Iron/NHC‐Catalyzed Regio‐ and Stereoselective 1,6‐Additions of Aliphatic Grignard Reagents to α,β,γ,δ‐Unsaturated Carbonyl Compounds: Asymmetric Variants with Chiral NHCs

Although conjugate addition to an α,β-unsaturated carbonyl compound is a well-established method in synthetic organic chemistry, controlling regioselectivity, olefin geometry, and positional isomerism in analogous 1,6-addition chemistry, which provides a powerful approach for constructing molecular complexity, remains a key challenge. Herein, we report the iron-catalyzed regio-, stereo-, and enantioselective 1,6-additions of aliphatic Grignard reagents to α,β,γ,δ-unsaturated carbonyl compounds. The incorporation of an N-heterocyclic carbene (NHC) ligand effectively suppresses undesired β-hydride elimination, thereby enabling the highly cis-selective installation of the aliphatic group. Remarkably, the use of a rigid tetracyclic chiral NHC ligand afforded the corresponding adducts with enantioselectivities of up to 99%. The developed reaction shows broad substrate scope, accommodating various aliphatic Grignard reagents and unsaturated carbonyl compounds, thereby providing direct access to optically active 1,6-adducts bearing cis-configured olefins. Mechanistic investigations, including deuterium-labeling experiments, support the involvement of magnesium enolates and an iron-NHC catalytic cycle. The developed transformation provides a powerful strategy for the remote functionalization of extended conjugated carbonyl frameworks.