Ellagitannin chemistry. Syntheses of tellimagrandin II and a dehydrodigalloyl ether-containing dimeric gallotannin analogue of coriariin A

Article abstract of DOI:10.1021/jo9816966

The first chemical synthesis of the naturally occurring ellagitannin tellimagrandin II is reported. Key steps of the synthesis include the atropselective oxidative coupling of suitably protected galloyl rings at the O(4) and O(6) positions of a glucopyranose core, and the stereoselective acylation of the derived anomeric alcohol with a galloyl chloride. In addition, the synthesis of a novel gallotannin-ellagitannin hybrid is described. This dimeric construct relied on a hetero-Diels-Alder cycloaddition/reductive rearrangement sequence to deliver the intact skeleton from a monomeric pentagalloylglucose-based orthoquinone.

Full text of DOI:10.1021/jo9816966

J . Org. Chem. 1999, 64, 209-216
209
Ella gita n n in Ch em istr y. Syn th eses of Tellim a gr a n d in II a n d a
Deh yd r od iga lloyl Eth er -Con ta in in g Dim er ic Ga llota n n in An a logu e
of Cor ia r iin A
Ken S. Feldman* and Kiran Sahasrabudhe
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802
Received August 20, 1998
The first chemical synthesis of the naturally occurring ellagitannin tellimagrandin II is reported.
Key steps of the synthesis include the atropselective oxidative coupling of suitably protected galloyl
rings at the O(4) and O(6) positions of a glucopyranose core, and the stereoselective acylation of
the derived anomeric alcohol with a galloyl chloride. In addition, the synthesis of a novel
gallotannin-ellagitannin hybrid is described. This dimeric construct relied on a hetero Diels-
Alder cycloaddition/reductive rearrangement sequence to deliver the intact skeleton from a
monomeric pentagalloylglucose-based orthoquinone.
The ellagitannin subfamily of the hydrolyzable tannins
spans over 500 structurally characterized members.1-4
An increasing interest in the role played by these
secondary plant metabolites in polyphenol-rich folk medi-
cines from China and J apan has led to the identification
of several ellagitannins which hold promise as potent
antiviral and anticancer therapeutic agents.1,5,6 The
challenge of selective C-C and C-O bond formation
within these complex structures has stimulated many
recent synthesis studies.7-13 The defining structural
feature of the ellagitannins is a h exah ydroxyd ip henoyl
(HHDP) moiety bridging two oxygens of a carbohydrate
core, typically glucose. Current hypotheses for the bio-
synthetic origin of ellagitannins suggest that the varia-
tions in ellagitannin skeletal architecture emerge from
the myriad C-C and C-O modes of oxidative galloyl
coupling available to a pivotal intermediate, the naturally
occurring gallotannin â-D-pentagalloylglucose (â-D-PGG,
1). Thus, the monomeric ellagitannin tellimagrandin II
(2) may arise from the intramolecular C-C oxidative
coupling of the O(4) and O(6) galloyl moieties of â-D-PGG,
whereas the dimeric ellagitannin coriariin A (5) may
presumably arise from intermolecular C-O oxidative
coupling of the anomeric galloyl groups of two tellima-
grandin II units.
(1) Berlinck, R. G. S.; Hatano, T.; Okuda, T.; Yoshida, T. In Progress
in the Chemistry of Organic Natural Products; Herz, W., Kirby, G. W.,
Moore, R. E., Steglich, W., Tamm, Ch., Eds.; Springer-Verlag: New
York, 1995; p 1.
(2) Haslam, E. Plant Polyphenols-Vegetable Tannins Revisited;
Cambridge University Press: Cambridge, 1989.
(3) Haslam, E.; Cai, Y. Nat. Prod. Rep. 1994, 41.
(4) Quideau, S.; Feldman, K. Chem. Rev. 1996, 96, 475.
(5) Okuda, T.; Yoshida, T.; Hatano, T. In Economic and medicinal
plant research, Vol. 5, plants and traditional medicines; Wagner, H.
S., Farnsworth, N. R., Eds.; Academic Press: London, 1991; p 129.
(6) Okuda, T.; Yoshida, T.; Hatano, T. In Phenolic Compounds in
Food and their Effects on Health, II; Huang, M.-T., Ho, C.-T., Lee, C.
Y., Eds.; American Chemical Society: Washington, DC, 1992; p 160.
(7) Feldman, K. S.; Ensel, S. M. J . Am. Chem. Soc. 1993, 115, 1162.
(8) Feldman, K. S.; Ensel, S. M.; Minard, R. D. J . Am. Chem. Soc.
1994, 116, 1742.
(9) (a) Feldman, K. S.; Sambandam, A. J . Org. Chem. 1995, 60, 8171.
(b) Zehari, U.; Amit, B.; Patchornik, A. J . Org. Chem. 1972, 37, 2281.
(10) Feldman, K. S.; Quideau, S.; Appel, H. M. J . Org. Chem. 1996,
61, 6656.
A number of oligomeric ellagitannins, including cori-
ariin A (5) and the structurally related species agrimoniin
and gemin A (not shown), induce tumor regression in
mice infected with sarcoma-180 tumors (1-3 regressors
out of 6, 100%-238% increase in life span).14,15 The
(11) (a) Nelson, T. D.; Meyers, A. I. J . Org. Chem. 1994, 59, 2577.
(b) Lipshutz, B. H.; Liu, Z.-P.; Kayser, F. Tetrahedron Lett. 1994, 35,
5567
(12) (a) Khanbabaee, K.; Lo¨tzerich, K. Tetrahedron 1997, 53, 10725.
(b) Khanbabaee, K.; Lo¨tzerich, K. Liebigs Ann. Chem. 1997, 1571.
(13) (a) Itoh, T.; Chika, J .-i. J . Org. Chem. 1995, 60, 4968. (b) Itoh,
T.; Chika, J .-i.; Shirakami, S.; Ito, H.; Yoshida, T.; Kubo, Y.; Uenishi,
J .-i. J . Org. Chem. 1996, 61, 3700.
(14) Miyamoto, K.-I.; Kishi, N.; Koshiura, R.; Yoshida, T.; Hatano,
T.; Okuda, T. Chem. Pharm. Bull. 1987, 35, 814.
(15) Miyamoto, K.-I.; Murayama, T.; Nomura, M.; Hatano, T.;
Yoshida, T.; Furukawa, T.; Koshiura, R.; Okuda, T. Anticancer Res.
1993, 13, 37.
10.1021/jo9816966 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/09/1998

210 J . Org. Chem., Vol. 64, No. 1, 1999
Feldman and Sahasrabudhe
Sch em e 1
monomeric tannins tellimagrandin I (3), tellimagrandin
II (2), â-D-PGG (1), and pedunculagin (4) are much less
effective antitumor agents (no regressors, 27%-82%
increase in life span). Some structural requirements for
antitumor activity among these ellagitannins are im-
mediately evident from these data. Among the monomeric
species, the presence of HHDP units is not critical for
biological activity, but the presence of an anomeric galloyl
group leads to improved potency. Within the dimeric
species, the anomeric stereochemistry does not affect
antitumor efficacy. Could a simple dimeric gallotannin
that meets these structural requirements exhibit biologi-
cal activity? To test this premise, the dimeric gallotannin
6 has been synthesized. Compound 6 is a gallotannin
analogue of the naturally occurring dimeric ellagitannin
coriariin A (5) and is identical to the parent compound
except that it lacks the O(4)/O(6) coupled HHDP units
of coriariin A. The synthesis of this compound also serves
to model a synthesis plan for coriariin A. In addition, the
biomimetic synthesis of the monomeric precursor to
coriariin A, tellimagrandin II (2), is reported.
Resu lts a n d Discu ssion
Sch em e 2
Any strategy directed toward the synthesis of 6 must
address two key issues: (1) formation of the dehydrodi-
galloyl ether linking unit and (2) establishment of the
â-anomeric galloyl linkage with stereochemical control.
The former goal might be approached by application of
methodology developed in-house for the synthesis of
simple dehydrodigalloyl ethers.10 The latter point will be
explored initially within the context of a tellimagrandin
II synthesis effort. In addition to anomeric ester stereo-
chemistry, the tellimagrandin II synthesis requires (1)
stereoselective formation of the (S)-atropisomer of the
HHDP moiety and (2) selective manipulation of the
anomeric center in a manner which is compatible with
other functional groups present in the molecule. Chemical
precedents that bear on these issues can be gleaned from
earlier work on the syntheses of tellimagrandin I and
sanguin H-5.8,9 Thus, Pb(OAc)4-mediated oxidative galloyl
coupling has proved to be a robust strategy for the
preparation of stereochemically secure (S)-HHDP units.7,8
In addition, the photolabile O(1)-o-nitrobenzyl moiety has
mediated selective protection/deprotection chemistry at
the anomeric center in similar polygalloylated glucose
systems.9 Finally, the â-anomeric galloyl linkages in both
6 and tellimagrandin II (2) might be secured by coupling
the anomeric hydroxyl group of an appropriately pro-
tected intermediate with a galloyl chloride in the pres-
ence of a suitable base.9,16
An initial attempt toward the construction of the
dimeric gallotannin 6 followed a strategy wherein the
alcohol 11, obtained by the selective ammonolysis of
perbenzyl â-D-PGG, would be coupled with the diacid
chloride 10, Scheme 1. To this end, the dehydrodigallic
acid 9 was synthesized from the methyl gallate-derived
orthoquinone 7 in five steps.10 The diacid chloride 10
proved to be extremely susceptible to hydrolysis, and all
efforts to isolate 10 failed to furnish acceptable amounts
of the pure compound. To circumvent this unanticipated
lability, the diacid 9 was treated with thionyl chloride,
the thionyl chloride was removed in vacuo, and the
resultant crude oil was used directly in the attempted
bis acylation. However, all efforts to effect this coupling
failed to furnish the fully acylated dimeric compound 12.
