title: A ring-closing metathesis (RCM)-based approach to mycolactones A/B.
abstract: 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.
authors.affiliation: Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH) Zürich, HCI H405, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Gersbach
authors.forename: Andrea
authors.initials: A
authors.lastname: Jantsch
authors.forename: Fabian
authors.initials: F
authors.lastname: Feyen
authors.forename: Nicole
authors.initials: N
authors.lastname: Scherr
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Dangy
authors.forename: Gerd
authors.initials: G
authors.lastname: Pluschke
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Altmann
mesh_terms: D000818:Animals; D017209:Apoptosis; D001427:Bacterial Toxins / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D018942:Macrolides; D051379:Mice; D015394:Molecular Structure; D019911:Mycobacterium ulcerans / Q000737:chemistry
chemical_list: D001427:Bacterial Toxins; D018942:Macrolides; C117218:mycolactone