Síntese enantiosseletiva de beta-aminoésteres quirais através de sistemas enzimáticos envolvendo transaminases
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Data
2016-03-04
Autores
Cruz, Raquel Sabará [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
Beta-aminoésteres/ácidos quirais enantiomericamente puros são blocos construtores quirais economicamente importantes para a indústria farmacêutica, de química fina, e agroquímica. As transaminases, também conhecidas como aminotransferases têm emergido como uma importante classe de enzimas com grande potencial na síntese enantiosseletiva desses compostos. Neste trabalho foi avaliada a reatividade de omega-transaminases frente a beta-cetoésteres arílicos (benzoilacetato de etila) e alquílicos (acetoacetato de etila) visando à síntese enantiosseletiva de beta-aminoésteres/ácidos. As enzimas utilizadas neste trabalho foram produzidas no laboratório a partir de plasmídeos contendo genes que codificam omega-transaminases (R) e (S)-seletivas provenientes de diferentes micro-organismos. Essas enzimas juntamente com uma enzima comercial (S)-seletiva foram empregadas em reações de aminação assimétrica utilizando substratos beta-cetoésteres, e na resolução cinética da (R,S)-feniletilamina. Parâmetros como concentração de enzima:substrato, compostos doadores de grupo amino, temperatura e pH foram avaliados visando à otimização dos rendimentos e enantiosseletividade. As enzimas produzidas apresentaram excelentes conversões (> 99 %) nas reações de síntese assimétrica e elevados excessos enantioméricos (> 99 %) em praticamente todas as reações de resolução cinética nas quais o acetoacetato de etila foi empregado como substrato. Por outro lado, nas reações onde o benzoilacetato de etila foi empregado como aceptor de amina, não se observou a formação do produto de interesse.
Optically pure beta-amino esters/ acids constitute economically important chiral building blocks for the pharmaceutical, fine chemical and agrochemical industries. Transaminases, also known as aminotransferases have emerged as an important class of enzymes with great potential in the enantioselective synthesis of these compounds. In this work, was evaluated the reactivity of omega-transaminase against aryl (ethyl benzoylacetate) and alkyl (ethyl acetoacetate) beta-keto esters for the enantioselective synthesis of beta-amino esters/acids. The enzymes used in this work were produced in the laboratory from plasmids containing genes encoding (R) and (S)-selective omega-transaminases from different micro-organisms. These enzymes along with a (S)-selective commercial enzyme were employed in the asymmetric amination reactions using beta-keto esters substrates and kinetic resolution of (R,S)-phenylethylamine. Parameters such as concentration of enzyme:substrate, amino group donors, temperature and pH were evaluated aiming to optimize yields and enantioselectivity. The enzymes produced showed excellent conversion (> 99%) in the asymmetric synthesis reactions and high enantiomeric excess (> 99%) in practically all kinetic resolution reactions in which ethyl acetoacetate was used as substrate. On the other hand, in reactions where the ethyl benzoylacetate was used as amino acceptor, was not observed the formation of the product of interest.
Optically pure beta-amino esters/ acids constitute economically important chiral building blocks for the pharmaceutical, fine chemical and agrochemical industries. Transaminases, also known as aminotransferases have emerged as an important class of enzymes with great potential in the enantioselective synthesis of these compounds. In this work, was evaluated the reactivity of omega-transaminase against aryl (ethyl benzoylacetate) and alkyl (ethyl acetoacetate) beta-keto esters for the enantioselective synthesis of beta-amino esters/acids. The enzymes used in this work were produced in the laboratory from plasmids containing genes encoding (R) and (S)-selective omega-transaminases from different micro-organisms. These enzymes along with a (S)-selective commercial enzyme were employed in the asymmetric amination reactions using beta-keto esters substrates and kinetic resolution of (R,S)-phenylethylamine. Parameters such as concentration of enzyme:substrate, amino group donors, temperature and pH were evaluated aiming to optimize yields and enantioselectivity. The enzymes produced showed excellent conversion (> 99%) in the asymmetric synthesis reactions and high enantiomeric excess (> 99%) in practically all kinetic resolution reactions in which ethyl acetoacetate was used as substrate. On the other hand, in reactions where the ethyl benzoylacetate was used as amino acceptor, was not observed the formation of the product of interest.
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Palavras-chave
Omega-transaminase, Beta-aminoéster, Biocatálise, Biocatalysis