Efficient stereoselective synthesis of proanthocyanidin trimers with TMSOTf-catalyzed intermolecular condensation

Article abstract of DOI:10.1055/s-2004-822905

A stereoselective synthesis of seven benzylated proanthocyanidin trimers with TMSOTf-catalyzed condensation reaction is described. In particular, epicatechin-(4β-8)-epicatechin-(4β-8)-epicatechin trimer (procyanidin C1), catechin-(4α-8)-catechin-(4α-8)-catechin trimer (procyanidin C2), epicatechin-(4β-8)-epicatechin-(4?-8)-catechin trimer and epicatechin-(4?-8)-catechin-(4α-8)-epicatechin trimer derivatives were obtained in excellent yields. The structure of benzylated procyanidin C2 was confirmed by comparing the ¹H NMR spectra of protected procyanidin C2 that was synthesized by two different condensation approaches. Finally, deprotection of (+)-catechin and (-)-epicatechin trimers derivatives gave four natural procyanidin trimers in good yields.

Full text of DOI:10.1055/s-2004-822905

LETTER
1069
Efficient Stereoselective Synthesis of Proanthocyanidin Trimers with
TMSOTf-Catalyzed Intermolecular Condensation1
Efficient
S
tereosel
k
ective Synthe
i
sis of
k
Proanthocyan
o
idin Trimers Saito,*a Akira Tanaka,b Makoto Ubukata,c Noriyuki Nakajima*d
a
b
c
d
Biotechnology Center, Toyama Prefecture, Japan
Department of Bioresources Science, College of Technology, Toyama Prefectural University, Japan
Graduate School of Agriculture, Hokkaido University, Japan
Biotechnology Center, Toyama Prefectural University, Kosugi, Toyama 939-0398, Japan
Fax +81(766)562498; E-mail: nori@pu-toyama.ac.jp
Received 29 January 2004
(Figure 1),11 but efficient methods for the stereoselective
synthesis of trimers have not been reported yet.
Abstract: A stereoselective synthesis of seven benzylated proan-
thocyanidin trimers with TMSOTf-catalyzed condensation reaction
is described. In particular, epicatechin-(4b-8)-epicatechin-(4b-8)-
epicatechin trimer (procyanidin C1), catechin-(4a-8)-catechin-(4a-
8)-catechin trimer (procyanidin C2), epicatechin-(4b-8)-epicat-
echin-(4b-8)-catechin trimer and epicatechin-(4b-8)-catechin-(4a-
8)-epicatechin trimer derivatives were obtained in excellent yields.
The structure of benzylated procyanidin C2 was confirmed by com-
So we applied the TMSOTf-catalyzed condensation to the
synthesis of procyanidin trimers. In our dimer synthesis,12
the diastereoselectivity of catechin-catechin condensation
is the lowest. Therefore, we tried first the condensation re-
action of a dimeric catechin-catechin electrophile with a
monomeric catechin nucleophile (Figure 2, Scheme 1).
Dimer electrophile 9, derived from octa-benzylated pro-
cyanidin B3 (15b) by DDQ oxidation in the presence of
ethoxyethanol (EEOH) and then acetylation (2 steps, 20–
50%), was reacted with monomer nucleophile (10) in the
presence of TMSOTf at –78 °C to give trimer 7d selec-
tively but only in 42% yield.13 So, we next examined re-
verse monomeric electrophiles (11 and 12), derived from
(–)-epicatechin in 64% yield and (+)-catechin in quantita-
tive yield, with dimeric nucleophiles (13b–16b) conden-
sation under same conditions.
1
paring the H NMR spectra of protected procyanidin C2 that was
synthesized by two different condensation approaches. Finally,
deprotection of (+)-catechin and (–)-epicatechin trimers derivatives
gave four natural procyanidin trimers in good yields.
