Stereodivergent and enantiodivergent pathways for the Friedel–Crafts reactions were computationally studied with DFT methods. This study aims to explain recently observed solvent-dependent regioselectivity, and enantioselectivity when cinchona catalyst is used. Deprotonation reaction, Frontier Kohn-Sham orbitals, dual descriptors, Mulliken charges, and Hirshfeld atomic charge for reactant were calculated and analyzed. The most probable position of electrophilic attack and nucleophilic attack in-silico predicted aligns with experimental observations. The calculation of the transition states on the anionic and neutral model in a vacuum show preference for the electrophilic attack in the para position. In comparison to the anionic system, the presence of potassium cation improves ortho/para selectivity and increases the energy barrier. For the key enantioselective step, 12 transition states were calculated which covers 4 representative product such: (R)-ortho, (S)-ortho, (R)-para, and (S)-para. The computational study suggests, that the presence of the cesium cation is essential for the arrangement of the reactant and catalyst in the transition state, which leads to observed selectivity.

Brief explanation and history of cinchona based Phase Transfer Catalysis (PTC). Studied aryl acetates in PTC, encompassing napthoyl, 6-methoxy napthoyl, phenyl and protected 4-hydroxy phenyl acetates. Investigated means of controlling the selectivity of the PTC reaction by changing the electrophile size, the ether side group size or by addition of inorganic salts. Found that either small or aromatic electophiles increased enantioselectivity more than aliphatic electrophiles, and that increasing the size of ether protecting group also increased selectivity. Positive effects of salt addition included either decreasing reaction time or increasing enantiomeric excess. Applied findings towards the synthesis of S-equol. Computational experiments working towards deducing the transition state between PTC and aryl acetate substrates.

Functionalized cyanophosphates are important starting materials for the synthesis of beta-lactam ring moiety of beta-lactam antibiotics. The cyanophosphates are synthesized starting from easily available acylphosphonate and ethylcyanoformate. Acylphosphonates are synthesized starting from acylchloride and trimethylphosphite. Addition of acylphoshonate to ethylcyanoformate furnishes the cyanophosphate with the quaternary center.

Submitted by Reginaldo Soares de Freitas (reginaldo.freitas@ufv.br) on 2015-11-09T13:01:45Z No. of bitstreams: 1 texto completo.pdf: 1860106 bytes, checksum: 353b8088a255cf3282d4aa52ad5a282a (MD5) / Made available in DSpace on 2015-11-09T13:01:45Z (GMT). No. of bitstreams: 1 texto completo.pdf: 1860106 bytes, checksum: 353b8088a255cf3282d4aa52ad5a282a (MD5) Previous issue date: 2207-07-31 / A utilização de plantas medicinais com fins terapêuticos, para tratamento, cura e prevenção de doenças, é uma das mais antigas formas de prática medicinal da humanidade. É cada vez mais freqüente o uso de plantas medicinais, mas muitas vezes as supostas propriedades farmacológicas anunciadas não possuem a validade científica, por não terem sido investigadas, ou por não tido suas ações farmacológicas comprovadas em testes científicos pré-clínicos e clínicos. O medicamento Kraftol é uma associação de extratos fluidos de Cinhona calisaya (Quina amarela), Cola acuminata (noz de cola), Paullinia cupana (guaraná), Iodo, Ácido tânico, Formato de sódio, Glicerofosfato de cálcio, Iodeto de potássio. É um medicamento indicado para o tratamento de convalescenças e nos estados de desnutrição, nas amgdalites, faringites e adenopatias. O objetivo do presente trabalho foi avaliar a ação antiedematogênica e antiulcerativa do medicamento Kraftol e do flavonóide Ipriflavona (7-isopropoxi-isoflavona), em processos inflamatórios como edema e ulcera gástrica em ratos machos da linhagem Wistar; e avaliar a atividade antiulcerativa dos extratos presentes no medicamento Kraftol de forma isoladamente e associados sem os sintéticos. Realizou-se também um estudo de toxicologia oral aguda e subcrônica (doses repetidas) do medicamento Kraftol, tendo como base a resolução No 90, de 16 de março de 2004 da ANVISA. Para o teste nos processos inflamatórios induziu-se edema na pata em ratos com a injeção de 0,02 ml da substância capsaicina (12,5 mg-1) e ácido araquidônico (2 mg/pata) e receberam o tratamento por via oral. As lesões gástricas foram induzidas com administração oral de ácido acetil salicílico (150mg/Kg em 1,5 ml de 0,2N HCl). Para avaliação da toxicidade pré-clínica os animais foram tratados por via oral com doses de acordo com Guia para realização de estudos de toxicidade pré-clínica de fitoterápicos, conforme a resolução vingente. Foram realizadas também análises bioquímicas complementares (leucograma, colesterol total, triglicerídeos, glicose , fosfatase alcalina, TGP, TGO, creatinina, uréia, potássio,ácido úrico, Gama GT) e análise macroscópica e microscópica dos órgãos quando necessário. / The use of medicinal plants with therapeutics purposes for treatment, cure and prevention of diseases is one of most ancient medical practices of humanity. The use of medicinal plants is increasingly spreading, but many times the allegedly pharmacological properties have no scientific validity either because they have not been investigated or because their pharmacological actions have not been proved in pre-clinical and clinical scientific tests. The medicine Kraftol is an association of fluid extracts of Cinhona calisaya (yellow kina), Cola acuminata (cola nut), Paullinia cupana (guaraná), Iodine, tannic acid, sodium phormate, calcium glycerophosphate, potassium iodate. It is a medicine indicated for the treatment of recovery and malnutrition, amygdalitis, pharingitis and adenophaties. The objective of the present work was to evaluate the antiedematogenic and antiulcer action of the medicine Kraftol and of the flavonoid Ipriflavone (7-isopropoxi-isoflavone), in inflammatory processes such as edema and gastric ulcer in Wistar breed male mice; and evaluate the antiulcer activity of the extracts present in the medicine Kraftol, isolatedly and associated without the synthetics. It was also carried out a study on oral sharp and subchronic toxology (repeated doses) of the medicine Kraftol, based on the ANVISA resolution 90, March 16, 2004. For the test in the inflammatory processes, an edema was induced in mice legs by injecting 0,02 ml of the capsaicin substance (12,5 mg -1) and arachdonic acid (2 mg/leg) as well as oral treatment. The gastric wounds were induced by oral administration of acetylsalicylic acid (150mg/Kg em 1,5 ml de 0,2N Hcl). In order to evaluate the pre-clinical toxicity, the animals were treated with oral doses according to the Guide for the accomplishment of studies on phytotherapic pre-clinical toxicity, following the current resolution. Complementary biochemical analyses were also carried out (leucogram, total cholesterol, triglicerids, glucose, alkaline phosphatase, TGP, TGO, creatinin, urea, potassium, uric acid, Gama GT) and microscopic and macroscopic analyses of the organs were performed as well, when necessary.

