Synthesis of methylated quercetin analogues for enhancement of radical-scavenging activity

Article abstract of DOI:10.1039/C7RA02329D

Three quercetin derivatives with enhanced radical-scavenging activity were designed and synthesised. Because the radical-scavenging reaction of quercetin is known to proceed via an electron transfer from quercetin to radicals, producing the corresponding quercetin radical cation intermediate, the introduction of electron-donating groups into the quercetin molecule is expected to enhance its radical-scavenging activity. Thus, methyl groups were introduced into the catechol moiety in the quercetin molecule at either the 2′- or 5′-position, or both. All three quercetin analogues were found to exhibit higher radical-scavenging activity than the parent quercetin. The activity of 5′-methylquercetin is the highest among the three analogues. The optimised structure of 5′-methylquercetin calculated by density functional theory demonstrated a coplanar structure between the 4H-curomen (AC rings) and catechol (B ring) moieties, while dimethylquercetin and 2′-methylquercetin have a twisted structure between the AC and B rings. These results demonstrate that the highest radical-scavenging activity of 5′-methylquercetin is due to the stabilisation of the radical cation intermediate by the electron-donating effect of the methyl group as well as by the planar structure of the molecule.

Full text of DOI:10.1039/C7RA02329D

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PAPER
Synthesis of methylated quercetin analogues for
enhancement of radical-scavenging activity†
Cite this: RSC Adv., 2017, 7, 17968
ab
b
bc
Yusuke Ohba,a Takuya Arai,a
*
*
*
Kohei Imai,
Ikuo Nakanishi, Kei Ohkubo,
Mirei Mizuno,a Shunichi Fukuzumi,de Ken-ichiro Matsumotob and Kiyoshi Fukuharaa
Three quercetin derivatives with enhanced radical-scavenging activity were designed and synthesised.
Because the radical-scavenging reaction of quercetin is known to proceed via an electron transfer from
quercetin to radicals, producing the corresponding quercetin radical cation intermediate, the
introduction of electron-donating groups into the quercetin molecule is expected to enhance its radical-
scavenging activity. Thus, methyl groups were introduced into the catechol moiety in the quercetin
molecule at either the 20- or 50-position, or both. All three quercetin analogues were found to exhibit
higher radical-scavenging activity than the parent quercetin. The activity of 50-methylquercetin is the
highest among the three analogues. The optimised structure of 50-methylquercetin calculated by density
functional theory demonstrated a coplanar structure between the 4H-curomen (AC rings) and catechol
(B ring) moieties, while dimethylquercetin and 20-methylquercetin have a twisted structure between the
Received 24th February 2017
Accepted 9th March 2017
AC and
B
rings. These results demonstrate that the highest radical-scavenging activity of 50-
DOI: 10.1039/c7ra02329d
methylquercetin is due to the stabilisation of the radical cation intermediate by the electron-donating
rsc.li/rsc-advances
effect of the methyl group as well as by the planar structure of the molecule.
of hydrogen-transfer reactions of phenolic antioxidants, namely
a one-step hydrogen-atom transfer (route A), or electron transfer
followed by proton transfer (route B), as shown in Fig. 1.12–14
Introduction
Flavonoids are natural compounds that are commonly found in
fruits and vegetables and exhibit numerous benecial physio-
logical activities.1–4 The antioxidative and radical-scavenging
activities of avonoids have been widely studied, and avo-
noid derivatives have been developed to enhance the radical-
scavenging activities.5–8 Flavonoids are a natural part of the
human diet, but can also be taken as supplements. The intake
of avonoids is believed to help prevention from certain
illnesses associated with high levels of reactive radicals, such as
Parkinson's disease and Alzheimer's disease.9–11 Reactive radi-
cals are known to be scavenged by antioxidants, such as avo-
noids, via hydrogen-transfer reactions from the phenolic OH
group to radicals. There are two possibilities for the mechanism
Resveratrol15 and avonoids, such as catechin16,17 and quer-
cetin,18 are known to scavenge radicals via the electron transfer
mechanism. In this case, solvents signicantly affect the
radical-scavenging mechanism.19 In fact, the radical-scavenging
reaction of a vitamin E analogue proceeds via the one-step
hydrogen-atom transfer in aprotic media, such as acetoni-
trile,20 while the electron-transfer process is involved in protic
solvents, such as methanol.21 In this study, we
focused on quercetin (2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-
4H-chromen-4-one), as a potential therapeutic agent to prevent
illnesses caused by reactive oxygen radicals. Quercetin, which is
the most common antioxidant found in citrus fruit and onions,
aSchool of Pharmacy, Showa University, Hatanodai, Shinagawa-ku, Tokyo 142-8555,
Japan. E-mail: imai@pharm.showa-u.ac.jp
bQuantitative RedOx Sensing Team (QRST), Department of Basic Medical Sciences for
Radiation Damages, National Institute of Radiological Sciences (NIRS), National
Institutes for Quantum and Radiological Science and Technology (QST), Inage-ku,
Chiba 263-8555, Japan
cDivision of Innovative Research for Drug Design, Institute of Academic Initiatives,
Osaka University, Suita, Osaka 565-0871, Japan
dDepartment of Chemistry and Nano Science, Ewha Womans University, Seoul 120-
750, Korea
eFaculty of Science and Technology, Meijo University, SENTAN, Japan Science and
Technology Agency (JST), Nagoya, Aichi 468-8502, Japan
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c7ra02329d
Fig. 1 Radical-scavenging mechanism of phenolic antioxidants.
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exhibits not only the ability to scavenge radicals, but also anti- an electron-donating group to enhance the radical-scavenging
inammatory and anticancer effects.22 Wai Mun Loke et al. activity. A planar-catechin analogue 7 (Fig. 2), in which an iso-
also reported that quercetin may attenuate atherosclerosis in propyl fragment was introduced into (+)-catechin, exhibited 5-
vivo.23 Furthermore, quercetin has been shown to inhibit the fold more potent radical-scavenging activity compared to
proliferation of breast cancer, human lung cancer and naso- (+)-catechin.30 The conformationally constrained epi-
pharyngeal carcinoma cells.1,14,24–26
gallocatechin analogue containing an isopropyl fragment 8
Increased importance of considering antioxidative capa- (Fig. 2) showed 16-fold more potent radical-scavenging activity
bilities in drug development has led to an interest in than the parent epigallocatechin.31 We report herein the design
improving the radical-scavenging activity of quercetin. and synthesis of 20,50-dimethylquercetin (1), 20-methylquercetin
Furthermore, the chemical modication of natural antioxi- (2), and 50-methylquercetin (3) for enhancement of the radical-
dants provides valuable fundamental information about the scavenging activity relative to the underivatised quercetin. The
structure–radical scavenging activity relationship of radical-scavenging activity of the quercetin analogues is ex-
compounds.
pected to be enhanced upon introduction of a methyl group at
Our efforts in derivatising quercetin to enhance its radical- positions ortho to the catechol hydroxy group, similar to the
scavenging activity were inspired by the methoxy group in the dimethylcatechin analogue 6. It should be noted that while it is
ferulic acid (caffeic acid structure), due to its proven anti- very difficult to control the stereochemistry during the synthesis
oxidative effects.27 The electron-donating group such as of the dimethylcatechin analogue 6, the synthesis of quercetin
methoxy group at the ortho position relative to the hydroxy analogues was expected to be easier, because there is no need to
group stabilises radical cation. In the electron-transfer mecha- control the stereochemistry. Herein, we also demonstrate their
nism, the ionisation potential (IP) of the compound is impor- enhanced radical-scavenging ability against galvinoxyl radical
tant for its radical-scavenging efficacy. Introduction of an (GOc) as a reactivity model of reactive oxygen species.
electron-donating group, such as methyl group, at positions
ortho and/or para to the phenolic hydroxy group would decrease
the IP of the phenolic compound, and thereby enhance the
radical-scavenging activity.
