Synthetic studies toward c-glucosidic ellagitannins: A biomimetic total synthesis of 5-O-desgalloylepipunicacortein A

Article abstract of DOI:10.1002/chem.201200517

C-glucosidic ellagitannins constitute a subclass of bioactive polyphenolic natural products with strong antioxidant properties, as well as promising antitumoral and antiviral activities that are related to their capacity to interact with both functional and structural proteins. To date, most synthetic efforts toward ellagitannins have concerned glucopyranosic species. The development of a synthetic strategy to access C-glucosidic ellagitannins, whose characteristic structural feature includes an atropoisomeric hexahydroxydiphenoyl (HHDP) or a nonahydroxyterphenoyl (NHTP) unit that is linked to an open-chain glucose core by a C-aryl glucosidic bond, is described herein. The total synthesis of the biarylic HHDP-containing 5-O- desgalloylepipunicacortein A (1 β) was achieved by either using the natural ellagic acid bis-lactone as a precursor of the requested HHDP unit or by implementing an atroposelective intramolecular oxidative biarylic coupling to forge this HHDP unit. Both routes converged in the penultimate step of this synthesis to enable a biomimetic formation of the key C-aryl glucosidic bond in the title compound.

Full text of DOI:10.1002/chem.201200517

FULL PAPER
DOI: 10.1002/chem.201200517
Synthetic Studies toward C-Glucosidic Ellagitannins: A Biomimetic Total
Synthesis of 5-O-Desgalloylepipunicacortein A
Gaꢀlle Malik,[a] Anna Natangelo,[a, b] Jaime Charris,[c] Laurent Pouysꢁgu,[a]
Stefano Manfredini,[b] Dominique Cavagnat,[d] Thierry Buffeteau,[d]
Denis Deffieux,*[a] and Stꢁphane Quideau*[a]
Abstract: C-glucosidic ellagitannins
constitute a subclass of bioactive poly-
phenolic natural products with strong
antioxidant properties, as well as prom-
ising antitumoral and antiviral activities
that are related to their capacity to in-
teract with both functional and struc-
tural proteins. To date, most synthetic
efforts toward ellagitannins have con-
cerned glucopyranosic species. The de-
velopment of a synthetic strategy to
access C-glucosidic ellagitannins, whose
characteristic structural feature in-
cludes an atropoisomeric hexahydroxy-
diphenoyl (HHDP) or a nonahydroxy-
terphenoyl (NHTP) unit that is linked
to an open-chain glucose core by a C-
aryl glucosidic bond, is described
herein. The total synthesis of the biar-
ylic HHDP-containing 5-O-desgalloyl-
epipunicacortein A (1b) was achieved
AHCTUNGTRENNUNG
by either using the natural ellagic acid
bis-lactone as a precursor of the re-
quested HHDP unit or by implement-
ing an atroposelective intramolecular
oxidative biarylic coupling to forge this
HHDP unit. Both routes converged in
the penultimate step of this synthesis
to enable a biomimetic formation of
the key C-aryl glucosidic bond in the
title compound.
Keywords: biomimetic synthesis
ellagitannins · natural products ·
AHCTUNGTRENNoGUN xidative coupling · total synthesis
·
Introduction
nation of their unusual molecular structures and remarkable
biological activities that are related to their antioxidant, an-
tiviral, and host-mediated antitumoral properties.[2] To date,
nearly 1000 fully characterized ellagitannins have been iso-
lated from various plant sources, thus constituting by far the
largest group of known tannin molecules.[1–3] The existence
of these hundreds of different molecular entities is really re-
markable when considering that they all plausibly emanate
from a single biosynthetic precursor, the penta-O-galloyl-b-
d-glucopyranose (b-PGG), itself elaborated from two simple
building blocks: d-glucopyranose and gallic acid (i.e., 3,4,5-
trihydroxybenzoic acid).[4] The defining structural feature of
all of the ellagitannins is the 6,6’-dicarbonyl-2,2’,3,3’,4,4’-
Ellagitannins constitute a family of biologically active plant
polyphenols that belong to the hydrolyzable tannin class.[1]
Research interest in these plant polyphenols, which are me-
tabolized by dicotyledonous plant species of the Angiosper-
mea, initially emerged from the discovery of their occur-
rence in numerous herbal remedies that are used in tradi-
tional Asian medicines and was further fed by the determi-
[a] Dr. G. Malik, Dr. A. Natangelo, Dr. L. Pouysꢀgu, Dr. D. Deffieux,
Prof. S. Quideau
Universitꢀ de Bordeaux
hexaACTHUNRTGNEUNGhydroxybiphenyl (bis-ester) moiety, commonly desig-
Institut des Sciences Molꢀculaires (CNRS-UMR 5255)
Institut Europꢀen de Chimie et Biologie
2 rue Robert Escarpit, 33607 Pessac Cedex (France)
E-mail: d.deffieux@iecb.u-bordeaux.fr
s.quideau@iecb.u-bordeaux.fr
nated by the trivial name hexahydroxydiphenoyl (HHDP),
whose hydrolysis releases the bis-lactone ellagic acid from
which these natural products are named. Such biACHTUNGTRENNUNGarylic
HHDP units are formed by oxidative (dehydrogenative)
À
[b] Dr. A. Natangelo, Prof. S. Manfredini
Universitꢁ di Ferrara
C C coupling between the phenolic galloyl groups that are
attached onto the glucopyranose core. The most common bi-
Dipartimento di Scienze Farmaceutiche
Via Fossato di Mortara, 17-19, I-44100 Ferrara (Italy)
AHCTUNGTREGaNNUN rylic coupling patterns occur at the 2,3- and/or 4,6-positions
4
of a glucopyranose core in its C1-conformation, as exempli-
[c] Prof. J. Charris
fied in the structures of tellimagrandin II[5] and peduncul-
Universidad Central de Venezuela
Facultad de Farmacia, Laboratorio de Sꢂntesis Orgꢃnica
Caracas 1051 (Venezuela)
AHCTUNGTRENNUNG
agin[6] (Scheme 1), although biarylic coupling reactions
across the 1,6- and 3,6-positions are also known in several
1
[d] Dr. D. Cavagnat, Dr. T. Buffeteau
Universitꢀ de Bordeaux
structures in which the glucose core adopts its C4-conforma-
tion.[1] The structural diversity of monomeric ellagitannins
emanates not only from the conformational changes in the
glucopyranose core and from the variation in the position
and number of the HHDP units, but also from the atropo-
Institut des Sciences Molꢀculaires (CNRS-UMR 5255)
