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Journal Article

Total Syntheses of Amphidinolide X and Y


Fürstner,  Alois
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;


Kattnig,  Egmont
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;


Lepage,  Olivier
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Fürstner, A., Kattnig, E., & Lepage, O. (2006). Total Syntheses of Amphidinolide X and Y. Journal of the American Chemical Society, 128(28), 9194-9204. doi:10.1021/ja061918e.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0025-AD64-4
Concise total syntheses of the cytotoxic marine natural products amphidinolide X (1) and amphidinolide Y (2) as well as of the nonnatural analogue 19-epi-amphidinolide X (47) are described. A pivotal step of the highly convergent routes to these structurally rather unusual secondary metabolites consists of a syn-selective formation of allenol 17 by an iron-catalyzed ring opening reaction of the enantioenriched propargyl epoxide 16 (derived from a Sharpless epoxidation) with a Grignard reagent. Allenol 17 was then cyclized with the aid of Ag(I) to give dihydrofuran 19 containing the (R)-configured tetrasubstituted sp3 chiral center at C.19, which was further elaborated into tetrahydrofuran 25 representing the common heterocyclic motif of 1 and 2. The aliphatic chain of amphidinolide X featuring an anti-configured stereodiad at C.10 and C.11 was generated by a palladium-catalyzed, Et2Zn-promoted addition of the enantiopure propargyl mesylate 29 to the functionalized aldehyde 28. The preparation of the corresponding C.1−C.12 segment of amphidinolide Y relies on asymmetric hydrogenation of an α-ketoester, a diastereoselective boron aldol reaction, and a chelate-controlled addition of MeMgBr in combination with suitable oxidation state management for the elaboration of the tertiary acyloin motif. Importantly, the end games of both total syntheses follow similar blueprints, involving key fragment coupling processes via the “9-MeO-9-BBN” variant of the alkyl-Suzuki reaction and final Yamaguchi esterifications to forge the 16-membered macrodiolide ring of amphidinolide X and the 17-membered macrolide frame of amphidinolide Y, respectively. This methodological convergence ensures high efficiency and an excellent overall economy of steps for the entire synthesis campaign.