An efficient synthesis of the four mono methylated isomers of (+)-catechin including the major metabolites and of some dimethylated and trimethylated analogues through selective protection of the catechol ring

Article abstract of DOI:10.1039/b107340k

The four monomethylated isomers of (+)-catechin in positions 3′, 4′, 5 and 7, two dimethylated derivatives, the 5,7-dimethylcatechin and the 3′, 4′-dimethylcatechin and two trimethylated isomers of (+)-catechin in positions 3′, 5, 7 and 4′, 5, 7 were synthesized by a new method based on successive and selective protections of the various phenol functions present on (+)-catechin. The key step was the selective protection of the catechol ring with dichlorodiphenylmethane and di-tert-butyldichlorosilane.

Full text of DOI:10.1039/b107340k

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An efficient synthesis of the four mono methylated isomers of
(؉)-catechin including the major metabolites and of some
dimethylated and trimethylated analogues through selective
protection of the catechol ring
1
Cécile Cren-Olivé, Stéphane Lebrun and Christian Rolando*
Université des Sciences et Technologies de Lille, UPRESA 8009,
Chimie Organique et Macromoléculaire, Equipe Polyphénols, 59655 Villeneuve d’Ascq, France.
E-mail: Christian.Rolando@univ-lille1.fr; Fax: ϩ333 20 33 61 36
Received (in Cambridge, UK) 14th August 2001, Accepted 19th December 2001
First published as an Advance Article on the web 14th February 2002
The four monomethylated isomers of (ϩ)-catechin in positions 3Ј, 4Ј, 5 and 7, two dimethylated derivatives, the
5,7-dimethylcatechin and the 3Ј,4Ј-dimethylcatechin and two trimethylated isomers of (ϩ)-catechin in positions
3Ј, 5, 7 and 4Ј, 5, 7 were synthesized by a new method based on successive and selective protections of the
various phenol functions present on (ϩ)-catechin. The key step was the selective protection of the catechol
ring with dichlorodiphenylmethane and di-tert-butyldichlorosilane.
allow the study of the intrinsic reactivity of each cycle or each
Introduction
catechin phenolic hydroxy. Total enantioselective syntheses of
flavan-3-ols15 appears to be difficult, long and expensive.
Recently, two enantioselective syntheses15a,15b of epigallo-
catechin-3-gallate have been proposed but neither the choice of
starting materials nor the yields of the epigallocatechin-3-gallate
are satisfactory for access to catechin analogues and metabolites.
On the other hand, the methylation of (ϩ)-catechin 1, under
standard chemical conditions, is not selective and leads, with a
very low yield, to a mixture of four monomethylated isomers.16
So these two extreme routes do not constitute a suitable way to
synthesize catechin metabolites for biological studies.
The syntheses of methylated derivatives of catechin is thus
very quickly directed towards strategies of protection-
deprotection of rings A and B. The only selective protections
of catechin described previously are based on the use of
cyclic borate17a or benzyl carbonate as protecting groups.17b,c
Hathway and Seakins17a used the in situ borate protection to
make 5,7-dimethylcatechin while Akimoto and Sugimoto17b
and more recently Van Dyk et al.17c reported a synthetic
sequence using both protecting groups leading to the 3Ј,4Ј-di-
O-methyl and 5,7-di-O-methyl ethers. However, in our hands
synthesis based on the use of selective protection of a B-ring by
borate under mild basic conditions appeared difficult to repro-
duce. No traces of the desired compounds were detected during
the analysis of the reaction mixture by HPLC-MS/MS. More-
over the use of benzyl carbonate, a protection which is not
specific to the catechol moiety, led to a mixture of products
since the difference of microscopic pKa’s between the different
hydroxy functions was too small (pK3Ј-OH = 9.02, pK4Ј-OH = 9.12,
pK5-OH = 9.43, and pK7-OH = 9.58 in water)18 to obtain regio-
specificity.17c So even if syntheses were proposed for these two
compounds 5,7-dimethylcatechin and 3Ј,4Ј-dimethylcatechin,
neither compound nor intermediate have been characterized.
Moreover, none of these methods permits obtainment of tri-
methylated isomers of (ϩ)-catechin and the four monomethyl-
ated derivatives of catechin, which are of capital importance for
the comprehension of biological effects of flavan-3-ols on the
human organism.
Interest in food phenolics has recently increased greatly because
of their protective effect against cancer,1 cardiovascular2 and
neurodegenerative3 diseases. Since these flavonoids are reported
to exhibit a wide range of other biological effects, including
antibacterial,4 antiviral,5 anti-inflammatory,6 and antiallergic,7
they are considered to be key compounds in the relationship
between health and diet.8 Indeed, flavan-3-ols are ubiquitously
distributed in the plant kingdom and widely found in a number
of foods.7a,9 Recent studies10 show the levels of flavan-3-ols,
typically (ϩ)-catechin, (Ϫ)-epicatechin, (ϩ)-gallocatechin,
(Ϫ)-epigallocatechin, (Ϫ)-epicatechin gallate and (Ϫ)-epigallo-
catechin range from 4.5 mg kgϪ1 in kiwi fruit to 610 mg kgϪ1 in
black chocolate10a and for the beverages, from 27–96 mg per
litre in red wine to 102–418 mg of total catechin per litre in
tea infusions10b leading to an average consumption of 100 mg
per day.
The protective effects have been mainly attributed to the
antioxidative activities of flavan-3-ols and their ability to
protect biomolecules from oxidative degradation by reactive
oxygen species.11 Therefore, the antioxidative properties of
flavonoids have been extensively studied in vivo and in vitro,12
but rather contradictory structure–activity relationships and
kinetics have been derived.12 Similar physical chemistry experi-
ments have been limited by the lack of convenient model com-
pounds giving access to the intrinsic reactivity of each ring
(A, B, C)13 and more precisely of each phenolic hydroxy. Until
now, most biological studies have been mainly performed on
polyphenols from either vegetal or commercially available
sources. However polyphenols are mainly found circulating in
blood as metabolites. For example, the most-studied flavan-
3-ol, catechin, is present almost exclusively as methylated
metabolites (3Ј-methylcatechin in majority) as well as sulfate
and glucuronide conjugates in plasma.14 These metabolites are
not commercially available and are difficult to extract in the
quantities required for biological or chemical studies from
enzymatic synthesis.
This situation gives an impetus to the synthesis of the
methylated metabolites of catechin and of selectively protected
catechin analogues which, preserving the parent reactivity,
In this work we developed specific access to methylated
flavan-3-ols starting from vegetal polyphenols available in pure
DOI: 10.1039/b107340k
J. Chem. Soc., Perkin Trans. 1, 2002, 821–830
This journal is © The Royal Society of Chemistry 2002
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enantiomeric form. We applied this strategy to the syntheses of
the four monomethylated isomers of (ϩ)-catechin in positions
3Ј, 4Ј, 5 and 7 respectively, two dimethylated derivatives, the 5,7-
dimethylcatechin and the 3Ј,4Ј-dimethylcatechin, and two tri-
methylated isomers of (ϩ)-catechin in positions 3Ј, 5, 7 and 4Ј,
5, 7 respectively. The key step was the sequential protection of
the catechol ring with dichlorodiphenylmethane and di-tert-
butyldichlorosilane.
we noticed that the yield of the reaction did not change further
with an increase in the temperature or reaction time (entries 4
and 5). However, the yield obtained here (22%) was comparable
to other phenol protecting groups reported in the literature, e.g.
benzyl protection as pointed out above.21
The protection of ring B with dichlorodiphenylmethane
opened two methods of synthesis: the first one leading to the
partial or total methylation of ring A (compounds 6–8), the
second one to the methylation of the same B ring (com-
pound 14) by the means of specific protection of ring A and
deprotection of ring B.
Results and discussion
We based our strategy for the selective protection of catechin on
the differentiation between catechol and other phenols.19 How-
ever the choice of the reagent is rather limited as catechin is
known to undergo quite readily a base-catalyzed epimerization
at C-2 to form ent-epicatechin through reversible opening of
ring C via a B ring quinone methide intermediate which
requires a free phenolic OH at the C4Ј position.20 This gave us
another reason to modify the B ring to protect the reactive
o-dihydroxyphenyl group. In the same way, it was shown by
Sears et al.20b that catechin undergoes rearrangement to cat-
echinic acid in hot alkaline solution. Thus it is imperative to
exclude any protective groups requiring particularly drastic pH
conditions during their introduction and removal to avoid
epimerization and rearrangement. Even benzylation under mild
conditions gave rather poor yields of only 20%.21 We investi-
gated various catechol-protecting groups: we recovered starting
material upon exposure of catechin 1 to a mixture of P2O5 and
anhydrous acetone at reflux. Treatment of catechin 1 with
phosgene (pyridine, 5 ЊC) involved the irreversible destruction
of the molecule. On the other hand, reaction of catechin with
di-tert-butyldichlorosilane22 and triethylamine in acetonitrile
gave a reproducable 85% yield of the corresponding di-tert-
butylsilylene derivative. Unfortunately, under basic conditions
or during TLC separation on silica gel, the protection under-
goes rapid hydrolysis to form hydroxysilyl mono ethers of the
parent catechol, as already noticed by Corey and Hopkins for
1,2- and 1,4-diols.23
Synthesis of methylated catechin derivatives on ring A
Under partial methylating conditions of compound 2 with
dimethyl sulfate (1 equivalent, 1.1 equivalents of potassium
carbonate at room temperature for 3 days), a mixture of two
monomethyl ethers 3,4 with a 9 : 1 ratio (determined from
1H NMR of the crude product) was obtained and could be sep-
arated by column chromatography using ethyl acetate–hexane
(30 : 70) as eluent (see Scheme 2).
