Chiral cyclic polyoxo-ketones are important structural units in many natural products, biologically active compouds, such as prostaglandins, didemnenones, sarkomycin, punaglandin, clavulone, etc. In this work, a chemoenzymatic synthesis of both enantiomers of the &amp / #945 / &rsquo / -acetoxy-&amp / #945 / -methyl and &amp / #947 / -hydroxy-&amp / #945 / -methyl cyclic enones starting from &amp / #945 / -methyl-&amp / #946 / -methoxy cyclic enone is described. Manganese (III) acetate-mediated acetoxylation followed by the enzyme-mediated hydrolysis of &amp / #945 / &rsquo / -acetoxy enone provides acetoxy enones. The reduction of the hydroxy enone, obtained from hydrolysis, furnished both enantiomers of 4-hydroxy enone or &amp / #947 / -hydroxy enone by using LiAlH4. This study is a model for the synthesis of these type compounds

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A convergent synthesis of a series of 16 new polysubstituted (5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)(quinolin-4-yl)methanones, starting from isatin and alky(aryl/heteroaryl) ketones, is described. The diheteroaryl methanones were achieved at yields of up to 95% by a (3 + 2) cyclocondensation reaction involving 4-alkyl(aryl/heteroaryl)-4-methoxy-1,1,1-trifluorobut-3-en-2-ones (by two-step reaction) and 2-alkyl(aryl/heteroaryl)-4-carbohydrazides (by three-step reaction). Subsequently, representative dehydrated heterocyclic derivatives were obtained from the respective 5-hydroxy-2-pyrazoline moieties by classical dehydration reactions, which resulted in the corresponding (5-(trifluoromethyl)-1H-pyrazol-1-yl)(quinolin-4-yl)methanones (three examples) at yields of 69 82%. The compounds were characterized by one- and two-dimensional 1H/13C NMR, X-ray diffraction, GC-MS and elemental analysis. The subsequent cytotoxicity evaluation showed that compounds with aromatic groups at the 2-position of the quinoline and a methyl moiety at the 3-position of the pyrazole have significant cytotoxicity in human leukocytes at high concentrations (200 μM). / Uma síntese convergente de uma série de 16 novos poli-substituídos (5-hidroxi-5-(trifluorometil)-4,5-di-hidro-1H-pirazol-1-il)(quinolin-4-il)metanonas, a partir da isatina e alquil(aril/heteroaril)cetonas, é descrito. As diheteroarilmetanonas foram obtidas com rendimentos de até 95% por uma reação de ciclocondensação (3 + 2) envolvendo 4-alquil(aril/heteroaril)-4-metóxi-1,1,1-trifluorbut-3-en-2-onas (reação em dois passos) e 2-alquil(aril/heteroaril)-4-carbohidrazidas (reação em três passos). Subsequentemente, os representantes desidratados dos heterociclos foram obtidos a partir das respectivas porções de 5-hidróxi-2-pirazolina por reações de desidratação clássicas, o que resultou nas correspondentes (5-(trifluormetil)-1H-pirazol-1-il)(quinolin-4-il )metanonas (três exemplos) com rendimentos de 69-82%. Os compostos foram caracterizados por RMN de 1H e 13C uni e bidimensional, difração de raios-X, CG-EM e análise elementar. As posteriores avaliações da citotoxicidade mostraram que os compostos com grupos aromáticos na posição 2 da quinolina e o grupo metila na posição 3 do pirazol, possuem significativa citotoxicidade em leucócitos humanos em concentrações elevadas (200 μM).

FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico / O estudo da biocatÃlise tem se intensificado nos Ãltimos anos devido à busca de rotas sintÃticas alternativas para a obtenÃÃo de compostos enantiomericamente puros. A utilizaÃÃo de sementes de Helianthus annuus L. ainda nÃo foi relatada na literatura em reaÃÃes de biorreduÃÃo e diante dessa perspectiva, foram investigadas na biorreduÃÃo de cetonas aromÃticas, para a obtenÃÃo de Ãlcoois enantiomericamente puros. O teor de proteÃnas das sementes foi determinado pelos mÃtodos de Lowry e Bradford e apresentaram valores correspondentes a 10,1 g/L e 8,8 g/L, respectivamente. As reaÃÃes de biorreduÃÃo foram otimizadas utilizando acetofenona (1), e nestas foram avaliados os fatores: quantidade de biocatalisador, meio tamponante (pH), co-solvente, germinaÃÃo de sementes e extrato bruto com polivilpirrolidona (PVP). Foram obtidos boas conversÃes (56,9%) em meio aquoso e, excelentes excessos enantiÃmericos (ee), (>99,0%) com o extrato bruto enzimÃtico em PVP do enantiÃmero (S). Derivados da acetofenona, uma cetona α-halogenada e duas outras cetonas aromÃticas, α-tetralona e α-indanona, foram submetidas Ãs metodologias otimizadas de conversÃo e ee, obtendo-se bons resultados, com produÃÃo do enantiÃmero S, exceto para a 3-metÃxi-acetofenona em meio aquoso, que apresentou o isÃmero R. A quantificaÃÃo dos teores de conversÃo foi realizada por intermÃdio da construÃÃo de curvas de calibraÃÃo em CromatogrÃfo LÃquido de Alta EficiÃncia (CLAE), bem como a resoluÃÃo dos Ãlcoois quirais utilizando coluna quiral OB-H. / The study of biocatalysis has intensified in recent years due to the search for alternative synthetic routes to obtain enantiomerically pure compounds. The use of seeds of Helianthus annuus L. has not been reported in the literature and bioreduction reactions at this point of view, were investigated in the bioreduction of aromatic ketones, to obtain enantiomerically pure alcohols. The protein content of the seeds was determined by Lowry and Bradford methods and gave values corresponding to 10,1g/L and 8,8g/L, respectively. The bioreduction reactions were optimized using acetophenone (1), and these factors were evaluated: the amount of biocatalyst, using buffer (pH), co-solvent, seed germination and the crude extract with polyvinylpyrrolidone (PVP). Good conversions were obtained (56,9%) in aqueous solution and excellent enantiomeric excess (ee) (>99,0%) crude extract with the enzyme in PVP enantiomer (S). Derivatives of acetophenone, an α-halogenated ketone and two other aromatic ketones, α-tetralone and α-indanone were subjected to the methods of conversion and ee optimized to yield good results, with production of the S enantiomer, except for the 3-methoxy-acetophenone in aqueous media, which made the R isomer. Quantitation of the conversion levels were determined by the construction of calibration curves in a High Efficiency Liquid Chromatograph (HPLC) and the resolution of chiral alcohols using a chiral column OB-H.

Orientador: Luiz Carlos Dias / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-12T23:49:44Z (GMT). No. of bitstreams: 1 Marchi_AndersonAparecidode_M.pdf: 3517303 bytes, checksum: 4fbe84bf0a557b032571d7cac8591000 (MD5) Previous issue date: 2008 / Resumo: Reações aldólicas entre enolatos de boro de metil-cetonas e aldeídos mostram-se como uma ferramenta bastante útil na formação de ligações carbono-carbono e tem sido empregada na síntese de fragmentos complexos de produtos naturais com potencial atividade biológica. O emprego de enolatos oriundos de b-alcoxi metil-cetonas leva a adutos com altas diastereosseletividades 1,5-anti dependendo da natureza estéreo-eletrônica do grupo b-alcóxi. Visando avaliar a influência de grupos fortemente retiradores de elétrons em reações aldólicas, esse trabalho vem ilustrar os resultados obtidos quando enolatos de boro de b-trialometil b-alcóxi metil-cetonas são colocados para reagir com aldeídos aquirais. Os adutos trialogenados são obtidos em diferentes graus de seletividade, no entanto, 1,5-syn sempre foi a estereoquímica relativa dos produtos principais, a qual foi determinada através de preparação de derivados bicíclicos. A reação aldólica de substratos trialogenados pode ser um recurso adicional na obtenção diastereosseletiva de moléculas com potenciais atividades biológicas ou mesmo como intermediários sintéticos visto que grupos trialometil são precursores de uma série de funções orgânicas / Abstract: The aldol reaction between boron enolates generated from methyl-ketones and aldehydes provides a very attractive method for carbon-carbon bond formation and has been applied for the syntheses of a wide variety of natural products with biological and pharmacological significance. The presence of a b-heteroatom substituent in the boron enolates of methylketones influences