351 cours de la Libꢀration
33405 Talence Cedex (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200517.
AHCTUNGTREGiNNNU somerism of their biaryl axis, as well as from the extent of
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derived unit is either part of a HHDP unit that bridges the
2- and 3-positions of the glucose core, as exemplified in the
structures of casuarinin and its C-1 epimer, stachyurin,[6d,7]
or part of a terarylic nonahydroxyterphenoyl (NHTP) var-
iant (also known as the flavogallonyl or flavogalloyl group)
that is attached through three ester bonds to the 2-, 3-, and
5-positions of the glucose core, as illustrated by the struc-
tures of castalagin and vescalagin, which are two ellagitan-
nins that are found in fagACTHNUTRGNEaNUG ceous woody plants, such as the
Quercus (oak) species (Scheme 1).[7e,8]
The biosynthetic steps that lead to glucopyranosic ellagi-
tannins from their precursor, b-PGG, are just today starting
to be elucidated, essentially thanks to the work initiated by
Gross and co-workers.[4] Of most significance was the obser-
vation of a b-PGG-oxidizing (phenol oxidase) enzyme that
promotes the formation of the 4,6-HHDP-containing telli-
magrandin II.[9] The biochemical event that mediates the
passage from the glucopyranosic ellagitannin class to the
open-chain C-glucosidic class still remains a matter of specu-
lation, but a biogenetic filiation has nevertheless been infer-
red from a phytochemical study on Liquidambar formosana
(Hamamelidaceae), in which members of the two classes co-
exist.[10] Thus, the proposed biosynthetic pathway starts from
tellimagrandin II to furnish pedunculagin through an oxida-
À
tive C C coupling reaction between the 2- and 3-galloyl
groups and a 1-O-desgalloylation step (Scheme 1). Opening
the pedunculagin glucopyranose ring, which would be bio-
chemically driven by an enzymatic 5-O-galloylation reaction,
is the first key event that opens the door to the C-glucosidic
ellagitannins. This step leads to the open-chain aldehyde liq-
uidambin, which was first isolated in 1987 by Okuda et al.[11]
It is then reasonable to suggest that the electrophilic alde-
hyde function hence unveiled could be exposed to an intra-
molecular aldol-type attack by the phenolic 2,3-HHDP unit
to forge the characteristic C-glucosidic bond of the casuari-
nin and stachyurin epimers. Their 5-O-desgalloylation would
give rise to casuariin and 5-O-desgalloylstachyurin,[6d,7b–e]
whereas oxidative coupling between their 5-galloyl and 2,3-
HHDP groups would furnish castalagin and vescalagin.[1b,12]
Other related examples of C-glucosidic ellagitannins are cas-
talin and vescalin,[7e,8a,13] both of which lack the 4,6-HHDP
unit, as well as the (epi)punicacorteins A[14] and their 5-O-
desgalloylated analogues, compounds 1a/b[14b,c] (Scheme 1).
Our previous investigations on the occurrence and chemi-
cal transformations of C-glucosidic ellagitannins in wines, as
a result of their aging in oak-made barrels,[15] and our con-
tinuing interest in the remarkable biological activities of
some of these polyphenols, notably through their interac-
tions with tumor- or virus-related proteins,[15d,e,16] led us to
contemplate their total synthesis. Furthermore, although
several ellagitannins of the glucopyranosic class have been
successfully synthesized,[17] the fact that no ellagitannin of
the C-glucosidic type had been generated by total synthesis
provided us with extra impetus to tackle the unprecedented
synthetic challenge posed by these structurally unique natu-
ral products.
Scheme 1. Putative biosynthetic route to C-glucosidic ellagitannins.
galloylation and from the anomeric stereochemistry of the
glucopyranose core. The C-glucosidic ellagitannins consti-
tute yet another subclass of ellagitannins in which a C C
bond links the carbon-1 (anomeric) atom of an “open-
chain” glucose core to the carbon-2’ atom of a galloyl-
derived unit that has been esterified to the 2-position of
À
the
glucose
core.
Their
C-1-linked
galloyl-
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Synthetic Studies toward C-Glucosidic Ellagitannins
FULL PAPER
Herein, we report our work on the exploration of meth-
odological tactics for the development of a biomimetic strat-
egy toward C-glucosidic ellagitannins that led to the first
total synthesis of a first member of this ellagitannin class, 5-
O-desgalloylepipunicacortein A (1b).[18]
Results and Discussion
Besides the challenge of the fact that no member of the C-
glucosidic ellagitannin class had yet succumbed to total syn-
thesis efforts, the main incentive to undertake this work was
to test the chemical plausibility of the glucopyranosic to C-
glucoACHTUNGTRENNUNGsidACHTUNGTRENNUNGic ellagitannins route that has been proposed for
their biosynthesis (Scheme 1). Thus, we selected the two 5-
O-desgalloylated (epi)punicacorteins A (1a/b) as targets for
this endeavor. Both compounds are likely to be metabolized
by ellagitannin-producing plant species, but so far only 1a
has been identified as a naturally occurring compound that
was first isolated from Obseckia Chinensis L. (Melastomat-
ACHTUNGTRENNUNG
aceae),[14b] whereas 1b was biochemically produced by the
hydrolytic action of a tannase on epipunicacortein A, which
was isolated from the leaves of the oak tree species Quercus
aliena BLUME (Fagaceae).[14c]. These two compounds (1a/
b) can be viewed as the simplest members of the C-glucosid-
ACHTUNGTRENNUNGic ellagitannin class, but they constitute ideal, yet challeng-
ing, targets to validate biomimetic chemical means that are
capable of forming their C-aryl open-chain glucosidic bond
from a glucopyranosic precursor. Therefore, our retrosyn-
thetic plan (Scheme 2) reflected the aim of developing a bio-
mimetic route to these HHDP-bearing C-glucosidic ellagi-
tannins with an opening of a glucopyranosic sugar core and
a concomitant formation of the C-glucosidic bond that were
deferred until the end of the synthesis. The 4,6-O-
benzylidene-2,3-(S)-HHDP-d-glucopyranose derivative (2,
Scheme 2) was elected as a synthetic surrogate of the natu-
ral glucopyranosic precursor pedunculagin (Scheme 1). This
key advanced intermediate, which contained the requisite
biarylic S atropoisomer, was elaborated by using two con-
ceptually different strategies.
The first approach (route A) relied on a bis-esterification
reaction between a 4,6-O-benzylidene-d-glucopyranoside (3)
and an adequately protected version of the (S)-atropoisomer
or racemate of hexahydroxydiphenic acid (4, Scheme 2).
