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Panacene   

26 October 2008 14,041 views 31 Comments

Canesi, Sabot and Berard. Org. Lett., 2008, 10(20), 4629-4632. DOI: 10.1021/ol801921d. Article PDF Supporting Information Group Website

I nearly missed this paper, published online at the beginning of last month, but it’s an incredibly neat solution for the synthesis of some funky little natural products.  The parent molecule, panacene, has some fairly unique biological properties, as it is a shark-antifeedant.  In otherwords, it puts sharks of their food, and makes the sea-hare in which it is produced that little bit less attractive to the peckish big-fish.  Okay, so it doesn’t cure cancer, but the next time you’re swimming in the Med…

I suspect (though I’ve no justification) that this paper was a get-the-methodology-then-find-the-target type of study, but it’s certainly methodology that seems to work rather well.  The key motif is a umpolung addition of furan to phenolic-type systems (or more largely electron-rich aromatics), using iodobenzene diacetate to generate a cationic intermediate that allows attack of furan.  Sort-of reminiscent of Friedel-Crafts chemistry.  The oxonium ion produced is then rearranged by attack of the ketone to provide a 6,5,5-fused system in a reasonable yield.  There is a selectivity issue as to which position ortho to the phenolic hydroxyl is fused, but this was overcome by using a TMS blocking group.

With the desired system in place, it was time to add the desired allenic sidechain.  Two different approaches were used to impart the different sidechains, with the unhalogenated desbromopanacene made most succinctly in only two steps from a common (desilylated) intermediate.  Firstly, the DHP DHF was oxidised hydrated to the hemiacetal using an oxo-mercuration (rather them than me…) / borohydride process.  Treatment of this with a propynylsilane under Lewis-acidic conditions allowed a Sakurai reaction, neatly completing the target in good yield.

For the parent molecule, panacene, the brominated allene moiety meant that a more complex route was required.  Using the same hemiacetal shown above, they did a Wittig olefination to give a enyne.  Again, a spot of mercuric acetate was used, but this time the product was a mercuric allene.  To give the target, they did an in-situ protiodemercuration using ethandithiol, which was impressively stereoselective.  Nice stuff!

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31 Comments

  • ..- says:

    “Firstly, the DHP was oxidised to the hemiacetal using an oxo-mercuration…”

    I don’t think there’s a dihydropyran here… Did you mean dihydrofuran?

  • Diyne says:

    Hydration, not oxidation.

  • Tot. Syn. says:

    It’s a sort-of oxidation (actually, it’s not), but point taken and corrected. However, DHP was just plain wrong…!

  • UBChem says:

    I really liked this synthesis. Interesting transformations and modest (most likely honest) yields. No messing about, just good chemistry. Well done.

  • Hendrick says:

    hey what’s the dot in the final product? have not seen that in my o-chem class before

  • antiaromatic says:

    It signifies an sp hybridized carbon, especially in allenated systems.

  • Sergey says:

    It is o.k., but not really interesting. very old chemistry.

  • mevans says:

    Can’t say why, but I really liked this synthesis. Perhaps because I actually understood it all? :-)

  • RBW says:

    Do the authors comment on the mechanism? I wondered if the dienone enolises to the electron-rich phenol first before it attacks the furanyl cation.

  • antiaromatic says:

    RBW:

    I think it would be very difficult to do any kind of mechanistic study of that kind as those steps are probably not rate limiting (intramolecular versus intermolecular).

  • omarion says:

    It’s always nice to see a good synthesis from a Quebec group. I also have a soft spot for this natural product. One of my PhD lab mate was working on the synthesis of panacene (see Org. Lett. 2006, 8, 3597 for a great total synthesis). It brings back lots of memories…

  • Truth Squad says:

    Panacene is indeed a fascinating molecule. Its correct relative and absolute stereostructure was only recently established by an asymmetric total synthesis of (-)-panacene (Boukouvalas et al, Org. Lett. 2006, 8, 3597). Ironically, the relative configuration of panacene was originally missasigned by total synthesis of the racemate (Feldman et al, J. Am. Chem. Soc. 1982, 104, 4011). This probably represents the first documented case where a natural product structure has been misassigned by total synthesis! Structure 6 in the Canesi paper (Org. Lett. 2008, 10, 4629) actually depicts the mirror image of natural panacene. As for desbromopanacene (compound 5), which is purportedly a plant metabolite, there is no natural product with this structure that can be found in the literature!

  • philip williams says:

    Truth Squad:

    “This probably represents the first documented case where a natural product structure has been misassigned by total synthesis!”

