The communication describes an enamine-based asymmetric retro-Claisen reaction of beta-diketones by primary amine catalysis. The reaction proceeds via a sequence of stereoselective C-C formation, C-C cleavage, and a highly stereospecific enamine protonation to afford chiral alpha-alkylated ketones or macrolides with high yields and enantioselectivities. A detailed mechanism was explored on the basis of experimental evidence and computational studies to account for the observed stereo control.