Efficient stereoselective synthesis of catechin trimer derivative using silver lewis acid-mediated equimolar condensation

Article abstract of DOI:10.3987/COM-11-12159

A stereoselective synthesis of benzylated catechin trimer under ntermolecular condensasion is achieved using equimolar amount of dimeric catechin nucleophile and monomeric catechin electrophile catalyzed by AgOTf or AgBF4. The coupled product can be trans

Full text of DOI:10.3987/COM-11-12159

HETEROCYCLES, Vol. 83, No. 4, 2011
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HETEROCYCLES, Vol. 83, No. 4, 2011, pp. 739 - 742. © The Japan Institute of Heterocyclic Chemistry
Received, 28th January, 2011, Accepted, 21st February, 2011, Published online, 2nd March, 2011
DOI: 10.3987/COM-11-12159
EFFICIENT STEREOSELECTIVE SYNTHESIS OF CATECHIN TRIMER
DERIVATIVE USING SILVER LEWIS ACID-MEDIATED EQUIMOLAR
CONDENSATION
a
a
b
Yukiko Oizumi, Yoshihiro Mohri, Yasunao Hattori, and Hidefumi
a
Makabe *
a
Sciences of Functional Foods, Graduate School of Agriculture, Shinshu
University, 8304 Minami-minowa, Kami-ina, Nagano 399-4598, Japan
b
Department of Chemistry, Graduate School of Medicinal Science, Kyoto
Prefectural University of Medicine, Kita-ku, Kyoto 603-8334, Japan
*
E-mail address: makabeh@shinshu-u.ac.jp
Abstract – A stereoselective synthesis of benzylated catechin trimer under
intermolecular condensasion is achieved using equimolar amount of dimeric
catechin nucleophile and monomeric catechin electrophile catalyzed by AgOTf or
4
AgBF . The coupled product can be transformed into procyanidin C2 by a known
procedure.
1
Proanthocyanidins are known as condensed or noncondensed hydrolysable tannins. These condensed
2
tannins can be found in the vegetables kingdom. In particular, they exist in grape seeds and skins and red
wines. Many biological activities, mainly a powerful free-radical scavenging 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. There are several reports about condensation studies for procyanidin trimers such as
3
procyanidin C2 (1) using catechin and/or epicatechin nucleophile and electrophile under Lewis acids.
However, excess amount of nucleophile was needed for oligomerization control. Thus we have pursued
equimolar condensation of nucleophile and electrophile to construct the skeleton of procyanidin
oligomers using various types of Lewis acids. We have already reported a stereoselective synthesis of
catechin and/or epicatechin dimers from equimolar amount of catechin nucleophile and electrophile using

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HETEROCYCLES, Vol. 83, No. 4, 2011
4
3
Yb(OTf) as a Lewis acid. In this communication, we would like to describe the stereoselective synthesis
of the protected catechin trimer using equimolar amount of dimeric catechin nucleophile 2 and
monomeric catechin electrophile 3 (Figure 1).
Figure 1. The structure of procyanidin C2 (1)
We chose octabenzylated catechin dimer 2 as a nucleophile and compound 3 as an electrophile prepared
4
by us before. Equimolar condensation of 2 with 3 was examined using transition metal Lewis acids and
Yb(OTf)
3
in CH
2
Cl
2
(Table 1). We paid attention to silver Lewis acid because condensation can be
as the thiophilic
performed under neutral conditions. Ferreira and co-workers reported that using AgBF
4
Lewis acid offered advantages to control the level of oligomeration in the procyanidin B1-B4 and C2
5
synthesis. As shown in Table 1, AgBF
4
and AgOTf gave 4 in excellent yield. However, Yb(OTf)
3
, which
gave good results for dimer condensation, afforded low yield. Due to the bulkiness of Yb(OTf) , it
3
seemed to be difficult for dimeric nucleophile 2, which is more bulky than monomeric nucleophile, to
2
attack C-4 position of electrophile 3 (Scheme 1, Table 1). In the case of Cu(OTf) , the yield was low
although starting materials were consumed within 3h.
Scheme 1. Lewis acid catalyzed equimolar condensation between nucleophile 2 and electrophile 3

