Stereoselection of 3,4-cis and 3,4-trans catechin and catechin condensation under intramolecular coupling method

Article abstract of DOI:10.1055/s-2004-830848

A high level of stereoselection between 3,4-cis and 3,4-trans catechin-catechin condensation under intramolecular coupling method has been realized by changing the diester linker between the nucleophile and the electrophile. The azelaic acid linker gave exclusively 3,4-trans catechin-catechin dimer, whereas glutaric acid linker gave 3,4-cis catechin-catechin dimer as the sole product.

Full text of DOI:10.1055/s-2004-830848

2040
LETTER
Stereoselection of 3,4-cis and 3,4-trans Catechin and Catechin Condensation
under Intramolecular Coupling Method1
Stereoselection of
k
3,4-cis and
3
i
,4-tran
k
s
Catechinan
o
d
Catechin
C
onden
S
sation aito,*a Akira Tanaka,b Makoto Ubukata,c Noriyuki Nakajima*d
a
b
c
d
Biotechnology Center, Toyama Prefecture, Kosugi, Toyama 939-0398, Japan
Department of Bioresources Science, College of Technology, Toyama Prefectural University, Kosugi, Toyama 939-0398, Japan
Graduate School of Agriculture, Hokkaido University, Kita-9, Nishi-9, Kita-ku, Sapporo 060-8589, Japan
Biotechnology Center, Toyama Prefectural University, Kosugi, Toyama 939-0398, Japan
Fax +81(766)567500; E-mail: nori@pu-toyama.ac.jp
Received 23 April 2004
Therefore, we developed an intramolecular condensation
method in which just equimolar amount of the nucleophile
and the electrophile is used to improve that point. As re-
sults of intramolecular reaction using succinic acid (n = 2)
Abstract: A high level of stereoselection between 3,4-cis and
3,4-trans catechin–catechin condensation under intramolecular
coupling method has been realized by changing the diester linker
between the nucleophile and the electrophile. The azelaic acid
linker gave exclusively 3,4-trans catechin–catechin dimer, whereas and glutalic acid (n = 3) as a linker, only the case of cat-
glutaric acid linker gave 3,4-cis catechin–catechin dimer as the sole
echin and catechin condensation gave 3,4-cis dimer 2
(Figure 1),8,9 although 3,4-trans oligomers are major iso-
product.
mers in nature.10,11 In this paper, we challenge to find the
Key word: polyphenol, oligomeric flavonoid, catechin dimmer, B-
type procyanidin, diester linker
conditions to synthesize 3,4-trans-(+)-catechin dimer 1
under intramolecular condensation conditions by chang-
ing the diester linker.
Proanthocyanidins are known as condensed tannins and/
Nucleophile-carboxylic acid units 6–12 (n = 2–8), were
derived from (+)-catechin and succinic and glutaric anhy-
or oligomeric flavonoids,2,3 and has now great attention
because of their various strong bioactivities.4 A large
dride or the corresponding dicarboxylic acid (adipic acid,
amount of pure oligomeric proanthocyanidins has been
pimelic acid, suberic acid, azelaic acid and sebacic acid).
required for the biological assay; however, efficient meth-
Following condensation with electrophile unit 55 by the
DCC method afforded diester compounds 13–19 (n = 2–
8) in 98%, 76%, 69%, 41%, 19%, 40% and 51% yields, re-
ods for the stereoselective synthesis of long oligomeric
proanthocyanidin have not been reported yet. So we have
embarked on research attempting to develop a simple and
spectively (Scheme 1). TMSOTf-catalyzed intramolecu-
efficient method to synthesize pure proanthocyanidin oli-
lar condensations were examined at –20 °C for 5 minutes.
gomers. Using TMSOTf as the catalyst, the stereoselec-
These results are summarized in Table 1 and Figure 2.
tive condensation reaction proceeded smoothly to afford
The cyclic catechin dimers 20–26 (n = 2–8) were obtained
in 35% (n = 2), 98% (n = 3), 23% (n = 4), 14% (n = 5),
3,4-trans dimers and trimers in excellent yields.5–7 Disad-
vantages of this intermolecular condensation method are
49% (n = 6), 42% and 41% (n = 7 and 8) yields, respec-
that the condensation reaction requires excess amount of
tively. It is thought that the linker length is very important
nucleophile (4.5 equiv) to avoid higher oligomer forma-
for cis/trans selection and reaction yields. Only when the
linker length matched with neighboring group participa-
tion. This makes it difficult to supply nucleophiles.
tion effect, the sole product was obtained in good yield.
OR
OR
OR
OR
Short linkers (n = 2–4) dominantly formed 3,4-cis prod-
ucts. As linker lengthened, the proportion of 3,4-trans
products tended to increase and the selectivity came closer
to the no linker (intermolecular) condensation.5 Particular
results are as follows; glutalic acid linker (n = 3) gave
only 3,4-cis-catechin dimer 248 in 98% yield and azelaic
acid linker (n = 7) gave the 3,4-trans-catechin dimer 2512
in 42% yield as the sole product. In contrast, adoption of
the other linkers gave the dimers in moderate yields as
cis:trans mixtures, 23 (n = 4) with 7:1 (14%), 24 (n = 5)
with 1:3 (49%), 25 (n = 6) with 1:8 (42%) and 26 (n = 8)
with 1:2 ratios (41%), respectively, in which so many by-
products were observed. As the temperature is lowered,
cis:trans ratio changed from 1:2 up to 1:5 in the case of 26.
However, the yields of dimeric products were dramati-
cally dropped to less than 5%.
B
8
RO
O
C
RO
O
4
A
6
OH
OH
O
3
OR
OR
OR
OR
OR
OR
E
RO
O
F
RO
D
OH
OH
OR
OR
2: 3,4-cis (+)-catechin-
(4ß-8)-(+)-catechin
4: R = H
1: 3,4-trans (+)-catechin-
(4α-8)-(+)-catechin
3: R = H
Figure 1 Structure of procyanidin dimers
SYNLETT 2004, No. 11, pp 2040–2042
Advanced online publication: 28.07.2004
DOI: 10.1055/s-2004-830848; Art ID: U12204ST
© Georg Thieme Verlag Stuttgart · New York
0
6
.0
9
.2
0
0
4

