Total Syntheses of\nDiepoxy-<i>ent-</i>Kaurane\nDiterpenoids Enabled by a Bridgehead-Enone-Initiated Intramolecular\nCycloaddition

Here, we report the enantioselective total syntheses\nof four diepoxy-<i>ent</i>-kaurane diterpenoids including\n(−)-Macrocalin\nB, (−)-Acetyl-macrocalin B, and (−)-Isoadenolin A and\nthe revised structure of (−)-Phyllostacin I, which hinges on\nthe strategic design of a regioselective and stereospecific trapping\nof a highly reactive [3.2.1]-bridgehead enone intermediate via a tethered\nintramolecular Diels–Alder reaction. Combined experimental\nand computational studies demonstrated that the novel bridgehead-enone-initiated\nintramolecular cycloaddition could proceed in a stepwise diradical\nmechanism. Although the key step partially led to unexpected [2 +\n2]-cycloaddition outcomes, we ultimately implemented an unprecedented\nTi<sup>III</sup>-catalyzed cyclobutane ring-opening-annulation radical\ncascade to reassemble a keystone pentacyclic core. Coupled with a\nsequence of organized oxidation-state manipulations and an efficient\nlate-stage assembly of the C-7,20 hemiketal bridge, our strategy would\nstreamline the synthetic design of diepoxy-<i>ent</i>-kaurane\nditerpenoids and pave the way for their modular syntheses as well\nas highlight the powerful utility of [3.2.1]-bridgehead enone intermediates\nin the construction of structural complexity.