Formation of 2,5-trans-tetrahydrofuran-3-one application towards the synthesis of natural products

The tetrahydrofuran backbone is one of the most common heterocyclic units found in natural products. Among them structurally complex substituted tetrahydrofuran rings which present a 2,5-trans stereochemistry have been of particular interest to many groups as polyether antibiotics and highly biologically active compounds, such as the potent anti cancer Amphidinolide, possess this kind of backbone. Different methodologies to synthesise this kind of structure have been developped starting in the late 70’s. The first efficient methodology was published by Fukuyama in Tetrahedron Letters in 1978. It involves the stereospecific epoxidation of bishomoallylic alcohol using VO(acac)2. Treatment of the epoxide with acetic acid led to the desired 2,5-trans-tetrahydrofuran in up to 20:1 ratio. In 1990, Inoki developed an efficient method for the synthesis of trans-tetrahydrofurans. Using this methodology, 5-hydroxy-1-alkenes can be converted to the desired cyclisation product via oxidative cyclisation with molecular oxygen using cobalt complex as a catalyst. The 5-hydroxy-1-alkene react with the Co complex and the oxygen. The radical complex thus formed could be converted to the cyclised intermediate. The cyclisation occurs in reasonable yields (up to 79 %) and exellent trans selectivity (99 %). More recently Panek published a methodology involving the chelation controlled formation of trans tetrahydrofuran. A Lewis acid such as SnCl4 is able to form chelate with a α-benzyloxy group of an aldehyde. This activated intermediate can then undergo the electrophilic substitution. This method led to the trans cyclisation product in up to 40:1 ratio. In order to increase the level of diastereocontrol our group have investigated a methodology based on an intramolecular tandem carbenoid insertion and ylide rearrangement reaction of a diazoketone. This diazoketone undergoes a nucleophilic attack onto an empty d orbital of the transition metal. The transition metal back donates the electrons of one of its d orbital to the carbon to form the metal carbenoid with elimination of nitrogen. Attack of one of the lone pair of the oxygen onto the carbon bonded to the 3 transition metal led to the formation of the oxonium ylide which undergoes [2,3]-sigmatropic rearrangement. Previous studies made within the group have proved Cu(acac)2 to be the best catalyst for the synthesis of the trans-2,5-dialkyl tetrahydrofuran-3-ones. The stereochemistry observed could be explained by the stereochemistry of the substituent R1. The transition state shows clearly that the trans- rearrangement product is favoured. We have decided to apply this methodology to the synthesis of the (6S, 7S, 9S, 10S)-6,9-epoxynonadec-18-ene-7,10-diol. and the functionalised A-ring fragment of gambieric acid

How the experimental knowledge of the irreversible fouling distribution can contribute to understand the fluid circulation in a spiral ultrafiltration membrane.

International audienceIt is commonly thought that in a spiral membrane the fouling is high at the module inlet and progressively decreases toward the outlet. Thanks to an exptl. mapping of the irreversible fouling existing in a spiral membrane of 6.5 m2 area, this paper shows that it is not systematically true and that the fouling distribution can be much more complex. This paper shows also in what extent the mapping of the irreversible fouling existing in a spiral membrane is a powerful approach to deal with the role of the velocity/turbulences gradient that can be exptl. studied independently of the transmembrane pressure gradient in appropriate filtering conditions. The fouling distribution suggests that the velocity/turbulences are roughly const. on 50% of the membrane area located in its center when dealing with a radial dimension, whereas part of this mean position, velocity/turbulences can increase or decrease. [on SciFinder(R)

Interactions of SUMO proteins

A large number of proteins have shown ability to bind to SUMO (Small Ubiquitin like Modifier) proteins through a short conserved motif called SIM (SUMO Interacting Motif). The work presented here shows that the different SUMO isoforms interact with the hydrophobic core of the SIM by forming an intermolecular b-sheet with the b2 strand of SUMO. This interaction is crucial for SUMO binding, and is modulated by interactions between SUMO and the amino acids flanking the core of the SIM. The SIM can be phosphorylated, providing a possibility for regulating the strength of SUMO binding in the lifetime of a protein. Furthermore, a concentration threshold effect is observed in the binding of the unphosphorylated SIM of PIAS (Protein inhibitor of activated STAT) to SUMO. The dependency on the amino acids flanking the hydrophobic core is stronger in binding to SUMO1 than to SUMO2, providing a mechanism for SUMO isoform discrimination

