probably contributes to maintaining the sugar core in
a conformational status propitious for this intramolecular
C-glucosidation reaction. With the same line of thought, we also
submitted the 4,6-O-benzylidene-2,3-O-digalloylglucopyranose 10
(Fig. 2) to similar reaction conditions, but again, no formation of
C-glucosidic bond was observed. In this case, we speculate that it
is the absence of the conformational constraint otherwise brought
by the biarylic 2,3-HHDP unit that seemingly prevented the
reaction from occurring.
thank Professor Stefano Manfredini from the Facolta di
Scienze Farmaceutiche, Universita di Ferrara and the Universita
Italo-Francese, Universita di Ferrara (FAR2007-2009, PRIN
20082L3NFT-003) for A. N.’s research assistantship, the
Ministere de la Recherche for G. M.’s research assistantship,
and CDCH-Universidad Central de Venezuela for permitting our
colleague Professor Jaime Charris to join our group in 2006–2007.
Notes and references
Thus, the reaction conditions we used to convert 7 into 8
expectedly engaged both anomers of 7 in a chemical equilibrium
with their transient open-chain aldehydic form 2 (see Schemes 1
and 2). Unfortunately, this equilibrium was deprived of its
participants over time because of the hydrolysis of 7 into 9,
hence causing a decrease in the yield of the desired C-glucosidic
product 8. Nevertheless, the major C-glucoside b-8 was obtained
in a modest but satisfying isolated yield (i.e., 32%) under these
conditions, mimicking those that are plausibly operational in
planta during the genesis of C-glucosidic ellagitannins. Our
experimental results are indeed in agreement with the current
hypothesis on the biosynthesis of C-glucosidic ellagitannins that
could all be most efficiently derived from a single glucopyranosic
ellagitannin precursor bearing conformationally-constraining
HHDP units at both its 2,3- and 4,6-positions, i.e., pedunculagin
(see Fig. 1).2,7 Plant species in which these metabolites are often
encountered, such as those of the Hamamelidae, Rosidae and
Dilleniidae subclasses,17 might have solved the inconvenience of
the fleeting nature of an open-chain aldehydic form of
pedunculagin by the action of a 5-O-galloyltransferase, as can be
inferred from the occurrence of C-glucosidic ellagitannins bearing
a galloyl unit at their 5-position (e.g., see 1a/b and vescalagin/
castalagin in Fig. 1). Hence, the absence of 4,6-HHDP and
5-galloyl units in C-glucosidic ellagitannins such as the epimeric
pair 1c/1d could be due to post-C-glucosidation hydrolytic events.
Finally, the major C-glucoside b-8 was cleared of its
benzylidene moiety upon exposure to hydrogenolysis in the
presence of Pearlman’s catalyst to furnish 5-O-
desgalloylepipunicacortein A (1d) in 93% yield (Scheme 2).
All spectral data and the specific rotation of this synthetic 1d
([a]2D5 = À38.9, c 0.18, MeOH) coincide with those reported for
the isolated compound ([a]2D2 = À37.5, c 1.0, MeOH).6c
In summary, 5-O-desgalloylepipunicacortein A (1d) is the first
C-glucosidic ellagitannin to be obtained via total synthesis,
in 10 steps with overall yields of 9% from 6 or 3% from
ellagic acid. The key step in this synthesis is the biomimetic
formation of the C-aryl glucosidic bond that simply relies on
an exploitation of the inherent chemical reactivity of a
glucopyranosic hemiacetal precursor without resorting to the
use of any activating or protecting groups. Moreover, this total
synthesis sheds light on the biogenetic filiation of C-glucosidic
ellagitannins, whose elaboration appears to necessitate the
presence of conformationally constraining units at both the
2,3- and 4,6-positions of their sugar core, hence confirming
pedunculagin as their most probable and unique glucopyranosic
parent. Furthermore, this work represents an important step
toward the chemical synthesis of more complex C-glucosidic
ellagitannins such as the epimeric vescalagin and castalagin.
This work was financially supported by the Agence Nationale
de la Recherche (ANR-06-BLAN-0139, EllagInnov). We also
1 (a) Chemistry and Biology of Ellagitannins—An Underestimated Class of
Bioactive Plant Polyphenols, ed. S. Quideau, World Scientific, Singapore,
2009; (b) S. Quideau, D. Deffieux, C. Douat-Casassus and L. Pouysegu,
Angew. Chem., Int. Ed., 2010, DOI: 10.1002/anie.201000044.
2 S. Quideau, M. Jourdes, D. Lefeuvre, P. Pardon, C. Saucier,
P.-L. Teissedre and Y. Glories, in Recent Advances in Polyphenol
Research, ed. C. Santos-Buelga, M. T. Escribano-Bailon and
V. Lattanzio, Wiley-Blackwell, Oxford, vol. 2, 2010, pp. 81–137.
3 (a) K. Khanbabaee and T. van Ree, Nat. Prod. Rep., 2001, 18, 641;
(b) S. Quideau and K. S. Feldman, Chem. Rev., 1996, 96, 475;
(c) E. Haslam and Y. Cai, Nat. Prod. Rep., 1994, 11, 41.
