Studies in polyphenol chemistry and bioactivity. 3. Stereocontrolled synthesis of epicatechin-4α,8-epicatechin, an unnatural isomer of the B-type procyanidins

Article abstract of DOI:10.1021/jo001462y

Oligomeric procyanidins containing 4α-linked epicatechin units are rare in nature and have hitherto not been accessible through stereoselective synthesis. We report herein the preparation of the prototypical dimer, epicatechin-4α,8-epicatechin (6), by reaction of the protected 4-ketones 11a,b with aryllithium reagents derived by halogen/metal exchange from the awl bromides 26a,b. Removal of the 4-hydroxyl group from the resulting tertiary benzylic alcohols 27a,b was effected by tri-n-butyltin hydride and trifluoroacetic acid in a completely stereoselective manner, resulting in hydride delivery exclusively from the β face. If benzyl was chosen for protection of the 3-hydroxyls, all protective groups could subsequently be removed in a single step by hydrogenolysis, tert-Butyldimethylsilyl groups, on the other hand, permitted selective deprotection of the 3-hydroxyls in preparation for their subsequent acylation with tri-O-benzylgalloyl chloride. Only monogalloylation at the "bottom" 3-hydroxyl took place when 28c was acylated under the previously reported conditions, reflecting the increased steric hindrance of the "top" 3-hydroxyl group in 28c compared with its 4β,8-isomer 3. The preparation of compounds 14 and 17 containing phloroglucinol trimethyl ether in the 4α and 4β linkages to epicatechin is also described. The 8-position of the bromine atom in 19, previously conjectured in analogy to the structurally characterized tetramethyl ether 20, was confirmed by transformation of both compounds into the common derivative 25.

Full text of DOI:10.1021/jo001462y

J . Org. Chem. 2001, 66, 1287-1296
1287
Stu d ies in P olyp h en ol Ch em istr y a n d Bioa ctivity. 3.1,2
Ster eocon tr olled Syn th esis of Ep ica tech in -4r,8-ep ica tech in , a n
Un n a tu r a l Isom er of th e B-Typ e P r ocya n id in s
Alan P. Kozikowski,* Werner Tu¨ckmantel,* and Youhong Hu
Georgetown University Medical Center, Drug Discovery Program, 3900 Reservoir Road NW,
Washington, DC 20007
tueckmaw@giccs.georgetown.edu
Received October 10, 2000
Oligomeric procyanidins containing 4R-linked epicatechin units are rare in nature and have hitherto
not been accessible through stereoselective synthesis. We report herein the preparation of the
prototypical dimer, epicatechin-4R,8-epicatechin (6), by reaction of the protected 4-ketones 11a ,b
with aryllithium reagents derived by halogen/metal exchange from the aryl bromides 26a ,b. Removal
of the 4-hydroxyl group from the resulting tertiary benzylic alcohols 27a ,b was effected by tri-n-
butyltin hydride and trifluoroacetic acid in a completely stereoselective manner, resulting in hydride
delivery exclusively from the â face. If benzyl was chosen for protection of the 3-hydroxyls, all
protective groups could subsequently be removed in a single step by hydrogenolysis. tert-
Butyldimethylsilyl groups, on the other hand, permitted selective deprotection of the 3-hydroxyls
in preparation for their subsequent acylation with tri-O-benzylgalloyl chloride. Only monogalloyl-
ation at the “bottom” 3-hydroxyl took place when 28c was acylated under the previously reported
conditions, reflecting the increased steric hindrance of the “top” 3-hydroxyl group in 28c compared
with its 4â,8-isomer 3. The preparation of compounds 14 and 17 containing phloroglucinol trimethyl
ether in the 4R and 4â linkages to epicatechin is also described. The 8-position of the bromine
atom in 19, previously conjectured in analogy to the structurally characterized tetramethyl ether
20, was confirmed by transformation of both compounds into the common derivative 25.
In tr od u ction
Proanthocyanidins (nonhydrolyzable tannins) are of
current interest because of their numerous biological
activities, their widespread occurrence in foodstuffs, and
their resulting relevance for human health.1 As the
starting point of a program directed at the synthesis
of defined epicatechin oligomers for comparison with
compounds isolated from cocoa, we have previously
performed the TiCl4-mediated alkylation of 5,7,3′,4′-tetra-
O-benzyl-(-)-epicatechin (1) with 5,7,3′,4′-tetra-O-benzyl-
4-(2-hydroxyethoxy)epicatechin (2) (eq 1).1 Besides higher
oligomers in yields rapidly decreasing with their molec-
ular mass, a single dimeric product was obtained that
was identified as the procyanidin B2 derivative 3 by
hydrogenolytic conversion to procyanidin B2 and com-
parison of this material and its peracetate with isolates
1
and preparations described in the literature. In the
process of examining the relevant literature, it did not
escape our attention that, until quite recently, the
analytical methods employed for the assignment of
interflavan bond regio- and stereochemistry in these
compounds were not validated by an independent con-
firmation of the structure of any dimeric B-type pro-
anthocyanidin.1 The application of X-ray cystallography
has been prevented by the poor crystallizability of pro-
anthocyanidins and their derivatives. Assignments of
stereochemistry on the basis of H NMR coupling con-
stants and circular dichroism disregard the basic fact
that the C rings are conformationally flexible. From a
conservative point of view, postulates of specific confor-
mations of flexible molecules, regardless of their source
(intuitive or computational), cannot be considered a
prudent approach to structure elucidation. Advances in
synthetic methodology that have taken place after the
isolation of numerous proanthocyanidins from natural
sources have recently enabled us2 to obtain a definitive
proof of the previously conjectured 4â stereochemistry
in procyanidin B2. Thus, the differentially protected epi-
catechin dimer 4, correlated with procyanidin B2 through
a common derivative, was subjected to a series of de-
functionalization steps and finally degraded to (R)-(-)-
(1) Part 1: Tu¨ckmantel, W.; Kozikowski, A. P.; Romanczyk, L. L.
J r. J . Am. Chem. Soc. 1999, 121, 12073. See here for
a general
introduction of plant polyphenols, especially condensed tannins.
(2) Part 2: Kozikowski, A. P.; Tu¨ckmantel, W.; George, C. J . Org.
Chem. 2000, 65, 5371.
10.1021/jo001462y CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/31/2001

1288 J . Org. Chem., Vol. 66, No. 4, 2001
Kozikowski et al.
2,4-diphenylbutyric acid, isolated as its benzhydryl ester
5 (eq 2). The sole remaining asymmetric center in 5 is
F igu r e 1. Model for the directing effect of the 2-aryl and
3-alkoxy substituents on the attack of nucleophiles at C-4
Sch em e 1
directly derived from C-4 of the “top” epicatechin moiety
in procyanidin B2, and the sign of the optical rotation of
5, the absolute configuration of which was established
by X-ray crystallography, thus revealed the absolute
configuration at C-4.2
In a parallel thrust, which is the subject of the present
paper, we set out to prepare the alternative stereoisomer,
now recognizable by default as epicatechin-4R,8-epi-
catechin (6). Literature reports of proanthocyanidins for
which simultaneously a 2,3-cis and a 3,4-cis relationship
of their C-ring substituents has been postulated are
scarce,3 and compound 6 has not (yet) been isolated from
natural sources. No stereoselective synthesis of any
procyanidin containing a 4R-linked epicatechin unit has
been reported to date. It is a plausible assumption that,
in the course of the formation of the 4â,8-dimer 3, the
2-aryl group and the 3-oxygen cooperate in directing the
approach of the flavan nucleophile to the presumed
carbocationic intermediate 7 toward its â-face (Figure 1).4
The accessibility of the 4R-stereoisomer by merely modi-
fying the reaction conditions or attaching protecting
groups to one or both of the 3-hydroxyl groups was
therefore deemed unlikely. We reasoned instead that a
C4-carbocation 8 that has the “bottom” flavan unit
already in place would analogously be attacked by a
hydride nucleophile from its â-face, and the 4-flavanyl
group would, therefore, be forced to occupy the R-face.
The carbocation would be conveniently generated from
a tertiary alcohol which in turn, as Weinges et al. have
demonstrated earlier,5 is accessible from an 8-lithiated
building block and a 4-ketone.
phloroglucinol trimethyl ether was used as the “bottom”
unit in place of another epicatechin moiety (Scheme 1).
The free hydroxyl group in 1 was protected by benzylation
or silylation2 and the products 9a ,b oxidized with DDQ6
in THF using water to capture the intermediate car-
benium ion 7. The resulting alcohols 10a ,b (presumably,
but not with certainty, of 4â stereochemistry) were
oxidized to the ketones 11a ,b using Ley’s method.7
Compound 11a was reacted with 2,4,6-trimethoxyphenyl-
lithium8 to produce the tertiary alcohol 12 as a single
stereoisomer. Steric hindrance exerted by the 2-substitu-
ent once more suggests that the incoming 4-aryl sub-
stituent should attack the carbonyl group from the â face.
The hydrogenolytic deoxygenation at C-4 in a similar
compound has been reported5 to be very inefficient and
was not taken into consideration by us. Instead, treat-
Resu lts
P r ep a r a t ion of E p ica t ech in -P h lor oglu cin ol Di-
m er s. Initially, a model study was conducted in which
(3) (a) Foo, L. Y. J . Chem. Soc., Chem. Commun. 1986, 236. (b) Foo,
L. Y.; Karchesy, J . J . Phytochemistry 1989, 28, 3185. (c) Steynberg, P.
J .; Steynberg, J . P.; Hemingway, R. W.; Ferreira, D.; McGraw, G. W.
J . Chem. Soc., Perkin Trans. 1 1997, 2395.
(4) A reviewer suggested that instead the bulky 2-aryl group might
occupy a pseudoequatorial position in the transition state and that
the observed product stereochemistry could then result from a pre-
ferred pseudoaxial attack of the nucleophile. We do not have evidence
for or against either possibility.
(6) (a) Steenkamp, J . A.; Ferreira, D.; Roux, D. G. Tetrahedron Lett.
1985, 26, 3045. (b) Steenkamp, J . A.; Mouton, C. H. L.; Ferreira, D.
Tetrahedron 1991, 47, 6705.
(7) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J .
Chem. Soc., Chem. Commun. 1987, 1625.
(8) Previously prepared by metalation of 1,3,5-trimethoxybenzene:
(a) Van Koten, G.; Leusink, A. J .; Noltes, J . G. J . Organomet. Chem.
1975, 85, 105. (b) Kroth, H. J .; Schumann, H.; Kuivila, H. G.; Schaeffer,
C. D.; Zuckerman, J . J . J . Am. Chem. Soc. 1975, 97, 1754.
(5) Weinges, K.; Perner, J .; Marx, H.-D. Chem. Ber. 1970, 103, 2344.

Studies in Polyphenol Chemistry and Bioactivity
J . Org. Chem., Vol. 66, No. 4, 2001 1289
Sch em e 2
Sch em e 3
ment of 12 with Et3SiH/CF3COOH9 gave the reduction
product 13 as a single stereoisomer in 68% yield. Its 4R
stereochemistry is assigned in analogy to that of the
epicatechin dimer 6 discussed below on the basis of its
mode of formation and its C-ring 1H NMR coupling
pattern. Significant loss of material is caused by a side
reaction, elimination of water from the C3-C4 bond.
Switching from Et3SiH to the more reactive hydride
source, n-Bu3SnH, raised the yield to 87%. Hydrogenoly-
sis and acetylation provided the pentaacetate 15.
