Total Synthesis of the Cyclic Depsipeptide Vioprolide D via its (Z)‐Diastereoisomer. Issue 30 (20th April 2020)

• Record Type: Journal Article
• Authors: Grab, Hanusch A.; Kirsch, Volker C.; Sieber, Stephan A.; Bach, Thorsten
• Is Part Of: Angewandte Chemie international edition. Volume 59:Issue 30(2020)
• Page Start: 12357
• Page End: 12361
• Publication Date: 2020-04-20
• Subjects: antitumor agents -- isomerization -- macrocycles -- peptides -- total synthesis; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.202002328
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: The first total synthesis of vioprolide D was accomplished in an overall yield of 2.0 % starting from methyl (2 S )‐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. Abstract : Better late than never : The key linkage between a proline and an ( E )‐dehydrobutyrine in vioprolide D was successfully tackled by a late‐stage double bond isomerization. The first member of this class of biologically potent depsipeptides has thus been efficiently synthesized (16 linear steps, 2.0 % overall yield).