Amide phosphonium salt catalyzed enantioselective Mannich addition of isoxazole-based nucleophiles to β,γ-alkynyl-α-ketimino esters

An enantioselective Mannich addition of 3,5-disubstituted 4-nitroisoxazoles to β,γ-alkynyl-α-ketimino esters promoted by an amide phosphonium salt-based catalyst has been developed. N -Cbz-protected ketimino esters with various aryl substituents attached to the alkyne unit were reacted with a series of isoxazoles with different substitution patterns. Chiral tertiary propargylic amine products were obtained with moderate to good yields and enantioselectivities. TIPS- and cyclopropyl-substituted alkynyl ketimines were also examined in the current system and the desired products were obtained with moderate yields and enantioselectivities. The potential scalability and utility of the current protocol were demonstrated by carrying out a relatively larger scale reaction followed by further transformations. Using 5 mol% of a phosphonium salt catalyst derived from a chiral amino alcohol, the enantioselective Mannich addition of 3,5-disubstituted 4-nitroisoxazoles to β,γ-alkynyl-α-ketimino esters has been developed.