Gin, Perl, Ide, Prajapati, Perfect, Duron. JACS, 2010, ASAP. 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. Looking back into the murky past of Tot Syn, an earlier post covered Gin’s synthesis of Batzelladine A, which was fairly guanidine-tastic. This bad-boy only has one, but with a bit of “anticancer, anti-HIV, antifungal, and Ca2+ ion channel blocking [activity]“, that grant-form presumably filled itself, especially at MSKCC. However, this compound does have previous, and if you had to guess, you’d guess Overman, right? And you be correct. And his synthesis features a Biginelli condensation, so how ya gonna beat that, Gin?
Well, through a trio of beautiful cyclisations, as it happens. The first comes from combination of two quite elaborate starting materials, which were actually easier to come-by than one might imagine. 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 a bit of triphenylphosphine to reduce to an amine beforehand. Neat. Anyway, one these fragments were in-hand, combination (using a fair-old 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 interesting silyl-ish protecting group on the imine (ammonium fluoride did that quite nicely without molesting 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 tosic-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
Bolting-on the greasy side-chain only took a couple more steps, rounding of a rather neat synthesis, building a complex ring-system with admirable ease.