Laurent Pouységu

Plant Polyphenols: Chemical Properties, Biological Activities, and Synthesis†

Eating five servings of fruits and vegetables per day! This is what is highly recommended and heavily advertised nowadays to the general public to stay fit and healthy! Drinking green tea on a regular basis, eating chocolate from time to time, as well as savoring a couple of glasses of red wine per day have been claimed to increase life expectancy even further! Why? The answer is in fact still under scientific scrutiny, but a particular class of compounds naturally occurring in fruits and vegetables is considered to be crucial for the expression of such human health benefits: the polyphenols! What are these plant products really? What are their physicochemical properties? How do they express their biological activity? Are they really valuable for disease prevention? Can they be used to develop new pharmaceutical drugs? What recent progress has been made toward their preparation by organic synthesis? This Review gives answers from a chemical perspective, summarizes the state of the art, and highlights the most significant advances in the field of polyphenol research.

SYNTHETIC USES OF ORTHOQUINONE MONOKETALS AND THEIR ORTHOQUINOL VARIANTS. A REVIEW

(1999). SYNTHETIC USES OF ORTHOQUINONE MONOKETALS AND THEIR ORTHOQUINOL VARIANTS. A REVIEW. Organic Preparations and Procedures International: Vol. 31, No. 6, pp. 617-680.

Cellulose phosphates as biomaterials. Mineralization of chemically modified regenerated cellulose hydrogels

Femoral implantation of regenerated cellulose hydrogels revealed their biocompatible and osteoconductive properties, but a complete osseointegration could not be observed. Phosphorylation was therefore envisaged as the means to enhance cellulose bioactivity. Once implanted, phosphorylated cellulose could promote the formation of calcium phosphates, having therefore closer resemblance to bone functionality and assuring a satisfactory bonding at the interface between hard tissue and biomaterial. In the present work, regenerated cellulose hydrogels were surface modified via phosphorylation. Phosphorylated materials, having varying degrees of substitution, were soaked in a Simulated Body Fluid (SBF) solution in order to investigate their ability to induce the formation of a calcium phosphate layer. Mineralization was assessed by Scanning Electron Microscopy (SEM), Energy Dispersive Spectroscopy (EDS) and Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) spectroscopy. It was demonstrated that the calcium salt of cellulose phosphates mineralized at a higher extent than materials only phosphorylated. The degree of phosphorylation influenced the extent of surface mineralization. Moderate degrees of surface phosphorylation promoted the highest extent of mineralization. This was attributed to inadequate functionality of the surface in terms of density of PO4 groups and overall surface charge, in the case of low and high phosphate contents.

Highly Diastereoselective Synthesis of Orthoquinone Monoketals through λ3-Iodane-Mediated Oxidative Dearomatization of Phenols†

Orthoquinone monoketals A and orthoquinols B are cyclohexa-2,4-dienone derivatives with valuable reactivity features for the construction of complex molecular architectures. Their conjugated dienone unit and the vicinal positioning of their oxygenated functionalities constitute a unique structural arrangement that can be transformed rapidly into various kinds of polyoxygenated (poly)cyclic systems (Scheme 1).

2-Alkoxyarenol-derived orthoquinols in carbon–oxygen, carbon–nitrogen and carbon–carbon bond-forming reactions

Abstract Silylated oxygen- and nitrogen-tethered orthoquinol acetates, generated by phenyliodine(III) diacetoxy-mediated oxidative acetoxylation of 2-alkoxyphenols in CH2Cl2 can be used to furnish regioselectively benzannulated heterocycles. Oxidative activation of 2-alkoxynaphthols with non-nucleophilic phenyliodine(III) bis(trifluoroacetoxy) in the presence of carbon nucleophiles, including oxidation sensitive silyl enol ethers, constitute a potentially valuable route to naturally occurring vicinally oxygenated benz[a]anthracene motifs.

