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Adsorption in porous materials plays a significant role in industrial separation processes. Here, the host-guest interaction and the pore shape influence the distribution of products. Metal-organic frameworks (MOFs) are promising materials for separation purposes as their diversity due to their building block synthesis from metal corners and organic linker gives rise to a wide range of porous structures. The selectivity differs from MOF to MOF as the size and shapes of their pores are tuneable by altering the organic linkers and thus changing the host-guest interactions in the pores. Using mainly molecular simulation techniques, this work focuses on three types of separations using MOFs. Firstly, the experimental incorporation of calix[4]arenes in MOFs as a linker to create additional adsorption sites is investigated. For a mixture of methane and hydrogen, it is shown that in the calix[4]arene-based MOFs, methane is adsorbed preferentially over hydrogen with much higher selectivities compared to other MOFs in the literature. Remarkably, it was shown that extra voids created by calix[4]arene-based linkers, were accessible to only hydrogen molecules. Secondly, the strong correlation between different pore sizes and shapes in MOFs and their capabilities to separate xylene isomers were investigated for a number of MOFs. Finally, the underlying molecular mechanism of enantioseparation behaviour in a homochiral MOF for a number of chiral diols is presented. The simulation results showed good agreement with experimental enantioselectivity values. It was observed that high enantioselectivity occurs only at high loadings and when a perfect match in terms of size and shape exists between the pore size and the adsorbates. Ultimately, the information obtained from molecular simulations will further our understanding of how network topology, pore size and shape in MOFs influence their performance as selective adsorbents for desired applications.

Orientadores: Carlos Roque Duarte Correia, Diogo Seibert Lüdtke / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-20T02:45:10Z (GMT). No. of bitstreams: 1 Leal_LuizHenriqueQueiroz_M.pdf: 1546385 bytes, checksum: 4ce60e2af123f00d362d203dcc39ae49 (MD5) Previous issue date: 2011 / Resumo: Álcoois secundários e propargílicos quirais são importantes blocos sintéticos por sua versatilidade e potencial aplicação na construção de estruturas mais complexas. O presente trabalho teve como objetivo a síntese de ligantes aminoálcoois quirais derivados de prolina, utilizando-se como etapa chave a arilação de Heck-Matsuda, e a aplicação desses ligantes nas reações de redução de cetonas pró quirais e nas reações de alquinilação de aldeídos pró quirais visando à produção de álcoois propargílico e/ou secundários quirais enantiomericamente enriquecidos. Nas reações de Redução de cetonas pró quirais, acetofenona foi reduzida por BH3.THF na presença dos ligantes quirais. O álcool secundário foi obtido em rendimentos de até 96 %, porém não foi obtido o controle da estereoquímica da reação, não sendo observado excesso enantiomérico. Para as reações de alquinilações de aldeídos pró quirais o foi feita a reação de fenilacetileno com dietilzinco na presença do aminoálcool quiral. A reação forneceu o álcool secundário quiral de interesse em 62% de rendimento e excesso enantiomérico de 44%. Destacam-se ainda que a troca do grupo protetor do nitrogênio ¿ de metila para o grupo Boc ¿ transformando o nitrogênio de amina em um nitrogênio de carbamato levou a uma inversão da configuração absoluta do estereocentro do álcool propargílico gerado / Abstract: Secondary and chiral propargylic alcohols are important synthetic blocks due their versatility and potential application in the construction of more complex structures. This work aimed at the synthesis of chiral amino alcohool ligands derived from proline using as the key step the Heck-Matsuda arylation. These ligands were tested in the reduction of prochiral ketones and alkynylations of prochiral aldehydes aiming the production of chiral propargylic and chiral secondary alcohols with enantiomeric excess. In the reductions of prochiral ketones, acetophenone was reduced using BH3 and THF in the presence of the chiral ligands. The secondary alcohol was obtained with yields up to 96% but no control of the reaction¿s stereochemistry was achieved, and no enantiomeric excess was observed. For alkynylations of the prochiral aldehydes, it was used the reaction between phenylacetylene and diethylzinc in the presence of the chiral amino alcohol. The reaction provided the chiral secondary alcohol of interest in 62% yeld and an enantiomeric excess of 44%. It is also remarkable to note that the change of the protecting group of the nitrogen atom ¿ from methyl to Boc ¿ therefore changing the nitrogen electronics (from an amine to carbamate) led to an inversion of the absolute configuration of the stereocenter generated in the propargylic alcohol / Mestrado / Quimica Organica / Mestre em Química

