Síntese de julolidinas empregando a reação multicomponente de Povarov e avaliação das atividades antifúngica e antiurease
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2019-07-19
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Universidade Federal de Viçosa
Resumo
A reação de Povarov é um processo que envolve a reação de uma imina gerada in situ por uma anilina e um composto carbonílico (aldeído ou cetona), seguida da reação de substituição eletrofílica aromática com um alqueno rica em densidade eletrônica. Geralmente a reação de Povarov é catalisada por ácidos de Lewis ou de Brønsted e dependendo das condições de reação, é possível acessar três diferentes classes de N- heterociclos: tetraidroquinolinas, quinolinas ou julolidinas. Neste trabalho foi avaliada a reação de Povarov multicomponente para a síntese de julolidinas, catalisada pelo ácido de Lewis BF 3. OEt 2 . Para tanto, foram avaliados diferentes anilinas, formaldeído e como alquenos o 2,3-diidrofurano e o trans-anetol como substratos. Empregando como substrato o 2,3-diidrofurano, formaldeído e diferentes anilinas foram sintetizadas 32 furanojulolidinas com rendimentos de 43 e 93%, das quais 16 possuem a estereoquímica trans 1-16 [(±)-T] e as outras 16 a estereoquímica cis 1-16 (C). As condições otimizadas para a síntese das furanojulolidinas 1-16(±)-T e 1-16 (C) foram: água como solvente, temperatura de 70 °C, 2 h de reação e 20 mol% de catalisador (BF 3. OEt 2 ). Na segunda parte do presente trabalho foram sintetizadas outras 24 julolidinas empregando como substratos diferentes anilinas, formaldeído e óleo de anis estrelado (trans-anetol). As condições otimizadas para a reação com o trans-anetol foram: água como solvente, temperatura ambiente, 4 h de reação e 25 mol% de catalisador (BF 3. OEt 2 ). Os rendimentos variaram entre 51 e 95%. As julolidinas foram obtidas como uma mistura de diastereoisômeros com excessos diastereoisoméricos que variaram de 1 a 36%. A estereoquímica das julolidinas foi estabelecida com auxílio de RMN de 1 H e por cristalografia de Raios-X. Para ambas as reações de Povarov, empregando 2,3- diidrofurano e trans-anetol foi possível estabelecer o reuso do catalisador, tendo rendimentos variando de 94 a 99% e de 89 a 99%, respectivamente. As furanojulolidinas foram avaliadas como agentes antifúngicos frente aos fungos Candida albicans e Cryptococcus neoformans e também a atividade antiurease frente a enzima urease purificada de Canavalia ensiformis tipo III. As furanojulolidinas 11 [(±)T e C] e 12 [(±)T e C], apresentaram uma melhor atividade sobre o fungo Cryptococcus neoformans, sendo os valores de CIM 50 15,3, 31,3, 3,4 e 3,4 µg.mL -1 respectivamente. Para a atividade antiurease as furanojulolidinas 11C e 12(±)T foram as que apresentaram as maiores porcentagens de inibição 79,3% e 71,6%, respectivamente, sendo o resultado similar ao obtido para o controle positivo hidroxiureia.
