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

Here, we report the enantioselective total syntheses of four diepoxy- ent -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- ent -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.