A Unified Strategy for the Synthesis of 7‑Membered-Ring-Containing <i>Lycopodium</i> Alkaloids

A unique subset of the <i>Lyco­podium</i> alkaloid natural products share a 7-membered-ring substructure and may potentially arise from a common biosynthetic precursor. To both explore and exploit these structural relationships, we sought to develop a unified biosynthetically inspired strategy to efficiently access these complex polycyclic alkaloids through the use of a cascade sequence. In pursuit of these goals, the first total synthesis of (+)-fastigiatine (<b>2</b>) was accomplished via a series of cascade reactions; we describe herein a full account of our efforts. Insight from these endeavors led to critical modifications of our synthetic strategy, which enabled the first total syntheses of (−)-himeradine A (<b>1</b>), (−)-lyco­pecurine (<b>3</b>), and (−)-dehydro­lyco­pecurine (<b>4</b>), as well as the syntheses of (+)-lyco­nadin A (<b>5</b>) and (−)-lyco­nadin B (<b>6</b>). Our approach features a diastereo­selective one-pot sequence for constructing the common 7-membered-ring core system, followed by either a biomimetic transannular Mannich reaction to access himeradine A (<b>1</b>), lyco­pecurine (<b>3</b>), and dehydro­lyco­pecurine (<b>4</b>) or an imine reduction for lyco­nadins A (<b>5</b>) and B (<b>6</b>). This strategy may potentially enable access to all 7-membered-ring-containing <i>Lyco­podium</i> alkaloids and provides additional insight into their biosynthetic origin