Origin of Enantio- and Chemoselectivity in the Synthesis of Spirocycles via Palladium/Xu-Phos-Catalyzed Cascade Heck/Remote C(sp)-H Alkylation: A Computational Mechanistic Study.

Density functional theory (DFT) calculations were performed to study the mechanism and factors affecting the enantio-, regio-, and chemoselectivities in the palladium/Xu-Phos-catalyzed cascade Heck/remote C(sp)-H alkylation reaction. The active catalyst is found to be able to sustain coordination with P and S atoms and can adapt its coordination mode to accommodate the significant steric hindrance between the ligand and substrate, unlike previous findings that showed coordination with P and O atoms. The reaction is established to occur in sequence through the oxidative addition of the aryl iodide to Pd(0), intramolecular alkene insertion, C(sp)-H bond activation, and C(sp)-C(sp) bond reductive elimination. The C(sp)-C(sp) bond reductive elimination is identified as the rate-determining step, and the intramolecular alkene insertion as the enantioselectivity-determining step. The high enantioselectivity originates from the stronger electronic interaction between the catalyst and substrate; the exclusive 5--regioselectivity is due to the stronger nucleophilicity of the terminal alkene carbon atom, and the chemoselectivity of C-H activation over carboiodination is driven by thermodynamics.