HETEROCYCLES, Vol. 83, No. 4, 2011
741
In order to confirm the stereochemistry at C-4 position, compound 4 was transformed into known
3
a
compound 5. Hydrolysis of the acetate of 4 using NaOMe under reflux did not give 5. Thus diol 4 was
6
acetylated using Ac
2
O in pyridine to give triacetate and subsequent DIBALH reduction afforded 5. The
1
13
3a
H and C NMR spectral data of 5 were identical with those of the reported values. This result indicated
that electrophile 3 reacted with nucleophile 2 at C-4 position in a stereoselective manner to afford
3
2
,4-trans trimer 4. Triol 5 can be transformed into procyanidin C2 (1) by a known procedure (Scheme
3
a
). The synthesis of various types of procyanidin oligomers using equimloar condensation of
nucleophile and electrophile in the presence of Lewis acid are currently underway.
OBn
OBn
OBn
BnO
O
BnO
O
OBn
3
4
OH
O
OAc
O
OBn
OBn
OBn
OBn
OBn
BnO
1
) Ac O, pyridine
known
OBn
BnO
2
1
2) DIBALH
5% (2 steps)
4
OH
OH
OBn
OBn
OBn
OBn
OBn
OBn
HO
BnO
O
O
OH
OH
OBn
OBn
4
5
Scheme 2. Tranformation of known compound 5 from 4
REFERENCES AND NOTES
1
2
3
.
.
.
D. Ferreira and X.-C. Li, Nat. Prod. Rep., 2000, 17, 193.
D. Ferreira and X.-C. Li, Nat. Prod. Rep., 2002, 19, 517.
For recent synthetic studies on catechin and/or epicatechin trimer: A. Saito, A. Tanaka, M. Ubukata,
and N. Nakajima, Synlett, 2004, 1069; (b) A. Saito, Y. Doi, A. Tanaka, N. Matsuura, M. Ubukata,
and N. Nakajima, Bioorg. Med. Chem., 2004, 12, 4783; (c) K-i. Oyama, M. Kuwano, M. Ito, K.

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HETEROCYCLES, Vol. 83, No. 4, 2011
Yoshida, and T. Kondo, Tetrahedron Lett., 2008, 49, 3176; (d) A. Saito, Y. Mizushina, A. Tanaka,
and N. Nakajima, Tetrahedron, 2009, 65, 7422; (e) K. Ohmori, N. Ushimaru, and K. Suzuki, Proc.
Natl. Acad. Sci. U.S.A., 2004, 101, 12002; (f) A. P. Kozikowski, W. Tückmantel, G. Boettcher, and
L. J. Romanczyk, Jr., J. Org. Chem., 2003, 68, 1641.
4
.
(a) Y. Mohri, M. Sagehashi, T. Yamada, Y. Hattori, K. Morimura, T. Kamo, M. Hirota, and H.
Makabe, Tetrahedron Lett., 2007, 48, 5891; (b) Y. Mohri, M. Sagehashi, T. Yamada, Y. Hattori, K.
Morimura, Y. Hamauzu, T. Kamo, M. Hirota, and H. Makabe, Heterocycles, 2009, 79, 549; (c) Y.
Oizumi, Y. Mohri, M. Hirota, and H. Makabe, J. Org. Chem., 2010, 75, 4884.
5
.
.
P. J. Steynberg, R. J. J. Nel, H. van Rensberg, B. C. B. Bezuidenhoudt, and D. Ferreira, Tetrahedron,
1
998, 54, 8153.
The data for 5 (0.82:0.18 mixture of rotational isomers): []
MHz, CDCl , major isomer)  = 7.44-6.40 (57.4H, m), 6.17 (0.82H, d, J = 2.3 Hz), 6.17 (0.82H, d, J
2.3 Hz), 6.09 (0.82H, d, J = 2.3 Hz), 6.08 (0.82H, s), 5.22-4.40 (21.32H, m), 4.25 (0.82H, d, J =
.8 Hz), 4.05-3.95 (1.64H, m), 3.81-3.75 (0.82H, m), 3.60 (0.82H, d, J = 8.9 Hz), 3.10 (0.82H, dd, J
16.0, 6.0 Hz), 2.96 (0.82H, d, J = 9.5 Hz), 2.37 (0.82H, dd, J = 16.5, 9.8 Hz), 1.33 (0.82H, d, J =
2
2
1
6
D
3
143 (c 0.85, CHCl ). H NMR (500
3
=
8
=
1
3
3
1
1
1
9
3
.5 Hz), 1.14 (0.82H, d, J = 3.5 Hz); C NMR (125MHz, CDCl , major isomer) = 157.9, 157.8,
56.7, 155.5, 155.4, 155.2, 155.1, 155.0, 153.8, 149.2, 149.2, 149.1, 148.8, 148.6, 137.7, 137.5,
37.5, 137.4, 137.3, 137.2, 137.2, 137.1, 137.1, 136.0, 132.4, 132.4, 131.7, 128.9-126.9, 121.1,
20.7, 120.6, 115.1, 114.9, 114.8, 114.6, 114.2, 113.8, 112.4, 109.4, 108.8, 102.4, 94.7, 93.8, 92.0,
+
1.8, 81.8, 81.0, 80.4, 73.1, 73.0, 71.9-69.8, 68.4, 37.6, 37.5, 28.5; ESIMS: m/z = 1969.8 [M+Na] .