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Polygalolide A   

11 September 2006 6,149 views 10 Comments

polygalolide_a.jpg
Hashimoto, Nakamura, Sugano and Kikuchi. ACIEE, 2006, Early View. DOI: 10.1002/anie.2006020307.

Some very smart cyclisation action in this paper by Hashimoto; the target is a component of a traditional Chinese herbal medicine, and their retrosynthesis hangs upon a powerful 1,3-dipolarcyclisation. The synthesis of the cyclisation precursor, whilst not trivial, was completed in a rather laborious fifteen steps. With this in hand, the cyclisation may commence!

polygalolide_a_2.jpg

Treatment of the diazo-compound with catalytic rhodium complex, and heating to 100 °C for five minutes allowed carbonyl-ylide formation, promptly follwed by 1,3-dipolar cyclisation. This tandem reaction sequence generated the complex tricyclic core of the target, which, using relatively well-known chemistry, was elaborated in twelve steps to the target (including the aldol condensation and lactonisation mentioned in the title diagram). Interestingly, the step after cyclisation was the removal of the PMP group, for which they employed (NH4)2Ce(NO3)6, introduced by Fukuyama. This was complete in 91% after 2 hours at RT, which is quite impressive for such a (potentially) sensative compound.

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10 Comments

  • HOMO-LUMO says:

    interesting paper,

    There is one part of their synthesis with similarities to my current project. And I am really dinnae ken how they just got a 20% for the aldol sequence 20 to 1 (3 steps 18% in overall). LDA( 1.5 equiv), aldehyde -78 to RT and goes as a whistle in just one step (PG technology)
    Their
    trouble was the spirolactone moiety which even with that steric hinderance may not tolerate
    LDA conditions. LHMDS/HMPA is an alternative
    but I would just do the lactonization once the aromatic thing is installed via aldol chemistry. However is easy to critisize from outside when their system looks quite complex.

    After been struggling a lot, and having to admire japanese chemist for make working stuff in many occasions that I just couldnt, for once is the opposite. :).

    The cycloaddition as far as I remember is similar to Wender chemistry (Classic in total synthesis II)

  • HOMO-LUMO says:

    Actually 19 to 1 LDA (1.5 equiv), excess aldehyde -78 to RT, and then lactonization as they reported. I would put my hand on fire that it would work with really high yield saving three steps and increasing their poor yield.

    PS: For once I know well what Im speaking about. :)

    PS: For all of you who need to employ enolate chemistry in total synthesis.

    A. PG (Prostaglandin synthesis) has been a field during many years in which some advances where done in that chemistry.

    B. In S.Danishefsky small sesquiterpenes total synthesis in the last 5 years, there is comprised a little compedium of lithium enolate chemistry. (Very reliable).

  • HOMO-LUMO says:

    To finish my post,

    The cycloaddition hightlighted by Tot.Synth. is just a masterpiece. But I am quite curious to know how big is possible to scale it up.

  • Peter says:

    The tandem carbonyl-ylide formation / dipolar cycloaddition is actually a pretty well-known trick these days it seems. Padwa had a review of it a few years ago, in Helv Chim I think. Actually I think it was used in a Zaragozic Acid synthesis, but not the one featured a few days ago. Plus Boger’s Vindoline synthesis uses it (also featured not long ago), but it wasn’t via a diazo decomposition. The hard part, as Tot Syn noted, is actually getting to the precursor; it tends to make these syntheses fairly linear.

  • Peter says:

    Oops actually Boger’s synthesis was via a diazo, but it was a thermal decomposition, not with Rhodium.

  • Tot. Syn. says:

    There’s some very interesting material in the recent literature regarding this type of transformation, as mentioned by the previous commentators.

    A JOC by Suga, on the use of Lewis Acid promotion. This also points to zaragozic acid as a target:
    http://dx.doi.org/10.1021/jo051743b

    Padwa’s synthesis of Ribasine, using similar chemistry (but way back in 1999):
    http://dx.doi.org/10.1021/jo990136j

    Earlier work on the cyclisation byt Hashimoto:
    http://dx.doi.org/10.1021/ja983748e

    And a particularly nice review of the area by Nakamura:
    http://dx.doi.org/10.1248/cpb.53.1

  • ddd says:

    damn…how come there were no words spilled on this website about Dali/Sezen JACS paper retractions??? lol I just learned this story which aparently happened half a year ago:)

  • Tot. Syn. says:

    ddd: Mainly because it all kicked-off just while I was starting the site – but also because it’s pretty far off-topic. Their case was really nasty – and far outstrips La Clair in terms of damage done, but at least Sames gave up under pressure in the end. Apparently, Sezen in working at a University in Germany now…

  • ddd says:

    so…we have to expect some “exciting discoveries” from cell biology soon

  • HOMO-LUMO says:

    Addendum.

    Domino Oxidopyrilium/1,3-Dipolar cycloaddition.

    Total synthesis of Resiniferatoxin. Wender, P.; et.Al., Reviewed in Classics in Total Synthesis II. 1st Ed.,2003, P.144.

    What changes in both cases is the precursor for the 1,3-dipolar cycloaddition.