Evidence for Ion-Templation During Macrocyclooligomerization of Depsipeptides.

The ion-mediated Mitsunobu macrocyclooligomerization (M-MCO) reaction of hydroxy acid depsipeptides provides small collections of cyclic depsipeptides with good mass recovery. The approach can produce good yields of a single macrocycle or provide rapid access to multiple oligomeric macrocycles in good overall yield. While Lewis acidic alkali metal salts are known to play a role in the outcome of MCO reactions, it is unclear whether their effect is due to an organizational (e.g., templating) mechanism. Isothermal titration calorimetry (ITC) was used to study macrocycle-metal ion binding interactions, and this report correlates these thermodynamic measurements to the (kinetically determined) size distributions of depsipeptides formed during a Mitsunobu-based macrocyclooligomerization (MCO). Key trends have been identified in quantitative metal ion-cyclic depsipeptide binding affinity ( K), enthalpy of binding (Δ H), and stoichiometry of complexation across discrete series of macrocycles, and they provide the first analytical platform to rationally select a metal-ion template for a targeted size regime of cyclic oligomeric depsipeptides.