The synthesis of enantiomerically pure compounds is of vital importance. Most biologically active natural products are chiral and require asymmetric synthesis, chiral resolution, or the use of naturally chiral starting materials for their preparation. Organocatalytic enantioselective reaction methodology is a continuously growing area in organic chemistry. The use of organocatalysts as a potentially environmentally friendly alternative to metal catalysts is appealing to the pharmaceutical industry. In this dissertation an enantioselective Mannich reaction using an organocatalyst was investigated. The reaction was between a ß-keto ester and an imine electrophile catalyzed by vaulted biphenanthrol (VAPOL) phosphoric acid. The reaction resulted in products with high yields, but low to moderate enantioselectivity and diastereoselectivity. The development of the first Brønsted acid-catalyzed desymmetrization of meso-aziridines was also investigated. This is one of the first instances where a phosphoric acid has been used to catalyze a reaction that did not involve an imine. It was shown that the chiral VAPOL phosphoric acid was an excellent catalyst for the reaction resulting in high yields and enantioselectivities for the chiral ring opened products. It was also shown, for the first time, that a vaulted binaphthol (VANOL) phosphoric acid can also catalyze the ring-opening of meso-aziridines with comparable results to the VAPOL phosphoric acid in some cases. Mechanistic NMR studies were used to probe the reaction, and it is believed that evidence leads one to conclude that a unique mechanism for phosphoric acid-catalysis is followed. The products that can be obtained from this reaction, 1,2-diamines, are of high value for synthetic chemists. They have been used as chiral auxiliaries, ligands, and precursors to natural products.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-09-23T12:23:32Z No. of bitstreams: 1 pedropossadecastro.pdf: 5686031 bytes, checksum: 9e1207fe7ed0dbf820e7976d236128f3 (MD5) / Approved for entry into archive by Diamantino Mayra (mayra.diamantino@ufjf.edu.br) on 2016-09-26T20:30:37Z (GMT) No. of bitstreams: 1 pedropossadecastro.pdf: 5686031 bytes, checksum: 9e1207fe7ed0dbf820e7976d236128f3 (MD5) / Made available in DSpace on 2016-09-26T20:30:37Z (GMT). No. of bitstreams: 1 pedropossadecastro.pdf: 5686031 bytes, checksum: 9e1207fe7ed0dbf820e7976d236128f3 (MD5) Previous issue date: 2016-07-22 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A síntese de aminoácidos biologicamente funcionais e pequenos peptídeos tem se mostrado uma área promissora da química orgânica. As azalactonas podem atuar como aminoácidos protegidos e serem utilizadas na síntese de derivados de aminoácidos e heterociclos complexos. Neste trabalho são descritas reações de abertura de azalactonas por aminoácidos catalisadas por um ácido de Brønsted, o (+/)-ácido canforsulfônico (ACS), resultando na formação de dipeptídeos. Os heterociclos azalactônicos foram preparados em duas etapas: uma acilação dos aminoácidos com cloreto de benzoíla em meio alcalino, levando aos N-benzoil aminoácidos com até 75% de rendimento, e uma reação de ciclização intramolecular mediada pelo EDC, um ativador de ácido carboxílico, culminando nas azalactonas desejadas em rendimentos que variaram de 8298%. As condições otimizadas para a reação para a formação dos dipeptídeos consistiram na utilização de 5 mol % de ácido canforsulfônico como catalisador, diclorometano como solvente, agitação e temperatura ambiente. Avaliou-se o escopo de reação variando as azalactonas utilizadas e também os aminoácidos empregados como nucleófilos. Os rendimentos foram de bons a excelentes (entre 66 e 99%) e mesmo o uso de aminoácidos e azalactonas mais impedidos do ponto de vista estéreo, como nos derivados de valina e leucina, forneceu os respectivos dipeptídeos em bons rendimentos. Os produtos foram caracterizados por RMN de 1H, 13C, DEPT135, IV e de EMAR. Foi demonstrada a possibilidade de ciclização intramolecular dos dipeptídeos obtidos utilizando-se EDC, resultando em uma nova azalactona