Synthetic studies of proanthocyanidins. Highly stereoselective synthesis of the catechin dimer, procyanidin-B3.

Article abstract of DOI:10.1271/bbb.66.1764

A stereoselective synthesis of benzylated procyanidin-B3, a condensed catechin dimer, is described. Condensation of 5,7,3',4'-tetrabenzylcatechin with (2R,3S,4S)-5,7,3',4'-tetrabenzyloxy-3-acetoxy-4-methoxyflavan as an electrophile in the presence of TiCl4 led to octabenzylated procyanidin-B3 stereoselectively.

Full text of DOI:10.1271/bbb.66.1764

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Synthetic Studies of Proanthocyanidins. Highly
Stereoselective Synthesis of the Catechin Dimer,
Procyanidin-B3
Akiko SAITOa, Noriyuki NAKAJIMAb, Akira TANAKAc & Makoto UBUKATAb
a Japan Science and Technology Corporation; Domestic Research Fellow
b Biotechnology Research Center, Toyama Prefectural University
c College of Technology, Toyama Prefectural University Kosugi Toyama 939-0398, Japan
Published online: 22 May 2014.
To cite this article: Akiko SAITO, Noriyuki NAKAJIMA, Akira TANAKA & Makoto UBUKATA (2002) Synthetic Studies of
Proanthocyanidins. Highly Stereoselective Synthesis of the Catechin Dimer, Procyanidin-B3, Bioscience, Biotechnology, and
Biochemistry, 66:8, 1764-1767, DOI: 10.1271/bbb.66.1764
To link to this article: http://dx.doi.org/10.1271/bbb.66.1764
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Biosci. Biotechnol. Biochem., 66 (8), 1764–1767, 2002
Note
Synthetic Studies of Proanthocyanidins. Highly Stereoselective Synthesis
of the Catechin Dimer, Procyanidin-B3
2,
†
Akiko SAITO,1 Noriyuki NAKAJIMA,2 Akira TANAKA,3 and Makoto UBUKATA
1Japan Science and Technology Corporation; Domestic Research Fellow
2Biotechnology Research Center, Toyama Prefectural University
3College of Technology, Toyama Prefectural University Kosugi, Toyama 939-0398, Japan
Received January 24, 2002; Accepted April 16, 2002
A stereoselective synthesis of benzylated procyanidin-
B3, a condensed catechin dimer, is described. Conden-
Synthetic studies of („)-procyanidin-B3, based on
the condensation reaction between two substituted
sation of 5,7,3
?
,4
?
-tetrabenzylcatechin with (2
R
,3
S
,4
S
)-
catechin units, have been reported by Roux et al.,5)
6)
Kawamoto et al
.
and Vercauteren et al.,7) but the
5,7,3 ,4 -tetrabenzyloxy-3-acetoxy-4-methoxy‰avan as
?
?
an electrophile in the presence of TiCl4 led to octaben-
zylated procyanidin-B3 stereoselectively.
stereoselectivity of the condensation has scarcely
been described.
Tetrabenzylated catechin 3, a nucleophilic unit,
was prepared by the Kawamoto procedure,6) and 4-
methoxy derivative 4 was obtained by oxidizing at the
Key words: polyphenol; proanthocyanidin; stereo-
selective synthesis; condensed tannins
C-4 atom with DDQ in the presence of 10
z
MeOH
The ‰avonoids are a very large and important
group of polyphenolic natural products which are
united by their derivation from the aromatic hetero-
cycle, ‰avone.1) Flavonoids occur widely in the
many plants that make up the human diet, and it has
been estimated that at least one gram of ‰avonoid is
ingested daily. Many biological activities have been
reported for ‰avonoids and their investigation is now
increasingly important. The proanthocyanidins are
oligomeric ‰avonoids, in which ‰avan-3-ol units are
linked together by carbon-carbon bonds from the 8-
position of one unit to the 4-position of the next unit.
Proanthocyanidins are also known as condensed
tannins and have the ability to bind with protein,
powerful free-radical-scavenging activity2) and an
anti-tumor-promoting eŠect.3) Proanthocyanidins
have been obtained from many kinds of plants, but
because they are usually obtained as a complex
mixture of structurally related compounds, it is very
di‹cult to isolate them. Consequently, we planned to
develop e‹cient synthetic methods leading to proc-
yanidins with a high level of purity and stereoselectiv-
ity. We describe in this paper a highly stereoselective
synthesis of benzylated („)-procyanidin-B3,4) (+)-
in CH2Cl2.8) Acetylation9) and benzoylation of 4 gave
acetate 5 and benzoate 6, respectively. Treatment of
3 with 2 eq. DDQ in the presence of 5
z
AcOH in
CH2Cl2 yielded acetate 7. Hydrolysis of 7 aŠorded
‰avan-3, 4-diol 8 in a quantitative yield (Scheme 1).
Condensation of these electrophiles and com-
pound 3 under various conditions was examined
(Table 1). Authentic samples of procyanidin-B3 1
and its diastereomer were respectively prepared by
the Kawamoto method6) (entry 1, 4
a
:4
b
＝
1.5:1) and
2.0:1). Puriˆ-
cation by silica gel PTLC led to pure benzylated
procyanidin-B3 (4 )-2 as the main product and di-
astereomer (4 )-2 as a minor product. This selectivi-
Vercauteren method7) (entry 2, 4
a:4b
＝
a
?
b
ty resulted from the nucleophilic attack of 3 on the
resulting carbocation from the less-hindered lower
side.10) In entries 3–8, the selectivity of the coupling
1
reaction was determined by a H-NMR analysis of
the 3,3?-diacetylated sample. As shown in Table 1,
catechin-(4aª8)-(+)-catechin dimer 2 (Fig. 1), by
the condensation reaction of tetrabenzylcatechin 3
with the various substituted ‰avan-3,4-diol deriva-
tives, 4, 5 and 6, and ‰avan-3,4-diol 8 by using TiCl4
in CH2Cl2. We also discuss the eŠect of the C-3 sub-
stituents of elecrophiles and solvents on the stereo-
selectivity.
Fig. 1. Structure of Procyanidin-B3.
pu-toyama.ac.jp
†
To whom correspondence should be addressed. Tel: +81-766-56-7500; Fax: +81-766-56-2498; E-mail: ubukata
＠

