Total Synthesis of Cyclodepsipeptide Xylaroamide A

Cyclodepsipeptides constitute a structurally diverse class of natural products composed of amino acid and hydroxy acid residues interconnected through both amide and ester bonds. Among them, xylaroamide A, a cyclic heptadepsipeptide, was recently identified from an endolichenic Xylaria species via a molecular networking-guided discovery approach. Despite xylaroamide A exhibiting intriguing structural features and notable bioactivity potential, its total synthesis has thus far remained unexplored. Herein, we report the first total synthesis of xylaroamide A, achieved through a hybrid solid/solution-phase synthetic approach. The linear precursor was assembled in accordance with the native amino acid sequence via Fmoc-based solid-phase peptide synthesis, incorporating the preassembled ester fragment at a later stage of assembly. Subsequent macrocyclization took place under high-dilution conditions to furnish the target cyclodepsipeptide. The structure of the synthetic product was confirmed by means of optical rotation and NMR and MS spectroscopic analyses, which exhibited good agreement with the reported data for the natural product. This work establishes a reliable and efficient synthetic route to xylaroamide A and provides a foundation for further bioactivity and structure optimization investigations.