From Pseudocyclic to Macrocyclic Ionophores: Strategies toward the Synthesis of Cyclic Monensin Derivatives

There has been a long search for a simple preparation
of new cyclic
analogues of ionophore antibiotics. We report a simple and general
synthesis of three new cyclic derivatives of polyether ionophore,
monensin A (MON). The application of the Huisgen 1,3-dipolar cycloaddition
of azides and terminal alkynes to macrocyclization results in a concise,
synthetic route to monensin lacton or lactam in only 4 steps. Additionally,
macrolactamization by a simple amidation reaction using HATU, a commonly
used conjugating agent, gives 72% yields and utilizes neither high
dilution techniques nor template effects in the cyclization step.
This in turn enables ready access to a range of unnatural MON analogues,
showing the ability to form complexes with monovalent and divalent
metal cations.