Reagent-controlled stereoselective synthesis of (±)-gallo- and (±)-epigallo-catechin gallates

Article abstract of DOI:10.1016/j.tetlet.2012.02.065

Synthesis of (±)-gallocatechin and (±)-epigallocatechin gallates by electrophilic cycloarylation is reported. The precursors for cyclization were prepared by reagent-controlled stereo-selective opening of epoxide with phenol. Activation of the S-oxidized S,O-acetal enabled electrophilic cycloarylation to stereoselectively provide the acylated catechins.

Full text of DOI:10.1016/j.tetlet.2012.02.065

Tetrahedron Letters 53 (2012) 2493–2495
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reagent-controlled stereoselective synthesis of ( )-gallo- and
( )-epigallo-catechin gallates
⇑
⇑
Hiroshi Tanaka , Ayaka Chino, Takashi Takahashi
Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1-H-101 Ookayama, Meguro, Tokyo 152-8552, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of ( )-gallocatechin and ( )-epigallocatechin gallates by electrophilic cycloarylation is reported.
The precursors for cyclization were prepared by reagent-controlled stereo-selective opening of epoxide
with phenol. Activation of the S-oxidized S,O-acetal enabled electrophilic cycloarylation to stereoselec-
tively provide the acylated catechins.
Received 16 January 2012
Revised 11 February 2012
Accepted 14 February 2012
Available online 21 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Flavonols
Epoxide
Enone
Sulfoxide
Trifluoroacetic acid
Introduction
The other approach is based on cycloarylation by C4–Ar bond
formation, which allows the preparation of both trans- and cis-
(ꢀ)-Epigallocatechin gallate (EGCG 1, Scheme 1) is an anti-
oxidative phytochemical and the most abundant catechin found
in green tea leaves. EGCG 1 is associated with various biological
activities1 and, for example, targeting the 67-kDa laminin receptor
(67LR) mediating anti-cancer and anti-allergic actions.2 The highly
oxygenated aromatic moieties make EGCG unstable under basic,
acidic, and oxidative conditions. In addition, EGCG easily under-
goes epimerization at the C2 position when heated, or under acidic
or basic conditions to provide gallocatechin gallate (GCG 2) com-
posed of a trans-2,3-disubstituted benzopyran. Therefore green
flavanols from the corresponding acyclic precursors.4 Suzuki and
co-workers reported on the synthesis of trans- and cis-flavanols
by intramolecular nucleophilic substitution with phenyl metal
species.5 On the other hand, we have recently reported on a unique
method for the synthesis of EGCG involving reductive etherifica-
tion of the
a-acyloxyketones under acidic conditions to directly
provide 3-O-acylated cis-flavanols.6 The acyl moiety acts as a
stereo-directing group for the synthesis of the 3-O-acyl cis-flavanol
and stabilized the cyclized products under acidic conditions.
However this C2–O1 bond formation approach cannot be used
for the synthesis of GCG and their derivatives. Herein we report
on a reagent-controlled stereoselective synthesis of racemic EGCG
and GCG based on C4–Ar bond formation.
tea contains
a considerable amount of GCG in comparison
with EGCG. Chemical synthesis of ample amounts of pure, well-
characterized EGCG and GCG could strongly assist the elucidation
of the biological activity and the mechanism of actions of these
important phytochemicals.
Most of the established methods for the synthesis of EGCG and
GCG derivatives are based on independent synthesis of cis- and
trans-flavan-3-ol derivatives, followed by acylation of the alcohol
with gallic acid. The syntheses of the flavan-3-ols are largely
divided into two approaches. One is based on cycloetherification
by a C2–O1 bond formation, which mainly provided thermody-
namically most stable trans-flavanols.3 Preparation of the cis-
flavanols needs the inversion of stereochemistry at the C3 position.
Strategy for the synthesis of EGCG 1 and GCG 2 involves an
intramolecular electrophilic cycloarylation of acetal 3 and a re-
agent-controlled anti- and syn-opening of epoxide 6 (Scheme 1).
The key 1,3-oxathiolane 3-oxide intermediates, the S-oxidized
S,O-acetals 3 and 4, undergo electrophilic cycloarylation via oxo-
nium cation 9. The remaining alkyloxy substituent at the benzylic
position can be subsequently reduced under acidic conditions. The
bromide on the A ring moderates reactivity of the aromatic moiety
and prevents self-condensation of the cyclized product.7 The
precursors 3 and 4 could be prepared by reagent-controlled
syn- and anti-epoxide opening of epoxide 6 with bromophenol 5,
followed by acylation of the resulting alcohol with gallic acid 7.