LETTER
Stereoselection of 3,4-cis and 3,4-trans Catechin and Catechin Condensation
2041
OBn
OBn
OBn
BnO
O
BnO
O
OBn
O
OH
O
OBn OEE
5
OBn
O
(CH2)n
6–12
OH
DCC, DMAP, CH2Cl2
OBn
OBn
BnO
O
3
4
OBn
OBn
O
O
Figure 2 Stereoselectivity of intramolecular condensation
BnO
BnO
EEO
O
(CH2)n
O
8'
13–19
O
was observed in the reaction mixture. After several
attempts, desired dimer 29 was finally obtained by use of
1,2-phenylenediacetic acid linker at 0 °C in 8% yield.
Used linkers were easily removed by DIBAL treatment at
–78 °C to room temperature or 2 step sequences; K2CO3–
MeOH and DIBAL treatment. The 3,3¢-diols (3 and 4)
were isolated in 44% (for 20), 77% (for 21), 100% (for 22
and 23), 54% (for 24), 67% (for 25), and 71% yield (for
26), respectively.
OBn
TMSOTf, CH2Cl2, –20 °C
OBn
BnO
O
OBn
OBn
3
4
O
O
BnO
BnO
O
8'
OBn
(CH2)n
OBn
O
O
20–26
OBn
2
BnO
O
OBn
Scheme 1
Table 1 Condensation of Nucleophile Unit with Electrophile Unit
O
O
3
OBn
OBn
BnO
BnO
O
8'
n
Carboxylic Diester
acid
Yield
(%)
Cyclic
diester
Yield
(%)
O
3' O
OBn
OBn
OBn
27: 84 %
2
3
4
5
6
7
8
6
7
13
14
15
16
17
18
19
98
76
69
41
19
40
51
20
21
22
23
24
25
26
35
98
23
14
49
42
41
OBn
OBn
2
BnO
O
8'
BnO
OBn
OBn
O
4
8
O
O
3
O
O
OBn
OBn
BnO
BnO
BnO
BnO
9
O
O
10
11
12
8
O
O
O
O
3'
OBn
OBn
28: 43 %
29: 8 %
Figure 3 Results of intramolecular condensation
Intramolecular condensation combined with epicatechin
series was also attempted using glutaric linker in the
presence of TMSOTf at –20 °C and 0 °C (Figure 3). From
the catechin electrophile, 3,4-trans-octa-O-benzylated
(+)-catechin-(4 a→8)-(–)-epicatechin dimer (27) was
obtained in 40% at –20 °C and in 84% yield at 0 °C. The
epicatechin electrophile was less reactive than catechin
electrophile and 3,4-trans-octa-O-benzylated (–)-epicat-
echin-(4 b→8)-(+)-catechin dimer (28) was obtained only
in 41% at –20 °C and in 43% yield at 0 °C. Interestingly,
(–)-epicatechin and (–)-epicatechin cyclization provided
only a messy product. No detectable amount of dimer 29
To our knowledge, this is the first example of simple
stereoselection in proanthocyanidin synthesis, in which
only the linker length was changed between an electro-
phile and a nucleophile. Further investigations are in
progress to the synthesis of longer oligomer, and applica-
tion to other combinations of catechin and epicatechin.
Acknowledgment
We gratefully acknowledge the Japan Society for the Promotion
of Science (JSPS) for the Young Scientists Research Fellowship
(to A. S.).
Synlett 2004, No. 11, 2040–2042 © Thieme Stuttgart · New York

