An efficient synthesis of (±)-epigallocatechin gallate by reductive intramolecular etherification

Article abstract of DOI:10.1055/s-2006-950283

The synthesis of (±)-epigallocatechin gallate by direct cyclization to the cis-3-acyloxy-2-arylbenzopyranee is described. α-Acyloxylketones, possessing a 2-hydroxylphenyl group at the β-position, underwent intramolecular reductive etherification to give c

Full text of DOI:10.1055/s-2006-950283

LETTER
2827
An Efficient Synthesis of ( )-Epigallocatechin Gallate by Reductive
Intramolecular Etherification
Synthesis of
(
)-Epigaa
k
Gallate oto Kitade,1 Yoshiaki Ohno,2 Hiroshi Tanaka, Takashi Takahashi*
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology, 2-12-1-S1-35 Ookayama,
Meguro, Tokyo 152-8552, Japan
Fax +81(3)57342120; E-mail: ttak@apc.titech.ac.jp
Received 21 June 2006
The strategy for the synthesis of 3-acyloxyepicatechin
Abstract: The synthesis of ( )-epigallocatechin gallate by direct
derivatives 1 involves the reductive cyclization of the a-
cyclization to the cis-3-acyloxy-2-arylbenzopyranee is described.
a-Acyloxylketones, possessing a 2-hydroxylphenyl group at the b-
position, underwent intramolecular reductive etherification to give
acyloxyketone 2 as shown in Scheme 1. Treatment of 2
with reducing reagents under acidic conditions would pro-
cis-3-acyloxy-2-arylbenzopyran due to neighboring group partici- mote removal of the phenol-protecting group, followed by
pation of the acyloxyl group at the a-position. Using this method,
we accomplished the stereoselective synthesis of ( )-epigallo-
catechin gallate.
hemiacetal formation to give 3. The hemiacetal 3 then un-
dergoes reductive cyclization to afford the cis-3-acyloxy-
2-arylbenzopyran 1 via oxonium cation 4 in one pot. The
acyloxy group at the 3-position blocks the attack of the
hydride at the same face by neighboring group partici-
pation. The precursor 2 for cyclization was prepared by
acylation of the corresponding alcohol 6 with the acid de-
rivative 5. The alcohol 6 was prepared by aldol condensa-
tion of aldehyde 7 with ketone 8, followed by oxidation of
the resulting enone at the a-position.
Key words: catechin, cyclizations, natural products, neighboring
group effects
Epigallocatechin gallate (Scheme 1, 1) is a member of the
catechin family and is composed of a cis-2-aryl-3-hydrox-
yl benzopyran unit. It shows various biological activity,
including antitumor activity and inhibition of proteasome,
uPA, and several tyrosine kinases.3,4 The 2,3 cis-stereo-
chemistry is important for most of the biological activi-
ties. We envisaged that the epicatechin skeleton would be
an effective template for developing new drug candidates
and biochemical probes. Therefore, we decided to start a
project involving the synthesis of various epicatechin
derivatives.
We first examined the synthesis of O-octamethyl epigal-
locatechin gallate (14a, Scheme 2). Treatment of alde-
hyde 7a with 3,4,5-trimethoxyphenylmethylketone (8a)
under basic conditions provided enone 9a in 92% yield.
Rhodium-catalyzed reduction of enone 9a with triethyl-
silane gave the silylenol ether 10a.7 Successive oxidation
of the vinyl ether 10a with dimethyldioxirane8 in acetone
at –78 °C provided a mixture of the silyl ether 11a and
alcohol 6a. Deprotection of the resulting silylether 11a
gave a-hydroxyketone 6a in 55% overall yield from
enone 9a. Acylation of the resultant alcohol 6a with 3,4,5-
trimethoxybenzoyl chloride (12) provided ester 2a in 94%
yield. We next examined an acid-catalyzed reductive
cyclization of ester 2a (Scheme 3).9 Treatment of ketone
2a with triethylsilane in the presence of trifluoroacetic
acid at room temperature resulted in deprotection of the
SEM group, followed by reductive etherification to pro-
vide cis-benzopyran 14a in 88% yield with good selectiv-
ity (>8:1).10 The coupling constants 3JH2–H3 (<1.0 Hz) for
14a indicated that the relative stereochemistry between
the C2 and C3 positions was cis. It is worth mentioning
here that p-methoxylbenzyl ether was not suitable as the
acid cleavable phenol-protecting group because a signifi-
cant amount of C-p-methoxybenzylated products were
observed.
Most of the reported syntheses of epicatechins are based
on epimerization of the C3 hydroxyl group on the catechin
skeleton with 2,3-trans-stereochemistry.5 Direct synthesis
of the epicatechin skeleton would be an attractive and ef-
fective approach for the synthesis of various epicatechin
derivatives. Chan and Li have reported the stereoselective
and direct synthesis of cis-3-acyloxy-2-phenylbenzo-
pyran by the intramolecular O-alkylation of phenol with
benzyl bromide.6 However, this method was not practi-
cally suitable for the synthesis of epigallolcatechin deriv-
atives because the electron-donating substituents on the
aromatic ring at the C2 position promote an SN1 type re-
action of the alkyl bromide, which would eventually give
trans-3-acyloxy-2-arybenzopyran as the major product.
Therefore, an effective methodology for direct cyclization
to epigallocatechins is still needed. Herein, we report an
efficient synthesis of ( )-epigallocatechin gallate (1) by
direct reductive cyclization of a-acyloxy ketone to give
cis-benzopyran.
Next, we conducted the total synthesis of ( )-epigallocat-
echin gallate (1). The dibenzyl-protected aldehyde 7b was
used as a starting material. Aldol condensation of 7b
with ketone 8b provided enone 9b in quantitative yield.
The enone 9b was converted to the corresponding a-hy-
droxyketone 6b in 55% overall yield from 9b by the estab-
lished procedure. Acylation of the alcohol 6b with acid 13
SYNLETT 2006, No. 17, pp 2827–2829
1
7
.1
0
.2
0
0
6
Advanced online publication: 09.10.2006
DOI: 10.1055/s-2006-950283; Art ID: U07406ST
© Georg Thieme Verlag Stuttgart · New York