Total Synthesis of Wasabidienones B1 and B0 via SIBX-Mediated Hydroxylative Phenol Dearomatization

The first total synthesis of the natural nondimerizing o-quinol (+)-wasabidienone B1 was achieved from commercially available 1,3,5-trimethoxybenzene. The key dearomatizing transformation was efficiently accomplished via a hydroxylative phenol dearomatization reaction using the stabilized lambda(5)-iodane reagent IBX (SIBX). (+)-Wasabidienone B1 was then converted into its congener (-)-wasabidienone B0 via an improved thermally induced ring-contracting isomerization reaction.

Orthoquinone monoketal chemistry. Experimental and density functional theory studies on orthoquinol acetate rearrangements

The non-dimerizing orthoquinone monoketal, 6-acetoxy-6-methoxy-3-methoxycarbonylcyclohexa-2,4-dienone, conveniently prepared from oxidative acetoxylation of its parent phenol with PhI(OAc)2 in CH2Cl2AcOH (3:1), cleanly undergoes 1,3-acetoxy migrations in the presence of silica gel at room temperature to furnish a 60:40 product mixture conceivably derived from [3,5] and [3,3] sigmatropic rearrangements. Density functional theory calculations indicate that the [3,5] shift is pseudopericyclic, has a remarkably low activation energy of 20.1 kcal/mol, and is favored by 5.4 kcal/mol over the pericyclic [3,3] shift, in qualitative agreement with the experimental observations.

Oxidative Dearomatization of Phenols and Anilines via λ3- and λ5-Iodane-Mediated Phenylation and Oxygenation

Treatment of 2-methylphenols with chloro(diphenyl)-λ3-iodane led to their regioselective dearomatizing 2-phenylation into cyclohexa-2,4-dienone derivatives via a proposed ligand coupling reaction. In the same vein of investigation, treatment of 2-methylanilines with the λ5-iodane 2-iodoxybenzoic acid IBX reagent led to their regioselective dearomatization into previously undescribed ortho-quinol imines.

The polyphenolic ellagitannin vescalagin acts as a preferential catalytic inhibitor of the α isoform of human DNA topoisomerase II.

Polyphenolic ellagitannins are natural compounds that are often associated with the therapeutic activity of plant extracts used in traditional medicine. They display cancer-preventing activity in animal models by a mechanism that remains unclear. Potential targets have been proposed, including DNA topoisomerases II (Top2). Top2α and Top2β, the two isoforms of the human Top2, play a crucial role in the regulation of replication, transcription, and chromosome segregation. They are the target of anticancer agents used in the clinic such as anthracyclines (e.g., doxorubicin) or the epipodophyllotoxin etoposide. It was recently shown that the antitumor activity of etoposide was due primarily to the inhibition of Top2α, whereas inhibition of Top2β was responsible for the development of secondary malignancies, pointing to the need for more selective Top2α inhibitors. Here, we show that the polyphenolic ellagitannin vescalagin preferentially inhibits the decatenation activity of Top2α in vitro, by a redox-independent mechanism. In CEM cells, we also show that transient small interfering RNA-mediated down-regulation of Top2α but not of Top2β conferred a resistance to vescalagin, indicating that the α isoform is a preferential target. We further confirmed that Top2α inhibition was due to a catalytic inhibition of the enzyme because it did not induce DNA double-strand breaks in CEM-treated cells but prevented the formation of Top2α- rather than Top2β-DNA covalent complexes induced by etoposide. To our knowledge, vescalagin is the first example of a catalytic inhibitor for which cytotoxicity is due, at least in part, to the preferential inhibition of Top2α.

A convenient synthesis of the Echinacea-derived immunostimulator and HIV-1 integrase inhibitor (-)-(2R, 3R)-chicoric acid

The Echinacea-derived immunostimulator and HIV-1 integrase inhibitor (−)-chicoric acid (=2,3-bis{[3-(3,4-dihydroxyphenyl)-1-oxoprop-2-enyl]oxy}butanedioic acid; 1a) was conveniently prepared via a silane-promoted Pd-mediated chemoselective hydrogenolysis of its perbenzylated derivative 12a, which was generated from an efficient and reliable carbodiimide-mediated coupling reaction between the caffeic acid dibenzyl ether derivative 7 and commercially available (+)-dibenzyl L-tartrate (9a). The other naturally occurring dextrorotatory chicoric acid (1b) can be similarly prepared.