<p>The first part of this thesis describes a synthetic strategythat provides all eight possible isomers of a given vic-aminoalcohol starting from vinylepoxides. The value of a generalroute is evident, as several isomers are needed ininvestigations of structure-activity relationships forpharmacologically active derivatives, and for optimizing theperformance of chiral ligands containing the amino alcoholmoiety.</p><p>Vinylepoxides, obtained in high enantiomeric excess, werering-opened both with inversion and retention ofstereochemistry, delivering two diastereomeric amino alcoholswith high regio- and stereoselectivity. Via ring-closure toaziridines and subsequent regioselective ring-opening withsuitable oxygen nucleophiles, the two remaining amino alcoholswere selectively achieved.</p><p>Within this study, two efficient protocols for theregioselective and stereospecific aminolysis of vinylepoxideshave been presented. Comparedto previous methods, theseprocedures use milder reaction conditions, shorter reactiontimes, generally give higher yields and are applicable to alarger set of substrates. Furthermore, the ring-closure ofvic-amino alcohols to the corresponding N-H vinylaziridines hasbeen investigated. Three routes have been found useful, whichone is preferred depends on substrate and scale.</p><p>In the second part of the thesis, the synthetic strategy isapplied on the synthesis of Sphingosine and its regio- andstereoisomers. Moreover, a rapid way of determining relativeconfiguration of vic-amino alcohols is described, which shouldbe of substantial use when amino alcohols are formed bydiastereoselective reactions.</p><p>amino alcohols, vinylepoxides, vinylaziridines, oxazolines,oxazolidinones, ring-opening, regioselective,diastereoselective, sphingosine, configuration, NMRspectroscopy.</p>

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-07-12T13:41:01Z No. of bitstreams: 1 samiragamareis.pdf: 1183975 bytes, checksum: 4d919d44dc79995d42cbfa4fd3437a68 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-07-13T16:48:27Z (GMT) No. of bitstreams: 1 samiragamareis.pdf: 1183975 bytes, checksum: 4d919d44dc79995d42cbfa4fd3437a68 (MD5) / Made available in DSpace on 2016-07-13T16:48:27Z (GMT). No. of bitstreams: 1 samiragamareis.pdf: 1183975 bytes, checksum: 4d919d44dc79995d42cbfa4fd3437a68 (MD5) Previous issue date: 2012-08-24 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Tem-se observado um aumento do número de bactérias e protozoários resistentes aos quimioterápicos em uso. Desta forma, esses fármacos correm o risco de se tornarem obsoletos, tornando imprescindível o desenvolvimento de novos compostos que sejam biologicamente ativos. Dentre as diversas classes de compostos antimicrobianos ou antiprotozoários têm tido destaque os grupos aminoalcoóis e os heterociclos aromáticos, presente em muitos fármacos. Dando continuidade aos estudos realizados por nosso grupo de pesquisa, neste trabalho são descritas as sínteses de aminas e aminoalcoóis por aminação redutiva de benzaldeídos substituídos (p-octiloxi-, p-nitrobenzaldeído, p-metóxi benzaldeído), e de 2- e 4-piridina carboxaldeídos com monoetanolamina, 2-amino-2-metilpropanol e com a octilamina. Na segunda parte do trabalho foram sintetizados compostos derivados do metronidazol, substância de amplo espectro de atividade. Os compostos foram obtidos a partir de substituição nucleofílica do mesilato de metronidazol, com diferentes amino álcoois e octilamina. Após purificação e caracterização através dos métodos espectroscópicos usuais (RMN 1H e 13C e IV), as propriedades biológicas dos compostos obtidos foram avaliados in vitro. A avaliação da