Organocatalytic diastereo- and enantioselective oxa-hetero-Diels–Alder reactions of enones with aryl trifluoromethyl ketones for the synthesis of trifluoromethyl-substituted tetrahydropyrans

Abstract

Tetrahydropyran derivatives are found in bioactives, and introduction of the trifluoromethyl group into molecules often improves biofunctions. Here we report diastereo- and enantioselective oxa-hetero-Diels–Alder reactions catalyzed by amine-based catalyst systems that afford trifluoromethyl-substituted tetrahydropyranones. Catalyst systems and conditions suitable for the reactions to provide the desired diastereomer products with high enantioselectivities were identified, and various trifluoromethyl-substituted tetrahydropyranones were synthesized with high diastereo- and enantioselectivities. Mechanistic investigation suggested that the reactions involve a [4 + 2] cycloaddition pathway, in which the enamine of the enone acts as the diene and the ketone carbonyl group of the aryl trifluoromethyl ketone acts as the dienophile. In this study, tetrahydropyran derivatives with the desired stereochemistry that are difficult to synthesize by previously reported methods were concisely obtained, and the range of tetrahydropyran derivatives that can be synthesized was expanded.