Enantioselective desymmetrization of 2-substituted and 2,2-disubstituted 1,3-propanediamines via asymmetric para-aminations of anilines

Abstract

Chiral 1,3-propanediamine moieties are present in a range of bioactive small molecules, chiral catalysts, and ligands. The enantioselective desymmetrization of 2-substituted 1,3-propanediamines is a straightforward and efficient method to give access to these types of enantioenriched compounds. However, the state of the art of this strategy is limited to enzymatic catalysis and 2-monosubstituted substrates. Herein, we report the nonenzymatic desymmetrization of C-2-substituted 1,3-propanediamines through chiral phosphoric-acid-catalyzed asymmetric para-aminations of anilines with azodicarboxylates. Both C-2-monosubstituted and C-2-disubstituted 1,3-propanediamine substrates are compatible with this method, providing chiral 1,3-propanediamines bearing C-2 tertiary and quaternary stereocenters with high enantioselectivities. Preliminary mechanistic studies are performed to shed light on the reaction mechanism and the key asymmetric induction transition state.