atividade antibacteriana contra diversos micro-organismos Gram-positivos e G ram-negativos foi feita através da análise do halo de inibição (método de difusão em Agar) e da concentração inibitória mínima (CIM). Os derivados de metronidazol estão sendo avaliados quanto a sua atividade antiparasitária. Os resultados mostraram que a atividade antibacteriana depende da lipofilia, já que todos os compostos possuindo a cadeia octila inibiram o crescimento bacteriana. / An increased number of bacteria and protozoa resistant to the usual chemotherapy has been observed. Thus, these drugs could become obsolete, making essential the development of new biologically active compounds. Among the various classes of antimicrobial and antiprotozoal compounds, amino alcohols and heterocyclic aromatic groups have been high lighted, as they are found in many drugs. Giving continuity to the ongoing studies conducted by our research group, in this work are described the synthesis of amines and amino alcohols by reductive amination of substituted benzaldehydes (p-octyloxy, p-methoxy and p-nitro benzaldehyde) and of 2-pyridil and 4- pyridil carboxaldehydes with monoethanolamine, 2-amino-2-methylproanol and octylamine. In the second part of the work compounds were synthesized from metronidazole, a substance with a broad spectrum of activity. The compounds were obtained by nucleophilic substitution of metronidazole mesylate with different amino alcohols and octylamine. After purification and characterization through the usual spectroscopic methods (1H NMR, 13C NMR and IR), the biologic properties of the obtained compounds were evaluated in vitro. The evaluation of the antibacterial activity was performed against gram-positive and gramnegative microorganisms, through the analysis of the halo of inhibition and of the minimum inhibitory concentration. The metronidazole derivatives are being evaluated for their antiparasitic properties. The results show that the antibacterial activity depends on lipophilicity, since all the compounds carrying the octyl chain were active.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-06-21T12:20:46Z No. of bitstreams: 1 elainedefreitascastroreis.pdf: 9019680 bytes, checksum: bdfd7990bb38d93c9a610109ce09ec5a (MD5) / Rejected by Adriana Oliveira (adriana.oliveira@ufjf.edu.br), reason: on 2017-06-21T12:44:20Z (GMT) / Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-06-21T12:44:55Z No. of bitstreams: 1 elainedefreitascastroreis.pdf: 9019680 bytes, checksum: bdfd7990bb38d93c9a610109ce09ec5a (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-08-07T19:05:21Z (GMT) No. of bitstreams: 1 elainedefreitascastroreis.pdf: 9019680 bytes, checksum: bdfd7990bb38d93c9a610109ce09ec5a (MD5) / Made available in DSpace on 2017-08-07T19:05:21Z (GMT). No. of bitstreams: 1 elainedefreitascastroreis.pdf: 9019680 bytes, checksum: bdfd7990bb38d93c9a610109ce09ec5a (MD5) Previous issue date: 2014-06-06 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico / FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais / O processo inflamatório é urna resposta coordenada do organismo a infecções e lesões teciduais, ativando a resposta imune e levando à liberação de substâncias pró- inflamatórias, como o óxido nítrico, TNF-α e IL-1β. Neste trabalho uma série de aminoálcoois lipofílicos de cadeia alifática longa foi avaliada na linhagem de macrófagos RAW 264.7 e macrófagos peritoneais inflamados de camundongos BALB/c, para verificar a viabilidade celular pelo Método do MTT, a produção de óxido nítrico pelo Método de Griess, assim como a dosagem de TNF-α e IL-1β por Elisa. Os aminoálcoois lipofilicos que apresentaram