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Hirsutellone B   

15 September 2009 15,391 views 23 Comments


Nicolaou, Sarlah, Wu, Zhan. ACIEE, 2009, ASAP. DOI: 10.1002/anie.200903382. Article PDF Supporting Information Group Website

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 a 70% 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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  • antiaromatic says:

    I think the Ramberg-Backlund reaction needs the CF2Br2 because it is more of a Myer’s modified procedure. It serves as the electrophilic source of halogen to form the alpha-bromo sulfone in-situ. I guess they needed a super electrophilic source of Br+…

    • Moody Blue says:

      I am not sure CF2Br2 is that super electrophilic source of Br+. May be on the contrary. Using more electrophilc Br+ reagents might mess with other sensitive functionalities – the alkenes (exocylic and internal) and somewhat electron-rich aromatic ring.

      • BK says:

        The use of CF2Br2 is a modified Meyer’s modification to reduce the propensity for dihalogenation before 1,3-elimination can occur; and to a lesser extent, utilize a halide source which forms carbenes less readily than say CCl4, which is used in the Meyer’s protocol.

  • milkshake says:

    I have no experience with bismuthanes – I bet that it is not the first reagent that they tried for the arylation. The nasty problem with the Hirsutellone core piece is that the alcohol is really hindered – its even less reactive than dicyclohexyl methanol. (I have it from a person who was just scooped by this KCN paper.) Lots of electrophiles that could be normally used to form the ether bond sooner crap up instead of reacting with this OH.

    There is a method for arylating alcohols where one uses boronic acids and stoechiometric copper(II) acetate, under air, it is quite mild and works generally with normal alcohol substrates under mild conditions, and supposedly goes through Cu(III) intermediate. I suppose it was the staring point before messing with the bismuth reagent.

  • The Next Phil Baran says:

    Well done Nicolaou, well done. Nice synthesis for sure. The cascade is great but it’s a bit slow on the cyclophane formation. Otherwise nice job.

  • UBChem says:

    Alright ‘Next Phil’, give me a faster way to make a 13-membered cyclophane.

  • dylan says:

    Copper(I) thiophenecarboxylate aka CuTC is the awesomest source of soluble Cu(I) ever. Why buy when you can make your own? It’s so easy! Many moons ago I followed this ref: JACS 1996(118) 2748 and got a few grams of tan-colored copper(I) goodness. It served me well for several years, sitting on the bench (parafilmed) the whole while. I highly recommend. -tenderbutton

  • TotalSyn says:

    The p-cyclophane looks highly strained. It could be extremely challenge to buid this 13-membered ring.

  • hanpisa says:

    I am not sure why everyone is so concerned about the price of CuTC.

    There are cheaper sources than I guess aldXXX, whose price is more expensive than alternative sources

    Such as MatrXXXX inc. (eg $83/25g)

    They also sell it in 100g.

    FrontXXX scientific? they also have similar price to MatrXXX.

    Just search SciXXXXer and you will get the information.

    Let me correct if I am wrong but I don’t think it is fair to say that CuTC is superexpensive.

    Yes we can make it but I am also providing information that we can easily buy decades of grams without spending crazy money.

  • nitrosonium says:

    is at least part of the other 50% in the LA-mediated cyclization the 7-membered ring rather than the 6-membered ring? looks like there would be a regiochemistry issue with the epoxide opening the other direction-it likely being a later transition state that would be somewhat stabilized allylically.

    just musing here before the first cup of coffee this morning.

  • nitrosonium says:

    never mind. had that cup of joe and if you follow the bouncing arrows of the cascade i don’t think you can make the 7-mem ring.

  • Ken Knott says:

    Buy a Pentax K7… much cheaper.. much easier to justify and a terrific camera.

    • Tot. Syn. says:

      Gotta whole load of Canon lenses, including some ‘L’ glass, so moving to another brand / mount isn’t happening. Plus, I’m used to Canon gear; this would be the fourth Canon body. But it’s an awful lotta money…

  • scepticus says:

    That cascade is amazing! They beat Sorensen (http://pubs.acs.org/doi/abs/10.1021/ol802768p) for almost 10 steps…
    I wonder if the cis-alkene geometry is necessary for this cyclization? Can it be stepwise?

  • TB says:

    Absolutely beautiful synthesis and I love that biological activity. I would like to get my hands on some of those compounds from Nicolaou.

  • Canuck Chemist says:

    A very nice synthesis indeed. I spent quite a bit of time writing up a more exotic but less elegant route to this molecule for a proposal, so kudos to these chemists from the Nicolaou group. It’s too bad that a more functionalized phenol couldn’t be used in the alcohol cross-coupling. That’s a very slick reaction which we thought would definitely be problematic.

  • Boron bodger (no badger) says:

    The phenol arylation with copper looks to be a modified Chan-Lam coupling (excellent review in here http://www3.interscience.wiley.com/cgi-bin/bookhome/112259144/) which are nominally catalytic in the presence of an oxidant such as air. Though 20 mol % isn’t very catalytic but they often aren’t.

    I guess the bismuthane must be more reactive than the corresponding boronic acid as it wouldn’t be the first thing I reached for from the cupboard.

  • Masa says:

    In this article, compound 16 to 17. Why did alcohol at only benzyl position deoxygenated? I think there is little difference of nucleophilicity between benzyl and aliphatic alcohol.

    • Martyn says:

      They’re both nucleophilic towards thiophosgene (everyone’s favourite compound), to give the thiocarbonate O-C(=S)-O. This can be decomposed by AIBN in two different directions to give a carbon-centred radical either way; the benzylic position gives a much more stable radical, so it goes that way preferentially.

  • Masa says:

    Why did not the olefine in tricyclic core be oxidized, but olefine at benzilic position be oxidized? I think, there are not steric hindrance.