Evidence for Ion-Templation During Macrocyclooligomerization of Depsipeptides

Area of Science:

• Organic Chemistry
• Supramolecular Chemistry
• Chemical Thermodynamics

Background:

• The ion-mediated Mitsunobu macrocyclooligomerization (M-MCO) is a method for synthesizing cyclic depsipeptides.
• The role of Lewis acidic alkali metal salts in MCO reactions, particularly regarding templating mechanisms, remains unclear.

Purpose of the Study:

• To investigate the binding interactions between metal ions and cyclic depsipeptides using isothermal titration calorimetry (ITC).
• To correlate thermodynamic binding data with the size distribution of depsipeptides produced via M-MCO.
• To establish an analytical platform for selecting metal-ion templates to control the size of cyclic oligomeric depsipeptides.

Main Methods:

• Mitsunobu-based macrocyclooligomerization (MCO) of hydroxy acid depsipeptides.
• Isothermal titration calorimetry (ITC) to quantify metal ion-cyclic depsipeptide binding affinity (Ka), enthalpy of binding (ΔH), and stoichiometry.
• Correlation of thermodynamic data with kinetically determined size distributions of macrocycles.

Main Results:

• Identified key trends in metal ion-cyclic depsipeptide binding affinity, enthalpy, and stoichiometry across different macrocycle series.
• Demonstrated a correlation between thermodynamic binding parameters and the size distribution of MCO products.
• Established that metal ion binding influences the outcome of M-MCO reactions.

Conclusions:

• Metal ion binding interactions are crucial for controlling the size and formation of cyclic depsipeptides in M-MCO reactions.
• ITC provides a valuable tool for understanding and predicting the templating effects of metal ions.
• This work presents the first analytical platform for rational selection of metal-ion templates to achieve targeted cyclic oligomeric depsipeptide sizes.