Key words: polyphenol, condensed tannin, oligomeric flavonoid,
catechin trimer, C-type procyanidin
Proanthocyanidins are known as condensed tannins and/
or oligomeric flavonoids.2,3 We describe here a stereose-
lective intermolecular condensation of benzylated procy-
anidin dimers with monomeric electrophiles leading to the
trimers, epicatechin-(4b-8)-epicatechin-(4b-8)-catechin
trimer (1a), epicatechin-(4b-8)-epicatechin-(4b-8)-epi-
catechin trimer (2a) epicatechin-(4b-8)-catechin-(4a-8)-
epicatechin trimer (4a), and catechin-(4a-8)-catechin-
(4a-8)-catechin trimer (7a) in excellent yields. The struc-
ture of benzyl protected procyanidin C2 (7a) was con-
firmed by comparing with the synthesized catechin trimer
by another approach in which a dimeric electrophile was
condensed with a monomeric nucleophile.
These condensations did work well to give the seven cor-
responding 3,4-trans-trimers except for 8c (Table 1, entry
8). These results were summarized in Table 1. Condensa-
tion of electrophile 12 with nucleophile 15b proceeded
smoothly at –78 °C and afforded 7c in 100% yield (entry
7). The epicatechin electrophile (11) and nucleophile 13b
condensed also at –78 °C to afford 1c in 90% yield (entry
1). Although other combinations of electrophile 11 and
nucleophiles (14b, 15b and 16b) gave corresponding tri-
mers in low yield at –78 °C (2c in 43%, 3c in 16%, 4c in
0%, respectively), the isolation yields were improved by
increasing reaction temperature to give trimers 2c in 91%
at –40 °C, 3c in 62% at –20 °C, and 4c in 90% at –20 °C,
respectively (entries 2, 3 and 4). Condensation of electro-
phile 12 with nucleophile 13b and 14b at –78 °C gave tri-
mers 5c and 6c in 47% and 44% yields, respectively
(entries 5 and 6). By our previous studies,12 increasing of
the reaction temperature expect to give the diastereomer
mixture of trimers at the C-4 position, further studies to
improve these isolation yields are not examined. Interest-
ingly, the condensation reaction of electrophile 12 with
nucleophile 15b reacted smoothly at –78 °C to give 7c in
100% yield.14 However, the condensation reaction of
electrophile 12 with nucleophile 16b did not give the cor-
responding trimer 8c at all, in spite of the rapid disappear-
ance of the starting electrophiles (entry 8). DIBAL
The investigation of proanthocyanidins is now increasing-
ly important because of their various strong bioactivi-
ties.4,5 In addition, absorption of procyanidin dimers into
the rat6 and human7 body has recently reported. We previ-
ously reported stereoselective syntheses of procyanidin
dimers, procyanidin B1–B4 (13a–16a) by the two differ-
ent way of inter-8 and intramolecular9,10 condensation in
the presence of TMSOTf as the catalyst, and we also re-
ported the Maillard reaction inhibitory activities of the
synthesized procyanidin dimers.9 There are many reports
about isolation and semi-synthesis of procyanidin trimers
SYNLETT 2004, No. 6, pp 1069–1073
0
6.
0
5.
2
0
0
4
Advanced online publication: 08.04.2004
DOI: 10.1055/s-2004-822905; Art ID: U02904ST
© Georg Thieme Verlag Stuttgart · New York

