Organocatalytic Asymmetric Benzylation and Aldol-Hemiacetalization of alpha,beta-Unsaturated Trifluoromethyl Ketones: Efficient Enantioselective Construction of 3,4-Dihydroisocoumarins

A new method has been developed for the organocatalytic enantioselective benzylation and aldol-hemiacetalization of alpha,beta-unsaturated trifluoromethyl ketones with toluene derivatives in the presence of a tertiary amine-thiourea catalyst. This method represents a facile and efficient strategy for the asymmetric synthesis of optically active 3,4-dihydroisocoumarins bearing a trifluoromethylated tetrasubstituted carbon stereocenter with high enantioselectivity. Notably, this strategy was used to synthesize several chiral trifluoromethylated analogues of typharin with high efficiency.