Steps To St. John's Wort Factor

Combining a Diels-Alder reaction with strategic rearrangements, chemists at the University of Tokyo have completed the first total synthesis of the nonnatural enantiomer of hyperforin, a complex plant natural product first reported nearly 40 years ago (Angew. Chem. Int. Ed., DOI: 10.1002/anie.200906678). Hyperforin is thought to be an active ingredient in St. John’s wort, a traditional but as-yet-unproven herbal remedy for depression that can dampen the effectiveness of several prescription drugs. Although related natural products have succumbed to total synthesis, hyperforin has remained a challenge. Now, Masakatsu Shibasaki and colleagues have worked out a route to ent-hyperforin centered on an iron-catalyzed asymmetric Diels-Alder reaction they previously developed (Org. Lett. 2004, 6, 4387). After using that reaction to set up two contiguous stereocenters, the team turned to a stereoselective Claisen rearrangement to fashion an adjacent quaternary center. An aldol reaction stitched the molecule’s bicyclic core together, and a vinylogous Pummerer rearrangement installed the last of the molecule’s oxygen-containing moieties. The team is working to make hyperforin via the enantiomer of their Diels-Alder catalyst, Shibasaki says.