An efficient synthesis of procyanidins. Rare earth metal Lewis acid catalyzed equimolar condensation of catechin and epicatechin

Article abstract of DOI:10.1016/j.tetlet.2007.06.047

Stereoselective synthesis of catechin and epicatechin dimers under intermolecular condensation is achieved by an equimolar amount of coupling catalyzed by Yb(OTf)₃. The coupled products were successfully converted to procyanidin B1, B2, B3, and B4.

Full text of DOI:10.1016/j.tetlet.2007.06.047

Tetrahedron Letters 48 (2007) 5891–5894
An efficient synthesis of procyanidins. Rare earth metal Lewis
acid catalyzed equimolar condensation of catechin and epicatechin
Yoshihiro Mohri,a Masayoshi Sagehashi,a Taiji Yamada,a Yasunao Hattori,b,c
Keiji Morimura,b,d Tsunashi Kamo,e Mitsuru Hirotae and Hidefumi Makabea,*
aSciences of Functional Foods, Graduate School of Agriculture, Shinshu University, 8304, Minami-minowa, Kami-ina,
Nagano 399-4598, Japan
bInterdisciplinary Graduate School of Science and Technology, Shinshu University, 8304, Minami-minowa, Kami-ina,
Nagano 399-4598, Japan
cSatellite Venture Business Laboratory, Shinshu University, 3-15-1, Tokida, Ueda, Nagano 386-8567, Japan
dGeol Cosmetics. Co., Ltd, 111-1, Shinmura, Katsuragi, Nara 639-2121, Japan
eDepartment of Bioscience and Biotechnology, Faculty of Agriculture, Shinshu University, 8304, Minami-minowa, Kami-ina,
Nagano 399-4598, Japan
Received 14 May 2007; revised 6 June 2007; accepted 8 June 2007
Available online 14 June 2007
Abstract—Stereoselective synthesis of catechin and epicatechin dimers under intermolecular condensation is achieved by an equimo-
lar amount of coupling catalyzed by Yb(OTf)3. The coupled products were successfully converted to procyanidin B1, B2, B3, and
B4.
Ó 2007 Elsevier Ltd. All rights reserved.
Proanthocyanidins are known as condensed or noncon-
densed hydrolyzable tannins.1 These condensed tannins
can be found in the vegetables kingdom.2 In particular,
they exist in grape seeds and skins and red wines. Many
biological activities, mainly a powerful free-radical scav-
enging activity, have been reported for flavonoids, and
their investigation is increasingly important. Tannin
extracts from plants give various types of polyphenols.
Because their identification as well as purification is
extremely difficult, further studies of proanthocyanidins
remains. Recently, to obtain procyanidin oligomers in
pure state, synthetic efforts were devoted.3 However,
efficient syntheses are very limited because the formation
of the intermolecular C-4–C-8 bond has some problems.
The typical synthetic methods are as follows. The first
example is nucleophilic addition of C-8 lithiated nucleo-
phile onto a C-4 protected ketocatechin as a substrate.4
This reaction generally proceeds with the regioselective
and oligomerization control demands of the coupling
reaction, however, it does not satisfy the stereochemi-
cal requirement of the newly formed C-4 asymmetric
center. The next is the nucleophilic substitution method,
which needs to use nucleophilic partner in large excess
*
Corresponding author. Tel.: +81 265 77 1630; fax: +81 265 77
1700; e-mail: makabeh@shinshu-u.ac.jp
Figure 1. The structures of procyanidin B1 (1)–B4 (4).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.047