the stereochemical outcome of the corresponding aldol reactions and controls the overall diastereoselectivity of the process leading to moderate to high levels of 1,5-anti stereoinduction. In order to investigate the stereochemical impact groups we have prepared the b-trihalomethyl b-alkoxy methyl-ketones, which corresponding kinetic enol borinate were used in the aldol reactions with achiral aldehydes. Moderate to good levels of substrate-controlled, 1,5-syn-stereoinduction were obtained in these aldol reactions independent of the nature of the b-alkoxy protecting group. The relative stereochemistries of the major aldol trihalogenated adducts were determined by H-NMR and NOESY analysis of bicyclic derivatives / Mestrado / Quimica Organica / Mestre em Química

Neste trabalho foram realizadas reações de redução de cetonas empregando diferentes organismos marinhos como biocatalisadores (algas, fungos e bactérias). Nas triagens foram utilizados derivados de acetofenonas (o-iodoacetofenona, m-iodoacetofenona, p-iodoacetofenona, o-fluoracetofenona, o-cloroacetofenona, o-bromoacetofenona, o-nitroacetofenona) e duas cetonas 1,3-dicarboniladas: a 4,4,4-triflúor-1-(furan-2-il)butano-1,3-diona e a 4,4,4-triflúor-1-(naftalen-2-il)butano-1,3-diona. As reações com as algas marinhas Bostrychia tenella e a Bostrychia radicans levaram aos álcoois com excelentes seletividades (ee >98%), contudo, obtiveram-se baixas conversões. Foram isoladas as bactérias Bt-01 (B. tenella) e Bt-02 (B. radicans), as quais catalisaram as reduções das acetofenonas com resultados similares aos obtidos com as algas. Os fungos (Br-09, Br-23, Br-27, Br-61) isolados da alga B. radicans reduziram as acetofenonas com boas seletividades e conversões. Ainda, reações de redução das acetofenonas com quatro linhagens de fungos isolados da alga Sargassum sp (SMA2-C, SMA2-8, SMA2-58, SGPY-41) levaram a obtenção dos respectivos álcoois com diferentes conversões e seletividades. As reduções das cetonas 1,3-dicarboniladas foram realizadas com as algas B. tenella e B. radicans, e com sete linhagens de fungos marinhos (Aspergillus sydowii Ce15, Aspergillus sydowii Ce19, Aspergillus sydowii Gc12, Bionectria sp Ce5, Penicillium raistrickii Ce16, Penicillium miczynskii Gc5 e Trichoderma sp Gc1). As algas e os fungos marinhos catalisaram a redução regiosseletiva e estereosseletiva das cetonas 1,3-dicarboniladas, onde ocorreu a redução do grupo α-trifluorcarbonílico. Concluiu-se que as algas e seus microrganismos associados, e os fungos marinhos têm potencial para serem utilizados como biocatalisadores em reações de redução. Este trabalho foi o primeiro estudo realizado no país envolvendo algas marinhas e seus microrganismos associados em reações de redução de cetonas, cujos resultados são bastante promissores. / In this work, were investigated the ketone reduction reactions using several marine organisms as biocatalysts (algae, fungi and bacteria). In the screening were utilized acetophenone derivatives (o-iodoacetophenone, m-iodoacetophenone, p-iodoacetophenone, o-fluoroacetophenone, o-chloroacetophenone, o-bromoacetophenone, o-nitroacetophenone) and two 1,3-dicarbonylated compounds: 4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione and 4,4,4-trifluoro-1-(naftalen-2-yl)butane-1,3-dione. The reactions with algae Bostrychia tenella and Bostrychia radicans afforded the alcohols with high selectivities (ee > 98%), however, with low conversions. The bacteria Bt-01 and Bt-02 were isolated from algae B. tenella and B. radicans, respectively, which catalyzed the reductions of acetophenones as the same as obtained with the algae. The acetophenones were reduced by several fungi (Br-09, Br-23, Br-27, Br-61) in good selectivities and conversions. These fungi were isolated from Bostrychia radicans. In addition, the acetophenone reduction reactions were screened with four strains of fungi, which were isolated from algae Sargassum sp (SMA2-C, SMA2-8, SMA2-58, SGPY-41). The alcohols were obtained with different conversions and selectivities. The reductions of 1,3-dicarbonylated compounds were carried out with the algae B. tenella and B. radicans, and marine fungi (Aspergillus sydowii Ce15, Aspergillus sydowii Ce19, Aspergillus sydowii Gc12, Bionectria sp Ce5, Penicillium raistrickii Ce16, Penicillium miczynskii Gc5 and Trichoderma sp Gc1). The algae and marine fungi catalyzed regio- and estereoselectively reductions of the 1,3-dicarbonylated compounds. The α-trifluoromethylcarbonyl group was reduced preferentially. In conclusion, the algae and associated micro-organisms and marine fungi have potential for catalyzing ketone reduction reactions. This investigation was the first study carried out in the Brazil by using algae and associated micro-organisms in the ketone reduction reactions. The obtained results here are promising and interesting.

