Asymmetric Catalytic 1,2-Azaarene Migration to α-Azaaryl-α-Hydroxy Esters Enabled by a Tailored Ligand

Abstract

Despite their prevalence in bioactive molecules, the stereoselective construction of α-azaaryl-α-hydroxycarboxylates remains a formidable challenge. Notably, although the benzilic ester rearrangement (BER) is an efficient approach to α-hydroxycarboxylates, asymmetric catalytic BER remains poorly developed, largely due to poor stereorecognition of the vicinal diketone substituents by common chiral catalysts. In response to these issues, here we report a copper-catalyzed asymmetric BER of azaarene-derived 1,2-diketones with simple alcohols to give diverse α-azaaryl-α-hydroxy esters. It is proposed that the azaarene nitrogen and the adjacent carbonyl group chelate copper to form a five-membered metallacycle, initiating the subsequent stereoselective 1,2-nucleophilic addition step. Meanwhile, enantiocontrol over vicinal diketones was achieved by a tailored bisoxazoline (BOX) ligand with two rigid, long, and terminally bulky sidearms. This study overcomes the incompatibility between azaarenes and BOX ligands, and also unlocks asymmetric catalytic 1,2-azaarene migrations.