The TiCl4-mediated condensation10 between 2 and
1,3,5-trimethoxybenzene (Scheme 2) gave a single 4-
arylepicatechin 16. Its hydrogenolysis and subsequent
acetylation resulted in a pentaacetate 18 different from
15, to which 4â stereochemistry is assigned in analogy
with 3. Related preparations of catechin- and epicatechin-
phloroglucinol condensation products involving differ-
ent patterns of phenol protection have been reported
previously.3b,10-12 The parent heptaphenol is a natural
product.12
Au th en tica tion of Br om id e 19. We have thus iden-
tified conditions for the efficient removal of the 4-OH
group and confirmed our hypothesis that this process
generates an interflavan bond stereochemistry different
from that obtained by electrophilic alkylation. To trans-
late these results into an unequivocal synthesis of epi-
catechin-4R,8-epicatechin (6), it was essential to have
certainty regarding the regiochemistry of the lithiated
epicatechin derivative to be employed. We have previ-
ously reported the preparation of the required bromide
26c from its C-3 epimer 19.1 3-O-Protected derivatives
of 19 have earlier been prepared by bromination of
appropriate halogen-free catechin derivatives.13 The
postulated regiochemistry of those bromides was not
commented upon by the earlier authors and appears
to have been derived by analogy from that of the
tetramethyl ether 20, for which the 8-position of the
Br substituent is known from an X-ray crystal structure
analysis.14 To dispel any possible doubt, 19 and 20 were
both converted to the common derivative 25 (Scheme 3).
It is worth mentioning that our sample of 8-benzyl-
catechin (24) displays a melting point (212-213.5 °C) and
an optical rotation substantially different from those
reported.15 On the other hand, the melting point of 24 in
ref 15 (176 °C) is essentially identical with that reported
in the patent literature (174-176 °C)16 for 6-benzyl-
catechin. The melting point of our intermediate 23
(129.5-130 °C) matches reasonably well that reported
by the patent authors for the same structure (133-134
°C).17 It is then surprising that O-methylation of the
mentioned literature sample of 24 has been reported15
to yield compound 25 with a melting point essentially
identical with and an optical rotation close to ours. An
erroneous switching in ref 15 of the physical data of 24
but not of 25 with those of a sample of the 6-benzyl
regioisomer would offer a likely explanation.
Syn t h esis of E p ica t ech in -4R,8-ep ica t ech in (6).
In preparation for the halogen-metal exchange, the
3-hydroxyl group in 26c was protected by benzylation or
silylation (Scheme 4). Subsequent treatment of the
products 26a ,b with tert-butyllithium, followed by addi-
tion of the ketones 11a (for 26a ) or 11b (for 26b), resulted
in smooth formation of the biflavanoid tertiary alcohols
27a ,b as single isomers. Treatment of 27a with Et3SiH/
CF3COOH caused predominantly elimination, besides
interflavan bond cleavage. If Et3SiH was replaced with
n-Bu3SnH, smooth reduction of 27a ,b to the protected
epicatechin dimers 28a ,b took place. Compound 28b was
readily desilylated to the diol 28c with aqueous HF in
CH3CN, whereas n-Bu4NF gave a complex mixture. The
hydrogenolytic deprotection of 28a ,c was not as clean as
in the 4â series. An analytically pure sample of 6 was
(9) Carey, F. A.; Tremper, H. S. J . Org. Chem. 1971, 36, 758.
(10) Kawamoto, H.; Nakatsubo, F.; Murakami, K. J . Wood Chem.
Technol. 1989, 9, 35.
(11) (a) Geissman, T. A.; Yoshimura, N. N. Tetrahedron Lett. 1966,
2669. (b) J urd, L.; Lundin, R. Tetrahedron 1968, 24, 2653. (c) Botha,
J . J .; Young, D. A.; Ferreira, D.; Roux, D. G. J . Chem. Soc., Perkin
Trans. 1 1981, 1213.
(12) Kolodziej, H. Tetrahedron Lett. 1983, 24, 1825.
(13) Ballenegger, M. E.; Rimbault, C. G.; Albert, A. I.; Weith, A. J .;
Courbat, P.; Tyson, R. G.; Palmer, D. R.; Thompson, D. G. Eur. Pat.
0096007, J uly 29, 1987 (Example Nos. 67-70); Chem. Abstr. 1984, 100,
209512w.
(14) Engel, D. W.; Hattingh, M.; Hundt, H. K. L.; Roux, D. G. J .
Chem. Soc., Chem. Commun. 1978, 695.
(15) Weinges, K.; Seiler, D. Liebigs Ann. Chem. 1968, 714, 193.
(16) Reference 13, Example No. 16.
(17) Reference 13, Example No. 17.

1290 J . Org. Chem., Vol. 66, No. 4, 2001
Kozikowski et al.
Sch em e 4
a narrow low-field multiplet (δ 5.39), indicating by its
chemical shift that the vicinal 3-hydroxyl group should
be acylated. 3-H of the C1 ring, on the other hand,
appears as a doublet of doublets at δ 4.25 for the major
rotamer. As a note of caution, however, it should be kept
in mind that signal assignments based on chemical shifts
are problematic here because of the presence of multiple
magnetically anisotropic functionality. An unequivocal
synthesis of 30 and its regioisomer could be conceived
starting from dimeric precursors bearing differential
protecting groups at the 3-hydroxyls, available from the
reaction of 11a with the aryllithium derived from 26b,
and of 11b with the aryllithium derived from 26a ,
respectively. We did, however, not pursue this avenue
as our target was the bisgallate. To our initial relief,
inclusion of molecular sieves in the reaction mixture
allowed further galloylation of the monogallate 30 to
what appeared to be the di-3-O-galloyl derivative. The
mechanism of action of the additive is not obvious;
certainly, the large excess of acylating agent used renders
a mere scavenging of adventitious moisture improbable.
Surface catalysis is therefore likely to be involved. The
supposed bisgallate upon hydrogenolysis yielded a mix-
ture of two compounds (according to HPLC) both of which
exhibited mass spectra in accordance with the desired
di-3-O-galloyl derivative of 6. Reexamination by HPLC
of the protected precursor under different conditions
subsequently revealed its inhomogeneity. The achieved
separation was, however, inadequate for preparative
purposes, and we abandoned our efforts toward the
synthesis of the bisgallate.
Sch em e 5
Con clu sion
A highly stereoselective synthesis of the hitherto
inaccessible, unnatural procyanidin stereoisomer, epi-
catechin-4R,8-epicatechin (6), has been achieved. The
preparation of higher 4,8-oligomers possessing R stereo-
chemistry in some or all of its interflavan bonds should
be possible by extending the previously reported electro-
philic substitution process to the precursors 28a -c or by
subjecting bromides derived from these compounds or
from compound 3 to the conditions of the present work.
Exp er im en ta l Section
obtained only if aliphatic impurities were removed before
the final lyophilization by extraction of the aqueous
solution with toluene. Alternatively, the crude hydro-
genolysis product was directly converted into its acetate
29. Both compounds 6 and 29 were different by 1H NMR
spectroscopy from their 4â isomers. As the 4,8-position
of their interflavan linkage is a necessary consequence
of the structure of the starting material 26c, compound
6 is unequivocally identified as the hitherto unknown
epicatechin-4R,8-epicatechin.
Gen er a l P r oced u r es. Pearlman’s catalyst (20% Pd(OH)2/
C) was obtained from Aldrich and contained e50% H2O. 1H
and 13C NMR spectra were acquired at nominal frequencies
of 300 and 75 MHz, respectively. 1H NMR spectra are
referenced to internal TMS, 13C NMR spectra to internal TMS
if so marked, otherwise to the CDCl3 signal (δ 77.00). Combus-
tion analyses: Micro-Analysis, Inc. (Wilmington, DE). Column
chromatography (CC): Merck silica gel 60 Geduran (No.
110832-1), particle size 63-200 µm. TLC: Merck silica gel 60
F254 (No. 5715-7), layer thickness 250 µm; visualization with
alkaline KMnO4 solution.
P r ep a r a tion of Ga llic Acid Ester s of 6. We were
initially surprised to find that the galloylation of 28c
under the conditions described for its 4â isomer 31 turned
out a monoester (Scheme 5). In hindsight, this is not
surprising as the C1 ring hydroxyl group in 28c is
severely hindered by two vicinal, cis-oriented aryl sub-
stituents. This rationale hints at 30 as the structure of
the major product. The same regiochemistry is suggested
by the observation of COSY cross-peaks between the 4-H
signals (narrow multiplets at δ 2.88 and 3.18 for the
major and minor rotamer, respectively) of the C2 ring and
3,5,7,3′,4′-P en ta -O-ben zylep ica tech in (9a ). To a suspen-
sion of 180 mg (4.5 mmol) of NaH (60% in oil) in 10 mL of dry
DMF was added at room temperature a solution of 2.60 g (4.00
mmol) of 1 in 10 mL of dry DMF. After 1 h, 0.56 mL (4.7 mmol)
of BnBr was added. The mixture was stirred overnight, poured
into ice-water, and extracted with 3 × 50 mL of CH2Cl2. The
combined organic phases were washed with H2O and brine,
dried over MgSO4, and evaporated. The residue was purified
by CC (CH2Cl2/EtOAc/hexane 1:1:6) to give 2.20 g (74%) of the
product as a colorless, amorphous solid: [R]D -30.7, [R]546
-37.2 (c 6 gL-1, EtOAc); 1H NMR (CDCl3) δ 7.48-7.25 (m, 20
H), 7.19 (s, 1 H), 7.17-7.12 (m, 3 H), 7.04-6.97 (m, 2 H), 6.91

Studies in Polyphenol Chemistry and Bioactivity
J . Org. Chem., Vol. 66, No. 4, 2001 1291
(narrow ABq, 2 H), 6.27, 6.25 (ABq, 2 H, J ) 2 Hz), 5.17 (s, 2
H), 5.05 (s, 2 H), 5.00 (s, 2 H), 4.98 (s, 2 H), 4.94 (s, 1 H), 4.44,
4.30 (ABq, 2 H, J ) 12.5 Hz), 3.91 (narrow m, 1 H), 2.99, 2.77
(ABq, 2 H, J ) 17 Hz, both parts d with J ) 2.5, 4 Hz,
respectively); 13C NMR (CDCl3) δ 158.59, 157.95, 155.56,
148.75, 148.33, 138.07, 137.37, 137.28, 137.07, 136.94, 132.20,
128.49, 128.45, 128.38, 128.32, 128.03, 127.87, 127.78, 127.67,
127.61, 127.57, 127.49, 127.32, 127.23, 127.17, 119.75, 114.69,
113.80, 101.45, 94.73, 93.73, 78.02, 72.55, 71.31, 71.14, 71.02,
70.03, 69.86, 24.47; IR (film) 1617, 1592, 1145, 1116, 735, 696
cm-1. Anal. Calcd for C50H44O6: C, 81.06; H, 5.99. Found: C,
81.19; H, 5.76.
1165, 1120, 1025, 736, 696 cm-1. Anal. Calcd for C50H42O7: C,
79.56; H, 5.61. Found: C, 79.99; H, 5.31.
(2R,3S)-5,7,3′,4′-Tetr a-O-ben zyl-3-O-[(ter t-bu tyldim eth yl-
silyl)oxy]fla va n -4-on e (11b). To a solution of 0.39 g (0.50
mmol) of 10b in 2 mL of dry CH2Cl2 was added at room
temperature 100 mg of 4 Å molecular sieves, 60 mg (0.55
mmol) of N-methylmorpholine N-oxide, and 20 mg (55 µmol)
of tetra-n-propylammonium perruthenate. The reaction mix-
ture was stirred overnight and evaporated, and the residue
was purified by CC (EtOAc/hexane 1:4) to give 0.38 g (99%) of
the ketone as a white foam: [R]D -32.5, [R]546 -39.2 (c 12 gL-1
,
EtOAc); 1H NMR (CDCl3) δ 7.52-7.26 (m, 20 H), 7.12 (br s, 1
H), 7.00, 6.94 (ABq, 2 H, J ) 8.5 Hz, A part d with J ) 1 Hz),
6.22, 6.18 (ABq, 2 H, J ) 2 Hz), 5.25 (s, 1 H), 5.22-5.12 (m, 6
H), 5.05, 5.01 (ABq, 2 H, J ) 11.5 Hz), 4.01 (d, 1 H, J ) 1.5
Hz), 0.72 (s, 9 H), -0.11 (s, 3 H), -0.25 (s, 3 H); 13C NMR
(CDCl3) δ 188.67, 164.60, 163.94, 161.18, 148.78, 148.73,
137.14, 136.53, 135.77, 129.59, 128.64, 128.46, 128.43, 128.40,
128.29, 127.78, 127.71, 127.62, 127.50, 127.38, 127.22, 126.41,
120.12, 114.90, 113.98, 104.51, 95.04, 94.32, 81.48, 75.10,
71.31, 71.28, 70.19, 70.14, 25.61, 18.12, -5.08, -5.37; IR (film)
1680, 1608, 1268, 1164, 1121, 736, 696 cm-1. Anal. Calcd for
3,5,7,3′,4′-P en ta -O-ben zyl-4-h yd r oxyep ica tech in (10a ).
