Asymmetric synthesis of trifluoromethyl substituted dihydropyrans via organocatalytic cascade Michael–hemiketalization reaction

Abstract

Asymmetric conjugate addition of ethyl 4,4,4-trifluoroacetoacetate and other trifluoromethyl substituted nucleophiles to β,γ-unsaturated α-keto esters has been developed. The reaction efficiently provided dihydropyrans via cascade Michael–hemiketalization pathways. Quinine-derived thiourea was identified to be the best catalyst. A number of trifluoromethyl substituted dihydropyrans with three consecutive chiral centers were obtained in excellent yields, diastereoselectivities, and enantioselectivities. The product was readily transformed to the corresponding tetrahydropyridine without the loss of the optical purity.