Sínteses quimioenzimáticas de moléculas bioativas: uma abordagem à química verde
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Data
2017-09-04
Autores
Santos, Luna Schlittler [UNESP]
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Universidade Estadual Paulista (Unesp)
Resumo
O emprego da Biocatálise utilizando enzimas isoladas ou células íntegras fornece alternativas eficientes e potencialmente quimio-, regio- e estereosseletivas para a transformação de uma ampla variedade de compostos orgânicos. Neste trabalho aplicamos a Biocatálise na síntese quimioenzimática de derivados de α-metil-β-hidroxiéster utilizando a levedura Saccharomyces cerevisiae na redução de α-metileno-β-cetoésteres e também na síntese de 4-tiazolidinonas através de uma reação multicomponente one-pot combinada com o uso de biocatalisadores. Dessa forma esta tese é composta de três capítulos, sendo o primeiro uma introdução geral seguida de dois capítulos de trabalho experimental, resultados e discussão. Os α-metil-β-hidroxiésteres são compostos importantes para a síntese orgânica assimétrica, onde são aplicados como blocos construtores para a síntese de diversos compostos. Nesse contexto, existe um grande interesse na busca por métodos convenientes e seletivos para sua síntese. Dentre as estratégias mais estudadas, a redução assimétrica de α-metileno-β-cetoésteres tem sido a via mais investigada. Neste trabalho, a rota sintética proposta para a obtenção dos substratos α-metileno-β-cetoéster consistiu na obtenção dos α-metileno-β-hidroxiésteres através da reação de Morita-Baylis-Hillman (rendimentos de 64 a 96%), seguida por uma reação de oxidação utilizando o ácido 2-iodoxibenzóico (IBX) (rendimentos de 88 a 95%). Os substratos α-metileno-β-cetoésteres foram submetidos a reação de redução utilizando a levedura Saccharomyces cerevisiae. Os α-metil-β-hidroxiésteres foram obtidos com conversões de 66 a 99%, diatereosseletividade de até 91:9 e excessos enantioméricos maiores que 99% para todos os diastereoisômeros. De maneira geral, podemos concluir que a levedura S. cerevisiae foi capaz de reduzir os α-metileno-β-cetoésteres à α-metil-β-hidroxiésteres com alta diastereo- e enantiosseletividade. As 4-tiazolidinonas são um importante núcleo heterocíclico presente em diversos compostos biologicamente e farmacologicamente ativos. Portanto, há um grande interesse no desenvolvimento de metodologias adequadas para sintetizá-lo. A eficiência das reações multicomponentes combinadas com os aspectos sustentáveis da Biocatálise foram empregadas na síntese desta classe de compostos. Uma coleção de células microbianas, enzimas isoladas e a albumina de soro bovino foram triados para atividades catalíticas nesta reação. A influência do solvente, a relação estequiométrica dos substratos e os substituintes no anel aromático dos aldeídos também foram avaliados. Em relação à proporção estequiométrica de substratos os melhores resultados foram observados quando se utilizou uma proporção de 1: 1: 3 de aldeído: amina: ácido carboxílico. A relação entre o substituinte do anel aromático dos aldeídos e a taxa de reação não ficou clara já que as conversões variam com os diferentes biocatalisadores testados. De maneira geral as 4-tiazolidinonas foram obtidas com rendimentos bons a moderados (52 a 69%), sob condições de reação suaves.
