Development of a Unified Enantioselective, Convergent Synthetic Approach Toward the Furanobutenolide-Derived Polycyclic Norcembranoid Diterpenes: Asymmetric Formation of the Polycyclic Norditerpenoid Carbocyclic Core by Tandem Annulation Cascade

An
enantioselective and diastereoselective approach toward the
synthesis of the tetracyclic scaffold of the furanobutenolide-derived
polycyclic norditerpenoids is described. Focusing on synthetic efforts
toward ineleganolide, the synthetic approach utilizes a palladium-catalyzed
enantioselective allylic alkylation for the construction of the requisite
chiral tertiary ether. A diastereoselective cyclopropanation–Cope
rearrangement cascade enabled the convergent assembly of the ineleganolide
[6,7,5,5]-tetracyclic scaffold. Investigation of substrates for this
critical tandem annulation process is discussed along with synthetic
manipulations of the [6,7,5,5]-tetracyclic scaffold and the attempted
interconversion of the [6,7,5,5]-tetracyclic scaffold of ineleganolide
to the isomeric [7,6,5,5]-core of scabrolide A and its naturally occurring
isomers. Computational evaluation of ground-state energies of late-stage
synthetic intermediates was used to guide synthetic development and
aid in the investigation of the conformational rigidity of these highly
constrained and compact polycyclic structures.