Dérivés phosphoniques polycycliques : synthèse et étude d’interactions supramoléculaires

This PhD work makes part of the « Action de Recherche Concertée » program (ARC number 08/13-009) which consists of organic or inorganic guest molecules insertion in a known polymer matrix endowed with pH-responsible properties, and the study of the non covalent interactions occurring between the guest molecules and the polymer matrix. Two complementary axes have been developed in order to answer to these problematics: the synthesis and characterization of phosphonated products on the one hand, and the preparation and the study of “guest / host” materials on the other hand. In a first time, it was necessary to have access to small water-soluble molecules (or molecules soluble in polar solvents) for compatibility with the host matrix in order to prepare “host / guest” materials. New phosphonated products were obtained by a methodology based on the Diels-Alder (DA) reaction using diethyl 1-phosphono-1,3-butadiene. The limits of reactivity of this diene in the Diels-Alder reaction have been highlighted. We were particularly interested in cycloadducts obtained by DA reaction between diethyl 1-phosphono-1,3-butadiene and N-fonctionnalized maleimides as dienophiles, giving access to cycloadducts featuring a « half-cage » particular shape. These molecules revealed to behave as excellent ligands of di- and trivalent cations (thank to a HRMS-ESI study). Many synthetic assays did not allow the preparation of 2-phosphonated diene, but a methodology based on the Horner-Wadsworth-Emmons reaction gave access to 1-phosphonated 3(4-di)-alkylsubstituted dienes, which were tested in Diels-Alder reaction with 3 representative dienophiles. Original bi- and tricyclic molecules were prepared using this method. Reactions sequences, such as Diels-Alder cycloaddition / first functionalization / second functionalization, gave access to linear or cyclic phosphonated multifunctionalized molecules. A particular attention was paid to the dialkylphosphonate deprotection to phosphonic acid function. Indeed, molecules with dialkyl phosphonate or phosphonic acid groups are used in multiple application domains, such as medicinal chemistry, agrochemistry, materials and polymers chemistry. In a second part, phosphonated synthetic products were selected as guest molecules of the host polymer matrix. A detailed study was realised about Eu(III) coordination complexes with ligands featuring a phosphonic ester function, their insertions into the host polymer matrix giving access to hybrids materials. The non covalent interactions between guest molecules and the host polymer matrix were evidenced using various analytical methods, such as X ray diffraction, infrared spectroscopy, 31P NMR and photoluminescence. Furthermore, the insertion of a phosphonated molecule bearing a pyrene fluorophore group revealed particularly interesting: this molecule could be a probe equipped with an anchorage function (PO(OEt)2) targeting the hydrophilic zones or metallic cations, and a pyrene motif able to give information about the pyrene environment polarity, near the anchorage group, thanks to the analysis of emission spectra.Ce travail de thèse s’inscrit au sein du projet Action de Recherche Concertée (ARC n° 08/13-009) qui consiste en l’insertion d’espèces invitées (organiques ou inorganiques) dans une matrice polymère hôte déjà connue, possédant des propriétés particulières modulables avec le pH, ainsi que l’étude des interactions non covalentes entre les espèces invitées et la matrice hôte. Dans ce cadre, deux axes complémentaires ont été développés: la synthèse et la caractérisation de produits phosphonés d’une part et la préparation et l’étude de matériaux de type « hôte / invité » d’autre part. Dans un premier temps, il a été nécessaire d’avoir accès à des molécules organiques de petite taille, hydrosolubles ou solubles dans des solvants polaires pour être compatibles avec la matrice polymère hôte lors de la préparation de matériaux de type « hôte / invité ». Dans ce but, nous avons mis au point la synthèse de nouveaux produits phosphonés par une méthodologie basée sur la réaction de Diels-Alder (DA) avec un diène phosphoné en position 1. Les limites de réactivité de ce diène dans la réaction de Diels-Alder ont été mises en évidence. Nous nous sommes particulièrement intéressés aux cycloadduits obtenus par la réaction de DA entre le 1-phosphono-1,3-butadiène de diéthyle et une série de diénophiles de type maléimides N-fonctionnalisés permettant l’accès à des cycloadduits possédant une forme particulière de « demi-cage ». Ces molécules se sont révélées (grâce à une étude HRMS en mode ESI) être d’excellents ligands de cations di- et trivalents. De nombreux essais de synthèse n’ont pas permis l’obtention du diène phosphoné en position 2, mais une méthodologie de synthèse basée sur la réaction d’Horner-Wadsworth-Emmons a été ensuite utilisée pour accéder aux diènes 1-phosphonés 3(4-di)-substitués par un (ou des) groupement(s) alkyle(s). Ces diènes ont été testés dans la réaction de Diels-Alder avec trois diénophiles représentatifs. Des structures bi- et tricycliques originales ont été obtenues. De plus des séquences réactionnelles: réaction de Diels-Alder / fonctionnalisation 1 / fonctionnalisation 2 ont permis d’accéder à des molécules phosphonées linéaires ou cycliques multifonctionnalisées. Une attention particulière a été donnée à la déprotection du motif phosphonate de dialkyle en acide phosphonique; en effet les molécules comportant un groupement acide phosphonique sont utilisées dans divers domaines d’application tels que la chimie médicinale, l’agrochimie ou encore la chimie des matériaux et des polymères. Dans une seconde partie, quelques produits phosphonés synthétisés ont été sélectionnés comme espèces invitées au sein de la matrice polymère hôte. Une étude approfondie a été réalisée pour des complexes d’Eu(III) comportant des ligands possédant une fonction ester phosphonique, leur insertion dans la matrice polymère hôte donnant accès à des matériaux hybrides. Les interactions non covalentes entre l’espèce invitée et la matrice hôte ont été mises en évidence à l’aide de diverses méthodes analytiques telles que la diffraction des rayons X, la spectroscopie infrarouge, la RMN du 31P ou encore la photoluminescence. De plus, l’insertion d’une molécule phosphonée substituée par un groupement fluorophore (pyrène) s’est révélée être particulièrement intéressante: cette molécule pourrait servir de sonde ciblant les zones hydrophiles ou les cations métalliques par sa fonction d’ancrage (PO(OEt)2) et permettant de déterminer la polarité de l’environnement du motif pyrène à proximité du point d’ancrage par l’analyse des spectres d’émission.(CHIM 3) -- UCL, 201