de estrutura mais complexa. Finalmente, a substituição do grupo N-benzoil por terc-butil carbamato tornou possível a síntese de uma azalactona sem que houvesse epimerização do centro estereogênico alfa à carbonila, sendo realizada ainda a posterior abertura deste heterociclo pela octilamina. / The synthesis of biologically functional amino acids and small peptides has been a promising area of organic chemistry. The azlactones can act as protected amino acids and are used in the synthesis of amino acid derivatives and complex heterocycles. This work describes azlactones ring opening by amino acids catalyzed by a Brønsted acid, the (+/-)-camphorsulfonic acid (CSA), resulting in the formation of dipeptides. The azlactone heterocycles were prepared in two steps: an acylation of the amino acid with benzoyl chloride under alkaline conditions leading to N-benzoyl amino acids with up to 75% yield, and an intramolecular cyclization reaction mediated by EDC, a carboxylic acid activator, affording the desired azlactones in yields ranging from 82-98%. The optimized conditions for the dipeptide formation reaction consisted of 5 mol % of camphorsulfonic acid as a catalyst, dichloromethane as solvent, stirring and at room temperature. The scope was evaluated varying the azlactones and the amino acids. Yields were satisfactory (ranging from 66 to 99%). Even the use of more sterically hindered amino acids and azlactones, such as valine and leucine derivatives, the dipeptides were obtained in good yields. The products were characterized by 1H NMR, 13C, DEPT135, IR and HRMS. The possibility of an intramolecular cyclization of the dipeptides using EDC has been demonstrated, resulting in a more complex azlactone. Finally, the substitution of the N-benzoyl group by tert-butyl carbamate allowed the synthesis of an azalactone without epimerization of the stereogenic center alpha to the carbonyl, a subsequent opening of the heterocycle by octylamine was also performed.

This thesis focuses on the development of methods for the activation of the hydroxyl group in non-derivatized alcohols in substitution reactions. The thesis is divided into two parts, describing three different catalytic systems. The first part of the thesis (Chapter 2) describes nucleophilic allylation of amines with allylic alcohols, using a palladium catalyst to generate unsymmetrical diallylated amines. The corresponding amines were further transformed by a one-pot ring-closing metathesis and aromatization reaction to afford β-substituted pyrroles with linear and branched alkyl, benzyl, and aryl groups in overall moderate to good yields. The second part (Chapters 3 and 4) describes the direct intramolecular stereospecific nucleophilic substitution of the hydroxyl group in enantioenriched alcohols by Lewis acid and Brønsted acid/base catalysis. In Chapter 3, the direct intramolecular substitution of non-derivatized alcohols has been developed using Fe(OTf)3 as catalyst. The hydroxyl groups of aryl, allyl, and alkyl alcohols were substituted by the attack of O- and N-centered nucleophiles, to provide five- and six-membered heterocycles in up to excellent yields with high enantiospecificities. Experimental studies showed that the reaction follows first-order dependence with respect to the catalyst, the internal nucleophile, and the internal electrophile of the substrate. Competition and catalyst-substrate interaction experiments demonstrated that this transformation proceeds via an SN2-type reaction pathway. In Chapter 4, a Brønsted acid/base catalyzed intramolecular substitution of non-derivatized alcohols was developed. The direct intramolecular and stereospecific substitution of different alcohols was successfully catalyzed by phosphinic acid (H3PO2). The hydroxyl groups of aryl, allyl, propargyl, and alkyl alcohols were substituted by O-, N-, and S-centered nucleophiles to generate five- and six-membered heterocycles in good to excellent yields with high enantiospecificities. Mechanistic studies (both experiments and density functional theory calculations) have been performed on the reaction forming five-membered heterocyclic compounds. Experimental studies showed that phosphinic acid does not promote SN1 reactivity. Rate-order determination indicated that the reaction follows first-order dependence with respect to the catalyst, the internal nucleophile, and the internal electrophile. DFT calculations corroborated with a reaction pathway in which the phosphinic acid has a dual activation mode and operates as a bifunctional Brønsted acid/Brønsted base to simultaneously activate both the nucleophile and nucleofuge, resulting in a unique bridging transition state in an SN2-type reaction mechanism. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 4: Manuscript.</p>

Previous studies have successfully used near and supercritical water (SCW) for cracking and desulfurization of heavy crude oil and bio-oil, suppressing coke formation as a low-value by-product. Some of these studies benefited from using zeolite catalysts to increase the activity and selectivity toward targeted products; however, in depth studies are required to identify the role of water on zeolite catalysis under supercritical condition. Using three common zeolites, ZSM-5, HY, and β for supercritical water cracking of dodecane at 400°C, 24±2 MPa (in a 100 ml batch reactor), we showed that ZSM-5 is the only catalyst that partially retains its crystalline structure and activity under hydrothermal conditions. Further characterization of the ZSM-5 (used under 50/50 wt% SCW/dodecane feed) revealed 95% decrease in Brønsted acid site (BAS) density and 80% decrease in microporous area after 2 h reaction time. However, compared to the runs where SCW was absent, the apparent dodecane cracking rate constant in SCW decreased only by a factor of 2.6. Examining catalytic activity of ZSM-5 degradation products and re-using ZSM-5 showed that the unexpected activity cannot be ascribed to ZSM-5 degradation products. Using a group-type model, we showed that SCW accelerated gas and suppressed coke formations. Additionally a coke gasification pathway was suggested to account for formation of CO and CO2 in the presence of SCW. Additional experiments with two different ZSM-5 particle sizes suggested that dodecane cracking reaction is diffusion-limited in the absence of SCW and reaction-limited in its presence. Zero length chromatography of calcined and hydrothermally treated ZSM-5 showed 10 times greater apparent diffusivity for un-treated catalyst. This, according to Weisz-Prater analysis, suggested a 250 times greater dodecane surface concentration in the absence of SCW. We successfully optimized the water content of feed (5-15 wt%) to decrease the destructive effects of SCW on the structure, increase the selectivity toward BTEX products and eliminate coke formation.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第22847号 / 工博第4787号 / 新制||工||1749(附属図書館) / 京都大学大学院工学研究科高分子化学専攻 / (主査)教授 山子 茂, 教授 田中 一生, 教授 辻井 敬亘 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

Previous studies have successfully used near and supercritical water (SCW) for cracking and desulfurization of heavy crude oil and bio-oil, suppressing coke formation as a low-value by-product. Some of these studies benefited from using zeolite catalysts to increase the activity and selectivity toward targeted products; however, in depth studies are required to identify the role of water on zeolite catalysis under supercritical condition. Using three common zeolites, ZSM-5, HY, and β for supercritical water cracking of dodecane at 400°C, 24±2 MPa (in a 100 ml batch reactor), we showed that ZSM-5 is the only catalyst that partially retains its crystalline structure and activity under hydrothermal conditions. Further characterization of the ZSM-5 (used under 50/50 wt% SCW/dodecane feed) revealed 95% decrease in Brønsted acid site (BAS) density and 80% decrease in microporous area after 2 h reaction time. However, compared to the runs where SCW was absent, the apparent dodecane cracking rate constant in SCW decreased only by a factor of 2.6. Examining catalytic activity of ZSM-5 degradation products and re-using ZSM-5 showed that the