A new and efficient synthesis of 6-O-methylscutellarein, the major metabolite of the natural medicine scutellarin

Article abstract of DOI:10.3390/molecules200610184

In this paper, a new and efficient synthesis of 6-O-methylscutellarein (3), the major metabolite of the natural medicine scutellarin, is reported. Two hydroxyl groups at C-4′ and C-7 in 2 were selectively protected by chloromethyl methyl ether after the reaction conditions were optimized, then 6-O-methyl-scutellarein (3) was produced in high yield after methylation of the hydroxyl group at C-6 and subsequent deprotection of the two methyl ether groups.

Full text of DOI:10.3390/molecules200610184

Molecules 2015, 20, 10184-10191; doi:10.3390/molecules200610184
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
A New and Efficient Synthesis of 6-O-Methylscutellarein, the
Major Metabolite of the Natural Medicine Scutellarin
1
1
1
1,
1
1
Wei Zhang , Ze-Xi Dong , Ting Gu , Nian-Guang Li *, Peng-Xuan Zhang , Wen-Yu Wu ,
1
1
1
2,
Shao-Peng Yu , Yu-Ping Tang , Jian-Ping Yang and Zhi-Hao Shi *
1
National and Local Collaborative Engineering Center of Chinese Medicinal Resources,
Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine,
Nanjing 210023, China; E-Mails: zhangwei20131405@163.com (W.Z.);
dongzexi1215@163.com (Z.-X.D.); guting1992@163.com (T.G.); zpx20130901@126.com (P.-X.Z.);
1
5150513147@163.com (W.-Y.W.); yushaopeng0405@163.com (S.-P.Y.);
yupingtang@njutcm.edu.cn (Y.-P.T.); jpyang-0828@163.com (J.-P.Y.)
2
Department of Organic Chemistry, China Pharmaceutical University, Nanjing 211198, China
*
Authors to whom correspondence should be addressed;
E-Mails: linianguang@njutcm.edu.cn (N.-G. L.); sszh163@163.com (Z.-H.S.);
Tel./Fax: +86-25-8581-1916 (N.-G.L.); +86-25-8618-5172 (Z.-H.S.).
Academic Editor: Derek J. McPhee
Received: 23 April 2015 / Accepted: 29 May 2015 / Published: 2 June 2015
Abstract: In this paper, a new and efficient synthesis of 6-O-methylscutellarein (3), the
major metabolite of the natural medicine scutellarin, is reported. Two hydroxyl groups at
C-4′ and C-7 in 2 were selectively protected by chloromethyl methyl ether after the
reaction conditions were optimized, then 6-O-methyl-scutellarein (3) was produced in high
yield after methylation of the hydroxyl group at C-6 and subsequent deprotection of the
two methyl ether groups.
Keywords: scutellarin; scutellarein; 6-O-methylscutellarein; metabolite; synthesis
1
. Introduction
As a frequently-occurring disease that seriously endangers human health, ischemic cerebrovascular
disease is one of the leading causes of disability and death worldwide [1]. The critical role that thrombin

Molecules 2015, 20
10185
plays in ischemic cerebrovascular disease has been suggested by increasing evidence [2] that thrombin
catalyzes the proteolytic cleavage of the soluble plasma-protein fibrinogen to form insoluble fibrin leading
to clot formation [3]. Furthermore, the excessive production of reactive oxygen species (ROS) [4,5]
including the superoxide anion radical (O −
•
), hydroxyl radical ( OH), hydrogen peroxide (H
), and nitric oxide (NO ) may result in increased levels of low-density lipoprotein
LDL), oxidative modification of LDL, and an impairment of endothelial derived relaxing factor
EDRF, nitric oxide, NO)-mediated bioactions [6], thus causing ischemic cerebrovascular disease.
