Concise Synthesis of Cinnamtannin A2 from Dimeric Epicatechin Electrophile and Nucleophile Prepared by Zn(OTf)2-Mediated Self-Condensation

Article abstract of DOI:10.1055/s-0035-1561390

The synthesis of cinnamtannin A2 from dimeric epicatechin nucleophile and electrophile was accomplished. Dimeric epicatechin nucleophile was prepared directly by reduction of the C-4′′ 1-ethoxy-?ethoxy group of the electrophile which was previously synthe

Full text of DOI:10.1055/s-0035-1561390

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
paper
A
M. Ichikawa et al.
Paper
Synthesis
Concise Synthesis of Cinnamtannin A2 from Dimeric Epicatechin
Electrophile and Nucleophile Prepared by Zn(OTf)2-Mediated
Self-Condensation
Mikihiro Ichikawa ◊a
Kohki Takanashi ◊a
Manato Suda ◊a
Yasunao Hattorib
Sei-ichi Kawaharac
Hiroshi Fujiid
OBn
OH
BnO
O
HO
O
OBn
OH
OBn
OBn
OBn
OBn
OAc
O
OH
O
OBn
OBn
OH
OH
OBn
BnO
OH
HO
BnO
O
BnO
+
O
OAc
O
OH
O
OAc
OH
O
OBn
BnO
OBn
BnO
OBn
OBn
OBn
OBn
OBn
OBn
OH
OH
Zn(OTf)2
61%
OBn
OH
BnO
O
HO
Hidefumi Makabe*a,d
OAc
OH
OH
O
OH
O
OBn OEE
electrophile
OBn
OBn
OBn
OH
OH
OBn
OH
nucleophile
BnO
HO
a Graduate School of Agriculture, Sciences of Functional Foods,
Shinshu University, 8304 Minami-minowa, Kami-ina, Nagano,
399-4598, Japan
OH
OH
OBn
OH
b Department of Medicinal Chemistry, Kyoto Pharmaceutical
University, Yamashina-ku, Kyoto 607-8412, Japan
c St. Cousair Co., Ltd., 1260 Imogawa, Kami-minochi, Iizuna,
Nagano, 389-1201, Japan
cinnamtannin A2 (1)
d Department of Interdisciplinary Genome Sciences and Cell
Metabolism, Institute for Biomedical Sciences, Interdisciplin-
ary Cluster for Cutting Edge Research, Shinshu University,
Minami-minowa, Kami-ina, Nagano, 399-4598, Japan
makabeh@shinshu-u.ac.jp
◊ These authors contributed equally
Received: 04.01.2016
Accepted after revision: 23.01.2016
Published online: 25.02.2016
OH
OH
HO
O
DOI: 10.1055/s-0035-1561390; Art ID: ss-2016-f0004-op
Abstract The synthesis of cinnamtannin A2 from dimeric epicatechin
nucleophile and electrophile was accomplished. Dimeric epicatechin
nucleophile was prepared directly by reduction of the C-4′′ 1-ethoxy-
ethoxy group of the electrophile which was previously synthesized by us.
OH
O
OH
OH
OH
HO
OH
O
Key words phenols, Lewis acids, oligomerization, natural products,
stereoselective synthesis
OH
OH
OH
HO
Cinnamtannin A2 (1) (epicatechin tetramer) is isolated
from mainly cocoa beans1 and black soybeans.2 This com-
pound shows significant biological activities, such as inhi-
bition of DNA polymerase,3 antiviral,4 antiherpetic,5 and re-
ducing blood glucose levels along with enhancing insulin
sensitivity6 activities. Although cinnamtannin A2 (1) pos-
sesses interesting biological activities, its mechanisms of
action still remain unclear. For biological studies, the syn-
thesis of cinnamtannin A2 (1) is necessary in order to ob-
tain a pure sample. There are only two reported synthetic
studies of cinnamtannin A2 (1) because of its complex
structure (Figure 1).3,7 As to the syntheses of highly oligom-
erized procyanidins, more than pentamers were reported
by four groups.3,7–9
OH
OH
OH
OH
OH
HO
O
HO
O
OH
OH
OH
OH
OH
(−)-epicatechin
cinnamtannin A2 (1)
Figure 1 The structures of cinnamtannin A2 (1) and (–)-epicatechin
On the other hand, there are many reports of procyani-
din dimers and trimers, respectively.10–12
The typical strategy to synthesize cinnamtannin A2 (1)