unexpected activity cannot be ascribed to ZSM-5 degradation products. Using a group-type model, we showed that SCW accelerated gas and suppressed coke formations. Additionally a coke gasification pathway was suggested to account for formation of CO and CO2 in the presence of SCW. Additional experiments with two different ZSM-5 particle sizes suggested that dodecane cracking reaction is diffusion-limited in the absence of SCW and reaction-limited in its presence. Zero length chromatography of calcined and hydrothermally treated ZSM-5 showed 10 times greater apparent diffusivity for un-treated catalyst. This, according to Weisz-Prater analysis, suggested a 250 times greater dodecane surface concentration in the absence of SCW. We successfully optimized the water content of feed (5-15 wt%) to decrease the destructive effects of SCW on the structure, increase the selectivity toward BTEX products and eliminate coke formation.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第17773号 / 理博第3896号 / 新制||理||1562(附属図書館) / 30580 / 京都大学大学院理学研究科化学専攻 / (主査)教授 丸岡 啓二, 教授 大須賀 篤弘, 教授 時任 宣博 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第18094号 / 理博第3972号 / 新制||理||1573(附属図書館) / 30952 / 京都大学大学院理学研究科化学専攻 / (主査)教授 丸岡 啓二, 教授 時任 宣博, 教授 大須賀 篤弘 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

Submitted by isabela.moljf@hotmail.com (isabela.moljf@hotmail.com) on 2016-08-08T16:30:15Z No. of bitstreams: 1 eloahpereiraavila.pdf: 8676610 bytes, checksum: f7166b43a9edcd733b8fff274c40aab9 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-08-09T11:54:32Z (GMT) No. of bitstreams: 1 eloahpereiraavila.pdf: 8676610 bytes, checksum: f7166b43a9edcd733b8fff274c40aab9 (MD5) / Made available in DSpace on 2016-08-09T11:54:32Z (GMT). No. of bitstreams: 1 eloahpereiraavila.pdf: 8676610 bytes, checksum: f7166b43a9edcd733b8fff274c40aab9 (MD5) Previous issue date: 2013-07-19 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Neste trabalho apresentamos a síntese de adutos de Michael obtidos pela reação diastereosseletiva entre azalactonas e enonas, catalisada por um ácido de Brønsted. A metodologia consistiu no emprego de um organocatalisador, no caso (+/-)ACS, que em apenas 7 mol% conduziu aos produtos de Michael em bons rendimentos (até 80%) e em alto controle da régio- e diastereosseletividade (apenas aduto de adição 1,4 e com rd > 20:1). Vários derivados azalactônicos e diversas enonas toleraram as condições dereação otimizadas, como por exemplo, azalactona contendo grupo volumoso forneceu o aduto de Michael em perfeito controle da estereoquímica relativa. Um ciclo catalítico para esta transformação foi proposto onde um intermediário par iônico seria responsável pela transferência de quiralidade, justificando aestereoquímica observada na etapa de formação de ligação C-C. Ressaltamos que a estereoquímica relativa foi determinada de forma inequívoca por cristalografia de raiosX. Os resultados obtidos neste trabalho, pelo nosso conhecimento, consistem noprimeiro exemplo onde um ácido de Brønsted catalisa uma reação de dessimetrizaçãoaltamente régio- e diastereosseletiva entre um derivado azalactônico e DBA. Ainda, além da formação de uma nova ligação σ C-C, dois centros estereogênicos estão sendo gerados e controlados, sendo um deles um centro não hidrogenado. / In this work the diastereoseletive synthesis of Michael adducts from azlactones andenones catalyzed by a Brønsted acid is presented. By using only 7 mol% of an organocatalyst, (+/-)-CSA, the corresponding Michael adducts were obtained in good yields (with up to 80%) and with high control of both regio- and diastereoselectivity (only 1,4 addition product was detected and with > 20:1 dr). Various azlactones and enones were well tolerated. For example, a steric bulk azlactone derivative gave the corresponding Michael adduct in perfect control of the relative stereochemistry. Based on the observed stereochemistry, a catalytic cycle for this transformationwas then proposed, in which an ion-pairing intermediate would be responsible for the chirality transfer in the new C-C bond formation. It is important mention that the relative stereochemistry was unambiguous determined by X-ray crystallography. To the best of our knowledge this constitutes the first reported diastereoselective dessymetrization of DBA with azlactones catalyzed by a Brønsted acid. Besides the new C-C bond formation, two consecutive stereogenic centers are created, one of them a quaternary center.