Hemisynthesis of all the O-monomethylated analogues of quercetin including the major metabolites, through selective protection of phenolic functions

Article abstract of DOI:10.1016/S0040-4020(02)01306-6

A new methodology for the hemisynthesis of all the five O-monomethylated analogues of quercetin (3′-O-methylquercetin (isorhamnetin), 4′-O-methylquercetin (tamarixetin), 3-O-methylquercetin, 5-O-methylquercetin (azaleatin) and 7-O-methylquercetin (rhamnetin)) through sequential protection of the different phenolic functions of quercetin is reported.

Full text of DOI:10.1016/S0040-4020(02)01306-6

Tetrahedron 58 (2002) 10001–10009
Hemisynthesis of all the O-monomethylated analogues of
quercetin including the major metabolites, through selective
protection of phenolic functions
a
b
a
,
Mohamed Bouktaib,a,b Stephane Lebrun, Aziz Atmani and Christian Rolando
*
´
a
´ ´ ˆ
Universite des Sciences et Technologies de Lille, Equipe Polyphenols, UMR CNRS 8009, Batiment C4,
59655 Villeneuve d’Ascq Cedex, France
´ ´ ´ `
Departement de Chimie, Faculte des Sciences D. Mehraz, Universite Sidi Mohamed Ben Abdellah, P.O. Box 1796, Fes-Atlas, Morocco
b
Received 3 July 2002; accepted 15 October 2002
Abstract—A new methodology for the hemisynthesis of all the five O-monomethylated analogues of quercetin (30-O-methylquercetin
(isorhamnetin), 40-O-methylquercetin (tamarixetin), 3-O-methylquercetin, 5-O-methylquercetin (azaleatin) and 7-O-methylquercetin
(rhamnetin)) through sequential protection of the different phenolic functions of quercetin is reported. q 2002 Published by Elsevier
Science Ltd.
1. Introduction
sulfation and glucuronidation.2 Plasma analysis of pig fed
with quercetin-rich diets show there is no querc0etin left but
only methylated metabolites, such as the 3 -O-methyl-
quercetin (isorhamnetin) and the 40-O-methylquercetin
(tamarixetin) along with the 30-dehydroxylated quercetin
(kaempferol), most of them being conjugated as glucuronide
or sulfate.13 The same metabolism was observed in rat14 and
in vivo cell culture15 with some variations in the relative
abundance of the methylation position. However, quercetin
metabolism in human is still controversial as the different
relative abundance depends of the diet habits and of the
quercetin content.16–19 These methylated metabolites are
presumably the active molecules as the glucuronide or
sulfate groups are readily deconjugated in tissues.20 There-
fore, we decided to develop a new general strategy leading
to quercetin metabolites in order to better identify them and
to provide enough materials for in vivo studies of
metabolites. We report here on the synthesis of the two
known methyl metabolites of quercetin, and on the synthesis
of the three others O-methylquercetin isomers. These
compounds will allow structure activity studies,21 will
help in the identification of unknown metabolites, and their
easily obtained labeled form will give access to isotopic
dilution dosage by LC-MS or LC-MS/MS.
Flavonoids, such as flavones and flavonols, are secondary
plant metabolites1,2 particularly found in the upper parts of
plants. As a consequence, they are present in a great variety
of food and especially in fruit and vegetables. Quercetin is
the main flavonoid occurring in food and is present at an
average level of 10 mg/kg. Higher concentrations can even
be found in some common vegetables like onions (300 mg/
kg). Nowadays, according to dietary habits, the average
daily intake3 of flavonoid has been assessed from 6 mg in
Finland to 70 mg in Japan, and more precisely, quercetin
amount represents 60–75% of this average intake. More-
over, quercetin is a very efficient antioxidant4 and appears to
be active in many diseases related to ageing like cancer,5
cardiovascular6 and neurodegenerative7 diseases, as widely
described in the literature (see Refs. 8,9 for recent reviews).
Furthermore, the quercetin skeleton is the main part of the
drug Flavopiridol, which is now under clinical trials.10,11
However in blood, quercetin is mainly found in conjugated
forms. The few existing comparative studies made by using
plasma samples show that the activities of the metabolites
are rather different from those of quercetin.12 Nevertheless,
most of the in vitro studies are performed on quercetin itself
and not on their metabolites as these latter are not readily
available from commercial sources. Non-degradative
metabolism of polyphenols involves three main modifi-
cations on the phenolic hydroxyl groups: methylation,
2. Results and discussion
2.1. Regiochemistry of quercetin alkylation
Keywords: quercetin; alkylation; metabolites.
*
Two pathways have already been developed for the
synthesis of these quercetin analogues.
Corresponding author. Tel.: þ33-320434977; fax: þ33-320336136;
e-mail: christian.rolando@univ-lille1.fr
0040–4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020(02)01306-6

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M. Bouktaib et al. / Tetrahedron 58 (2002) 10001–10009
The first one is based on total synthesis using either: (i)
condensation between an ortho-hydroxylated acetophenone
and an activated benzoic acid according to the Allan–
Robinson condensation or according to its variant, the
Baker–Venkataraman rearrangement;1 or (ii) an oxidative
cyclisation of chalcones according to the Algar–Flynn–
Oyamada reaction.22 For example, the coupling strategy
between an ortho-hydroxylated acetophenone and an
activated benzoic acid has recently been reported for the
synthesis of 3-O-methylquercetin,23 40-O-b-D-glucoside
quercetin24 and modified flavonols.25 Recently, a new
method combining both strategies has been introduced by
Brouillard et al.26
The second route is based on hemisynthesis starting from
quercetin and relies on direct alkylation of the parent
compound, which depends on the relative reactivity of the
different positions. Rao et al.27 have shown that this
methylation occurs 0gradually following a specific sequential
positions order: 4 .7.3.30.5. Previous studies have
revealed that the direct quercetin alkylation using a limited
amount of alkyl halide gave mixtures composed of ‘native’
quercetin and highly O-alkylated products. Therefore, in the
early sixties, Jurd28,29 used quercetin pentaacetate as
starting material. Acetyl groups, which are attached to the
flavone skeleton, are successively replac0ed by alkyl groups
with the preferential positions order 7.4 .3.5.30. There-
fore, this reaction presents an inversion of reactivity
compared to the direct alkylation one and the reaction
selectivity is slightly better. Farkas et al.30 have developed a
close method starting from quercetin pentabenzoate.
However, in our hands, this method gave compounds of
poor chemical purity.
Figure 1. LC-UV (reverse phase C18 column, 280 nm) trace of the reaction
mixture from the alkylation of quercetin using different amounts of methyl
iodide and sodium carbonate. Bottom: 1 equiv; middle: 2 equiv; top:
3 equiv.
