Abstract
The development of efficient synthetic methods for α-boryl ureas is of significant interest due to their potential as drug-like scaffolds in medicinal chemistry. Herein, we present a multicomponent strategy that transforms α-haloboronates, trimethylsilyl isocyanate, sodium iodide, and amines into diverse drug-like scaffold α-boryl ureas under mild conditions. This protocol features broad substrate scope and great functional-group tolerance, and enables the regioselective synthesis of previously inaccessible α-boryl ureas, including late-stage functionalization of drug molecules. Mechanistic studies suggest that a regioselective 1,2-boronate migration pathway may underlie the different regioselectivities observed with primary and secondary amines. To highlight the potential of this methodology in drug discovery, an α-boryl urea analog of nirmatrelvir was synthesized, exhibiting remarkable inhibitory activity (IC(50) = 12 nM) against the SARS-CoV-2 main protease. This work not only provides a streamlined and practical synthetic route to diverse α-boryl ureas, but also underscores their potential as valuable scaffolds in the development of new therapeutics.