bons resultados in vitro, foram utilizados in vivo no tratamento de camundongos nos modelos de indução de edema em patas de camundongos pela carragenina, na dosagem de TNF-a e IL-1β no sobrenadante do macerado de coxins plantares de patas de camundongos, assim como no modelo de reação de hipersensibilidade tardia (RHT) à ovalbumina. Foram realizadas culturas com macrófagos da linhagem RAW 264.7 na presença de aminoálcoois com diferentes concentrações (1, 0,5 , 0,05 e 0,005 µg/mL). Os aminoálcoois testados não alteraram a viabilidade celular e inibiram a produção de NO e de TNF-α, na maioria das concentrações testadas, porém sem alterar a produção de IL-1β. Nas culturas de macrófagos primários foram testados os aminoálcoois 4a e 413, que alteraram a viabilidade celular, e não induziram a diminuição da produção de NO e das citocinas pro-inflamatórias TNF-α e IL-1β. Os aminoálcoois 4a e 4h foram escolhidos para os testes in vivo. A dexametasona foi escolhida como referência, por ser um dos fármacos de escolha para o tratamento das desordens inflamatórias, porém apresenta efeitos secundários indesejados dêvido à supressão total da resposta imune. O aminoálcool 413 mostrou redução do edema induzido em pata de camundongo pela carragenina, e diminuição de TNF-α e IL-1β tão eficiente quanto o tratamento com dexametasona. Na reação de hipersensibilidade tardia à OVA os aminoálcoois 4a e 4b apresentaram redução no edema em pata de camundongo similar a dexametasona. Em função dos resultados observados in vitro e in vivo o composto 4b mostrou propriedades anti-inflamatórias promissoras. / The inflammatory process is a coordinated response to infections and tissue damage by activating the immune response and leading to the release of pro-inflammatory substances, such as nitric oxide, TNF-a and IL-1β. In this study a series of lipophilic long chain aliphatic aminoalcohols was evaluated in RAW 264.7 macrophage lineage and inflamed peritoneal macrophages of mice BALB/c, to verify cell viability by the MTT method, the production of nitric oxide by Griess method, as well as dosage TNF-a and IL-1β by ELISA. Lipophilic amino alcohols that presented good results in vitro, were used in vivo treatment of mice in models of the carrageenan- induced paw edema in mouse and measure the levels of TNF-a and IL-1β in the supernatant of macerated of footpad mice as well as in the delayed hypersensitivity reaction (RHT) to ovalbumin model. Cultures of RAW 264.7 macrophage lineage with aminoalcohols in the presence of different concentrations (1, 0.5, 0.05 and 0.005 mg / mL) were evaluated. The aminoalcohols tested did not affect cell viability and inhibit the production of NO and TNF-a, most of the concentrations tested, but without altering the production of IL-1β. In cultures of primary macrophages the amino alcohols 4a and 4b, which altered cell viability and did not induce a decrease in NO production and pro-inflammatory cytokines TNF-a and IL-1β were tested. The amino alcohols 4a and 4b were chosen for testing in vivo. Dexamethasone is chosen as the reference drug for treating various inflammatory diseases, but have unwanted side effects due to the complete suppression of immune response. The amino alcohol 4b showed reduced edema induced in mouse paw by carrageenan, and decreased TNF-a and IL-1β as effective as treatment with dexamethasone. In the anti-ovalbumin delayed hypersensitivity reaction the aminoalcohols 4a and 4b showed reduction in paw edema mice similar dexamethasone. In function of the results observed in vitro and in vivo compound 4b showed promissory anti-inflammatory properties.

No description available.