Therefore, we first decided to reinvestigate the direct
methylation of quercetin using up-to-date analytical tech-
niques in order to get an insight into the reactivity of each
position. In this aim, we performed direct methylation of
quercetin using DMF as solvent in order to work at room
temperature. The reaction mixture was then analyzed by
(LC-ESI-MS/MS).31 The reaction mixture was so separated
by liquid chromatography on a reverse phase and the
different products identified by mass spectrometry on the
basis of their collision activated dissociation spectra: ions
produced by electrospray ionization in positive mode were
fragmented in a collision activated dissociation cell and the
resulting fragmentation pattern allowed determination of
the methylation position. Fig. 1 shows the UV traces at
280 nm obtained for different reagent amounts, from 1 to
3 equiv. of methyl iodide and 1.25 times more equivalent of
sodium carbonate. This wavelength was used as it
corresponds to a plate in quercetin and methylquercetin
spectra exhibiting small sensitivity to the substitution
pattern. Therefore, for the following discussion and
quantification (Table 1), a similar molar extinction coeffi-
cient was assumed for all the compounds. Fig. 1 and Table 1
show that even using 1 equiv. of methyl iodide, the reaction
is not selective and leads to a mixture of mono, di and a trace
of tri O-methylated compounds.
isomers were assigned to be 3,7 and 3,40-O-dimethyl-
quercetin (67,33 relative yield respectively). No C-alkylated
products can be detected in those conditions. Inspection of
the results with 1 equiv. leads to ascertain a reactivity order
7.3<40, which is in agreement with Jurd data but not with
Rao’s results. The relative reactivity appeared preserved in
the synthesis of O-dimethylquercetins, which leads prefer-
entially to the formation of 3,7-O-dimethylquercetin.
Therefore, this brute force route only allows synthesis of
three of the five monomethylquercetin and involves tedious
Table 1. Direct methylation of quercetin 1 in DMF at room temperature
1 equiv.a
2 equiv.a
3 equiv.a
Quercetinb
70
25 (20, 55, 25)
4 (67, 33)
0
0
4
45 (72, 8, 20)
46 (63,37)
5
0
0
2 (100,0,0)
57 (77,23)
35
5
Monomethylb,c
Dimethylb,d
Trimethylb,e
Tetramethylb,f
a
1 equiv. is defined as the stoichiometric amount of MeI in presence of
1.25 equiv. of K2CO3.
b
c
d
Yield determined by LC-UV at 280 nm assuming a similar molar
extinction coefficient for all the compounds.
Total yield of methylquercetin, (3-O-methylquercetin, 7,40, compo-
sition%).
Total yield of dimethylquercetin (3,7-O-dimethylquercetin, 3,40, compo-
sition%).
The three mono O-methylquercetin isomers were identified
as 3, 7 and 40 isomers obtained respectively in a 20, 55, 25
relative yield; whereas the two O-dimethylquercetin
e
f
Yield of 3,7,40-O-trimethylquercetin.
Yield of 3,7,30,40-O-tetramethylquercetin.

M. Bouktaib et al. / Tetrahedron 58 (2002) 10001–10009
Table 2. Benzylation of quercetin 1 with various quantities of BnBr
10003
Conditionsa
0.5 equiv.a
1 equiv.a
2 equiv.a
3 equiv.a
3.5 equiv.a
6 equiv.a
Monobenzylb
Dibenzylb
70
25
5
0
0
32
49
19
0
0
48
44
8
0
0
52
36
12
0
0
24
72
4
0
0
0
0
100
Tribenzylb
Tetrabenzylb
Pentabenzylb
0
0
a
1 equiv. is defined as the stoichiometric amount of BnBr in presence of 1.25 equiv. of K2CO3.
Relative proportion determined by infusion ESI-MS assuming the same ionization yield for all the compounds.
b
separations if pure compounds are required. So we chose to
develop a synthesis strategy based on successive and
selective protections of the different quercetin phenolic
functions for synthesizing the five monomethylated isomers
with the methyl group in position 30 (isorhamnetin), 40
(tamarixetin), 3 (3-O-methylquercetin), 5 (azaleatin) and 7
(rhamnetin).
5-hydroxyl group and the 4-keto group.34,35 Secondly, the
quercetin acidic 3-hydroxyl group can be readily benzyl-
ated. Assuming that the 5-hydroxyl group remains free,
there are four possibilities left for the tribenzylation of
Quercetin leading 0 to the potential tribenzyl ethers 3
regioisomers: 3,30,4 ; 3,30,7; 3,40,7 and 30,40,7. The position
of the benzyl group in 3 was unambiguously determined
using one-dimensional (1D)-nuclear Overhauser effect
(NOE) spectroscopy on the O-dimethylated analogue 3a
obtained in a near quantitative yield by permethylation in
mild conditions (methyl iodide in DMF and K2CO3 as base).
The irradiation of the methyl peaks results in an increase of
H-6 and H-20 resonance frequencies, while H-8 and H-50
frequencies are not affected, ind0 icating that the methyl
groups are located on the 5 and 3 positi0ons. Consequently,
the benzyl groups are located on the 3, 4 ,7 positions. These
results are in agreement with the 0recently reported NMR
spectra of 3,7,40-tri- and 3,7,30,4 -O-tetrabenzylquercetin
obtained using harder alkylation conditions (t-BuOK, DMF)
and two successive additions of benzyl bromide.36
2.2. Optimization of quercetin benzylation
We decided first to optimize the partial benzylation of
quercetin 1 using different amounts of benzyl bromide and
K2CO3 (Table 2).
The inspection of Table 2 shows that quercetin benzylation
occurs in several steps. The use of 1 equiv. of benzyl
bromide provides a mixture of mono-, di- and tribenzylated
isomers of quercetin, respectively in 32:49:19 proportions.
The relative proportions of mono- and dibenzylated
analogues decrease when 2 or 3 equiv. of benzyl bromide
are used, whereas proportions of tri- and tetrabenzylated
analogues increase. Quercetin benzylation with 3.5 equiv.
of benzyl bromide and K2CO3 leads mainly to the formation
of two products: a tetrabenzylated isomer 2 (60% isolated
yield) and a tribenzylated one 3 (20% isolated yield)
(Scheme 1 and Table 2). Pentabenzylquercetin is also
detected as traces (3% isolated yield). The melting points
reported in the literature for the tetrabenzylated isomer 2
varies from 12832 to 145 8C,33 which pushed us to ascertain
the structure of the obtained compound.
2.3. Synthesis of 5-O-methylquercetin
The synthesis of 5-O-methylquercetin (azaleatin) 5 is
performed in two steps starting from 2: methylation of the
free phenolic function at 5 position with an excess of MeI
and K2CO3 gives 4; a final deprotection step, involving the
cleavage of the benzyl groups by hydrogenolysis on
palladium hydroxide in EtOH–THF at room temperature
affords 5 (Scheme 2). As expected from the behavior of
quercetin for which the most common crystalline form is the
dihydrate, 5-O-methylquercetin (azaleatin) crystallizes also
as the dihydrate as shown by the elemental analysis data. In
all the series, in fact, the unprotected compounds crystallize
as hydrates.
It is well-known that the hydroxyl function on the 5 position
resists to benzylation under these conditions. This group is
indeed less acidic than the other quercetin phenolic
functions, which may be accounted for by an acid-
weakening effect of an intramolecular H-bond between the
2.4. Synthesis of 30-O-methylquercetin
The synthesis of 30-O-methylquercetin (isorhamnetin) 7 was
Scheme 1. Synthesis of 3,7,40-O-tribenzylquercetin and 3,7,30,40-O-
tetrabenzylquercetin.