The application of biocatalysis using isolated enzymes and entire cells is a powerful tool to transform a wide range of organic compounds in chemo-, regio- and stereoselective mode. In this work, we applied the biocatalysis in the chemical enzymatic synthesis of α-methyl-β-hydroxy ester using Saccharomyces cerevisiae by the bioreduction of α-methylene-β-keto ester and 4-thiazolidinones by a one-pot multicomponent reaction combined biocatalysts. This work is composed by a general introduction followed by two chapters of experimental work, results and discussion. The α-methyl-β-hydroxy ester is an important compound for asymmetric organic synthesis, where they are applied as building blocks to the synthesis of several compounds. This synthesis is getting attention following appropriate methodologies and high selectivity. In the most studied strategies, the asymmetric reduction of α-methylene-β-keto ester in the chemical or enzymatic path are one of the most investigated approaches. The synthesis route to the formation of α-methylene-β-keto ester was the conversion of α-methylene-β-hydroxy ester by Morita-Baylis-Hillman reaction (yields of 64 to 96%), followed by an oxidation reaction using IBX (yields of 88 to 95%). The α-methylene-β-keto ester substrates were exposed as a reactant to the bioreduction reaction applying Saccharomyces cerevisiae. The product α-methyl-β-hydroxy ester were produced with 66 to 99% of conversion, the diasteroselectivity of 91:9 and enantiomeric excess higher than 99% to all diasteroisomers. Concluding, the S. cerevisiae could bioreduce the α-methylene-β-keto ester to α-methyl-β-hydroxy ester with high diastereo- and enantioselectivity. The 4-thiazolidinones are an important heterocyclic scaffolds present in many biologically and pharmacologically active compounds. Therefore, the development of a proper methodology to synthesize this compound is an actual concern. The efficiency of multicomponent reactions combined with the sustainable feature of biocatalysis were employed in the synthesis of these compounds. A collection of microbial cells, isolated enzymes and bovine serum albumin were screened for catalytic activities. The solvent influence, stoichiometric relations between substrates and the aromatic ring substitutes in the aldehydes were evaluated either. The stoichiometric relation were the greater in the proportion of 1 : 1 : 3 aldehyde : amine : carboxylic acid. The relation between the aldehyde aromatic ring substitutes and the reaction rate was not clear, since the conversions vary with the tested biocatalysts. Summarizing, the 4-thiazolidinones were obtained with good and moderate yields (52 to 69%), under mild reaction conditions.
The application of biocatalysis using isolated enzymes and entire cells is a powerful tool to transform a wide range of organic compounds in chemo-, regio- and stereoselective mode. In this work, we applied the biocatalysis in the chemical enzymatic synthesis of α-methyl-β-hydroxy ester using Saccharomyces cerevisiae by the bioreduction of α-methylene-β-keto ester and 4-thiazolidinones by a one-pot multicomponent reaction combined biocatalysts. This work is composed by a general introduction followed by two chapters of experimental work, results and discussion. The α-methyl-β-hydroxy ester is an important compound for asymmetric organic synthesis, where they are applied as building blocks to the synthesis of several compounds. This synthesis is getting attention following appropriate methodologies and high selectivity. In the most studied strategies, the asymmetric reduction of α-methylene-β-keto ester in the chemical or enzymatic path are one of the most investigated approaches. The synthesis route to the formation of α-methylene-β-keto ester was the conversion of α-methylene-β-hydroxy ester by Morita-Baylis-Hillman reaction (yields of 64 to 96%), followed by an oxidation reaction using IBX (yields of 88 to 95%). The α-methylene-β-keto ester substrates were exposed as a reactant to the bioreduction reaction applying Saccharomyces cerevisiae. The product α-methyl-β-hydroxy ester were produced with 66 to 99% of conversion, the diasteroselectivity of 91:9 and enantiomeric excess higher than 99% to all diasteroisomers. Concluding, the S. cerevisiae could bioreduce the α-methylene-β-keto ester to α-methyl-β-hydroxy ester with high diastereo- and enantioselectivity. The 4-thiazolidinones are an important heterocyclic scaffolds present in many biologically and pharmacologically active compounds. Therefore, the development of a proper methodology to synthesize this compound is an actual concern. The efficiency of multicomponent reactions combined with the sustainable feature of biocatalysis were employed in the synthesis of these compounds. A collection of microbial cells, isolated enzymes and bovine serum albumin were screened for catalytic activities. The solvent influence, stoichiometric relations between substrates and the aromatic ring substitutes in the aldehydes were evaluated either. The stoichiometric relation were the greater in the proportion of 1 : 1 : 3 aldehyde : amine : carboxylic acid. The relation between the aldehyde aromatic ring substitutes and the reaction rate was not clear, since the conversions vary with the tested biocatalysts. Summarizing, the 4-thiazolidinones were obtained with good and moderate yields (52 to 69%), under mild reaction conditions.
Descrição
Palavras-chave
Biocatálise, Síntese assimétrica, Saccharomyces cerevisiae, Compostos heterocíclicos, Química verde, Bioreduction, Morita-Baylis-Hillman adducts, Multicomponent reactions, 4-Thiazolidinones