Selective synthesis of epicatechin dimers by zinc(II) triflate mediated self-condensation

Article abstract of DOI:10.1055/s-0034-1378998

Epicatechin dimers were synthesized by zinc(II) triflate mediated self-condensation reactions of epicatechin monomer derivatives. One synthesized dimer was successfully converted into procyanidin C1.

Full text of DOI:10.1055/s-0034-1378998

PAPER
▌3351
paper
Selective Synthesis of Epicatechin Dimers By Zinc(II) Triflate Mediated Self-
Condensation
Selective Synthesis of Epicatechin Dimers
Manato Suda,a Wataru Fujii,a Kohki Takanashi,a Yasunao Hattori,b Hidefumi Makabe*a
a
Graduate School of Agriculture, Sciences of Functional Foods, Shinshu University, 8304 Minami-minowa, Kami-ina, Nagano, 399-4598,
Japan
Fax +81(265)771700; E-mail: makabeh@shinshu-u.ac.jp
b
Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan
Received: 01.07.2014; Accepted after revision: 27.07.2014
usefulness of this reaction, we performed an efficient syn-
Abstract: Epicatechin dimers were synthesized by zinc(II) triflate
thesis of an epicatechin trimer, procyanidin C1 (2).
mediated self-condensation reactions of epicatechin monomer de-
rivatives. One synthesized dimer was successfully converted into
procyanidin C1.
OH
Key words: phenols, Lewis acids, oligomerization, natural prod-
ucts, stereoselective synthesis
HO
O
OH
OH
O
OH
OH
OH
HO
Proanthocyanidins are condensed or nonhydrolyzable tan-
nins with structures that basically consist of oligomerized
flavan-3-ols.1 Most of these compounds contain C-4 to C-
8′ internal flavan bonds. Proanthocyanidins are widely
distributed in nature, and are found in plants, vegetables,
fruits, crops, and barks of trees.2 They possess strong free-
radical-scavenging and antioxidative activities,3 and
many significant biological activities have been reported,
including antitumor,4,5 antiviral,6 and antiinflammatory
activities7 and inhibition of DNA polymerase.8 Because of
these potential beneficial effects for human health, many
scientists have paid a great deal of attention to proantho-
cyanidins. However, the identification and purification of
these compounds, especially the higher oligomers, is ex-
tremely difficult even with modern isolation techniques,
so extended investigations on their biological activities,
such as their mechanisms of action, have not been possi-
ble. Synthesis studies have therefore been devoted to ob-
taining pure proanthocyanidins, such as procyanidin B2
(1) and C1 (2), for biological testing (Figure 1).9–12
OH
O
OH
OH
OH
OH
HO
O1
HO
OH
OH
O
OH
4
OH
OH
HO
OH
8'
procyanidin C1 (2)
OH
OH
OH
procyanidin B2 (1)
Figure 1 The structures of procyanidins B2 and C1
First, we examined the Lewis acid mediated self-conden-
sation of epicatechin derivative 3, previously prepared by
Saito and co-workers,11f to form the epicatechin dimer 4.
The epicatechin derivative 3 gave the self-condensed
product 4 in 58% yield when zinc(II) triflate was used as
the Lewis acid (Table 1).11b Unidentified higher oligomers
were also formed in this reaction. When the reaction was
performed at 0 °C, the self-condensation product 4 was
obtained in 55% yield, along with unreacted starting ma-
terial (21%). The yield of the condensed product based on
the recovery of starting material was 70%.
Typical strategies for synthesizing catechin and/or epicat-
echin oligomers involve the use of catechin and/or epicat-
echin nucleophiles and electrophiles in the presence of
Lewis acids. In most cases, an excess of the nucleophilic
partner is required.10m To avoid the use of an excess of the
nucleophile, we have developed a strategy involving equi-
molar condensation.10i However, this strategy neverthe-
less requires the preparation of both the nucleophilic and
the electrophilic partners. To simplify the construction of
catechin and/or epicatechin dimers, we have developed a
self-condensation strategy for the formation of epicate-
chin and/or epigallocatechin dimers. To demonstrate the
We also applied this reaction to the epigallocatechin de-
rivative 5,13 and we found that this was useful for the syn-
thesis of the epigallocatechin dimer 6 (Scheme 1). We
confirmed the structure of 6 by two-dimensional NMR
spectroscopy; the small coupling constants in the hetero-
cyclic ring (J2,3 and J3,4 < 2.5 Hz) confirmed the relative
2,3-cis-3,4-trans stereochemistry. When we used catechin
and gallocatechin derivatives, no selective formation of
dimeric products was observed. We found that the stereo-
chemistry at the C-3 position greatly affected the self-con-
densation reaction.
