| Abstract
| - Concise total syntheses of the cytotoxic marine natural products amphidinolide X (1) andamphidinolide Y (2) as well as of the nonnatural analogue 19-epi-amphidinolide X (47) are described. Apivotal step of the highly convergent routes to these structurally rather unusual secondary metabolitesconsists of a syn-selective formation of allenol 17 by an iron-catalyzed ring opening reaction of theenantioenriched 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)-configuredtetrasubstituted sp3 chiral center at C.19, which was further elaborated into tetrahydrofuran 25 representingthe common heterocyclic motif of 1 and 2. The aliphatic chain of amphidinolide X featuring an anti-configuredstereodiad at C.10 and C.11 was generated by a palladium-catalyzed, Et2Zn-promoted addition of theenantiopure propargyl mesylate 29 to the functionalized aldehyde 28. The preparation of the correspondingC.1−C.12 segment of amphidinolide Y relies on asymmetric hydrogenation of an α-ketoester, adiastereoselective boron aldol reaction, and a chelate-controlled addition of MeMgBr in combination withsuitable oxidation state management for the elaboration of the tertiary acyloin motif. Importantly, the endgames 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 amphidinolideY, respectively. This methodological convergence ensures high efficiency and an excellent overall economyof steps for the entire synthesis campaign.
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