The reaction of Povarov is a process involving the reaction of an imine generated in situ by aniline and a carbonylate compound (aldehyde or ketone), followed by the aromatic electrophilic reaction with an electron-rich alkene. Generally, Lewis or Brønsted acids catalyze the Povarov reaction and depending on the reaction conditions are acquired, three types of N-heterocycles: tetrahydroquinolines, quinolines or julolidines. In this work, a multicomponent Povarov reaction for an enzyme synthesis catalyzed by Lewis lactic acid BF 3. OEt 2 was evaluate. For this, the different anilines, formaldehyde, and 2,3- dihydrofuran or trans-anethole were evaluated as substrates. Using as substrate 2,3- dihydrofuran, formaldehyde and anilines, 32 furanojulolidines were synthesized with yields between 43 and 93%, of which 16 had trans 1-16 [(±) -T] stereochemistry and the other 16 the cis stereochemistry 1-16 (C). The optimized conditions for the synthesis of furanojulolidines 1-16 (±) -T and 1-16 (C) were: temperature 70 °C, 2 h reaction and 20% catalyst (BF 3. OEt 2 ). In the second part of the present work, 24 other julidines were synthesized using different anilines, formaldehyde and star anise oil (trans-anethole) as substrates. The optimized conditions for the trans-anethole reaction were: water as solvent, room temperature, 4 h reaction and 25 mol% catalyst (BF 3. OEt 2 ). The values range between 51 and 95%. The obtained julolidines consist of a mixture of diastereoisomers with excess diastereoisomeric ranging from 1 to 36%. The stereochemistry of the julolidines was determined with the aid of 1 H NMR and X-Ray crystallography. For both Povarov reactions, using 2,3-dihydrofuran and trans-anethole it was possible to establish the catalyst reuse, varying from 94 to 99% and from 89 to 99%, respectively. Furanojulolidines were evaluated as antifungal agents against Candida albicans and Cryptococcus neoformans fungi and also an antiurease activity against a purified Canavalia ensiformis type III enzyme. Furanojulolidines 11 [(±) T+C] and 12 [(±) T+C] are the best activities on the fungus Cryptococcus neoformans, with MIC 50 values 15,3,31,3,4,4 and 3,4 µg.mL-1 respectively. For antirease activity, the furanojulolidines 11C and 12 (±) have been presented the highest inhibition percentages 79.3% and 71.6%, while the result was similar to that obtained for the positive control of hydroxyurea.
The reaction of Povarov is a process involving the reaction of an imine generated in situ by aniline and a carbonylate compound (aldehyde or ketone), followed by the aromatic electrophilic reaction with an electron-rich alkene. Generally, Lewis or Brønsted acids catalyze the Povarov reaction and depending on the reaction conditions are acquired, three types of N-heterocycles: tetrahydroquinolines, quinolines or julolidines. In this work, a multicomponent Povarov reaction for an enzyme synthesis catalyzed by Lewis lactic acid BF 3. OEt 2 was evaluate. For this, the different anilines, formaldehyde, and 2,3- dihydrofuran or trans-anethole were evaluated as substrates. Using as substrate 2,3- dihydrofuran, formaldehyde and anilines, 32 furanojulolidines were synthesized with yields between 43 and 93%, of which 16 had trans 1-16 [(±) -T] stereochemistry and the other 16 the cis stereochemistry 1-16 (C). The optimized conditions for the synthesis of furanojulolidines 1-16 (±) -T and 1-16 (C) were: temperature 70 °C, 2 h reaction and 20% catalyst (BF 3. OEt 2 ). In the second part of the present work, 24 other julidines were synthesized using different anilines, formaldehyde and star anise oil (trans-anethole) as substrates. The optimized conditions for the trans-anethole reaction were: water as solvent, room temperature, 4 h reaction and 25 mol% catalyst (BF 3. OEt 2 ). The values range between 51 and 95%. The obtained julolidines consist of a mixture of diastereoisomers with excess diastereoisomeric ranging from 1 to 36%. The stereochemistry of the julolidines was determined with the aid of 1 H NMR and X-Ray crystallography. For both Povarov reactions, using 2,3-dihydrofuran and trans-anethole it was possible to establish the catalyst reuse, varying from 94 to 99% and from 89 to 99%, respectively. Furanojulolidines were evaluated as antifungal agents against Candida albicans and Cryptococcus neoformans fungi and also an antiurease activity against a purified Canavalia ensiformis type III enzyme. Furanojulolidines 11 [(±) T+C] and 12 [(±) T+C] are the best activities on the fungus Cryptococcus neoformans, with MIC 50 values 15,3,31,3,4,4 and 3,4 µg.mL-1 respectively. For antirease activity, the furanojulolidines 11C and 12 (±) have been presented the highest inhibition percentages 79.3% and 71.6%, while the result was similar to that obtained for the positive control of hydroxyurea.
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Julolidina, Povarov, Reação de
Citação
BONILLA CASTAÑEDA, Sandra Milena. Síntese de julolidinas empregando a reação multicomponente de Povarov e avaliação das atividades antifúngica e antiurease. 2019. 242 f. Tese (Doutorado em Agroquímica) - Universidade Federal de Viçosa, Viçosa. 2019.