SYNTHESIS 2014, 46, 3351–3355
Advanced online publication: 25.08.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0034-1378998; Art ID: ss-2014-f0408-op
© Georg Thieme Verlag Stuttgart · New York

3352
M. Suda et al.
PAPER
5,6-dicyano-1,4-benzoquinone (DDQ) in the presence of
2-ethoxyethanol did not proceed satisfactorily (Scheme
2). Therefore, compound 4, prepared by zinc(II) triflate-
mediated self-condensation, is useful for preparing di-
meric epicatechin and/or epigallocatechin electrophiles.
Table 1 Self-Condensation of Epicatechin Derivative 3
OBn
OBn
BnO
O
OAc
O
OBn
OBn
Next, we examined the condensation of the dimeric epi-
catechin electrophile 4 with the epicatechin nucleophile 8
with the aim of preparing the epicatechin trimer derivative
9 (Scheme 3). The use of 2.0 equivalents of zinc(II) tri-
flate as a Lewis acid gave the epicatechin trimer 9 in 67%
yield. The removal of the two acetyl groups by treatment
with tetrabutylammonium hydroxide, however, took a
long time. We therefore adopted an alternative method for
deacetylation. Acetylation of the hydroxy group of trimer
9 with acetic anhydride and 4-(N,N-dimethylamino)pyri-
dine in pyridine, followed by reduction of the three acetyl
groups of the resulting triacetate with diisobutylaluminum
hydride (DIBAL-H) gave triol trimer 10. The spectral data
for trimer 10 agreed well with the values that we previous-
ly reported.11b Finally, deprotection of the twelve benzyl
groups by treatment with palladium(II) hydroxide in a hy-
drogen atmosphere followed by lyophilization gave a
good yield of procyanidin C1 (2). HPLC analysis con-
firmed the purity of the synthetic 2.14 The physical and
spectral data for 2 were consistent with the reported val-
ues for procyanidin C1.11b
OBn
OBn
OBn
BnO
BnO
O
Lewis acid
OAc
OAc
O(CH2)2OEt
OBn O(CH2)2OEt
OBn
3
4
Lewis acid (equiv)
Time (h)
Yield (%) of 4
Yb(OTf)3 (0.5)
Yb(OTf)3 (0.8)
Yb(OTf)3 (1.0)
Zn(OTf)2 (0.5)
Zn(OTf)2 (0.8)
24
24
21
24
24
38
52
38
48
58
Because the condensed product 4 has an alkoxy group at
the C-4′ position, it is possible to activate this position
with a Lewis acid. Product 4 might, therefore, act as an
electrophile for the synthesis of epicatechin oligomers.
