Dispersion-Driven Ligand Design for Cu(II)/Bis(oxazoline)-Catalyzed Asymmetric IEDDA Reactions

The strategic exploitation of attractive London dispersion interactions in asymmetric catalysis, while not without precedent, has yet to become a mainstream design principle. Herein, we report a dispersion-driven ligand strategy that simultaneously enhances both efficiency and stereoselectivity in the chiral Cu(II)/bis(oxazoline)-catalyzed IEDDA reaction between 1,3-cyclohexadienes (CHDs) and 2-pyrones. Strategic incorporation of a <i>tert</i>-butyl group into the ligand framework enabled significant attractive dispersion interactions, which concurrently (i) increased the stereomeric transition state energy gap (ΔΔ<i>G</i>^⧧) and (ii) decreased the reaction barrier (Δ<i>G</i>^⧧). A combined energy decomposition analysis (EDA) and independent gradient model (IGMH) study quantitatively decoupled these interactions, unequivocally establishing their critical roles in governing stereocontrol.