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Totally Synthetic by Paul H. Docherty, 24 January 2010

Total Synthesis of Crambidine


N. R. Perl, N. D. Ide, S. Prajapati, H. H. Perfect, S. G. Durón, D. Y. Gin, J. Am. Chem. Soc. 2010, 132, 1802-1803.

DOI: 10.1021/ja910831k

When I see targets containing guanidine moieties these days, I immediately think of David Gin, which goes to show how much he owns that motif just now. An earlier post covered Gin’s synthesis of Batzelladine A, which contained guanidine-moieties too. Crambidine only has one, but offers "anticancer, anti-HIV, antifungal, and Ca2+ ion channel blocking [activity]", that grant-form presumably filled itself. A previous synthesiy by Overman features even a Biginelli condensation, so the question is, how this can be beaten?

Well, through a trio of beautiful cyclisations, as it happens. The first combines quite elaborated starting materials. The skipped ene-yne was produced via a Wittig and a primary-iodide displacement, reducing the compound to two small, asymmetric building-blocks and an acetylene. The other fragment, containing the precarious-looking carbodiimide, was produced in a second efficient route - three steps from literature material. One step I hadn’t seen before was the synthesis of the carbodiimide by condensation of a isocyanate onto an azide using triphenylphosphine to reduce it to an amine beforehand. Neat. Anyway, once these fragments were in hand, combination (using an excess of the carbodiimide) resulted in a pretty efficient cyclisation onto the thioimidate, producing the guanidine-containing aminopyrimidine.

This [4+2] approach has some history, but Gin’s implementation was particularly neat as it worked well on a heavily elaborated system. This allowed them to quickly remove the silyl protecting group on the imine (ammonium fluoride did that quite nicely without affecting the TBS groups). Treatment of the now-free imine with gold (III) chloride allowed a second cyclisation onto the nearby acetylene, neatly forming the second pyrimidine, and providing an exocyclic olefin with the correct geometry. This also stands as a somewhat rare example of metal-catalysed hydroamination of alkynes. But they were far from done here - that unsaturated system was perfectly set for an addition reaction, which is exactly what happened after treatment with tosylic acid. Gin doesn’t comment on the stereoselectivity here, so I guess we have to assume that the spirocyclisation was entirely selective for the desired tetrahydrooxepine

Attaching the fatty side-chain only took a couple more steps, rounding of a rather neat synthesis, building a complex ring-system with admirable ease.