Inspirados em reações catalisadas por enzimas a partir de micro-organismos encontrados em ambientes marinhos severos (psicrofílicos), em que a quantidade de oxigênio é restrita, observou-se que a Arthrobacter sp. CCT 7749 realizou diferentes transformações químicas mudando de condições reacionais anaeróbias para aeróbias. Dependendo da presença ou ausência de oxigênio, ambas desracemização de alcoóis ou redução de cetonas com seletividades enantiocomplementares foram realizadas pelo mesmo microorganismo. Estes conceitos foram aplicados tanto para desracemização quanto para redução enantiosseletiva de compostos contendo heteroátomos (silício, fósforo, estanho e boro). Visando a identificação molecular das enzimas responsáveis pelas reações de oxido-redução, buscou-se desenvolver uma metodologia de purificação enzimática usando diferentes técnicas. Inicialmente a lise celular da Arthrobacter sp. CCT 7749 empregando a liticase na presença de β-mercaptoetanol e usando ondas ultrassônicas produziu 28 mg/mL de proteínas. A purificação da oxidorredutase ocorreu através de colunas cromatográficas de troca iônica DEAE FF, seguida por ANX FF. O extrato protéico contendo a enzima parcialmente pura apresentou atividade específica de 4,23 U/mg na oxidação do (R,S)-1-(4-metilfenil)etanol à cetona correspondente. Através do uso das técnicas native-PAGE e zimografia detectou-se uma massa molecular da enzima de ≈240 kDa e que provavelmente se encontrava na forma hetero-hexamérica apresentando três subunidades em ~35 kDa e três em ~45 kDa. Observou-se que, surpreendentemente, a fração protéica parcialmente pura também foi capaz de reduzir a 4-metilacetofenona obtendo-se 17% do (S)-1-(4-metilfenil)etanol com excelente excesso enantiomérico >99%. / Inspired by enzyme-catalyzed reactions with microorganisms found in harsh marine environments (psychrophilic), in which the amount of oxygen is restrict, we have shown that Arthrobacter sp. CCT 7749 can perform different chemical transformations by switching from anaerobic to aerobic reaction conditions. Depending on the presence or absence of oxygen, either alcohol deracemization or ketone reduction with enantiocomplementary selectivities can be performed by the same microorganism. These concepts were applied for both deracemization and enantioselective reduction of heteroatom-containing molecules (silicon, phosphorus, tin and boron). Aiming Enzyme purification, different techniques were employed. Cell lysate of Arthrobacter sp. CCT 7749. Was prepared using lyticase and β-mercaptoethanol bu ultrasonication. Purification of this enzyme occurred through chromatographic columns of DEAE FF ion exchange, followed by ANX FF. The partially pure oxidoreductase presented specific activity of 4.23/mg in the oxidation (RS)-1-(4- methylphenyl)ethanol to the corresponding ketone. Native-PAGE and zymography have shown that the enzyme had ≈240 kDa molecular mass, probably in the form hetero-hexameric with 3 subunits ~35 kDa and three ~45 kDa. Surprisingly, the partially pure protein fraction was able to reduce the 4- methylacetophenone giving 17% of (S)-1-(4-methylphenyl)ethanol with excellent enantiomeric excess >99%.

