Iridium-Catalyzed Nitrene-Mediated Enantioselective 1,2-Hydride Shift Enabled by Attractive Noncovalent Interactions...

In modern organic chemistry, 1,2-hydride shifts of carbocations are generally considered to be highly rapid processes, typically exhibiting activation barriers of ∼2-4 kcal/mol─significantly faster than conventional S_N1 or E1 reactions. Consequently, achieving a catalytic enantioselective 1,2-hydride shift remains a significant challenge. Herein, we introduce a nitrene-mediated strategy that generates carbocation intermediates through intramolecular metal-nitrenoid transfer to alkenes, followed by a ligand-enabled, stereocontrolled, and accelerated 1,2-hydride shift facilitated by attractive noncovalent interactions. This methodology yields δ-lactams bearing contiguous γ,δ-stereocenters with excellent yields, diastereoselectivities, and enantioselectivities (most examples >95% ee, >20:1 dr). The versatility of this catalytic enantioselective carbocation rearrangement platform is demonstrated by its mild reaction conditions and wide substrate scope, accommodating diverse nucleophiles, including carbon, oxygen, and nitrogen-based species, as well as biologically relevant molecules. Mechanistic investigations revealed that the enantioselective 1,2-hydride shift serves as the stereodetermining step, driven by attractive noncovalent interactions. Complementary computational studies further demonstrated that enhanced C-H···π interactions play a critical role by increasing the interaction energy, which directs the reaction pathway and ensures high stereoselectivity.