A flexible and scalable synthesis of 4′-thionucleosides

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.