Reações de bromoaminociclização enantiosseletivas visando a síntese de bases esfingóides
Data
2022-03-04
Autores
Ohira, Bianca Yumi 
Orientadores
Rodrigues, Alessandro
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A porção aminoálcool é um constituinte estrutural presente em diversas moléculas, sejam elas de ocorrência natural ou não, que apresentam diversas atividades biológicas relevantes. Dentre elas, existem os aminoálcoois de cadeia longa, conhecidos como bases esfingóides e que são subunidades presentes em um vasto número de moléculas de ocorrência natural e que são biologicamente ativos, como a esfingosina, esfinganina, xestoaminol C e os clavaminóis. Estes compostos desempenham diversos papéis, seja na sinalização celular, inibição da proteína quinase C, atividade antineoplásica, atividade antifúngica, atividade anti-helmíntica, dentre outras.
Devido à importância biológica desses compostos houve o desenvolvimento de inúmeras metodologias, sendo que a maioria envolve a aplicação “chiral pool”. Este trabalho propôs uma rota sintética que não foi descrita até o presente momento, que possui como materiais de partida ácidos carboxílicos ou álcoois. O ácido hexadecanóico foi reduzido ao álcool correspondente (rendimento de 51%), os álcoois foram oxidados a aldeídos (rendimentos entre 37-95%). Estes foram submetidos a uma reação de Horner-Wadsworth-Emmons para a obtenção dos respectivos ésteres (rendimentos entre 16-92%), que sofreram redução na presença de DIBAL-H para formação dos álcoois alílicos (rendimento entre 52-79%) e posterior reação com o isocianato selecionado, levando à formação dos carbamatos alílicos que foram obtidos com rendimento entre 92-100%. Para a reação de bromoaminociclização dos carbamatos, nos inspiramos no trabalho de Shi e colaboradores que fazem uso do fosfinóxido quiral complexado ao Sc(OTf)3. Os produtos ciclizados foram obtidos com rendimento variando de 43-100% e excessos enantioméricos 43-96%. Esses produtos de ciclização podem ser submetidos à hidrólise alcalina a fim de obter-se as bases esfingóides relevantes.
The aminoalcohol moiety is a structural constituent present in several molecules, whether naturally occurring or not, which have several relevant biological activities. Among them, there are the long-chain amino alcohols, known as sphingoid bases, which are subunits present in a vast number of naturally occurring molecules that are biologically active, such as sphingosine, sphinganine, xestoaminol C and clavaminols. These compounds play several roles, whether in cell signaling, protein kinase C inhibition, antineoplastic activity, antifungal activity, anthelmintic activity, among others. Due to the biological importance of these compounds, lots of methodologies have been developed, most of which involve the “chiral pool” application. This work proposed a synthetic route that has not been described so far, which has carboxylic acids or alcohols as starting materials. Hexadecanoic acid was reduced to the corresponding alcohol (51% yield), the alcohols were oxidized to aldehydes (37-95% yield). These were subjected to a Horner-Wadsworth-Emmons reaction to obtain the respective esters (16-92% yield), which were reduced in the presence of DIBAL-H to give allylic alcohols (52-79% yield) and subsequent reaction with the selected isocyanate, leading to the formation of allylic carbamates, which were obtained in 92-100% yield. For the bromoaminocyclization reaction of carbamates, we were inspired by the work of Shi et al. who use chiral phosphinoxide complexed to Sc(OTf)3. Cyclized products were obtained with yields ranging from 43-100% and enantiomeric excesses 43-96%. These cyclization products can be subjected to alkaline hydrolysis to obtain relevant sphingoid bases.
The aminoalcohol moiety is a structural constituent present in several molecules, whether naturally occurring or not, which have several relevant biological activities. Among them, there are the long-chain amino alcohols, known as sphingoid bases, which are subunits present in a vast number of naturally occurring molecules that are biologically active, such as sphingosine, sphinganine, xestoaminol C and clavaminols. These compounds play several roles, whether in cell signaling, protein kinase C inhibition, antineoplastic activity, antifungal activity, anthelmintic activity, among others. Due to the biological importance of these compounds, lots of methodologies have been developed, most of which involve the “chiral pool” application. This work proposed a synthetic route that has not been described so far, which has carboxylic acids or alcohols as starting materials. Hexadecanoic acid was reduced to the corresponding alcohol (51% yield), the alcohols were oxidized to aldehydes (37-95% yield). These were subjected to a Horner-Wadsworth-Emmons reaction to obtain the respective esters (16-92% yield), which were reduced in the presence of DIBAL-H to give allylic alcohols (52-79% yield) and subsequent reaction with the selected isocyanate, leading to the formation of allylic carbamates, which were obtained in 92-100% yield. For the bromoaminocyclization reaction of carbamates, we were inspired by the work of Shi et al. who use chiral phosphinoxide complexed to Sc(OTf)3. Cyclized products were obtained with yields ranging from 43-100% and enantiomeric excesses 43-96%. These cyclization products can be subjected to alkaline hydrolysis to obtain relevant sphingoid bases.