<p>This thesis deals with the preparation and use of chiralbispyridylamides as ligands in metal-catalyzed asymmetricreactions.</p><p>The compounds were prepared by amide formation usingdifferent coupling reagents. Bispyridylamides havingsubstituents in the 4- or 6- positions of the pyridine ringswere prepared by functional group interconversion of the 4- or6- halopyridine derivatives. These synthetic approaches provedto be useful for various types of chiral backbones. Pseudo C₂-symmetric bispyridylamides were also synthesizedby means of stepwise amide formation.</p><p>The compounds were used as ligands in themicrowave-accelerated Mocatalyzed asymmetric allylic alkylationreaction. Ligands having ð-donating substituents in the4-positions of the pyridine rings gave rise to products withhigher branched to linear ratio. The catalytic reaction, whichproved to be rather general for allylic carbonates with anaromatic substituent, was used as the key step in thepreparation of (R)-baclofen. The Mo-bispyridylamide catalystprecursor was studied by NMR spectroscopy.</p><p>Bispyridylamide complexes of metal alkoxides were alsoevaluated in the asymmetric addition of cyanide to aldehydesand the metal complexes involved were studied by NMRspectroscopy and X-ray crystallography. Chiral diamines wereused as additives to study the ring opening of cyclohexeneoxide with azide, catalyzed by Zr(IV)-bispyridylamidecomplexes.</p><p>Various bispyridylamides were attached to solid supports oforganic or inorganic nature. The solid-supported ligands wereused in Mo-catalyzed asymmetric allylic alkylation reactionsand in the asymmetric addition of cyanide to benzaldehyde.</p><p><b>Keywords:</b>asymmetric catalysis, chiral ligand, pyridine,amide, allylic alkylation, enantioselective, cyanation,ring-opening, chiral Lewis acid.</p>

The mechanism by which chiral selectivity takes place is complicated by the surface morphology, the possible involvement of the solvent, and the characteristics of the chiral molecules at the surface. My goal is to model and understand the factors which lead to significant discrimination in the case of three closely related chiral stationary phases: N-(1-phenylethyl)-N’-[3-(triethoxysilyl)propyl]-urea (PEPU), [(3,5-dinitrobenzoyl)-amino]-N-[3-(triethoxysilyl)propyl]-2-phenylacetamide (DNB-phenyglycine), and [(3,5-dinitrobenzoyl)amino]-N-[3-(triethoxysilyl)propyl]-4-methylpentanamide (DNB-leucine). Ab initio calculations are used to develop molecular models of these chiral selectors. These models are employed in molecular dynamics (MD) simulations, which provide the theoretical framework for modelling chiral interfaces in different solvent mixtures. The MD simulations of PEPU interfaces show that, in alcohol/water mixtures, the alcohols form domains at the interface with the hydrophobic portions of the molecule tending to orient towards the surface. This disrupts the water hydrogen bonding networks at the interface and leads to the exclusion of water from the surface region relative to the bulk. The MD simulations of DNB-phenylglycine and DNB-leucine selectors in hexane/2-propanol mixtures demonstrate that the interfaces are distinct both in terms of the selector orientations at the surface and in the number of hydrogen bonds formed with 2-propanol. This occurs despite the structural similarity between these two selectors. The interfaces are also prepared experimentally by attaching the chiral selectors onto oxidized Si(111) samples and AFM tips. In particular, for DNB-phenylglycine and DNB-leucine samples, two synthetic routes have been explored. Using AFM, the morphologies of the resulting chiral interfaces are obtained. X-ray photoelectron spectroscopy and refraction-absorption infrared spectroscopy provide information regarding the relative distribution of the compounds on the surface. Using chemical force microscopy (CFM) measurements, chiral self-selectivity is examined in various solvent mixtures. For PEPU interfaces, the extent of hydrogen bonding at the surface is the dominant contributor to the measured forces. In the case of DNB-phenylglycine and DNB-leucine, CFM measurements of the chiral self-selectivity in 2-propanol demonstrate that chiral discrimination is present in both systems, but larger forces are observed for DNB-phenylglycine, consistent with the molecular dynamics study that shows much weaker solvent interactions with this species. / Thesis (Ph.D, Chemistry) -- Queen's University, 2008-08-14 11:26:37.436