Orientador: Carlos Roque Duarte Correia / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-25T07:38:41Z (GMT). No. of bitstreams: 1 Schwalm_CristianeStorck_D.pdf: 13409001 bytes, checksum: 641c6de21f40f4ad79f3a11d0a95ad9d (MD5) Previous issue date: 2014 / Resumo: O presente trabalho teve como objetivo geral o estudo da reação de Heck-Matsuda, tanto no âmbito de novas aplicações sintéticas como no seu desenvolvimento metodológico. Na primeira parte deste trabalho, uma metodologia para obtenção de derivados 2- e 3-arilpirrólicos utilizando a reação de Heck-Matsuda como etapa chave foi desenvolvida, sendo esta posteriormente aplicada na síntese total do produto natural pentabromopseudilina. Na segunda parte do trabalho, esta metodologia foi estendida para a obtenção de uma pirroloanilina utilizada como intermediário chave na síntese total das marinoquinolinas, a qual foi completada pela reação de Pictet-Spengler com diferentes aldeídos. A rota sintética utilizada permitiu a preparação de quatro membros desta família de produtos naturais (marinoquinolinas A, B, C e E), bem como nove análogos não naturais, os quais foram encaminhados para avaliação de atividade antichagásica e antimalarial. Na parte final deste trabalho, esforços foram direcionados para o desenvolvimento de uma metodologia para a arilação enantiosseletiva do 2,3-diidrofurano via reação de Heck-Matsuda. Os resultados obtidos demonstraram que a escolha do ligante apropriado permite a modulação da reação, sendo que ligantes do tipo PyBOX levam aos adutos de Heck primários de configuração S, enquanto ligantes do tipo BOX levam aos respectivos acetais cíclicos de configuração R, formados pela isomerização do aduto primário seguida de adição de metanol na ligação dupla. Os dois tipos de produto puderam ser obtidos com rendimentos de moderados a bons e razões enantioméricas moderadas, e uma racionalização para a estereoquímica observada é proposta para ambos os casos. Por fim, um dos adutos obtidos foi utilizado na síntese de um análogo do produto natural (-)-gloeosporiol / Abstract: The present work had as general objective the study of the Heck-Matsuda reaction, aiming at new synthetic applications and its methodological development. In the first part of this work, a method was developed for the synthesis of 2- and 3- arylpyrrole derivatives using the Heck-Matsuda reaction as the key step, which was then applied to the total synthesis of the natural product pentabromopseudilin. In the second part of this work, this methodology was extended to the preparation of a pyrroloaniline compound, which was used as a key intermediate in the total syntheses of marinoquinolines, that were completed by the Pictet-Spengler reaction with different aldehydes. This synthetic route enabled the preparation of four members from this family of natural products (marinoquinolines A, B, C and E) as well as nine non-natural analogues, which were submitted to antichagasic and antimalarial activities evaluation. In the final part of this study, efforts were directed towards developing a methodology for the enantioselective arylation of 2,3-dihydrofuran by the Heck-Matsuda reaction. The results have shown that the appropriate choice of ligands modulates the reaction. PyBOX-type ligands lead to the primary Heck adducts with S configuration, while BOX-type ligands lead to the respective cyclic acetals with R configuration, formed by isomerization of the primary adduct followed by addition of methanol across the double bond. The two types of products were obtained in moderate to good yields with moderate enantiomeric ratios, and a rationalization for the observed stereochemistry is proposed for both cases. Finally, one of the adducts was used in the synthesis of an analogue of the natural product (-)-gloeosporiol / Doutorado / Quimica Organica / Doutora em Ciências

Rhodium-catalysed enantioselective allylation reaction of imines in the presence of chiral diene ligands has been investigated. Under the optimised conditions, cyclic imines provided homoallylic amines in high yield and excellent enantioselectivities. The reaction most likely proceeds via allylrhodium(I) intermediates, and represents the first rhodium-catalysed enantioselective nucleophilic allylation of π-electrophiles with allylboron compounds. Furthermore, the allylations display a strong preference for carbon–carbon bond formation at the more substituted terminus of the allyl fragment of the allyltrifluoroborate. To demonstrate the utility of the allylation products, representative manipulations were conducted. Enantioselective Nickel-Catalysed Michael Additions of 2-Acetylazaarenes to Nitroalkenes An enantioselective Michael addition of acylazaarenes with α-substituted β-nitroacrylates in the presence of a chiral Ni(II)–bis(oxazoline) complexes has been developed. A range of azaaryl nucleophiles were shown to react with a variety of nitroalkenes to construct highly functionalised Michael addition products which contain a stereogenic all-carbon quaternary stereocentre with moderate to high yields and enantioselectivities. A possible mechanism for this reaction has been proposed.

No description available.

