
tive,[1] anti-inflammatory,[2,3] antimicrobiotic,[4] and anticancer activities.[5]
In particular, because of its structural and functional similarities to endogenous
Received in Japan July 12, 2007
Address correspondence to Hai-Liang Zhu, Institute of Functional Biomolecules,
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing
210093, China. E-mail: zhuhl@nju.edu.cn
525

526
Z.-P. Xiao et al.
estrogens, tectorigenin (4) has attracted interest as alternative estrogen and a
modulator of estrogenic actions. Thus, it has extensively been studied for a
potential role in many estrogen-dependent diseases, including osteoporosis.[6]
The interest in 4 has been matched by a corresponding interest in its synthesis.
General methods for the synthesis of isoflavones involve the reaction of appro-
priated deoxybenzoins with ethoxalyl chloride, ethyl orthoformate, or metha-
nesulfonyl chloride. However, several attempts were failed when this method
was applied to directly synthesize tectorigenin (4).[7,8] The main problem in
the synthesis of 4 from the corresponding deoxybenzoin 6 was that the
reaction led to a mixture of 5,7,6-orientation and 5,7,8-orientation isomers
(i.e., a mixture of tectorigenin 4 and C-tectorigenin 7). Moreover, it was
quite expensive to separate this mixture into its constituents. In 1956, Kagal
et al. reported a direct synthesis of 4. However, this report did not attract
much attention because the yields were rather low,[9] so we aimed at synthesiz-
ing 4 in a simple way with good yield.
RESULTS AND DISCUSSION
At the beginning of the study, we tried to synthesize 4 by the route shown in
Scheme 1. Obviously, the reaction leading to the formation of the heterocyclic
ring would yield only one product (compound 3), which after debenzylation
should give 4. To our surprise, the condensation of compound 1 with 4-hydro-
xyphenylacetonitrile failed under the Hoesch reaction condition. A possible
reason could be significant steric hindrance by benzyl group.
´
In 1965, Varady reported that C-tectorigenin (7) was isomerized to tec-
torigenin (4) by refluxing in alcohol in the presence of K2CO3 under
anhydrous conditions.[10] This made us think that we did not need to
remove C-tectorigenin (7) from the mixture in advance, and in a mixed
state it should be isomerized to tectorigenin (4) under similar conditions.
Based on this consideration, we developed a modified synthesis of 4
(Scheme 2). The projected synthesis required 2,4,6-trihydroxyanisole (5) as
Scheme 1.

Synthesis of Tectorigenin
527
Scheme 2.
a starting material, which was prepared by application of the published
method.[11] Subsequently, by a Hoesch reaction with 4-hydroxyphenylaceto-
nitrile, compound 5 gave the required intermediate deoxybenzoin (6). The
procedure with the ethoxalylation method involved the following three steps
to yield a mixture of 4 and 7 from deoxybenzoin 6:[8] The reaction of the deox-
ybenzoin (6) with ethoxalyl chloride in the presence of pyridine afforded a
mixture of 2-carboxylate-substituted tectorigenin and C-tectorigenin. The
obtained product was sequently hydrolyzed directly to the corresponding
2-carboxylic acid–substituted derivatives. The result mixture was then
thermally decarboxylated to yield the mixture of 4 and 7. This made the
synthetic process complicated and resulted in a low yield. In contrast, by
application of the conditions outlined in Scheme 2, cyclization of deoxyben-
zoin (6) with methanesulfonyl chloride gave the same product in a one-pot
1
synthesis with a good yield. The H NMR suggested that 4 and 7 were
formed in almost equimolar amounts. The resultant mixture was subsequently
1
isomerized into 4 under the conditions described by Varady. The H NMR,
´
electron spray ionization mass spectrometry (ESI-MS), and elemental
analyses confirmed that the synthetic tectorigenin (4) was identical with the
natural product. The successful synthesis of tectorigenin (4) encouraged us
to apply this method to synthesizing other 5,7-dihydroxy-6-methoxyisofla-
vones such as muningin and irigenin, which is in process.
EXPERIMENTAL
General
Unless otherwise indicated, all chemicals (reagent grade) used were purchased
from Aldrich (USA). Melting points (uncorrected) were determined on an XT4
MP apparatus (Taike Corp., Beijing, China). ESI mass spectra were obtained
1
on a Mariner System 5303 mass spectrometer, and H NMR spectra were
recorded at DRX500 on a Bruker spectrometer. Elemental analyses were

