Total Synthesis and Functional Analysis of Loihichelin C: Structural Basis for Mn(III) Stabilization and Mn(II)...

Loihichelin C (1a) is a peptidic siderophore isolated from cultures of the bacterium Halomonas LOB-5 collected from deep-sea vent environments. Compound 1a is believed to promote microbial growth by coordinating to an Fe-(III) ion via one hydroxycarboxylate and two hydroxamates and facilitating the uptake of Fe-(III). In addition, 1a is implicated in Mn-(II)-oxidation by the producing bacterium. To obtain insights into the Fe-(III)-chelating and Mn-(II)-oxidizing functions of 1a, we chemically synthesized and functionally assessed 1a, and two analogs 1b and 1c, in which the hydroxy group of hydroxycarboxylate was stereochemically inverted and deleted, respectively. We devised an efficient solid-phase synthetic strategy to assemble the unusual sequences of 1a-1c. The strong binding affinity of 1a toward Fe-(III) surpassed the affinities of 1b and 1c. Furthermore, 1a facilitated Mn-(II) oxidation under aerobic conditions and stabilized metastable Mn-(III), whereas 1b and 1c underwent oxidative degradation by Mn-(III). These data indicated that the properly oriented hydroxy group of 1a not only promotes single electron transfer from Mn-(II) to electron-deficient O₂ by forming a negatively charged Mn-(II) complex but also protects further oxidation of the resultant Mn-(III) to Mn-(IV) by preventing the coordination of O₂. Overall, this molecular editing approach revealed the structural requirements for stabilizing the Mn-(III) oxidation state and identified the mechanism of Mn-(II) oxidation in the presence of 1a for the first time.