Nicolaou, Sarlah, Wu, Zhan. ACIEE, 2009, ASAP. DOI: 10.1002/anie.200903382. 
Yep, I took my sweet time about blogging this. Hell, it’s been over a week since my last post… no excuses, I’ve been living on Spotify, and trying to justify buying a Canon 7D. So not reading much chemistry then, but I did see this (actually, it was my former labmate, Phil, who linked-me-up). A damn nice piece of work, with an interesting mix of old and new chemistry. The target was found in a fungus, but was found to have a particular disliking for tuberculosis pathogens, so the biological profile is looking nice. And the chemistry is too, with that tightly functionalised 6,5,6-system, with a stereo-septad (not sure if that’s English…). However, it’s the 13-membered p-cyclophane that looks most troubling – tight to say the least…
First up was the rather beautiful LA-activated cyclisation – Diels-Alder cascade, requiring a fairly sensative looking tetraene. This was built quickly from citronellal, where a pair of olefinations built up complexity, delivering an olefin for a Jørgensen asymmetric epoxidation of a unsaturated aldehyde. The triene moiety was installed using a Stille-type coupling, using copper thiophene carboxylate (CuTC) as the coupling agent. I’ve mentioned this stuff before, but for those still unenlightened, this stuff often pushes reluctant Stille couplings (vinyl stannanes with vinyl iodides are typical cases) to a higher yield. The catch is that it isn’t cheap, and one needs at least one equivalent (AFAIK). Hoever, if it gives product (and in this case, in a70% yield), it’s all good.
A bit of Lewis acid thrown into this very unsaturated pot was bound to do something (part of me would be expecting that oh-so-welcome black tar); in this case, a cracking yield of the desired product. Nicolaou suggests that the cascade course is first LA-assisted opening of the epoxide by the proximal alkene, prompted by a displacement of TMS by chloride. The intermediate formed is perfectly set-up for a bit of cycloaddition, resulting in formation of the 6,5,6-system in one tasty step, and as a single diastereoisomer. I have to wonder what the mass-balance was though…
With this done using one of the simplest Lewis-acids, it was definitely time to show-case that incredible Nicolaou-lab inventory – this time a Bismuth-based reagent for forming a phenolic ether. More specifically, they used pTol4BiF to introduce the ether, using a Mukaiyama protocol and achieving a cracking yield. Now, anyone want to tell me about this chemistry (I’m looking at you, Milkshake…)?
The next reaction looks fairly simple until one considers that it was all done in one pot. A bit of zinc iodide, a little ethanethioic S-acid (just gotta stink, right?), and we get a selective reaction in which the benzylic alcohol is displaced by thioacetate, and the aliphatic alcohol iodinated. I’m not drawing it all out, but the postulated mechanism is elimination of the benzylic alcohol to give a stabilised oxocarbenium cation, trapped with AcSH. The iodation 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, resulting in a sulfide bridge. Aftert oxidation, a bit of basic alumina, along withCF2Br2 (???), resulted in a Ramberg–Backlund reaction, depositing the required cis alkene in a refreshing change to the RCM norm. I then liked the carboxymethylation, which was entirely diastereoselective for the wrong diastereomer of product…
…but this wasn’t a problem, as a bit of ammonia passed though this late-stage intermediate resulted in a nice little cascade. Nicolaou suggest the order is amidation, epimerisation and finally cyclisation, generating the product with ease (50%). Awesome work – but it shows that my chemical knowledge is still severely lacking…
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