Synthetic studies of proanthocyanidins. Part 3: Stereoselective 3,4-cis catechin and catechin condensation by TMSOTf-catalyzed intramolecular coupling method

Article abstract of DOI:10.1016/S0040-4039(03)01311-X

TMSOTf-catalyzed intramolecular condensation for catechin and epicatechin units are described. A potential electrophile and a nucleophile were connected with diester linkers and TMSOTf-catalyzed condensation was examined. In comparison with intermolecular

Full text of DOI:10.1016/S0040-4039(03)01311-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5449–5452
Synthetic studies of proanthocyanidins. Part 3: Stereoselective
3,4-cis catechin and catechin condensation by
TMSOTf-catalyzed intramolecular coupling methodꢀ
Akiko Saito,a Noriyuki Nakajima,b,* Akira Tanakac and Makoto Ubukatab,*
aJapan Society for the Promotion of Science Domestic Research Fellow, Kosugi, Toyama 939-0398, Japan
bBiotechnology Research Center, Toyama Prefectural University, Kosugi, Toyama 939-0398, Japan
cCollege of Technology, Toyama Prefectural University, Kosugi, Toyama 939-0398, Japan
Received 6 February 2003; revised 8 May 2003; accepted 23 May 2003
Abstract—TMSOTf-catalyzed intramolecular condensation for catechin and epicatechin units are described. A potential elec-
trophile and a nucleophile were connected with diester linkers and TMSOTf-catalyzed condensation was examined. In comparison
with intermolecular catechin and catechin condensation, the intramolecular condensation required high reaction temperature and
reversed 3,4-cis product was obtained. The condensed product was transformed into the natural 3,4-cis (+)-catechin-(4b“8)-(+)-
catechin dimer. © 2003 Elsevier Science Ltd. All rights reserved.
Proanthocyanidins are known as condensed tannins
and/or oligomeric flavonoids.2,3 Many biological activi-
ties, powerful free-radical-scavenging activity4 and an
anti-tumor-promoting effect,5 have been reported for
flavonoids, and their investigation is now increasingly
important. In the previous paper,1 we described Lewis
acid-catalyzed condensation of benzylated catechin as a
potential nucleophile, with various 4-O-alkylated cate-
chin derivatives as an electrophile. During the examina-
tion, we have been able to achieve high levels of
3,4-trans stereoselectivity in excellent isolation yields
under the TMSOTf-catalyzed intermolecular condensa-
tion (Fig. 1).
Natural B-type procyanidins, procyanidin B1 (1), B2
(2), B3 (3)6–9 and B4 (4), are consisted from the combi-
nation of (+)-catechin and (−)-epicatechin units domi-
nantly with 3,4-trans manner. The TMSOTf-catalyzed
intermolecular condensation is well suited for the con-
struction of 3,4-trans stereochemistry. However, the
Figure 1.
Keywords: polyphenol; condensed tannin; oligomeric flavonoid; catechin dimer; procyanidin B3.
ꢀ See Ref. 1.
* Corresponding authors. Tel.: +81-766-56-7500, ext. 568; fax: +81-766-56-2498; e-mail: nori@pu-toyama.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01311-X

