The ion-mediated Mitsunobu macrocydooligomerization (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 macrocydooligomerization (MCO). Key trends have been identified in quantitative metal ion-cyclic depsipeptide binding affinity (K-a), enthalpy of binding (OH), 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 cydic oligomeric depsipeptides.