Chemoselective Difluoromethylation of Nucleosides
Otto Linden1,2, Alexander Axer1,2, Andrea Taladriz-Sender1,2
1Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.
None:
A profiling platform to define the chemoselectivity of the carbene-mediated difluoromethylation of nucleosides is described. First, the optimized reaction conditions for the difluoromethylation of silyl-protected nucleosides are established using TMS-CF2Br and KOAc to form the difluoromethyl carbene in situ. Second, the scope of these reaction conditions to difluoromethylate uridine- and cytidine-based 2'-deoxyribonucleoside and ribonucleoside analogues is established. When uridine analogues are substrates, O-difluoromethylation at the 4-position is observed, whereas O-difluoromethylation at the 2-position of cytidine analogues predominates. S-Difluoromethylation is preferable over O-difluoromethylation when thionucleosides are used. In all cases, no N-difluoromethylation is observed. Finally, silyl deprotection afforded difluoromethylated free nucleosides, thereby enabling the exploration of their utility for broader applications in medicinal chemistry and chemical biology.
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