This thesis involves the synthesis of two main classes of triaminocyclopropenium (tac) Ionic Liquids (ILs) (i) Amino Acid Ionic Liquids (AAILs) and (ii) reduced-symmetry cations. [C₃(NEt₂)₂(NRR’)]X (X = TFSA and MeSO₄) were prepared, whereby NHR is derived from amino acids. Optically pure AAILs, [E₄AminoAcid]X (X = TFSA and MeSO₄) were obtained as a mixture of the IL and its zwitterion. The ratios of these mixtures were determined by pH titration and microanalysis. The AAILs specific rotations and pKa values were determined. AAILs can be used for chiral discrimination and form diasterreomeric salts with the entioenriched sodium salt of Mosher’s acid. The AAILs were also successfully used as a solvent and/or catalyst in an aldol reaction and a Diels-Alder reaction. The low-molecular weight series, [C₃(NMe₂)₂(NRR’)]X and [C₃(NMe₂)₂(NR’2)]X was synthesized and characterized: protic ILs NRR’, where R = ethyl, propyl, allyl, butyl, - CH2CH2OCH₃ and pentyl, R’ = H and X = TFSA: and aprotic ILs NRR’, where R = Me, R’ = ethyl, allyl, propyl, butyl, -CH2CH2OCH₃ and hexyl and X = TFSA and DCA. ILs with C2v symmetry [C₃(NEt₂)₂(NH2)]X (X = TFSA and MeSO₄), [C₃(NEt₂)₂(NBu2)]I, [C₃(NEt₂)₂(NHex₂)]I and [C₃(NEt₂)₂(NHex₂)]OTf were also synthesized and characterized. The C₃h cations, [C₃(NMeR)₃]X (R = ethyl, allyl, -CH2CH2OCH₃ and phenyl, X = TFSA and DCA) were successfully prepared as well. The D₃h cation salts [C₃(NEt₂)₃]X (X = MeC6H4SO₃, OTf, I and F5C6O) and [C₃(NBu2)₃]X (X = B(CN)4 and FAP) were also prepared. The tac-based ILs [C₃(NEt₂)₃]+ and [C₃(NBu2)₃]+ were also complexed with metal halides - - 2- 2- forming salts with FeCl₄ , SnCl₃ , CuCl₄ and ZnCl₄ . Reaction of pentachlorocyclopropane (C₃Cl5H) with BuNH2 gave the open ring allylium product [H2C₃(NBuH)4]2+. This was characterized as Cl- and TFSA- salt. During the synthesis of [C₃(NMe₂)₃]Cl, the open ring cation [HC₃(NMe₂)4]+ was also isolated and was characterized as the TFSA- salt. XX Abstract The TGA, DSC, density, viscosity, conductivity, and molar conductivity properties for the ILs were measured where possible. The viscosity and conductivity data was fitted for the Arrhenius and Vogel-Fulcher Tamman equations. The entire tac-based ILs lie below the KCl ideal line in Walden plot. A fragility plot was obtained by fitting the viscosity data and all the tac-based ILs were fragile. The crystal structures of [C₃(NPhH)₃]TFSA, [C₃(NEt₂)₃]FeCl₄ and [HC₃(NMe₂)4]Cl.2CH₃Cl were determined.

