Nickel‐Catalyzed Kinetic Resolution of Racemic Unactivated Alkenes via Enantio‐, Diastereo‐, and Regioselective Hydroamination

Abstract

Kinetic resolution is a powerful strategy for the isolation of enantioenriched compounds from racemic mixtures, and the development of selective catalytic processes is an active area of research. Here, we present a nickel-catalyzed kinetic resolution of racemic αsubstituted unconjugated carbonyl alkenes via the enantio-, diastereo-, and regioselective hydroamination. This protocol affords both chiral α-substituted butenamides and syn-β 2,3 -amino acid derivatives with high enantiomeric purity (up to 99 % ee) and selectivity factor up to > 684. The key to the excellent kinetic resolution efficiency is the distinctive architecture of the chiral nickel complex, which enables successful resolution and enantioselective CÀ N bond construction. Mechanistic investigations reveal that the unique structure of the chiral ligand facilitates a rapid migratory insertion step with one enantiomer. This strategy provides a practical and versatile approach to prepare a wide range of chiral compounds.

Nickel Catalyzed Enantioselective 1,4-Hydroamination of 1,3-Dienes

“…According to the above results and literature, − a plausible reaction mechanism was proposed (Figure c). The nickel­(I) hydride species I , generated from SKP-bound Ni precursor with a silane in the presence of a base, , would insert into the terminal double bond of the 1,3-diene, generating the corresponding π-allyl-Ni­(I) intermediate II .…”

“…Recently, metal hydride-catalyzed hydrofunctionalization of alkenes has attracted considerable attention. − It has been reported that some NiH complexes demonstrate robust catalytic activity for enantioselective C–N bond-forming processes, − wherein O-benzoyl hydroxylamines (BzO–NR 2 ) are used as electrophilic amination reagent which is compatible to the presence of reductant reagents in the reaction system . Accordingly, we commenced our studies on the Ni-catalyzed model reaction of phenylbutadiene 1a and morpholino benzoate 2a , and a preliminary parameter survey revealed that the reaction was best run at rt in 2-Me-THF with Ni­(COD) 2 as the Ni source in the presence of trimethoxysilane and K 2 CO 3 (for details, see SI).…”

Silanes as a versatile hydride source for Ni–H catalysis: a promising tool for π-hydro functionalization

“…The key hypothesis of this approach was the selection of a particular distinct architecture of chiral ligand (L46) bound to a nickel complex, which creates a typical chiral binding pocket that favourably recognizes one enantiomer of α-substituted alkene substrates, which led to enantioselective C-N bond construction (Scheme 42b). 73 The origin of the kinetic resolution process was confirmed by employing both (S) and (R) isomers of a model substrates for conformational analysis to envision the plausible transition state model of the migratory insertion step using DFT calculations. The favoured transition state with (S) isomer ( 52) was energetically more (1.8 kcal mol −1 ) preferable than the transition state associated with the (R) isomer (53).…”

NiH-catalyzed C–N bond formation: insights and advancements in hydroamination of unsaturated hydrocarbons

“…In 2023, the Hong group marked a pivotal milestone in asymmetric hydroamination, employing kinetic resolution, which extracts enantioenriched compounds from racemic mixtures ( Scheme 22 ). 82 Their focus sharpened on a nickel-catalyzed kinetic resolution tailored for racemic α-substituted unconjugated carbonyl alkenes. This meticulously engineered method harmoniously combined enantioselectivity, diastereoselectivity, and regioselectivity in hydroamination.…”