is by condensation of epicatechin nucleophile and electro-
phile under Lewis acid catalysis. Two pioneering synthetic
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
M. Ichikawa et al.
Paper
Synthesis
OBn
OBn
BnO
O
OBn
OBn
OAc
O
BnO
O
OBn
BnO
Zn(OTf)2 (0.8 equiv)
CH2Cl2, 24 h
58%
OBn
OBn
OAc
OBn OEE
OAc
2
OBn OEE
3
Scheme 1 Synthesis of dimeric epicatechin electrophile 3 using self-condensation
studies were reported as follows. The first is by Kozikowski
and co-workers,7 who synthesized epicatechin dimer to
nonamer using 3-O-acetyl-4-[(benzothiazol-2-yl)thio]-
5,7,3′,4′-tetra-O-benzylepicatechin as the electrophile and
dimeric epicatechin derivative as the nucleophile. However,
selective formation of each oligomer was not accomplished
and thus purification of each oligomer was needed. The
second is by Saito and Nakajima,3 who used an excess
amount of trimeric epicatechin nucleophilic partner to pre-
vent further polymerization. To avoid using an excess of nu-
cleophile, we have developed equimolar condensation of
catechin and/or epicatechin nucleophile and electrophile
for the synthesis of procyanidin dimers.11j However, prepa-
ration of both of nucleophile and electrophile epicatechin
derivative was required for our strategy. To construct epi-
catechin dimers in a simple manner, we have developed a
‘self-condensation’ strategy to form dimeric epicatechin
electrophile 3. This compound would be useful to prepare
epicatechin oligomers (Scheme 1).13,14
chin nucleophile is reduction of the C-4′′ alkoxy group of
epicatechin electrophile 3 followed by hydrolysis of the two
acetyl groups (Scheme 2).
In this paper, we wish to report the concise synthesis of
cinnamtannin A2 (1) from dimeric epicatechin electrophile
3 and nucleophile 4. The synthetic strategy is shown in
Scheme 3. Cinnamtannin A2 (1) would be synthesized from
dimeric electrophile 3 and nucleophile 4. The dimeric elec-
trophile 3 would be prepared using the self-condensation of
monomeric epicatechin derivative 2 as previously report-
ed.13 The dimeric nucleophile 4 would be prepared by re-
duction of the OEE group followed by deacetylation
(Scheme 3).
At first, we examined the reduction of the C-4′′ 1-
ethoxyethoxy (OEE) group of epicatechin electrophile 3 us-
ing Et3SiH in the presence of a Lewis acid. As shown in Table
1, 4.0 equivalents of Et3SiH as a reducing agent and 2.0
equivalent of BF3·Et2O or TMSOTf as Lewis acids at –40 °C
both gave the desired product in moderate yield. On the
other hand, TiCl4 and Zn(OTf)2 gave rather sluggish results
(Table 1).
Formation of more oligomerized products, such as the
trimer and tetramer, were not detected in this reaction.