Synthetic Studies of Proanthocyanidins
1765
Scheme 1. Synthesis of the Electrophiles.
Table 1. Stereoselective Condensation of the Electrophiles and Compound 3
Electrophile
TiCl4
Temp.
Couplinga
Selectivityb
2 (4 ):2 (4b)
Entry
Solvent
equiv.
(
9
C)
yield (
z
)
a
?
No.
R1
R2
1
2
3
4
5
6
7
8
9
8
4
5
5
5
5
5
5
6
H
H
H
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
1
1
1
1
1
2
1
1
1
0
0
0
80
74
81
83
1.5:1e
2.0:1e
7.4:1
23:1
55:1
9.1:1
Me
Me
Me
Me
Me
Me
Me
Me
Ac
Ac
Ac
Ac
Ac
Ac
Bz
－
20
„40
„40
35c
64
0d
0
0
0
0
—
CH2Cl2
70
20:1f
a
Isolated yield of the dimeric mixture.
b
The selectivity of entries 3–8 was determined by 1H-NMR of the acetylated dimeric mixture. The selectivity of entry 9 was determined by 1H-NMR of the ben-
zoylated dimeric mixture.
c
d
e
f
10
z of the starting material was recovered.
The 4-methoxy group of 5 was deprotected, and no dimerized product was detected.
R1
R1
＝
＝
H.
Bz.
the best result for selectivity was obtained when
electrophile 5 in CH2Cl2 was reacted at „40 C (entry
55:1). Under these conditions, however,
the isolated yield of the dimerization product was
very low and part of 5 suŠered from demethylation.
The best conditions were those for entry 4 that result-
KOH, NaOMe or KCN did not proceed at all.
The 3- -acetyl group of the diastereomerically en-
riched sample obtained in entry 4 was hydrolyzed
with 5 eq. KCN in 95 f value for ben-
EtOH11) (the
zylated B3 2 was 0.27, and for diastereomer 2 was
9
O
＝
5, 4a:4b
z
R
?
0.11 in 1.6
z EtOAc in CH2Cl2), and again no
ed in an 83
z
isolated yield and good selectivity
epimerized product12) could be detected. The eight
remaining benzyl protecting groups were submitted
＝
(4a:4b
23:1). On the other hand, condensation in
7)
toluene (entry 7) also gave the demethylated com-
pound of 5, and no dimerizated product could be de-
tected. In entry 8, for which THF was used as the sol-
vent, starting material 5 was recovered. Condensa-
tion of benzoylated electrophile 6 with 3 (entry 9)
resulted in very good selectivity, but subsequent
deprotection of the benzoyl group with NaOH,
to hydrogenolysis with Pd(OH)2 and puriˆed by
Sephadex} LH-20 and normal-phase HPLC puriˆca-
tion (Kanto Chemical Co., Mightysil Si 60, EtOAc)
24
＝
to give procyanidin-B3 1 in a pure form, [
a
]
D
20
＝
„221.2 (
EtOH)
In conclusion, we synthesized procyanidin-B3 1 in
c
0.38, EtOH)
s
lit.4 [
a
]
„244.7 (c 2.0,
578
t.