Attempts at the direct introduction of an alkoxy group at In conclusion, we synthesized an epicatechin dimer by
the C-4′ position of dimer 7 by treated with 2,3-dichloro- zinc(II) triflate mediated self-condensation of an epicate-
OBn
OBn
BnO
O
OBn
OBn
OAc
O
OBn
OBn
BnO
OBn
OBn
OBn
OBn
Zn(OTf)2
(0.8 equiv)
BnO
O
CH2Cl2, 1 h
59%
OAc
OAc
OBn O(CH2)2OEt
OBn O(CH2)2OEt
5
6
Scheme 1 Self-condensation of epigallocatechin derivative 5
OBn
OBn
BnO
O
BnO
O
OBn
OBn
OAc
O
OAc
O
DDQ, EtOCH2CH2OH
OBn
BnO
OBn
BnO
OBn
OBn
OBn
OBn
OAc
OAc
OBn
OBn O(CH2)2OEt
7
4
Scheme 2 Attempt to prepare a dimeric epicatechin electrophile by using DDQ and 2-ethoxyethanol
Synthesis 2014, 46, 3351–3355
© Georg Thieme Verlag Stuttgart · New York

PAPER
Selective Synthesis of Epicatechin Dimers
3353
OBn
OBn
OBn
BnO
O
OBn
Zn(OTf)2
(2.0 equiv)
BnO
O
OAc
O
OBn
+
OBn
BnO
67%
OH
OBn
OBn
8
OAc
OBn O(CH2)2OEt
4
OBn
OBn
OBn
OBn
BnO
O
BnO
O
OH
O
OAc
O
1) Ac2O, DMAP, py
2) DIBAL-H
OBn
OBn
OBn
OBn
OBn
BnO
OBn
BnO
83% (2 steps)
OH
O
OAc
OBn
OBn
OBn
OBn
OBn
OBn
BnO
BnO
O
OH
OH
OBn
OBn
10
9
OH
HO
O
OH
OH
OH
OH
OH
HO
O
OH
O
OH
OH
ref. 11b
OH
HO
OH
OH
procyanidin C1 (2)
Scheme 3 Synthesis of procyanidin C1 (2) by using the self-condensed product 4
mL) and brine (10 mL), dried (MgSO4), and concentrated. The res-
idue was purified by preparative TLC (hexane–EtOAc–CH2Cl2,
5:1:2) to give a pale-yellow oil; yield: 44 mg (58%); [α]D22 +28.2 (c
0.500, CHCl3).
chin monomer derivative. The synthesized dimer acted as
an electrophile for the synthesis a trimer derivative that
was successfully converted into procyanidin C1 (2).
IR (film): 3088, 3062, 3032, 2928, 2870, 1742, 1604, 1513, 1498,
1429, 1373, 1266, 1222, 1122, 1028, 737, 697 cm–1.
CH2Cl2 was distilled from CaH2; Silica gel and other materials were
used as received. All reactions were carried out under argon. NMR
spectra were recorded at r.t. on a Bruker Avance 500 MHz instru-
ment with TMS as an internal standard. Mass spectra were recorded
on JEOL JMS-SX102A and TMS-T100 LC mass spectrometers. IR
spectra were recorded on a JASCO FT-IR 480 Plus spectrometer.
Optical rotations were determined with a JASCO DIP-1000 po-
larimeter.
1H NMR (500 MHz, CDCl3): δ (78:22 rotational isomers; major iso-
mer) = 7.50–6.75 (m, 46 H), 6.55 (dd, J = 8.0, 1.5 Hz, 1 H), 6.25 (s,
1 H), 6.00 (d, J = 2.0 Hz, 1 H), 5.66 (s, 1 H), 5.62 (d, J = 2.5 Hz, 1
H), 5.40 (s, 1 H), 5.15–4.25 (m, 19 H), 3.95–3.85 (m, 1 H), 3.83–
3.75 (m, 1 H), 3.56–3.45 (m, 2 H), 3.41 (q, J = 7.0 Hz, 2 H), 1.71 (s,
6 H), 1.12 (t, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ (major isomer) = 169.9, 169.1,
158.4, 158.2, 157.6, 155.5, 154.7, 149.3, 149.0, 148.6, 148.5,
128.6–126.7, 119.9, 114.8, 114.1, 113.9, 112.9, 109.9, 104.3, 103.2,
93.9, 93.1, 91.3, 74.8, 74.4, 72.2, 71.6, 71.4, 71.3, 70.6, 70.3, 70.1,
69.9, 69.5, 69.4, 66.3, 33.1, 20.8, 15.2.
