Novel synthesis of flavonoids of Scutellaria baicalensis Georgi.
ABSTRACT A concise and efficient total synthesis of the flavonoids baicalein, oroxylin A and wogonin was described. Intramolecular oxidative cyclization followed by demethylation of chalcone 1, readily prepared from trimethoxyphenol, afforded, depending upon the controlled conditions, baicalein or oroxylin A in excellent yields. Demethylation of 1 yielded 3, which, by oxidation with I(2)/dimethyl sulfoxide (DMSO), was readily converted to oroxylin A and wogonin after column chromatography.
- SourceAvailable from: ocean.kisti.re.krJournal of the Korean Chemical Society 01/2009; 53(3).
- [Show abstract] [Hide abstract]
ABSTRACT: A series of chalcones, a flavone and one flavanone were synthesized and elucidated structurally by IR and 1 H NMR spectroscopies. The synthetic compounds were then screened for acetylcholinesterase inhibitory activity using thin layer chromatography (TLC) and microplate assays. In the TLC assay, only 2′-hydroxy-4-methoxychalcone and 2′-hydroxy-4′-O-prenyl-2,6-dichlorochalcone were found to show moderate and weak activity respectively against acetylcholinesterase (AchE) at 0.1 mM concentration compared to the control galanthamine. 4′-Hydroxy-2,6-dichlorochalcone, 2′-hydroxy-4-nitrochalcone, 2′-hydroxy-4-(dimethyl)aminochalcone and 2′-hydroxy-4-methoxychalcone showed moderate AchE inhibitory activity with percentage inhibition of 54.24, 46.14 and 49.32 % respectively in the microplate assay.Jurnal Pengurusan 06/2014; 691(69:1):97-102.
- [Show abstract] [Hide abstract]
ABSTRACT: The objective of the current research work was to evaluate the neuroprotective effect of the ethanol extract of Scutellaria baicalensis (S.B.) on the excitotoxic neuronal cell death in primary rat cortical cell cultures. The inhibitory effects of the extract were qualitatively and quantitatively estimated by phase-contrast microscopy and lactate dehydrogenase (LDH) assays. The extract exhibited a potent and dose-dependent inhibition of the glutamate-induced excitotoxicity in the culture media. Further, using radioligand binding assays, it was observed that the inhibitory effect of the extract was more potent and selective for the N-methyl-D-aspartate (NMDA) receptor-mediated toxicity. The S.B. ethanol extract competed with [(3)H] MDL 105,519 for the specific binding to the NMDA receptor glycine site with 50% inhibition occurring at 35.1 μ g/mL. Further, NMDA receptor inactivation by the S.B. ethanol extract was concluded from the decreasing binding capability of [(3)H]MK-801 in the presence of the extract. Thus, S.B. extract exhibited neuroprotection against excitotoxic cell death, and this neuroprotection was mediated through the inhibition of NMDA receptor function by interacting with the glycine binding site of the NMDA receptor. Phytochemical analysis of the bioactive extract revealed the presence of six phytochemical constituents including baicalein, baicalin, wogonin, wogonoside, scutellarin, and Oroxylin A.TheScientificWorldJournal. 01/2014; 2014:459549.
Baicalein, oroxylin A and wogonin are the three major
flavonoids of Scutellaria baicalensis GEORGI, a traditional
Chinese herb used since the ancient time, characterized by
possessing a very broad spectrum of biological activities, no-
tably anti-oxidant.1)In literature, there have been no appro-
priate approaches available for a facile synthesis of those
structurally similar flavonoids. Our interests in their unique
pharmacological properties prompted us to pursue a perti-
nent route toward the very efficient preparation of such
highly prized targets.