Le jeu de rôle en classe d'histoire

Role play is a pedagogical practice developed by some teachers, especially history and geography teachers. For this essay, a role play has been tested in a 1ère ES class, in order to analyze how this type of exercise helped pupils to learn new things. It was the role play Cuba 1962, simulating the Cuban crisis during the Cold War and the opposition between historical figures, who were interpreted by pupils. As pupils-actors, they had to take decisions mainly during the negotiations to resolve the Cuban crisis, and so, understand that men of the past were actors. These decisions determined the future of the characters they were performing. Thus, they were able to understand that men of the past had an unpredictable futur. This role play could simulate a different history and raise the realm of possibles, which could have happened in October 1962. Comparing after the game, their result and historical reality, pupils could observe the uncertainty of this past event, dependent on men's action.Le jeu de rôle est une pratique pédagogique développée par certains enseignants, notamment d'histoire-géographie. Pour ce mémoire, un jeu de rôle a donc été expérimenté en classe de 1ère ES afin d'analyser les apprentissages permis par cette pratique. Il s'agit du jeu de rôle Cuba 1962, simulant la crise de Cuba pendant la guerre froide, opposant des acteurs du conflit, interprétés par les élèves. En tant qu'élèves-acteurs, ils ont dû prendre des décisions pour résoudre la crise de Cuba, notamment pendant les négociations, et ainsi comprendre que les hommes du passé étaient des acteurs. Ces décisions déterminaient le futur des personnages qu'ils interprétaient. Ainsi, ils ont pu comprendre que ces hommes du passé avaient un futur incertain. Ce jeu a pu simuler une histoire différente et soulever un large champ des possibles, qui auraient pu advenir en octobre 1962. En comparant après le jeu, leur résultat avec la réalité historique, les élèves ont pu constater l'incertitude de cet événement du passé, dépendant de l'action des hommes

Huge excitonic effects in layered hexagonal boron nitride

The calculated quasiparticle band structure of bulk hexagonal boron nitride using the all-electron GW approximation shows that this compound is an indirect-band-gap semiconductor. The solution of the Bethe-Salpeter equation for the electron-hole two-particle Green function has been used to compute its optical spectra and the results are found in excellent agreement with available experimental data. A detailed analysis is made for the excitonic structures within the band gap and found that the excitons belong to the Frenkel class and are tightly confined within the layers. The calculated exciton binding energy is much larger than that obtained by Watanabe {\it et al} using a Wannier model to interpret their experimental results and assuming that h-BN is a direct-band-gap semiconductor.Comment: 4 pages, 3 figure

Les opioïdes : un verrou à la régénération chez le mammifère adulte ? Dialogue avec le système immunitaire et l'innervation sensorielle

