An improved synthesis of procyanidin dimers: Regio- and stereocontrol of the interflavan bond

Article abstract of DOI:10.1002/ejoc.200600668

A direct and general synthesis of procyanidin dimers B1, B2, B3 and B4 (10a-d) is presented. The approach is based on the stoichiometric coupling of two protected monomeric units (the nucleophilic 2a-b and electrophilic 4a-b partners) and deals with the regio- and stereocontrol of the C4-C8 interflavan bond as well as the control of the degree of oligomerization. The synthesis involves a five-step pathway starting from the native catechin (1a) or epicatechin (1b) to the fully deprotected dimers 10a-d. Furthermore, the process appears to be iterative as the coupling intermediates 9a-d themselves can be readily used in further selective syntheses of trimers or higher oligomers. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600668

FULL PAPER
DOI: 10.1002/ejoc.200600668
An Improved Synthesis of Procyanidin Dimers: Regio- and Stereocontrol of the
Interflavan Bond
Isabelle Tarascou,[a] Karine Barathieu,[a,b] Yann André,[a,b] Isabelle Pianet,[a,c]
Erick J. Dufourc,[b] and Eric Fouquet*[a]
Keywords: Polyphenol / Procyanidin dimer / Synthetic methods / Stereoselectivity / Oligomerization
A direct and general synthesis of procyanidin dimers B1, B2,
B3 and B4 (10a–d) is presented. The approach is based on
the stoichiometric coupling of two protected monomeric units
(the nucleophilic 2a–b and electrophilic 4a–b partners) and
deals with the regio- and stereocontrol of the C4–C8 interfla-
van bond as well as the control of the degree of oligomeriza-
tion. The synthesis involves a five-step pathway starting from
the native catechin (1a) or epicatechin (1b) to the fully depro-
tected dimers 10a–d. Furthermore, the process appears to be
iterative as the coupling intermediates 9a–d themselves can
be readily used in further selective syntheses of trimers or
higher oligomers.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
As a part of a wider research project aiming to study the
tannin–tannin and tannin–protein aggregation phenom-
ena,[1] we have been engaged in the selective synthesis of
proanthocyanidin dimers and oligomers. These condensed
tannins represent a major family of the polyphenolic com-
pounds that are widespread in the vegetable kingdom.[2] In
particular, they can be found in grape seeds[3] and skins[4]
and, interestingly, may be present in red wines[5] at concen-
trations of up to 4 gL–1. Tannin extractions from plants
may give a common access to these different polyphenols.
However, their identification, as well as their purification,
remains tedious such that the small amounts available by
such methods are not suitable for use in further studies. As
the overall interest in tannins increased in the past decade[6]
synthetic processes emerged to overcome the extraction
limitations. For all the synthetic methods, the creation of
the interflavan C4–C8 bond remains the key step
(Scheme 1).
Scheme 1. Usual ring and atom mapping of flavonoid dimer B3
(catechin-4α,8-catechin).
gioselective and oligomerization control demands of the
coupling reaction, but does not fulfil the stereochemical
requirement of the newly formed C4 asymmetric carbon
atom. In contrast, and in spite of recent advances made in
the regio- and stereocontrol of the reaction,[8] the substitu-
tion method still suffers from a lack of selectivity in the
control of the degree of oligomerization, thus requiring the
nucleophilic partner to be used in large excess and re-
stricting the actual synthetic methods to the preparation of
procyanidin dimers. To the best of our knowledge, only two
attempts to prepare procyanidin dimers under stoichiomet-
ric conditions have been reported in the literature. While
total stereocontrol of the C4 benzylic carbon atom failed in
the intermolecular approach,[9] the only approach that deals
efficiently with the three elements to be controlled involves
an eight-step synthesis that is based on an intramolecular
coupling of monomeric units bound by a temporary diester
link.[10] This method was successfully applied to the synthe-
sis of the epicatechin–catechin (B1) and catechin–catechin
dimers (B3). Nevertheless the method failed to be of general
use as the stereochemistry of the C3 hydroxy moieties en-
gaged in the connection prevented some coupling reactions,
The proposed syntheses can be roughly divided into two
different types of approaches involving either a nucleophilic
addition or a nucleophilic substitution as the coupling reac-
tion. The first method involves the nucleophilic addition of
a C8-lithiated nucleophile onto a C4-protected ketoprocy-
anidin as substrate.[7] This reaction generally meets the re-
[a] Laboratoire de Chimie Organique et Organométallique, UMR
5802, Université Bordeaux 1,
351 Cours de la Libération, 33405 Talence, France
E-mail: e.fouquet@lcoo.u-bordeaux1.fr
[b] MOBIOS, UMR 5144, IECB,
2 rue Robert Escarpit, 33607 Pessac, France
[c] Centre d’Etude Structurale des Molécules Organiques CES-
AMO, Université Bordeaux 1,
351 Cours de la Libération, 33405 Talence, France
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I. Tarascou, K. Barathieu, Y. André, I. Pianet, E. J. Dufourc, E. Fouquet
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Scheme 2.
such as the synthesis of B2 and B4 dimers. In the course above, the coupling reaction through nucleophilic substitu-
of our research we have developed a simple and efficient tion on the C4 carbon atom requires activation of the ben-
intermolecular synthesis of procyanidin dimers that deals zylic position with a potent leaving group. This was gen-
with the required regio- and stereoselectivity as well as the erally achieved by heteroatom functionalization with, for
oligomerization control of the reaction (Scheme 2). The key example, bromine,[16] sulfur[17] or oxygen.[8a–8b,18] In view of
step involves a coupling reaction between equimolar this we decided to make use of the potential of the carbon–
amounts of a tetra-protected monomer A (the nucleophilic oxygen bond which offers a good balance between the sta-
partner) and a C4-activated, C8-protected monomer C (the bility of the precursor and its reactivity in the presence of
electrophilic partner). Furthermore, the process appears to a Lewis acid. Thus, the C4 position of 2a and 2b was acti-
be general and iterative considering that any coupling prod- vated by DDQ oxidation of the C4 benzylic carbon atom
uct of type D could be used as an intermediate for further in the presence of ethylene glycol. This reaction, initially
sequential coupling reactions.
developed by Roux and co-workers[18d] and exemplified by
others,[8a,8b] can then be carried out with various nucleo-
philes including water and alcohols. As the nature of the
alcohol presumably plays a significant role in the stereo-
chemical control of the interflavan bond, we decided to use
ethylene glycol as the nucleophile. Indeed, although ethyl-
ene glycol was not the most efficient alcohol for such acti-
vation, it has been shown that the subsequent coupling re-
action of 4-hydroxyethoxyepicatechin 3b could proceed
with total stereocontrol of the interflavan bond.[8a] Acti-
vated catechin 3a and epicatechin 3b were obtained in 69
and 63% yields, respectively, and interestingly this reaction
appeared to be totally diastereoselective. Owing to the con-
formational flexibility of the pyranyl ring C, the stereo-
chemistry of the resulting asymmetric carbon atom could
not be established directly from the H3,H4 coupling con-
stants. For this reason, in the original paper dealing with
the preparation of 3b the uncertainty around the C4 stereo-
chemistry was not eliminated.[8a] This was unambiguously
resolved by NMR experiments coupled with molecular
modelling[19] which showed that both catechin and epicate-
chin gave the same S diastereomers independently of the
Results and Discussion
Synthesis of the Precursors
When the very first proanthocyanidin oligomers were
synthesized using native catechin units[11] it quickly became
apparent that protection of the phenolic functionalities was
essential in order to achieve some regioselective control of
the interflavan bond. Such protection is commonly
achieved by using methyl,[12] acetyl[13] or benzyl[14] groups.
Benzylic protection was chosen in order to benefit from the
stability of benzyl ethers under basic or acidic conditions
as well as to have the opportunity of deprotecting phenolic
units simultaneously with a suitable C8 protecting group if
necessary. The protection of the phenolic hydroxy moieties
of catechin (1a) and epicatechin (1b) was then achieved in
good yields, 81 and 82%, respectively, by using a modifica-
tion of the literature method.[15] Note that control of the
initial temperature remains crucial if undesired C6 and C8
alkylation side-products are to be avoided. As outlined
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An Improved Synthesis of Procyanidin Dimers
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stereochemistry of the contiguous C3 carbon atom and 7a, but in significantly lower yields than those ob-
(Scheme 3). These results are in agreement with the initial served for the activation of non-halogenated substrates
suggestion that the approach of DDQ could be controlled (Scheme 4). This may be explained by the lack of reactivity
by the stereochemistry at the C2 atom and occurs on the of the monoelectronic charge-transfer complex formed with
lower face of the aromatic ring A in order to avoid interac- DDQ when using halogenated catechins 5a and 6a as the
tions with the axial H2 atom.[18e] Finally, the last step of substrates.
the precursor synthesis involves the regioselective aromatic
halogenation of the C8 position to circumvent an uncon-
trolled oligomerization process during the coupling reac-
The Coupling Reaction
tion. Regioselective halogenation reactions can be per-
formed on catechins either at the C6 or C8 position,[20] de-
The coupling reaction of an activated unit with a pro-
pending mainly on the nature of the solvent used. Such tected monomer in the presence of a Lewis acid, first de-
functionalization was used in the nucleophilic addition ap- scribed by Kawamoto et al.,[14a] involved a C4-hydroxylated
proach[7] as well as in the intermolecular substitution coup- catechin as the electrophilic partner, giving a 3:2 mixture of
ling reaction.[9] This functionalization was achieved by the natural and nonnatural protected dimer. The stereose-
using 1 equivalent of N-bromosuccinimide (NBS) in lective control was greatly improved by replacing the C4
[8a]
CH2Cl2
to give the C4-activated, C8-protected catechin hydroxy group with
a
methoxy[21] or other alkoxy
4a or epicatechin 4b in quantitative yield.
group,[8,22] including the hydroxyethoxy functionality.[8a]
Alternatively, several attempts were made to activate Note that all of these methodologies required a large excess
tetra-O-benzylbromocatechin 5a prepared from 2a and N- (5–10 equiv.) of the nucleophile in order to limit the reac-
bromosuccinimide (NBS) in CH2Cl2 or tetra-O-benzyliodo- tion of the activated monomer with itself or with the di-
catechin 6a prepared from 2a and N-iodosuccinimide (NIS) meric product leading in both cases to oligomeric side-
in DMF.[20] The reaction led to the expected products 4a products. The first attempt at the coupling reaction was
Scheme 3. Reagents and conditions: i. K2CO3 (6 equiv.), BnBr (4.5 equiv.), DMF, 0 °C, 2 h, then room temp., 48 h; ii. ethylene glycol
(6 equiv.), DDQ (2 equiv.), CH2Cl2, room temp., 3 h, then DMAP (2 equiv.), 10 min; iii. NBS (1 equiv.), CH2Cl2, –78 °C, 3 h, then room
temp., 8 h.
