Monday, November 23, 2009

Pauciflorol F - Larock annulation & misassigned spectra(?)

If you’re familiar with the current organic chemical literature, I’m sure you’re aware of the huge influx of research about resveratrol and polyphenol natural products and their antioxidant properties in the past few years.  Not only are polyphenols being studied for their potent antioxidant capability, but also their anti-cancer and anti- other things as well.  

With that said, I’ll admit that I haven’t been super psyched about the chemistry to make the little guys, since all the molecules are so similar and a lot of the chemistry is radical-based, until I saw one recently in Org. Lett. (doi: 10.1021/ol902141z) that featured a Larock annulation to form the 5-membered ring of an indenone, the double bond of which was subsequently reduced to produce pauciflorol F.  Two total syntheses of this polyphenol have been reported (She, Pan, et. al. [Chin. J. Org. Chem. 2006, 26, 1300] and Snyder [doi: 10.1021/ja806183r]).  This paper differs in that the authors use a palladium-mediated cyclization approach to the indenone.

The chemistry developed by Richard Larock found its way into my heart as an undergraduate; I was already enamored with transition metals, but watching palladium bounce around in these reactions really just wow’ed me.  You can check out the group’s webpage for an idea of the substrate scope of this chemistry.  Kurti and Czako included the Larock Indole Synthesis in their named reaction text, the mechanism of which is detailed below:

Alternatively, bromoarenes have been used as well as applied to other target motifs.  This paper uses o-bromobenzaldehyde substrates and cyclizes with a di-arylated alkyne with polymethylether substituents, which in the last step are globally deprotected to produce the polyphenol. 

They naturally obtained both regioisomers as there is not much steric difference between the substituents, but both were useful because they could be used to form different natural products.  The rest of the first sequence attempted follows: 

What made me squint my eyes at the details was the structural revision of a key intermediate, one step prior to the final pauciflorol F, compared to the previously reported structure - the last one just shown.   According to Snyder, the enolization attempted in hopes of epimerization of C2 of the compound shown with KHMDS and water quench provided the trans-product; however, the authors of this paper found that enolization with substoichiometric K2CO3 in 3:1 MeOH:MeCN in an effort to epimerize C2 resulted in the formation of the a-hydroxyindanone instead (but reducing the double bond in the presence of KOH induces epimerization in-situ so they can get around this inadvertent oxidation).  The 1H NMR data, shown below, displays two singlets, one broad, shifts of which agree well with the revised structure – compare these two the peaks as reported in the current paper and decide for yourself whether this was an accidental interpretation of the spectrum, seeing as how in the original paper, the mass coincides with the desired product and not the actual product…. who is correct?  (2a is the Pan paper, 2b is the Snyder paper, and 6 is the current paper - click on the image to see the full thing.)  

The top 2 spectra are published for the product that Snyder reported; the second is Snyder's spectrum for that compound, supposedly, while the 4th is the current author's spectrum for the reassigned structure.  The last is the starting material.  

Personally, my organic 1 students would not accept that the two singlets describe the trans-product.  How can two papers report strikingly similar 1H NMR spectra, but completely different masses as the result of the same reaction?  Fishy.  Sure, the conditions were different.   Fortunately for Snyder, the global deprotection with BBr3 that followed resulted in a reductive removal of the inadvertently installed OH group and did, in fact, furnish pauciflorol F.  The current paper confirmed that this was indeed possible, and poked around the mechanism a little bit. Was the original structure misassigned purposefully because there was no way to explain it and the fact that the natural product was still formed made sense?  Or are the different reaction conditions enough to cause two different pathways/structures to form?  Oxidation happens in one case but not the other?  Was it just ignorance? Who knows… if there's something I'm missing, please let me know! 


  1. Wait, what's with the OH? Now it's there, now it's not. If it got introduced by air, where did it go after BBr3 step?

  2. According to notes in the paper:

    "One possible mechanism for the reductive removal of the C(2)hydroxyl group of 13 involves a BBr3-mediated disproportionation."

    They tried adding excess Me3SiH to the reaction to see how it would affect the outcome, and find that it increases the efficiency of the reaction - I don't see how this proves anything, but the authors (Sarpong) claim that it provides some support for an ionic mechanism of reduction by BBr3.

    I also just noticed the note that supports the authors reassignment - Snyder got low yields. The paper claimed that the reassigned intermediate, when deprotected with 10 eq BBr3, resulted in 10% yield, whereas the actual trans intermediate resulted in 35% yield - but I'm not sure what "low" indicates in this report. Why would Snyder not specify, or did he? So freaking confusing.
    (15) Following our own studies in this area, it came to our attention that Snyder obtained low yields in the BBr3-mediated phenol deprotection
    of the compound we now believe to be 13. Dnyder, S. A. Personal communication (Email correspondence on Sep 16, 2009).

  3. "The compound we now believe to be". I like that.

    Ok, I guess I could've just read the paper. Thanks though. :) I think it makes sense, benzylketone enolates get oxidized really easily. Disproportionation is a little harder to believe in, but I'll buy it.

    You should do something with the column width...
    I like your schemes.

  4. Thanks! As in, bigger column width? I knew it would end up a problem, but I liked this template the best from what blogger has to offer! I'll see if I can fiddle with the html and widen it up.

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Constructive criticism welcome; criticism for judgement's sake, not.