Resolução cinética dinâmica da (R,S)-1-feniletilamina, visando à síntese de análogos da rasagilina
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Data
2020-09-14
Autores
Fernandes, Thayná Nunes de Carvalho [UNIFESP]
Orientadores
Siqueira, Fernanda Amaral de [UNIFESP]
Tipo
Trabalho de conclusão de curso de graduação
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Resumo
A resolução cinética dinâmica (DKR, do inglês dynamic kinetic resolution)
consiste em uma reação na qual são utilizados uma enzima e um catalisador metálico
com o intuito de produzir moléculas enantiomericamente puras. Neste trabalho, a
metodologia da DKR foi utilizada como primeira etapa de uma rota sintética proposta
para a síntese de análogos da rasagilina, um fármaco utilizado como adjuvante no
tratamento da Doença Parkinson, (R)-N-(1-feniletil)prop-2-ino-1-amina e (R)-N-(1-
feniletil)-N-di(prop-2-ino)-1-amina. Foi avaliada a atividade dos catalisadores
perovskitas de níquel (La0,9Ce0,1NiO3, La0,9Sm0,1NiO3 e La0,9Pr0,1NiO3) na etapa de
racemização da DKR da (R,S)-1-feniletilamina. Os resultados obtidos indicaram que
este catalisador tem boa seletividade, pois foi observado que as reações, em
condições otimizadas, ocorreram com conversão acima de 72%, determinadas por
GC-MS. Também foram estudadas a variação das condições reacionais, como agente
acilante, temperatura e tempo, a fim de proporcionar melhores resultados para
obtenção da correspondente acetamida quiral. Além disso, foram utilizados outros
materiais de partida, (R,S)-1-(4’-fluoro)feniletilamina, (R,S)-1-(4’-metil)feniletilamina e
(R,S)-1,2,3,4-tetra-hidro-1-naftilamina, para obter informações generalizadas sobre a
metodologia estudada. As etapas posteriores à DKR, hidrólise da (R)-1-
feniletilacetamida e a alquilação da (R)-1-feniletilamina, foram realizadas inicialmente
com os substratos racêmicos, buscando a otimização das etapas. Após a descoberta
das condições reacionais mais adequadas para estas etapas, foi possível realizá-las
com os substratos quirais. Dessa forma, ao final da síntese, a molécula de interesse,
(R)-N-(1-feniletil)prop-2-ino-1-amina (composto monoalquilado), foi obtida em 38% de
conversão. Após a síntese e purificação, foram realizados ensaios de viabilidade
celular (VC) para avaliar a toxicidade dos racematos dos compostos N-propargilados,
no qual foi verificado que o composto monoalquilado era viável e não causava morte
celular.
Dynamic kinetic resolution (DKR) is a reaction catalyzed by an enzyme and a metal catalyst for the synthesis of enantiomerically pure compounds, such as amides and esters, for example. In this work, DKR was used as the first step of a synthetic route proposed to synthesize rasagiline analogues, (R)-N-(1-phenylethyl)prop-2-yne1-amine and (R)-N-(1-phenylethyl)-N-di(prop-2-yne)-1-amine. Rasagiline is a drug used as adjuvant in the treatment of Parkinson’s disease. The activity of nickel perovskite catalysts (La0,9Ce0,1NiO3, La0,9Sm0,1NiO3 and La0,9Pr0,1NiO3) in the DKR racemization stage was evaluated. Studies have shown that these catalysts have good selectivity, since the conversion values were above 72% determined by GC-MS, in optimized conditions. Changes of some reaction conditions such as acylating agent, temperature and reaction time were also studied, in order to evaluate their effects on the reactivity of the amines with perovskite catalysts. Substituted substrates were used in our studies, (R,S)-1-(4’-fluoro)phenylethylamine, (R,S)-1-(4’- methyl)phenylethylamine and (R,S)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)ethanamine, in order to obtain more general information about the studied methodology. The second and third steps, which were consisted of hydrolysis of (R)-1- phenylethylacetamide and alkylation of (R)-1-phenylethylamine, respectively, were performed with racemic substrates so that the chiral substrates were used only after optimization. The analog (R)-N-(1-phenylethyl)prop-2-yne-1-amine was obtained 38% non-isolated yield. After synthesis and purification, a cell viability assay was performed to assess the toxicity of racemic N-propargylated compounds. The results indicated that the monoalkylated analog did not cause cell death.
Dynamic kinetic resolution (DKR) is a reaction catalyzed by an enzyme and a metal catalyst for the synthesis of enantiomerically pure compounds, such as amides and esters, for example. In this work, DKR was used as the first step of a synthetic route proposed to synthesize rasagiline analogues, (R)-N-(1-phenylethyl)prop-2-yne1-amine and (R)-N-(1-phenylethyl)-N-di(prop-2-yne)-1-amine. Rasagiline is a drug used as adjuvant in the treatment of Parkinson’s disease. The activity of nickel perovskite catalysts (La0,9Ce0,1NiO3, La0,9Sm0,1NiO3 and La0,9Pr0,1NiO3) in the DKR racemization stage was evaluated. Studies have shown that these catalysts have good selectivity, since the conversion values were above 72% determined by GC-MS, in optimized conditions. Changes of some reaction conditions such as acylating agent, temperature and reaction time were also studied, in order to evaluate their effects on the reactivity of the amines with perovskite catalysts. Substituted substrates were used in our studies, (R,S)-1-(4’-fluoro)phenylethylamine, (R,S)-1-(4’- methyl)phenylethylamine and (R,S)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)ethanamine, in order to obtain more general information about the studied methodology. The second and third steps, which were consisted of hydrolysis of (R)-1- phenylethylacetamide and alkylation of (R)-1-phenylethylamine, respectively, were performed with racemic substrates so that the chiral substrates were used only after optimization. The analog (R)-N-(1-phenylethyl)prop-2-yne-1-amine was obtained 38% non-isolated yield. After synthesis and purification, a cell viability assay was performed to assess the toxicity of racemic N-propargylated compounds. The results indicated that the monoalkylated analog did not cause cell death.