The following study investigates the intramolecular and intermolecular interactions responsible for invoking stereoselectivity and stereospecificity in the synthesis of a chiral original species and amino acid receptor. The former commences with a brief overview of the nature, scope and applications of helical chirality, and culminates in the formation of a permanent helix via the synthesis of a novel chiral lactone. The latter is discussed as an extension of a naturally occurring cofactor whose identity is modulated to furnish a tailored receptor selective to the binding of amino-acid enantiomers. The study and analysis is executed via both synthetic and computational methods.

The following study investigates the intramolecular and intermolecular interactions responsible for invoking stereoselectivity and stereospecificity in the synthesis of a chiral original species and amino acid receptor. The former commences with a brief overview of the nature, scope and applications of helical chirality, and culminates in the formation of a permanent helix via the synthesis of a novel chiral lactone. The latter is discussed as an extension of a naturally occurring cofactor whose identity is modulated to furnish a tailored receptor selective to the binding of amino-acid enantiomers. The study and analysis is executed via both synthetic and computational methods.

Single-isomer sulfated cyclodextrins (SISCDs) have proven to be reliable, effective, robust means for separation of enantiomers by capillary electrophoresis (CE). SISCD derivatives used as chiral resolving agents in CE can carry the sulfo groups either at the C2, C3 or C6 positions of the glucopyranose subunits which provides varied intermolecular interactions to bring about favorable enantioselectivities. The first single-isomer, sulfated β-CD that carries the sulfo group at the C2 position, the sodium salt of heptakis(2-O-sulfo-3-O-methyl-6-Oacetyl) cyclomaltoheptaose (HAMS) has been synthesized. The purity of each synthetic intermediate and of the final product was determined by HILIC and reversed phase HPLC. The structural identity of each intermediate and the final product was verified by 1D, and 2D NMR, and MALDI-TOF mass spectrometry. HAMS has been used as chiral resolving agent for the CE separation of a set of nonionic, weak base and strong acid enantiomers in pH 2.5 background electrolytes. Rapid separations with satisfactory peak resolution values were obtained for the enantiomers of most of the nonionic and weak base analytes. Typically, low concentrations of HAMS were required to effect good enantiomer resolution. The trends in the effective mobilities and separation selectivities as a function of HAMS concentrations followed the predictions of the ionic strength-corrected charged resolving agent migration model (CHARM model). HAMS showed poor complexation with the anionic strong electrolyte enantiomers for which no peak resolution was observed. The separation patterns observed with HAMS as chiral resolving agent were compared with those of other β-cyclodextrin analogues, including heptakis(2-O-methyl- 3-O-acetyl-6-O-sulfo)-b-cyclodextrin (HMAS), heptakis(2-O-methyl-3,6-di-O-sulfo)-b- cyclodextrin (HMdiSu), heptakis(2,3-di-O-acetyl-6-O-sulfo)-b-cyclodextrin (HDAS) and heptakis(2,3-di-O-methyl-6-O-sulfo)-b-cyclodextrin (HDMS).

No description available.

The first three, pure, single-isomer, 6-O-sulfo a-cyclodextrins, the sodium salts of hexakis(6-O-sulfo)-a-CD (HxS), hexakis(2,3-di-O-methyl-6-O-sulfo)-a-cyclodextrin (HxDMS) and hexakis(2,3-di-O-acetyl-6-O-sulfo)-a-cyclodextrin (HxDAS) have been synthesized, analytically characterized and utilized as chiral resolving agents in capillary electrophoresis. The purity of each synthetic intermediate and of the final product was determined by HPLC-ELSD and indirect UV-detection capillary electrophoresis. The structural identity of each intermediate and final product was verified by 1D and 2D NMR, and mass spectrometry.HxS, HxDMS and HxDAS have been used to separate a series of neutral, basic, ampholytic and acidic enantiomers in pH 2.5 and pH 9.5 aqueous and acidic methanol background electrolytes using capillary electrophoresis. Rapid separations with satisfactory peak resolution values were obtained for most of the analytes, indicating that HxS, HxDAS and HxDMS can serve as chiral resolving agent for a wide range of analytes. The observed separation patterns follow the predictions of the CHArged Resolving agent Migration (CHARM) model. The separation patterns observed with HxS, HxDAS and HxDMS as chiral resolving agent were compared with those of (1) b-cyclodextrin analogues, such as, heptakis(6-O-sulfo)-b-cyclodextrin (HS), heptakis(2,3-di-O-acetyl-6-O-sulfo)-b-cyclodextrin (HDAS) and heptakis(2,3-di-O-methyl-6-O-sulfo)-b-cyclodextrin (HDMS); (2) g-cyclodextrin analogues, such as, octakis(6-O-sulfo)-g-cyclodextrin (OS), octakis(2,3-di-O-acetyl-6-Osulfo)- g-cyclodextrin (ODAS) and octakis(2,3-di-O-methyl-6-O-sulfo)-g-cyclodextrin (ODMS). The effects of the structure of the analytes, and those of the pH and the solvent of the background electrolyte were also studied.

