An efficient partial synthesis of 4'-O-methylquercetin via regioselective protection and alkylation of quercetin

Article abstract of DOI:10.3762/bjoc.5.60

An efficient partial 5-step synthesis of 4'-O-methylquercetin from quercetin in 63% yield is reported. This strategy relies on the selective protection of the catechol group with dichlorodiphenylmethane in diphenyl ether as solvent and on the selective pr

Full text of DOI:10.3762/bjoc.5.60

An efficient partial synthesis of
4′-O-methylquercetin via regioselective protection
and alkylation of quercetin
Nian-Guang Li1,2, Zhi-Hao Shi3, Yu-Ping Tang*1, Jian-Ping Yang1
and Jin-Ao Duan1
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 60.
1Jiangsu Key Laboratory for TCM Formulae Research, Nanjing
University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu
210046, China, Tel/Fax: +86-25-85811916, 2Department of Medicinal
Chemistry, Nanjing University of Chinese Medicine, Nanjing, Jiangsu
210046, P.R. China and 3Division of Organic Chemistry, China
Pharmaceutical University, Nanjing, Jiangsu 211198, China
doi:10.3762/bjoc.5.60
Received: 22 July 2009
Accepted: 22 October 2009
Published: 04 November 2009
Editor-in-Chief: J. Clayden
Email:
Yu-Ping Tang* - yupingtang@njutcm.edu.cn
© 2009 Li et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
alkylation; high yield; 4′-O-methylquercetin; partial synthesis;
regioselective protection
Abstract
An efficient partial 5-step synthesis of 4′-O-methylquercetin from quercetin in 63% yield is reported. This strategy relies on the
selective protection of the catechol group with dichlorodiphenylmethane in diphenyl ether as solvent and on the selective protec-
tion of the hydroxyl groups at positions 3 and 7 with chloromethyl ether.
Introduction
Flavonoids, such as flavones and flavonols, are secondary plant cetin involves three main modifications of the phenolic
metabolites found in many foods, especially in fruits and vege- hydroxyl groups: methylation, sulfation and glucuronidation
tables [1,2]. Quercetin (1) (Figure 1), the major individual non- [2]. Plasma analysis of pigs fed with quercetin-rich diets show
polymeric molecule among the polyphenols represents 60–75% that quercetin is absent and only methylated metabolites such as
of the flavonoid intake [3]. Quercetin is a very efficient antioxi- 4′-O-methylquercetin (2, tamarixetin) and 3′-O-methylquer-
dant [4] and appears to be active against many diseases related cetin (3, isorhamnetin, Figure 1), mainly conjugated as
to ageing such as cancer [5], cardiovascular [6] and neurode- glucuronides or sulfates [8], are present. With some variations
generative [7] diseases. In blood, quercetin is found mainly in in the relative abundance of the methylation positions, the same
metabolized forms. The non-degradative metabolism of quer- metabolism was also observed in rat [9] and in vivo cell
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Beilstein Journal of Organic Chemistry 2009, 5, No. 60.
Figure 1: Structures of quercetin and methylated metabolites.
cultures [10]. As the glucuronide or sulfate groups are readily cetins) in consequently very low yield. Recently, Rolando’s
deconjugated in tissues [11], these methylated metabolites are, group [18] obtained 2 in only 15% yield by sequential protec-
presumably, the active molecules. Some studies using plasma tion of the different phenolic functions of quercetin by using
samples show that the activities of the metabolites are rather dichlorodiphenylmethane and benzyl bromide.
different from those of quercetin itself [12].
In this paper, a convenient and highly developed method is
These quercetin metabolites are not readily available commer- reported by using firstly dichlorodiphenylmethane in diphenyl
cially. Therefore, synthetic methods for the construction of ether to protect the hydroxy groups at positions 3′ and 4′ in
these metabolites have become important in recent years. Liver quercetin (1). Then, chloromethyl ether is used to protect the
microsomal preparation can be used [13,14] but this is not hydroxy groups at positions 3 and 7 selectively in quercetin 4,
convenient for the preparation of larger quantities of the meta- leaving the hydroxy group at position 5 unaffected. Thus, only
bolites. Existing chemical syntheses of these metabolites five steps are needed to obtain 4′-O-methylquercetin (2, tamar-
[15-20] – where available – are either involved and/or low ixetin) in 63% yield.
yielding. For example, 4′-O-methylquercetin (2, tamarixetin,
Figure 1), one of the in vivo metabolites, was first synthesized Results and Discussion
by Jurd [15] from quercetin pentaacetate. The acetyl groups, 4′-O-Methylquercetin (2, tamarixetin) is synthesized as shown
which were attached to the flavone skeleton, were successively in Scheme 1. This route is based on partial synthesis from quer-
replaced by alkyl groups in the preferential order cetin (1) and relies on successive and selective protection of the
7 > 4′ > 3 > 5 > 3′ to give 2 (along with many other methylquer- different quercetin phenolic functions.
