Total Syntheses of Diepoxy-<i>ent-</i>Kaurane Diterpenoids Enabled by a Bridgehead-Enone-Initiated Intramolecular Cycloaddition

Here, we report the enantioselective total syntheses of four diepoxy-<i>ent</i>-kaurane diterpenoids including (-)-Macrocalin B, (-)-Acetyl-macrocalin B, and (-)-Isoadenolin A and the revised structure of (-)-Phyllostacin I, which hinges on the strategic design of a regioselective and stereospecific trapping of a highly reactive [3.2.1]-bridgehead enone intermediate via a tethered intramolecular Diels-Alder reaction. Combined experimental and computational studies demonstrated that the novel bridgehead-enone-initiated intramolecular cycloaddition could proceed in a stepwise diradical mechanism. Although the key step partially led to unexpected [2 + 2]-cycloaddition outcomes, we ultimately implemented an unprecedented Ti^III-catalyzed cyclobutane ring-opening-annulation radical cascade to reassemble a keystone pentacyclic core. Coupled with a sequence of organized oxidation-state manipulations and an efficient late-stage assembly of the C-7,20 hemiketal bridge, our strategy would streamline the synthetic design of diepoxy-<i>ent</i>-kaurane diterpenoids and pave the way for their modular syntheses as well as highlight the powerful utility of [3.2.1]-bridgehead enone intermediates in the construction of structural complexity.