[4,8′]-2,3-cis-3,4-trans:2′,3′-cis-Octa-O-benzyl-3,3′-O-diacetyl-
4′-(2-ethoxyethoxy)bi-(–)-epicatechin (4); Typical Procedure
A solution of epicatechin derivative 3 (81 mg, 0.10 mmol) in
CH2Cl2 (3 mL) was treated with Zn(OTf)2 (30 mg, 0.08 mmol) at
r.t., and the mixture was stirred for 24 h, The reaction was then
quenched with H2O, and the mixture was extracted with EtOAc (2
× 10 mL). The organic layers were combined, washed with H2O (10
HRMS-FAB: m/z [M + Na]+ calcd for C94H86NaO16: 1493.5815;
found: 1493.5819.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3351–3355

3354
M. Suda et al.
PAPER
[4,8′]-2,3-cis-3,4-trans:2′,3′-cis-Dodeca-O-benzyl-3,3′-O-diace-
tyl-4′-(2-ethoxyethoxy)bi-(–)-epigallocatechin (6)
References
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In the same manner as described above, derivative 5 (25 mg, 0.03
19
mmol) gave dimer 6 as a pale-yellow oil; yield: 14 mg (59%); [α]D
+26.7 (c 0.350, CHCl3).
IR (film): 3089, 3062, 3032, 2926, 2869, 1743, 1594, 1498, 1454,
1432, 1372, 1226, 1120, 736, 697 cm–1.
1H NMR (500 MHz, CDCl3): δ (75:25 rotational isomers; major iso-
mer) = 7.46–6.74 (m, 49 H), 6.85 (s, 2 H), 6.47 (s, 2 H), 6.03 (d, J =
2.0 Hz, 1 H), 5.64 (d, J = 2.0 Hz, 1 H), 5.44 (s, 1 H), 5.10–4.78 (m,
23 H), 4.69 (d, J = 10.5 Hz, 1 H), 4.58 (s, 1 H), 4.53 (d, J = 10.5 Hz,
1 H), 4.40 (d, J = 2.5 Hz, 1 H), 3.95–3.90 (m, 1 H), 3.82–3.77 (m, 1
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(s, 3 H), 1.13 (t, J = 7.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ (major isomer) = 169.9, 169.0,
158.3, 157.5, 156.6, 155.3, 153.0, 152.4, 138.3–136.8, 134.7, 132.5,
128.6–127.0, 109.7, 106.5, 106.1, 93.2, 91.2, 75.2, 74.9, 72.0, 71.4,
71.2, 70.4, 70.2, 70.0, 69.9, 69.7, 69.6, 69.4, 66.3, 32.9, 29.7, 20.8,
15.3. HRMS-FAB: m/z [M + Na]+ calcd for C108H98O18Na:
1705.6651; found: 1705.6658.
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Mizushina, Y.; Ikawa, H.; Yoshida, H.; Matsuura, N.;
Nakajima, N. Tetrahedron 2004, 60, 12043.
(9) For recent reviews on the synthesis of proanthocyanidins,
see: (a) Makabe, H. Heterocycles 2013, 87, 2225.
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3,3′-O-Diacetyl-4′′-hydroxytris(5,7,3′,4′-tetra-O-benzyl)epicat-
echin (4β/8)2-Trimer (9)
A solution of dimer 4 (25 mg, 0.017 mmol) and derivative 8 (11 mg,
0.017 mmol) in CH2Cl2 (3 mL) was treated with Zn(OTf)2 (13 mg,
0.034 mmol) at r.t., and the mixture was stirred for 5.5 h. The reac-
tion was quenched with H2O (10 mL), and the mixture was extract-
ed with EtOAc (2 × 10 mL). The organic layers were combined,
washed with H2O (10 mL) and brine (10 mL), dried (MgSO4), and
concentrated. The residue was purified by preparative TLC
(hexane–EtOAc–CH2Cl2, 5:1:2) to give a pale-yellow oil; yield: 23
mg (67%); [α]D20 +100 (c 0.800, CHCl3).
(10) For recent syntheses of procyanidin dimers, see: (a) Ishihara,
S.; Doi, S.; Harui, K.; Okamoto, T.; Okamoto, S.; Uenishi,
J.; Kawasaki, T.; Nakajima, N.; Saito, A. Heterocycles 2014,
88, 1595. (b) Nakajima, N.; Horikawa, K.; Takekawa, N.;
Hamada, M.; Kishimoto, T. Heterocycles 2012, 84, 349.
