Vanderbilt Summer Science Academy

Catalytic Asymmetric Carboxylic Acid Activation in the Enantioselective Iodolactonization of Symmetric Alkenes

The use of carboxylic acids is ubiquitous in nature and synthetic chemistry due to their symmetry and their ability to hydrogen bond. Carboxylic acids have two oxygen atoms with equal reactivity but there is not yet an established catalytic mode to differentiate between carboxylate oxygens. In nature, one mechanism of activation of a carbamic acid by dethiobiotin synthetase proceeds via oxygen atom differentiation. This is achieved by hydrogen bond donation from an amide N-H and water molecule to one oxygen, and ionic hydrogen bonding from a lysine residue to the other. This activation mode is hypothesized to cause selective phosphorylation of one oxygen atom over the other.  The Johnston group hypothesized that a similar three-point binding strategy could be employed to generate a chiral carboxylate with oxygen atoms differentiated. For high enantioselectivity to be achieved, two parameters must be accounted by the catalyst: the conformation of the central C-C bond and the nucleophilicity of each carboxylate oxygen. The Johnston group was able to optimize the organocatalyst through the enantioselective iodolactonization of cyclopentene carboxylic acid substrate. We are trying to extend this result to cyclohexadiene carboxylic acid substrate. While synthesizing the organocatalyst in two steps, different cyclohexadiene carboxylic acid substrates are synthesized through the Birch Reduction of benzoic acid. Catalytic iodolactonization of these substrates is achieved in subsequent reactions. Characterizing this enantioselective iodolactionization methodology could ultimately provide novel approaches towards synthetic chemistry and the derivatization of bicyclic lactone products could lead to new approaches to carbocyclic nucleoside based drugs.