Influence of an 8-trifluoroacetyl group on flavanol couplings

Article abstract of DOI:10.1016/j.tet.2005.12.019

The effect of an electron attracting substituent in the Lewis acid catalyzed oligomerization of flavanols was investigated. The results showed that the presence of a COCF₃, at the 8 position of a (+)-catechin unit strongly influenced the attack of the 6 free nucleophile flavanol position by the electrophile generated from a 4-O-alkyloxy protected catechin unit. This was observed either with TiCl₄ or TMSOTf as Lewis acids in which the carbon-carbon bond formation was inhibited and the corresponding dimer was detected in small amount. On the contrary, the formation of a carbon-oxygen bond was observed and the corresponding C-4→O→C-3 ether linked procyanidin dimer was isolated in a good yield. In order to avoid the participation of the C-3 hydroxyl group in the dimerization reaction, the two flavanol units were forced into C-4→C-8 coupling by use of an internal link. The structural elucidation of the isolated compounds was achieved through MS and NMR spectroscopy.

Full text of DOI:10.1016/j.tet.2005.12.019

Tetrahedron 62 (2006) 2705–2714
Influence of an 8-trifluoroacetyl group on flavanol couplings
c
a
a
Nour-Eddine Es-Safi,a,b, Christine Le Guerneve, Lucien Kerhoas and Paul-Henri Ducrot
*
´
a
´ ´
Unite de Phytopharmacie et Mediateurs Chimiques, Inra, Route de Saint-Cyr 78026 Versailles Cedex, France
´
b
Laboratoire de Chimie Organique et d’Etudes Physico-Chimiques, Ecole Normale Superieure, B.P 5118 Takaddoum Rabat, Morocco
cUMR Sciences pour l’Œnologie, Inra, 2 place Viala 34060 Montpellier Cedex, France
Received 29 September 2005; revised 28 November 2005; accepted 9 December 2005
Available online 10 January 2006
Abstract—The effect of an electron attracting substituent in the Lewis acid catalyzed oligomerization of flavanols was investigated. The
results showed that the presence of a COCF3, at the 8 position of a (C)-catechin unit strongly influenced the attack of the 6 free nucleophile
flavanol position by the electrophile generated from a 4-O-alkyloxy protected catechin unit. This was observed either with TiCl4 or TMSOTf
as Lewis acids in which the carbon–carbon bond formation was inhibited and the corresponding dimer was detected in small amount. On the
contrary, the formation of a carbon–oxygen bond was observed and the corresponding C-4/O/C-3 ether linked procyanidin dimer was
isolated in a good yield. In order to avoid the participation of the C-3 hydroxyl group in the dimerization reaction, the two flavanol units were
forced into C-4/C-8 coupling by use of an internal link. The structural elucidation of the isolated compounds was achieved through MS and
NMR spectroscopy.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Proanthocyanidins (condensed tannins) are a class of
bioactive polyphenolic natural compounds found in a
variety of plant foods and beverages. They have been
attributed numerous therapeutic properties and many
clinical researches suggest that their pronounced biologi-
cal activities might prevent age-related chronic diseases,
cancers and heart diseases.1–3 These beneficial health
effects have led to several investigations on their
chemical structures and have initiated a number of
synthetic efforts to access condensed tannins.4–12
Figure 1. Structures of flavan-3-ols monomers (1a–1d) and oligo/
polymers (2).
Proanthocyanidins are generally mixtures of oligomers
and polymers of flavan-3-ol units, linked either through
carbon–carbon and/or carbon–oxygen bonds. The most
encountered flavan-3-ols involved in proanthocyanidin
formation are derived from catechin 1a, epicatechin 1b,
gallocatechin 1c, or epigallocatechin 1d (Fig. 1). The
synthesis of proanthocyanidins 2 is generally achieved by
coupling the C-4 of an electrophilic flavanyl unit to a C-
6/C-8 of a nucleophilic flavanyl unit. The nucleophilicity
of the aromatic A ring may play a crucial role in these
coupling reactions during which a new bond is
established between the C-4 position of the electrophile
and the C-6/C-8 of the nucleophile unit.
The stability of proanthocyanidins is primarily dependent on
that of this newly established linkage, which is sensitive to
acidic and alkalinic conditions and might a priori also be
influenced by the type of flavanol unit. Additionally, the
reactivity of the electrophilic/nucleophilic species involved in
the coupling reaction could also be influenced by the flavanol
types. While the synthesis of proanthocyanidins from natural
flavanols is well documented,4–12 little is known about the
effect of an A ring substitution on the reactivity of a flavanol
unit involved either as nucleophilic or electrophilic species
during the coupling reaction and its impact on the
proanthocyanidin synthesis course.13 In an ongoing program
directed to the synthesis of modified proanthocyanidins, we
described the preparation of modified catechin derivatives
involving introduction of substituents either at C-6 and/or C-8
positions.14,15 In this paper, we report the results dealing with
Keywords: Flavanol; C–C coupling; Dimerization; Substituent effects;
Lewis acids; Regioselectivity.
*
Corresponding author. Address: Laboratoire de Chimie Organique et
´
d’Etudes Physico-Chimiques, Ecole Normale Superieure, B.P 5118
Takaddoum Rabat, Morocco; e-mail: nouressafi@yahoo.fr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.019

2706
N.-E. Es-Safi et al. / Tetrahedron 62 (2006) 2705–2714
Scheme 1. Formation of tetrabenzylated trifluroacylated catechin derivatives 4, 5, 6.
the effect of an electron deficient substituent linked to the C-8
position of a flavanol subunit on the Lewis acid catalyzed
dimerisation of flavanols and offer new information on the
reactivity of modified flavanols during such coupling
reactions.
The position of the COCF3 group on the aromatic A ring
was elucidated by 2D NMR HMBC analysis. The usual
pyran ring protons H-4 (2.67 and 3.08 ppm), H3 (3.95 ppm)
and H-2 (4.78 ppm) were easily assigned by 1H NMR
analysis. The three B ring protons were observed between
6.89 and 7.01 ppm. For the aromatic A ring, only one proton
signal appearing as a singlet at 6.28 ppm was present
indicating a monosubstitution. The presence of the COCF3
group was confirmed through 13C NMR analysis showing a
quartet at 184.31 ppm and corresponding to the carbonyl
group. The protonated carbon chemical shifts were assigned
through NMR DEPT analysis.
2. Results and discussion
2.1. Synthesis of modified flavanols
In the course of a program dealing with the synthesis and the
reactivity of modified condensed tannins, we started an
investigation on the synthesis of new procyanidin derivatives
withmodifiedmonomericsubunitsderivedfromcatechin. Our
objectivesweretoexplore the impactofthe A ringsubstitution
on the course of Lewis acid catalyzed classic procyanidin
formation reaction. For this study, the 8-trifluoroacetyltetra-
benzyloxycatechin 6 was used as the electrophile acceptor in
coupling reactions with a C-4 activated catechin derivative.
Compound6 was preparedbyaction of trifluoacetic anhydride
on tetrabenzylated catechin 3 according to Scheme 1. During
this reaction, the trifluoroacylation occurred first at the 3-OH
giving the ester 4. Compound 5 was then formed following a
Friedel–Craft’s reaction on the 8 nucleophile position.
