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.
Key words
carbohydrates - nucleosides - fluorine - medicinal chemistry - bioorganic chemistry
