Laboratoire d'innovation moléculaire et applications

The ever-growing number of fluorinated compounds in medicinal and agrochemical applications has led to a remarkable positive emulation in research. The last few years have been the witness of several advances in the search of more effective and user-friendlier methods for the introduction of fluorine as substituent or of fluorinated groups on various structures. In particular, the synthesis of trifluoromethyl ethers and thioethers is receiving increasing attention due to the peculiar properties of the OCF3 and SCF3 groups. This review will cover the different methods for the preparation of trifluoromethyl ethers and thioethers, and will emphasize on the most recent developments, including the use of catalytic methods or of methodologies for trifluoromethylation or trifluoromethanesulfanylation.

In the last few years, transition metal-mediated reactions have joined the toolbox of chemists working in the field of fluorination for Life-Science oriented research. The successful execution of transition metal-catalyzed carbon-fluorine bond formation has become a landmark achievement in fluorine chemistry. This rapidly growing research field has been the subject of some excellent reviews. Our approach focuses exclusively on transition metal-catalyzed reactions that allow the introduction of -CFH2, -CF2H, -C n F2 n +1 and -SCF3 groups onto sp² carbon atoms. Transformations are discussed according to the reaction-type and the metal employed. The review will not extend to conventional non-transition metal methods to these fluorinated groups.

A "niche" topic in the past decade, the asymmetric C-H bond activation has been attracting growing interest over the last few years. Particularly significant advances have been achieved in the field of direct, stereoselective transformations of C(sp(2) )-H bonds. This Concept article intends to showcase different types of asymmetric C(sp(2) )-H bond activation reactions, emphasising both the nature of the stereo-discriminating step and the variability of valuable scaffolds that could be rapidly constructed by means of such strategies.

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Abstract A stereoselective method for the synthesis of axially chiral biaryl scaffolds by CH bond functionalization was accomplished using chiral sulfoxide both as the directing group enabling the regioselective activation of a CH bond and as the chiral auxiliary generating an asymmetric environment in the coordination sphere of the metal complex. We have demonstrated the directing ability of the p ‐tolylsulfinyl group in promoting the Pd(II)‐catalyzed CH olefination of biphenyls. magnified image

While aiming at sustainable organic synthesis, over the last decade particular attention has been focused on two modern fields, C-H bond activation, and visible-light-induced photocatalysis. Couplings through C-H bond activation involve the use of non-prefunctionalized substrates that are directly converted into more complex molecules, without the need of a previous functionalization, thus considerably reduce waste generation and a number of synthetic steps. In parallel, transformations involving photoredox catalysis promote radical reactions in the absence of radical initiators. They are conducted under particularly mild conditions while using the visible light as a cheap and economic energy source. In this way, these strategies follow the requirements of environment-friendly chemistry. Regarding intrinsic advantages as well as the complementary mode of action of the two catalytic transformations previously introduced, their merging in a synergistic dual catalytic system is extremely appealing. In that perspective, the scope of this review aims to present innovative reactions combining C-H activation and visible-light induced photocatalysis.

With the aim to clarify the mechanism(s) of action of nitroaromatic compounds against the malaria parasite Plasmodium falciparum, we examined the single-electron reduction by P. falciparum ferredoxin:NADP+ oxidoreductase (PfFNR) of a series of nitrofurans and nitrobenzenes (n = 23), and their ability to inhibit P. falciparum glutathione reductase (PfGR). The reactivity of nitroaromatics in PfFNR-catalyzed reactions increased with their single-electron reduction midpoint potential (E17). Nitroaromatic compounds acted as non- or uncompetitive inhibitors towards PfGR with respect to NADPH and glutathione substrates. Using multiparameter regression analysis, we found that the in vitro activity of these compounds against P. falciparum strain FcB1 increased with their E17 values, octanol/water distribution coefficients at pH 7.0 (log D), and their activity as PfGR inhibitors. Our data demonstrate that both factors, the ease of reductive activation and the inhibition of PfGR, are important in the antiplasmodial in vitro activity of nitroaromatics. To the best of our knowledge, this is the first quantitative demonstration of this kind of relationship. No correlation between antiplasmodial activity and ability to inhibit human erythrocyte GR was detected in tested nitroaromatics. Our data suggest that the efficacy of prooxidant antiparasitic agents may be achieved through their combined action, namely inhibition of antioxidant NADPH:disulfide reductases, and the rapid reduction by single-electron transferring dehydrogenases-electrontransferases.