Scheme 4. Reagents and conditions: i. NBS (1 equiv.), CH2Cl2, –78 °C then room temp., 7 h; ii. NIS (1 equiv.), DMF, room temp., 24 h;
iii. ethylene glycol (6 equiv.), DDQ (2 equiv.), CH2Cl2, room temp., 3.5 h; iv. ethylene glycol (6 equiv.), DDQ (2 equiv.), CH2Cl2, room
temp., 2 h.
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conducted with equimolar amounts of the protected cate-
Importantly, each dimer 9a–d was obtained as a mixture
chin 2a and the iodinated substrate 7a. In the presence of of two rotamers (compact and extended forms) that result
TiCl4 as Lewis acid, the reaction led to the expected dimer from slow rotational exchange around the C4(C)–C8(D) in-
8 in 42% yield (Scheme 5). However this was accompanied terflavan bond. Furthermore, the ratio observed for each
by some trimeric (17%), tetrameric (6%) and pentameric pair of rotamers depends on the nature of the solvent.[24]
(3%) oligomers.[23] The presence in nearly equimolar Finally, as pointed out above, the flexibility of the heterocy-
amounts of both iodinated 8a and non-iodinated 8b forms cles C and F allows a rapid equilibrium between the pseu-
suggested that the carbon–iodine bond is far too fragile to doaxial or pseudoequatorial forms resulting in average val-
resist under acidic conditions, thus leading in situ to C8- ues for the 3JH,H coupling constants. Considering all of this,
deprotected intermediates prone to subsequent oligomeriza- the unambiguous assignment of the three-dimensional
tion processes.
structures of the native procyanidin dimers B1, B2, B3 and
This encouraging result led us to replace the iodinated B4 derived from 9a–d was not a trivial task and was
electrophile 7a with its brominated congener 4a, which was achieved by a combination of two-dimensional NMR ex-
thought to be more resistant to acidic conditions. As ex- periments (TOCSY, ROESY, HMQC, HMBC) and NOE
pected, the reaction furnished the corresponding dimers 9a experiments correlated with MM3 calculations.[25]
(B3) and 9b (B4) with no trace of either debrominated di-
Looking at the reversal of the reactivity that occurred
mers or higher oligomers (Scheme 6). In marked contrast simply by replacing 4a with its epimer 4b, it would seem
to other approaches involving acetate or thiophenyl as the obvious that the stereochemistry at the C3 atom governs the
activating group,[9] the reaction appears to be totally stereo- stereoinduction of the newly formed C4 asymmetric carbon
selective leading to the natural configuration of the interfla- atom. However, this is not the only factor to take into ac-
van bond as a result of a clean inversion at the C4 asymmet- count as previous work by Kawamoto[14] and Vercauteren
ric centre. The reaction was carried out under the same con- and their co-workers,[21] carried out under similar condi-
ditions with the bromide 4b derived from epicatechin to tions and with the same Lewis acid, led only to partial ste-
give the dimers 9c (B1) or 9d (B2) as the sole products. In reocontrol depending on the nature of the substitution at
this case however the reaction occurs with total retention the C4 position (3:2 with a hydroxy leaving group and 2:1
of the configuration at the attacked C4 carbon atom.
with methoxy as the leaving groups). Considering that TiCl4
Scheme 5. Coupling reaction with iodide 7a.
Scheme 6. TiCl4-mediated coupling procedure with bromide 4a.
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An Improved Synthesis of Procyanidin Dimers
FULL PAPER
preferentially adopts a bis-chelated state when possible and debenzylation. Thus we changed to Pearlman’s catalyst,
that the hydroxyethoxy substituent is a particularly good which was found to be far more efficient. Various solvents
bidentate ligand, the origin of the total stereoinduction can were tried, including alcohols, ethyl acetate and THF, and
be found in the mode of complexation of TiCl4 and its con- a 1:1 mixture of methanol/ethyl acetate was found to offer
sequences on the rigidification of the C cycle conformation a good balance between dissolution of the starting bro-
which modifies the facial stereodifferentiation of the incom- mides 9a–d and all the partially deprotected intermediates.
ing nucleophile (Scheme 7).
Promisingly, the first attempt led to a mixture of partially
debrominated procyanidin dimers. We were then able to op-
timize the reaction by using triethylamine as additive, which
has been reported to activate the palladium-mediated
hydrodechlorination of aromatic compounds.[28] In this case
the amine first activates the catalyst by reducing it in situ
to Pd0, but also traps the generated hydrobromic acid, thus
avoiding premature degradation of the native procyanidin
dimers 10a–d (Scheme 9). After careful optimization of the
amine/palladium/substrate ratio, the native procyanidin di-
mers B1, B2, B3 and B4 were isolated in quantitative yields.
Scheme 7. Comparison of mono- and bidentate activating groups.
A similar activated intermediate would explain the rever-
sal of the stereoselectivity observed when using 4b. Indeed,
because the C3 hydroxy group is not engaged in the coordi-
nation sphere of the titanium, it is available to provide an-
chimeric assistance as a result of the axial–axial position
of the neighbouring groups. This would lead to a transient
protonated epoxide, which could be regiospecifically
opened by attack by the nucleophilic at the benzylic carbon
to provide 9c and 9d with an overall retention of configura-
tion at the C4 position (Scheme 8).
Conclusions
In conclusion, we have developed an efficient synthesis
of procyanidin dimers based on the intermolecular nucleo-
philic substitution of activated monomers 4 with equimolar
amounts of protected monomers 2 acting as nucleophiles.
This reaction fulfils the three conditions required for selec-
tive preparation of procyanidin dimers: i) control of the re-
gioselectivity of the interflavan C4–C8 bond, ii) control of
the created C4 stereocentre, giving exclusive access to the
natural isomer and iii) total control of the degree of oligo-
merization. Furthermore, the synthesis involves only five
steps from the native monomers 1 to the totally deprotected
dimers 10, and although the reactions have not been fully
optimized yet, the overall yields are in the range of 22% for
10d to 37% for 10a. Finally, the coupling intermediates 9
can be used in further syntheses, either by activating the C4
position of the lower unit or by deprotecting the C8 posi-
tion of the upper unit. This last point, which highlights the
iterative aspect of the process, is currently under investiga-
tion.
Scheme 8. Nucleophilic substitution mechanism with 4b.
The last step of the synthesis involves the debenzylation
of the phenolic units and the debromination of the C8 posi-
tion. Usually, dehalogenation of procyanidins can be
achieved with BuLi, leading to the corresponding lithiated
derivatives,[26] or with reducing agents such as LAH.[9]
However, we anticipated that the bromine–carbon bond
Experimental Section
could be sufficiently reactive for a one-pot procedure to be
All reactions were performed under argon with magnetic stirring
and with anhydrous solvents. Tetrahydrofuran was distilled from
[13b,14]
successful. The first attempts using Pd/C and H2
or
cyclohexadiene[27] were deceiving, leading only to partial sodium benzophenone ketyl. Methylene chloride, ethyl acetate,
Scheme 9. One-pot deprotection procedure to give native procyanidin dimers.
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I. Tarascou, K. Barathieu, Y. André, I. Pianet, E. J. Dufourc, E. Fouquet
CH2Ph), 4.93 (s, 1 H, 2-H), 4.23 (m, 1 H, 3-H), 3.02 and 2.95
FULL PAPER
methanol and triethylamine were distilled from calcium hydride
and DMF, from magnesium sulfate. (+)-Catechin and (–)-epicate-
chin were purchased from Fluka. PearlmanЈs catalyst [20% Pd-
(OH)2/C] was obtained from Aldrich and contained up to 50%
H2O. The reactions were monitored by thin-layer chromatography
carried out on SDS silica gel plates (silica 60 F254) using UV light
and phosphomolybdic acid solution in 2-propanol for detection.
Column chromatography was performed using silica gel 60 (0.063–
2
3
3
(ABX, J4α,4β = 17.2 Hz, J4α,3 = 1.5 Hz, J4β,3 = 4.3 Hz, 2 H, 4α-
H and 4β-H) ppm. 13C NMR (100.6 MHz, CDCl3, 22 °C): δ =
159.19 (C-7), 158.74 (C-5), 155.69 (C-8a), 149.45 (C-3Ј), 149.27 (C-
4Ј), 137.68 (CqPh), 137.58 (CqPh), 137.42 (CqPh), 137.35 (CqPh),
131.90 (C-1Ј), 129.02 (2 CHPh), 128.94 (2 CHPh), 128.92 (2
CHPh), 128.90 (2 CHPh), 128.40 (CHPh), 128.29 (CHPh), 128.27
(CHPh), 128.23 (CHPh), 127.96 (2 CHPh), 127.93 (2 CHPh),
0.200 mm, Merck) or silica gel 40 (0.040–0.060 mm, Merck) for 127.69 (2 CHPh), 127.63 (2 CHPh), 119.92 (C-6Ј), 115.49 (C-5Ј),
flash chromatography. Melting points (m.p.) were determined with
a Stuart Scientific SMP3 melting point apparatus and are uncor-
rected. Infrared spectra were recorded using a Perkin–Elmer FTIR
Paragon 1000 spectrometer (KBr disc) and values are reported in
cm–1. 1H and 13C NMR spectra were recorded with either a Bruker
Avance DPX 300 or a Bruker Avance NB 400 spectrometer at room
113.95 (C-2Ј), 101.41 (C-4a), 95.11 (C-8), 94.49 (C-6), 78.79 (C-2),
71.80 (2 CH2Bn), 70.56 (CH2Bn), 70.36 (CH2Bn), 66.76 (C-3),
28.63 (C-4) ppm. MS (LSIMS): m/z (%) = 673 (31) [M + Na]+, 651
(65) [M]+, 409 (47), 332 (17), 319 (100), 229 (18). HRMS: calcd.
for C43H39O6 651.2747; found 651.2739.
3Ј,4Ј,5,7-Tetra-O-benzyl-4β-(2-hydroxyethoxy)catechin (3a):[8a] Eth-
ylene glycol (1 mL, 6 equiv.) and DDQ (1.5 g, 2 equiv.) were added
1
temperature (22 °C). The H and 13C NMR spectra were recorded
in CDCl3 for protected compounds and H2O/D2O (90:10) or D2O/
[D6]ethanol (88:12) for deprotected compounds with TMS as an
internal standard. Chemical shifts δ and coupling constants J are
given in ppm and Hz, respectively. Mass spectra were obtained on
a Micromass Autospec-Q mass spectrophotometer [electron-impact
ionization (70 eV) or LSIMS].
