Catalytic decarboxylative aldol and Mannich reactions

The development of metal-catalyzed aldol and Mannich reactions using malonic acid half thiol esters (MAHTs) as thiol ester enolate equivalents is presented in this thesis. Inspiration for this work came from biosyntheses of polyketides and fatty acids, both of which rely on MAHTs as nucleophiles in a key Claisen condensation step.; Through an extensive screening of potential catalysts and optimization of the reaction conditions a general copper-catalyzed MART-based aldol reaction was developed. The unique properties of MAHTs allowed the use of mild and practical reaction conditions in a highly chemoselective reaction. The most interesting aspect of the new methodology is the use of decarboxylation coupled to an aldol reaction as a general strategy for overcoming the problems associated with the development of metal catalyzed aldol reactions. Kinetic measurements in combination with kinetic isotope effect experiments provided an insight into the mechanism of the catalytic decarboxylative aldol reaction.; In an effort to develop an enantioselective aldol reaction, an alternative set of reaction conditions was discovered that allowed the formation of acetate aldol products in high yield and moderate enantioselectivity using a copper(II)-Box catalyst. Ultimately this discovery led to the development of general enantioselective propionate and acetate aldol reactions.; The MAHTs have also been successfully applied as thieol ester enolate equivalents in the decarboxylative Mannich-type reactions. Initial experiments revealed that zinc(II) triflate in the presence of Hiinig's base catalyzes an efficient three-component Mannich-type reaction involving aldehydes, MAHTs, and acyl hydrazides. These initial results will serve as a starting point for the development of a general enantioselective Mannich-type reaction.