Enantioconvergent synthesis by sequential asymmetric Horner-Wadsworth-Emmons and palladium-catalyzed allylic substitution reactions

A new method for enantioconvergent synthesis has been developed. The strate gy relies on the combination of an asymmetric Homer-Wadsworth-Emmons (HWE) reaction and a palladium-catalyzed allylic substitution. Different alpha -o xygen-substituted, racemic aldehydes were initially transformed by asymmetr ic HWE reactions into mixtures of two major alpha,beta -unsaturated esters, possessing opposite configurations at their allylic stereocenters as well as opposite alkene geometry. Subsequently, these isomeric mixtures of alken es could be subjected to palladium-catalyzed allylic substitution reactions with carbon, nitrogen, and oxygen nucleophiles, In this latter step, the r espective (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 allyli c stereocenter and the alkene geometry. Thus, a single gamma -substituted e ster was obtained as the overall product, in high isomeric purity. The meth od was applied to a synthesis of a subunit of the iejimalides, a group of c ytotoxic macrolides.