2042
A. Saito et al.
LETTER
with CHCl3 and the combined organic phase were washed
with H2O and brine, and dried (Na2SO4). Filtration,
References
(1) This report is Part 7 in the series ‘Synthetic studies of
proanthocyanidins’. For part 6 see ref.7
(2) Harborne, J. B. The Flavonoids: Advances in research from
1986; Chapman and Hall: London, 1993.
(3) Harborne, F. R. S. J. B.; Baxter, H. The Handbook of Natural
Flavonoids; John Wiley and Sons: New York, 1999.
(4) There are many reports describing the biological activities of
proanthocyanidins. A recent noteworthy report is:
Kozikowski, A. P.; Tuckmantel, W.; Böttcher, G.;
Romanczyk, L. J. Jr. J. Org. Chem. 2003, 68, 1641.
(5) Saito, A.; Nakajima, N.; Tanaka, A.; Ubukata, M.
Tetrahedron 2002, 58, 7829.
(6) Saito, A.; Nakajima, N.; Matsuura, N.; Tanaka, A.; Ubukata,
M. Heterocycles 2004, 62, 479.
(7) Saito, A.; Tanaka, A.; Ubukata, M.; Nakajima, N. Synlett
2004, 1069.
(8) Saito, A.; Nakajima, N.; Tanaka, A.; Ubukata, M.
Tetrahedron Lett. 2003, 44, 5449.
(9) Saito, A.; Nakajima, N.; Tanaka, A.; Ubukata, M.
Heterocycles 2003, 61, 287.
(10) Kolodziej, H. Phytochemistry 1985, 24, 2460.
(11) Schleep, S.; Friedrich, H.; Kolodziej, H. J. Chem. Soc.,
Chem. Commun. 1986, 392.
(12) Data for 23: To a solution of (2R,3S,4S)-5,7,3¢,4¢-tetra-
benzyloxy-4-ethoxyethyloxy-flavan-3-yl (2R,3S)-5,7,3¢,4¢-
tetrabenzyloxy-flavan-3-yl azelate (44 mg, 0.028 mmol) in
CH2Cl2 (20 mL) was added dropwise TMSOTf (0.056 mL,
0.028 mmol, 0.5 M solution in CH2Cl2) at –20 °C. After
stirring for 5 min, the pale yellow reaction mixture was
quenched with sat. NaHCO3. The aq solution was extracted
concentration and preparative silica gel TLC purification
(hexane–EtOAc, 2:1) afforded 17 mg (0.012 mmol, 42%) of
cyclic compound 23 as a single product. [a]D25 –93.1 (c 0.34,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 7.40–7.18 (35 H,
m), 7.06–6.93 (5 H, m), 6.84–6.76 (3 H, m), 6.56 (1 H, d,
J = 2.2 Hz), 6.37 (1 H, d, J = 8.3 Hz), 6.10 (1 H, d, J = 2.1
Hz), 6.01 (1 H, dd, J = 9.6, 10.0 Hz), 6.00 (1 H, d, J = 2.1
Hz), 5.89 (1 H, s), 5.87 (1 H, dd, J = 2.2, 8.3 Hz), 5.36 (1 H,
br s), 5.25–5.22 (1 H, m), 5.08–4.81 (8 H, m), 5.05 (1 H, d,
J = 9.6 Hz), 4.86 (1 H, d, J = 11.9 Hz), 4.77 (1 H, d, J = 11.9
Hz), 4.75 (1 H, d, J = 11.4 Hz), 4.73 (1 H, d, J = 12.0 Hz),
4.68 (1 H, d, J = 10.0 Hz), 4.64 (1 H, d, J = 11.4 Hz), 4.61 (1
H, d, J = 11.7 Hz), 4.56 (1 H, d, J = 12.0 Hz), 4.46 (1 H, d,
J = 11.7 Hz), 2.99–2.93 (1 H, m), 2.32–2.22 (1 H, m), 2.03
(1 H, dd, J = 2.4, 16.6 Hz), 1.97–1.90 (1 H, m), 1.84–1.74 (2
H, m), 1.25–0.80 (10 H, m). 13C NMR (100 MHz, CDCl3):
d = 174.3, 171.4, 158.4, 157.5, 157.4, 155.7, 151.7, 148.9,
148.6, 148.51, 148.48, 138.0, 137.5, 137.31, 137.25, 137.21,
137.17, 136.9, 132.1, 130.8, 128.5-126.9 (C × 27), 121.0,
118.9, 117.1, 114.8, 114.6, 114.4, 112.0, 109.8, 108.2,
100.9, 94.8, 94.5, 90.4, 80.7, 71.6, 71.4, 71.11, 71.05, 70.2,
70.1, 70.0, 69.9, 69.0, 35.4, 34.4, 32.9, 29.7, 26.3, 24.9, 24.0,
23.0, 19.0. IR (neat): 3065 (w), 3032 (w), 2930 (m), 2862
(w), 2361 (w), 1732 (s), 1606 (s), 1512 (s), 1454 (s), 1379
(m), 1263 (m), 1213 (m), 1124 (s), 1026 (m), 910 (w), 851
(w), 812 (w), 737 (s), 696 (s) cm-1. FAB-MS: m/z = 1450.6
(81), 1451.6 (100) [M + H]+, 1452.6 (79), 1453.6 (43). FAB-
HRMS: m/z calcd for C95H87O14 [M + H]+: 1451.6096.
Found: 1451.6136.
Synlett 2004, No. 11, 2040–2042 © Thieme Stuttgart · New York