Glucose and ketones are important energy substrates in the human body and brain. Their use is highly regulated depending on energy status which can vary according to multiple factors such as type of cell, fed or fasted state, type of diet, or health state. Use of either substrate is also subject to multiple homeostatic feedback loops. Energy substrate availability has implications in several disorders including declining cognitive function in the elderly. While glucose availability is known to decrease in elderly with cognitive deficits, it is unclear whether this also occurs in healthy elderly, either in the body or brain. Also unknown is whether, in healthy elderly, the use of ketones as energy substrates is affected, and whether ketones could be used as an alternative energy substrate in situations of a decline in glucose availability. A clearer understanding of the use of glucose and ketones in aging is necessary to determine whether declining energy substrate availability that may occur in the elderly is a contributing factor to cognitive deficits, a result of cognitive pathology, or simply a feature of the physiological aging process. Objective. The overall goal of the laboratory where this research was carried out is to ascertain whether alternate energy sources to glucose, i.e. ketones, may help alleviate the risk of declining cognitive function during aging. The specific objective of the research project presented in this thesis was to evaluate the metabolism of glucose and ketones in the healthy elderly compared to young or middle age subjects during mild, short-term ketosis induced by a ketogenic breakfast. Results. Elderly people in relatively good health have a similar capacity to produce ketones and to oxidize [superscript 13]C-glucose and [superscript 13]C-β-hydroxybutyrate as middle-aged or young adults. Discussion. The results of this project encourage further exploration of whether ketones could be used as and alternative energy substrate to glucose as, at least in healthy elderly, there is no impedance of raising plasma ketones in response to a ketogenic intervention. // Résumé : Introduction. Le glucose et les cétones sont des substrats énergétiques importants pour le corps et le cerveau humain. Leur utilisation est spécifiquement régulée selon I'état énergétique qui varie en fonction du type de cellule, de I'état nourrie ou à jeun, du type de diète, de I'état de la santé. L'utilisation est également régulée par des voies de rétrocontrôle homéostatique. La disponibilité des substrats énergétiques est impliquée dans plusieurs désordres, dont le déclin des fonctions cognitives, chez les personnes âgées où une diminution de la disponibilité du glucose est démontrée. Cependant, il n'est pas encore connu si cette diminution est présente chez les personnes âgées en bonne santé ; soit dans le corps ou le cerveau. La capacité d'utiliser les cétones comme substrats énergétiques chez les personnes âgées saines et la possibilité d'utiliser les cétones comme substrat énergétique alternatif dans le cas d'un déclin de la disponibilité de glucose sont inconnues. Une meilleure compréhension de I'utilisation du glucose et des cétones sera nécessaire pour clarifier si une diminution de la disponibilité des substrats énergétique contribue au déclin cognitif, se manifeste à la suite des pathologies cognitives, ou encore est simplement une caractéristique du processus physiologique du vieillissement. Objectif. L'objectif principal du laboratoire est de déterminer si les sources d'énergie alternatives au glucose, c'est-à-dire les cétones, pourraient ralentir le déclin cognitif chez les personnes âgées. L'objectif du projet de recherche de ce mémoire était d'évaluer le métabolisme du glucose et des cétones chez les sujets âgés, d'âge moyen, et jeune après la prise d'un déjeuner induisant une faible cétogénèse de courte durée. Résultats. Les personnes âgées en santé ont une capacité similaire au sujet d'âge moyen et jeune à produire des cétones et à oxyder le [indice supérieur 13]C-glucose et le [indice supérieur 13]C-β- hydroxybutyrate. Perspectives. Les résultats de ce projet incitent à continuer à explorer si les cétones pourraient être utilisés comme substrats énergétiques afin de contourner le problème d'un déclin de I'utilisation du glucose, car il n'y a aucun obstacle dans la production des cétones suite a une intervention cétonique chez des sujets âgées en bonne santé.

