Biomimetic synthesis of urukthapelstatin A by Aza-Wittig ring contraction

Marine bacteria produce highly cytotoxic polyheterocyclic cyclopeptide natural products by ribosomal peptide biosynthesis. Among them, urukthapelstatin A features a chain of five 2,4′-connected azole rings within a cyclo-octapeptide framework. We report a novel synthesis design that uses only α-amino acids as starting materials that leads to an efficient and stereoselective total synthesis of urukthapelstatin A. Kinetically favored macro-thiolactonization and high-yielding aza-Wittig heterocyclization to contract the macrocycle were crucial for success. These investigations additionally uncovered the unsuspected configurational lability of the embedded enamide substructure in solution.