1766
A. SAITO et al.
a diastereomerically pure form without any tedious
puriˆcation procedure. Neighboring group participa-
TiCl4 (0.13 ml of a 1.0
M
solution in CH2Cl2) at
C, the
„20 C. After stirring for 5 min at „20
9
9
tion of the 3-
O
-acetyl group was very eŠective for
reaction mixture was quenched with sat. sodium
hydrogen carbonate (3 ml). The aq. solution was ex-
tracted with ethyl acetate, and the organic phase was
successively washed with water and brine, and dried
(Na2SO4). Filtration, concentration and silica gel
stereoselective condensation. Further investigations
to extend this method to the synthesis of procyanidin
oligomers involving the trimer, tetramer and more
condensed forms are underway.
＝
column chromatography (hexane:ethyl acetate
6:1–1.5:1) aŠorded 3- -acetyl-octa- -benzylated
; 23:1
O
O
Experimental
procyanidin-B3 2 (145 mg, 0.11 mmol, 83
z
Optical rotation was measured with a Horiba
SEPA-300 spectrometer. 1H-NMR spectra were
measured with Jeol JNM-LA400 spectrometer, and
mass spectra were recorded with a Jeol JMS-AX500
instrument.
selectivity). Reprecipitation of this sample from hex-
ane-ethyl acetate gave 3-acetylated 2 as a white pow-
der. MS (+) FAB (NBA) (m z): 1365(7), 1364(9)
W
[M+Na]+, 1344(6), 1343(10) [M+H]+, 1342(11).
Acetylation with Ac2O in pyridine to determine the
selectivity of the condensation reaction aŠorded a
diacetyl derivative. Characteristic peaks from 1H-
General DDQ oxidation procedure. To a solution
of 3 in CH2Cl2 was slowly added DDQ (2 eq.) at 0
9
C.
and 13C-NMR: (4
a
)-3,3
derivative (a 1:1 mixture of the rotational isomer);
1H-NMR (400 MHz, CDCl3)
: 5.76–5.86 (2H, m,
?-di-O-acetyl-procyanidin-B3
After stirring for 2–4 hours at r.t., an excess of
DMAP (4 eq.) was added, and the mixture stirred for
10 min. The resulting solid was removed by ˆltration,
and the ˆltrate was successively washed with water
and brine, and dried (Na2SO4). Filtration, concentra-
tion and short silica gel column chromatography
(CHCl3) gave an oxidized product.
d
3-H), 1.83 (1.5 H, s, Ac), 1.74 (1.5 H, s, Ac), 1.57
(1.5H, s, Ac), 1.53 (1.5H, s, Ac); 13C-NMR
(100 MHz, CDCl3)
bonyl carbon). (4
derivative (a 1:0.5 mixture of the rotational isomer);
1H-NMR (400 MHz, CDCl3)
: 5.49–5.59 (2H, m,
d
: 170.2, 169.6, 169.1, 168.9 (car-
b
)-3 3 -di- -acetyl-procyanidin-B3
?
O
d
(2R,3
methoxy‰avan (5). To a solution of (2
5,7,3 ,4 -tetrabenzyloxy-4-methoxy‰avan-3-ol
S
,4
S
)-5,7,3
?
,4
?
-Tetrabenzyloxy-3-acetoxy-4-
3H), 1.90 (1 H, s, Ac), 1.73 (2 H, s, Ac), 1.66 (1 H, s,
R
,3
S
,4
S
)-
Ac), 1.57 (2 H, s, Ac); 13C-NMR (100 MHz, CDCl3)
?
?
4
d: 169.9, 169.8 (carbonyl carbon).
(150 mg, 0.22 mmol) in pyridine (10 ml) were added
9
Ac2O (0.041 ml, 0.44 mmol) and cat. DMAP at 0 C.
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After stirring for 1 h at r.t., the reaction mixture was
quenched with water. The organic phase was washed
with brine, and dried (Na2SO4). Filtration, concen-
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Synthetic Studies of Proanthocyanidins
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