A Unified Strategy for the Synthesis of 7‑Membered-Ring-Containing Lycopodium Alkaloids

A unique subset of the Lyco­podium 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 (2) 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 (1), (−)-lyco­pecurine (3), and (−)-dehydro­lyco­pecurine (4), as well as the syntheses of (+)-lyco­nadin A (5) and (−)-lyco­nadin B (6). 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 (1), lyco­pecurine (3), and dehydro­lyco­pecurine (4) or an imine reduction for lyco­nadins A (5) and B (6). This strategy may potentially enable access to all 7-membered-ring-containing Lyco­podium alkaloids and provides additional insight into their biosynthetic origin.