Enantioselective synthesis of epigallocatechin-3-gallate (EGCG), the active polyphenol component from green tea.

Article abstract of DOI:10.1021/ol000394z

[reaction: see text]. Enantioselective synthesis of epigallocatechin-3-gallate (EGCG, 3b), the active polyphenol component from green tea, has been achieved by using a stereospecific cyclization of the Sharpless asymmetric dihydroxylation product 7c as the key step.

Full text of DOI:10.1021/ol000394z

ORGANIC
LETTERS
2001
Vol. 3, No. 5
739-741
Enantioselective Synthesis of
Epigallocatechin-3-gallate (EGCG), the
Active Polyphenol Component from
Green Tea
Lianhai Li and Tak Hang Chan*
Department of Chemistry, McGill UniVersity, Montreal, Quebec H3A 2K6, Canada
thchan@chemistry.mcgill.ca
Received December 27, 2000
ABSTRACT
Enantioselective synthesis of epigallocatechin-3-gallate (EGCG, 3b), the active polyphenol component from green tea, has been achieved by
using a stereospecific cyclization of the Sharpless asymmetric dihydroxylation product 7c as the key step.
Second to water, tea is probably the most widely consumed
beverage worldwide. Regular consumption of tea has been
associated with reduced risk of several forms of cancer and
other health benefits according to some epidemiological
studies.1 Tea leaves contain many constituents,2 and the
biological effects of tea are often attributed to the polyphenols
among the tea constituents.3 In freshly harvested tea leaves,
the following flavanols, known collectively as the catechins,
are present: (+)-catechin (1a), (+)-gallocatechin (1b), (-)-
epicatechin (2a), (-)-epigallocatechin (2b), (-)-epicatechin-
3-gallate (3a), and (-)-epigallocatechin-3-gallate (3b, EGCG).
In particular, (-)-epigallocatechin-3-gallate (3b, EGCG), the
main ingredient of green tea extract, has been shown to
inhibit growth in a number of tumor cell lines such as human
leukemia cell lines, mouse NFS60 cell line,4 MCF-7 breast
carcinoma, HT-29 colon carcinoma, A-427 lung carcinoma,
UACC-375 melanoma,5 the prostate cancer cell lines LNCaP,
PC-3 and DU145,6 leukemia blast cells from AML patients,7
and human epidermoid carcinoma cell line A431.8 In 1996,
the Division of Cancer Prevention and Control, National
Cancer Institute of the United States, published a clinical
development plan with respect to tea.9 At the present time,
EGCG (3b) can be obtained by isolation from green tea
extract, and the yield depends on the processing and the
source of the tea. As far as we are aware, no synthesis of
(4) Otsuka, T.; Ogo, T.; Eto, T.; Asano, Y.; Suganuma, M.; Niho, Y.
Life Sci. 1998, 63, 1397.
(5) Valcic, S.; Timmermann, B. N.; Alberts, D. S.; Watcher, G. A.;
Krutzsch, M.; Wymer, J.; Guillen, J. M. Anticancer Drugs 1996, 7, 461.
(6) Paschka, A. G.; Butler, R.; Young, C. Y. Cancer Lett. 1998, 130, 1.
(7) Asano, T.; Okamura, S.; Ogo, T.; Eto, T.; Otsukat, T.; Niho, Y. Life
Sci. 1997, 60, 135.
(1) For selected recent reviews, see: (a) Bushman, J. L. Nutr. Cancer
1998, 31, 151. (b) Weisburger, J. H. Proc. Soc. Exp. Biol. Med. 1999, 220,
271. (c) Hollman, P. C.; Feskens, E. J.; Katan, M. B. Proc. Soc. Exp. Biol.
Med. 1999, 220, 198. (d) Stensvold, I.; Tverdal, A.; Solvoll, K.; Per Foss
O. PreV. Med. 1992, 21, 546.
(2) Haslam, E. Plant Polyphenols. Vegetable Tannins ReVisited. Cam-
bridge University Press: Cambridge, 1989.
(3) The effect of the nonpolyphenolic fraction of green tea leaves has
recently been studied: Higashi-Okai, K.; Otani, S.; Okai, Y. Cancer Lett.
1998, 129, 223.
(8) Liang, Y. C.; Lin-Shiau, S. Y.; Chen, C. F.; Lin, J. K. J. Cell.
Biochem. 1997, 67, 55.
(9) Kelloff, G. J.; Crowell, J. A.; Hawk, E. T.; Steele, V. E.; Lubet, R.
A.; Boone, C. W.; Covey, J. M.; Doody, L. A.; Omenn, G. S.; Greenwald,
P.; Hong, W. K.; Parkinson, D. R.; Bagheri, D.; Baxter, G. T.; Blunden,
M.; Doeltx, M. K.; Eisenhauer, K. M.; Johnson, K.; Knapp, G. G.;
Longfellow, D. G.; Malone, W. F.; Nayfield, S. G.; Seifried, H. E.; Swall,
L. M.; Sigman, C. C. J. Cell. Biochem. Suppl. 1996, 26, 54.
10.1021/ol000394z CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/13/2001

