Stereoelectronic effects dictate mechanistic dichotomy between Cu(II)-catalyzed and enzyme-catalyzed reactions of malonic acid half thioesters

Previously we developed a Cu(II)-catalyzed, enantioselective aldol reaction between malonic acid half thioesters (MAHTs) and aldehydes based on the biosynthesis of polyketides and fatty acids in which MAHTs are decarboxylated enzymatically to afford ester enolates that condense with thioesters. We report evidence based on steric effects, kinetics, kinetic isotope effects, and crossover experiments in support of a different mechanism for the Cu(II)-catalyzed aldol reaction involving enolization of MAHTs by deprotonation, addition to the aldehyde, decarboxylation, and protonation of the -hydroxy enolate. We also provide an explanation, based on stereoelectronic effects, for the mechanistic dichotomy between Cu(II)-catalyzed and enzyme-catalyzed reactions of MAHTs.