Other unsuccessful trials to achieve this coupling
included the reaction of the alcohol 11 directly with the
diacid 9 (or with activated derivatives) under various
esterification protocols and the reaction of the diacid 9
with the trichloroacetimidate 13 derived from the alcohol
11 (Scheme 2).17,18 The reaction of the trichloroacetimi-
date 13 with the acid 14 afforded the O(1)-esterified
product 15 in 33% yield but failed to furnish any desired
product 12 upon reaction with the diacid 9.
These failures forced a reevaluation of the synthesis
strategy, and eventually a possibly more biomimetic
approach via dimerization of two activated â-D-PGG units
was pursued. In this route, acylation of 11 with the
galloyl chloride 16 in the presence of triethylamine
provided the pentaester 17 featuring strictly â-stereo-
chemistry at the anomeric position (Scheme 3). Desily-
lation of compound 17 furnished the catechol 18 which
was oxidized to the orthoquinone 19 with orthochlo-
ranil.10 The orthoquinone 19 precipitated cleanly from
the reaction mixture, obviating the need for further
purification of this sensitive compound. The B(OAc)3-
(17) Schmidt, R. R.; Michel, J . J . Carbohydr. Chem. 1985, 4, 141.
(18) Schmidt, R. R.; Michel, J . Angew. Chem., Int. Ed. Engl. 1980,
19, 731.
(16) Bols, M.; Hansen, H. C. Acta Chem. Scand. 1993, 47, 818.

Ellagitannin Chemistry
Sch em e 3
J . Org. Chem., Vol. 64, No. 1, 1999 211
Sch em e 4
mediated Diels-Alder dimerization of the orthoquinone
19 followed by a three-step reduction/rearrangement
sequence10 furnished the perbenzylated gallotannin dimer
12 in 44% yield starting from the orthoquinone 19, in
analogy with the preparation of the simple dehydrodi-
galloyl ether 8 from orthoquinone 7. In the final step,
hydrogenolysis of the benzyl ethers in 12 furnished the
dimeric gallotannin 6 in 50% yield.
The synthesis of tellimagrandin II (2) began with the
known acetal 20 (Scheme 4).9 Galloylation at the 2 and
3 positions of the carbohydrate core furnished the diester
21 in 78% yield. Deprotection of the O(4), O(6) ben-
zylidene acetal in 21 provided an 84% yield of an
intermediate diol which was immediately esterified at
both the O(4) and O(6) positions with excess 22 to provide
the tetragalloyl compound 23. Desilylation of bis silyl
ether 23 provided the oxidative cyclization precursor.
Intramolecular Pb(OAc)4-mediated oxidative coupling of
the galloyl groups at the O(4) and O(6) positions in this
bis phenol furnished the 4,6-(S)-HHDP-bearing com-
pounds 24a -c in 67% yield as a mixture of three
regioisomers. Hydrogenolysis of the diphenylmethylene
ketals in 24a -c proved to be a capricious reaction, and
hence a two-step deprotection/protection strategy was
adopted. The diphenylmethylene ketals of 24a -c were
cleaved with 80% HOAc, and the resulting hexaphenolic
compound was directly benzylated to provide 25, now as
a single isomer, in 50% yield over two steps. The presence
of benzyl ethers at all of the phenolic positions proved to
be advantageous in the final stages of the tellimagrandin
II synthesis because they imparted favorable chromato-
graphic and spectroscopic properties to late intermediates
while preserving the means to deliver pure polyphenolic
product in the final step. Selective photochemical cleav-
age of the O(1)-nitrobenzyl ether of 25 furnished a 66%
yield of the perbenzylated tellimagrandin I derivative 26
featuring a free anomeric hydroxyl group. Esterification
of 3,4,5-tribenzyloxybenzoyl chloride with this alcohol in
the presence of triethylamine provided 27 as the exclu-
sively â-esterified product in 41% yield. In the final step,
hydrogenolysis of the benzyl ethers in 27 furnished crude
tellimagrandin II, which was purified by repeated filtra-
tion and trituration with hexanes and diethyl ether to
yield 2 in 30% yield as a gray solid. All spectral data for
the chemically synthesized tellimagrandin II (2) cor-
related with the published data for the naturally occur-
ring compound.19,20 The presence of the (S)-HHDP atro-
pisomer was further confirmed by CD measurement.
In summary, the first total synthesis of a dehydrodi-
galloyl ether-containing dimeric gallotannin 6, an ana-
logue of coriariin A, from a gallotannin orthoquinone
intermediate has been achieved. This synthesis demon-
strates the value of the B(OAc)3-mediated Diels-Alder
dimerization of orthoquinones in accessing this class of
compounds. Additionally, the synthesis of tellimagrandin
II (2), a possible biosynthetic precursor to coriariin A, has
been completed. The application of the methodology
developed for the synthesis of these two compounds
(19) Gupta, R. K.; Al-Shafi, S. M. K.; Layden, K.; Haslam, E. J .
Chem. Soc., Perkin Trans. 1 1982, 2525.
(20) Nonaka, G.-I.; Harada, M.; Nishioka, I. Chem. Pharm. Bull.
1980, 28, 687.

212 J . Org. Chem., Vol. 64, No. 1, 1999
Feldman and Sahasrabudhe
layer was separated, washed with water and then brine, dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo.
Flash column chromatography of the crude residue using the
indicated solvents provided the pure product.
toward the synthesis of the more complex target coriariin
A is currently in progress.
Exp er im en ta l Section
2,3,4,6-Tetr a k is(3,4,5-tr is(ben zyloxy)ben zoyl)-r-D-glu -
cop yr a n ose (11). 1,2,3,4,6-Pentakis(3,4,5-tris(benzyloxy)ben-
zoyl)-â-D-glucopyranoside26 (7.0 g, 3.1 mmol) was dissolved in
a mixture of 200 mL of dry THF and 100 mL of dry MeOH
and cooled to 0 °C. Ammonia gas was bubbled through the
solution for 10 min. The reaction was stirred at 0 °C for 30
min, allowed to warm to room temperature, and stirred for a
further period of 2.5 h. Removal of the solvents followed by
flash column chromatography eluting with 10%, 25%, and then
50%, EtOAc in hexanes furnished 4.16 g (73%) of 2,3,4,6-
tetrakis(3,4,5-tris(benzyloxy)benzoyl)-D-glucopyranose (11) as
a white solid froth (mixture of R and â anomers). A portion of
this product (30 mg) was further purified by preparative TLC
using 10% EtOAc in benzene to provide 22 mg of 11: IR (CH2-
Cl2) 3483, 1725 cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.42-6.64
(m, 68 H), 6.23, (t, J ) 9.9 Hz, 1 H), 5.79 (d, J ) 3.7 Hz, 1 H),
5.70 (t, J ) 9.9 Hz, 1 H), 5.75-4.65 (m, 27 H), 4.29 (dd, J )
4.3 Hz, 12.1 Hz, 1 H), 3.40 (bs, 1 H); 13C NMR (CDCl3, 90 MHz)
δ 166.7, 165.7, 165.4, 165.1, 152.54, 152.50, 152.4, 143.1, 142.9,
142.8, 142.7, 142.6, 137.4, 137.35, 137.3, 136.6, 136.45, 136.4,
136.33, 136.3, 128.5, 128.4, 128.33, 128.2, 128.1, 128.07,
128.05, 128.0, 127.94, 127.9, 127.86, 127.8, 127.78, 127.56,
127,51, 127.4, 127.3, 124.6, 124.1, 123.9, 109.4, 109.3, 109.1,
90.4, 75.1, 75.0, 72.8, 71.2, 71.1, 70.9, 70.0, 67.6, 63.1; MS
(+FAB) 1869 (MH+, 0.5). Anal. Calcd for C118H100O22: C, 75.80;
H, 5.35. Found: C, 76.13; H, 5.45.
Nuclear magnetic resonance spectra (1H NMR, 13C NMR)
were recorded on either 200, 300, or 360 MHz (1H) spectrom-
eters. Low-resolution fast atom bombardment mass spectra
(FABMS) were obtained in a 2-nitrophenyl octyl ether (NPOE)
matrix or in
a nitrobenzyl alcohol (NBA) matrix. High-
resolution fast atom bombardment mass spectra were run at
the University of Texas at Austin. Circular dichroism (CD)21,22
measurements used the wavelength range 200-350 nm,
scanning at 0.5 nm intervals with an averaging time of 10.0 s
at 25 °C in a 1 mm cell. The concentration of the solution(s)
used was 1 mg/ mL. Liquid (flash) column chromatography23
was carried out using 32-63 µm silica gel and the indicated
solvent. Combustion analyses were performed by Midwest
Microlab, Indianapolis, IN or Galbraith Laboratories, Knox-
ville, TN. Ether (Et2O) and tetrahydrofuran (THF) were
purified by distillation from sodium/benzophenone under
nitrogen. Benzene, methylene chloride (CH2Cl2), methanol, and
toluene were distilled from CaH2 under nitrogen. Moisture-
sensitive reactions were carried out in predried glassware
1
under an inert atmosphere of Ar. Copies of H and 13C NMR
spectra are provided in the Supporting Information to establish
purity for those compounds that were not subjected to combus-
tion analyses.