Cycloaddition/aromatization sequence for the synthesis of 2,3-disubstituted benzenephosphonates

The [4+2] cycloaddition of diethyl 1-phosphonobuta-1,3-diene with tetracyanoethylene, (E)-1,4-diphenylbut-2-ene-1,4-dione, N-phenylmaleimide, and dialkyl acetylenedicarboxylates is described. For the last two cases, treatment of the cycloadducts with nitrobenzene and a palladium catalyst allows the aromatization. Selective deprotections lead to phthalimide/phthalate derivatives with an ortho-phosphonic acid function. © Georg Thieme Verlag Stuttgart · New York

Europium (III) coordination complex with a novel phosphonated ligand

An original Eu(III) complex with a phosphonated half-cage ligand (CCNPh) was synthesized and characterized. Coordination between Eu(III) and the selected ligand was investigated by FT-IR, 1H, 13C and 31P NMR spectroscopies. The stoichiometry of the Eu(III) complex in acetonitrile was determined by titrations using 1H, 31P NMR and photoluminescence. The 1M:2L stoichiometry, i.e. two CCNPh ligands for one Eu(III), has been measured. In contrast, the 1M:3L stoichiometry occurred in the solid state, from the elemental analysis. This particular behavior may be explained by the addition of a third CCNPh ligand to Eu(III) metallic core during the treatment and evaporation process for the obtention of the solid sample. An antenna effect has been observed consisting in the energy transfer from N-Ph (λexc = 276 nm) to Eu(III) (λem = 618 nm). © 2012 Elsevier B.V. All rights reserved

Phosphonated bicycles bearing a N-N junction

The Diels-Alder reaction between diethyl 1-phosphono-1,3-butadiene and cyclic azo dienophiles, such as 4-phenyl- and 4-methyl-1,2,4-triazoline-3,5- diones and phthalazine-1,4-dione gave access to phosphonated bicyclic cycloadducts bearing a N-N junction. Various functionalizations (dihydroxylation, hydrogenation and phosphonic ester deprotection) have been performed with success. The selective N-N cleavage was not possible for the preparation of large heterocycles. The coordination properties of selected bicycles were tested by ESI-HRMS. © 2013 The Japan Institute of Heterocyclic Chemistry

