The reaction conditions are developed using 3-substituted azetidines containing 1-naphthyl (1-Nap) units and cyclohexane (Cy) carbonyl chloride, with the optimal solvent being methyl-substituted tetrahydrofuran (THF). Highly polar solvents are found to give a decrease in selectivity, which supports a mechanism involving noncovalent interactions with the catalyst. A wide range of 3-substituents on the azetidine are tolerated by these conditions, including aryl, alkynyl and halide groups, delivering ring-opened products in high yield and enantiomeric excess. A range of acyl chlorides beyond cyclohexyl substitution are also amenable to the reaction, as well as allyl and benzyl halides, demonstrating the broad reaction scope.
Increasing the amount of fluorine-substitution on the pink aryl group of 1 leads to a decrease in the enantioselectivity of the products, suggesting the participation of cation-π interactions in the enantioinduction. Additionally, a computational study of a range of different catalyst structures supports a mechanism of enantioinduction through attractive electrostatic interactions, with the different steric and functional features of the catalysts appearing to contribute less to the enantioinduction. In situ infrared spectroscopy indicates that catalyst 1 rapidly forms an intermediate under the reaction conditions consisting of 1 bound to an N-acyl-azetidinium chloride ion pair. Density functional theory calculations further suggest that the NH groups of 1 (pictured in blue) utilize hydrogen bonding interactions with the Cl˗ anion of the N-acyl-azetidinium chloride intermediate, while the pink aryl unit of 1 stabilizes the cationic azetidinium.
This is a preview of subscription content, access via your institution