Mod ified Steglich Ester ifica tion 24,25 Rea ction : Gen -
er a l P r oced u r e A. A solution of the appropriate polyol (1.0
equiv), acid (1 equiv per hydroxyl), 4-(dimethylamino)pyridine
(DMAP) (0.5 equiv), DMAP‚HCl (0.5 equiv), and 1,3-dicyclo-
hexylcarbodiimide (DCC) (1.25 equiv per hydroxyl) in dry CH2-
Cl2 (0.1 M in acid) was purged with Ar and heated under Ar
at reflux for 15-20 h. The solution was cooled to room
temperature, diluted with an equal volume of Et2O, and
filtered through Celite; the filtrate was poured into ice-cold 1
M H3PO4. The organic layer was separated, washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo. The crude product was purified by flash column
chromatography using the solvents indicated.
Met h yl 3-Ben zyloxy-1,2-d ioxocycloh exa -3,5-d ien e-5-
ben zoa te (7). To a solution of orthochloranil (1.97 g, 8.02
mmol) in 5 mL of Et2O cooled to -30 °C was added dropwise
via an addition funnel over 6 h a solution of methyl 3-benzyl-
oxy-4,5-dihydroxybenzoate (2.0 g, 7.3 mmol) in 115 mL of Et2O.
The reaction was stirred for a further 0.5 h at -30 °C and
then stored at -20 °C for 20 h. The precipitated red solid was
collected by filtration, washed with cold Et2O, and dried on a
vacuum pump to afford 1.11 g (55%) of the orthoquinone 7:
IR (CDCl3) 1727, 1671 cm-1 1H NMR (CDCl3, 300 MHz) δ
;
7.41-7.26 (m, 5 H), 6.74 (s, 1 H), 6.73 (s, 1 H), 6.56 (s, 2 H),
3.92 (s, 3 H); 13C NMR (CDCl3, 75 MHz) δ 179.9, 174.2, 164.7,
152.1, 141.3, 134.3, 128.8, 128.7, 127.7, 124.4, 107.7, 71.1, 53.4;
MS (-FAB) 272 (M-, 12). Anal. Calc for C15H12O5: C, 66.18;
H, 4.41; Found: C, 65.75; H, 4.45.
Mod ified Steglich Ester ifica tion Rea ction : Gen er a l
P r oced u r e B. A solution of the appropriate polyol (1.0 equiv),
acid (1 equiv per hydroxyl), 4-(dimethylamino)pyridine (DMAP)
(0.5 equiv), DMAP‚HCl (0.5 equiv), and 1,3-dicyclohexylcar-
bodiimide (DCC) (1.5 equiv per hydroxyl) in dry CH2Cl2 (0.1
M in acid) was purged with Ar and heated under Ar at reflux
for 15-20 h. The solution was cooled to room temperature and
filtered through Celite. The filtrate was diluted with an equal
volume of EtOAc and poured into ice-cold 1 M H3PO4. The
organic layer was separated, washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The
crude product was purified by flash column chromatography
with the indicated eluent to furnish the desired esters.
Silyl Eth er Dep r otection Rea ction : Gen er a l P r oce-
d u r e C. To a solution of the appropriate tert-butyldimethylsilyl
(TBDMS)-protected glucose derivative (1.0 equiv) in dry THF
(0.01-0.05 M in TBDMS-protected glucose derivative) was
added a solution of tetra-n-butylammonium fluoride (TBAF)
in THF (1.0 M solution in THF) (1.5 equiv per TBDMS group).
The reaction was stirred at room temperature and followed
by TLC (10-45 min). At the end of the indicated time period,
the reaction solution was carefully treated with ice-cold 1 M
H3PO4, and the product was extracted with Et2O. The Et2O
Dia r yl Eth er 8. The orthoquinone 7 (200 mg, 0.72 mmol)
was dissolved in 5 mL of CDCl3. B(OAc)3 (136 mg, 0.72 mmol)
was added, and the heterogeneous mixture was heated at 62-
1
65 °C (oil bath temperature) for 15 h, at which time H NMR
analysis indicated the absence of the orthoquinone. The
reaction mixture was cooled and filtered. The B(OAc)3 pellet
was washed with cold CH2Cl2, and the filtrate and washings
were evaporated to give a brown oil which was immediately
stirred with NaOAc (60 mg, 0.76 mmol) in 5 mL of HOAc for
2 h. This reaction mixture was partitioned between EtOAc and
water, and the organic layer was washed with brine and dried
(Na2SO4). Concentration of the organic layer in vacuo fur-
nished a yellow oil which was purified by flash column
chromatography (-78 °C, under argon) to yield 150 mg of a
regioisomeric mixture of dehydrodigalloyl quinones as a yellow
solid. The mixture of quinones was immediately stirred with
Na2S2O4 (180 mg, 1.08 mmol) in 8 mL of THF/ 2 mL of water
at 0 °C for 10 min. The dark yellow reaction mixture decol-
orized to a pale yellow solution over this time. The reaction
mixture was partitioned between EtOAc and water, and the
organic layer was washed with brine and dried (Na2SO4). The
solvent was removed in vacuo to furnish 150 mg of a white
solid (regioisomeric mixture of dehydrodigalloyl ethers). The
crude white solid (150 mg, 0.27 mmol) was benzylated with
BnCl (126 µL, 1.10 mmol), K2CO3 (190 mg, 1.37 mmol), and
KI (27 mg, 0.16 mmol) in 30 mL of refluxing acetone for 24 h.
The reaction mixture was cooled and filtered through Celite,
and the filtrate was concentrated in vacuo to an oil which was
purified by flash column chromatography using 1:1 Et2O/
hexanes to furnish 98 mg of 8 (44%, starting from 7): IR (CH2-
(21) Okuda, T.; Yoshida, T.; Hatano, T.; Koga, T.; Toh, N.; Kuriyama,
K. Tetrahedron Lett. 1982, 23, 3937.
(22) Okuda, T.; Yoshida, T.; Hatano, T. J . Nat. Prod. 1989, 52, 1.
(23) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(24) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17,
522.
(25) Keck, G. E.; Boden, E. P. J . Org. Chem. 1985, 50, 2394.
(26) Armitage, R.; Bayliss, G. S.; Gramshaw, J . W.; Haslam, E.;
Haworth, R. D.; J ones, K.; Rogers, H. J .; Searle, T. J . Chem. Soc. 1961,
1842.

Ellagitannin Chemistry
J . Org. Chem., Vol. 64, No. 1, 1999 213
1
Cl2) 1718 cm-1; H NMR (CDCl3, 300 MHz) δ 7.45-7.13 (m,
128.7, 128.6, 128.53, 128.50, 128.4, 128.3, 128.21, 128.20,
128.1, 128.0, 127.8, 127.79, 127.75, 126.8, 124.7, 123.8, 123.7,
123.1, 109.6, 109.5, 109.3, 109.2, 93.3, 75.33, 75.3, 73.53, 73.5,
71.4, 71.3, 71.2, 69.9, 63.4, 20.8, 20.3; MS (+FAB) 2147 (MH+,
25). Anal. Calcd for C131H110O29: C, 73.25; H, 5.13. Found: C,
72.84; H, 5.34.
27 H), 6.90 (d, J ) 1.8 Hz, 1 H), 5.14 (s, 4 H), 5.12 (s, 4 H),
4.97 (s, 2 H), 3.79 (s, 3 H), 3.71 (s, 3 H); 13C NMR (CDCl3, 90
MHz) δ 166.4, 165.2, 152.6, 149.9, 146.8, 146.5, 142.5, 141.7,
137.9, 136.8, 136.7, 136.6, 136.3, 128.61, 128.6, 128.5, 128.34,
128.3, 129.2, 128.1, 127.96, 127.9, 127.7, 127.5, 125.0, 119.8,
110.8, 109.14, 109.12, 75.6, 75.3, 75.1, 71.4, 71.2, 52.3, 52.1;
MS (+FAB) 816.5 (M+, 100); HRFABMS calcd for C51H44O10
816.2934, found 816.2933.