To a solution of 2.20 g (3.38 mmol) of 9a in 20 mL of THF and
0.16 mL (8.9 mmol) of H2O was added at room temperature
2.00 g (7.4 mmol) of DDQ. The mixture was stirred overnight,
and then 0.91 g (7.4 mmol) of DMAP was added, stirring was
continued for 5 min, and 20 g of silica gel was added. After
evaporation, the residue was filtered over SiO2 (EtOAc/hexane
1:4, then CH2Cl2/EtOAc/hexane 1:1:4) to give 1.05 g (47%) of
the product as a white foam: [R]D +6.6, [R]546 +7.2 (c 10 gL-1
,
1
EtOAc); H NMR (CDCl3) δ 7.50-7.28 (m, 20 H), 7.20-7.11
(m, 4 H), 7.04-6.92 (m, 4 H), 6.30 (narrow m, 2 H), 5.20 (s, 2
H), 5.09 (narrow ABq, 2 H), 5.06 (s, 2 H), 5.03 (s, 1 H), 5.01 (s,
2 H), 4.95 (narrow m, 1 H), 4.39, 4.25 (ABq, 2 H, J ) 12 Hz),
3.70 (narrow m, 1 H), 2.41 (d, 1 H, J ) 2 Hz); 13C NMR (CDCl3)
δ 160.32, 159.00, 156.09, 148.88, 148.39, 137.61, 137.38,
137.26, 136.64, 136.48, 131.58, 128.70, 128.59, 128.43, 128.38,
128.14, 128.06, 127.78, 127.63, 127.68, 127.54, 127.49, 127.35,
127.31, 127.28, 119.88, 114.82, 113.61, 104.77, 94.79, 94.06,
77.07, 74.83, 72.49, 71.34, 70.98, 70.20, 70.10, 61.10; IR (film)
1616, 1592, 1152, 1120, 736, 696 cm-1. Anal. Calcd for
C
49H50O7Si: C, 75.55; H, 6.47. Found: C, 75.67; H, 6.39.
3,5,7,3′,4′-P en ta-O-ben zyl-4-h ydr oxy-4-(2,4,6-tr im eth oxy-
p h en yl)ep ica tech in (12). To a solution of 32 mg (130 µmol)
of 1-bromo-2,4,6-trimethoxybenzene in 1 mL of dry THF was
added at -78 °C 85 µL (145 µmol) of t-BuLi (1.7 M in pentane).
After 1 h at -78 °C, a solution of 50 mg (66 µmol) of 11a in 1
mL of dry THF was added. After another 3 h at -78 °C, 2 mL
of aqueous NH4Cl solution was added, and the product was
extracted into 3 × 10 mL of CH2Cl2. The combined organic
phases were dried over MgSO4 and evaporated, and the residue
was purified by CC (EtOAc/hexane 1:4) to give 25 mg (45%) of
C
50H44O7: C, 79.34; H, 5.86. Found: C, 79.91; H, 5.60.
1
5,7,3′,4′-Tet r a -O-b en zyl-3-O-(ter t-b u t yld im et h ylsilyl)-
the product: [R]D +22.7, [R]546 +27.2 (c 12 gL-1, EtOAc); H
4-h yd r oxyep ica tech in (10b). To a solution of 1.52 g (1.98
mmol) of 9b in 10 mL of THF and 0.10 mL (5.6 mmol) of H2O
was added at room temperature 1.34 g (5.9 mmol) of DDQ.
The mixture was stirred overnight, and then 0.61 g (5.0 mmol)
of DMAP was added, stirring was continued for 5 min, and 20
g of silica gel was added. After evaporation, the residue was
filtered over SiO2 (EtOAc/hexane 1:4) to give 1.12 g (72%) of
NMR (CDCl3) δ 7.48-7.26 (m, 15 H), 7.21-7.10 (m, 7 H), 7.08-
7.03 (m, 2 H), 6.96-6.90 (m, 2 H), 6.81, 6.78 (ABq, 2 H, J )
8.5 Hz, B part br), 6.32 (d, 1 H, J ) 2 Hz), 6.29-6.24 (m, 2 H),
6.05 (d, 1 H, J ) 2.5 Hz), 5.15 (s, 2 H), 5.05 (s, 2 H), 5.04-4.80
(m, 6 H), 4.54 (d, 1 H, J ) 12.5 Hz), 4.23 (s, 1 H), 3.83 (s, 3 H),
3.77 (s, 3 H), 3.21 (s, 3 H); 13C NMR (CDCl3) δ 160.27, 160.04,
159.28, 158.63, 158.44, 154.61, 148.65, 147.95, 138.78, 137.46,
137.40, 137.03, 136.88, 132.67, 128.47, 128.35, 128.28, 128.17,
128.08, 127.83, 127.77, 127.63, 127.53, 127.39, 127.29, 127.24,
126.99, 126.72, 119.51, 114.96, 114.61, 113.74, 111.39, 94.62,
94.27, 93.47, 92.20, 79.90, 76.13, 74.69, 74.52, 71.30, 70.95,
69.96, 69.86, 56.60, 56.00, 55.20; IR (film) 3535, 1605, 1590,
1151, 1117, 736, 697 cm-1. Anal. Calcd for C59H54O10: C, 76.77;
H, 5.90. Found: C, 76.43; H, 5.48.
the product as a white foam: [R]D +2.0, [R]546 +2.2 (c 10 gL-1
,
EtOAc); 1H NMR (CDCl3) δ 7.49-7.22 (m, 20 H), 7.14 (d, 1 H,
J ) 2 Hz), 7.02, 6.95 (ABq, 2 H, J ) 8.5 Hz, A part d with J
) 1.5 Hz), 6.27, 6.25 (ABq, 2 H, J ) 2.5 Hz), 5.17 (s, 4 H), 5.11
(narrow ABq, 2 H), 5.02 (s, 2 H), 5.00 (s, 1 H), 4.79 (d, 1 H, J
) 2 Hz), 3.88 (dd, 1 H, J ) 1, 2.5 Hz), 2.35 (s, 1 H), 0.70 (s, 9
H), -0.21 (s, 3 H), -0.45 (s, 3 H); 13C NMR (CDCl3) δ 160.11,
158.86, 156.27, 148.87, 148.26, 137.32, 137.28, 136.67, 132.20,
128.64, 128.57, 128.41, 128.38, 128.02, 127.99, 127.74, 127.66,
127.62, 127.46, 127.29, 127.09, 120.09, 115.25, 113.98, 104.63,
94.51, 93.67, 75.37, 71.66, 71.47, 71.28, 70.03, 64.18, 25.67,
17.98, -5.37, -5.51; IR (film) 1617, 1593, 1259, 1153, 1026,
835, 736, 697 cm-1. Anal. Calcd for C49H52O7Si: C, 75.35; H,
6.71. Found: C, 75.21; H, 6.65.
3,5,7,3′,4′-P en ta -O-ben zyl-4r-(2,4,6-tr im eth oxyp h en yl)-
ep ica tech in (13). (a ) Red u ction w ith Et3SiH/CF 3COOH.
To a solution of 22 mg (24 µmol) of 12 in 1 mL of CH2Cl2 was
added at room temperature 38 µL (0.24 mmol) of Et3SiH and
then 22 µL (0.29 mmol) of CF3COOH. After 2 h, solid Na2CO3
was added. Filtration, evaporation, and purification by TLC
(EtOAc/hexane 1:3) gave 15 mg (69%) of the product. (b)
Red u ction w ith Bu 3Sn H/CF 3COOH. To a solution of 46 mg
(50 µmol) of 12 in 1 mL of CH2Cl2 was added at room
temperature 20 µL (74 µmol) of Bu3SnH and then 75 µL of 1
M CF3COOH/CH2Cl2. After 10 min, solid Na2CO3 was added.
Filtration, evaporation, and purification by TLC (EtOAc/
hexane 1:2) gave 39 mg (86%) of the product: [R]D -29.0, [R]546
(2R,3S)-3,5,7,3′,4′-P en takis(ben zyloxy)flavan -4-on e (11a).
To a solution of 1.00 g (1.32 mmol) of 10a in 8 mL of dry CH2-
Cl2 was added at room temperature 300 mg of 4 Å molecular
sieves, 180 mg (1.54 mmol) of N-methylmorpholine N-oxide,
and 58 mg (165 µmol) of tetra-n-propylammonium perruth-
enate. The reaction mixture was stirred overnight and evapo-
rated, and the residue was purified by CC (EtOAc/CH2Cl2/
hexane 1:1:10) to give 0.66 g (66%) of the ketone as a white
foam: [R]D -47.9, [R]546 -58.5 (c 10 gL-1, EtOAc); 1H NMR
(CDCl3) δ 7.67-7.38 (m, 20 H), 7.27 (s, 1 H), 7.24-7.22 (m, 3
H), 7.12-7.10 (m, 2 H), 7.02 (m, 2 H), 6.33 (d, 1 H, J ) 2.1
Hz), 6.29 (d, 1 H, J ) 2.1 Hz), 5.34 (d, 1 H, J ) 1.2 Hz), 5.26
(d, 2 H), 5.24 (s, 2 H), 5.14 (s, 2 H), 5.09 (s, 2 H), 4.78 (d, 1 H,
J ) 12.0 Hz), 4.50 (d, 1 H, J ) 12.0 Hz), 3.85 (d, 1 H, J ) 1.8
Hz); 13C NMR (CDCl3) δ 187.59, 165.12, 164.53, 161.71, 149.06,
148.96, 137.37, 137.32, 137.30, 136.56, 135.89, 129.25, 128.85,
128.71, 128.63, 128.57, 128.49, 128.219, 128.154, 127.94,
127.91, 127.78, 127.72, 127.50, 127.37, 126.30, 120.29, 114.64,
114.08, 104.70, 95.47, 94.76, 80.96, 79.26, 72.30, 71.34, 71.22,
70.44; IR (film) 3031, 2870, 1673, 1606, 1572, 1512, 1454, 1269,
1
-43.7 (c 12 gL-1, EtOAc); H NMR (CDCl3) δ 7.48-7.25 (m,
16 H), 7.21-7.14 (m, 3 H), 7.06-6.97 (m, 4 H), 6.90 (d, 1 H, J
) 8 Hz), 6.79-6.74 (m, 2 H), 6.66-6.61 (m, 2 H), 6.33 (d, 1 H,
J ) 2.5 Hz), 6.20 (d, 1 H, J ) 2 Hz), 6.11 (d, 1 H, J ) 2.5 Hz),
6.03 (d, 1 H, J ) 2 Hz), 5.16 (s, 2 H), 5.05-4.97 (m, 3 H), 4.94-
4.88 (m, 3 H), 4.77, 4.68 (ABq, 2 H, J ) 11.5 Hz), 3.94 (d, 1 H,
J ) 6.5 Hz), 3.78 (s, 3 H), 3.69 (s, 3 H), 3.58, 3.49 (ABq, 2 H,
J ) 11 Hz), 3.26 (s, 3 H); 13C NMR (CDCl3) δ 161.04, 159.26,
158.17, 158.14, 157.44, 156.54, 148.97, 148.15, 138.04, 137.43,
137.39, 137.17, 137.01, 132.82, 128.51, 128.49, 128.39, 128.31,
127.88, 127.82, 127.68, 127.61, 127.55, 127.51, 127.42, 127.31,
127.12, 126.88, 126.84, 119.72, 114.94, 113.72, 110.80, 108.07,
94.99, 93.30, 92.22, 90.82, 79.98, 74.95, 71.45, 71.02, 69.97,
69.52, 56.21, 55.97, 55.25, 35.11; IR (film) 1605, 1590, 1151,

1292 J . Org. Chem., Vol. 66, No. 4, 2001
Kozikowski et al.