The epoxide 6 is prepared from the corresponding olefin 8. The
S-oxidized S,O-acetals tolerate epoxidation conditions and could
⇑
Corresponding authors. Tel.: +81 3 5734 2471; fax: +81 3 5734 2884 (H.T.); tel.:
+81 3 5734 2120; fax: +81 3 5734 2884 (T.T.).
E-mail addresses: thiroshi@apc.titech.ac.jp (H. Tanaka), ttak@apc.titech.ac.jp (T.
Takahashi).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.065

2494
H. Tanaka et al. / Tetrahedron Letters 53 (2012) 2493–2495
OH
B
OH
MnO2
OBn
OBn
OH
OH
OH
OBn
OBn
CH2Cl2
OBn
2
3
HO
O
C
HO
O
OH
A
OBn
r.t., 12 h
91%
O
O
4
OH
OH
OH
OH
OH
OH
O
O
O
OH
D
11
10
OH
OH
(-)-EGCG (1)
(-)-GCG (2)
mCPBA
OBn
HOCH2CH2SH
HBr/CH3COOH
toluene
OBn
OBn
NaHCO3 aq.
O
CH2Cl2, 0 oC
O
8 h, 98%
dr. = 5:3
0 oC to r.t.
2 h, 85%;
O
O
Ar
S
O
RX
12
9
OBn
OBn
OBn
OBn
Br
Br
OBn
BnO
O
BnO
O
OBn
OBn
OBn
OBn
OBn
OH
NBS, H2O
CH2Cl2
OBn
OBn
O
O
Br
O
S O
O
O
BnO
S O
O
O
BnO
OBn
OBn
OBn
-50 oC to r.t.
5 h, 38%
S
O
OBn
OBn
OBn
S
O
O
3
4
8
13
Scheme 2. Preparation of bromohydrine 13.
OBn
OBn
OBn
OBn
Br
OBn
OBn
BnO
OH
Cs2CO3
OBn
OBn
OH
acetone
O
OH
OBn
OBn
OBn
OBn
O
S O
0 oC, 5 h.
OBn
OBn
OBn
O
S
O
O
8
Br
5
O
6
OBn
O
S O
O
S O
7
6
Br
13
Scheme 1. Strategy for the synthesis of EGCG 1 and GCG 2.
BnO
OH
CH2Cl2, 45 oC,
54 h
K2CO3, CH2Cl2,
45 oC, 50 h
BnO
generate the intermediate oxonium ion under sufficiently mild
acidic condition that do not leave to cleavage the benzyl phenyl
ether.8 Noteworthy, this strategy to EGCG 1 or GCG 2 involves only
four diverse steps from epoxide 6: regio- and stereo-selective
opening of epoxide 6 with phenol 5, esterification of the resulting
alcohol with appropriately protected gallic acid, cycloarylation,
and deprotection.
5
O
S
O
Ar
S
H
Ar
O
O
H
Ar
O
H
O
H
H
O
O
Ar
Preparation of bromohydrin 13 is shown in Scheme 2. Oxidation
of the allyl alcohol 103d with MnO2 provided aldehyde 11 in 91%.
The aldehyde 11 was converted to the cyclic S,O-acetal 12 in 85%
yield by treatment with 2-mercaptoethanol in the presence of
HBr.9 The oxidation of the S,O-acetal 12 with mCPBA at 0 °C pro-
vided the oxidized S,O-acetal 8 in 98% as a mixture of two diaste-
reomers (5:3). Treatment of the stereoisomeric 8 with NBS in the
presence of H2O resulted in the disappearance of the substrates
and the yield of bromohydrin 13 in 38% yield as a single diastereo-
mer with a significant amount of enone 11. Relative stereochemis-
try of the bromohydrin 13 was not determined. Dynamic kinetic or
kinetic resolution of the oxidized S,O-acetal via epoxidation might
be involved during the reaction.
14
15
64%
68%
OBn
OBn
OBn
OBn
OBn
OBn
Br
Br
BnO
O
BnO
O
OH
OH
S O
S O
O
O
BnO
BnO
16
Scheme 3. Anti- and syn-epoxide opening of 6.