3Ј,4Ј,5,7-Tetra-O-benzyl-(+)-catechin (2a):[14b] Benzyl bromide
(3.7 mL, 4.5 equiv.) and K2CO3 (5.71 g, 6 equiv.) were added to a
solution of (+)-catechin (1a) (2.00 g, 6.89 mmol) in DMF (35 mL)
at 0 °C. The mixture was stirred at 0 °C for 2 h and then at room
temperature for 48 h. The mixture was then diluted with ethyl ace-
tate and washed successively with water and brine. The organic
layer was dried with MgSO4. Removal of the solvents gave a vis-
cous brown residue; the title compound 2a was purified by silica
gel chromatography (CH2Cl2) to give a white solid (3.64 g,
to
a solution of 3Ј,4Ј,5,7-tetra-O-benzylcatechin (2a) (2.0 g,
3.07 mmol) in dichloromethane (40 mL) at room temperature. A
black-green colour appeared instantaneously. After 3 h of vigorous
stirring at room temperature, 4-(dimethylamino)pyridine (0.75 g,
2 equiv.) was added. After another 10 min of stirring, the solvent
was evaporated. The resulting crude material was purified by
chromatography on silica gel (pentane/EtOAc, 1:1) to obtain after
evaporation and drying in vacuo the product 3a as a beige solid
(1.51 g, 2.12 mmol, 69% yield). M.p. 120–122 °C. IR (KBr): ν =
˜
3583, 3063, 3031, 2908, 1635, 1604, 1513, 1499, 1454, 1423, 1380,
1320, 1263, 1216, 1179, 1128, 1027, 735, 696 cm–1. 1H NMR
(300 MHz, CDCl3, 22 °C): δ = 7.62–7.30 (m, 20 H, Ar-H), 7.21 (d,
3
4J2Ј,6Ј = 1.5 Hz, 1 H, 2Ј-H), 7.09 (dd, J6Ј,5Ј = 8.3 Hz, 1 H, 6Ј-H),
4
6.97 (d, 1 H, 5Ј-H), 6.37 (d, J6,8 = 1.9 Hz, 1 H, 6-H), 6.27 (d, 1
H, 8-H), 5.27 (s, 2 H, CH2Ph), 5.19 (s, 2 H, CH2Ph), 5.12 (m, 4 H,
5.59 mmol, 81% yield). M.p. 124–126 °C. IR (KBr): ν = 3465,
2 CH2Ph), 5.03 (s, 2 H, CH2Ph), 4.96 (d, J2,3 = 12.0 Hz, 1 H, 2-
H), 4.86 (d, J4,3 = 3.4 Hz, 1 H, 4-H), 3.98–3.83 (m, 3 H, 9-H, 3-
˜
3
3417, 1618, 1592, 1513, 1498, 1454, 1378, 1143, 1217, 1116, 1026,
1
753, 696 cm–1. H NMR (300 MHz, CDCl3, 22 °C): δ = 7.48–7.28
H), 3.76–3.58 (m, 2 H, 10-H) ppm. 13C NMR (100.6 MHz, CDCl3,
22 °C): δ = 161.41 (C-7), 159.11 (C-5), 156.55 (C-8a), 149.88 (C-
4Ј), 149.59 (C-3Ј), 137.83 (4Ј-CqPh), 137.79 (3Ј-CqPh), 137.18 (7-
CqPh), 137.00 (5-CqPh), 131.97 (C-1Ј), 130.06 (2 CHPh), 129.21
(2 CHPh), 129.18 (2 CHPh), 129.03 (2 CHPh), 128.99 (CHPh),
128.77 (CHPh), 128.63 (CHPh), 128.34 (CHPh), 128.22 (2 CHPh),
128.08 (4 CHPh), 127.84 (2 CHPh), 122.02 (C-6Ј), 115.31 (C-2Ј),
115.17 (C-5Ј), 104.62 (C-4a), 94.93 (C-8), 94.22 (C-6), 77.36 (C-
(m, 20 H, Ar-H), 7.05 (s, 1 H, 2Ј-H), 6.98 (s, 2 H, 5Ј-H, 6Ј-H), 6.29
and 6.23 (AM, 4J6,8 = 2.3 Hz, 2 H, 6-H, 8-H), 5.20 (s, 2 H, CH2Ph),
5.19 (s, 2 H, CH2Ph), 5.05 (s, 2 H, CH2Ph), 5.01 (s, 2 H, CH2Ph),
3
4.65 (d, J2,3 = 8.3 Hz, 1 H, 2-H), 4.03 (m, 1 H, 3-H), 3.13 and
3
3
2.67 (ABX, 2J4α,4β = 16.4 Hz, J4α,3 = 5.6 Hz, J4β,3 = 8.9 Hz, 2 H,
4α-H and 4β-H) ppm. 13C NMR (100.6 MHz, CDCl3, 22 °C): δ =
158.82 (C-7), 157.79 (C-5), 155.29 (C-8a), 149.37 and 149.10 (C-
4Ј,C-3Ј), 137.15 (CqPh), 137.00 (CqPh), 136.93 (CqPh), 136.88 2), 73.56 (C-9), 71.89 (CH2Bn), 71.83 (C-3), 71.71 (CH2Bn), 71.01
(CqPh), 130.92 (C-1Ј), 128.59 (2 CHPh), 128.52 (4 CHPh), 128.48 (CH2Bn), 70.62 (C-4), 70.58 (CH2Bn), 62.72 (C-10) ppm. MS
(2 CHPh), 127.99 (CHPh), 127.89 (CHPh), 127.85 (2 CHPh), (LSIMS): m/z (%) = 710 (3) [M]+, 374 (9), 181 (7), 91 (100), 65 (8).
127.52 (2 CHPh), 127.49 (2 CHPh), 127.24 (2 CHPh), 127.12 (2
CHPh), 120.60 (C-6Ј), 115.04 (C-5Ј), 113.93 (C-2Ј), 102.30 (C-4a),
94.41 (C-8), 93.85 (C-6), 81.58 (C-2), 71.32 (CH2Bn), 71.25
(CH2Bn), 70.13 (CH2Bn), 69.92 (CH2Bn), 68.20 (C-3), 27.62 (C-
4) ppm. MS (LSIMS): m/z (%) = 651 (40) [M]+, 409 (14), 332 (13),
319 (100), 307 (38), 229 (19). HRMS: calcd. for C43H39O6 651.2747;
found 651.2748.
3Ј,4Ј,5,7-Tetra-O-benzyl-(–)-epicatechin (2b):[8a] This title com-
pound was prepared following the same procedure as that de-
scribed for 3Ј,4Ј,5,7-tetra-O-benzyl-(+)-catechin (2a) except that
(–)-epicatechin (1b) (1.00 g, 3.45 mmol) was used in place of (+)-
catechin 1a. Compound 2b was purified by silica gel chromatog-
raphy (CH2Cl2) to give a white solid (1.84 g, 2.82 mmol, 82%
HRMS: calcd. for C45H42O8 710.2879; found 710.2876.
3Ј,4Ј,5,7-Tetra-O-benzyl-4β-(2-hydroxyethoxy)epicatechin (3b):[8a]
Ethylene glycol (1.22 mL, 22.0 mmol, 20 equiv.) and DDQ (0.558 g,
2.46 mmol, 2 equiv.) were added to a solution of 3Ј,4Ј,5,7-tetra-
O-benzylepicatechin (2b) (0.800 g, 1.23 mmol) in dichloromethane
(40 mL) at room temperature. A black-green colour appeared in-
stantaneously. After 3 h of vigorous stirring at room temperature,
4-(dimethylamino)pyridine (0.600 g, 4.91 mmol, 4 equiv.) was
added. After another 20 min of stirring, the organic layer was
washed with a 5% aqueous solution of sodium hydrogen carbonate
(2×20 mL) and with brine (20 mL). Then the organic layer was
dried with magnesium sulfate and the solvent evaporated. A purple
solid was obtained and purified by chromatography on silica gel
yield). M.p. 125.6–126.2 °C. IR (KBr): ν = 3440, 1618, 1592, 1512, (cyclohexane/ethyl acetate, 7:3) giving 3b as a pale pink solid
˜
1
1498, 1454, 1378, 1263, 1142, 1217, 1113, 1026, 735, 696 cm–1. H
(0.555 g, 0.77 mmol, 63% yield). IR (KBr): ν = 3583, 1615, 1591,
˜
NMR (300 MHz, CDCl3, 22 °C): δ = 7.47–7.35 (m, 20 H, Ar-H),
1511, 1497, 1453, 1377, 1265, 1214, 1151, 1115, 1026, 736,
4
1
7.18 (d, J2Ј,6Ј = 1.2 Hz, 1 H, 2Ј-H), 7.02 (dd, 3J6Ј,5Ј = 8.4 Hz, 1 H,
696 cm–1. H NMR (300 MHz, CDCl3, 22 °C): δ = 7.50–7.20 (m,
4
3
6Ј-H), 6.99 (d, 1 H, 5Ј-H), 6.30 (s, 2 H, 6-H, 8-H), 5.21 (s, 2 H, 20 H, Ar-H), 7.19 (d, J2Ј,6Ј = 1.5 Hz, 1 H, 2Ј-H), 7.08 (dd, J6Ј,5Ј
CH2Ph), 5.17 (s, 2 H, CH2Ph), 5.07 (s, 2 H, CH2Ph), 5.03 (s, 2 H,
= 8.3 Hz, 4J6Ј,2Ј = 1.5 Hz, 1 H, 6Ј-H), 6.97 (d, 3J5Ј,6Ј = 8.3 Hz, 1 H,
5372
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 5367–5377

An Improved Synthesis of Procyanidin Dimers
FULL PAPER
4
4
5Ј-H), 6.33 (d, J6,8 = 2.3 Hz, 1 H, 6-H), 6.30 (d, J8,6 = 2.3 Hz, 1 tetra-O-benzyl-4β-(2-hydroxyethoxy)epicatechin (3b) (0.902 g,
H, 8-H), 5.23 (s, 2 H, CH2Ph), 5.21 (s, 2 H, CH2Ph), 5.14 (s, 2 H, 1.27 mmol). After work up, the product 4b was obtained without
3
CH2Ph), 5.09 (d, J2,3 = 6.8 Hz, 1 H, 2-H), 4.96 (s, 2 H, CH2Ph), further purification as a pale pink solid (0.990 g, 1.25 mmol, 99%
3
3
3
1
4.63 (d, J4,3 = 2.6 Hz, 1 H, 4-H), 4.00 (dd, J3,4 = 2.6 Hz, J3,2
=
yield). M.p. 110–111 °C. H NMR (300 MHz, CDCl3, 22 °C): δ =
5.3 Hz, 1 H, 3-H), 3.98–3.65 (m, 4 H, 9-H and 10-H) ppm. 13C
NMR (75,0 MHz, CDCl3, 22 °C): δ = 160.7 (C-7), 159.7 (C-5),
7.53–7.26 (m, 20 H, Ar-H), 7.24 (d, J2Ј,6Ј = 1.5 Hz, 1 H, 2Ј-H),
4
7.05 (dd, 3J6Ј,5Ј = 8.3 Hz, 4J6Ј,2Ј = 1.5 Hz, 1 H, 6Ј-H), 6.99 (d, 3J5Ј,6Ј
156.1 (C-8a), 149.1 (C-4Ј), 149.0 (C-3Ј), 137.3 (4Ј-CqPh), 137.2 (3Ј- = 8.3 Hz, 1 H, 5Ј-H), 6.29 (s, 1 H, 6-H), 5.24–5.05 (m, 8 H, 4
3
3
CqPh), 136.7 (7-CqPh), 136.5 (5-CqPh), 130.9 (C-1Ј), 128.7
CH2Ph), 5.03 (d, J2,3 = 6.8 Hz, 1 H, 2-H), 4.65 (d, J4,3 = 2.6 Hz,
(CHPh), 128.5 (2 CHPh), 128.2 (CHPh), 128.1 (CHPh), 127.9 (2 1 H, 4-H), 4.05 (m, 1 H, 3-H), 3.84–3.66 (m, 4 H, 9-H and 10-
CHPh), 127.8 (CHPh), 127.6 (2 CHPh), 127.3 (CHPh), 119.8 (C-
6Ј), 115.2 (C-5Ј), 113.9 (C-2Ј), 101.9 (C-4a), 94.7 (C-8), 94.5 (C-6),
H) ppm. 13C NMR (100 MHz, CDCl3, 22 °C): δ = 158.7 (C-7),
157.0 (C-5), 152.6 (C-8a), 149.4 (C-4Ј), 149.0 (C-3Ј), 137.5 (4Ј-
74.8 (C-2), 71.5 (CH2Bn), 71.4 (CH2Bn), 70.7 (C-4), 70.6 (CH2Bn), CqPh), 137.4 (3Ј-CqPh) 136.7 (7-CqPh), 136.4 (5-CqPh), 130.6 (C-
70.6 (C-9), 70.1 (CH2Bn), 68.2 (C-3), 62.0 (C-10) ppm.