(c) Katoh, M.; Oizumi, Y.; Mohri, Y.; Hirota, M.; Makabe,
H. Lett. Org. Chem. 2012, 9, 233. (d) Alharthy, R. D.;
Hayes, C. J. Tetrahedron Lett. 2010, 51, 1193. (e) Oizumi,
Y.; Mohri, Y.; Hirota, M.; Makabe, H. J. Org. Chem. 2010,
75, 4884. (f) Mohri, Y.; Sagehashi, M.; Yamada, T.; Hattori,
Y.; Morimura, K.; Hamauzu, Y.; Kamo, T.; Hirota, M.;
Makabe, H. Heterocycles 2009, 79, 549. (g) Oyama, K.-i.;
Kuwano, M.; Ito, M.; Yoshida, K.; Kondo, T. Tetrahedron
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T.; Hattori, Y.; Morimura, K.; Kamo, T.; Hirota, M.;
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I.; Barathieu, K.; André, Y.; Pianet, I.; Dufourc, E. J.;
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(m) Saito, A.; Nakajima, N.; Tanaka, A.; Ubukata, M.
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(11) For recent syntheses of procyanidin trimers and related
compounds, see: (a) Yano, T.; Ohmori, K.; Takahashi, H.;
Kusumi, T.; Suzuki, K. Org. Biomol. Chem. 2012, 10, 7685.
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IR (film): 3569, 3087, 3063, 3032, 2931, 2869, 1740, 1601, 1512,
1498, 1454, 1428, 1373, 1265, 1220, 1123, 1028, 910, 735, 697 cm–1.
HRMS-FAB: m/z [M + Na]+ calcd for C133H114NaO20: 2053.7785;
found: 2053.7793.
Tris(5,7,3′,4′-tetra-O-benzyl)epicatechin (4β/8)2-Trimer (10)
Ac2O (6.7 μL, 0.071 mmol) was added to a solution of diacetate 9
(72 mg, 0.035 mmol) and pyridine (5.7 μL, 0.071 mmol) in CH2Cl2
(2.5 mL) at 0 °C, and the mixture was stirred for 7.5 h. The reaction
was quenched with H2O (10 mL), and the mixture was extracted
with EtOAc (2 × 10 mL). The organic layers were combined,
washed with H2O (10 mL) and brine (10 mL), dried (MgSO4), and
concentrated. The residue was purified with preparative TLC
(hexane–EtOAc–CH2Cl2, 4:1:2) to give the corresponding triacetate
as a pale-yellow oil. This was dissolved in CH2Cl2 (2.0 mL) and
treated with a 1 M solution of DIBAL-H in hexane (0.35 mL, 0.35
mmol) at –78 °C. The mixture was stirred for 2 h and then the reac-
tion was quenched with MeOH (5 mL). The mixture was filtered
through Celite and the filtrate was concentrated. The residue was
purified with preparative TLC (hexane–EtOAc–CH2Cl2, 6:1:2) to
give trimer 10 as a pale-yellow oil; yield: 57 mg (83%, two steps).
The physicochemical and spectral data for 10 were identical to
those that we previously reported.11b
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunpfgIpi
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Synthesis 2014, 46, 3351–3355
© Georg Thieme Verlag Stuttgart · New York

PAPER
Selective Synthesis of Epicatechin Dimers
3355
(12) For syntheses of procyanidin oligomers, see: (a) Ohmori, K.;
Shono, T.; Hatakoshi, Y.; Yano, T.; Suzuki, K. Angew.
Chem. Int. Ed. 2011, 50, 4862. (b) Saito, A.; Mizushina, Y.;
Tanaka, A.; Nakajima, N. Tetrahedron 2009, 65, 7422.
(13) Fujii, W.; Toda, K.; Matsumoto, K.; Kawaguchi, K.;
Kawahara, S.-i.; Hattori, Y.; Fujii, H.; Makabe, H.
Tetrahedron Lett. 2013, 54, 7188.
(14) HPLC measurement conditions: column, Inertsil ODS-3,
250 × 4.6 mm GL-Sciences; eluent: MeOH–0.2% AcOH
(5:95 to 25:75), flow rate: 0.8 mL/min; detection: UV, λ =
280 nm; retention time: 23.60 min.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3351–3355