Axially chiral C–N compounds are an emerging but scarcely investigated class of stereogenic molecules with potential applications as biologically active scaffolds and chiral ligands. The synthesis of these compounds is extremely challenging, and in particular, no metal-catalyzed asymmetric, intermolecular C–N coupling has been previously reported. Herein we disclose an intermolecular atropselective C–N coupling, occurring with excellent stereoselectivity. This Cu-catalyzed transformation is based on the use of highly active coupling partners (i.e., chiral iodanes bearing a very cheap and traceless sulfoxide auxiliary). Use of such original ortho-sulfoxide iodanes enables this unprecedented coupling to occur at room temperature, guaranteeing high atropselectivity and atropselectivity of the coupling products under reaction conditions. Because of extensive possible postmodifications of the optically pure products, a panel of C–N axially chiral scaffolds can now be accessed.

Undirected/Directed Cross-Coupling: A new dehydrogenative RhIII-catalyzed cross-coupling reaction between bromoarenes bearing no directing group and vinylic substrates substituted by a chelating group is reported. An original reaction mechanism enables the use of internal alkenes in a Z-selective coupling. The application of 1,3-disubstituted or 1,2-homodisubstituted arenes leads to the formation of highly functionalized, complex, and valuable olefins as one single isomer. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Polyplexes prepared from DNA and globular compact polycationic derivatives constructed around a fullerene hexakis-adduct core have shown remarkable gene delivery capabilities.

Grapevine ( Vitis vinifera L.) is one of the most important crops worldwide but is subjected to multiple biotic and abiotic stresses, especially related to climate change. In this context, the grapevine culture could take advantage of symbiosis through association with arbuscular mycorrhizal fungi (AMF), which are able to establish symbiosis with most terrestrial plants. Indeed, it is well established that mycorrhization improves grapevine nutrition and resistance to stresses, especially water stress and resistance to root pathogens. Thus, it appears essential to understand the effect of mycorrhization on grapevine metabolism and defense responses. In this study, we combined a non-targeted metabolomic approach and a targeted transcriptomic study to analyze changes induced in both the roots and leaves of V. vinifera cv. Gewurztraminer by colonization with Rhizophagus irregularis (Ri). We showed that colonization of grapevine with AMF triggers major reprogramming of primary metabolism in the roots, especially sugar and fatty acid metabolism. On the other hand, mycorrhizal roots had decreased contents of most sugars and sugar acids. A significant increase in several fatty acids (C16:1, linoleic and linolenic acids and the C20 arachidonic and eicosapentaenoic acids) was also detected. However, a downregulation of the JA biosynthesis pathway was evidenced. We also found strong induction of the expression of PR proteins from the proteinase inhibitor (PR6) and subtilase (PR7) families in roots, suggesting that these proteins are involved in the mycorrhiza development but could also confer higher resistance to root pathogens. Metabolic changes induced by mycorrhization were less marked in leaves but involved higher levels of linoleic and linolenic acids and decreased sucrose, quinic, and shikimic acid contents. In addition, Ri colonization resulted in enhanced JA and SA levels in leaves. Overall, this study provides a detailed picture of metabolic changes induced by AMF colonization in a woody, economically important species. Moreover, stimulation of fatty acid biosynthesis and PR protein expression in roots and enhanced defense hormone contents in leaves establish first insight in favor of better resistance of grapevine to various pathogens provided by AMF colonization.

Direct metal-free near infra-red photoredox catalysis is applied to organic oxidation, photosensitization and reduction, involving cyanines as photocatalysts. This photocatalyst is competitive with conventional reactions catalyzed under visible light. Kinetic and quenching experiments are also reported. Interestingly, these systems are compatible with water media, opening perspective for various applications.

