4'-Thionucleosides (thNAs) are synthetic nucleoside analogues that have attracted attention as leads for drug discovery in oncology and virology. Here we report a de novo thNA synthesis that relies on a scalable α-fluorination and aldol reaction of α-heteroaryl acetaldehydes followed by a streamlined process involving carbonyl reduction, mesylate formation and a double displacement reaction using NaSH. We demonstrate the multigram preparation of 4'-thio-5-methyluridine and highlight the production of purine and pyrimidine thNAs as well as C2'-modified thNAs.
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