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Y. Mohri et al. / Tetrahedron Letters 48 (2007) 5891–5894
Scheme 1. Lewis acids mediated coupling reaction between 5a and 6a.
Table 1. Equimolar coupling reaction of 5a and 6a by Lewis acidsa
made in the regio and stereoselective reaction.3 Until
now, only a few attempts to prepare procyanidin dimers
under stoichiometric conditions have been reported in
the literature. The first example is an intramolecular
coupling of monomeric units bound by a temporary
diester link.5 This method is suitable for synthesizing
procyanidin B1 (1) and B3 (3), however, it suffers from
low yield of condensation for synthesizing B2 (2) and
B4 (4). The second is reported by Fouquet and co-work-
ers.6 They synthesized procyanidin dimers based on the
intermolecular nucleophilic substitution of C-4 activated
and C-8 halogenated monomer to prevent further oligo-
merization using TiCl4 as a Lewis acid. This reaction
needs large excess of TiCl4. In the course of our
research, we have developed a very simple and efficient
intermolecular synthesis of procyanidin dimers. The
key step is a coupling reaction between equimolar
amounts of tetra-benzylated monomer 5a (nucleophile)
and a C-4 activated monomer 6a (electrophile) using
1 equiv of rare earth metal Lewis acid such as Yb(OTf)3
(Fig. 1).
Lewis acidsb
Time
Yield (%)
Selectivity (a:b)c
TiCl4
0.5
3
2
7.5
0.5
0.5
0.5
72
2
36
ND
38
50
43
45
50
34
64
42
75:25
—
BF3ÆEt2O
B(C6H5)3
AgBF4
Cu(OTf)3
In(OTf)3
89:11
98:2
91:9
91:9
67:33
98:2
98:2
91:9
Sc(OTf)3
La(OTf)3
Yb(OTf)3
10 mol % of Yb(OTf)3
12
a The reaction was carried out at room temperature in CH2Cl2.
b 1 equiv of Lewis acid was used otherwise noted.
c The selectivity was determined by 1H NMR analysis of C-3 position
of diacetate derivative of a-7 (5.80 and 5.83 ppm) and b-7 (5.53 and
5.58 ppm) according to the reported procedure.3b
(3.0–4.5 equiv) to prevent further oligomerization. Thus
the efficient synthetic method to prepare procyanidin di-
mers has some restrictions, although recent advance was
Table 2. Examples of condensation of the catechin nucleophile and electrophile by Lewis acids
Entry
Nucleophile
Electrophile
Nucleophile/electrophile
Lewis acids
T (°C)
Product
Yield (%)
Selectivity (a:b)
1
2
3
4
5
6
5a
5a
5a
5a
8
9
6a
6a
6a
10
10
5
TiCl4
TiCl4
TMSOTf
Yb(OTf)3
BF3ÆEt2O
BF3ÆEt2O
0
À20
À78
rt
11
7
92
83
Quant.
64
94
60:40
96:4
4.5
4.5
1.0
3
7
97:3
7
98:2a
90:10
90:10
À30
12
12
8
1.2
À30
59
a The selectivity was determined by 1H NMR analysis of C-3 position of diacetate derivative of a-7 (5.80 and 5.83 ppm) and b-7 (5.53 and 5.58 ppm)
according to the reported procedure.3b
Scheme 2. Examples of Lewis acids mediated coupling reaction between catechin nucleophile and catechin electrophile.

Y. Mohri et al. / Tetrahedron Letters 48 (2007) 5891–5894
5893
We chose tetra-benzylated catechin 5a, a nucleophilic
unit, prepared by the Kawamoto’s procedure7 and elec-
trophile unit 6a prepared by the Saito’s method.8 Equi-
molar condensation of 5a and 6a at room temperature
was examined using various Lewis acids including rare
earth metal at room temperature in CH2Cl2 (Scheme
1, Table 1). The first attempt at the coupling reaction
was conducted with equimolar amounts of the protected
catechin 5a and the acetylated substrate 6a to obtain a-
7, which is the precursor of procyanidin B3 (3). Typical
Lewis acids, such as TiCl4 and BF3ÆEt2O gave sluggish
results. These reactions required a large excess of the
Scheme 3. Equimolar coupling of epicatechin–catechin, epicatechin–epicatechin, catechin–catechin, and catechin–epicatechin using Yb(OTf)3 as a
Lewis acid toward the synthesis of procyanidin B1(1)–B4 (4). Reagents and conditions: (a) (i) K2CO3, MeOH; (ii) H2, 20 wt % Pd(OH)2, THF–
MeOH–H2O (47–67%).