In order to construct the framework of epicatechin te-
tramer, the synthesis of dimeric epicatechin nucleophile 4
is necessary. One of the simplest ways to prepare epicate-
The two acetyl groups of compound 5 were removed us-
ing n-Bu4NOH to furnish dimeric epicatechin nucleophile 4
(Scheme 4).7
OBn
OBn
1
BnO
O
BnO
O
OBn
OBn
2
3
OAc
OH
O
4
1) reduction at C-4''
OBn
BnO
OBn
BnO
OBn
OBn
OBn
OBn
OEE group
1"
O
2"
2) removal of acetyl
group
3"
4''
OAc
OH
OBn OEE
OBn
3
4
Scheme 2 Synthetic strategy for dimeric epicatechin nucleophile 4 from dimeric epicatechin electrophile 3 [OEE = OCH(OEt)Me]
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

C
M. Ichikawa et al.
Paper
Synthesis
OBn
OBn
BnO
O
OAc
OBn OEE
2
self-condensation
OBn
BnO
O
OH
OBn
HO
O
OAc
OH
OBn
BnO
OBn
OH
O
OH
OH
O
OH
HO
OBn
equimolar
condensation
OAc
OBn OEE
OH
O
reduction of
OH
OH
OEE group
followed by
deacetylation
OH
electrophile (3)
HO
OBn
OBn
OH
O
BnO
O
OH
OH
OH
HO
OH
O
OBn
BnO
OBn
OBn
OH
OH
cinnamtannin A2 (1)
OH
OBn
nucleophile (4)
Scheme 3 Synthetic strategy for cinnamtannin A2 (1)
OBn
OBn
OBn
OBn
BnO
O
BnO
O
OAc
O
OH
OBn
BnO
OBn
BnO
OBn
OBn
OBn
n-Bu4NOH, THF
O
88%
OBn
OAc
OH
OBn
OBn
5
4
Scheme 4 Preparation of dimeric epicatechin nucleophile 4
With the dimeric epicatechin electrophile 3 and nucleo-
phile 4 in hand, we focused on the equimolar condensation
between 3 and 4. We investigated Yb, Ag, and Zn Lewis
acids for equimolar condensation; Yb(OTf)3 and AgOTf both
afforded condensed product 6 in low yield. Thus we exam-
ined reaction conditions using Zn(OTf)2 as shown in Table 2.
We found that 2.5 equivalents of Zn(OTf)2 gave condensed
product 6 in 61% yield along with unidentified more oligo-
merized products (Table 2).
The two acetyl groups of compound 6 were removed us-
ing the procedure reported by Kozikowski and co-workers
to furnish tetraol 7.7 Confirmation of the stereochemistry of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

D
M. Ichikawa et al.
Paper
Synthesis
Table 1 Reduction of OEE Group at C-4′′ Position of 3
OBn
OBn
OBn
OBn
1
BnO
O
BnO
O
2
3
OAc
OAc
O
4
OBn
BnO
OBn
BnO
OBn
OBn
OBn
OBn
Et3SiH, CH2Cl2
Lewis acid
O
4'
OAc
OAc
OBn OEE
OBn
3
5
Lewis acid (equiv)
Equiv of Et3SiH
Temp (°C)
Time (min)
Yield (%) of 5
BF3·Et2O (2.0)
BF3·Et2O (2.3)
BF3·Et2O (2.0)
TMSOTf (2.0)
TiCl4 (2.0)
4.0
5.0
4.1
4.0
4.0
4.0
4.0
–78
0
840
5
32
27
–40
–40
–40
–80
–40
40
55
75
50
10
22
TiCl4 (1.0)
720
1185
decomp.
22
Zn(OTf)2 (2.0)
Table 2 Equimolar Condensation between 3 and 4
OBn
BnO
O
OBn
OAc
OBn
OBn
OBn
OBn
OBn
BnO
BnO
O
BnO
O
O
OBn
OBn
OH
OAc
O
Zn(OTf)2
OAc
OBn
OBn
OBn
OBn
OBn
BnO
OBn
BnO
CH2Cl2, r.t.
