Nickel-Catalyzed Asymmetric α-Alkenylations of Acyclic Amides that Provide Tertiary Stereocenters

Carbonyl groups and alkenes are ubiquitous in organic chemistry─present in target molecules as well as versatile handles for conversion into other functional groups. Whereas the coupling of the α position of a carbonyl compound with an alkenyl electrophile represents an attractive approach to uniting these useful functionalities, to date there have been few reports of catalytic asymmetric variants of this bond construction. Most of the progress to date has involved cyclic carbonyl compounds (obviates the issue of controlling the E/Z geometry of the nucleophile) and the generation of quaternary stereocenters (obviates undesired side reactions of the β,γ-unsaturated carbonyl product, such as racemization or isomerization to the more stable α,β-unsaturated carbonyl compound). Herein, we establish that a chiral nickel catalyst can couple acyclic racemic Reformatsky-type reagents (α-zincated amides) with alkenyl halides to generate β,γ-unsaturated amides that bear a tertiary α stereocenter with good enantioselectivity and good yield. The products can be transformed into other useful families of enantioenriched compounds, including intermediates in total synthesis. Mechanistic studies are consistent with a nickel(0)/nickel(II) pathway for asymmetric carbon-carbon bond formation.