The position of the methyl groups in both compounds were
1
unambiguously assigned from H NMR spectra and further
confirmed by one-dimensional (1D)-nuclear Overhauser effect
(NOE) spectroscopy which was conducted using two experi-
ments: the first one with irradiation of the resonance frequency
of the methyl peak and the second one with irradiation off-
resonance. NOESY and ROESY experiments have also been
done to ascertain the results. Fig. 1 shows the spectra (region
The protection of the o-dihydroxyphenyl group was then
achieved with dichlorodiphenylmethane24 which can be
removed in the final step by a hydrogenolysis reaction that is
usually clean and efficient (see Scheme 1). The reaction of
Fig. 1 Region of H6 at δ = 6.07 ppm and H8 at δ = 5.96 ppm obtained
by one-dimensional nuclear Overhauser effect spectroscopy on the
Scheme 1 Reagents, conditions and yield: Ph2CCl2 (1.1 eq.), Et3N
(5 eq.), CH3CN, 0 ЊC to rt, 12 h (22%).
major compound 3: spectrum
1 with sustained off-resonance
irradiation, spectrum 2 with irradiation of the resonance frequency of
the methyl peak, and curve 3 (displayed on a magnified scale) exhibits
the difference of the first two spectra.
(ϩ)-catechin 1 with 1.1 equivalents of dichlorodiphenylmeth-
ane and 5 equivalents of potassium carbonate in acetonitrile
starting at 0 ЊC to room temperature (Table 1, entry 6) gave
the target compound 2 with a yield of 15%. Variation of the
quantity of dichlorodiphenylmethane or base led to compar-
able yields ranging from 10–15% (entries 7 and 8). A slight
improvement of yield was gained using triethylamine as base,
which afforded compound 2 in up to 22% (entries 1–3). Also,
of H6 at δ = 6.07 ppm and H8 at δ = 5.96 ppm) obtained by
one-dimensional nuclear Overhauser effect spectroscopy on the
major compound 3: spectrum 1 with sustained off-resonance
irradiation, spectrum 2 with irradiation of the resonance fre-
quency of the methyl peak (δ = 3.75), and curve 3 exhibits the
822
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Table 1 Reaction of (ϩ)-catechin 1 with dichlorodiphenylmethane (Ph2CCl2)a
Entry
Base (equiv.)
Ph2CCl2/equiv.
Time/h
T /ЊCb
Yield (%)
1
2
3
4
5
6
7
8
Et3N (5)
Et3N (2)
Et3N (5)
Et3N (5)
Et3N (5)
K2CO3 (5)
K2CO3 (2)
K2CO3 (5)
1.1
1.1
3
1.1
1.1
1.1
1.1
3
12
12
12
12
24
12
12
12
20
20
20
80
20
20
20
20
22
15
18
20
22
15
10
15
a Reactions were performed using (ϩ)-catechin 1 (1.72 mmol) and dichlorodiphenylmethane (Ph2CCl2) in 30 mL of acetonitrile. b All reactions
were started at 0 ЊC.
Scheme 2 Reagents, conditions and yields: (i) Me2SO4 (1 eq.), K2CO3 (1.1 eq.), rt, 3 d (3 63%, 4 7%); (ii) Me2SO4 (3 eq.), K2CO3 (3 eq.), reflux, 5 h
(5 90%); (iii) H2, atmospheric pressure, Pd(OH)2, THF–Et2O, rt, (6 92%, 7 86%, 8 90%).
difference of the two first spectra. So we can note that the
intensity of the H6 signal was decreased by irradiation of the
resonance frequency of the methyl peak while the intensity of
the H8 peak was not affected, indicating that the methyl group
is located at the 5 position. For the minor compound, both
protons were affected by the irradiation of the methyl peak
confirming that methylation occurred at the 7 position.
products. Furthermore, catechin exists in the solid form either
as the pure compound or as an hydrate with very different
melting points (175–177 ЊC and 93–96 ЊC respectively). So, the
optical rotation power and melting points reported here may be
affected by the presence of impurities or water of crystallis-
ation ascertained by some poor elemental microanalysis of the
synthesized compounds after the final deprotection step.
These experiments suggest that the major isomer is com-
pound 3. Moreover, an exhaustive methylation (3 equivalents of
dimethyl sulfate, 3 equivalents of potassium carbonate, reflux
for 5 h) of compound 2 led to the dimethylated compound 5
with a high yield (90%). Final deprotection of the catechol
group by hydrogenolysis on palladium hydroxide in EtOH–
THF (1 : 2) at room temperature delivered millimolar quantities
of pure compounds 6–8 with very acceptable yields. In a pre-
liminary communication13 we reported antioxidant properties
of compounds 6, 7, and 8 but no experimental details of their
syntheses were given. Yet, to the best of our knowledge
5-methylcatechin has not been described previously. 1H and
13C spectra are in agreement with the previously described
7-methylcatechin.25 The melting point of compound 8 is in
agreement with those previously reported.17a,b,26 The observed
optical rotatory powers for compounds 7 and 8 (ϩ 6.0Њ, ϩ 9Њ
respectively) are quite different from the values previously
described (ϩ15Њ and Ϫ2Њ respectively) for natural prod-
ucts.17a,b,25,26 However in the flavan-3-ol series the optical
rotatory power is very sensitive to the substitution pattern;
catechin and epicatechin which differ only by the configuration
of the C3 carbon have optical rotatory powers of opposite signs
(ϩ16Њ and Ϫ51Њ respectively). So the optical rotatory power is
very sensitive to traces of similar compounds, which are dif-
ficult to purify in the case of a complex mixture of natural
Synthesis of dimethylated catechin derivative on ring B
The crucial step in the synthesis of compounds methylated on
the B ring consists of the selective and successive protection of
rings B and A . Indeed, after protecting the B ring catechol
moiety selectively, we had to find a protection of ring A whose
deprotection conditions were different from those of the B ring
protection, to allow selective deprotection of the B ring and so
selective methylation on ring B.
Unlike A ring methylated derivatives 6–8, the dimethylated
compound and the two monomethylated compounds were
synthesized by two different methods: while the 3Ј,4Ј-
(diphenylmethylenedioxy)catechin 2 initiated the synthesis of
3Ј,4Ј-dimethylcatechin (Scheme 3) the two hydroxysilyl mono
ethers 16a,b led to the two isomeric monomethylcatechins
(Scheme 4).
Scheme 3 shows the synthesis of 3Ј,4Ј-dimethylcatechin,
which involved as a key step the formation of the 3,5,7-
triacetate derivative of catechin 9 readily obtained after acetyl-
ation of 3Ј,4Ј-(diphenylmethylenedioxy)catechin 2 by action
of acetic anhydride in the presence of pyridine in very good
yield (90%). Hydrogenolysis of this product by treatment
with palladium hydroxide in THF followed by the action of
dimethyl sulfate and potassium carbonate in acetone allowed
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Scheme 3 Reagents, conditions and yields: (i) Ac2O, pyridine, rt, 10 h (90%); (ii) H2, atmospheric pressure, Pd(OH)2, THF–Et2O, rt; (iii) Me2SO4
(3 eq.), K2CO3 (3 eq.), reflux, 5 h (88%); (iv) Na2SO3, MeOH, rt, 3 h (90%); (v) BnBr, K2CO3, DMF (85%); (vi) MeONa, MeOH, rt, 30 min (92%);
(vii) H2, Pd–C, THF, rt, 10 h (96%).
Scheme 4 Reagents, conditions and yields: (i) Cl2Si(t-Bu)2, CH3CN, 0 ЊC to rt, 12 h; (ii) chromatography on silica gel, acetone–petroleum ether
60:40 (16a ϩ 16b 75%); (iii) BnBr, K2CO3, DMF (17a ϩ 17b 70%); (iv) Bu4NF, THF, rt, 30 min (18a ϩ 18b 93%); (v) Me2SO4 (3 eq.), K2CO3 (3 eq.),
reflux, 4 h (19 35%, 20 30%); (vi) H2, atmospheric pressure, Pd–C, THF, rt, 10 h (21 85%, 22 87%).
the methylation of the free hydroxys in position 3Ј and 4Ј and
delivered the triacetate compound 10 in a quantitative way.