OBn
BnO
+
O
O
OBn
OBn
OH
OAc
OH
OBn
OBn OEE
OBn
OBn
OBn
3
4
BnO
O
OH
OBn
6
Equiv of Zn(OTf)2
Time (h)
Yield (%) of 6
2.0
2.5
3.0
4.5
25
24
19
51
34
61
45
26
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

E
M. Ichikawa et al.
Paper
Synthesis
newly formed flavan bond at the C-4′′ position was per-
cleavage of internal flavan bonds of 1 was observed. Thus
we switched to the use of diacetate 6. Acetylation of two
hydroxy groups of 6 followed by removal of benzyl groups
and acetylation of phenolic hydroxy groups afforded 8 in
33% yield through three steps. The 1H and 13C NMR spectra
of 8 were consistent with reported values (Scheme 5).3
In conclusion, we have accomplished the synthesis of
cinnamtannin A2 (1) using dimeric epicatechin nucleophile
4 and electrophile 3 that were prepared by Zn(OTf)2-medi-
ated self-condensation of epicatechin monomer derivative.
Zn(OTf)2-mediated equimolar condensation of dimeric
1
formed at this stage. The H and 13C NMR data of 7 was
identical to those of the reported values.7 Thus we conclud-
ed the stereochemistry at the C-3′′ and C-4′′ positions was
trans. Finally, deprotection of the sixteen benzyl groups of 7
using Pd(OH)2/C in the presence of hydrogen followed by
lyophilization afforded cinnamtannin A2 (1) in good yield.
The physicochemical and spectral data of 1 were consistent
3
with reported values. Synthetic 1 was pure judging from
HPLC analysis and 13C NMR.15 We also tried to prepare the
peracetate 8 from cinnamtannin A2 (1). However, serious
OBn
OBn
BnO
O
BnO
O
OBn
OBn
OH
O
OAc
O
OBn
OBn
OBn
OBn
OBn
BnO
OBn
BnO
OH
O
OAc
OBn
OBn
OBn
OBn
n-Bu4NOH
OBn
OBn
BnO
BnO
O
THF
70%
OH
OH
O
OBn
OBn
OBn
OBn
OBn
OBn
BnO
O
BnO
1) Ac2O, Py
2) H2, Pd(OH)2/C
THF–MeOH–H2O
3) Ac2O, Py
OH
OH
OBn
OBn
6
7
33% (3 steps)
O
OH
OH
OAc
AcO
HO
O
OAc
OAc
OH
O
OH
OH
OAc
OAc
OH
HO
OAc
AcO
O
OAc
OH
O
OAc
OAc
OH
OH
H2, Pd(OH)2/C
OH
OAc
AcO
O
HO
THF–MeOH–H2O
quant.
OH
OAc
OAc
OAc
OH
OH
OH
OAc
HO
O
AcO
O
OAc
OH
OH
OAc
cinnamtannin A2 (1)
Scheme 5 Synthesis of cinnamtannin A2 (1) and its peracetate 8
8
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

F
M. Ichikawa et al.
Paper
Synthesis
electrophile 3 and nucleophile 4 gave epicatechin tetramer
derivative 6 in 61% yield. This compound was successfully
converted into cinnamtannin A2 (1).
Tetrakis(5,7,3′,4′-tetra-O-benzyl)epicatechin (4β/8)3-Tetramer (7)
To a solution of 6 (56 mg, 0.021 mmol) in THF (5 mL) was added n-
Bu4NOH (40%, 0.16 mL, 0.25 mmol). The resulting mixture was stirred
for 140 h at r.t., and the reaction was quenched with water. The mix-
ture was extracted with EtOAc (2 × 20 mL), and the combined organic
layers were washed with brine, dried (MgSO4), filtered, and concen-
trated. The residue was purified by preparative TLC (hexane/EtOAc/
CH2Cl2 5:1:2) to afford 7 (38 mg, 70%) as a colorless oil; [α]D19 +112 (c
CH2Cl2 was distilled from CaH2; silica gel and other materials were
used as received. All reactions were carried out under argon. NMR
spectra were obtained at r.t. on a Bruker Avance 500 MHz instrument.
