Li, Yang, Liu,Han, Yue. JACS, 2010, AOP. DOI: 10.1021/ja106585n
It’s weird how diseases that seemed to belong to Charles Dickens can come back to haunt the modern world – except this time armed against our battery of treatments. One such beastie is TB, which is something that’s becoming increasingly prevalent in the UK, about 60 years after it had been banished to historical literature. Coupled with the fact that many other nations have just had to deal with it, and we’ve got a new grant-winning target – something Caribenol A has taken a fancy to. (BTW, I caught my own Victorian ailment when I was at Cambridge – I was hospitalised with pleuracy of all things. It hurt. A lot.). This brings us (with validated interest) to Zhen Yang’s synthesis of the target, the first so far – I’m sure other strategies will appear over the next few years.
Yang get’s into the nitty-gritty fast, referring us to literature syntheses for two chiral building blocks – and handily pointing-out that their syntheses are over 5 and 7 steps in the endnote. After a further eight steps, his group had completed a precursor to the key step in this synthesis, a rather neat intramolecular Diels-Alder. By using an activated acetylene, coupling with a fairly unadorned diene, Yang hoped to build a pretty busy cyclohexadiene in one step. However, with no additive, the reaction failed to progress. And even with a variety of Lewis acids (all the usual suspects – MgBr2, ZnCl2, TMSOTf, AlC3, MeAlCl2, and BF3·Et2O were tried), nothing was doing. Moving into the throwing-everything-we’ve-got-at-it phase (or to quote ‘With continuous effort, we subsequently found…‘), Yang found that BHT, in catalytic quantities, did the job nicely. (BHT is addressed as 2,6-di-tert-butyl-4-methylphenol if we’re still bring all formal about this…). So what’s going on? It’s a fairly heavily stabilised phenol, so I guess it’s fairly acidic, but I’m sure they must have tried other Bronsted acids… It also acts as a singlet oxygen scavenger, but I’m not sure I can see why that helps.
Regardless, the result is pretty neat – one tricyclic ringsystem installed, and plenty of useful functionality to play with. The next few steps reduced-down the least-substitited alkene and formed the gamma-lactone, with only one more piece of carbon to install – the methyl group on the cyclopentene. Yang was slightly luck here, in my opinion, as a simple triflation of a cyclopentanone gave him the correct enol isomer such that a Pd-catalysed coupling reaction with dimethyl zinc gave the group the desired methyl-cyclopentene. But then a lot of my chemical trimuphs came down to a healthy dose of luck!
Yang clearly like to take the odd chance, though, as he left one of the more challanging steps right to the end of the synthesis. As can be seen in the final intermediate, the group were missing a hydroxyl group (as part of a 5-hydroxyfuran-2(5H)-one), and left it’s installation to last. He admits that ‘various oxidative methods were screened in anattempt to achieve this goal…‘ (I wonder how many in reality), but the one that worked is one I’d forgotten – the Corey-Ensley oxidation. Simple treatment of the substrate and triethylphosphite with oxygen (presumably bubbling through the solution) did what some might call a C-H activation (it isn’t really, and Yang doen’t call that either) to deliver the target in cracking yield.
Nice work – setting the bar for this target rather high.