Academic literature on the topic 'Furanoside'

The studies on the recently discovered pyranoside-into-furanoside rearrangement have led us to conformational investigations of furanosides upon their total sulfation. Experimental NMR data showed that in some cases drastic changes of the ring conformation occurred while sometimes only the conformation of the exocyclic C4–C5 linkage changed. Herein we describe a combined quantum chemical and NMR conformational investigation of three common monosaccharide furanosides as their propyl glycosides: α-mannose, β-glucose and β-galactose. Full exploration of the furanoside ring by means of ab initio calculations was performed and coupling constants were calculated for each of the low-energy conformers. The results demonstrated preferred trans-orientation of H4–H5 protons in the non-sulfated molecules which changed to gauche-orientation upon sulfation. The effect is less pronounced in the galactosides. For all the studied structures changes in the conformational distribution were revealed by quantum mechanical calculations, that explained the observed changes in intraring coupling constants occurring upon introduction of sulfates.

Herein we report a one-pot and efficient method for the synthesis of a 1,2-cis fused furanoside bicyclic oxazolidinone derivative of d-glucosamine via pyranose to furanose conversion and concomitant cyclization involving the N-Troc group.

Sugar analysis involving permethylation followed by methanolysis can lead to significant results, given that permethylated monosaccharide standards are available for comparison of spectral and chromatographic data. Such standards are not readily commercially available, especially the furanoside forms. This note describes the isolation and characterization of permethylated pyranoside and furanoside species of D(+)-galactose and L(-)-fucose. Separation of the isomers was optimized using a combination of column chromatography and continuous elution thin-layer chromatography (TLC). TLC, gas chromatography - mass spectrometry, and 1H nuclear magnetic resonance (NMR) spectroscopy were used as the characterization methods. The isolation of furanosides is emphasized, since no specific NMR data have been reported on those to date, while several reports have already discussed the structural aspects of pyranosides.Key words: permethylation, monosaccharide, GC-MS, TLC, NMR.

Methylation analysis has been widely used for determination of carbohydrate structures by mass spectrometry. Permethylation of monosaccharides yields mixtures of anomeric pyranosides and furanosides. This paper discusses the influence of some of the permethylation reaction parameters on the proportions of isomeric products obtained. The ratios of three five- and six-membered ring products obtained from two permethylated monosaccharides, D-galactose and L-fucose, have been determined as a function of reaction parameters. The method of Ciucanu and Kerek (1) (methyl iodide in dimethyl sulfoxide (DMSO) in the presence of sodium hydroxide (NaOH)) was used as a starting point. The "conventional" method consists of mixing all of the reagents with the substrate and allowing the reaction to proceed with stirring. Both D-galactose and L-fucose under these conditions produced two main permethylated isomers, a furanoside and a pyranoside, along with two other minor isomeric components. We have investigated the effect on the proportion of products obtained of mixing DMSO, substrate, and NaOH for various times prior to the addition of methyl iodide. Results for D-galactose showed that shorter times enhanced the formation of permethylated furanoside isomers, while reducing the proportion of pyranosides. In other sets of experiments, the time and temperature of reaction, following the addition of methyl iodide, were studied. The indication is that 15 min are sufficient to produce complete methylation, with longer reaction times yielding the same results. Again for D-galactose, low reaction temperatures (ca. 10 °C) favored formation of furanoside products. Higher temperatures yielded higher pyranoside/furanoside ratios. Higher quantities of NaOH also favored formation of the main galactopyranoside product. As for L-fucose, the ratio of the main furanoside vs. pyranoside products obtained by permethylation varied in a way similar to permethylated galactoside. Thus, higher temperatures and longer reaction times favored the main fucopyranoside product. Gentler conditions (i.e., shorter reaction times and lower temperatures) significantly favored the formation of the main fucofuranoside product. These results are interesting as they show the possibility of controlling the relative abundance of permethylated isomers of fucose and galactose. They also constitute a warning to chemists who use methylation procedures in their analyses, to the effect that permethylation products may vary considerably if the reaction conditions are not carefully controlled. Keywords: glucose, galactose, fucose, TLC, GC–MS, permethylation, monosaccharides.

Abstract Polysulfated carbohydrates play an important role in many biological processes because of their ability to bind to various protein receptors such as different growth factors, blood coagulation factors, adhesion lectins etc. Precise information about spatial organization of sulfated derivatives is of high demand for molecular modelling of such interactions as well as for understanding of the mechanism of pyranoside-into-furanoside rearrangement. In this review we summarize the changes recently revealed for the conformations of common pyranosides and furanosides upon total O-sulfation which were studied by means of NMR spectroscopy as well as molecular modelling. It was found that pentoses, being more flexible, undergo complete conformational chair inversion. Meanwhile, for hexoses the situation strongly depends on the monosaccharide configuration. Conformational changes are most pronounced in gluco-compounds though quantum chemical calculations helped to establish that no complete chair inversion occurred. In furanosides distortions of two types were observed: either the ring conformation or the conformation of the side chain changed. The presented data may be used for the analysis of chemical, physical and biological properties of sulfated carbohydrates.