Hydrolysis of compound 5 gave the target product 6 with a
yield of 64%. The structures of the three trifluoroacylated
derivatives 4, 5 and 6 were determined through UV, MS and
NMR spectroscopy. Structure elucidation of compound 6,
which was used in the synthesis described below, was initiated
by UV spectroscopy, which showed, in addition to the usual
280 nm flavan-3-ols maximum, another maximum located
around 300 nm more probably due to the presence of the
COCF3 group. Its ESMS spectrum recorded in the positive ion
mode showed signals located at m/z: 747, 764 and 769 amu
corresponding to [MCH]C, [MCNH4]C and [MCNa]C
ions, respectively, and indicating a molecular weight of
746 amu in agreement with the structure of compound 6. The
usual flavan-3-ols characteristic RDA fragmentation was also
observed at m/z: 415 amu, [MCHK332]C ion and corres-
ponding to the protonated A moiety (Fig. 2).
The definitive structure elucidation of compound 6 was
achieved by HMBC experiment, which allowed assignment
of all hydrogen and carbon atoms. In addition to their
correlations with C-2 (81.94 ppm) and C-3 (67.63 ppm),
H-4 protons (2.67 and 3.08 ppm) correlated with 3 carbons
located at 103.19, 154.18 and 157.77 ppm. Carbons C-4a,
C-8a and C-5 are in a favorable position to give such
correlations. The signal observed at 103.19 ppm was
attributed to C-4a due to its chemical shift position
compared to C-8a and C-5, which are linked to an oxygen
atom. The carbon signal located at 154.18 ppm also gave a
correlation with H-2, which pointed to the C-8a carbon and
thus the remaining signal observed at 157.77 ppm was
attributed to C-5. The C-8a signal thus attributed did not
show any correlation with the residual A ring aromatic
protons, which is thus H-6. This was confirmed by the
presence of a correlation between C-5 and the residual
aromatic proton (Fig. 2).
2.2. Synthesis of activated catechin derivatives
Oxidation at the benzylic C-4 position of flavanols is a
fundamental step in proanthocyanidin synthesis. Over the
years, three main reagents have been used in the literature
for this purpose, namely K2S2O8, lead(IV) acetate and
DDQ, which is now the most widely used.16–22 In this study,
DDQ was used as oxidant of tetrabenzylated catechin 3 in
presence of ethylene glycol or 2-ethoxyethanol giving
access to the corresponding 4-O-alkylated catechin 7, 8 with
yields up to 70% (Scheme 2).
2.3. TiCl4-catalyzed flavanol coupling reaction
Lewis acids have been employed in literature to synthesize
proanthocyanidins. Thus, TiCl4, AgBF4, SnCl4, TMSOTf
have been used to synthesize dimeric and oligomeric
procyanidins of (C)-catechin and (K)-epicatechin
Figure 2. Main fragmentations and 1H–13C long range characteristic
correlations observed for compound 6.

N.-E. Es-Safi et al. / Tetrahedron 62 (2006) 2705–2714
2707
Scheme 2. Synthesis of the 4-activated catechin derivatives 7, 8, 9.
units.8,9,13,23–26 In these reactions, the role of Lewis acids is
to promote the formation of the benzylic carbocation at C-4
of a flavanol subunit starting from a C-4 hetero substituted
flavanol, which thereafter undergoes a Friedel–Craft-like
addition on a second flavanol subunit. For this preliminary
study, the Lewis acid TiCl4 was first used as a carbocation
promoting agent from the 4-(2-hydroxyethyloxy) flavan-3-
ol 7. Coupling reaction between compound 6 and 7 in a 6/1
molar ratio was investigated in CH2Cl2 according to
Scheme 3. The reaction was monitored by CCM and
HPLC and showed the disappearance of compound 6 and
appearance of new compounds. Among the products
formed, compound 10 was obtained in sufficient amounts
to allow its structure investigation. This was achieved
through UV, LC/ESMS, ES CAD MS/MS and NMR
analysis.
The UV spectrum of compound 10 exhibited similar
maxima (285 and 305 nm) to that of compound 6, indicating
that the original flavan structure with the COCF3 group was
retained. The mass spectrum obtained in the positive ion
mode (Fig. 3) showed signals at m/z: 1395, 1412, 1417 and
1433 amu corresponding, respectively, to [MCH]C, [MC
NH4]C, [MCNa]C and [MCK]C indicating a molecular
weight of 1394 amu in agreement with a dimeric structure
consisting of tetrabenzylated (C)-catechin 3 linked to its
trifluoroacylated derivative 6. However, the remaining
problem was the establishment of the position of linkage
to compound 6, as the tetrabenzylated catechin moiety is
linked through its 4 position.
In addition to the signals indicated above, the mass spectrum
of compound 10 also showed signals at m/z: 747 and 649 amu
Scheme 3. TiCl4-catalyzed formation of compounds 10, 11.
Figure 3. MS spectrum of 10 recorded in a positive ion mode.

2708
N.-E. Es-Safi et al. / Tetrahedron 62 (2006) 2705–2714
corresponding to the fission of the bond between the two
constitutive units. Among the other observed signals two of
them were located at m/z: 1063 and 981 amu and were also
observed in the spectrum obtained through positive ES CAD
MS/MS fragmentation of the signal located at m/z: 1395 amu
([MCH]C ion). The signal observed at m/z: 1063 amu was
attributed to the characteristic RDA fragmentation corres-
ponding to the [MCHK332]C ion as what was observed for
compound 6 through a loss of the B moiety. The second
fragmentation observed at m/z: 981 amu correspond in fact to
the [MCHK414]C ion, meaning a loss of the A moiety of
compound 6 unit (Fig. 4) and corresponding to another RDA
fragmentation. The occurrence of this fission indicated the
presence of the A moiety in the structure of compound 10. In
other words, this means that the isolated compound is not a
C-4/C-6 dimer since only one RDA fragmentation
corresponding to the [MCHK332]C ion could be possible
in this case. The possible linkage is thus expected to occur via
the 2 or 3 position of the F ring or possibly the 20, 50 or 60
positions of the ring E.
proton each located at 6.10 and 6.26 ppm and a singlet
integrating one proton located at 6.20 ppm. The first
doublets were assigned to H-6 and H-8 protons of the A
ring while the singlet was assigned to H-6 of the D ring. This
indicated that the interflavanyl linkage did not involve the D
ring confirming thus the conclusion deduced from the MS
results described above. It did not neither involve the E ring
since the three corresponding protons were observed
through 13C and DEPT NMR spectra.
In conjunction with the absence of a doubly benzylic
methylene proton characteristic of a C4/C6 linkage and
taking into account the dimeric structure of the compound
as supported by MS analysis, the NMR data collectively
indicated a dimeric structure with an interflavanyl
ether bond connecting the two heterocyclic C and F rings.
Taking into account the fact that the linkage did not involve
the H-2, H-3, H-4 F ring protons since they were all
evidenced through NMR analysis, a (4-O-3) mode of
linkage was thus concluded to occur between the two
flavan-3-ols units. This was also confirmed by comparison
of the chemical shifts of the H-4 and H-3 resonances of both
the C and the F rings with those of their precursors. Finally,
the structure of compound was univocally confirmed
through HMBC analysis where several long range corre-
lations were observed. In particular correlations involving
proton and carbon of both C and F rings via the oxygen atom
were observed and confirmed thus the ether linkage
involved in compound 10. Full assignment of the protons
and carbon chemical shifts was achieved through HMBC
analysis. Figure 4 showed some of the main correlations
involving H/C of the C and F rings in agreement with the
proposed structure.
Through NMR analysis, the presence of two distinct
catechin proton systems was observed. This was confirmed
1
1
through 1D H and 2D H–1H COSY NMR spectra, which
showed the presence of an AMX and AA’MX spin systems
corresponding to the two catechin units. Thus, the signals,
which resonate at 2.52, 2.71, 4.48 and 4.90 ppm could
be readily assigned to the H-4 (a and b), H-3 and H-2 of the
F ring, while those located at 3.82, 4.85 and 5.10 ppm
were assigned, respectively, to the H-3, H-4 and H-2 of
the C ring.
