Epimeric Face-Selective Oxidations and Diastereodivergent Transannular Oxonium Ion Formation Fragmentations: Computational Modeling and Total Syntheses of 12-Epoxyobtusallene IV, 12-Epoxyobtusallene II, Obtusallene X, Marilzabicycloallene C, and Marilzabicycloallene D

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.