AbstractThe driving force for the constant improvement and development of new synthetic methodologies in carbohydrate chemistry is a growing demand for biologically important oligosaccharide ligands and neoglycoconjugates thereof for numerous biochemical investigations such as cell-to-pathogen interactions, immune response, cell adhesion, etc. Here we report our syntheses of the spacer-armed antigenic oligosaccharides related to three groups of the polysaccharides of the fungal cell-wall including α- and β-mannan, α- and β-glucan and galactomannan chains, which include new rationally designed synthetic blocks, efficient solutions for the stereoselective construction of glycoside bonds, and novel strategy for preparation of furanoside-containing oligosaccharides based on recently discovered pyranoside-into-furanoside (PIF) rearrangement.

Dans notre laboratoire rémois, le travail sur les sucres est à la base de toutes les recherches, que ce soit pour la synthèse de molécules d'intérêt biologique telles que des analogues du KRN 7000 (un glycolipide présentant une activité antitumorale), ou encore la mise en place de stratégies de synthèse (avec par exemple la stratégie NOE : addition nucléophile stéréosélective suivie d'une ouverture intramoléculaire régiosélective d'un époxyde). Mon trravail a consisté à étudier la flexibilité, et donc les conformations stables ou moins stables, de petites molécules que sont les C-furanosides, le but étant d'établir un certain nombre de règles permettant d'anticiper les questions concernant à la fois l'entrée et la pose de la structure dans un site actif. J'ai donc débuté avec une étude théorique dans le vide, puis j'ai considéré le milieu solvaté, l'objectif à long terme étant la prise en compte d'un site actif. Durant ces études, jai aussi eu la possibilité de réaliser un certain nombre de travaux en synthèse organique, allant jusqu'à l'établissement d'une voie de synthèse vers différents C-furanosides possédant un bras alcyne pouvant être personnalisé par notre partenaire lyonnais via une réaction de chimie click, pour la synthèse de molécules actives contre le diabète
In our laboratory (in Reims), working on sugars is the base of all researches, whether for biologically interesting molecules synthesis as analogues of KRN 7000 (a glycolipid showing antitumor effects), or for the development of strategies for synthesis (for example the NEO stragegy : stereoselective nucleophilic addition followed by a regioselective intramolecular epoxide opening). My work was about studying the flexibility, and consequently stable and less stable conformations of small molecules : C-furanosides, the aim being the establishment of several rules anticipating the questions concerning the entry and the pose of the structure in an active site. So I have started with a theoretical study in vacuum, then I have considered solvation. The long term goal being the consideration of an active site. During these stdies, I have also realized several works in the field of organic chemistry, going to the establishment of a synthetic pathway to different C-furanosides with an alkyne arm, which could be functionalized by our partner (in Lyon) with a click reaction, for the synthesis of bioactive molecules against diabetes

La catàlisi asimètrica es part de la síntesi asimètrica i fa possible la transformació de substrats pro-quirals o racèmics en productes quirals emprant quantitats catalítiques de compostos que contenen informació quiral. El disseny de nous lligands es l'etapa clau per a obtenir alts nivells de reactivitat i selectivitat. Els carbohidrats son uns dels membres més importants dintre de la "chiral pool".
Aquesta tesi esta enfocada en el desenvolupament i aplicació en catàlisi asimètrica de nous lligands amb esquelet carbohidrat.
Aquestos lligands foren aplicats amb èxit a la hidroformilació asimètrica catalitzada per Rh d'alquens monosubstituïts, interns disubstituïts i 1,1´-disubstituïts.
L'efecte de les modificacions estructurals dels lligands 1,3-difosfit sobre els resultats catalítics a l'alquilació al·lílica catalitzada per Pd de compostos fenil-al·lílics ha sigut també estudiat en aquesta tesis.
Finalment, els lligands 1,3-difosfit han sigut aplicats a l'estabilització de nanopartícules metàl·liques, i la seva aplicació a la hidrogenació de o- i m-metilanisol.
Asymmetric catalysis is part of the asymmetric synthesis and makes possible the transformation of a pro-chiral or racemic substrate into a chiral product using catalytic amounts of the compounds which contain the chiral information. The design of new ligands is perhaps the most crucial step to achieve the highest levels of reactivity and selectivity. Carbohydrates are the most prominent members of the "chiral pool".
This thesis focus on the development and application in asymmetric catalysis of new 1,3-diphosphite with carbohydrate backbone.
These ligands were successful applied in the Rh-asymmetric hydroformylation of monosubstituted, disubstituted internal and 1,1´-disubstituted alkenes.
The effect of the structural modification of these 1,3-diphosphite ligands on the catalytic results of the Pd-allylic alkylation of phenyl-allyl compounds was also studied in this thesis.
Finally, the 1,3-diphosphites ligands were applied to stabilize metal nanoparticles. These nanocatalysts were tested in the hydrogenation of pro-chiral o- and m-methylanisole.

