Harnessing Noncovalent Interactions in Transition-Metal Catalysis: An Asymmetric Allylation/Lactonization Cascade to Chiral γ-Butyrolactones

Abstract

Achieving α-regioselective functionalization in vinylogous reactions remains a significant challenge due to the inherent thermodynamic preference for distal γ-functionalization. Herein, we report a transition-metal-catalyzed asymmetric allylation/lactonization cascade that enables proximal α-selective functionalization of olefinic azlactones through a synergistic interplay of noncovalent interactions. By leveraging zwitterionic oxy π-allyl-Ir/Pd intermediates and olefinic azlactones as masked dienolates, this method overcomes intrinsic regiochemical biases to afford chiral γ-butyrolactones bearing contiguous quaternary and tertiary stereocenters with complete α-selectivity, high E/Z control, high diastereoselectivity, and enantioselectivity. DFT calculations reveal that the α/γ regioselectivity is primarily governed by the overall balance of weak noncovalent interactions—particularly attractive dispersion forces—rather than by hydrogen bonding alone. Instead, hydrogen bonding instead plays a supporting role in facilitating substrate−catalyst association and enhancing overall reactivity. Mechanistically, Ir-catalysis proceeds via kinetic resolution, whereas Pd-catalysis operates through dynamic kinetic asymmetric transformation via rapid allyl−palladium interconversion. Synthetic utility is demonstrated through scale-up experiments and diverse derivatizations, enabling efficient access to complex architectures relevant to bioactive molecules. This work provides an efficient strategy for manipulating reactivity in extended π-systems through noncovalent interactions.