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Piperkadsin C [Isolation] – Updated   

11 January 2010 42,094 views 41 Comments

piperkadsin-c

Lee, Kim, Choi, Ha, Kim. BOMCL, 2010, 20, 409-412. DOI: 10.1016/j.bmcl.2009.10.016. Article PDF Supporting Information Group Website

The Tot. Syn. bull-shit detector is at eleven just now, having just read Derek Lowe’s post on Piperkadsin C.  This natural product was isolated by Kang Ro Lee of Sungkyunkwan University in a assay-guided chromatographic separation of isolates from Piper kadsura (Piperaceae).  It doesn’t take much more than a glance to see that something seems very wrong with this structure, as it seems to contain a bridged cyclobutene, partially containing a dieneone.  From a chemical stability aspect, this is scary enough, but the real concern is of course in the sterics.  I’ve done some very simple MM2-minimisations in Chem3D:

piperkadsin-c_1 piperkadsin-c_2

I’ll ask the geeks chaps in our comp-chem office to try and do something a bit more meaningful tomorrow.  In the meantime, have a look at the NMR data in the SI.  Having trouble finding it?  I did too, ’cause all we’ve got is the tabulated data in the main paper.  Really, I thought all isolations came with scans of the actual NMR data?

I’m still wading through the assignments, and trying to match the 13C data with predicted data in ChemDraw (which is pretty good in 13C).  But what strikes me is the fact that a search of the PDF has no hits for words like, uh, butane or butene or even frickin’ strain.  Seriously, WTF?!

Part II

Okay, my colleague, James, has done a bit of proper 3D modelling for us (and also provided some tips for modelling) – I quote:

For the sake of all thing decent in comp chem you really should dump the chemdraw 3D stuff and use something decent!!  These were done using omega 3D, the minimisation of all confs produced with MM3, the images are of the lowest energy conf.  Aside from the method, one complaint with the chemdraw images is that you can’t see which are single and which are double bonds

mm3-1

mm3-2

One approach that is slightly preferable is to use a free demo of a commercial tool like corina (a farily industry standard 2D to 3D converter)

http://www.molecular-networks.com/online_demos/corina_demo

1. Select your mol in chemdraw and do Edit -> Copy As -> Smiles

2. Paste the smiles into the above web page, download the results into whatever free viewer you like (pymol is my favourite freeby) and generate some images.

If you get problems, put all explicit H’s in the mol in chemdraw and corina will behave better, I’m not too sure if the simple web app will handle things without H’s.

8th of February – more modeling

I’m currently not well disposed to the bloody French, but I’ll consider one chap and his colleague - Yoann Coquerel & M. Rajzmann – who have added to the modeling work above, and done some proper, AM1 (semi-empirical) and DFT (ab inito) calculations on the proposed structure of Piperkadsin C.  I quote:

We have performed AM1 calculations on the proposed structure of piperkadsin C and a possible alternative structure. Note that we have not been through the reported characterization data to propose the alternative structure, and it may not be realistic at all given the reported data; we just used it as a reference point. Remarkably, the molecule looks stable, although its enthalpy of formation is much higher than the proposed alternative structure. To confirm these results, we have performed DFT calculations on a simplified analogue, and the results are similar. It may be noticed that the results obtained by both methods are very similar, but the AM1 method required less than 5 second on my laptop. If some people are interested, we can continue this study to determine the energy profile of the transformation from the proposed structure of piperkadsin C to the alternative one. Feel free to ask.

The result of their labours can be seen in the lovely graphic below:

(Click for an even bigger image)

Thanks, chaps!

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41 Comments

  • thomas says:

    If the authors assigned that one correctly, we’ll have (the first?) cyclohexadienone which isn’t able to tautomerize to its phenolic enol-form – due to “frickin’ strain” in its cyclobutene moiety.

  • Gui says:

    OMG if that is the true structure then its begging to rearrange.

  • milkshake says:

    I think it cannot be that hard to figure out the real structure, at least approximately because the molecule is quite small – it is a heterodimeric lignan based on oxidative coupling of safrole-like pieces. My guess right from the hip would be something similar to the compound 2 in the paper without one of the O-methyls. I suppose there is one more ring compared to compound 2, and perhaps the signals got shifted in funny ways because of the shielding/de-shielding from the benzene ring that swings in once you close that extra O-ring

  • NP says:

    There are a number of issues. The couplings to terminal methylene protons are wrong (acylic cis alkene with a 5.5 Hz 3JHH value, no geminal coupling?). There are 4JHH couplings reported from the methyl group to alkene carbons (H-9 to H-2′ and H-4′). The 1740 cm-1 vibration reported in the text makes little sense with the proposed alpha,beta-unsaturated ketone. It is also not listed with the other IR vibrations in the SI. The reported FABMS data is assigned as M+, not MH+ or MNa+ as would be expected with FAB. This makes me wonder if the assigned M+ is really a fragment. It wouldn’t be the first time.