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A δ-aminolevulinato desidratase (δ-ALA-D) é uma metaloenzima que requer íons zinco para sua atividade catalítica máxima. Devido a sua natureza sulfidrílica, a δ-ALA-D é extremamente sensível à presença de agentes oxidantes, sendo inibida por metais pesados que possuam elevada afinidade por grupamentos sulfidrílicos, como o Cádmio (Cd). O Cd é um metal pesado e um elemento não essencial utilizado industrialmente. É um dos poluentes mais tóxicos distribuídos no meio ambiente, uma vez que atividades antropogênicas fizeram com que sua concentração aumentasse na atmosfera e se tornasse um contaminante de alimentos e água. Uma importante fonte de Cd nos seres humanos é através da inalação da fumaça de cigarro, pois já que possui uma alta biodisponibilidade, é facilmente depositado em vários tecidos, especialmente o trato reprodutivo. Embora este metal possa causar graves danos aos embriões e aos órgãos reprodutivos, os mecanismos precisos referentes à sua toxicidade permanecem incertos. O objetivo deste tabalho foi avaliar o efeito do cádmio e do seleno-furanosídeo sobre a atividade da enzima δ-ALA-D de ovário, in vitro e ex vivo. Observou-se que baixas concentrações de Cd inibiram a atividade da enzima δ-ALA-D em ovário de vaca in vitro, e o valor da IC 50 obtido foi de 19,17 μM. O Seleno- furanosídeo (10, 50, 100, 200, 400 e 1000 μM) não foi capaz de reverter a toxicidade do Cd no tecido ovariano bovino in vitro. Foi demonstrado também o possível mecanismo pelo qual o Cd inibe a atividade da enzima δ-ALA-D, utilizando o ditiotreitol (DTT) e o Cloreto de Zinco (ZnCl 2 ), onde foi demonstrado que o DTT (3mM) protegeu a inibição da atividade da enzima causada pelo Cd, enquanto o ZnCl 2 (100μM) não protegeu o efeito inibitório do metal, sugerindo que a inibição da atividade da enzima estaria relacionado a oxidação dos grupos tiólicos. No estudo ex vivo utilizando camundongos Swiss (fêmeas adultas), a exposição aguda ao Cd (2,5 e 5 mg/kg intraperitoneal) provocou uma inibição significativa da atividade da δ-ALA-D de ovário (cerca de 27% e 34%, respectivamente). A terapia com o seleno- furanosídeo ex vivo (100 μmol/kg) foi capaz de restaurar a atividade enzimática. Assim, foi demonstrado pela primeira vez que a atividade da enzima δ-ALA-D ovariana é inibida pelo Cd tanto in vitro como ex vivo. Além disso, a terapia com o seleno-furanosídeo foi eficaz em restaurar a atividade da enzima inibida pela exposição ao Cd em ovário de camundongas, mas não foi eficaz em reverter o efeito do metal in vitro. Neste estudo, foi encontrado um novo marcador de toxicidade de Cd no tecido ovariano, bem como o efeito benéfico de um novo composto para tratar o efeito do metal após a exposição aguda do Cd.
δ- aminolevulinate dehydratase (δ-ALA-D) is a metalloenzyme that requires zinc ions for maximum catalytic activity. Due to its sulphidrilic nature, δ-ALA-D is very sensitive to the presence of oxidizing agents being inhibited by heavy metals that have a high affinity for sulfhydryl groups such as cadmium (Cd). Cd is a heavy metal and a non-essential element used industrially. It is one of the most toxic pollutants distributed in the environment, since anthropogenic activities have increased its concentration in the atmosphere and become a contaminant of food and water. An important source of Cd in humans is through inhalation of cigarette smoke, because since it has a high bioavailability, is easily deposited in various tissues, especially the reproductive tract. Although this metal can cause serious damage to embryos and reproductive organs, the precise mechanisms relating to its toxicity remain uncertain . The objective of this work was to evaluate the effect of cadmium and seleno - furanoside on the activity of the enzyme δ-ALA-D ovary , in vitro and ex vivo. We observed that low concentrations of Cd inhibited cow ovary δ-ALA-D activity in vitro and the IC 50 value obtained was 19.17 μM. The Seleno-furanoside (10, 50, 100, 200, 400 and 1000 μM) did not reverse the Cd toxicity in bovine ovarian tissue in vitro. It was also shown possible mechanism by which Cd inhibits the enzyme activity of δ-ALA-D using dithiothreitol (DTT) and Zinc Chloride (ZnCl 2 ), where it was shown that DTT (3 mM) protected against enzyme activity inhibited by Cd while the ZnCl 2 (100μM) did not protect the inhibitory effect of the metal, suggesting that the inhibition of enzyme activity is related to the oxidation of thiol groups. In the ex vivo sturdy using Swiss (adult females), acute exposure to Cd (2.5 and 5 mg / kg intraperitoneally) caused a significant inhibition of δ-ALA-D ovarian (about 27% and 34% activity, respectively). Therapy with seleno-furanosídeo ex vivo (100 μmol /kg) was able to restore enzyme activity. Thus, it was demonstred for the first time that the activity of δ-ALA-D ovarian enzyme is inhibited by Cd both in vitro and ex vivo. In addition, therapy with seleno-furanoside was effective in restoring the enzyme activity inhibited by Cd exposure in mice ovary but was not effective in reversing the effect of metal in vitro. This study found a new marker of toxicity of Cd in ovarian tissue, as well as the beneficial effect of a new compound for treating metal effect after acute exposure of Cd.
Effect of Cadmium and Seleno-furanoside on the Δ-Aminolevulinate Dehydratase Activity In Vitro and Ex Vivo.