The usual deprotection of phenyl acetates in slightly basic
medium led to the formation of a complex mixture of tars in
the case of compound 10. In order to deprotect the phenol
acetate we thought that a reagent both nucleophilic and reduc-
tive would give the desired deprotected products. Indeed,
sodium borohydride gave a better result giving diol 11 in 60%
yield. Gratifyingly, the rarely employed method using sodium
sulfite27 in methanol led to the removal of acetyl protecting
groups on ring A and gave straightforward access to compound
11 with an excellent yield (90%). Unfortunately all attempts to
deacetylate the C ring by this protocol were unrewarding. So,
a reprotection step was a prerequisite to the deacetylation of
the hydroxy group at the 3 position. Treatment of compound 11
with benzyl bromide followed by the action of sodium meth-
oxide afforded the expected product 13 in 78% yield. Final
removal of the benzyl protecting group delivered the 3Ј,4Ј-
dimethylcatechin 14 with quite a good yield (53% over the last
seven steps). The melting point of 3Ј,4Ј-dimethylcatechin 14
(247–248 ЊC) is in agreement with the only value previously
described (246–247 ЊC).17b
Synthesis of monomethylated catechin derivatives of ring B
For the synthesis of the two monomethylated isomers of the
(ϩ)-catechin in position 3Ј or 4Ј 21 and 22, we decided to adopt
an alternative strategy which is depicted in Scheme 4, based
on the use of di-tert-butyldichlorosilane instead of dichloro-
diphenylmethane during the protection of the B ring hydroxy.
Indeed during the screening for protection of the catechol ring
of cycle B in catechin we observed the cleavage of the O–Si
bond and the formation of two hydroxysilyl ethers, 16a,b, of 1
(with a ratio 1 : 1) during purification by chromatography on
silica gel. The instability of this protecting group opened new
and expeditious syntheses of monomethylated derivatives of
(ϩ)-catechin in position 3Ј or 4Ј. This protocol proceeded in
four steps (see Scheme 4) from the two hydroxysilyl ethers. The
first one consisted of a benzylation of the phenolic hydroxys of
triols 16a,b under standard conditions (BnBr, K2CO3 in DMF
824
J. Chem. Soc., Perkin Trans. 1, 2002, 821–830

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Scheme 5 Reagents, conditions and yields: (i) CH3I (4 eq.), K2CO3 (4 eq.), rt, 12 h (23a ϩ 23b 83%); (ii) Bu4NF, THF, rt, 30 min; (iii) HPLC RP C18
(24 35% ϩ 25 40%).
at room temperature for 10 h). Compounds 17a,b were sub-
sequently subjected to a fluoride ion source to induce desilyl-
ation. The reaction proceeded smoothly at room temperature
(using tetrabutylammonium fluoride as initiator) and gave the
expected desilylated products 18a,b in high yield (93%). These
compounds were then easily methylated by treatment with
dimethyl sulfate and potassium carbonate in acetone to
afford a mixture of derivatives 19 and 20. Subsequent separ-
ation of this mixture by flash column chromatography and
successive recrystallizations from petroleum ether–AcOEt
followed by final removal of the benzyl protecting groups
completed the synthesis of the target compounds 21 and 22.
The position of the methyl groups in both compounds were
assigned from LC-ESI-MS/MS experiments16a and confirmed
by one-dimensional NOE experiments. Compound 21 with a
methyl group at the 4Ј position showed a strong enhancement
of the intensity of the doublet at 6.91 ppm upon irradiation of
the resonance frequency of the methyl group (3.83 ppm)
whereas the 3Ј-methyl ether of (ϩ)-catechin (compound 22)
gave a strong enhancement of the intensity of the doublet at
7.02 ppm by irradiation of the resonance frequency of the
methyl peak (3.84 ppm). 3Ј-Methylcatechin has been reported
many times in the literature28 but has never been chemically
characterized, so our physical data cannot be compared
with literature values. The reported melting point for 4Ј-
methylcatechin varies in a wide range (152 ЊC–228 ЊC)16b,29 and
the value for compound 22 (186–187 ЊC) lies between these two
extremes. The observed optical rotatory power is in rough
agreement with the value previously reported (ϩ4.0Њ and ϩ6.7Њ
respectively).29
Conclusion
This work describes the first chemical syntheses of 3Ј- and
4Ј-methylcatechin, the major metabolites of catechin in humans
and rats respectively. These metabolites are not available from
natural sources but deserved biological studies as they are more
abundant than the parent flavan-3-ol in plasma. Furthermore
the two other monomethylated isomers of (ϩ)-catechin in
positions 5 and 7, two dimethylated derivatives: 5,7-dimethyl-
catechin and 3Ј,4Ј-dimethylcatechin and two trimethylated
isomers of (ϩ)-catechin in positions 3Ј, 5, 7 and 4Ј, 5, 7 respect-
ively were also obtained. These trimethylated and dimethyl
analogues bearing only one or two free phenolic groups are key
model compounds for establishing reliable structure–activity
relationships in biological tests and for the determination of
thermodynamic constants.18 The key step of this synthesis is the
differentiation of the catechol B ring of catechin from the
resorcinol-like A ring by the formation of permanent or
transient dioxolanes. Until now acetylation has been limited
mainly to increase the solubility of polyphenols as no efficient
deprotection was available. We have shown that the use of a
nucleophilic reducing reagent like sodium sulfite allows the
quantitative deprotection of the acetylated phenolic hydroxys
in catechin. The efficiency of the methodology and the bio-
logical need deserves further work to expand the scope of these
reactions to other flavan-3-ols. The syntheses of more polar
catechin metabolites such as sulfated and glucuronidated
compounds are currently under investigation in our laboratory.
Experimental
Tetrahydrofuran (THF) was distilled from sodium benzo-
phenone ketyl under Ar before use and NEt3 was distilled from
CaH2. For flash chromatography, Merck silica-gel 60 (230–400
mesh ASTM) was used. The melting points were taken on a
Reichert-Thermopan apparatus and are not corrected. NMR:
Bruker AM 300 (300 and 75 MHz, for 1H and 13C NMR,
respectively) and AM 600 (600 MHz for 1H) for NOE, NOESY
and ROESY experiments. For 1H and 13C NMR, CDCl3,
[D6]acetone, [D4]MeOH, and [D6]DMSO were used as solvents,
TMS as an internal standard. J values are given in Hz. MS
experiments (Electronic Ionization, Chemical Ionization) were
carried out on a JEOL mass Station 700 spectrometer. Micro-
analyses were performed by the CNRS “Service central
d’analyse” (Vernaison, France); for each sample carbon,
hydrogen and oxygen contents were determined.
Synthesis of trimethylated isomers of (؉)-catechin
The syntheses of the two trimethylated isomers of (ϩ)-catechin
in positions 3Ј, 5, 7 and 4Ј, 5, 7 respectively was ensured
according to the same synthetic approach described for the two
monomethylated compounds 21 and 22 (Scheme 5).
Starting from a mixture of compounds 16a,b we envisioned
the methylation of the three free phenolic functions. Reaction
of compounds 16a,b with dimethyl sulfate and potassium
carbonate in acetone at reflux led to the partial removal of the
hydroxysilyl function and furnished the tetramethylated isomer
of catechin. However, treatment of compounds 16a,b with
methyl iodide (4 equivalents), potassium carbonate (4 equiv-
alents) in DMF at room temperature during one night gave
access to a 50 : 50 mixture of trimethylated catechin derivatives
23a,b. Final deprotection with tetrabutylammonium fluoride,
delivered compounds 24 and 25 in a 1 : 1 ratio. The separation
of these compounds was accomplished by preparative HPLC
(Scheme 5). The position of the methyl groups in both
compounds 24 and 25 were determined from 1H NMR spectra
and confirmed by a ROESY experiment. To the best of
our knowledge 3Ј,5,7-trimethylcatechin has not been described
previously, 4Ј,5,7-trimethylcatechin has been isolated from
Cinnamomun cassia. The melting point of compound 25 is
higher than those previously reported (154–155 ЊC versus
125 ЊC) but exhibits a similar rotatory power.30
(2R,3S)-2-(2,2-Diphenylbenzo[1,3]dioxol-5-yl)chroman-3,5,7-
triol (2)
To a stirred solution of (ϩ)-catechin 1 (500 mg, 1.72 mmol)
in acetonitrile (30 mL) was added triethylamine (1.2 mL,
8.6 mmol) and dichlorodiphenylmethane (0.36 mL, 1.9 mmol)
over 30 min at 0 ЊC and under Ar. When addition was complete,
the reaction mixture was stirred at room temperature for 12 h.
The resulting mixture was washed with water (30 mL). The
aqueous layer was extracted twice with AcOEt (2 × 50 mL). The
organic layer was then dried over MgSO4. The dried extract was
J. Chem. Soc., Perkin Trans. 1, 2002, 821–830
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concentrated in vacuo to afford a brown oil. The crude product
was separated by flash column chromatography using AcOEt–
hexane (75 : 25) as eluent and finally recrystallized from
acetone, yielding protected catechin 2 (172 mg, 22%) as a pale
yellow solid which is an hydrate according to the elemental
analysis data, mp 121–122 ЊC (Found: C, 68.79; H, 5.68%;
C28H22O6ؒ2H2O requires C, 68.56; H, 5.34%; [α]2D0 ϩ20.4Њ (c 0.9
in acetone); λmax (CH3CN)/nm 217 (ε/dm3 molϪ1 cmϪ1 5600),
286 (1980); δH (300 MHz, CD3OD) 2.48 (1 H, dd, J 16.0 and
8.8, 4a-H), 2.90 (1 H, dd, J 16.0 and 5.4, 4b-H), 3.93 (1 H, m,
3-H), 4.55 (1 H, d, J 8.0, 2-H), 5.84 (1 H, d, J 2.0, 8-H), 5.93
(1 H, d, J 2.0, 6-H), 6.88–6.91 (2 H, m, 6Ј-H and 5Ј-H), 6.97
(1 H, s, 2Ј-H), 7.33–7.41 (6 H, m, Ph), 7.52–7.60 (4 H, m, Ph); δC
(75 MHz, CD3OD) 30.7, 68.2, 82.7, 95.3, 96.2, 100.6, 108.5,
108.6, 122.5, 127.3, 129.3, 130.2, 134.7, 141.4, 147.8, 156.7,
157.1, 157.7; m/z (EI, 70 eV) 454 (Mϩ, 64%), 316 (100), 287 (28),
239 (52), 165 (27), 105 (18); m/z (CI, NH3) 455 (100%), 216 (10);
HR m/z (EI) 454.1412 1 ppm C28H22O6.