•
O
),
2
2
2
1
•
singlet oxygen ( O
2
(
(
Some natural products with anticoagulant capacity and antioxidant activity have been proposed to
treat ischemic cerebrovascular disease. Traditional Chinese Medicines can be regarded as potential rich
sources for the discovery of drug lead compounds because they have been used clinically for thousands
years. Breviscapine, which is a natural drug consisting of total flavonoids of Erigeron breviscapus
(Vant.) Hand-Mazz. (Compositae), has a large market share in China for the treatment of angina pectoris,
cerebral infarction and coronary heart disease [7]. Pharmacological studies have found that scutellarin (1,
Figure 1), the main effective constituent (>85%) of breviscapine, exhibited anticoagulant and antioxidant
activities that attenuate neuronal damage, and thus has a wide range of benefits for brain injury caused
by cerebral ischemia/reperfusion [8–10].
Figure 1. Chemical structures of scutellarin (1), scutellarein (2) and 6-O-methylscutellarein (3).
Interestingly, pharmacokinetic studies showed that the oral bioavailability of scutellarin (1) was quite
poor [11] in humans [12], because scutellarin (1) is hydrolyzed to scutellarein (2, Figure 1) before
absorption, and scutellarein (2) can metabolize into methylated, sulfated or glucuronidated forms [13]
in the blood. 6-O-Methylscutellarein (3, Figure 1), which is one of the major in vivo metabolites might be
responsible for the therapeutic effects of scutellarin (1), however, this interesting scutellarin metabolite
is not commercially available, so the chemical synthesis of 6-O-methyl-scutellarein (3) [14] is very
important for further study.
Recently, we reported a synthetic route (Scheme 1) for the construction of 6-O-methylscutellarein
(
3) [15]. Dichlorodiphenylmethane was used first to protect the dihydroxyl groups at C-6 and C-7 in
scutellarein (2). Subsequently, benzyl bromide was used to selectively protect the hydroxyl groups at
C-4′ in 4 and at C-7 in 5, respectively. Finally, 6-O-methylscutellarein (3) was obtained after methylation
at C-6 in 6 followed by deprotection of the two benzyl groups at C-7 and C-4′.
However, the above reaction conditions using dichlorodiphenylmethane at 175 °C to protect the
dihydroxy groups at C-6 and C-7 in scutellarein (2) would hamper the large-scale preparation of
6
-O-methylscutellarein (3). After an extensive study, we optimized the reaction conditions and used
the chloromethyl methyl ether to directly protect the hydroxyl groups at C-4′ and C-7 in 2, so
-O-methyl-scutellarein (3) was obtained in high yield in only four steps from scutellarin (1). Herein,
we report the details of this new synthetic route.
6

Molecules 2015, 20
10186
OH
Ph CCl , Ph O
OH
HO
HO
O
O
O
O
7
6
O
O
2
2
2
Ph
Ph
o
C
1
75 C, 30 min
OH
OH
2
4
4
'
OCH Ph
OCH Ph
OH
2
2
HO
HO
O
O
PhH CO
O
HO
CO
O
O
2
PhCH Br, K CO
3
2
2
o
DMF, 25 C, 12 h
HO
H
3
OH
OH
O
OH
5
6
3
Scheme 1. The previous synthetic route of 6-O-methylscutellarein (3).