Mechanistically and structurally chloroperoxidase (CPO) occupies a unique niche among heme containing enzymes. Chloroperoxidase catalyzes a broad range of reactions, such as oxidation of organic substrates, dismutation of hydrogen peroxide, and mono-oxygenation of organic molecules. To expand the synthetic utility of CPO and to appreciate the important interactions that lead to CPO’s exceptional properties, a site-directed mutagenesis study was undertaken. Recombinant CPO and CPO mutants were heterologously expressed in Aspergillus niger. The overall protein structure was almost the same as that of wild type CPO, as determined by UV-vis, NMR and CD spectroscopies. Phenylalanine103, which was proposed to regulate substrate access to the active site by restricting the size of substrates and to control CPO’s enantioselectivity, was mutated to Ala. The ligand binding affinity and most importantly the catalytic activity of F103A was dramatically different from wild type CPO. The mutation essentially eliminated the chlorination and dismutation activities but enhanced, 4-10 fold, the epoxidation, peroxidation, and N-demethylation activities. As expected, the F103A mutant displayed dramatically improved epoxidation activity for larger, more branched styrene derivatives. Furthermore, F103A showed a distinctive enantioselectivity profile: losing enantioselectivity to styrene and cis-β-methylstyrene; having a different configuration preference on α-methylstyrene; showing higher enatioselectivites and conversion rates on larger, more branched substrates. Our results show that F103 acts as a switch box that controls the catalytic activity, substrate specificity, and product enantioselectivity of CPO. Given that no other mutant of CPO has displayed distinct properties, the results with F103A are dramatic. The diverse catalytic activity of CPO has long been attributed to the presence of the proximal thiolate ligand. Surprisingly, a recent report on a C29H mutant suggested otherwise. A new CPO triple mutant C29H/C79H/C87H was prepared, in which all the cysteines were replaced by histidine to eliminate the possibility of cysteine coordinating to the heme. No active form protein was isolated, although, successful transformation and transcription was confirmed. The result suggests that Cys79 and Cys87 are critical to maintaining the structural scaffold of CPO. In vitro biodegradation of nanotubes by CPO were examined by scanning electron microscope method, but little oxidation was observed.

Thesis advisor: Marc L. Snapper / A survey of silicon-based reactions and potential for Lewis base catalysis was presented. An efficient site- and enantioselective catalytic silylation of triols is disclosed. The protocol is applied to total syntheses of cleroindicins D, F and C. Catalytic kinetic resolution of β-hydroxyketones is disclosed. A readily available amino acid-based catalyst promotes the kinetic resolution with high efficiency. A presentation of catalytic enantioselective tosylation of syn-1,2-diols is disclosed. / Thesis (PhD) — Boston College, 2009. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

A ipalbidina é um alcaloide indolizidínico com propriedades analgésica e antirradicais livres. Este alcaloide possui como fonte natural a Ipomoea alba L., uma espécie de dama-da-noite, sendo isolado das suas sementes na forma de aglicona da ipalbina (ligada à D-glicose). A ipalbidina possui estrutura química relativamente simples, porém sua síntese na forma enantiomericamente pura se apresenta como um desafio sintético. Dentre as inúmeras rotas de síntese da ipalbidina, apenas quatro são enantiosseletivas. Neste trabalho de dissertação é apresentada uma nova estratégia sintética visando a preparação da S-(+)-ipalbidina. A estratégia tem como etapas chaves: uma reação de olefinação (Wittig e Horner-Wadsworth-Emmons); a preparação de uma diazocetona e de α-clorocetonas; e a conversão destas no esqueleto indolizidínico por uma reação de ciclização. Como material de partida para a reação de olefinação foi empregado o S-prolinal protegido (Boc e Cbz). Este aminoaldeído foi empregado como fonte do centro estereogênico e de um dos anéis presentes na estrutura final. A partir das reações de olefinação, foram obtidos compostos carbonílicos α, β-insaturados que, em seguida, sofreram redução da dupla ligação (28-94%). A partir dos produtos hidrogenados, foram preparados ácidos carboxílicos (66-83%) que, em seguida, foram convertidos na diazocetona (32%) e nas α-clorocetonas (34-70% a partir de