L'étude des processus de réparation tissulaire constitue, de nos jours, un axe majeur de recherche dans le domaine biomédical. En effet, la capacité d'un tissu à régénérer après une lésion a été progressivement perdue au cours de l'évolution, laissant place au développement d'un tissu fibrotique associé à une perte de fonction, aussi appelé cicatrisation. L'étude de la régénération chez les espèces encore dotées de cette capacité, comme chez l'hydre, le poisson zèbre ou encore la salamandre, a permis de mettre en évidence le rôle substantiel du système immunitaire et de l'innervation. En revanche, la nature du verrou mis en place au cours de l'évolution, empêchant la régénération d'avoir lieu chez le mammifère reste très peu documentée. Des résultats publiés précédemment par mon laboratoire montrent qu'il est possible de déclencher les processus de régénération chez une souris C57BL/6 qui n'en n'est pas capable spontanément, grâce à l'administration d'un antagoniste des récepteurs aux opioïdes, la Naloxone Méthiodide. Les opioïdes exogènes comme la Morphine, en plus des opioïdes sécrétés de façon endogène après une lésion, sont utilisés depuis très longtemps pour prendre en charge la douleur péri-opératoire. Par ailleurs, les opioïdes sont décrits comme étant i) de puissants immunosuppresseurs et ii) capables d'agir sur les fibres sensorielles à l'origine de la perception douloureuse, en inhibant l'activité de ces dernières. Lors de ma thèse nous avons donc proposé que les opioïdes puissent constituer un verrou au processus de régénération chez les mammifères en empêchant la mise en place d'une réponse inflammatoire adéquate et/ou l'activation efficace des fibres sensorielles suite à une lésion. D'une part, nos résultats montrent, i) que la signature cellulaire (neutrophiles, monocytes, macrophages) et moléculaire (cytokines, chémiokines et médiateurs lipidiques) des phases précoces de l'inflammation post-lésionnelle permet de prédire l'issue de la réparation tissulaire (i.e cicatrisation versus régénération),ii) que les neutrophiles sont la source cellulaire d'espèces actives de l'oxygène (EAOs) requises pour permettre la régénération et iii) que les macrophages dérivés de l'hématopoïèse endogène du tissu adipeux sous cutané permettent au tissu de régénérer grâce à leur haut potentiel d'élimination des neutrophiles (aussi appelé efférocytose), contrairement aux macrophages d'origine médullaire qui, eux, favorisent la mise en place d'une cicatrice. D'autre part, nous montrons grâce à l'utilisation i) du test comportemental Von Frey classiquement utilisé dans le domaine de la douleur et ii) d'un outil développé au laboratoire basé sur la mesure de la pupille, que la régénération induite après un traitement à la Naloxone Méthiodide est associée à une perception douloureuse significativement augmentée. La douleur pouvant être un reflet de l'activation des fibres sensorielles, nous avons donc spécifiquement détruit ces dernières. Cette dénervation des fibres sensorielles inhibe la régénération induite après un traitement à la Naloxone Méthiodide. Enfin, les fibres sensorielles semblent être indispensables en raison de leur sécrétion locale du neuropeptide CGRP, qui contrôlerait i) la mise en place de la réponse inflammatoire requise à la régénération et ii) le remodelage tissulaire en activant la migration des cellules mésenchymateuses vers le site de lésion. L'ensemble de ces résultats nous permet aujourd'hui de proposer comme traitement péri-opératoire/post-lésionnel, la co-administration de Morphine et de CGRP, permettant ainsi à la régénération tissulaire d'avoir lieu tout en gérant la douleur, chez le mammifère adulte.Inhibition of regeneration mechanisms and induction of tissue fibrosis are classic outcomes of tissue repair in adult mammals. Because fibrosis leads to loss of tissue function, studying the processes of tissue repair remains a major issue in regenerative medicine. Studying regeneration in species with this ability, such as hydra, planarian, zebrafish or salamander, has highlighted the substantial role of immune system and innervation during regeneration processes. The nature of the locks developed during the evolution that prevent regeneration in mammals remains poorly documented. Previously published results from my laboratory showed that administration of an opioid receptor antagonist, also called Naloxone Methiodide, can induce tissue regeneration in a non-regenerative strain of mice (C57Bl/6). Exogenous opioids such as morphine, in addition to those being endogenously secreted after injury, have been used for decades in the management of perioperative pain. Opioids are also described as i) potent immunosuppressors and ii) able to act on the sensory fibers to silence electrical activity of these fibers. During my thesis, we hypothesized that opioids could be a lock for regeneration processes by preventing an acute and intense inflammatory response and/or the activation of sensory fibers after injury. On one hand, our results demonstrate for the first time in mice, i) that the cellular (neutrophils, monocytes, macrophages) and molecular (cytokines, chemokines and lipid mediators) signature of the early phases of post-lesional inflammation can predict the outcome of tissue repair (i.e scar healing versus regeneration), ii) granulocytes are the cellular source of reactive oxygen species required for regeneration, and iii) that, unlike classical macrophages derived from medullar hematopoiesis which promote scar formation after injury, macrophages derived from endogenous hematopoiesis of subcutaneous adipose tissue allow tissue regeneration thanks to their high neutrophil clearance potential after Naloxone methiodide treatment. On the other hand, by using the behavioral Von Frey test and the measurement of pupil diameter in order to assess pain perception, we also show that the regeneration induced after Naloxone Methiodide treatment is strongly correlated with an increase in pain perception. As pain depend on harmful signals detection by sensory fibers, we specifically destroyed these peripheral neurons. This denervation leads to the inhibition of previously induced tissue regeneration. Moreover, these sensory fibers appear to act through their peripheral secretion of the CGRP neuropeptide. This molecule could control the establishment of adequate inflammatory response and initiate efficient tissue remodeling by activating mesenchymal cells migration to the injured area. Altogether, our results allow us to propose co-administration of Morphine with CGRP as a perioperative/post-lesional treatment allowing tissue regeneration and pain management

Evidencing the chemical degradation of a hydrophilized pes ultrafiltration membrane despite protein fouling