. Results and Discussion
2
As shown in Scheme 2, scutellarein (2) was obtained from the hydrolysis of scutellarin (1) by
refluxing it with 6 N HCl in 90% ethanol under the N protection [16,17]. Based on the different
2
reactivity of the four hydroxyl groups in scutellarein (2) which follows the specific sequential position
order 7 > 4ʹ > 6 > 5, the direct alkylation of scutellarein (2) with chloromethyl ether should lead mainly
to the formation of disubstituted product 8. Firstly, the treatment of 2 with 4.0 equiv. of chloromethyl
ether and 4.2 equiv. K
2
CO
3
in acetone under reflux afforded three products 7, 8 and 9 in 14.8%, 28.9%
and 34.2%, repectively. The location of MOM groups in these three compounds was confirmed by
1
1
H-NMR and ROESY. In the H-NMR (in DMSO-d
-OH remained unchanged, and a cross-peak observed in the ROESY spectrum of 7 between 5.35
-OCH ) with 6.66 (8-H) indicated that the only one MOM group was at the C7 position. In the
1H-NMR spectrum of 8 (in DMSO-d
), a signal at δ 12.76 indicated that the 5-OH group remained
unchanged. One cross-peak observed in the ROESY spectrum of 8 between 5.35 (-OCH ) with 6.69
8-H) indicating that one of the two MOM groups was at C7, while another cross-peak between 5.22
6
) spectrum of 7, a signal at δ 12.40 suggested that
5
(
2
6
2
(
(
1
-OCH
2
) with 7.05 (3′,5′-H) indicated that the second MOM group was at C4′. In the H-NMR
), a signal at δ 12.93 indicated that the 5-OH group remained unchanged,
spectrum of 9 (in DMSO-d
6
and three signals at δ 5.35, 5.48 and 5.60 showed that three MOM groups had been substituted at the
C4′, C6 and C7 positions.
In order to improve the yield of the target compound 8, we subsequently optimized this reaction
conditions by changing the ratio of chloromethyl ether. When the amount of chloromethyl ether was
increased to 4.2 equiv. (Table 1, Run 2) and 4.4 equiv. (Table 1, Run 3), the yield of 8 was reduced to
24.3% and 21.6%, and the yield of the side product 9 was increased to 38.7% and 41.8%, respectively.
This result indicated that the ratio of chloromethyl ether should be decreased. As shown in Run 4, the
yield of 8 increased to 32.1% when the ratio of chloromethyl ether was set at 3.8 equiv. Furthermore,
the yield of 8 could be increased to 43.2% (Table 1, Run 6) after 2 reacted with 3.4 equiv. of MOMCl
and 3.6 equiv. of K
2
CO under reflux in acetone. Unfortunately, the yield of the target compound 8
3
decreased to 38.4% and 36.2% and that of the side product 7 increased to 20.6% and 21.3% when the
amount of chloromethyl ether was decreased to 3.4 equiv. and 3.2 equiv. respectively, so the best
reaction conditions for the synthesis of the target compound 8 were a ratio of MOMCl and K
2
CO of 3.4
3
equiv. and 3.6 equiv. respectively.

Molecules 2015, 20
Table 1. Optimization of reaction conditions in the synthesis of 8.
10187
Run
1
Reaction Conditions
Yield (%)
MOMCl (4.0 equiv.), K
MOMCl (4.2 equiv.), K
MOMCl (4.4 equiv.), K
MOMCl (3.8 equiv.), K
MOMCl (3.6 equiv.), K
MOMCl (3.4 equiv.), K
MOMCl (3.2 equiv.), K
MOMCl (3.0 equiv.), K
2
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
(4.2 equiv.), acetone, reflux, N
(4.4 equiv.), acetone, reflux, N
(4.6 equiv.), acetone, reflux, N
(4.0 equiv.), acetone, reflux, N
(3.8 equiv.), acetone, reflux, N
(3.6 equiv.), acetone, reflux, N
(3.4 equiv.), acetone, reflux, N
(3.2 equiv.), acetone, reflux, N
2
2
2
2
2
2
2
2
, 8 h 7 (14.8), 8 (28.9), 9 (34.2)
, 8 h 7 (12.1), 8 (24.3), 9 (38.7)
, 8 h 7 (10.2), 8 (21.6), 9 (41.8)
, 8 h 7 (16.4), 8 (32.1), 9 (31.6)
, 8 h 7 (18.2), 8 (35.8), 9 (26.5)
, 8 h 7 (19.2), 8 (43.2), 9 (18.7)
, 8 h 7 (20.6), 8 (38.4), 9 (16.4)
, 8 h 7 (21.3), 8 (36.2), 9 (14.2)
2
3
4
5
6
7
8
OH
O
OH
OH
O
HO
HO
O
O
O
HO
HO
O
O
OH
HO
i
ii
OH
OH
1
2
OH
+
OMOM
OMOM
MOMO
HO
O
MOMO
HO
O
MOMO
MOMO
O
O
+
OH
O
OH
O
OH
7
8
9
iii
OMOM
iv
OH
MOMO
O
O
HO
CO
O
O
H CO
H
3
3
OH
1
OH
0
3
Reagents and conditions: (i) HCl, EtOH, N
acetone, reflux; (iii) CH I (1.2 equiv.), K
Et O/CH Cl (1:1), 25 °C, 1 h, 92%.
