Studies on the Curtius rearrangement of proline derivatives and preparation of N-carbamoyl indoline derivatives for asymmetric catalysis

• Autor(a) principal: Alves, Diana Filipa Lopes
• Data de Publicação: 2022
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/158894
• topic: Curtius rearrangement; L-proline; amino-pyrrolidine; S-indoline; guanidine; Michael addition; Domínio/Área Científica::Engenharia e Tecnologia::Engenharia Química

In the synthesis of cernumidine (1) and its derivatives was previously developed in the research group, which involved the Curtius rearrangement as a key step. However, the com-pounds obtained showed some degree of racemization which was dependent on the substitu-ents used in the trapping of the formed isocyanate. In the first part of this work, N-pyrimidine, N-alkyl and N-acyl derivatives of proline were synthesized and subsequently subjected to Curtius rearrangement. The isocyanate was trapped with phenylmagnesium bromide to study the influence the substituents on the nitro-gen atom can have on the observed racemization. The N-pyrimidinyl proline (8) derivative was, after the Curtius rearrangement, trapped with benzylamine and cyclohexylamine both led resulted in racemic ureas (9) and (10), with 12% and 3% yield, respectively. The N-methyl (4), N-benzyl (5) and N-benzoyl (7) proline derivatives presented inconsistent results and resulted in complex mixtures of de-graded starting material, while the N-acetyl proline (6) derivative afforded a complex mixture of compounds. Due to this, we weren't able to study the influence of the substituent on the nitrogen atom. In the second part of this work, we worked on a synthetic route to synthesize guanidine pyrrolidine catalysts for the Michael addition reaction, between ethyl 2-oxocyclopentsnecar-boxylate (2) and trans-β-nitrostyrene (3). The developed catalysts were (S)-indoline derivatives that were derivatized to amide derivatives and functionalized with a carbodiimide group on the nitrogen atom. The goal was to study their performance as bifunctional catalyst and to study the stereoselectivity induced in the reaction described above. The synthesis of these compounds involved four steps in which the most challenging one was the last step, the guanylation. The guanylation was achieved using the guanylating agent 1,3-di-Boc-2-methylisothiourea and the catalyst SmI2. Three different guanylated com-pounds were attained (19), (20) and (21), with 23%, 70% and 6% yield, respectively. The Michael addition assays employing the synthesized compounds (19) and (20), did-n't achieve satisfactory yields. The 1H NMR of the assay using compound (19) revealed a dia-stereoisomeric excess of 59% for the anti-isomer, but the evolution of the reaction was very slow. The assay with compound (20) showed an excess of the anti-isomer, but the diastereoi-someric excess wasn’t calculated due to the low resolution of the NMR spectrum and conse-quently the error associated with its calculation of the diastereoisomeric excess. It was not possible to perform the analysis of the enantiomeric excess, because the HPLC equipment was not operational.