New approaches to amino-pyrrolidine guanidine compounds

• Autor(a) principal: Leitão, Flávia Lidónio
• Data de Publicação: 2021
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/132846
• topic: Cernumidine; aminal; aminopyrrolidine; guanidine; L-proline; Curtius rearrangement; Domínio/Área Científica::Engenharia e Tecnologia::Engenharia Química

Cernumidine is an alkaloid of natural origin isolated from the plant Solanum cernuum Vell with the ability to inhibit the production of IL-8 from HT-29 colon carcinoma. Chemically, this molecule is equally interesting and challenging, it presents an aminal-guanidine core and an asymmetric center resulting in a challenging aminopyrrolidine nucleus. From a sustainability point of view, it is important to design a synthetic pathway to attain cernumidine to bypass the difficulties found in the isolation and purification of the natural product. In this work a synthetic pathway, for the synthesis of cernumidine and derivatives, was designed having the N-Boc protected amino acid L-Proline as the starting material and with Curtius rearrangement, from acyl azides, as the key step to originate the aminal moiety after the trapping of the isocyanate with Grignard reagents. When vinyl magnesium bromide was the Grignard reagent used, it was possible to obtain, starting with the attained vinyl amides though palladium catalyzed Heck coupling, seven different acrylamides in yields ranging from 58% to 84%. The synthesis of cernumidine and derivatives involved a total of six reactional steps, starting with the N-Boc protected proline, the deprotection of the nitrogen of the pyrrolidine ring and guanylation steps, revealed to be the most challenging due to instability and reactivity of the aminal moiety. For the removal of the Boc group AlMe3 proved to be the most efficient reagent with a yield of 84% in the deprotection of compound 5, without the degradation of the aminal moiety. For the guanylation step, from the tested guanylation reagents, 1H-pyrazole-1-carboxamidine, proved to be the most suitable. Surprisingly, Curtius rearrangement, in literature, is associated with configuration retention, occurs in this derivative with partial racemization confirmed by X-ray crystallography analysis of compound 16. Cernumidine was obtained in a global yield of 9%, in a mixture of both enantiomers with a slight enantiomeric excess having a specific optical rotation of +12.4 ([] 29+12.4 (c 0.36, MeOH)). Nine other synthetic derivatives were also obtained with global yields ranging from 3% to 37%.