2828
M. Kitade et al.
LETTER
X
OR
OR
OR
OH
O
SEM
O
OR
OR
OH
OH
SEM
O
OR
2
RO
O
HO
O
OR
5
RO
OR
OR
OH
O
3
O
OR
OR
OH
OH
O
O
OR
O
OR
OR
OH
6
OR
OH
1
2
SEM
O
OR
+
OR
H–
OR
OR
RO
OR
OR
OR
OR
HO
RO
O
RO
O
O
O
OR O
O
Ar
O
7
8
OR
OR
Ar
O
3
4
Scheme 1 Strategy for the synthesis of epigallocatechin gallate 1
OR1
OR1
OR1
OR1
OSEM
OR1
Et3SiH
10 mol% (Ph3P)3RhCl
toluene
OR1
8
O
R1O
OSEM
O
R1O
OSEM
OR1
OR1
A
NaOMe
THF–MeOH (5:1)
OR1
R1O
R1O
OTES
R1O
O
92% for 9a
quant. for 9b
7
9
a: R1 = Me
b: R1 =Bn
10
OR1
OR1
OR1
12, DMAP, py
94% for 2a
SEMO
OR1
OR1
R1O
OSEM
R1O
OR1
OR1
OR1
OR1
OR2
O
O
O O
X
R1O
OR1
13, EDCI, DMAP
R1O
O
O
O
acetone
CSA, MeOH
98%, CH2Cl2 for 2b
OR1
OR1
11: R2 = TES
6: R2 = H
12: R1 = Me, X = Cl
13: R1 = Bn, X = OH
55%, 3 steps for 6a
55%, 3 steps for 6b
2
Scheme 2 Synthesis of the precursors 2 for the cyclization
OR1
1) TFA (25%)
Et3SiH (10%)
CH2Cl2
OMe
TFA (25%)
Et3SiH (10%)
CH2Cl2
88%
OH
OR1
OR1
OMe
OH
OH
SEMO
R1O
MeO
O
HO
O
2) H2, Pd(OH)2
OMe
OMe
O
O
O
O
50%
R1O
OR1
OR1
OMe
OH
OH
OH
O
O
O
OMe
OMe
OR1
OH
2a: R1 = Me
2b: R1 = Bn
14a
( )-1
Scheme 3 Reductive cyclization of 2
gave ester 2b in 98% yield. The reductive cyclization of tives by intramolecular reductive etherification. The total
2b, followed by deprotection of the benzyl groups provid- yield of the synthesis of 1 based on 7b over seven steps
ed ( )-epigallocatechin gallate (1) in 50% yield from 2b.11 was 25%. The neighboring group participation of the C3
The analytical data (1H and 13C NMR) of 1 was identical acyloxy group promoted the stereoselective reduction of
with a commercially available authentic sample.
an oxocarbenium ion to provide cis-2,3-disubstituted
benzopyran. Application of the method to the synthesis of
various epicatechin derivatives is now in progress.
In conclusion, we described an efficient approach for the
synthesis of cis-3-acyloxy-2-arylbenzopyranee deriva-
Synlett 2006, No. 17, 2827–2829 © Thieme Stuttgart · New York