ilídeos β-ceto sulfoxônios). As α -clorocetonas também foram preparadas a partir de ésteres com bons rendimentos (60-70%). O esqueleto indolizidínico foi obtido a partir da reação de ciclização da diazocetona e das α -clorocetonas, porém os rendimentos não foram satisfatórios e a metodologia deve ser melhorada. Uma α-clorocetona mais simples foi reduzida ao álcool correspondente. A β-cloridrina obtida foi convertida no aminoálcool cíclico (indolizidina monoidroxilada, 16%). A preparação deste aminoálcool cíclico sugere que a metodologia desenvolvida é promissora. A nova estratégia sintética pode levar à síntese da (+)-ipalbidina em seis ou sete etapas (uma rota curta). A funcionalização da α-clorocetona e o melhoramento do método a partir da diazocetona podem também levar à síntese outras indolizidinas. / Ipalbidine is an indolizidine alkaloid with analgesic and antioxidant properties. This alkaloid is isolated from the seeds of Ipomoea alba L., as the aglycone of ipalbine (associated to the D-glucose). The ipalbidine has a relatively simple chemical structure, but its synthesis in the enantiomerically pure form is a synthetic challenge. Although a great number of synthetic routes of ipalbidine have been reported, only four are enantioselective. This dissertation reports new studies toward the synthesis of (+)-ipalbidine. The key steps of the synthetic strategy are: olefination reaction (Wittig or Horner-Wadsworth-Emmons); preparation of a diazoketone and α -chloroketones; and the cyclization reaction from the diazoketone and α -chloroketones. A (Boc and Cbz) protected-S-prolinal was used as the initial reagent. This amino aldehyde was employed as the chiral pool and it provides one the rings necessary to build the indolizidine skeleton. A Wittig reaction (88-94%) and a Horner-Wadsworth-Emmons reaction (60-70%) were evaluated for the first step of the synthesis. α, β-Unsaturated carbonyl compounds were prepared from the olefination reactions and, after that, double bond reduction was carried out under some hydrogenation conditions (28-90%). The carboxylic acids were prepared from the hydrogenated compounds (66-83%). The carboxylic acids were used to prepare the diazoketone (32%) and the α -chloroketones (34-70% from sulfoxonium ylides). The cyclization reaction from the diazoketone and α -chloroketones afforded the indolizidine skeleton, but the yields were not satisfactory. The reaction conditions, in this case, need to have to be improved. The α -chloroketones were also prepared from esters in good yields (60-70%). A simple α -chloroketone was reduced to the corresponding β-chlorohydrin. After the preparation of this β-chlorohydrin, the cyclization afforded a cyclic amino alcohol (a mono hydroxylated indolizidine, in 16% yield). These results suggest a promising methodology. The present strategy on the synthesis of (+)-ipalbidine can provide this alkaloid in six or seven steps (a short route) and can also be applicable to the syntheses of other indolizidine alkaloids.

Le thème principal de la thèse est l'utilisation de l’organocatalyse en vue de synthétiser des dérivés de cyclobutanones. Ces dérivés de cyclobutanones sont utiles car ils constituent des briques moléculaires pour la construction d’édifices structurels plus complexes. Cependant et d’une façon surprenante, l'utilisation d’organocatalyseurs simples pour fonctionnaliser les cyclobutanones est rare, surtout lorsque le substrat porte des substituants. Dans cette thèse, nous présentons la synthèse de cyclobutanones substituées issues de fonctionnalisations et de transformations énantiosélectives catalysées par des aminoacides ou de la thiourée.- La première transformation consiste en une réaction d’aldolisation énantiosélective de la 2-hydroxycyclobutanone avec une sélection d'aldéhydes aromatiques. Par catalyse avec la L-thréonine, des aldols sont obtenus efficacement avec un stéréocontrôle raisonnable.- Ensuite, sont synthétisées des cyclobutanones 2,3-disubstituées soit par aldolisation de cyclobutanones 3-substituées par des aldéhydes aromatiques et catalysées par la N-phénylsulfonyl (S)-proline ou soit par nitro-Michael asymétrique avect différents nitrostyrènes, réactions catalysées par les dérivés de la thiourée. Dans le premier cas, les produits relatifs aldoliques ont été obtenus avec un contrôle des trois stéréocentres contigus ; par contre, dans le second cas, les γ-nitro cyclobutanones ont été obtenues avec une énantiosélectivité modeste. - Le dernier cas concerne la conversion de cyclobutanones 3-substituées en 5-hydroxy- γ-lactame substitué en position 4 par l’utilisation de nitrosobenzène électrophile et de L-proline.. Cette réaction implique une séquence domino et d’extension de cycle d’ O-nitroso-aldol-cyclisation. On accède à un système cyclique à