Chemoselective Organocatalyzed Aldol Reactions

Chemoselectivity is the selectivity observed when a chemical reagent reacts preferentially with a particular functional group in a molecule having two or more different functional groups. The concept is routinely applied during complex syntheses to avoid the use of protecting groups. Thus, broadening chemoselectivity should lead to increased tactical or yield or waste reduction advantages during natural product or drug syntheses. With this in mind, I have investigated the reaction of aldehydes with cyclohexanones containing a 4-substituted linear or branched 1,3-diketone unit (triketones). The question was, could amino acid catalysis chemoselectively provide either the aldol or Knoevenagel condensation product? The key to this question was understanding the different mechanisms of these reactions and then exploiting those differences by tailoring the reaction medium to favor one over the other. A comprehensive experimental section detailing the synthesis of the aldol catalysts, synthesis of the triketone substrates, and formation of Knoevenagel and aldol products is additionally provided.