3,4,5,3′,4′-P en ta ben zyloxyd eh yd r od iga llic Acid (9). The
diaryl ether 8 (0.30 g, 0.37 mmol) and lithium hydroxide
hydrate (0.15 g, 3.7 mmol) in 16 mL of a 3:1 MeOH/water
mixture were brought to reflux and held there with TLC
monitoring for 3.5 h. The reaction mixture was cooled, and
the solvents were removed in vacuo. Flash column chroma-
tography on the residue using 50% EtOAc in hexanes and then
1% HOAc in EtOAc as eluents furnished 0.18 g (62%) of the
diacid 9 as a white solid: IR (KBr pellet) 2629, 1688 cm-1; 1H
NMR (acetone-d6, 300 MHz) δ 7.57-7.17 (m, 27 H), 6.96 (d, J
) 1.7 Hz, 1 H), 5.26 (s, 2 H), 5.22 (s, 2 H), 5.20 (s, 2 H), 5.15
(s, 2 H), 5.01 (s, 2 H); 13C NMR (acetone-d6, 50 MHz) δ 167.2,
165.9, 153.8, 150.9, 150.5, 149.0, 147.5, 147.2, 143.1, 142.5,
139.1, 138.0, 137.9, 137.7, 137.6, 129.4, 129.3, 129.2, 129.1,
128.97, 128.92, 128.9, 128.8, 128.7, 128.5, 128.3, 128.2, 126.3,
121.3, 111.7, 109.8, 76.1, 75.9, 75.6, 71.9, 71.7, 52.2, 52.0; MS
(+FAB) 788.5 (M+, 100); HRFABMS calcd for C49H40O10
788.2621, found 788.2614.
3,4-Di-ter t-b u t yld im et h ylsiloxy-5-b en zyloxyb en zoic
Acid . A solution of 3-benzyloxy-4,5-dihydroxybenzoic acid (3.00
g, 11.5 mmol) and tert-butyldimethylsilyl chloride (4.34 g, 28.8
mmol) in 13 mL of DMF (minimum volume required to dissolve
the reactants) was treated with N,N′-diisopropylethylamine
(6.0 mL, 35 mmol). The turbid brown solution was stirred at
room temperature for 18 h, at which time TLC indicated
complete absence of starting material and the presence of 3,4-
di-tert-butyldimethylsiloxy-5-benzyloxybenzoic acid along with
3,4-di-tert-butyldimethylsilyl (3,4-di-tert-butyldimethylsiloxy-
5-benzyloxy)benzoate. The reaction mixture was treated with
20 mL of 1 M H3PO4 and extracted with 200 mL of Et2O. The
organic layer was separated and washed with water (10 × 50
mL) and then brine, dried (Na2SO4) and concentrated in vacuo.
The residue was purified by flash column chromatography
eluting with 10%, and then 25%, EtOAc in hexanes, to yield
1.53 g of the title compound as a white solid along with 3.61
g of 3,4-di-tert-butyldimethylsilyl (3,4-di-tert-butyldimethylsi-
loxy-5-benzyloxy)benzoate as a yellow oil. The silyl ester
product was stirred in 60 mL of a 1:6:2 solution of HOAc/THF/
water at room temperature for 2.5 h, at which time TLC
showed the presence of only the title compound. The reaction
solution was treated with a saturated aqueous solution of
sodium bicarbonate and extracted into EtOAc. The organic
layer was separated, washed with water and brine, and dried
(Na2SO4). Removal of the solvent in vacuo followed by tritu-
ration of the residue with hexanes afforded a further 2.52 g of
3,4-di-tert-butyldimethylsiloxy-5-benzyloxybenzoic acid (4.05
g over two steps, 71%): IR (CH2Cl2) 3504, 1684 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 7.42-7.33 (m, 7 H), 5.05 (s, 2 H), 0.99 (s,
9 H), 0.90 (s, 9 H), 0.24 (s, 6 H), 0.07 (s, 6 H); 13C NMR (CDCl3,
75 MHz) δ 171.9, 151.2, 147.7, 136.2, 128.6, 128.4, 128.2, 116.3,
107.8, 70.9, 26.1, 25.8, 19.0, 18.6, -3.8, -4.1; MS (+FAB) 488
(MH+, 52). Anal. Calcd for C26H40O5Si2: C, 63.93; H, 8.19.
Found: C, 64.17, H, 8.00.
1-O-2,3,4,6-Tetr a k is(3,4,5-tr is(ben zyloxy)ben zoyl)-r-D-
glu cop yr a n osyl Tr ich lor oa cetim id a te (13). A solution of
2,3,4,6-tetrakis(3,4,5-tris(benzyloxy)benzoyl)-D-glucopyra-
nose (11) (1.0 g, 0.54 mmol) in 10 mL of dry benzene was added
to degreased sodium hydride (0.014 g, 0.58 mmol), followed
by addition of trichloroacetonitrile (536 µL, 5.20 mmol), and
the resultant solution was stirred at room temperature for 18
h. The reaction was diluted with water, and the product was
extracted into 25 mL of EtOAc. The organic layer was
separated, washed with brine, and dried (Na2SO4). The solu-
tion was concentrated in vacuo and purified by flash column
chromatography using 10% and then 20% EtOAc in hexanes
as eluent to afford 0.90 g (84%) of 1-O -2,3,4,6-tetrakis(3,4,5-
tris(benzyloxy)benzoyl)-R-D-glucopyranosyl trichloroacetimi-
date (13) as a white solid: IR (CH2Cl2) 3342, 1728, 1678 cm-1
;
3,4-Di-ter t-b u t yld im et h ylsiloxy-5-b en zyloxyb en zoyl
Ch lor id e (16). A solution of 3,4-di-tert-butyldimethylsiloxy-
5-benzyloxybenzoic acid (1.50 g, 3.07 mmol) in 30 mL of CH2-
Cl2 was treated with oxalyl chloride (295 µL, 3.38 mmol) and
then a catalytic amount of DMF. The reaction was stirred at
room temperature with monitoring by TLC. After 2 h, con-
sumption of starting material was indicated, and removal of
solvents in vacuo and drying under high vacuum provided 1.55
1H NMR (CDCl3, 300 MHz) δ 8.65 (S, 1 H), 7.41-7.15 (m, 68
H), 6.88 (d, J ) 3.6 Hz, 1 H), 6.21 (t, J ) 10.1 Hz, 1 H), 5.73
(t, J ) 10.1 Hz, 1 H), 5.54 (dd, J ) 3.7 Hz, 10.2 Hz, 1 H), 5.13-
4.88 (m, 24 H), 4.82-4.65 (m, 2 H), 4.32 (dd, J ) 5.0 Hz, 12.2
Hz, 1 H); 13C NMR (CDCl3, 90 MHz) δ 165.54, 165.50, 165.1,
165.0, 160.5, 152.60, 152.57, 152.51, 152.50, 143.3, 143.1,
142.8, 137.4, 137.3, 136.6, 136.5, 136.4, 136.3, 128.52, 128.50,
128.43, 128.40, 128.34, 128.30, 128.24, 128.20, 128.13, 128.11,
128.10, 128.0, 127.96, 127.9, 127.82, 127.8, 127.6, 127.52,
127.50, 124.6, 123.9, 123.5, 109.6, 109.4, 109.2, 109.1, 93.2,
90.8, 75.1, 71.3, 71.21, 71.20, 71.11, 71.1, 70.8, 69.2, 62.8; MS
(+FAB) 2012 (MH+, 78). Anal. Calcd for C120H100Cl3NO22: C,
71.61; H, 4.97; Cl, 5.22; N, 0.70. Found: C, 71.61; H, 5.07; Cl,
5.42; N, 0.72.
1
g (100%) of 16: IR (CH2Cl2) 1742 cm-1; H NMR (CDCl3, 300
MHz) δ 7.44-7.34 (m, 7 H), 5.05 (s, 2 H), 0.99 (s, 9 H), 0.90 (s,
9 H), 0.26 (s, 6 H), 0.07 (s, 6 H); 13C NMR (CDCl3, 75 MHz) δ
167.3, 151.3, 147.9, 143.9, 135.7, 128.8, 128.5, 128.4, 124.6,
118.2, 108.9, 71.2, 26.0, 25.7, 18.7, 18.6, -4.0, -4.1; MS (+
FAB) (MH+, 24); HRFABMS calcd for C26H39O4Si2Cl 507.2154,
found 507.2126.
1-O-3,4,5-Tr ia cetoxyben zoyl-2,3,4,6-tetr a k is(3,4,5-tr is-
(ben zyloxy)ben zoyl)-â-D-glu cop yr a n osid e (15). A solution
of 1-O-2,3,4,6-tetrakis(3,4,5-tris(benzyloxy)benzoyl)-R-D-glu-
copyranosyl trichloroacetimidate (13) (170 mg, 0.08 mmol) and
3,4,5-triacetoxybenzoic acid (14) (25 mg, 0.08 mmol) in 0.8 mL
of dry toluene was brought to reflux and held there for 18 h.
