A Ring-Closing Metathesis (RCM)-Based Approach to Mycolactones A/B

The total synthesis of the mycobacterial toxins mycolactones A/B (1 a/b) has been accomplished based on a strategy built around the construction of the mycolactone core through ring‐closing metathesis. By employing the Grubbs second‐generation catalyst, the 12‐membered core macrocycle of mycolactone...

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Bibliographic Details
Published in:Chemistry : a European journal 2011-11, Vol.17 (46), p.13017-13031
Main Authors: Gersbach, Philipp, Jantsch, Andrea, Feyen, Fabian, Scherr, Nicole, Dangy, Jean-Pierre, Pluschke, Gerd, Altmann, Karl-Heinz
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Bacterial Toxins - chemical synthesis
Bacterial Toxins - chemistry
Buruli ulcer
Catalysis
Macrolides
metathesis
Mice
Molecular Structure
Mycobacterium ulcerans - chemistry
mycolactones
natural products
total synthesis
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Summary:The total synthesis of the mycobacterial toxins mycolactones A/B (1 a/b) has been accomplished based on a strategy built around the construction of the mycolactone core through ring‐closing metathesis. By employing the Grubbs second‐generation catalyst, the 12‐membered core macrocycle of mycolactones, with a functionalized C2 handle attached to C11, was obtained in 60–80 % yield. The C‐linked upper side chain (comprising C12–C20) was completed by a highly efficient modified Suzuki coupling between C13 and C14, while the attachment of the C5‐O‐linked polyunsaturated acyl side chain was achieved by Yamaguchi esterification. Surprisingly, a diene containing a simple isopropyl group attached to C11 could not be induced to undergo ring‐closing metathesis. By employing fluorescence microscopy and flow cytometry techniques, the synthetic mycolactones A/B (1 a/b) were demonstrated to display similar apoptosis‐inducing and cytopathic effects as mycolactones A/B extracted from Mycobacterium ulcerans. In contrast, a simplified analogue with truncated upper and lower side chains was found to be inactive. RCM…︁.What else? The total synthesis of the mycobacterial toxins mycolactones A/B (1 a/b) has been accomplished based on the construction of the mycolactone core through ring‐closing olefin metathesis (RCM) of diene 2 (see scheme). Synthetic 1 a/b showed similar apoptosis‐inducing and cytopathic effects as natural mycolactones A/B.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201101799