Chemical shifts are relative to TMS as an internal standard. Mass
spectra were obtained on Shimadzu LCMS-IT-TOF and Waters Xevo
QTOF mass spectrometer. IR spectra were recorded with JASCO FT-IR
480 Plus infrared spectrophotometer. Optical rotations were deter-
mined with a JASCO DIP-1000 polarimeter.
24
2.10, CHCl3) {Lit.3 [α]D +104.8 (c 0.94, CHCl3)}; 1:1 mixture of rota-
tional isomers.
IR (film): 3567, 3031, 2929, 1598, 1509, 1454, 1421, 1377, 1264,
1216, 1120, 1026, 735, 696 cm–1
.
1H NMR (CDCl3): δ = 7.50–6.39 (m, 89 H), 6.39 (s, 0.5 H), 6.37 (d, J =
8.2 Hz, 0.5 H), 6.33 (d, J = 8.2 Hz, 0.5 H), 6.27 (d, J = 2.0 Hz, 0.5 H), 6.23
(s, 0.5 H), 6.14 (dd, J = 8.2, 1.5 Hz, 0.5 H), 6.07 (d, J = 2.0 Hz, 0.5 H), 6.05
(d, J = 8.2 Hz, 0.5 H), 6.03 (dd, J = 8.2, 1.5 Hz, 0.5 H), 5.91 (s, 0.5 H), 5.90
(s, 0.5 H), 5.88 (s, 1 H), 5.86 (d, J = 2.0 Hz, 0.5 H), 5.74 (s, 1 H), 5.63 (d,
J = 2.0 Hz, 0.5 H), 5.52 (s, 0.5 H), 5.43 (dd, J = 1.5, 8.2 Hz, 0.5 H), 5.39 (s,
0.5 H), 5.37 (s, 0.5 H), 5.20–3.92 (m, 40 H), 3.66 (m, 0.5 H), 2.93–2.84
(m, 2 H), 1.79 (d, J = 6.0 Hz, 0.5 H), 1.60 (d, J = 6.0 Hz, 0.5 H), 1.50–1.43
(m, 1 H), 1.37 (d, J = 7.5 Hz, 0.5 H), 1.34 (d, J = 7.0 Hz, 0.5 H), 1.14 (d, J =
8.0 Hz, 0.5 H), 1.05 (d, J = 8.0 Hz, 0.5 H).
13C NMR (CDCl3): δ = 158.3, 158.0, 157.5, 156.7, 156.6, 156.4, 156.3,
156.2, 156.1, 156.0, 155.7, 155.4, 155.3, 154.8, 153.2, 153.1, 152.8,
149.4, 149.2, 149.1, 149.0, 148.9, 148.8, 148.6, 148.5, 148.2, 148.1,
147.8, 147.7, 138.9, 138.1, 137.6–137.0, 133.0., 132.6, 132.5, 132.2,
131.3, 128.6–126.0, 119.9, 119.7, 119.3, 119.1, 119.0, 118.8, 118.7,
118.5, 115.1, 115.0, 114.8, 114.1, 113.8, 113.6, 113.4, 113.3, 113.2,
111.3, 111.1, 110.6, 110.3, 110.0, 106.4, 105.7, 105.1, 104.8, 104.5,
104.2, 101.1, 100.0, 94.4, 94.0, 93.8, 93.5, 92.5, 92.4, 92.3, 92.2, 91.4,
90.5, 76.2, 75.9, 75.7, 72.8, 72.6, 71.7, 71.4–69.0, 65.0, 60.4, 36.9, 36.3,
35.6, 35.5, 35.2, 28.5.
Bis(3-O-acetyl-5,7,3′,4′-tetra-O-benzyl)epicatechin 4β,8-Dimer (5)
To a solution of 3 (91 mg, 6.6 mmol) in CH2Cl2 (5 mL) at –40 °C was
added Et3SiH (4.3 mg, 27 mmol) then BF3·Et2O (1.9 mg, 13.2 mmol).
