Totally Synthetic by Paul H. Docherty, 13 April 2008
Total Synthesis of Oocydin A
E. Roulland, Angew. Chem. Int. Ed. 2008, 47, 3762-3765.
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 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.