Results and discussion
Design and synthesis of quercetin analogues
Recently, we reported that resveratrol derivatives, in which Quercetin analogues (1, 2, and 3) were synthesised in which
methyl groups were introduced at the position ortho to the methyl groups were introduced at the positions ortho to the
hydroxy group, showed enhanced radical-scavenging activities. hydroxy groups of the catechol moiety to enhance the radical-
The radical-scavenging activities of resveratrol derivatives 4 and scavenging activity. These analogues were designed with refer-
5 were shown to be about 14- and 36-fold higher than that of the ence to the dimethylcatechin analogue 6. Similar to catechin,
parent resveratrol (Fig. 2).28 Similarly, introduction of methyl quercetin scavenges free radicals via an electron-transfer reac-
groups into the catechol moiety of catechin resulted in an tion.18 Radical cations formed aer the electron-transfer reac-
enhanced radical-scavenging activity relative to the under- tion are delocalised and stabilised by the introduction of an
ivatised catechin. Specically, the radical-scavenging activity of electron-donating group. Moreover, the radical cation inter-
the dimethylcatechin derivative 6 (Fig. 2) was shown to be about mediate of quercetin was expected to be even further stabilised
28-fold higher than that of (+)-catechin.29 In addition to by the effect of both electron donation and hyperconjugation of
a methyl group, an isopropyl fragment was also introduced as the methyl group.
The retrosynthesis of quercetin analogues 1, 2 and 3 is
shown in Scheme 1. The avone scaffold can be synthesised via
the Algar–Flynn–Oyamada (AFO) reaction from the chalcone
structure, which is a useful way to form the avone scaffold.32–34
The chalcone structure can be synthesised by Aldol condensa-
tion using an aldehyde and an acetophenone. The acetophe-
none forms the A ring of the quercetin molecule, while the
aldehyde forms the B ring. The target molecules (1, 2 and 3)
contain methyl groups in the B ring, which are introduced into
the starting aldehyde. Previously, the aldehyde derivative 9a, in
which methyl groups were introduced at both positions ortho to
the catechol hydroxy groups, had been synthesised to obtain the
dimethyl catechin analogue 6. The intermediate (11) of 9a had
been obtained by catalytic reduction aer introduction of
morpholine structure to catechol with Mannich reaction.29
Because the catalytic reduction is a dangerous reaction that is
carried out at 70 ꢀC and 5 atm, another route was employed for
the synthesis of 9a.
Synthesis of the aldehyde derivative 9a used in this study is
Fig. 2 Chemical structures of synthetic antioxidants.
shown in Scheme 2. Dimethyl catechol 11 was obtained by the
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Scheme 1 Retrosynthesis of methyl quercetin analogues.
When the catalytic reduction was performed, the resulting
yellow reaction solution turned colorless. This reduction reac-
tion was performed not only for deprotection, but also for
reduction of the unsaturated aurone bond. If, instead, the
quercetin structure (15) had been synthesised by the AFO
reaction, only the deprotection reaction of the benzyl group
would have occurred following catalytic hydrogen reduction,
and the color of reaction solution should have remained yellow.
However, the reaction solution became colorless upon catalytic
hydrogen reduction. Thus, the AFO reaction of 14 yielded the
aurone structure (16) without the quercetin structure (15).
Epoxide may be predicted to be formed as an intermediate
when the chalcone structure contains a substituent at the 6-
position, as in 14. The AFO reaction of chalcone with a substit-
uent at the 6-position has previously been reported by various
authors. Formation of the epoxide intermediate takes place by
attack of the 2-O group at the a- rather than at the b-position.36,37
Therefore, the AFO reaction of 14 yielded the aurone structure
(16) (Scheme 4).
Scheme 2 Synthesis of dimethyl aldehyde derivative 9a.
Dakin reaction aer formylation of 2,5-dimethylphenol.35
Following formylation of 11 at the 4-position, protection of the
hydroxy groups of 13 with benzyl bromide was accomplished to
yield 9a. The AFO reaction, aer Aldol condensation of 9a and
10a, is shown in Scheme 3. Acetophenone derivative (10a) was
obtained by benzylation of the hydroxy groups at the 2- and 4-
positions of 2,4,6-trihydroxyacetophenone. The chalcone 14 was
obtained by the aldol condensation of 9a with 10a. We initially
attempted formation of avone structure by the AFO reaction;
however, the avone structure was not formed. Instead, the
aurone structure (16) was formed, followed by hydrogenation to
yield 17.
We attempted to introduce a hydroxy group to 18 at the 3-
position with dimethyldioxirane (DMDO) to yield 15. The chal-
cone structure (14) was reacted with I2 in DMSO to yield 18.
While the cyclisation reaction was successful, hydroxylation of
18 with DMDO failed to yield 15.
We had deluded ourselves into taking that 15 was obtained by
the AFO reaction because the 1H-NMR spectra of 15 and 16 were
similar. Therefore, the catalytic reduction to give 1 was carried
out, however, the compound 17 instead of 1 was obtained.
Following these initial attempts, quercetin analogues were
subsequently synthesised with other scheme which is via the
taxifolin framework (22a) intermediate, as shown in Scheme 5.
The synthetic scheme was employed with reference to the
Scheme 3 Formation of dimethyl aurone structure 17.
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Scheme 7 Synthesis of monomethyl aldehyde derivative 9b and 9c.
Scheme 4 AFO reaction.
Formylation of 24, which was benzylated using 3-methyl-
catechol, at the 4-position was carried out by the Vilsmeier–
Haack reaction to yield 9b. The aldehyde derivative 9c was also
synthesised from 3-methylcatechol. Specically, 3-methyl-
catechol was rst benzylated at the 1-position of the hydroxy
group to yield 25. Formylation of 25 at the 5-position was then
achieved via the Duff reaction using hexamethylenetetramine
(HMTA).43,44 The aldehyde derivative 9c was then obtained by
benzylation at the 2-position of the hydroxy group. Quercetin
analogues 2 and 3 were synthesised with the resulting 9b and
9c, respectively, by the same scheme used to obtain dime-
thylquercetin (1) (Scheme 6).
Scheme 5 Synthesis of 19.
synthesis of isorhamnetin, tamarixetin, and kaempferide. The
protective group of acetophenone derivative (19) was changed
from a benzyl group to methoxymethyl (MOM). The protection
of all the hydroxy groups of acetophenone allows for termina-
tion of the reaction of epoxide conversion to aurone. The MOM
was employed to be easily deprotected aer formation of
epoxide. The taxifolin framework (22a) should be obtained by
the deprotection of MOM and cyclisation in a 1-pot reaction
with 21a. The 2,4,6-tri-MOM phloracetophenone (19) was rst
synthesised, in which three hydroxy groups were protected by
MOM groups (Scheme 5).38–40 The chalcone derivative 20a was
subsequently obtained by condensation of 19 with the aldehyde
derivative 9a. Next, epoxidation of 20a with hydrogen peroxide
in the presence of sodium hydroxide as a base yielded 21a.41
Cyclisation of 21a was achieved at the same time as depro-
tection of MOM with hydrochloric acid. Catalytic hydrogenation
of 22a with 20% Pd(OH)2 yielded 23a. Finally, oxidation of 23a
with potassium metabisulte solution was performed to yield
dimethyl quercetin (1) (Scheme 6).42
Radical-scavenging activity of quercetin analogues monitored
by the stopped ow technique
The radical-scavenging activity of quercetin analogues was
evaluated in a non-aqueous system using the galvinoxyl radical
(GOc) as a reactivity model of reactive oxygen species. GOc
exhibits a strong absorption band at 428 nm, and a solution of
GOc appears yellow in color.21,45 Upon mixing of GOc with an
antioxidant, the visible absorption band immediately vanishes,
and the resulting decolorization is stoichiometric with respect
to the number of electrons taken up. The rates of GOc-scav-
enging by the quercetin analogues were measured based on the
color change of GOc in the presence of antioxidants. Because
this spectral change occurs very fast, the rates of the radical-
scavenging reaction of quercetin analogues were measured by
monitoring the decrease in absorbance at 428 nm using
a stopped ow technique in deaerated acetonitrile at 298 K. The
The aldehyde derivatives 9b and 9c were synthesised to
obtain the quercetin analogues 2 and 3, respectively (Scheme 7).
Scheme 6 Formation of quercetin analogues 1, 2 and 3.
