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. 2022 Dec 16;24(49):8931-8935.
doi: 10.1021/acs.orglett.2c03152. Epub 2022 Nov 4.

Pyrimidine Nucleosides Syntheses by Late-Stage Base Heterocyclization Reactions

Elfie S Cavalli  1 , Thomas Mies  1 , Henry S Rzepa  1 , Andrew J P White  1 , Philip J Parsons  1 , Anthony G M Barrett  1
Affiliations

Pyrimidine Nucleosides Syntheses by Late-Stage Base Heterocyclization Reactions

Elfie S Cavalli et al. Org Lett. .

Abstract

An efficient two-step procedure for the syntheses of pyrimidine nucleosides is presented. A series of glycosyl 5-(aminomethylene)-1,3-dioxane-4,6-dione derivatives were prepared from β-anomeric isonitriles by reaction with Meldrum's acid or by allowing aminomethylene Meldrum's acid to react with an 1-aldofuranosyl halide or acetate. The resultant 5-(aminomethylene)-1,3-dioxane-4,6-dione derivatives underwent reaction with benzyl- or 2,4-dimethoxybenzyl isocyanate via transacylation to provide uridine-5-carboxylic acid derivatives and related nucleosides. These nucleoside carboxylic acids were converted into other C-5 derivatives by bromo-decarboxylation with N-bromosuccinimide.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Structures of gemcitabine (1) and sofosbuvir (2).
Scheme 1
Scheme 1. Three Distinct Strategies for the Synthesis of Modified Nucleosides
Scheme 2
Scheme 2. Enamide 15 Syntheses
Scheme 3
Scheme 3. Heterocyclization with Benzyl Isocyanate and Subsequent Bromodecarboxylation Using NBS and Cyclization with 2,4-Dimethoxybenzyl Isocyanate and Derivatization of Nucleoside Core
Scheme 4
Scheme 4. Calculated Transition States in the Heterocyclization Reaction
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