cinq chaînons avec un bon rendement et formation de deux nouveaux centres stéréogéniques avec complète stéréochimie.Ainsi, le premier chapitre traite de l’organocatalyse et des applications les plus courantes des organocatalyseurs. La grande majorité des réactions organocatalytiques utilisent des amines chirales pour réaliser de l’aminocatalyse asymétrique ou également des acides et bases de Brønsted, des acides de Lewis via liaison hydrogène interposée, transfert de phase ou même carbène N-hétérocyclique.Le deuxième chapitre traite de la réactivité des cyclobutanones : l’électrophilie élevée et la tension de cycle font de la cyclobutanone et de ses dérivés un bon substrat pour les réactions de transformation de cycle telles que ouverture, contraction ou extension de cycle.Dans le troisième chapitre, la synthèse de cyclobutanones 2,2-disubstituées via aldolisation directe de la 2-hydroxycyclobutanone avec plusieurs aldéhydes ont été organocatalysées par des amines primaires. Les résultats montrent que la 2-hydroxycyclobutanone utilisée sans solvant et avec la L-thréonine fournit des aldols avec un stéréocontrôle raisonnable. / The main topic of thesis is the use of organocatalysis to synthesize cyclobutanones derivatives. Cyclobutanone derivatives are useful molecular building blocks for the construction of complex molecular structures. Surprisingly, however, the use of organocatalysts to functionalize cyclobutanones is rare, especially when the substrate bears substituents. In this thesis, we present the enantioselective transformations and functionalizations of substituted cyclobutanones which employ readily-available amino acids (or derivatives) and thiourea derivatives as organocatalysts. - The first transformation involves the enantioselective aldol reaction between 2-hydroxy-cyclobutanone with a selection of aromatic aldehyde. The results show that the 2-hydroxycyclobutanone is particularly amenable to solvent-free L-threonine-catalyzed direct aldol reactions with reasonable stereocontrol. - After, we synthesized 2,3-disubstituted cyclobutanones through direct aldol reactions involving 3-substituted cyclobutanones and aryl aldehydes catalyzed by N-phenylsulfonyl (S)-proline and via asymmetric nitro-Michael reaction of 3-substituted cyclobutanones and several nitrostyrenes catalyzed by thiourea derivatives. In the first case the relative aldol products were obtained with an unprecedented control of all three contiguous stereocenters in the latter the relatives γ-nitro cyclobutanones were obtained in good yield but in modest enantioselectivity. - The last case concerns the conversion of 3-substituted cyclobutanones into 4-substituted-5-hydroxy-γ-lactam using as electrophile nitrosobenzene and L-proline as catalysts. This reaction involves a ring-expanding O-nitroso-aldol–cyclization domino sequence. The synthetic protocol provides access to the five-membered ring system in good yield, and the formation of two new stereogenic centers is achieved with complete stereochemical control. Thus, the main topic of the first chapter is the organocatalysis, applications of the most common organocatalysts are discussed. The vast majority of organocatalytic reactions use chiral amine as catalysis (asymmetric aminocatalysis). Different types of organocatalysis involve the use of Br¿nsted acids and bases, Lewis acids, hydrogen bond-mediated catalysis, phase transfer and N-heterocyclic carbene catalysis. The second chapter deals with the reactivity of cyclobutanones. High electrophilicity and ring strain make the cyclobutanone and its derivatives a good substrate for ring transformation reactions. Characteristic reactions of functionalized cyclobutanones involve the ring opening, ring contraction and ring expansion reactions. In the third chapter, the synthesis of 2,2-disubstituted cyclobutanones via direct aldol reaction of 2-hydroxycyclobutanone with several aldehydes catalyzed by primary amines is presented. The results show that the 2-hydroxycyclobutanone is particularly amenable to solvent-free L-threonine-catalyzed direct aldol reactions with reasonable stereocontrol. In the fourth chapter we describe the synthesis of 2,3-disubstituted cyclobutanones through direct aldol reactions of 3-substituted cyclobutanones and aryl aldehydes, catalyzed by N-phenylsulfonyl (S)-proline and through asymmetric nitro-Michael reaction of 3-substituted cyclobutanones and several nitrostyrenes, catalyzed by derivatives of thiourea. In this last chapter an organocatalyzed enantioselective desymmetrization reaction of 3-substituted cyclobutanones is presented using nitrosobenzene as an electrophile and proline derivatives as catalysts. This reaction give an original 5-hydroxy-γ-lactam in good yield and with the generation of two new stereogenic centers.

