Total Synthesis of Nosiheptide

Total synthesis of the bismacrocyclic thiopeptide antibiotic nosiheptide was achieved through the assembly of a fully functionalized linear precursor followed by consecutive macrocyclizations. Key features are a critical macrothiolactonization and a mild deprotection strategy for the 3‐hydroxypyridine core. The natural product was identical to isolated authentic material in terms of spectral data and antibiotic activity. Each ring is different: A total synthesis of the bismacrocyclic thiopetide antibiotic nosiheptide was achieved through the assembly of a fully functionalized linear precursor, followed by consecutive macrocyclizations. Key to success were the late‐stage formation of a dehydroalanine residue and finely tuned deprotection of the hydroxypyridine core. The synthesis product was identical to the natural material in terms of structure and function.