Amino alcohols are valuable bioactive substances and frequently used as chiral catalyst in various asymmetric transformation reactions. In the synthetic route, the asymmetric synthesis of novel chiral N,N-dialkyl substituted chiral 1,4-amino alcohols are performed starting with meso-anhydride 38. Quinine-mediated desymmetrization of the anhydride with methanol afforded (2S,3R)-cis-monoester 39 with a high enantiomeric excess (up to 98% ee). Chemoselective amidation of hemiester with various N,N-dialkyl substituted amines resulted in amido esters and they were subjected to LAH reduction to afford chiral 1,4-amino alcohol ligands. The activities of the chiral ligands, (2S,3R)-43, (2S,3R)-44, (2S,3R)-45, (2S,3R)-46 were tested in various asymmetric transformation reactions, i.e. asymmetric diethylzinc addition and asymmetric Diels-Alder reactions. Keywords: 1,4-Amino alcohols, chiral ligand, asymmetric diethylzinc addition reaction, Diels-Alder reaction

Dans ce manuscrit, un travail hautement multidisciplinaire, de la synthèse de ligands organiques à la caractérisation de couches minces, est présenté. L'objectif principal de cette étude était d'élaborer de nouveaux précurseurs de niobium, de titane et d'alcalino-terreux adaptés au procédé de dépôt de couches minces par CBVD développé par la société 3D-OXIDES. Afin de répondre aux exigences de ce procédé, deux classes innovantes de dérivés moléculaires à base de ß-amino-alcool ou de ß-dicétone ?-modifiée ont été élaborées grâce à la synthèse organique de nouveaux ligands. Les complexes métalliques ont ensuite été entièrement caractériser et leur intérêt respectif dans le processus de dépôt par CBVD a été étudié à travers la détermination des pressions de vapeur, les taux de croissance, les caractérisations spectroscopiques et analyses des couches minces / In this manuscript, a highly multidisciplinary work from organic ligand syntheses to thin films characterizations is presented. The main objective of this study was to elaborate new suitable niobium-, titanium-, and alkaline earth-based precursors for CBVD thin film deposition process developed by 3D-OXIDES company. In order to reach the requirements for CBVD deposits applications, two innovative classes of molecular derivatives based on either ß-amino-alcohol or ?-modified ß-diketone ligand have been elaborated, starting from the organic synthesis of new ligands, and thoroughly characterized. Their respective interest in CBVD deposition process was fully analyzed through the determination of vapor pressures, growth rates and spectroscopic and thin film characterizations

The development and application of unnatural amino alcohols,prepared via hetero-Diels-Alder reactions,in synthesis and catalysis is described.The studies are concerned with the [i]scope of the hetero-Diels-Alder reaction and preparation of important intermediates in the synthesis of antiviral agents,[ii ]application of amino alcohols in the ruthenium transfer hydrogenation of ketones,[iii ]use of similar precursors in the in situ generation of oxazaborolidines for reduction of ketones,and [iv] development and application of new chiral auxiliaries for dialkylzinc additions to activated imines, respectively. [i ]The use of chiral exo -2-azanorbornyl-3-carboxylates in the preparation of enantiopure cyclopentyl-amines is described.At the same time the scope of the hetero-Diels-Alder reaction,used in their preparation,is extended by manipulations of the dienophiles. [ii ]Application of 2-azanorbornyl-3-methanol as a very efficient ligand in the ruthenium-catalysed asymmetric transfer hydrogenation of aromatic ketones.This ligand (2 mol%)in combination with [RuCl2(p -cymene)]2 (0.25 mol%)gave rise to a very fast reaction (1.5 h)leading to the reduced products in excellent yields and enantioselectivities (up to 97%ee ). [iii ]Preparation of α-disubstituded 2-azanorbornyl-3-methanols,in situ generation of the corresponding oxazaborolidines,and use of the latter in reduction of aromatic ketones.Concentration, solvent,and temperature effects on the reaction outcome are described. [iv ]Development of two generations of chiral auxiliaries for the addition of dialkylzinc reagents to N - (diphenylphosphinoyl)imines.Studies using density functional computations allowed the rationalisation of the reaction mechanism and the development of a second generation of ligands that improved the previously reported results.Up to 98%ee could be obtained with these new ligands. Solvent effects on the outcome of the reaction and extension of the work to a larger variety of N - (diphenylphosphinoyl)imines are described.

