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DOI: 10.1055/a-2079-9310
Chemical Diversification of Carbocyclic Fluorinated Pyrimidine Nucleosides: Introducing 2′-Arabino Analogues and Ring Unsaturation
Keele University, Riboscience LLC, and the Royal Society of Chemistry (Research Enablement Grant E21-7055928079) are thanked for funding to C.M.M.B. UK Research and Innovation (UKRI, Future Leaders Fellowship, MR/T019522/1) are thanked for project grant funding to G.J.M.
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-difluorouridine, 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.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-2079-9310.
- Supporting Information
Publikationsverlauf
Eingereicht: 22. März 2023
Angenommen nach Revision: 24. April 2023
Accepted Manuscript online:
24. April 2023
Artikel online veröffentlicht:
31. Mai 2023
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