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Y. Mohri et al. / Tetrahedron Letters 48 (2007) 5891–5894
nucleophile at low temperature in order to limit the reac-
tion of the activated monomer with itself or with the di-
meric product leading in both cases to oligomeric side
products.7,8 The next attempt at the coupling reaction
was conducted with late transition metals as Lewis
acids. Among Ag, Cu, and In, especially AgBF4 gave
a good selectivity with moderate chemical yield. We fur-
ther paid attention to rare metal Lewis acids such as Sc
and La. While Sc gave poor stereoselectivity, La affor-
ded high selectivity although the chemical yield was
34%. This result encouraged us to replace La by Yb.
The reaction furnished good selectivity with 64% yield.9
The catalytic amount of Yb(OTf)3 (10 mol %) also affor-
ded a coupled product in 42% yield at 91:9 ratio of the
desired product. This result indicates that this reaction
could be carried out using catalytic amount of
Yb(OTf)3. Further optimization of the catalytic reaction
system is now underway.
K2CO3 in MeOH followed by debenzylidation by
Pd(OH)2 in THF–MeOH–H2O catalyzed hydrogenoly-
sis to give procyanidin B1 (1)–B4 (4). All the spectral
data for 1–4 were similar to those of the reported
value.3a,d,5a
Acknowledgement
We thank Geol Cosmetics. Co., Ltd, for financial
support.
Supplementary data
Physical data of procyanidin B1 (1), B2 (2), B3 (3), B4
1
(4), H NMR spectra for 1–4, 13C NMR spectra for 3,
4, and their data in the literature can be found, in the
online version, at doi:10.1016/j.tetlet.2007.06.047.
As shown in Table 2, the reported condensation reaction
between catechin nucleophile 5a or 8 and catechin elec-
trophile 6a, 9, and 10 required large amount excess of
catechin nucleophile 5a or 8 to obtain desired dimer in
high yield. As shown in entry 1, the first report of con-
densation by Kawamoto et al. used 5 equiv of nucleo-
phile 5a. They obtained coupled product in high yield,
however, the stereoselectivity of a-11 and b-11 was only
60:40 ratio.7 Saito et al. used nucleophile 5a and electro-
phile 6a and the combination of which was same as ours.
This condensation afforded a coupled product in high
yield with good stereoselectivity, however, it required
4.5 equiv of nucleophile.3b,8 Suzuki and co-workers re-
ported the condensation reaction using 8 and 10 to ob-
tain 12.10 Although the amount of nucleophile was
smaller than Kawamoto and Saito, they still used
3 equiv of nucleophile with 90:10 selectivity of the de-
sired product. When they used 1.2 equiv of nucleophile
8, the yield was 59% with same selectivity. Our result
of equimolar condensation between 5a and 6a was
shown in entry 4. Although the yield was lower than
other groups, the stereoselectivity was superior to oth-
ers. Using large excess amount of nucleophile is a big
problem because composition of the desired coupled
product is only a small part in the reaction system and
it is necessary to get rid of large amount of starting
material by chromatography. Optimized equimolar con-
densation is extremely important for an efficient synthe-
sis of catechin dimers (Scheme 2, Table 2).
References and notes
1. Ferreira, D.; Li, X.-C. Nat. Prod. Rep. 2000, 17, 193–
212.
2. Ferreira, D.; Li, X.-C. Nat. Prod. Rep. 2002, 19, 517–541.
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Jr. J. Am. Chem. Soc. 1999, 121, 12073–12081; (b) Saito,
A.; Nakajima, N.; Tanaka, A.; Ubukata, M. Tetrahedron
2002, 58, 7829–7837; (c) Kozikowski, A. P.; Tuckmantel,
W.; Bo¨ttcher, G.; Romanczyk, L. J., Jr. J. Org. Chem.
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4. Kozikowski, A. P.; Tuckmantel, W.; Hu, Y. J. Org. Chem.
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2001, 66, 1287–1296.
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Heterocycles 2003, 61, 287–298; (b) Saito, A.; Nakajima,
N.; Tanaka, A.; Ubukata, M. Tetrahedron Lett. 2003, 44,
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E. J.; Fouquet, E. Eur. J. Org. Chem. 2006, 5367–5377.
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8. Saito, A.; Nakajima, N.; Tanaka, A.; Ubukata, M. Biosci.
Biotechnol. Biochem. 2002, 66, 1764–1767.
9. General procedure for the equimolar coupling reaction using
Yb(OTf)3 (Table 1): To a solution of nucleophile 5a
(190 mg, 0.263 mmol) and electrophile 6a (171 mg,
0.263 mmol) in CH2Cl2 (10 mL) under an argon atmo-
sphere was added Yb(OTf)3 (163 mg, 0.263 mmol). After
the resulting mixture had been stirred for 2 h, the reaction
was quenched with water. The mixture was extracted with
diethyl ether, and the combined organic layer were washed
with brine, dried over MgSO4, and concentrated. The
crude product was purified with silica gel chromatography
(hexane–EtOAc–CH2Cl2 = 4:1:2) to give diastereomeric
Next, we examined the condensation of the combination
of catechin nucleophile 5a and epicatechin nucleophile
5b with catechin electrophile 6a and/or epicatechin elec-
trophile 6b using Yb(OTf)3 as a Lewis acid. In each case,
the reaction worked well. As to the stereoselectivity,
however, the epicatechin electrophile 5b gave a little
bit poor result compared to catechin nucleophile 5a.
In case of tri-benzylated phloroglucinol, the stereoselec-
tivity of 16 showed 75:25 ratio.11 Some stereochemical
requirement of the nucleophile seems to be necessary
to get high selectivity (Scheme 3).
1
mixture a-7 and b-7 (226 mg, 64%) as a colorless oil. H
NMR analysis of diacetate derivative showed more than
98:2 ratio of a-7 and b-7.3b,7 The selectivity was deter-
1
mined by H NMR analysis of C-3 position of diacetate
derivative of a-7 (5.80 and 5.83 ppm) and b-7 (5.53 and
5.58 ppm) according to the reported procedure.3b
10. Ohomori, K.; Ushimaru, N.; Suzuki, K. Proc. Nat. Acad.
Sci. U.S.A. 2004, 101, 12002–12007.
Finally, condensed compounds a-7, b-13, b-14, and a-15
were subjected to the hydrolysis of the acetate with
11. Hayes, C. J.; Whittaker, B. P.; Watson, S. A.; Grabowska,
A. M. J. Org. Chem. 2006, 71, 9701–9712.