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Totally Synthetic by Paul H. Docherty, 15 September 2010

Total Synthesis of Caribenol A

Li, Yang

L.-Z. Liu, J.-C. Han, G.-Z. Yue, C.-C. Li, Z. Yang, J. Am. Chem. Soc. 2010, 132, 13608-13609.

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 nightmare 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: Caribenol A. This brings us (with validated interest) to Zhen Yang’s total synthesis of the target, the first so far - I’m sure other strategies will appear over the next few years.

Yang refers us to literature syntheses for two chiral building blocks - and handily point 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, an intramolecular Diels-Alder. By using an activated acetylene, coupling with a fairly unadorned diene, Yang hoped to build a highly decorated 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, AlCl3, MeAlCl2, and BF3·Et2O were tried), nothing happened. With continuous effort, Yang found that BHT, in catalytic quantities, did the job nicely. (BHT is 2,6-di-tert-butyl-4-methylphenol). So what’s going on? It’s a fairly heavily stabilised and acidic phenol, but I’m sure they must have tried other Bronsted acids… It also acts as a singlet oxygen scavenger, but I’m not sure why that would help.

Regardless, the result is impressive - one tricyclic ringsystem installed, and plenty of useful functionality. The next few steps reduced the least-substitited alkene and formed the γ-lactone, with only one more piece of carbon to install - the methyl group on the cyclopentene. Yang was slightly lucky 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.

Yang clearly likes 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 an attempt to achieve this goal…‘, but the one that worked is the Corey-Ensley oxidation. Simple treatment of the substrate and triethylphosphite with oxygen  deliver the target in an astonishing yield.

Nice work - setting the bar for this target rather high.