Chiral primary-amine-catalyzed conjugate addition to α-substituted vinyl ketones/aldehydes: divergent stereocontrol modes on enamine protonation.Chemistry. 2013 Nov 11; 19(46):15669-81.C
Enantioselective protonation with a catalytic enamine intermediate represents a challenging, yet fundamentally important process for the synthesis of α-chiral carbonyls. We describe herein chiral primary-amine-catalyzed conjugate additions of indoles to both α-substituted acroleins and vinyl ketones. These reactions feature enamine protonation as the stereogenic step. A simple primary-tertiary vicinal diamine 1 with trifluoromethanesulfonic acid (TfOH) was found to enable both of the reactions of acroleins and vinyl ketones with good activity and high enantioselectivity. Detailed mechanistic studies reveal that these reactions are rate-limiting in iminium formation and they all involve a uniform H2 O/acid-bridged proton transfer in the stereogenic steps but divergent stereocontrol modes for the protonation stereoselectivity. For the reactions of α-branched acroleins, facial selections on H2 O-bridged protonation determine the enantioselectivity, which is enhanced by an OH⋅⋅⋅π interaction with indole as uncovered by DFT calculations. On the other hand, the stereoselectivity of the reactions with vinyl ketones is controlled according to the Curtin-Hammett principle in the CC bond-formation step, which precedes a highly stereospecific enamine protonation.