Regioselective Homolytic C2-H Borylation of Unprotected Adenosine and Adenine Derivatives via Minisci Reaction.

ABSTRACT

A Minisci-type borylation of unprotected adenosine, adenine nucleotide, and adenosine analogues was successfully achieved through photocatalysis or thermal activation. Despite the challenges posed by the presence of two potential reactive sites (C2 and C8) in the purine motif, the unique nucleophilic amine-ligated boryl radicals effortlessly achieved excellent C2 site selectivity and simultaneously avoided the formation of multifunctionalized products. This protocol proved effective for the late-stage borylation of some important biomolecules as well as a few antiviral and antitumor drug molecules, such as AMP, cAMP, Vidarabine, Cordycepin, Tenofovir, Adefovir, GS-441524, etc. Theoretical calculations shed light on the site selectivity, revealing that the free energy barriers for the C2-Minisci addition are further lowered through the chelation of additive Mg2+ to N3 and furyl oxygen. This phenomenon has been confirmed by an IGMH analysis. Preliminary antitumor evaluation, derivation of the C2-borylated adenosine to other analogues with high-value functionalities, along with the CuAAC click reactions, suggest the potential application of this methodology in drug molecular optimization studies and chemical biology.