Publicação
Development of new methodologies for C-H insertion
| Resumo: | Antibiotics are a fundamental tool for modern medicine to treat bacterial infections. One of the first antibiotics to be discovered was penicillin which is a natural occurring β-lactam isolated form Penicillium fungi. β-lactam-derived antibiotics own a broad antibacterial spectrum, clinical efficiency and an excellent safety profile. This made them one of the antibiotics still more prescribed. The chemical manipulation of this core allowed more potent variants which increased the demand for such processes. Among these the C-H insertion reaction with C-C bond formation offers new possibilities of retrosynthetic disconnections on β-lactam synthesis by dirhodium (II)-catalyzed α-diazoacetamides decomposition. This catalyst has two axial positions and on one of them a N-heterocyclic carbene (NHC) was previously complexed but the authors claimed that this NHC was instable and was removed during the catalytic cycle. We used other monocoordinated NHCs ligands which showed to be stable on this position on α-diazoacetamides decomposition. Longer reaction times were observed as well as a preference for β-lactam over β-lactam formation and a decarbonylated product derived from the Wolff rearrangement was also observed. Since diazo compounds are potentially explosive and toxic reagents their use is very restricted to large scale applications, despite being a common laboratorial reagent. Therefore the demand for a stable surrogate is highly demanded. Here, iodonium ylides were used for the C-H insertion with C-C bond formation for the synthesis of β-lactams and up to good yields were obtained under very smooth conditions. The method here developed is diazo- and transition metal-free. Besides, the substrate activation and subsequent C-H insertion reaction occurs in a single synthetic step, instead of the two usually required for the diazo moiety transfer and its decomposition. Mechanistic experiments allowed to propose that the C-H insertion also occurs via a carbene intermediate.Os antibióticos são uma ferramenta fundamental na medicina moderna no tratamento de infeções bacterianas. |
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| Autores principais: | Gomes, Luís Filipe Rodrigues, 1984- |
| Assunto: | Teses de doutoramento - 2014 |
| Ano: | 2014 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Antibiotics are a fundamental tool for modern medicine to treat bacterial infections. One of the first antibiotics to be discovered was penicillin which is a natural occurring β-lactam isolated form Penicillium fungi. β-lactam-derived antibiotics own a broad antibacterial spectrum, clinical efficiency and an excellent safety profile. This made them one of the antibiotics still more prescribed. The chemical manipulation of this core allowed more potent variants which increased the demand for such processes. Among these the C-H insertion reaction with C-C bond formation offers new possibilities of retrosynthetic disconnections on β-lactam synthesis by dirhodium (II)-catalyzed α-diazoacetamides decomposition. This catalyst has two axial positions and on one of them a N-heterocyclic carbene (NHC) was previously complexed but the authors claimed that this NHC was instable and was removed during the catalytic cycle. We used other monocoordinated NHCs ligands which showed to be stable on this position on α-diazoacetamides decomposition. Longer reaction times were observed as well as a preference for β-lactam over β-lactam formation and a decarbonylated product derived from the Wolff rearrangement was also observed. Since diazo compounds are potentially explosive and toxic reagents their use is very restricted to large scale applications, despite being a common laboratorial reagent. Therefore the demand for a stable surrogate is highly demanded. Here, iodonium ylides were used for the C-H insertion with C-C bond formation for the synthesis of β-lactams and up to good yields were obtained under very smooth conditions. The method here developed is diazo- and transition metal-free. Besides, the substrate activation and subsequent C-H insertion reaction occurs in a single synthetic step, instead of the two usually required for the diazo moiety transfer and its decomposition. Mechanistic experiments allowed to propose that the C-H insertion also occurs via a carbene intermediate.Os antibióticos são uma ferramenta fundamental na medicina moderna no tratamento de infeções bacterianas. |
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