1113, 736, 697 cm-1. Anal. Calcd for C59H54O9: C, 78.12; H,
6.00. Found: C, 77.78; H, 5.89.
NMR (CDCl3) δ 169.45, 169.13, 168.31, 168.15, 168.12, 160.81,
155.69, 148.95, 148.66, 141.84, 141.44, 136.91, 124.37, 122.92,
121.86, 113.79, 108.86, 108.47, 106.77, 92.39, 91.38, 74.41,
71.12, 55.93, 55.29, 32.73, 21.16, 20.76, 20.66, 20.03; IR (film)
3,5,7,3′,4′-P en ta -O-a cetyl-4r-(2,4,6-tr im eth oxyp h en yl)-
ep ica tech in (15). To a solution of 100 mg (110 µmol) of 13 in
6 mL of MeOH/EtOAc 2:1 was added 20 mg of 20% Pd(OH)2/
C. The mixture was stirred under 1 bar of H2 for 3 h, after
which period TLC indicated completion of the reaction. The
catalyst was filtered off and washed with MeOH. The solution
was evaporated, and the residue was dried in vacuo and
dissolved at room temperature in 4 mL of Ac2O/pyridine. After
being stirred overnight, the mixture was evaporated, 40 mL
of CH2Cl2 was added, the phases were separated, and the
organic phase was washed with 5 × 10 mL of H2O and 10 mL
of brine and dried over MgSO4. The solution was evaporated,
and the crude product was purified by TLC (EtOAc/hexane
1:1) to give 30 mg (41%) of the pentaacetate: [R]D -38.8, [R]546
-48.0 (c 12 gL-1, EtOAc); 1H NMR (CDCl3) δ 7.44 (d, 1 H, J )
2 Hz), 7.33, 7.18 (ABq, 2 H, J ) 8.5 Hz, A part d with J ) 2
Hz), 6.73, 6.44 (ABq, 2 H, J ) 2.5 Hz), 6.11, 5.98 (ABq, 2 H, J
) 2.5 Hz), 5.68 (d, 1 H, J ) 5.5 Hz), 5.25 (s, 1 H), 5.00 (d, 1 H,
J ) 5.5 Hz), 3.88 (s, 3 H), 3.77 (s, 3 H), 3.36 (s, 3 H), 2.27 (s,
9 H), 1.58 (s, 6 H); 13C NMR (CDCl3) δ 169.57, 169.02, 168.07,
168.05, 167.74, 160.34, 160.00, 158.55, 155.37, 148.98, 148.46,
141.87, 141.54, 136.10, 124.18, 123.04, 121.77, 115.91, 108.74,
108.15, 105.86, 90.83, 90.17, 77.63, 68.46, 56.11, 55.38, 55.16,
33.78, 21.11, 20.63, 20.06, 19.77; IR (film) 1766, 1741, 1589,
1369, 1202, 1114 cm-1. Anal. Calcd for C34H34O14: C, 61.26;
H, 5.14. Found: C, 61.08; H, 5.02.
1770, 1747, 1606, 1590, 1206, 1118 cm-1
.
3,5,7,3′,4′-P en t a -O-b en zyl-8-b r om oca t ech in . To 0.23 g
(5.8 mmol) of NaH (60% suspension in mineral oil) was added
with stirring at room temperature under N2 within 5 min 2.82
g (3.87 mmol) of 191 in 8 mL of anhydrous DMF. After 10 min,
0.74 mL (6.2 mmol) of neat BnBr was added in 10 min with
water cooling. The mixture was stirred at room temperature
for 70 min and then cautiously hydrolyzed with 1 mL of water.
Eighty milliliters of water was added, the product was
extracted into 40 + 20 mL of toluene, and the combined organic
phases were washed with 80 mL of water and evaporated. The
residue was chromatographed on SiO2; a forerun was removed
with EtOAc/CHCl3/hexane 1:2:17 and the product eluted with
EtOAc/CHCl3/hexane 1:9:10. Evaporation and drying in vacuo
(rt, then 80 °C) yielded 3.13 g (99%) of the product as a
colorless glass: [R]D -15.7, [R]546 -18.8 (EtOAc, c 41.2 gL-1);
1H NMR (CDCl3) δ 7.48-7.21 (m, 23 H), 7.10 (m, 2 H), 7.00 (s,
1 H), 6.91 (narrow ABq, 2 H), 6.22 (s, 1 H), 5.17 (s, 2 H), 5.10
(narrow ABq, 4 H), 4.99 (d, 1 H, J ) 7 Hz), 4.97 (s, 2 H), 4.34,
4.22 (ABq, 2 H, J ) 12 Hz), 3.72 (dt, 1 H, J ) 5.5 Hz (d), 7 Hz
(t)), 2.88, 2.73 (ABq, 2 H, J ) 17.5 Hz, both parts d with J )
5.5, 7.5 Hz, respectively); 13C NMR (CDCl3) δ 156.14, 154.66,
151.23, 148.69, 148.62, 137.87, 137.28, 137.12, 136.71, 136.65,
131.88, 128.59, 128.55, 128.46, 128.42, 128.27, 128.01, 127.89,
127.77, 127.71, 127.63, 127.36, 127.24, 127.17, 127.03, 119.80,
114.78, 113.37, 104.00, 92.72, 79.71, 74.03, 71.49, 71.29, 71.26,
70.99, 70.23, 25.32; IR (film) 1605, 1580, 1513, 1126, 1097,
5,7,3′,4′-Tet r a -O-b en zyl-4â-(2,4,6-t r im et h oxyp h en yl)-
ep ica tech in (16). To a solution of 28 mg (39 µmol) of 2 and
20 mg (0.12 mmol) of 1,3,5-trimethoxybenzene in 1 mL of CH2-
Cl2/THF 4:5 was added at room temperature 80 µL of TiCl4 (1
M in CH2Cl2). After 2 h, 1 mL of saturated aqueous NaHCO3
(1 mL) was added, the phases were separated, and the aqueous
phase was extracted with 3 × 5 mL of CH2Cl2. The combined
organic phases were dried over MgSO4 and evaporated.
Purification by CC (EtOAc/hexane 1:6) gave 17 mg (53%) of
736, 696 cm-1
.
3,5,7,3′,4′-P en ta -O-ben zyl-8-(r-h yd r oxyben zyl)ca tech in
(21). To a solution of 549 mg (670 µmol) of 3,5,7,3′,4′-
penta-O-benzyl-8-bromocatechin in 6.7 mL of anhydrous
THF was added dropwise with stirring at -78 °C under N2
0.99 mL (1.68 mmol, 2.5 equiv) of t-BuLi (1.7 M in pentane).
After 5 min, 136 µL (1.34 mmol, 2 equiv) of PhCHO in
1.3 mL of anhydrous THF was added dropwise in 3 min. After
another 20 min, the cold bath was removed, 5 mL of H2O was
added, and the THF was evaporated. The product was ex-
tracted into 2 × 10 mL of EtOAc, and the combined organic
phases were dried over MgSO4 and evaporated. CC with
EtOAc/hexane 1:4 (for forerun) then 1:3 gave, after evaporation
and drying in vacuo, 397 mg (70%) of 21 as a yellowish
glass: 1H NMR (CDCl3; ratio of diastereoisomers 5:4; MD )
major, md ) minor diastereoisomer) δ 7.50-7.13 (m, 28 H),
7.00 (m, 2 H), 6.92 (d, 1 H, MD, J ) 1 Hz), 6.91, 6.86 (ABq,
2 H, MD, J ) 8.5 Hz, B part d with J ) 1 Hz), 6.84, 6.68
(ABq, 2 H, md, J ) 8.5 Hz, B part d with J ) 1.5 Hz), 6.77 (d,
1 H, md, J ) 1 Hz), 6.33 (d, 1 H, md, J ) 12 Hz), 6.26 (d, 1 H,
MD, J ) 11.5 Hz), 6.25 (s, 1 H, md), 6.23 (s, 1 H, MD), 5.18
(s, 2 H, MD), 5.17 (s, 2 H, md), 5.07-4.87 (m, 6 H), 4.80 (d,
1 H, md, J ) 8 Hz), 4.70 (d, 1 H, MD, J ) 8 Hz), 4.25, 4.06
(ABq, 2 H, MD, J ) 12 Hz), 4.18, 4.01 (ABq, 2 H, md, J )
12 Hz), 4.10 (d, 1 H, MD + md, J ) 12 Hz), 3.70 (dt, 1 H, MD,
J ) 5.5 Hz (d), 9 Hz (t)), 3.56 (dt, 1 H, md, J ) 5.5 Hz (d),
9 Hz (t)), 3.08, 3.04, 2.70, 2.67 (2 ABq, 2 H, MD + md, J )
16.5 Hz, A parts d with J ) 5.5 Hz, B parts d with J ) 2 Hz);
IR (film) 3544, 1603, 1513, 1499, 1454, 1264, 1211, 1121, 1023,
1
the product: [R]D +101, [R]546 +123 (c 12.5 gL-1, EtOAc); H
NMR (CDCl3) δ 7.47-7.14 (m, 19 H), 7.00-6.90 (m, 4 H), 6.34
(s, 1 H), 6.20 (m, 2 H), 6.07 (s, 1 H), 5.28 (s, 1 H), 5.14 (s, 4 H),
5.06 (s, 2 H), 4.83 (s, 2 H), 4.75 (s, 1 H), 3.91 (d, 1 H, J )
4.Hz), 3.81 (s, 3 H), 3.73 (s, 3 H), 3.24 (s, 3 H), 1.76 (d, 1 H, J
) 5 Hz); 13C NMR (CDCl3) δ 159.94, 159.88, 158.86, 158.25,
157.72, 155.60, 149.07, 148.41, 137.32, 137.27, 137.14, 132.45,
128.50, 128.41, 128.39, 128.01, 127.86, 127.73, 127.70, 127.59,
127.55, 127.26, 127.22, 126.75, 119.57, 115.13, 113.55, 111.82,
104.78, 94.20, 93.33, 92.63, 91.34, 75.63, 71.82, 71.41, 71.35,
70.06, 69.36, 56.25, 55.69, 55.25, 34.80; IR (film) 1603, 1266,
1149, 1122, 737, 697 cm-1. Anal. Calcd for C52H48O9: C, 76.45;
H, 5.92. Found: C, 77.05; H, 5.57.
4â-(2,4,6-Tr im eth oxyp h en yl)ep ica tech in (17). A solution
of 17 mg (21 µmol) of 16 in 1 mL of MeOH was hydrogenated
overnight at atmospheric pressure and room temperature over
1 mg of 20% Pd(OH)2/C. The catalyst was filtered off and
washed with MeOH. After evaporation, the crude product was
purified by TLC (CH2Cl2/MeOH 10:1) to give 8 mg (84%) of a
white solid: 1H NMR (CD3OD) δ 6.86 (d, 1 H, J ) 1.5 Hz),
6.70, 6.63 (ABq, 2 H, J ) 8 Hz, B part d with J ) 1.5 Hz), 6.26
(br, 1 H), 6.13 (br, 1 H), 5.97, 5.86 (ABq, 2 H, J ) 2.5 Hz),
5.02 (s, 1 H), 4.55 (s, 1H), 3.86 (br, 3 H), 3.77 (s, 3 H), 3.75 (s,
1 H); one OCH3 signal concealed by the CD2HOD signal at δ
3.30.
