Convenient synthesis of wogonin, a flavonoid natural product with extensive pharmacological activity

Full text of DOI:10.1080/00304940903102739

Organic Preparations and Procedures International, 41:327–330, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940903102739
OPPI BRIEFS
Convenient Synthesis of Wogonin,
A Flavonoid Natural Product with Extensive
Pharmacological Activity
Zhi-Yu Li,1,2 Xin Cao,1,2 Xin Wang,2 Qing-Long Guo,1
and Qi-Dong You1,2
1Jiangsu Key Laboratory of Carcinogenesis and Intervention,
China Pharmaceutical University Nanjing, P. R. China
2Department of Medicinal Chemistry, China Pharmaceutical University Nanjing,
P. R. China
Wogonin (5,7-dihydroxy-8-methoxyflavone, 5), a flavonoid natural product first isolated
from Scutellaria Radix, is well-known for its anti-inflammation,1 anti-allergy,2 anti-tumor3
and anti-hepatitis B virus4 properties. Owing to its extensive applications in medical treat-
ment, researchers have developed several synthetic pathways to obtain this important natural
product since the early part of the last century.5, 6 The initial total syntheses of wogonin
were based on the common synthetic approaches to flavonoids through Baker-Venkataraman
rearrangement6, 7 or intramolecular Wittig reaction.8 However, neither of these two strate-
gies was efficient for large scale production of the compound. Recently Huang et al.9 re-
ported a simplified synthesis of wogonin (5) and oroxylin A (6) from 3,4,5-trimethoxyphenol
(1) and cinnamoyl chloride (2). As shown in Figure 1, the flavone nucleus was obtained
from intermediate 4 wherein the two hydroxyl groups compete for the addition to the α,β-
unsaturated ketone moiety. Evidently, the C6-OH is more active than C2-OH since the yield
of oroxylin A was nearly double that of wogonin. Moreover, this synthetic route is not an
ideal process for industrial production because the two products are difficult to separate.
Prompted by this earlier report on the construction of the flavone nucleus, we launched
our own studies, focusing on avoiding the undesired flavone derivative 6 in the total syn-
thesis of pure wogonin (Figure 2). To avoid the competitive addition process while forming
the flavone nucleus, we utilized intermediate 8 which has only one reactive position.
Intermediate 8 was synthesized in >90% yield from 2,5-dimethoxybenzene-1,3-diol (7)
Submitted March 12, 2009.
Address correspondence to Qi-Dong You, Jiangsu Key Laboratory of Carcinogenesis and In-
tervention, China Pharmaceutical University Nanjing 210009, P. R. China. E-mail: youqidong@
gmail.com
327

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You et al.
Figure 1
which was prepared according to Geissman et al.10 and cinnamoyl chloride (2) in the pres-
ence of BF3-Et2O. Subsequently, 8 was smoothly cyclized with I2 in dimethyl sulfoxide
(DMSO) to afford 5-methoxywogonin (9) in > 90% yield.11 Finally, wogonin was ob-
tained after selective removal of the 5-methoxy group with anhydrous AlCl3 in acetonitrile
(CH3CN) in good yield (84%). The overall yield of 5 from 7 was 68%.
After paying attention to the avoidance of the undesired flavone derivative 6 during
the synthesis of wogonin following the method of Huang et al,9 we evaluated two other
literature approaches of the final intermediate 5-methoxywogonin (9). Suan et al. reported
that 9 could be obtained from 7 by two steps: firstly acetylating and then reacting with
sodium benzoate and benzoic anhydride.12 Additionally, Rivaille et al.13 reported that
9 could be obtained directly by cyclization of compound 7 with acetyl benzoylacetate.
However, both of these methods have many drawbacks such as poor yields, high reaction
temperature and long reaction time, all of which made these approaches unsuitable for scale
up. Thus, our synthesis was comparatively more efficient and simple.
Figure 2

Convenient Synthesis of Wogonin
329
In conclusion, an improved strategy for the total syntheses of wogonin is reported.
Compared with the previously reported methods, this synthetic route is more convenient
and proceeds to give pure wogonin in an overall yield of 68%. This novel synthetic pathway
to wogonin is of great value for the large scale and industrial preparation of this important
flavonoid natural product.
Experimental Section
Reagents, solvents and starting materials were purchased from commercial sources and
were used without further purification unless noted. Melting points were determined on a
micro-melting point apparatus XT-4(Beijing Taike instrument company, China). 1H-NMR
spectra were recorded on a Brucker AMX-300 spectrometer. Chemical shifts are reported
in δ values relative to TMS as an internal standard. Coupling constants were in units of
Hertz (Hz). Mass spectra (EI) were obtained on Shimadzu GCMS-QP2010. IR spectra were
collected using a Nicolet Impact 410 instrument. All of the reactions were performed under
an inert atmosphere of nitrogen.
(E)-1-(2,4-Dihydroxy-3,6-dimethoxyphenyl)-3-phenylprop-2-en-1-one (8)
A solution of commercially available 2,5-dimethoxybenzene-1,3-diol (7, 10.0 g, 60 mmol)
and cinnamoyl chloride (2, 18.0 g, 70 mmol) in BF3-Et2O solution (20 mL) was heated
at reflux for 30 min, cooled and poured into water. The resulting solid was collected
and recrystallized from methanol to give compound 8 (16.2 g, 94%) as reddish-yellow
crystals, mp 210◦C, lit.14 124–125◦C. The literature report14 indicates that compound 8
was separated from the seeds and leaves of Polygonum senegalense by chromatography on
silica gel. However, we found that authentic 8 prepared by our method when mixed with
authentic 2 and 7, could not be separated and purified by chromatography on silica gel since
it was totally adsorbed on the silica gel. This would explain the much lower mp. reported
in the literature.14
1H-NMR (300 MHz, CDCl3): δ 4.00 (6H, s), 6.13 (1H, s), 7.48–7.52 (3H, m), 7.68–7.70
(2H, m), 8.03 (1H, d, J = 15.2 Hz), 8.33(1H, d, J = 15.2 Hz). The OH hydrogens could not
be observed neither in DMSO-d6 nor in CDCl3. The two methoxy groups appear to have
identical chemical shifts. 13C-NMR (75MHz, DMSO-d6): δ 56.9, 60.2, 93.9, 104.3, 121.7,
129.3, 129.7, 130.1, 132.2, 134.1, 148.7, 158.2, 160.7, 165.6, 180.5. IR (KBr): 3400, 3216,
3011, 1606, 1526, 1445, 1374, 1250, 1129 cm−1. EI-MS (m/z): 300 (M+), 285, 269, 230,
223, 196, 181, 167, 153.
Anal. Calcd for C17H16O5: C, 67.99; H, 5.37. Found: C, 67.92; H, 5.45.
7-Hydroxy-5,8-dimethoxy-2-phenyl-4H-chromen-4-one (9)
A solution of 8 (8.0 g, 27 mmol) and iodine (50 mg) in DMSO (35 mL) was stirred at
140◦C for 1 h and then carefully poured onto crushed ice. The precipitate was collected and
washed with 20% Na2SO3 solution and pure water. The crude product was recrystallized
from aqueous methanol (3:1) to give 9 as a pale yellow solid (7.3 g, 95%), mp 287–288◦C,
lit.12,13 287–288◦C.