1070
A. Saito et al.
LETTER
OR1
OR1
OR1
OR1
R1O
O
R1O
O
OR2
O
OR2
O
OR1
OR1
OR1
OR1
OR1
R1O
OR1
R1O
OR3
OR3
OR1
OR1
OR1
OR1
OR1
OR1
R1O
O
R1O
O
R4
R4
R5
R5
OR1
OR1
3a: R1 = R2 = R3 = R5 =H, R4 = OH
1a: R1 = R2 = R3 = H, R4 = OH, R5 =H
3b: R1 = R2 = R3 = Ac, R4 = OAc, R5 =H
3c: R1 = Bn, R2 = R3 = R5 =H, R4 = OH
4a: R1 = R2 = R3 = R4 =H, R5 =OH
1b: R1 = R2 = R3 = Ac, R4 = OAc, R5 =H
1c: R1 = Bn, R2 = R3 = R5 =H, R4 = OH
2a: R1 = R2 = R3 = R4 =H, R5 =OH
4b: R1 = R2 = R3 =Ac, R4 =H, R5 =OAc
4c: R1 = Bn, R2 = R3 = R4 =H, R5 =OH
2b: R1 = R2 = R3 =Ac, R4 =H, R5 =OAc
2c: R1 =Bn, R2 = R3 =R4 =H, R5 =OH
OR1
OR1
R1O
O
R1O
O
OR1
OR1
OR2
O
OR2
O
OR1
OR1
OR1
OR1
OR1
R1O
OR1
R1O
OR3
OR3
OR1
OR1
OR1
OR1
OR1
OR1
R1O
O
R1O
O
R4
R4
R5
R5
OR1
OR1
7a: R1 = R2 = R3 = R5 =H, R4 = OH
7b: R1 = R2 = R3 = Ac, R4 = OAc, R5 =H
5a: R1 = R2 = R3 = R5 =H, R4 = OH
5b: R1 = R2 = R3 = Ac, R4 = OAc, R5 =H
7c: R1 = Bn, R2 =Ac, R3 = R5 =H, R4 = OH
7d: R1 = Bn, R2 = R3 = Ac, R4 = OH, R5 =H
7e: R1 = Bn, R2 = R3 = R5 =H, R4 = OH
7f: R1 = Bn, R2 = R3 = Ac, R4 =OAc, R5 = H
8a: R1 = R2 = R3 = R4 =H, R5 =OH
5c: R1 = Bn, R2 = Ac, R3 = R5 =H, R4 = OH
6a: R1 = R2 = R3 = R4 =H, R5 =OH
6b: R1 = R2 = R3 =Ac, R4 =H, R5 =OAc
6c: R1 = Bn, R2 = Ac, R3 = R4 =H, R5 =OH
8b: R1 = R2 = R3 =Ac, R4 =H, R5 =OAc
8c: R1 = Bn, R2 = Ac, R3 = R4 =H, R5 =OH
Figure 1 Structure of procyanidin trimers
1
reduction of the acetyl groups of 7c and 7d gave the same analysis16 and the H NMR spectra of its peracetate 7b
1
trimer 7e, and H NMR spectra of 7e and tri-acetate 7f agreed with the reported data.11a,e,17,18 Similarly the spec-
were completely identical (Scheme 2). These results indi- tral data of 1a19 and 4a20 were in agreement with the re-
cated that an electrophile reacted with a nucleophile at C- ported data,11b–d and synthesized procyanidin C1 was
4 position stereoselectively to give 3,4-trans-trimer pref- identical with the commercial sample (Funakoshi CO.,
erentially.
LTD.), and the all spectral data agreed with reported data
by A. P. Kozikowski et al.22
Natural epicatechin-(4b-8)-epicatechin-(4b-8)-catechin
trimer (1a), procyanidin C1 (2a),21 epicatechin-(4b-8)- In conclusion, the TMSOTf-catalyzed intermolecular
catechin-(4a-8)-epicatechin trimer (4a) and procyanidin condensation method was effective for the synthesis of
C2 (7a) were synthesized in good yields from 1c, 2c, 4c 3,4-trans-procyanidin trimers, procyanidin C2 (1a),
and 7c by deprotection as shown in Scheme 2. Synthe- procyanidin C1 (2a), 3a and 4a, although further works
sized procyanidin C2 (7a)15 was identical with the authen- were needed to improve the yields of other trimers.