4 (a) W. Mayer, H. Seitz and J. C. Jochims, Justus Liebigs Ann.
Chem., 1969, 721, 186; (b) W. Mayer, H. Seitz, J. C. Jochims,
K. Schauerte and G. Schilling, Justus Liebigs Ann. Chem., 1971,
751, 60; (c) G.-i. Nonaka, T. Sakai, T. Tanaka, K. Mihashi and
I. Nishioka, Chem. Pharm. Bull., 1990, 38, 2151.
5 (a) Y. Kashiwada, G.-i. Nonaka, I. Nishioka, J.-J. Chang and
K.-H. Lee, J. Nat. Prod., 1992, 55, 1033; (b) Y. Kashiwada,
G.-i. Nonaka, I. Nishioka, K. J.-H. Lee, I. Bori, Y. Fukushima,
K. F. Bastow and K.-H. Lee, J. Pharm. Sci., 1993, 82, 487;
(c) S. Quideau, T. Varadinova, T. Diakov, D. Karagiozova,
P. Genova, R. Petrova, M. Jourdes, P. Pardon and C. Baudry,
Chemistry & Biodiversity, 2004, 4, 10; (d) S. Quideau, M. Jourdes,
D. Lefeuvre, D. Montaudon, C. Saucier, Y. Glories, P. Pardon and
P. Pourquier, Chem. Eur. J., 2005, 11, 6503.
6 (a) T. Tanaka, G.-i. Nonaka and I. Nishioka, Chem. Pharm. Bull.,
1986, 34, 656; (b) J.-D. Su, T. Osawa, S. Kawakishi and M. Namiki,
Phytochemistry, 1988, 27, 1315; (c) G.-i. Nonaka, T. Sakai,
K. Mihashi and I. Nishioka, Chem. Pharm. Bull., 1991, 39, 884;
(d) J.-H. Lin and Y.-F. Huang, Chin. Pharm. J., 1996, 48, 231.
7 For related and early discussions on this biosynthetic origin of
C-glucosidic ellagitannins, see: (a) T. Okuda, T. Yoshida, T. Hatano,
K. Yazaki and M. Ashida, Phytochemistry, 1982, 21, 2871;
(b) T. Hatano, R. Kira, M. Yoshizaki and T. Okuda,
Phytochemistry, 1986, 25, 2787; (c) T. Okuda, T. Hatano, T. Kaneda,
M. Yoshizaki and T. Shingu, Phytochemistry, 1987, 26, 2053.
8 K. S. Feldman, S. M. Ensel and R. D. Minard, J. Am. Chem. Soc.,
1994, 116, 1742.
9 (a) K. S. Feldman, Phytochemistry, 2005, 66, 1984; (b) K. Khanbabaee
and T. Ree, Synthesis, 2001, 1585; (c) K. S. Feldman,
K. Sahasrabudhe, S. Quideau, K. L. Hunter and M. D. Lawlor, in
Plant Polyphenols 2—Chemistry, Biology, Pharmacology, Ecology,
ed. G. G. Gross, R. W. Hemingway and T. Yoshida, Kluwer
Academic/Plenum Publishers, New York, 1999, pp. 101–125.
10 A. K. Sen and N. Banerji, Indian J. Chem., Sect. B, 1989, 28, 818.
11 T. D. Nelson and A. I. Meyers, J. Org. Chem., 1994, 59, 2577.
12 C. S. Rye and S. G. Withers, J. Am. Chem. Soc., 2002, 124, 9756.
13 (a) K. S. Feldman and A. Sambandam, J. Org. Chem., 1995, 60,
8171; (b) J. J. Oltvoort, M. Kloosterman and J. H. V. Boom, J. R.
Neth. Chem. Soc., 1983, 102, 501.
14 (a) Y. Kashiwada, L. Huang, L. M. Ballas, J. B. Jiang, W. P. Janzen and
K.-H. Lee, J. Med. Chem., 1994, 37, 195; (b) V. O. T. Schmidt, H. Voigt,
W. Puff and R. Koster, Justus Liebigs Ann. Chem., 1954, 586, 165.
15 This absence of diastereoselectivity has previously been observed in
similar 2,3-O-bis-acylation of glucose derivatives, whereas significant
atropodiastereoselectivity is usually operational in related 4,6-O-bis-
acylation reactions using (rac)-5, see: (a) K. Khanbabaee and
K. Lotzerich, J. Org. Chem., 1998, 63, 8723; (b) K. Khanbabaee
and M. Großer, Tetrahedron, 2002, 58, 1159.
16 T. Tanaka, S. Kirihara, G.-i. Nonaka and I. Nishioka, Chem.
Pharm. Bull., 1993, 41, 1708.
17 T. Okuda, T. Yoshida and T. Hatano, Phytochemistry, 2000, 55,
513.
c
1630 Chem. Commun., 2011, 47, 1628–1630
This journal is The Royal Society of Chemistry 2011