Tetrahedron Letters
Syntheses of prodelphinidin B1, B2, and B4 and their antitumor
activities against human PC-3 prostate cancer cell lines
Wataru Fujii a, Kazuya Toda b, Kiriko Matsumoto b, Koichiro Kawaguchi b, Sei-ichi Kawahara c,
Yasunao Hattori d, Hiroshi Fujii b, , Hidefumi Makabe a,
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a Graduate School of Agriculture, Sciences of Functional Foods, Shinshu University, 8304 Minami-minowa Kami-ina, Nagano 399-4598, Japan
b Department of Bioscience and Biotechnology, Faculty of Agriculture, Shinshu University, 8304 Minami-minowa Kami-ina, Nagano 399-4598, Japan
c St. Cousair Co., Ltd, 1260 Imogawa, Kami-minochi, Nagano 389-1201, Japan
d Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Total synthesis of prodelphinidin B1, B2, and B4 has been accomplished. The key step is Lewis acid-
mediated equimolar condensations between an epigallocatechin and/or a gallocatechin nucleophile
Received 24 September 2013
Revised 16 October 2013
Accepted 23 October 2013
Available online 31 October 2013
and an epigallocatechin and/or
a gallocatechin electrophile. The antitumor effects of synthetic
prodelphinidin B1–B4 against human PC-3 prostate cancer cell lines have been investigated. These com-
pounds showed significant antitumor effects. Their activity seemed to be little bit stronger than EGCG
and prodelphinidin B3, known antitumor agent.
Keywords:
Polyphenols
Synthesis
Ó 2013 Elsevier Ltd. All rights reserved.
Natural product
Anticancer agents
Prodelphinidins are paid much attention due to their significant
biological activities. For example, prodelphinidin B2 3-O-gallate
and 3,30-di-O-gallate inhibit proliferation of A549 cancer cells,1,2
and prodelphinidin B4 30-O-gallate inhibits COX-2 and iNOS.3 As
to the prodelphinidins B1, B2, and B4, a number of isolation form
plants have been reported; prodelphinidin B1 (1) from Citstus inc-
anus4 and Lotus peduncultus,5 and prodelphinidin B2 (2) from Lotus
peduncultus,5 and prodelphinidin B4 (4) from Ribes nigrum,6 Vicia
faba,7 and Stryphnodendron adstringens.8 Because purification and
identification of prodelphinidins from plants are very difficult,
the mechanism for their biological activities remains unknown.
Thus syntheses of prodelphinidins are quite important to obtain
pure materials for evaluating their biological activities. The many
examples of the syntheses of procyanidins were reported in this
decade including our syntheses,9–14 however, synthetic studies
on prodelphinidins are quite limited due to difficulty in obtaining
(ꢀ)-gallocatechin or (+)-epigallocatechin as synthetic starting
materials.15 Although (ꢀ)-gallocatechin or (+)-epigallocatechin is
commercially available, both compounds are very expensive. Thus
it was necessary to prepare enough amount of (ꢀ)-gallocatechin or
(+)-epigallocatechin derivatives according to the reported
procedure.16 Until now only an example of total synthesis of pro-
delphinidin B3 (3) and C2 has been reported by us using equimolar
coupling between nucleophilic and electrophilic partners using
Lewis acid.17 Herein we demonstrate equimolar condensation of
(ꢀ)-gallocatechin and/or (+)-gallocatechin nucleophile with a gal-
locatechin and/or epigallocatechin derived electrophile and the
first total syntheses of prodelphinidin B1 (1), B2 (2), and B4 (4)
(Fig. 1).
The gallocatechin-derived nucleophile 5 was constructed as
Chan and co-workers reported.16 Gallocatechin-derived electro-
philes 6 and 7 were prepared as we reported earlier.17 The epigal-
locatechin-drived nucleophile 8 was prepared according to the
Chan and co-workers’ method.16 DDQ oxidation of 8 in the pres-
ence of methanol or ethoxyethanol followed by acetylation gave
epigallocatechin-drived electrophiles
(Scheme 1).
9 and 10, respectively
First, we examined the condition of equimolar condensation of
gallocatechin nucleophile 5 with epigallocatechin electrophile 9 or
10 to construct prodelphinidin B1 (1) skeleton. We chose Yb(OTf)3
as a Lewis acid for condensation because equimolar coupling
worked well in the case of procyaninidin dimers.10d,h We also
examined silver Lewis acids because Ferreira and co-workers re-
ported that using AgBF4 as the thiophilic Lewis acid offered advan-
tages to control the level of oligomeration in the synthesis of
procyanidin B1–B4.18 As shown in Table 1, 4-(200-ethoxyethoxy)
derivative 10 afforded condensed product 11 in 66% yield when
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Corresponding authors. Tel./fax: +81 265 77 1626 (H. Fujii), tel.: +81 265 77
1630; fax: +81 265 77 1700 (H. Makabe).
(H. Makabe).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
Fujii, Wataru