In general, procedures for laboratory synthesis of
flavonoids are still based today on the approaches originally
developed by Robinson2)or exerted by the Baker–Venkatara-
man rearrangement,3,4)synthesis via chalcones,5)and synthe-
sis via an intramolecular Wittig reaction.6)At the outset, we
followed the reported methods specifically for the synthesis
of baicalein,7,8)oroxylin A9)and wogonin.10)However, we
found that they all suffered either from involving a number of
steps giving too low overall yields or from encountering con-
siderable challenges due to irreproducible workout. Attempts
to synthesize baicalein from trimethoxyphenol by either the
modified conventional Baker–Venkataraman approach11)
proved to be impractical (below 10% yield) or the Wittig
strategy6)completely failed. Therefore, our strategy for syn-
thesis of baicalein turned to employing chalcone 1 as the
starting material while the demethylation was performed at
the last stage.
Our approaches (Chart 1) for construction of baicalein,
oroxylin A and wogonin relied on the preparation of flavone
Chem. Pharm. Bull. 51(3) 339—340 (2003) 339
* To whom correspondence should be addressed.e-mail: firstname.lastname@example.org © 2003 Pharmaceutical Society of Japan
Novel Synthesis of Flavonoids of Scutellaria baicalensis GEORGI
Wen-Hsin HUANG, Pei-Yu CHIEN, Ching-Huey YANG, and An-Rong LEE*
School of Pharmacy, National Defense Medical Center; Taipei, Taiwan.
Received October 15, 2002; accepted December 12, 2002
A concise and efficient total synthesis of the flavonoids baicalein, oroxylin A and wogonin was described. In-
tramolecular oxidative cyclization followed by demethylation of chalcone 1, readily prepared from trimethoxyphe-
nol, afforded, depending upon the controlled conditions, baicalein or oroxylin A in excellent yields. Demethyla-
tion of 1 yielded 3, which, by oxidation with I2/dimethyl sulfoxide (DMSO), was readily converted to oroxylin A
and wogonin after column chromatography.
baicalein; oroxylin A; wogonin
2 and chalcone 3 as penultimate targets derived from chal-
cone 1, readily prepared by treatment of easily accessible
trimethoxyphenol with excessive acetic acid in the presence
of BF3–Et2O,12)followed by a Claisen-Schmidt condensation
with equimolar benzaldehyde,3,4)best catalyzed by KOH, in
66% overall yield. Alternatively, a better yield (90%) was
achieved by direct acylation of trimethoxyphenol with
equimolar cinnamoyl chloride, also in the presence of
One of the most common methods in preparation for
flavonoids such as 2 involves an intramolecular oxidative cy-
clization of chalcone,5)i.e. 1. However, formation of the pre-
requisite flavone 2 triggered by SeO2/EtOH7,13)or Pd(OAc)2/
AcCN14)consistently led to extremely low yields (below
10%). This difficulty of cyclization, the phenyl ring bearing
polyphenols (more than 3 OH’s) later turned out to be the
culprit, made us turn to non-metal oxidants. Among them,
I2/dimethyl sulfoxide (DMSO)15)proved to be the most
promising and the reaction proceeded smoothly and ended up
with 2 in a much superior yield (87%). Surprisingly, at-
tempted demethylation of 2 to obtain baicalein in a solution
of 47% HBr/AcOH (1:2) at reflux for 2h gave, after isola-
tion, an unexpected yet desired product oroxylin A (88%) ex-
clusively, validated by fruitless acetonidation in addition to
spectroscopy.16)Further reaction under the same condition
over 12h yielded baicalein (81%). Alternatively, a straight
18-h hydrolysis of 2 proceeded in the same methodology also
afforded baicalein in excellent yield (89%).
In a similar fashion, demethylation of 1 in a solution of
47% HBr/HOAc (1:2) at reflux for 2h gave 3 (91%) which
was susceptible to oxidation with I2/DMSO to procure a mix-
ture of oroxylin A (46%) and wogonin (24%), readily sepa-
rated by flash chromatography.