1Ј), 129.0–127.3 (CHPh), 119.4 (C-6Ј), 115.5 (C-5Ј), 113.7 (C-2Ј),
103.8 (C-4a), 93.1 (C-8), 93.0 (C-6), 75.5 (C-2), 71.6–71.0 (CH2Bn),
70.6 (C-9), 68.1 (C-3), 62.2 (C-10), 29.8 (C-4) ppm. MS (LSIMS):
m/z (%) = 813 (100) [M + Na]+, 790 (45) [M + H]+, 727 (52), 637
(15), 547 (19), 479 (10), 457 (83), 413 (28), 381 (38), 361 (41), 329
(60), 289 (53). HRMS: calcd. for C45H41BrNaO8 811.1883 found
811.1893.
3Ј,4Ј,5,7-Tetra-O-benzyl-8-bromo-4β-(2-hydroxyethoxy)catechin
(4a). (a) From 3Ј,4Ј,5,7-Tetra-O-benzyl-4β-(2-hydroxyethoxy)cate-
chin (3a): Recrystallized N-bromosuccinimide (501 mg, 1 equiv.)
dissolved in dichloromethane (15 mL) was added dropwise to a
solution of 3Ј,4Ј,5,7-tetra-O-benzyl-4β-(2-hydroxyethoxy)catechin
(3a) (2.0 g, 2.81 mmol) in dichloromethane (20 mL) at –78 °C (ad-
dition in 5 min). The reaction mixture was warmed to room tem-
perature and stirring was continued at room temperature for 8 h.
The mixture was extracted with ethyl acetate (100 mL). The organic
layer was washed with brine (3 × 100 mL) and then dried with
MgSO4. The solvent was evaporated under reduced pressure and
after drying in vacuo, the title product 4a was obtained as a beige
solid (2.17 g, 2.76 mmol, 98% yield).
3Ј,4Ј,5,7-Tetra-O-benzyl-8-bromocatechin (5a):[8a] Recrystallized N-
bromosuccinimide (547 mg, 1 equiv.) dissolved in dichloromethane
(15 mL) was added dropwise to a solution of 3Ј,4Ј,5,7-tetra-O-ben-
zyl-(+)-catechin (2a) (2.00 g, 3.07 mmol) in dichloromethane
(25 mL) at –78 °C (addition in 25 min). The reaction mixture was
warmed to room temperature and stirring was continued at room
temperature for 7 h. The mixture was extracted with ethyl acetate
(50 mL), washed with brine (40 mL) and then dried with MgSO4.
The solvent was evaporated under reduce pressure and after drying
in vacuo the title compound 5a was purified by recrystallization in
diethyl ether, giving a white solid (1.97 g, 2.70 mmol, 88% yield).
M.p. 121.7–122.5 °C. 1H NMR (300 MHz, CDCl3, 22 °C): δ =
7.56–7.29 (m, 20 H, Ar-H), 7.07 (s, 1 H, 2Ј-H), 6.96 (s, 2 H, 5Ј-H
and 6Ј-H), 6.28 (s, 1 H, 6-H), 5.19 (s, 4 H, 2 CH2Bn), 5.14 (s, 2 H,
(b) From 3Ј,4Ј,5,7-tetra-O-benzyl-8-bromocatechin (5a): Ethylene
glycol (0.5 mL, 6 equiv.) and DDQ (0.62 g, 2 equiv.) were added to
a solution of 3Ј,4Ј,5,7-tetra-O-benzyl-8-bromocatechin (5a) (2.25 g,
3.08 mmol) in dichloromethane (20 mL) at room temperature. A
black-green colour appeared instantaneously. After 3.5 h of vigor-
ous stirring at room temperature, 4-(dimethylamino)pyridine
(0.34 g, 2.0 equiv.) was added. After another 15 min of stirring, the
solvent was evaporated. The resulting crude material was purified
by chromatography on silica gel (petroleum ether/EtOAc, 1:1) to
obtain after evaporation and drying in vacuo the product 4a as a
white solid (1,09 g, 1.39 mmol, 45% yield). M.p. 149–151 °C (dec.).
3
CH2Bn), 5.01 (s, 2 H, CH2Bn), 4.84 (d, J2,3 = 7.5 Hz, 1 H, 2-H),
2
3
4.00 (m, 1 H, 3-H), 3.02 and 2.71 (ABX, J4α,4β = 16.6 Hz, J4α,3
= 5.6 Hz, J4β,3 = 8.3 Hz, 2 H, 4α-H and 4β-H) ppm. 13C NMR
3
(100.6 MHz, CDCl3, 22 °C): δ = 156.34 (C-7), 154.82 (C-5), 151.67
(C-8a), 149.16 (C-4Ј), 148.97 (C-3Ј), 137.20 (CqPh), 137.01 (CqPh),
136.69 (CqPh), 136.57 (CqPh), 130.69 (C-1Ј), 128.59 (4 CHPh),
128.52 (2 CHPh), 128.48 (2 CHPh), 128.04 (CHPh), 127.95
(CHPh), 127.84 (2 CHPh), 127.47 (2 CHPh), 127.23 (2 CHPh),
127.14 (2 CHPh), 127.07 (2 CHPh), 119.88 (C-6Ј), 114.92 (C-5Ј),
113.46 (C-2Ј), 103.95 (C-4a), 92.90 (C-6), 92.80 (C-8), 81.60 (C-2),
71.36 (CH2Bn), 71.25 (CH2Bn), 71.21 (CH2Bn), 70.24 (CH2Bn),
67.79 (C-3), 27.21 (C-4) ppm. MS (LSIMS): m/z (%) = 753 (100)
[M + Na]+, 730 (63) [M + H]+, 661 (16), 421 (16), 409 (18), 397
(72), 329 (40), 307 (39), 289 (27). HRMS: calcd. for C43H37BrO6
728.1774; found 728.1781.
IR (KBr): ν = 3385, 3063, 3031, 2924, 2868, 1604, 1578, 1516, 1498,
˜
1454, 1421, 1380, 1346, 1265, 1216, 1185, 1126, 1069, 1028, 885,
1
855, 812, 782, 735, 696 cm–1. H NMR (300 MHz, CDCl3, 22 °C):
4
δ = 7.53–7.23 (m, 20 H, Ar-H), 7.17 (d, J2Ј,6Ј = 1.9 Hz, 1 H, 2Ј-
3
H), 7.05 (dd, J6Ј,5Ј = 8.3 Hz, 1 H, 6Ј-H), 6.96 (d, 1 H, 5Ј-H), 6.28
(s, 1 H, 6-H), 5.23–4.99 (m, 8 H, 4 CH2Bn), 5.09 (d, 3J2,3 = 10.6 Hz,
3
1 H, 2-H), 4.82 (d, J4,3 = 3.4 Hz, 1 H, 4-H), 3.86 (m, 2 H, 9-H),
3.77 (m, 1 H, 3-H), 3.66 (m, 2 H, 10-H) ppm. 13 C NMR
(100.6 MHz, CDCl3, 22 °C): δ = 156.89 (C-5), 156.60 (C-7), 152.16
(C-8a), 149.03 (C-4Ј), 148.69 (C-3Ј), 137.05 (CqPh), 136.95 (CqPh),
136.17 (CqPh), 135.82 (CqPh), 130.70 (C-1Ј), 128.50 (2 CHPh),
128.41 (2 CHPh), 128.25 (2 CHPh), 128.21 (2 CHPh), 128.14
(CHPh), 127.79 (CHPh), 127.54 (2 CHPh), 127.35 (2 CHPh),
127.29 (2 CHPh), 127.01 (2 CHPh), 126.73 (2 CHPh), 120.80 (C-
6Ј), 114.43 (C-5Ј), 114.03 (C-2Ј), 105.21 (C-4a), 92.47 (C-8), 91.90
(C-6), 76.72 (C-2), 72.86 (C-9), 71.38 (C-3), 71.07 (CH2Bn), 70.99
(CH2Bn), 70.90 (CH2Bn), 70.53 (CH2Bn), 69.63 (C-4), 62.02 (C-
10) ppm. MS (LSIMS): m/z (%) = 813 (100) [M + Na]+, 790 (16)
[M + H]+, 749 (5), 729 (24), 571 (46), 549 (25), 457 (20), 361 (12),
329 (65), 307 (43), 289 (27). HRMS: calcd. for C45H41BrNaO8
811.1883; found 811.1893.
