Lewis Acid-Initiated Cleavage of a Large Ionophore: Molecular Deactivation by Potassium Ion Binding

Herein, it is demonstrated that the addition of Lewis acids such as Zn(OTf)₂ to a large ionophoric natural product effects a fast cleavage of the molecule into two distinct fragments. The exploration of the mechanism implicates acidification of the carboxylic acid through metal coordination, and protonation of unbound molecules in a catalyzed cleavage; merck molecular force field (MMFF) conformational searches and density functional theory (DFT) calculations support these hypotheses. When a competing, more tightly binding metal such as K + is introduced, Zn(II) binding is precluded, and the rate of cleavage drops drastically. It is believed that these results may be helpful in understanding the role that metal ions play in drug degradation as well as illuminating their general role in altering the reactivity of ionophores.