Synthesis of Carbocyclic Nucleoside Analogues

The synthesis of carbocyclic nucleoside analogues has emerged as a cornerstone of modern medicinal chemistry, offering structurally rigid mimics of natural nucleosides with enhanced metabolic stability and unique biological profiles. By replacing the furanose oxygen with a methylene or cyclopentane framework, chemists gain access to scaffolds that resist enzymatic cleavage while retaining key hydrogen-bonding and conformational properties. Advances in stereoselective catalysis, chiral building-block design and protecting-group strategies have enabled concise routes to both purine and pyrimidine carbocyclic analogues. These methods address challenges in stereochemical control, ring-closure efficiency and functionalisation of the carbocycle. The resulting compounds have found applications as antiviral agents, anticancer leads and mechanistic probes of nucleoside-processing enzymes. Recent efforts have focused on new C-nucleoside bond-forming reactions, enantioselective access to chiral cyclopentane cores and modular approaches that facilitate rapid analogue generation for biological screening. Collectively, these developments underscore the global significance of carbocyclic nucleoside chemistry in the discovery of next-generation therapeutics.

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Synthesis of Carbocyclic Nucleoside Analogues publication trend

The graph below shows the total number of articles in synthesis of carbocyclic nucleoside analogues across all publications each year (not limited to Nature Index journals).

Technical terms

Carbocyclic nucleoside analogue: A nucleoside mimic in which the sugar ring oxygen is replaced by a carbon atom, forming a carbocycle.

Stereoselective synthesis: A chemical route that preferentially forms one stereoisomer over others.

C-nucleoside: A nucleoside analogue featuring a direct carbon–carbon bond between the carbocycle and the nucleobase.

Cyclopentenyl building block: A five-membered carbocyclic precursor used to construct carbocyclic nucleoside analogues.

Dioxolane intermediate: A chiral cyclic acetal used to impart stereocontrol in nucleoside synthesis.

References

1. Cobalt-assisted route to rare carbocyclic C -ribonucleosides. RSC Advances (2023).
2. Enantioselective Synthesis of β‑l‑5-[(E)‑2-Bromovinyl)-1-((2S,4S)‑2-(hydroxymethyl)-1,3-(dioxolane-4-yl) Uracil)] (l‑BHDU) via Chiral Pure l‑Dioxolane. The Journal of Organic Chemistry (2024).
3. A novel route to a chiral building block for the preparation of cyclopentenyl carbocyclic nucleosides. Synthesis and anticancer activity of enantiomeric neplanocins A. RSC Advances (2020).