The reaction was cooled, the solvent was removed in vacuo,
and the residue was purified by silica gel flash column
chromatography using 20%, 40%, and then 60% EtOAc in
hexanes as eluent to yield 60 mg (33%) of 1-O-3,4,5-triacetoxy-
benzoyl-2,3,4,6-tetrakis(3,4,5-tris(benzyloxy)benzoyl)-â-D-glu-
copyranoside (15) as a white solid: IR (CH2Cl2) 1738, 1731
1-O-(3,4-Di-ter t-bu tyld im eth ylsiloxy-5-ben zyloxyben -
zoyl)-2,3,4,6-t et r a k is(3,4,5-t r is(b en zyloxy)b en zoyl)-â-D-
glu cop yr a n osid e (17). Triethylamine (116 µL, 1.62 mmol)
was added to a solution of 2,3,4,6-tetrakis(3,4,5-tris(benzyloxy)-
benzoyl)-D-glucopyranose (11) (1.00 g, 0.54 mmol) and 3,4-di-
tert-butyldimethylsiloxy-5-benzyloxybenzoyl chloride (16) (0.33
g, 0.65 mmol) in 12 mL of dry CH2Cl2 (0.05 M in alcohol), and
the solution was stirred at room temperature for 18 h. The
reaction was treated with 10 mL of 1 M HCl and extracted
with 25 mL of EtOAc. The organic layer was separated and
washed with water and then brine, dried (Na2SO4), and
concentrated in vacuo. Flash column chromatography of the
crude mixture using 10% and then 25% EtOAc in hexanes as
eluents afforded 0.96 g (76%) of 1-O-(3,4-tert-butyldimethyl-
siloxy-5-benzyloxybenzoyl)-2,3,4,6-tetrakis(3,4,5-tris(benzyloxy)-
benzoyl)-â-D-glucopyranoside (17) as a white solid froth: IR
cm-1 1H NMR (CDCl3, 300 MHz) δ 7.81(s, 1 H), 7.46-7.16
;
(m, 69 H), 6.27 (d, J ) 8.2 Hz, 1 H), 6.05 (t, J ) 9.7 Hz, 1 H),
5.81 (t, J ) 9.1 Hz, 1 H), 5.69 (t, J ) 9.6 Hz, 1 H), 5.15-4.88
(m, 24 H), 4.75 (d, J ) 10.1 Hz, 1 H), 4.42-4.32 (m, 2 H), 2.27
(s, 3 H), 2.25 (s, 6 H); 13C NMR (CDCl3, 90 MHz) δ 167.6, 166.4,
165.8, 165.2, 165.1, 162.9, 152.8, 152.73, 152.7, 143.8, 143.3,
142.7, 139.7, 137.7, 137.6, 137.5, 136.9, 136.7, 136.6, 136.5,
1
(CH2Cl2) 1732 cm-1; H NMR (CDCl3, 300 MHz) δ 7.48-7.13
(m, 75 H), 6.28 (d, J ) 8.2 Hz, 1 H), 6.08 (t, J ) 9.7 Hz, 1 H),
5.88 (dd, J ) 9.9 Hz, 8.3 Hz, 1 H), 5.78 (t, J ) 9.6 Hz, 1 H),

214 J . Org. Chem., Vol. 64, No. 1, 1999
Feldman and Sahasrabudhe
5.17-4.79 (m, 27 H), 4.43-4.38 (m, 2 H), 0.98 (s, 9 H), 0.87 (s,
water for 10 min at 0 °C. The dark yellow reaction mixture
decolorized to a pale yellow solution over this time. The
reaction mixture was partitioned between EtOAc and water,
and the organic phase was washed with brine, dried (Na2SO4),
and concentrated in vacuo to a white solid which was dried
under high vacuum. The crude white solid (78 mg, 0.018 mmol)
was benzylated with benzyl chloride (9 µL, 0.07 mmol), K2-
CO3 (13 mg, 0.09 mmol), and KI (92 mg, 0.01 mmol) in 5 mL
of refluxing acetone for 24 h. The reaction mixture was cooled
and filtered through Celite, and the filtrate was concentrated
in vacuo to an oil which was purified by flash column
chromatography using 10% and then 20% EtOAc in hexanes
as eluents to furnish 46 mg (44%, over four steps) of the
9 H), 0.25 (s, 3 H), 0.20 (s, 3 H), 0.03 (s, 3 H), 0.02 (s, 3 H); 13
C
NMR (CDCl3, 75 MHz) δ 165.6, 165.5, 164.9, 164.7, 164.4,
152.5, 152.4, 152.3, 151.1, 147.7, 143.1, 143.0, 142.9, 142.5,
142.2, 137.4, 137.3, 137.2, 136.7, 136.3, 135.9, 128.7, 128.5,
128.4, 128.35, 128.32, 128.24, 128.21, 128.1, 128.06, 128.03,
127.96, 127.90, 127.81, 127.7, 127.5, 127.4, 124.5, 123.8, 123.7,
123.66, 123.6, 120.0, 116.1, 109.3, 109.1, 107.8, 92.7, 75.1, 75.0,
73.5, 73.1, 71.1, 71.0, 70.9, 70.8, 69.8, 63.2, 26.0, 25.7, 18.5,
18.4, -3.4, -3.5. Anal. Calcd for C144H138O26Si: C, 73.90; H,
5.90. Found: C, 73.91; H, 5.94.
1-O-(2-Ben zyloxy-4,5-dih ydr oxyben zoyl)-2,3,4,6-tetr akis-
(3,4,5-tr is(ben zyloxy)ben zoyl)-â-D-glu cop yr a n osid e (18).
By use of general procedure C, 1-O-(3,4-di-tert-butyldimeth-
ylsiloxy-5-benzyloxybenzoyl)-2,3,4,6-tetrakis(3,4,5-tris(benzyl-
oxy)benzoyl)-â-D-glucopyranoside (17) (1.10 g, 0.47 mmol) (0.02
M solution in THF) was desilylated in 45 min to provide 0.80
g (80%) of 1-O-(3-benzyloxy-4,5-dihydroxybenzoyl)-2,3,4,6-tet-
rakis(3,4,5-tris(benzyloxy)benzoyl)-â-D-glucopyranoside (18) af-
ter flash column chromatography using 10%, 25%, and then
perbenzylated dimeric gallotannin 12: IR (CH2Cl2) 1731 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 7.64-7.05 (m, 163 H), 7.04 (s, 1
H), 6.23 (d, J ) 8.1 Hz, 1 H), 6.08 (m, 2 H), 5.94 (t, J ) 9.8 Hz,
1 H), 5.84 (t, J ) 9.0 Hz, 1 H), 5.74 (t, J ) 9.7 Hz, 1 H), 5.70-
5.62 (m, 2 H), 5.15-4.70 (m, 59 H), 4.58-4.31 (m, 5 H); 13C
NMR (CDCl3, 90 MHz) δ 169.0, 165.62, 165.6, 165.0, 164.9,
164.7, 164.2, 152.6, 152.54, 152.5, 143.3, 143.21, 143.2, 143.1,
142.7, 137.5, 137.4, 136.7, 136.5, 136.4, 136.3, 128.51, 128.5,
128.42, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.61,
127.6, 127.5, 124.6, 123.7, 123.6, 123.3, 19.5, 109.41, 109.4,
109.2, 93.0, 92.2, 75.1, 73.5, 73.3, 73.2, 71.4, 71.3, 71.2, 71.1,
71.0, 69.8, 69.7, 63.1; MS (+FAB) 4493 (MH+, 35). Anal. Calcd
for C285H236O52: C, 76.20; H, 5.26. Found: C, 76.07; H, 5.52.
P h en olic Dim er 6. A solution of the dimer 12 (32 mg, 0.007
mmol) and 10% Pd on C (6 mg, 20 wt % of 12) in 2.5 mL of dry
THF was stirred at room temperature under a balloon of H2
at 1 atm for 20 h, purged several times with argon, filtered
twice through Celite, and concentrated under reduced pres-
sure. The resultant brown-gray residue was triturated with
Et2O, hexanes, and then benzene to yield 6 mg (50%) of the
debenzylated dimeric gallotannin 6 as a pale gray solid: 1H
NMR (acetone-d6, 300 MHz) δ 7.42-6.93 (m, 18 H), 6.78 (s, 1
H), 6.32 (d, J ) 8.3 Hz, 1 H), 6.18 (d, J ) 8.3 Hz, 1 H), 6.09-
5.87 (m, 2 H), 5.69-5.39 (m, 4 H), 4.56-4.25 (m, 6 H); 13C NMR
(acetone-d6, 90 MHz) δ 169.4, 166.4, 165.9, 165.8, 165.6, 165.5,
164.9, 146.0, 145.8, 139.3, 139.1, 129.3, 129.2, 128.5, 121.5,
120.7, 120.6, 120.0, 110.4, 110.3, 110.1, 93.4, 92.9, 74.0,73.3,
71.8, 69.3, 69.2, 66.9, 62.8; MS (+FAB) 1879 (MH+, 22), 1901
(M + Na+, 36); HRFABMS calcd for C82H62O52 1878.2207,
found 1878.2190; calcd for C82H62O52Na 1901.2105, found
1901.2085.
50% EtOAc in hexanes as eluents: IR (CDCl3) 3534, 1732 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 7.45-7.16 (m, 75 H), 6.24 (d, J
) 8.1 Hz, 1 H), 6.04 (t, J ) 9.6 Hz, 1 H), 5.96 (bs, 1 H), 5.83
(dd, J ) 9.7, 8.1 Hz, 1 H), 5.73 (t, J ) 0.6 Hz, 1 H), 5.50 (bs,
1 H), 5.14-4.76 (m,27 H), 4.43-4.34 (m, 2 H); 13C NMR
(CDCl3, 75 MHz) δ 165.6, 165.5, 165.0, 164.9, 164.3, 152.59,
152.57, 152.47, 145.7, 143.7, 143.3, 143.2, 143.1, 142.6, 138.1,
137.5, 137.3, 136.4, 136.3, 135.6, 128.7, 128.6, 128.5, 128.45,
128.40, 128.3, 128.2, 128.1, 128.09, 128.06, 127.9, 127.8, 127.5,
124.6, 123.8, 123.7, 123.6, 119.9, 111.9, 109.4, 109.3, 109.2,
106.7, 92.9, 75.1, 75.08, 73.4, 73.37, 73.3, 71.4, 71.34, 71.3,
71.22, 71.2, 71.1, 69.9, 63.2. Anal. Calcd for C132H110O26: C,
75.07; H, 5.21. Found: C, 74.88; H, 5.22.
