Towards the first total synthesis of C-arylglucosidic ellagitannins. A biomimetic approach.

C-arylglucosidic ellagitannins represent a unique sub-class of hydrolyzable tannins. Polyphenols such these have attracted considerable interest in the past fifteen years because of possible benefits in human health care and prevention of diseases such as carcinogenesis and arteriosclerosis. However, this class of natural product, with such unique structural architectures and potent biological activities, has not yet been fully explored for therapeutic potential. From here our interest in developing a synthetic strategy for generation of these compounds and their analogues with enhanced pharmacological properties. Our synthetic efforts were so focused on the synthesis of 5-O-degalloyl epipunicacortein A (1) as simple structures of this class of natural compounds. C-arylglucosidic ellagitannins constitute a tannin subclass in which a C–C bond links the C-1 atom of an “open-chain” glucose core to the C- 2’ atom of a galloyl-derived unit esterified to the 2-position of the glucose core. Their C-1-linked galloyl-derived unit is either part of a HHDP ester group bridging the 2- and 3-positions of the glucose core. It is possible to identify three key issues that must be addressed in order to accomplish the synthesis of C-arylglucosidic ellagitannins: - Opening of the sugar - C-arylglucosidation reaction - Atroposelective intramolecular biaryl coupling for the HHDP construction In the end of this work we managed to obtain a route to access the C-arylglucosidic ellagitannins. In the meantime an intramolecular atroposelective methodology for the construction of the hexahydroxyterphenolyl unit (HHDP) was developed, inspired to the Yamada’s total synthesis of corilagin. We are confident it could be successfully applied to the NHTP construction. This strategy required the preparation of a precursor featuring a para-protected galloyl units. Our methodology for the C-arylglucosidic bond formation into biomimetic conditions resulted applicable even on differently protected substrates. So a biomimetic route to C-glucosidic ellagitannins have been developed. The introduction of a conveniently protected galloyl unit on the intermediates A gives access to the a product that could be further submitted to an oxidative coupling in the Yamada’s conditions to give, after deprotection, the NHTP-bearing C-arylglucosidic ellagitannin vescalin (17) First galloylation attempts on compound 17 resulted unsatisfactory. Studies are still on going to address this point. At this point of the synthesis it was possible to obtain a first member of the C-arylglucosidic ellagitannin family. The benzylidene cleavage of compound 7 delivered the degalloyl epi-punicacortein A 1 (1). This molecule has not yet isolated form a natural source, but it is reasonable to suppose that its structure corresponds to a natural compound. The hydrolysis of esters is the most frequent modification incurred by ellagitannins so O-5-degalloyl epipunicacortein A could derive from epipunicacortein A as O-5-degalloyl punicacortein A derives from hydrolysis of its precursor punicacortein A

Towards the first total synthesis of C-arylglucosidic ellagitannins : a biomimetic approach

Les ellagitannins C-arylglucosidiques sont des polyphenols naturels capable d’inhiber totalement la topoisomérase 2, une enzyme ciblée par les chimiothérapies utilisées contre le cancer. La challenge de cette these c’était trouver une approche biomimétique a la synthèse de ces molecules. La synthèse totale de la punicacorteine A, un simple membre de cette classe, a demande le développement de nouvelle méthodologies liée (i) à la chimie des sucres, pour la formation de la liaison C-arylglucosidique sur le glucose en forme ouverte et (ii) à la chimie des phénols pour générer l’unité biarylique en façon atroposelective. L’utilisation de complexes de cuivre-amine a permis de réaliser le couplage. L’étape suivante de la liaison C-arylglucosidation a ainsi pu être étudiée et le composé attendu a pu être obtenu par réaction dans une solution de tampon phosphate. Le dernière étape de la synthèse (galloylation sélective) n’est pas encore réalisée mais, à ce stade, une déprotection permettre d’obtenir un premier ellagitannin C-arylglucosidique naturel, l’épi-punicacortéine A 5-O-dégalloylée.C-arylglucosidic ellagitannins belong to a family of biologically-active plant-derived polyphenols. Preliminary studies by Prof. Quideau’s group showed that some of these ellagitannins are potent inhibitors of human topoisomerase 2, current target of anticancer chemotherapies. The challenge of this thesis was the development of a biomimetic synthetic approach to this class of molecule. The total synthesis of punicacortein A, a simple member of this class, required the development of novel methodologies related (i) to sugar chemistry, to install the C-arylglucosidic bond on an open chain glucose, and (ii) to phenol chemistry, to generate the biaryl-unit in an atropoisomerically-controlled manner. This issue was addressed by using copper-amine complexes as oxidizing agents. We managed to obtain the C-arylglycosidic compound by reaction in phosphate buffer. At this stage, a single deprotection step led to the first natural C-arylglucosidic ellagitannin, 5-O-degalloyl epipunicacortein A

Vers la première synthèse totale d’ellagitannins C-arylglucosidiques : une approche biomimétique