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decay of the absorbance at 428 nm obeyed pseudo-rst-order
kinetics when the concentration of 2 ([2]) was maintained at
more than 10-fold excess to the GOc concentration. The decay of
the absorbance at 428 nm of GOc is shown in Fig. 3. The pseudo-
rst-order rate constant (kobs) increased linearly with an
increase in the concentration of quercetin analogues. An
extended gure for 1, 2 and quercetin is included as an insert in
Fig. 4 because the k value of 3 is too large; the insert shows
a magnied axis for kobs from 0 to 2 sꢁ1. From the slope of
a linear plot of kobs vs. [2], the second-order rate constant (k) for
the radical-scavenging reaction was determined to be 6.1 ꢂ 10
Mꢁ1 sꢁ1. The k values for dimethylquercetin (1), 50-methyl-
quercetin (3), and the parent quercetin were determined in the
same manner to be 2.1 ꢂ 103 Mꢁ1 sꢁ1, 1.6 ꢂ 105 Mꢁ1 sꢁ1, and
1.1 ꢂ 10 Mꢁ1 sꢁ1, respectively (Fig. 4). These results demon-
strate that the k values for 1, 2 and 3 were about 191-, 5.5- and
14 500-fold greater than that of the underivatised quercetin,
respectively. Thus, structurally modied quercetin analogues (1,
2 and 3) could afford signicantly larger k values than the
parent quercetin. The k value for 3 is the largest among the
quercetin analogues examined in this study. The GOc-scav-
enging activity of 3 is about 2600-fold larger than that of 2. The
large difference in k values between 2 and 3 demonstrates that
the radical-scavenging activity of the quercetin derivatives
largely depends on the position of the methyl group. The k
values of aurone derivative 17 and dimethylcatechin 6 were 7.2
Mꢁ1 sꢁ1 and 1.1 ꢂ 103 Mꢁ1 sꢁ1, respectively, indicating that
delocalisation of the radical cation might operate a high radical-
scavenging activity. The delocalisation of radical cation of 6 and
17 may remain limited to the catechol moiety, and these radical
cations may not be delocalised throughout the entire molecule.
IPs and energy difference values (DHT, HT: hydrogen trans-
fer) between quercetins and the corresponding phenoxyl radi-
cals, which equal the O–H bond dissociation energies (BDE) of
their phenolic hydroxy groups, were calculated to elucidate the
effect of the methyl groups in the quercetin analogues on their
radical-scavenging activity by the density functional theory
(DFT). As shown in Fig. 1, phenolic compounds scavenge radi-
cals via two mechanisms. Thus, the IP and DHT values are reli-
able parameters to distinguish these two different radical-
scavenging mechanisms. If the phenolic compound scavenges
Fig. 4 Plots of the pseudo-first-order rate constant (kobs) vs. the
concentrations of 1 (green triangles), 2 (purple diamonds), 3 (blue
circles) and quercetin (red squares) for radical-scavenging reaction
against GOc. Inset: enlargement of the same plots from kobs values of
0 to 2.
GOc via a one-step hydrogen-atom transfer reaction, i.e., route B,
the compound with lower DHT value exhibit the higher radical-
scavenging activity. In contrast, the reactivity of the electron-
transfer reaction of phenolic compounds, i.e., route A, is
related to the IP values. Because, the lower of the IP, the easier is
the electron abstraction. The DHT and IP values of quercetin
analogues were determined by DFT calculations at the B3LYP/6-
31G(d) level and the results are shown in Table 1. The IP value of
3, which exhibits a markedly enhanced radical-scavenging
activity, was the lowest among all the quercetin analogues.
Therefore, the mechanism of radical-scavenging of 3 may occur
via an electron transfer followed by proton transfer. If the
radical-scavenging mechanism of 3 is a one-step hydrogen
atom-transfer reaction, the DHT value at the 40-OH position
should be the lowest among all the quercetin analogues.
However, the DHT value of 3 is higher than that of 1. Thus,
enhancement of the radical-scavenging activity of 3 may be the
result of electron donation by the introduced methyl group.
We also evaluated the most stable structures of quercetin
and quercetin analogues by DFT calculations, as shown in
Fig. 5. Quercetin exhibits a coplanar structure between the 4H-
curomen (AC rings) and catechol (B ring) moieties (Fig. 5a). In
Table 1 The DHT and IP values for quercetin analogues
DHT (kcal molꢁ1
)
k (Mꢁ1 sꢁ1
)
30-OH
40-OH
IP (eV)
1
2
3
2.1 ꢂ 103
6.1 ꢂ 10
1.5 ꢂ 105
1.1 ꢂ 10
390.02
390.19
392.91
397.17
388.58
390.46
389.10
390.44
6.84
6.92
6.80
6.88
Fig. 3 Spectral change (interval: 4 s) observed during the reaction
between 2 (4.7 ꢂ 10ꢁ5 M) and GOc (4.7 ꢂ 10ꢁ6 M) in deaerated MeCN
at 298 K.
Quercetin
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group was introduced into both 2 and 3, the radical-scavenging
activities of both quercetin derivatives varied greatly as a result
of the different positions of the introduced methyl group. The
radical-scavenging activity of 3 was enhanced by the electron
donating effect. In addition, the radical cation of 3 was found to
be stabilised by the planar structure between the AC and B
rings. The signicant enhancement in radical-scavenging
activity observed for 3 was due to both the electron-donating
effect and the planar quercetin structure. Results reported
herein suggest that future design and synthesis of novel anti-
oxidant agents with enhanced radical-scavenging activities
should consider not only the introduction of electron-donating
groups but also stabilisation of radical cations by to atten
throughout the entire molecule. The 3 with high radical-scav-
enging activity would also be studied not only radical-scav-
enging activity but also physiological effects of quercetin such
as anti-inammatory and anticancer.
Fig. 5 DFT optimised structures of (a) quercetin, (b) 1, (c) 2, and (d) 3
calculated using DFT (B3LYP/6-31G(d) level).
contrast to the structure of quercetin, analogues 1 and 2, which
contain methyl groups at the 20-position, exhibit a twisted
structure between the AC and B rings due to steric hindrance of
the hydroxyl group of the C ring. The torsional angles between
the AC and B rings of 1 and 2 were 49.5ꢀ and 49.8ꢀ, respectively
(Fig. 5b and c). On the other hand, 3, which exhibited the
highest radical-scavenging activity, formed a coplanar structure
similar to the parent quercetin (Fig. 5d). The planar structure of
quercetin was maintained even aer introduction of a methyl
group at the 50-position. When 3 gives an electron to GOc to
produce the corresponding radical cation of 3, the planar
structure allows for delocalisation of the radical cation
throughout the entire molecule, resulting in enhanced radical-
scavenging activity. The hydrogen transfer from 3 to GOc pro-
ceeded via electron transfer from 3 to GOc followed by proton
transfer from the resultant radical cation intermediate 3c+ to the
one-electron reduced species of GOc, i.e. GOꢁ. Thus, enhance-
ment of the radical-scavenging activity of 3 is thought to be due
to the introduction of an electron-donating methyl group into
the catechol moiety. In addition, the planar structure of 3
promoted the enhancement of radical-scavenging activity by
stabilisation of 3c+. The structure of synthetic analogues 1, 2
exhibited a twisted structure by introduction of methyl group at
20-position. As a result, the radical cation, which was generated
by radical-scavenging reaction, was not able to be delocalised
throughout the entire molecule. On the other hands, intro-
duction of methyl group at 50-position did not affect the planar
structure. Thus, the quercetin analogue with methyl group at 50-
position exhibited the highest radical-scavenging activity
because delocalised radical cation might be stabilised effi-
ciently by the electron-donating methyl group.
Experimental section
General methods
Unless otherwise noted, all commercially available compounds
were used as provided without further purication. Solvents for
chromatography were technical grade, and acetonitrile for
antioxidant activity measurements was analytical grade. Proton
(1H) NMR spectra and (13C) NMR spectra were recorded on
a JEOL JNMAL-400 (400 MHz) instrument and JNM-ECX-500
(500 MHz). Chemical shis (d) are given in parts per million
(ppm) and are referenced to residual protonated solvent (CHCl3:
d H 7.26 ppm, d C 77.16 ppm; CH3OH: d H 3.31 ppm, d C
49.00 ppm; (CH3)2CO: d H 2.05 ppm, d C 29.84 ppm; (CH3)2SO:
d H 2.50 ppm, d C 39.52 ppm). J values are given in Hz. Mass
spectra were obtained FAB mode with m-nitrobenzyl alcohol as
a matrix. The progress of all reactions was monitored by thin-
layer chromatography (TLC) on silica gel 60 F254 (0.25 nm,
Merck). Column chromatography was performed on silica gel
60 (0.063–0.200 mm, Merck).