Abstract : Normal aging is accompanied by several metabolic and structural changes in the brain and a heightened risk of cognitive decline. These brain changes may increase the chances of later developing Alzheimer’s disease. The first major objective of the present work was to quantify, through positron emission tomography (PET) and volumetric magnetic resonance (MR) imaging techniques, the effects of normal aging on brain metabolism and structure. Our results indicate that brain glucose hypometabolism can be present in older individuals who remain cognitively normal. Cognitive status was assessed using age-normalised neuropsychological tests. Brain glucose hypometabolism was quite specific and affected primarily the prefrontal cortex and the caudate nucleus. Due to the high variation in plasma ketones, brain ketone hypometabolism per se was not present in older persons (≥65 years old). However, a lower rate constant for brain ketone uptake was fairly widespread in our healthy older group. Lower regional brain volume during normal aging was widespread throughout the cortex and was more apparent than cortical thickness loss. The second major objective was to characterize brain ketone and glucose metabolism in the context of mild Alzheimer’s disease. Glucose hypometabolism in Alzheimer’s disease was present in the temporoparietal cortex when compared with cognitively normal older adults. However, no significant differences in brain ketone metabolism or rate constant were found between the two groups. Alternative energy sources to glucose may therefore be beneficial to the Alzheimer’s disease brain, at least early in the disease process, in order to maintain neuronal capacity and limit synaptic loss and decline in memory and cognition. // Résumé : Au cours du vieillissement normal, le cerveau va subir plusieurs changements métaboliques et structuraux qui vont accroitre le risque de déclin cognitif et du fait même augmenter le risque de développer la maladie d’Alzheimer. Les objectifs du présent travail étaient de : 1) quantifier l’effet du vieillissement normal sur la structure et le métabolisme du cerveau, grâce aux techniquesd’imagerie tomographie par émission de positons et l’imagerie par résonance magnétique ; 2) caractériser le métabolisme cérébral des deux substrats énergétiques du cerveau, le glucose et les cétones, dans un contexte de la maladie d’Alzheimer. Nos résultats indiquent qu’un hypométabolisme du glucose est présent chez des personnes âgées (65 ans et plus) qui démontrent pourtant une cognition normale. Cette diminution du métabolisme cérébral du glucose est observée spécifiquement au niveau des régions du cortex préfrontal et du noyau caudé. Du fait d’une grande variabilité au niveau des concentrations plasmatiques en cétones, aucune diminution du métabolisme des cétones n’a été constatée chez les personnes âgées. En revanche, la constante de transfert des cétones au cerveau était globalement diminuée. En ce qui concerne l’atrophie cérébrale au cours du vieillissement normal, nous avons observé qu’elle était globale, qu’elle concerne l’ensemble du cerveau et qu’elle était plus marquée que la diminution de l’épaisseur corticale. En comparant des personnes âgées en bonne santé à des personnes ayant la maladie d’Alzheimer, nous avons également confirmé que chez ces dernières, le métabolisme du glucose est diminué spécifiquement au niveau du cortex temporopariétal. Cependant, aucune différence entre les deux groupes de personnes n’a été observée en ce qui concerne le métabolisme cérébral des cétones. Ainsi en fournissant des substrats énergétiques autres que le glucose, il serait donc possible de maintenir les capacités neuronales, limiter la perte synaptique et ralentir le déclin cognitif. Ceci pourrait constituer une stratégie prometteuse dans la prévention et le traitement complémentaire au début de la maladie d’Alzheimer.