Scheme 2. Synthesis of 5-O-methylquercetin (azaleatin).

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M. Bouktaib et al. / Tetrahedron 58 (2002) 10001–10009
Scheme 3. Synthesis of 30-O-methylquercetin (isorhamnetin).
carried out under the same conditions starting from 3,7,40-
O-tribenzylquercetin 3. The partial methylation of the 30
position free phenolic function with one equivalent of MeI
and K2CO3 (the 5 position is less reactive) which leads to 6
(90% yield) is followed by a final deprotection of the benzyl
groups to reach isorhamnetin 7 in a 85% yield (Scheme 3).
Scheme 5. Synthesis of 40-O-methylquercetin (tamarixetin).
2.6. Synthesis of 40-O-methylquercetin
Treatment of 8 with an excess of benzyl bromide (4 equiv.)
and K2CO3 (4 equiv.) in DMF leads to the formation of 9,
whose all phenolic functions are protected. Synthesis of
40-O-methylquercetin (tamarixetin) 12 is then performed in
three steps (Scheme 5). Starting from 9, we first focus on the
catechol ring deprotection by cleaving the diphenylmethyl-
ene ketal. Two different methods are available for the
cleavage of such diphenylmethylene ketal: either hydro-
genolysis or hydrolysis. As may be expected, hydro-
genolysis catalyzed by palladium hydroxide fails in the
partial deprotection of 9, as the ketal seems more resistant to
hydrogenolysis than the benzyl group. Nonetheless, we
were delighted that under acidic conditions the ketal can be
cleaved selectively. The best results were obtained using a
mixture of acetic acid/water (80:20) heated. TLC monitor-
ing shows that the reaction is completed after 2 hours at
reflux. This method allows deprotection in a 60% yield and
no side products are detected by TLC or NMR analysis. This
method appears to be easy, efficient and fast. TLC
monitoring shows that the reaction is completed after 2 h
at reflux. Hence, flavonol 10 is reached after the deprotec-
tion of the catechol ring and the selective debenzylation of
the 5-hydroxy group. This phenomenon may account for by
the assistance from the benzopyran skeleton carbonyl group.
Three phenolic functions, the 30, 40 and 5 ones, are free at
this stage of the synthesis. Treatment of 10 with 1 equiv. of
2.5. Selective protection of quercetin catechol ring
For the synthesis of the 40, 3 and 7 monomethylated
quercetins (12, 17 and 20), we decided to adopt an
alternative strategy which relies upon a selective protection
of the catechol ring, so as to make the selective methylation
and benzylation easier. Quercetin O-dihydroxyl groups may
be protected after chelation with borax.37 However, Wender
et al. reported that quercetin methylation under these
conditions provided a complex mixture with at least three
non-identified partially methylated Quercetin ethers.38
A
similar behavior was observed, in our laboratory, for
catechin methylation in presence of borax.39 So we decided
to use the same strategy we developed for catechin based on
the protection of the O-dihydroxyphenyl group with
dichlorodiphenylmethane.39,40 On the contrary to Jurd,41
who reported that quercetin protection with dichlorodiphe-
nylmethane cannot be achieved directly and requires a first
protection step of the 7-hydroxyl group, but in agreement
with the recent paper by Alluis and Dangles,36 we observed
that dichlorodiphenylmethane is an efficient protecting
group for the quercetin B ring vicinal hydroxyl group. We
first tested the conditions developed for the very sensitive
compound catechin. However, the reaction of quercetin 1
with 1.1 equiv. of dichlorodiphenylmethane and 5 equiv. of
base (K2CO3 or NEt3) in acetonitrile at room temperature
provides the desired compound 8 but with a very low yield
(10%). Variations in dichlorodiphenylmethane or base
amount do not change the reaction yield. On the other
hand, the protected quercetin 8 is readily prepared by
heating 1 at 1808C for 10 minutes with 3 equiv. of
dichlorodiphenylmethane The desired product 8 is so
obtained with a 37% yield after recrystallization (Scheme 4).
Scheme 6. Methylation and benzylation of B-ring protected quercetin
(isolated yield).
Scheme 4. Synthesis of B-ring protected quercetin.

M. Bouktaib et al. / Tetrahedron 58 (2002) 10001–10009
10005
3. Conclusion
In conclusion, we have developed a general methodology
for the hemisynthesis of the five O-monomethylquercetin
isomers. Our strategy relies, on one hand on the difference in
reactivity of the different sites and, on the other hand, on the
selective protection of the catechol group with dichloro-
diphenylmethane. Using the same strategy, we succeeded in
synthesizing several O-dimethylquercetin, such as 30,40-O-
dimethylquercetin and 3,7-O-dimethylquercetin which will
be reported elsewhere. The reported protocol could be
applied to the synthesis of other quercetin metabolites,
which include non-labile groups such as a sulfate or a
glucuronide groups.
Scheme 7. Synthesis of 3-O-methylquercetin.
MeI leads selectively to 11 presenting a methyl group in the
40 position, in a 90% yield. The methyl group position is
confirmed by a one-dimensional (1D)-nuclear Overhauser
effect (NOE) spectroscopy. Irradiation of this methyl group
(3.95 ppm) results in a strong enhancement of0the doublet
(J¼8.6 Hz) at 6.88 ppm, corresponding to H-5 resonance.
The ultimate step of this synthesis consists of the
hydrogenolysis of the protecting group catalyzed by
palladium hydroxide, which provides the 40-O-methyl-
quercetin (tamarixetin) 12. The overall yield from 8 to 12
is 41% (Scheme 5).
4. Experimental
4.1. General
2.7. Synthesis of 3-O-methylquercetin
All commercially available products were purchased from
Aldrich (Saint-Quentin Fallavier, France) and used as
received. Deuterated solvents (99.9% or better) were
purchased from Euriso-Top (Saint-Aubin, France). Tetra-
hydrofuran (THF) was distilled from sodium benzophenone
ketyl under argon before use. Dimethylformamide (DMF)
was distilled at atmospheric pressure before use. For flash
chromatography, Merck silica-gel 60 (230–400 mesh
ASTM) was used. The melting points were measured on
an Electrothermal (Dubuque, Iowa USA) 9100 apparatus
and were not corrected. NMR were recorded on a Bruker
(Wissembourg, France) AM 300 spectrometer (300 and
75 MHz, for 1H and 13C, respectively) using CDCl3,
[D6]acetone, [D4]MeOH, [D6]DMSO as solvents and TMS
as internal standard; chemical shifts and J values are given
in d and Hz, respectively. MS experiments: Electron
Ionization were carried out on a JEOL Mass Station 700
The synthesis of quercetin 3- and 7-O-monomethyl isomers
(17 and 20) is based on the same synthetic strategy. This
synthesis, which is depicted in Scheme 6, involves one
single step, the selective alkylation of compound 8 on the 3
position. Treatment of 8 with 1 equiv. of MeI or BnBr in the
presence of K2CO3 affords a mixture of two products: the
3-methyl (or benzyl) isomer (13 or 15) and the 3,7-dimethyl
(or dibenzyl) isomer (14 or 16) (Scheme 6) which are
readily separated by chromatography on silica gel.
