Total Synthesis of the Cyclic Depsipeptide Vioprolide D via its (Z)‐Diastereoisomer

The first total synthesis of vioprolide D was accomplished in an overall yield of 2.0 % starting from methyl (2S)‐3‐benzyloxy‐2‐hydroxypropanoate (16 steps in the longest linear sequence). The cyclic depsipeptide was assembled from two building blocks of similar size and complexity in a modular, highly convergent approach. Peptide bond formation at the C‐terminal dehydrobutyrine amino acid of the northern fragment was possible via its (Z)‐diastereoisomer. After macrolactamization and formation of the thiazoline ring, the (Z)‐double bond of the dehydrobutyrine unit was isomerized to the (E)‐double bond of the natural product. The cytotoxicity of vioprolide D is significantly higher than that of its (Z)‐diastereoisomer.