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Totally Synthetic by Paul H. Docherty, 13 March 2008

Total Synthesis of Spirastrellolide A


I. Paterson, E. A. Anderson, S. M. Dalby, J. H. Lim, J. Genovino, P. Maltas, C. Moessner, Angew. Chem. Int. Ed. 2008, 47, 3016-3020.

DOI: 10.1002/anie.200705565

I. Paterson, E. A. Anderson, S. M. Dalby, J. H. Lim, J. Genovino, P. Maltas, C. Moessner, Angew. Chem. Int. Ed. 2008, 47, 3021-3025

DOI: 10.1002/anie.200705566

Spirastrellolide A is certainly an ambitious target - with 21 stereocenters - and when Paterson started the work, the absolute stereochemistry was yet to be assigned! Plenty of other groups are working on a total synthesis of this structure, including Phillips and Fürstner, but this is the first - so let’s get on with the retroanalysis.

The big fragment couplings are outlined below, with an interesting π-allyl Stille coupling to append the short sidechain and a macrolactonisation to close the ring. The seco-acid could then be split into three large fragments, with an alkyne addition allowing construction of the smaller spiroketal moiety, and a Julia olefination or Suzuki coupling to unite the remaining fragment.

The Julia route started with construction of the C-17 to C-25 fragment, for which I’ve shown a retrosynthesis, as most of the chemistry is reasonably well known. I did like the Seebach chemistry to methylate malic acid methyl ester, though.

Next was the C-40 to C-26 fragment to which the sulfone would be coupled. This began with an “Oehlschlager-Brown chloroallylation”, which I certainly hadn’t come across before. The paper referenced is a 1996 JOC article by Oehlschlager, which creates a structural motif that might be time consuming to provide otherwise.

The ketone produced in this reaction was used to couple the other half of this fragment in a conventional boron aldol reaction to give epimeric products; these were then eliminated to give the corresponding unsaturated ketone product. They then reduced this with catalytic [{(Ph3P)CuH}6] and stoichiometric PhSiH3 using a method developed by Lipshutz.

After a few more functional group transformations, it was time for the difficult formation of the bis-spiroketal. This isn’t actually covered in any detail in this paper - for the specifics, we need to look at a paper in Chem. Commun., which was published two years ago. This paper describes the use of a double Sharpless asymmetric dihydroxylation sequence, in which the internal alkene reacts first, forming the tetrahydrofuran, and then the terminal alkene to form the larger ring. NMR analysis indicated a mixture of products, which performed further cyclisation in the presence of pyridinium p-toluenesulfonate (PPTS) followed by silylation to aid purification.

What I really loved was the fact that PPTS was now used for the removal of the TES protecting groups of the undesired isomers of the reaction and a subsequent in situ spiroacetal equilibration. After one additional run, they achieved a remarkable 65% yield, creating 5 stereocenters and three rings in the process. Incredible!

However, their success with this chemistry was limited as they could the Julia coupling afforded a yield of only 32%. Although they were able to continue with the product of this reaction, they decided to change strategy, and use an ambitious sp2-sp3 Suzuki coupling to join these fragments. This required some modifications of the functional groups to make them suitable for the coupling, but nothing too dramatic. The coupling itself, though, is sweet: in situ hydroboration of the terminal olefin gave the electropositive partner, and addition of the vinyl iodide led to product in a very satisfying yield of 83%.

Another retrosynthetic diagram now illustrates the construction of the C1-C-16 fragment, which is described in another paper in Chem. Comm. Most notable was the use of a Reetz titanium-mediated allylation with allyltrimethylsilane, and their own 1,4-syn boron mediated aldol reaction. Simple deprotonation of this alkyne and addition into an aldehyde analogue of the bis-spiroketal above gave them the propargyl alcohol in good yield, and allowed swift transformation into the cyclisation precursor for the next scheme.

Removal of the PMB groups caused cyclisation onto the ketone and delivery of the desired spiroketal product. It's not a surprising strategy. However, it’s just a very useful reaction, and nicely selective.

With that last ketal formation complete, they only needed to perform a selective oxidation of the C-1 hydroxyl group to finish the seco-acid, and complete the macrocycle. Their attention then turned to the sidechain, for which an interesting π-allyl Stille coupling should be used. For the synthesis of the vinyl stannane using a Corey-Fuchs product, the fact that trans- and cis-bromides react differently is important, causing selective reductive (E)-debromination, and (Z) bromine-tin exchange. A very smart synthetic step!

They optimized the π-allyl Stille coupling with a truncated fragment containing only the bis-spiroketal, unsure of how the allylic carbonate might react. Their model studies suggested that the hindered Z stannane and bulky allylic carbonate would favour terminal substitution and a trans-configured product, which worked beautifully in practice, resulting in an excellent 96% yield.

Removal of the acetonide protecting groups then left the methyl ester of the natural product, completing a tour-de-force of total synthesis. I’ve learnt an amazing amount of chemistry reading this, and take my hat off to Professor Paterson!