The natural product thapsigargin, a plant extract from Thapsia garnica L., was shown to have an important
biological profile, namely its ability to induce cell death of prostate cancer cell lines at nanomolecular
concentrations. This activity and the challenge of creating its highly functionalised structure (tricyclic backbone
with 8 stereogenic centres, 4 different and densely packed ester groups, 2 tertiary alkohols and a gamma-lactone)
make this molecule an interesting target for total synthesis. The proposed route to the first total synthesis of
thapsigargin is highly flexible and should furthermore allow the synthesis of labelled derivatives and analogues for
metabolic studies and biological testing. The C1-C5 cyclopentane is planned to be derived from enantiomerically
pure carvone, featuring a stereoselective Favorskii rearrangement as a key step. Addition of a second fragment by
cuprate addition and some functional group manipulation should reveal the precursor for the second key feature, a
Prins cyclisation, to furnish the [3.5.0] ring system. A directed dihydroxylation is expected to introduce the
remaining alkohol functionalities and enolate manipulation of the ketone at C3 should establish the desired
structural pattern. Applying this strategy, analogues of the natural product would be accessible, allowing further
investigations of structure activity relationships and metabolical studies.