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Discodermolide / dictyostatin hybrid   

26 November 2006 4,828 views 8 Comments

hybrid.jpg

Paterson and Gardner. Chem. Comm., 2006, Advance Article. DOI: 10.1039/b615122a.

Not strictly a total synthesis, this paper discussed the synthesis of a hybrid of discodermolide and dictyostatin, both previous conquests of the Paterson group. Clearly, from the structures shown below, these molecules are intimately related in construction, and Curran has shown that a constrained macrocycle hybrid may be more potent. This led them to the structure above, containing elements of both molecules, that could be assembled in part from fragments from other work.

hybrid_1.jpg

I’m not going into a full discussion of the synthesis, because as impressive as it is, most of the work is in the previous articles. However, the retro below shows the synthesis from the most advanced fragment. The most ambitious step is definitely the aldol, utilising the groups experience with 1,6-induction in similar boron aldol reactions to gain an impressive 95:5 d.r.
hybrid_2.jpg

The hybrid, at the end of the day, showed impressive cancer cell growth inhibitory properties, proving it to be the most active discodermolide/dictyostatin hybrid so far.

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8 Comments

  • regular says:

    Nice example of a 100% unnatural product ;-)
    “What I cannot create, I do not understand.”
    Richard Feynman

  • ddd says:

    it is a product of natural origin it clearly says DISCODERMOLIDE/DICTYOSTATIN. So it is not a pure artificial product. You can also call any taxol analog as “pure unnatural product”

  • ddd says:

    OT: try to google “worst postdoc” or “worst about science”…you will find a lot

  • sborn says:

    Kinda reminds me of back when Djerassi was in Mexico and cookin up all sortsa steroids via those yam extracts. If you look in them JACS publications, you just might dig up the time when they combined the functional groups of testosterone and estrogen onto a single steroid backbone, and then fed it to mice to see what would happen.
    All they need to do now, is ligate Phorboxazole w/Spongistatin, & see what kind of a ruckus that might cause.

  • ddd says:

    yep, and then combain Taxole (it is already approved drug :)) with diazonamide :)) But..whatever works, life is on the stakes.

    OT:
    A blonde was asked “What are your chance to meet a real, live dinosaur at London’s downtown?”

    She goes “50% chance”
    How come????

    I either meet the dinosaur or I will not…

  • HOMO-LUMO says:

    Paterson doesnt do many different things but he has achieved a high level of perfection in his chemistry, the experimental support to his publications are granite solid, and there are many steps in his synthesis which are difficult to perceive but really valuable (at least to me).i.e:

    If I would have a diol (1 and secondary) and I’d want to oxidize only the primary without touching the secondary(in a molecule with several chiral centers, hence watch with the conditions) in the most efficient way and if possible catalytically, how? well he does that in a 99% of yield and catalitically. To me sometimes, is that sort of reliable chemitry shown, which gives credit to the synthesis, and not a funky step to create 4 stereocenters with 90%,90%ee which at the end is only reproducible in the hands of the person who made it.

  • European Chemist says:

    I don’t want to get too far away from the main point, but how sure can you be about the reproducibility of a yield? We’ve all been there, we all know about it; specially late in a synthesis, when you’re doing reactions on 10 mg or less, how accurate are your yield measurements? Even in the beginning, when you’ll get away with that extra solvent peaks and – surprise, surprise!- your yield goes up another 10%…
    I’m sorry to say so, but if I find a great method for some transformation to use in my synthesis, I’ll believe it 10 times more if the publication is from before 1990-1995 than nowadays… remember the “Sames-gate affair”…. :-S

  • European Chemist says:

    I suppose the synthesis of an Amphidinolide just out by Roush will be the next feature in this blog… not bad at all. ;-)

    http://dx.doi.org/10.1021/ja066663j