Computational insight into gold(i)-catalyzed intramolecular regioselectivity of tryptamine-ynamide cycloisomerizations

The regioselectivity for gold(i)-catalyzed intramolecular cycloisomerizations of tryptamine-ynamides has long been elusive despite various synthetic examples of similar substrates being available. Computational studies were carried out to provide insight into the mechanisms and the origin of the substrate-dependent regioselectivity of these transformations. Based on the analyses of non-covalent interactions, distortion/interaction, and energy decomposition on the interactions between the terminal substituent of alkynes and the gold(i) catalytic ligand, the electrostatic effect was determined to be the key factor for alpha-position selectivity while the dispersion effect was determined to be the key factor for beta-position selectivity. Our computational results were consistent with the experimental observations. This study provides useful guidance for understanding other similar gold(i)-catalyzed asymmetric alkyne cyclization reactions.