3,5,7,3′,4′-P en ta -O-a cetyl-4â-(2,4,6-tr im eth oxyp h en yl)-
ep ica tech in (18). A 64 mg (140 µmol) sample of 17 was
dissolved in 1.5 mL of Ac2O/pyridine 1:2, and the solution was
stirred overnight at room temperature. After evaporation, 20
mL of CH2Cl2 was added, and the solution was washed with 5
× 5 mL of H2O and 5 mL of brine, dried over MgSO4, and
evaporated. Purification by CC (EtOAc/hexane 2:1) gave 81
736, 697 cm-1
.
8-Br om o-5,7,3′,4′-tetr a -O-m eth ylca tech in (20).5,14 To a
solution of 2.62 g (7.56 mmol) of 5,7,3′,4′-tetra-O-methylcate-
chin18 in 50 mL of anhydrous CH2Cl2 was added with stirring
all at once at -45 °C 1.35 g (7.56 mmol) of NBS (recrystallized
from water). The mixture was stirred for 100 min, during
which time the bath temperature was allowed to rise to
-9 °C. A solution of 0.5 g of Na2S2O3‚5H2O in 20 mL of water
was added, and the mixture was stirred vigorously at room
temperature for 15 min. Fifty mL of 5% aqueous NaOH was
added, the mixture was shaken in a separatory funnel, and
the separated aqueous phase was back-extracted with 50 mL
mg (87%) of the product: [R]D +123, [R]546 +152 (c 8 gL-1
,
EtOAc); 1H NMR (CDCl3) δ 7.30 (s, 1 H), 7.21, 7.13 (ABq, 2 H,
J ) 8.5 Hz, A part d with J ) 1.5 Hz), 6.71, 6.44 (ABq, 2 H, J
) 2 Hz), 6.18 (br s, 1 H), 6.02 (br s, 1 H), 5.48 (s, 1 H), 5.25 (s,
1 H), 4.58 (s, 1 H), 3.87 (br s, 3 H), 3.80 (s, 3 H), 3.31 (br s, 3
H), 2.28 (s, 3 H), 2.27 (s, 6 H), 1.88 (s, 3 H), 1.82 (s, 3 H); 13C
(18) (a) Kostanecki, St. v.; Tambor, J . Ber. Dtsch. Chem. Ges. 1902,
35, 1867. (b) Mehta, P. P.; Whalley, W. B. J . Chem. Soc. 1963, 5327.

Studies in Polyphenol Chemistry and Bioactivity
J . Org. Chem., Vol. 66, No. 4, 2001 1293
of CH2Cl2. The combined organic phases were dried over
MgSO4 and evaporated to yield 3.22 g (100%) of the product
as a colorless solid. An aliquot was recrystallized from boiling
EtOAc to furnish colorless needles: mp 165 °C if sample
inserted at 160 °C and heated slowly, 172 °C if inserted at
164 °C and heated faster (discoloration sets in before melting,
melt is blackish-red) (lit.5 mp 174 °C, no mention of decom-
position); [R]D -96.3, [R]546 -116 (CHCl3, c 20.3 gL-1) (lit.5
55.73, 55.47, 26.46, 26.21; IR (film) 3542, 1611, 1517, 1463,
1454, 1262, 1206, 1127, 1028, 733, 699 cm-1
.
3,5,7,3′,4′-P en ta -O-ben zyl-8-ben zylca tech in (23). To a
solution of 363 mg (429 µmol) of 21 and 205 µL (1.28 mmol, 3
equiv) of Et3SiH in 2.2 mL of anhydrous CH2Cl2 was added
dropwise in 5 min with stirring and exclusion of moisture at
0 °C 0.33 mL (4.3 mmol, 10 equiv) of CF3COOH. The orange-
colored solution was stirred in the ice bath for 12 min. After
addition of 5 mL of saturated aqueous NaHCO3 solution, the
phases were separated, and the aqueous phase was extracted
with 2 × 5 mL of CH2Cl2. The evaporation residue of the
combined organic phases was filtered over SiO2 with EtOAc/
hexane 1:4. Evaporation and drying in vacuo gave 332 mg of
crude product, which remained contaminated by a SiEt3-
containing byproduct. Pure material was obtained by dissolu-
tion in 6 mL of hot ethyl acetate, addition of 6 mL of hexane,
and crystallization at room temperature; a total of 313 mg
(88%) of colorless, cotton-like crystals was obtained in three
crops: mp 129.5-130 °C; [R]D +8.2, [R]546 +9.7 (EtOAc, c 22.6
gL-1); 1H NMR (CDCl3) δ 7.50-7.06 (m, 28 H), 7.02 (m, 2 H),
6.91 (overlapping, 1 H), 6.90, 6.84 (ABq, 2 H, J ) 8 Hz, B part
d with J ) 1.5 Hz), 5.19 (s, 2 H), 5.02 (s, 2 H), 5.00 (s, 2 H),
5.00, 4.94 (ABq, 2 H, J ) 12.5 Hz), 4.23, 4.07 (ABq, 2 H, J )
11.5 Hz), 4.02, 3.89 (ABq, 2 H, J ) 14 Hz), 3.62 (dt, 1 H, J )
5.5 Hz (d), 8.5 Hz (t)), 3.03, 2.69 (ABq, 2 H, J ) 16.5 Hz, both
parts d with J ) 5.5, 9 Hz, respectively); 13C NMR (CDCl3,
TMS) δ 155.79, 155.49, 153.11, 148.72, 148.58, 142.33, 138.07,
137.35, 137.31, 137.20, 132.67, 128.82, 128.53, 128.45, 128.39,
128.17, 127.87, 127.85, 127.72, 127.67, 127.48, 127.35, 127.30,
127.19, 125.21, 120.46, 114.72, 113.46, 110.35, 102.63, 91.15,
79.89, 74.96, 71.58, 71.36, 70.88, 70.56, 70.10, 28.72, 26.36;
IR (KBr) 1603, 1519, 1498, 1453, 1423, 1384, 1212, 1126, 733,
695 cm-1. Anal. Calcd for C57H50O6: C, 82.38; H, 6.06. Found:
C, 82.22; H, 6.06.
1
[R]578 -105.2 (CHCl3, c 20 gL-1)); H NMR19 (CDCl3) δ 7.01-
6.94 (m, 2 H), 6.89 (d, 1 H, J ) 8 Hz), 6.17 (s, 1 H), 4.09 (m,
1 H), 3.91, 3.89, 3.88, 3.84 (each s, 3 H), 2.99, 2.67 (ABq, 2 H,
J ) 16.5 Hz, both parts d with J ) 5 and 8 Hz, respectively),
1.80 (d, 1 H, J ) 4 Hz); 13C NMR (CDCl3, TMS) δ 157.46,
155.76, 151.46, 149.16, 149.04, 130.02, 119.01, 111.10, 109.62,
102.96, 91.25, 89.12, 81.64, 67.73, 56.49, 55.89, 55.60, 27.05;
IR (KBr) 3430 (br), 1607, 1518, 1213, 1129, 1103, 1053, 1028,
791 cm-1; MS m/z 426/424 (M+, 11/11), 247/245 (96/100), 180,
165, 151.
3-O-Ben zyl-8-br om o-5,7,3′,4′-tetr a -O-m eth ylca tech in .15
To 48 mg (1.2 mmol) of NaH (60% suspension in mineral oil)
was added with stirring at room temperature under N2 342
mg (804 µmol) of 20 in 1.5 mL of anhydrous DMF. After 5 min,
0.15 mL (1.3 mmol) of neat BnBr was added (mild exotherm).
The mixture was stirred at room temperature for 35 min,
diluted with 1 mL of CH2Cl2, and directly chromatographed
on SiO2 with EtOAc/hexane 2:7 (forerun) and then 2:3.
Evaporation and drying in vacuo yielded 393 mg (95%) of the
benzyl ether as a colorless glass: 1H NMR (CDCl3) δ 7.31-
7.22 (m, 3 H), 7.16-7.11 (m, 2 H), 6.98 (dd, 1 H, J ) 2, 8.5
Hz), 6.93 (d, 1 H, J ) 2 Hz), 6.87 (d, 1 H, J ) 8.5 Hz), 6.14 (s,
1 H), 5.01 (d, 1 H, J ) 7 Hz), 4.44, 4.33 (ABq, 2 H, J ) 12 Hz),
3.89, 3.88, 3.82, 3.81 (each s, 3 H), 3.79 (dt, 1 H, J ) 5.5 Hz
(d), 7.5 Hz (t)), 2.97, 2.72 (ABq, 2 H, J ) 16.5 Hz, both parts
d with J ) 5.5, 8 Hz, respectively); 13C NMR (CDCl3, TMS) δ
157.28, 155.72, 151.63, 148.76, 137.86, 131.18, 128.27, 127.76,
127.65, 119.02, 110.88, 109.98, 103.03, 91.28, 88.94, 79.87,
74.03, 71.38, 56.50, 55.91, 55.82, 55.57, 25.38; IR (film) 1606,
1518, 1464, 1130, 1101, 1027, 735 cm-1; MS m/z 516/514 (M+,
4/4), 270, 247/245, 241, 179 (100), 151, 91.
3-O-Ben zyl-8-(r-h yd r oxyben zyl)-5,7,3′,4′-tetr a -O-m eth -
ylca tech in (22).15 To a solution of 349 mg (677 µmol) of 3-O-
benzyl-8-bromo-5,7,3′,4′-tetra-O-methylcatechin in 6.8 mL of
anhydrous THF was added dropwise with stirring at -78 °C
under N2 1.55 mL (1.7 mmol, 2.5 equiv) of t-BuLi (1.1 M in
pentane). After 5 min, 138 µL (1.35 mmol, 2 equiv) of PhCHO
in 1.3 mL of anhydrous THF was added dropwise in 2 min.