In the HETCOR spectra, these aliphatic protons correlate
with carbons located at 27.15, 70.80 and 76.69 ppm,
respectively, for the first system and at 66.03, 70.17 and
80.52 ppm, respectively, for the second system. The furthest
upfield carbon chemical shifts is in agreement with a carbon
resonance deshielded by the presence of an oxygen atom. In
addition, the HETCOR spectra showed correlations between
the B and E rings protons and their corresponding carbons,
which were thus assigned in connection with the results also
obtained through 13C and DEPT NMR analysis.
It was concluded that a (4-O-3) linkage was occured between
the two flavan-3-ol units. Moreover, coupling constants for
the AMX spin system of the C ring protons (J3,4Z3.2 Hz)
indicated a 3,4 cis relative configuration for this ring, that is a
4b linkage between both flavanol units. The complete
stereoselectivity of the reaction remains, however, to be
explained and should presumably be due to a participation of
the hydroxy group at C-3 of 6. However, its involvement
in the stereochemical course of the reaction cannot
be, in our case, related to the formation of a protonated
In the aromatic proton chemical shift region, the spectrum
also showed two doublets (JZ1.8 Hz) integrating one
Figure 4. Main fragmentations and 1H–13C long range characteristic correlations observed for compound 10.

N.-E. Es-Safi et al. / Tetrahedron 62 (2006) 2705–2714
2709
epoxide similar to that reported by Bennie et al.,27 in a work
dealing with the dimerization of epioritin-4-ol derivatives.
analogue reflects the importance of electronic features in the
formation of flavan-3-ol dimers. The poor nucleophilicity of
the A ring monomeric precursor, caused by the presence of
the COCF3 group, permits alternative centers to participate
in the interflavanyl bond formation.
Indeed, the stereochemical outcome of the reaction in our
case should be rather more consistent with a chelation
process of the Lewis acid by both hydroxy groups of 7 and 6,
therefore inducing the approach of the nucleophile from the
b face of 7. The possible participation of the oxygen atoms
of the ethylene glycol moiety of 7, in such a chelation
process, thereby inducing a quasi-concerted process has also
to be considered.
2.4. TMSOTf-catalyzed flavanol coupling reaction
As indicated above, various Lewis acids were used as
coupling agents for proanthocyanidin synthesis. After
having used TiCl4, the same reaction was investigated
using TMSOTf, which was recently used to synthesize
octabenzylated procyanidin-B3 with high levels of setereo-
selectivity and in excellent isolated yields.7,8,28 The reaction
was conducted by using the acetylated compound 9 as
electrophile, which was prepared through DDQ mediated
oxidation of tetrabenzylated catechin 3 in presence of
ethoxyethanol followed by an acetylation using acetic
anhydride (Scheme 2). The structures of the compounds
obtained were confirmed by MS and NMR analysis. The
coupling reaction in the presence of TMSOTf was achieved
at K78 8C using the same 8-trifluoroacetylated adduct 6 as
nucleophile. After isolation by column chromatography
eluting with ethylacetate/cyclohexane mixture, the major
compound obtained was submitted to spectral analysis. The
mass spectrum obtained in the positive ion mode showed
signals at m/z: 1437, 1454 and 1459 amu and corresponding
to [MCH]C, [MCNH4]C and [MCNa]C ions, respec-
tively, in agreement with a dimeric structure consisting of
an acetoxy-tetrabenzyloxy- and a trifluoroacetyl-tetra-
benzyloxy catechin. The full structure elucidation of
compound 12 was achieved using 1D and 2D NMR
analysis. The presence of the three A and D rings aromatic
protons was observed indicating that they were not involved
during the coupling reaction and that the interflavanic bond
was not a C-4/C-6 type. Further NMR analysis similar to
those described for compounds 10 was used to confirm the
regiochemistry of the reaction and indicated the predomi-
nant formation of a C-4/O/C-3 ether bond type between
the two flavanol moieties. The 3,4 stereochemistry of the
upper unit was also determined by NMR and was shown to
be cis (Scheme 4).
In order to verify the presence of other dimeric structures
the mixture was explored by HPLC coupled to a mass
spectrometry detection operating in the positive ion mode.
An extracted ion current chromatogram recorded at m/z:
1395 and 1412 amu (Fig. 5) and corresponding to a dimeric
structure molecular weight showed the presence, in addition
to compound 10, of a minor compound, which is possibly
the carbon–carbon coupled dimer 11. The fragmentations
observed for compound 11 were in agreement with
the proposed dimeric structure consisting of tetrabenzylated
(C)-catechin 3 coupled to its trifluroacylated derivative 6
through a C4/C6 linkage (Fig. 6).
Figure 5. XIC recorded at m/z: 1395 amu showing the presence of the main
4-O-3 ether 10 and the probable C-4/C-6 linked dimers 11.
The formation of the ether linked procyanidins as main
products of dimerisation rather than the carbon–carbon
C-4/C-6 coupled analogues showed that the inhibition
effect of the trifluoroacetyl group when using TiCl4 as
catalysing Lewis acid was also observed in the case of
TMSOTf. This confirms the effect of the A ring substitution
on the nucleophilicity of the flavanol, so allowing other
nucleophilic centers to participate to the coupling reaction.
2.5. TMSOTf-catalyzed intramolecular flavanol
coupling reaction
After having tested these two Lewis acid in the conden-
sation reaction and after having showed the participation of
the 3-hydroxyl group as a nucleophilic site in interflavanyl
linkage formation, we decided to protect this group and to
try to achieve coupling reaction with increased C–C linkage
formation yield. To avoid the undesirable intervention of the
3-hydroxyl group in the chain elongation process, this group
was protected in both the electrophilic and the nucleophilic
Figure 6. Main fragmentations observed for compound 11.
The almost exclusive, high yielding formation, in these
conditions of the novel ether linked procyanidins as main
compound rather than its carbon–carbon C-4/C-6 coupled

2710
N.-E. Es-Safi et al. / Tetrahedron 62 (2006) 2705–2714
Scheme 4. TMSOTf-catalyzed formation of compounds 12, 13.
Scheme 5. TMSOTf-catalyzed formation of compounds 18.
reaction partner by a diester linker glutaric anhydride in two
steps (Scheme 5) and the TMSOTf-catalyzed condensation
reaction was reinvestigated.
respectively, and where the fragment m/z: 731 resulting from
two successive RDA scissions was observed showing the
presence of the C-4/C-6 linkage. In the 1H NMR spectrum,
the particular disappearance of the H-6A proton was observed
confirming such C–C linkage. The low yield obtained in the
coupling reaction confirms once again the negative effect of
the 8-trifluoroacetyl substituent on the nucleophilicity of the
C-6 center. This could also be due to geometrical factors,
which are obviously important in such coupling reaction.
The8-trifluoroacetylderivative6wasfirsttreatedwithglutaric
anhydride to yield the corresponding esterified compound 14,
in addition to which compound 15 resulting from a double
esterification was also obtained. The isolated carboxylic
mono-ester 14 was further coupled with the electrophile unit 8
in presence of DCC to give the desired diester 17. In this
reaction, the intermediate 16 was also isolated and identified.
