An Unexpected Isomerization for the Total Synthesis of Daphnepapytone A

We report a high-yielding total synthesis of sesquiterpenoid daphnepapytone A from (<i>S</i>)-glycidol. The groundwork for the synthesis is laid via reductive cleavage of a bicyclic Pauson-Khand-derived cyclopentenone ether, giving efficient access to a trisubstituted chiral cyclopentenone which is difficult to obtain by other means. To introduce the cyclobutane motif, the enone was irradiated in the presence of allene gas, yielding the unwanted exo-cyclobutane at worst and 1:1 mixtures of the endo- and exo-product at best. A serendipitous epimerization of an aldehyde in the following steps converted the unwanted exo-epimer into the endoenantiomer, which significantly improved the final yield. The final cage was connected with a second Pauson-Khand reaction, requiring only one more step to yield the natural product.