Total Synthesis of Anti‐Cancer Meroterpenoids Dysideanone B and Dysiherbol A and Structural Reassignment of Dysiherbol A

Abstract

The first total synthesis of marine anti‐cancer meroterpenoids dysideanone B and dysiherbol A have been accomplished in a divergent way. The synthetic route features: 1) a site and stereoselective α‐position alkylation of a Wieland–Miescher ketone derivative with a bulky benzyl bromide to join the terpene and aromatic moieties together and set the stage for subsequent cyclization reactions; 2) an intramolecular radical cyclization to construct the 6/6/6/6‐tetracycle of dysideanone B and an intramolecular Heck reaction to forge the 6/6/5/6‐fused core structure of dysiherbol A. A late‐stage introduction of the ethoxy group in dysideanone B reveals that this group might come from the solvent ethanol. The structure of dysiherbol A has been revised based on our chemical total synthesis.

Enantioselective Total Synthesis and Structural Revision of Dysiherbol A

“…[3] Last but not least we would like to mention that while we were in the process of finalizing this manuscript, a publication by Lu and co-workers appeared describing a total synthesis of (racemic) (AE)-dysiherbol A following a different strategy. [31] Scheme 5. Acid-mediated conversion of cyclopropane 30 to either the pentacyclic avarane 32 or the aureane 33.…”

Practical and Scalable Total Syntheses of (+)-Dysidavarones A–C

“…(+)-Dysidavarone B (2) was obtained in 92% yield by transformation of (+)-dysidavarone C (3) through double-bond migration under acidic conditions. 17 In summary, we have elaborated a practical and scalable total syntheses of the marine anticancer sesquiterpene quinone meroterpenoids (+)-dysidavarones A-C. The central structure of the dysidavarones was efficiently constructed by an unprecedented direct diastereoselective domino alkylation and subsequent intramolecular arylation reaction of a Wieland-Miescher ketone derivative employing bulky benzylic bromides.…”

“…Finally, (+)-dysidavarone A (1) was synthesized in 92% yield from (+)dysidavarone 'E ( 5) by an acid-catalyzed double-bond shift. 17 The syntheses of (+)-dysidavarones B and C (2 and 3) were accomplished by using the same protocol as that used for the syntheses of (+)-dysidavarones A and 'E' (1 and 5). As shown in Scheme 2, the one-pot intermolecular diastereoselective alkylation of Wieland-Miescher ketone derivative 8 with benzylic bromide 10 and subsequent t-BuOKpromoted arylation of the resulting alkylation product constructed the core bridged bicyclo[3.3.1]nonane structure, affording tetracyclic diketone 7 in 60% yield.…”

“…(+)-Dysidavarone B ( 2 ) was obtained in 92% yield by transformation of (+)-dysidavarone C ( 3 ) through double-bond migration under acidic conditions. 17…”

Enantioselektive Totalsynthese und Strukturrevision von Dysiherbol A

“…Zu guter Letzt mçchten wir noch erwähnen, dass, während wir dabei waren, dieses Manuskript fertigzustellen, eine Publikation von Lu und Mitarbeitern erschienen ist, in der eine Totalsynthese von (racemischem) (AE)-Dysiherbol A nach einer anderen Strategie beschrieben wird. [31] Danksagung Diese Arbeit wurde durch den Fonds der Chemischen Industrie (Doktorandenstipendium für J.B.), die Jürgen Manchot Stiftung (Doktorandenstipendium für I.G.) und die Universität zu Kçln unterstützt.…”