Having the 4-O-alkoxy derivative 17 in hand, the stage was set
for its possible conversion to the corresponding C–C coupled
adduct 18 (Scheme 5) through intramolecular TMSOTf-
catalyzed coupling reaction.7 The reaction was conducted in
CH2Cl2 at K78 8C to give coupled product 18 with a low
yield. In order to increase the reaction yield, several attempts
were made in various conditions; however the C–C bond
formation was always observed with a low yield. The mass
spectrum of compound 18 showed signals at m/z: 1491 and
1598 amu corresponding to [MCH]C and [MCNH4]C ions,
3. Conclusion
Our results delineate thus the influence of an electron
deficient substituent on C-8 of the aromatic A ring of a
catechin subunit on the course of the Lewis acid catalyzed
classical procyanidin formation reaction. The results
obtained showed that the presence of a COCF3 substituent
linked to the 8 position of a (C)-catechin unit strongly
influenced the attack on the flavanol moiety by the
electrophile generated from a 4-O-alkyloxy protected
catechin unit and indicates the importance of electronic

N.-E. Es-Safi et al. / Tetrahedron 62 (2006) 2705–2714
2711
features in the establishment of the carbon–carbon
interflavanic bond. When using either TiCl4 or TMSOTf
as Lewis acids, C–C bond formation was inhibited and the
corresponding C/C dimer was detected only in a very
small amount. By contrast the formation of a carbon–
oxygen bond was observed and the corresponding C-4/
O/C-3 ether linked procyanidin dimer was isolated in a
good yield. The poor nucleophilicity of the A ring
electrophile acceptor subunit probably caused by the
presence of the electron deficient COCF3 group, allows
alternative nucleophilic sites of the molecules to participate
in interflavanyl bond formation.
Carlo Erba) and water with 0.2% acetic acid. The flow rate
was 0.2 mL/min, the analyses were performed with the
column and the samples kept at ambient temperature and
5.0–10 mL was injected for each analysis. The effluent from
the UV detector was introduced without any split into the
mass spectrometer. The HPLC system was coupled on line
to a Quattro LC MS/MS triple quadrupole mass spectro-
meter (Micromass, Manchester, UK) equipped with a
pneumatically assisted electrospray source ionisation
(ESI). Data acquisition and processing were performed
using a MassLynx NT 3.5 data system. The electrospray
source parameters were fixed as follow: electrospray
capillary voltage 3.25 kV in positive mode and 3 kV in
negative mode, source block temperature 120 8C, desolva-
tion gas temperature 400 8C. Nitrogen was used as drying
gas and nebulising gas at flow rates of approximately 50 and
450 L/h.
Our results report the production of ether linked dimeric
procyanidins based on (C)-catechin skeleton and obtained
in good yield. Its formation is a new concept in
proanthocyanidin synthesis since until now only flavanols
with pyrogallol moiety were described as precursors of 4-O-
4 and 4-O-3 ether linked proanthocyanidins. They finally
open perspectives for further investigations of similar
compounds. A number of properties such as temperature
and hydrolytic stability, in addition to its biological
activities, remain of a high interest, and will be investigated.
4.2. Synthesis
4.2.1. 30,40,5,7-Tetrabenzyloxycatechin (3). To a stirred
suspension of NaH (144.5 mmol) in dry DMF (170 mL) under
nitrogen at K78 8C, was sequentially added a solution of (C)-
catechin 1a (10 g, 34 mmol) in anhydrous DMF (170 mL) and
benzyl chloride (170 mmol). The mixture was stirred at
K78 8C for 15 min then at room temperature for 7 h. Progress
of the reaction was monitored by TLC and was quenched by
addition of 1 N HCl and water. The aqueous layer was
extracted with EtOAc and the organic layer washed with
water, dried over MgSO4 and concentrated under reduced
pressure. Purification by silica gel chromatography (eluent,
cyclohexane/EtOAc, 80:20) afforded 30,40,5,7-tetrabenzylox-
ycatechin 3 (33 mmol, 97%) as white amorphous powder.
Spectral data were similar to those previously described.29
4. Experimental
4.1. General
All reactions were performed under argon and monitored by
TLC and analytical HPLC. Unless otherwise indicated, the
1H and 13C NMR spectra were recorded in CDCl3 with a
Varian Gemini-300 spectrometer at 300 and 75 MHz,
respectively (proton decoupling mode for carbon). 1H
NMR spectra were referenced to the signal at dZ
7.27 ppm of residual CHCl3. 13C NMR spectra were
referenced to signals of CDCl3 (dZ77.0 ppm). Resonances
of the benzyl group are not mentioned. FT-IR spectra were
recorded with a Nicolet Avatar 320 FT-IR spectro-
photometer. UV–visible spectra were recorded with a
Kontron Uvikon 930 spectrophotometer fitted with a quartz
cell.
4.2.2. 30,40,5,7-Tetrabenzyloxy-8-trifluoroacetylcatechin
(6). To a solution of tetra-O-benzylated catechin 3 (2 g,
3.0 mmol) in CH2Cl2 (12 mL) was added dropwise
(CF3CO)2O (20 mL) at 0 8C. The mixture was stirred at
room temperature and the progress of the reaction was
followed by TLC. The formation of 4 as primary product of
the reaction was first observed. The formation of compound
5 was then observed. Hydrolysis of compound 5 gave the
target product 6. The crude mixture so obtained was
concentrated and chromatographed on silica gel (eluent,
cyclohexane/EtOAc, 80:20) giving 1.43 g (1.9 mmol, 64%)
of 30,40,5,7-tetrabenzyloxy-8-trifluoroacetylcatechin 6. The
Analytical TLC was performed on Merck silica gel 60 F254
plates. Column chromatography was performed using a
mixture of ethyl acetate/cyclohexane as eluent on silica gel
˚
60 A 70–200 mm (SDS, 13124 PEYPIN, France). Analytical
1
purity of 6 was controlled through analytical HPLC. H
HPLC analysis was performed on a Varian apparatus
including a 9012 solvent delivery system, a 9100
autosampler and a 9065 polychrom diode array detector.
Analysis were performed on a C18 column eluting with a
mixture of solvents A: acetonitrile and B: water with 0.5%
orthophosphoric acid eluting from 15 to 100% A in 18 min
followed by a washing and a reequilibrating of the column.
LC/MS analysis were performed with a chromatographic
system (Alliance) consisted of a Waters 2695 separations
module equipped with an autosampler and a Waters 2487
dual lambda absorbance detector (Waters, Milford, MA,
USA). The column was a 150!2.1 mm Interchrom
UP5ODB#15E (Uptisphere 5 mm ODB) with a 10!
2.1 mm precolumn from Interchim (Montluc¸on, France).
Chromatography was ran in isocratic mode using a 60/40
mixture of acetonitrile (RS-Plus quality for HPLC from
NMR (300 MHz, CDCl3) 7.01 (d, JZ1.6 Hz, 1H, H-20),
6.89 (dd, JZ1.6, 8.4 Hz, 1H, H-60), 6.95 (d, JZ8.4 Hz, 1H,
H-50), 6.28 (s, 1H, H-6), 4.72 (d, JZ7.8 Hz, 1H, H-2), 3.95
(m, 1H, H-3), 3.08 (dd, JZ5.4, 16.5 Hz, 1H, H-4b), 2.67
(dd, JZ8.7, 16.5 Hz, 1H, H-4a). 13C NMR (125 MHz,
CDCl3) 184.3 (CO), 160.6 (C-7), 157.8 (C-5), 154.2 (C-8a),
149.5 (C-40), 149.2 (C-30), 130.4 (C-10), 121.1 (CF3), 120.4
(C-60), 115.1 (C-50), 113.8 (C-20), 105.7 (C-8), 103.2 (C-4a),
81.9 (C-2), 91.3 (C-6), 67.6 (C-3), 27.5 (C-4). ESI-MS m/z:
747 [MCH]C, 764 [MCNH4]C, 769 [MCNa]C.