tic sample kindly provided by Prof. Kolodziej by HPLC Studies on synthesizing other natural trimers and applying
Synlett 2004, No. 6, 1069–1073 © Thieme Stuttgart · New York

LETTER
Efficient Stereoselective Synthesis of Proanthocyanidin Trimers
1071
OBn
OBn
OBn
OBn
BnO
O
BnO
O
OAc
OH
OBn OEE
OBn OEE
12
11
OR1
OR1
OR1
OR1
R1O
O
R1O
O
OR2
OR1
OR1
OR2
OR1
OR1
OR1
R1O
OR1
R1O
O
O
R3
R3
R4
R4
OR1
OR1
13a: R1 =R2 =R4 = H, R3= OH
15a: R1 = R2 = R4 = H, R3 = OH
13b: R1 = Bn, R2 =R4 = H, R3 = OH
14a: R1 =R2 =R3 = H, R4= OH
15b: R1 = Bn, R2 = R4 = H, R3 = OH
16a: R1 = R2 = R3 = H, R4= OH
16b: R1 = Bn, R2 = R3 = H, R4= OH
14b: R1 = Bn, R2 =R3= H, R4 = OH
Figure 2 Structure of monomeric electrophiles and dimeric nucleophiles
Dimer Electrophile
OBn
OBn
BnO
O
BnO
O
OBn
OBn
8
3
4
OAc
OAc
OBn
OBn
OBn
OBn
OBn
BnO
OBn
BnO
O
O
TMSOTf
8'
4'
4'
–78 °C, CH2Cl2
42 %
OAc
OAc
OBn
OBn
OBn
OBn
BnO
OEE
9
O
OBn
+
8''
BnO
O
OBn
OH
8''
OBn
OH
10
OBn
Trimer 7d
Monomer Nucleophile
Scheme 1
the intramolecular condensation approach to the trimer
synthesis are now underway. Further studies for the
bioactivities of the synthesized trimers are under investi-
gation.
b
a
1c
1a
1b
73%
90 %
b
a
2c
4c
7c
2a
4a
7e
2b
4b
7d
48 %
95 %
b
a
Acknowledgment
92 %
c
87 %
c
We gratefully acknowledge Professor Herbert Kolodziej for his
providing authentic sample of procyanidin C2. And we thank the
Japan Society for the Promotion of Science (JSPS) for the Young
Science Research Fellowship (to A. S.).
75 %
81 %
a
92%
b
7a
7b
54 %
Scheme 2 Reagents and conditions: (a) Pd(OH)2, H2, THF–MeOH–
H2O; (b) Ac2O, DMAP, pyridine; c) DIBAL, CH2Cl2.
Synlett 2004, No. 6, 1069–1073 © Thieme Stuttgart · New York

1072
A. Saito et al.
LETTER
Table 1 Condensation of Monomeric Electrophiles and Dimeric Nucleophiles
Monomer Electrophiles
OBn
OBn
OBn
BnO
O
OBn
BnO
O
4
8
OR
O
3
4
OBn
OR
OEE
+
8'
OBn
OBn
OBn
BnO
TMSOTf
CH2Cl2
O
OBn
OBn
8'
4'
BnO
OH
OBn
OBn
OBn
BnO
O
OH
OBn
OBn
8''
OBn
BnO
O
OH
OBn
OH
OBn
Trimers
Dimer Nucleophiles
Entry
Electrophile
Nucleophile
13b
Trimer product
Temp (°C)
–78
Yield (%)
1
2
3
4
5
6
7
8
11
11
11
11
12
12
12
12
1c
2c
3c
4c
5c
6c
7c
8c
90
91
62
90
47
44
100
0
14b
–40
15b
–20
16b
–20
13b
–78
14b
–78
15b
–78
16b
–78
(11) (a) Thompson, R. S.; Jacques, D.; Haslam, E.; Tanner, R. J.
N. J. Chem. Soc., Perkin Trans. 1 1972, 1387.
References
(1) This report is Part 6 in the series ‘Synthetic studies of
proanthocyanidins’.
(b) Kolodziej, H. Phytochemistry 1989, 28, 3487. (c) Hsu,
F.; Nonaka, G.; Nishioka, I. Chem. Pharm. Bull. 1985, 33,
3293. (d) Nonaka, G.; Hsu, F.; Nishioka, I. J. Chem. Soc.,
Chem. Commun. 1981, 781. (e) Delcour, A.; Vercruysse, A.
R. J. Inst. Brew. 1986, 92, 244. (f) Balas, L.; Vercauteren, J.
Magn. Reson. Chem. 1994, 32, 386. (g) Hemingway, R. W.;
Foo, L. Y.; Porter, L. J. J. Chem. Soc., Perkin Trans. 1 1982,
1209.
(2) Harborne, J. B. The Flavonoids: Advances in Research from
1986; Chapman and Hall: London, 1993.
(3) Harborne, J. B.; Baxter, H. The Handbook of Natural
Flavonoids; John Wiley and Sons: New York, 1999.