The main topic of thesis is the use of organocatalysis to synthesize cyclobutanones derivatives. Cyclobutanone derivatives are useful molecular building blocks for the construction of complex molecular structures. Surprisingly, however, the use of organocatalysts to functionalize cyclobutanones is rare, especially when the substrate bears substituents. In this thesis, we present the enantioselective transformations and functionalizations of substituted cyclobutanones which employ readily-available amino acids (or derivatives) and thiourea derivatives as organocatalysts. - The first transformation involves the enantioselective aldol reaction between 2-hydroxy-cyclobutanone with a selection of aromatic aldehyde. The results show that the 2-hydroxycyclobutanone is particularly amenable to solvent-free L-threonine-catalyzed direct aldol reactions with reasonable stereocontrol. - After, we synthesized 2,3-disubstituted cyclobutanones through direct aldol reactions involving 3-substituted cyclobutanones and aryl aldehydes catalyzed by N-phenylsulfonyl (S)-proline and via asymmetric nitro-Michael reaction of 3-substituted cyclobutanones and several nitrostyrenes catalyzed by thiourea derivatives. In the first case the relative aldol products were obtained with an unprecedented control of all three contiguous stereocenters in the latter the relatives γ-nitro cyclobutanones were obtained in good yield but in modest enantioselectivity. - The last case concerns the conversion of 3-substituted cyclobutanones into 4-substituted-5-hydroxy-γ-lactam using as electrophile nitrosobenzene and L-proline as catalysts. This reaction involves a ring-expanding O-nitroso-aldol-cyclization domino sequence. The synthetic protocol provides access to the five-membered ring system in good yield, and the formation of two new stereogenic centers is achieved with complete stereochemical control. Thus, the main topic of the first chapter is the organocatalysis, applications of the most common organocatalysts are discussed. The vast majority of organocatalytic reactions use chiral amine as catalysis (asymmetric aminocatalysis). Different types of organocatalysis involve the use of Br¿nsted acids and bases, Lewis acids, hydrogen bond-mediated catalysis, phase transfer and N-heterocyclic carbene catalysis. The second chapter deals with the reactivity of cyclobutanones. High electrophilicity and ring strain make the cyclobutanone and its derivatives a good substrate for ring transformation reactions. Characteristic reactions of functionalized cyclobutanones involve the ring opening, ring contraction and ring expansion reactions. In the third chapter, the synthesis of 2,2-disubstituted cyclobutanones via direct aldol reaction of 2-hydroxycyclobutanone with several aldehydes catalyzed by primary amines is presented. The results show that the 2-hydroxycyclobutanone is particularly amenable to solvent-free L-threonine-catalyzed direct aldol reactions with reasonable stereocontrol. In the fourth chapter we describe the synthesis of 2,3-disubstituted cyclobutanones through direct aldol reactions of 3-substituted cyclobutanones and aryl aldehydes, catalyzed by N-phenylsulfonyl (S)-proline and through asymmetric nitro-Michael reaction of 3-substituted cyclobutanones and several nitrostyrenes, catalyzed by derivatives of thiourea. In this last chapter an organocatalyzed enantioselective desymmetrization reaction of 3-substituted cyclobutanones is presented using nitrosobenzene as an electrophile and proline derivatives as catalysts. This reaction give an original 5-hydroxy-γ-lactam in good yield and with the generation of two new stereogenic centers.

Computational methods are very useful tools in the study of enzymatic reactions, as they can provide a detailed understanding of reaction mechanisms and the sources of various selectivities. In this thesis, density functional theory has been employed to examine four different enzymes of potential importance for biocatalytic applications. The enzymes considered are limonene epoxide hydrolase, soluble epoxide hydrolase, arylmalonate decarboxylase and phenolic acid decarboxylase. Besides the reaction mechanisms, the enantioselectivities in three of these enzymes have also been investigated in detail. In all studies, quite large quantum chemical cluster models of the active sites have been used. In particular, the models have to account for the chiral environment of the active site in order to reproduce and rationalize the experimentally observed selectivities. For both epoxide hydrolases, the calculated enantioselectivities are in good agreement with experiments. In addition, explanations for the change in stereochemical outcome for the mutants of limonene epoxide hydrolase, and for the observed enantioconvergency in the soluble epoxide hydrolase are presented. The reaction mechanisms of the two decarboxylases are found to involve the formation of an enediolate- or a quinone methide intermediate, supporting thus the main features of the proposed mechanisms in both cases. For arylmalonate decarboxylase, an explanation for the observed enantioselectivity is also presented. In addition to the obtained chemical insights, the results presented in this thesis demonstrate that the quantum chemical cluster approach is indeed a valuable tool in the field of asymmetric biocatalysis. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.</p><p> </p>