Letters in Organic Chemistry, 2012, 9, 233-238
233
Synthesis of Procyanidin B1, B2, and B4 and Their Anti-Inflammatory
Activity: The Effect of 4-Alkoxy Group of Catechin and/or Epicatechin
Electrophiles for Condensation
M. Katoha, Y. Oizumia, Y. Mohria, M. Hirotab and H. Makabe*,a
aSciences of Functional Foods, Graduate School of Agriculture, Shinshu University, 8304 Minami-minowa, Kami-ina,
Nagano 399-4598, Japan
bDepartment of Bioscience and Biotechnology, Faculty of Agriculture, Shinshu University, 8304 Minami-minowa, Kami-
ina, Nagano 399-4598, Japan
Received November 22, 2011: Revised February 08, 2012: Accepted February 23, 2012
Abstract: Procyanidin B1, B2, and B3 were synthesized based on a Yb(OTf)3 catalyzed equimolar condensation using
methoxy and/or 4-(2”-ethoxyethoxy)drivatives as electrophiles. The anti-inflammatory effect of synthetic procyanidin B1,
B2, and B4 on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation of mouse ears was examined.
Procyanidin B1, B2, B 4 suppressed TPA-induced inflammation of mouse ears by 48%, 34%, and 29%, respectively, at a
dose of 200 µg. Their activities are stronger than those of indomethacin and glycyrrhetinic acid, the normally used anti-
inflammatory agent.
Keywords: Anti-inflammatory, equimolar condensation, polyphenol, procyanidin.
INTRODUCTION
4-alkoxy catechin and/or epicatechin derivatives as
electrophiles. We also wish to report the anti-inflammatory
activity of 1, 2, and 4, respectively.
Procyanidins are known as condensed or noncondensed
hydrolysable tannins [1]. These condensed tannins are
widely distributed in the plant kingdom [2]. In particular,
grape seeds and skins and red wines are rich sources of
polyphenols. Many biological activities, especially powerful
freeradical scavenging activity, have been reported for
flavonoids. Procyanidins have various types of structures
derived from monomers of flavan-3-ol typically via a C(4)-
C(8) intermolecular bond. The procyanidins are often
isolated as complex stereochemical and oligomeric mixtures.
In addition to these facts, procyanidins have rotational
isomers. Thus, it is very difficult to obtain pure materials.
Due to these problems, stereoselective synthetic efforts were
devoted. However, efficient syntheses are very limited
because condensation reaction requires large excess of
nucleophile at low temperature to limit the reaction of
activated monomer with itself or with the dimeric product,
leading in both cases to oligomeric side products. In previous
reports, we described Yb(OTf)3 catalyzed equimolar
condensations of catechin and/or epicatechin nucleophilic
and electrophilic derivatives and its application to the
synthesis of procyanidin B1 (1), B2 (2), B3 (3), and B4 (4)
[3, 4] (Fig. 1).
We chose the tetrabenzylated catechin nucleophile 5 and
epicatechin nucleophile 6, prepared by Kawamoto and co-
workers [6]. As to the electrophilic unit, DDQ oxidation at
the C(4) position of catechin and /or epicatechin derivatives
using MeOH gave low yield. Thus we prepared compounds
7-11 as epicatechin electrophile and 13-17 as catechin
electrophile according to Saito’s procedure [7, 8]. Especially,
the introduction of the 2-ethoxyethoxy group at C(4) position
worked well compared to the methoxy group as Saito
reported (Schemes 1, 2) [7, 8].
Equimolar condensation of 5 with 4-alkoxy epicatechin
derivatives 7-11 was examined using Yb(OTf)3 at room
temperature in CH2Cl2, see [5]. As shown in Table 1, ethoxy,
isopropyloxy, ethylene glycol derivative, and 4-(2”-
ethoxyethoxy)drivative gave condensed products in low
yield. On the other hand, the methoxy derivative 7 gave the
β-12 in 62% yield as we have reported before [3]. In all
cases, the ratio of α-12/β-12 was 9:91 (Table 1) [3].
Next, we investigated the equimolar condensation of
epicatechin nucleophile 6 with epicatechin electrophiles 7-
11. As shown in Table 2, 4-alkoxy epicatechin electrophiles
7-11 gave more than moderate yield. Especially methoxy
and 4-(2”-ethoxyethoxy)drivative gave good results. In all
cases, the ratio of α-13/β-13 was 12:88 (Table 2) [3].
As to the synthesis of 3, we have improved the yield of
condensation and investigated its anti-inflammatory activity
[5]. In this paper, we wish to report further investigation of
the Yb(OTf)3 catalyzed equimolar condensation with various
We also examined the equimolar condensation of
epicatechin nucleophile 6 with catechin electrophiles 13-17.
As shown in Table 3, 4-(2”-ethoxyethoxy)derivative 7 gave
the product in moderate yield as well as in the case of the
methoxy derivative. In all cases, the ratio of α-18/β-18 was
higher than 98:2 (Table 3) [3].
*Address correspondence to this author at the Sciences of Functional Foods,
Graduate School of Agriculture, Shinshu University, 8304 Minami-minowa,
Kami-ina, Nagano 399-4598, Japan; Tel: +81-265-77-1630; Fax: +81-265-
77-1700; E-mail: makabeh@shinshu-u.ac.jp
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers
Katoh