3,4-Bis(benzyloxy)-2,5-dimethylbenzaldehyde (9a). Magne-
sium chloride anhydrous (1.94 g, 20.4 mmol) and para-
formaldehyde (1.52 g) were added to a solution of 2,5-xylenol
(1.74 g, 14.3 mmol) in dry acetonitrile (9 mL), followed by the
dropwise addition of triethylamine (5.45 mL). Aer stirring at
ꢀ
100 C for 3 h, the mixture was cooled in ice and the solution
was diluted with diethyl ether, washed with 1 N HCl, dried over
sodium sulfate, ltered, and evaporated under reduced pres-
sure to afford compound 12. 30% of hydrogen peroxide (1.35
mL) and H2O (1 mL) were added to solution of 12 and 5 M of
sodium hydroxide (3.24 mL) in THF (5.45 mL), and the mixture
was stirred at rt for 15 min, the mixture was diluted with diethyl
ether, washed with 2 N HCl, dried over sodium sulfate, ltered,
and evaporated under reduced pressure to afford 11. Alumi-
Conclusion
In this study, we designed and synthesised quercetin analogues num(III) chloride (3.82 g, 28.6 mmol) was slowly added to
to enhance radical-scavenging activity of quercetin. The radical- a solution of 11 and triethyl orthoformate (2.3 mL, 13.86 mmol)
scavenging activity of quercetin, which scavenges free radicals in dry toluene (25 mL), and the mixture was stirred at 60 ꢀC for
via the electron-transfer process, was enhanced by the intro- 3 h. 3 N hydrochloric acid was added, and the reaction mixture
duction of an electron-donating methyl group into the catechol was further stirred at rt for 1 h. Ethyl acetate was then added,
moiety in the quercetin molecule. Although a single methyl the reaction mixture was ltered, and ltrate was evaporated
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under reduced pressure. The resulting residue was dissolved in mL, 9.61 mmol) in dry DMF (10 mL) and dry acetone (4 mL),
ethyl acetate, washed with brine, dried over sodium sulfate K2CO3 (3.70 g, 26.2 mmol) was added, and stirring for 4 h at rt.
ltered, and evaporated under reduced pressure. Since NMR The ltrate was diluted with diethyl ether, washed with 1 N of
and MS analyses of the residue showed the formation of 13, the HCl, dried over Na2SO4, ltered and the solvent was evaporated.
crude material was subjected to the next reaction without The resultant solid was puried by column chromatography on
purication. Benzyl bromide (3.55 mL, 29.84 mmol) was added silica gel (7 : 1 n-hexane–ethyl acetate) to give 338 mg (18%) of
dropwise to a solution of crude 13, potassium carbonate (6.1 g, 25 as white solid; mp 51–52 ꢀC; 1H-NMR (CDCl3) d 2.30 (s, 3H),
44.14) in dry DMF (15 mL), and the mixture was stirred at rt for 4.85 (s, 2H), 5.55 (s, 1H), 6.69 (dd, J ¼ 1.2, 8.0 Hz, 1H), 6.76 (dd, J
13 h. The solution was diluted with ethyl acetate, washed with ¼ 1.2, 8.0 Hz, 1H), 6.89 (t, J ¼ 8.0 Hz, 1H), 7.30–7.41 (m, 5H), 13C-
brine, and dried over sodium sulfate. Aer removal of the NMR (CDCl3) d 15.4, 71.1, 109.7, 119.1, 123.5, 124.2, 127.7,
solvent under reduced pressure, the residue was puried by 128.3, 128.7, 136.5, 144.0, 145.4; HR-MS (ESI) calcd for C14H14O2
column chromatography on silica gel (10 : 1 n-hexane–ethyl- [M]+: 214.0994, found 214.0978.
acetate) to give 1.61 g (total yield from 2,5-xylenol: 33%) of
3-(Benzyloxy)-4-hydroxy-5-methylbenzaldehyde (26).43,44 To
compound 9a as yellow liquid; 1H-NMR (CDCl3)29 d 2.23 (s, 3H), a solution of compound 25 (1.07 g, 5.00 mmol) in acetic acid (33
2.53 (s, 3H), 4.98 (s, 2H), 5.10 (s, 2H), 7.33–7.44 (m, 11H), 10.15 mL), hexamethylenetetramine (1.76 g, 12.51 mmol) was added.
(s, 1H); 13C-NMR (CDCl3) d 11.2, 16.0, 74.6, 74.9, 128.1, 128.3, The resulting solution was stirred at 100 ꢀC for 4 days under Ar.
128.3, 128.4, 128.4, 130.0, 130.4, 130.4, 136.8, 150.4, 155.3, The reaction mixture was added saturated aqueous solution of
191.7; HR-MS (ESI) calcd for C23H23O3 [M + H]+: 347.1687, found NaHCO3 and extracted with CH2Cl2. The organic phase was
347.1647.
dried over Na2SO4, ltered and the solvent was evaporated. The
1
13: H-NMR (acetone-d6) d 2.24 (s, 3H), 2.53 (s, 3H), 5.00 (s, residue was puried by column chromatography on silica gel
2H), 5.11 (s, 2H), 7.34–7.44 (m, 11H), 10.15 (s, 1H); [M ꢁ H]ꢁ (7 : 1 n-hexane–ethyl acetate) to give 676.4 mg (56%) of 26 as
165.
white solid; mp 113–114 ꢀC; 1H-NMR (acetone-d6) d 2.28 (s, 3H),
(((3-Methyl-1,2-phenylene)bis(oxy))bis(methylene))dibenzene 5.25 (s, 2H), 7.36–7.51 (m, 7H), 8.69 (brs, 1H), 9.77 (s, 1H) 13C-
(24). To a solution of 3-methylcatechol (51.9 mg, 0.40 mmol) NMR (CDCl3) d 15.4, 71.1, 109.9, 125.2, 127.9, 128.6, 128.6,
and benzyl bromide (142 mL, 1.19 mmol) in dry DMF (540 mL), 129.0, 129.3, 137.2, 147.0, 151.2, 190.8; HR-MS (ESI) calcd for
K2CO3 (169 mg, 1.22 mmol) was added, and stirring overnight at
C
15H15O3 [M + H]+: 243.1021, found 243.1071.
rt. The ltrate was diluted with ethyl acetate, washed with brine,
3,4-Bis(benzyloxy)-5-methylbenzaldehyde (9c). To a solution
dried over Na2SO4, ltered and the solvent was evaporated. The of compound 26 (654.8 mg, 2.70 mmol) and benzyl bromide
resultant solid was puried by column chromatography on (386 mL, 3.24 mmol) in dry DMF (2 mL), K2CO3 (451.9 mg, 3.24
silica gel (3 : 2 : 0 to 4 : 3 : 1 n-hexane–CH2Cl2–ethyl acetate) to mmol) was added, and stirring for 13 h at rt. The ltrate was
1
ꢀ
give 118 mg (97%) of 24 as white solid; mp 49–50 C; H-NMR diluted with CH2Cl2, washed with water, dried over Na2SO4,
(CDCl3) d 2.24 (s, 3H), 5.00 (s, 2H), 5.11 (s, 2H), 6.79 (d, J ¼ ltered and the solvent was evaporated. The resultant solid was
8.0 Hz, 1H), 6.84 (d, J ¼ 8.0 Hz, 1H), 6.93 (t, J ¼ 8.0 Hz, 1H) 7.27 puried by column chromatography on silica gel (10 : 1 n-
(m, 10H); 13C-NMR (CDCl3) d 16.2, 70.8, 74.4, 112.0, 123.3, hexane–ethyl acetate) to give 841 mg (94%) of 9c as white solid;
1
123.7, 127.4, 127.8, 127.9, 128.1, 128.3, 128.3, 128.5, 132.6, mp 62–64 C; H-NMR (CD3OD)46,47 d 2.24 (s, 3H), 5.14 (s, 2H),
ꢀ
137.2, 137.9, 146.7, 151.9; HR-MS (ESI) calcd for C21H21O2 [M + 5.27 (s, 2H), 7.29–7.44 (m, 9H), 7.51 (d, J ¼ 2.0 Hz, 1H), 7.57–7.58
H]+: 305.1542, found 305.1520.
