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Totally Synthetic by Paul H. Docherty, 14 May 2007

Total Synthesis of Thapsigargin


S. P. Andrews, M. Ball, F. Wierschem, E. Cleator, S. Oliver, K. Högenauer, O. Simic, A. Antonello, U. Hünger, M. D. Smith, S. V. Ley, Chem. Eur. J. 2007, 13, 5688-5712.

DOI: 10.1002/chem.200700302

S. V. Ley, A. Antonello, E. P. Balskus, D. T. Booth, S. B. Christensen, E. Cleator, H. Gold, K. Högenauer, U. Hünger, R. M. Myers, S. F. Oliver, O. Simic, M. D. Smith, H. Sohoel, A. J. A. Woolford, Proc. Natl. Acad. Sci. 2004, 101, 12073-12078.

DOI: 10.1073/pnas.0403300101

Many of you will have seen this PNAS article from back in 2004; however, this is the real deal - a full paper on the total synthesis of five Thapsigargins. The biological activity is discussed in detail, explaining that the first use of this family in medical preparations was noted by Hippocrates; back in 400 BC! Its activity arises from sub-nanomolar inhibiton of molecular Ca2+ pumps, and has been used in conjunction with a His-Ser-Ser-Lys-Leu-Gln peptide, resulting in specific cytotoxicity to prostate tumours. More information can be found in the paper…

So, to the retrosynthesis; disconnecting the acyl groups is a fairly trivial move, but the practical aspects of acylating selectively might be a little daunting. From thence we get the 5,7,5 core of the compound, and extensive manipulations of the hydroxyl groups on the carbocyclic skeleton. The seven membered ring was built from an RCM step, providing an olefinic handle for dihydroxylation. Lastly, and quite neatly, they built the cyclopentane from a ring-contraction, starting with an elaborate cyclohexanone.

And thus we start with some old-school rearrangement chemistry, doing a rather tasty Favorskii rearrrangement on the cyclohexanone (built itself from an epoxidation on carvone, and then opening with chloride). This also generated a fourth stereocenter, creating a rather complex cyclopentane very quickly.

They then did an Upjohn oxidation on the olefin and cleavage with periodate to provide a ketone, alkylated with Felkin-Ahn control to give the corresponding alcohol, using titanium(IV) isopropoxide and then addition of allylmagnesium bromide. Elaboration of the lower sidechain gave them an enolether, which was reacted with Grubbs II catalyst to give the seven member ring, with that enol ether still intact. Dihydroxylation conditions then oxidised this to the α-hydroxy ketone; not a method I’d seen before, but quite logical.

Skipping some work, they used a HWE reaction to bolt on the α,β-unsaturated lactone unit, which was opened and dihydroxylated. This, in fairly quick succession, lead to a tetraol moiety, which was selectively oxidised using Ley’s own methodology, resulting in relactonisation. Top stuff!

To introduce another hydroxyl centre stereoselectively, they took a derivative of the latter lactone in which the cyclopentane has been oxidised to a cyclopentanone, and form the TMS enol ether. Substrate controled epoxidation then released the TMS group and left the desired α-hydroxy cyclopentane.

Lastly, reduction of that cyclopentane with sodium borohydride gave attack from the wrong face with respect to the target. However, simply moving to the zinc analogue happily gave the desired stereochemistry in a pretty decent selectivity. They were then able to selectively deprotect in order to acylate the compound to the natural product, taking advantage of orthogonal protection and some hindered hydroxyls. Particularly impressive was the final esterification, which provided Thapsigargin A via preferential esterification of one secondary hydroxyl over another in 92% yield.

An impressive example of a complex polyoxgenated natural product, and a fine read (they also note that the average yield in the synthesis was 88.6% per step!).