Abstract

Thapsigargin, a sesquiterpene lactone isolated from the roots of Thapsia garganica, is a known histamine liberator and a ubiquitous inhibitor of SERCA, a Ca²⁺-dependent ATPase.  Its structure is very unique with a high degree of oxidation on the tricyclic ring system. Our research study presumes that the 7,10-endoperoxide Guaianolide 3 could be an important intermediate generated during the biosynthesis of Thapsigargin by a biomimetic ¹O₂-like [4+2] cycloaddition. The C-8 hydroxyl group may be then introduced by intramolecular oxymercuration-demercuration and the functional groups on the newly formed five membered ring may be achieved by a conventional functional group manipulations. The structure of 3 has already been confirmed by crystallographic analysis. The synthesis of 3, starting from S-(+)-carvone, contains two key steps: a ring-closing metathesis and a photochemical oxygenation. Details of the synthesis and further progress toward the target will be described.