(m, 2H), 9.87 (s, 1H); 13C-NMR (CD3OD) d 16.4, 71.3, 74.9, 111.6,
3,4-Bis(benzyloxy)-2-methylbenzaldehyde (9b). The mixture 127.1, 128.7, 128.8, 128.8, 129.1, 129.3, 129.3, 133.4, 133.7,
of N-methylformanilide (10 mL, 171 mmol) and phosphoryl 137.8, 138.5, 152.4, 153.2, 191.7; HR-MS (FAB+) calcd for
chloride (4.50 mL, 48.3 mmol) was stirred for 30 min at 0 ꢀC to rt
C
22H21O3 [M + H]+: 333.1491, found 333.1507.
under Ar. Aer complex was deposited, o-dichlorobenzene (2.64
1-(2,4,6-Tris(methoxymethoxy)phenyl)ethan-1-one (19). The
mL) and benzylated 3-methyl catechol 24 were added, and then compound 19 was prepared in analogy to a procedure by Yang
stirred at 70 ꢀC for 5.25 h. Aer sodium acetate solution was et al.,40 Pandurangan et al.39 and Jiang et al.38 A solution of
added to stop the reaction, o-dichlorobenzene was evaporated. 20,40,60-trihydroxyacetophenone monohydrate (4.00 g, 21.8
The reaction mixture was diluted with ethyl acetate, washed mmol) in dry DMF (10 mL) was added dropwise to a suspension
with 0.5 N of HCl, dried over Na2SO4, ltered and the solvent of sodium hydride (5.23 g, 109 mmol) in CH2Cl2 (45 mL) at 0 ꢀC.
was evaporated. The reaction mixture was puried by column Chloromethyl methyl ether (8.20 mL, 109 mmol) was added
chromatography on silica gel (5 : 1 n-hexane–ethyl acetate) to dropwise to a reaction mixture and then stirred for overnight at
1
ꢀ
give 2.43 g (44%) of 9b as white solid; mp 92–94 C; H-NMR rt. The reaction mixture was quenched by adding water and
(CDCl3) d 2.55 (s, 3H), 4.96 (s, 2H), 5.21 (s, 2H), 6.98 (d, J ¼ extracted with CH2Cl2. The organic solution was washed with 1
8.5 Hz, 1H), 7.31–7.46 (m, 10H), 7.58 (d, J ¼ 8.5 Hz, 1H), 10.10 (s, N of HCl, dried over Na2SO4, ltered and the solvent was
1H); 13C-NMR (CDCl3) d 11.5, 70.6, 74.7, 110.5, 127.5, 128.1, evaporated. The residue was puried by column chromatog-
128.3, 128.4, 128.5, 128.7, 129.8, 135.5, 136.0, 137.2, 146.4, raphy on silica gel (1 : 3 ethyl acetate–n-hexane) to give 2.81 g
156.5, 191.5; HR-MS (ESI) calcd for C22H21O3 [M + H]+: (43%) of 19 as white solid; mp 37–38 ꢀC; 1H-NMR (CDCl3) d 2.50
333.14907, found 333.14835.
(s, 3H), 3.46 (s, 9H), 5.14 (s, 6H), 6.51 (s, 2H); 13C-NMR (CDCl3)
2-(Benzyloxy)-6-methylphenol (25).43,44 To a solution of 3- d 32.5, 56.2, 56.3, 94.4, 94.7, 96.9, 116.8, 155.1, 159.4, 201.4; HR-
methylcatechol (1.08 g, 8.73 mmol) and benzyl bromide (1.14 MS (ESI) calcd for C14H21O7 [M + H]+: 301.1287, found 301.1267.
17974 | RSC Adv., 2017, 7, 17968–17979
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(E)-3-(3,4-Bis(benzyloxy)-2,5-dimethylphenyl)-1-(2,4,6-tris
RSC Advances
137.4, 145.3, 148.8, 152.0, 155.7, 159.5, 194.3; HR-MS (FAB+)
calcd for C36H39O9 [M + H]+: 615.2638, found 615.2594.
(methoxymethoxy)phenyl)prop-2-en-1-one (20a). To a stirred
solution of 19 (723 mg, 2.39 mmol) and 9a (981 mg, 2.83 mmol)
in dry DMF (1 mL) at rt under Ar, ethanol (6 mL) and 40%
aqueous potassium hydroxide (2.2 mL) were added. The
resulting solution was stirred at rt for 18.5 h, the solution was
diluted with ethyl acetate, washed with brain. The organic
phase was dried over Na2SO4, ltered and the solvent was
evaporated. The residue was puried by column chromatog-
raphy on silica gel (3 : 1 to 2 : 1 n-hexane–ethyl acetate) to give
1.26 g (85%) of chalcone structure 20a as yellow liquid; 1H-NMR
(CDCl3) d 2.21 (s, 3H), 2.21 (s, 3H), 3.41 (s, 6H), 3.46 (s, 3H), 4.96
(s, 2H), 5.03 (s, 2H), 5.12 (s, 4H), 5.18 (s, 2H), 6.57 (s, 2H), 6.83
(d, J ¼ 16.0 Hz, 1H), 7.25 (s, 1H), 7.32–7.41 (m, 10H), 7.63 (d, J ¼
16.0 Hz, 1H); 13C-NMR (CDCl3) d 12.1, 16.2, 56.2, 56.3, 56.3,
74.8, 74.9, 94.5, 94.7, 94.7, 97.0, 97.2, 115.1, 124.5, 128.1, 128.4,
128.4, 128.4, 128.5, 129.2, 130.0, 130.2, 130.8, 137.2, 137.3,
142.3, 150.4, 152.2, 155.8, 159.4, 159.6, 194.0; HR-MS (ESI) calcd
for C37H41O9 [M + H]+: 629.2751, found 629.2786.
2-(3,4-Bis(benzyloxy)-2,5-dimethylphenyl)-3,5,7-trihydroxy-
chroman-4-one (22a). Methanol (5 mL) and 5.4% aqueous
sodium hydroxide (5 mL) were added to a solution of 20a
(324 mg, 516 mmol) in 1,4-dioxiane (5 mL), and then added 30%
hydrogen peroxide solution (5 mL). The resulting mixture was
stirred at rt for 4 h, the solution was diluted with ethyl acetate,
washed with water. The organic phase was dried over Na2SO4,
ltered and the solvent was evaporated to afford epoxide
intermediate 21a, which was subjected to the next step without
purication. 12 N HCl (1 mL) was slowly added to a solution of
crude 21a in methanol (22 mL), and the mixture was reuxed for
1.0 h. The reaction mixture was evaporated, and then the crude
material was diluted with ethyl acetate, washed with water. The
organic phase was dried over Na2SO4, ltered and the solvent
was evaporated. The residue was puried by column chroma-
tography on silica gel (4 : 1 n-hexane–ethyl acetate) to give
105 mg (total yield from 20a: 40%) of 22a as white solid; mp
207–210 ꢀC; 1H-NMR (acetone-d6) d 2.22 (s, 3H), 2.27 (s, 3H),
4.36 (m, 1H), 4.89 (d, J ¼ 3.2 Hz, 1H), 4.96 (s, 2H), 5.00 (s, 2H),
5.43 (m, 1H), 5.99 (s, 2H), 7.16 (s, 1H), 7.32–7.49 (m, 10H); 13C-
NMR (acetone-d6) d 11.7, 16.1, 74.8, 75.0, 78.4, 81.6, 95.8, 103.4,
126.9, 128.3, 128.7, 128.8, 129.2, 129.4, 133.2, 128.6, 138.7,
150.3, 150.3, 164.6, 203.1; HR-MS (FAB+) calcd for C31H29O7 [M +
H]+: 513.1893, found 513.1913.