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A. Saito et al. / Tetrahedron Letters 44 (2003) 5449–5452
reaction required 4.5-fold excess nucleophile to avoid
higher oligomer formation. In this paper, we challenge
to find the coupling conditions, which used just
equimolar amount of nucleophile and electrophile in
good yield. After several attempts, we were pleased to
find the intramolecular [4,8]-catechin–catechin coupling
proceeded in good yield with reversed 3,4-cis stereo-
selectivity. The 3,4-cis catechin units are rare in nature
and there is a few report accessible through 3,4-cis
dimer construction.10 The most straightforward method
for 3,4-cis formation is TiCl4-catalyzed intermolecular
condensation between tetra-O-benzylated 3-hydroxy-
catechin (8) and (2R,3S,4S)-5,7,3%,4%-tetrabenzyloxy-4-
ethoxyethoxyflavan (9) to provide 2:1 ratio of 5 and 6
in 84% yield (Scheme 1).1
successfully obtained by increasing the reaction temper-
ature, and 14 was obtained in 35% yield at −20°C and
in 50% yield at 0°C. Best results were obtained by using
glutaryl diester 13 under the same conditions, 98% yield
of cyclization product (15) was generated at −20°C as
the sole product.11 All peaks except for the benzyl
group were easily assigned by the usual NMR measure-
ment.12 The conformations of 14 and 15 were analyzed
using the combination of NOE data and molecular
mechanics calculation.13,14 It was found that cyclized
product has rigid conformation, rotational isomerism
about the interflavanyl linkages was not observed in
NMR (Scheme 2).
When the intramolecular condensation of epicatechin–
catechin and catechin–epicatechin combination (18 and
20) were performed under the same conditions at 0°C,
3,4-trans products (19 and 21) were isolated in 47 and
43% yield, respectively.15 Any amounts of 3,4-cis prod-
ucts were not detected in the reaction mixture. Unfortu-
nately, (−)-epicatechin and (−)-epicatechin condensa-
tion provided no any amount of dimer product
(Scheme 3).
We designed to connect two units, a potential elec-
trophile and a nucleophile, with diester linker and
reinvestigated the TMSOTf-catalyzed condensation at
various temperatures. Tetra-O-benzylated catechin (8)
was esterified with succinyl and glutaryl anhydride and
the resulting carboxylic mono-esters (10 and 11) were
coupled with an electrophile unit (9) by the DCC
method to give diesters (12 and 13) in 94 and 84% yield,
respectively. Intramolecular TMSOTf-catalyzed cou-
pling of succinyl diester (12) was first performed at
−78°C to give [4,8]-condensed product (14) in 20% yield
with unconsumed 12. An improved isolation yield was
Succinyl linker was removed by DIBAL treatment at
−30°C, desired 3,3%-diol (6) was obtained in 55% yield
from 14. A better result was obtained in two-step
sequences via methyl ester. By the K2CO3/MeOH treat-
Scheme 1.
Scheme 2.

A. Saito et al. / Tetrahedron Letters 44 (2003) 5449–5452
5451
Scheme 3.
ment of 15, less hindered F ring ester was first cleaved
and the following DIBAL treatment furnished 6 in 77%
yield. All the spectral data [NMR, IR, mass] collected
for 6 were identical with those of authentic samples
reported before.1b Compound 6 was finally converted
into 3,4-cis-(+)-catechin-(4b“8)-(+)-catechin dimer
(7)16 by Pd(OH)2–catalyzed hydrogenolysis in 67%
yield.
8. Fonknechten, G.; Moll, M.; Cagniant, D.; Kirsch, G.;
Muller, J. F. J. Inst. Brew. 1983, 89, 424–431.
9. Kawamoto, H.; Nakatsubo, F.; Murakami, K. Mokuzai
Gakkaishi 1991, 37, 488–493.
10. Kozikowski reported stereocontrolled synthesis of epi-
catechin-4a,8-epicatechin. Kozikowski, A. P.; Tuckman-
tel, W.; Hu, Y. J. Org. Chem. 2001, 66, 1287–1296.
11. A typical procedure for Intramolecular TMSOTf-cata-
lyzed coupling: To a solution of (2R,3S)-5,7,3%,4%-tetra-
benzyloxy-flavan-3-yl (2R,3S,4S)-5,7,3%,4%-tetrabenzyloxy-
4-ethoxyethyloxy-flavan-3-yl glutarate (206 mg, 0.139
mmol) in CH2Cl2 (80 mL) was added dropwise
TMSOTf (0.28 mL, 0.14 mmol, 0.5 M solution in
CH2Cl2) at −20°C. After stirring for 10 min, the pale
yellow reaction mixture was quenched with sat.
NaHCO3. The aq. solution was extracted with CHCl3
and the organic phase was washed with water and
brine, and dried (Na2SO4). Filtration, concentration
and silica gel column purification (hexane/EtOAc, 6/1
to 2/1) afforded a 190 mg (0.136 mmol, 98%) of a
mixture of 15 as a amorphous solid.
Conclusion
The TMSOTf-catalyzed intramolecular one-to-one cou-
pling method was developed. (+)-Catechin and (+)-cate-
chin condensation produced 3,4-cis condensed product.
This method will be expected to develop a good
oligomerization method.
References
12. Data for 15: [h]D24=+87.6 (c 1.14, CHCl3); 1H NMR
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m), 6.26 (1H, s, D6), 6.21 (1H, d, J=8.5 Hz), 6.02
(1H, d, J=2.2 Hz, A6), 5.88 (1H, d, J=2.2 Hz, A8),
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A. Saito et al. / Tetrahedron Letters 44 (2003) 5449–5452
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