In conclusion, we have successfully attained an extremely
efficient route for the preparation of baicalein, oroxylin A,
and wogonin. To our best knowledge, for total synthesis of
these three pharmacologically diversified flavonoids, our ap-
proach is the only practical path featuring in beginning with
a common starting material, using affordable reagents and
proceeding under mild conditions and thus suitable for large-
scale pilot-plant synthesis. Various flavone derivatives are
now being prepared in our laboratory by the above-men-
tioned methodology with a view to extensively evaluating
their biological activities. The experimental details and bio-
logical data will be published shortly.
Melting points were determined on a Buchi-530 melting point apparatus
(uncorrected). IR spectra were recorded on a Perkin-Elmer FT-IR 1600 se-
ries FT-IR spectrophotometer. 1H-NMR spectra were determined on a Varian
Gemini-300 NMR instrument. Mass spectra were recorded on a Finnigan
MAT TSQ-46 or Finnigan MAT TSQ-700 mass spectrometer. UV spectra
were recorded on a Shimadzu UV-160A spectrophotometer.
mixture of 3,4,5-trimethoxyphenol (3.7g, 20mmol) and cinnamoyl chloride
(3.7g, 22mmol) was dissolved in BF3–Et2O complex (20ml) and heated to
reflux for 15min, and then quenched with excess of water. Filtration and re-
crystallization from hexane:EtOAc (3:1) gave chalcone 1 (5.6g, 90%) as
reddish-yellow crystals. Alternatively, 1 could be prepared by acylation of
3,4,5-trimethoxyphenol12)and, without further purification, followed by con-
densation with benzaldehyde in the presence of KOH3,4)(66%): mp 98—
100°C. 1H-NMR (CDCl3) d: 3.82 (3H, s), 3.96 (3H, s), 4.03 (3H, s), 6.34
(1H, s), 7.45—7.48 (3H, m), 7.67 (2H, d, J?9.3Hz), 8.06 (2H, d, J?15.5
Hz), 8.33 (2H, d, J?15.5Hz). IR (KBr) cm?1: 3419, 1608. MS m/z: 315
dine (200mg) in DMSO (25ml) was refluxed for 2h, and then carefully
poured onto crushed ice (200g). The precipitate was filtered and washed
with 20% Na2SO3. Purification by flash column chromatography (SiO2,
hexane:EtOAc?3:1) yielded 6.3g (87%) of 2 as white crystals, which
turned into pale yellow after standing for about one month, and recovered
0.8g (2.5%) of 1: mp 146—147°C (lit.17)164—165°C). 1H-NMR (DMSO-
d6) d: 3.93 (3H, s), 3.97 (3H, s), 3.99 (3H, s), 6.72 (1H, s), 6.83 (1H, s), 7.50
(3H, m), 7.88 (2H, d, J?8.7Hz). IR (KBr) cm?1: 1633. MS m/z: 313
A solution of 2 (0.20g, 0.64mmol) in 47% HBr (5ml) and
glacial acetic acid (10ml) was refluxed for 2h, and then carefully poured
onto crushed ice (200g). The resulting yellow precipitate was filtered and
collected. Recrystallization from ethanol afforded 160mg (88%) of oroxylin
A as bright yellow crystals: mp 203—204°C. (lit.9)195—197°C). 1H-NMR
(DMSO-d6) d: 3.91 (3H, s), 6.94 (1H, s), 6.98 (1H, s), 7.59 (3H, m), 8.10
(2H, d, J?6.3Hz), 8.77 (1H, s), 12.49 (1H, s). IR (KBr) cm?1: 3435, 1667.
UV lmax(EtOH) nm (loge): 322 (4.12), 278 (4.35), 216 (4.42). MS m/z: 285
Baicalein, as bright yellow crystals, was prepared by the
modified procedure outlined above either from oroxylin A (reflux, 12h) or 2
(reflux, 18h) in 81% and 89% yield, respectively: mp 258—260°C (lit.7)
263—264°C). 1H-NMR (DMSO-d6) d: 6.61 (1H, s), 6.92 (1H, s), 7.56 (3H,
m), 8.05 (2H, d, J?8.1Hz), 8.81 (1H, s), 10.57 (1H, s), 12.65 (1H, s). IR
(KBr) cm?1: 3411, 1654. UV lmax(EtOH) nm (loge): 326 (4.17), 276
(4.42), 215 (4.49). MS m/z: 270 (M?).