The methyl group position in 13 is confirmed once more by
a 1D difference nuclear Overhauser experiment, whereas
irradiation of the methyl group does not affect the H-6 and
H-8 resonance frequencies. The 3-O-methylquercetin 17
and 3,7-O-dimethylquercetin are directly obtained after an
acidic hydrolysis, with a mixture of acetic acid/water
(80:20) (Scheme 7) in a 85% yield.
´
spectrometer at the Ecole Normale Superieure (Paris,
France), ESI on a Micromass (Manchester, United-
Kingdom) Quattro II spectrometer fitted with a Hewlett–
Packard (Palo Alto, USA) series 1100 HPLC using a C18
reverse stationary phase column (250£2.1 mm) from
Beckman (Coulter Fullerton, California, USA). Micro-
analyses were performed by the CNRS ‘Service Central
d’Analyse’ (Vernaison, France).
2.8. Synthesis of 7-O-methylquercetin
Finally, the synthesis of 7-O-methylquercetin 20
(rhamnetin) requires the methylation of the 7-hydroxyl
position using 1 equiv. of MeI and K2CO3 (60% yield) to
give 19 followed by the hydrogenolysis of the benzyl
protecting group in 3 position using palladium hydroxide in
a EtOH/THF (1:1) mixture at room temperature. The
deprotection of the catechol ring with a mixture of acetic
acid/water 80:20 (80% yield, Scheme 8) affords the target
compound 7-O-methylquercetin 20 (rhamnetin).
4.2. Quercetin benzylation. Synthesis of compounds 2
and 3
To a solution of quercetin 1 (5.00 g, 14.79 mmol) in DMF
(100 mL), potassium carbonate (3.5 equiv., 7.14 g,
51.77 mmol) and benzyl bromide (3.5 equiv., 6.19 mL,
51.77 mmol) were added under argon. After vigorous
stirring at 08C for 2 h, the reaction mixture was allowed to
warm to room temperature over 2 h and the stirring was
maintained for 12 h. The resulting mixture was diluted with
water (400 mL), extracted with EtOAc (500 mL), then the
organic layer was washed with water (400 mL) and dried
over MgSO4. The residue obtained after removal of the
solvent was purified by flash column chromatography using
dichloromethane as eluent to afford three products: the
tribenzylether 3 (1.69 g, 20% yield), the tetrabenzylether 2
Scheme 8. Synthesis of 7-O-methylquercetin (rhamnetin).

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M. Bouktaib et al. / Tetrahedron 58 (2002) 10001–10009
(5.88 g, 60% yield) and traces of pentabenzylether (0.33 g,
3% yield).
4.55 mmol) and methyl iodide (2 equiv., 0.28 mL,
4.55 mmol) in DMF (50 mL) were stirred at room
temperature for 12 h under argon. The resulting mixture
was diluted in water (150 mL), extracted with EtOAc
(200 mL) and the organic layer washed with water
(150 mL). The organic layer was dried over MgSO4 and
the residue obtained after evaporation of the solvent was
purified by recrystallization from EtOAc to afford 5 (1.42 g,
93% yield). Mp 156–1588C [lit.32 1608C]. 1H NMR
(CDCl3): 3.90 (s, 3H, OCH3), 4.95 (s, 2H, OCH2Ph), 5.08
(s, 2H, OCH2Ph), 5.11 (s, 2H, OCH2Ph), 5.22 (s, 2H,
OCH2Ph), 6.37 (d, J¼2.0 Hz, 1H, aromatic H), 6.51 (d,
J¼2.0 Hz, 1H, aromatic H), 6.96 (d, J¼8.6 Hz, 1H,
aromatic H), 7.18–7.47 (m, 20H, aromatic H), 7.56 (d,
J¼8.6, 2.0 Hz, 1H, aromatic H), 7.78 (d, J¼2.0 Hz, 1H,
aromatic H). 13C NMR (CDCl3): 56.4 (OCH3), 70.5
(OCH2Ph), 70.8 (OCH2Ph), 71.0 (OCH2Ph), 74.0
(OCH2Ph), 93.2, 96.3, 109.5, 113.7, 115.1, 122.0, 123.9,
127.2, 127.4, 127.8, 127.9, 128.0, 128.1, 128.3, 128.5,
128.6, 128.8, 129.0, 135.7, 136.8, 137.0, 137.1, 139.8,
148.2, 150.5, 153.0, 158.7, 161.0, 162.9, 174.0 (CvO).
4.2.1. 3,7-Bisbenzyloxy-2-(3,4-bisbenzyloxyphenyl)-5-
hydroxychromen-4-one 2. Mp 140–1428C [lit.32 1288C,
lit.33 140–1428C]. 1H NMR (CDCl3): 4.96 (s, 2H,
OCH2Ph), 5.01 (s, 2H, OCH2Ph), 5.12 (s, 2H, OCH2Ph),
5.25 (s, 2H, OCH2Ph), 6.44 (d, J¼2.1 Hz, 1H, aromatic H),
6.46 (d, J¼2.1 Hz, 1H, aromatic H), 6.96 (d, J¼8.7 Hz, 1H,
aromatic H), 7.21–7.45 (m, 20H, aromatic H), 7.54 (dd,
J¼8.7, 2.1 Hz, 1H, aromatic H), 7.72 (d, J¼2.1 Hz, 1H,
aromatic H). 13C NMR (CDCl3): 70.4 (OCH2Ph), 70.8
(OCH2Ph), 71.0 (OCH2Ph), 74.3 (OCH2Ph), 93.0, 98.5,
106.1, 113.6, 115.2, 122.6, 123.4, 127.2, 127.4, 127.5,
127.9, 128.0, 128.3, 128.4, 128.5 128.6, 128.8, 128.9, 135.8,
136.0, 136.7, 136.9, 137.5, 148.2, 151.1, 156.2, 156.7,
162.1, 164.4, 178.8 (CvO).
4.2.2. 3,7-Bisbenzyloxy-2-(4-benzyloxy-3-hydroxy-
phenyl)-5-hydroxychromen-4-one 3. Mp 150–1528C
1
[lit.29 144–1458C, lit.33 148–1508C]. H NMR (CDCl3):
5.03 (s, 2H, OCH2Ph), 5.12 (s, 2H, OCH2Ph), 5.18 (s, 2H,
OCH2Ph), 6.41 (d, J¼2.1 Hz, 1H, aromatic H), 6.50 (d,
J¼2.1 Hz, 1H, aromatic H), 6.94 (d, J¼8.7 Hz, 1H,
aromatic H), 7.21–7.47 (m, 15H, aromatic H), 7.70 (dd,
J¼8.7, 2.1 Hz, 1H, aromatic H), 7.72 (d, J¼2.1 Hz, 1H,
aromatic H). 13C NMR (CDCl3): 70.4 (OCH2Ph), 71.0
(OCH2Ph), 74.2 (OCH2Ph), 93.0, 98.7, 106.2, 111.6, 115.0,
121.9, 123.8, 127.5, 127.9, 128.2, 128.3, 128.6, 128.7,
128.8, 135.7, 135.8, 136.5, 137.6, 145.6, 148.0, 156.3,
156.7, 161.9, 164.4, 178.8 (CvO).
