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Totally Synthetic by Paul H. Docherty, 15 September 2009

Total Synthesis of Hirsutellone B


K. C. Nicolaou, D. Sarlah, R. Wu, W. Zhang, Angew. Chem. Int. Ed. 2009, 48, 6870-6874.

DOI: 10.1002/anie.200903382

A very nice piece of work, with an interesting mix of old and new chemistry. The target was found in a fungus, but is particularly active against tuberculosis pathogens, so the biological profile is looking nice. And the chemistry is too, with a tightly functionalised 6,5,6-system, with 7 stereocenters. However, it’s the 13-membered p-cyclophane that looks most troubling…

First up was the rather beautiful Lewis acid activated cyclisation - Diels-Alder cascade, requiring a fairly sensitive looking tetraene. This was built quickly from citronellal, where a pair of olefinations added complexity, delivering an olefin for a assymetric Jørgensen epoxidation of an unsaturated aldehyde. The triene moiety was installed using a Stille-type coupling, using copper thiophene carboxylate (CuTC) as the coupling agent. This reagent often pushes reluctant Stille couplings (vinyl stannanes with vinyl iodides are typical cases) to a higher yield. However, it isn’t cheap, and one needs at least one equivalent.

Addition of Lewis acid (LA) led to very high yield of the desired product, altough I would have expected more side products. Nicolaou suggests that the cascade course starts with LA assisted opening of the epoxide by the proximal alkene, prompted by a nucleophilic attack of the chloride ion on the TMS group. The intermediate formed underwent a cycloaddition, resulting in formation of the 6,5,6-system in one step, and as a single diastereoisomer.

Right after the use of the simplest Lewis acids, it was definitely time to showcase more exotic reagents: a Bismuth based reagent for forming a phenolic ether. More specifically, they used a protocol developed by Mukaiyama with pTol4BiF to introduce the ether in a very high yield.

The next reaction looks fairly simple until one considers the amount of functional group transformations in one pot. Addition of zinc iodide, and ethanethioic S-acid (so the reaction stinks), and we get selective displacements of the benzylic alcohol by thioacetate and the aliphatic alcohol by iodine. The postulated mechanism contians an elimination of the benzylic alcohol to give a stabilised oxocarbenium cation, trapped with AcSH. The iodination works by zinc mediated formation of a furanium cation, which was then trapped by iodide. Amazingly selective!

In an interesting, and rather old-school route, they formally formed the macrocycle by using the pendant sulfur to bridge the two arms. Aftert oxidation and treatment with basic alumina along with CF2Br2, a Ramberg-Bäcklund reaction resulted in the required cis alkene - this time without using any RCM. I then liked the carboxymethylation, which was entirely diastereoselective for the wrong diastereomer…

…which wasn’t a problem, as addition of ammonia resulted in a nice little cascade reaction. Nicolaou suggest the order is amidation, epimerisation and finally cyclisation, generating the product with ease (50%).


An awesome total synthesis…