2
, reflux, 36 h, 17%; (ii) MOMCl (3.4 equiv.), K
2 3
CO (3.6 equiv.),
3
2
CO (1.4 equiv.), DMF, 25 °C, 6 h, 94%; (iv) HCl (1.0 M) in
3
2
2
2
Scheme 2. The new synthetic route of 6-O-methylscutellarein (3).
With 4ʹ,7-dimethoxymethylated scutellarein (8) in hand, 6-O-methylscutellarein (3) was synthesized
according to our previous procedure [15]. The reaction of 8 with 1.2 equiv. of iodomethane led selectively
to 10 with the desired methyl group on the C6-OH in 94% yield. Then the deprotection of di-MOM
groups under hydrolysis conditions in Et
in 92% yield.
2
O/CH
2
Cl using hydrochloric acid as the catalyst afforded 3
2
In summary, we have developed a new and efficient process for the synthesis of 6-O-methyl-scutellarein
3) in only four steps. Based on the fact the relative activity of the four hydroxyl groups is different in
(
the order 7 > 4′ > 6 > 5, chloromethyl methyl ether was used to protect the hydroxyl groups at C-4′ and
C-7 in 2 after the reaction conditions were optimized, then 6-O-methylscutellarein (3) was produced in
high yield after methylation of the hydroxyl group at C-6 and deprotection of the two methyl ether groups.
This synthetic procedure is very efficient and effective and could be applied to the selective synthesis
of other O-methylflavonoid isomers as well as the other flavonoid sulfate- and glucuronide-metabolites
in vivo.

Molecules 2015, 20
. Experimental Section
General Information
10188
3
Reagents and solvents were purchased from commercial sources and used without further purification
unless otherwise specified. Air- and moisture-sensitive liquids and solutions were transferred via syringe
or stainless steel cannula. Organic solutions were concentrated by rotary evaporation below 45 °C at
approximately 20 mm Hg. All non-aqueous reactions were carried out under anhydrous conditions using
flame-dried glassware in nitrogen atmosphere in dry, freshly distilled solvents, unless otherwise noted.
1
Yields refer to chromatographically and spectroscopically ( H-NMR) homogeneous materials, unless
otherwise stated. Reactions were monitored by thin-layer chromatography (TLC) carried out on
0
.15–0.20 mm silica gel plates (RSGF 254, Yantai, China) using UV light as the visualizing agent.
Chromatography was performed on silica gel (160–200 mesh, Qingdao, China) with petroleum ether
1
(
60–90) and ethyl acetate mixtures as eluant. H-NMR spectra were obtained with an AV-300
300 MHz) instrument (Bruker, Karlsruhe, Germany) Chemical shifts are recorded in ppm downfield
(
from tetramethylsilane. J values are given in Hz. Abbreviations used are s (singlet), d (doublet), t
triplet), q (quartet), b (broad) and m (multiplet). ESI-MS spectra were recorded on a Synapt HDMS
spectrometer (Waters, Milford, MA, USA).