4.4.2. 2-(3,4-Dihydroxyphenyl)-3,7-dihydroxy-5-methoxy-
chromen-4-one 5. A suspension of 4 (0.30 g, 0.6 mmol) in a
mixture of EtOH (20 mL) and THF (20 mL) was treated at
room temperature with 10% palladium hydroxide (10 mg)
under a flow of hydrogen for 10 h. The reaction mixture was
then filtered on Celitew and eluted with EtOH (20 mL). After
concentration of the filtrate under vacuum, the resulting
compound 5 was recrystallized in MeOH to afford a yellow
solid (0.12 g, 85% yield). Mp 259–2618C. [lit.42 250–2608C].
1H NMR ([D6]DMSO): 3.74 (s, 3H, OCH3), 6.33 (d,
J¼2.1 Hz, 1H, aromatic H), 6.48 (d, J¼2.1 Hz, 1H, aromatic
H), 6.87 (d, J¼8.4 Hz, 1H, aromatic H), 7.47 (dd, J¼8.4,
2.1 Hz, 1H, aromatic H), 7.58 (d, J¼2.1 Hz, 1H, aromatic H).
13C NMR ([D6]DMSO): 56.0 (OCH3), 94.6, 95.9, 105.0,
114.5, 115.6, 119.1, 120.3, 137.0, 141.9, 145.0, 146.9, 157.9,
160.5, 162.7, 170.9 (CvO). MS m/z 316 (Mþz) 315,301,284,
270, 229, 205, 166, 141, 137, 110. HRMS (EI, 70 eV)
(C16H12O7) calcd: 316.0583; found 316.0586. C16H12O7,
2H2O (352.29): calcd C 54.55, H 4.58; found C 54.12, H 4.94.
4.3. Methylation of 3 for NOE investigation
4.3.1. 3,7-Bisbenzyloxy-2-(4-benzyloxy-3-methoxy-
phenyl)-5-methoxychromen-4-one 3a. Methyl iodide
(0.05 mL, 0.8 mmol) and potassium carbonate (140 mg,
1.02 mmol) were added to a solution of the tribenzylether 3
(200 mg, 0.34 mmol) in DMF (5 mL) under argon and
stirring was maintained overnight. The resulting mixture
was diluted with water (15 mL), extracted with EtOAc
(20 mL), then the organic layer was washed with water
(15 mL) and dried over MgSO4. The residue obtained after
evaporation of the solvent was purified by recrystallization
from EtOAc to afford 3a (205 mg, 98% yield). Mp 112–
4.5. Synthesis of 30-O-methylquercetin
4.5.1. 3,7-Bisbenzyloxy-2-(4-benzyloxy-3-methoxy-
phenyl)-5-hydroxychromen-4-one 6. Methyl iodide
(0.13 mL, 2.08 mmol) and potassium carbonate (378 mg,
2.74 mmol) were added to a solution of the tribenzylether 3
(1.20 g, 2.08 mmol) in DMF (30 mL) under argon flow and
stirring. After standing overnight, the resulting mixture was
diluted with water (70 mL), extracted with EtOAc
(100 mL), then the organic layer was washed with water
(70 mL) and finally dried over MgSO4. Solvent was
removed under vacuum to leave a yellow solid 7, which
was purified by flash column chromatography using CH2-
Cl2/EtOAc (95:5) as eluent (1.11 g, 90% yield). Mp 142–
1448C. 1H NMR (CDCl3): 3.71 (s, 3H, OCH3), 5.06 (s, 2H,
OCH2Ph), 5.11 (s, 2H, OCH2Ph), 5.23 (s, 2H, OCH2Ph), 6.43
(d, J¼2.2 Hz, 1H, aromatic H), 6.50 (d, J¼2.2 Hz, 1H,
aromatic H), 6.93 (d, J¼8.6 Hz, 1H, aromatic H), 7.26–7.49
(m, 15H, aromatic H), 7.55 (dd, J¼8.6, 2.0 Hz, 1H, aromatic
H), 7.72 (d, J¼2.0 Hz, 1H, aromatic H). 13C NMR (CDCl3):
55.9 (OCH3), 70.4 (OCH2Ph), 70.7 (OCH2Ph), 74.5
1
1168C [lit.33 116–1188C]. H NMR (CDCl3): 3.54 (s, 3H,
OCH3), 3.71 (s, 3H, OCH3), 4.98 (s, 2H, OCH2Ph), 4.99 (s,
2H, OCH2Ph), 5.11 (s, 2H, OCH2Ph), 6.17 (d, J¼2.1 Hz,
1H, aromatic H), 6.43 (d, J¼2.1 Hz, 1H, aromatic H), 6.83
(d, J¼8.7 Hz, 1H, aromatic H), 7.17–7.40 (m, 15H,
aromatic H), 7.43 (dd, J¼8.6, 2.0 Hz, 1H, aromatic H),
7.63 (d, J¼2.0 Hz, 1H, aromatic H). 13C NMR (CDCl3):
55.7 (OCH3), 56.2 (OCH3), 70.4 (OCH2Ph), 70.6
(OCH2Ph), 74.0 (OCH2Ph), 93.2, 99.2, 109.3, 112.2,
112.8, 121.2, 123.7, 127.2, 127.8, 128.0, 128.2, 128.3,
128.5, 128.6, 128.9, 135.7, 136.5, 137.1, 139.8, 148.9,
152.9, 158.5, 160.7, 162.4, 162.8, 173.9 (CvO).
4.4. Synthesis of 5-O-methylquercetin
4.4.1. 3,7-Bisbenzyloxy-2-(3,4-bisbenzyloxyphenyl)-5-
methoxychromen-4-one 4. A solution of 2 (1.50 g,
2.28 mmol), potassium carbonate (2 equiv., 0.63 g,

M. Bouktaib et al. / Tetrahedron 58 (2002) 10001–10009
10007
(OCH2Ph), 93.1,98.5,106.2, 112.2, 112.8,122.0, 123.3, 127.3,
127.5, 128.1, 128.3, 128.3, 128.7, 128.7, 135.8, 136.4, 136.5,
137.6, 149.0, 150.3, 156.4, 157.0, 162.1, 164.4, 178.8 (CvO).
(80:20, 50 mL). The solution was refluxed for 2 h. Then
EtOAc (50 mL) and water (50 mL) were added. The organic
layer was washed with a NaHCO3 saturated aqueous
solution (40 mL) and dried over MgSO4. After solvent
evaporation, the residue was purified by recrystallization
from CH2Cl2 to give 10 (390 mg, 60% yield). Mp 202–
2048C. 1H NMR ([D6]DMSO): 5.01 (s, 2H, OCH2Ph), 5.21
(s, 2H, OCH2Ph), 6.43 (d, J¼2.0 Hz, 1H, aromatic H), 6.75
(d, J¼2.0 Hz, 1H, aromatic H), 6.87 (d, J¼8.4 Hz, 1H,
aromatic H), 7.28–7.46 (m, 11H, aromatic H), 7.55 (d,
J¼2.0 Hz, 1H, aromatic H), 9.36 (s, 1H, OH), 9.83 (s, 1H,
OH), 12.7 (s, 1H, OH). 13C NMR ([D6]DMSO): 70.0
(OCH2Ph), 73.3 (OCH2Ph), 93.0, 98.4, 105.3, 115.5, 115.7,
120.8, 121.0, 136.1, 136.5, 136.6, 145.2, 148.8, 156.2,
156.8, 161.0, 164.1, 178.0 (CvO).