This strategy was first introduced by Nelson and Meyers[19]
and was largely developed thereafter by Khanbabaee et al.
in a series of total syntheses of glucopyranosic ellagitan-
nins.[17,20] Alternatively, compound (S)-2 can be generated
by a strategy that is analogous to the biosynthetic construc-
tion of HHDP through an intramolecular and atroposelec-
tive oxidative-coupling reaction (Scheme 1). This biomimet-
ic strategy, first developed by Feldman et al.,[21] has also en-
Scheme 2. Retrosynthetic analysis of the epimers of 5-O-desgalloyl-
AHCTUNGTRENGN(UN epi)punicacortein A (1a and 1b).
full advantage of the efficient and correct induction of asym-
metry that is brought by the chiral glucopyranose core to
the HHDP atropoisomer. Our implementation of this
second approach to compound (S)-2 (route B) resulted in
the double acylation of compound 3 into oxidative-coupling
precursor 5 by using two suitably protected gallic acids (6,
Scheme 2).
Synthesis of compound (S)-2 by route A: Although this
route has no biomimetic features and, thus, might be seen as
being less elegant than the alternative route (route B), it
nevertheless allows a rapid access to the key, late intermedi-
ate of our planned synthesis, (S)-2. Our first synthesis of
compound (S)-2 by using this approach involved the bis-
acylation of benzyl 4,6-O-benzylidene-b-d-glucopyranoside
(3a) with racemic hexabenzyloxydiphenic acid (4a,
Scheme 3). Sugar 3a was synthesized in three steps from the
commercially available 2,3,4,6-tetra-O-acetyl-a-d-glucopyr-
ACHTUNGTRENNUNGabled them and a few other research groups to achieve the
chemical synthesis of various glucopyranosic ellagitannins
and their derivatives by using different tactics.[17,22] Although
this strategy imposes the installation of two adequately pro-
tected galloyl groups on a glucopyranose species, it takes
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
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D. Deffieux, S. Quideau et al.
with the predicted VCD spectra of both atropoisomers,
which were calculated by using density functional theory
(DFT) at the B3PW91/6-31G* level (for details, see the Sup-
porting Information). These comparisons unambiguously es-
tablished that the axial chirality of our levogyre diphenic
acid (4a) was S and, therefore, also that of the 2,3-HHDP-
bearing glucopyranose derivative (2a) from which it was de-
rived (Figure 1).
Scheme 3. Synthesis of the 2,3-HHDP-4,6-O-benzylidene-d-glucopyr-
anose derivative (S)-2b by route A. a) DCC, DMAP, CH2Cl2, RT, 18 h
ACHTUNGTRENNUNG
(35%); b) KOtBu, H2O (approx. 6 equiv.),THF, RT, 12 h (quant.); c) H2,
Pd/C, THF, RT, 48 h (quant.).
yield by the Schmidt three-step alkaline benzylation of the
commercially available ellagic acid bis-lactone.[24]
The bis-esterification of (rac)-4a with 1-O-benzyl-b-d-glu-
copyranoside 3a was accomplished under Steglich condi-
tions by using dicyclohexylcarbodiimide (DCC) and 4-di-
ACHTUNGTRENNUNGmethACHTUNGTRENNUNGylaminopyridine (DMAP). No diastereoinduction from
the most-proximal glucose C-2 and/or C-3 stereocenters was
observed in this reaction; the two diastereoisomers, (S)-2a
and (R)-2a, were observed in a ratio that was very close to
Figure 1. Comparison of the experimental VCD spectrum for compound
(À)-4a in CDCl3 (33 mm, path length: 200 mm) with the predicted VCD
spectrum of compound (S)-4a.
1
1:1 by H NMR analysis of the crude reaction mixture. This
lack of diastereoselectivity has previously been observed by
Khanbabaee et al. in the similar 2,3-O-bis-acylation of glu-
cose derivatives, whereas the related 4,6-O-bis-acylation re-
actions that use compound (rac)-4a surprisingly do express
a significant level of atropodiastereoselectivity.[20] Thus, we
had to rely on column chromatography on silica gel to sepa-
rate the two diastereoisomers of 2a, with some difficulties.
In fact, we could not purify the (R)-2a atropoisomer, which
remained embedded in a fraction that was contaminated
with what we assumed to be some oligomeric materials.[18]
Fortunately, the S-configured atropoisomer that was re-
quired for the continuation of the synthesis was isolated
with a satisfactory level of purity in 35% yield. Verification
of the absolute configuration of this first HHDP-containing
intermediate, compound (S)-2a, was initially attempted by
following the procedure developed by Khanbabaee et al.[20]
This procedure involves subjecting the compound to hydrol-
ysis under Gassman conditions (i.e., KOtBu in dry THF plus
a trace of water)[25] to compare the specific optical rotation
of the resulting hexabenzyloxydiphenic acid (4a) to those
reported for individual compounds (S)-(+)-4a and (R)-(À)-
4a.[20a,26] Unfortunately, despite the observation by circular
dichroism (CD) spectroscopy of a strong positive Cotton
effect near 235 nm, which is characteristic of an S-config-
ured biaryl unit,[27] the diphenic acid that was hydrolytically
released from our presumed compound (S)-2a was mea-
sured to be levogyre ([a]2D2 =À30.3; c=1.0, CH2Cl2). This
unexpected and confusing observation led us to rely on vi-
brational circular dichroism (VCD)[28] to determine the ab-
solute configuration of compound 4a. The VCD spectrum
of compound 4a was recorded in CDCl3 and then compared
Pure atropoisomer (S)-2a was then submitted to standard
hydrogenolysis conditions that, gratifyingly, did not affect
the benzylidene acetal protecting group, even after 24 h.
Thus, the desired heptahydroxylated compound, (S)-2b, was
obtained in quantitative yield as a 1:1 (a/b) anomeric mix-
ture (Scheme 3).
Synthesis of compound (S)-2 by route B: The most-appeal-
ing aspects of this route are that it is conducted in an intra-
molecular, atroposelective, and thus biomimetic fashion
(Scheme 2). However, previously reported ellagitannin syn-
theses that took advantage of this route usually implied
a constraining selective functionalization of the phenolic hy-
droxy groups of the galloyl units to be coupled. For exam-
ple, the pioneering method reported by Feldman and co-
workers[1d,17,21] involves the intramolecular oxidative phenol-
ic coupling of diphenylmethylene-protected glucopyranosyl
gallates. Their preparation requires orthogonal-protection/
deprotection steps and their lead tetraacetate-mediated oxi-
dative coupling generates mixtures of regioisomers that for-
tunately easily converge to a single product upon cleavage
of their diphenyl ketal units. Thus, we wanted to examine
the possibility of biomimetically forming the HHDP unit of
(S)-2 by using chemical oxidative-coupling methods still in
an intramolecular fashion but from unprotected, instead of
partially protected, galloyl groups.