17
Anti- and syn-opening of the epoxide 6 was examined (Scheme
3). The bromohydrin 13 was converted into epoxide 6 under basic
conditions, which was used for the next reaction without further
purification due to its instability. According to the reported meth-
od,4 treatment of epoxide 6 with phenol 510 under basic conditions
at 45 °C for 5 days provided the trans-opening product 17 in 68%
yield by a conventional SN2 reaction via 15. On the other hand,
heating the mixture of epoxide 6 and phenol 5 at 45 °C without
the presence of base provided the cis-opening product 16 in 64%
yield based on 13. The mechanism of the reaction might involve
activation of epoxide 14 with the proton of incoming phenol 5, fol-
lowed by the attack of the phenol to the benzylic position at the
same face of the epoxide.11 The relative stereochemistry between
the C2 and C3 stereogenic centers of each product was determined
by analysis of the corresponding cyclized products.

H. Tanaka et al. / Tetrahedron Letters 53 (2012) 2493–2495
2495
OH
OBn
OBn
OH
OH
OBn
OBn
OBn
OH
OBn
OBn
H2, Pd(OH)2
TFAA (100 eq.)
Et3SiH (10 L/mol)
CH2Cl2 (100 L/mol)
Br
Br
OBn
OBn
MeOH/THF = 1:1
HO
O
BnO
O
DIC, DMAP
CH2Cl2, r.t.
Br
BnO
O
20 atm, 50 o
C
BnO
O
O
O
O
O
S O
O
-78 oC, 2 h
then r.t., 3 days
58%
1 mg/ml, 1 ml/min
1 cycle, 45%
in H-Cube®
OH
BnO
18 h, 82%
BnO
OH
OBn
OBn
OBn
O
S O
O
BnO
O
OH
OBn
OH
OH
OBn
OBn
OBn
OBn
O
17
4
18
( ) - 2
OBn
OH
OBn
OBn
O
7
OH
OH
OBn
OBn
OBn
OBn
H2, Pd(OH)2
Br
Br
TFAA (50 eq.)
Et3SiH (10 L/mol)
CH2Cl2 (100 L/mol)
MeOH/THF = 1:1 HO
O
OBn
OH
BnO
O
BnO
O
DIC, DMAP
CH2Cl2, r.t.
20 atm, 50 o
C
OBn
OBn
Br
O
O
BnO
O
OH
O
S O
O
1 mg/ml, 1 ml/min
1 cycle, 47%
in H-Cube®
BnO
-78 oC, 0.5 h
then r.t., 27 h
55%
BnO
22 h, 91%
OH
OH
OBn
OBn
OBn
O
O
O
S O
OBn
BnO
OH
OBn
OBn
16
3
19
( ) - 1
Scheme 4. Synthesis of rac-EGCG (( )-(1)) and rac-GCG (( )-(2)).
Synthesis of rac-EGCG (( )-(1)) and rac-GCG (( )-(2)) is shown
in Scheme 4. Acylation of the resulting alcohols 17 and 16 with
the tri-O-benzylgallic acid 7 in the presence of N,N0-diisopropyl
carbodiimide (DIC) provided esters 4 and 3 in 82% and 91% yields,
respectively. We next examined the cyclization of 4 and 3. Treat-
ment of 4 with a large excess of trifluoroacetic anhydride (TFAA)
in a solution of Et3SiH and CH2Cl2 (1:10) at ꢀ78 °C for 2 h, followed
by additional stirring at room temperature for 3 days successfully
provided the protected GCG 18 as a single diastereomer. Based
on the coupling constant between H2 and H3 (JH2-H3 = 6.3 Hz),
the relative stereochemistry between the C2 and C3 positions
was assigned to be trans. Attempts to use trifluoroacetic acid in-
stead of TFAA did not lead to the cyclized products, indicated that
O-acylation of the sulfoxide could be an initial reaction leading to
cyclization. Likewise, treating 3 with 50 equiv. of TFAA in a solu-
tion of Et3SiH and CH2Cl2 (1:10) at ꢀ78 °C for 30 min, followed
by additional stirring at room temperature for 27 h, provided the
protected EGCG 19 as a single diastereomer. To our delight, these
results indicated that epimerization at the C2 position did not oc-
cur during the required reaction conditions. The relative stereo-
chemistry of the cyclized products depended only on that of the
precursors. Deprotection of the protected GCG 18 and EGCG 19
was achieved by hydrogenolysis using a continuous flow hydrogen
reactor H-Cube with a CatCartÒ (70 mm) containing 20% Pd(OH)2/C
at 20 atm at 50 °C provided the racemic GCG 2 and EGCG 1 in 45%
and 47% yields, respectively.12
In conclusion, we have described the synthesis of the racemic
GCG 2 and EGCG 1 by reagent-controlled anti- and syn-epoxide
opening and electrophilic cycloarylation. The epoxide 6 selectively
undergoes anti- and syn-epoxide opening with phenol 5 with base
and without base, respectively. The key S-oxidized S,O-acetals 3
and 4 (1,3-oxathiolane 3-oxides) can generate oxonium cation 9
by treatment with a mixture of Et3SiH and TFAA and undergo
electrophilic cycloarylation without cleavage and epimerization
of the benzylic ethers. This method requires only four diverse
steps from epoxide 6 to the acylated catechins 1 and 2 and would
be effective for the synthesis of various acylated catechin deriva-
Acknowledgment
This work was supported by Grant-in-Aid for Scientific Re-
search (S) (Grant-in-aid No. 22228002) from the Ministry of Educa-
tion, Culture, Sports, Science, and Technology.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.02.065.