(E)-3-(3,4-Bis(benzyloxy)-2-methylphenyl)-1-(2,4,6-tris(me-
thoxymethoxy)phenyl)prop-2-en-1-one (20b). To a stirred solu-
tion of 19 (893 mg, 2.93 mmol) and 9b (1.17 g, 3.52 mmol) in dry
DMF (1.3 mL) at rt under Ar, ethanol (7.4 mL) and 40% aqueous
potassium hydroxide (2.7 mL) were added. The resulting solu-
tion was stirred at rt for 46 h, the solution was diluted with ethyl
acetate, washed with brain. The organic phase was dried over
Na2SO4, ltered and the solvent was evaporated. The residue
was puried by column chromatography on silica gel (3 : 1 to
1 : 1 n-hexane–ethyl acetate) to give 1.67 g (91%) of chalcone
21a: 1H-NMR (acetone-d6) d 2.17 (s, 3H), 2.26 (S, 3H), 3.40 (s,
6H), 3.43 (s, 3H), 3.72 (d, J ¼ 1.5 Hz, 1H), 4.05 (d, J ¼ 1.5 Hz, 1H),
4.99 (s, 2H), 4.99 (s, 2H), 5.16 (s, 2H), 5.20 (s, 2H), 6.57 (s, 2H),
6.81 (s, 1H), 7.32–7.46 (m, 10H); 13C-NMR (acetone-d6) d 11.6,
16.2, 56.3, 56.5, 57.4, 63.9, 75.2, 75.4, 95.1, 95.6, 97.5, 113.5,
122.3, 128.7, 128.8, 129.1, 129.2, 129.5, 130.8, 131.4, 138.5,
138.7, 150.9, 151.2, 157.3, 161.3, 197.4; HR-MS (ESI) calcd for
1
structure 20b as yellow liquid; H-NMR (CDCl3) d 2.21 (s, 3H),
3.39 (s, 6H), 3.49 (s, 3H), 4.95 (s, 2H), 5.11 (s, 4H), 5.16 (s, 2H),
5.17 (s, 2H), 6.56 (s, 2H), 6.82 (d, J ¼ 16.0 Hz, 1H), 6.88 (d, J ¼
9.0 Hz, 1H), 7.30–7.46 (m, 11H), 7.63 (d, J ¼ 16.0 Hz, 1H); 13C-
NMR (CDCl3) d 12.2, 56.3, 70.6, 74.6, 94.5, 94.6, 97.1, 111.4,
115.1, 123.0, 127.4, 127.5, 128.0, 128.1, 128.3, 128.4, 128.6,
133.0, 136.5, 137.4, 142.5, 146.4, 153.4, 155.8, 159.5, 194.1; HR-
MS (FAB+) calcd for C36H39O9 [M + H]+: 615.2581, found
615.2594.
(E)-3-(3,4-Bis(benzyloxy)-5-methylphenyl)-1-(2,4,6-tris(me-
thoxymethoxy)phenyl)prop-2-en-1-one (20c). To a stirred solu-
tion of 19 (477 mg, 1.55 mmol) and 9c (620 mg, 1.86 mmol) in
dry DMF (672 mL) at rt under Ar, ethanol (3.9 mL) and 40%
aqueous potassium hydroxide (1.4 mL) were added. The
resulting solution was stirred at rt for 18.5 h, the solution was
diluted with ethyl acetate, washed with brain. The organic
phase was dried over Na2SO4, ltered and the solvent was
evaporated. The residue was puried by column chromatog-
raphy on silica gel (4 : 1 to 2 : 1 n-hexane–ethyl acetate) to give
838 mg (86%) of chalcone structure 20c as yellow liquid; 1H-
NMR (CDCl3) d 2.20 (s, 3H), 3.38 (s, 6H), 3.51 (s, 3H), 5.04 (s,
2H), 5.11 (s, 4H), 5.13 (s, 2H), 5.18 (s, 2H), 6.57 (s, 2H), 6.85 (d, J
¼ 16.0 Hz, 1H), 6.96 (d, J ¼ 1.0 Hz, 1H), 7.04 (d, J ¼ 2.0 Hz, 1H),
7.25 (d, J ¼ 17.0 Hz, 1H), 7.30–7.46 (m, 10H); 13C-NMR (CDCl3)
d 16.3, 56.3, 70.8, 76.7, 94.5, 97.1, 111.0, 114.8, 127.4, 128.0,
128.0, 128.0, 128.2, 128.3, 128.4, 128.6, 130.3, 132.9, 136.6,
C
37H41O10 [M + H]+: 645.2700, found 645.2699.
2-(3,4-Bis(benzyloxy)-2-methylphenyl)-3,5,7-trihydroxychro-
man-4-one (22b). Methanol (2.5 mL) and 5.4% aqueous sodium
hydroxide (2.5 mL) were added to a solution of 20b (290 mg, 472
mmol) in 1,4-dioxiane (7.5 mL), and then added 30% hydrogen
peroxide solution (2.5 mL). The resulting mixture was stirred at
rt for 5 h, the solution was diluted with ethyl acetate, washed
with brain. The organic phase was dried over Na2SO4, ltered
and the solvent was evaporated to afford epoxide intermediate
21b, which was subjected to the next step without purication.
12 N HCl (1 mL) was slowly added to a solution of crude 21b in
1,4-dioxiane (5 mL) and methanol (17 mL), and the mixture was
stirred at 55 ꢀC for 1.0 h. The reaction mixture was evaporated,
and then the crude material was taken into ethyl acetate,
washed with water. The organic phase was dried over Na2SO4,
ltered and the solvent was evaporated. The residue was puri-
ed by column chromatography on silica gel (2 : 1 n-hexane–
ethyl acetate) to give 230 mg (total yield from 20b: 32%) of 22b
1
ꢀ
as white solid; mp 164–166 C; H-NMR (acetone-d6) d 2.31 (s,
3H), 4.68 (d, J ¼ 12.0 Hz, 1H), 4.97 (s, 2H), 5.21 (s, 2H), 5.40 (d, J
¼ 12.0 Hz, 1H), 5.89 (d, 2.0 Hz, 1H), 5.94 (d, J ¼ 2.5 Hz, 1H), 7.08
(d, J ¼ 9.0 Hz, 1H), 7.26–7.53 (m, 11H); 13C-NMR (acetone-d6)
d 12.2, 71.1, 73.2, 75.1, 80.7, 95.9, 97.0, 101.5, 112.1, 124.1,
128.5, 128.6, 128.7, 129.1, 129.2, 129.3, 129.9, 133.2, 138.3,
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139.0, 147.0, 153.0, 164.3, 164.8, 167.9, 198.3; HR-MS (FAB+) 151.5, 158.9, 162.8, 165.6, 177.8; HR-MS (FAB+) calcd for
calcd for C30H27O7 [M + H]+: 499.1752, found 499.1757.
C
17H15O7 [M + H]+: 331.0817, found 331.0818.
2-(3,4-Dihydroxy-2-methylphenyl)-3,5,7-trihydroxy-4H-
21b: 1H-NMR (CDCl3) d 2.13 (s, 3H), 3.41 (s, 6H), 3.48 (s, 3H),
5.08–5.17 (m, 11H), 5.45 (d, J ¼ 1.7 Hz, 1H), 6.56 (s, 2H), 6.89 (d, chromen-4-one (2). A solution of 22b (64 mg, 129 mmol) in dry
J ¼ 9.2 Hz, 1H), 7.30–7.44 (m, 10H), 7.59 (d, J ¼ 9.2 Hz, 1H); 13C- THF (12 mL) was hydrogenated at rt in the presence of 20%
NMR (CDCl3) d 11.3, 56.3, 56.5, 59.4, 70.6, 74.6, 79.3, 94.3, 94.9, palladium hydroxide on carbon (35 mg). Aer stirring for
96.9, 110.6, 111.4, 124.7, 127.4, 127.9, 128.3, 128.5, 129.7, 130.6, approximately 2 h until TLC showed that the reaction was
136.8, 137.6, 145.8, 151.7, 156.9, 161.1, 199.7; HR-MS (FAB+) complete, the catalyst was ltered, and the solvent was evapo-
calcd for C36H38O10 [M + H]+: 630.2472, found 630.2465.
rated to afford 23b, which was subjected to the next step without
2-(3,4-Bis(benzyloxy)-5-methylphenyl)-3,5,7-trihydroxychro- purication. Dimethyl taxifolin 23b in ethanol (1 mL) was added
man-4-one (22c). Methanol (1.5 mL) and 5.4% aqueous sodium to 20% potassium metabisulphite (2.1 mL), and then stirred at
ꢀ
hydroxide (1.5 mL) were added to a solution of 20c (165 mg, 269 100 C for 5 h. The reaction mixture wad taken into ice water,
mmol) in 1,4-dioxiane (4.3 mL), and then added 30% hydrogen the precipitate was ltered to give 33.8 mg (total yield from 22b:
peroxide solution (1.5 mL). The resulting mixture was stirred at 82%) of 2 as yellow solid; mp > 290 ꢀC; 1H-NMR (CD3OD) d 2.16
rt for 1 h, the solution was diluted with ethyl acetate, washed (s, 3H), 6.18 (d, J ¼ 1.6 Hz, 1H), 6.28 (d, J ¼ 1.2 Hz, 1H), 7.73 (d, J
with aqueous sodium thiosulfate and brain. The organic phase ¼ 6.8 Hz, 1H), 6.87 (d, J ¼ 6.8 Hz, 1H); 13C-NMR (CD3OD) d 13.5,
was dried over Na2SO4, ltered and the solvent was evaporated 94.5, 99.3, 105.1, 113.1, 122.4, 123.8, 126.0, 137.9, 144.8, 147.8,
to afford epoxide intermediate 21c, which was subjected to the 151.4, 158.9, 162.8, 165.6, 177.8; HR-MS (FAB+) calcd for
next step without purication. 12 N HCl (0.5 mL) was slowly
added to a solution of crude 21c in 1,4-dioxiane (3 mL) and
C
16H13O7 [M + H]+: 317.0654, found 317.0661.