To evaluate the feasibility of such a route to compound
(S)-2, we prepared several 2,3-O-bis-galloylated sugar deriv-
atives of type 7, as shown in Scheme 4. For the bis-galloyl-
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Synthetic Studies toward C-Glucosidic Ellagitannins
FULL PAPER
The next objective was to identify oxidative conditions to
efficiently and atroposelectively couple the galloyl groups of
these 2,3-O-bis-galloylated glucopyranosides (7). To this
end, we initially selected the most-readily available com-
pound (7c) and made the choice of staying away from the
use of any highly toxic heavy-metal-based oxidant. Our in-
terest in the development of the chemistry of hypervalent
iodine reagents[31] led us first to try some of their commer-
cially available versions, such as PhI
ACHTUNGRTENUN(NG OAc)2 and PhI-
AHCTUNGTRENNUNG
coupling reactions of oxygenated arenes,[32] including phe-
nolic species.[32b] Unfortunately, our attempts to couple the
galloyl groups of compound 7c by using these iodanes af-
forded complex mixtures from which we could not isolate
any product. These failures led us to contemplate the use of
the organic oxidant ortho-chloranil, which has previously
been reported to mediate the intermolecular coupling of
methyl gallate in Et2O into a dehydrogenated HHDP unit
through dimerization of the a-hydroxy ortho-quinone that
was initially produced by the oxidation of methyl gallate by
ortho-chloranil. The reduction of this dehydrogenated
HHDP species by using sodium dithionite (Na2S2O4) afford-
ed dimethyl hexahydroxydiphenoate in 79%.[33] The com-
plete lack of solubility of compound 7c in Et2O obliged us
to modify the reaction conditions. After extensive variation
of the reaction parameters (solvent, temperature, and dura-
tion), the reaction was finally performed in MeCN by using
2 equivalents of ortho-chloranil at a temperature that was
increased from 08C to room temperature over 2 h, followed
by reductive treatment of the reaction mixture with aqueous
Scheme 4. Synthesis of 2,3-O-bis-galloylated glucopyranose derivatives of
type 7. a) esterification and b) deprotection (Table 1 and Table 2).
ACHTUNGTRENNUNGations of 4,6-O-benzylidene-d-glucopyranosides of type 3,
four different galloylating reaction partners (6a–6d), which
were protected with either benzyl (Bn) or tert-butyldi-
ACHTUNGTRENNUNGmethylsilyl (TBDMS) groups and used as either the free car-
boxylic acids or as acyl-chloride entities, were prepared ac-
cording to literature procedures.[29] In addition to compound
3a, we also utilized two other glucosides that contained
either a photocleavable ortho-nitrobenzyl group (3b) or
a simple methyl group at the anomeric position (3c, com-
mercially available).
The 2,3-O-bis-galloylated glucopyranosides of type 5 were
then generated according to three different procedures:
a standard Steglich esterification reaction (condi-
tions i),[30a] its modified version (conditions ii)[30b]
Table 1. Bis-galloylation of 4,6-O-benzylidene-d-glucopyranosides (3).
with gallic acid derivatives 6a or 6b, or an esterifi-
cation reaction with acyl chlorides 6c or 6d (condi-
tions iii). The results are summarized in Table 1. Al-
though the use of acyl chlorides adds one step onto
the synthesis, it turned out to be beneficial when
using the silylated galloylating compounds because
bis-galloylated products 5c and 5e were obtained in
much-higher yields (Table 1, entries 3 and 4 and en-
tries 7 and 8). Next, all of the resulting bis-galloy-
lated sugar products (5a–5e) were submitted to
either hydrogenolysis (R=Bn) or desilylation (R=
Entry
Glucoside
Galloylating
unit 6 (R, X)
Conditions[a]
Product
Yield
[%][b]
3 (R1)
1
2
3
4
5
6
7
8
3a (b-OBn)
6a (Bn, OH)
6a (Bn, OH)
6b (TBDMS, OH)
6d (TBDMS, Cl)
6a (Bn, OH)
6c (Bn, Cl)
6b (TBDMS, OH)
6d (TBDMS, Cl)
i
ii
ii
iii
ii
iii
ii
iii
5a
5b
5c
5c
5d
5d
5e
5e
76
100
35
59
97
80
57
80
3b (b-OoNO2Bn)
3b (b-OoNO2Bn)
3b (b-OoNO2Bn)
3c (a-OMe)
3c (a-OMe)
3c (a-OMe)
3c (a-OMe)
[a] (i) Compound 6 (2.2 equiv), DCC (4.4 equiv), DMAP (2.2 equiv), CH2Cl2, RT;
(ii) compound (2.2 equiv), DCC (2.2 equiv), DMAP (0.5 equiv), DMAP·HCl
6
TBDMS) to afford the desired oxidative-coupling (0.5 equiv), CH2Cl2, reflux; (iii) compound 6 (2.4 equiv), DMAP (3.3 equiv), CH2Cl2,
RT. [b] Isolated by column chromatography.
precursors (7a–7c) in excellent yields (Table 2).
The only notable exception was the case of 1-O-ni-
trobenzylated compound 5b, which led to an in-
tractable mixture of products upon hydrogenolysis
Table 2. Selective deprotection of 2,3-O-bis-galloylated 4,6-O-benzylidene-d-glucopyr-
anosides (5).
(Table 2, entry 2). The ortho-nitrobenzyl group
Entry
Compound
5
R1
R
Conditions[a]
Product
Yield
[%][b]
probably did not resist these reaction conditions
but we were unable to even pinpoint any product
that contained a free anomeric hydroxy group on
the 1H NMR spectrum of the reaction mixture.
However, we were pleased to observe that the 4,6-
O-benzylidene acetal protecting group again resist-
ed hydrogenolysis (Table 2, entries 1 and 4).
1
2
3
4
5
5a
5b
5c
5d
5e
b-OBn
Bn
Bn
TBDMS
Bn
TBDMS
i
i
ii
i
ii
7a[c]
7b[d]
7b
7c
7c
100
0
97
100
100
b-OoNO2Bn
b-OoNO2Bn
a-OMe
a-OMe
[a] (i) H2, Pd/C, THF, RT, 24 h; (ii) TBAF, THF, RT, 45 min–2 h. [b] Isolated by
column chromatography. [c] R1 =a,b-OH. [d] Complex mixture.
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D. Deffieux, S. Quideau et al.
