Changed reactivity of secondary hydroxy groups in C8-modified adenosine – lessons learned from silylation (Beilstein Journal of Organic Chemistry)

Abstract Synthesis of site-specifically modified oligonucleotides has become a major tool for RNA structure and function studies. Reporter groups or specific functional entities are required to be attached at a pre-defined site of the oligomer. An attractive strategy is the incorporation of suitably functionalized building blocks that allow post-synthetic conjugation of the desired moiety. A C8-alkynyl-modified adenosine derivative was synthesized, reviving an old synthetic pathway for iodination of purine nucleobases. Silylation of the C8-alkynyl-modified adenosine revealed unexpected selectivity of the two secondary sugar hydroxy groups, with the 3'-O-isomer being preferentially formed. Optimization of the protection scheme lead to a new and economic route to the desired C8-alkynylated building block and its incorporation in RNA. Beilstein J. Org. Chem. 2020, 16, 2854–2861. doi:10.3762/bjoc.16.234