Stereocontrolled Formation of Ketomethylene Isosteres through Tandem Chain Extension Reactions

A zinc-mediated chain extension reaction is the key step in the preparation of γ-keto amides derived from amino acids. The use of tandem reaction sequences, in which the intermediate zinc enolate is trapped with electrophilic reagents, results in the incorporation of α-substituents, which mimic the side chains found in natural amino acid systems. Use of the chiral amino acid l-proline as a stereo-directing element provides a diastereoselective route to various ketomethylene isosteres.