(
5
,6,7-Trihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one (2). To a stirring mixture of 1 (10.0 g, 21.6 mmol)
and concentrated hydrochloric acid (120 mL) in ethanol (120 mL) was added water (10 mL), and the
reaction mixture was refluxed under a N atmosphere for 36 h. After cooling down to room temperature,
2
the mixture was poured into water. The solid obtained was filtered followed by silica gel column
chromatography purification of the residue using 50% ethyl acetate in petroleum ether to afford
1
compound 2 (1.05 g, 17.0% yield) as yellow solid. H-NMR (DMSO-d
6
) δ 6.57 (s, 1H, 8-H), 6.74 (s,
1
H, 3-H), 6.91 (d, J = 8.8 Hz, 2H, 3′,5′-H), 7.90 (d, J = 8.8 Hz, 2H, 2′,6′-H), 8.71 (s, 1H, 6-OH), 10.29
(
s, 1H, 7-OH), 10.44 (s, 1H, 4′-OH), 12.78 (s, 1H, 5-OH); ESI-MS: m/z 287 [M + H]+.
Synthesis of MOM substituted products 7, 8 and 9. To a stirring mixture of 2 (2 g, 7 mmol) and K
2
CO
3.48 g, 25.2 mmol, 3.6 equiv.) in dry acetone (100 mL) at room temperature was added chloromethyl ether
1.78 mL, 23.8 mmol, 3.4 equiv.), the reaction mixture was refluxed gently for 8 h. After cooling to room
3
(
(
temperature, the reaction mixture was filtered. Removal of the solvent in vacuo followed by purification
of the residue by column chromatography on silica gel with 20% ethyl acetate in petroleum ether as
eluent afforded 7 (0.44 g, 19.2%), 8 (1.13 g, 43.2%) and 9 (0.55 g, 18.7%) as yellow solids, respectively.
1
5
3
3
,6-Dihydroxy-2-(4-hydroxyphenyl)-7-(methoxymethoxy)-4H-chromen-4-one (7). H-NMR (DMSO-d
6
) δ
.50 (s, 3H, -OCH
3
), 5.35 (s, 2H, -OCH ), 6.60 (s, 1H, 3-H), 6.66 (s, 1H, 8-H), 7.04 (d, 2H, J = 8.6 Hz,
2
′,5′-H), 8.02 (d, 2H, J = 8.6 Hz, 2′,6′-H), 10.33 (s, 1H, 4′-OH), 12.40 (s, 1H, 5-OH); ESI-MS: m/z 329
[
M − H]−.
1
5
,6-Dihydroxy-7-(methoxymethoxy)-2-(4-(methoxymethoxy)phenyl)-4H-chromen-4-one (8). H-NMR
(
DMSO-d ) δ 3.52 (s, 3H, -OCH ), 3.61 (s, 3H, -OCH ), 5.22 (s, 2H, -OCH ), 5.35 (s, 2H, -OCH ),
6
3
3
2
2

Molecules 2015, 20
10189
6
1
.61 (s, 1H, 3-H), 6.69 (s, 1H, 8-H), 7.05 (d, 2H, J = 8.6 Hz, 3′,5′-H), 8.01 (d, 2H, J = 8.6 Hz, 2′,6′-H),
2.76 (s, 1H, 5-OH); ESI-MS: m/z 373 [M − H]−.
1
5
-Hydroxy-6,7-bis(methoxymethoxy)-2-(4-(methoxymethoxy)phenyl)-4H-chromen-4-one (9). H-NMR
) δ 3.66 (s, 3H, -OCH ), 3.76 (s, 3H, -OCH ), 3.87 (s, 9H, -OCH ), 5.35 (s, 2H,
), 5.48 (s, 2H, -OCH ), 5.60 (s, 2H, -OCH ), 6.95 (s, 1H, 3-H), 7.09 (s, 1H, 8-H), 7.15 (d, 2H,
(DMSO-d
6
3
3
3
-OCH
2
2
2
J = 8.7 Hz, 3′,5′-H), 8.06 (d, 2H, J = 8.7 Hz, 2′,6′-H), 12.93 (s, 1H, 5-OH); ESI-MS: m/z 419 [M + H]+.