Scheme 1: Synthesis of 4′-O-methylquercetin (2, tamarixetin). a) Ph2CCl2, Ph2O, 175 °C, 30 min, 86%; b) MOMCl, K2CO3, acetone, reflux, 6 h, 93%;
c) Pd/C (10 wt %), H2 (1 atm), THF/EtOH, 8 h, 95%; d) MeI, K2CO3, DMF, 8 h, 92%; e) HCl (1.0 M) in Et2O/CH2Cl2 (1:1), 25 °C, 6 h, 90%.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 60.
Initially, we decided to adopt an alternative strategy which (Figure 2). This corresponds to the one-dimensional (1D)-
relies upon a selective protection of the catechol ring to make nuclear Overhauser effect (NOE) reported by the Rolando
the later selective methylation easier. Hydroxy groups at posi- group [18].
tion 3′ and 4′ in quercetin may be protected after chelation with
borax [21]. However, the Wender group [22] and the Rolando
group [23] reported that under these conditions quercetin
methylation gave a complex mixture with at least three non-
identified partially methylated quercetin ethers. So we decided
to use the same strategy we developed for catechin based on the
protection of the hydroxy groups at position 3′ and 4′ with
dichlorodiphenylmethane in diphenyl ether [24]. In contrast to
Jurd [25], who reported that quercetin protection with
dichlorodiphenylmethane cannot be achieved directly and
required initial protection of the 7-hydroxyl group, but in agree-
Figure 2: ROESY correlations of compound 2.
ment with the recent paper by the Dangles group [26] and the
Rolando group [18], we observed that diphenylmethylene is an
efficient protecting group for the quercetin B ring vicinal The last step of the synthesis, the hydrolysis of the methyl ether
hydroxyl groups. However, on following the latter method [18], group with hydrochloric acid, gave 4′-O-methylquercetin (2,
the yield of the desired product 4 was very low when quercetin tamarixetin) in 90% yield. The overall yield from 1 to 2 was
(1) was treated with 3 equiv of dichlorodiphenylmethane in the 63%, which is much higher than during the previous procedure
absence of solvent at 180 °C for 10 min. One reason might be [18].
that quercetin is a solid whilst dichlorodiphenylmethane is an
oil and this could lead to mixing problems. We therefore Conclusion
applied the method developed by us [24] and treated 1 with 1.5 In conclusion, we have succeeded in devising a partial synthesis
equiv of dichlorodiphenylmethane in diphenyl ether at 175 °C. of 4′-O-methylquercetin (tamarixetin) from quercetin in high
The desired product 4 was obtained in 86% yield after a reac- yield. The strategy relies on the selective protection of the
tion time of only 30 min. We selected chloromethyl ether to catechol group with dichlorodiphenylmethane at 175 °C using
protect the hydroxy groups at positions 3 and 7 in compound 4. diphenyl ether as solvent and on the selective protection of the
The deprotection conditions of methoxymethyl ether and hydroxy groups at positions 3 and 7 with chloromethyl ether as
diphenyl methyl groups are different, the methoxymethyl ether well as the ability to remove the protecting groups under
groups are labile under acidic conditions whilst the diphenyl- different reaction conditions. This reported protocol could be
methyl groups can be removed by hydrogenation. Treatment of applied to the selective synthesis of other O-methylflavonoid
4 with an excess of chloromethyl ether (4 equiv) and K2CO3 isomers as well as to other flavonoid metabolites with other
(4.2 equiv) in acetone led to the formation of 5, whose phenolic functions such as sulfate or glucuronide groups. These
functions with the exception of the hydroxyl group at position 5 compounds will allow structure–activity relationship studies of
were protected. From compound 5, we first focused on the flavonoids to be carried out. Their easily obtained labeled forms
catechol ring deprotection by cleaving the diphenylmethylene will give access to isotopic dilution dosage by LC-MS or
ketal. Two different methods were available for the cleavage of LC-MS/MS and will help in the identification of unknown
such diphenylmethylene ketals: hydrogenolysis or hydrolysis. flavonoid metabolites.