Na2S2O4 over 15 h (for the HPLC profile of reaction mix-
ture, see the Supporting Information, Figure S1). The mix-
ture was then filtered through Celite, the filtrate was evapo-
rated, and the residue was triturated with Et2O to remove
the reduced form of ortho-chloranil (i.e., tetrachlorocate-
chol). Thus, the expected coupled product (2c) was obtained
in 31% yield (Scheme 5). Considering the susceptibility of
then separately subjected to hydrolysis by using anhydrous
potassium hydroxide and the absolute axial configuration of
the resulting diphenic acids, (S)-4a and (R)-4a, was unam-
biguously determined by VCD measurements (for VCD
spectra of the two enantiomers, see the Supporting Informa-
tion, Figure S2). The two compounds, (S)-2d and (R)-2d,
were also finally debenzylated in THF under standard hy-
drogenolysis conditions to afford compounds (S)-2c and
(R)-2c, respectively (Scheme 6). Surprisingly, in the case of
the R-atropoisomer, hydrogenolysis also affected the 4,6-O-
benzylidene acetal group and the fully deprotected com-
pound S8 was isolated in 36% yield (see the Supporting In-
formation). The reasons for this dramatic change in reactivi-
ty between the two atropoisomers of compound 2d are un-
clear, but one could perhaps argue that the R-configured
2,3-HHDP biaryl axis imposes a deleterious level of strain
in this methyl a-d-glucopyranoside. This developing strain
would probably also interfere with the formation of the R-
configured 2,3-HHDP unit, as can be inferred from the
lower yield of compound (R)-2d compared to that of (S)-2d
(4% versus 24%, Scheme 6). Thus, it is reasonable to sug-
gest that the hydrogenolysis of the benzyl acetal in com-
pound (R)-2d would then, at least in part, relieve this strain
by offering extra conformational flexibility to the glucopyr-
Scheme 5. Intramolecular ortho-chloranil-mediated bigalloyl coupling re-
action (route B). a) (i) ortho-chloranil (2 equiv), CH3CN, 08C to RT, 2 h;
(ii) aq. Na2S2O4, RT, 15 h.
pyrogallol systems toward oxidative transformations, often
leading to complex oligomerized materials, we were quite
satisfied by this yield of compound 2c, which was, gratifying-
ly, solely obtained as its S-atropoisomer.
AHCTUNGTREGaNNNU noside core. The expected debenzylated product, (R)-2c,
was isolated in only 4% yield. Nevertheless, the correspond-
1
To confirm the absolute configuration of compound 2c,
we also prepared it by route A. To this end, we relied on the
conditions reported by Itoh et al.[34a] to achieve a bis-esterifi-
cation reaction between commercially available sugar deriv-
ative 3c and the racemic hexabenzyloxydiphenoyl chloride
4b[24] by using 4-dimethylaminopyridine (DMAP) in CH2Cl2
(Scheme 6). Separation of the product mixture by column
chromatography on silica gel afforded atropoisomers (S)-2d
and (R)-2d in 24% and 4% yield, respectively, thus indicat-
ing a significant level of diastereoselectivity in this reaction,
in contrast to what was observed by Itoh and co-workers
who used a permethylated diphenoyl chloride instead of the
perbenzylated variant (4b).[34] The two compounds were
ing amount of material was sufficient to obtain a H NMR
spectrum of compound (R)-2c for comparison with that of
compound (S)-2c.
A clear difference between these two diastereoisomers
can be observed in the aromatic region of their 1H NMR
spectra (Figure 2). The two aromatic protons of the 2,3-
HHDP unit appear as sharp singlets in the case of the S-
atropoisomer, but as slightly downfield-shifted, low-intensi-
ty, broad singlets in the case of the R-atropoisomer. This
Scheme 6. Synthesis of the two atropoisomers (S)-2c and (R)-2c by
route A. a) Oxalyl chloride, DMF (cat.), benzene, reflux, 12 h (91%).
b) DMAP, CH2Cl2, RT, 12 h (S: 24%, R: 4%). c) KOtBu, H2O (approx. 6
equiv.), THF, RT, 12 h (quant.). d) H2, Pd/C, THF, RT, 36 h ((S)-2c:
quant., (R)-2c: 4%, (R)-S8: 36%).
Figure 2. Diagnostic aromatic region of the 1H NMR spectra of atro-
poisomers (S)-2c (a) and (R)-2c (b).
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Synthetic Studies toward C-Glucosidic Ellagitannins
FULL PAPER
line-broadening attests to the existence of some (ring) strain
in this non-natural 2,3-HHDP-coupled product ((R)-2c).
Similarly, sharp singlets were also observed in the aromatic
region of compound (S)-2b for the signals of their 2,3-
HHDP units.[18] Therefore, these diagnostic differences in
the shape of 1H NMR resonances could likely be relied
upon to rapidly determine the configuration of the biaryl
axis in 2,3-HHDP-containing compounds without having to
perform any chemical degradation.
The NMR spectrum of compound (S)-2c was identical to
that generated by route B, thereby confirming the 2,3-
HHDP S-configuration of the latter product. Thus, in spite
of a relatively low-yielding production of compound (S)-2c
(31%, Scheme 5), the ortho-chloranil-mediated oxidative
coupling of compound 7c occurred with the same sense of
diastereoselectivity as that followed in the biosynthesis of el-
lagitannins. Thus, this stereochemical outcome is also in full
agreement with the Haslam–Schmidt hypothesis[1d,3g,35] that
states that stereocontrol in the coupling reactions of ellagi-
tannin galloyl units is induced by the chirality of the sugar
core rather than owing to the action of some stereodirigent
oxidase enzymes. To the best of our knowledge, this conver-
sion of compound 7c into compound (S)-2c is the first ex-
ample of intramolecular atroposelective oxidative coupling
of galloyl units that was successfully achieved in a protect-
ing-group-free manner.
Scheme 7. Synthesis of 2,3-HHDP-4,6-O-benzylidene-d-glucopyranose
derivative (S)-2 f by using Yamada’s copper(II)–amine-complex method-
ology (route B). a) Compound 6e, EDCI, DMAP, CH2Cl2, RT, 18 h;
b) compound 6 f, DMAP, CH2Cl2, RT, 16–22 h; c) TBAF, THF, RT, 2.5 h;
d) hn (365 nm), THF/EtOH/H2O (30:10:1), RT, 36 h; e) CuCl2, nBuNH2,
MeOH, 45 min. *Incomplete reaction: an inseparable 5:2 mixture of
compounds 2e and 5g (for details, see the text and the Supporting Infor-
mation).
Unfortunately, this oxidative-coupling methodology was
ineffective on both the ortho-nitrobenzyl b-d-glucopyrano-
side (7b) and the hemiacetal (7a), which only gave rise to
intractable mixtures of products. These disappointing results
forced us to consider other oxidants, among which more-tra-
ditional metal-based reagents that are known for their ca-
pacity to promote the coupling reactions of phenolic biaryls,
conditions by using DMAP and N-ethyl-N’-(3-dimethylami-
nopropyl)carbodiimide hydrochloride (EDCI) in CH2Cl2.