3Ј,4Ј,5,7-Tetra-O-benzyl-8-iodocatechin (6a): N-Iodosuccinimide
(450 mg, 1 equiv.) dissolved in DMF (6 mL) was added dropwise
to a solution of 3Ј,4Ј,5,7-tetra-O-benzyl-(+)-catechin (2a) (1.30 g,
2.0 mmol) in DMF (14 mL) (addition in 15 min). Stirring was con-
tinued at room temperature for 24 h. The mixture was diluted with
ethyl acetate (50 mL) and washed with water (5×40 mL). The or-
ganic layer was washed with water and then dried with MgSO4.
After evaporation of the solvent under reduce pressure and purifi-
cation by recrystallization in diethyl ether, the title compound 6a
was obtained as a yellow solid (1.48 g, 1.91 mmol, 95% yield). M.p.
149.4–150.4 °C. IR (KBr): ν = 3583, 3420, 2923, 1600, 1595, 1513,
˜
3Ј,4Ј,5,7-Tetra-O-benzyl-8-bromo-4β-(2-hydroxyethyloxy)epicate-
chin (4b):[29] The title compound was prepared following the same
procedure as that described for the synthesis of 3Ј,4Ј,5,7-tetra-O-
benzyl-8-bromo-4β-(2-hydroxyethoxy)catechin (4a) using 3Ј,4Ј,5,7-
1498, 1454, 1381, 1262, 1167, 1221, 1119, 1026, 735, 696, 667 cm–1.
1H NMR (400 MHz, CDCl3, 22 °C): δ = 7.41–7.22 (m, 20 H, Ar-
H), 6.99 (s, 1 H, 2Ј-H), 6.85 (s, 2 H, 5Ј-H and 6Ј-H), 6.15 (s, 1 H,
6-H), 5.10 (s, 2 H, CH2Bn), 5.06 (s, 2 H, CH2Bn), 5.03 (s, 2 H,
Eur. J. Org. Chem. 2006, 5367–5377
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5373

I. Tarascou, K. Barathieu, Y. André, I. Pianet, E. J. Dufourc, E. Fouquet
CH2Bn), 4.91 (s, 2 H, CH2Bn), 4.75 (d, J2,3 = 7.3 Hz, 1 H, 2-H), 6.32 (s, 6D-H, maj), 6.26 (s, 6A-H, min), 6.24 (s, 6A-H, maj), 6.15
FULL PAPER
3
2
3
3.88 (m, 1 H, 3-H), 2.89 and 2.57 (ABX, J4α,4β = 16.6 Hz, J4α,3 (s, 6D-H, min), 5.34–4.49 (m, CH2Bn, min and maj), 4.88 (d,
3
3
= 5.3 Hz, J4β,3 = 8.0 Hz, 2 H, 4α-H and 4β-H) ppm. 13C NMR
3J4C,3Cmin = 8.3 Hz, 4C-H, min), 4.80 (d, J4C,3Cmaj = 9.0 Hz, 4C-
3
(100.6 MHz, CDCl3, 22 °C): δ = 158.43 (C-8a), 157.64 (C-7), H, maj), 4.62 (d, J2C,3C = 9.8 Hz, 2C-H, min and maj), 4.44 (d,
154.23 (C-5), 149.42 (C-3Ј), 149.35 (C-4Ј), 137.66 (CqPh), 137.50
3J2F,3Fmin = 8.7 Hz, 2F-H, min), 4.32 (m, 3C-H, maj), 4.19 (m, 3C-
(CqPh), 137.12 (CqPh), 137.04 (CqPh), 131.30 (C-1Ј), 129.04 (2 H, min), 3.73 (m, 3F-H, min and maj), 3.72 (d, 3J2F,3Fmaj = 12.1 Hz,
CHPh), 129.01 (2 CHPh), 128.97 (2 CHPh), 128.93 (2 CHPh), 2F-H, maj), 3.26 and 2.70 (ABX, 2J4Fα,4Fβmin = 16.6 Hz, 3J4Fα,3Fmin
3
128.48 (CHPh), 128.32 (CHPh), 128.27 (2 CHPh), 127.92 (2
= 5.8 Hz, J4Fβ,3Fmin = 9.4 Hz, 4Fα-H and 4Fβ-H, min), 3.11 and
2
3
3
CHPh), 127.70 (2 CHPh), 127.59 (2 CHPh), 127.49 (2 CHPh), 2.46 (ABX, J4Fα,4Fβmaj = 16.2 Hz, J4Fα,3Fmaj = 4.9 Hz, J4Fβ,3Fmaj
120.23 (C-6Ј), 115.24 (C-5Ј), 113.82 (C-2Ј), 103.91 (C-4a), 92.62 (C- = 8.5 Hz, 4Fα-H and 4Fβ-H, maj) ppm. 13C NMR (100.6 MHz,
6), 82.17 (C-2), 71.71 (CH2Bn), 71.66 (CH2Bn), 71.61 (CH2Bn),
70.65 (CH2Bn), 68.39 (C-8), 67.79 (C-3), 27.65 (C-4) ppm. MS
CDCl3, 22 °C): δ = 157.57 (C-7A, min), 156.88 (C-7A, maj), 156.77
(C-7D, min), 156.24 (C-7D, maj), 156.15 (C-5D, min), 156.06 (C-
(LSIMS): m/z (%) = 800 (10) [M + Na]+, 777 (59) [M + H]+, 650 5D, maj), 154.74 (C-5A, maj), 154.69 (C-5A, min), 154.50 (C-8aA,
(13), 445 (100), 319 (50).
maj), 154.24 (C-8aA, min), 154.00 (C-8aD, maj), 153.43 (C-8aD,
min), 149.77–148.61 (C-3ЈB, C-3ЈE, C-4ЈB, C-4ЈE, min and maj),
137.23–136.97 (CqPh, min and maj), 132.31 (C-1ЈE, maj), 132.15
(C-1ЈB, min), 132.07 (C-1ЈB, maj), 130.61 (C-1ЈE, min), 130.19–
127.46 (CHPh, min and maj), 121.62 (C-6ЈB, maj), 121.09 (C-6ЈB,
min), 120.71 (C-6ЈE, maj), 120.30 (C-6ЈE, min), 116.09 (C-5ЈB,
min), 115.39 and 115.18 (C-5ЈB and C-5ЈE, maj), 115.07 (C-5ЈE,
min), 114.51 (C-2ЈB and C-2ЈE, min), 114.10 (C-2ЈB and C-2ЈE,
maj), 112.17 (C-8D, min), 111.90 (C-8D, maj), 111.23 (C-4aA,
maj), 111.13 (C-4aA, min), 104.04 (C-4aD, min), 103.04 (C-4aD,
maj), 94.39 (C-8A, min), 94.33 (C-8A, maj), 94.06 (C-6A, maj),
93.83 (C-6A, min), 92.31 (C-6D, min), 91.79 (C-6D, maj), 82.76
(C-2C, maj), 82.33 (C-2C, min), 81.93 (C-2F, min), 81.28 (C-2F,
maj), 73.82 (C-3C, min), 73.60 (C-3C, maj), 71.90–70.46 (CH2Bn,
min and maj), 69.27 (C-3F, min), 68.97 (C-3F, maj), 38.04 (C-4C,
min), 37.94 (C-4C, maj), 29.07 (C-4F, min), 28.58 (C-4F, maj) ppm.
MS (LSIMS): m/z (%) = 1401 (87) [M + Na]+, 1378 (58) [M]+,
1309 (16), 1045 (25), 937 (26), 727 (35), 647 (21), 395 (64), 307 (42),
211 (100). HRMS: calcd. for C86H73O12BrNa 1399.4183; found
1399.4160.
3Ј,4Ј,5,7-Tetra-O-benzyl-4β-(2-hydroxyethoxy)-8-iodocatechin (7a):
3Ј,4Ј,5,7-Tetra-O-benzyl-8-iodocatechin (6a) (2.0 g, 2.6 mmol) was
dissolved in dichloromethane (40 mL). Ethylene glycol (0.86 mL,
6 equiv.) and DDQ (1.17 g, 2 equiv.) were then added at room tem-
perature. A black-green colour appeared instantaneously. After 2 h
of vigorous stirring at room temperature, 4-(dimethylamino)pyri-
dine (0.63 g, 2 equiv.) was added. The solvent was evaporated and
the resulting crude material was purified by chromatography on
silica gel (petroleum ether/EtOAc, 1:1) to obtain after evaporation
and drying in vacuo the product 7a as an orange solid (914 mg,
1.09 mmol, 42% yield). 1H NMR (400 MHz, CDCl3, 22 °C): δ =
4
7.34–7.14 (m, 20 H, Ar-H), 7.07 (d, J2Ј,6Ј = 1.9 Hz, 1 H, 2Ј-H),
3
6.93 (dd, J6Ј,5Ј = 8.3 Hz, 1 H, 6Ј-H), 6.84 (d, 1 H, 5Ј-H), 6.11 (s,
3
1 H, 6-H), 5.08–4.88 (m, 8 H, 4 CH2Bn), 5.08 (d, J2,3 = 5.7 Hz, 1
3
H, 2-H), 3.72 (d, J4,3 = 3.5 Hz, 1 H, 4-H), 3.73 (m, 2 H, 9-H),
3.63 (m, 1 H, 3-H), 3.53 (m, 2 H, 10-H) ppm. 13 C NMR
(100.6 MHz, CDCl3, 22 °C): δ = 159.61 (C-7), 159.16 (C-5), 154.95
(C-8a), 149.56 (C-3Ј), 149.33 (C-4Ј), 137.71 (CqPh), 137.63 (CqPh),
136.79 (CqPh), 136.45 (CqPh), 131.35 (C-1Ј), 129.13 (CHPh),
129.02 (CHPh), 128.88 (2 CHPh), 128.86 (3 CHPh), 128.78
(CHPh), 128.35 (CHPh), 128.16 (CHPh), 127.99 (3 CHPh), 127.88
(3 CHPh), 127.63 (2 CHPh), 127.35 (2 CHPh), 121.29 (C-6Ј),
114.99 (C-5Ј), 114.49 (C-2Ј), 105.35 (C-4a), 91.93 (C-6), 77.48 (C-
8), 73.55 (C-2), 72.27 (C-9), 71.67 (CH2Bn), 71.63 (CH2Bn), 71.55
(CH2Bn), 71.17 (CH2Bn), 70.16 (C-4), 67.84 (C-3), 62.70 (C-
10) ppm. MS (LSIMS): m/z (%) = 859 (100) [M + Na]+, 676 (13),
649 (25), 557 (14), 527 (29), 505 (34), 487 (13). HRMS: calcd. for
C45H41O8INa 859.1743; found 859.1741.
