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

Loihichelin C (<b>1a</b>) is a peptidic siderophore isolated from cultures of the bacterium <i>Halomonas</i> LOB-5 collected from deep-sea vent environments. Compound <b>1a</b> 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, <b>1a</b> is implicated in Mn-(II)-oxidation by the producing bacterium. To obtain insights into the Fe-(III)-chelating and Mn-(II)-oxidizing functions of <b>1a</b>, we chemically synthesized and functionally assessed <b>1a</b>, and two analogs <b>1b</b> and <b>1c</b>, 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 <b>1a</b>-<b>1c</b>. The strong binding affinity of <b>1a</b> toward Fe-(III) surpassed the affinities of <b>1b</b> and <b>1c</b>. Furthermore, <b>1a</b> facilitated Mn-(II) oxidation under aerobic conditions and stabilized metastable Mn-(III), whereas <b>1b</b> and <b>1c</b> underwent oxidative degradation by Mn-(III). These data indicated that the properly oriented hydroxy group of <b>1a</b> 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 <b>1a</b> for the first time.