This thesis describes the development and rationalization of processes involved in a new methodology developed in our group, minor enantiomer recycling. The first part of the thesis addresses mechanistic studies of one of the reactions involved in minor enantiomer recycling, dual Lewis acid-Lewis base catalyzed acetylcyanation of aldehydes. The methodology uses a combination of a chiral titanium-salen  complex with a tertiary amine as a catalytic  system  in  the enantioselective  synthesis  of  O-acylated  cyanohydrins from aldehydes and ketonitriles. Mechanistic investigations revealed that the rate-determining step in the reaction changes, depending on the nature of the aldehyde that was used. It was also concluded that cyanohydrin is coordinated to the Lewis acid in the acylation step. The second part of the thesis deals with minor enantiomer recycling, a highly selective one-pot recycling system. In a first step the product is formed as a minor and a major enantiomer by asymmetric catalysis. Recycling of the minor enantiomer, by selective kinetic resolution, regenerates the starting material. Continuous addition of a second reagent, also involved in a coupled exergonic process, leads to an increase of both yield and enantiomeric excess. Recycling procedures for the synthesis of O-acylated and O-formylated cyanohydrins have been developed with high yield and high enantiomeric excess of the products. The study includes development of the systems, comparison to other methodologies in asymmetric catalysis, and attempts to understand the processes involved. / <p>QC 20141202</p>

A ifosfamida é um pró-fármaco que apresenta um átomo de fósforo quiral, disponível na clínica como mistura racêmica dos enantiômeros(+)-(R)-ifosfamida e (-)-(S)-ifosfamida para a utilização na quimioterapia. O objetivo do presente estudo foi o de avaliar a disposição cinética dos enantiômeros da ifosfamida em plasma de pacientes portadoras de câncer de colo do útero. As pacientes investigadas (n=6) receberam 2,5 g/m2 de ifosfamida racêmica administrada como infusão de 12 horas, sendo coletadas amostras de sangue imediatamente antes da administração e em 6, 10, 11, 12, 13, 14, 16, 18, 20 e 22 horas após a administração do fármaco. Os enantiômeros da ifosfamida foram quantificados por LC-MS/MS, sendo separados na coluna OD-R em aproximadamente 14 min empregando como fase móvel mistura de acetonitrila e água (20:80) adicionada de 0,2% de ácido fórmico. O método é linear no intervalo de 1-100 ?g de cada enantiômero/mL de plasma a partir de extrações de alíquotas de 25 ?L de plasma, compatíveis com a aplicação em farmacocinética de infusão de curta duração da ifosfamida em pacientes com câncer de colo do útero.A disposição cinética da ifosfamidaéenantiosseletiva, com observação de maiores valores de AUC (437,31 vs349,18 h.?g/mL) e menores valores de clearance(4,17 vs5,22 L/h) para o enantiômero(+)-(R)-ifosfamida. / The prodrugifosfamide has a chiral phosphorus atom, and is available clinically as a racemic mixture of the enantiomers (+)-(R)-ifosfamide and (-)-(S)-ifosfamide for use in chemotherapy. The aim of this study was to evaluate the kinetic disposition of the enantiomers of ifosfamide in plasma of patients with cancer of the cervix. The investigated patients (n = 6) received 2.5 g/m2 of racemic ifosfamide administered as infusion of 12 hours and blood samples were collected immediately before administration and at 6, 10, 11, 12, 13, 14, 16, 18, 20 and 22 hours after drug administration. The enantiomers of ifosfamide were quantified by LC-MS/MS and were separated in an OD-R column in about 14 min using as mobile phase a mixture of acetonitrile and water (20:80) plus 0.2% of formic acid. The method is linear within the range of 1-100 mg of each enantiomer/mL of plasma from extractions of 25 mL aliquots of plasma, suitable for the application in pharmacokinetics of short duration infusion of ifosfamide in patients with cervical cancer. The kineticdisposition of ifosfamide is enantioselective, with observation of higher values of AUC (437.31 vs 349.18 h.?g/mL) and lower values of clearance (4.17 vs 5.22 L/h) for the enantiomer (+)-(R)-ifosfamide.