4.5.2. 2-(4-Hydroxy-3-methoxyphenyl)-3,5,7-trihydroxy-
chromen-4-one 7. A suspension of 6 (200 mg, 0.33 mmol)
in a mixture of EtOH (30 mL) and THF (30 mL) was treated
with palladium hydroxide (10%, 10 mg) under hydrogen
flow for 6 h. The reaction mixture was then filtered on
Celitew and eluted with EtOH (30 mL). The filtrate was
concentrated under vacuum and the resulting product 7 was
recrystallized from MeOH, to give a pale yellow solid
(91 mg, 85% yield). Mp 301–3038C [lit.28 305–3068C]. 1H
NMR ([D6]DMSO): 3.82 (s, 3H, OCH3), 6.18 (s, 1H,
aromatic H), 6.46 (s, 1H, aromatic H), 6.93 (d, J¼8.4 Hz,
1H, aromatic H), 7.67 (d, J¼8.4 Hz, 1H, aromatic H), 7.74
(s, 1H, aromatic H). 13C NMR ([D6]DMSO): 55.7 (OCH3),
93.6, 98.2, 102.9, 111.6, 115.5, 121.7, 122.0, 135.8, 146.5,
147.3, 148.7, 156.1, 160.6, 164.0, 175.8 (CvO).). MS m/z 316
(Mþz) 315, 301, 287, 245, 217, 168, 151, 141, 125, 123. HRMS
(C16H12O7) calcd: 316.0583; found 316.0576. C16H12O7,
2.25H2O (356.80): calcd C 53.86, H 4.66; found C 53.96, H
4.87.
4.6.4. 3,7-Bisbenzyloxy-2-(3-hydroxy-4-methoxyphenyl)-
5-hydroxychromen-4-one 11. Compound 11 was syn-
thesized according to the procedure reported for 7.
Compound 11 was purified by flash column chromato-
graphy using EtOAc/petroleum ether (40:60) as eluent
(185 mg starting from 200 mg of 10, 90% yield). Mp 144–
1468C. 1H NMR (CDCl3): 3.95 (s, 3H, OCH3), 5.05 (s, 2H,
OCH2Ph), 5.12 (s, 2H, OCH2Ph), 6.43 (d, J¼2.0 Hz, 1H,
aromatic H), 6.51 (d, J¼2.0 Hz, 1H, aromatic H), 6.88 (d,
J¼8.6 Hz, 1H, aromatic H), 7.26–7.45 (m, 10H, aromatic
H), 7.58–7.65 (m, 2H, aromatic H). 13C NMR (CDCl3):
56.0 (OCH3), 70.4 (OCH2Ph), 74.2 (OCH2Ph), 93.0, 98.6,
106.2, 110.1, 122.0, 123.6, 127.5, 128.2, 128.3, 128.5,
128.7, 128.8, 135.8, 136.4, 137.5, 145.3, 148.7, 156.4,
156.7, 162.0, 164.4, 178.8 (CvO).
4.6. Synthesis of 40-O-methylquercetin
4.6.1. Protection of quercetin catechol ring. 2-(2,2-
Diphenylbenzo[1,3]dioxol-5-yl)-3,5,7-trihydroxychro-
men-4-one 8. A mixture of quercetin 1 (2.00 g, 5.92 mmol)
and
dichlorodiphenylmethane
(3 equiv.,
3.39 mL,
17.76 mmol) was intimately mixed then heated at 1808C for
10 min. The crude resulting products mixture was then
purified by flash column chromatography using CH2Cl2/
EtOAc (85:15) as eluent and was recrystallized from CHCl3 to
afford 8 (1.00 g, 37% yield). Mp 222–2248C. 1H NMR
([D6]DMSO): 6.20 (d, J¼1.9 Hz, 1H, aromatic H), 6.47 (d,
J¼1.9 Hz, 1H, aromatic H), 7.17 (d, J¼8.3 Hz, 1H, aromatic
H), 7.44–7.58 (m, 10H, aromatic H), 7.79 (dd, J¼8.3, 1.6 Hz,
1H, aromatic H), 7.81 (d, J¼1.6 Hz, 1H, aromatic H). 13C
NMR ([D6]DMSO): 93.6, 98.3, 103.1, 107.8, 108.8, 117.0,
123.0, 125.2, 125.7, 128.6, 129.5, 136.4, 139.4, 145.5, 146.6,
147.6, 156.2,160.7, 164.1, 178.0 (CvO).
4.6.5. 2-(3-Hydroxy-4-methoxyphenyl)-3,5,7-trihydroxy-
chromen-4-one 12. Compound 12 was synthesized using
the same procedure as for 5. The resulting residue was
purified by recrystallization from MeOH to give 12, a pale
yellow solid, in 80% yield (94 mg starting from 185 mg of
11). Mp 252–2548C [lit.43 253–2568C]. 1H NMR
([D6]DMSO): 3.81 (s, 3H, OCH3), 6.17 (s, 1H, aromatic
H), 6.41 (s, 1H, aromatic H), 7.03 (d, J¼8.6 Hz, 1H,
aromatic H), 7.60 (d, J¼8.6 Hz, 1H, aromatic H), 7.63 (s,
1H, aromatic H). 13C NMR ([D6]DMSO): 55.9 (OCH3),
93.5, 98.3, 102.9, 111.6, 114.4, 119.8, 123.3, 136.0, 146.0,
146.2, 149.3, 156.2, 160.6, 164.2, 175.79 (CvO). MS m/z 316
(Mþz) 315, 301, 287, 273, 245, 217, 153, 149, 123. HRMS
(C16H12O7) calcd: 316.0583; found 316.0576. C16H12O7, H2O
(334.28): calcd C 57.49, H 4.22; found C 57.12, H 4.63.
4.6.2. 2-(2,2-Diphenylbenzo[1,3]dioxol-5-yl)-3,5,7-tri-
benzyloxychromen-4-one 9. Compound 9 was prepared
by benzylation of the parent phenolic compound 8 under
classical conditions (BnBr 4 equiv., K2CO3 4 equiv., DMF
at room temperature for 12 h). Compound 9 was then
purified by recrystallization from EtOAc (3.00 g starting
4.7. Synthesis of 3-O-methylquercetin
1
from 2.00 g of 8, 95% yield). Mp 120–1228C. H NMR
(CDCl3): 5.08 (s, 2H, OCH2Ph), 5.09 (s, 2H, OCH2Ph), 5.28
(s, 2H, OCH2Ph), 6.47 (d, J¼1.9 Hz, 1H, aromatic H), 6.56
(d, J¼1.9 Hz, 1H, aromatic H), 6.90 (d, J¼8.2 Hz, 1H,
aromatic H), 7.12–7.25 (m, 2H, aromatic H), 7.37–7.65 (m,
15H, aromatic H). 13C NMR (CDCl3): 70.5 (OCH2Ph), 70.8
(OCH2Ph), 74.2 (OCH2Ph), 93.9, 98.1, 108.2, 108.9, 110.0,
123.6, 124.7, 126.3, 126.7, 127.7, 128.0, 128.1, 128.5,
128.7, 128.8, 129.1, 129.4, 135.7, 136.8, 139.5, 139.9,
147.2, 148.7, 153.7, 158.7, 159.8, 162.8, 173.9 (CvO).
