A one-pot zinc-mediated chain extension reaction has been developed in which a b-keto ester(amide) is converted in converted to a g-keto ester(amide) by treatment with a zinc carbenoid. A variety of amino acid substrates have been converted ketomethylene peptide isosteres through application of this methodology. Three tandem reactions, based upon the intermediacy of a zinc organometallic reagent, have been developed to facilitate the stereocontrolled incorporation of a-substituents that mimic amino acid side chains. The application of this strategy for the generation of a mimic of the human CMV protease cleavage site has been developed.