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Totally Synthetic by Paul H. Docherty, 13 April 2008

Total Synthesis of Oocydin A


E. Roulland, Angew. Chem. Int. Ed. 2008, 47, 3762-3765.

DOI: 10.1002/anie.200800585

An impressive total synthesis for just one researcher. Even the target has more names - Oocydin A was independently isolated three times, gaining haterumalide NA and FR177391as. In a synthesis of the methyl ester by Snider in 2003 a biological profile states “Haterumalide NA is cytotoxic to P388 cells with an IC50 of 0.32 ug/mL and has a MIC (Minimum inhibitory concentration) of approximately 0.03 ug/mL against phytopathogenic oomycetes”. This is a reasonable activity profile and explains the odd name. The acid was also synthesised by Hoye and Wang.

The retroanalysis:

The total synthesis includes a sp2-sp3 Suzuki reaction with a gem-dihalo-olefin and a very interesting palladium catalysed tetrahydrofuran (THF) formation. Using an easily accessible starting material derived from tartrate, he screened a range of palladium sources and ligands, finally optimising to an impressive yield and d.r. This Tsuji-Trost-type reaction resulted in an easily diversified product.

Then Roulland installed the dichloroolefin using samarium diiodide, eliminating the acetoxy group to give the desired electrophilic partner for the Suzuki coupling.

The electropositive partner was produced by in situ hydroboration of the terminal olefin bearing THF fragment, and then the use of slightly exotic conditions resulting in an excellent yield of the desired product. Previous work on this modified Suzuki Miyaura reaction by Roulland can be read in this paper in JOC.

Functional group transformation and a Yamaguchi esterification resulted in the macolactone. He then was able to perform a Nozaki-Hiyama-Kishi coupling to complete the molecule. However, a special workup with sodium serinate to sequester the chromium cations was necessary to obtain product in acceptable yield.

Selected Comments

18 April, 2008 at 16:52, WestCoast85 says:
I’ve got a question Mr Roulland !
What do you think about the Jamison’s methodology using Nickel as transition metal for the reductive coupling of an alkyne and an aldehyde?
Is it an interesting alternative method to the NHK coupling ?
18 April, 2008 at 17:04, ER says:
I thought about it. Nevertheless it is not certain you will obtain the right anti configuration for the alcohol function. But using the asymmetric version of this reaction (JACS 2003, 125, 3442) yes why not? but for this reaction a regioselectivity issue on the alcyne function would remain. The NHK is quite diastereoselective and gave the right stereochemistry moreover it is a straightforward manner to introduce the side chain. Even if NHK is a very capricious reaction and is not very "green".