Total synthesis of oxaphenalenone natural products
Embargo Date
2022-03-17
OA Version
Citation
Abstract
Oxaphenalenone (OP) natural products are a diverse class of biologically active and structurally interesting molecules most commonly isolated from fungi. Despite their important biological properties and fascinating structures, these molecules have eluded thorough synthetic studies for over fifty years. We report herein a general synthetic platform for construction of these compelling natural products. Specifically, our synthetic strategy harnessed the chemistry of two simple OP natural products possessing the characteristic benzo[de]isochromenone ring system, SF226 and corymbiferan lactone E.
Our initial efforts achieved the synthesis of corymbiferan lactone E through the use of crossed-Claisen condensation of an isochromanone substrate followed by an interesting Au(I)-mediated 6-endo-dig hydroarylation. Subsequent studies implemented closely-related synthetic operations to assemble a masked ortho-quinone methide (o-QM) bearing the OP framework via interrupted Rieche formylation. The masked o-QM intermediate was utilized in the syntheses of additional OP natural products such as SF226 and the para-quinone methide (p-QM) corymbiferone C, as well as towards a more efficient and scalable synthesis of corymbiferan lactone E. We then employed corymbiferan lactone E as a key synthetic intermediate towards the natural products neonectrolides A–E. Studies culminating in the syntheses of congeners B–E using a powerful cycloisomerization/cycloaddition strategy will be presented along with efforts to construct the spiroketal congener neonectrolide A.
We will also discuss our synthetic efforts towards dimeric members of this natural product family. Namely, Ag(I)-mediated oxidative dimerization of SF226 has allowed for the biomimetic synthesis of the homodimeric OP natural product bacillisporin C. Additional studies towards other dimeric metabolites of interest such as duclauxin, the flagship member of this natural product family, will also be presented.