528
Z.-P. Xiao et al.
performed on a CHN-O-Rapid instrument and were within +0.4% of the
theoretical values.
Synthesis of 2,4,40,6-Tetrahydroxy-3-methoxydeoxybenzoin (6)
2,4,6-Trihydroxyanisole (5) (1.56 g, 10 mmol) and 1.33 g (10 mmol) of
4-hydroxyphenylacetonitrile were dissolved in 40 mL of dry ether. The
solution was saturated with dry hydrogen chloride for 2 h at 08C, and the
mixture was then kept at 08C for 2 days, after which a heavy red solid
was separated. The ethereal layer was removed by decantation, and the
remaining solid was shaken with anhydrous ether (45 mL) and dissolved in
water (30 mL). The solution was heated to reflux for 1 h. The shallow
yellow precipitate was collected as needle crystals (2.26 g, 78%). Further puri-
fication was not necessary. Mp 224–2258C. 1H NMR (500 MHz, d6-DMSO):
3.59 (s, 3H); 4.21 (s, 2H); 5.91 (s, 1H); 6.67 (d, J ¼ 8.4 Hz, 2H); 7.01
(d, J ¼ 8.4 Hz, 2H); 9.21 (s, 1H); 10.36 (s, 1H); 11.54 (s, 1H); 12.50
(s, 1H). ESI-MS: 291.1 (C15H15O6, [M þ H]þ). Anal. calcd. for C15H14O6:
C, 62.07; H, 4.86; Found: C, 62.19; H, 4.82.
Synthesis of Tectorigenin (4) and C-Tectorigenin (7)
Deoxybenzoin (6) (5 mmol, 1.45 g) was dissolved in 11 mL of anhydrous
.
DMF. BF3 Et2O (3 mL) was added at 608C, and a vigorous exothermic
reaction occurred after 2 mL of methanesulfonyl chloride in 5 mL of
anhydrous DMF were added. The reaction mixture was heated at 908C for
2.5 h. Addition of cold water (400 mL) led to the formation of a dark
yellow precipitate. The precipitate was collected and washed with water.
Pale yellow solid (1.23 g, 82%) was afforded after drying. Thin-layer chrom-
atography (TLC) suggested the product was a mixture of tectorigenin (4) and
C-tectorigenin (7).
Syntheisis of Tectorigenin (4)
The mixture of tectorigenin (4) and C-tectorigenin (7) (1.50 g) dissolved in
n-BuOH (15 mL). After K2CO3 (0.5 g) was added, the result mixture was
refluxed for 3 h under a nitrogen atmosphere and cooled. Removal of
K2CO3 gave a brown solution, and the solvent was evaporated under
reduced pressure. The residue thus obtained crystallized from ethyl acetate–
petroleum ether in very pale yellow needles (1.26 g, 84%). Mp 228–2308C;
1H NMR (500 MHz, d6-DMSO): 3.73 (s, 3H); 6.37 (s, 1H); 6.80
(d, J ¼ 8.4 Hz, 2H); 7.36 (d, J ¼ 8.4 Hz, 2H); 8.23 (s, 1H); 9.50 (s, 1H);

Synthesis of Tectorigenin
529
10.68 (s, 1H); 13.02 (s, 1H). ESI-MS: 301.1 (C16H13O6, [M þ H]þ). Anal.
calcd. for C16H12O6: C, 64.00; H, 4.03. Found: C, 64.20; H, 4.01.
REFERENCES
1. Park, K. Y.; Jung, G. O.; Choi, J.; Lee, K. T.; Park, H. J. Potent antimutagenic and
their anti-lipid peroxidative effect of kaikasaponin III and tectorigenin from the
flower of Pueraria thunbergiana. Arch. Pharm. Res. 2002, 25, 320–324.
2. Kim, Y. P.; Yamada, M.; Lim, S. S.; Lee, S. H.; Ryu, N.; Shin, K. H.; Ohuchi, K.
Inhibition by tectorigenin and tectoridin of prostaglandin E2 production and
caclooxygenase-2 induction in rats peritoneal macrophages. Biochim. Biophys.
Acta. 1999, 1438, 399–407.
3. Li, H. Q.; Xu, C.; Li, H. S.; Xiao, Z. P.; Shi, L.; Shi, L.; Zhu, H. L. Metronidazole-
flavonoid derivatives as anti-Helicobacter pylori agents with potent inhibitory
activity against HPE-induced interleukin-8 production by AGS Cells. Chem.
Med. Chem. 2007, 2, 1361–1369.
4. Oh, K. B.; Kang, H.; Matsuoka, H. Detection of antifungal activity in Belamcanda
chinensis by a single-cell bioassay method and isolation of its active compound,
tectorigenin. Biosci. Biotechnol. Biochem. 2001, 65, 939–942.
5. Thelen, P.; Scharf, J. G.; Burfeind, P.; Hemmerlein, B.; Wuttke, W.; Spengler, B.;
Christoffel, V.; Ringert, R. H.; Seidlova-Wuttke, D. Tectorigenin and other phyto-
chemicals extracted from leopard lily Belamcanda chinensis affect new and estab-
lished targets for therapies in prostate cancer. Carcinogenesis 2005, 26, 1360–1367.
´
6. Seidlova-Wuttke, D.; Hesse, O.; Jarry, H.; Rimoldi, G.; Thelen, P.; Christoffel, V.;
Wuttke, W. Belamcanda chinensis and the thereof purified tectorigenin have
selective estrogen receptor modulator activities. Phytomedicine 2004, 11, 392–403.
7. Baker, W.; Downing, D. F.; Floyd, A. J.; Gilbert, B.; Ollis, W. D.; Russell, R. C.
Synthesis of irigenin and of tectorigenin, derivatives of 5,7-dihydroxy-6-methox-
yisoflavone. Tetrahedron Lett. 1960, 5, 6–10.
8. Baker, W.; Downing, D. F.; Floyd, A. J.; Gilbert, B.; Ollis, W. D.; Russell, R. C. J.
Synthesis of isoflavone, part V: Irigenin and tectorigenin. J. Chem. Soc. (C) 1970,
1219–1223.
9. Kagal, S. A.; Karmarkar, S. S.; Venkataraman, K. Part xxxii: a synthesis of tectori-
genin. Proc. Ind. Acad. Sci. 1956, 44 (A), 36–41.
´
10. Varady, J. A new method for the isomerization of isoflavone: direct synthesis of
tectorigenin, 40-methoxy-tectorigenin, caviunin and other isoflavones. Tetrahe-
dron Lett. 1965, 48, 4273–4275.
11. Xiao, Z. P.; Shi, D. H.; Li, H. Q.; Zhang, L. N.; Xu, C.; Zhu, H. L. Polyphenols
based on isoflavones as inhibitors of Helicobacter pylori urease. Bioorgan. Med.
Chem. 2007, 15, 3703–3710.