1628 Chem. Commun., 2011, 47, 1628–1630 This journal is c The Royal Society of Chemistry 2011 First and biomimetic total synthesis of a member of the C-glucosidic subclass of ellagitannins, 5-O-desgalloylepipunicacortein Aw Denis Deffieux, a Anna Natangelo, ab Gae¨lle Malik, a Laurent Pouyse´gu, a Jaime Charris c and Ste´ phane Quideau* a Received 21st September 2010, Accepted 25th October 2010 DOI: 10.1039/c0cc04007j The first total synthesis of a member of the C-glucosidic subclass of ellagitannins, 5-O-desgalloylepipunicacortein A, was accomplished by relying on a biomimetic aldol-type formation of its character- istic C-aryl glucosidic bond through the exploitation of the inherent chemical reactivity of a glucopyranosic hemiacetal precursor. Ellagitannins constitute one of the major classes of polyphenolic natural products derived from the secondary metabolism of dicotyledonous plant species of the Angiospermea. 1 Nearly 1000 members of this class of so-called hydrolyzable tannins have today been isolated from various plant sources, fully characterized, and shown to exhibit remarkable biological activities related to inter alia their antioxidant, antiviral and host-mediated antitumor properties. 1–3 Such a natural molecular diversity is really impressive when one considers that the core structure of all of these metabolites initially relies on the assembly of two simple building blocks, D-glucopyranose and gallic acid (i.e., 3,4, 5-trihydroxybenzoic acid). Typical examples of monomeric ellagitannins are the tellimagrandins and pedunculagin, which feature biarylic hexahydroxydiphenoyl (HHDP) ester units at the 2,3- and/or 4,6-positions of their glucopyranose core (Fig. 1). C-Aryl glucosidic variants constitute an intriguing subclass of ellagitannins featuring the structural characteristic C–C linkage between the carbon-1 atom of an open-chain glucose core and an aromatic carbon of a galloyl-derived unit esterified to the 2-position of the glucose core. This C-1-linked galloyl-derived moiety can be part of a terarylic nonahydroxyterphenoyl (NHTP) unit triply esterified to the 2-, 3- and 5-positions of the glucose core, such as in vescalagin and its C-1 epimer castalagin (Fig. 1). These two ellagitannins are notably found in fagaceous woody plants such as Quercus (oak) species 4 and are known to exhibit antiviral and antitumor activities. 5 The C-1-linked galloyl- derived moiety can also be part of a 2,3-HHDP unit such as in simpler structures of the punicacortein A series (1a–d, Fig. 1). 6 Punicacortein A (1a) and/or its C-1 epimer 1b have notably been isolated from the bark of the pomegranate tree (Punica granatum L., Lythraceae), 6a from the leaves of the oak tree species Quercus aliena BLUME (Fagaceae), 6c and from the roots of Rosa taiwanensis Nakai (Rosaceae). 6d The 5-O-desgalloylated variant 1c has been isolated from Osbeckia chinensis L. (Melastomataceae) 6b and 1d has been biochemically generated from 1b by the hydrolytic action of a tannase. 6c It is reasonable to suppose that these open-chain C-glucosidic ellagitannins have 1-O-desgalloylated glucopyranosic precursors, the hemiacetal function of which acts as the trigger for the glucose ring opening. The electrophilic aldehyde function hence unveiled would thus be exposed to an intramolecular aldol-type attack by the phenolic 2,3-HHDP unit that would then result in the formation of the characteristic C-glucosidic bond of these ellagitannins (vide infra). 2,7 Several ellagitannins have been successfully synthesized since the pioneering and first total synthesis of tellimagrandin I (Fig. 1) in 1994 by Feldman and co-workers, 8 but a large majority of these ellagitannins belong to the glucopyranosic type. 8,9 No ellagitannin of the C-glucosidic type has yet succumbed to total synthesis efforts. We thus decided to embark on such an enterprise with the aim of testing the biosynthetic plausibility of the aforementioned pathway from glucopyranosic to C-glucosidic ellagitannins. The 5-O-desgalloyl(epi)punicacorteins A (1c and 1d, Fig. 1) were selected as targets for this work. Our retrosynthetic analysis of these two epimeric compounds implied the synthesis of the glucopyranosic derivative (S)-3 (Scheme 1). This perbenzylated compound constitutes the immediate precursor of a phenolic Fig. 1 Structures of tellimagrandins, pedunculagin, vescalagin, castalagin and punicacorteins A (1a–d). a Universite ´ de Bordeaux, Institut des Sciences Mole ´culaires (CNRS-UMR 5255), Institut Europe ´en de Chimie et Biologie, 2 rue Robert Escarpit, 33607 Pessac Cedex, France. E-mail: s.quideau@iecb.u-bordeaux.fr; Fax: (+33) (0)5-4000-2215; Tel: (+33) (0)5-4000-3010 b Universita ` di Ferrara, Facolta ` di Scienze Farmaceutiche, via Fossato di Mortara 14–19, 44100 Ferrara, Italy c Facultad de Farmacı´a, Universidad Central de Venezuela, Caracas 1051, Venezuela w Electronic supplementary information (ESI) available: Experimental procedures and characterization data for all new compounds along with copies of 1 H and 13 C NMR spectra. See DOI: 10.1039/c0cc04007j COMMUNICATION www.rsc.org/chemcomm | ChemComm Downloaded by GFZ POTSDAM WISSENSCHAFTSPARK on 23 February 2011 Published on 29 November 2010 on http://pubs.rsc.org | doi:10.1039/C0CC04007J View Online