Publicação
Asymmetric Neber Reaction in the Synthesis of 2-(Tetrazol-5-yl)-2H-Azirines
| Resumo: | The main purpose of the work developed in this dissertation was to establish an asymmetric version of the Neber reaction for the synthesis of 2-(tetrazol-5-yl)-2H-azirines resorting on organocatalysis which could be applied to the synthesis of the bioisosteres of naturally occurring biological active 2H-azirine-2-carboxylates (azirinomycin, (-)-dysidazirine and antazirine).Earlier studies developed in the group where this MSc project was carried out, already demonstrated that the alkaloid-mediated Neber reactions of β-ketoxime tosylates allows the asymmetric synthesis of 2-(tetrazol-5-yl)-2H-azirines. One of the main goals of this MSc project was to explore an one-pot procedure by carrying out the in situ tosylation of β-ketoxime tetrazoles followed by the Neber reaction in presence of chiral organocatalysts. Thus, the conversion of 2-(1-(4-nitrobenzyl)-1H-tetrazol-5-yl)-1-phenylethanone oxime into the corresponding 2H-azirine was selected as model reaction. An initial solvent screening using quinidine as organocatalyst was carried out and, within the studied solvents, the best results were obtained when the reactions were carried out in toluene. Other parameters such as temperature, catalyst loading, time reaction and co-base were also studied.Under the optimized reaction conditions for quinidine, other organocatalysts, namely quinine, cinchona alkaloid derivatives bearing amino acids and several heterocycle moieties, as well as chiral bifunctional thioureas incorporating thiazolidine moieties were explored. The synthesis of new 6β-aminopenicilanic acid derived thioureas, (2S,6R)-benzhydryl 6β-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-aminopenicillanate and (2S,6R)-benzhydryl 6β-(3-(phenyl)thioureido)-aminopenicillanate, was also accomplished and their application as catalysts in the asymmetric Neber reaction was studied as well. This study showed that within the screened cinchona alkaloid derivatives, quinidine is the most efficient catalyst to obtain the R isomer in the asymmetric synthesis of 2-(tetrazol-5-yl)-2H-azirines, since it presented the highest yields and ee, 87% and 66%, respectively. As for the S isomer the best results were achieved when the asymmetric Neber reaction was carried out with quinine leading to the target isomer in 61% yield and 44% ee.Moreover, our best catalyst for the asymmetric Neber reactions were the 6β-aminopenicilanic acid derived thioureas. To our delight, these new organocatalysts afforded the (2R)-3-phenyl-2-(1-(4-nitrobenzyl)-1H-tetrazol-5-yl)-2H-azirine R isomer in very high enantiomeric excess (>99%). |
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| Autores principais: | Alves, Cláudia Daniela da Cruz |
| Assunto: | Reação Assimétrica de Neber Bioisósteros Organocatálise 2H-Azirinas Tetrazole Asymmetric Neber Reaction Bioisosteres Organocatalysis 2H-Azirine Tetrazole |
| Ano: | 2018 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Coimbra |
| Idioma: | inglês |
| Origem: | Estudo Geral - Universidade de Coimbra |
| Resumo: | The main purpose of the work developed in this dissertation was to establish an asymmetric version of the Neber reaction for the synthesis of 2-(tetrazol-5-yl)-2H-azirines resorting on organocatalysis which could be applied to the synthesis of the bioisosteres of naturally occurring biological active 2H-azirine-2-carboxylates (azirinomycin, (-)-dysidazirine and antazirine).Earlier studies developed in the group where this MSc project was carried out, already demonstrated that the alkaloid-mediated Neber reactions of β-ketoxime tosylates allows the asymmetric synthesis of 2-(tetrazol-5-yl)-2H-azirines. One of the main goals of this MSc project was to explore an one-pot procedure by carrying out the in situ tosylation of β-ketoxime tetrazoles followed by the Neber reaction in presence of chiral organocatalysts. Thus, the conversion of 2-(1-(4-nitrobenzyl)-1H-tetrazol-5-yl)-1-phenylethanone oxime into the corresponding 2H-azirine was selected as model reaction. An initial solvent screening using quinidine as organocatalyst was carried out and, within the studied solvents, the best results were obtained when the reactions were carried out in toluene. Other parameters such as temperature, catalyst loading, time reaction and co-base were also studied.Under the optimized reaction conditions for quinidine, other organocatalysts, namely quinine, cinchona alkaloid derivatives bearing amino acids and several heterocycle moieties, as well as chiral bifunctional thioureas incorporating thiazolidine moieties were explored. The synthesis of new 6β-aminopenicilanic acid derived thioureas, (2S,6R)-benzhydryl 6β-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-aminopenicillanate and (2S,6R)-benzhydryl 6β-(3-(phenyl)thioureido)-aminopenicillanate, was also accomplished and their application as catalysts in the asymmetric Neber reaction was studied as well. This study showed that within the screened cinchona alkaloid derivatives, quinidine is the most efficient catalyst to obtain the R isomer in the asymmetric synthesis of 2-(tetrazol-5-yl)-2H-azirines, since it presented the highest yields and ee, 87% and 66%, respectively. As for the S isomer the best results were achieved when the asymmetric Neber reaction was carried out with quinine leading to the target isomer in 61% yield and 44% ee.Moreover, our best catalyst for the asymmetric Neber reactions were the 6β-aminopenicilanic acid derived thioureas. To our delight, these new organocatalysts afforded the (2R)-3-phenyl-2-(1-(4-nitrobenzyl)-1H-tetrazol-5-yl)-2H-azirine R isomer in very high enantiomeric excess (>99%). |
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