Transglycosylation replacement of a nucleobase on certain complex nucleosides with other nucleobases has been shown to be effective using Vorbrüggen conditions (for example, Y. Gong et al, Org. Lett. 2020, 22, 5577).  We describe the application of this method to the synthesis of 14C-Lumicitabine (14C-ALS-8176), as well as the exploration of substituent effects (Cl, Br, NO2) at the 5-position of the uracil ring of protected 2’-deoxyuridine and uridine analogues of pyrimidine nucleoside analogues (1 to 2 to 3).  The 2′-O-acyl group in uridine analogues with electron-withdrawing groups at the 5-position is thought to form a 1’,2’-dioxolenium intermediate, which contributes to high beta-stereoselectivity as well as improved reactivity in the transglycosylation in comparison to 2’-deoxyuridine analogues.  This synthetic method was applied to the production of radioisotope-labeled Lumicitabine (ALS-8176, 4) by activation of a pyrimidine nucleobase via substitution of the electron-withdrawing group at the 5-position of the uracil ring of the 2-deoxyuridine analogues, followed by replacement of the activated uracil with a 14C-labeled uracil (Vorbrüggen reaction with BSA/TMSOTf), producing a high specific activity 14C tracer in respectable radiochemical yield, thus demonstrating the utility of the method for the production of a complex nucleoside analogues.  The results will be presented.

Expedient synthesis of nucleoside analogues by activation and replacement of pyrimidine nucleobases: Application for synthesis of radio-labeled lumicitabine via Vorbrüggen transglycosylation

ACS Spring Meeting 2021

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