The resulting mixture was stirred for 40 min at –40 °C and the reac-
tion was quenched with sat. NaHCO3. The mixture was extracted with
EtOAc (2 × 12 mL) and the combined organic layers were washed with
water (25 mL) and brine (25 mL), dried (MgSO4), filtered, and concen-
trated. The crude product was purified by preparative TLC (hex-
ane/EtOAc/CH2Cl2 8:1:4) to afford 5 (47 mg, 55%) as a colorless oil.
The physicochemical and spectral data were identical with those of
the reported values.7
3,3′′-O-Diacetyltetrakis(5,7,3′,4′-tetra-O-benzyl)epicatechin
(4β/8)3-Tetramer (6)
To a solution of dimeric nucleophile 4 (23 mg, 0.016 mmol) and di-
meric electrophile 3 (20 mg, 0.016 mmol) in CH2Cl2 (3 mL) under an
argon atmosphere was added Zn(OTf)2 (14 mg, 0.039 mmol). The re-
sulting mixture was stirred for 24 h at r.t., and the reaction was
quenched with water. The mixture was extracted with EtOAc (2 × 20
mL), and the combined organic layers were washed with brine, dried
(MgSO4), filtered, and concentrated. The crude product was purified
by preparative TLC (hexane/EtOAc/CH2Cl2 4:1:2) to give 6 (26 mg,
61%) as a colorless oil; [α]D19 +130 (c 0.49, CHCl3); 4:1 mixture of rota-
tional isomers.
HRMS (ESI): m/z [M + Na]+ calcd for C172H146O24Na: 2618.0102; found:
2618.0095.
Cinnamtannin A2 (Epicatechin Tetramer) (1)
A solution of 7 (42 mg, 0.016 mmol) in THF/MeOH/H2O (20:20:1, 4.1
mL) was hydrogenated over Pd(OH)2/C (27 mg) for 4 h. The mixture
was filtered and filtration residue was washed with MeOH (10 mL).
The combined filtrates were evaporated, and the residue was taken
up in distilled water (10 mL). The solution was filtered and lyo-
IR (film): 3566, 3062, 3031, 2931, 1740, 1599, 1511, 1454, 1428,
1373, 1329, 1266, 1219, 1125, 1027, 735, 697 cm–1
.
1H NMR (CDCl3): δ (major isomer) = 7.49–6.79 (m, 86 H), 6.70–6.62
(m, 4 H), 6.37 (d, J = 5.5 Hz, 1 H), 6.35 (s, 1 H), 5.98 (s, 1 H), 5.96 (s, 1
H), 5.92 (s, 1 H), 5.88 (s, 1 H), 5.77 (s, 1 H), 5.59 (d, J = 1.5 Hz, 1 H), 5.53
(s, 1 H), 5.15–4.22 (m, 40 H), 3.94 (d, J = 7.0 Hz, 1 H), 2.89–2.80 (m, 2
H), 1.74 (s, 3 H), 1.34 (d, J = 7.0 Hz, 1 H), 1.30 (s, 3 H), 1.04 (d, J = 7.0
Hz, 1 H).
13C NMR (CDCl3): δ (major isomer) = 169.1, 168.7, 157.9, 156.6, 156.4,
156.2, 156.0, 155.8, 155.6, 155.5, 155.2, 154.5, 152.9, 152.8, 149.2,
148.9, 148.8, 148.3, 147.9, 147.6, 138.6, 137.9, 137.5–137.0, 133.0,
132.5, 131.3, 128.9–125.8, 119.6, 118.7, 114.9, 114.6, 114.5, 113.5,
113.1, 110.4, 110.2, 109.6, 106.4, 104.5, 104.4, 100.4, 93.6, 93.3, 91.6,
91.0, 90.3, 77.9, 76.0, 75.5, 75.0, 74.7, 73.5, 72.4, 71.7, 71.3–71.1, 70.9,
70.7, 70.4, 70.3, 70.0, 69.8–69.5, 69.1, 68.8, 68.3, 64.8, 34.8, 34.6, 28.5,
20.9, 20.3, 20.2.