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-05-09T14:52:34Z No. of bitstreams: 1 adrianeantoniapereira.pdf: 4227832 bytes, checksum: c75e5a3802fd9faef6e64104b4d14e9d (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-05-17T14:26:31Z (GMT) No. of bitstreams: 1 adrianeantoniapereira.pdf: 4227832 bytes, checksum: c75e5a3802fd9faef6e64104b4d14e9d (MD5) / Made available in DSpace on 2017-05-17T14:26:31Z (GMT). No. of bitstreams: 1 adrianeantoniapereira.pdf: 4227832 bytes, checksum: c75e5a3802fd9faef6e64104b4d14e9d (MD5) Previous issue date: 2015-03-27 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / As azalactonas são basicamente aminoácidos protegidos que podem ser utilizados na síntese de produtos naturais ou sintéticos. Apesar de serem excelentes pró-nucleófilos, este esqueleto apresenta dois sítios eletrofílicos podendo se comportar como eletrófilo em reações com nucleófilos. Neste trabalho são descritas reações de abertura de azalactonas catalisadas por um ácido de Brønsted, o ácido canforssulfônico (ACS). Para esse fim, as azalactonas foram preparadas em duas etapas, sendo que a primeira consistiu na acilação dos aminoácidos com cloreto de benzoíla em meio alcalino levando aos precursores azalactônicos com até 75% de rendimento e subsequentemente uma reação de ciclização intramolecular mediada por um ativador de ácido carboxílico, o EDC, conduzindo aos compostos desejados com rendimentos que variaram de 8298%. As condições otimizadas para a reação de abertura de azalactonas consistiu no emprego de 10 mol % de ácido canforssulfônico como catalisador, diclorometano como solvente, sem agitação a temperatura ambiente. Avaliou-se o escopo para diversas azalactonas e também para diversos nucleófilos. Os rendimentos foram satisfatórios variando de 43-96%, onde mesmo utilizando substratos impedidos do ponto de vista estéreo, como é o caso do terc-butanol, conduziu ao produto de abertura com 57% de rendimento. Os produtos foram caracterizados por RMN de 1H, 13C, IV e EMAE. Após o preparo e caracterização, voltou-se a atenção para a compreensão do mecanismo de reação envolvido em reações de abertura de azalactonas por nucleófilos catalisadas por ACS. O estudo por ESI(+)-MS/MS evidenciou que o catalisador participa do ciclo catalítico protonando a azalactona em uma etapa anterior ao ataque do nucleófilo, contribuindo assim para diminuição da energia do sistema. / Azlactones are basically protected amino acids which can be used in the synthesis of natural and synthetic products. Despite of being excellent pro-nucleophiles, their structures have two electrophilic sites which could be involved in reactions in the presence of nucleophiles. In this work, azlactone ring opening reactions catalyzed by a Brønsted acid, camphorsulfonic acid (CSA), are described. First we prepared azlactone rings in two steps, amidation using benzoyl chloride in basic conditions following by intramolecular ciclization using EDC. Azlactones were isolated with good to excellent yields (82-98%). The optimized reaction condition consists in the use of 10 mol% of camphorsulfonic acid as catalyst, dichloromethane as solvent, at room temperature without stirring. Next, the scope of various azlactones and nucleophiles were evaluated. Chemical yields were good to excellent, and even by using high sterically bulky substrates such as tert-butanol, leads to the product with a good yield (57%). All synthesized compounds were fully characterized by 1H NMR, 13C NMR, IR and HRMS. Finally, we turned our attention to understand the reaction mechanism. The study by ESI-MS revealed the catalyst participates in the catalytic cycle as a proton donor in a previous step to nucleophilic attack, thereby contributing for a decreased energy system.