EGCG has been reported.10 A totally synthetic approach will
provide access to both the racemate and the individual
enantiomers of EGCG as well as its analogues. Their
biological studies might reveal more information about how
EGCG acts as an anticancer agent. Our retrosynthetic
Scheme 2
Figure 1.
approach to the total synthesis of (-)-epigallocatechin-3-
gallate and its analogues is depicted in Scheme 1. By
Scheme 1
assembling the structure using the three separate aromatic
fragments A, B, and C, the scheme provides a potential route
to combinatorial library construction. The challenge resides
in the selective formation of the thermodynamically less
stable cis-disubstituted benzopyran and in the maintenance
of stereochemical integrity at the benzylic 2-position, which
is activated by the electron-donating oxygen functions on
the B phenyl ring.
droxylation of 6a with NMO in the presence of a catalytic
amount of OsO4 to give the diol 7a was accomplished
readily. Conversion of 7a to the ortho ester 8a was achieved
by reaction with triethyl orthoformate in the presence of
PPTS in CH2Cl2. When 8a was treated with acetyl bromide,
compound 9a was formed together with minor amounts of
its regioisomer. Without purification, the crude 9a was treated
with potassium carbonate in acetone to afford the cyclized
benzopyrans 10a and 11a. After removal of the formate ester
group, compound 12a was obtained together with its trans
isomer 13a in a ratio of 9:1. When the same sequence of
reactions was repeated starting from 3,4,5-trimethoxycin-
namyl alcohol (4b) and 5a, the cyclization of 9b followed
by removal of the formate group gave instead a mixture of
cis-12b and trans-13b in a ratio of 1:4, i.e., with the trans
isomer predominating. This suggested that the activated
benzylic position in the methoxy-substituted 9b could not
maintain its stereochemical integrity under these reaction
Coupling of cinnamyl alcohol (4a) and 3,5-dimethoxyphe-
nol (5a) with H2SO4/SiO2 as catalyst in CS2/CH2Cl2 gave
the product 6a in 55% isolated yield (Scheme 2). Dihy-
(10) For the syntheses of simpler catechins, see: (a) Keogh, E. J.; Philbin,
E. M. Chem. Ind. 1961, 2100. (b) Jain, A. C.; Prabhat, A.; Nayyar, N. K.
Indian J. Chem. 1983, 22B, 1116. (c) van Rensburg, H.; van Heerden, P.
S.; Bezuidenhoudt, B. C. B.; Ferreira, D. Tetrahedron Lett. 1997, 38, 3089.
(d) van Rensburg, H.; van Heerden, P. S.; Ferreira, D. J. Chem. Soc., Perkin
Trans. 1 1997, 3415. (e) Jew, S.; Kim, H.; Bae, S.; Kim, J.; Park, H.
Tetrahedron Lett. 2000, 41, 7925. (f) Nay, B.; Monti, J.-P.; Nuhrich, A.;
Deffieux, G.; Merillon, J.-M.; Vercauteren, J. Tetrahedron Lett. 2000, 41,
9049.
740
Org. Lett., Vol. 3, No. 5, 2001

