Transesterificação enantiosseletiva de álcoois terciários propargílicos: estudos de resolução cinética e resolução cinética dinâmica
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Data
2023-02-27
Autores
Ganéo Neto, Laerte
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
Os álcoois terciários propargílicos são importantes blocos construtores de interesse da indústria farmacêutica. No entanto, a síntese enantiosseletiva dos mesmos ainda é um grande desafio para os químicos orgânicos sintéticos. A resolução cinética enzimática desses álcoois, via transesterificação, foi pouco explorada e não existe até o presente momento uma metodologia de resolução cinética dinâmica para tais compostos. Neste contexto, o presente trabalho visou o desenvolvimento de uma metodologia de resolução cinética dinâmica quimioenzimática para a obtenção de álcoois terciários propargílicos enantiomericamente puros utilizando um sistema composto por uma lipase e um catalisador heterogêneo de vanádio. Neste sistema catalítico, a enzima foi responsável pela etapa enantiosseletiva e o catalisador de vanádio pela etapa de racemização. O substrato modelo utilizado foi o 2-fenil-3-butin-2-ol, por ser o mais explorado em trabalhos anteriores. Inicialmente, foi realizada uma triagem com uma série de lipases disponíveis comercialmente, utilizando o acetato de vinila como doador de acila e heptano como solvente. A única enzima que demonstrou atividade perante o substrato, entretanto, foi a lipase A de Candida antarctica (CAL-A), o que corrobora com os resultados da literatura. Em seguida, foram investigados os efeitos dos demais componentes envolvidos na resolução cinética: temperatura, solvente, identidade e concentração do doador de acila e carga de enzima. O melhor resultado foi obtido utilizando um sistema composto pelo substrato, CAL-A, butirato de vinila e isooctano a 30 °C, no qual a conversão foi de 33% e o ee de 95% após 48 horas. Outros álcoois terciários com modificações em cada um dos substituintes do substrato modelo foram investigados, embora nenhum deles tenha fornecido resultados promissores. Foram realizadas também tentativas de combinar o protocolo de resolução cinética desenvolvido com o catalisador de vanádio (VOSO4), mas diversos fatores cooperaram para que o resultado fosse inferior ao anterior. Como conclusão, foi desenvolvido um protocolo inédito para a resolução cinética do 2-fenil-3-butin-2-ol, com melhoria frente ao tempo de reação e utilização da CAL-A disponível comercialmente.
Propargyl tertiary alcohols are essential building blocks for the pharmaceutical industry. However, their enantioselective synthesis is still a great challenge for organic chemists. The enzymatic kinetic resolution of these alcohols via transesterification was little explored, and there is no methodology of dynamic kinetic resolution employing such compounds until now. In this context, the present work aimed to develop a chemoenzymatic dynamic kinetic resolution protocol for obtaining enantiomerically pure propargyl tertiary alcohols using a system composed of a lipase and a heterogeneous vanadium catalyst. In this catalytical system, the enzyme was responsible for the enantioselective step, while the vanadium catalyst was responsible for the racemization step. The model substrate used was 2-phenyl-3-butyn-2-ol, for being the most explored in previous works. Initially, a screening was performed with a series of lipases, using vinyl acetate as the acyl donor and heptane as the solvent. However, the only enzyme that showed activity towards the substrate was lipase A from Candida antarctica (CAL-A), which corroborates the literature results. Then, the effects of the other components involved in the kinetic resolution were investigated: temperature, solvent, identity and concentration of acyl donor, and enzyme loading. The best result was obtained using a system composed of the substrate, CAL-A, vinyl butyrate, and isooctane at 30 °C, in which the conversion was 33% and the ee 95% after 48 hours. Other tertiary alcohols with modifications in each of the substituents of the model substrate were investigated, although none provided promising results. Attempts were also made to combine the kinetic resolution protocol with the vanadium catalyst (VOSO4), but several factors cooperated so that the result was inferior to the previous one. In conclusion, an unprecedented methodology for the kinetic resolution of 2-phenyl-3-butyn-2-ol was developed, with improvements in reaction time and using a commercially available CAL-A.
Propargyl tertiary alcohols are essential building blocks for the pharmaceutical industry. However, their enantioselective synthesis is still a great challenge for organic chemists. The enzymatic kinetic resolution of these alcohols via transesterification was little explored, and there is no methodology of dynamic kinetic resolution employing such compounds until now. In this context, the present work aimed to develop a chemoenzymatic dynamic kinetic resolution protocol for obtaining enantiomerically pure propargyl tertiary alcohols using a system composed of a lipase and a heterogeneous vanadium catalyst. In this catalytical system, the enzyme was responsible for the enantioselective step, while the vanadium catalyst was responsible for the racemization step. The model substrate used was 2-phenyl-3-butyn-2-ol, for being the most explored in previous works. Initially, a screening was performed with a series of lipases, using vinyl acetate as the acyl donor and heptane as the solvent. However, the only enzyme that showed activity towards the substrate was lipase A from Candida antarctica (CAL-A), which corroborates the literature results. Then, the effects of the other components involved in the kinetic resolution were investigated: temperature, solvent, identity and concentration of acyl donor, and enzyme loading. The best result was obtained using a system composed of the substrate, CAL-A, vinyl butyrate, and isooctane at 30 °C, in which the conversion was 33% and the ee 95% after 48 hours. Other tertiary alcohols with modifications in each of the substituents of the model substrate were investigated, although none provided promising results. Attempts were also made to combine the kinetic resolution protocol with the vanadium catalyst (VOSO4), but several factors cooperated so that the result was inferior to the previous one. In conclusion, an unprecedented methodology for the kinetic resolution of 2-phenyl-3-butyn-2-ol was developed, with improvements in reaction time and using a commercially available CAL-A.
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Palavras-chave
Biocatálise, Transesterificação, Lipase, Catalisadores de vanádio, Química verde