5
-Hydroxy-6-methoxy-7-(methoxymethoxy)-2-(4-(methoxymethoxy)phenyl)-4H-chromen-4-one
(10).
To a stirring solution of 8 (67 mg, 0.18 mmol) in dry DMF (20 mL) was added K CO
2
3
(48 mg,
0
1
.35 mmol, 1.4 equiv.) and iodomethane (0.014 mL, 0.22 mmol, 1.2 equiv.) at room temperature. After
2 h, the reaction mixture was then partitioned between ethyl acetate (100 mL) and water (100 mL).
The ethyl acetate layer was then washed with brine (100 mL), dried over Na
2
SO , filtered and
4
concentrated. The crude material was purified by column chromatography (25% ethyl acetate in
1
1
petroleum ether) to yield 10 (66 mg, 94% yield) as a yellow solid. H-NMR (DMSO-d
6
) δ H-NMR
), 5.31 (s, 2H,
), 6.48 (s, 1H, 3-H), 6.62 (s, 1H, 8-H), 7.13 (d, 2H, J = 8.6 Hz, 3′,5′-H),
.02 (d, 2H, J = 8.6 Hz, 2′,6′-H), 12.71 (s, 1H, 5-OH); ESI-MS: m/z 389 [M + H]+.
(
300 MHz, DMSO-d
6
) δ 3.46 (s, 3H, -OCH
3
), 3.51 (s, 3H, -OCH
3
), 3.96 (s, 3H, -OCH
3
-
OCH ), 5.34 (s, 2H, -OCH
2
2
8
5
,7-Dihydroxy-2-(4-hydroxyphenyl)-6-methoxy-4H-chromen-4-one (3). Hydrochloric acid (1 mL) was
Cl (5 mL) and ether (5 mL) at 0 °C. The
added to a stirred solution 10 (388 mg, 1 mmol) in CH
2
2
reaction mixture was allowed to warm to room temperature and stirred for a further 1 h. The reaction
mixture was diluted with a large amount of ethyl acetate and washed with water and brine. The ethyl
acetate layer was dried over MgSO , filtered, then concentrated and the crude material purified by
4
column chromatography (50% ethyl acetate in petroleum ether) to yield 3 (276 mg, 92%) as a yellow
1
solid. H-NMR (DMSO-d
6
) δ 3.72 (s, 3H, -OCH ), 6.58 (s, 1H, 3-H), 6.89 (d, 2H, J = 8.6 Hz, 3′,5′-H),
3
7
.11 (s, 1H, 8-H), 7.87 (d, 2H, J = 8.6 Hz, 2′,6′-H), 10.19 (s, 1H, 4′-OH), 10.72 (s, 1H, 7-OH), 12.76
(
s, 1H, 5-OH); ESI-MS: m/z 299 [M − H]−.
Acknowledgments
This work was supported by National Natural Science Foundation of China (No. 81274058), the
Program for New Century Excellent Talents by the Ministry of Education (NCET-12-0741), 333
High-level Talents Training Project Funded by Jiangsu Province, Six Talents Project Funded by
Jiangsu Province (2013-YY-010), Technology Innovation Venture Fund by Nanjing University of
Chinese Medicine (CX201301), Jiangsu Collaborative Innovation Center of Chinese Medicinal
Resources Industrialization (ZDXMHT-1-13) and Project Funded by the Priority Academic Program
Development of Jiangsu Higher Education Institutions.
Author Contributions
W.Z., Z.-X.D., T.G., P.-X.Z., W.-Y.W. and S.-P.Y. did the experiments, N.-G.L. designed the
synthetic route, Z.-H.S. wrote this paper, J.-P.Y. and Y.-P.T. revised this paper.

Molecules 2015, 20
10190
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 1, 2, 3, 7, 8, 9, 10 are available from the authors.
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