conditions. We also found that the ortho ester 8b could be
cyclized directly to trans-11b in good yield with PPTS in
1,2-dichloroethane. Methanolic K2CO3 treatment of 11b gave
the pentamethylated gallocatechin 13b.
Compound 6c was therefore converted to the TBS derivative
18. Asymmetric dihydroxylations of 18 with either AD-
mix-R or -â were carried out to give the two enantiomers of
19. Desilylation of 19 with fluoride gave optically active
7c. The same sequence of reactions as discussed above was
An alternative approach to the cis isomer was therefore
sought.11 Dess-Martin oxidation of 13b gave the ketone 14b,
which on reduction with L-selectride in THF gave selectively
cis-15b. We have therefore a route to either diastereoisomer
at hand. The removal of the methyl protection proved to be
inconvenient. The whole sequence according to Scheme 2
was therefore repeated starting with the coupling of 3,4,5-
tris(benzyloxy)cinnamyl alcohol (4c) and 3,5-bis(benzyloxy)-
phenol (5c). In this manner, the pentabenzylated epigallo-
catechin 15c was obtained uneventfully. Esterification of 15c
with 3,4,5-tri-O-benzylgalloyl chloride (16) and DMAP in
CH2Cl2 gave the ester 17. Catalytic hydrogenation of 17 with
20% Pd(OH)2 afforded racemic epigallocatechin-3-gallate
(3b). Preliminary investigations showed that Sharpless asym-
Scheme 4
then applied to the enantiomer of 7c derived from AD-mix-R
to give (-)-epigallocatechin-3-gallate ((-)-3b), identical in
all respects with natural EGCG. The enantiomeric (+)-3b
obtained with AD-mix-â showed the same spectroscopic
properties but opposite optical rotation.13 NMR study of the
Mosher ester derivatives of 15c suggested that the two
enantiomers were essentially enantiomerically pure. The
overall yield of (-)-3b, based on the starting cinnamyl
alcohol 4c, is 19%.
Scheme 3
We have therefore accomplished the diastereo- and enan-
tioselective synthesis of EGCG. The approach should be
amenable to the synthesis of analogues with diverse substitu-
tion patterns in the aromatic rings.
Acknowledgment. We thank Quebepharma Recherche
Inc. for financial support of this research.
Supporting Information Available: Experimental details
and spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL000394Z
(12) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
(13) Spectroscopic and optical data of (-)-EGCG: 1H NMR (acetone/
D2O (2:1), 400 MHz) δ 6.96 (s, 2 H), 6.60 (s, 2 H), 5.97 (d, J ) 2.4 Hz,
1 H), 5.36 (d, J ) 1.2 Hz, 1 H), 4.96 (s, 1 H), 2.94 (dd, J ) 17.2, 4.4 Hz,
1 H), 3.10 (dd, J ) 17.2, 1.6 Hz, 1 H); 13C NMR (CDCl3, 100 MHz) δ
166.4, 156.6, 156.0, 145.5, 145.2, 138.5, 132.4, 129.9, 120.5, 109.4, 106.1,
98.1, 95.8, 95.0, 77.4, 69.5, 25.9; [R]D ) -148 (c ) 1.0, THF). The
synthetic compound had completely identical NMR spectra as the com-
mercially available sample (Sigma, [R]D ) -147.6 (c ) 1.0, THF)). By
using the same synthetic procedures described in the supplementary
information, (+)-EGCG ([R]D ) +148.2 (c ) 1.0, THF)) and the racemic
metric dihydroxylation12 could not be performed on 6a
directly or on its acetate. However, protection of the free
phenolic hydroxyl group as the tert-butyldimethylsilyl ether
permitted the dihydroxylation to proceed with AD-mix.
(11) The sequence Dess-Martin oxidation/L-Selectride reduction has
previously been applied to the stereochemical inversion at C-3 of 5,7,3′,4′-
tetra-O-benzylcatechin: Tuckmantel, W.; Kozikowski, A. P.; Romanczyk,
L. J., Jr. J. Am. Chem. Soc. 1999, 121, 12073.
1
form of EGCG were also obtained and had identical H NMR spectra as
the (-)-isomer.
Org. Lett., Vol. 3, No. 5, 2001
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