Gold(I)-Mediated Cycloisomerization/Cycloaddition Enables Bioinspired Syntheses of Neonectrolides B-E and Analogues

Development of a synthetic route to the oxaphenalenone (OP) natural products neonectrolides B-E is described. The synthesis relies on gold-catalyzed 6-endo-dighydroarylation of an unusual enynol substrate as well as a one-pot Rieche formylation/cyclization/deprotection sequence to efficiently construct the tricyclic oxaphenalenone framework in the form of a masked ortho-quinone methide (o-QM). A tandem cycloisomerization/[4 + 2] cycloaddition strategy was employed to quickly construct molecules resembling the neonectrolides. The tricyclic OP natural product SF226 could be converted to corymbiferan lactone E and a related masked o-QM. Our study culminates with the application of the tandem reaction sequence to syntheses of neonectrolides B-E as well as previously unreported exo-diastereomers.