2-(3,4-Dihydroxy-5-methylphenyl)-3,5,7-trihydroxy-4H-
methanol (10 mL), and the mixture was stirred at 55 ꢀC for 1.0 h. chromen-4-one (3). A solution of 22c (61 mg, 122 mmol) in dry
The reaction mixture was evaporated, and then the crude THF (3 mL) was hydrogenated at rt in the presence of 20%
material was taken into ethyl acetate, washed with water. The palladium hydroxide on carbon (10 mg). Aer stirring for
organic phase was dried over Na2SO4, ltered and the solvent approximately 3 h until TLC showed that the reaction was
was evaporated. The residue was puried by column chroma- complete, the catalyst was ltered, and the solvent was evapo-
tography on silica gel (4 : 1 to 2 : 1 n-hexane–ethyl acetate) to rated to afford 23c, which was subjected to the next step without
give 33 mg (total yield from 20c: 25%) of 22c as white solid; mp purication. Dimethyl taxifolin 23c in ethanol (1 mL) was added
120–121 ꢀC; 1H-NMR (acetone-d6) d 2.24 (s, 3H), 4.70 (d, 12.0 Hz, to 20% potassium metabisulphite (2 mL), and then stirred at
ꢀ
1H), 4.77 (brs, 1H), 5.04 (s, 2H), 5.09 (d, J ¼ 11.0 Hz, 1H), 5.20 (s, 100 C for 5 h. The reaction mixture wad taken into ice water,
2H), 5.98 (d, J ¼ 1.5 Hz, 1H), 6.01 (d, J ¼ 2.5 Hz, 1H), 7.03 (d, J ¼ the precipitate was ltered to give 33.2 mg (total yield from 22c:
1.5 Hz, 1H), 7.28–7.56 (m, 11H), 9.71 (brs, 1H), 11.71 (s, 1H); 13C- 86%) of 3 as yellow solid; mp > 290 ꢀC; 1H-NMR (CD3OD) d 2.25
NMR (acetone-d6) d 17.3, 72.1, 73.8, 75.5, 85.2, 96.8, 97.9, 102.2, (s, 3H), 6.16 (d, J ¼ 2.0 Hz, 1H), 6.37 (d, J ¼ 2.0 Hz, 1H), 7.50 (d, J
113.3, 124.5, 129.3, 129.4, 129.8, 129.9, 130.0, 133.3, 134.4, ¼ 1.5 Hz, 1H), 7.60 (d, J ¼ 2.0 Hz, 1H); 13C-NMR (CD3OD) d 16.3,
138.9, 139.8, 148.5, 153.4, 164.8, 165.7, 168.5, 196.7; HR-MS 94.4, 99.2, 104.5, 113.5, 122.9, 123.1, 125.7, 137.1, 145.6, 147.1,
(FAB+) calcd for C30H27O7 [M + H]+: 499.1757, found 499.1756. 148.2, 158.2, 162.5, 165.5, 177.2; HR-MS (FAB+) calcd for
21c: 1H-NMR (CDCl3) d 2.20 (s, 3H), 3.36 (s, 6H), 3.46 (s, 3H),
3.90 (s, 1H), 3.90 (s, 1H), 4.99 (s, 2H), 5.07–5.11 (m, 4H), 5.14 (s,
C
16H13O7 [M + H]+: 317.0694, found 317.0661.
1-(2,4-Bis(benzyloxy)-6-hydroxyphenyl)ethan-1-one
(10a).
2H), 5.17 (s, 2H), 6.53 (s, 2H), 6.78 (s, 1H), 6.84 (d, J ¼ 1.8 Hz, The benzylation compound 10 was prepared in analogy to
1H), 7.29–7.47 (m, 10H); 13C-NMR (CDCl3) d 15.6, 55.6, 55.6, a procedure by Yamasaki et al.48 Benzyl bromide (11.80 mL,
58.9, 63.7, 70.1, 73.8, 93.7, 94.3, 96.3, 108.2, 112.0, 120.2, 126.9, 99.33 mmol) was added dropwise to a solution of 2,4,6-trihy-
127.4, 127.7, 127.9, 128.0, 131.0, 132.1, 136.3, 137.1, 146.3, droxyacetophenone monohydrate (7.396 g, 39.73 mmol) and
151.5, 156.5, 160.3, 195.4; HR-MS (FAB+) calcd for C36H38O10 [M potassium carbonate (13.96 g, 99.33 mmol) in dry DMF (20 mL),
+ H]+: 630.2476, found 630.2465.
and mixture was stirred for overnight at rt. The solution was
2-(3,4-Dihydroxy-2,5-dimethylphenyl)-3,5,7-trihydroxy-4H- diluted with CH2Cl2, washed with brain, and dried over Na2SO4.
chromen-4-one (1). A solution of 22a (105 mg, 205 mmol) in dry Aer removal of the solvent under reduced pressure, the residue
THF (40 mL) was hydrogenated at rt in the presence of 20% was puried by column chromatography on silica gel (20 : 1 to
palladium hydroxide on carbon (40 mg). Aer stirring for 10 : 1 n-hexane–ethyl acetate) to give 4.516 g (33%) of 10a as
approximately 5.5 h, the catalyst was ltered, and the solvent white solid; mp 110–111 ꢀC; 1H-NMR (CDCl3) d 2.54 (s, 3H), 5.04
was evaporated to afford 23a, which was subjected to the next (s, 2H), 5.05 (s, 2H), 6.09 (d, J ¼ 2.4 Hz, 1H), 6.15 (d, J ¼ 2.4 Hz,
step without purication. Dimethyl taxifolin 23a in ethanol (1.5 1H), 7.31–7.40 (m, 10H), 14.02 (s 1H); 13C-NMR (CD3Cl) d 32.9,
mL) was added to 20% potassium metabisulphite (3 mL), and 69.9, 70.7, 92.0, 94.4, 106.0, 127.3, 127.6, 128.0, 128.1, 128.3,
ꢀ
then stirred at 100 C for 7 h. The reaction mixture was taken 128.4, 135.2, 135.5, 161.6, 164.7, 167.2, 202.8; HR-MS (ESI) calcd
into ice water, the precipitate was ltered to give 21 mg (total for C22H21O4 [M + H]+: 349.1440, found 349.1440.
yield from 22a: 31%) of 1 as yellow solid; mp > 290 ꢀC; 1H-NMR
(E)-3-(3,4-Bis(benzyloxy)-2,5-dimethylphenyl)-1-(2,4-bis
(CD3OD) d 2.14 (s, 3H), 2.22 (s, 3H), 6.13 (d, J ¼ 2.3 Hz, 1H), 6.21 (benzyloxy)-6-hydroxyphenyl)prop-2-en-1-one (14). To a mixture
(d, J ¼ 1.8 Hz, 1H), 6.80 (s, 1H); 13C-NMR (CD3OD) d 13.6, 16.0, of 9a (1.68 g, 4.74 mmol) and 10a (1.64 g, 4.74 mmol) in dry
94.5, 99.3, 105.1, 123.1, 123.3, 123.9, 124.2, 137.8, 144.5, 146.5, dioxane (8.0 mL) at rt under Ar, ethanol (13.5 mL) and 40%
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aqueous potassium hydroxide (3.9 mL) were added. The 1H), 6.52 (d, J ¼ 2.5 Hz, 1H), 6.57 (d, J ¼ 2.5 Hz, 1H), 7.13 (s, 1H),
resulting solution was stirred at rt for overnight, the solution 7.37–7.64 (m, 20H); 13C-NMR (CD3Cl) d 13.6, 16.1, 70.5, 70.7,
was diluted with ethyl acetate, washed with 1 N HCl and brain. 74.9, 74.9, 94.2, 98.3, 109.7, 113.5, 126.6, 126.8, 127.6, 128.2,
The organic phase was dried over Na2SO4, ltered and the 128.4, 128.4, 128.4, 128.5, 128.6, 128.8, 128.8, 129.6, 130.6,
solvent was evaporated. The residue was puried by column 135.6, 136.4, 137.2, 137.3, 150.8, 152.3, 159.8, 160.0, 162.7,
chromatography on silica gel (3 : 1 to 2 : 1 n-hexane–CH2Cl2) to 162.9, 177.2; HR-MS (ESI) calcd for C45H38O6 [M + H]+: 675.2741,
give 2.70 g (84%) of 14 as yellow liquid; 1H-NMR (CDCl3) d 1.98 found 675.2710.