Chloroperoxidase (CPO) is the most versatile heme-containing enzyme that catalyzes a broad spectrum of reactions. The remarkable feature of this enzyme is the high regio- and enantio-selectivity exhibited in CPO-catalyzed oxidation reactions. The aim of this dissertation is to elucidate the structural basis for regio- and enantio-selective transformations and investigate the application of CPO in biodegradation of synthetic dyes. To unravel the mechanism of CPO-catalyzed regioselective oxidation of indole, the dissertation explored the structure of CPO-indole complex using paramagnetic relaxation and molecular modeling. The distances between the protons of indole and the heme iron revealed that the pyrrole ring of indole is oriented toward the heme with its 2-H pointing directly at the heme iron. This provides the first experimental and theoretical explanation for the "unexpected" regioselectivity of CPO-catalyzed indole oxidation. Furthermore, the residues including Leu 70, Phe 103, Ile 179, Val 182, Glu 183, and Phe 186 were found essential to the substrate binding to CPO. These results will serve as a lighthouse in guiding the design of CPO mutants with tailor-made activities for biotechnological applications. To understand the origin of the enantioselectivity of CPO-catalyzed oxidation reactions, the interactions of CPO with substrates such as 2-(methylthio)thiophene were investigated by nuclear magnetic resonance spectroscopy (NMR) and computational techniques. In particular, the enantioselectivity is partly explained by the binding orientation of substrates. In third facet of this dissertation, a green and efficient system for degradation of synthetic dyes was developed. Several commercial dyes such as orange G were tested in the CPO-H2O2-Cl- system, where degradation of these dyes was found very efficient. The presence of halide ions and acidic pH were found necessary to the decomposition of dyes. Significantly, the results revealed that this degradation of azo dyes involves a ferric hypochlorite intermediate of CPO (Fe-OCl), compound X.

Part 1: Transition-metal-catalyzed direct transformations of aromatic C-H bonds are emerging as valuable tools in organic synthesis. These reactions are attractive because of they allow for inherently efficient construction of organic building blocks by minimizing the pre-activation of substrates. Of these processes, direct arylation has recently received much attention due to the importance of the biaryl core in medicinal and materials chemistry. Also, alkyne hydroarylation has garnered interest because it allows for the atom-economical synthesis of functionalized alkenes directly from simple arenes and alkynes. Described in this thesis are number of advancements in these areas. First, palladium catalyzed direct arylation of azine N-oxides using synthetically important aryl triflates is described. Interesting reactivity of aryl triflates compared to aryl bromides was uncovered and exploited in the synthesis of a compound that exhibits antimalarial and antimicrobial activity. Also reported is the efficient, direct arylation enabled (formal) synthesis of six thiophene based organic electronic materials in high yields using simple starting materials. Additionally, the site-selective direct arylation of both sp2 and sp3 sites on azine N-oxide substrates is described. The arylation reactions are carried out in either a divergent manner or a sequential manner and is applied to the synthesis of the natural products, Papaverine and Crykonisine. Mechanistic investigations point towards the intimate involvement of the base in the mechanism of these reactions. Next, the rhodium(III)-catalyzed hydroarylation of internal alkynes is described. Good yields are obtained for a variety of alkynes and arenes with excellent regioselectivity for unsymmetrically substituted alkynes. Mechanistic investigations suggest that this reaction proceeds through arene metalation with the cationic rhodium catalyst, which enables challenging intermolecular reactivity. Part 2: Access to single enantiomer compounds is a fundamental goal in organic chemistry and despite remarkable advances in enantioselective synthesis, their preparation remains a challenge. Kinetic resolution of racemic products is an important method to access enantioenriched compounds, especially when alternative methods are scarce. Described in this thesis is the resolution of tertiary and secondary alcohols, which arise from ketone and aldehyde aldol additions. The method is technically simple, easily scalable, and provides tertiary and secondary alcohols in high enantiomeric ratios. A rationale for the unique reactivity/selectivity associated with (1S,2R)-N-methylephedrine in the resolution is proposed. Organocatalysis is a rapidly developing, powerful field for the construction of enantioenriched organic molecules. Described here is a complimentary class of organocatalysis using simple aldehydes as temporary tethers to perform challenging formally intermolecular reactions at room temperature. This strategy allows for the enantioselective, intermolecular cope-type hydroamination of allylic amines with hydroxyl amines. Also, interesting catalytic reactivity for dichloromethane is revealed.