After another 20 min, the cold bath was removed, 5 mL of H2O
was added, and the THF was evaporated. The product was
extracted into 3 × 10 mL of EtOAc, and the combined organic
phases were dried over MgSO4 and evaporated. CC with
EtOAc/hexane 1:2 gave, after evaporation and drying in vacuo,
in the sequence of their elution: 40 mg (13%) of the debromi-
nation product, 3-O-benzyl-5,7,3′,4′-tetra-O-methylcatechin; 71
mg (20%) of unreacted starting material; and 397 mg (70%) of
22 as a colorless glass: 1H NMR (CDCl3; ratio of diastereoi-
somers approximately 1:1) δ 7.34-7.12 (m, 8 H), 7.08-7.00
(m, 2 H), 6.91, 6.86 (ABq, 1 H, J ) 8.5 Hz, A part d with J )
2 Hz), 6.79, 6.73 (ABq, 1 H, J ) 8.5 Hz, B part d with J ) 2
Hz), 6.79 (d, 0.5 H, J ) 2 Hz), 6.66 (d, 0.5 H, J ) 2 Hz), 6.26
(d, 0.5 H, J ) 12 Hz), 6.21 (d, 0.5 H, J ) 11.5 Hz), 6.16 (s, 0.5
H), 6.15 (s, 0.5 H), 4.80 (d, 0.5 H, J ) 8.5 Hz), 4.72 (d, 0.5 H,
J ) 8.5 Hz), 4.37, 4.24 (ABq, 1 H, J ) 12 Hz), 4.31, 4.17 (ABq,
1 H, J ) 12 Hz), 4.22 (d, 0.5 H, J ) 11.5 Hz), 4.13 (d, 0.5 H,
J ) 12 Hz), 3.91, 3.90, 3.85, 3.84, 3.81, 3.80, 3.73, 3.65 (each
s, 1.5 H), 3.76 (dt, 0.5 H, J ) 5 Hz (d), 8.5 Hz (t)), 3.62 (dt, 0.5
H, J ) 5 Hz (d), 9 Hz (t)), 3.14 (t, 0.5 H, J ) 6 Hz), 3.08 (t, 0.5
H, J ) 5.5 Hz), 2.68 (d, 0.5 H, J ) 9.5 Hz), 2.62 (d, 0.5 H, J )
9.5 Hz); 13C NMR (CDCl3, TMS) δ 157.53, 157.47, 156.53,
156.42, 152.65, 152.53, 148.83, 148.74, 145.29, 145.17, 137.85,
131.30, 130.94, 128.21, 127.79, 127.75, 127.69, 127.59, 126.32,
126.22, 125.71, 125.58, 119.75, 119.61, 111.41, 110.82, 110.62,
109.87, 109.79, 102.52, 102.48, 88.58, 88.51, 80.30, 80.26,
74.49, 74.15, 71.46, 71.30, 68.68, 68.08, 56.05, 55.95, 55.92,
8-Ben zylca tech in (24) fr om 21. A solution of 242 mg (286
µmol) of 21 in a mixture of 7 mL of THF, 7 mL of MeOH, and
1 mL of water was stirred with 41 mg of 20% Pd(OH)2/C under
1 bar of H2 at room temperature for 4 h. After filtration from
the catalyst, the dissolved product was adsorbed on 2 g of SiO2
and chromatographed on SiO2. A forerun was eluted with CH2-
Cl2/MeOH 10:1 and then the desired product with CH2Cl2/
MeOH 6:1. Crystallization of the evaporated eluate was
effected from a minimum volume of acetone by addition of
water, yielding 30 mg (28%) of the product as an off-white
solid: mp 212-213.5 °C; [R]D -41.4, [R]546 -50.2 (MeOH, c
1
9.5 gL-1); H NMR (acetone-d6) δ 8.00 (s, 1 H), 7.97 (s, 1 H),
7.85 (s, 2 H), 7.27 (d, 2 H, J ) 7 Hz), 7.14 (t, 2 H, J ) 7.5 Hz),
7.04 (t, 1 H, J ) 7 Hz), 6.91 (d, 1 H, J ) 2 Hz), 6.79, 6.73
(ABq, 2 H, J ) 8 Hz, B part d with J ) 2 Hz), 6.13 (s, 1 H),
4.56 (d, 1 H, J ) 8 Hz), 4.00-3.87 (m, 2 H), 3.91, 3.80 (ABq,
2 H, J ) 14 Hz), 2.96, 2.55 (ABq, 2 H, J ) 16 Hz, both parts
d with J ) 5.5, 8.5 Hz, respectively), 2.88 (s, aliphat. OH +
H2O); 13C NMR (acetone-d6, TMS) δ 154.86, 154.82, 154.54,
145.64, 145.58, 143.65, 132.26, 129.63, 128.49, 125.80, 120.04,
115.67, 115.38, 107.50, 100.82, 96.02, 82.91, 68.47, 29.23; IR
(Nujol) 1614, 1456, 1377, 1283, 1094, 1056 cm-1; MS (EI) m/z
380 (M+, 15), 229 (100), 152, 151, 124, 123.
8-Ben zyl-5,7,3′,4′-tetr a-O-m eth ylcatech in (25).15 (a) Fr om
24. To 54 mg (0.39 mmol, 40 equiv) of anhydrous K2CO3 was
added a solution of 3.7 mg (9.7 µmol) of 24 in 0.3 mL of
anhydrous 3-pentanone followed by 34 µL (0.39 mmol) of Me2-
SO4 (highly toxic; carcinogen!). The mixture was stirred in a
closed vial at 60 °C for 135 min. After cooling, residual Me2-
SO4 was destroyed by addition of 0.1 mL of concd aqueous NH3
and stirring at room temperature for 40 min. The resulting
mixture was directly filtered over SiO2 with EtOAc/hexane 1:1
to give 4.7 mg of crude 25. Preparative HPLC (Whatman
Partisil 10, 500 × 9.4 mm, EtOAc/hexane 1:1, 5 mL/min, UV
detection at 280 nm; tR 18.4 min) yielded 3.1 mg (73%) of pure
25, identical with the material prepared on the following route.
(b) from 22: A solution of 231 mg (426 µmol) of 22 in a mixture
of 5 mL of EtOAc and 5 mL of MeOH was hydrogenated at
1 bar and room temperature over 113 mg of 50% Pd(OH)2/C
for 65 min. After filtration over cotton and evaporation, the
residue was filtered over SiO2 with EtOAc/hexane to yield
(19) Kiehlmann, E.; Tracey, A. S. Can. J . Chem. 1986, 64, 1998.

1294 J . Org. Chem., Vol. 66, No. 4, 2001
Kozikowski et al.
166 mg (89%) of 25 as a colorless glass. The analytical sample
was obtained by crystallization from boiling EtOH and drying
of the cotton-like crystals at 90 °C/oil pump vacuum: mp
136.5-138 °C (lit.15 mp 136-137 °C); [R]D -54.0, [R]546 -66.1
(CHCl3, c 12.1 gL-1) (lit.15 [R]578 -46 (Cl2CHCHCl2, c 20 gL-1));
1H NMR (CDCl3) δ 7.25-7.07 (m, 5 H), 6.90 (dd, 1 H, J ) 2, 8
Hz), 6.86 (d, 1 H, J ) 2 Hz), 6.85 (d, 1 H, J ) 8 Hz), 6.17 (s,
1 H), 4.67 (d, 1 H, J ) 8.5 Hz), 3.99, 3.87 (ABq, 2 H, J ) 14.5
Hz), 3.95 (m, 1 H), 3.89 (s, 3 H), 3.84 (s, 6 H), 3.74 (s, 3 H),
3.07, 2.61 (ABq, 2 H, J ) 16.5 Hz, both parts d with J ) 5.5,
9.5 Hz, respectively); 13C NMR (CDCl3, TMS) δ 156.95, 156.63,
152.90, 149.15, 149.00, 130.72, 128.58, 127.87, 125.19, 119.64,
110.83, 109.54, 109.35, 101.72, 88.29, 81.46, 68.42, 55.91,
55.89, 55.75, 55.47, 28.43, 27.74; IR (film) 3490 (br), 1610,
1518, 1463, 1453, 1263, 1121, 1027, 910, 733 cm-1; MS m/z
436 (M+, 16), 257 (100), 180, 179, 165, 152, 151, 91.
3,5,7,3′,4′-P en ta -O-ben zyl-8-br om oep ica tech in (26a ). To
a suspension of 29 mg (0.73 mmol) of NaH (60% in oil) in 2
mL of anhydrous DMF was added at room temperature 450
mg (617 µmol) of 26c1 in 3 mL of anhydrous DMF. After the
mixture was stirred for 30 min, 90 µL (0.73 mmol) of BnBr
and 20 mg (54 µmol) of n-Bu4NI were added. The mixture was
stirred overnight, poured into ice-water, and extracted with
3 × 50 mL of EtOAc. The combined organic phases were
washed with 3 × 50 mL of water and 50 mL of brine, dried
over MgSO4, and evaporated. CC (EtOAc/hexane 1:2) gave 480
mg (95%) of the product: 1H NMR (CDCl3) δ 7.50-7.15 (m,
23 H), 6.99 (m, 2 H), 6.95, 6.90 (ABq, 2 H, J ) 8.5 Hz, A part
d with J ) 1.5 Hz), 6.23 (s, 1 H), 5.19 (s, 2 H), 5.11 (s, 4 H),
4.97 (s, 2 H), 4.38, 4.29 (ABq, 2 H, J ) 12.5 Hz), 3.97 (narrow
m, 1 H), 2.95, 2.80 (ABq, 2 H, J ) 17 Hz, both parts d with J
) 3.5, 4.5 Hz, respectively); 13C NMR δ 156.44, 154.62, 151.94,
148.65, 148.12, 137.92, 137.41, 137.26, 136.75, 136.71, 131.68,
119.15, 114.74, 113.29, 103.40, 93.11, 92.76, 78.06, 72.13,
71.32, 71.26, 71.21, 70.83, 70.22, 24.73; IR (film) 1605, 1580,
1177, 1125, 1095, 735, 697 cm-1. Anal. Calcd for C50H43BrO6:
C, 73.26; H, 5.29. Found: C, 72.81; H, 5.12.
5,7,3′,4′-Tetr a -O-ben zyl-8-br om o-3-O-(ter t-bu tyld im eth -
ylsilyl)ep ica tech in (26b). A solution of 180 mg (247 µmol)
of 26c,1 56 mg (0.37 mmol) of TBDMS-Cl, and 49 mg (0.72
mmol) of imidazole in 1 mL of anhydrous DMF was stirred at
room temperature overnight. The mixture was poured into ice
water and extracted with 3 × 20 mL of ether. The combined
organic phases were washed with 3 × 20 mL of water and 20
mL of brine and dried over MgSO4. Evaporation and CC (SiO2,
CH2Cl2/EtOAc/hexane 1:1:4) gave 187 mg (88%) of 26b as a
foam: 1H NMR (CDCl3) δ 7.49-7.27 (m, 20 H), 7.19 (d, 1 H, J
) 1.5 Hz), 6.95, 6.89 (ABq, 1 H, J ) 8.5 Hz, A part d with J )
1.5 Hz), 6.20 (s, 1 H), 5.15 (s, 4 H), 5.08 (s, 3 H), 4.99 (s, 2 H),
4.22 (m, 1 H), 2.89-2.73 (m, 2 H), 0.72 (s, 9 H), -0.16 (s, 3 H),
-0.33 (s, 3 H); 13C NMR (CDCl3) δ 156.28, 154.40, 151.82,
148.60, 148.02, 137.37, 137.25, 136.81, 136.72, 132.19, 128.51,
128.48, 128.37, 128.35, 127.87, 127.79, 127.64, 127.61, 127.35,
127.22, 127.02, 127.00, 119.44, 114.96, 113.62, 103.48, 92.46,
79.18, 71.38, 71.13, 70.96, 70.16, 28.36, 25.63, -5.22, -5.26.
3,5,7,3′,4′-P en t a -O-b en zyl-4-h yd r oxyep ica t ech in -4,8-
(p en ta -O-ben zylep ica tech in ) (27a ). To a solution of 200 mg
(244 µmol) of 26a in 1 mL of dry THF was added under N2 at
-78 °C 0.30 mL (0.51 mmol) of tert-BuLi (1.7 M in pentane).
