Concise Total Synthesis of the Cage-Like Sesquiterpenoid (+)-Daphnepapytone A

We report a non-biomimetic total synthesis of (+)-daphnepapytone A, an unprecedented member of the guaiane-derived sesquiterpenoids that displays moderate inhibitory activity against -glycosidase (IC50 = 159 ± 2.1 M) and possesses a highly strained bridging cyclobutane motif. Our de novo approach provided expedient access to the tetracyclic core of (+)-daphnepapytone A through an intramolecular allenyl thermal [2+2] cycloaddition and a Pauson–Khand reaction with a labile cyclobutane. Finally, a late-stage oxidation/reduction sequence delivered (+)-daphnepapytone A with striking chemoselectivity and excellent diastereoselectivity.