Orientador: Antonio Claudio Herrera Braga / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-12T16:47:01Z (GMT). No. of bitstreams: 1 Rocha_DanieleFernandadeOliveira_M.pdf: 3918609 bytes, checksum: ca79955ba1bba5d8eb4ed332338d0115 (MD5) Previous issue date: 2008 / Resumo: Neste trabalho foi estudado o comportamento de uma série de iminas estruturalmente análogas quando submetidas à biocatálise com fermento de pão e cenoura. Também foi testado NaBH4 em conjunto com alguns aminoálcoois de diferentes tamanhos, como 1-amino-2-propanol, prolinol e 2-a-hidroxibenzil-benzimidazol ou ácido tartárico. A utilização da biocatálise já é consolidada para a redução assimétrica de carbonilas, mas para a ligação C=N há poucos relatos na literatura, devido à facilidade com que esta ligação sofre hidrólise em meios aquosos. Os resultados foram negativos para biocatálise, apresentando hidrólise do substrato em diversas condições e solventes testados, mesmo com a utilização de 18-C-6 como aditivo e com a imobilização do substrato ou do fermento. As causas destes resultados podem ser tanto a falta de afinidade das enzimas com os substratos testados quanto a instabilidade dos mesmos nos meios utilizados. Foi aplicada uma metodologia bastante simples, com mistura manual de ambos em um almofariz. Testadas várias condições e diferentes solventes, nenhuma delas proporcionou um bom excesso enantiomérico. Uma provável causa para estes resultados pode ser a não eficiência da complexação entre o NaBH4 e os reagentes quirais. Testes de EM e RMN de B e H mostram a formação de um boroidreto quiral, mas não em quantidade suficiente para gerar maior assimetria na redução. Uma grande contribuição deste trabalho é a caracterização de um boroidreto quiral formado a partir de NaBH4 e S-(+)-2- a-hidroxibenzil-benzimidazol já reportado na literatura, mas sem um conjunto de dados conciso acerca de sua estrutura. Este composto gerou o maior excesso enantiomérico 27%, para a redução de N-benzil-(1-feniletilideno)amina / Abstract: This project studies the behavior of a series of imines structurally analogues in bioreductions with baker yeast and carrots, and also with NaBH4 using alternative chiral reagents like 1-amine-2-propanol, prolinol and 2-a- hidroxybenzyl-benzimidazole or tartaric acid. For biocatalysis we investigated different temperatures, solvents and proportions of reagents, but all conditions resulted in hydrolysis of the substrate. The instability of the imines or the lack of affinity can be the cause for these results, even using 18-C-6 as additive and immobilized yeast or substrate. By the chemical imine reduction we tried a simple method of induction, mixing manually NaBH4 and the chiral reagent in a mortar, using different solvents and temperatures, but none of them gave a good enantiomeric excess. Probably there was no coupling between NaBH4 and the chiral reagents, and consequently no preference in for one face in the reduction transition state. MS and NMR analysis have shown the formation of a chiral borohydride, but not an enough amount to give asymmetry in the reduction. A great contribution of this project is the characterization of a chiral borohydride obtained from NaBH4 and S-(+)-2-a-hydroxybenzyl-benzimidazole. It was previously reported, but with no confirmation of its structure. This compound reduced Nbenzyl-(1-phenyletilidene)amine with 27% enantiomeric excess / Mestrado / Quimica Organica / Mestre em Química

Le but de cette thèse est de construire un modèle décrivant la matière nucléaire symétrique et asymétrique dans une approche relativiste incluant des effets de la chromodynamique quantique, en particulier la symétrie chirale et le confinement. Le système considéré est une assemblée de nucléons en interaction {\it via} l'échange de mésons. L'attraction est assurée par la présence d'un champ scalaire invariant chiral lié aux fluctuations du condensat de quarks. La saturation est obtenue après ajout de la réponse scalaire nucléo- nique liée à la sous-structure en quarks du nucléon. Les paramètres liés au secteur scalaire de l'interaction et au confinement des quarks dans le nucléon sont estimés à partir de données sur réseau. Le reste des paramètres est contraint autant que possible par la phénoménologie hadronique. Le modèle n'est ainsi quasiment pas ajustable, le fait qu'il donne de si bons résultats constitue l'originalité de ce travail de thèse. Dans un premier temps, nous avons choisi de travailler à l'approximation de champ moyen dans le schéma Hartree--Fock. La propagation du champ scalaire dans les termes de Fock conduit à des effets de réarrangement qui permettent de satisfaire le théorème de Hugenhotz--Van Hove. Nous soulignons également le rôle du terme tenseur du $\rho$ dans l'énergie d'asymétrie ainsi que dans la dépendance en isospin de la masse effective de Landau. Enfin, nous donnons l'équation d'état des étoiles à neutrons prédite par ce modèle. Dans un deuxième temps, nous avons décidé d'inclure des effets au-delà du champ moyen en incluant l'énergie de corrélation due aux boucles de pions. Un ingrédient important est l'introduction d'un paramètre de Landau--Migdal contrôlant les interactions à courte portée. L'énergie de corrélation améliore la description des propriétés de la matière nucléaire au niveau du point de saturation. / This work aims at constructing a model for symmetric and asymmetric nuclear matter in a relativistic approach including effects from quantum chromodynamics, in particular chiral symmetry and confinement. We consider an assembly of nucleons interacting via meson exchange. The attraction is due to a chiral invariant scalar field associated with the fluctuations of the chiral condensate. The inclusion of scalar nucleonic effects due to the quark substructure of the nucleon ensures the saturation to occur. The parameters corresponding to the scalar sector of the interaction and to the quarks confinement in the nucleon are obtained from lattice calculations. The rest of the parameters are obtained as much as possible by hadron phenomenology. With such constrained inputs, the results are nevertheless very good: this constitutes the originality of this work. In one part, we chood to work at the mean-field level in the Hartree--Fock scheme. The propagation of the scalar field in the Hartree-Fock terms induce some rearrangement effects which play an essential role in the Hugenhotz--Van hove theorem. We discuss also the role of the tensor part of the $\rho$ interaction in the symmetry energy and the isospin dependance of the Landau effective mass. Then, in the idea to enlarge this work to neutron stars, we give the equation of state predicted by our model. The last step corresponds to the introduction of effects after the mean-field including the correlation energy due to pion loops. An important ingredient is the Landau-Migdal parameter controling short range interactions. The correlation energy enhances the description of the saturation point of nuclear matter