After stirring at -78 °C for 90 min, a solution of 120 mg (159
µmol) of 11a in 1 mL of dry THF was added. After another 3
h at -78 °C, 2 mL of aqueous NH4Cl was added, and the
mixture was allowed to warm to room temperature and
extracted with 3 × 20 mL of CH2Cl2. The combined organic
phases were dried over MgSO4 and evaporated, and the residue
was chromatographed on SiO2 (CH2Cl2/EtOAc/hexane 1:1:8)
to give 165 mg (69%) of the product as a colorless foam: [R]D
-14.7, [R]546 -18.7 (c 10 gL-1, EtOAc); 1H NMR (CDCl3; 2
rotamers, ratio 1:5.5) major rotamer (or overlapping multiplets
of both rotamers) δ 7.47-6.84 (m, 52 H), 6.79-6.70 (m, 4 H),
6.44 (s, 1 H), 6.37 (dd, 1 H, J ) 8, 1 Hz), 5.95, 5.71 (ABq, 2 H,
J ) 2 Hz), 5.44 (s, 1 H), 5.12 (s, 2 H), approximately 5.1-4.8
(m, 3 H), 5.08 (s, 2 H), 4.94 (s, 2 H), 4.85 (s, 2 H), 4.78, 4.73
(ABq, 2 H, J ) 11.5 Hz), 4.61 (d, 1 H, J ) 11.5 Hz), 4.61, 4.53
(ABq, 2 H, J ) 11.5 Hz), 4.60 (d, 1 H, J ) 12 Hz), 4.31 (d, 1 H,
J ) 12 Hz), 4.21 (s, 1 H), 4.16 (s, 1 H), 4.12 (d, 1 H, J ) 12
Hz), 4.04 (d, 1 H, J ) 12.5 Hz), 3.60 (d, 1 H, J ) 2.5 Hz), 3.12,
2.68 (ABq, 2 H, J ) 17.5 Hz, B part d with J ) 4.5 Hz), minor
rotamer (discernible signals) δ 6.14, 5.90 (ABq, 2 H, J ) 2 Hz),
6.09 (s, 1 H), 3.90 (narrow m, 1 H), 3.15, 2.91 (ABq, 2 H, J )
17.5 Hz, both parts d with J ) 2, 4 Hz, respectively); 13C NMR
(CDCl3, major rotamer only) δ 158.15, 157.86, 157.23, 156.96,
154.30, 154.07, 149.01, 148.13, 148.10, 147.77, 138.90, 138.38,
137.59, 137.55, 137.47, 137.38, 137.35, 137.30, 137.08, 136.72,
133.07, 131.62, 128.62, 128.54, 128.39, 128.28, 128.24, 128.20,
128.14, 128.08, 128.00, 127.91, 127.76, 127.60, 127.48, 127.46,
127.22, 127.14, 127.07, 126.73, 126.99, 119.96, 119.80, 118.92,
114.74, 114.67, 113.67, 113.59, 113.44, 111.15, 102.28, 94.22,
93.84, 93.43, 81.34, 78.73, 76.30, 74.70, 74.56, 72.46, 72.19,
71.43, 71.01, 70.75, 69.91, 69.53, 69.38, 69.36, 25.56; IR (film)
3520 (br), 1592, 1511, 1267, 1118, 735, 696 cm-1. Anal. Calcd
for C100H86O13: C, 80.30; H, 5.80. Found: C, 80.20; H, 5.66.
5,7,3′,4′-Tet r a -O-b en zyl-3-O-(ter t-b u t yld im et h ylsilyl)-
4-h yd r oxyep ica t ech in -4,8-[5,7,3′,4′-t et r a -O-b en zyl-3-O-
(ter t-bu tyld im eth ylsilyl)ep ica tech in ] (27b). To a solution
of 450 mg (533 µmol) of 26b in 2 mL of dry THF was added
under N2 at -78 °C 0.64 mL (1.1 mmol) of t-BuLi (1.7 M in
pentane). After the mixture was stirred at -78 °C for 60 min,
a solution of 280 mg (359 µmol) of 11b in 2 mL of dry THF
was added. After another 3 h at -78 °C, 2 mL of aqueous NH4-
Cl was added, and the mixture was allowed to warm to room
temperature and extracted with 3 × 20 mL of CH2Cl2. The
combined organic phases were dried over MgSO4 and evapo-
rated, and the residue was chromatographed on SiO2 (CH2-
Cl2/EtOAc/hexane 1:1:10) to give 410 mg (74%) of the product
as a colorless foam: [R]D -9.2, [R]546 -11.6 (c 24 gL-1, EtOAc);
1H NMR (CDCl3) δ 7.45-7.10 (m, 37 H), 7.07 (t, 2 H, J ) 7.5
Hz), 6.95-6.84 (m, 4 H), 6.79 (t, 2 H, J ) 8 Hz), 6.48 (d, 1 H,
J ) 8 Hz), 6.14 (s, 1 H), 5.95 (d, 1 H, J ) 2 Hz), 5.65 (d, 1 H,
J ) 2 Hz), 5.43 (d, 1 H, J ) 2.5 Hz), 5.32 (d, 1 H, J ) 11.5 Hz),
5.12- approximately 4.8 (m, 9 H), 4.93, 4.85 (ABq, 2 H, J ) 12
Hz), 4.80-4.70 (m, 3 H), 4.63, 4.41 (ABq, 2 H, J ) 11 Hz),
4.61 (d, 1 H, J ) 11.5 Hz), 4.09 (s, 1 H), 3.84 (br s, 1 H), 2.88,
2.79 (ABq, 2 H, J ) 17 Hz, B part d with J ) 4 Hz), 0.78 (s, 9
H), 0.70 (s, 9 H), -0.25 (s, 3 H), -0.27 (s, 3 H), -0.33 (s, 3 H),
-0.46 (s, 3 H); 13C NMR (CDCl3) δ 158.46, 157.95, 157.32,
155.93, 154.14, 153.06, 148.42, 148.37, 147.71, 147.62, 137.72,
137.63, 137.61, 137.51, 137.35, 137.26, 137.21, 137.18, 133.41,
132.68, 128.56, 128.47, 128.33, 128.30, 128.28, 128.26, 128.21,
127.95, 127.64, 127.60, 127.51, 127.43, 127.26, 127.20, 127.12,
126.95, 119.99, 118.89, 115.46, 114.65, 114.54, 114.43, 113.63,
111.74, 103.42, 94.96, 94.31, 93.71, 79.37, 76.14, 75.40, 73.89,
72.79, 71.47, 71.31, 71.23, 70.15, 69.88, 69.62, 66.88, 29.90,
26.12, 25.76, 18.12, 16.98, -4.90, -5.03, -5.32, -5.40; IR (film)
1591, 1511, 1266, 1119, 1026, 835, 735, 696 cm-1
.
P en t a -O-b en zylep ica t ech in -4r,8-(p en t a -O-b en zylep i-
ca tech in ) (28a ). To a solution of 70 mg (46.8 µmol) of 27a in
1 mL of dry CH2Cl2 was added at 0 °C 20 µL (74 µmol) of n-Bu3-
SnH followed by 71 µL of CF3COOH (1 M in CH2Cl2). After 1
h, 1 g of solid Na2CO3 was added, and the solution was filtered
and evaporated. The residue was chromatographed on SiO2
(CH2Cl2/EtOAc/hexane 1:1:8) to give 55 mg (79%) of the
product as a colorless foam: [R]D -48.7, [R]546 -59.6 (c 25 gL-1
,
1
EtOAc); H NMR (CDCl3; 2 rotamers, ratio 2.8:1; MR major,
mr minor rotamer) δ 7.48-6.74 (m, 56 H), 6.62 (d, MR, 1 H, J
) 8.5 Hz), 6.49 (br s, mr, 1 H), 6.28-6.04 (m, 3 H), 5.18-3.45
(series of m, 25 H), 3.14, 2.77 (ABq, MR, 2 H, J ) 17 Hz, both
parts d with J ) 1, 4 Hz, respectively), 2.93, 2.54 (ABq, mr, 2
H, J ) 17.5 Hz, B part d with J ) 5 Hz); 13C NMR (CDCl3;
low intensity signals of minor rotamer omitted) δ 158.04,
157.48, 156.79, 155.65, 152.93, 148.94, 148.76, 148.43, 148.10,
138.51, 138.34, 137.91, 137.47, 137.44, 137.39, 137.32, 137.24,
137.11, 132.98, 132.77, 128.57, 128.49, 128.47, 128.44, 128.38,
128.36, 128.28, 127.96, 127.75, 127.69, 127.61, 127.55, 127.50,
127.48, 127.38, 127.29, 127.27, 127.21, 127.17, 126.77, 119.77,
119.48, 114.51, 114.10, 113.83, 110.53, 108.29, 100.98, 94.96,
93.40, 92.31, 80.21, 78.13, 77.58, 75.06, 72.49, 71.39, 71.18,
71.11, 70.87, 70.70, 70.65, 70.03, 69.84, 69.60, 34.89, 24.89;
IR (film) 1606, 1593, 1266, 1112, 734, 696 cm-1. Anal. Calcd
for C100H86O12: C, 81.17; H, 5.86. Found: C, 80.89; H, 5.62.

Studies in Polyphenol Chemistry and Bioactivity
J . Org. Chem., Vol. 66, No. 4, 2001 1295
5,7,3′,4′-Tet r a -O-b en zyl-3-O-(ter t-b u t yld im et h ylsilyl)-
ep ica tech in -4r,8-[5,7,3′,4′-tetr a -O-ben zyl-3-O-(ter t-bu tyl-
d im eth ylsilyl)ep ica tech in ] (28b). To a solution of 240 mg
(155 µmol) of 27b in 1 mL of dry CH2Cl2 was added at 0 °C 50
µL (186 µmol) of n-Bu3SnH followed by 154 µL of CF3COOH
(1 M in CH2Cl2). After 1 h, 1 g of solid Na2CO3 was added,
and the solution was filtered and evaporated. The residue was
chromatographed on SiO2 (CH2Cl2/EtOAc/hexane 1:1:10) to
give 181 mg (76%) of the product as a colorless foam: [R]D
-14.9, [R]546 -19.1 (c 15 gL-1, EtOAc); 1H NMR (CDCl3) δ 7.49
(t, 4 H, J ) 7 Hz), 7.44-7.15 (m, 34 H), 7.13 (s, 1 H), 7.09 (d,
1 H, J ) 8.5 Hz), 6.97, 6.93 (ABq, 2 H, J ) 8 Hz, B part br),
6.82, 6.61 (ABq, 2 H, J ) 8 Hz, A part br), 6.77 (d, 2 H, J )
6.5 Hz), 6.08 (s, 1 H), 6.05, 5.93 (ABq, 2 H, J ) 2 Hz), 5.22-
5.00 (m, 12 H), 4.89 (s, 1 H), 4.80 (d, 1 H, J ) 11.5 Hz), 4.74,
4.68 (ABq, 2 H, J ) 11 Hz), 4.59, 4.48 (ABq, 2 H, J ) 11 Hz),
4.43 (d, 1 H, J ) 5.5 Hz), 4.34 (d, 1 H, partly overlapping),
4.31 (s, 1 H), 4.02 (br d, 1 H, J ) 2 Hz), 2.97, 2.85 (ABq, 2 H,
J ) 17 Hz, B part d with J ) 4.5 Hz), 0.71 (s, 9 H), 0.61 (s, 9
H), -0.32, -0.39, -0.89, -0.99 (each s, 3 H); 13C NMR (CDCl3)
δ 157.92, 157.34, 157.25, 155.52, 153.63, 148.97, 148.95,
148.40, 147.99, 137.67, 137.47, 137.43, 137.39, 137.26, 137.24,
137.19, 137.14, 133.84, 133.46, 128.51, 128.45, 128.39, 128.34,
127.89, 127.79, 127.73, 127.66, 127.62, 127.59, 127.55, 127.46,
127.35, 127.33, 127.08, 127.03, 126.65, 126.55, 119.87, 119.72,
115.29, 115.15, 114.47, 114.32, 110.32, 108.59, 101.60, 94.91,
93.18, 91.38, 81.25, 78.79, 71.67, 71.61, 71.40, 71.35, 71.28,
69.90, 69.70, 69.46, 69.15, 67.56, 36.90, 29.57, 26.09, 25.81,
18.16, 17.96, -5.21, -5.24, -5.42, -6.22. Anal. Calcd for
respectively); 13C NMR (CD3OD, TMS; only signals listed
which by their intensity appear to belong to the major rotamer)
δ 157.78, 156.82, 156.69, 154.48, 146.04, 145.94, 145.82,
145.76, 132.32, 132.30, 129.56, 128.92, 128.82, 119.21, 115.97,
115.89, 115.24, 100.74, 97.62, 97.49, 96.60, 80.98, 79.98, 72.33,
66.98, 36.71, 29.68; MS (electrospray) m/z 1155.6 ((2M)+; calcd
for C60H52O24: 1156.3), 577.3 (M+; calcd for C30H26O12: 578.1).
Anal. Calcd for C30H26O12‚3.4H2O: C, 56.32; H, 5.17. Found:
C, 56.27; H, 4.82.
