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Batzelladine A   

19 September 2006 11,117 views 15 Comments


Gin, Arnold, Day, and Durón. JACS, 2006, ASAP. DOI: 10.1021/ja063860+.

Yet another top synthesis by David Gin, who really must be one of the most prolific total synthesisers this year! I really appreciate the fact that each molecule completed this year is completely different to the others, and they often contain hugely varying functionality. This time he has turned his attention on the batzelladines, working on structures A & D using some top new methodology. Focusing on batzelladine A, he uses their new methodology quite early-on, setting up the stereochemistry about both of the guanidine centers using a new [4 + 2]-annulation approach, combining a carbodiimide (made via a with a Staudinger-aza-Wittig condensation) with a chiral imine to produce the product in good yield.


He gives a few examples of this cyclisation, one as a lone test case and another in the synthesis of the batzelladine core, and discusses the possible mechanism for the reaction (with four different proposals). My money’s on the inverse electron demand hetero-Diels-Alder, generally cause it’s got a better name :). Also, they completed the cyclisation with both geometries of olefin in the carbodiimide, to the same result.

For the left-handside, the five-member ring is opened to a terminal olefin, and the sidechain bolted-on with a bit of Grubbs II action, and transesterification attaches the guanidine sidechain. With this component prepared, they took the other side, a common feature in all batzelladines, and prepared the cesium carboxylate to O-alkylate with the alkyl methanesulfonate of the left-handside. Coupling gave the ester, in a fashion I hadn’t seen used much. Completion of the final ring, salt formation, and deprotection then gave the product, in a rather quick twenty steps!

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  • Ochemist says:

    Wow! That’s smth new.
    4 Tot.Syn. papers in few months from his lab and all are both beautiful and elegant…

  • Thio says:

    Nice synthesis in a typically Overman territory. Its surprizing to know that this guy is not listed among the faculty of UIUC ! Probably hasn’t moved in there yet.

  • Peter says:

    Gin moved -from- UIUC to Sloane-Kettering in New York.

  • Tot. Syn. says:

    Yep, but the UIUC page still has more info than the SK one so far… I really liked this synthesis – the dude puts in loads of effort to understand his chemistry, and applies it to tot syn with style. Exactly what I like about Overmann’s chemistry too.

  • JerseyPharmer says:

    I have done some work on some guanidine-like compounds and was never able to duplicate that annulation (at least with a yield that warranted the route). One problem in particular was the purification. Even with all of those boc protecting groups I am surprised they were able to purify such a polar beast late stage (typically just 10% MeOH in CH2Cl2). How many lives have been shattered by attempting purify late stage intermediates toward the synthesis of palau`amine (Or other natural products too polar for even the likes of Overman)?

  • On this kind of guanidines, people often do C-18 prep HPLC purification with perfluorobutyric acid in the mobile phase, to make the salts greasier (to get any retention on the reverse-phase)

  • Chemist of Sorts says:

    Hey totallysynthetic,
    How about doing a linked index of all the natural products covered on your blog? Also, I highly approve of the batzelladine paper. Well done, Michael!

  • Tot. Syn. says:

    I’ve thought about that… I might do it between columns tomorrow… two days left on my industrial placement – gotta make sure all my samples are clean whilst I’ve still got the power of Companion Chromatography! What do you think – just text links, or with images too?

  • Chemist of Sorts says:

    Images would be nice, but text links would be OK too if the images make the page too difficult to quickly navigate. Maybe reduced size images would work well?

  • (7) I think this is an excellent idea. It would be very good to include an InChI (http://en.wikipedia.org/wiki/Inchi) in each one so that the site would be chemically searchable. We have shown that Google indexes InChIs very accurately so that the blogs will light up in Google searches for the compounds. At the moment the search is exact (you cannot do substructures) but this will almost certainly come soon.

    We have a site (http://wwmm-svc.ch.cam.ac.uk/wwmm/html/inchiserver.html) where you can draw in structures using Marvin or drop in a Mol file so you don’t have to know how to creat an InChI.

    If all chemical blogs did this then the blogosphere will start to act as a highly valuable chemically oriented index.

  • Tot. Syn. says:

    I had a look at the Inchi format, and whilst it’s a good idea, it seems to trip-up in certain ways – for instance, it doesn’t seem to differentiate between atropisomers, such as Abyssomicin. I haven’t checked, but I feel it will probably trip up with other types of conformational isomerism too.

  • You are right, of course – there are many compounds that InChI can’t do. But (a) it’s a small propertion and (b) there are no other ways of doing them either. Examples in organic chemistry are helicenes, catenates and other beasts. In Abyssomicin you have depicted the isomerism with wedge bonds which give a perspective view – this is something a human can make a reasonable guess at but a machine can’t. (I must admit that if I came across the diagram at first hand I would think it was a typo). As soon as you get out of mainstream organics into coordination compounds, van der Waals complexes, etc. then there is no standard way in chemistry of representing them.

    InChI tracks the IUPAC representations and does its best.

    So you couldn’t use InChI or any other system that I know of to search for atropisomers. But if you searched for the connection table of Abyssomicin there wouldn’t be any noise.


  • TWYI says:

    Hasn’t Andrew Evenas just finished this beast….?

  • […]  Looking back into the murky past of Tot Syn, an earlier post covered Gin’s synthesis of Batzelladine A, which was fairly guanidine-tastic.  This bad-boy only has one, but with a bit of […]

  • aile chat says:

    Thanks admin. Have a nice page layout. Thank you for your interest