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22 August 2006 7,129 views 12 Comments

Gin, Kim, Wang, Navarro-Villalobos, Rohde and Derryberry. JACS, 2006, ASAP. DOI: 10.1021/ja062364i.

Amazing beast, this, and I’m using an abbreviated form! David Gin and his group have used deft control of their sugar chemistry to build this huge immunoadjuvant, containing an astounding array of functionalities. The steroid-type core is taken completely from quillaic acid, which they use as the starting point for this work. Of couse, they had to complete many glycosidations in this paper, which can look a deceptively simple coupling, but as this table shows, it can be a tricky sort:

I’m not going throught the rest of the sugar chemistry, mostly because I’ve seen it before, but it’s really worth looking at. Particularly noteworthy was the use of Nishimura chemistry to build the glucuronic acid unit, and use of Schmidt’s trichloroacetimidate species to couple sugar units. Here’s a summary fo the disconnections:


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  • ddd says:

    I tell you what Tot Synth…KEEP THIS WEBSITE GOING !!! I come here more often than to “acs asap” section…

    Web design – 10/10
    Science – 10/10
    Blogs – 10/10

  • HOMO-LUMO says:

    I worked on sugars, the chemistry involved is not amazing but all my credit to people working on the field.
    That molecules are really tough to work with. I dont want to know how were the purifications (columns) involved in the last steps of the synthesis.

  • HOMO-LUMO says:

    Well about the purifications, at the end one column was done in benzene/hexane (9:1). And the last purification was done using HPLC (1 mg scale purification!!)

  • Canuck Chemist says:

    Unless I’m mistaken, I think you’re missing a hydroxyl group from one of the glycosides…

  • European Chemist says:

    I was going to say the same thing, Canuck Chemist! At first sight this coupling seemed quite… odd….. (8 a.m. and still trying to wake up)

  • Tot. Syn. says:

    Oh, probably… I don’t see which one (try and give me a hint), but if I’ve only made one mistake in that monster of a natural product, I’ll feel quite happy.
    Sugar chemistry is well known for bringing otherwise excellent synthetic chemists to their knees. The NMR alone is hardcore, and even “simple” glycosidations are next to impossible to predict. I know I haven’t gone into the details of the synthesis here, but that should hold back from the feeling of awe when I saw the paper.

  • Tot. Syn. says:

    Cheers, ddd… I’m glad this website makes some sort of impact! I nearly became a webdesigner… but doing toluene columns is too good!

  • European Chemist says:

    Sorry Tot. Syn… didn’t want to look like the guy who only looks for the faults, actually this site is simply GREAT. For details: the OH missing is at C2 of the PMB-protected glycoside.

    Please go on highlighting the most interesting total syntheses on the literature! It’s a pleasure to read….

  • JerseyPharmer says:

    I saw the communication on this monstrosity last year, very impressive work. I did not think much of it then, but the paper really shows all the effort that went into it. Still, I don’t think it demonstrates Gin’s synthetic mastery so much as his glycosylation method. I sort of scooted carbo chem under the rug in my head, but I never realized every facet of synthesis is more challenging. The purification (thank the lord for uv activity), spectral identification (a complete lack of reliable splitting) and the chemistry itself (apparently most epimers have completely different reactivity).

  • Tot. Syn. says:

    The case of the missing hydroxyl has been solved, and I’ve shrunk the larger pictures, as they were giving IE a bit of trouble. Researchers like David Gin should really take that into account – working on such large targets is quite selfish, and they should consider the fact that it won’t fit on my blog without a whole 30 seconds of photoshop effort… ;)

  • insider says:

    …sorry tot.syn there seems to be another mistake. Without checking the right structure, if it is as you say, the fucose bit should have a methyl group off it.

  • […] This is an occasional series indebted to Hammer House of Horrors. You don’t need to be a chemist to understand the message. It’s sparked off by a comment from Totally Synthetic in this blog: A good deal of the reasoning behind transcription of spectral data in publication is to impart meaning to the spectra. The 1H NMR spectrum of rasfonin, for instance, would be indeciferable to me, but the data written in the publication, transribed by the author and annoted for every peak would make (more) sense. It’s great to get an idea what the spectra look like, but more often than not, the actual spectra can be found in the supplementory data as a scan of the original. The combination of these two data sources gives the synthetic chemist everything they need. […]