Functionalized Phosphonated Half-Cage Molecules as Ligands for Metal Complexes

Phosphonated molecules, featuring a half-cage structure and a N-lateral chain with additional metal coordinating groups were designed as ligands of metal cations. These compounds were synthesized by a Diels-Alder (DA) strategy, using 1-diethoxyphosphoryl-1,3-butadiene and a series of N-substituted maleimides as dienophiles. Two cycloadducts, bearing a terminal primary alcohol and a terminal iodide, respectively, were used as key intermediates for further functionalizations. Metal coordination properties of the ligands equipped with functionalized N-lateral chains were proven by an ESI-HRMS study. The stoichiometry of one selected Eu III complex with a diphosphonated ligand was determined by photoluminescence spectroscopy in emission mod

Polymer encapsulation of ruthenium complexes for biological and medicinal applications

International audienceSome Ru complexes have extremely promising anticancer or antibacterial properties, but the poor H2O solubility and/or low stability of many Ru complexes in aqueous solution under physiological conditions and/or metabolic or biodistribution profiles prevent their therapeutic use. To overcome these drawbacks, various strategies have been developed to improve the delivery of these compounds to their target tissues. The first strategy is based on physical encapsulation of Ru complexes in carriers, such as polymeric micelles, microparticles, nanoparticles and polymer–lipid hybrids, which enables the delivery and controlled release of the active Ru drug candidate. The second strategy involves covalent conjugation of the Ru complex to a polymer to give a prodrug that can be converted into the active drug at a more controllable rate. In this Review, we provide an overview of recent developments in polymer encapsulation of Ru complexes for biological and medicinal applications. We place particular emphasis on how polymer structure affects Ru delivery

A Pyrene- and Phosphonate-Containing Fluorescent Probe as Guest Molecule in a Host Polymer Matrix

New host-guest materials have been prepared by incorporation of a home-made organic probe displaying a pyrene motif and a phosphonate function into a regular amphiphilic copolymer. Using powder X-Ray diffraction, photoluminescence and FT-IR spectroscopy, we have been able to study the non-covalent interactions between the host matrix and the guest molecule in the solid state. Interestingly, we have shown that the matrix directs the guest spatial localization and alters its properties. Thanks to the comparison of pyrene vs. N-pyrenylmaleimide derivatives, the influence of the chemical nature of the guest molecules on the non-covalent interactions with the host have been studied. In addition, using polyethylene glycol as a reference host, we have been able to evidence a true matrix effect within our new insertion materials. The phosphonated guest molecule appears to be a novel probe targeting the hydrophilic domain of the host copolymer

Polymer encapsulation of ruthenium complexes for biological and medicinal applications

International audienceSome Ru complexes have extremely promising anticancer or antibacterial properties, but the poor H2O solubility and/or low stability of many Ru complexes in aqueous solution under physiological conditions and/or metabolic or biodistribution profiles prevent their therapeutic use. To overcome these drawbacks, various strategies have been developed to improve the delivery of these compounds to their target tissues. The first strategy is based on physical encapsulation of Ru complexes in carriers, such as polymeric micelles, microparticles, nanoparticles and polymer–lipid hybrids, which enables the delivery and controlled release of the active Ru drug candidate. The second strategy involves covalent conjugation of the Ru complex to a polymer to give a prodrug that can be converted into the active drug at a more controllable rate. In this Review, we provide an overview of recent developments in polymer encapsulation of Ru complexes for biological and medicinal applications. We place particular emphasis on how polymer structure affects Ru delivery

Hetero Diels-Alder (HDA) reactions of 1-phosphono-1,3-butadienes with azo and nitroso dienophiles : an entry towards versatile heterocyclic synthons for aminophosphonic compounds

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Co-catalytic oxidative coupling of primary amines to imines using an organic nanotube-gold nanohybrid

International audienceA novel nanohybrid structure was synthesized by assembling gold nanoparticles on polymerized polydiacetylene nanotubes. Combination of the nanohybrid with gallacetophenone afforded an efficient cooperative co-catalytic system for the oxidative coupling of primary amines into imines. The system is highly efficient and sustainable as it operates in high yields using minimal amounts of the metal and the quinone, under ambient atmosphere, at room temperature, in water, and is easily recycled