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A Ring‐Closing Metathesis (RCM)‐Based Approach to Mycolactones A/B
Author(s) -
Gersbach Philipp,
Jantsch Andrea,
Feyen Fabian,
Scherr Nicole,
Dangy JeanPierre,
Pluschke Gerd,
Altmann KarlHeinz
Publication year - 2011
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201101799
Subject(s) - metathesis , ring closing metathesis , chemistry , side chain , stereochemistry , combinatorial chemistry , organic chemistry , polymerization , polymer
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.