I. Synthesis of cyclooctenones using intramolecular hydroacylation. II. Development of a catalytic enantioselective thiol ester aldol reaction

The discovery and development of a catalytic reaction to synthesize cyclooctenones via intramolecular hydroacylation is described in this thesis. Rhodium catalysts were found to promote an intramolecular hydrometallation of 5-cyclopropyl-pent-4-enals, followed by cyclopropane ring fragmentation and reductive elimination, to afford cyclooctenones. Cationic Rh(I) catalysts, of the type [Rh(dppe)]X, were found to be superior to neutral Rh(I) catalysts for promoting the reaction and facilitating cyclopropane ring fragmentation. Substituted cyclooctenones, including fused 5-8 and 6-8 ring systems, were constructed. A deuterium labeling study indicated that E- and Z-5-cyclopropyl-pent-4-enals proceed through different reaction mechanisms to their 8-membered ring products.; Also described in this thesis is the development of a catalytic enantioselective thiol ester aldol reaction. Methyl malonic acid half thiol esters (MAHTs) and a variety of aldehydes were found to participate in a decarboxylative propionate aldol reaction that directly afforded α-methyl-β-hydroxythiol esters with syn diastereoselectivity. The reaction was catalyzed by 20 mol% of copper(II) 2-ethylhexanoate in combination with 20 mol% of 5-methoxybenzimidazole and carried out at room temperature. The use of chiral bis(oxazoline) ligands in combination with copper(II) triflate was found to promote catalytic enantioselective decarboxylative aldol reactions in up to 95% yield and 95% enantiomeric excess. A stereochemical model is presented that accounts for the observed aldol product distribution and stereochemistry.