4.2.3. 30,40,5,7-Tetrabenzyloxy-4-(2-hydroxyethoxy)-
catechin (7). To a solution of 30,40,5,7-tetrabenzyloxyca-
techin 3 (1.3 g, 2.0 mmol) in anhydrous CH2Cl2 (13 mL)
was added at room temperature 0.6 mL (11.5 mmol) of

2712
N.-E. Es-Safi et al. / Tetrahedron 62 (2006) 2705–2714
ethylene glycol and then all at once and with a good stirring
0.9 g (3.9 mmol) of DDQ. A black-green colour appeared
instantaneously and gradually faded to a dark brown. After
120 min of vigorous stirring at room temperature under a
CaCl2 tube, excess of 4-(dimethylamino)-pyridine was
added to the solution at 0 8C and the mixture was stirred
for 5 min. The resulting purple solid was removed by
filtration and the filtrate was washed with water and brine,
and dried (MgSO4). Filtration, concentration and silica gel
column c0hromatography (eluent, hexane/EtOAc, 1:2–2:3)
gave 30,4 ,5,7-tetrabenzyloxy-4-(2-hydroxyethoxy)catechin
7 (990 mg, 1.4 mmol, 70%) as white foam. 1H NMR
(300 MHz, CDCl3) 7.13 (d, JZ1.6 Hz, 1H, H-20B), 7.08 (d,
JZ8.1 Hz, 1H, H-50B), 7.02 (dd, JZ1.6, 8.1 Hz, 1H, H-
60B), 6.50 (d, JZ2.1 Hz, 1H, H-6A), 6.25 (d, JZ2.1 Hz, 1H,
H-8A), 5.10 (d, JZ10.0 Hz, 1H, H-2C), 4.95 (m, 1H, H-3C),
4.82 (d, JZ7.1 Hz, 1H, H-4C), 3.50–3.90 (m, 4H, OCH2-
CH2O). 13C NMR (125 MHz, CDCl3) 161.5 (C-7A), 160.7
(C-5A), 157.6 (C-8aD), 147.5 (C-300B), 147.3 (C-400B), 131.2
(C-10B), 121.2 (C-60B), 116.3 (C-5 B), 113.8 (C-2 B), 105.8
(C-4aA), 94.2 (C-8A), 93.2 (C-6A), 78.8 (C-2C), 74.2 (C-
3C), 71.3 (C-4C), 68.3 (OCH2CH2OH), 61.8 (OCH2CH2-
OH). ESI-MS m/z: 711 [MCH]C, 728 [MCNH4]C, 733
[MCNa]C.
(C-10B), 120.9 (C-60B), 116.5 (C-50B), 114.5 (C-20B), 105.3
(C-4aA), 94.2 (C-8A), 93.4 (C-6A), 76.3 (C-3C), 75.8 (C-
3C), 71.2 (C-4C), 70.1 (OCH2), 70.0 (CH2O), 66.3
(CH2CH3), 20.1 (CH3CO), 14.2 (CH2CH3). ESI-MS m/z:
7381 [MCH]C, 803 [MCNa]C.
4.2.6. 30,40,5,7-Tetrabenzyloxycatechin-(4b/O/3)-
30,40,5,7-tetrabenzyloxy-8-trifluoroacetylcatechin (10).
To a solution of 30,40,5,7-tetrabenzyloxy-8-trifluoroacetyl-
catechin 6 (895 mg, 1.2 mmol, 6 equiv) and 30,40,5,7-
tetrabenzyloxy-4-(2-hydroxyethoxy)catechin 7 (142 mg,
0.2 mmol) in CH2Cl2 (40 mL) was added dropwise
0.2 mmol of TiCl4 at 0 8C. The reaction mixture was stirred
for 5 min and then quenched with saturated sodium
hydrogen carbonate. The aqueous solution was extracted
with EtOAc and the combined organic phase was washed
with water and brine, and dried over MgSO4. Filtration,
concentration and silica gel column chromatography (eluent
cyclohexane/EtOAc, 80:20) afforded 180 mg of 10
(0.13 mmol, 66%). The purity of 10 was controlled through
analytical HPLC. 1H NMR (500 MHz, CDCl3) 7.08 (d, JZ
1.8 Hz, 1H, H-20B), 7.01 (d0, JZ8.2 Hz, 1H, H-50B), 7.00
(dd, JZ1.8, 8.2 Hz, 1H, H-6 B), 6.80 (d, JZ8.2 Hz, 1H, H-
50E), 6.78 (d, JZ1.3 Hz, 1H, H-20E), 6.63 (dd, JZ1.3,
8.2 Hz, 1H, H-60E), 6.27 (d, JZ2.2 Hz, 1H, H-6A), 6.20 (s,
1H, H-6D), 6.12 (d, JZ2.2 Hz, 1H, H-8A), 5.06 (m, 1H, H-
4C), 4.99 (m, 1H, H-2F), 4.85 (d, JZ10 Hz, 1H, H-2C),
4.49 (m, 1H, H-3F), 3.83 (m, 1H, H-3C), 2.78 (dd, JZ4.4,
16.7 Hz, 1H, H-4bF), 2.61 (dd, JZ4.4, 16.7 Hz, 1H,
H-4aF). 13C NMR (125 MHz, CDCl3) 188.9 (CO, q, JZ
38 Hz), 165.6 (C-7A), 165.3 (C-5D), 162.7 (C-5A), 161.9
(C-7D), 161.0 (C-8aA), 0 158.8 (C-8aD), 153.7 (C-300B),
153.6 (C-400B), 153.4 (C-30 E), 152.9 (C-400E), 136.7 (C-10B),
136.2 (C-10E), 125.3 (C-60B), 123.5 (C-6 0E), 119.1 (C-5 B),
118.6 (C-5 E), 118.6 (C-2 B), 116.4 (C-2 E), 115.7 (CF3, q,
JZ292 Hz), 109.6 (C-8D), 106.8 (C-4aA), 106.6 (C-4aD),
98.8 (C-8A), 97.6 (C-6A), 95.2 (C-6D), 84.6 (C-2F), 80.8
(C-2C), 74.6 (C-3F), 74.0 (C-3C), 70.3 (C-4C), 27.2 (C-4F).
ESI-MS m/z: 1395.9 [MCH]C, 1412 [MCNH4]C, 1417
[MCNa]C, 1433 [MCK]C.
4.2.4. 30,40,5,7-Tetrabenzyloxy-4-(2-ethoxyethoxy)-
catechin (8). DDQ oxidation according to the above
procedure using 30,40,5,7-tetrabenzyloxycatechin
3
(500 mg, 0.77 mmol), DDQ (350 mg, 1.54 mmol) and
2-ethoxyethanol (1.5 mL) in CH2Cl2 (15 mL) for 2 h
afforded 8 as a pale yellow solid, which was crystallized
from hexane/EtOAc to give 550 mg (0.75 mmol, 97%) of
30,40,5,7-tetrabenzyloxy-4-(2-ethoxyethoxy)catechin 8 as
1
colourless needles. H NMR (300 MHz, CDCl3) 7.20 (d,
JZ1.7 Hz, 1H, H-20B), 7.01 (d, JZ8.0 Hz, 1H, H-50B),
6.97 (dd, JZ1.7, 8.0 Hz, 1H, H-60B), 6.17 (d, JZ2.0 Hz,
1H, H-6A), 6.03 (d, JZ2.0 Hz, 1H, H-8A), 4.98 (d, JZ
10.05 Hz, 1H, H-2C), 4.89 (m, 1H, H-3C), 4.85 (d, JZ
7.0 Hz, 1H, H-4C), 3.50–3.90 (m, 4H, OCH2CH2O), 3.30
(q, JZ7.0 Hz, 2H, OCH2CH3), 1.20 (t, JZ7.0 Hz, 2H,
OCH2CH3). 13C NMR (125 MHz, CDCl3) 161.2 (C-7A),
160.3 (C-5A), 156.6 (C-8aD), 148.3 (C-300B), 148.1 (C-400B),
131.1 (C-10B), 121.1 (C-60B), 115.6 (C-5 B), 114.1 (C-2 B),
104.7 (C-4aA), 94.5 (C-8A), 93.6 (C-6A), 76.5 (C-2C), 74.2
(C-3C), 72.1 (C-4C), 70.8 (OCH2), 70.2 (CH2O), 66.5
(CH2CH3), 14.0 (CH2CH3). ESI-MS m/z: 739 [MCH]C,
756 [MCNH4]C, 761 [MCNa]C.
