Chemical Diversification of Carbocyclic Fluorinated Pyrimidine Nucleosides: Introducing 2'-Arabino Analogues and Ring Unsaturation

Benckendorff, Caecilie M. M.; Hawes, Chris S.; Smith, Mark; Miller, Gavin J.

Abstract

Analogues of the canonical nucleosides have a longstanding presence and proven capability within medicinal chemistry and drug-discovery research. Herein, we report chemical diversification of carbocyclic pyrimidine nucleosides containing CF2 and CHF in place of the furanose oxygen to introduce ring unsaturation and 2'-epimers. Utilizing gram-scale access to 6'-(R)-monofluoro-and 6'-gem-difluoro-uridine, we explore the provision of 2',3'-didehydro-2',3'-dideoxy, and 1',2'-didehydro-2'-deoxy analogues, alongside the first example of a 6'-(R)-fluoro arabino-carbauridine. Key stereochemistries and the presence of unsaturation are confirmed using X-ray crystallography and NMR, and an indicative conformational preference for a monofluoro 2',3'-didehydro-2',3'-dideoxy system is presented. This synthetic blueprint offers a potential to explore biological activity for these hitherto unavailable materials, including a direct comparison to established nucleoside analogue drugs.

Citation

Benckendorff, C. M. M., Hawes, C. S., Smith, M., & Miller, G. J. (2023). Chemical Diversification of Carbocyclic Fluorinated Pyrimidine Nucleosides: Introducing 2'-Arabino Analogues and Ring Unsaturation. SYNLETT, 35(06), 659-664. https://doi.org/10.1055/a-2079-9310

• Journal Article Type: Article
• Acceptance Date: Apr 24, 2023
• Online Publication Date: May 31, 2023
• Publication Date: May 31, 2023
• Deposit Date: Aug 1, 2023
• Journal: SYNLETT
• Print ISSN: 0936-5214
• Electronic ISSN: 1437-2096
• Publisher: Thieme Gruppe
• Peer Reviewed: Peer Reviewed
• Volume: 35
• Issue: 06
• Pages: 659-664
• DOI: https://doi.org/10.1055/a-2079-9310
• Keywords: Organic Chemistry