Late-stage adenine N6-alkylation of nucleos(t)ides and oligonucleotides via photoredox and copper co-catalytic decarboxylative C(sp3)-N coupling.

Abstract

Nucleosi(ti)des and nucleic acids with N6 modified adenosine play an important role in the areas of disease diagnosis and treatment, biological chemistry, as well as nanotechnology. The conventional way to achieve N6 alkylation includes nucleophilic aromatic substitution reaction from N6 activated adenosine and direct reductive amination from adenosine. However, nucleophilic aromatic substitution reaction needs pre-functionalization of adenosine and reductive amination has limited alkyl substrate groups, especially not compatible with the secondary and tertiary alkyl groups. Herein, we develop a practical alkylation at the N6-position of adenines in adenosine and its analogues as well as late-stage functionalization of nucleotides/oligonucleotides through photoredox and copper co-catalyzed decarboxylative C(sp3)-N cross-coupling reaction. This method features simplicity and directness with various free radical precursors which is promising for medicinal and biological applications.