(Mϩ, 35%), 316 (100), 287 (74), 239 (68), 153 (53), 105 (38), 77
(21); m/z (CI, NH3) 469 (100%), 317 (27%); HR m/z (EI)
468.1570 0.5 ppm C29H24O6.
(2R,3S)-2-(2,2-Diphenylbenzo[1,3]dioxol-5-yl)-7-methoxy-
chroman-3,5-diol (4). Yield 7%; mp 111–112 ЊC; [α]2D0 ϩ17.0Њ
(c 0.57, acetone); λmax (CH3CN)/nm 209 (ε/dm3 molϪ1 cmϪ1
2250), 284 (350); δH (300 MHz, [D6]acetone) 2.54 (1 H, dd,
J 16.2 and 8.8, 4a-H), 2.96 (1 H, dd, J 16.2 and 5.6, 4b-H), 3.67
(3 H, s, OMe), 3.97–4.05 (2 H, m, 3-H and OH), 4.62 (1 H, d,
J 8.1, 2-H), 5.95 (1 H, d, J 2.2, 8-H), 6.07 (1 H, d, J 2.2, 6-H),
6.88 (1 H, d, J 8.1, 6Ј-H), 6.90 (1 H, d, J 8.1, 5Ј-H), 6.98 (1 H, s,
2Ј-H), 7.34–7.39 (6 H, m, Ph), 7.52–7.56 (4 H, m, Ph); δC (75
MHz, [D6]acetone) 29.0, 55.3, 68.1, 82.8, 93.4, 95.3, 101.8,
108.5, 108.7, 122.5, 126.9, 129.2, 130.0, 134.6, 141.4, 147.8,
148.6, 156.7, 157.1, 158.0; m/z (EI, 70 eV) 468 (Mϩ, 54%), 316
(100), 287 (26), 239 (51), 165 (35), 153 (33), 105 (27); m/z
(CI, NH3) 469 (100%); HR m/z (EI) 468.1572
0.1 ppm
C29H24O6.
(2R,3S)-2-(2,2-Diphenylbenzo[1,3]dioxol-5-yl)-5,7-dimethoxy-
chroman-3-ol (5)
General procedure for the deprotection of ring B (access to
products 6–8)
A solution of compound 2 (500 mg, 1 mmol), potassium
carbonate (420 mg, 3 mmol) and dimethyl sulfate (0.3 mL,
3 mmol) in acetone (50 mL) was refluxed for 5 h. Acetone was
removed under vacuum and the resulting mixture was washed
with water (30 mL). The aqueous layer was extracted with
AcOEt (3 × 50 mL). The solvent was removed under vacuum
and the residue was purified by flash column chromatography
with AcOEt–hexane (50 : 50) as eluent. Recrystallization from
acetone afforded the dimethylcatechin derivative 5 (480 mg,
90%) as a colourless oil; [α]2D0 3.0Њ (c 1.3, CHCl3); δH (300 MHz,
CDCl3) 2.51 (1 H, dd, J 16.3 and 8.8, 4a-H), 2.93 (1 H, dd,
J 16.3 and 5.6, 4b-H), 3.72 (3 H, s, OMe), 3.78 (3 H, s, OMe),
4.01–4.08 (1 H, m, 3-H), 4.15 (1 H, d, J 5.0, OH), 4.62 (1 H, d,
J 8.1, 2-H), 6.03 (1 H, d, J 2.2, 8-H), 6.12 (1 H, d, J 2.2, 6-H),
6.93–6.98 (2 H, m, 6Ј-H and 5Ј-H), 7.04 (1 H, s, 2Ј-H), 7.37–
7.44 (6 H, m, aromatic H), 7.56–7.63 (4 H, m, aromatic H); δC
(75 MHz, CDCl3) 27.5, 55.3, 55.5, 68.1, 81.8, 91.9, 92.9, 101.6,
107.3, 108.5, 121.4, 126.3, 128.3, 129.2, 131.6, 140.1, 147.6,
148.8, 155.2, 158.7, 159.7; m/z (EI, 70 eV) 482 (Mϩ, 78%) 316
(51), 239 (42), 167 (100), 105 (22); m/z (CI, NH3) 483 (100%);
HR m/z (EI) 482.1727 0.6 ppm C30H26O6.
10% Palladium hydroxide on carbon (0.018 mmol) was added
to a stirring solution of flavanol 3, 4 or 5 (0.18 mmol) in EtOH–
THF (1 : 2, 20 mL) under an atmosphere of hydrogen. The
suspension was stirred overnight and then the solution was fil-
tered through a plug of Celite eluting with EtOH (20 mL) and
CH2Cl2 (20 mL). The filtrate was concentrated under vacuum
and the resulting solid recrystallized from EtOH to give the
flavanol 6, 7 or 8.
(2R,3S)-2-(3Ј,4Ј-Dihydroxyphenyl)-5-methoxychroman-3,7-
diol (6). Yield 92%; mp 222–223 ЊC (Found: C, 63.23; H, 5.88%;
C16H16O6 requires C, 63.15; H, 5.30%; C16H16O6ؒH2O requires
C, 59.62; H, 5.63%; [α]2D0 Ϫ1.2Њ (c 0.85, acetone); λmax (CH3CN)/
nm 210 (ε/dm3 molϪ1 cmϪ1 3990), 282 (600); δH (300 MHz,
[D6]acetone) 2.49 (1 H, dd, J 16.2 and 8.0, 4a-H), 2.85 (1 H, dd,
J 16.2 and 5.2, 4b-H), 3.75 (3 H, s, OMe), 3.95–3.99 (2 H, m,
3-H and OH), 4.56 (1 H, d, J 7.3, 2-H), 5.95 (1 H, d, J 2.2, 8-H),
6.04 (1 H, d, J 2.2, 6-H), 6.73–6.89 (3 H, m, 6Ј-H, 5Ј-H, 2Ј-H),
7.86 (1 H, s, OH), 7.90 (1 H, s, OH), 8.17 (1 H, s, OH); δC
(75 MHz, [D6]acetone) 28.6, 55.6, 68.1, 82.6, 92.4, 96.0, 101.4,
115.1, 115.6, 119.9, 132.0, 145.5, 145.6, 156.4, 157.9, 159.6;
m/z (EI, 70 eV) 304 (Mϩ, 34%), 167 (18), 153 (100), 123 (33); m/z
(CI, NH3) 305 (100), 219 (5); HR m/z (EI) 304.0951 1.3 ppm
C16H16O6.
General procedure for the synthesis of the two monomethyl
catechin isomers 3, 4
A solution of compound 2 (300 mg, 0.6 mmol), potassium
carbonate (105 mg, 0.66 mmol) and dimethyl sulfate (0.13 mL,
0.66 mmol) in acetone (30 mL) was stirred at room temperature
under Ar for 3 days. Acetone was removed under vacuum and
water (30 mL) was added to the reaction mixture. The aqueous
layer was extracted with AcOEt (3 × 30 mL). The organic layer
was dried (MgSO4) and the residue obtained after removal
of the solvent was purified by flash column chromatography
using AcOEt–hexane (30 : 70) as eluent to afford the two mono-
methyl ethers 3 and 4 in a ratio 9 : 1 (70% yield) and a trace of
dimethylated compound 5.
(2R,3S)-2-(3’,4’-Dihydroxyphenyl)-7-methoxychroman-3,5-
diol (7).25 Yield 86%; mp 205–206 ЊC; [α]2D0 ϩ6.0Њ (c 0.48, acet-
one); λmax (CH3CN)/nm 208 (ε/dm3 molϪ1 cmϪ1 3850), 284 (460);
δH (300 MHz, [D6]acetone) 2.50 (1 H, dd, J 16.2 and 8.1, 4a-H),
2.87 (1 H, dd, J 16.2 and 5.3, 4b-H), 3.77 (3 H, s, OMe), 3.92–
3.96 (2 H, m, 3-H and OH), 4.59 (1 H, d, J 7.3, 2-H), 5.98 (1 H,
d, J 2.2, 8-H), 6.06 (1 H, d, J 2.2, 6-H), 6.70–6.85 (3 H, m, 6Ј-H
and 5Ј-H and 2Ј-H), 7.85 (1 H, s, OH), 7.90 (1 H, s, OH), 8.15
(1 H, s, OH); δC (75 MHz, [D6]acetone) 28.5, 55.6, 68.0, 82.9,
92.7, 94.8, 101.6, 115.2, 115.7, 119.8, 131.9, 145.5, 145.7, 156.5,
157.8, 159.5.