Pure 3 (0.52g, 1.8mmol), prepared by the procedure outlined
above (reflux, 2h) from chalcone 1 (0.62g, 2.0mmol) in 91% yield, was
subject to oxidative cyclization as previously described. Purification by flash
chromatography (silica gel, CH2Cl2®hexane/EtOAc (3/1)®CH2Cl2/EtOAc
(5/1)) and then recrystallization from ethanol gave oroxylin A (238mg,
46%) and bright yellow crystals of wogonin (124mg, 24%), respectively.
Chalcone 3: mp 121—122°C. 1H-NMR (DMSO-d6) d: 2.78 (1H, d, J?13.4
Hz), 3.82 (3H, s), 5.56 (1H, d, J?13.4Hz), 6.27 (1H, s), 7.40—7.54 (5H,
m), 8.21 (1H, s), 11.72 (1H, s). IR (KBr) cm?1: 3445, 1666. FAB-MS m/z: 287
(MH?); Wogonin: mp 198—199°C. (lit.10)203°C). 1H-NMR (DMSO-d6) d:
3.81 (3H, s), 6.30 (1H, s), 7.00 (1H, s), 7.37 (1H, s), 7.64 (3H, m), 8.10 (2H,
d, J?6.3Hz), 12.51 (1H, s). IR (KBr) cm?1: 3445, 1667. UV lmax(EtOH)
nm (loge): 321 (4.15), 276 (4.36), 216 (4.44). FAB-MS m/z: 285 (MH?).
A mixture of 1 (7.2g, 23mmol) and io-
NSC 91WFE0100105 and 91WFE0100114 supported in part from the Na-
tional Science Council of the Republic of China.
We gratefully acknowledge the research grants
1)Gao D., Sakuria K., Chen J., Ogiso T., Res. Commun. Mol. Pathol.
Pharm., 90, 103—114 (1995).
Allan J., Robinson R., J. Chem. Soc., 2192—2194 (1924).
Mahal H. S., Venkataraman K., Curr. Sci., 4, 214—216 (1933).
Wheeler T. S., “Organic Syntheses,” Collective Vol. IV, 2nd ed. by
Rabojohn N., John Wiley & Sons, New York, 1967, pp. 478—481.
Iinuma M., Iwashima K., Matsuura S., Chem. Pharm. Bull., 32,
Hercouet A., LeCorre M., LeFloc’h Y., Synthesis, 1982, 597—598
Schonberg A., Badran N., Starkowsky N. A., J. Am. Chem. Soc., 77,
Agasimundin Y. S., Siddappa S., J. Chem. Soc., Perkin Trans. I, 503—
Popova T. P., Chem. Nat. Compd. (Engl. Transl.), 11, 97—99 (1975).
Hattori S., Hayashi K., Chem. Ber., 66, 1279—1280 (1933).
Ares J. J., Outt P. E., Kakodkar S. V., Buss R. C., Geiger J. C., J. Org.
Chem., 58, 7903—7905 (1993).
Chiba K., Takakuwa T., Tada M., Yoshii T., Biosci. Biotechnol.
Biochem., 56, 1769—1772 (1992).
Price W. A., Silva A. M. S., Cavaleiro J. A. S., Heterocycles, 36,
Kasahara A., Izumi T., Oshima M., Bull. Chem. Soc. Jpn., 47, 2526—
Pinto D. C. G. A., Silva A. M. S., Cavaleiro J. A. S., J. Heterocyclic
Chem., 33, 1887—1893 (1996).
Levene P. A., Raymond A. L., J. Biol. Chem., 102, 317—346 (1933).
McGarry L. W., Detty M. R., J. Org. Chem., 55, 4349—4356 (1990).
340 Vol. 51, No. 3