Enantioconvergent Synthesis by Sequential Asymmetric Horner−Wadsworth−Emmons and Palladium-Catalyzed Allylic Substitution Reactions

A new method for enantioconvergent synthesis has been developed. The strategy relies on the combination of an asymmetric Horner−Wadsworth−Emmons (HWE) reaction and a palladium-catalyzed allylic substitution. Different α-oxygen-substituted, racemic aldehydes were initially transformed by asymmetric HWE reactions into mixtures of two major α,β-unsaturated esters, possessing opposite configurations at their allylic stereocenters as well as opposite alkene geometry. Subsequently, these isomeric mixtures of alkenes could be subjected to palladium-catalyzed allylic substitution reactions with carbon, nitrogen, and oxygen nucleophiles. In this latter step, the respective (E) and (Z) alkene substrate isomers were observed to react with opposite stereospecificity: the (E) alkene reacted with retention and the (Z) alkene with inversion of stereochemistry with respect to both the allylic stereocenter and the alkene geometry. Thus, a single γ-substituted ester was obtained as the overall product, in high isomeric purity. The method was applied to a synthesis of a subunit of the iejimalides, a group of cytotoxic macrolides.