(s, 3H), 2.31 (s, 3H), 4.96 (s, 2H), 5.04 (s, 2H), 5.09 (s, 2H), 5.10 (s,
2H), 6.17 (d, J ¼ 2.5 Hz, 1H), 6.23 (d, J ¼ 2.5 Hz, 1H), 6.79 (s, 1H),
Antioxidant activity measurements
7.26–7.43 (m, 20H), 7.77 (d, J ¼ 15.5 Hz, 1H), 8.03 (d, J ¼ 15.5 Hz,
1H); 13C-NMR (CD3Cl) d 12.1, 16.2, 70.3, 71.3, 74.8, 74.9, 92.8,
Since phenoxyl radical generated in the reaction of quercetin
95.0, 106.7, 124.4, 127.5, 127.6, 127.7, 127.7, 128.0, 128.1, 128.4,
128.5, 128.5, 128.6, 128.7, 129.9, 130.4, 131.2, 135.6, 135.9,
137.3, 137.5, 140.2, 150.2, 152.0, 161.6, 165.1, 168.4, 192.8; HR-
MS (ESI) calcd for C45H40O6 [M + Na]+: 699.2717, found
699.2686.
analogues with oxyl radicals readily reacts with molecular
oxygen, the reactions were carried out under strictly deaerated
conditions. A continuous ow of argon gas was bubbled
through an acetonitrile solution (3.0 mL) containing galvi-
noxyl radical (GOc, 2.0 ꢂ 10ꢁ6 M) in a square quartz cuvette
with a glass tube neck for 7 min. Air was prevented from
leaking into the neck of the cuvette with a rubber septum.
Typically, an aliquot of quercetin analogues (quercetins were
maintained at more than 10-fold excess to the GOc concen-
tration), which were dissolved in deaerated acetonitrile, were
added to the cuvette with a microsyringe to initiate the reac-
tion of quercetin analogues with GOc. UV-vis spectral changes
associated with the reaction were monitored using an Agilent
8453 photodiode array spectrometer. The rate of the GOc
scavenging reaction of quercetin analogues was determined
by monitoring the absorbance change at 428 nm due to GOc (3
¼ 1.32 ꢂ 105 Mꢁ1 cmꢁ1) using a stopped ow technique on
a UNISOKU RSP-1000-02NM spectrophotometer. The pseudo
rst-order rate constants (kobs) were determined by least-
squares curve t using an Apple MacBook Pro personal
computer. The rst-order plots of ln(A ꢁ AN) vs. time (A and
AN denote the absorbance at the reaction time and the nal
absorbance, respectively) were linear until three or more half-
lives with a correlation coefficient r > 0.999.
(Z)-4,6-Bis(benzyloxy)-2-(3,4-bis(benzyloxy)-2,5-dimethyl
benzylidene)benzofuran-3(2H)-one (16). Ethanol (100 mL) and
5.4% aqueous sodium hydroxide (35 mL) were added to a solu-
tion of 14 (1.88 g, 2.78 mmol) in 1,4-dioxiane (40 mL), and then
added 30% hydrogen peroxide solution (3.8 mL) at 0 ꢀC. The
resulting mixture was stirred at rt for overnight, the solution
was diluted with CH2Cl2, washed with 1 N HCl. The organic
phase was dried over Na2SO4, ltered and the solvent was
evaporated. The residue was puried by column chromatog-
raphy on silica gel (6 : 4 : 1 n-hexane–CH2Cl2–MeOH) to give
1.02 g (53.2%) of 16 as a yellow solid; mp 152–155 ꢀC; 1H-NMR
(CDCl3) d 2.29 (s, 3H), 2.36 (s, 3H), 4.98 (s, 2H), 5.06 (s, 2H), 5.11
(s, 2H), 5.28 (s, 2H), 6.25 (d, J ¼ 2.0 Hz, 1H), 6.47 (d, J ¼ 2.0 Hz,
1H), 6.94 (s, 1H), 7.33–7.49 (m, 20H), 7.79 (s, 1H); 13C-NMR
(CD3Cl) d 12.5, 16.4, 70.6, 70.8, 74.8, 75.0, 90.6, 96.4, 106.0,
107.9, 126.7, 127.4, 127.6, 127.9, 128.1, 128.1, 128.4, 128.5,
128.5, 128.6, 128.8, 130.1, 131.8, 135.5, 136.0, 137.3, 137.5,
147.6, 150.4, 151.6, 158.4, 167.6, 168.9, 180.5; HR-MS (ESI) calcd
for C45H38O6 [M + Na]+: 697.2561, found 697.2526.
2-(3,4-Dihydroxy-2,5-dimethylbenzyl)-4,6-dihydroxybenzofuran-
3(2H)-one (17). A solution of 16 (260.1 mg, 396 mmol) in dry THF
(16 mL) was hydrogenated at rt in the presence of 20% palladium
hydroxide on carbon (120 mg). Aer stirring for approximately 2 h,
the catalyst was ltered, and the solvent was evaporated to afford
17 as gray solid; 233–236 ꢀC; 1H-NMR (CD3OD) d 2.13 (s, 3H), 2.16
(s, 3H), 2.76 (dd, J ¼ 9.0, 15.0 Hz, 1H), 3.17 (dd, J ¼ 4.0, 15.5 Hz,
1H), 4.66 (dd, J ¼ 4.0, 9.0 Hz, 1H), 5.84 (d, J ¼ 1.5 Hz, 1H), 5.88 (d, J
¼ 1.5 Hz, 1H), 6.52 (s, 1H); 13C-NMR (CD3OD) d 12.7, 16.5, 36.2,
88.8, 91.8, 97.6, 104.4, 123.2, 123.4, 124.8, 128.1, 143.6, 145.0,
159.9, 171.0, 176.8, 199.7; HR-MS (ESI) calcd for C17H17O6 [M +
H]+: 317.1025, found 317.1012.
Theoretical calculations
Density functional theory (DFT) calculations were carried out on
an 8CPU workstation (PQS, Quantum Cube QS8-2400C-064).
The geometry optimisations were performed using the B3LYP/
6-31G(d) basis set for the radical with the unrestricted Har-
tree–Fock (UHF) formalism as implemented in the Gaussian 09
program Revision A. 02. The BDE values were determined by the
single point energy calculations at the B3LYP/6-31G(d) basis set
with the restricted open-shell Hartree–Fock (ROHF) formalism.
5,7-Bis(benzyloxy)-2-(3,4-bis(benzyloxy)-2,5-dimethylphenyl)-
4H-chromen-4-one (18). To a mixture of 14 (138.1 mg, 198.9
Acknowledgements
mmol) and iodine (13.0 mg, 51.2 mmol) in DMSO (2.7 mL) was
ꢀ
heated at 110 C for overnight. The solution was diluted with This work was partially supported by Grant-in-Aid (15K18901 to
ethyl acetate, washed with 1 N HCl and brain, and dried over K. I. and 26460056 to I. N.) from the Ministry of Education,
Na2SO4, ltered and the solvent was evaporated. The residue Culture, Sports, Science and Technology, Japan, and the Sasa-
was puried by column chromatography on silica gel (3 : 1 to kawa Scientic Research Grant from the Japan Science Society
2 : 1 n-hexane–ethyl acetate) to give 131.2 mg (82%) of 18 as (K. I.). We thank Ms Y. Odanaka and Ms S. Matsubayashi at the
brown solid; mp 55–57 ꢀC; 1H-NMR (CDCl3) d 2.28 (s, 3H), 2.31 Center for Instrumental Analysis of Showa University for assis-
(s, 3H), 5.04 (s, 2H), 5.07 (s, 2H), 5.09 (s, 2H), 5.24 (s, 2H), 6.28 (s, tance with NMR and MS measurements.
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