3Ј,4Ј,5,7-Tetra-O-benzyl-8-bromocatechin-4α,8-(3Ј,4Ј,5,7-tetra-O-
benzylepicatechin) (9b): The title compound was prepared after
coupling 3Ј,4Ј,5,7-tetra-O-benzyl-8-bromo-4β-(2-hydroxyethoxy)-
catechin (4a) (582 mg, 0.74 mmol, 1.2 equiv.) and 3Ј,4Ј,5,7-tetra-O-
benzylepicatechin (2b) (400 mg, 0.61 mmol, 1 equiv.) following the
same procedure as that described for 3Ј,4Ј,5,7-tetra-O-benzyl-8-
bromocatechin-4α,8-(3Ј,4Ј,5,7-tetra-O-benzylcatechin) (9a). The re-
sulting dark-red solution was stirred at room temperature for 5 h.
After work up and purification on silica gel (pentane/EtOAc, 4:1),
the protected B4 dimer 9b was isolated (449 mg, 0.33 mmol, 53%
3Ј,4Ј,5,7-Tetra-O-benzyl-8-bromocatechin-4α,8-(3Ј,4Ј,5,7-tetra-O-
benzylcatechin) (9a): TiCl4 (1  in CH2Cl2) (1.5 mL, 2 equiv.) was
added dropwise with ice cooling to 3Ј,4Ј,5,7-tetra-O-benzylcatechin
(2a) (500 mg, 0.77 mmol) and 3Ј,4Ј,5,7-tetra-O-benzyl-8-bromo-4β-
(2-hydroxyethoxy)catechin (4a) (728 mg, 1.2 equiv.) in THF (5 mL)
and dichloromethane (5 mL). The resulting dark-red solution was
stirred at room temperature for 3 h. The reaction mixture was
treated with saturated aqueous NaHCO3 (10 mL) and water
(10 mL). The TiO2·xH2O precipitate was removed by filtration and
rinsed with dichloromethane and water. The organic layer was
washed with brine and the aqueous phases were extracted with
dichloromethane. The organic phases were then dried with MgSO4.
After evaporation of the solvents, the resulting dark-red oil was
purified by flash chromatography on silica gel (pentane/EtOAc,
4:1) to obtain after evaporation and drying in vacuo the title com-
pound 9a as a beige solid (710 mg, 0.515 mmol, 67% yield). M.p.
yield). M.p. 73–75 °C. IR (KBr): ν = 3422, 3062, 3030, 2925, 2856,
˜
1600, 1512, 1498, 1454, 1418, 1382, 1340, 1265, 1216, 1173, 1116,
1027, 910, 848, 786, 735, 696, 620 cm–1 1H NMR (400 MHz,
.
CDCl3, 22 °C): (two rotamers: maj/min 85:15): δ = 7.49–6.80 (m,
40 H, Ar-H), 7.22–6.67 (m, 6 H, 2ЈB-H, 5ЈB-H, 6ЈB-H, 2ЈE-H, 5ЈE-
H, 6ЈE-H), 6.22 (s, 1 H, 6D-H), 6.18 (s, 1 H, 6A-H), 5.24–4.38 (m,
3
16 H, CH2Bn), 4.83 (d, J4C,3C = 8.3 Hz, 1 H, 4C-H), 4.58 (d,
3J2C,3C = 9.6 Hz, 1 H, 2C-H), 4.19 (m, 1 H, 3C-H), 3.88 (m, 1 H,
2
3F-H), 3.78 (s, 1 H, 2F-H), 2.88 and 2.57 (ABX, J4Fα,4Fβ
=
3
3
17.1 Hz, J4Fα,3F = 4.4 Hz, J4Fβ,3F Ͻ 1 Hz, 2 H, 4Fα-H and 4Fβ-
H) ppm. 13C NMR (100.6 MHz, CDCl3, 22 °C): δ = 156.58 (C-
5A), 156.48 (C-5D), 155.63 (C-7D), 154.38 (C-7A), 153.87 (C-
8aD), 153.65 (C-8aA), 149.24, 149.05, 148.77, 148.56 (C-3ЈB, C-
3ЈE, C-4ЈB, C-4ЈE), 138.20–136.50 (CqPh), 132.29 (C-1ЈE), 131.63
(C-1ЈB), 129.10–127.00 (CHPh), 121.25 (C-6ЈB), 118.95 (C-6ЈE),
74–76 °C. IR (KBr): ν = 3568, 3062, 3029, 2865, 1600, 1509, 1498, 115.43, 114.78 (C-5ЈB, C-5ЈE), 113.58 (C-2ЈB), 113.18 (C-2ЈE),
˜
1454, 1419, 1380, 1339, 1263, 1213, 1172, 1114, 1026, 909, 847,
808, 734, 695 cm–1. 1H NMR (300 MHz, CDCl3, 22 °C): (two rota-
mers: maj/min, 63:37): δ = 7.56–7.24 (m, Ar-H, min and maj), 7.19–
6.76 (2ЈB-H, 2ЈE-H, 5ЈB-H, 5ЈE-H, 6ЈB-H, 6ЈE-H, min and maj),
111.49 (C-8D), 110.97 (C-4aA), 100.98 (C-4aD), 94.04 (C-8A),
93.89 (C-6A), 91.36 (C-6D), 82.43 (C-2C), 77.49 (C-2F), 73.14 (C-
3C), 71.90–69.80 (CH2Bn), 66.23 (C-3F), 37.35 (C-4C), 28.42 (C-
4F) ppm (chemical shifts and coupling constants J are only given
5374
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 5367–5377

An Improved Synthesis of Procyanidin Dimers
FULL PAPER
for the major rotamer). MS (LSIMS): m/z (%) = 1401 (100) [M +
137.9–136.7 (CqPh), 132.0, 130.9 (C-1ЈB, C-1ЈE), 128.9–127.0
Na]+, 1379 (38) [M]+, 1309 (18), 1045 (13), 727 (7), 647 (21), 381 (CHPh), 119.5, 118.4 (C-6ЈB, C-6ЈE), 115.4 (C-5ЈB and C-5ЈE),
(30), 353 (14), 329 (24), 307 (16), 289 (15), 211 (7). HRMS: calcd.
for C86H73O12BrNa 1399.4183; found 1399.4215.
113.3 (C-2ЈE and C-2ЈB), 111.5 (C-8D), 107.4 (C-4aA), 102.5 (C-
4aD), 93.3 (C-6D), 93.0 (C-8A), 91.8 (C-6A), 79.1 (C-2F, maj), 78.4
(C-2F, min), 76.4 (C-2C, maj), 76.3 (C-2C, min), 72.5–69.6
(CH2Bn, C-3C, maj and min), 66.7 (C-3F, maj), 65.4 (C-3F, min),
36.1 (C-4C, maj), 35.9 (C-4C, min), 28.9 (C-4F, min), 28.7 (C-4F,
maj) ppm. MS (LSIMS): m/z (%) = 1417.3 (14) [M + K]+, 1401.3
(100) [M + Na]+, 712.3 (5). HRMS: calcd. for C26H76BrO12
1399.4183; found 1399.4234.
Catechin-4α,8-catechin (10a):[30] In a reaction flask washed with
aqueous hydrogen carbonate, 3Ј,4Ј,5,7-tetra-O-benzyl-8-bromocat-
echin-4α,8-(3Ј,4Ј,5,7-tetra-O-benzylcatechin) (9a) (40 mg, 29 µmol)
was dissolved in ethyl acetate (2 mL) and methanol (2 mL). Pe-
3Ј,4Ј,5,7-Tetra-O-benzyl-8-bromoepicatechin-4β,8-(3Ј,4Ј,5,7-tetra-O-
benzylcatechin) (9c): The title compound was prepared after coup-
ling 3Ј,4Ј,5,7-tetra-O-benzyl-8-bromo-4β-(2-hydroxyethoxy)-epica-
techin (4b) (0.467 g, 0.591 mmol, 1.2 equiv.) and 3Ј,4Ј,5,7-tetra-O-
benzylcatechin (2a) (0.321 g, 0.493 mmol, 1 equiv.) following the
same procedure as described for 3Ј,4Ј,5,7-tetra-O-benzyl-8-bromo-
catechin-4α,8-(3Ј,4Ј,5,7-tetra-O-benzylcatechin) (9a). The resulting
dark-red solution was stirred at room temperature for 3 h. After
work up and purification on silica gel (cyclohexane/ethyl acetate,
7:3) the protected B1 dimer 9c was isolated (0.321 g, 0.232 mmol,
47% yield). 1H NMR (300 MHz, CDCl3, 22 °C): (two rotamers: arlman’s catalyst Pd(OH)2/C (40 mg) and triethylamine (40 µL,
maj/min 77:23): δ = 7.50–7.26 (m, Ar-H), 7.21–6.80 (2ЈB/E-H, 5ЈB- 287 µmol) were added and the mixture was then stirred under H2
4
H, 6ЈB/E-H, 5ЈE-H, maj and min), 6.64 (d, J2Ј,6Ј = 1.5 Hz, 2ЈE/B-
at room temperature for 18 h. After filtration through Celite, wash-
ing with ethyl acetate and evaporation of the solvents, the B3 dimer
3
4
H, maj), 6.35 (s, 6D-H, maj), 6.32 (dd, J6Ј,5Ј = 8.3 Hz, J6Ј,2Ј
=
1.9 Hz, 6ЈE/B-H, maj), 6.20 (s, 6A-H, min), 6.17 (s, 6D-H, min), was obtained accompanied by the triethylamine hydrobromide salt.
6.05 (s, 6A-H, maj), 5.45 (s, 2C-H, maj), 5.38 (s, 2C-H, min), 5.17–
Rapid filtration through silica gel (acetone/4% methanol) followed
by evaporation and drying in vacuo gave the B3 dimer 10a as a
white solid in quantitative yield. M.p. 218–220 °C (dec.). IR (KBr):
3
4.76 (m, CH2Bn, maj and min), 4.85 (d, J3C,4Cmaj = 1.1 Hz, 4C-
H, maj), 4.73 (d, J Ͻ 1 Hz, 4C-H, min), 4.62 (d, 3J2F,3Fmin = 3.4 Hz,
2F-H, min), 4.07 (d, 3J3C,4Cmaj = 1.1 Hz, 3C-H, maj), 3.93 (m, J Ͻ
ν = 3375, 1610, 1522, 1451, 1375, 1283, 1207, 1144, 1106, 1092,
˜
3
3
1 Hz, 3C-H, min), 3.69 (dd, J3F,4Fα/βmaj = 8.7 Hz, J3F,4Fα/βmaj
=
1061, 870, 818, 780, 668, 621 cm–1. 1H NMR (400 MHz, H2O/10%
3
3
7.5 Hz, 3F-H, maj), 3.58 (d, J2F,3Fmaj Ͻ 1 Hz, 2F-H, maj), 3.23 D2O, 22 °C): (two rotamers: maj/min 95:5): δ = 6.87 (d, J5ЈE,6ЈE
=
(dd, 2J4Fα,4Fβmaj = 16.7 Hz, 3J4Fβ,3Fmaj = 6.4 Hz, 4Fβ-H, maj), 3.14 8.2 Hz, 1 H, 5ЈE-H), 6.83 (d, J5ЈB,6ЈB = 8.2 Hz, 1 H, 5ЈB-H), 6.80
3
(dd, 2J4Fβ,4Fβmin = 16.2 Hz, 3J4Fβ,3Fmin = 5.3 Hz, 4Fβ-H, min), 2.68
(dd, 2J4Fα,4Fβmin = 16.2 Hz, 3J4Fα,3Fmin = 9.0 Hz, 4Fα-H, min), 2.55
(dd, 3J4Fα,4Fβmaj = 16.7 Hz, 3J4Fα,3Fmaj = 9.8 Hz, 4Fα-H, maj) ppm.
