Nickel-Catalyzed Remote Asymmetric Hydroalkylation of Alkenyl Ethers to Access Ethers of Chiral Dialkyl Carbinols

Abstract

Site- and enantio-selective alkyl–alkyl bond formation is privileged in the retrosynthetic analysis due to the universality of sp3-hybridized carbon atoms in organic molecules. Herein, we report a nickel-catalyzed remote asymmetric hydroalkylation of alkenyl ethers via synchronous implementation of alkene isomerization and enantioselective C(sp3)–C(sp3) bond formation. Regression analysis of catalyst structure–activity relationships accelerates the rational ligand modification through modular regulation. This reaction has several advantages for synthesizing chiral dialkyl carbinols and their ether derivatives, including the broad substrate scope, good functional group tolerance, excellent regioselectivity (>20:1 regioisomeric ratio), and high enantioselectivity (up to 95% enantiomeric excess).

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

“…The rise of NiH catalysis has notably shied the landscape of this eld. [48][49][50][51][52][53][54][55][56][57][58][59] While nickel has historically been valued as a competitive alternative to precious metals like palladium and platinum due to its catalytic properties, recent applications have elevated its signicance beyond being merely costeffective. The comparative analysis of CuH and NiH in hydroamination and hydroamidation reactions reveals their unique chemical properties and reactivities.…”

Selective Hydrofunctionalization of Alkenyl Fluorides Enabled by Nickel-Catalyzed Hydrogen Atoms and Group Transfer: Reaction Development and Mechanistic Study

“…As a continuation of our research interest in nickel-catalyzed radical asymmetric functionalization of alkenes, precisely, we speculated that nickel-catalyzed HAT , or group transfer of alkyl radicals to alkenyl fluorides would generate α-fluoro radical/Ni cage pair, which could engage in stereoselective protometalation or cross-couplings with organohalides in the presence of chiral nickel complexes . If successful, this innovative strategy would not only enable efficient and facile access to fluorinated sp 3 stereocenters from planar alkenyl fluorides, but it would also complement the previously well explored nickel-hydride-catalyzed asymmetric hydroalkylation of alkenes (which is predominantly limited to primary and secondary alkyl electrophiles), , with distinct selectivity and an expanded reservoir of alkyl halides. Accordingly, we report the successful execution of radical-transfer-enabled asymmetric hydrogenation and hydroalkylation of alkenyl fluorides with tertiary, secondary, and primary alkyl halides to access structurally diverse, enantioenriched secondary and tertiary α-fluoro amides via nickel catalysis (Figure b).…”

CoH-catalyzed asymmetric remote hydroalkylation of heterocyclic alkenes: a rapid approach to chiral five-membered S- and O-heterocycles

“…Moreover, the rarity can be ascribed to the inherent challenges linked with establishing chiral C(sp 3 )–C(sp 3 ) bonds in these reactions. 10 To this end, CoH-catalyzed enantioselective reductive hydrocarbonation of alkenes 11 has proven to be a feasible and promising method for enantioselective C–C bond formation compared to other transition metals, despite the remaining challenges in the enantioselectivity control. In 2021, Lu and Fu's research group achieved a significant breakthrough in the field of cobalt-catalyzed hydroalkylation reactions, enabling the highly efficient synthesis of chiral alkylated fluoroalkanes.…”