Nickel-Catalyzed Enantioselective Desymmetrizing Aza-Heck Cyclization of Oxime Esters

Abstract

Densely functionalized chiral nitrogen-containing heterocycles are ubiquitous in bioactive synthetic compounds and natural products. Herein, we report a nickel (Ni)-catalyzed enantioselective desymmetrizing aza-Heck cyclization of oxime esters with a commercially available chiral pyridinebis(oxazoline) (pybox) ligand. This reaction proceeds under mild reaction conditions, tolerates various functional groups, and leads to chiral 2-substituted-3,7a-dihy-dro-3aH-indoles. Experiments and density functional theory (DFT) investigations show a two-electron pathway in which the Ni-triplet state is the ground state for most of the steps and the β-H elimination, but not alkene insertion, is the stereodetermining step. The pentafluorobenzoyl leaving group and chiral pybox ligand appear to be critical factors for the chemo- and stereoselectivity of the reaction and a base-driven E2-like pathway is competitive with β-H elimination at the enantioselectivity determining step.