22
philized to give 1 (15 mg, quant.) as a fluffy amorphous solid; [α]D
+98 (c 0.10, MeOH) {Lit.3 [α] +102.9 (c 0.11, MeOH)}.
IR (film): 3291, 1608, 1521, 1437, 1109, 682 cm–1
.
1H NMR (CD3OD): δ = 7.14 (s, 1 H), 7.09 (d, J = 1.5 Hz, 1 H), 7.04 (s, 1
H), 6.93 (m, 2 H), 6.85–6.65 (m, 7 H), 6.05 (d, J = 2.2 Hz, 1 H), 6.00 (d,
J = 2.2 Hz, 1 H), 5.94 (m, 3 H), 5.31–5.20 (m, 2 H), 5.08 (br s, 1 H), 5.00
(s, 1 H), 4.78 (s, 1 H), 4.73 (br s, 2 H), 4.33 (m, 1 H), 4.07 (d, J = 1.5 Hz,
1 H), 4.00–4.10 (m, 2 H), 2.95 (dd, J = 17.0, 2.5 Hz, 1 H), 2.82 (d, J =
17.0 Hz, 1 H).
13C NMR (CD3OD): δ = 158.1, 157.9, 157.8, 157.0, 156.9, 156.7, 156.6,
156.3, 155.0, 154.8, 154.6, 146.0, 145.8, 145.7, 145.6, 145.4, 145.2,
132.6, 132.5, 132.0, 119.1, 118.8, 118.6, 116.0, 115.8, 115.3, 115.0,
114.8, 107.6, 107.3, 107.2, 102.4, 102.2, 101.8, 101.0, 97.7, 97.4, 96.8,
96.3, 95.8, 79.8, 77.1, 76.9, 76.7, 73.5, 72.8, 66.8, 37.5, 37.4, 37.2, 30.0.
HRMS (ESI): m/z [M + Na]+ calcd for C176H150O26Na: 2702.0282; found:
HRMS (ESI): m/z [M – H]– calcd for C60H49O24: 1153.2613; found:
2702.0308.
1153.2578.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

G
M. Ichikawa et al.
Paper
Synthesis
Cinnamtannin A2 Peracetate 8
References
To a solution of 6 (63 mg, 24 μmol) in pyridine (0.6 mL) was added
Ac2O (0.23 mL) and the resulting mixture was stirred for 6 h. When
the reaction was complete, the mixture was diluted with EtOAc (30
mL). The mixture was washed with H2O (30 mL) and sat. aq NaCl (20
mL) and dried (MgSO4). The organic layer was concentrated to give an
oil, which was roughly purified by preparative TLC (hexane/EtOAc/
CH2Cl2 6:1:2) to afford the tetraacetate. A solution of the tetraacetate
(56 mg, 20 μmol) in THF/MeOH/H2O (20:20:1, 8.2 mL) was hydroge-
nated over 20% Pd(OH)2/C (45 mg) for 13 h at r.t. The mixture was fil-
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combined filtrates were evaporated, and the residue was taken up in
distilled water (5.0 mL). The solution was filtered and dried in vacuo
to give the crude material. This crude material was used in the next
step without further purification. A mixture of pyridine (0.4 mL) and
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in a closed flask at r.t. for 6 h, and then CH2Cl2 (1 mL) and MeOH (1
mL) were added. The mixture was stirred for a further 60 min at r.t.,
and then it was diluted with EtOAc (20 mL). The mixture was washed
with water (10 mL) and sat. aq NaCl (20 mL) and dried (MgSO4). The
crude product was purified by preparative TLC (hexane/EtOAc 1:4) to
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19
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IR (film): 2935, 2935, 1771, 1652, 1603, 1558, 1541, 1507, 1419,
1371, 1260, 1203, 1110, 1043, 1015, 901, 840 cm–1
.
