Abstract
The total syntheses of 12-epoxyobtusallene IV, 12-epoxyobtusallene II, obtusallene X, marilzabicycloallene C, and marilzabicycloallene D as halogenated C15-acetogenin 12-membered bicyclic and tricyclic ether bromoallene-containing marine metabolites from Laurencia species are described. Two enantiomerically pure C4-epimeric dioxabicyclo[8.2.1]tridecenes were synthesized by E-selective ring-closing metathesis where their absolute stereochemistry was previously set via catalytic asymmetric homoallylic epoxidation and elaborated via regioselective epoxide-ring opening and diastereoselective bromoetherification. Epimeric face-selective oxidation of their Δ12,13 olefins followed by bromoallene installation allowed access to the oppositely configured 12,13-epoxides of 12-epoxyobtusallene II and 12-epoxyobtusallene IV. Subsequent exploration of their putative biomimetic oxonium ion formation-fragmentations reactions revealed diastereodivergent pathways giving marilzabicycloallene C and obtusallene X, respectively. The original configurations of the substrates evidently control oxonium ion formation and their subsequent preferred mode of fragmentation by nucleophilic attack at C9 or C12. Quantum modeling of this stereoselectivity at the ωB97X-D/Def2-TZVPPD/SCRF = methanol level revealed that in addition to direction resulting from hydrogen bonding, the dipole moment of the ion-pair transition state is an important factor. Marilzabicycloallene D as a pentahalogenated 12-membered bicyclic ether bromoallene was synthesized by a face-selective chloronium ion initiated oxonium ion formation-fragmentation process followed by subsequent bromoallene installation.
Highlights
Since the first report in the 1960s,1 red algae of the familyRhodomelaceae, in particular of the genus Laurencia, have been found to give rise to fascinating structurally diverse nonterpenoid C15-acetogenin (ACG) metabolites as halogenated monocyclic, bicyclic, and tricyclic ring ethers2,3 where these metabolites can be usefully classified on the basis of the largest ether ring size present.4 These complex structures have attracted much attention as synthetic target molecules,5,6 and recent further efforts have been directed at further elucidating7 and unifying8 their biosynthetic origins
On the basis of their absolute configurations at C12 and C13, we propose that obtusallene X [8] arises biogenetically from 12epoxyobtusallene IV [7] via diastereomeric 12S-oxonium ion B′ in a transannular oxonium ion formation−fragmentation with a diastereodivergent nucleophilic attack at C12
We demonstrate that the latter can serve as an advanced precursor for the synthesis of 12-epoxyobtusallene IV [7], thereby achieving the first total synthesis of a C15-ACG with a 12-membered ether ring from Laurencia species
Summary
Since the first report in the 1960s,1 red algae of the familyRhodomelaceae, in particular of the genus Laurencia, have been found to give rise to fascinating structurally diverse nonterpenoid C15-acetogenin (ACG) metabolites as halogenated monocyclic, bicyclic, and tricyclic ring ethers2,3 where these metabolites can be usefully classified on the basis of the largest ether ring size present.4 These complex structures have attracted much attention as synthetic target molecules,5,6 and recent further efforts have been directed at further elucidating7 and unifying8 their biosynthetic origins. After a further 30 min at 40 °C, water (5 mL) was added, the mixture was extracted with CH2Cl2 (3 × 5 mL), dried over Na2SO4, filtered, and the solvent was removed in vacuo to give a colorless oil (699 mg).
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