(4) Ariga, T.; Koshiyama, I.; Fukushima, D. Agric. Biol. Chem.
1988, 52, 2717.
(5) Zhao, J.; Wang, J.; Chen, Y.; Agarwal, R. Carcinogenesis
1999, 20, 1737.
(6) Baba, S.; Osakabe, N.; Natsume, M.; Terao, J. Free Radical
Biol. Med. 2002, 33, 142.
(7) Sano, A.; Yamakoshi, J.; Tokutake, S.; Tobe, K.; Kubota,
Y.; Kikuchi, M. Biosci., Biotechnol., Biochem. 2003, 67,
1140.
(8) Saito, A.; Nakajima, N.; Tanaka, A.; Ubukata, M.
Heterocycles 2003, 61, 287.
(9) Part 5: Saito, A.; Nakajima, N.; Matsuura, N.; Tanaka, A.;
Ubukata, M. Heterocycles 2004, 62, 479.
(10) Saito, A.; Nakajima, N.; Tanaka, A.; Ubukata, M.
Tetrahedron Lett. 2003, 44, 5449.
(12) Saito, A.; Nakajima, N.; Tanaka, A.; Ubukata, M.
Tetrahedron 2002, 58, 7829.
(13) In this condensation reaction, excess amount (4.0–4.5 equiv)
of a monomer nucleophile was used to avoid higher
oligomer formation.
(14) Data for 7c: [a]D26 –82.2 (c 0.12, CHCl3). 1H NMR (400
MHz, CDCl3, 0.83:0.17 mixture of rotational isomers) d
(major isomer) = 7.35–6.35 (57.27 H, m), 6.11 (0.83 H, s),
6.10 (0.83 H, d, J = 2.2 Hz), 6.02 (0.83 H, d, J = 2.2 Hz),
6.00 (0.83 H, s), 5.17–4.33 (21.58 H, m), 4.19 (0.83 H, d,
J = 8.8 Hz), 3.97–3.86 (1.66 H, m), 3.73–3.68 (0.83 H, m),
3.53 (0.83 H, d, J = 9.0 Hz), 3.03 (0.83 H, dd, J = 6.1 and
16.1 Hz), 2.89 (0.83 H, d, J = 9.6 Hz), 2.78 (0.83 H, dd,
J = 9.7 and 16.1 Hz), 1.31 (0.83 H, d, J = 2.6 Hz, OH), 1.78
(0.83 H, d, J = 3.9 Hz, OH), 1.07 (0.83 H, d, J = 3.7 Hz,
Synlett 2004, No. 6, 1069–1073 © Thieme Stuttgart · New York

LETTER
Efficient Stereoselective Synthesis of Proanthocyanidin Trimers
1073
OH); d (minor isomer) = 7.35–6.35 (11.22 H, m), 6.28 (0.17
in H2O: Elution was done with a linear gradient 5% to 100%
A in 40 min (flow rate: 0.5 mL/min.).
H, d, J = 1.7 Hz), 6.21 (0.17 H, d, J = 8.3 Hz), 6.18 (0.17 H,
s), 6.15 (0.17 H, s), 6.05 (0.17 H, d, J = 2.2 Hz), 5.97 (0.17
H, d, J = 2.2 Hz), 5.80 (0.17 H, dd, J = 1.7 and 8.3 Hz),
5.17–4.33 (5.27 H, m), 4.06–3.86 (0.34 H, m), 3.73–3.68
(0.17 H, m), 3.58–3.57 (0.17 H, m), 2.93 (0.17 H, d, J = 10.0
Hz), 2.66 (0.17 H, m), 2.37–2.32 (0.17 H, m), 1.44–1.41
(0.17 H, m, OH), 1.36–1.34 (0.17 H, m, OH), 1.20–1.17
(0.17 H, m, OH). 13C NMR (100 MHz, CDCl3): d (major
isomer) = 157.9, 157.8, 156.7, 155.5, 155.4, 155.1, 155.1,
154.9, 153.8, 149.2, 149.1, 149.0, 148.8 (× 2), 148.5, 137.6,
137.4, 137.4, 137.4, 137.3, 137.2, 137.2, 137.1, 137.1,
137.0, 136.0, 132.4, 132.3, 131.7, 128.8–126.9 (C × 37),
121.1, 120.6, 120.5, 115.0, 114.8, 114.7, 114.5, 114.1,
113.6, 112.2, 109.4, 108.6, 102.4, 101.1, 94.7, 93.8, 92.0,
91.8, 81.7, 81.0, 80.4, 73.0, 72.9, 71.9–69.8 (C × 11), 68.4,
65.2, 37.5, 37.4, 28.4; minor isomer was not identified.