13C NMR (75.0 MHz, CDCl3, 22 °C): δ = 156.0 (C-5D), 155.8 (C-
(d, J2ЈB,6ЈB Ͻ 1 Hz, 1 H, 2ЈB-H), 6.61 (d, J2ЈE,6ЈE Ͻ 1 Hz, 1 H,
4
4
2ЈE-H), 6.61 (dd, 1 H, 6ЈB-H), 6.46 (dd, 1 H, 6ЈE-H), 6.15 (s, 1 H,
3
6D-H), 6.00 (s, 1 H, 6A-H), 5.71 (s, 1 H, 8A-H), 4.58 (d, J2F,3F
=
3
7.9 Hz, 1 H, 2F-H), 4.39 (d, J2C,3C = 10.0 Hz, 1 H, 2C-H), 4.36
3
7D), 155.6 (C-5A), 154.3 (C-7A and C-8aD), 151.4 (C-8aA), 149.8, (d, J4C,3C = 10.5 Hz, 1 H, 4C-H), 4.29 (m, 1 H, 3C-H), 3.92 (m,
2
3
149.4, 149.2, 148.6 (C-3ЈB, C-3ЈE, C-4ЈB, C-4ЈE), 137.6–136.9 1 H, 3F-H), 2.85 and 2.49 (ABX, J4Fα,4Fβ = 15.8 Hz, J4Fα,3F
(CqPh), 131.8, 129.5 (C-1ЈB, C-1ЈE), 128.6–126.8 (CHPh), 120.3,
5.3 Hz, 3J4Fβ,3F = 8.5 Hz, 2 H, 4Fα-H and 4Fβ-H) ppm. 13C NMR
119.1 (C-6ЈB, C-6ЈE), 115.2, 114.3 (C-5ЈB, C-5ЈE), 113.1, 111.3 (C- (100.6 MHz, H2O/10% D2O, 22 °C): δ = 156.83 (C-8aA), 155.24
=
2ЈE, C-2ЈB), 110.8 (C-8D), 106.8 (C-4aA), 104.3 (C-4aD), 93.4 (C-
8A), 92.5 (C-6D), 92.4 (C-6A), 81.6 (C-2F, maj), 81.4 (C-2F, min),
77.2 (C-2C, min), 75.9 (C-2C, maj), 72.1–69.5 (CH2Bn, C-3C, maj
and min), 68.5 (C-3F, maj), 68.2 (C-3F, min), 35.8 (C-4C, maj and
(C-5A), 154.73 (C-7A), 154.07 (C-7D), 153.15 (C-8aD), 153.02 (C-
5D), 144.73 (C-3ЈB), 144.08 (C-3ЈE), 144.03 (C-4ЈE), 143.91 (C-
4ЈB), 130.84 (C-1ЈE), 130.65 (C-1ЈB), 120.54 (C-6ЈB), 120.17 (C-
6ЈE), 116.40 (C-5ЈE), 116.04 (C-2ЈB), 115.84 (C-5ЈB), 115.16 (C-
min), 29.7 (C-4F, maj), 28.9 (C-4F, min) ppm. MS (LSIMS): m/z 2ЈE), 109.25 (C-8D), 107.27 (C-4aA), 101.51 (C-4aD), 96.89 (C-
(%) = 1417.3 (18) [M + K]+, 1401.3 (100) [M + Na]+, 1103.3 (6),
901.3 (6), 887.3 (15), 873.3 (25), 859.3 (23), 722.2 (13). HRMS:
calcd. for C86H73BrO12 1376.4285 found 1376.4270.
6A), 95.65 (C-6D), 95.61 (C-8A), 82.04 (C-2C), 80.57 (C-2F), 72.85
(C-3C), 67.28 (C-3F), 37.07 (C-4C), 27.52 (C-4F) ppm. MS
(LSIMS): m/z (%) = 579 (15) [M]+, 473 (13), 449 (22), 433 (14),
413 (21), 329 (30), 306 (23), 289 (27), 284 (100), 247 (27). HRMS:
calcd. for C30H26NaO12 601.1322; found 601.1319.
Catechin-4α,8-epicatechin (10b):[10a,30] This title compound was pre-
pared following the same procedure as described for catechin-4α,8-
catechin (10a) except that 3Ј,4Ј,5,7-tetra-O-benzyl-8-bromocate-
chin-4β,8-(3Ј,4Ј,5,7-tetra-O-benzylepicatechin) (9b) was used in
place of 3Ј,4Ј,5,7-tetra-O-benzyl-8-bromocatechin-4α,8-(3Ј,4Ј,5,7-
tetra-O-benzylcatechin) (9a). The B4 dimer 10b was quantitatively
3Ј,4Ј,5,7-Tetra-O-benzyl-8-bromoepicatechin-4β,8-(3Ј,4Ј,5,7-tetra-O-
benzylepicatechin) (9d):[29] The title compound was prepared after
coupling 3Ј,4Ј,5,7-tetra-O-benzyl-8-bromo-4β-(2-hydroxyethoxy)-
epicatechin (4b) (0.502 g, 0.636 mmol, 1.2 equiv.) and 3Ј,4Ј,5,7-
tetra-O-benzylepicatechin (2b) (0.345 g, 0.530 mmol, 1 equiv.) fol-
lowing the same procedure as described for 3Ј,4Ј,5,7-tetra-O-ben-
zyl-8-bromocatechin-4α,8-(3Ј,4Ј,5,7-tetra-O-benzylcatechin) (9a).
The resulting dark-red solution was stirred at room temperature
for 3 h. After work up and purification on silica gel (cyclohexane/
ethyl acetate, 7:3) the protected B2 dimer 9d was isolated (0.314 g,
isolated as a white solid. M.p. 178–180 °C (dec.). IR (KBr): ν =
˜
3385, 1617, 1602, 1522, 1458, 1450, 1384, 1283, 1205, 1145, 1095,
0.228 mmol, 43% yield). 1H NMR (400 MHz, CDCl3, 22 °C): (two 1062, 819, 783 cm–1. 1H NMR (400 MHz, D2O/[D6]ethanol, 88:12,
rotamers: maj/min 67:33): δ = 7.52–7.25 (m, Ar-H), 7.22–6.74 (m, 22 °C): (two rotamers: maj/min 76:24): δ = 6.68 (d, J5ЈE,6ЈE
3
=
3
2ЈB-H, 2ЈE-H, 5ЈB-H, 5ЈE-H, 6ЈE/B-H), 6.35 (s, 6D-H, maj), 6.28 8.2 Hz, 1 H, 5ЈE-H), 6.63 (d, J5ЈB,6ЈB = 8.2 Hz, 1 H, 5ЈB-H), 6.57
3
4
(d, J2Ј,6Ј = 8.3 Hz, 6ЈB/E-H), 6.23 (s, 6A-H, min), 6.20 (s, 6D-H,
(d, 4J2ЈB,6ЈB = 1.6 Hz, 1 H, 2ЈB-H), 6.55 (d, J2ЈE,6ЈE = 1.8 Hz, 1 H,
min), 6.13 (s, 6A-H, maj), 5.57 (s, 2F-H, maj), 5.37 (s, 2F-H, min),
5.25–4.96 (m, CH2Bn, 2F-H, min), 4.89 (s, 2F-H, maj), 4.33 (m,
3F-H, maj), 4.12 (s, 3C-H, min), 4.00 (s, 3C-H, maj), 3.81 (d, 3J
= 3.6 Hz, 3F-H, min), 3.00–2.84 (m, 4Fα-H and 4Fβ-H, maj and
min) ppm. 13C NMR (100 MHz, CDCl3, 22 °C): δ = 156.8 (C-5D),
156.1 (C-7D), 155.9 (C-5A), 154.6 (C-7A), 154.5 (C-8aA), 151.7
2ЈE-H), 6.34 (dd, 1 H, 6ЈB-H), 6.29 (dd, 1 H, 6ЈE-H), 6.02 (s, 1 H,
6D-H), 5.89 and 5.82 (AM, J6A,8A = 2.0 Hz, 2 H, 6A-H and 8A-
4
3
3
H), 4.70 (d, J2F,3F Ͻ 1 Hz, 1 H, 2F-H), 4.31 (d, J2C,3C = 9.7 Hz,
3
1 H, 2C-H), 4.28 (d, J4C,3C = 8.5 Hz, 1 H, 4C-H), 4.13 (dd, 1 H,
3C-H), 4.00 (m, 1 H, 3F-H), 2.78 and 2.55 (ABX, J4Fα,4Fβ
2
=
3
3
17.2 Hz, J4Fα,3F = 4.7 Hz, J4Fβ,3F Ͻ 1 Hz, 2 H, 4Fα-H and 4Fβ-
(C-8aD), 149.5, 149.3, 148.8, 148.7 (C-3ЈB, C-3ЈE,C-4ЈB, C-4ЈE), H) ppm. 13C NMR (100.6 MHz, D2O/[D6]ethanol, 88:12, 22 °C): δ
Eur. J. Org. Chem. 2006, 5367–5377
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5375

I. Tarascou, K. Barathieu, Y. André, I. Pianet, E. J. Dufourc, E. Fouquet
FULL PAPER
= 156.89 (C-5A), 155.49 (C-7A), 155.01 (C-5D), 154.25 (C-7D), H), 4.67 (m, 4C-H), 4.30 (m, 3F-H), 3.98 (m, 3C-H), 2.84 (dd, 4Fβ-
153.83 (C-8aA), 153.52 (C-8aD), 144.65 (C-4ЈB), 144.12 (C-3ЈB), H), 2.76 (m, 4Fα-H) ppm. 13C NMR (125,1 MHz, H2O/D2O 90:10,
143.81 and 143.77 (C-3ЈE and C-4ЈE), 131.24 (C-1ЈE), 130.94 (C- 5 °C): δ = 158.6 (C-8aD), 158.5 (C-5A), 157.8 (C-5D), 157.7 (C-
1ЈB), 120.43 (C-6ЈB), 119.81 (C-6ЈE), 116.40 (C-5ЈB), 116.25 (C- 8aA), 157.2 (C-7A), 155.9 (C-7D), 146.8 (C-4ЈE), 146.6 (C-3ЈE),
2ЈB), 115.64 (C-5ЈE), 114.78 (C-2ЈE), 109.14 (C-4aA), 107.53 (C-
146.4 (C-4ЈB), 146.3 (C-3ЈB), 133.8 (C-1ЈE), 133.6 (C-1ЈB), 121.8
8D), 100.83 (C-4aD), 97.19 (C-6A), 96.31 (C-8A), 96.00 (C-6D), (C-6ЈB), 121.2 (C-6ЈE), 117.7 (C-5ЈE), 117.7 (C-5ЈB), 117.2 (C-2ЈB),
82.26 (C-2C), 78.32 (C-2F), 72.69 (C-3C), 66.22 (C-3F), 37.30 (C- 116.9 (C-2ЈE), 109.7 (C-8D), 105.0 (C-4aA), 102.3 (C-4aD), 99.7
4C), 27.99 (C-4F) ppm (chemical shifts and coupling constants J
are only given for the major rotamer). MS (LSIMS): m/z (%) = 601
(4) [M + Na]+, 413 (15), 376 (7), 357 (10), 329 (58), 306 (19), 301
(16), 289 (13), 241 (53), 219 (100), 212 (33). HRMS: calcd. for
C30H26NaO12 601.1322; found 601.1319.