En els últims anys, la creixent demanda de compostos enantiomèricament purs (fàrmacs, agroquímics, additius.) ha impulsat el desenvolupament de la catàlisi asimètrica, sobretot emprant compostos organometàl·lics quirals com a catalitzadors. En aquest context, la síntesi de nous lligands quirals és essencial per descobrir bons sistemes catalítics en catàlisi asimètrica. Els sucres són una font important de lligands per l'elevada disponibilitat i baix preu. A més, són compostos altament funcionalitzats amb centres estereogènics. Això permet la síntesi de sèries sistemàtiques de lligands amb l'objectiu d'obtenir altes activitats i selectivitats per cada reacció en particular.
Aquesta tesi s'ha centrat en la síntesi de compostos derivats de la D-(+)-xilosa i l'aplicació com a lligands de catalitzadors homogenis quirals en quatre reaccions asimètriques d'interès industrial: hidrogenació, substitució al·lílica, addició 1,4 i hidroformilació. Per assolir aquest objectiu s'ha plantejat la síntesi de dues famílies de compostos: difosfinits i tioèter-fosfinit (figura 1). Els difosfinits es diferencien en la configuració del carboni-3 de l'esquelet furanòsid (els dos esquelets resultants són xilofuranòsid i ribofuranòsid). Els tioèter-fosfinits es diferencien dels anteriors per la introducció d'un grup tioèter al carboni-5 de l'anell furanòsid i contenen tres grups tioèters amb diferents propietats electròniques i estèriques.


Figura 1. Compostos sintetitzats a partir de la D-(+)-xilosa.


