Preparation of 5‐Hydroxymethyl‐pyrimidine Based Nucleosides: A Reinvestigation

Abstract 5‐Hydroxymethyl‐pyrimidine‐based nucleobases have attracted attention in the last years due to their important role in gene regulation. It prompted the development of efficient routes to the corresponding nucleoside building blocks for further incorporation into oligonucleotides. Several pathways have been employed in recent years to access properly protected 5‐hydroxymethyl‐pyrimidine based nucleosides, including hydroxymethylation of 2’‐deoxyuridine, radical bromination of thymidine followed by bromine substitution, or carbonylative coupling through Stille conditions starting from 5‐iodo‐2’‐deoxyuridine. In this study, we review the different approaches currently used to introduce the 5‐hydroxymethyl moiety, we reinvestigate some of them, and finally, we propose an alternative route based on the oxidation of the methyl of thymidine followed by its reduction that allows access to protected 5‐hydroxymethyl‐2’‐deoxyuridine in a simple way with good yields. Finally, we present some examples of application including the synthesis of base J and 5‐azidomethyl‐2’‐deoxyuridine.