The development of catalytic, asymmetric decarboxylative coupling reactions

Abstract

The generation, and subsequent allylation, of ketone enolates from β-keto allylic esters via the transition metal-catalyzed decarboxylative allylation reaction has been thoroughly investigated in regard to the scope, regioselectivity, and enantioselectivity of the reaction. The Pd(0)/Trost ligand-catalyzed transformation with symmetrically substituted acyclic and cyclic allyl groups has been shown to afford high yields of γ,δ-unsaturated ketone products with ee's typically greater than 90% under very mild reaction conditions. In addition, the reaction has been shown to be highly regiospecific; products arise exclusively from the allylation of kinetic enolates. A catalytic system comprised of Pd(0) and either the PHOX ligand or Quinap has also been developed for the enantioselective decarboxylative allylation of fluorinated ketone enolates to yield α-fluoro ketones with ee's typically between 80% and 90%. The enantioselectivity of the reaction with α substituents other than fluorine has also been explored. While iridium, rhodium, and molybdenum catalysts were found to display only moderate reactivity in the decarboxylative allylation reaction, the ruthenium complex Cp*RuCl(bpy) is capable of transforming β-keto esters possessing aryl-substituted allyl groups to γ,δ-unsaturated ketones with yields generally greater than 90%. In addition, the reaction in highly regioselective; products arising from attack of the enolate at the substituted terminus of mono-substituted Ru π-allyls are favored by as much as 101:1 over the other regioisomer. The reaction is also stereospecific, and it has been demonstrated that the extent of stereospecificity is dependent upon the electronic and steric nature of substituents on the β-keto ester starting material. Elucidation of the mechanism of racemization allowed for the isolation of products with high enantiopurity. Lastly, the scope of nucleophiles generated following the transition metal-catalyzed loss of CO2 has been broadened to include anions other than ketone enolates. The decarboxylation of allyl esters of α-amino acids protected as diphenyl ketimines has been shown to proceed with palladium catalysts. Nucleophilic α-imino anions react with electrophilic Pd π-allyls to yield protected homoallylic amines, although for certain substrates aziridines are the predominate products. The addition of chiral ligands has been shown to induce modest levels of selectivity in the transformation.