Total Synthesis of Thapsigargin and Nortrilobolide

Key words

thapsigargin - nortrilobolide - pinacol coupling - sesquiterpene lactone

Significance

Thapsigargin has attracted great interest over the past 40 years due to its highly oxygenated, complex framework combined with high biological activity. Thapsigargin inhibits intracellular calcium transport at picomolar concentrations. A closely related analogue is currently in phase II clinical trials against liver, brain, prostate, and kidney cancer.

Comment

(R)-(–)-Carvone is transformed into D through allylic chlorination and substitution. An ozonolysis–aldol sequence followed by a pinacol coupling delivers the characteristic 5-7-5 framework in G. Further redox manipulation and side-chain introductions then concisely deliver synthetic thapsigargin. Nortrilobolide lacking the α-acyl­oxy side chain at the ketone was similarly synthesized.