1-O-(3-Ben zyloxy-1,2-d ioxocycloh exa -3,5-d ien e-5-ben -
zoyl)-2,3,4,6-t et r a k is(3,4,5-t r is(b en zyloxy)b en zoyl)-â-D-
glu cop yr a n osid e (19). To a solution of orthochloranil (100
mg, 0.38 mmol) in 4 mL of dry Et2O (0.1 M in orthochloranil),
cooled to -30 °C, was added dropwise via an addition funnel
over 1.5 h a solution of 1-O-(2-benzyloxy-4,5-dihydroxyben-
zoyl)-2,3,4,6-tetrakis(3,4,5-tris(benzyloxy)benzoyl)-â-D-glucopy-
ranoside (18) (0.80 g, 0.38 mmol) in 12 mL of dry Et2O (0.03
M in diphenol). After the addition was completed, the resulting
deep red solution was stirred at -30 °C for a further 3 h, and
then it was stored in a freezer at - 20 °C for 18 h. The
precipitated red solid was collected by filtration, washed with
cold Et2O, and dried on a vacuum pump to afford 0.53 g (66%)
2-Nitr oben zyl 4,6-O-Ben zylid en e-2,3-bis(3,4,5-tr is(ben -
zyloxy)ben zoyl)-â-D-glu cop yr a n osid e (21). By use of gen-
eral procedure A, 2-nitrobenzyl 4,6-O-benzylidene-â-D-glucopy-
ranoside (20)9 (5.20 g, 12.9 mmol) and 3,4,5-tribenzyloxybenzoic
acid (11.4 g, 25.8 mmol) were coupled to afford 12.6 g (78%) of
2-nitrobenzyl 4,6-O-benzylidene-2,3-bis(3,4,5-tris(benzyloxy)-
benzoyl)-â-D-glucopyranoside (21) as a white solid foam fol-
lowing flash column chromatography using 10% and then 20%
EtOAc in hexanes as eluent: IR (CDCl3) 1728 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 8.06-8.03 (m, 1 H), 7.67-7.64 (m, 1 H),
7.44-7.17 (m, 41 H), 5.78 (t, J ) 9.5 Hz, 1 H), 5.60-5.55 (m,
2 H), 5.33 (d, J ) 15.4 Hz, 1 H), 5.12-4.99 (m, 13 H), 4.94 (d,
J ) 7.8 Hz, 1 H), 4.49 (dd, J ) 10.3 Hz, 4.6 Hz, 1 H), 3.99-
3.87 (m, 2 H), 3.77 (dd, J ) 9.4 Hz, 4.7 Hz, 2 H); 13C NMR
(CDCl3, 75 MHz) δ 165.2, 164.9, 152.5, 152.4, 146.6, 142.8,
142.7, 137.3, 136.6, 136.5, 136.4, 133.8, 133.7,129.1, 128.4,
128.3, 128.2, 128.1, 128.06, 128.0, 127.9, 127.8, 127.5, 127.4,
126.1, 124.6, 124.3, 124.0, 109.3, 109.2, 101.5, 101.3, 78.7, 75.1,
72.1, 72.2, 71.2, 68.5, 68.1, 66.8; MS (+FAB) 1248 (MH+, 22).
of 19 as a red amorphous powder: IR (CDCl3) 1730, 1672 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 7.45-7.17 (m, 73 H), 6.79 (d, J
) 1.4 Hz, 1 H), 6.47 (s, 1 H), 6.13 (d, J ) 7.9 Hz, 1 H), 6.03 (t,
J ) 9.6 Hz, 1 H), 5.74 (t, J ) 9.2 Hz, 2 H), 5.15-4.85 (m, 26
H), 4.79 (d, J ) 9.5 Hz, 1 H), 4.41-4.32 (m, 2 H); 13C NMR
(CDCl3, 90 MHz) δ 179.6, 173.8, 165.6, 165.5, 164.9, 164.8,
162.8, 152.6, 152.5, 152.4, 143.3, 143.2, 140.1, 137.4, 137.3,
136.6, 136.3, 136.2, 134.2, 128.8, 128.6, 128.5, 128.49, 128.42,
128.3, 128.2, 128.14, 128.10, 127.99, 127.92, 127.88, 127.85,
127.83, 127.76, 127.5, 125.6, 124.4, 123.4, 123.3, 109.4, 109.3,
109.2, 106.8, 93.8, 75.1, 73.5, 72.9, 71.2, 71.18, 71.12, 71.0, 69.3,
62.8; MS (+FAB) 2109 (MH+, 21). Anal. Calcd for
C
132H108O26: C, 75.14; H, 5.12. Found: C, 74.75; H, 5.29.
Ben zyla ted Dim er 12. The orthoquinone 19 (100 mg, 0.047
mmol) was dissolved in 1.5 mL of CDCl3. B(OAc)3 (10 mg, 0.052
mmol) was added, and the heterogeneous mixture was heated
1
at 62-65 °C (oil bath temperature) for 24 h, at which time H
NMR analysis indicated absence of the orthoquinone. The
reaction mixture was cooled and filtered. The residue was
washed with CH2Cl2, and the filtrate and washings were
evaporated to give a reddish brown solid which was im-
mediately treated with NaOAc (4 mg, 0.052 mmol) in HOAc
(2 mL)/THF (0.5 mL) for 2 h. This reaction mixture was
partitioned between EtOAc and water. The EtOAc layer was
washed with brine, dried (Na2SO4), and concentrated in vacuo
to yield a yellow residue. Flash column chromatography at -78
°C using 10% and then 50% EtOAc in hexanes as eluents
provided 78 mg of a yellow solid which was immediately
treated with Na2S2O4 (2 mg, 0.071 mmol) in 10 mL of 8:2 THF/
Anal. Calcd for C76H65NO16: C, 73.13; H, 5.21; N, 1.12.
Found: C, 73.11; H, 5.17; N, 0.92.
2-Nitr oben zyl 2,3-Bis(3,4,5-tr is(ben zyloxy)ben zoyl)-â-
D-glu cop yr a n osid e. A solution of 2-nitrobenzyl 4,6-O-ben-
zylidene-2,3-bis(3,4,5-tris(benzyloxy)benzoyl)-â-D-glucopyra-
noside (21) (1.4 g, 1.1 mmol) and iodine (0.28 g, 1.1 mmol) in
17 mL of dry CH3OH and 17 mL of dry CH2Cl2 was heated at
reflux under Ar for 48 h. The solution was cooled to room
temperature, treated with a saturated aqueous solution of
Na2S2O3, and extracted with EtOAc. The organic layer was
separated, washed with water and then brine, dried (Na2SO4),
and concentrated in vacuo. Flash column chromatography

Ellagitannin Chemistry
J . Org. Chem., Vol. 64, No. 1, 1999 215
using 30% and then 50% EtOAc in benzene provided 1.10 g
(84%) of 2-nitrobenzyl 2,3-bis(3,4,5-tris(benzyloxy)benzoyl)-â-
D-glucopyranoside as a white solid froth: IR (CH2Cl2) 1726
cm-1; 1H NMR (CDCl3, 300 MHz) δ 8.04-8.01 (m, 1 H), 7.64-
7.60 (m, 1 H), 7.43-7.17 (m, 36 H), 5.53 (dd, J ) 9.7 Hz, 8.0
Hz, 1 H), 5.33-5.27 (m, 2 H), 5.13-4.83 (m, 13 H), 4.96 (d, J
) 8.0 Hz, 1 H), 4.91-4.84 (m, 1 H), 4.04-3.93 (m, 3 H), 3.64-
3.60 (m, 1 H), 3.56 (bs, 1 H); 13C NMR (CDCl3, 75 MHz) δ 167.5,
165.1, 152.6, 146.8, 137.3, 136.4, 133.8, 133.7, 128.52, 128.5,
128.44, 128.4, 128.14, 128.1, 127.99, 127.91, 127.6, 127.53,
127.5, 124.7, 124.0, 123.5, 109.3, 109.2, 100.7, 78.1, 75.1, 71.6,
71.2, 71.1, 71.0, 69.9, 68.1, 62.1; MS (+FAB) 1159 (M+, 18).
NaHCO3, and extracted with 250 mL of EtOAc. The organic
layer was washed with 75 mL of 1 M H3PO4 and then brine
and dried (Na2SO4). Concentration in vacuo, followed by
purification of the resultant yellow residue by silica gel
chromatography using 10%, 20%, and then 35% EtOAc in
hexanes furnished 1.21 g (67%) of a mixture of three regio-
isomers 24a -c as a yellow solid: IR (CH2Cl2) 1747, 1731 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 8.05-8.02 (m, 1 H), 7.98-7.00
(m, 57 H), 6.79-6.71 (m, 2 H), 5.66-5.56 (m, 2 H), 5.48-5.29
(m, 2 H), 5.18-4.79 (m, 15 H), 4.14-3.90 (m, 2 H); MS (+FAB)
1790 (MH+, 80). Anal. Calcd for C109H83NO24: C, 73.11; H, 4.64;
N, 0.78. Found: C, 72.89; H, 4.88; N, 0.67.
