Enantioselective palladium catalysis: Synthetic and mechanistic investigations of allylic alkylation reactions

Chiral ligands based on 2-diphenylphosphinobenzoic acid and some related diphenylphosphinonaphthoic acids give high enantioselectivities in a variety of palladium catalyzed allylic alkylation reactions. Cyclic and acyclic substrates which proceed through meso intermediates or, in one case, a rapidly racemizing intermediate give good results. Nucleophiles derived from dimethyl malonate and phthalimide add to simple five, six, and seven member ring allylic acetates and methyl carbonates in high ee (enantiomeric excess). With a substituted six member ring substrate containing a remote asymmetric center, the chiral ligand completely controls the stereochemistry of nucleophilic addition. A newly synthesized chiral ligand based on 2-diphenylphosphino-1-naphthoic acid gives high ee in the addition of phthalimide to butadiene monoepoxide. A new method employing O-methylmandelic acid determines the ee and absolute configuration of ;Proper control of the reaction conditions proves critical for attaining these enantioselectivities typically greater than 90% ee. The solvent and cation effects suggest that the manner in which the nucleophile and its counterion interact with the "chiral pocket" formed by the ligand as it embraces the substrate affects the enantioselectivity. A size complementarity exists between the chiral pocket formed by the ligand and the nucleophile and counterion as they approach during the nucleophilic addition step. Generally, larger counterions such as cesium and tetrahexylammonium give the highest enantioselectivities due to the correct fit with the substrate in the chiral pocket. With one of the newly synthesized chiral ligands which has a narrower chiral pocket, smaller cations such as sodium give the highest enantioselectivity with a simple cyclic substrate. Thus, a better understanding of the factors which influence the enantioselectivity of palladium catalyzed allylic alkylation reactions provides relatively simple experimental procedures that routinely give synthetically useful alkylation and amination products in very high ee.