Grapevine trunk diseases: Eutypa dieback, esca and Botryosphaeria dieback, which incidence has increased recently, are associated with several symptoms finally leading to the plant death. In the absence of efficient treatments, these diseases are a major problem for the viticulture; however, the factors involved in disease progression are not still fully identified. In order to get a better understanding of Botryosphaeria dieback development in grapevine, we have investigated different factors involved in Botryosphaeriaceae fungi aggressiveness. We first evaluated the activity of the wood-degrading enzymes of different isolates of Neofusicoccum parvum and Diplodia seriata, two major fungi associated with Botryosphaeria dieback. We further examinated the ability of these fungi to metabolize major grapevine phytoalexins: resveratrol and δ-viniferin. Our results demonstrate that Botryosphaeriaceae were characterized by differential wood decay enzymatic activities and have the capacity to rapidly degrade stilbenes. N. parvum is able to degrade parietal polysaccharides, whereas D. seriata has a better capacity to degrade lignin. Growth of both fungi exhibited a low sensitivity to resveratrol, whereas δ-viniferin has a fungistatic effect, especially on N. parvum Bourgogne S-116. We further show that Botryosphaeriaceae are able to metabolize rapidly resveratrol and δ-viniferin. The best stilbene metabolizing activity was measured for D. seriata. In conclusion, the different Botryosphaeriaceae isolates are characterized by a specific aggressiveness repertory. Wood and phenolic compound decay enzymatic activities could enable Botryosphaeriaceae to bypass chemical and physical barriers of the grapevine plant. The specific signature of Botryosphaeriaceae aggressiveness factors could explain the importance of fungi complexes in synergistic activity in order to fully colonize the host.

Sugar transport and partitioning play key roles in the regulation of plant development and responses to biotic and abiotic factors. During plant/pathogen interactions, there is a competition for sugar that is controlled by membrane transporters and their regulation is decisive for the outcome of the interaction. SWEET proteins are a class of sugar transporters playing important roles in the first step in phloem loading, in nectar production as well as in seed and pollen development. SWEET transporters are the targets of extracellular pathogens, which modify their expression to acquire the sugars necessary to their growth (Chen et al., 2010). Grapevine (Vitis vinifera) is an economically important crop that is susceptible to diverse pathogens. The regulation of carbon allocation and sugar partitioning in the interaction between grapevine and its pathogens is poorly understood. We previously characterized the SWEET family in V. vinifera and showed that SWEET4 could be involved in resistance to the necrotrophic fungus B. cinerea in Arabidopsis (Chong et al., 2014). To study the role of VvSWEET4 in grapevine, we produced Vitis vinifera cv. Syrah hairy roots overexpressing VvSWEET4 under the control of the CaMV 35S promoter (VvSWEET4OX). High levels of VvSWEET4 expression in hairy roots resulted in enhanced growth on media containing glucose or sucrose and increased contents in glucose and fructose. Sugar uptake assays further showed an improved glucose absorption in VvSWEET4 overexpressors. In parallel, we observed that VvSWEET4 expression was significantly induced after infection of wild type grapevine hairy roots with Pythium irregulare, a soilborne necrotrophic pathogen. Importantly, grapevine hairy roots overexpressing VvSWEET4 exhibited an improved resistance level to P. irregulare infection. This resistance phenotype was correlated to higher glucose pools in roots after infection, higher constitutive expression of several genes involved in flavonoid biosynthesis, and higher flavanol contents. We propose that high sugar levels in VvSWEET4OX hairy roots provides a better support to the increased energy demand during pathogen infection. In addition, high sugar levels promote biosynthesis of flavonoids with antifungal properties. Overall, this work highlights the key role of sugar transport mediated by SWEET transporters for secondary metabolism regulation and pathogen resistance in grapevine.

Abstract Hybrid sol–gel films were prepared via a simultaneous organic‐inorganic UV‐curing process using a diaryliodonium salt as a superacid photogenerator. In this single‐step procedure, an epoxy functionalized reactive resin mixed with a variable amount of either of two epoxy trialkoxysilane precursors was UV‐irradiated, causing both the initiation of epoxy ring‐opening copolymerization and the catalysis of trialkoxysilyl sol–gel reactions. The concomitant photo‐induced sol–gel process was found to have a significant effect on the two related propagation mechanisms in competition for the oxirane ring‐opening—the active chain‐end and the activated monomer mechanisms—as proved by a systematic examination of the hybrid material microstructure through 29 Si and 13 C solid‐state NMR spectroscopy. The effect of the oxo‐silica network generation on the epoxy reaction kinetics was also evaluated using real‐time Fourier transform infrared spectroscopy upon varying the epoxysilane structure and its concentration. Thermal and dynamic mechanical analyses were systematically performed on these hybrids, by studying thoroughly their structure–property interdependence. Other mechanical characterizations through tribological and scratch tests suggested that the present photopolymer–silica hybrid material provides a powerful tool to tailor mechanical property profiles. Copyright © 2010 Society of Chemical Industry