References and notes
1. (a) Yamamoto, T.; Juneja, L. R.; Chu, D.-C.; Kim, M. Chemistry and Applications of
Green Tea; CRC: Boca Raton, 1997; (b) Stuart, E. C.; Scandlyn, M. J.; Rosengren,
R. J. Life Sci. 2006, 79, 2329.
2. Tachibana, H.; Koga, K.; Fujimura, Y.; Yamada, K. Nat. Struct. Mol. Biol. 2004, 11,
380.
3. (a) Rensburg, H.; Heerden, P. S.; Ferreira, D. J. Chem. Soc. Perkin Trans. 1 1997,
3415; (b) Nay, B.; Arnaudinaud, V.; Peyrat, J. F.; Nuhrich, A.; Deffieux, G.;
Merillon, J. M.; Vercauteren, J. Eur. J. Org. Chem. 2000, 1279; (c) Zaveri, N. T. Org.
Lett. 2001, 3, 843; (d) Li, L.; Chan, T. H. Org. Lett. 2001, 3, 739; (e) 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; (f) Anderson, J. C.; Headley, C.; Stapleton, P. D.;
Taylor, P. W. Tetrahedron 2005, 61, 7703; (g) Wan, S. B.; Dou, Q. P.; Chan, T. H.
Tetrahedron 2006, 62, 5897; (h) Furuta, T.; Hirooka, Y.; Abe, A.; Sugata, Y.; Ueda,
M.; Murakami, K.; Suzuki, T.; Tanaka, K.; Kan, T. Bioorg. Med. Chem. Lett. 2007,
17, 3095.
4. Liu, Y.; Li, Z.; Lin, G.; Xiang, Z.; Xiang, J.; Zhao, M.; Chen, J.; Yang, Z. Z. J. Org.
Chem. 2008, 73, 4625.
5. (a) Ohmori, K.; Takeda, M.; Higuchi, T.; Shono, T.; Suzuki, K. Chem. Lett. 2009,
38, 934; (b) Higuchi, T.; Ohmori, K.; Suzuki, K. Chem. Lett. 2009, 38, 1006; (c)
Ohmori, K.; Yano, T.; Suzuki Org, K. Biomol. Chem. 2010, 8, 2693.
6. (a) Tanaka, H.; Kitade, M.; Ohno, Y.; Tanaka, H.; Takahashi, T. Synlett 2006,
2827; (b) Kitade, M.; Tanaka, H. T. Takahashi Heterocycles 2007, 73, 183; (c)
Tanaka, H.; Miyoshi, H.; Chuang, Y.-C.; Ando, Y.; Takahashi Angew, T. Chem. Int.
Ed. 2007, 46, 5934; (d) Tanaka, H.; Yamanouchi, M.; Miyoshi, H.; Hirotsu, K.;
Tachibana, H.; Takahashi, T. Chem. Asian J. 2010, 5, 2231.
7. Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem. Soc. 1989, 111,
6881.
8. Ohmori, K.; Ushimaru, K.; Suzuki, K. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12002.
9. Kamal, A.; Chouhan, G.; Ahmed, K. Tetrahedron Lett. 2002, 43, 6947.
10. Tadross, P. M.; Gilmore, C. D.; Bugga, P.; Virgil, S. C.; Stoltz, B. M. Org. Lett. 2010,
12, 1224.
11. Pineschi, M.; Bertolini, F.; Haak, R. M.; Crotti, P.; Macchia, F. Chem. Commun.
2005, 1426.
tives composed of
skeleton.
a 2,3-cis- or trans-substituted chroman
12. H-CubeÒ is made by ThalesNano; Richard, V. J.; Norbert, V.; Lajos, G.; Laszlo, U.;
Daniel, S.; Ferenc, D. J. Comb. Chem. 2006, 8, 110.