Sínteses totais de alcaloides aporfinoides via química de benzino: progresso em hidrogenação enantiosseletiva de intermediário avançado e avaliações biológicas
Data
2023-05-24
Autores
Silva, Tamiris Reissa Cipriano da 
Orientadores
Raminelli, Cristiano
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Na literatura, podemos encontrar inúmeras aplicações para a química de benzino na química orgânica sintética, compreendendo preparações de materiais funcionais e sínteses totais de produtos naturais. Desta maneira, 2-(trimetilsilil)aril trifluorometanossulfonatos surgem como uma alternativa importante para a formação de benzino e derivados sob condições reacionais brandas. Considerando produtos naturais bioativos, alcaloides aporfinoides compõem uma importante classe de compostos que atuam como ligantes de receptores da dopamina. Diversas rotas têm sido reportadas na literatura para as sínteses de esqueletos aporfínicos, no entanto, em muitos casos, envolvendo nas etapas chaves condições relativamente drásticas. Neste contexto, realizamos a síntese total enantiosseletiva do alcaloide aporfinoide (S)-nuciferina [(S)-1], por abordagem inédita, empregando nas etapas chaves química de benzino, envolvendo condições reacionais brandas e hidrogenação enantiosseletiva de intermediário avançado. A (S)-nuciferina [(S)-1] foi obtida através de 8 etapas reacionais, com um rendimento global de 3,3% e razão enantiomérica de 81:19. Adicionalmente, empregando um intermediário em comum, realizamos a primeira síntese total do alcaloide bisaporfinoide ()-urabaína (2) via acoplamento oxidativo para formação da ligação entre C7 e C7’, bem como a síntese total de segunda geração do alcaloide oxaporfínico lisicamina (3) através de reação de oxidação. Além disso, através de ensaios biológicos, os compostos 2 e 3 apresentaram baixa citotoxidade em células de neuroblastoma humano (SH-SY5Y) e desmostraram efeito neuroprotetor frente à citotoxicidade induzida por aminocromo. Adicionalmente, a lisicamina (3) foi avaliada contra quatro linhagens de células de câncer de tireóide (KTC2, HTH83, BCPAP e TPC1), apresentando diminuição da viabilidade celular e possível ação indutora de necroptose.
In the literature, we can find numerous applications for benzyne chemistry in synthetic organic chemistry, including preparations of functional materials and total syntheses of natural products. In this way, 2-(trimethylsilyl)aryl trifluoromethanesulfonates appear as an important alternative for the formation of benzene and derivatives under mild reaction conditions. Considering bioactive natural products, aporphine alkaloids compose an important class of compounds that act as dopamine receptor ligands. Several routes have been reported in the literature for the synthesis of aporphine skeletons, however, in several cases, involving relatively harsh conditions in the key steps. In this context, we carried out the enantioselective total synthesis of aporphynoid alkaloid (S)-nuciferine [(S)-1], using an unprecedented approach, employing benzyne chemistry in the key steps, involving mild reaction conditions and enantioselective hydrogenation of an advanced intermediate. (S)-nuciferine [(S)-1] was obtained through 8 reaction steps, with an overall yield of 3.3% and an enantiomeric ratio of 81:19. In addition, employing a common intermediary, we accomplished the first total synthesis of bisaporphine alkaloid ()-urabaine (2) via oxidative coupling to form the bond between C7 and C7', as well as the second-generation total synthesis of oxaporphine alkaloid lisicamine (3) through oxidation reaction. Furthermore, by means of biological assays, compounds 2 and 3 showed low cytotoxicity in human neuroblastoma cells (SH-SY5Y) and presented a neuroprotective effect against aminochrome-induced cytotoxicity. In addition, lysicamine (3) was evaluated agaist four thyroid cancer cell lines (KTC2, HTH83, BCPAP, and TPC1), showing decreased cell viability and possible necroptosis-inducing action.
In the literature, we can find numerous applications for benzyne chemistry in synthetic organic chemistry, including preparations of functional materials and total syntheses of natural products. In this way, 2-(trimethylsilyl)aryl trifluoromethanesulfonates appear as an important alternative for the formation of benzene and derivatives under mild reaction conditions. Considering bioactive natural products, aporphine alkaloids compose an important class of compounds that act as dopamine receptor ligands. Several routes have been reported in the literature for the synthesis of aporphine skeletons, however, in several cases, involving relatively harsh conditions in the key steps. In this context, we carried out the enantioselective total synthesis of aporphynoid alkaloid (S)-nuciferine [(S)-1], using an unprecedented approach, employing benzyne chemistry in the key steps, involving mild reaction conditions and enantioselective hydrogenation of an advanced intermediate. (S)-nuciferine [(S)-1] was obtained through 8 reaction steps, with an overall yield of 3.3% and an enantiomeric ratio of 81:19. In addition, employing a common intermediary, we accomplished the first total synthesis of bisaporphine alkaloid ()-urabaine (2) via oxidative coupling to form the bond between C7 and C7', as well as the second-generation total synthesis of oxaporphine alkaloid lisicamine (3) through oxidation reaction. Furthermore, by means of biological assays, compounds 2 and 3 showed low cytotoxicity in human neuroblastoma cells (SH-SY5Y) and presented a neuroprotective effect against aminochrome-induced cytotoxicity. In addition, lysicamine (3) was evaluated agaist four thyroid cancer cell lines (KTC2, HTH83, BCPAP, and TPC1), showing decreased cell viability and possible necroptosis-inducing action.