LETTER
Synthesis of ( )-Epigallocatechin Gallate
2829
(9) (a) Kaus, G. A.; Molina, T.; Walling, J. A. J. Chem. Soc.,
Chem. Commun. 1986, 1568. (b) Luengo, J. I.; Konialian-
Beck, A.; Rozamus, L. W.; Holt, D. A. J. Org. Chem. 1994,
59, 6512.
Acknowledgment
This work was financially supported by the Naito Foundation.
(10) Procedure for the reductive cyclization to give (2R*,3R*)-
3,4-dihydro-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-
2H-chromen-3-yl 3,4,5-trimethoxybenzoate (14a): To a
stirred solution of 2a (17 mg, 0.024 mmol) in CH2Cl2 (0.5
mL) was added a solution of triethylsilane (10%) and
trifluoroacetic acid (25%) in CH2Cl2 at 0 °C. The reaction
mixture was then warmed to r.t. for 4 h. Toluene (5 mL) was
added to the reaction mixture and the volatile components
were removed by evaporation in vacuo. The product was
purified using column chromatography on silica gel, eluting
with hexane–EtOAc (5:1 → 2:1) to afford 2a (12 mg, 0.021
mmol, 88%) as a white solid; mp 155–157 °C; IR (solid)
2940, 2839, 1717, 1621, 1592 cm–1; 1H NMR (400 MHz,
CDCl3): d = 7.17 (s, 2 H), 6.70 (s, 2 H), 6.25 (d, J = 1.9 Hz,
1 H), 6.12 (d, J = 1.9 Hz, 1 H), 5.67 (m, 1 H), 5.09 (s, 1 H),
3.86 (s, 3 H), 3.81 (s, 6 H), 3.80 (s, 3 H), 3.79 (s, 3 H), 3.78
(s, 3 H), 3.72 (s, 6 H), 3.05 (d, J = 3.4 Hz, 2 H); 13C NMR
(100 MHz, CDCl3): d = 165.1, 159.7, 158.8, 155.5, 153.1,
152.8, 142.5, 137.9, 133.3, 125.1, 107.2, 103.9, 100.1, 93.2,
91.9, 77.7, 68.6, 60.9, 60.8, 56.2, 56.0, 55.4, 25.9.
References and Notes
(1) Current Address: Cancer Research Lab. Hanno Advanced
Research Lab., Taiho Pharmaceutical Co., Ltd. 1-27,
Misugidai, Hanno-shi, Saitama, 357-8527, Japan.
(2) Current Address: Fukaya Plant Tokyo Kasei Kogyo Co.,
LTD. 725 Kashiai Fukaya-shi, Saitama 366-0816, Japan.
(3) (a) Yang, C. S.; Chung, J. Y.; Yang, G.; Chhabra, S. K.; Lee,
M. J. J. Nutr.; 2000, 130, 472S. (b) Tosetti, F.; Ferrari, N.;
De Flora, S.; Albini, A. FASEB J. 2002, 16, 2.
(4) (a) Nam, S.; Smith, D. M.; Dou, Q. P. J. Biol. Chem. 2001,
276, 13322. (b) Smith, D. M.; Daniel, K. G.; Wang, Z.;
Guida, W. C.; Chan, T. H.; Dou, Q. P. Proteins: Struct.
Funct. Bioinform. 2004, 54, 58. (c) Jankun, J.; Selman, S.
H.; Swiercz, R.; Skrzypczak-Jankun, E. Nature 1997, 387,
561. (d) Sachinidis, A.; Hescheler, J. Drug News Perspect.
2002, 15, 432.
(5) (a) Rensburg, H.; Heerden, P. S.; Ferreira, D. J. Chem. Soc.,
Perkin Trans. 1 1997, 3415. (b) Jew, S.-S.; Lim, D.-y.; Bae,
S.-y.; Kim, H.-a.; Kim, J.-h.; Lee, J.; Park, H.-g.
Tetrahedron: Asymmetry 2002, 13, 715. (c) Nay, B.;
Arnaudinaud, V.; Peyrat, J. F.; Nuhrich, A.; Deffieux, G.;
Merillon, J. M.; Vercauteren, J. Eur. J. Org. Chem. 2000,
1279. (d) Zaveri, N. T. Org. Lett. 2001, 3, 843.
(6) (a) Li, L.; Chan, T. H. Org. Lett. 2001, 3, 739.
(b) Anderson, J. C.; Headley, C.; Stapleton, P. D.; Taylor, P.
W. Tetrahedron 2005, 61, 7703.
(11) ( )-Epigallocatechin gallate(1): mp 220 °C (dec); 1H NMR
[400 MHz, acetone-d6–D2O (2:1)]: d = 6.89 (s, 2 H), 6.53 (s,
2 H), 5.90 (d, J = 2.4 Hz, 1 H), 5.89 (d, J = 2.4 Hz, 1 H), 4.89
(s, 1 H), 5.28 (s, 1 H), 2.87 (dd, J = 17.5, 4.4 Hz, 1 H), 2.78
(dd, J = 17.5, 1.6 Hz, 1 H); 13C NMR [100 MHz, acetone-d6–
D2O (2:1)]: d = 212.2, 167.2, 157.3, 156.8, 146.2, 145.9,
139.3, 133.1, 130.6, 121.3, 110.2, 106.8, 98.9, 96.6, 95.7,
78.1, 70.3, 26.6. The analytical data (1H and 13C NMR) of 1
was identical to the commercially available authentic sample
[(–)–EGCG, Wako Pure Chemical industries, Ltd.].
(7) Miles, C. O.; Main, L.; Nicholson, B. K. Aust. J. Chem.
1989, 42, 1103.
(8) Murray, R. W.; Jeyaram, R. J. Org. Chem. 1985, 50, 2847.
Synlett 2006, No. 17, 2827–2829 © Thieme Stuttgart · New York