Organocatalytic Asymmetric Synthesis of Pyran Derivatives with Adjacent F- and CF3-Tetrasubstituted Centers

Abstract

Molecules containing fluorine atoms and trifluoromethyl groups are highly significant in medicinal chemistry. However, synthesizing compounds with adjacent F- and CF₃-substituted tetrasubstituted centers remains a formidable challenge. Herein, we report an organocatalytic asymmetric approach for synthesizing pyran heterocycles bearing adjacent F- and CF₃-substituted quaternary carbon stereocenters with excellent diastereo- and enantioselectivity (>20:1 dr, >99% ee). The process involves dehydration to generate fluorinated enolates, followed by trifluoroacetylation and cyclization with enones. This method is also applicable to the functionalization of bioactive molecules and drug derivatives, offering a versatile platform for constructing fluorinated architectures.