4.2.7. 3-Acetoxy-30,40,5,7-tetrabenzyloxycatechin-(4b/
O/3)-30,40,5,7-tetrabenzyloxy-8-trifluoroacetylcatechin
(12). To a solution of 30,40,5,7-tetrabenzyloxy-8-trifluoro-
acetylcatechin 6 (895 mg, 1.2 mmol, 6 equiv) and
3-acetoxy-30,40,5,7-tetrabenzyloxy-4-(2-ethoxyethoxy)cate-
chin 9 (156 mg, 0.2 mmol) in dry CH2Cl2 (40 mL) was
added dropwise TMSOTf (0.4 mL, 0.2 mmol, 0.5 M
solution in CH2Cl2) at K78 8C. After stirring for 5 min,
the reaction mixture was quenched with saturated sodium
hydrogen carbonate. The aqueous solution was extracted
with EtOAc and the organic phase was washed with water
and brine, and dried over MgSO4. Filtration, concentration
and silica gel column chromatography (cyclohexane/
EtOAc, 80:20) afforded 143 mg of 12 (0.1 mmol, 50%).
1H NMR (300 MHz, CDCl3) 7.11 (m, 2H, H-20B, H-50E),
7.00 (m, 2H, H-600B, H-20E), 6.81 (d, JZ8.7 Hz, 1H, H-50B),
6.63 (m, 1H, H-6 E), 6.26 (d, JZ2.0 Hz, 1H, H-8A), 6.20 (s,
1H, H-6D), 6.10 (d, JZ2.0 Hz, 1H, H-6A), 5.10 (m, 1H,
H-2F), 4.90 (m, 1H, H-4C), 4.85 (d, JZ10.2 Hz, 1H, H-2C),
4.48 (m, 1H, H-3F), 3.82 (m, 1H, H-3C), 2.71 (dd, JZ6.6,
16.5 Hz, 1H, H-4bF), 2.52 (dd, JZ4.5, 16.5 Hz, 1H,
H-4aF), 1.9 (s, 3H, CH3CO). 13C NMR (125 MHz,
4.2.5. 3-Acetoxy-30,40,5,7-tetrabenzyloxy-4-(2-ethoxy-
ethoxy)catechin (9). Acetylation using 30,40,5,7-tetraben-
zyloxy-4-(2-ethoxyethoxy)catechin 8 (500 mg, 0.67 mmol),
Ac2O and 4-(dimethylamino)pyridine afforded 510 mg
(0.65 mmol) of 3-acetoxy-30,40,5,7-tetrabenzyloxy-4-
(2-ethoxyethoxy)catechin 9 as white foam. 1H NMR
(300 MHz, CDCl3) 7.30 (d, JZ1.6 Hz, 1H, H-20B), 7.10
(d, JZ8.1 Hz, 1H, H-50B), 6.96 (dd, JZ1.6, 8.1 Hz, 1H,
H-60B), 6.20 (d, JZ2.0 Hz, 1H, H-6A), 6.10 (d, JZ2.0 Hz,
1H, H-8A), 5.30 (m, 1H, H-3C), 5.20 (d, JZ10.17 Hz, 1H,
H-2C), 4.80 (d, JZ7.4 Hz, 1H, H-4C), 3.30–3.7 (m, 4H,
OCH2CH2O), 3.20 (q, JZ7.0 Hz, 2H, OCH2CH3), 1.7 (s,
3H, CH3CO), 1.10 (t, JZ7.0 Hz, 3H, OCH2CH3). 13C NMR
(125 MHz, CDCl3) 170.2 (CH3CO), 161.0 (C-7A), 160.5
(C-5A), 156.8 (C-8aD), 147.5 (C-30B), 147.0 (C-40B), 130.6

N.-E. Es-Safi et al. / Tetrahedron 62 (2006) 2705–2714
2713
CDCl3) 184.5 (CF3CO), 169.8 (CH3CO), 161.3 (C-7D),
160.8 (C-7A), 158.4 (C-5D), 157.6 (C-5A), 156.7 (C-8aD),
154.3 (C-8aA), 149.5 (C-400E), 149.3 (C-40B), 149.2 (C-30E),
148.8 (C-30B), 132.1 (C-1 E), 131.8 (C-10B), 122.2 (CF3),
121.4 (C-600E), 119.7 (C-600B), 115.1 (C-50E), 114.9 (C-50B),
114.8 (C-2 E), 112.6 (C-2 B), 110.2 (C-4aA), 105.6 (C-8D),
102.7 (C-4aD), 94.3 (C-6A), 93.3 (C-8A), 92.5 (C-6D), 80.5
(C-2C), 76.7 (C-2F), 70.8 (C-3F), 70.2 (C-4C), 66.0 (C-3C),
27.2 (C-4F), 21.1 (CH3CO). ESI-MS m/z: 1437 [MCH]C,
1454 [MCNH4]C, 1459 [MCNa]C.
(eluent, cyclohexane/EtOAc, 80:20) gave 50 mg
(0.05 mmol, 12.5%) of the intermediate compound 16 and
126 mg (0.08 mmol, 40%) of the target product 17, which
1
was obtained as amorphous powder. H NMR (300 MHz,
CDCl3) 7.21 (d, JZ8.1 Hz, 1H, H-50E), 7.06 (d, JZ1.5 Hz,
1H, H-20E), 6.95 (dd, JZ1.5, 8.1 Hz, 1H, H-60E), 6.84 (d,
JZ1.7 Hz, 1H, H-20B), 6.74 (d, JZ8.4 Hz, 1H, H-50B),
6.26 (dd, JZ1.7, 8.4 Hz, 1H, H-60B), 6.19 (s, 1H, H-6A),
6.16 (d, JZ2 Hz, 1H, H-6D), 6.03 (d, JZ2 Hz, 1H, H-8D),
4.95–5.31 (m, 4H, H-2C, H-3C, H-2F, H-3F), 4.87 (d, JZ
3 Hz, 1H, H-4F), 3.4 (q, JZ7 Hz, 2H, CH2CH3), 3.33–3.52
(m, 4H, OCH2CH2O), 2.82 (dd, JZ6.4, 16.2 Hz, 1H,
H-4bC), 2.65 (dd, JZ5.4, 16.2 Hz, 1H, H-4aC), 1.98–2.40
(m, 6H, CH2CH2CH2), 1.1 (t, JZ7 Hz, 3H, CH3CH2). 13C
NMR (125 MHz, CDCl3) 185.6 (COCF3), 171.3 (COO),
170.9 (COO), 160.6 (C-7A), 159.9 (C-7D), 158.1 (C-5A),
157.4 (C-5D), 155.4 (C-8aA), 153.0 (C-8aD), 148.9
(C-30B), 148.5 (3C, C-40B, C-30E, C-40E), 130.1 (C-10B),
129.9 (C-10E), 120.9 (C-60B), 118.8 (C-60E), 117.4 (CF3),
114.4 (2C, C-50B, C-50E), 114.3 (2C, C-20B, C-20E), 103.3
(C-4aA), 101.4 (C-4aD), 94.0 (C-8D), 93.4 (C-6D), 90.5
(C-6A), 78.2 (C-2C), 77.6 (C-2F), 74.5 (C-3C), 72.8 (C-3F),
70.2 (OCH2CH2O), 70.0 (OCH2CH2O), 66.5 (OCH2CH3),
35.1 (2C, CH2CO), 27.1 (C-4), 19.8 (CH2CH2CH2), 13.9
(CH3CH2). ESI-MS m/z: 1581 [MCH]C, 1603 [MCNa]C.
