Direct Pyridine Dearomatization via Organocatalytic Enantioselective [4 + 2] Cycloaddition Accessing Polyfused Aza-[2.2.2] Scaffolds.

Herein, we report the first chiral phosphoric-acid-catalyzed asymmetric [4 + 2] dearomatization of monocyclic pyridines. Distinct from previous activation modes, this transformation proceeds under purely thermal conditions and does not require external irradiation or photoredox catalysis. Readily accessible nicotinic acid derivatives undergo efficient intramolecular [4 + 2] cycloaddition to furnish polyfused aza-bicyclo[2.2.2]octane frameworks with high levels of enantiocontrol. This work addresses the longstanding challenge associated with the functionalization of monocyclic pyridines and represents the first example of an asymmetric [4 + 2]-cycloaddition-based dearomatization of pyridines.