Under hydrogenation conditions the ketal could be cleaved
Experimental
selectively. The best results were obtained with 10% palladium
on carbon as the catalyst in THF/EtOH. TLC showed that the General
reaction was complete after 8 h. This method gave 6 in a 95% Reagents and solvents were purchased from commercial
yield and no side products were detected by TLC analysis. This sources and used without further purification unless otherwise
method is easy, efficient and fast. Treatment of 6 with 1.2 equiv specified. Air- and moisture-sensitive liquids and solutions were
of iodomethane led selectively to 7 with the desired methyl transferred via syringe or stainless steel cannula. Organic solu-
group in the 4′ position in 92% yield. The methyl group posi- tions were concentrated by rotary evaporation below 45 °C at
tion was confirmed by Rotating Frame Overhauser Effect Spec- approximately 20 mm Hg. All non-aqueous reactions were
troscopy (ROESY) (Figure 2). A cross-peak observed in the carried out under anhydrous conditions using flame-dried glass-
ROESY spectrum between δ 3.98 (C4′-OCH3) with 6.96 (C5′-H) ware in an argon atmosphere in dry, freshly distilled solvents,
confirmed that the position of the methyl group was at C4′-O unless otherwise noted. Yields refer to chromatographically and
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Beilstein Journal of Organic Chemistry 2009, 5, No. 60.
spectroscopically (1H NMR) homogeneous materials, unless 477 [M+Na]+; Anal. calcd. for C32H26O9: C, 69.31; H, 4.73.
otherwise stated. Reactions were monitored by thin-layer chro- Found: C, 69.38; H, 4.71.
matography (TLC) carried out on 0.15–0.20 mm Yantai silica
2-(3,4-dihydroxyphenyl)-5-hydroxy-3,7-
gel plates (RSGF 254) using UV light as the visualizing agent.
Chromatography was performed on Qingdao silica gel bis(methoxymethoxy)-4H-chromen-4-one (6)
(160–200 mesh) with petroleum ether (60–90) and ethyl acetate To a solution of 5 (100 mg, 0.18 mmol) dissolved in ethanol (10
mixtures as eluant. Melting points (mp) were measured on a ml) and THF (10 ml) 10% Pd/C (2 mg) was added with
WRS-1B apparatus and were uncorrected. 1H NMR spectra vigorous stirring. Then the reaction vessel was evacuated and
were obtained with a Bruker AV-300 (300 MHz). Chemical the atmosphere replaced with hydrogen. After 8 h, the reaction
shifts are recorded in ppm downfield from tetramethylsilane. J mixture was filtered through celite and the filtrate concentrated.
values are given in Hz. Abbreviations used are s (singlet), d The crude material was then chromatographed on silica gel
(doublet), t (triplet), q (quartet), b (broad) and m (multiplet). (50% ethyl acetate in petroleum ether) to yield 6 (67 mg, 95%)
ESI-MS spectra were recorded on a Waters Synapt HDMS as a yellow solid; mp 142–143 °C; 1H NMR (DMSO-d6, 300
spectrometer.
MHz) δ 3.18 (s, 3H, -OCH3), 3.41 (s, 3H, -OCH3), 5.12 (s, 2H,
-OCH2O-), 5.32 (s, 2H, -OCH2O-), 6.44 (d, J = 2.2 Hz, 1H,
6-H), 6.75 (d, J = 2.2 Hz, 1H, 8-H), 6.91 (d, J = 8.4 Hz, 1H,
5′-H), 7.47 (dd, J = 8.4, 2.4 Hz, 1H, 6′-H), 7.54 (d, J = 2.4 Hz,
2-(2,2-diphenylbenzo[d][1,3]dioxol-5-yl)-
3,5,7-trihydroxy-4H-chromen-4-one (4)
Dichlorodiphenylmethane (354 mg, 0.30 ml, 1.5 mmol) was 1H, 2′-H), 9.34 (s, 1H, 3-OH), 9.76 (s, 1H, 7-OH), 12.59 (s, 1H,
added to a stirred mixture of quercetin (1) (302 mg, 1 mmol) in 5-OH); ESI-MS m/z: 391 [M+H]+, 413 [M+Na]+; Anal. calcd.
diphenyl ether (20 ml) and the reaction mixture was heated at for C19H18O9: C, 58.46; H, 4.65. Found: C, 58.49; H, 4.61.
175 °C for 30 min. The mixture was cooled to room tempera-
5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-
ture and petroleum ether (50 ml) was added to give a solid
3,7-bis(methoxymethoxy)-4H-chromen-4-one
(7)
compound. Then the solid was filtered and purified by column
chromatography (25% ethyl acetate in petroleum ether) to yield
4 (400 mg, 86%) as a yellow solid [18]; mp 218–219 °C (lit.