Orientador: Marco Aurélio Cremasco / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Química / Made available in DSpace on 2018-08-26T01:42:10Z (GMT). No. of bitstreams: 1 Ferrari_WilsonMuriloCorreadaSilva_M.pdf: 1651565 bytes, checksum: 0f832d37a7639460ca0f629ffdc222f7 (MD5) Previous issue date: 2014 / Resumo: O ácido (RS)-2-(4-(2-metilpropil)fenil)propanoico, conhecido como ibuprofeno, é um importante fármaco anti-inflamatório não esteroidal, também notório por suas propriedades analgésicas e antipiréticas. A droga é comercializada em sua forma racêmica, no entanto em alguns países é empregado apenas o S-(+)-ibuprofeno que detém o princípio ativo. Além disso, o R-(-)-ibuprofeno provoca toxicidade devido à formação de triglicerídeos híbridos no organismo humano. Substâncias que desempenham funções biológicas no corpo necessitam de métodos eficazes de separação e purificação. Os métodos cromatográficos se apresentam como uma alternativa para obter as formas isoladas de enantiômeros com elevado grau de pureza. No presente trabalho, estudou-se estabelecer condições necessárias para a separação eficaz em escala analítica por meio da abordagem termodinâmica do fenômeno. A separação foi realizada com o método direto empregando uma coluna quiral recheada com sílica recoberta por tris (3,5-dimetilfenilcarbamato) de celulose. A fase móvel composta por n-hexano e isopropanol na proporção 99/1 foi definida com base nos parâmetros cromatográficos seletividade e resolução. O aditivo ácido trifluoracético também foi utilizado na fase móvel para melhorar a definição dos picos cromatográficos. Após a determinação das fases estacionária e móvel, iniciou-se a caracterização da adsorção envolvida na separação. A ordem de eluição dos enantiômero foi verificada por dicroísmo circular e polarimetria, desta forma constatou-se que o S-(+)-ibuprofeno é o composto mais retido. A porosidade total foi determinada com o método do primeiro momento utilizando o 1,3,5-tri-terc-butilbenzeno, um composto pequeno o suficiente para se difundir tanto entre as partículas do leito quanto em seus interstícios. O valor obtido foi de 0,647. A abordagem do primeiro momento do pulso cromatográfico também possibilitou a determinação da constante de equilíbrio de adsorção para cinco temperaturas entre 15 °C e 35 °C. Neste estudo utilizou-se a porosidade total e o comprimento do leito como parâmetros do método para realizar a linearização do tempo de retenção versus o inverso velocidade da fase móvel. Por fim, os parâmetros entálpicos e entrópicos de adsorção foram calculados por meio da abordagem cromatográfico da equação de van¿t Hoff. Este equacionamento possibilitou definir o fenômeno como endotérmico, no qual ocorreu adsorção física. O composto mais retido apresentou valor de 8,76 kJ mol-1 para a variação de entalpia, enquanto o R-(-)-ibuprofeno 7,21 kJ mol-1. A temperatura isoenantiosseletiva calculada foi 237,38 K / Abstract: The (RS)-2-(4-(2-methylpropyl)phenyl) propanoic acid, known as ibuprofen, is an important non-steroidal anti-inflammatory drug, notorious for its analgesic and antipyretic properties. The drug is commercialized in its racemic form. However in some countries only the S-(+)-ibuprofen is used, which it is the active isomer. Since the R-(-)-ibuprofen is toxic due to forms hybrid triglycerides in the human body. Substances with biological functions in the body must undergo effective methods of separation and purification. Chromatographic methods are an alternative for the separation of enantiomers with high purity. In the present study the necessary conditions for effective separation in analytical scale by means of thermodynamic approach of the phenomenon was studies. The separation was carried out employing a chiral column packed with silica coated with cellulose tris (3,5-dimethylphenylcarbamate). The mobile phase consisting of n-hexane and isopropanol in ratio 99/1 was defined on the basis in chromatographic parameters as selectivity and resolution. The trifluoroacetic acid additive also was used on the mobile phase to improve the resolution of the chromatographic peaks. After the determination of stationary and mobile phases, the characterization the adsorption involved in the separation was studies. The order of elution of the enantiomers was checked by circular dichroism and polarimetry. It was observed that the S-(+)-ibuprofen is the most retained compound. The total porosity was determined by first moment using 1,3,5-tri-tert-butylbenzene. This molecule is small enough to diffuse through the bed particles, but also the between the particles interstices. The value obtained was 0,647. The approach of first moment of the chromatographic pulse also allowed the determination of the adsorption equilibrium constant for five temperatures between 15 °C and 35 °C. In this study, the bed void and bed length were used as input parameters in the perform linearization of retention time versus the mobile phase inverse velocity. Finally, the enthalpy and entropy of adsorption were calculated by means of chromatographic approach usual the van't Hoff equation. The adsorptions of enantiomers were endothermic. Both molecules adsorbed physically. The enthalpy of the most retained compound was 8,76 kJ mol-1 and 7,21 kJ mol-1 for R-(-)-ibuprofeno. The enantioselective temperature was 237,38 K / Mestrado / Engenharia de Processos / Mestre em Engenharia Química

