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Diazonamide A   

22 September 2007 25,284 views 15 Comments

Magnus, Cheung, Goldberg, Russell, Turnbull and Lynch. JACS, 2007, ASAP. DOI: 10.1021/ja0744448.

Another “big target”, another JACS… And this is another molecule that has been in the making for several years. Phil Magnus isn’t the first in this case – Nicolaou and Harran have both been there and done that. However, a worthy point made by Magnus is that both of the previous syntheses have involved rather inefficient H ring formation. That C-10 stereocenter is a pig! However, let’s look at a bit of a retro first:


I say a bit of a retro because this only takes us back to a key intermediate. But that’s enough for now. The fragments are made very quickly and with apparent ease… I particularly liked the alkyl-lithium alkylation – three deprotonations on the oxazoline! A peptide coupling put in the other fragment, leaving us set for more exciting transformations.

The macrocycle was first formed by simply deprotecting the aryl silylether, promoting displacement of the freshly installed chloride. (I’m actually interested in the stereochemistry of the chlorination, as thionyl chloride displacements of secondary alcohols are supposed to go SNi. However, this is apparently very substrate dependant. No way to tell in this case, however, as the both the product and SM are 1:1 mixtures of diastereoisomers…)

I must say that the aryl ether formation goes in particularly good yield. It might be intramolecular, but that bond formation looks fairly congested. I wonder if the adjacent carbonyl group assists…

Either way, the ether bond formation was great, and gave them an easier entry to the C-arylation. This rearrangement was performed both on the separated isomers of the aryl ether, and also on the 1:1 mixture, with the ratios above quoted for 100% conversion. The group performed these reactions with a broad range of solvents, varying the polarity to probe the reaction mechanism. They found from this that when using very polar solvents that stabilise separate ion formation, the product ratio is close to 1:1. However, using chloroform, a predominance of the desired product could be achieved. I’m not going into the full justification – this is a really nice piece of chemistry that is best explained in the paper. So read it.

The approach reminds me somewhat of Steve Ley’s chemistry; his synthese of both Rapamycin and Azadirachtin included formation of difficult bonds by “rearrangement of a tether”. Nice work!

InChiKey Data:

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  • Anonymous says:

    ‘Oxygen’ is missing in the H ring of the target structure!

  • Tot. Syn. says:

    Fixed. Dammit, there’s always something…

  • Paul, Glad to see that you’ve adopted the inChIKeys as I suggested. I could see the traffic hitting the ChemSpider server while working on the transactions analysis. Glad to see that what we put up last night for you worked as expected!

  • One more request re. the InChIKeys (or strings for that matter). On this page there are six of them…however, it’s not clear which key is associated with which structure. WOuld it be possible to maybe label the structures as 1 to 6 and then number the Keys or some other way of doing the association.

    You might have seen my previous posting regarding “will the real Taxol stand up? http://www.chemspider.com/blog/?p=64

    The same issue exists with the various sources of Diazonamide A sitting on the ChemSPider database (the data are all sourced from other depositors and we are doing the job of curating when possible.

    None of the 6 InChIKeys you have listed exist in the ChemSpider database but there ARE 6 structures labeled as Diazonamide A. http://www.chemspider.com/Search.aspx?q=Diazonamide+A

    2 of these are REALLY badly drawn! We will resolve this shortly with a new structure cleaning algorithm.

    Can you list the InChI Strings too? Those can be converted back to real structures easily, and submitted to the database. However, InChIKeys are for look up only.


  • TWYI says:

    Personally, I love the Harran synthesis (of the correct structure) and it is still my fav of all the syntheses so far.

    Anyway, a group in the UK are very close to finishing this beast, I expect to see it in the lit soon.

  • I checked the 6 structures in more detail…we have a dereplication issue it appears…this resolves a couple of the structures. The other issues are differences in stereochemistry. You might want to check the explicit stereochemistry…notice the ? in the InCHI for 39? below


  • […] Totally Synthetic, Chemspider and I have been discussing the value of InChIs in blogs. TS’s blog is, of course Openly available under CC licence, and he is widely revered in the community for the beauty and acuuracy of his structural diagrams. This post is a slightly light-hearted voyage through what can be discovered with Toll-Access barriers in place. I leave readers to judge whether TSand Pubmed are up to the ease and value of the information from commercial providers. I’m reading this from outside the University and I do not have a VPN. This is useful as it shows me what it’s like to be an information-impoverished reader. TS blogged today about Diazonamide A , a natural product which was billed as the next big breakthrough in cancer some years ago. (It has 4 reports in Pubmed about its biology, and 26 ones about the chemical synthesis. Taxol has 30,000). Anyway TS has taken the advice of the Blue Obelisk list and managed to put InChIs into his blog. […]

  • […] As discussed in an earlier blog I spent some time chatting with Paul Doherty and Peter Murray Rust this weekend…specifically around InChIs and InChIKeys. I’d originally suggested to Paul that he put InChIs on the site so that I could use them to check for presence of the structures he draws in the ChemSpider database. Well, now he’s started to include them on his postings I get to check them. […]

  • […] Following on from my posting last night about Diazonamide A I note that PMR has blogged about this. Peter’s conclusion was that “the blogosphere is starting to emerge as a serious place to look for chemistry.” I have to agree! Just Paul’s one posting on Diazonamide A has resulted in a lot of additional trackbacks! […]

  • Paul…I’ve spent some time tonight looking more deeply into the chemical structure details especially. I made a couple of posts about this this evening…one before seeing PMRs post above and one afterwards. Your readers especially should be interested in the ChemRefer service I talk about to search publications online.


    This has given me an interesting opportunity to validate structures across databases. Can you do me a favor and send me the chemical structure you drew in ChemDraw? Thanks.

  • diketene says:

    Totallysynthetic got a face lift. But it looks uglier…

  • milkshake says:

    SOCl2 gives products of SNi with secondary alcohols only in absence of base (like pyridine). The effect of base is that enough Cl(-) stays in the solution so that the substitution goes usually with inversion.

    Tertiary alcohols are supposed to go by SN1 except that in this particular case of alpha carbonyl and oxazol in alpha position the carbocation is destabilised so one should expect situation similar to the case of secondary alcohol.

  • BMChem says:

    I’m not sure I care for the title of this paper so much. A “powerful” stereoselective migration…

    What exactly is a powerful migration? How powerful is it? Can it lift a truck?


  • Mike says:

    You’ve got to love reference 16 in this paper:

    Bould, L. Studies on the synthesis of tetracycline. Ph.D. Thesis; Imperial
    College, London, 1968; pp 91 and 153 […] In 1968, Magnus was a
    Ph.D. student working next to Bould, and as a consequence knew about
    the transformation of 56 into 57. This information initiated the notion (36
    years later!) that this type of reaction could be used for the construction of
    the C-10 quaternary center in diazonamide A.

    So take note of what your co-workers are doing… you never know when it might come in useful!

  • todays says:

    Hey where did you find the information in your post?