Neglected parasitic diseases remain a major public health issue worldwide, especially in tropical and subtropical areas. Human parasite diversity is very large, ranging from protozoa to worms. In most cases, more effective and new drugs are urgently needed. Previous studies indicated that the gold(I) drug auranofin (Ridaura®) is effective against several parasites. Among new gold(I) complexes, the phosphole-containing gold(I) complex {1-phenyl-2,5-di(2-pyridyl)phosphole}AuCl (abbreviated as GoPI) is an irreversible inhibitor of both purified human glutathione and thioredoxin reductases. GoPI-sugar is a novel 1-thio-β-d-glucopyranose 2,3,4,6-tetraacetato-S-derivative that is a chimera of the structures of GoPI and auranofin, designed to improve stability and bioavailability of GoPI. These metal-ligand complexes are of particular interest because of their combined abilities to irreversibly target the essential dithiol/selenol catalytic pair of selenium-dependent thioredoxin reductase activity, and to kill cells from breast and brain tumors. In this work, screening of various parasites—protozoans, trematodes, and nematodes—was undertaken to determine the in vitro killing activity of GoPI-sugar compared to auranofin. GoPI-sugar was found to efficiently kill intramacrophagic Leishmania donovani amastigotes and adult filarial and trematode worms.

The transformation of light into chemical energy is a leitmotiv in the development of sustainable and environmentally concerned chemical processes. Chemists invented original concepts to address this purpose, like photoredox catalysis, which became a wonderful tool to transform simple organic compounds into high‐value products. Nevertheless, the most relevant transition metal based photocatalysts suffer from major disadvantages like toxicity, cost, and poor recyclability potential. To circumvent this, we propose a new generation of heterogeneous photoredox catalysts resulting from the combination of porous silica materials and Rose Bengal. They promote carbon–carbon bond formations under visible‐light in environmentally benign solvent using air as the only stoichiometric redox partner. The pure covalent photocatalytic system provides a robust and recyclable system for greener catalysis. This report would be of broad significance because it addresses important sustainability issues: recycling, non‐toxic metal‐free photocatalysts, and less‐waste‐producing chemical process.

Abstract Atropisomeric molecules are privileged scaffolds, not only as ligands for asymmetric synthesis, but also as biologically active products and advanced materials. Although very attractive from a sustainability viewpoint, the direct construction of the stereogenic axis through asymmetric C–H arylation is very challenging and consequently only a few examples have been reported. This short review summarizes these very recent results on the atropo-enantio or diastereo­selective synthesis of atropisomeric (hetero)biaryl molecules; transformations during which the Ar–Ar atropisomeric axis is formed during the C–H activation process. 1 Introduction 2 Atropo-enantioselective Intermolecular Pd-Catalyzed C–H Arylation of Thiophene Derivatives 3 Atropodiastereoselective Intermolecular Pd-Catalyzed C–H Arylation towards Terphenyl Scaffolds Bearing Two Atropisomeric Axes 4 Atropo-enantioselective Intramolecular Pd-Catalyzed C–H Arylation towards Atropisomeric Benzodiazepinones 5 Atropo-enantioselective Intermolecular Pd-Catalyzed C–H Arylation of Heteroarenes 6 Rh-Catalyzed Atropo-enantioselective C–H Arylation of Diazonaphthoquinones 7 Conclusion

BACKGROUND: Selenium (Se) is a trace element active in selenoproteins, which can regulate oxidative stress. It is generally perceived as an import factor for maintaining health in the elderly. METHODS: The goal of this review is to discuss selenium concentration in biological samples, primarily serum or plasma, as a function of age and its relation with longevity. The elemental level in various age-related diseases is reviewed. CONCLUSION: Highest selenium values were observed in healthy adults, while in an elderly population significantly lower concentrations were reported. Variables responsible for contradictory findings are mentioned. Risk and benefits of Se-supplementation still remain under debate.

The efficient synthesis of sterically demanding tetra-substituted biaryls by means of a one-pot threestep low-temperature modification of the classical Ullmann reaction is reported. The major benefit of this methodology lies in the ready synthesis of polybrominated biaryls, which can be subsequently functionalized into various target molecules by means of regioselective halogen/metal permutations. Keywords: Ullmann reaction, C-C coupling, aryllithium, copper