Enantioselective α-Functionalization of Tropones with Cyclic β-Keto Esters Enabled by an Organocatalytic SNAr Reaction

Abstract

This paper presents the first organocatalytic enantioselective nucleophilic aromatic substitution of β-keto esters with tropones, generating a quaternary all-carbon stereocenter in the α-position of tropone. The reaction proceeds in excellent yield by employing a commercially available cinchona alkaloid catalyst and readily available substrates under mild reaction conditions. The enantioselectivity of the nucleophilic aromatic substitution is dependent on substituent effects, confirmed by a Hammett study. Recrystallization affords highly enantioenriched products with up to >99% ee. Quantitative deuterium-labeling studies have elucidated that the reaction proceeds through a tele-substitution pathway.