Les acides phosphoriques chiraux sont des organocatalyseurs très efficaces qui permettent de catalyser une grande variété de réactions asymétriques. Depuis leur développement en 2004, de nombreux acides phosphoriques à chiralité axiale ou à chiralité centrale ont vu le jour. Cependant, aucun exemple d’acides phosphoriques à chiralité planaire n’avait été reporté.Deux nouvelles familles d’acides phosphoriques à chiralité planaire, possédant un motif paracyclophane et un espaceur ferrocénique ou biphénylène, ont été développées au laboratoire. Les propriétés catalytiques de ces nouvelles familles ont été étudiées, notamment dans la réaction de réduction de quinoléines par les esters de Hantzsch. Une bonne activité et des excès énantiomériques allant jusqu’à 92% ont été obtenus. Ces squelettes à motif paracyclophane ont également été exploités pour développer de nouveaux catalyseurs organométalliques chiraux, qui ont été testés dans des réactions de catalyses organométalliques avec des complexes d’or et de rhodium. / Chiral phosphoric acids as organocatalysts have shown high efficiency and versatility in order to catalyze a lot of reactions. Since their development in 2004, a number of chiral phosphoric acids displaying an axial or a central chirality have been synthesized. Nevertheless, there was no example of planar chiral phosphoric acids.We have developed two new families of planar chiral phosphoric acids, based on a paracyclophane scaffold and displaying a ferrocenic or a biphenylene linker. These phosphoric acids have been evaluated, as organocatalysts, in an organocatalytic reaction of quinolines reduction using Hantzsch esters. Good yields and enantiomeric excess up to 92% have been obtained. These new paracyclophane scaffolds have been used to develop chiral organomelallic catalysts, which have been engaged in gold and rhodium complexes catalysis reactions.

E-492, actinofuranone A, and JBIR-108 are natural compounds isolated from actinobacteria Streptomyces genus and can lead to the development of new pharmaceuticals as they have some biological interesting activities. Although the synthesis of these actinofuranones has been already published, this work brings new methods for the preparation of their fragments. The key step of the synthesis is enantioselective crotylboration of an aldehyde catalyzed by a chiral Brønsted acid and by which two centres of chirality are introduced in one step. The other crucial steps of the synthesis are composed of Ru-catalyzed alkene-alkene cross-metathesis and Pd- catalyzed Suzuki cross-coupling. Keywords: natural compound, enantioselective syntheses, crotylation, catalysis, actinofuranone fragment

The current methodologies of catalytic enantioselective allylation of aldehydes were studied on conjugated dienals and later on haloacrylaldehydes as the substrates. The resulting enantioenriched homoallylalcohols were prepared by reactions promoted either by commercial Brønsted acid catalysts or by Lewis base catalysts developed by our group, often with high enantio- and diastereoselectivities. Subsequently, the methodology was expanded on catalytic enantioselective crotylation and pentenylation reactions, practically unknown not only with these substrates. The applicability of this synthetic approach was demonstrated on preparation of several natural products or their intermediates.

The ability of gold(I) to activate many types of unsaturated bonds toward nucleophilic attack was not widely recognized until the early 2000s. One major challenge in gold catalysis is the control over regioselectivity when there are two or more possible products as a result of complicated mechanistic pathways. It is well know that the choice of ligand can have dramatic effects on which pathway is being followed but very rarely are the reasons for this selectivity understood. The synthesis of new acyclic diaminocarbenes was developed and a study of the ligand effects on the regioselectivity of a gold-catalyzed domino enyne cyclization hydroarylation reaction and a Nazarov cyclization was undertaken. New chiral acyclic diaminocarbenes were also developed and tested along side new C3-symmetric phosphite ligands in an asymmetric intramolecular hydroamination of allenes. Structure activity correlations were developed for the potential use in further rational ligand design. The synthesis of 6a,7-dihydro-5-amino-dibenzo[c,g]chromene derivatives via a gold-catalyzed domino reaction of alkynylbenzaldehydes in the presence of secondary amines was developed. These were sent to be screened for biological activity.