After cleavage of the four tert-butyldimethylsilyl ether
protecting groups, a first attempt at bigalloyl coupling was
performed on the resulting compound (5g) by using CuCl2
(5 equiv) and n-butylamine (20 equiv) in MeOH, according
to the experimental conditions reported by Yamada et al.[22a]
such as ironACHTUNGTRENNUNG(III) and copper(II)–amine-complex species,
were tried.[36] Various attempts all resulted in either the
complete recovery of the starting digalloylated sugars (7a–
7c) or the cleavage of their 4,6-O-benzylidene acetal group
without any observation of biaryl-coupling products. Thus,
we had to resign ourselves to construct the 2,3-HHDP
bridge by relying on the use of phenol protecting groups on
the galloyl units to direct their reactivity toward the desired
coupling transformation. We opted for the methodology that
has recently been developed by Yamada and co-worker-
s,[22a,37] which makes use of 4-O-benzylgallates that are oxi-
datively coupled by using copper(II)–amine complexes.[36b]
Yamada and co-workers successfully applied this elegant ox-
idative-phenolic-coupling tactic in the total synthesis of cori-
Monitoring the reaction by H NMR spectroscopy indicated
1
partial conversion of compound 5g into the desired coupling
product ((S)-2e) after 30 min. After this time, a 5:2 mixture
of compounds (S)-2e and 5g had been generated, but ex-
tending the reaction time to 45 min led to extensive degra-
dation of the reaction mixture. We envisaged processing the
reaction mixture after only 30 min, but we could not identify
appropriate conditions to separate the mixture by column
chromatography, because both compounds had the same re-
tention time in all of the solvent systems that we tested. The
same oxidative-coupling conditions were then applied to
compound 5h, which was conveniently generated by the
photolysis of compound 5g. We hoped that this removal of
the ortho-nitrobenzyl group would allow chromatographic
separation of the reaction mixture, even though we feared
the possible incompatibility of the anomeric hemiacetal
group of compound 5h with the oxidative reaction condi-
tions used. Thus, we were extremely pleased to observe the
complete consumption of compound 5h after only 45 min
and to isolate the product (2 f), once again as the correct S-
atropoisomer, in 54% yield after rapid flash chromatogra-
phy of the reaction mixture.
1
lagin, a C4-glucopyranosic ellagitannin that contains a 3,6-
(R)-HHDP unit.[22a] Our adaptation of this methodology to
4
the synthesis of 2,3-HHDP-bearing C1-glucopyranosic enti-
ties began with the preparation of the orthogonally protect-
ed gallic acid derivatives (6e and 6 f, respectively, 4 and
5 steps from methyl gallate; for details, see the Supporting
Information), which were then mounted onto ortho-nitro-
benzyl b-d-glucopyranoside 3b to furnish compound 5 f. The
highest yield of compound 5 f (80%, Scheme 7) was ob-
tained from compound 6e under Steglich-type esterification
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D. Deffieux, S. Quideau et al.
At this stage, we had obtained two advanced intermedi-
ates, compounds (S)-2b (route A) and (S)-2 f (route B),
which were ready to be used in the key C-arylglucosidation
step of our planned synthesis of 5-O-desgalloyl-
an even faster 5-O-galloyltransferase (Scheme 1 and
Scheme 8).
The above concerns notwithstanding, we explored the re-
action conditions reported by Tanaka et al., and variations
thereof, to treat compounds (S)-2b and (S)-2 f. In the case
of free bipyrogallolic compound (S)-2b, the close-to-neutral
conditions (pH 7.5) were not suitable and consistently pro-
voked significant degradation of the starting material. Fine-
tuning of the reaction conditions (pH 5.3, 658C, 48 h) ena-
bled a partial, yet effective, conversion of compound (S)-2b
into compound 9a as a 14:1 (b/a) epimeric mixture. Purifi-
cation of the reaction mixture by preparative reverse-phase
HPLC led to the isolation of the major C-arylglucoside
product (b-9a) in 32% yield (the minor a-9a epimer could
not be isolated), together with a 1:1 anomeric mixture of
glucopyranose derivative 10a (23%, Figure 3), which result-
ACHTUNGTRENNUNG(epi)punicacorteins A (1a and/or 1b).
The biomimetic C-arylglucosidation step: This step implies
the opening of the glucopyranosyl ring with the concomitant
formation of the C-arylglucosidic bond. This route from
a glucopyranosic system to an open-chain C-glucosidic
entity had not been previously investigated in the total syn-
thesis of ellagitannins,[18] but a related hemisynthesis prece-
dent was reported in the work of Tanaka et al.[38] They man-
aged to convert pedunculagin into the C-glucosidic ellagi-
tannins casuariin and its b-epimer, 5-O-desgalloylstachyurin
(Scheme 1), in 6% and 34% yield, respectively, by simply
heating a solution of pedunculagin in potassium phosphate
buffer (pH 7.5) at 708C. This enlightening precedent gave us
the confidence we needed to pursue our objective, because,
at first, we were not totally convinced of the preparative
À
feasibility of the intended C C bond formation during the
conversion of compounds (S)-2b or (S)-2 f into the ultimate
intermediates of our planned synthesis (9a or 9b,
Scheme 8). Indeed, putting such a synthetic transformation
in perspective with what probably occurs in the biosynthetic
pathway to C-glucosidic ellagitannins underlines the fact
that the inconvenience of having to go through transient
open-chain aldehyde precursors that are prone to fast re-
closing, such as our proposed synthetic intermediates 8a and
8b, has perhaps been solved in planta by the mobilization of
Figure 3. 2-O-Galloylated glucopyranosic compounds that could not be
converted into C-glucosidic species under the biomimetic C-arylgluco-
AHCTUNGERTGsNNUN idation conditions used.
ed from hydrolytic cleavage of the benzylidene acetal group
of compound (S)-2b, which was itself recovered in 27%
yield. At a slightly higher pH value (i.e., pH 6.4), intensive
degradation of compound (S)-2b occurred, whereas slightly
more acidic conditions (i.e., pH 4) systematically led to com-
pound 10a being the major product. Interestingly, this com-
pound resisted the conditions of C-arylglucosidation (see
below). Starting with bis-p-benzyloxylated compound (S)-2 f,
the addition of MeOH was necessary for improved solubili-
ty. In a MeOH/phosphate-buffer (pH 5.3) mixture (1:1), the
C-arylglucosidation reaction was rather ineffective, thereby
leading only to a small amount of an epimeric mixture of
compound 9b after 48 h at 658C. The highest conversion of
compound (S)-2 f was observed by increasing the pH value
of the phosphate buffer to 7.5. In such a reaction medium,
compound (S)-2 f did not suffer from any extensive degrada-
tion, as observed for compound (S)-2b in pure phosphate
buffer solvent system (pH 7.5), and led, after only 2.5 h at
658C, to compound b-9b, which was isolated in 25% yield
after purification by preparative HPLC. The formation of
small amounts of compound a-9b was also observed, but
again we could not separate this C-1 epimer in a pure state
from the reaction mixture.
