Evolution of a Strategy for the Total Synthesis of the <i>Ganoderma</i> Meroterpenoid Ganoapplanin

Herein, a detailed account of the efforts leading to the recently published synthesis of the <i>Ganoderma</i> meroterpenoid ganoapplanin, a natural product identified as an inhibitor of T-type voltage-gated calcium channels, is provided. Ganoapplanin, which was isolated as a racemate from the fungus <i>Ganoderma applanatum</i> in 2016, features a complex structure, including a characteristic spiro bisacetal structure, a highly functionalized tetra-<i>ortho</i>-substituted biaryl motif, and a propellane-like dioxatricyclo[4.3.3.0]dodecane scaffold. While the southern terpenoid fragment is available via a diastereoselective titanium-mediated iodolactonization, considerable efforts are required to fuse this fragment with various aromatic fragments. The breakthrough was achieved by a highly efficient two-component coupling strategy that simultaneously fuses the fragments and establishes the crucial biaryl bond. This transformation involves an intramolecular 6-<i>exo</i>-trig radical addition of a quinone monoacetal, followed by an intermolecular aldol addition. Finally, strategic late-stage oxidations enabled the formation of the characteristic spiro bisacetal motif and the completion of the synthesis of ganoapplanin.