Regioselective Homolytic C<sup>2</sup>–H Borylation of Unprotected Adenosine and Adenine Derivatives via Minisci Reaction
Yangyan Li, Yutong Zhou, Dazhi Zhou, Yujie Jiang, Madiha Butt, Hui Yang, Yingchuan Que, Zhiming Li, Gang Chen
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 (C 2 and C 8 ) in the purine motif, the unique nucleophilic amine-ligated boryl radicals effortlessly achieved excellent C 2 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 C 2 -Minisci addition are further lowered through the chelation of additive Mg 2+ to N 3 and furyl oxygen. This phenomenon has been confirmed by an IGMH analysis. Preliminary antitumor evaluation, derivation of the C 2 -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.