Synthesis of compounds 13 and 14. A solution of methyl
iodide (0.134 mL, 2.15 mmol) in DMF (1 mL) and potas-
sium carbonate (0.44 g, 3.22 mmol) were added under argon
to a solution of 8 (1.00 g, 2.15 mmol) in DMF (20 mL). The
mixture was stirred at room temperature for 12 h. The
resulting mixture was diluted with water (100 mL),
extracted with EtOAc (150 mL), then the organic layer
was washed with water (100 mL) and dried over MgSO4.
The solvent was evaporated and the residue was purified by
flash column chromatography using EtOAc/petroleum
ether (30:70) as eluent. Two products were isolated: a
monomethylated compound 13 (0.38 g, 37% yield) and a
dimethylated compound 14 (0.38 g, 36% yield).
4.6.3. 3,7-Bisbenzyloxy-2-(3,4-dihydroxyphenyl)-5-
hydroxychromen-4-one 10. Compound 9 was added
(1.00 g, 1.36 mmol) to a mixture of acetic acid/water

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M. Bouktaib et al. / Tetrahedron 58 (2002) 10001–10009
4.7.1. 2-(2,2-Diphenylbenzo[1,3]dioxol-5-yl)-5,7-di-
hydroxy-3-methoxychromen-4-one 13. Mp 130–1328C.
1H NMR (CDCl3): 3.84 (s, 3H, OCH3), 6.43 (d, J¼2.0 Hz,
1H, aromatic H), 6.51 (d, J¼2.0 Hz, 1H, aromatic H), 6.97
(d, J¼8.2 Hz, 1H, aromatic H), 7.35–7.48 (m, 6H, aromatic
H), 7.53–7.62 (m, 4H, aromatic H), 7.72 (dd, J¼8.2, 1.7 Hz,
1H, aromatic H), 7.76 (d, J¼1.7 Hz, 1H, aromatic H). 13C
NMR (CDCl3): 60.9 (OCH3), 94.3, 99.6, 105.4, 108.6, 108.7,
118.1, 124.0, 126.2, 128.4, 129.4, 138.8, 139.7, 147.6, 149.6,
156.1, 156.9, 161.8, 163.8, 172.3, 178.8 (CvO).
13 (200 mg, 0.41 mmol) or 14 (300 mg, 0.61 mmol) in a
mixture of acetic acid/water (80:20, 50 mL) was refluxed
overnight under stirring. EtOAc (50 mL) and water (50 mL)
were then added. The organic layer was washed with an
aqueous solution saturated in NaHCO3 (30 mL) and dried
over MgSO4. After evaporation of the solvent, the solid
obtained was recrystallized from CH2Cl2 to afford com-
pound 17 (112 mg) or 18 (170 mg) in a 85% yield.
4.7.5. 2-(3,4-Dihydroxyphenyl)-5,7-dihydroxy-3-methoxy-
1
chromen-4-one 17. Mp 271–2738C [lit.44 273–2768C]. H
4.7.2. 2-(2,2-Diphenylbenzo[1,3]dioxol-5-yl)-3,7-
dimethoxy-5-hydroxychromen-4-one 14. Mp 149–1518C
[lit.41 1508C]. 1H NMR (CDCl3): 3.82 (s, 3H, OCH3), 3.85
(s, 3H, OCH3), 6.32 (s, 1H, aromatic H), 6.39 (s, 1H,
aromatic H), 7.00 (d, J¼8.3 Hz, 1H, aromatic H), 7.36–7.50
(m, 6H, aromatic H), 7.53–7.61 (m, 4H, aromatic H), 7.66
(dd, J¼8.2, 1.7 Hz, 1H, aromatic H), 7.68 (d, J¼1.7 Hz, 1H,
aromatic H). 13C NMR (CDCl3): 55.8 (OCH3), 60.2 (OCH3),
92.0, 97.9, 106.0, 108.6, 118.0, 123.9, 123.7, 124.2, 126.2,
128.4, 128.8, 129.4, 131.1, 131.6, 139.0, 139.8, 147.6, 149.4,
155.5, 156.6, 161.9, 165.4, 178.7 (CvO).
NMR ([D6]DMSO): 3.75 (s, 3H, OCH3), 6.14 (s, 1H, aromatic
H), 6.32 (s, 1H, aromatic H), 6.87 (d, J¼8.3 Hz, 1H, aromatic
H), 7.48 (d, J¼8.3 Hz, 1H, aromatic H), 7.59 (s, 1H, aromatic
H). 13C NMR ([D6]DMSO): 60.5 (OCH3), 94.7, 99.8, 105.8,
116.4, 116.5, 122.4, 122.9, 139.5, 146.4, 149.9, 157.9, 158.3,
163.0, 165.8, 179.9 (CvO). MS m/z 316 (Mþz) 315, 301, 284,
270, 229, 228, 166, 141, 137, 110. HRMS (C16H12O7) calcd:
316.0583; found 316.0587. C16H12O7, 1.5H2O (343.29): calcd
C 55.98, H 4.40; found C 56.12, H 4.12.
4.7.6. 2-(3,4-Dihydroxyphenyl)-5-hydroxy-3,7-methoxy-
chromen-4-one 18. Mp 238–2408C [lit.41 2358C]. 1H NMR
([D6]DMSO): 3.79 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 6.32
(s, 1H, aromatic H), 6.58 (s, 1H, aromatic H), 6.90 (d,
J¼8.3 Hz, 1H, aromatic H), 7.55 (d, J¼8.3 Hz, 1H,
aromatic H), 7.64 (s, 1H, aromatic H). 13C NMR
([D6]DMSO): 56.5 (OCH3), 60.5 (OCH3), 93.1, 98.9,
106.7, 116.4, 116.5, 122.4, 122.8, 139.7, 146.5, 150.1,
158.2, 158.3, 162.8, 167.3, 180.1 (CvO). MS (EI, 70 eV)
m/z 330 (Mþz) 329, 316, 312, 301, 287, 256, 244, 203, 151,
135. HRMS (C17H14O7) calcd: 330.0740; found 330.0739.
C17H14O7, 1.25H2O (352.81): calcd C 57.87, H 4.71; found
C 57.40, H 4.13.
Synthesis of compounds 15 and 16. Potassium carbonate
(0.38 g, 2.74 mmol) and benzyl bromide (0.24 mL,
1.99 mmol) were added to a solution of protected quercetin
8 (1.00 g, 1.99 mmol) in DMF (30 mL) under argon. The
mixture was stirred at 08C for 2 h, and then 12 h at room
temperature. The resulting mixture was diluted with water
(150 mL), extracted with EtOAc (200 mL), then the organic
layer was washed with water (150 mL) and dried over
MgSO4. The residue resulting from the solvent evaporation
was purified by flash column chromatography using a
mixture CH2Cl2/ EtOAc (95:5) to give two products: a
monobenzylether 15 (0.76 g, 64% yield) and a dibenzyl-
ether 16 (0.29 g, 21% yield).