The focus of these studies has been toward the development of new synthetic methods and procedures for the synthesis of novel compounds with unique biological properties. This research has led to the development of two new synthetic strategies for the construction of two novel amphibian alkaloids. In addition, the efforts have led to the large-scale process for the preparation of a novel analgesic compound. The regioselective ring opening of lactones (δ-valerolactone and γ-butyrolactone) with aryllithium reagents is reported for the construction of a series of δ-hydroxyarylketones and γ-hydroxyarylketones. Both the R and S enantiomers of the amphibian alkaloid noranabasamine were prepared in >30% overall yield with 80% ee and 86% ee, respectively. An enantioselective iridium-catalyzed N-heterocyclization reaction with either (R)- or (S)-1-phenylethylamine and 1-(5-methoxypyridin-3-yl)-1, 5-pentanediol was employed to generate the 2-(pyridin-3-yl)-piperidine ring system in 69-72% yield. A cis-2, 5-disubstitued pyrrolidine building block derived from (-)-Cocaine•HCl was prepared. We utilized this compound as a chiral building block for the formal synthesis of (+)-gephyrotoxin. Using this pyrrolidine building block, Kishi's intermediate was obtained enantiospecifically in 15 steps and 9.4% overall yield. A large-scale process for the preparation of the analgesic compounds SCP-123 and its sodium salt, SCP-123ss•monohydrate has been developed. The process for the preparation of SCP-123 required three synthetic steps with no chromatography, while the process for the preparation of SCP-123ss required four synthetic steps and no chromatography. The overall yields for both SCP-123 and SCP-123ss were 47% and 46%, respectively, and both compounds were obtained in exceptionally high purity (>99%).

Na primeira parte deste trabalho, desenvolvemos duas metodologias para a preparação de α-dicloroteluro cetonas. A primeira utiliza a reação direta de tricloretos de ariltelúrio com cetonas e a segunda envolve a reação do mesmo reagente com éteres enólicos de silício de cetonas. As dicloroteluro cetonas preparadas foram transformadas em α-halo cetonas pela reação com cloro ou bromo, ou utilizando condições de termólise sob pressão reduzida. Dados de ressonância magnética nuclear de 1H e de 13C, de difração de raios-X e de espectros no infra-vermelho foram utilizados na determinação estrutural dos compostos preparados. Numa segunda arte foram preparados α-halo-α-seleno alcanos através da adição de HBr a selenetos vinílicos obtidos por reação de acetilenos aromáticos com selenofenol. Os α-halo-α-seleno alcanos foram transformados em α-selenofenil acetaldeídos por reação de solvólise em DMSO. / In the first parto of this work two methodologies for the synthesis of α-dichlorotelluroketones were developed. The first one employs the reaction of aryltellurium tricholorides with ketones and the second one involves the reaction of the same reagent with silylenol ethers of ketones. The α-dichlorotelluroketones prepared were transformed into α-halo ketones by means of the reaction with chlorine or bromine or by pyrolysis at reduced pressure. 1H and 13C nuclear magnetic ressonance, x-ray difraction and infrared data were used in the structure elucidations of the compounds prepared. In the second part of the work α-halo- α-seleno-alkanes were prepared by addition of hydrogen bromide to vinylic selenides which were prepared by reacting aromatic acetylenes with selenophenol. The α-halo-α-seleno-alkanes were transformed into α-selenophenyl acetaldehydes by solvolysis in DMSO.

The thermal decomposition products (TDP) generated during fire suppression with 1,1,1,2,2,4,5,5,5 nonafluoro-4-trifluoromethyl pentan-3-one were studied using wet chemistry and FTIR. Small-scale testing was conducted in a 1.28-m3 (45-ft3) enclosure. The effects of fire size, agent discharge time, and agent concentration on TDP are reported. A comparison of the two methods is presented. In terms of magnitude and generation trends, the TDPs were found to be comparable to other in-kind halon alternatives.