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Neodysiherbaine A   

21 June 2006 5,620 views 8 Comments


Sasaki, Shoji, Akiyama, Tsubone, Lash, Sanders, Swanson, Sakai, Shimamoto and Oikawa. JOC, 2006, ASAP. DOI: 10.1021/jo0605593.

This target came up in our group problems a few weeks back (thanks Steve), and Sasaki et al. have provided a very neat solution to this small yet complex molecule. Isolated from the sponge Dysidea herbacea, it is a excitatory amino acid, containing a glutamic acid unit attached to a cis-fused 5,6-pyran ring system. I’m not going to discuss it here, but it shows an interesting and potent biological activity, worth noting in the paper.

Having completed a synthesis of 8,9-epi-Neodysiherbaine A (doi:10.1016/j.tetlet.2005.06.093), they were well prepared for this work, reconsidering their previous efforts to complete the natural product rather quickly. However, a late-stage epimerisation was required on the pyran unit, which was completed using two methods. One was relatively simple – Ley oxidation and treatment with NaBH4 to deliver hydride from the desired face. However, they also used a more interesting approach, inverting using neighbouring-group participation:

One can rationalise the attack of the acetate unit into the triflate, but, as they state in the paper, why does the acetyl remain on the same hydroxyl? The result, however, was more clear; inversion of stereochemistry in 71% yield. This step was required as part of a two-stage inverstion of both hydroxyls; SAD of the cis-alkene clearly not an option. The initial inversion was completed in another interesting manner, using a cyclic sulfate.


Formation was in two steps; sulfite initially, then catalytic oxidation (though presumably stoichiometric in periodate). Then regioselective delivery of acetate and treatment with acid delivered the first inversion. Although the yields for this process are individually respectable, the overall yield for the inversion of a pair of hydroxyls was 53%, or loss of half of their material over six steps (not including saponification).

However, this natural product is a tricky beast, and their synthesis has allowed much biological characterisation to be completed.

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  • ddd says:

    another synthesis is coming up soon :) I know it;)

  • Tot. Syn. says:

    I hope it doesn’t involve another bloody hydroxyl inversion… I like the idea of using an iodocyclisation to put in the 5-ring…

  • secret milkshake says:

    I happened to do a similar bloody inversion recently, on epoxide (only Jacobsen asym epoxidation worked well with my C=C). The whole routine was epoxide -> trans iodoacetoxy -> cis diol monoacetate. Stoechiometric Ag salt. I hated it.

  • ddd says:

    why bloody?

  • Tot. Syn. says:

    Nasty. People are always saying “yeah, but we could invert it with a Mitsunubo…”, but it never seems to work well in practice. I’ve got a lot of stereodefined hydroxyls in my natural product – we’ll see how I get on with them.

  • ddd says:

    Overall I think inversion is stupid :lol:, why wouldn’t you make them anti at at first place? If there is no way, then develop methodology to make it possible, and then apply to your case. It does not look elegant otherwise ;).

    But I understand that when 15 steps are behind you and you are desperate, you go for inversion…I would try to devise the synthetic route avoiding inversions… But this is just my humble opinion.

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