Total synthesis of nine longiborneol sesquiterpenoids using a functionalized camphor strategy

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. 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.

Automated summary

A strategy orthogonal to classic approaches and coupled with C-H functionalization methods has been used to achieve the shortest synthesis and divergent syntheses of a sesquiterpenoid longiborneol, providing inspiration for the synthesis of other topologically complex natural products.