Bioinspired Total Syntheses of Skeletally Diverse <i>Lycopodium</i> Alkaloids

The phlegmarine skeleton is widely recognized as a key biogenetic intermediate in <i>Lycopodium</i> alkaloids. On this basis, we designed a phlegmarine-derived common intermediate that enables the collective, asymmetric total syntheses of 12 <i>Lycopodium</i> alkaloids with five distinct carbon skeletons. This intermediate was prepared on a decagram scale using commercially available (<i>R</i>)-pulegone in an eight-step sequence, with a stereoselective Michael addition as a key transformation. Subsequent selective carbon-carbon bond formation of this pivotal intermediate─(C4-C10, C4-C12, C1-C14, and C4-C13)─along with a skeletal rearrangement, delivered five frameworks: the huperzimine, lycodine, lycopodine, and phlegmarine classes, which were represented by (-)-hupserrine A, (-)-β-obscurine, (-)-lycopodine, (-)-cermizine B, and the lyconadin C diastereomer, respectively. Furthermore, we developed the first asymmetric total synthesis of (-)-hupserrine A, which bears a complex [6/6/5/6/7] pentacyclic cage structure and inhibits the 5-HT3A receptor (IC₅₀ = 10.6 μM).