    It has happened before. For example, Danishefsky’s misassignment of the absolute stereochemistry of frondosin B, was later rather quietly corrected by his former post-doc Trauner (Tetrahedron, 2004, 9675).

    As for desbromopanacene, does anyone have access to the original 1915 paper in Yakugaku Zasshi to confirm?

  • GYA says:

    Correction Philip Williams: MacMillan actually corrected Trauner’s “correction” and agrees with Danishefsky’s assignment (Trauner was apparently wrong!). I believe this disclosure was originally made at a Gordon Conference.

  • TS says:

    From” Dembitsy, V. M.; Takashi, M. Progress in Lipid Research 2007, 46, 328.”

    The first allenic sesquiterpene named panacene was isolated from mixture of H2O–Et2O–MeOH extract of a
    perennial shrub Korean ginseng (also called Panax ginseng) in 1915 by Kondo and Tanaka [25]. In 1931, Min
    re-discovered the sesquiterpene previously named panacene from Panax ginseng and Panax quinquefolius [26]. In 1964, Lee and Lee confirmed the presence of sesquiterpene panacene in Panax ginseng [27]. More recently, brominated analog of panacene was isolated from the sea hare Aplysia brasiliana, and it acts as a fish antifeedent [28].”

  • TS says:

    From”Dembitsy, V. M.; Takashi, M. Progress in Lipid Research 2007, 46, 328.”

    “Although the debrominated sesquiterpene panacene was isolated from the plants Panax ginseng and P.
    quinquefolius [22–27], more recently, brominated analog of panacene (144) was isolated from the marine gastropod
    mollusc Aplysia brasiliana [28].”

  • Truth Squad says:

    The panacene from Panax ginseng has nothing to do with the “marine” panacene, isolated near Panacea (West coast of Florida). As far as I know, there is no original paper cited in the Dembitsy-Takashi review, or elsewhere, describing the isolation of “desbromopanacene” from a natural source.

  • Truth Squad says:

    Moreover, panacene and despromopanacene are clearly not sesquiterpenes. They both have an UNBRANCHED polyketide-derived C15-skeleton.

  • TS says:

    The constitution of ginseng-derived panacene can be found in US Patent 5589182 (http://144.202.252.20/5589182.html) where the empirical formula C15H24 is given. It is not even close to that of desbromopanacene (C15H16O2).

  • TS says:

    just a message to say TS of 05.11.08 it is not the same TS of 07.11.08.
    So i would appreciate that nobody will use my pseudonym .

  • Truth Squad says:

    To avoid any confusion, I suggest that nobody uses the initials of my pseudonym.

  • ZZZZZ says:

    zzzzz

    …the zzzzz who is posting this message is not the same as the zzzzz who posts other messages. Sometimes. At least I think…

    zzzzz

  • cheminlove says:

    This work is pretty nice. The authors described an imaginative and modern access to panacene. Only one or two groups reached this compound in the past (jacs 80`s). Complexity is not always link to the molecule size.

  • enzosyn says:

    The route to racemic panacene is short but the use of equimolar amounts of mercury acetate in two of the nine steps raises a couple of red flags. It is also hard to envision an enantioselective version…

  • Mike SN says:

    After a thorough literature search of structure 5 (desbromopanacene), I was stunned to find that 5 has not been reported anywhere before. It seems that it was picked as a convenient synthetic target and turned into a natural product. What a fiasco!

  • chinachem says:

    I have liked the assymetric synthesis by the group of Pr. Snieckus

  • Mike SN says:

    There has been only one asymmetric synthesis of panacene reported so far, by the Boukouvalas group from Quebec.

  • Totally Natural says:

    The synthesis of the invented structure of the so-called “terrestrial” panacene is hell of a hoax. LOL: “No synthesis of this substance has been reported as of this writing”

  • cheminlove says:

    I saw that Boukouvalas group reported an enantioselective synthesis of panacene in 17 steps. Good but rather long job as regard the target. However few steps are unelegant..(specially the stoechiometric amount of Pd at the very beginning of the synthesis).

    • EUChem says:

      The Boukouvalas route is 15 steps, not 17. It would be nice to have another enantioselective synthesis for comparison, but be that as it may, there has been none reported in the 30+ years passed since panacene was discovered by Meinwwald. Mr or Ms chemlove would be most welcome to rise to the task, now that the relative and absolute configuration of the natural product have been clarified by the Boukouvalas synthesis.

  • [...] This is the silliest biological activity I've seen reported for a while, after panacene's (Tot. Syn.) "shark antifeedent" qualities. After testing against cancer cell lines and other biological [...]