Catalytic Asymmetric Construction of Quaternary Stereocenters via Synergistic Au/SPA Catalysis: Mechanistic Insights from DFT Studies

This computational study sheds light on the mechanism and stereochemical origins in synergistic gold/chiral spiro phosphoric acid (SPA) catalysis for the enantioselective construction of quaternary stereocenters via alkyne gem-dialkylation. Density functional theory (DFT) analyses reveal two distinct reaction pathways: for propargyl alcohols, the Mannich-type addition proceeds via a semipinacol rearrangement, where regioselectivity in the nucleophilic attack is governed by stronger electrostatic and orbital interactions, despite the higher steric repulsion in the transition state. Enantioselectivity arises from a lower distortion energy in the S-selective transition state. For diaryl alkynes, the stepwise [3 + 2] cycloaddition is driven by SPA-substrate interactions, with the RSS-configured transition state being favored due to enhanced π-π stacking and C-H···O interactions. Distortion/interaction analysis and energy decomposition (ALMO-EDA) provide insight into the selectivity determinants, while strong linear correlations (<i>R</i>² > 0.86) between distortion energies and enantiomeric excess highlight SPA's pivotal role in controlling stereochemistry.