Synergistic Pd/Amine-Catalyzed Stereodivergent Hydroalkylation of 1,3-Dienes with Aldehydes: Reaction Development, Mechanism, and Stereochemical Origins

Metal-hydride-catalyzed hydroalkylation of 1,3-dienes with enolizable carbonyl compounds is an atom- and step-economical method for preparing chiral molecules with allylic stereocenters. Although high diastereo- and enantioselectivities have been achieved for many coupling partners, aldehydes have not yet been used for this purpose because they are less stable than other carbonyl compounds under basic conditions and they have the potential to rapidly epimerize at the a-position. Moreover, stereodivergent hydroalkylation reactions of 1,3-dienes to access complementary diastereomers with vicinal stereocenters is challenging. Herein, we describe a synergistic palladium/amine catalyst system that allowed us to achieve the first stereodivergent hydroalkylation reactions of 1,3-dienes with aldehydes. By choosing an appropriate combination of chiral palladium and amine catalysts, we could obtain either syn or anti coupling products, and this method therefore provides highly diastereo- and enantioselective access to complementary diastereomers of chiral aldehydes with alpha,beta-vicinal stereocenters. Density functional theory calculations revealed a mechanism involving PdH formation and migratory insertion into the alkene, followed by C-C bond formation. The origin of the stereoselectivities was investigated by means of distortion/interaction analysis.

Automated summary

A new method for metal-hydride-catalyzed hydroalkylation of 1,3-dienes with aldehydes is described, providing access to chiral molecules with allylic stereocenters. By choosing a combination of chiral palladium and amine catalysts, highly diastereo- and enantioselective access to complementary diastereomers is achieved. The mechanism involves PdH formation and migratory insertion into the alkene, followed by C-C bond formation, with the origin of stereoselectivities investigated through distortion/interaction analysis.