4.8. Synthesis of 7-O-methylquercetin
4.7.3. 2-(2,2-Diphenylbenzo[1,3]dioxol-5-yl)-3-benzyl-
1
oxy-5,7-dihydroxychromen-4-one 15. H NMR (CDCl3):
4.8.1. 2-(2,2-Diphenylbenzo[1,3]dioxol-5-yl)-3-benzyl-
oxy-5-hydroxy-7-methoxychromen-4-one 19. Potassium
carbonate (0.15 g, 1.1 mmol) and methyl iodide (0.056 mL,
0.9 mmol) were added to a solution of 15 (500 mg,
0.9 mmol) in DMF (30 mL). Stirring was maintained for
6 h. The resulting mixture was diluted with water (50 mL),
extracted with EtOAc (100 mL), then the organic layer was
washed with water (50 mL) and dried over MgSO4.
After removal of the solvent, the product was purified by
4.98 (s, 2H, OCH2Ph), 6.35 (d, J¼2.1 Hz, 1H, aromatic H),
6.40 (d, J¼2.1 Hz, 1H, aromatic H), 6.89 (d, J¼8.1 Hz, 1H,
aromatic H), 7.41–7.48 (m, 11H, aromatic H), 7.60–7.65
(m, 4H, aromatic H), 7.53 (dd, J¼8.1, 1.8 Hz, 1H, aromatic
H), 7.58 (d, J¼1.8 Hz, 1H, aromatic H). 13C NMR(CDCl3):
74.7 (OCH2Ph), 94.2, 99.4, 105.6, 108.3, 109.0, 117.8,
124.1, 124.2, 126.3, 128.1, 128.2, 128.4, 129.0, 129.4,
135.9, 137.8, 147.2, 149.3, 156.9, 157.0, 162.0, 163.2, 178.8
(CvO).
flash column chromatography with
a
mixture of
EtOAc/petroleum ether (20:80 to 50:50) as eluent to provide
19 (307 mg, 60% yield). Mp 134–1368C. 1H NMR
(CDCl3): 3.84 (s, 3H, OCH3), 5.02 (s, 2H, OCH2Ph), 6.34
(d, J¼2.3 Hz, 1H, aromatic H), 6.37 (d, J¼2.3 Hz, 1H,
aromatic H), 6.94 (d, J¼8.3 Hz, 1H, aromatic H), 7.12–7.21
(m, 5H, aromatic H), 7.32 (dd, J¼8.3, 1.8 Hz, 1H, aromatic
H), 7.40–7.46 (m, 6H, aromatic H), 7.52 (d, J¼1.8 Hz, 1H,
aromatic H), 7.61–7.66 (m, 4H, aromatic H). 13C NMR
(CDCl3): 55.8 (OCH3), 74.4 (OCH2Ph), 92.1, 97.9, 106.0,
108.4, 109.0, 117.8, 124.1, 124.3, 126.3, 128.2, 128.4,
128.9, 129.4, 136.2, 137.3, 139.8, 147.3, 149.3, 156.6,
162.0, 165.4, 178.8 (CvO).
4.7.4. 2-(2,2-Diphenylbenzo[1,3]dioxol-5-yl)-3,7-bis-
benzyloxy-5-hydroxychromen-4-one 16. Mp 90–928C.
1H NMR (CDCl3): 5.08 (s, 2H, OCH2Ph), 5.12 (s, 2H,
OCH2Ph), 6.47 (d, J¼2.1 Hz, 1H, aromatic H), 6.51 (d,
J¼2.1 Hz, 1H, aromatic H), 6.95 (d, J¼8.3 Hz, 1H,
aromatic H), 7.18–7.46 (m, 16H, aromatic H), 7.58 (dd,
J¼8.3, 1.7 Hz, 1H, aromatic H), 7.63 (d, J¼1.7 Hz, 1H,
aromatic H), 7.65–7.72 (m, 4H, aromatic H). 13C NMR
(CDCl3): 70.5 (OCH2Ph), 74.5 (OCH2Ph), 93.0, 98.7, 106.2,
108.4, 109.1, 117.9, 124.2, 124.3, 126.3, 127.5, 128.3,
128.5, 128.8, 129.0, 129.5, 135.8, 136.3, 137.3, 139.8,
147.3, 149.3, 156.6, 156.7, 162.1, 164.5, 178.8 (CvO).
4.8.2. 2-(3,4-Dihydroxyphenyl)-3,5-dihydroxy-7-methox-
ychromen-4-one 20. 10% Palladium hydroxide
(0.12 mmol) was added to a stirred solution of 17 (0.7 g,
Synthesis of compounds 17 and 18. A solution of compound

M. Bouktaib et al. / Tetrahedron 58 (2002) 10001–10009
10009
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1.21 mmol) in EtOH/THF (1:2, 20 mL) under a hydrogen
flow. The suspension was stirred overnight and then the
solution was filtered through a plug of Celitew and eluted
with EtOH (20 mL). The filtrate was concentrated under
vacuum and the crude resulting solid was directly dissolved
in a mixture of acetic acid/water (80:20, 30 mL). The
deprotection of the catechol ring was performed as
previously described for the quercetin derivatives 17 and
18 to give 20 (311 mg, 80% yield). Mp 283–2858C [lit.45
16. Graefe, E. U.; Derendorf, H.; Veit, M. Int. J. Clin. Pharmacol.
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17. Graefe, E. U.; Wittig, J.; Mueller, S.; Riethling, A. K.;
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´
18. Manach, C.; Morand, C.; Crespy, V.; Demigne, C.; Texier, O.;
1
´ ´
´ ´
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280–2858C]. H NMR ([D6]DMSO): 3.84 (s, 3H, OCH3),
6.32 (d, J¼2.0 Hz, 1H, aromatic H), 6.67 (d, J¼2.0 Hz, 1H,
aromatic H), 6.89 (d, J¼8.3 Hz, 1H, aromatic H), 7.57 (d,
J¼8.3 Hz, 1H, aromatic H), 7.72 (s, 1H, aromatic H). 13C
NMR ([D6]DMSO): 56.0 (OCH3), 91.8, 97.4, 105.4, 115.2,
115.6, 120.0, 121.8, 136.0, 145.1, 147.8, 158.5, 160.3,
164.8, 166.3, 175.9 (CvOMS m/z 316 (Mþz) 315, 301, 287,
273, 259, 242, 227, 182, 167,137, 123, HRMS (C16H12O7)
calcd: 316.0583; found 316.0578. C16H12O7, 1.25H2O
(338.78): calcd C 56.72, H 4.31; found C 56.49, H 3.97.
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This work was supported by the European Community
(European Contract QLK1-CT-199-00505 POLYBIND)
25. Tanaka, H.; Stohlmeyer, M. M.; Wandless, T. J.; Taylor, L. P.
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and the Conseil Regional Nord, Pas-de-Calais, France.
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