(2R,3S)-2-(2,2-Diphenylbenzo[1,3]dioxol-5-yl)-5-methoxy-
chroman-3,7-diol (3). Yield 63%; mp 179–180 ЊC; [α]2D0 ϩ4.7Њ
(c 1.3, acetone); λmax (CH3CN)/nm 208 (ε/dm3 molϪ1 cmϪ1
2250), 284 (250); δH (300 MHz, [D6]acetone) 2.48 (1 H, dd,
J 16.3 and 8.7, 4a-H), 2.90 (1 H, dd, J 16.3 and 5.6, 4b-H), 3.75
(3 H, s, OMe), 3.96–4.03 (1 H, m, 3-H), 4.08 (1 H, d, J 5.0, OH),
4.60 (1 H, d, J 8.1, 2-H), 5.96 (1 H, d, J 2.2, 8-H), 6.07 (1 H, d,
J 2.2, 6-H), 6.92 (1 H, d, J 8.1, 6Ј-H), 6.95 (1 H, d, J 8.1, 5Ј-H),
7.04 (1 H, s, 2Ј-H), 7.40–7.46 (6 H, m, aromatic H), 7.59–7.63
(4 H, m, aromatic H); δC (75 MHz, [D6]acetone) 29.3, 55.6, 68.0,
82.7, 92.5, 96.1, 101.7, 108.5, 108.7, 122.4, 126.8, 129.2, 130.2,
134.6, 141.5, 147.8, 151.3, 156.5, 158.3; m/z (EI, 70 eV) 468
(2R,3S)-4-(3-Hydroxy-5,7-dimethoxychroman-2-yl)benzene-
1,2-diol (8).26,17a,17c Yield 90%; mp 219–220 ЊC (Found: C, 61.43;
H, 5.70%; C17H18O6ؒH2O requires C, 60.71; H, 5.99%); [α]2D0
ϩ9.0Њ (c 0.69, acetone); λmax (CH3CN)/nm 208 (ε/dm3 molϪ1
cmϪ1 4390), 228 (1440), 280 (500); δH (300 MHz, [D6]acetone)
2.50 (1 H, dd, J 16.3 and 8.3, 4a-H), 2.86 (1 H, dd, J 16.3 and
5.4, 4b-H), 3.76 (3 H, s, OMe), 3.78 (3 H, s, OMe), 3.97–4.02
(1 H, m, 3-H), 4.59 (1 H, d, J 7.6, 2-H), 6.03 (1 H, d, J 2.2, 8-H),
6.11 (1 H, d, J 2.2, 6-H), 6.75 (1 H, dd, J 8.1 and 2.2, 6Ј-H), 6.79
(1 H, d, J 8.1, 5Ј-H), 6.88 (1 H, d, J 2.2, 2Ј-H); δC (75 MHz,
826
J. Chem. Soc., Perkin Trans. 1, 2002, 821–830

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[D6]acetone) 28.5, 55.4, 55.7, 68.0, 82.7, 91.9, 93.9, 102.6, 115.1,
115.7, 119.9, 131.9, 145.5, 145.6, 156.5, 159.5, 160.6; m/z (EI,
70 eV) 318 (Mϩ, 42%), 167 (100); m/z (CI, NH3) 319 (100); HR
m/z (EI) 318.1100 1.0 ppm C17H18O6.
60.31; H, 5.86%; [α]2D0 ϩ1.5Њ (c 0.49, acetone); δH (300 MHz,
CDCl3) 1.91 (3 H, s, OAc), 2.63 (1 H, dd, J 16.2 and 7.3, 4a-H),
2.88 (1 H, dd, J 16.2 and 5.2, 4b-H), 3.79 (3 H, s, OMe), 3.82
(3 H, s, OMe), 4.94 (1 H, d, J 7.3, 2-H), 5.27–5.31 (1 H, m, 3-H),
5.92 (1 H, d, J 2.2, 8-H), 6.04 (1 H, d, J 2.2, 6-H), 6.77–6.96
(3 H, m, 6Ј-H and 5Ј-H and 2Ј-H); δC (75 MHz, CDCl3) 21.0,
24.0, 55.9, 69.4, 79.2, 95.6, 95.9, 99.4, 109.7, 110.9, 119.4, 130.2,
148.8, 155.2, 155.3, 155.8, 170.8; m/z (EI, 70 eV) 360 (Mϩ, 13%),
342 (14), 314 (55), 300 (91), 299 (40), 180 (100), 151 (36); m/z
(CI, NH3) 361 (100%); HR m/z (CI, NH3) [M ϩ Hϩ] 361.1290
0.8 ppm C19H21O7.
Acetic acid 3,5-diacetoxy-2-(2,2-diphenylbenzo[1,3]dioxol-5-
yl)chroman-7-yl ester (9)
A solution of compound 2 (850 mg, 1.72 mmol), pyridine
(0.7 mL, 8.6 mmol) and acetic anhydride (2.43 mL, 25.8 mmol)
was stirred at room temperature for 10 h. The excess of acetic
anhydride and pyridine was removed in vacuo and the residue
was purified by flash column chromatography with AcOEt–
hexane (60 : 40) as eluent to afford compound 9 (977 mg, 90%)
as a white crystalline material, mp 78–79 ЊC (Found: C, 69.52;
H, 4.73%; C34H28O9ؒH2O requires C, 68.22; H, 5.05%; C34H28O9
requires C, 70.34; H, 4.86%; [α]2D0 ϩ35.0Њ (c 0.57, CHCl3); δH
(300 MHz, CDCl3) 1.94 (3 H, s, OAc), 2.25 (3 H, s, OAc), 2.26
(3 H, s, OAc), 2.62 (1 H, dd, J 16.7 and 6.3, 4a-H), 2.85 (1 H,
dd, J 16.7 and 5.1, 4b-H), 5.04 (1 H, d, J 6.3, 2-H), 5.25 (1 H, m,
3-H), 6.57 (1H, d, J 2.2, 8-H), 6.62 (1 H, d, J 2.2, 6-H), 6.78–
6.86 (3 H, m, 6Ј-H and 5Ј-H and 2Ј-H), 7.35–7.38 (6 H, m, Ph),
7.54–7.58 (4 H, m, Ph); δC (75 MHz, CDCl3) 20.7, 21.0, 21.1,
23.9, 68.4, 78.4, 106.8, 107.6, 108.5, 108.6, 110.3, 120.1, 126.2,
126.3, 128.3, 129.1, 131.1, 140.2, 147.3, 147.5, 149.4, 149.8,
154.7, 168.4, 169.0, 170.2; m/z (EI, 70 eV) 580 (Mϩ, 18%), 520
(32), 461 (100), 316 (53), 239 (39), 105 (28); m/z (CI, NH3) 597
(100%); HR m/z (EI) 580.1727 1.1 ppm C34H28O9.
(2R,3S)-5,7-Bis(benzyloxy)-2-(3Ј,4Ј-dimethoxyphenyl)chroman-
3-yl acetate (12)
A solution of benzyl bromide (0.15 mL, 1.2 mmol) was added
dropwise under Ar to a cooled (0 ЊC) solution of compound
11 (145 mg, 0.4 mmol) and potassium carbonate (165 mg,
1.2 mmol) in DMF (10 mL). Stirring was maintained for
2 hours at 0 ЊC and then allowed to come to room temperature
over 10 hours. The reaction mixture was diluted in 50 mL of
AcOEt, washed with 30 mL of water and 30 mL of brine and
finally dried over MgSO4. Evaporation of the solvent furnished
an oily product which was purified by flash column chrom-
atography using AcOEt–hexane (35 : 65) as eluent to give prod-
uct 12 (185 mg, 85%) as a colourless oil, [α]2D0 ϩ27.8Њ (c 0.65,
CHCl3); δH (300 MHz, CDCl3) 1.95 (3 H, s, OAc), 2.71 (1 H, dd,
J 16.8 and 6.8, 4a-H), 2.96 (1 H, dd, J 16.8 and 5.5, 4b-H), 3.82
(3 H, s, OMe), 3.86 (3 H, s, OMe), 5.02–5.04 (5 H, m, 2 OBn
and 2-H), 5.36–5.42 (1 H, m, 3-H), 6.16 (1 H, d, J 2.2, 8-H),
6.28 (1 H, d, J 2.2, 6-H), 6.78–6.93 (3 H, m, 6Ј-H and 5Ј-H and
2Ј-H), 7.30–7.45 (10 H, m, Ph); δC (75 MHz, CDCl3) 21.1, 24.2,
55.9, 69.0, 70.0, 70.1, 78.3, 93.8, 94.4, 101.4, 109.5, 111.0, 119.2,
127.3, 127.6, 127.9, 128.0, 128.5, 128.6, 130.2, 136.8, 148.9,
154.9, 157.7, 158.9, 170.2.