Scheme 8. Completion of the total synthesis of compound 1b. a) Phos-
phate buffer (0.2m), 658C, pH 5.3 for compound (S)-2b and 0.2m phos-
phate buffer/MeOH (1:1), 658C, pH 7.5 for compound (S)-2 f; b) H2,
Pd(OH)2/C, THF, RT, 24 h; c) H2, Pd(OH)2/C, THF, RT, 5 days.
Evidence for the formation of the C-arylglucosidic bond
was obtained by the observation of a two-bond correlation
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Synthetic Studies toward C-Glucosidic Ellagitannins
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between the H-1 and C-2’ atoms in the HMBC NMR data
map of either compounds b-9a or b-9b (see the Supporting
1
Information, Figure S9). In addition, their H NMR spectra
showed one singlet at dꢀ6.45 ppm, which integrated to one
proton and was assigned to the sole remaining aromatic
proton on the C-1-linked HHDP unit. Furthermore, the
values of the coupling constants between the H-1, H-2, and
H-3 atoms were only about 2–3 Hz, which are characteristic
for the open-chain glucose core of C-glucosidic ellagitannins.
The configuration of the C-1 center for both compounds
was deduced from either the value of the coupling constant
between the H-1 and H-2 atoms (i.e., 1.7 Hz for b-9a, and
2.1 Hz for b-9b) or by selective NOE experiments that
showed through-space correlations between the H-1 and H-
3 atoms (see the Supporting Information). These NMR data
and their interpretation are in accordance with the results of
Nishioka and co-workers,[7e] who, after accumulating data on
related C-glucosidic ellagitannins, concluded that a small
coupling constant between the H-1 and H-2 atoms (about 0–
2 Hz) is indicative of a b-orientation of the sugar C-1-OH
bond, whereas a larger coupling constant (about 5 Hz) indi-
cates an a-orientation of the same bond. Even though we
could not purify the a-epimeric products, analysis of the
1H NMR spectra of the crude reaction mixtures clearly indi-
cated H-1/H-2 coupling constants with values that were ex-
pected for an a-orientation of their C-1-OH bond (i.e.,
4.6 Hz for a-9a and 4.7 Hz for a-9b; see the Supporting In-
formation).
Figure 4. Structures of the presumed aldehyde intermediates (S)-8a,
(S)-11, and 12.
and 7a, respectively (Figure 4; for details on these calcula-
tions, see the Supporting Information). The results of these
calculations provided us with some evidence that both the
4,6-O-benzylidene and the 2,3-HHDP ring systems lend sup-
port to the establishment of a potentially reactive confor-
mer. A shortest distance of 2.8 ꢅ was found between the py-
rogallolic C-2’ and the aldehydic C-1 centers for one of the
conformers of compound (S)-8a. The same distance was
also calculated for compound (S)-11, but for a more tran-
At this stage, we also conducted additional experiments
on some of our synthetic intermediates and by-products to
further examine the structural requirements of the C-aryl-
glucosidation reaction with regards to the hypotheses on the
biosynthesis of C-glucosidic ellagitannins (Scheme 1). In par-
ticular, similar C-arylglucosidation reactions on non-coupled
intermediates 7a and 5h, as well as on coupled compounds
(S)-10a and (S)-10b, which lacked the 4,6-O-benzylidene
moiety, were all non-operational (Figure 3). These failures
are quite instructive, because they indicate that a free gal-
ACHTUNGTRENsNUGN ient conformer with a smaller energy gap relative to the
lowest-energy conformer (6 kcalmolÀ1 versus 14 kcalmolÀ1
in the case of 8a). For the 2,3-O-bis-galloylated species (12),
all of its more-flexible conformers exhibited longer distances
of between 3.2 and 5.9 ꢅ. Moreover, calculations that were
performed on both epimers of C-glucosidic product 9a indi-
cated that the b-epimer was more stable than the a-epimer
by about 20 kcalmolÀ1, which was in accordance with the
preferred formation of compounds b-9a and b-9b over that
of their corresponding a-epimers (Scheme 8). However, we
could not pinpoint any structural feature that could underlie
this preference, neither by comparing the calculated con-
formers of compounds b-9a and a-9a with the aim of ratio-
ACHTUNGTRENNUNGloyl group at the O-2 position does not seem to be capable
of trapping a transient aldehyde function at the C-1 position
and that the absence of the cyclic benzylidene protecting
group at the O-4/O-6 positions (which can be viewed as
AHCTUNGTREGnNNUN alizing the difference between their thermodynamic stabili-
a
surrogate of the 4,6-HHDP unit in pedunculagin;
Scheme 1) still prevents the formation of the C-arylglucosid-
ACHTUNGTRENNUNGic bond, even though the O-2-galloyl group is part of a 2,3-
ties, nor by scrutinizing the positioning of the pyrogallolic
C-2’ nucleophilic center with respect to the orientation of
the electrophilic carbonyl group at the C-1 position in the
conformers of compound (S)-8a with the aim of rationaliz-
ing any difference in the kinetic lability of such an inter-
mediate.
Nevertheless, the above experimental and theoretical re-
sults are in agreement with the currently held hypothesis on
the biosynthesis of C-glucosidic ellagitannins that they could
all conceivably be derived from a single glucopyranosic
ellagitannin precursor that contains HHDP units at both its
2,3- and 4,6-positions, that is, pedunculagin (Sche-
me 1).[1b,7c,10–12] Numerous plant species do contain C-gluco-
sidic ellagitannins, but certain species, such as those of the
Hamamelidae, Rosidae, and Dilleniidae subclasses, that are
AHCTUNGTRENNUNG
HHDP unit. All together, these observations suggest that
some level of conformational constraint is required for ena-
bling the C-arylglucosidation event. In other words, both the
4,6-O-benzylidene and the 2,3-HHDP ring systems mutually
contribute to maintain the sugar core and the O-2-galloyl
group in a conformational status that is propitious for the
intramolecular C-arylglucosidation reaction.
Next, theoretical calculations were performed at the semi-
empirical RM1 level by using the simulated annealing
method[39,40] to characterize the conformers of transient al-
dehyde intermediates (S)-8a, (S)-11, and 12 that would have
presumably been derived from compounds (S)-2b, (S)-10a,
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D. Deffieux, S. Quideau et al.
particularly rich in C-glucosidic ellagitannins might have
evolved to systematically anabolize these metabolites.[3a] As
alluded to above, such plant species would have solved the
inconvenience of the fleeting nature of an open-chain alde-
mations that are likely to be required for the efficient bio-
synthesis of C-glucosidic ellagitannins, and hence on their
biogenetic filiation. Therefore, this synthesis work should
provide biochemists with useful pointers towards the eluci-
dation of the biogenesis of these unique natural products.
