Asymmetric Dearomative Cyclization Using Chiral Biaryl Imidazo[1,5-a]pyridine Carbene Ligand

Abstract

Dearomatization reactions have emerged as powerful synthetic tools for constructing structurally complex polycyclic frameworks that are of considerable importance in the pharmaceutical industry. While transition-metal-catalyzed asymmetric dearomatization of heteroarenes has been extensively investigated owing to their low aromatic stabilization energies, the dearomatization of unactivated arenes remains significantly underdeveloped. Our research aims to develop a highly enantioselective dearomatization of unactivated arene substrates using a novel chiral ligand framework based on the Imidazo[1,5-a]pyridin-3-ylidene （ImPy） scaffold, applying systematic steric and electronic modifications to the ligand framework. Application of our optimized ImPy ligand to the palladium-catalyzed dearomative cyclization successfully afforded the desired product in 95% yield and 43% ee. Although the enantioselectivity falls below that achieved with conventional chiral monophosphine ligands, these results nonetheless demonstrate that ImPy-based ligands can render the transformation asymmetric in the dearomatization of carbocyclic arenes. Based on the insights gained from this ligand screening, further structural modifications of the ImPy scaffold will be undertaken to optimize the chiral environment and improve enantioselectivity. To achieve this, determination of the absolute configuration through X-ray crystallographic analysis and DFT computational studies will be pursued to gain deeper insight into the structural and electronic factors governing stereocontrol.