FAB-MS: m/z (%) = 1947 (0.26) [M + H]+. FAB-HRMS
calcd for C129H110O18 [M + H]+: 1947.7770; found:
1947.7694.
(17) Kolodziej, H. Plant Polyphenols; Hemingway, R. W.; Laks,
P. E., Eds.; Plenum Press: New York, 1992, 295–319.
(18) Balas, L.; Vercauteren, J. Magn. Reson. Chem. 1995, 33, 85.
(19) Data for 1a: [a]D25 +56.9 (c 0.30, EtOH) {lit.11c [a]D +76.9};
HPLC Rt 1a = 20.5 min. 1H NMR (400 MHz, CD3COCD3/
D2O, 15/1): d = 7.13–6.69 (9 H, br), 6.10–5.83 (4 H, br),
5.30–5.05 (1 H, br), 5.04–5.03 (1 H, br), 4.89–4.54 (3 H, br),
4.16–3.95 (3 H, br), 2.75–2.60 (1 H, br), 2.58–2.51 (1 H, br).
FAB-MS: m/z (%) = 889 (12.8) [M + Na]+, 888 (7.1), 887
(5.8), 867 (9.0) [M + H]+, 866 (6.7), 329 (100). FAB-HRMS
calcd for C45H38O18Na [M + Na]+: 889.1956; found:
889.1927.
(20) Data for 4a: [a]D24 –112.6 (c 0.40, MeOH) {lit.11d [a]D
27
–97.6 (c 1.0, MeOH)}; HPLC Rt 4a = 20.3 min. FAB-MS:
m/z (%) = 890 (2.2), 889 (4.0) [M + Na]+, 888 (3.3), 887
(2.1), 868 (2.2), 867 (3.9) [M + H]+, 866 (3.1), 613 (4.2), 483
(11.7), 482 (25.2), 460 (48.2), 328 (100), 306 (100). FAB-
HRMS calcd for C45H38O18Na [M + Na]+: 889.1956; found:
889.1882.
(15) Data for 7a: [a]D25 –233.7 (c 0.38, EtOH) {lit.11a [a]578 –173
(c 1.03, EtOH)}; HPLC Rt 7a = 18.8 min. FAB-MS: m/z (%)
= 890 (12.5), 889 (21.5) [M + Na]+, 888 (14.7), 887 (12.4),
868 (6.9), 867 (12.6) [M + H]+, 866 (10.9), 328 (100). FAB-
HRMS calcd for C45H38O18Na [M + Na]+: 889.1956; found:
889.2018.
(21) Data for 2a: [a]D27 +59.3 (c 0.30, MeOH) {lit. [a]D +70.4 (c
2.2, MeOH)}; HPLC20 Rt 2a = 22.0 min. FAB-MS: m/z (%)
= 890 (1.9), 889 (3.3) [M + Na]+, 888 (2.2), 887 (1.7), 868
(1.6), 867 (3.3) [M + H]+, 866 (2.5), 613 (8.3), 482 (25.5),
459 (45.8), 328 (100), 306 (100). FAB-HRMS calcd for
C45H38O18Na [M + Na]+: 889.1956; found: 889.2031.
(22) Kozikowski, A. P.; Tückmantel, W.; Hu, Y. J. Org. Chem.
2003, 68, 1641.
(16) HPLC analysis conditions: Mightysil® RP-18 GP column
(Kanto Chemical Co. Inc., Japan; 250 × 4.6 mm, 5mm);
solvent (A) 0.1% CF3CO2H in MeCN, (B) 0.1% CF3CO2H
Synlett 2004, No. 6, 1069–1073 © Thieme Stuttgart · New York