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Article

Novel Ansa-Chain Conformation of a Semi-Synthetic Rifamycin Prepared Employing the Alder-Ene Reaction: Crystal Structure and Absolute Stereochemistry

1
Experimental Techniques Centre, Brunel University London, Kingston Road, Uxbridge, Middlesex UB8 3PH, UK
2
School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK
*
Authors to whom correspondence should be addressed.
Dedicated to Dr. Howard Flack (1943–2017).
Academic Editors: Catherine Housecroft and Katharina M. Fromm
Received: 26 May 2021 / Revised: 5 July 2021 / Accepted: 9 July 2021 / Published: 11 July 2021
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, 1 and diethyl azodicarboxylate, yielding 2, 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 3 of the diethyl azodicarboxylate adduct 2 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, P212121. The unique conformation and absolute stereochemistry of 3 revealed through X-ray crystal structure analysis is described. View Full-Text
Keywords: Rifamycin O; ansamysin; antibacterial; semi-synthesis; Alder-Ene; conformation; zwitterionic; hydrogen bonding; absolute configuration; chirality; crystal structure; X-ray crystallography Rifamycin O; ansamysin; antibacterial; semi-synthesis; Alder-Ene; conformation; zwitterionic; hydrogen bonding; absolute configuration; chirality; crystal structure; X-ray crystallography
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MDPI and ACS Style

Frampton, C.S.; Gall, J.H.; MacNicol, D.D. Novel Ansa-Chain Conformation of a Semi-Synthetic Rifamycin Prepared Employing the Alder-Ene Reaction: Crystal Structure and Absolute Stereochemistry. Chemistry 2021, 3, 734-743. https://0-doi-org.brum.beds.ac.uk/10.3390/chemistry3030052

AMA Style

Frampton CS, Gall JH, MacNicol DD. Novel Ansa-Chain Conformation of a Semi-Synthetic Rifamycin Prepared Employing the Alder-Ene Reaction: Crystal Structure and Absolute Stereochemistry. Chemistry. 2021; 3(3):734-743. https://0-doi-org.brum.beds.ac.uk/10.3390/chemistry3030052

Chicago/Turabian Style

Frampton, Christopher S., James H. Gall, and David D. MacNicol 2021. "Novel Ansa-Chain Conformation of a Semi-Synthetic Rifamycin Prepared Employing the Alder-Ene Reaction: Crystal Structure and Absolute Stereochemistry" Chemistry 3, no. 3: 734-743. https://0-doi-org.brum.beds.ac.uk/10.3390/chemistry3030052

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