Os sais derivados de alcalóides da Cinchona têm sido muito utilizados como catalisadores de transferência de fase, em reações assimétricas. No entanto, sua performance como agentes de discriminação quiral tem sido pouco explorada. Com o objetivo de melhor compreender as bases moleculares que comandam o reconhecimento quiral dos isômeros ópticos de compostos carbonílicos e carboxílicos, quando em mistura com a quinina ou com sais de alcalóides da Cinchona, foi realizada uma série de experimentos, utilizando a técnica da RMN de 1H. A atribuição dos deslocamentos químicos aos solvatos de cada enantiômero foi feita pelo registro do espectro de RMN de 1H de misturas dos agentes de discriminação quiral com amostras enantiopuras ou enantiomericamente enriquecidas dos substratos. A estabilidade relativa dos solvatos foi estimada utilizando-se modelos moleculares, nos quais foi possível identificar a existência de interações do tipo π-π e de ligações de hidrogênio. As conclusões baseadas nos experimentos de RMN de 1H foram concordantes com as resultantes da análise dos modelos moleculares, construídos para cada par substrato/agente de discriminação quiral / Salts of Cinchone alcaloids are common chiral catalysts for asymmetric phase-transfer reactions. However, studies on their performance as chiral discriminating are still scarce. In order to investigate the molecular basis of chiral recognition for such compounds, the 1H NMR spectra of admixtures of quinine or Cinchone alkaloids salts with carbonyl and carboxyl derivatives were recorded and analyzed. The relative stabilities of the solvated complexes were estimated on the basis of preferential π-π and hydrogen bonding interactions between substrates and the chiral discriminating agent. Conclusions based on results of the 1H NMR experiments were in line with those arising from the analysis of molecular models for the substrate/chiral discriminating agent pairs

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.

Os sais derivados de alcalóides da Cinchona têm sido muito utilizados como catalisadores de transferência de fase, em reações assimétricas. No entanto, sua performance como agentes de discriminação quiral tem sido pouco explorada. Com o objetivo de melhor compreender as bases moleculares que comandam o reconhecimento quiral dos isômeros ópticos de compostos carbonílicos e carboxílicos, quando em mistura com a quinina ou com sais de alcalóides da Cinchona, foi realizada uma série de experimentos, utilizando a técnica da RMN de 1H. A atribuição dos deslocamentos químicos aos solvatos de cada enantiômero foi feita pelo registro do espectro de RMN de 1H de misturas dos agentes de discriminação quiral com amostras enantiopuras ou enantiomericamente enriquecidas dos substratos. A estabilidade relativa dos solvatos foi estimada utilizando-se modelos moleculares, nos quais foi possível identificar a existência de interações do tipo π-π e de ligações de hidrogênio. As conclusões baseadas nos experimentos de RMN de 1H foram concordantes com as resultantes da análise dos modelos moleculares, construídos para cada par substrato/agente de discriminação quiral / Salts of Cinchone alcaloids are common chiral catalysts for asymmetric phase-transfer reactions. However, studies on their performance as chiral discriminating are still scarce. In order to investigate the molecular basis of chiral recognition for such compounds, the 1H NMR spectra of admixtures of quinine or Cinchone alkaloids salts with carbonyl and carboxyl derivatives were recorded and analyzed. The relative stabilities of the solvated complexes were estimated on the basis of preferential π-π and hydrogen bonding interactions between substrates and the chiral discriminating agent. Conclusions based on results of the 1H NMR experiments were in line with those arising from the analysis of molecular models for the substrate/chiral discriminating agent pairs

