An Enantioselective Nucleophilic Aromatic tele-Substitution.

Abstract

This work presents the first leaving-group-directed aminocatalytic enantioselective nucleophilic aromatic tele-substitution on the tropone scaffold. The integration of an appropriate leaving group on tropone enables the nucleophilic aromatic substitution with carbon nucleophiles under mild reaction conditions, a reaction which has previously only been reported under harsh reaction conditions. An efficient and highly enantioselective approach for the remote installation of quaternary all-carbon stereocenters via tele-substitution is reported. Mild reaction conditions are achieved by employing a primary amine catalyst with α-branched aldehydes affording enantioenriched tropones in up to 96% yield and up to 97% ee. The tele-substitution pathway is elucidated by a series of both qualitative and quantitative deuterium-labeling studies and different substitution patterns on the tropone scaffold. DFT calculations reveal that the geometry of the enamine governs the stereochemical outcome. H-Bonding, π-π interaction, and a cation-π interaction were found to be crucial in the stereodetermining step.