Total synthesis of nine longiborneol sesquiterpenoids using a functionalized camphor strategy

Natural product total synthesis inspires the development of synthesis strategies to access important classes of molecules. 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. Subsequently, similar strategies have proved general for the syntheses of a wide variety of bridged, polycyclic molecules. Here, we demonstrate that an orthogonal strategy where topological complexity is introduced at the outset leads to the short synthesis of the longifolene-related terpenoid longiborneol. To implement this strategy, we access a bicyclo[2.2.1] starting material through scaffold remodelling of readily available (S)-carvone. We also employ a variety of late-stage C–H functionalization tactics in divergent syntheses of many longiborneol congeners. Our strategy may prove effective for the preparation of other topologically complex natural products that contain the bicyclo[2.2.1] framework. Generating strategies that use modern synthetic methods to access privileged chemical space is a central goal of total synthesis. Now, a strategy that is orthogonal to classic approaches, coupled with C–H functionalization methods, leads to the shortest synthesis of the sesquiterpenoid longiborneol and divergent syntheses of oxygenated longiborneol congeners.