(C-6D), 98.2 (C-6A), 97.6 (C-8A), 80.5 (C-2F), 78.4 (C-2C), 74.2
(C-3C), 68.1 (C-3F), 37.9 (C-4C), 30.8 (C-4F) ppm (coupling con-
stants J are only given for the major rotamer). MS (LSIMS): m/z
(%) = 599.5 (18) [M + Na]+, 577.5 (100) [M]+, 425.5 (17), 407.7
(11), 289.5 (15). HRMS: calcd. for C30H23O12 575.1190; found
575.1160.
Epicatechin-4β,8-catechin (10c):[30] This title compound was pre-
pared following the same procedure as described for catechin-4α,8-
catechin (10a) except that 3Ј,4Ј,5,7-tetra-O-benzyl-8-bromoepicate-
chin-4β,8-(3Ј,4Ј,5,7-tetra-O-benzylcatechin) (9c) (0.430 g,
0.312 mmol, 1 equiv.) was used in place of 3Ј,4Ј,5,7-tetra-O-benzyl-
8-bromocatechin-4α,8-(3Ј,4Ј,5,7-tetra-O-benzylcatechin) (9a). The
B1 dimer 10c was quantitatively obtained as a beige solid (0.179 g,
0.310 mmol). M.p. 204–205 °C (dec.). 1H NMR (400 MHz, H2O/
D2O 90:10, 22 °C): (two rotamers: maj/min 95:5): δ = 7.01 (d, 2ЈB-
H), 6.89 (d, 5ЈB-H), 6.80 (d, 5ЈB-H and 6ЈE-H), 6.66 (d, J = 2.3 Hz,
2ЈE-H), 6.56 (d, 6ЈE-H), 6.24 (s, 6D-H), 5.86 (s, 6A-H), 5.37 (s, 8A-
Acknowledgments
We are deeply grateful to the Regional Council of Aquitaine for a
grant to K. B. as well as the Inter-Professional Council of Bor-
deaux Wine (C. I. V. B.) for their very generous financial support
to I. T. and Y. A.
3
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try 1994, 36, 781–784.
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H), 5.18 (d, J2C,3C = 1.1 Hz, 2C-H), 4.40 (m, 4C-H), 4.01 (m,
3
3
3J3F,2F = 9.1 Hz, J3F,4Fα = 5.6 Hz, J3F,4Fβ = 9.8 Hz, 3F-H), 3.97
3
(m, 3C-H), 3.92 (m, 2F-H), 3.07 (m, J3F,4Fβ = 9.8 Hz, 4Fβ-H),
2.46 (m, 4Fα-H) ppm. 13C NMR (100.6 MHz, H2O/D2O 90:10,
22 °C): δ = 155.3 (C-8aA), 154.5 (C-7A), 154.2 (C-5A), 153.1 (C-
8aD), 153.1 (C-5D), 153.1 (C-7D), 143.9 (C-4ЈE), 143.8 (C-3ЈB),
143.6 (C-4ЈB), 143.5 (C-3ЈE), 131.2 (C-1ЈB), 130.0 (C-1ЈE), 120.7
(C-6ЈE), 119.1 (C-6ЈB), 115.9 (C-5ЈB), 115.5 (C-5ЈE), 115.0 (C-2ЈE),
114.5 (C-2ЈB), 107.7 (C-8D), 102.9 (C-4aA), 101.7 (C-4aD), 95.8
(C-6D), 94.8 (C-6A), 94.6 (C-8A), 81.2 (C-2F), 75.2 (C-2C), 71.4
(C-3C), 67.4 (C-3F), 35.5 (C-4C), 28.8 (C-4F) ppm. MS (LSIMS):
m/z (%) = 601 (2) [M + Na]+, 409 (4), 381 (12), 353 (15), 329
(48), 311 (5), 242 (100), 212 (14). HRMS: calcd. for C30H26O12Na
601.1322; found 601,1319.
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Epicatechin-4β,8-epicatechin (10d):[10a,30] The title compound was
prepared following the same procedure as described for catechin-
4α,8-catechin (10a) except that 3Ј,4Ј,5,7-tetra-O-benzyl-8-bromo-
epicatechin-4β,8-(3Ј,4Ј,5,7-tetra-O-benzylepicatechin) (9d) (0.260 g,
0.189 mmol) was used in place of 3Ј,4Ј,5,7-tetra-O-benzyl-8-bromo-
catechin-4α,8-(3Ј,4Ј,5,7-tetra-O-benzylcatechin) (9a). The B2 dimer
10d was obtained as a beige solid (0.107 g, 0.187 mmol, 99%). M.p.
197–198 °C (dec.). Compact form (55 %): 1H NMR (500 MHz,
[7] a) K. Weinges, J. Perner, Chem. Commun. (London) 1967, 351–
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4
H2O/D2O 90:10, 5 °C):[31] δ = 7.08 (d, J2ЈB,6ЈB Ͻ 1 Hz, 2ЈB-H),
6.93 (m, 6ЈB-H), 6.92 (m, 5ЈB-H and 5ЈE-H), 6.72 (4J2ЈE,6ЈE Ͻ 1 Hz,
2ЈE-H), 6.52 (m, 6ЈE-H), 6.26 (s, 6D-H), 5.82 (s, 6A-H), 5.67 (s,
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3
8A-H), 5.42 (d, J2C,3C = 1.1 Hz, 2C-H), 4.47 (m, 4C-H), 4.32 (m,
2F-H), 4.06 (m, 3C-H), 4.02 (m, 3J3F,4Fβ = 4.5 Hz, 3J3F,4Fα Ͻ 1 Hz,
3
3
3J3F,2F Ͻ 1 Hz, 1 H, 3F-H), 2.86 (dd, J4Fα,4Fβ = 16.9 Hz, J3F,4Fβ
3
= 4.5 Hz, 4Fβ-H), 2.71 (br. d, J4Fα,4Fβ = 16.9 Hz, 4Fα-H) ppm.
13C NMR (125.1 MHz, H2O/D2O 90:10, 5 °C): δ = 158.0 (C-7D),
157.7 (C-8aA), 157.0 (C-8aD), 156.9 (C-5D), 156.5 (C-7A), 156.1
(C-5A), 146.7 (C-4ЈB), 146.5 (C-3ЈB), 146.0 (C-4ЈE), 145.8 (C-3ЈE),
134.2 (C-1ЈE), 133.5 (C-1ЈB), 122.2 (C-6ЈE), 122.1 (C-6ЈB), 118.7
(C-5ЈB), 118.7 (C-5ЈE), 118.0 (C-2ЈE), 117.4 (C-2ЈB), 110.6 (C-8D),
105.9 (C-4aA), 103.0 (C-4aD), 98.6 (C-6D), 97.8 (C-8A), 97.7 (C-
6A), 81.3 (C-2F), 78.1 (C-2C), 74.6 (C-3C), 68.4 (C-3F), 38.7 (C-
4C), 31.1 (C-4F) ppm. Extended form (45%): 1H NMR (500 MHz,
H2O/D2O 90:10, 5 °C): δ = 7.14 (2ЈE-H), 6.98 (2ЈB-H), 6.89 (6ЈE-
H), 6.77 (d, 2 H, 5ЈB-H and 5ЈE-H), 6.60 (6ЈB-H), 6.15 (s, 8A-H),
6.12 (s, 6A-H), 6.06 (s, 6D-H), 5.20 (d, 1 H, 2C-H), 4.82 (m, 2F-
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 5367–5377

An Improved Synthesis of Procyanidin Dimers
FULL PAPER
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9a–d are: 77:23 for B1, 67:33 for B2, 63:37 for B3 and 85:15
for B4.
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[19] As the C ring of 3a preferentially adopts a conformation in
which the C2 aromatic ring B and the C3 hydroxy group are
3
both equatorial, the JH3,H4 coupling constant (3.4 Hz) is in
accordance with a cis orientation of H3 and H4, giving an
RSS stereochemistry for 3a. The S configuration of C4 was
confirmed by ROESY NMR experiments for which the selec-
tive pulse of the H4 proton highlighted a NOE correlation peak
between H3 and H4 and no correlation between H4 and H2,
confirming that H4 and H3 are on the same side of the C
3
ring. In contrast, the JH3,H4 coupling constant (2.6 Hz) of the
epicatechin derivative 3b does not allow any conclusion con-
cerning the stereochemistry of C4 to be drawn. However, the
selective pulse of the H4 proton gave a NOE correlation with
H3, but no correlation with H2, while the selective pulse of H3
gave correlations with both H2 and H4 suggesting that H3
would preferably be in an equatorial conformation and that
the H4 and H2 protons would be on the opposite side of the
C ring, in accordance with an RRS stereochemistry for 3b.
Moreover the comparison through molecular modelling
(MM3* force field, Monte Carlo style conformational search)
of the interproton distances between H2,H3 and H3,H4 with
the NOE correlation peak intensity measured for these protons
confirmed the S configuration of C4.
[31] NMR spectra for 10d were recorded at 5 °C in order to avoid
the coalescence phenomena observed at 22 °C due to the spe-
cific rate of rotational isomerization of 10d.
Received: August 1, 2006
Published Online: October 2, 2006
Eur. J. Org. Chem. 2006, 5367–5377
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5377