Chiral cyclic alpha azido ketones are very important compounds in organic chemistry. Because, the reduced forms of them are amino alcohols and these amino alcohols are interesting compounds for their biological activities. They have some pharmaceutical activities such as: potassium channel open up properties, treatment of central nervous system, antihypertensive properties, the agent of dopamin receptor activator, hypolipemic agent and dopamine agonist. These types of compounds have highly acidic alpha-protons, and many kinds of reactions can be performed with them. In this study, mainly, selective protonation of racemic compounds was performed with a new practical method and there are not so many examples related to deracemization in the literature. Alpha-azido derivatives of tetralone, indanone, chromanone, and thiochromanone structures are chosen as starting materials because of their importance for biological activities arising from their cyclic structures. Firstly, these &alpha / -azido compounds were synthesized according to literature. The acidic alpha-protons do not require strong bases. Their enantioselective deracemization and deracemization processes were screened by using Cinchona derivatives as organocatalysts. This screening process was monitored by chiral HPLC columns. The parameters such as catalyst loading, solvent, temperature, reaction time and additives were optimized to obtain high enantioselectivities up to 98%. In addition to deracemization reactions, Michael addition reactions were also performed by starting from &alpha / -azido chromanones. In these reactions different type of urea catalyst was used to activate the electrophilic part of trans-&beta / -nitrostyrene compound. Again by controlling the temperature, time and catalyst loading, two diastereomers were formed and the screening process was monitored by chiral HPLC columns again. The Michael products were obtained in up to 94% ee and 75% yield.

The research work reported in this thesis is focused on the chiral analysis, quantification of enantiomeric composition, assignment of absolute configuration of molecules with chosen functional groups. The weak intra-molecular hydrogen bonding interactions are detected by exploiting several multinuclear and multi-dimensional techniques. Pulse sequences have been designed to manipulate the spin dynamics to derive specific information from the complex NMR spectra encountered in diverse situations. Broadly, the thesis can be classified in to three sections. The section I containing two chapters reports the introduction of new chiral auxiliaries and protocols developed for enantiomeric discrimination, measurement of enantiomeric contents, assignment of absolute configuration for molecules possessing specific functional groups using chiral solvating and derivatizing agents. The section II, reports NMR experimental evidence for the observation of the rare type of intramolecular hydrogen bonds involving organic fluorine in biologically important organic molecules, that are corroborated by extensive DFT based theoretical calculations. The section II also discusses the H/D exchange mechanism as a tool for quantification of HB strengths in organic building blocks. The section III reports the two different novel NMR methodologies designed for deriving information on the scalar interaction strengths in an orchestrated manner. The designed sequences are able to completely eradicate the axial peaks, prevents the evolution of unwanted couplings and also yields ultrahigh resolution in the direct dimension, permitting the accurate measurement of scalar couplings for a particular spin. The brief summary about each chapter is given below. Chapter 1 provides a general introduction to one and two dimensional NMR spectroscopy. The pedagogical approach has been followed to discuss the conceptual understanding of spin physics and the NMR spectral parameters. The basic introduction to chirality, existing approaches in the literature for discrimination of enantiomers and the assignment of absolute configuration of molecules with chosen functional groups and their limitations are briefly discussed. The brief introduction to hydrogen bond, experimental methods to obtain the qualitative information about the strengths of hydrogen bonds, and the theoretical approaches employed in the thesis to corroborate the NMR experimental findings have been provided. The mechanism of H/D exchange, the utilization of exchange rates to derive strengths of intra-molecular hydrogen bond in small molecules have also been discussed. This chapter builds the bridge for the rest of the chapters. Each of these topics are discussed at length in the corresponding chapters. Part I: NMR Chiral Analysis: Novel Protocols Chapter 2 discusses a simple mix and shake method for testing the enantiopurity of primary, secondary and tertiary chiral amines and their derivatives, amino alcohols. The protocol involves the in-situ formation of chiral ammonium borate salt from a mixture of C2 symmetric chiral BINOL, trialkoxyborane and chiral amines. The proposed concept has been convincingly demonstrated for the visualization of enantiomers of a large number of chiral and pro-chiral amines and amino alcohols. The protocol also permits the precise measurement of enantiomeric