Synthesis of 7α-Methoxy-7-(4-phenyl-1<i>H</i>-1,2,3-triazol-1-yl)acetamino-3′-arylthio-cephalosporic Acid Derivatives from 7-Aminocephalosporic Acid
The aim of this project was to develop a synthetic protocol for the preparation of a cephamycin scaffold that would readily allow the synthesis of its analogues with variations at the C-7 amino group and the C-3′ position. We also aimed to develop a method that avoided the use of toxic and potential...
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MDPI AG
2023-10-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/21/7338 |
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| author | Wendy Y. Cun Paul A. Keller Stephen G. Pyne |
| author_facet | Wendy Y. Cun Paul A. Keller Stephen G. Pyne |
| author_sort | Wendy Y. Cun |
| collection | DOAJ |
| description | The aim of this project was to develop a synthetic protocol for the preparation of a cephamycin scaffold that would readily allow the synthesis of its analogues with variations at the C-7 amino group and the C-3′ position. We also aimed to develop a method that avoided the use of toxic and potentially explosive diphenyldiazomethane. These aims were achieved via the synthesis of the novel α-bromo acetamide <b>18</b> which allowed functionalization at the α-bromo acetamide position by azide and then the introduction of a 4-phenyl-1<i>H</i>-1,2,3-triazol-1-yl moiety via a Cu(I)-catalysed azide–alkyne cycloaddition reaction with phenylacetylene. Palladium-catalyzed arylthioallylation reactions then allowed the introduction of 3′-arylthiol substituents. We also report for the first time the synthesis of the 4-methoxybenzyl ester of (6<i>R</i>,7<i>S</i>)-3-[(acetyloxy)methyl]-7-amino-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and the use of diphenyl trichloroacetimidate, instead of diphenyldiazomethane, and 4-methoxybenzyl trichloroacetimidate to prepare related 4-methoxybenzyl esters. The chemistry described, and several of the synthetic intermediates reported here, are potentially valuable methods and scaffolds, respectively, for further development of β-lactam antibiotics. |
| first_indexed | 2024-03-11T11:24:09Z |
| format | Article |
| id | doaj.art-44f19f50d58845fcb4a9992da32f7e89 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T11:24:09Z |
| publishDate | 2023-10-01 |
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| record_format | Article |
| series | Molecules |
| spelling | doaj.art-44f19f50d58845fcb4a9992da32f7e892023-11-10T15:08:39ZengMDPI AGMolecules1420-30492023-10-012821733810.3390/molecules28217338Synthesis of 7α-Methoxy-7-(4-phenyl-1<i>H</i>-1,2,3-triazol-1-yl)acetamino-3′-arylthio-cephalosporic Acid Derivatives from 7-Aminocephalosporic AcidWendy Y. Cun0Paul A. Keller1Stephen G. Pyne2School of Chemistry and Molecular Bioscience, Molecular Horizons Research Institute, University of Wollongong, Wollongong, NSW 2522, AustraliaSchool of Chemistry and Molecular Bioscience, Molecular Horizons Research Institute, University of Wollongong, Wollongong, NSW 2522, AustraliaSchool of Chemistry and Molecular Bioscience, Molecular Horizons Research Institute, University of Wollongong, Wollongong, NSW 2522, AustraliaThe aim of this project was to develop a synthetic protocol for the preparation of a cephamycin scaffold that would readily allow the synthesis of its analogues with variations at the C-7 amino group and the C-3′ position. We also aimed to develop a method that avoided the use of toxic and potentially explosive diphenyldiazomethane. These aims were achieved via the synthesis of the novel α-bromo acetamide <b>18</b> which allowed functionalization at the α-bromo acetamide position by azide and then the introduction of a 4-phenyl-1<i>H</i>-1,2,3-triazol-1-yl moiety via a Cu(I)-catalysed azide–alkyne cycloaddition reaction with phenylacetylene. Palladium-catalyzed arylthioallylation reactions then allowed the introduction of 3′-arylthiol substituents. We also report for the first time the synthesis of the 4-methoxybenzyl ester of (6<i>R</i>,7<i>S</i>)-3-[(acetyloxy)methyl]-7-amino-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and the use of diphenyl trichloroacetimidate, instead of diphenyldiazomethane, and 4-methoxybenzyl trichloroacetimidate to prepare related 4-methoxybenzyl esters. The chemistry described, and several of the synthetic intermediates reported here, are potentially valuable methods and scaffolds, respectively, for further development of β-lactam antibiotics.https://www.mdpi.com/1420-3049/28/21/7338cephamycincefotetanantibioticstriazolethioallylation |
| spellingShingle | Wendy Y. Cun Paul A. Keller Stephen G. Pyne Synthesis of 7α-Methoxy-7-(4-phenyl-1<i>H</i>-1,2,3-triazol-1-yl)acetamino-3′-arylthio-cephalosporic Acid Derivatives from 7-Aminocephalosporic Acid Molecules cephamycin cefotetan antibiotics triazole thioallylation |
| title | Synthesis of 7α-Methoxy-7-(4-phenyl-1<i>H</i>-1,2,3-triazol-1-yl)acetamino-3′-arylthio-cephalosporic Acid Derivatives from 7-Aminocephalosporic Acid |
| title_full | Synthesis of 7α-Methoxy-7-(4-phenyl-1<i>H</i>-1,2,3-triazol-1-yl)acetamino-3′-arylthio-cephalosporic Acid Derivatives from 7-Aminocephalosporic Acid |
| title_fullStr | Synthesis of 7α-Methoxy-7-(4-phenyl-1<i>H</i>-1,2,3-triazol-1-yl)acetamino-3′-arylthio-cephalosporic Acid Derivatives from 7-Aminocephalosporic Acid |
| title_full_unstemmed | Synthesis of 7α-Methoxy-7-(4-phenyl-1<i>H</i>-1,2,3-triazol-1-yl)acetamino-3′-arylthio-cephalosporic Acid Derivatives from 7-Aminocephalosporic Acid |
| title_short | Synthesis of 7α-Methoxy-7-(4-phenyl-1<i>H</i>-1,2,3-triazol-1-yl)acetamino-3′-arylthio-cephalosporic Acid Derivatives from 7-Aminocephalosporic Acid |
| title_sort | synthesis of 7α methoxy 7 4 phenyl 1 i h i 1 2 3 triazol 1 yl acetamino 3 arylthio cephalosporic acid derivatives from 7 aminocephalosporic acid |
| topic | cephamycin cefotetan antibiotics triazole thioallylation |
| url | https://www.mdpi.com/1420-3049/28/21/7338 |
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