4.2.8. 30,40,5,7-Tetrabenzyloxy-8-trifluoroacetylcatechin-
3-yl glutarate (14). A mixture of 30,40,5,7-tetrabenzyloxy-
8-trifluoroacetylcatechin 6 (400 mg, 0.53 mmol), glutaric
anhydride (183 mg, 1.6 mmol) and 4-(dimethylamino)-
pyridine (5 mg) in pyridine (15 mL) was stirred at 0 8C for
1 h. After stirring for 48 h at room temperature, the reaction
was quenched with water, and extracted with EtOAc. The
combined organic acid phases were washed with brine, and
dried (MgSO4). Filtration, concentration and silica gel
column chromatography (eluent, hexane/EtOAc, 1:1) gave
210 mg (0.24 mmol, 45%) of 14 and 160 mg of 15
1
(0.1 mmol, 19%). H NMR of 14 (300 MHz, CDCl3) 6.99
(d, JZ1.5 Hz, 1H, H-20), 6.901 (d, JZ8.4 Hz, 1H, H-50), 6.84
(dd, JZ1.5, 8.4 Hz, 1H, H-6 ), 6.24 (s, 1H, H-6), 5.3 (m, 1H,
H-3), 4.95 (d, JZ7.8 Hz, 1H, H-2), 2.81 (dd, JZ5.1,
16.0 Hz, 1H, H-4b), 2.72 (dd, JZ5.7, 16.0 Hz, 1H, H-4a),
2.4 (m, 4H, CH2COOR, CH2COOH), 1.7 (m, 2H, CH2-
CH2CH2). 13C NMR (125 MHz, CDCl3) 184.7 (COCF3),
177.5 (COOH), 172.2 (COOR), 159.6 (C-7), 158.0 (C-5),
153.2 (C-8a), 149.2 (C-30), 148.7 (C-40), 130.4 (C-10), 124.3
(C-60), 117.8 (CF3), 116.5 (C-50), 114.4 (C-20), 105.6 (C-8),
102.0 (C-4a), 91.1 (C-6), 78.5 (C-2), 68.4 (C-3), 35.5
(CH2COOH), 33.6 (CH2COOR), 27.9 (C-4), 19.9 (CH2-
CH2COOH). ESI-MS m/z: 861 [MCH]C, 883 [MCNa]C.
4.2.11.
30,40,5,7-Tetrabenzyloxy-8-trifluoroacetyl-
catechin-3-yl-dicyclohexyl-carbodiimidoyl-glutarate
1
(16). H NMR (300 MHz, CDCl3) 7.05 (d, JZ1.5 Hz, 1H,
H-20), 6.95 (d, 0 JZ8.4 Hz, 1H, H-50), 6.78 (dd, JZ1.5,
8.2 Hz, 1H, H-6 ), 6.20 (s, 1H, H-6), 5.1 (d, JZ7.8 Hz, 1H,
H-2), 4.90 (m, 1H, H-3), 2.90 (dd, JZ5.1, 16.0 Hz, 1H, H-
4b), 2.60 (dd, JZ5.7, 16.0 Hz, 1H, H-4a), 2.4 (m, 4H,
CH2CO), 1.6 (m, 2H, CH2CH2CH2), 1.1–2.8 (m, 22H, H
Cyclo). 13C NMR (125 MHz, CDCl3) 184.6 (COCF3), 172.5
(COO), 172.2 (COOC]N), 160.6 (C-7), 158.0 (C-5), 154.1
(C-8a), 153.7 (C]N), 149.2 (C-30), 149.1 (0C-40), 130.6 (C-
10), 120.6 (C-60), 117.4 (CF3), 116.5 (C-5 ), 114.3 (C-20),
105.6 (C-8), 102.0 (C-4a), 91.1 (C-6), 78.4 (C-2), 68.4 (C-
3), 55.7 (CH–N]), 50.0 (CH–NH), 34.1 (CH2–CO), 33.8
(CH2–CO), 33.5 (CH2 Cyclo), 33.5 (CH2 Cyclo), 32.8 (CH2
Cyclo), 32.7 (CH2 Cyclo), 31.1 (CH2 Cyclo), 31.0 (CH2
Cyclo), 27.3 (C-4), 25.6 (CH2 Cyclo), 25.5 (CH2 Cyclo),
24.9 (CH2 Cyclo), 23.2 (CH2 Cyclo), 20.5 (CH2CH2CH2).
ESI-MS m/z: 1067.6 [MCH]C, 1089.6 [MCNa]C.
4.2.9. Di-(5,7,30,40-tetrabenzyloxy-8-trifluoroacetylcate-
chin-3-yl) glutarate (15).0 1H NMR (300 MHz, CDCl3)
7.10 (d, JZ1.5 Hz, 2H, H-2 ), 6.96 (d, JZ8.2 Hz, 2H, H-50),
6.90 (dd, JZ1.5, 8.2 Hz, 2H, H-60), 6.20 (s, 2H, H-6), 5.20
(d, JZ7.8 Hz, 2H, H-2), 4.89 (m, 2H, H-3), 3.02 (dd, JZ
5.1, 15.0 Hz, 2H, H-4b), 2.72 (dd, JZ5.7, 15.0 Hz, 2H,
H-4a), 2.3 (m, 4H, CH2CO), 1.8 (m, 2H, CH2CH2CH2). 13
C
NMR (125 MHz, CDCl3) 185.0 (COCF3), 172.1 (COOR),
160.6 (C-7), 158.0 (C-5), 153.7 (C-8a), 149.2 (C-30), 1480.5
(C-40), 130.2 (C-10), 121.0 (C-60), 117.9 (CF3), 117.5 (C-5 ),
115.1 (C-20), 105.6 (C-8), 102.0 (C4a), 91.1 (C-6),
78.5 (C-2), 68.4 (C-3), 33.5 (CH2CO), 27.5 (C-4),
20.5 (CH2CH2CO). ESI-MS m/z: 1589 [MCH]C, 1611
[MCNa]C.
