Roulland, ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200800585.
Yep, just one name. And an impressive synthesis for just one chap (and I don’t think he even had the backing of “Bioic Bros. GMBH” like La Clair). Even the target has more names – this one was independantly isolated three times, gaining haterumalide NA and FR177391as alternative monikers (albeit with different optical rotations…). No mention is made of its biological profile in this paper, but a synthesis of the methyl ester by Snider in 2003 states “Haterumalide NA is cytotoxic to P388 cells with an IC50 of 0.32 ug/mL [and] has MICs of approximately 0.03 ug/mL against phytopathogenic oomycetes”. That neatly explains the odd name, and shows a reasonable activity profile. Other syntheses of the target include one of the actual acid by Hoye and Wang, but for some reason they didn’t quote the optical rotation… Anyway – retro:
I always love a bit of sp2-sp3 Suzuki action, especially on a gem-dihalo-olefin! However, the synthetic action gets interesting with a paladium-catalysed THF formation. Starting with an easily accessible SM, derived from tartarte, he screened a range of palladium sources and ligands, finally optimising to an impressive yield and d.r.. The reaction, to me at least, is very much like a Tsuji-Trost, resulting in an easily diversified product.
Synthesis of the other main fragment was more routine, but I was interested to see how Roulland would install the dichloroolefin. Typically, he used a bit more French chemistry (it might not actually be French, but to me samarium diiodide = Henry Kagan), eliminating the acetoxy group to give the desired electrophilic partner for the Suzuki coupling.
The electropositive partner was produced by in-situ hydroboration of terminal-olefin bearing THF fragment, and then use of slightly exotic conditions resulting in an excellent yield of the desired product. (I’ve mentioned this in several other posts, but remember that the trans- halogen tends to perform oxidative addition faster than the cis-). Previous work on this modified Suzuki Miyaura reaction by Roulland can be read in this JOC.
Functional group transformation and some Yamaguchi action resulted in the macolactone, so soon he was able to do the NHK chemistry to complete the molecule. This went well, with one proviso: ‘…a special workup with sodium serinate to sequester the chromium cations was necessary to obtain [product] in acceptable yield.’. I’ve never done an NHK – anyone with experience like to comment? Also, why does Roulland speak in the plural?
Additional – I can hardly believe this – but this is blog-post number 200. That gives an approximate average of 100 per year… and I still feel entirely under-qualified for this! Thanks for reading folks – hears to the next 200!
Roulland, E. (2008). Total Synthesis of (+)-Oocydin A: Application of the SuzukiÃ¢â‚¬â€œMiyaura Cross-Coupling of 1,1-Dichloro-1-alkenes with 9-Alkyl 9-BBN. Angewandte Chemie International Edition DOI: 10.1002/anie.200800585
OAWOFENLLWPBEQ-VXLXENEIBB BXJWNHUXROCRCE-HMXCVIKNBS NFSYWHAEMPOEFR-RAXLEYEMBJ CUUUYLULMKBICZ-PMFPUCIMBR PJWDDPOFBZDVFJ-MULDZMIYBB NLTMGJFECAQKCM-BPLDGKMQBD UCOBGBWAOODAMK-RAXLEYEMBW