Total syntheses of amphidinolide T1, T3, T4, and T5.
A concise, flexible, and high yielding entry into the family of amphidinolide T macrolides, a series of cytotoxic natural products of marine origin, has been developed. All individual members, except amphidinolide T3 (3), derive from compound 39 as a common synthetic intermediate which is formed from three building blocks of similar size and complexity. The fragment coupling steps involve a highly diastereoselective SnCl(4) mediated reaction of the furanosyl sulfone derivative 11 with the silyl enol ether 18 and a palladium-catalyzed Negishi type coupling reaction between the polyfunctional organozinc reagent derived from iodide 32a and the enantiopure acid chloride 24b. The 19-membered macrocyclic ring is then formed by a high yielding ring closing metathesis (RCM) reaction of diene 33 catalyzed by the "second generation" ruthenium carbene complex 34. The efficiency of the RCM transformation stems, to a large extent, from the conformational bias introduced by the syn-syn-configured stereotriad at C12-C14 of the substrate which constitutes a key design element of the synthesis plan. The use of Nysted's reagent 38 in combination with TiCl(4) was required for the olefination of the sterically hindered ketone group in 36, whereas more conventional alkene formations were unsuccessful for this elaboration. Finally, it is shown that the inversion of a single and seemingly remote stereocenter (C12) in one of the building blocks not only affects the efficiency and stereochemical outcome of the RCM step but also exerts a significant influence on the course of the acyl-Negishi reaction, allowing a radical manifold to compete with productive cross coupling.
Aïssa
Christophe
C
Max-Planck-Institut für Kohlenforschung, D-45470 Mülheim/Ruhr, Germany.
Riveiros
Ricardo
R
Ragot
Jacques
J
Fürstner
Alois
A
D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D005663:Furans / Q000737:chemistry; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry; D018942:Macrolides; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D000097442:Amphidinolides
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005663:Furans; D007783:Lactones; D018942:Macrolides; C414522:amphidinolide T; D000097442:Amphidinolides