Després de la introducció (capítol 1) i els objectius (capítol 2), al capítol 3 es discuteix la síntesi i caracterització de les dues famílies de compostos. També s'estudia la coordinació d'aquests compostos a Rh i Ir, la reactivitat respecte a l'hidrogen i l'aplicació en la hidrogenació d'olefines proquirals.
Per sintetitzar els compostos difosfinit i tioèter-fosfinit s'ha realitzat un ampli estudi explorant i avaluant diferents condicions de reacció. Els compostos difosfinit s'han preparat per reacció del corresponent diol amb clorur de difenilfosfina en presència de piridina i 4-dimetilaminopiridina. Els compostos tioèter-fosfinits s'han obtingut a partir del corresponent tioèter-alcohol per reacció amb clorur de difenilfosfina en presència de piridina i 4-dimetilaminopiridina. Els compostos intermedis diols i tioèter-alcohols s'han sintetitzat prèviament seguint rutes descrites a la bibliografia a partir de la D-(+)-xilosa. Els compostos s'han caracteritzat per espectroscòpia de ressonància magnètica nuclear (RMN) monodimensional de 1H, 13C i 31P i bidimensional de 13C-1H i 31P-1H.
Aquests compostos s'han fet reaccionar amb [M(cod)2]BF4 (M= Rh i Ir, cod= 1,5-ciclooctadiè). Els complexos organometàl·lics resultants [M(cod)(P-P)]BF4 i [M(cod)(P-SR)]BF4 (P-P=difosfinit i P-SR=tioèter-fosfinit) s'han caracteritzat per RMN monodimensional de 1H, 13C i 31P i bidimensional de 1H-1H, 13C-1H i 31P-1H. La caracterització dels complexos M/difosfinit ha mostrat que tots, excepte el complex Ir/difosfinit amb esquelet xilofuranòsid, presenten un únic isòmer. La caracterització dels complexos M/tioèter-fosfinit ha mostrat la presència d'un únic diastereoisòmer en què el substituent del sofre té una disposició pseudoaxial, que és important per obtenir una elevada enantioselectivitat en hidrogenació asimètrica. L'addició d'hidrogen als complexos d'iridi/tioèter-fosfinit ha permès formar les espècies cis-dihidruriridi (III) en les quals el substituent del sofre manté la disposició pseudoaxial.
Els sistemes M/difosfinit i M/tioèter-fosfinit (M= Rh i Ir) s'han provat com a catalitzadors quirals en la reacció d'hidrogenació asimètrica d'olefines proquirals. Els sistemes M/disfosfinit han proporcionat elevades activitats i excessos enantiomèrics de fins al 81%. S'ha observat un important efecte de la configuració del carboni-3 de l'esquelet furanòsid, del metall i del substrat que s'ha d'hidrogenar. Així, les millors enantioselectivitats s'obtenen en la hidrogenació del N-acetoamidoacrilat de metil amb el sistemes Rh/ribofuranòsid i Ir/xilofuranòsid. Els sistemes M/tioèter-fosfinit han proporcionat elevades activitats i millors enantioselectivitats (96%) que els sistemes M/difosfinit. Els resultats mostren que l'excés enantiomèric depèn de les propietats estèriques del substituent del grup tioèter, del metall i del substrat. Les millors enantioselectivitats s'obtenen en la hidrogenació del N-acetoamidoacrilat de metil i del N-acetoamidocinamat de metil amb el sistema de rodi que conté el lligand amb el substituent isopropil en la funció tioèter.
El capítol 4 descriu l'ús dels compostos difosfinit i tioèter-fosfinit com a lligands en reaccions de substitució al·lílica asimètrica (alquilació i aminació) catalitzades per pal·ladi. Concretament s'ha estudiat la reacció d'alquilació al·lílica de dos substrats amb propietats estèriques diferents: el substrat lineal rac-1,3-difenil-3-acetoxi-1-propè i el substrat cíclic rac-3-acetoxiciclohexè. El sistemes Pd-difosfinit han presentat bones activitats però baixa enantioselectivitat (fins al 31%). Els resultats indiquen que la configuració del carboni-3 de l'esquelet furanòsid controla el sentit de l'enantioselectivitat i que l'atac nucleofílic té lloc en posició trans al grup fosfinit unit al carboni-5 de l'esquelet furanòsid. Els sistemes Pd/tioèter-fosfinit han presentat millors activitats i enantioselectivitats més grans (93%) que els sistemes Pd/difosfinit. Els resultats mostren que l'excés enantiomèric depèn de les propietats estèriques del substituent del grup tioèter i del substrat. Així, les millors enantioselectivitats s'han assolit en la substitució al·lílica del substrat lineal amb el sistema de Pd que conté el lligand tioèter-fosfinit amb el grup voluminós isopropil. Els resultats també indiquen que l'atac nucleofílic, a diferència dels sistemes Pd/difosfinit, té lloc en posició trans al carboni al·lílic unit al grup fosfinit (carboni-3). D'altra banda, aquests lligands són més actius en alquilació al·lílica que en aminació al·lílica.
El capítol 5 descriu l'aplicació dels compostos difosfinits i tioèter-fosfinits com a lligands en la reacció d'addició 1,4 de compostos organometàl·lics a la 2-ciclohexenona catalitzada per coure. S'han obtingut bones enantioselectivitats (72%), elevades activitats (TOF > 1225 mols producte x (mol precursor catalític x h)-1) i excel·lents regioselectivitats en el producte d'addició 1,4 (100%)). Els resultats mostren que l'activitat i l'enantioselectivitat depenen del tipus de grup funcional unit al carboni-5 de l'esquelet furanòsid, de les propietats estèriques del substituent tioèter, del precursor de catalitzador i de l'agent alquilant. Les millors enantioselectivitats s'obtenen amb el sistema Cu/tioèter-fosfinit que conté el grup isopropil. No obstant això, l'activitat és millor amb els sistemes Cu/difosfinit. La utilització d'AlEt3 com a agent alquilant condueix a millors activitats però pitjors enantioselectivitats que el ZnEt2.
El capítol 6 exposa l'aplicació dels compostos difosfinits amb esquelet furanòsid com a auxiliars quirals en la reacció d'hidroformilació asimètrica de vinilarens catalitzada per rodi. Aquests sistemes han proporcionat elevades regioselectivitats en l'aldehid ramificat (99%) i moderats excessos enantiomèrics (fins al 63%). La presència de substituents para-metoxi i naftil al substrat té un efecte positiu sobre l'enantioselectivitat. Per primera vegada, s'ha determinat l'estructura de les espècies formades sota condicions d'hidroformilació amb lligands difosfinit mitjançant infraroig i RMN a alta pressió. L'estudi indica la presència d'un únic diastereoisòmer [HRh(P-P)(CO)2] on el lligand difosfinit es coordina en una estructura de bipiràmide trigonal en forma equatorial-equatorial. No obstant això, aquesta forma diastereoisomèrica no permet assolir una enantioselectivitat elevada.
In the last years, the growing demand of enantiomerically pure compounds (pharmacs, agrochemicals, additives...) has captured the interest of asymmetric catalysis. Asymmetric processes catalyzed by chiral transition-metal complexes have found many applications in this field. In this context, the synthesis of new chiral ligands is important to develop good catalytic systems in asymmetric catalysis. Carbohydrates have many advantages: they are readily available, are highly functionalized and have several stereogenic centers. This enables series of chiral ligands to be synthesized in the search for high activities and selectivities for each particular reaction.
This thesis has focused on the synthesis of compounds derived from D-(+)-xylose and their application as ligands of chiral homogeneous catalyst in four asymmetric industrial processes: hydrogenation, allylic substitution, 1,4-addition and hydroformylation. Thus, new diphosphinite and thioeter-phosphinite compounds have developed (figure 1). Diphosphinites have the opposite configuration at C-3 (two backbones are xylofuranoside and ribofuranoside). Thioether-phosphinites have a thiother moiety at C-5 bearing substituents with different steric and electronic properties.



Figura 1. Compounds synthetized from D-(+)-xylose.



