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

Abstract

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.