Novel Ansa-Chain Conformation of a Semi-Synthetic Rifamycin Prepared Employing the Alder-Ene Reaction: Crystal Structure and Absolute Stereochemistry
Rifamycins are an extremely important class of antibacterial agents whose action results from the inhibition of DNA-dependent RNA synthesis. A special arrangement of unsubstituted hydroxy groups at C21 and C23, with oxygen atoms at C1 and C8 is essential for activity. Moreover, it is known that the...
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MDPI AG
2021-07-01
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| Series: | Chemistry |
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| Online Access: | https://www.mdpi.com/2624-8549/3/3/52 |
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| author | Christopher S. Frampton James H. Gall David D. MacNicol |
| author_facet | Christopher S. Frampton James H. Gall David D. MacNicol |
| author_sort | Christopher S. Frampton |
| collection | DOAJ |
| description | Rifamycins are an extremely important class of antibacterial agents whose action results from the inhibition of DNA-dependent RNA synthesis. A special arrangement of unsubstituted hydroxy groups at C21 and C23, with oxygen atoms at C1 and C8 is essential for activity. Moreover, it is known that the antibacterial action of rifamycin is lost if either of the two former hydroxy groups undergo substitution and are no longer free to act in enzyme inhibition. In the present work, we describe the successful use of an Alder-Ene reaction between Rifamycin O, <b>1</b> and diethyl azodicarboxylate, yielding <b>2</b>, which was a targeted introduction of a relatively bulky group close to C21 to protect its hydroxy group. Many related azo diesters were found to react analogously, giving one predominant product in each case. To determine unambiguously the stereochemistry of the Alder-Ene addition process, a crystalline zwitterionic derivative <b>3</b> of the diethyl azodicarboxylate adduct <b>2</b> was prepared by reductive amination at its spirocyclic centre C4. The adduct, as a mono chloroform solvate, crystallized in the non-centrosymmetric Sohnke orthorhombic space group, <i>P</i>2<sub>1</sub>2<sub>1</sub>2<sub>1</sub>. The unique conformation and absolute stereochemistry of <b>3</b> revealed through X-ray crystal structure analysis is described. |
| first_indexed | 2024-03-10T07:48:24Z |
| format | Article |
| id | doaj.art-71faa3cd602d412993f54f539f7e762d |
| institution | Directory Open Access Journal |
| issn | 2624-8549 |
| language | English |
| last_indexed | 2024-03-10T07:48:24Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Chemistry |
| spelling | doaj.art-71faa3cd602d412993f54f539f7e762d2023-11-22T12:27:59ZengMDPI AGChemistry2624-85492021-07-013373474310.3390/chemistry3030052Novel Ansa-Chain Conformation of a Semi-Synthetic Rifamycin Prepared Employing the Alder-Ene Reaction: Crystal Structure and Absolute StereochemistryChristopher S. Frampton0James H. Gall1David D. MacNicol2Experimental Techniques Centre, Brunel University London, Kingston Road, Uxbridge, Middlesex UB8 3PH, UKSchool of Chemistry, University of Glasgow, Glasgow G12 8QQ, UKSchool of Chemistry, University of Glasgow, Glasgow G12 8QQ, UKRifamycins are an extremely important class of antibacterial agents whose action results from the inhibition of DNA-dependent RNA synthesis. A special arrangement of unsubstituted hydroxy groups at C21 and C23, with oxygen atoms at C1 and C8 is essential for activity. Moreover, it is known that the antibacterial action of rifamycin is lost if either of the two former hydroxy groups undergo substitution and are no longer free to act in enzyme inhibition. In the present work, we describe the successful use of an Alder-Ene reaction between Rifamycin O, <b>1</b> and diethyl azodicarboxylate, yielding <b>2</b>, which was a targeted introduction of a relatively bulky group close to C21 to protect its hydroxy group. Many related azo diesters were found to react analogously, giving one predominant product in each case. To determine unambiguously the stereochemistry of the Alder-Ene addition process, a crystalline zwitterionic derivative <b>3</b> of the diethyl azodicarboxylate adduct <b>2</b> was prepared by reductive amination at its spirocyclic centre C4. The adduct, as a mono chloroform solvate, crystallized in the non-centrosymmetric Sohnke orthorhombic space group, <i>P</i>2<sub>1</sub>2<sub>1</sub>2<sub>1</sub>. The unique conformation and absolute stereochemistry of <b>3</b> revealed through X-ray crystal structure analysis is described.https://www.mdpi.com/2624-8549/3/3/52Rifamycin Oansamysinantibacterialsemi-synthesisAlder-Eneconformation |
| spellingShingle | Christopher S. Frampton James H. Gall David D. MacNicol Novel Ansa-Chain Conformation of a Semi-Synthetic Rifamycin Prepared Employing the Alder-Ene Reaction: Crystal Structure and Absolute Stereochemistry Chemistry Rifamycin O ansamysin antibacterial semi-synthesis Alder-Ene conformation |
| title | Novel Ansa-Chain Conformation of a Semi-Synthetic Rifamycin Prepared Employing the Alder-Ene Reaction: Crystal Structure and Absolute Stereochemistry |
| title_full | Novel Ansa-Chain Conformation of a Semi-Synthetic Rifamycin Prepared Employing the Alder-Ene Reaction: Crystal Structure and Absolute Stereochemistry |
| title_fullStr | Novel Ansa-Chain Conformation of a Semi-Synthetic Rifamycin Prepared Employing the Alder-Ene Reaction: Crystal Structure and Absolute Stereochemistry |
| title_full_unstemmed | Novel Ansa-Chain Conformation of a Semi-Synthetic Rifamycin Prepared Employing the Alder-Ene Reaction: Crystal Structure and Absolute Stereochemistry |
| title_short | Novel Ansa-Chain Conformation of a Semi-Synthetic Rifamycin Prepared Employing the Alder-Ene Reaction: Crystal Structure and Absolute Stereochemistry |
| title_sort | novel ansa chain conformation of a semi synthetic rifamycin prepared employing the alder ene reaction crystal structure and absolute stereochemistry |
| topic | Rifamycin O ansamysin antibacterial semi-synthesis Alder-Ene conformation |
| url | https://www.mdpi.com/2624-8549/3/3/52 |
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