After the introduction (chapter 1) and the objectives (chapter 2), chapter 3 contains the synthesis and characterization of the two families of compounds. This chapter also discusses the characterization of their Rh(I) and Ir(I) catalytic precursors and their application in the asymmetric hydrogenation of prochiral olefins.
Diphosphinite and thioether-phosphinite compounds have been synthesized from the corresponding alcohols. The reaction of diols with chlorodiphenylphosphine in the presence of pyridine and 4-(dimethylamino)-pyridine has provided the corresponding phosphinite ligands. The reaction of thioether-alcohols with chlorodiphenylphosphine in the presence of pyridine and 4-(dimethylamino)-pyridine has provided the corresponding thioether-phosphinite ligands. Diol and thioether-alcohol intermediates have been prepared on a large scales from D-(+)-xylose using standard procedures. Diphosphinites and thioether-phosphinites have been characterized by 1H, 13C and 31P and 13C-1H i 31P-1H MNR spectroscopy.
The reaction of these compounds with [M(cod)2]BF4 (M = Rh and Ir, cod = 1,5-ciclooctadiene) has led to [M(cod)(P-P)]BF4 and [M(cod)(P-SR)]BF4 (P-P = diphosphinite and P-SR = thioether-phosphinite) complexes. These complexes have been characterized by 1H, 13C and 31P and 13C-1H i 31P-1H MNR spectroscopy.
The characterization of M/diphosphinite complexes has showed that all, except Ir/diphosphinite complex with xylofuranoside backbone, have only one isomer. The characterization of M/thioether-phosphinite complexes has indicated that only one diastereomer, with pseudoaxial location of the sulfur substituents, is present in solution. Adding hydrogen to the iridium complexes has given cis-dihydridoiridium(III) complexes with pseudoaxial location of the sulfur substituents.
The M/diphosphinite and M/thioether-phosphinite systems have been tested as chiral catalysts in the asymmetric hydrogenation of prochiral olefins. Enantiomeric excesses of up to 81% with moderate to high activities have been obtained with M/diphosphinite systems. Our results have shown that enantioselectivity is dependent on the absolute configuration of the C-3 stereocenter of the carbohydrate bakcbone, on the metal source and on the substrate. Enantiomeric excesses of up to 96% with good activities have been obtained with M/thioether-phosphinite systems. Our results have shown that enantioselectivity depends on the steric properties of the substituent in the thioether moiety, the metal source and the substrate structure.
Chapter 4 reports the use of dihosphinite and thioether-phoshinite compounds as ligands in the palladium-catalyzed asymmetric allylic substitution reactions (alkylation and amination) of hindered linear and unhindered cyclic substrates. The use of diphosphinite ligands has provided good activity but low enantioselectivity (ee's up to 31%). Our results have indicated that the absolute configuration at carbon C-3 of the carbohydrate backbone controlles the sense of enantioselectivity and that the nucleophilic attack takes place trans to the phosphinite moiety attached to C-5. The Pd/thioether-phosphinite systems have led to best activities and enantioselectivities (ee's up to 93%) than the Pd/diphosphinite systems. Our results have shown that enantiomeric excesses depend on the steric properties of the substituent in the thioether moiety and the structure of substrate. Our results have showed that the nucleophilic attack takes place trans to the phosphinite moiety attached to C-3. Moreover, these ligands are more actives in allylic alkylation than allylic amination.
Chapter 5 contains the application of diphosphinite and thioether-phoshinite compounds as ligands in the asymmetric copper-catalyzed asymmetric 1,4-addition to 2-cyclohexenone. Good enantioselectivities (ee's up to 72%), high activities (TOF > 1225 mol product x (mol catalytic precursor x h)-1) and excellent regioselectivities in 1,4 product (100%) have been obtained. Our results show that activity and selectivity (chemo- and enantioselectivity) depend strongly on the type of functional group at C-5 position of the carbohydrate backbone, the steric properties of the substituent in the thioether moiety, the catalyst precursor and the alkylating agent. The best enantioselectivities have been obtained with Cu/thioether-phosphinite system containing isopropyl substituent. However, activity is better with Cu/diphosphinite systems. The use of AlEt3 as alkylating agent has led to better activities but worse enantioselectivities than the use of ZnEt2.
Chapter 6 discuss the application of diphosphinite compounds as chiral auxiliares in the rhodium-catalyzed asymmetric hydroformylation of vinyl arenes. These catalytic systems have led to high regioselectivities in the branched aldehyde (99%) and moderate enantiomeric excesses (up to 63%). The results have shown a remarkable substrate effect on enantioselectivity. Thus, the presence of para-methoxy and naphthyl substituents in the substrate has a positive effect on enantioselectivities. For the first time, the structure in solution of the species formed under hydroformylation conditions with diphosphinite ligands has been determined. The characterization of these rhodium complexes by NMR techniques and in situ IR spectroscopy have shown that the hydridorhodium dicarbonyl species exist in one diastereosiomeric equatorial-equatorial form. However, this strong coordination preference does not allow high enantioselectivity.