Les ellagitannins C-arylglucosidiques sont des polyphenols naturels capable d’inhiber totalement la topoisomérase 2, une enzyme ciblée par les chimiothérapies utilisées contre le cancer. La challenge de cette these c’était trouver une approche biomimétique a la synthèse de ces molecules. La synthèse totale de la punicacorteine A, un simple membre de cette classe, a demande le développement de nouvelle méthodologies liée (i) à la chimie des sucres, pour la formation de la liaison C-arylglucosidique sur le glucose en forme ouverte et (ii) à la chimie des phénols pour générer l’unité biarylique en façon atroposelective. L’utilisation de complexes de cuivre-amine a permis de réaliser le couplage. L’étape suivante de la liaison C-arylglucosidation a ainsi pu être étudiée et le composé attendu a pu être obtenu par réaction dans une solution de tampon phosphate. Le dernière étape de la synthèse (galloylation sélective) n’est pas encore réalisée mais, à ce stade, une déprotection permettre d’obtenir un premier ellagitannin C-arylglucosidique naturel, l’épi-punicacortéine A 5-O-dégalloylée.C-arylglucosidic ellagitannins belong to a family of biologically-active plant-derived polyphenols. Preliminary studies by Prof. Quideau’s group showed that some of these ellagitannins are potent inhibitors of human topoisomerase 2, current target of anticancer chemotherapies. The challenge of this thesis was the development of a biomimetic synthetic approach to this class of molecule. The total synthesis of punicacortein A, a simple member of this class, required the development of novel methodologies related (i) to sugar chemistry, to install the C-arylglucosidic bond on an open chain glucose, and (ii) to phenol chemistry, to generate the biaryl-unit in an atropoisomerically-controlled manner. This issue was addressed by using copper-amine complexes as oxidizing agents. We managed to obtain the C-arylglycosidic compound by reaction in phosphate buffer. At this stage, a single deprotection step led to the first natural C-arylglucosidic ellagitannin, 5-O-degalloyl epipunicacortein A

Vers la première synthèse totale d ellagitannins C-arylglucosidiques (une approche biomimétique)

Les ellagitannins C-arylglucosidiques sont des polyphenols naturels capable d inhiber totalement la topoisomérase 2, une enzyme ciblée par les chimiothérapies utilisées contre le cancer. La challenge de cette these c était trouver une approche biomimétique a la synthèse de ces molecules. La synthèse totale de la punicacorteine A, un simple membre de cette classe, a demande le développement de nouvelle méthodologies liée (i) à la chimie des sucres, pour la formation de la liaison C-arylglucosidique sur le glucose en forme ouverte et (ii) à la chimie des phénols pour générer l unité biarylique en façon atroposelective. L utilisation de complexes de cuivre-amine a permis de réaliser le couplage. L étape suivante de la liaison C-arylglucosidation a ainsi pu être étudiée et le composé attendu a pu être obtenu par réaction dans une solution de tampon phosphate. Le dernière étape de la synthèse (galloylation sélective) n est pas encore réalisée mais, à ce stade, une déprotection permettre d obtenir un premier ellagitannin C-arylglucosidique naturel, l épi-punicacortéine A 5-O-dégalloylée.C-arylglucosidic ellagitannins belong to a family of biologically-active plant-derived polyphenols. Preliminary studies by Prof. Quideau s group showed that some of these ellagitannins are potent inhibitors of human topoisomerase 2, current target of anticancer chemotherapies. The challenge of this thesis was the development of a biomimetic synthetic approach to this class of molecule. The total synthesis of punicacortein A, a simple member of this class, required the development of novel methodologies related (i) to sugar chemistry, to install the C-arylglucosidic bond on an open chain glucose, and (ii) to phenol chemistry, to generate the biaryl-unit in an atropoisomerically-controlled manner. This issue was addressed by using copper-amine complexes as oxidizing agents. We managed to obtain the C-arylglycosidic compound by reaction in phosphate buffer. At this stage, a single deprotection step led to the first natural C-arylglucosidic ellagitannin, 5-O-degalloyl epipunicacortein A.BORDEAUX1-Bib.electronique (335229901) / SudocSudocFranceF

5,6-Dihydroxyindole Tetramers with "Anomalous" Interunit Bonding Patterns by Oxidative Coupling of 5,5',6,6'-Tetrahydroxy-2,7'-biindolyl: Emerging Complexities on the Way toward an Improved Model of Eumelanin Buildup.

Chem. or enzymic oxidn. of 5,6-dihydroxyindole (I) leads to the rapid deposition of a black solid resembling eumelanin pigments by way of a complex oligomerization/polymn. process that proceeds in the early stages via dimers and trimers characterized by 2,4'- and 2,7'-couplings. Despite extensive efforts, the structures of the higher oligomers, which define the structural architecture and physicochem. properties of the eumelanin particles, have so far defied elucidation. Using a dimer-dimer coupling strategy that has recently allowed the first successful entry to a tetramer of I, the authors report now three addnl. tetramers obtained by oxidn. of 5,5',6,6'-tetrahydroxy-2,7'-biindolyl with the peroxidase/H2O2 system. On the basis of extensive 2D NMR and mass spectrometric anal., the products were identified as acetylated II (3%), III (4%), and IV (5%), in which the inner units are linked through unexpected 3,3'-, 4,4'-, and 2,3'-linkages. If verified in further studies, the newly uncovered coupling patterns would entail important consequences for current models of eumelanin structure based on one-dimensional structural chains with extended p-electron conjugation or p-stacked flat oligomer aggregates