The mechanism and stereoselectivity of the BF3-catalyzed, enamide-based domino reaction developed by Manolikakes et al. for tetrahydropyran synthesis have been studied using density functional theory calculations. All σ-bond formations were found to proceed through highly ordered cyclic or bicyclic transition states, leading to remarkable levels of diastereoselectivity. The role of the BF3 catalyst was demonstrated to be essential in both substrate activation and stereocontrol.