La biocontamination de surface par des microorganismes provoque d’importantes conséquences économiques et sanitaires. Les différents moyens de prévention mis en place de nos jours utilisent des composés biocides nocifs pour l’environnement et participent à la recrudescence de l’antibiorésistance des organismes pathogènes. Ces travaux de recherche étudient une approche alternative non-biocide et non-toxique. Elle consiste à inhiber l’adhésion microbienne en appliquant une couche de monofuranosides sur une surface. La conception des surfaces a débuté par les synthèses glycosidiques des furanosides cibles à partir du D-Glucose, D-Galactose et D- Mannose. Des homologues pyranosidiques, connus pour leur activité antiadhésive, ont été réalisés afin de comparer l’intérêt de la forme cyclique. Ces sucres ont ensuite été greffés par chimie click sur une surface de verre préfonctionnalisée et au travers d’un lien O-glycosidique ou S- glycosidique via un groupe triazole. Les surfaces résultantes ont été caractérisées à l’aide de la goniométrie et de la spectroscopie photoélectron par rayons X. Les études d’adhésion avec Pseudomonas aeruginosa ont révélé une activité anti-biodhésion des surfaces furanosidiques et pyranosidiques. Les interactions spécifiques et non-spécifiques ont été explorées gràce à l’adhésion de mutants déficiants en lectine et d’un modèle thermodynamique. Les résultats ont conclu que l’activité antiadhésive des monosaccharides était davantage liée aux propriétés physicochimiques des sucres plutôt qu’à des interactions biologiques
Surface biocontamination from microorganisms leads to serious economic and health issues. Nowadays, biocide compounds are mostly used as prevention. Nonetheless, they are known to be toxic for environment and to participate in the rise of the antibiotic resistance of pathogens. These research works examine a non-biocide and non-toxic approach. It is based on the inhibition of the microbial adhesion with a monofuranoside-functionalized surface. The development of surfaces was started with the glycosidic synthesis of target furanosides from D-Glucose, D-Galactose and D-Mannose. In order to compare the interest of the cyclic form, pyranosidic homologues, known for their anti-adhesive activity, were also achieved. The modified glycosides were then grafted to a prefunctionalized glass surface linked through an O-glycosidic or S-glycosidic via a triazole group. The resulted surfaces were characterized using goniometry and X-ray photoelectron spectroscopy. The adhesion studies with Pseudomonas aeruginosa have shown an anti-bioadhesion activity with furanosidic and glycosidic surfaces. Specific and non-specific interactions were explored through lectin deficient mutant strains and a thermodynamic approach. The anti-bioadhesive activity was concluded to depent more on the carbohydrate physicochemical properties, rather than the biological interactions

L’émergence de résistances de Leishmania vis-à-vis de certaines molécules ainsi que le coût élevé des traitements de la leishmaniose constituent une problématique dans les zones d’endémie défavorisées. Le développement de nouvelles molécules efficaces et à bas coût est donc un enjeu majeur dans la prise en charge de cette maladie tropicale négligée. La voie métabolique du furanose présente chez Leishmania, mais complètement absente chez l’Homme, est une voie identifiée comme une cible potentielle. Chez Leishmania, cette voie est associée à la production de plusieurs facteurs de virulence, le LPG, et les GIPLs (espèce-dépendant). L’octyle de galactofuranose, analogue du substrat original a été développé et testé dans le cadre d’un modèle d’infection à Leishmania donovani. In vitro, une efficacité doseindépendante contre la forme amastigote a étédémontrée dans un modèle de macrophages humains. In vivo sur modèle murin infecté, l’oct-galf a montré des effets immunomodulateurs marqués, au-delà d’une activité anti-parasitaire plus modeste. Pour comprendre ces résultats, une nouvelle approche mécanistique a été envisagée. L’intelectin-1 (aussi appelé omentin-1) qui fait l’objet de nombreuses publications, est capable de lier les motifs furanosidiques. Les capacités de cette lectine à modifier les voies métaboliques énergétiques via l’AMPK corrèlent avec les résultats retrouvés dans nos modèles d’étude et suggèrent son implication dans l’effet anti-parasitaire observé
The emergence of Leishmania resistance against various molecules as well as high cost of treatment of leishmaniasis represent a health problem in endemic developing countries. Development of new molecules, effective and at low-cost, is a key challenge in the management of this neglected disease. Furanose pathway is reported in Leishmania parasites, but is completely absent in Human. It was identified as a potential drug target. InLeishmania, this pathway is associated with production of virulence factors, LPG and GIPLs (species-dependant). Octyl-galactofuranose (oct-galf), an analogue of the original substrate, was developed and evaluate in the context of Leishmania donovani infection. In vitro, a dose-independent efficacy against amastigote form was demonstrated in a human macrophages model. Using a murine model, oct-galf showed strong immunomodulatory effects in vivo, while a moderate anti-parasitic effect. In order to better understand theseresults, a new mechanistic approach was considered. Intelectin-1 (also named omentin- 1) relating to a large number of publications, is able to bind furanosidic moieties. Abilities of this lectin to regulate energetic metabolic pathways via AMPK correlate with results we observed in our models and suggest its involvement in the anti-parasitic effects

