Novel ansa-chain conformation of a semi-synthetic rifamycin prepared employing the Alder-Ene reaction: crystal structure and absolute stereochemistry

Frampton, C. S., Gall, J. H. and MacNicol, D. D. (2021) Novel ansa-chain conformation of a semi-synthetic rifamycin prepared employing the Alder-Ene reaction: crystal structure and absolute stereochemistry. Chemistry, 3(3), pp. 734-743. (doi: 10.3390/chemistry3030052)

Abstract

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.

• Item Type: Articles
• Additional Information: Financial support from the Malaysia HIR MOHE, Grant No.F000009-21001 is gratefully acknowledged.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Gall, Mr Jim and MacNicol, Dr David

Creator Roles

Gall, J. H.: Conceptualization, Methodology, Investigation
MacNicol, D. D.: Conceptualization, Methodology, Formal analysis, Investigation, Resources, Writing – original draft, Writing – review and editing, Visualization, Funding acquisition

• Authors: Frampton, C. S., Gall, J. H., and MacNicol, D. D.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: Chemistry
• Publisher: MDPI
• ISSN: 2624-8549
• ISSN (Online): 2624-8549
• Published Online: 11 July 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Chemistry 3(3): 734-743
• Publisher Policy: Reproduced under a Creative Commons License