Publicação
Development of new synthetic methodologies for organic synthesis based on biocatalysis
| Resumo: | Enantiomerically pure sec-alcohols are valuable molecules for several applications, due to their biological relevance and versatile functional group transformation. In most cases both enantiomers are important so the resolution of racemic alcohols is especially important. Herein, is aimed to develop appealing, competitive and more sustainable processes in new acylating agents for the enzymatic-resolution of sec-alcohols in order to isolate both enantiomers without the use of chromatography separations, organic solvents and post-chemical transformations. This methodology is quite simple, robust and reliable allowing the reuse of the medium and enzyme. The first approach is based on the screening of Ionic Liquids (ILs) as reaction medium and ionic acylating agents mediated by CAL B. This approach was demonstrated to 1-phenylethanol and 2-hydroxycyclohexanecarbonitrile in the presence of 1-methyl-3-(11-ethoxycarbonyl-undecyl)imidazolium hexafluorofosfate in [bmim][PF6] with good ee and yields. Also, we demonstrated the process recyclability and the possibility to perform the reaction under solvent free conditions. The second approach is based on fatty esters that act as acylating agents and reaction medium catalysed by CAL B. Therefore, we resolved and separated both enantiomers of 1-phenylethanol and pheromone sulcatol in very good ee and yields (>90% ee, >45%) by simple distillation. Additionally, we could recycle the reaction medium and enzyme 10 times. We also explored extraction and distillation as useful separation techniques to resolve 1-phenylethanol, sulcatol, 2-hydroxy-cyclohexanecarbonitrile, 3-chloro-1- phenylpropan-1-ol using PEG600-carboxylates as acylating agents. Furthermore, we demonstrated the reuse of the process and the reaction scale up to a 5g scale of the high value molecule 3-chloro-1-phenylpropan-1-ol. The nanofiltration was also tested as separation technique. Finally, we faced an unexpected enzymatic dynanic kinetic resolution (EDKR) of sulcatol in the presence of ionic acylating agent, IL and lipase. After investigate the influence of each parameter we found out that the EDKR only occurs with specific components of the reaction. However, further investigations should be carry out to identify experimental requirements for EDKR and mechanism elucidation. |
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| Autores principais: | Monteiro, Carlos Manuel Fortes Tavares, 1983- |
| Assunto: | Teses de doutoramento - 2013 |
| Ano: | 2013 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso restrito |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Enantiomerically pure sec-alcohols are valuable molecules for several applications, due to their biological relevance and versatile functional group transformation. In most cases both enantiomers are important so the resolution of racemic alcohols is especially important. Herein, is aimed to develop appealing, competitive and more sustainable processes in new acylating agents for the enzymatic-resolution of sec-alcohols in order to isolate both enantiomers without the use of chromatography separations, organic solvents and post-chemical transformations. This methodology is quite simple, robust and reliable allowing the reuse of the medium and enzyme. The first approach is based on the screening of Ionic Liquids (ILs) as reaction medium and ionic acylating agents mediated by CAL B. This approach was demonstrated to 1-phenylethanol and 2-hydroxycyclohexanecarbonitrile in the presence of 1-methyl-3-(11-ethoxycarbonyl-undecyl)imidazolium hexafluorofosfate in [bmim][PF6] with good ee and yields. Also, we demonstrated the process recyclability and the possibility to perform the reaction under solvent free conditions. The second approach is based on fatty esters that act as acylating agents and reaction medium catalysed by CAL B. Therefore, we resolved and separated both enantiomers of 1-phenylethanol and pheromone sulcatol in very good ee and yields (>90% ee, >45%) by simple distillation. Additionally, we could recycle the reaction medium and enzyme 10 times. We also explored extraction and distillation as useful separation techniques to resolve 1-phenylethanol, sulcatol, 2-hydroxy-cyclohexanecarbonitrile, 3-chloro-1- phenylpropan-1-ol using PEG600-carboxylates as acylating agents. Furthermore, we demonstrated the reuse of the process and the reaction scale up to a 5g scale of the high value molecule 3-chloro-1-phenylpropan-1-ol. The nanofiltration was also tested as separation technique. Finally, we faced an unexpected enzymatic dynanic kinetic resolution (EDKR) of sulcatol in the presence of ionic acylating agent, IL and lipase. After investigate the influence of each parameter we found out that the EDKR only occurs with specific components of the reaction. However, further investigations should be carry out to identify experimental requirements for EDKR and mechanism elucidation. |
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