Le développement de nouvelles méthodologies énantiosélectives organocatalysées est au centre des projets de cette thèse. Nous avons plus particulièrement considéré le potentiel de "paires d'ions coopératifs" chirales possédant une partie ammonium dérivée des alcaloïdes de quinquina et une partie anionique à caractère nucléophile permettant d'activer un réactif. Dans un premier temps, nous avons employé un amidure d'ammonium chiral (généré in situ par réaction entre un amide N-silylé et un phénolate de quininium) comme base de Brønsted délivrée en quantité catalytiques en deux réactions distinctes. Initialement, cette stratégie nous a permis de mettre au point un procédé de désymétrisation de cétones prochirales par déprotonation éniantosélective. Bien que les excès énantiométriques obtenus restent modestes, notre approche constitue la première version organocatalysée. Puis, nous avons pu développer avec succès une nouvelle réaction d'aldolisation directe vinylogue énantiosélective de (5H)-furan-2-ones avec de bons rendements et diastérosélectivités anti et des excès énantiométriques allant jusqu'à 94 %. Dans un second temps, nous avons décrit deux nouveaux cycles catalytiques de protonation énantiosélective d'énolates masqués. Tout d'abord, l'utilisation d'hydrogénocarbonate de potassium et d'une amine chirale a conduit à l'obtention de cétones énantioenrichies α-substituées avec des excès énantiométriques allant jusqu'à 93 % à partir des trifluoacétates d'énols correspondants. Puis, les propriétés de base de Lewis de nos phénolates d'ammoniums quaternaires chiraux ont été valorisés lors de la protonation énantiosélectives d'éthers d'énols silylés en présence de phénols. / This work deals with the development of new asymetric organocatalyzed methodologies. More particularly we were focused on using "cooperative chiral ion pairs" having an ammonium moiety derived from cinchona alkaloids and an anionic moiety with nucleophilic properties able to activate a reagent.Firstly, we used an in situ generated chiral ammonium amide (from the combination of an aminosilane and a quininium aryloxide) as a Brønsted base in two distinct reactions. Initially, this strategy was applied to an organocatalyzed desymmetrization of prochiral ketones by enantioselective deprotonation. Despite modest enantiometric excesses, this report constitutes the first example of an enantioselective orgonacatalyc approach. Then, an anti-selective direct vinylogous asymmetric aldol reaction of (5H)-furan-2-ones was achieved in good yields and enantioselectivities up to 94%.Secondly, we described two new catalytic cycles for the enantioselective protonation of latent enolates. By means of cinchona alkaloids and hydrogenocarbonates, enantioenriched α-substituted ketones were obtained with good enantiometric excesses up to 93% starting from the corresponding enol trifluoacetates. Finally, the nucleophilic properties of our ammonium phenoxide catalysts prompted us to develop an enantioselective protonation reaction of silyl enol ethers in the presence of phenol as achiral proton source.

Project I. Cinchona alkaloid-derived quaternary ammonium salts have been successfully used as phase-transfer catalysts, particularly in asymmetric alkylations. Our group applied this type of catalyst in the synthesis of β-hydroxy α-amino acids via aldol reactions and discovered that the Park-Jew catalyst afforded good yields and good enantiomeric excess of the syn diasteromers, but negligible diastereoselectivity. This project was therefore focused on the synthesis of novel cinchonidine-derived catalysts with the Park-Jew catalyst as the lead structure. The C3 position of cinchonidine nucleus was modified to achieve dimers and catalysts possessing electron-deficient alkyne and alkene moieties. Synthesized catalysts were tested in the asymmetric aldol reactions, with some of them yielding improvements relative to the Park-Jew catalyst. Project II. Celogentin C is a natural product that was isolated from the seeds of Celosia argentea by Kobayashi in 2001. It is the most potent inhibitor of the polymerization of tubulin from among the celogentin family. The novel bicyclic octapeptide structure contains unusual linkages between leucine β-carbon and indole C-6 of tryptophan and between tryptophan indole C-2 and imidazole N-1 of histidine. The project culminated in the first total synthesis of celogentin C. Reaction conditions were developed by synthesizing the left-hand ring and the right-hand ring separately, and the total synthesis was accomplished via a left to right strategy. Key transformations in the construction included intermolecular Knoevenagel condensation, radical conjugate addition, macrolactamization, and oxidative coupling.