DFT study of Ni-catalyzed intramolecular asymmetric anti-hydrometalative cyclization of alkynone: mechanism and origins of selectivity

The intramolecular cyclization of alkynones catalyzed by Ni catalysts has attracted much attention due to its versatile application in the synthesis of cyclic compounds. Herein, we present a comprehensive investigation into the mechanism and origins of selectivities of this reaction using density functional theory (DFT) computations. The Ni(0) catalyst system selectively forms 5-exocyclic products while the Ni(ii) catalyst system generates 6-endocyclic or 5-exocyclic products because they follow different mechanisms. The Ni(0) system follows an oxidative cyclometalation, hydride transfer, and reductive elimination pathway. However, in the Ni(ii) system, the reaction starts with the alkyne insertion followed by cis/trans isomerization, carbonyl insertion, hydrolysis, and catalyst regeneration, among which the alkyne insertion determines the regioselectivity and the carbonyl insertion determines the enantioselectivity. In particular, the C = C bond of the Ph-alkynone substrate prefers 1,2-insertion due to the conjugation effect, while the C C bond of the Bu-alkynone substrate favors 2,1-insertion owing to the electron-donating property of the Bu group. It is notable that a cis/trans isomerization process is necessary for the formation of the 6-endocyclic product but not for the formation of the 5-endocyclic product. The rationale for the (S)-enantioselectivity observed for both substrates is ascribed to favorable hydrogen bonding interactions and the less steric repulsions in the (S)-transition states of carbonyl insertion.