Chemoselective Minisci alkylation in aqueous medium: a general strategy for functionalization of complex N-heteroarenes and biomolecules

Abstract

Efficiently constructing highly functionalized N-heteroarenes under mild reaction conditions is one of the most important approaches for facilitating the discovery of bioactive molecules. In this context, boronic ester derivatives as radical precursors for achieving the Minisci reaction present a straightforward method to modify N-heteroarenes, arousing broad interest. However, the relatively high oxidative potential of these reagents always requires customary harsh reaction conditions, which will be incompatible with N-heteroarenes bearing multiple functional groups. Herein, we disclosed a dual-activated photocatalyst-free Minisci alkylation reaction under aqueous conditions, tackling the intrinsic problem of boronic ester derivatives via an ate complex intermediate. This approach enables late-stage modification of natural products, peptides, drugs and nucleotides under mild conditions. Notably, the new strategy could be applied for efficient construction and discovery of potent Gαq/11 protein inhibitors with anti-uveal melanoma (UM) activities, providing new opportunities against UM.