A new approach towards the synthesis of Transtaganolides/Basiliolides: C-19 Terpenolides from Thapsia with SERCA-inhibiting Activity

Abstract The Transtaganolides/Basiliolides (T/B) are C-19 terpenolides found in the plants Thapsia Garganica L., Thapsia Transtagana Brot and Thapsia Villosa var. Villosa L. from the Umbelliferae family. Reports suggest that these compounds have reversible SERCA-inhibiting properties and therefore are of great interest for the treatment of neurodegenerative disorders, such as Alzheimer’s or Parkinson’s disease. The ground structure of the T/B is tetracyclic and has 6 contiguous stereocenters, suggesting a difficult and very challenging synthesis. This of course attracted synthetic chemists who saw a great challenge in finding a synthetic path for the total synthesis of these C-19 terpenolides. Several groups from around the world have been working towards the total synthesis, and most of them used an Ireland-Claisen rearrangement/intramolecular Diels-Alder reaction sequence as a key step. An intermediate with all carbon-carbon bonds from the T/B carbon skeleton has been obtained so far, however the total synthesis is yet to be completed as the introduction of a methyl ester needed for the last step proved very hard.28 A new approach for synthesizing a key intermediate for the total synthesis of Transtaganolides/Basiliolides has been attempted in order to reduce the amount of steps. This reaction path includes an alkynylation (addition of a terminal alkyne to an aldehyde), followed by a Tandem reaction (Stille like coupling followed by a cyclization reaction to get the important 2-pyranone derivative). The starting material for the alkynylation reaction was made by TBDMS protection of 3-butyn-1-ol and the addition to the ethyl glyoxalate was catalyzed by the use of a rhodium-phosphine complex. This alkynylation returned a secondary alcohol which was activated by mesylation. The last step (the Tandem reaction) is yet to be performed as time was insufficient