Depuis une trentaine d'année, l'obtention de composés chiraux énantiopurs tient un rôle prépondérant dans la synthèse de molécules biologiquement actives, tout particulièrement dans les domaines de la pharmacie de l'agrochimie et de la parfumerie. Cet engouement pour la synthèse énantiosélective a conduit à la mise au point de multiples ligands chiraux et notamment les diphosphines chirales par atropoisomérie initiées par les travaux de Noyori et Takaya. Nous nous sommes intéressés à la synthèse de nouveaux ligands hétérocycliques bidents et chiraux par atropoisomérie par des voies de synthèse originale où une double construction des hétérocycles sera mise en œuvre dans l'étape clé. En parallèle, nous avons aussi développé une approche de synthèse permettant l'obtention de mono et bis phosphonates atropochiraux utilisant des allènes comme précurseurs de la synthèse. / Atropisomeric diphosphine ligands play a crucial role in the synthesis of enantiopur molecules, particularly in pharmaceutical, agrochemical and flavors industries. Growing demand in asymmetric synthesis, impose to develop news ligands by rapid, economic and effective strategies of synthesis. This optically pure ligand was combined with multiples transition metal to form catalyst what will have used wide variety of entioselective reaction type.Over the past few years, a new family of ligands has emerged, possessing biheterocyclic skeleton and thus allowing the introduction of different steric and electronic interactions. We will report a efficient syntheses of the new atropisomeric five-membered heterocyclic diphosphines with original strategy of synthesis whose the main stages consist in a double heterocyclic construction. In the second part, we will develop an approach permitting to obtain atropochiral phosphonates with a similar strategy of synthesis from allenylphosphine oxides or allenylphosphonates as precursors.

Les réactions permettant la création de liaisons carbone-carbone sont des outils essentiels dans le domaine de la synthèse organique. Elles permettent d'accéder à des structures de plus en plus complexes. Cependant le contrôle de ces réactions en utilisant des partenaires hautement fonctionnalisés reste un enjeu majeur.Le développement de nouvelles méthodologies de synthèse basées sur la réactivité des acrylamides chiraux dérivés d'acides aminés est étudié dans ces travaux. Une nouvelle version de la réaction d'alkylation de pyrroles de type Friedel-Crafts a été développée en utilisant le caractère électrophile d'acrylamides chiraux hautement fonctionnalisés. Le pyrrole peut être monoalkylé ou dialkylé de façon sélective conduisant à de nouvelles structures hétérocycliques portant des enchaînements peptidiques pouvant contenir jusqu'à quatre résidus d'acides aminés. Les acrylamides chiraux portant un motif allyltriméthylsilane conjugué ont été utilisés comme nouveaux réactifs permettant des réactions d'allylation hautement diastéréosélectives et chimiospécifiques vis-à-vis d'aldéhydes. L'extension de cette méthodologie aux aldéhydes α- aminés a été réalisée et permet un accès aisé à des structures analogues des acides γ-aminés. / Reactions allowing carbon-carbon bond creation are essential tools in the field of organic synthesis. These reactions are used to access to more and more complex structures. However their control in the case of highly functionnalized partners is still a serious concern.Development of new methodologies based on the reactivity of aminoacid derivating chiral acrylamides is reported. A new version of pyrrole alkylation reaction was developed using the electrophilic behaviour of highly functionnalized chiral acrylamides. Pyrrole can be selectivly monoalkylated or dialkylated leading to new heterocyclic structures bearing peptidic sequences containing up to four aminoacids residues. Chiral acrylamides bearing a conjuguated allyltrimethylsilane moiety have been used as new reagent in highly diastereoselective and chemospecific towards aldehydes allylation reactions. This methodology was extended to α-aminoaldehydes allowing easy access to γ-aminoacidsanalogues.

