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Zaragozic Acid (Part II)   

16 November 2006 8,169 views 6 Comments

zaragozic_acid.jpg
Hashimoto, Hirata, Nakamura, Watanabe, Kataoka, Kurosaki, Anada, Kitagaki and Shiro. Chem. Eur. J., 2006, Early View. DOI: 10.1002/chem.200601212.

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.

To make the cyclisation substrate, they needed a diazo group adjacent to a carbonyl; I’m impressed with the way they did this, using a protocol developed by Wenkert.

zaragozic_acid_4.jpg

I’m just surprised that the diazo group stays intact! They initially did quite a bit of screening, and had to determine the levels of diastereomeric control. For this they cyclised the product, and the diazo group still stays on! I was quite taken with this transformation, but it obviously shows that I need to brush up on my diazo chemistry…
zaragozic_acid_5.jpg

They were then set for the cyclisation, which was rigorously screened to find the right dipolarophile, catalyst and solvent, and settled upon those shown, completing the transformation in a remarkably good yield. Left with the olefin and the methyl ester, a dihydoxylation and cleavage of the extraneous carbon unit left the complex bridged system complete.
zaragozic_acid_6.jpg

Appendage of the sidechains was initially commenced with a Kocienski–Julia olefination, but returned starting material! Thus, they then tried some metathesis, again screening conditions; Blechert’s catalyst was most successful (effectively a derivative of Hoveyda’s catalyst). This consituted a formal synthesis of the target, but they finished the job anyway, following Carreira and Du Bois’s route. Now that’s a load of screening!

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6 Comments

  • yepyep says:

    The DOI link doesn’t work. Can’t comment on the synthesis yet. Takes a while to read 29 pages. Or maybe I just go through it the reviewer-style, that shouldn’t take so long.

  • Tot. Syn. says:

    I don’t know what the problem is with the link; the DOI is valid! Anyway, here’s a HREF:

    http://www3.interscience.wiley.com/cgi-bin/abstract/113467477/ABSTRACT

  • Rof5 says:

    Nice work.

    Tot.Syn. Says: [To make the cyclisation substrate, they needed a diazo group adjacent to a carbonyl; I’m impressed with the way they did this, using a protocol developed by Wenkert]
    I just wonder why they come up with the idea of using DCM as the co-solvent to increase the selectivity(8:1) dramatically in this step?

    • ABD says:

      I see a lot of “teaching” and “learning” chemistry consist of textbook and chalk in regard to the transformations themselves, however there seems to be disturbingly little technology transfer to new students of chemistry about the brass tacks of the following grueling processes:

      “They initially did quite a bit of screening, and had to determine the levels of diastereomeric control. ”

      - and -

      “They were then set for the cyclisation, which was rigorously screened to find the right dipolarophile, catalyst and solvent….”

      It would be nice sometime to actually hear the gory details of the planning, reasoning, experimental design, scale, method of analysis, time and cost associated with all of the work that often never even makes it into the paper or the supporting information!

      Not everyone has a great advisor or post-doctoral student to guide them and learn how to be a GOOD chemist. Are there any good books or websites that address this critical but all-to-often overlooked skill?

      Thanks!

  • regularchem says:

    I was going through D.W.C. MacMillan’s group today and came across one of his former member’s website. She is a assistant prof. at Toronto. On her website, she claimed that she completed the total synthesis of erythronolide B, which was presented at Gordon Research conference(Total synthesis of erythronolide B,” Dong, V. M.; MacMillan, D. W. C., Gordon Research Conference on Organic Reactions and Process, Bryant University, Smithfield, RI, USA, July 2004. ). Why was this never published? Anyone knows the inside story?

  • Bill says:

    I saw this presented at ACS in DC, it was a very interesting presentation.