Fluorine-containing nucleosides for 19F NMR-based structural studies of nucleic acids: synthesis and characterization of 8-CF3-2’-deoxyguanosine

Aiming at the preparation of 19F-labelled monomers, allowing to exploit 19F nuclei as probes for NMR studies on nucleic acids, and particularly G-quadruples structures, we focused our attention on the unprecedented 8-CF3 analog of 2’-deoxyguanosine. CF3 is an isostere of CH3. The presence of a CH3 group at C-8 favors the sin conformation of the guanine with respect to the N-glycosidic bond. Tagging this position with a CF3 group is expected to produce similar effects, and thus to stabilize/destabilize a G-quadruplex structure in a predictable manner, in addition providing a selective probe to detect 1H-19F correlations useful in the assignment of spatially close residues. We here describe a synthetic study to obtain a 2’-deoxyguanosine derivative carrying a CF3 residue on the nucleobase. Key reaction to obtain this building block is the trifluoromethylation, carried out on 3’,5’-di-O-acetyl-2’-deoxyguanosine using CF3SO2Na and tert-butylhydroperoxide in a biphasic system, adapted from a recently published protocol to obtain CF3-derivatized aromatic heterocycles.