title: Total syntheses of amphidinolides B1, B4, G1, H1 and structure revision of amphidinolide H2.
abstract: Nature is a pretty unselective "chemist" when it comes to making the highly cytotoxic amphidinolide macrolides of the B/G/H series. To date, 16 different such compounds have been isolated, all of which could now be approached by a highly convergent and largely catalysis-based route (see figure). This notion is exemplified by the total synthesis of five prototype members of this family.Dinoflagellates of the genus Amphidinium produce a "library" of closely related secondary metabolites of mixed polyketide origin, which are extremely scarce but highly promising owing to the exceptional cytotoxicity against various cancer cell lines. Because of the dense array of sensitive functionalities on their largely conserved macrocyclic frame, however, these amphidinolides of the B, D, G and H types elapsed many previous attempts at their synthesis. Described herein is a robust, convergent and hence general blueprint which allowed not only to conquest five prototype members of these series, but also holds the promise of making "non-natural" analogues available by diverted total synthesis. This notion transpires for a synthesis-driven structure revision of amphidinolide H2. The successful route hinges upon a highly productive Stille-Migita cross-coupling reaction at the congested and chemically labile 1,3-diene site present in all such targets, which required the development of a modified chloride- and fluoride-free protocol. The macrocyclic ring could be formed with high efficiency and selectivity by ring-closing metathesis (RCM) engaging a vinyl epoxide unit as one of the reaction partners. Because of the sensitivity of the targets to oxidizing and reducing conditions as well as to pH changes, the proper adjustment of the protecting group pattern for the peripheral -OH functions also constitutes a critical aspect, which has to converge to silyl groups only once the diene is in place. Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) turned out to be a sufficiently mild fluoride source to allow for the final deprotection without damaging the precious macrolides.
authors.affiliation: Max-Planck-Institut für Kohlenforschung, 45470 Mülheim/Ruhr, Germany. fuerstner@mpi-muelheim.mpg.de
authors.forename: Alois
authors.initials: A
authors.lastname: Fürstner
authors.forename: Laure C
authors.initials: LC
authors.lastname: Bouchez
authors.forename: Louis
authors.initials: L
authors.lastname: Morency
authors.forename: Jaques-Alexis
authors.initials: JA
authors.lastname: Funel
authors.forename: Vilnis
authors.initials: V
authors.lastname: Liepins
authors.forename: François-Hugues
authors.initials: FH
authors.lastname: Porée
authors.forename: Ryan
authors.initials: R
authors.lastname: Gilmour
authors.forename: Daniel
authors.initials: D
authors.lastname: Laurich
authors.forename: Florent
authors.initials: F
authors.lastname: Beaufils
authors.forename: Minoru
authors.initials: M
authors.lastname: Tamiya
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D002384:Catalysis; D020650:Combinatorial Chemistry Techniques; D004141:Dinoflagellida / Q000737:chemistry; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D008387:Marine Toxins / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D013329:Structure-Activity Relationship; D000097442:Amphidinolides
chemical_list: D000970:Antineoplastic Agents; D018942:Macrolides; D008387:Marine Toxins; C511225:amphidinolide B1; D000097442:Amphidinolides