(2R,3S)-5,7-Diacetoxy-2-(3Ј,4Ј-dimethoxyphenyl)chroman-3-yl
acetate (10)
A suspension of compound 9 (300 mg, 0.52 mmol) in THF
(30 mL) was vigorously stirred with palladium hydroxide (10%)
under an atmosphere of hydrogen. The reaction mixture was
stirred for 12 h, filtered on Celite, and CH2Cl2 (20 mL) was
added. The organic layer was dried over MgSO4. Concentration
in vacuo left an oily product which was used without any more
purification.
(2R,3S)-5,7-Bis(benzyloxy)-2-(3Ј,4Ј-dimethoxyphenyl)chroman-
3-ol (13)
A solution of this product (200 mg, 0.48 mmol), potassium
carbonate (200 mg, 1.44 mmol) and dimethyl sulfate (0.14 mL,
1.44 mmol) in acetone (30 mL) was refluxed for 5 h. After
removal of the solvent, water (30 mL) and AcOEt (40 mL) were
added to the reaction mixture. The organic layer was dried
(MgSO4) and the product obtained was purified by flash col-
umn chromatography with AcOEt–hexane (40 : 60) as eluent
and recrystallized from methanol to give compound 10 (202
mg, 88%) as a colourless oil (Found: C, 59.66; H, 5.67%;
C23H24O9ؒH2O requires C, 59.74; H, 5.67%; [α]2D0 Ϫ23.0Њ (c 0.15,
CHCl3); δH (300 MHz, CDCl3) 1.90 (3 H, s, OAc), 2.26 (6 H, s, 2
OAc), 2.65 (1 H, dd, J 16.6 and 6.7, 4a-H), 2.85 (1 H, dd, J 16.6
and 5.2, 4b-H), 3.83 (3 H, s, OMe), 3.85 (3 H, s, OMe), 5.07
(1 H, d, J 5.2, 2-H), 5.30 (1 H, m, 3-H), 6.55 (1 H, d, J 2.2, 8-H),
6.64 (1 H, d, J 2.2 6-H), 6.82–6.89 (3 H, m, 6Ј-H and 5Ј-H and
2Ј-H); δC (75 MHz, CDCl3) 20.8, 21.0, 21.2, 24.3, 55.9, 56.1,
68.5, 78.2, 106.7, 107.8, 109.4, 109.5, 110.7, 119.4, 130.3, 147.4,
148.1, 154.8, 157.7, 159.0, 168.6, 169.0, 170.3.
A solution of MeONa (15 mL prepared from sodium (1 g) and
methanol (40 mL)) was added dropwise to a solution of
compound 12 (340 mg, 0.63 mmol) in 15 mL of CH2Cl2 at
room temperature with stirring under Ar. The reaction mixture
was stirred for an additional 30 min and after removal of the
solvent, washed with water (30 mL) and extracted with CH2Cl2
(3 × 40 mL). The organic layer was separated, rinsed with
brine, dried (MgSO4) and concentrated to dryness. The crude
product was finally purified by flash column chromatography
with AcOEt–hexane (40 : 60) as eluent and recrystallized from
hexane–CH2Cl2 to afford compound 13 (290 mg, 92%) as a
pale yellow solid, mp 115–116 ЊC (Found: C, 72.80; H, 6.29%;
C31H30O6ؒH2O requires C, 72.08; H, 6.24%; [α]2D0 Ϫ5.0Њ (c 0.79,
CHCl3); δH (300 MHz, CDCl3) 2.66 (1 H, dd, J 16.3 and 9.2,
4a-H), 3.18 (1 H, dd, J 16.3 and 5.3, 4b-H), 3.89 (3 H, s, OMe),
3.90 (3 H, s, OMe), 4.09 (1 H, m, 3-H), 4.67 (1 H, d, J 9.2, 2-H),
4.99 (2 H, s, CH2-Bn), 5.03 (2 H, s, CH2-Bn), 6.23 (1 H, d, J 2.2,
8-H), 6.27 (1 H, d, J 2.2, 6-H), 6.89–7.01 (3 H, m, 6Ј-H and 5Ј-H
and 2Ј-H), 7.31–7.46 (10 H, m, Ph); δC (75 MHz, CDCl3) 27.9,
55.8, 55.9, 68.2, 69.9, 70.1, 93.8, 94.4, 102.4, 109.9, 111.2, 120.0,
127.1, 127.5, 127.9, 128.0, 128.5, 128.6, 130.2, 136.9, 148.9,
149.3, 155.4, 157.8, 158.8; m/z (EI, 70 eV) 498 (Mϩ, 18%), 292
(61), 263 (94), 149 (49), 91 (100), 77 (58); m/z (CI, NH3) 499,
(2R,3S)-3Ј,4Ј-Dimethoxyphenyl-5,7-dihydroxychroman-3-yl
acetate (11)
To a solution of 500 mg (1.12 mmol) of compound 10 in 10 mL
of methanol was added a solution of 500 mg (3.97 mmol) of
sodium sulfite in 10 mL of water. After stirring the reaction
mixture for 3 h under nitrogen, the methanol was flash evapor-
ated (45 ЊC) and the remaining aqueous layer extracted with
diethyl ether (3 × 40 mL). Drying (MgSO4) and evaporation of
the ether gave a product which was purified by flash column
chromatography with AcOEt–hexane (40 : 60) as eluent to
afford compound 11 (365 mg, 90%) as a white solid, mp 90–91
ЊC (Found: C, 60.29; H, 5.87%; C19H20O7ؒH2O requires C,
423; HR m/z (CI, NH3) [M ϩ Hϩ] 499.2116
0.9 ppm
C31H31O6.
(2R,3S)-2-(3Ј,4Ј-Dimethoxyphenyl)chroman-3,5,7-triol
(14)16b,17b,17c,30
A suspension of compound 13 (200 mg, 0.4 mmol) in THF
(15 mL) was stirred with activated Pd–C (10%, 10 mg) under an
atmosphere of hydrogen for 10 h, filtered on Celite and eluted
J. Chem. Soc., Perkin Trans. 1, 2002, 821–830
827

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with EtOH (30 mL) and CH2Cl2 (30 mL). The filtrate was con-
centrated under vacuum and the resulting product 14 was
recrystallized from CHCl3–MeOH to give a white solid (122
mg, 96%); mp 247–248 ЊC (Found: C, 63.10; H, 6.22%;
C17H18O6ؒH2O requires C, 60.71; H, 5.99%; C17H18O6 requires
C, 64.15; H, 5.70%; [α]2D0 ϩ6.0Њ (c 0.33, acetone); λmax (CH3CN)/
nm 211 (ε/dm3 molϪ1 cmϪ1 3600), 282 (550); δH (300 MHz,
[D6]DMSO) 2.36 (1 H, dd, J 16.0 and 8.6, 4a-H), 2.72 (1 H, dd,
J 16.0 and 5.4, 4b-H), 3.73 (6 H, s, 2 OMe), 3.87–3.96 (1 H, m,
3-H), 4.55 (1 H, d, J 8.6, 2-H), 4.95 (1 H, br s, OH), 5.69 (1 H, d,
J 2.2, 8-H), 5.90 (1 H, d, J 2.2, 6-H), 6.86–6.94 (3 H, m, 6Ј-H
and 5Ј-H and 2Ј-H), 8.97 (1 H, br s, OH), 9.23 (1 H, br s, OH);
δC (75 MHz, [D6]DMSO) 31.5, 59.0, 71.4, 85.4, 98.0, 98.9,
103.4, 114.5, 115.2, 123.7, 135.9, 152.8, 159.4, 160.2, 160.4;
m/z (EI, 70 eV) 318 (Mϩ, 65 %), 180 (100), 165 (30), 151 (42);
m/z (CI, NH3) 319 (100 %); HR m/z (EI) 318.1104 0.1 ppm
C17H18O6.
(1 H, d, J 2.2, 6-H), 6.86–7.18 (6 H, m, 2(6Ј-H, 5Ј-H, 2Ј-H)),
7.23–7.49 (30 H, m, Ph); δC (75 MHz, [D6]acetone) 20.8, 27.3,
27.7, 68.2, 68.3, 69.9, 70.1, 71.4, 81.1, 81.7, 93.9, 94.4, 102.3,
102.4, 112.7, 114.1, 120.3, 120.4, 120.8, 121.7, 127.2, 127.5,
127.6, 127.9, 128.0, 128.2, 128.5, 128.6, 128.7, 128.8, 131.1,
135.8, 136.0, 136.9, 137.0, 145.6, 145.7, 149.1, 155.3, 155.4,
157.8, 158.8; m/z (EI, 70 eV) 718 (Mϩ, 24%), 610 (36), 319 (100),
292 (64), 91 (100); m/z (CI, NH3) 719 (M ϩ Hϩ, 100%), 611
(20); HR m/z (EI) 718.3331 0.8 ppm C44H50O7Si.