Le ciblage spécifique des infections virales et bactériennes revêt une importance majeure pour le diagnostic précoce de nombreuses maladies. Le galactofuranose (Galf) est absent chez l'homme mais se trouve en tant que fragment de glycoconjugués dans un grand nombre d'agents pathogènes pour les Hommes (Aspergillus, Leishmania, Trypanosoma, Mycobacterium), offrant ainsi la possibilité de cibler ce sucre dans des applications biotechnologiques utilisant des enzymes impliquées dans son métabolisme (UDP-galactose), mutase (UGM), galactofuranosyl transférase (GalfT), galactofuranosidase (Galf-ase). Récemment, la première enzyme spécifique du Galf de Streptomyces spp. et son gène codant ont été rapportés.Ce travail de thèse se concentre sur Galf-ase et se compose de trois parties principales. La première partie concerne la caractérisation de cette enzyme, y compris le sous-clonage, la surexpression, la purification et la cinétique (kcat, KM, kcat,/KM), la détermination de l'activité optimale (pH et température) et de la stabilité au stockage.La deuxième partie consiste à appliquer une technologie d'ingénierie enzymatique (mutagenèse dirigée par site) pour générer des néolectines (protéines de reconnaissance des sucres) à partir du type sauvage. Plusieurs enzymes Galf-ase mutantes ont été surexprimées, purifiées et caractérisées cinétiquement (kcat, KM, kcat,/KM) pour leur potentiel d'utilisation en tant que néolectines et thioglycoligases pour la synthèse de furanothioglycosides.La troisième et dernière partie porte sur les procédures à suivre pour créer des nanoparticules luminescentes destinées à contenir des complexes de lanthanides et à lier les néolectines de Galf-ase à sa surface. Les conjugués luminescents résultants ont été testés en tant que sondes dans l'imagerie optique proche infrarouge de Galf située à la surface de microorganismes
Specific targeting of viral and bacterial infections is of major importance for early diagnosis of many diseases. Galactofuranose (Galf) is absent in humans but is found as glycoconjugate moiety in a large number of human pathogens (Aspergillus, Leishmania, Trypanosoma, Mycobacterium) thus offering possibilities to target this carbohydrate in biotechnological applications using enzymes involved it its metabolism (UDP-galactopyranose mutase (UGM), Galactofuranosyl transferase (GalfT), Galactofuranosidase (Galf-ase). Recently, the first Galf-specific enzyme from Streptomyces spp. and gene encoding it has been reported.This thesis work focuses on Galf-ase and consists of three main parts. First part is groundwork characterization of this enzyme including subcloning, overexpression, purification and kinetic characterized (kcat, KM, kcat,/KM). Also, determination of optimum activity (pH and temperature) and storage stability conditions.Second part consists of applying enzyme engineering technology (site-directed mutagenesis) to generate neolectins (carbohydrate-binding proteins) from the wild-type. Several mutant Galf-ase enzymes have been overexpressed, purified and kinetically characterised (kcat, KM, kcat,/KM) on their potential to be used as neolectins and thioglycoligases for furanothioglycoside synthesis.Final, third part focuses on procedures in order to create luminescent nanoparticle scaffold to bear lanthanide complexes and to bind Galf-ase neolectins onto its surface. The resulting luminescent conjugates were tested as probes in near-infrared optical imaging of Galf located on the surface of microorganisms

Les hexofuranoses constituent une catégorie de glucides présents chez de nombreux microorganismes mais totalement absents chez les mammifères. Cette spécificité, ainsi que leur présence au sein de glycoconjugués de nombreux agents pathogènes comme Mycobacterium tuberculosis ou Leishmania donovani, font des enzymes responsables de leur biosynthèse des cibles thérapeutiques de premier plan. Ainsi, toutes ces espèces utilisent un donneur commun d’unité galactofuranose, l UDP-a-D-Galf. La synthèse d’analogues structuraux de cette entité, ainsi que l’évaluation de leurs propriétés antiparasitaires, fait l’objet de ce travail. Dans un premier temps, une voie d’accès rapide et originale à des précurseurs d’UDPfuranoses, des glycofuranoses peracétylés, a été mise en place aux travers d’étapes successives de silylation et d’acétylation. Cette synthèse rapide facilitera l’accès aux nucléotide-sucres finaux. Dans un second temps, une séquence réactionnelle complémentaire a été instaurée pour accéder à des dérivés furanosidiques encore plus complexes, modifiés sur le bras en C-4 du galactofuranose. Les propriétés antimycobactériennes ont été étudiées pour deux familles de monofuranosides : des furanosides d’octyle et les thioimidates correspondants. Les premières relations structure-activité ont ensuite été établies. Enfin, le concept d’activation à distance appliqué aux thioimidates précédents, cette fois-ci utilisés comme donneurs de furanosyle, a permis de préparer de nouveaux UDP-furanoses. Des études in vitro sur L. Donovani ont confirmé que plusieurs de ces composés possèdent bien des effets antiparasitaires
Hexofuranosides are carbohydrates with fivemembered ring which are present in several microorganisms but absent from mammals. This natural occurrence and their presence into glycoconjugates of pathogenic species like Mycobacterium tuberculosis or Leishmania donovani make their biosynthesis a valuable therapeutic target. Thus, a donor of galactofuranose unit, namely UDP-a-D-Galf, is commonly found in these microorganisms. In this context, this manuscript presents the synthesis of structural analogs of this moiety, and their evaluation as antiparasitic agent. First, we proposed a new and straightforward route to precursors of UDP-furanoses, namely peracetylated glycofuranoses. This method consists in successive silylation and acetylation steps. Such a protocol facilitates the formation of corresponding nucleotidesugars. The second part of this work describes a complementary multi-step synthesis in order to obtain more complex derivatives, modified at the C-4 arm of the Galf. Antimycobacterian properties were then studied using two different families of compounds: octyl glycofuranosides and the corresponding thioimidates. Finally, new structure-activity relationships were established. Finally, the remote activation concept was applied to the previously synthesized thioimidates, alternatively used as furanosyl donors to form the targeted UDP-furanoses. In vitro studies on L. Donovani then confirmed that several analogs indeed displayed inhibition effect

Thesis (Ph. D.)--Ohio State University, 2003.
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