1H NMR (CDCl3): δ = 7.37–6.91 (m, 12 H), 6.89 (s, 0.5 H), 6.77 (d, J =
1.5 Hz, 0.5 H), 6.75 (s, 0.5 H), 6.71 (s, 0.5 H), 6.64 (s, 1 H), 6.62 (s, 0.5
H), 6.58 (d, J = 1.5 Hz, 0.5 H), 6.25 (d, J = 2.0 Hz, 0.5 H), 5.88 (d, J = 2.0
Hz, 0.5 H), 5.74 (s, 0.5 H), 5.50–5.46 (br m, 1 H), 5.45 (s, 1 H), 5.36 (s, 1
H), 5.34 (s, 0.5 H), 5.31 (s, 0.5 H), 5.29 (s, 1 H), 5.20–5.18 (br s, 1 H),
5.15 (s, 0.5 H), 4.95 (s, 0.5 H), 4.84 (s, 0.5 H), 4.80 (s, 0.5 H), 4.78 (s, 0.5
H), 4.66 (s, 0.5 H), 4.61 (s, 0.5 H), 4.56 (s, 0.5 H), 4.51 (d, J = 2.0 Hz, 0.5
H), 3.10–3.05 (m, 1 H), 2.97 (dd, J = 18.8, 9.3 Hz, 1 H), 2.38 (s, 1.5 H),
2.29–2.17 (m, 30 H), 2.05 (s, 1.5 H), 2.02–1.79 (m, 15 H), 1.64 (s, 1.5
H), 1.63 (s, 1.5 H), 1.53 (s, 1.5 H), 1.46–1.41 (m, 4.5 H), 1.36 (s, 1.5 H),
1.25 (s, 1.5 H).
13C NMR (CDCl3): δ = 170.1, 169.9–167.6, 155.9, 154.9, 154.0, 151.8,
151.6, 149.9, 149.8, 148.7, 148.5, 147.9, 147.4, 147.3, 147.2, 142.2–
141.7, 136.5, 135.7, 135.5, 135.3, 135.0, 133.0, 128.6, 128.2, 124.9–
121.4, 118.4, 118.1, 117.8, 117.3, 112.5, 112.2, 111.6, 111.3, 110.8,
110.7, 110.6, 110.5, 109.9, 109.3, 108.2, 107.6, 107.3, 77.6, 77.2–76.6,
76.4, 75.3, 75.0, 74.6, 73.8, 71.4, 71.2, 70.9, 70.6, 66.5, 35.7, 35.2, 35.1,
34.2, 32.9, 29.7, 26.3, 21.0–19.3.
Acknowledgement
This work was supported in part by Chinomori Foundation, Shinshu
University (to H.M. and H.F.) and NARO: Integration research for agri-
culture and interdisciplinary fields (to H.M. and H.F.). We also thank
Mr. Hideyuki Karasawa for obtaining ESI-MS data.
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12002. (e) Saito, A.; Doi, Y.; Tanaka, A.; Matsuura, N.; Ubukata,
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561390.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

H
M. Ichikawa et al.
Paper
Synthesis
(13) Suda, M.; Fujii, W.; Takanashi, K.; Hattori, Y.; Makabe, H. Synthe-
sis 2014, 46, 3351.
(14) Suda, M.; Takanashi, K.; Katoh, M.; Matsumoto, K.; Kawaguchi,
K.; Kawahara, S.; Fujii, H.; Makabe, H. Nat. Prod. Commun. 2015,
10, 959.
(15) Cinnamtannin A2: HPLC (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 280 nm): tR = 25.10 min.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H