Highly Regio- and Enantioselective γ-Alkylation of Linear α,β-Unsaturated Aldehydes

Asymmetric alkylation is one of the most useful carbon-carbon bond-forming reactions in synthetic organic chemistry. Chiral-amine-catalyzed alkylation reactions often lack regioselectivity owing to multiple reactive centers. In particular, the alkylation of linear 2-enals through dienamine catalysis produces a mixture of regioisomers owing to reactive alpha-and gamma-positions. A few attempts have been made to mask the a-reactive center to achieve gamma-selectivity. Controlling the enantioselectivity at the remote gamma-position has also been found to be quite challenging. Herein, we achieved the highly regioselective gamma-alkylation of linear alpha,beta-unsaturated aldehydes by using trifluoroethanol (TFE) as a cosolvent. Further, we demonstrated in situ kinetic resolution for enantioenrichment of the gamma-alkylated products. This method brings together the activation of an electrophile facilitated by TFE and in situ kinetic resolution to achieve excellent selectivity in dienamine catalysis.