Enantioselective reactions are one of the ways to produce pure chiral compounds. Understanding the basis of this selectivity makes it possible to guide enzyme design towards more efficient catalysts. One approach to study enzymes involved in chiral chemistry is through the use of computational models that are able to simulate the chemical reaction taking place. The potato epoxide hydrolase is one enzyme that is known to be both highly enantioselective, while still being robust upon mutation of residues to change substrate scope. The enzyme was used to investigate the epoxide hydrolysis mechanism for a number of different substrates, using the EVB approach to the reaction both in solution and in several enzyme variants. In addition to this, work has been performed on new ways of performing simulations of divalent transition metals, as well as development of new simulation software.

Le développement de molécules chirales est devenu un enjeu majeur pour l’industrie pharmaceutique. Lors de la mise au point d’un nouveau principe actif, la chromatographie en phase supercritique (CPS) sur phases stationnaires énantiosélectives, est devenue une méthode incontournable pour l’analyse ou la purification d’énantiomères. Il n’en demeure pas moins que certains composés tels que les composés basiques restent délicats à analyser par cette technique et que l’ajout d’un additif basique dans la phase mobile est très souvent nécessaire. La quantité d’additif ajoutée dans la phase mobile est souvent choisie de manière arbitraire en se basant sur les spécifications des fournisseurs de phases stationnaires et sur les travaux publiés dans le domaine, sans se soucier de l’effet potentiel sur la résolution d’une modification de sa concentration. Ce travail de thèse a démontré l’importance de la concentration en additif dans la phase mobile lors de l’analyse de mélanges d’énantiomères par CPS, avec notamment des effets significatifs sur l’énantiosélectivité allant jusqu’à une inversion de leur ordre d’élution selon la concentration en additif. Dans un deuxième temps cette étude a consisté en une amélioration de notre compréhension des modes d’actions de l’additif, sur la phase stationnaire et sur la phase mobile permettant de poser des hypothèses sur les effets observés lors de la séparation d’énantiomères. La dernière partie est consacrée à la présentation de différents exemples, justifiant l’intérêt de moduler la concentration en additif lors de séparations d’énantiomères. / Nowadays, the development of chiral molecule is a strategic issue for the pharmaceutical industry. During the development of a new molecular entity, supercritical fluid chromatography using enantioselective stationary phases is essential for the analysis or the purification of racemates. Despite the advantages of SFC, the analysis of some compounds like basic compounds may still be a challenge. Their analysis most of the time, requires an additive in the mobile phase. In many cases additives concentration is chosen arbitrarily, based on the columns supplier guidelines and work already published, regardless of the impact of the additive concentration on the resolution. This work has shown the impact of the additives concentration for the analysis of enantiomers by SFC, in particular a significative impact on the enantioselectivity of chiral stationary phases, with for some of them a reversal elution order depending on the additive concentration. The second objective is to improve our knowledge on the mechanism of action of the additive both on the stationary phase and the mobile phase. The last part is dedicated to the presentation of a few examples highlighting the positive impact of the variation of the additives concentration for enantiomer separation.