4.2.12. Octabenzyloxy-3,30-O-glutarylcatechin-(4/6)-8-
trifluoroacetylcatechin (18). To a solution of 17 (100 mg,
0.06 mmol) in CH2Cl2 (20 mL) was added dropwise
TMSOTf (0.11 mL, 0.06 mmol, 0.5 M solution in CH2Cl2)
at 0 8C. After stirring for 5 min, the pale yellow reaction
mixture was quenched with saturated sodium hydrogen
carbonate. The aqueous solution was extracted with CHCl3
and the organic phase was washed with water and brine, and
dried (MgSO4). Filtration, concentration and short silica
gel column chromatography (eluent, cyclohexane/EtOAc,
80:20) afforded 2 mg (0.001 mmol, 2.2%) of 18 as
amorphous powder. 1H NMR (300 MHz, CDCl3) 7.01
(1H, d, J0Z1.5 Hz, 1H, H-20E), 6.90 (1H, dd, JZ1.5, 8.1 Hz,
1H, H-6 E), 6.75 (1H,0 d, JZ1.6 Hz, 1H, H-20B), 6.70 (1H,
d, JZ8.1 Hz, 1H, H-5 E), 6.40 (1H, dd, JZ1.6, 8.3 Hz, 1H,
H-60B), 6.21 (1H, d, JZ8.3 Hz, 1H, H-50B), 6.10 (1H, d,
JZ2.0 Hz, 1H, H-6D), 6.05 (1H, d, JZ2.0 Hz, 1H, H-8D),
4.2.10. 30,40,5,7-Tetrabenzyloxy-4-(2-ethoxyethoxy)-
catechin-3-yl-30,40,5,7-tetrabenzyloxy-8-trifluoroacetyl-
catechin-3-yl glutarate (17). A solution of 30,40,5,7-
tetrabenzyloxy-40-(2-ethoxyethoxy)catechin 8 (150 mg,
0.20 mmol), 30,4 ,5,7-tetrabenzyloxy-8-trifluoroacetylcate-
chin-3-yl glutarate 14 (300 mg, 0.40 mmol), DCC (82.6 mg,
0.40 mmol) and DMAP (10.00 mg) in CH2Cl2 (20 mL) was
stirred at 0 8C for 1 h. After stirring for 12 h at room
temperature, the reaction mixture was quenched with water,
and extracted with CH2Cl2. The combined organic phases
were washed with brine, and dried (MgSO4). Filtration,
concentration and silica gel column chromatography

2714
N.-E. Es-Safi et al. / Tetrahedron 62 (2006) 2705–2714
14. Beauhaire, J.; Es-Safi, N.; Boyer, F. D.; Kerhoas, L.; Le
5.05 (m, 1H, H-2F), 4.95 (m, 1H, H-4F), 4.80 (d, JZ
10.2 Hz, 1H, H-2C), 4.42 (m, 1H, H-3F), 3.85 (m, 1H, H-
3C), 2.76 (dd, JZ6.6, 16.3 Hz, 1H, H-4bF), 2.45 (dd, JZ
4.5, 16.3 Hz, 1H, H-4aF), 2.20–2.40 (m, 4H, CH2CH2CH2),
1.70–1.92 (m, 2H, CH2CH2CH2). ESI-MS m/z: 1491 [MC
H]C, 1513 [MCNa]C.
´
Guerneve, C.; Ducrot, P. H. Bioorg. Med. Chem. Lett. 2005,
15, 559–562.
´
15. Boyer, F. D.; Es-Safi, N.; Beauhaire, J.; Le Guerneve, C.;
Ducrot, P. H. Bioorg. Med. Chem. Lett. 2005, 15, 563–566.
16. Bhatt, M. V.; Perumal, P. T. Tetrahedron Lett. 1981, 22,
2605–2608.
17. Mouton, C. H. L.; Steenkamp, J. A.; Young, D. A.;
Bezuidenhoudt, B. C. D.; Ferreira, D. Tetrahedron 1990, 46,
6885–6894.
References and notes
1. Ariga, T.; Koshiyama, I.; Fukushima, D. Agric. Biol. Chem.
1988, 52, 2717–2722.
18. Kawamoto, H.; Nakatsubo, F.; Murakami, K. Mokuzai
Gakkaishi 1991, 37, 488–493.
2. Landraut, N.; Poucheret, P.; Ravel, P.; Gasc, F.; Cros, G.;
Teisseidre, P.-L. J. Agric. Food Chem. 2001, 49, 3341–3348.
3. Zhao, J.; Wang, J.; Chen, Y.; Agarwal, R. Carcinogenesis
1999, 20, 1737–1745.
19. Bokadia, M. M.; Brown, B. R.; Cummings, W. J. Chem. Soc.
1960, 3308.
20. Betts, M. J.; Brown, B. R.; Shaw, M. R. J. Chem. Soc. (C)
1969, 1178.
4. Saito, A.; Mizushina, Y.; Ikawa, H.; Yoshida, H.; Doi, Y.;
Tanaka, A.; Nakajima, N. Bioorg. Med. Chem. Lett. 2005, 13,
2759–2771.
21. Steenkamp, J. A.; Ferreira, D.; Roux, D. G. Tetrahedron Lett.
1985, 26, 3045–3048.
22. Steenkamp, J. A.; Mouton, C. H. L.; Ferreira, D. Tetrahedron
1991, 47, 6705–6716.
5. Saito, A.; Emoto, M.; Tanaka, A.; Doi, Y.; Shoji, K.;
Mizushina, Y.; Ikawa, H.; Yoshida, H.; Matsuura, N.;
Nakajima, N. Tetrahedron 2004, 60, 12043–12049.
6. Saito, A.; Doi, Y.; Tanaka, A.; Matsuura, N.; Ubukata, M.;
Nakajima, N. Bioorg. Med. Chem. Lett. 2004, 12, 4783–4790.
7. Saito, A.; Nakajima, N.; Tanaka, A.; Ubukata, M. Tetrahedron
Lett. 2003, 44, 5449–5452.
23. Yoneda, S.; Kawamoto, H.; Nakatsubo, J. J. Chem. Soc.,
Perkin Trans. 1 1997, 1025–1043.
24. Steinberg, P. J.; Nel, R. J. J.; Van Rensburg, H.;
Bezuidenhoudt, B. C. B.; Ferreira, D. Tetrahedron 1998, 54,
8153–8158.
25. Arnaudinaud, V.; Nay, B.; Verge, S.; Nuhrich, A.; Deffieux, G.;
Merillon, J.-M.; Monti, J.-P.; Vercauteren, J. Tetrahedron Lett.
2001, 42, 5669–5671.
8. Saito, A.; Nakajima, N.; Tanaka, A.; Ubukata, M. Tetrahedron
2002, 39, 7829–7837.
9. Tuckmantel, W.; Kozikowski, A. P.; Romanczk, L. J., Jr.
J. Am. Chem. Soc. 1999, 121, 12073–12081.
26. Arnaudinaud, V.; Nay, B.; Verge, S.; Nuhrich, A.; Deffieux, G.;
Merillon, J.-M.; Monti, J.-P.; Vercauteren, J. Tetrahedron Lett.
2001, 42, 1279–1281.
10. Kozikowski, A. P.; Tuckmantel, W.; Clifford, G. J. Org.
Chem. 2000, 65, 5371–5381.
27. Bennie, L.; Coetzee, J.; Malan, E.; Woolfrey, J. R.; Ferreira, D.
Tetrahedron 2001, 57, 661–667.
11. Kozikowski, A. P.; Tuckmantel, W.; Hu, Y. J. Org. Chem.
2001, 66, 1287–1296.
28. Saito, A.; Tanaka, A.; Ubukata, M.; Nakajima, N. Synlett
2004, 6, 1069–1073.
12. Kozikowski, A. P.; Tuckmantel, W.; Bottcher, G.;
Romanczyk, L. J., Jr. J. Org. Chem. 2003, 68, 1641–1658.
13. Kawamoto, H.; Nakatsubo, F.; Murakami, K. Mokuzai
Gakkaishi 1991, 37, 488–493.
29. Mustapha, J.; Khan, R.; Khan, I. A.; Ferreira, D. Org. Prep.
Proced. Int. 2004, 36, 61–67.