Synthesis-Supported Discovery of Prefusahexin, a Direct Fusahexin Biosynthetic Precursor

Cyclic hexapeptide fusahexin features a unique fused
6,5-bicyclic N,O-acetal, the biosynthetic origin
of which is unresolved.
Metabolomics analysis of a gene deletion in Fusarium graminearum revealed an Orn-containing intermediate, prefusahexin, as the product
of nonribosomal peptide synthetase NRPS4. The chemical structure
of prefusahexin was verified by total synthesis, and its predicted
oxidized intermediate was synthesized and cyclized to fusahexin. These
results establish prefusahexin as the key biosynthetic precursor to
fusahexin.