(2R,3S)-5,7-Bis(benzyloxy)-2-(3Ј-benzyloxy-4Ј-hydroxyphenyl)-
chroman-3-ol and (2R,3S)-5,7-bis(benzyloxy)-2-(4Ј-benzyloxy-
3Ј-hydroxyphenyl)chroman-3-ol (18a,b) (50 : 50 mixture)
A solution of Bu4NF (1 M in THF, 11.2 mL, 11.1 mmol) was
added dropwise to a solution of the compounds 17a,b (1.6 g,
2.3 mmol) in THF (30 mL) at room temperature with stirring
under Ar. The yellow solution was stirred for an additional
30 min, washed with water (30 mL) and extracted with CH2Cl2
(3 × 40 mL). The organic layer was dried (MgSO4) and concen-
trated in vacuo. The crude product was finally purified by flash
column chromatography with AcOEt–hexane (40 : 60) as eluent
to furnish a mixture of two products 18a,b (1.16 g, 93%) as a
pale yellow solid, mp 92–96 ЊC (Found: C, 74.95; H, 6.68%;
C36H32O6ؒH2O requires C, 74.72; H, 5.92%; δH (300 MHz,
CDCl3) 2.58–2.71 (2 H, m, 2 4a-H), 3.07–3.22 (2 H, m, 2 4b-H),
4.01–4.09 (2 H, m, 2 3-H), 4.64 (1 H, d, J 5.7, 2-H), 4.67 (1 H,
d, J 6.0, 2-H), 4.98–5.13 (12 H, m, 6 CH2-Bn), 6.21–6.32
(4 H, m, 2 8-H and 2 6-H), 6.91–7.09 (6 H, m, 2 (6ЈH, 5Ј-H,
2Ј-H)), 7.29–7.51 (30 H, m, Ph); δC (75 MHz, CDCl3) 28.3,
68.1, 68.3, 69.9, 70.1, 71.2, 81.5, 81.8, 93.8, 94.4, 102.2, 102.4,
111.0, 112.2, 113.5, 114.9, 119.2, 121.0, 127.1, 127.5, 127.6,
127.8, 128.0, 128.1, 128.5, 128.6, 128.8, 129.6, 135.9, 136.1,
136.9, 146.1, 146.2, 146.3, 155.3, 157.8, 158.8; m/z (EI, 70 eV)
560 (Mϩ, 14%), 409 (7), 332 (7), 319 (37), 181 (12), 91 (100);
m/z (CI, NH3) 561 (100%); HR m/z (EI) 560.2198 0.1 ppm
C36H32O6.
(2R,3S)-2-[4Ј-(Di-tert-butylhydroxysilyloxy)-3Ј-hydroxy-
phenyl]chroman-3,5,7-triol and (2R,3S)-2-[3Ј-(di-tert-butyl-
hydroxysilyloxy)-4Ј-hydroxyphenyl]chroman-3,5,7-triol (16a,b)
(50 : 50 mixture)
To a stirred solution of (ϩ)-catechin 1 (1 g, 3.45 mmol)
in acetonitrile (50 mL) was added triethylamine (2.4 mL,
17.2 mmol) and di-tert-butyldichlorosilane (1.46 mL, 6.9 mmol)
at 0 ЊC and under Ar. Upon completion of the addition, the
reaction mixture was stirred at room temperature for 12 h and
the resulting mixture washed with water (40 mL). The aqueous
layer was extracted with AcOEt (3 × 40 mL). Drying (MgSO4)
and evaporation of the solvent gave an oily product. The crude
1
product was analyzed by H NMR and illustrated an effective
protection of the catechol group (compound 15). After
purification by flash column chromatography with acetone–
petroleum ether (60 : 40) as eluent, we observed the formation
of a 50 : 50 mixture of two compounds 16a,b (1.16 g, 75%) as a
colourless oil which corresponds to the product of cleavage of
the O–Si bond; δH (300 MHz, [D6]acetone) 1.09 (36 H, br s,
4-tBu), 2.50 (1 H, dd, J 16.0 and 7.9, 4a-H), 2.52 (1 H, dd,
J 16.0 and 8.0, 4b-H), 2.89 (1 H, dd, J 16.0 and 5.1, 4a-H), 2.91
(1 H, dd, J 16.0 and 5.0, 4b-H), 3.96–4.03 (2 H, m, 3-H), 4.52
(1 H, d, J 7.0, 2-H), 4.54 (1 H, d, J 7.2, 2-H), 5.87 (1 H, d, J 2.3,
8-H), 5.88 (1 H, d, J 2.2, 8-H), 6.02 (1 H, d, J 2.3, 6-H), 6.03
(1 H, d, J 2.2, 6-H), 6.75–7.17 (6 H, m, 6Ј-H and 5Ј-H and
2Ј-H); δC (75 MHz, [D6]acetone) 21.3, 26.3, 27.6, 27.7, 68.2,
68.3, 82.4, 82.7, 95.4, 96.0, 100.5, 116.1, 119.8, 120.4, 120.7,
121.2, 133.4, 134.2, 144.2, 147.6, 156.8, 157.1, 157.7; m/z (EI,
70 eV) 448 (Mϩ, 3%), 430 (50), 292 (100), 263 (30), 236 (17),
193 (19), 139 (22); m/z (CI, NH3) 431 (100%); HR m/z (EI)
448.1949 7.0 ppm C23H32O7Si.
General procedure for the preparation of compounds 19 and 20
Compounds 19, 20 were prepared by methylation of the parent
phenolic compounds 18a,b (1 eq.) under standard conditions
[dimethyl sulfate (5 eq.), potassium carbonate (5 eq.), acetone,
reflux 4 h]. The separation of the two isomeric compounds 19
and 20 was effected by flash column chromatography with
AcOEt–hexane (30 : 70) and successive recrystallizations from
petroleum ether–AcOEt.
(2R,3S)-5,7-Bis(benzyloxy)-2-(3Ј-benzyloxy-4Ј-methoxy-
phenyl)chroman-3-ol (19). Yield 30%; mp 131–132 ЊC (Found:
C, 76.11; H, 6.01%; C37H34O6ؒH2O requires C, 74.98; H, 6.12%;
C37H34O6 requires C, 77.33; H, 5.96%; [α]2D0 ϩ3.0Њ (c 0.21,
CHCl3); δH (300 MHz, CDCl3) 2.66 (1 H, dd, J 16.3 and 8.0,
4a-H), 3.17 (1 H, dd, J 16.3 and 5.6, 4b-H), 3.90 (3H, s, OMe),
4.02–4.10 (1 H, m, 3-H), 4.64 (1 H, d, J 8.4, 2-H), 4.98 (2 H, s, 2
CH2-Bn), 5.03 (2 H, s, 2 CH2-Bn), 5.18 (2 H, s, 2 CH2-Bn), 6.22
(1 H, d, J 1.9, 8-H), 6.27 (1 H, d, J 1.9, 6-H), 6.88–7.02 (3 H, m,
6Ј-H and 5Ј-H and 2Ј-H), 7.29–7.48 (15 H, m, Ph); δC (75 MHz,
CDCl3) 27.8, 56.0, 68.2, 69.9, 70.1, 71.0, 81.8, 93.8, 94.3, 102.4,
110.5, 113.9, 119.9, 127.1, 127.5, 127.9, 128.5, 128.6, 130.6,
136.9, 148.5, 150.0, 155.3, 157.7, 158.8; m/z (EI, 70 eV) 574 (54),
319 (100), 256 (62), 91 (75); m/z (CI, NH3) 575 (M ϩ Hϩ,
100%); HR m/z (EI) 574.2354 0.3 ppm C37H34O6.
(2R,3S)-5,7-Bis(benzyloxy)-2-[3Ј-benzyloxy-4Ј-(di-tert-
butylhydroxysilyloxy)phenyl]chroman-3-ol and (2R,3S)-5,7-
bis(benzyloxy)-2-[4Ј-benzyloxy-3Ј-(di-tert-butylhydroxysilyl-
oxy)phenyl]chroman-3-ol (17a,b) (50 : 50 mixture)
Compounds 17a,b were prepared by benzylation of the parent
phenol compounds 16a,b (500 mg, 1.12 mmol) under standard
conditions (BnBr 3.4 mmol, K2CO3 3.4 mmol, DMF, rt, 12 h).