[18] 222–224 °C); 1H NMR (DMSO-d6, 300 MHz) δ 6.20 (d, J
= 2.0 Hz, 1H, 6-H), 6.47 (d, J = 2.0 Hz, 1H, 8-H), 7.22 (d, J =
8.8 Hz, 1H, 5′-H), 7.46 (m, 6H, aromatic H), 7.58 (m, 4H,
aromatic H), 7.79 (dd, J = 8.8, 1.8 Hz, 1H, 6′-H), 7.82 (d, J =
1.8 Hz, 1H, 2′-H), 9.61 (s, 1H, 3-OH), 10.81 (s, 1H, 7-OH),
12.37 (s, 1H, 5-OH); ESI-MS m/z: 467 [M+H]+, 489 [M+Na]+;
Anal. calcd. for C28H18O7: C, 72.10; H, 3.89. Found: C, 72.18;
H, 3.81.
Iodomethane (0.019 ml, 0.31 mmol) was added to a solution of
6 (100 mg, 0.26 mmol) in dry DMF (20 ml) K2CO3 (20 mg,
0.47 mmol) at room temperature. After 8 h, the reaction mixture
was partitioned between 100 ml ethyl acetate and 100 ml water.
The ethyl acetate layer was washed with brine, dried over
MgSO4, filtered and concentrated. The crude material was puri-
fied by column chromatography (25% ethyl acetate in petro-
leum ether) to yield 7 (97 mg, 92%) as a yellow solid; mp
136–138 °C; 1H NMR (CDCl3, 300 MHz) δ 3.25 (s, 3H,
-OCH3), 3.50 (s, 3H, -OCH3), 3.98 (s, 3H, -OCH3), 5.19 (s, 2H,
-OCH2O-), 5.23 (s, 2H, -OCH2O-), 5.67 (s, 1H, 3′-OH), 6.45 (d,
J = 2.1 Hz, 1H, 6-H), 6.61 (d, J = 2.1 Hz, 1H, 8-H), 6.96 (d, J =
9.2 Hz, 1H, 5′-H), 7.66 (dd, J = 9.2, 2.0 Hz, 1H, 6′-H), 7.68 (d,
2-(2,2-diphenylbenzo[d][1,3]dioxol-5-yl)-5-
hydroxy-3,7-bis(methoxymethoxy)-4H-
chromen-4-one (5)
Chloromethyl ether was added (1.28 ml, 16.84 mmol) to a J = 2.0 Hz, 1H, 2′-H), 12.53 (s, 1H, 5-OH); ESI-MS m/z: 405
stirred mixture of 4 (1.96 g, 4.21 mmol) and K2CO3 (2.45 g, [M+H]+, 427 [M+Na]+; Anal. calcd. for C20H20O9: C, 59.40;
17.68 mmol) in dry acetone at room temperature. The reaction H, 4.99. Found: C, 59.36; H, 5.01.
mixture was refluxed gently for 6 h. After cooling to room
3,5,7-trihydroxy-2-(3-hydroxy-4-methoxy-
phenyl)-4H-chromen-4-one (2)
temperature, the reaction mixture was filtered. Removal of the
solvent in vacuo followed by purification by column chromato-
graphy on silica gel of the residue with 20% ethyl acetate in
petroleum ether afforded 5 (2.17 g, 93%) as a yellow solid; mp
102–104 °C; 1H NMR (CDCl3, 300 MHz) δ 3.21 (s, 3H,
-OCH3), 3.48 (s, 3H, -OCH3), 5.16 (s, 2H, -OCH2O-), 5.22 (s,
2H, -OCH2O-), 6.45 (d, J = 2.2 Hz, 1H, 6-H), 6.59 (d, J = 2.2
Hz, 1H, 8-H), 6.98 (d, J = 8.2 Hz, 1H, 5′-H), 7.39 (m, 6H,
aromatic H), 7.59 (m, 5H, aromatic H), 7.65 (dd, J = 8.2, 1.7
Hz, 1H, 6′-H), 12.51 (s, 1H, 5-OH); ESI-MS m/z: 555 [M+H]+,
Hydrochloric acid (1 ml) was added to a stirred solution 7 (404
mg, 1 mmol) in CH2Cl2 (5 ml) and ether (5 ml) at 0 °C. The
reaction mixture was allowed to warm to room temperature and
stirred for a further 6 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 MgSO4, filtered, then
concentrated and the crude material purified by column chroma-
tography (50% ethyl acetate in petroleum ether) to yield 2 (284
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Beilstein Journal of Organic Chemistry 2009, 5, No. 60.
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This work was supported by Key Research Project in Basic
Science of Jiangsu College and University (NO. 06KJA36022,
07KJA36024), the Natural Science Foundation of the Jiangsu
Higher Education Institutions of China (NO. 08KJD350001)
and 2006’ Training Program of Scientific and Technological
Innovation Team for “Qinglan Project” of Jiangsu College and
University.
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