Asymmetric synthesis of isoxazole and trifluoromethyl-containing 3,2′-pyrrolidinyl dispirooxindoles via squaramide-catalysed [3+2] cycloaddition reactions

A highly efficient squaramide-catalysed asymmetric domino Michael/Mannich [3 + 2] cycloaddition of 3-methyl-4-nitro-5-isatylidenyl-isoxazoles and N-2,2,2-trifluoroethylisatin ketimines was developed. A new class of complex and diverse-skeleton isoxazole and trifluoromethyl-containing 3,2 '-pyrrolidinyl dispirooxindoles bearing four contiguous stereogenic centers including two adjacent spiro quaternary stereocentres were obtained in good to excellent yields (up to 99%) with excellent diastereoselectivities (>20 : 1 dr, in all cases) and enantioselectivities (up to 96% ee). Moreover, the potential utilities of the protocol have been demonstrated by gram-scale synthesis and further transformation experiments.

Automated summary

A highly efficient squaramide-catalysed asymmetric domino Michael/Mannich [3 + 2] cycloaddition synthesis method was used to obtain a new class of complex and diverse-skeleton isoxazole compounds with good yields and excellent diastereoselectivities and enantioselectivities. The potential applications of this method were demonstrated through gram-scale synthesis and further transformation experiments.