330
You et al.
1H-NMR (300 MHz, CDCl3): δ 3.76 (3H, s), 3.85 (3H, s), 6.48 (1H, s), 6.77 (1H,
s), 7.57–7.60 (3H, m), 8.01–8.05 (m, 2H). 13C-NMR (75MHz, DMSO-d6): δ55.7, 60.9,
96.9, 106.2, 107.8, 125.7, 128.8, 129.1, 131.1, 131.3, 151.5, 155.4, 155.7, 159.0, 175.7. IR
(KBr): 3123, 1635, 1579, 1501, 1397, 1339, 1207, 1114 cm−1. EI-MS (m/z): 298 (M+),
283, 255, 153.
Wogonin (5,7-Dihydroxy-8-methoxyflavone, 5)
A solution of 9 (5.0 g, 17 mmol) in acetonitrile (250 mL) was added anhydrous AlCl3
(11.0 g, 17 mmol) at 0◦C under a nitrogen atmosphere. The reaction mixture was heated at
reflux for 4 h and then poured into 200 mL of 3N HCl. Extraction with ethyl acetate (200
mL), drying over anhydrous Na2SO4 followed by evaporation of the solvent gave the crude
product which was recrystallized from ethanol to give a yellow solid (15.0 g, 84%), mp
201–202◦C, lit.7198–199◦C.
1H-NMR (300MHz, DMSO-d6): δ 3.86 (3H, d, J = 1.8 Hz), 6.32 (1H, s), 7.01 (1H, s),
7.61–7.64 (3H, m), 8.07–8.09 (2H, m), 10.82 (1H, s), 12.51 (1H, d, J = 1.8 Hz). 13C-NMR
(75MHz, DMSO-d6): δ 61.0, 99.1, 103.7, 105.3, 126.2, 127.8, 129.2, 130.8, 132.0, 149.6,
156.2, 157.3, 163.0, 182.0. IR (KBr) : 3411, 1660, 1579 cm−1. EI-MS (m/z): 284 (M+).
Acknowledgements
The authors gratefully acknowledge financial support from the National Natural Science
Foundations of China (Grant No. 30701032 and 90713038).
References
1. C. K. Han, M. J. Son, H. W. Chang, Y. S. Chi, H. Park and H. P. Kim, Biol. Pharm. Bull., 28,
1366 (2005).
2. M. C. Tai, S. Y. Tsang, L. Y. F. Chang and H. Xue, CNS Drug Reviews, 11, 141 (2005).
3. S. C. Fas, S. Baumann, J. Y. Zhu, M. Giaisi, M. K. Treiber, U. Mahlknecht, P. H. Krammer and
M. L. Weber, Blood, 108, 3700 (2006).
4. Q. L. Guo, L. Zhao, Q. D. You, Y. Yang, H. Y. Gu, G. L. Song, N. Lu, and J. Xin, Antiviral Res.,
74, 16 (2007).
5. J. Allan and R. Robinson, J. Chem. Soc., 12s, 2192 (1924).
6. P. K. Venkatswara, R. K. Visweswara and R. Seshadri, Proc. Indian Acad. Sci., 26A, 13 (1943).
7. H. S. Mahal and K. Venkataraman, Curr. Sci., 2, 214 (1933).
8. A. Hercouet, M. LeCorre and Y. LeFloc’h, Synthesis, 597 (1982).
9. W. H. Huang, P. Y. Chien and C. H. Yang, Chem. Pharm. Bull., 51, 339 (2003), Chem. Abstr.,
139, 149434r, (2003).
10. T. A. Geissman and T. G. Halsall, J. Am.Chem. Soc., 73, 1280 (1951).
11. D. C. G. A. Pinto, A. M. S. Silva and J. A. S. Cavaleiro, J. Heterocyclic. Chem., 33, 1887 (1996).
12. R. C. Shah, C. R. Mehta and T. S. Wheeler, J. Chem. Soc., 1555 (1938).
13. P. Rivaille and C. Mentzer, C. R Acad. Sc. Paris, Se´rie C, 268, 2213 (1969), Chem. Abstr., 71,
61142k, (1969).
14. A. Maradufu and J. H. Ouma, Phytochemistry, 17, 823 (1978).