Revised structures proposed previously for obtusallenes V−VII (5–7) have been confirmed on the basis of computed GIAO-DFT 13C NMR chemical shifts.

The obtusallenes are a significant subset of C15-halogenated acetogenins that incorporate 12-membered cyclic ethers. We have recently reported the isolation from Laurencia marilzae of 12-epoxyobtusallene IV (1) and its related α,β-unsaturated carboxylate ester (2), both of special biogenetic relevance. Here we describe the final step of our study, the isolation of three new analogues (3–5), among these, the first bromopropargylic derivative (3) of this class of macrocyclic C15-acetogenins. The structures were elucidated by analysis of NMR and X-ray data. 12-Epoxyobtusallene IV (1), its new isomer 4, and known obtusallene IV (6) were evaluated for their apoptosis-inducing activities in a human hepatocarcinoma cell line.

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.