International audienceHydrophilisation of polyethersulfone (PES) based membrane is often achieved by addition of polyvinylpyrrolidone (PVP) leading to a physical blend of the two polymers. This paper shows that the most commonly used membrane for UF in dairy industry is a PES/PVP based one. Nevertheless if hydrophilisation limits the organic fouling, PVP is also the Achilles heel of these membranes. It is particularly true when membranes are exposed to hypochlorite as it is the case for cleaning/disinfection steps. Evidencing the disappearance of PVP from a pristine PES/PVP membrane can be easily achieved by FTIR-ATR analyses. But when one wants to study the ageing of a membrane used in UF it gets more complicated: regardless of the cleaning efficiency the membrane always remains fouled by some proteins. As both PVP and proteins own chemical bounds leading to absorption at the same wavenumber in FTIR-ATR, it thereby prevents the easy highlighting of the PVP degradation. The aim of this paper is to propose a simple treatment of raw FTIR-ATR spectra to dissociate these two contributions, allowing consequently the study of the degradation of a fouled membrane. Then the procedure is applied to a real case study on a spiral membrane

Comparison of two nanofiltration membrane reactors for a model reaction of olefin metathesis achieved in toluene

International audienceThe recent commercialisation of nanofiltration membranes resistant toward organic solvents is a real opportunity for fine chemistry. This study deals with different ways of integration of organic solvent nanofiltration for a specific type of reactions known as olefin metathesis and shows the use of two nanofiltration membrane reactors both running in cross-flow filtration mode (0.1 m s- 1). They are used either in semi-continuous or continuous mode. A model ring closing metathesis reaction is chosen for the demonstration. A commercially available pre-catalyst, namely Grubbs-Hoveyda II, as well as a commercial polyimide membrane (Starmem 122, MWCO 220 g mol- 1) are used. Firstly, nanofiltration of the single pre-catalyst allows establishing that the highest retention is obtained with a 40 bar pressure. Secondly, this pressure is used with the two membrane reactors before testing other conditions. Finally, interests and limitations of the two reactors are discussed

Exploration des difficultés dans la prise de traitements au long cours chez le patient transplanté rénal (comment le rendre acteur de sa santé)

Le patient transplanté rénal, atteint ou non d autres maladies chroniques, est amené à prendre, tout au long de sa vie, des traitements lourds et contraignants dans le but d assurer la survie de son greffon. Aussi, la prise de traitements au long cours peut soumettre le malade à rencontrer certaines difficultés, notamment dans la prise des médicaments immunosuppresseurs. Dans le but de recueillir ces problématiques, quatorze entretiens ont été réalisés avec des patients greffés rénaux dans le service de Néphrologie-Dialyse-Transplantation au CHU d Angers au cours de l année 2012. L analyse de ces entretiens a permis de faire émerger des besoins de connaissances émanant à la fois des patients et des prescripteurs mais aussi des besoins de réévaluation des prescriptions médicales. Des besoins d ordres organisationnels, sociaux et émotionnels ont également été notés. Ce travail permet de réfléchir sur les moyens à mettre en place à l hôpital mais aussi dans les pharmacies d officine afin d aider le patient à être acteur de sa santé. Il en résulte également que l éducation thérapeutique du patient tient une place éminente dans la prise en charge de celui-ci.Renal transplant patient, achieved or not other chronic diseases, is required to take, throughout his life, heavy treatments and binding in order to ensure the survival of the graft. Also, taking long-term treatments may refer the patient to meet some difficulties, particularly in taking immunosuppressive drugs.In order to raise these issues, fourteen interviews were conducted with renal transplant patients in the Nephrology-Dialysis-Transplantation service in the University Hospital of Angers during 2012. The analysis of these interviews led to the emergence of knowledge needs from both patients and prescribers but also needs reassessment of medical prescriptions. Orders organizational needs, social and emotional were also noted. This work allows us to reflect on how to set up the hospital but also in community pharmacies to help the patient to be an actor of his health. It also follows that therapeutic patient education plays an eminent support of the latter.ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Numerical computation of critical properties and atomic basins from three-dimensional grid electron densities

Claudine Katan ‘s present address : CNRS UMR6082 FOTON, INSA de Rennes, 20 avenue des Buttes de Coësmes, CS 70839, 35708 RENNES cedex 7, FranceInternational audienceInteGriTy is a software package that performs topological analysis following the AIM (atoms in molecules) approach on electron densities given on three-dimensional grids. Tricubic interpolation is used to obtain the density, its gradient and the Hessian matrix at any required position. Critical points and integrated atomic properties have been derived from theoretical densities calculated for the compounds NaCl and TTF-(2,5)Cl(2)BQ (tetrathiafulvalene-2,5-dichlorobenzoquinone), thus covering the different kinds of chemical bonds: ionic, covalent, hydrogen bonds and other intermolecular contacts