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Zaragozic Acid   

30 August 2006 9,209 views 19 Comments

zaragozic_acid.jpg

Rizzacasa, Bunte, Cuzzupe and Daly. ACIEE, 2006, Early View. DOI: 10.1002/anie.200602507.

A short formal synthesis of zaragozic acid C, this paper is a good reminder of the power of the Claisen rearrangement, this time in the Ireland modification. These targets were isolated in the last decade, and are inhibitors of squalene synthase, and thus have cholesterol-lowering properties. The SM shown below was made from a bit of sugar-bashing (L-arabinose), and coupling of the differentially protected unsaturated diol.

zaragozic_acid_2.jpg

Ireland-Claisen, followed by diazomethane methyl-esterification and deprotection returned the terminal olefin, which, upon hydrogenation, cyclised to give the crystalline spiro lactone. However, this reduced the compound excessively, as they require the terminal olefin to stay intact, so alternative conditions were used.

zaragozic_acid_3.jpg

With the desired compound in hand, functional group manipulations and the addition of the side chain left them ready to construct the polycyclic core. This required heating in acid for three days, though admittedly in a rather dilute solution. This created the core in one smooth transformation, allowing a formal synthesis in only a few more steps (an intermediate in Erick Carreira’s synthesis).

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19 Comments

  • Alica Daly says:

    Ooohhh, I feel like I’ve made it, my work has been featured on Totally Synthetic!!

  • Alica Daly says:

    and everyone else’s of course :)

  • Tot. Syn. says:

    It’s a really nice paper. Congratulations on the work!

  • ddd says:

    Congrats Aussie ! :))))

  • Renan_s2 says:

    As a computer/network guy which is interested in organic chemistry, I must say: congratulations! Great work!

  • secret milkshake says:

    Tot.Syn, Renan: Sorry for changing the subject, I am desperate – please, what is the right way of getting jpeg or gif files from ChemDraw ir Isis files? I do envy your beautiful graphics…

  • Chemist Down Under says:

    More fine work from the Rizzacasa group. By the way, chemistry blogs should be given impact factors.

  • Tot. Syn. says:

    Two methods. Either own ChemOffice 2005* or later (automatically antialiased structures) or do the following:

    1. Draw your sketch as a normal ACS settings scheme.
    2. Double the size to 200%, so everything is too large.
    3. Save this as a jpeg/bmp/gif or whatever, or do a screen grab (Print Scrn button on your keyboard)
    4. Take this ugly, oversized file into Photoshop (or whatever image editor you like).
    5. Do a resize down to 50%, which will bring back your scheme to a normal size. There should be an option to do a “smooth” (antialiased) resize, which will give you a nice, clean image.
    6. Bask in awe at your creation.

    *BTW, if you have an older version of ChemDraw, you *might* be able to use the free version of ChemDraw Net Plugin to render your previously created schemes in all-singing-all-dancing antialiased-o-vision.

  • Tot. Syn. says:

    I think this should do it:

    http://scistore.cambridgesoft.com/software/product.cfm?pid=4014

    But you can’t save, so you’ll need to do a screen-grab to get the image.

  • secret milkshake says:

    thanks a bunch, this is most helpful!

  • insider says:

    Actually, my spies tell me it was the German postdoc (Bunte) that really nailed the work…

    Go Deutsche Go!

  • Mark Rizzacasa says:

    Nice blog. Just a few points need clarification:
    1. The spirolactone shown was made for charactization purposes to hopefully secure a crystalline derivative. Fortunately, this worked well and we established the stereochemistry of the Claisen rearrangement by X-ray analysis of the derived spirolactone.
    2. Author contributions: The early Claisen work and synthesis of the spirolactone was done by Cuzzupe (PhD). Some anion addition studies were also conducted by the this student too.
    Daly (PhD) synthesized the sidechain and did early anion addition studies and the first successful cyclization to the core on a very small scale in low yield.
    Bunte (postdoc) optimized the anion additon/cyclization then completed the route to the final target but had to return to Germany soon afterwards.
    Daly then repeated these final steps and optimized them to obtain enough material for complete characterization.
    That’s the whole story!

  • HOMO-LUMO says:

    Hope, Im lucky enough to get answers,

    The 3,3 rearrangement from the silyl ketene acetal of the corresponding spirolactone is a really nice reaction. I would like to ask, how would be the rate of formation of a non-hindered silyl ketene acetal, in relation to a normal silyl enol ether.

    You have an acetal that you hydrolysed to a lactone by a three step sequence:acetolysis/methanolysis/PCC oxidation. What oxidative conditions were tried?

    Impressive paper.

  • HOMO-LUMO says:

    Sorry I had to try. :)

  • Tot. Syn. says:

    Professor Rizzacasa,
    Thanks for your comments – any clarification from the original authors is appreciated. I really liked the paper – and I’m sure that Andy Holmes appreciated the use of Claisen rearrangements!

  • Tot. Syn. says:

    Guys,

    After a few emails regarding the comments on this post, I’ve deleted a few of the most controversial. Interestingly, all came from exactly the same IP address at UniMelbourne. You guys should keep your slagging matches to your tea room!

    Paul.

  • [...] A second appearance for zaragozic acid on this blog (the first was by Rizzacasa), and a second synthesis by this group (the first). However, there’s been lots of work on this natural product family, most of which construct the ketal using the same approach (Heathcock’s route was an exception). In this synthesis, however, they’ve used a carbonyl ylide cyclisation, an exceptionally elegant route to that complex bridged system. [...]

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