Anal. Calcd for C69H61NO16
: C, 71.44; H, 5.26; N, 1.21.
2-Nitr oben zyl 4,6-(3,4,5,3′,4′,5′-Hexa ben zyloxy)d ip h en -
oyl-2,3-bis(3,4,5-tr is(ben zyloxy)ben zoyl)-â-D-glu cop yr a -
n osid e (25). 2-Nitrobenzyl 4,6-(3,4-diphenylmethylenedioxy-
5-hydroxy-3′,4′-diphenylmethylenedioxy-5′-hydroxy)diphenoyl-
2,3-bis(3,4,5-tris(benzyloxy)benzoyl)-â-D-glucopyranoside (24a-
c) (1.30 g, 0.73 mmol) was brought to reflux in 75 mL of 80%
HOAc and held there for 16 h. The solvent was removed to
yield an oil which was triturated with hexanes to afford 1.10
g of crude 2-nitrobenzyl 4,6-(3,4,5,3′,4′,5′-hexahydroxy)dipheno-
yl-2,3-bis(3,4,5-tris(benzyloxy)benzoyl)-â-D-glucopyranoside as
a yellow solid. The crude hexahydroxy compound (1.10 g, 0.75
mmol) and sodium hydride (0.22 g, 9.03 mmol) (60% suspen-
sion in oil) were stirred in 10 mL of dry THF at 0 °C for 10
min. After addition of benzyl bromide (0.81 mL, 6.8 mmol) and
then tetra-n-butylammonium iodide (TBAI) (0.25 g, 0.68
mmol), the resulting turbid brown suspension was allowed to
warm to room temperature over 30 min and was stirred for a
further 18 h at room temperature. The reaction was diluted
with water and extracted with Et2O. The organic layer was
separated, washed with water and then brine, dried (Na2SO4),
and concentrated to a yellow oil. Purification of this residue
by flash column chromatography using 10%, 20%, and then
30% EtOAc in hexanes as eluents yielded 0.75 g (50%) of
2-nitrobenzyl 4,6-(3,4,5,3′,4′,5′-hexabenzyloxy)diphenoyl-2,3-
bis(3,4,5-tris(benzyloxy)benzoyl)-â-D-glucopyranoside (25) as a
Found: C, 71.30; H, 5.45; N, 1.18
2-Nitr oben zyl 4,6-Bis(3-ter t-bu tyld im eth ylsiloxy-4,5-
d ip h en ylm eth yl-en ed ioxyben zoyl)-2,3-bis(3,4,5-tr is(ben -
zyloxy)ben zoyl)-â-D-glu cop yr a n osid e (23). By use of gen-
eral procedure B, 2-nitrobenzyl 2,3-bis(3,4,5-tris(benzyloxy)-
benzoyl)-â-D-glucopyranoside (2.10 g, 1.81 mmol) was coupled
with 3-tert-butyldimethylsiloxy-4,5-diphenylmethylenedioxy-
benzoic acid (22) (1.62 g, 3.62 mmol) to afford 2.99 g (80%) of
2-nitrobenzyl 4,6-bis(3-tert-butyldimethylsiloxy-4,5-diphenyl-
methylenedioxybenzoyl)-2,3-bis(3,4,5-tris(benzyloxy)benzoyl)-
â-D-glucopyranoside (23) as a white solid foam following flash
column chromatography using 10% and then 20% EtOAc in
1
hexanes as eluent: IR (CH2Cl2) 1729 cm-1; H NMR (CDCl3,
75 MHz) δ 8.05(d, J ) 1.3 Hz, 1 H), 7.98 (d, J ) 4 Hz, 1 H),
7.70-7.15 (m, 60 H), 5.84 (t, J ) 9.7 Hz, 1 H), 5.67-5.56 (m,
2 H), 5.31 (d, J ) 15.2 Hz, 2 H), 5.13-4.89 (m, 14 H), 4.64, (d,
J ) 10.6 Hz, 1 H), 4.38-4.32 (m, 1 H), 4.15-4.12 (m, 1 H),
0.99 (s, 9 H), 0.96 (s, 9 H), 0.19 (s, 6 H), 0.18 (s, 6 H); 13C NMR
(CDCl3, 75 MHz) δ 165.5, 165.3, 164.9, 164.4, 152.5, 148.6,
146.8, 142.8, 142.0, 141.7, 139.9, 139.6, 138.6, 137.4, 136.5,
133.7, 129.2, 128.9, 128.4, 128.3, 128.1, 128.0, 127.6, 127.5,
126.2, 124.6, 124.2, 124.0, 123.5, 122.5, 119.1, 118.8, 118.2,
109.3, 109.1, 104.1, 100.1, 75.1, 75.0, 73.3, 72.8, 72.3, 71.2, 71.1,
68.9, 68.3, 62.5, 26.05, 26.04, 18.3, 18.2, -4.0; MS (+FAB) 2020
(MH+, 23). Anal. Calcd for C121H113NO24Si2: C, 71.92; H, 5.59;
N, 0.69. Found: C, 72.16; H, 5.80; N, 0.58.
white solid froth: IR (CH2Cl2) 1728 cm-1 1H NMR (CDCl3,
;
300 MHz) δ 8.08-8.05 (m, 1 H), 7.70-7.67, (m, 1 H), 7.49-
6.85 (m, 68 H), 5.73-5.61 (m, 2 H), 5.47-5.34 (m, 2 H), 5.23-
4.73 (m, 27 H), 4.22-4.17 (m, 1 H), 4.11 (d, J ) 13.2 Hz, 1 H);
13C NMR (CDCl3, 90 MHz) δ 167.4, 166.7, 165.9, 164.9, 152.7,
152.6, 152.5, 152.3, 152.2, 146.8, 144.7, 144.5, 143.1, 137.7,
137.6, 137.5, 137.4, 16.5, 136.4, 133.9, 133.7, 128.7, 128., 128.5,
128.46, 128.39, 128.36, 128.33, 128.26, 128.22, 128.1, 128.02,
128.01, 127.9, 127.87, 127.84, 127.7, 127.6, 127.56, 127.50,
127.4, 127.3, 127.2, 126.7, 124.6, 124.1, 123.9, 123.6, 123.4,
109.5, 108.0, 107.9, 101.3, 75.4, 75.1, 75.0, 74.9, 73.4, 72.4, 71.9,
71.3, 71.2, 71.1, 70.3, 68.1, 67.9, 63.1; MS (+FAB) 2002 (MH+,
56). Anal. Calcd for C125H103NO24: C, 74.96; H, 5.15; N, 0.69.
Found: C, 74.73; H, 5.17; N, 0.64.
4,6-(3,4,5,3′,4′,5′-Hexaben zyloxy)diph en oyl-2,3-bis(3,4,5-
tr is(ben zyl-oxy)ben zoyl)-r-D-glu cop yr a n ose (26). 2-Ni-
trobenzyl 4,6-(3,4,5,3′,4′,5′-hexabenzyloxy)diphenoyl-2,3-bis-
(3,4,5-tris(benzyloxy)benzoyl)-â-D-glucopyranoside (25) (100
mg, 0.05 mmol) was dissolved in a mixture of 6 mL of THF, 6
mL of EtOH, and 1 mL of distilled water and irradiated in a
Pyrex tube suspended in a Rayonet photochemical apparatus
at 350 nm for 7.5 h. Removal of solvents in vacuo yielded an
oil which upon flash column chromatography using 10% and
then 20% EtOAc in hexanes as eluents provided 62 mg (66%)
of 4,6-(3,4,5,3′,4′,5′-hexabenzyloxy)diphenoyl-2,3-bis(3,4,5-tris-
(benzyloxy)benzoyl)-D-glucopyranose as a white solid (mixture
of R and â anomers). A sample (25 mg) of this product was
further purified by preparative thin-layer chromatography
using 5% EtOAc in benzene as eluent to provide 15 mg of
(26): IR (CH2Cl2) 3512, 1725 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 7.47-6.83 (m, 66 H), 6.05 (t, J ) 10.1 Hz, 1 H), 5.72 (d, J )
3.7 Hz, 1 H), 5.40-4.69 (m, 28 H), 3.94 (d, J ) 12.9 Hz, 1 H),
3.37 (bs, 1 H); 13C NMR (CDCl3, 90 MHz) δ 167.7, 167.0, 165.9,
165.3, 152.64, 152.6, 152.54, 152.52, 152.3, 152.2, 144.7, 144.3,
142.9, 142.8, 137.7, 137.6, 137.5, 137.4, 137.3, 136.5, 136.42,
136.4, 136.31, 136.3, 128.8, 128.5, 128.4, 128.4, 128.32, 128.3,
128.2, 128.1, 128.0, 127.97, 127.91, 127.88, 127.83, 127.7,
127.6, 127.56, 127.53, 127.3, 127.6, 127.56, 127.53, 127.3,
2-Nitr oben zyl 4,6-Bis(3,4-d ip h en ylm eth ylen ed ioxy-5-
h yd r oxyben zoyl)-2,3-bis(3,4,5-tr is(ben zyloxy)ben zoyl)-â-
D-glu cop yr a n osid e. By use of general procedure C, 2-nitro-
benzyl 4,6-bis(3-tert-butyldimethylsiloxy-4,5-diphenylmethylene-
dioxybenzoyl)-2,3-bis(3,4,5-tris(benzyloxy)benzoyl)-â-D-glucopy-
ranoside (23) (2.64 g, 1.31 mmol) (0.05 M solution in THF)
was desilylated in 35 min to afford 1.80 g (77%) of 2-nitroben-
zyl 4,6-bis(3,4-diphenylmethylenedioxy-5-hydroxybenzoyl)-2,3-
bis(3,4,5-tris(benzyloxy)benzoyl)-â-D-glucopyranoside following
flash column chromatography using 10% and then 40% EtOAc
1
in hexanes as eluent: IR (CH2Cl2) 3554, 1729 cm-1; H NMR
(CDCl3, 300 MHz) δ 8.05-8.02 (m, 1 H), 7.68 (d, J ) 7.8 Hz,
1 H), 7.68-7.08 (m, 60 H), 6.26 (bs, 1 H), 5.83 (t, J ) 9.6 Hz,
1 H), 5.63-5.52 (m, 2 H), 5.42 (d, J ) 15.8 Hz, 1 H), 5.14-
4.87 (m, 14 H), 4.62 (d, J ) 12.1 Hz, 1 H), 4.31-4.25 (m, 1 H),
4.11-4.06 (m, 1 H); 13C NMR (CDCl3, 75 MHz) δ 165.6, 165.4,
164.9, 164.5, 152.5, 148.5, 148.3, 146.3, 142.8, 139.6, 139.2,
138., 138.7, 138.6, 137.4, 137.3, 135.5, 134.4, 134.2, 129.4,
129.3, 128.5, 128.4, 128.35, 128.31, 128.3, 128.2, 128.1, 127.99,
127.90, 127.8, 127.6, 127.5, 126.3, 126.2, 124.8, 124.1, 123.7,
123.6, 122.7, 118.9, 118.7, 114.4, 113.6, 109.3, 109.2, 103.6,
100.7, 75.1, 73.2, 72.7, 72.3, 71.2, 71.1, 69.5, 67.7, 63.2; MS
(+FAB) 1792 (MH+,40). Anal. Calcd for C109H85NO24: C, 73.03;
H, 4.75; N, 0,78. Found: C, 73.23; H, 4.88; N, 0.55.
