The Formation of Impossible Rings in Macrocyclooligomerizations for Cyclodepsipeptide Synthesis: The 18-from-12 Paradox

A reinvestigation into the macrocyclooligomerization (MCO) of a tetradepsipeptide is reported, uncovering a paradox in which the MCO of depsipeptide monomers can produce impossible ring sizes: a 12-atom chain produced the expected 24-membered ring, alongside unexpected 18- and 30-membered cyclic oligomeric depsipeptides (CODs). We report an alternative preparation of authentic 18- and 36-membered macrocycles for this case using a stepwise synthesis that provides definitive analytical characterization for each ring size. Our investigation yields a recharacterization and reassignment of two macrocycles originally reported in this MCO series, along with updated yields and isothermal titration calorimetry data after implementation of new critical protocols for purification and subsequent analysis. Initial studies to probe this mechanistic conundrum are described.

Automated summary

The reinvestigation into the macrocyclooligomerization (MCO) of a tetradepsipeptide revealed a paradox where the MCO of depsipeptide monomers could result in impossible ring sizes, leading to unexpected findings of 18- and 30-membered cyclic oligomeric depsipeptides (CODs). An alternative method for preparing authentic 18- and 36-membered macrocycles was reported, providing definitive analytical characterization for each ring size. The study also included recharacterization and reassignment of two macrocycles originally reported in the MCO series, along with updated data on yields and isothermal titration calorimetry after the implementation of new critical protocols.