The crude product was purified by silica gel flash chrom-
atography with AcOEt–hexane (40 : 60) as eluent affording
a 50 : 50 mixture of products 17a,b (561 mg, 70%) as a yellow
solid, mp 58–63 ЊC (Found: C, 72.62; H, 7.11%, C44H50-
O7SiؒH2O requires C, 71.71; H, 7.11%; δH (300 MHz; [D6]-
acetone) 1.10 (36 H, br s, 4-tBu), 2.66 (1 H, dd, J 16.1 and 8.3,
4a-H), 2.67 (1 H, dd, J 16.2 and 8.1, 4a-H), 3.01 (1 H, dd, J 16.1
and 5.1, 4b-H), 3.04 (1 H, dd, J 16.2 and 5.1 Hz, 4b-H), 4.01–
4.09 (2 H, m, 3-H), 4.67 (1 H, d, J 4.6, 2-H), 4.70 (1 H, d, J 4.6
Hz, 2-H), 5.05–5.11 (12 H, m, 6 CH2-OBn), 6.20 (1 H, d, J 2.2,
8-H), 6.21 (1 H, d, J 2.2, 8-H), 6.36 (1 H, d, J 2.2, 6-H), 6.37
(2R,3S)-5,7-Bis(benzyloxy)-2-(4Ј-benzyloxy-3Ј-methoxy-
phenyl)chroman-3-ol (20). Yield 35%; mp 168–169 ЊC (Found:
C, 76.55; H, 6.31%; C37H34O6ؒH2O requires C, 74.98; H, 6.12%;
C37H34O6 requires C, 77.33; H, 5.96%; [α]2D0 ϩ3.5Њ (c 0.88,
CHCl3); δH (300 MHz; CDCl3) 2.64 (1 H, dd, J 16.3 and 8.9,
4a-H), 3.10 (1 H, dd, J 16.3 and 5.6, 4b-H), 3.89 (3H, s,
828
J. Chem. Soc., Perkin Trans. 1, 2002, 821–830

View Article Online
OMe), 3.95–4.02 (1 H, m, 3-H), 4.63 (1 H, d, J 8.2, 2-H), 4.99
(2 H, s, CH2-Bn), 5.02 (2 H, s, CH2-Bn), 5.15 (2 H, s, CH2-Bn),
6.21 (1 H, d, J 2.2, 8-H), 6.27 (1 H, d, J 2.2, 6-H), 6.91 (1 H, d,
J 7.9, 5Ј-H), 6.95 (1 H, dd, J 7.9 and 1.8, 6Ј-H), 7.02 (1 H, d,
J 1.8, 2Ј-H), 7.27–7.43 (15 H, m, Ph); δC (75 MHz, CDCl3) 27.6,
56.1, 68.2, 69.9, 70.1, 71.0, 81.6, 93.8, 94.3, 102.3, 111.8, 112.8,
120.5, 127.1, 127.5, 127.9, 128.5, 128.6, 130.0, 136.8, 148.9,
150.1, 155.3, 157.8, 158.8; m/z (EI, 70 eV) 574 (Mϩ, 60%), 319
(100), 165 (43), 91 (95); m/z (CI, NH3) 575 (100%), 485 (26), 274
(47); HR m/z (EI) 574.2347 1.4 ppm C37H34O6.
Synthesis of trimethylated catechin derivatives 24 and 25
The final deprotection of compounds 23a,b was carried out as
described previously for compounds 18a,b. After purification
by flash column chromatography with AcOEt–hexane (50 : 50)
as eluent, a mixture of compounds 24 and 25 was separated by
preparative HPLC. HPLC separations of the two trimethylated
analogues were achieved on a 250 × 4.6 mm id column packed
with 5 µm Hypersil ODS C18 stationary phase. The mobile
phase consisted of acetonitrile–methanol 38 : 62, and with
0.2% formic acid. The column eluent was directed to a UV
detector set at 280 nm.
Synthesis of 4Ј-methylcatechin 21 and 3Ј-methylcatechin 22
(2R,3S)-5,7-Dimethoxy-2-(4Ј-hydroxy-3Ј-methoxyphenyl)-
chroman-3-ol (24). Yield 35%; mp 157–158 ЊC; [α]2D0 Ϫ12.5Њ
(c 0.15, MeOH); δH (300 MHz, CDCl3) 2.58 (1 H, dd, J 16.2
and 9.0, 4a-H), 3.07 (1 H, dd, J 16.2 and 5.8, 4b-H), 3.74 (3H,
s, OMe), 3.80 (3 H, s, OMe), 3.90 (3 H, s, OMe), 4.01–4.08
(1 H, m, 3-H), 4.63 (1 H, d, J 8.4, 2-H), 6.10 (1 H, d, J 2.2,
8-H), 6.13 (1 H, d, J 2.2, 6-H), 6.93–6.97 (3 H, br d, 6Ј-H and
5Ј-H and 2Ј-H); δC (75 MHz, CDCl3) 27.7, 55.4, 55.5, 55.9,
68.3, 81.9, 91.9, 93.0, 101.7, 109.4, 114.6, 120.6, 129.6, 146.1,
146.9, 155.3, 158.7, 159.7.
The final deprotection of compounds 19 and 20 was carried out
as described previously for 3Ј,4Ј-dimethylcatechin 14.
(2R,3S)-2-(4Ј-Hydroxy-3Ј-methoxyphenyl)chroman-3,5,7-triol
(21).14a,16b,29c,30 Yield 85%; mp 186–187 ЊC; [α]2D0 ϩ4.0Њ (c 0.28,
acetone); δH (300 MHz, [D6]acetone) 2.52 (1 H, dd, J 16.0 and
8.8, 4a-H), 2.97 (1 H, dd, J 16.0 and 5.5, 4b-H), 3.84 (3H, s,
OMe), 3.94–4.05 (1 H, m, 3-H), 4.56 (1 H, d, J 8.1, 2-H), 5.87
(1 H, d, J 2.1, 8-H), 6.03 (1 H, d, J 2.1, 6-H), 6.80 (1 H, d, J 8.1,
6Ј-H), 6.88 (1 H, dd, J 8.1 and 1.7, 5Ј-H), 7.02 (1 H, d, J 1.7,
2Ј-H); δC (75 MHz, [D6]acetone) 27.9, 56.1, 68.0, 82.9, 95.4,
96.0, 100.7, 111.7, 115.3, 121.4, 131.7, 147.2, 148.0, 156.9,
157.1, 157.7; m/z (EI, 70 eV) 304 (59), 166 (100), 139 (76), 128
(72), 77 (73); m/z (CI, NH3) 305 (100); HR m/z (EI) 304.0948
0.4 ppm C16H16O6.
(2R,3S)-5,7-Dimethoxy-2-(3Ј-hydroxy-4Ј-methoxyphenyl)-
chroman-3-ol (25).30a Yield 40%; mp 154–155 ЊC; [α]2D0 Ϫ8.0Њ
(c 1.00, acetone); δH (300 MHz, CDCl3) 2.58 (1 H, dd, J 16.3
and 8.8, 4a-H), 3.02 (1 H, dd, J 16.3 and 5.5, 4b-H), 3.74
(3H, s, OMe), 3.79 (3 H, s, OMe), 3.90 (3 H, s, OMe), 4.02–
4.12 (1 H, m, 3-H), 4.66 (1 H, d, J 8.1, 2-H), 6.09 (1 H, d, J 2.3,
8-H), 6.12 (1 H, d, J 2.3, 6-H), 6.87 (1 H, d, J 8.2, 5Ј-H), 6.93
(1 H, dd, J 8.2 and 1.9, 6Ј-H), 7.02 (1 H, d, J 1.9, 2Ј-H);
δC (75 MHz, CDCl3) 27.3, 55.3, 55.5, 56.0, 68.1, 81.5, 91.9,
93.0, 101.5, 110.7, 113.1, 119.2, 131.0, 146.0, 146.9, 155.2,
158.7, 159.7.
(2R,3S)-2-(3Ј-Hydroxy-4Ј-methoxyphenyl)chroman-3,5,7-triol
(22).15b,28,30a,30b Yield 87%; mp 152–153 ЊC (Found: C, 59.25; H,
5.82%; C16H16O6ؒH2O requires C, 59.62; H, 5.63%; [α]2D0 ϩ20.6Њ
(c 0.65, acetone); δH (300 MHz, [D6]acetone) 2.52 (1 H, dd,
J 16.0 and 8.2, 4a-H), 2.91 (1 H, dd, J 16.0 and 5.4, 4b-H), 3.83
(3H, s, OMe), 3.97–4.03 (1 H, m, 3-H), 4.59 (1 H, d, J 7.5, 2-H),
5.88 (1 H, d, J 2.0, 8-H), 6.02 (1 H, d, J 2.0, 6-H), 6.84 (1 H, dd,
J 8.3 and 1.8, 5Ј-H), 6.91 (1 H, d, J 8.3, 6Ј-H), 6. 92 (1 H, d,
J 1.8, 2Ј-H); δC (75 MHz, [D6]acetone) 29.0, 56.2, 68.2, 82.5,
95.4, 96.0, 100.5, 111.9, 114.9, 119.6, 133.4, 147.1, 148.0, 156.8,
157.1, 157.7; m/z (EI, 70 eV) 304 (Mϩ, 100%), 166 (99), 139 (95);
m/z (CI, NH3) 305 (100%); HR m/z (EI) 304.0951 1.3 ppm
C16H16O6.
Acknowledgements
We thank Dr Yves Plancke for the purification of the methyl-
ated catechin isomers and Dr Jean-Michel Wieruszeski for the
NOE, NOESY and ROESY experiments. The authors grate-
fully acknowledge the reviewers for their suggestions and for
the careful reading of the manuscript. This work was supported
by the European Community (European Contract QLK1-
CT-199–00505 POLYBIND) and the Conseil Régional Nord,
Pas-de-Calais.
Synthesis of the compounds 23a,b
To a stirred solution of compounds 16a,b (0.5 g, 1.12 mmol)
in acetone (30 mL) was added potassium carbonate (0.16 g,
4.48 mmol) and methyl iodide (0.28 mL, 4.48 mmol). The reac-
tion was stirred at room temperature for 12 h. Acetone was
removed under vacuum and the resulting mixture was washed
with water (20 mL). The aqueous layer was extracted with
AcOEt (3 × 30 mL) and dried over MgSO4. Evaporation of
the solvent furnished on oily product which was purified by
flash column chromatography using AcOEt–hexane (40 : 60) as
eluent to give a 50 : 50 mixture of products 23a,b.
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