composition. The significant advantage of the protocol is that it can be performed directly in the NMR tube, without any physical purification. The structure of the borate complex responsible for the enantiodifferentiation of amines has also been established by employing multinuclear NMR techniques and DFT calculations. From DOSY and 11B NMR experiments it has been ascertained that there are only two possible complexes or entities which are responsible for differentiating enantiomers. From the combined utility of DFT calculations and the 11B NMR chemical shifts, the structure of the borate complex has been determined to be an amine-coordinated complex with the N atom of the amine. Chapter 3 discusses a simple chiral derivatizing protocol involving the coupling of 2-formylphenylboronic acid and an optically pure [1,1-binaphthalene]-2,2-diamine for the rapid and accurate determination of the enantiopurity of hydroxy acids and their derivatives, possessing one or two optically active centers. It is established that this protocol is not only rapid method for discrimination of enantiomers but also highly effective for assigning the absolute configuration of various chiral hydroxy acids and their derivatives. The developed protocol involves the coupling of 2-formylphenylboronic acid with (R)-[1,1-binaphthalene]-2,2-diamine, and 2-formylphenylboronic acid with (S)-[1,1-binaphthalene]-2,2-diamine as chiral derivatizing agents. The absence of aliphatic peaks from the derivatizing agent, large chemical shift separation between the discriminated peaks of diastereomers, and the systematic change in the direction of displacement of peaks for an enantiomer in a particular diastereomeric complex, permitted the unambiguous assignment of absolute configuration. Part II : Rare Type of Intramolecular Hydrogen Bonding In chapter 4 The rare occurrence of intramolecular hydrogen bonds of the type N–H˖˖˖F–C, in the derivatives of imides and hydrazides in a low polarity solvent, is convincingly established by employing multi-dimensional and multinuclear solution state NMR experiments. The observation of 1hJFH, 2hJFN, and 2hJFF of significant strengths, where the spin polarization is transmitted through space among the interacting NMR active nuclei, provided strong and conclusive evidence for the existence of intra-molecular hydrogen bonds. Solvent induced perturbations and the variable temperature NMR experiments unambiguously supported the presence of intramolecular hydrogen bond. The two dimensional HOESY and 15N–1H HSQC experiments reveals the existence of multiple conformers in some of the investigated molecules. The 1H DOSY experimental results discarded any possibility of self or cross-dimerization of the molecules. The results of DFT based calculations, viz., Quantum Theory of Atoms In Molecules (QTAIM) and Non Covalent Interaction (NCI), are in close agreement with the NMR experimental findings. In chapter 5 the rates of hydrogen/deuterium (H/D) exchange determined by 1H NMR spectra have been utilized to derive the strength of hydrogen bonds and to monitor the electronic effects in the site-specific halogen substituted benzamides and anilines. The theoretical fitting of the time dependent variation in the integral areas of 1H NMR resonances to the first order decay function permitted the determination of H/D exchange rate constants (k) and their precise half-lives (t1/2) with high degree of reproducibility. The comparative study also permitted the determination of relative strengths of hydrogen bonds and the contribution from electronic effects on the H/D exchange rates. Part III: Novel NMR Methodologies for the Precise Measurement of 1H-1H Couplings Chapter 6 describes two novel NMR methodologies developed for the precise measurement of 1H-1H couplings. Poor chemical shift dispersion and the pairwise interaction among the entire coupled network of protons results in the severely complex and overcrowded one dimensional 1H NMR spectra, hampering both the resonance assignments and the accurate determination of nJHH. The available two-dimensional selective refocusing (SERF) based experiments suffer from the evolution of magnetization from uncoupled protons as intense uninformative axial peaks. This creates ambiguity in the identification of peaks belonging to the coupled partners of a selectively excited proton, hindering the extraction of their interaction strengths. This challenge has been circumvented by designing two novel experimental technique, cited as “Clean-G-SERF” and “PS-Clean-G-SERF”. The Clean-G-SERF technique completely eradicates the axial peaks and suppresses the evolution of unwanted couplings while retaining only the couplings to the selectively excited proton. The method permits the accurate determination of spin-spin couplings even from a complex proton NMR spectrum in an orchestrated manner. The PS-Clean-G-SERF technique has been designed for the complete elimination of axial peaks and undesired couplings, with a blend of ultra-high resolution achieved by real time broad band homonuclear decoupling has been discussed in this chapter. The spin dynamics involved in both these pulse sequences have been discussed. The diverse applications of both these novel experiments have been demonstrated.

No description available.