Total Synthesis of Nine Longiborneol Sesquiterpenoids Using a Functionalized Camphor Strategy

<p>Natural product total synthesis inspires strategy development in chemical synthesis. In the 1960s, Corey and coworkers demonstrated a visionary preparation of the terpenoid longifolene, using “strategic bond analysis” to craft a synthesis route. This approach proposes that efficient synthesis routes to bridged, polycyclic, structures should be formulated to introduce the bulk of the target’s topological complexity at a late stage. In subsequent decades, similar strategies have proved general for the syntheses of a wide variety of bridged, polycyclic molecules. Here, we demonstrate that an orthogonal strategy, which utilizes a topologically complex bicyclo[2.2.1] starting material accessed through a scaffold rearrangement of (<i>S</i>)-carvone, leads to a remarkably short synthesis of the longifolene-related terpenoid longiborneol. We also employ a variety of late-stage C–H functionalization tactics in divergent syntheses of many longiborneol congeners. Our strategy should prove effective for the preparation of other topologically complex natural products that contain the bicyclo[2.2.1] framework.</p>