Regioisom er ic Mixtu r e of 2-Nitr oben zyl 4,6-(3,4-Diph en -
ylm et h ylen ed ioxy-5-h yd r oxy-3′,4′-d ip h en ylm et h ylen e-
d ioxy-5′h yd r oxy)d ip h en oyl-2,3-bis(3,4,5-tr is(ben zyloxy)-
b en zoyl)-â-D-glu cop yr a n osid e (24a -c).
A solution of
Pb(OAc)4 (0.49 g, 1.10 mmol) in 5 mL of dry CH2Cl2 was added
dropwise to a cooled (-30 °C) deoxygenated solution of
2-nitrobenzyl 4,6-bis(3,4-diphenylmethylenedioxy-5-hydroxy-
benzoyl)-2,3-bis(3,4,5-tris(benzyloxy)benzoyl)-â-D-glucopyrano-
side (1.80 g, 1.0 mmol) and pyridine (326 µL, 4.0 mmol) in 180
mL of dry CH2Cl2 (0.005 M in bis phenol) over 30 min. The
deep orange solution was stirred at -30 °C for a further 1 h,
treated with 100 mL of a saturated aqueous solution of

216 J . Org. Chem., Vol. 64, No. 1, 1999
Feldman and Sahasrabudhe
124.1, 123.9, 123.7, 123.4, 109.3, 108.0, 107.8, 90.7, 75.5, 75.4,
75.1, 75.0, 74.8, 73.1, 71.2, 71.1, 71.0, 70.9, 70.4, 67.0, 63.5;
MS (+FAB) 1867 (MH+, 16); HRMS calcd for C118H98O22
1866.6549, found 1866.6528.
Tellim a gr a n d in II (2). A solution of 4,6-(3,4,5,3′,4′,5′-
hexabenzyloxy)diphenoyl-1,2,3-tris(3,4,5-tris(benzyloxy)benzoyl)-
â-D-glucopyranoside (27) (26 mg, 0.01 mmol) and 10% Pd/C (5
mg, 20 wt % of starting material) in 1.5 mL of THF was purged
with hydrogen six times and stirred at room temperature
under a balloon of hydrogen for 18 h. The reaction mixture
was then purged with argon twice and filtered twice through
Celite. The filtrate was concentrated to a dark brown solid
which was triturated several times with hexanes and diethyl
ether and dried to furnish 3 mg (30%) of tellimagrandin II (2)
as a gray solid: 1H NMR (acetone-d6, 200 MHz) δ 7.11 (s, 2
H), 6.99 (s, 2 H), 6.96 (s, 2 H), 6.65 (s, 1 H), 6.45 (s, 1 H), 6.20
(d, J ) 8.3 Hz, 1 H), 5.84 (t, J ) 9.7 Hz, 1 H), 5.59 (t, J ) 8.9
Hz, 1 H), 5.37 (dd, J ) 6.4 Hz, 13.4 Hz, 1 H), 5.21(t, J ) 10
Hz, 1 H), 4.54 (dd, J ) 5.9 Hz, 9.9 Hz, 1 H), 3.88 (d, J ) 14
Hz, 1 H); 13C NMR (acetone-d6, 90 MHz) δ 168.0, 167.6, 166.2,
165.4, 165.0, 146.1, 145.9, 145.8, 145.3, 144.5, 139.8, 139.3,
139.1, 136.6, 126.6, 126.0, 120.6, 120.5, 119.9, 115.5, 110.4,
110.2, 110.1, 108.3, 107.9, 93.7, 73.2, 73.1, 71.7, 70.7, 63.1; MS
(+FAB) 938 (M+, 56), 937 (M - 1, 95); CD (MeOH) 235 nm,
+31.7, 261 nm, -7.5, 281.5 nm, +7.7; HRMS calcd for
4,6-(3,4,5,3′,4′,5′-H exa b en zyloxy)d ip h en oyl-1,2,3-t r is-
(3,4,5-tr is(ben zyloxy)ben zoyl)-â-D-glu cop yr a n osid e (27).
A solution of 4,6-(3,4,5,3′,4′,5′-hexabenzyloxy)diphenoyl-2,3-
bis(3,4,5-tribenzyloxybenzoyl)-D-glucopyranose (26) (100 mg,
0.05 mmol) in 5 mL of benzene was added to a flask containing
a solution of the 3,4,5-tribenzyloxybenzoyl chloride (30 mg, 0.06
mmol) and triethylamine (22 µL, 0.15 mmol) in 2 mL of
benzene. The reaction mixture was stirred at room tempera-
ture for 18 h. The solution was then treated with 5 mL of ice-
cold 1 M HCl and extracted with 15 mL of EtOAc. The organic
layer was washed with water and then brine and dried (Na2-
SO4). Removal of solvents in vacuo furnished a white solid
which was purified by flash column chromatography using 10%
and then 25% EtOAc in hexanes as eluents to provide 50 mg
(41%) of 4,6-(3,4,5,3′,4′,5′-hexabenzyloxy)diphenoyl-1,2,3-tris-
(3,4,5-tribenzyloxy)benzoyl-â-D-glucopyranoside (27) as a white
solid: IR (CDCl3) 1735 cm-1 1H NMR (CDCl3, 300 MHz) δ
;
7.50-6.84 (m, 83 H), 6.10 (d, J ) 7.6 Hz, 1 H), 5.82 (m, 2 H),
5.51 (t, J ) 9.7 Hz, 1 H), 5.42 (dd, J ) 6.4 Hz, 13.3 Hz), 5.21-
4.72 (m, 30 H), 4.38 (dd, J ) 6.0 Hz, 9.9 Hz, 1 H), 4.10 (d, J )
12.9 Hz, 1 H); 13C NMR (CDCl3, 90 MHz) δ 167.4, 166.8, 165.7,
164.8, 164.2, 152.7, 152.61, 152.6, 152.5, 152.3, 152.2, 144.8,
144.4, 143.3, 143.2, 143.1, 137.64, 137.6, 137.5, 137.34, 137.31,
137.3, 136.44, 136.4, 136.3, 128.6, 128.42, 128.4, 128.38, 128.3,
128.22, 128.2, 128.03, 128.0, 127.97, 127.91, 127.9, 127.7,
127.6, 127.5, 127.3, 123.8, 123.6, 123.4, 123.2, 109.5, 109.4,
109.3, 107.91, 107.9, 93.1, 75.5, 75.4, 75.1, 75.0, 74.8, 73.1, 72.7,
71.6, 71.2, 70.1, 63.0; MS (+FAB) 2288 (M+, 20). Anal. Calcd
for C146H120O26: C, 76.57; H, 5.24. Found: C, 76.38, H, 5.40.
C
41H29O26 937.0947, found 937.0943.
Ack n ow led gm en t. We thank the NIH (GM35727)
for financial support.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for compounds 2, 6, 8, 9, 16, and 26. (12 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
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J O9816966