Ce travail a été consacré à l’utilisation d’un sulfoxyde chiral pour effectuer une réaction de cyclisation polarisée de Nazarov asymétrique. Une méthodologie mettant en jeu une condensation de Knoevenagel a été mise au point pour la synthèse de divinylcétones portant un sulfoxyde chiral en position α. Cet auxiliaire a mené à une sélectivité du sens de rotation, appelée torquosélectivité, des orbitales π impliquées dans l’électrocyclisation. Une diastéréodivergence de la pentannelation a pu être développée à partir de substrats dihydropyraniques qui ont mis en évidence une inversion de torquosélectivité selon l’acide de Lewis employé. La cyclisation de différents substrats (hétéro)-aromatiques a aussi montré des torquosélectivités importantes, ceci ayant permis de réaliser la première synthèse non-racémique d’une indanone dérivée de l’acide gallique, composé anticancéreux. Par la suite, une réduction stéréodivergente du carbonyle de la cyclopenténone formé a pu conduire aux carbinols épimères correspondants. Parallèlement, l’oxydation de l’inducteur chiral en sulfone a donné lieu à une allylation avec une totale diastéréosélectivité. Enfin, le clivage de la liaison C-S sous forme de sulfure ou de sulfone a permis d’élaborer, avec un excellent stéréocontrôle, des bicycles dihydropyrane-cyclopentane fusionnés à substituants fonctionnalisés. / This work was devoted to the use of a chiral sulfoxide to perform an asymmetric polarized Nazarov cyclization. A methodology involving a Knoevenagel condensation has been developed for the synthesis of divinylketones bearing a chiral sulfoxide in α-position.This auxiliary led to a rotation direction selectivity, called torquoselectivity, for the orbitals involving during the electrocyclization. A pentannelation diastereodivergence could be developed from dihydropyran-containing substrats that showed a torquoselectivity switch depending to the used Lewis acid.(Hétéro)-aromatic substrates cyclization also showed significant torquoselectivities, this allowed the first non-racemic synthesis of a gallic acid-based indanone, an anticancer agent.Thereafter, stereodivergente reduction of the cyclopentenone carbonyl gave the two corresponding carbinolic epimers. In parallel, the chiral inductor oxidation into sulfone allowed a total diastereoselective allylation. Finally, C-S bond cleavage, as sulfide or sulfone, afforded dihydropyran-fused-cyclopentane rings bearing functionalized substituents with excellent stereocontrol.

No description available.

The aim of this work was finding suitable conditions for separation of enantiomers of citalopram and citadiol, optimization of chromatographic system and validation of the analytical method for determination of selected enantiomers in drugs. Drugs are often chiral compounds. In many cases, only enantiomer has required pharmacological effects. Advanced chemical technologies associated with the synthesis, separation and analysis of the individual enantiomers caused an increase of the number of new chiral drugs in the form of single pure enantiomers, the chiral switch. Citalopram is one of the widely used antidepressants of selective serotonin reuptake inhibitors (SSRI). Citalopram is used for treatment of depression, panic anxienty or obsessive compulsive disorder of pathological laughing and crying. The pharmacological activity is associated with the S-citalopram, while R-enantiomer is essentially inactive and even counteracts the activity of escitalopram. Citadiol is a chiral syntetic precursor of citalopram. This thesis was focused on monitoring enantioseparation "behaviour" of selected enantiomers. HPLC method with chiral stationary phases based on macrocyclic antibiotics, cyclofructans and cellulose was applied for enantioseparation of the above-mentioned compounds. The optimized chromatographic...