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

Abstract

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.