Furthermore, we believe that these syntheses of 5-O-desgal-
loylepipunicacortein A (1b) represent an important step
toward the chemical preparations of other C-glucosidic el-
hyde form of ped
transferase, as can be inferred from the occurrence of liqui-
dambin in Liquidam
bar formosana (Hamamelidaceae),[11] as
ACHTUNGTRENNUNGunculagin by the action of a 5-O-galloyl-
A
ACHTUNGTRENNUNG
well as from the existence of several liquidambin-derived 5-
O-galloylated and 2,3,5-NHTP-bearing C-glucosidic ellagi-
tannins, such as those shown in Scheme 1. Hence, the ab-
sence of a 5-galloyl unit, as well as that of a 4,6-HHDP unit,
ACHUTNGERNlNUG agiHCATUNGTRENNtUGN annins because extensions of this work should lead to
the total synthesis of more-complex NHTP-bearing mem-
bers of this class of plant polyphenols, such as vescalin and
vescalagin.
in C-glucosidic elACHTUNGTRENNUNGlagiACHTUGNTRENtNUGN annins, such as the epimeric pair 1a/
1b, should logically be due to hydrolytic transformations
that occur after the C-arylglucosidation event.
The total synthesis of 5-O-desgalloylepipunicacortein A
(1b) was completed by hydrogenolysis of either main
epimer b-9a or b-9b. However, this last, supposedly simple
step gave us cause for concern because we had to screen
many reaction conditions (i.e., the nature of the catalyst,
solvent, duration of the reaction, and type of workup/purifi-
cation procedure) before reaching success. The two ether
groups of compound b-9b could be efficiently cleaved after
24 h in dry THF under H2 in the presence of Pearlman’s
Pd(OH)2/C to furnish b-9a in 97% yield. The hydrogenoly-
Acknowledgements
This work was financially supported by the Agence Nationale de la Re-
cherche (ANR-06-BLAN-0139, project EllagInnov). We also thank the
French Ministry of Research, as well as Universitꢁ Italo-Francese and the
Italian Ministry of Education and Research (PRIN, Grant No.:
20082L3NFT-003) for research assistantships to G.M. and A.N., respec-
tively. We also thank the CDCH-Universidad Central de Venezuela for
having enabled our colleague Prof. Jaime Charris to join our group
during the academic year 2006–2007.
ACHTUNGTRENNUNGtic cleavage of the 4,6-O-benzylidene group of compound b-
[1] a) S. Quideau, D. Deffieux, C. Douat-Casassus, L. Pouysꢀgu, Angew.
Chem. 2011, 123, 610–646; Angew. Chem. Int. Ed. 2011, 50, 586–
621; b) S. Quideau, M. Jourdes, D. Lefeuvre, P. Pardon, C. Saucier,
P.-L. Teissedre, Y. Glories, in Recent Advances in Polyphenol Re-
search, Vol. 2 (Eds.: C. Santos Buelga, M. T. Escribano-Bailon, V.
Lattanzio), Wiley-Blackwell, Oxford, 2010, pp. 81–137; c) K. Khan-
babaee, T. van Ree, Nat. Prod. Rep. 2001, 18, 641–649; d) S. Qui-
deau, K. S. Feldman, Chem. Rev. 1996, 96, 475–503; e) E. Haslam,
Y. Cai, Nat. Prod. Rep. 1994, 11, 41–66.
[2] a) Chemistry and Biology of Ellagitannins: An Underestimated Class
of Bioactive Plant Polyphenols (Ed.: S. Quideau), World Scientific
Publishing/Imperial College, Singapore, 2009; b) T. Okuda, Phyto-
chemistry 2005, 66, 2012–2031; c) K.-i. Miyamoto, T. Murayama, T.
Hatano, T. Yoshida, T. Okuda, in Plant Polyphenols 2: Chemistry,
Biology, Pharmacology, Ecology (Eds.: G. G. Gross, R. W. Hem-
9a required a much longer reaction time and the daily addi-
tion of Pd(OH)2/C for 5 days at room temperature (for de-
tails, see the Supporting Information). This procedure fur-
nished compound 1b as a yellowish amorphous solid in
93% yield (Scheme 8). This material was dissolved in water,
passed through a Sephadex LH-20 column, and lyophilized
before analysis. The spectroscopic data and the specific rota-
tion of this synthetic compound 1b ([a]2D5 =À38.9, c=0.18,
MeOH) were in agreement with those reported for the iso-
lated compound ([a]2D2 =À37.5; c=1.0, MeOH).[14c]
AHCTUNGTREGiNNUN ngway, T. Yoshida), Kluwer Academic/Plenum, New York, 1999,
Conclusion
pp. 643–663; d) T. Okuda, T. Yoshida, T. Hatano, in Phenolic Com-
pounds in Food and their Effects on Health, Vol. II, ACS Symposium
Series 507 (Eds.: M.-T. Huang, C.-T. Ho, C. Y. Lee), ACS, Washing-
ton, DC, 1992, pp. 160–183; e) T. Okuda, T. Yoshida, T. Hatano, in
Plant Polyphenols: Synthesis, Properties, Significance (Eds.: R. W.
Hemingway, P. E. Laks), Plenum, New York, 1992, pp. 539–569;
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Two strategies have been implemented to open up synthetic
accesses to C-glucosidic ellagitannins; herein, both were suc-
cessfully put to use in the first chemical syntheses of
a member of this class of natural products: 5-O-desgalloyl-
ACHTUNGTRENNUNGepipunicacortein A (1b). This ellagitannin was synthesized
by route A in 4 steps with an overall yield of 10% from glu-
coside 3a and racemic hexabenzyloxydiphenic acid (4a) and
by route B in 7 steps with an overall yield of 6% from glu-
coside 3b and the protected gallic acid (6e). The focal step
of both of these syntheses is an intramolecular C-arylgluco-
sidation of a reducing glucopyranose derivative into an
open-chain C-glucosidic system in a manner that parallels
the current hypothesis on the biosynthesis of these natural
products. The observations that we made and the limitations
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Synthetic Studies toward C-Glucosidic Ellagitannins
FULL PAPER
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Received: February 16, 2012
Published online: && &&, 0000
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ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Synthetic Studies toward C-Glucosidic Ellagitannins
FULL PAPER
A route to C-glucosidic ellagitannins
was exemplified by the synthesis of 5-
O-desgalloylepipunicacortein A (see
structure). The hexahydroxydiphenoyl
unit of the natural product was either
derived from ellagic acid or built atro-
poselectively. The key step was a bio-
mimetic ring-opening C-arylglucosida-
tion.
Natural Products
G. Malik, A. Natangelo, J. Charris,
L. Pouysꢀgu, S. Manfredini,
D. Cavagnat, T. Buffeteau,
D. Deffieux,* S. Quideau* . . &&&& — &&&&
Synthetic Studies toward C-Glucosidic
Ellagitannins: A Biomimetic Total
Synthesis of 5-O-Desgalloylepipunica-
cortein A
Chem. Eur. J. 2012, 00, 0 – 0
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!