P en t a -O-a cet ylep ica t ech in -4r,8-(p en t a -O-a cet ylep i-
ca tech in ) (29). To a solution of 75 mg (51 µmol) of 28a in 2
mL of MeOH and 1 mL of EtOAc was added 10 mg of 20%
Pd(OH)2/C. The mixture was stirred under 1 bar of H2 for 10
h, filtered, and evaporated. The crude deprotected dimer 6 was
dissolved in 3 mL of Ac2O/pyridine 1:2, and the mixture was
stirred overnight. After evaporation, 30 mL of EtOAc was
added. The solution was washed with 5 × 20 mL of H2O and
20 mL of brine, dried over MgSO4, and evaporated. The residue
was chromatographed on SiO2 (EtOAc/hexane 2:1) to give 12
mg (24%) of the peracetate: [R]D +10.0, [R]546 +11.3 (c 6 gL-1
,
1
EtOAc); H NMR (CDCl3/benzene-d6 1:1) δ 7.63 (s, 1 H), 7.44
(s, 1 H), 7.19 (s, 2 H), 7.13 (s, 2 H), 6.75, 6.64 (ABq, 2 H, J )
2 Hz), 6.62 (s, 1 H), 6.57 (s, 2 H), 5.85 (d, 1 H, J ) 5.5 Hz),
5.24 (narrow m, 1 H), 5.13 (d, 1 H, J ) 5.5 Hz), 5.01 (s, 1 H),
4.64 (s, 1 H), 2.91, 2.69 (ABq, 2 H, J ) 17. Hz, both parts d
with J ) 2.5, 3.5 Hz, respectively), 2.023 (s, 3 H), 2.018 (s, 3
H), 1.97 (s, 3 H), 1.96 (s, 3 H), 1.94 (s, 3 H), 1.92 (s, 3 H), 1.82
(s, 3 H), 1.74 (s, 3 H), 1.70 (s, 3 H), 1.63 (s, 3 H); 13C NMR
(CDCl3/benzene-d6 1:1, TMS) δ 170.47, 169.45, 168.68, 168.31,
168.04, 167.95, 167.78, 167.73, 167.67, 167.25, 155.79, 152.11,
149.99, 149.50, 148.92, 148.26, 142.69, 142.62, 142.20, 141.99,
136.18, 136.10, 125.00, 124.64, 123.34, 123.17, 122.01, 114.72,
114.26, 109.67, 109.60, 108.74, 108.51, 77.96, 77.83, 67.80,
65.80, 34.60, 25.70, 20.63, 20.44, 20.42, 20.32, 20.31, 20.27,
20.20, 19.96; IR (film) 1770, 1746, 1621, 1595, 1371, 1207, 903,
C
98H102O12Si2: C, 77.03; H, 6.73. Found: C, 77.02; H, 6.63.
5,7,3′,4′-Tetr a -O-ben zylep ica tech in -4r,8-(5,7,3′,4′-tetr a -
O-ben zylep ica tech in ) (28c). To a solution of 130 mg (85
µmol) of 28b in 1 mL of CH3CN was added at 0 °C 50 µL of
48% aqueous HF. The mixture was stirred at room tempera-
ture for 8 h, 10 mL of EtOAc was added, and the solution was
washed with 10 mL each of aqueous NaHCO3, H2O, and brine.
After drying over MgSO4 and evaporation, the residue was
chromatographed on SiO2 with CH2Cl2/EtOAc/hexane 1:1:5 to
give 89 mg (81%) of the product as a foam: [R]D -94.2, [R]546
-115 (c 9 gL-1, EtOAc); 1H NMR (selection; two rotamers,
approximately 3:2, MR ) major, mr ) minor rotamer) δ 6.63
(d, 1 H, MR, J ) 2 Hz), 6.35, 6.30 (ABq, 2 H, MR, J ) 2 Hz),
6.05 (d, 1 H, mr, J ) 1.5 Hz), 6.02 (s, 1 H, MR), 4.25 (dd, 1 H,
MR, J ) 5.5, 9.5 Hz), 4.16 (dd, 1 H, mr, J ) 5, 9 Hz), 3.60 (d,
1 H, MR, J ) 9.5 Hz), 3.24 (d, 1 H, mr, J ) 9 Hz), 2.99, 2.87
(ABq, 2 H, mr, J ) 17.5 Hz, B part overlapping), 2.85, 2.69
(ABq, 2 H, MR, J ) 17.5 Hz, B part d with J ) 5 Hz), 1.59 (d,
1 H, MR, J ) 8 Hz), 1.39 (d, 1 H, mr, J ) 5 Hz); 13C NMR
(CDCl3) δ 159.03, 158.31, 158.14, 157.99, 157.02, 156.50,
156.29, 156.05, 155.94, 155.48, 153.38, 152.76, 149.1-148.4,
137.6-136.9, 136.55, 136.44, 132.07, 131.65, 130.51, 128.6-
127.0, 120.49, 120.43, 119.42, 119.22, 115.0-114.2, 113.41,
113.30, 110.76, 110.29, 106.97, 106.30, 102.22, 101.40, 95.64,
95.03, 94.31, 93.98, 92.41, 91.98, 80.52, 79.84, 78.16, 77.88,
71.7-69.6, 66.07, 65.94, 35.89, 35.37, 28.84, 28.41. MS (API-
ES, in MeOH/NH4OH) m/z 1316.6 (M + NH4+; calcd for
13C12C85H78NO12 1317.6), 1299.5 (M+; calcd for 13C12C85H74O12
1299.5), 967.4, 649.3 (M2+). Anal. Calcd for C86H74O12: C, 79.49;
H, 5.74. Found: C, 79.59; H, 6.21.
734 cm-1
.
5,7,3′,4′-Tetr a -O-ben zylep ica tech in -4r,8-[5,7,3′,4′-tetr a -
O-ben zyl-3-O-(3,4,5-tr i-O-ben zylga lloyl)ep ica tech in ] (30).
To a suspension of 68 mg (154 µmol) of tri-O-benzylgallic acid20
and 1 µL of DMF in 1 mL of anhydrous CH2Cl2 was added 15
µL (0.17 mmol) of oxalyl chloride. After stirring at room
temperature for 2 h with exclusion of moisture, the resulting
solution was evaporated and the residue dried in vacuo. A
solution of 40 mg (31 µmol) of 28c in 0.5 mL of anhydrous
pyridine was added to the crude acid chloride, 24 mg (0.20
mmol) of DMAP was added, and the mixture was stirred at
room temperature in a closed flask for 48 h. After addition of
20 µL of water, stirring at room temperature was continued
for 2 h. Ten milliliters of 5% HCl was added, and the product
was extracted into 3 × 5 mL of CH2Cl2. The organic phases
were dried over MgSO4 and concentrated, and the crude
material was purified by CC on SiO2 with EtOAc/hexane 1:4.
Evaporation and drying in vacuo yielded 50 mg (94%) of the
1
product: [R]D -122, [R]546 -149 (EtOAc, c 12 gL-1); H NMR
(CDCl3; selection; two rotamers, approximately 3:1, MR )
major, mr ) minor rotamer) δ 6.54 (d, 1 H, MR, J ) 8.5 Hz),
6.35 (d, 1 H, mr, J ) 2 Hz), 6.08 (s, 1 H, mr), 5.39 (narrow m,
1 H, MR + mr), 5.18 (d, 1 H, MR, J ) 5.5 Hz), 5.10 (d, 1 H,
MR, J ) 5 Hz), 4.30 (dd, 1 H, MR, J ) 5.5, 9.5 Hz), 4.18 (s, 1
H, MR), 4.12 (dd, 1 H, mr, J ) 4.5, 9.5 Hz), 3.58 (d, 1 H, MR,
J ) 9.5 Hz), 3.18 (narrow m, 2 H, mr), 3.10 (d, 1 H, mr, J )
9.5 Hz), 2.88 (narrow m, 2 H, MR); 13C NMR (CDCl3; weak
signals of the minor rotamer omitted) δ 165.10, 158.14, 158.00,
157.06, 156.47, 155.59, 153.00, 152.33, 148.67, 148.63, 148.44,
142.43, 137.5-136.4, 132.04, 131.31, 128.6-127.0, 124.92,
119.97, 119.55, 114.53, 114.36, 114.29, 113.26, 110.85, 108.74,
107.03, 101.98, 95.03, 94.01, 91.80, 80.69, 74.94, 71.14, 71.10,
70.99, 70.77, 69.94, 68.28, 35.53, 26.13. Anal. Calcd for
Ep ica tech in -4r,8-ep ica tech in (6). A solution of 40 mg (31
µmol) of 28c in 5 mL of MeOH/THF/water (20:20:1) was
hydrogenated over 60 mg of 20% Pd(OH)2/C at room temper-
ature and 5 bar for 5 h. The catalyst was filtered off over Celite,
the solids were washed with 10 mL of MeOH, and the solution
was evaporated. The residue was taken up in HPLC-grade
water, and the solution was washed with 5 mL of toluene to
remove nonpolar impurities. The solution was evaporated
again and then lyophilized from 5 mL of HPLC grade water
to give 13 mg (73%) of 6 as a colorless, amorphous solid: [R]D
-38.6 (c 1.4 gL-1, MeOH); 1H NMR (CD3OD, TMS; major
rotamer only) δ 7.06 (d, 1 H, J ) 1 Hz), 7.01 (d, 1 H, J ) 1
Hz), 6.90-6.68 (m, 4 H), 5.99 (d, 1 H, J ) 2 Hz), 5.92 (s, 1 H),
5.83 (d, 1 H, J ) 2 Hz), 5.04 (d, 1 H, J ) 4.5 Hz), 4.96 (s, 1 H),
4.94 (s, 1 H), 4.30 (d, 1 H, J ) 4.5 Hz), 4.29 (br, 1 H), 2.95,
2.80 (ABq, 2 H, J ) 17 Hz, both parts d with J ) 1.5 Hz,
C
114H96O16: C, 79.51; H, 5.62. Found: C, 79.65; H, 5.38.
Ep ica tech in -4r,8-(3-O-ga lloylep ica tech in ) (31). A solu-
tion of 22 mg (13 µmol) of 30 in 4 mL of EtOAc/MeOH (1:1)
was hydrogenated at 3.5 bar and room temperature over 33
mg of 20% Pd(OH)2/C for 4.5 h. After filtration over cotton and
(20) Cavallito, C. J .; Buck, J . S. J . Am. Chem. Soc. 1943, 65, 2140.

1296 J . Org. Chem., Vol. 66, No. 4, 2001
Kozikowski et al.
evaporation, the residue was lyophilized from 2 mL of H2O
(HPLC grade) to give 6.3 mg (67%) of 31 as a colorless,
amorphous solid: 1H NMR (CDCl3; selection; two rotamers,
approximately 3:1, MR ) major, mr ) minor rotamer) δ 7.06
(d, 1 H, MR, J ) 1.5 Hz), 7.0-6.65 (m), 6.54 (d, 1 H, mr, J )
8.5 Hz), 6.47 (d, 1 H, mr, J ) 2 Hz), 6.20 (d, 1 H, mr, J ) 2
Hz), 6.15 (s, 1 H, mr), 6.03 (dd, 1 H, mr, J ) 2, 8.5 Hz), 5.99
(d, 1 H, mr, J ) 2.5 Hz), 5.96 (d, 1 H, MR, J ) 2 Hz), 5.93 (s,
MR, 1 H), 5.82 (d, 1 H, MR, J ) 2 Hz), 5.56 (narrow m, 1 H,
MR + mr), 5.32 (narrow m, 1 H, mr), 5.18 (s, 1 H, MR), 5.08
(d, 1 H, MR, J ) 5 Hz), 5.05 (d, 1 H, mr, J ) 5 Hz), 4.28 (d, 1
H, MR, J ) 5 Hz), 4.00 (d, 1 H, mr, J ) 5 Hz), 3.07, 2.87 (ABq,
2 H, MR, J ) 17.5 Hz, A part d with J ) 4.5 Hz), 2.96, 2.80
(ABq, 2H, mr, partially overlapping with the preceding signal);
MS (electrospray) m/z 729.2 (M+; calcd for C37H30O16: 730.2).
Ack n ow led gm en t. We are grateful to MARS, In-
corporated, for funding of this work.
J O001462Y