Highly regio- and enantioselective g-alkylation of linear a,b-Unsaturated aldehydes

Abstract

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 due to multiple reactive centers. Particularly, alkylation of linear 2-enals through dienamine catalysis produces a mixture of regioisomers due to the reactive a- and b-positions. There are few attempts made to mask a-reactive center to achieve g-selectivity. Controlling enantioselectivity at the remote g-position has also been found to be quite challenging. We have achieved a highly regioselective g-alkylation of linear a,b-unsaturated aldehydes using trifluoroethanol (TFE) as a co-solvent. Further, we have demonstrated an in situ kinetic resolution for the enantioenrichment of g-alkylated products. This methodology brings a novel activation of electrophile facilitated by TFE and an in situ kinetic resolution to achieve excellent selectivity in dienamine catalysis.