  • PotStirrer says:

    Sorry to hijack this thread, but…does anyone know of a good way to search PhD theses for certain subjects? I noticed, for example, that Baran referenced many theses in both his vinigrol and palau’amine papers. Does one simply need to know the community and who is working on what or is there a good electronic source out there? Thanks.

    • sjb says:

      Many theses are probably under copyright of the author, if not their institution and / or funding body as well. Though there are some that are released under CC licences or similar as well.

  • Boron bodger (no badger) says:

    I’m not sure if this is the place for suggestions for pieces but this Celogentin C is rather good IMHO
    DOI: 10.1002/anie.200905134 even if it does contain nasty peptides.

    WRT theses google can be successful if they are stored on an electronic data base, otherwise http://www.theses.com/idx/registered_users/search/quick.html and searches university by university

  • claud says:

    PotStirrer,

    I don’t think Scifinder will.
    sometimes university library catalogs return thesis hits from a search. I know when I turned mine in, way back in the 1990s, I needed to provide two dozen keywords for the library catalogue. Mine was submitted in paper form, now I suspect that they are all *.doc or *.pdf, so the keywords are automatically extracted.

    Maybe google scholar?

  • sufuric says:

    PotStirrer,

    try using proquest dissertation and thesis search. most university libraries have a subscribtion. You can search the citation/abstract of most theses (at least granted from US schools).

  • Rich Apodaca says:

    For the sake of all thing decent in comp chem you really should dump the chemdraw 3D stuff and use something decent!!

    From what I hear, Avogadro is a pretty decent, free alternative.

  • DBstad says:

    I think La Clair has a total synthesis of this compound submitted to Org. Lett.

  • optional says:

    Woooooo Hoooooooooooooo! The molecule is more bent than Beckham!

  • Andrei says:

    nobody complains about double bond on a bridghead-like carbon (bredt’s rule almost applicable)

  • Jack Bauer says:

    Perhaps we are not giving these guys enough credit. They’ve proposed a structure that can’t be synthesized. Might be hard to prove these nut cases wrong.

  • European Chemist says:

    Actually, you’d be surprised to know that less than 50% of natural products isolation papers have copies of the relevant spectra – you typically have to e-mail the authors once you’re close enough to the target for NMR data (and/or samples for direct comparison if they are available).

    At the risk of repeating what everyone else wrote here: Compound looks extremely strained, and I’m surprised that the authors don’t make much mention to it. Elsevier Journals are not the only ones around there that don’t demand hyper-complete Supporting Information – and let’s not forget that even with SI and copies of spectra, stuff like the LaClair Hexacyclinol synthesis can still easily happen.

    I’ll have a closer look at the data reported – since Tot Syn’s 3D models actually seem to defy our general assumptions this might not be completely misassigned (although that anti-Bredt issue is hard to reconcile)…

  • Twist Boat says:

    Don’t know if someone has already commented on this, but Paul’s BS detector is pretty spot on.

    http://pubs.acs.org/doi/full/10.1021/ja910615z

  • J-bone says:

    I’m a little surprised that less than 50% of Nat Pro papers have proper supporting, but I’m not in that field of research so I wouldn’t have any idea what’s common.

    ElSevier standards are as loose as Vegas prostitutes. Add to it that if the journal ends in “Letters” that they require absolutely no SI of any form and that peer review for all journals is an absolute joke, and this type of thing doesn’t surprise me at all.

    • NP says:

      Having worked in the field for almost 20 years, I would say the number is lower, especially for more recent publications. It does ultimately depend on the journal’s standards. For ACS publications, copies of the relevant spectra are expected. I have argued for years though that the inclusion of processed NMR spectra in the supporting information has a limited value, unless extensive expansions are provided. How much information can really be extracted from a pdf copy of a HMBC spectrum of a complex natural product? Can you really tell if the proton coupling differs? There needs to be a central repository like the CSD for X-ray, where raw NMR data is deposited and accessed free of charge.

      • European Chemist says:

        Spot on, NP. Most of the time reviewers are just arguing about trace solvent peaks or minor impurities so they can find something to bitch about – not serious peer-review IMO. Spectra can be fabricated and misassignment of structures is definitely NOT going to be detected by looking at pdf copies of NMR.

  • Alkaloid says:

    Has anyone emailed the corresponding author (krlee@skku.ac.kr) to ask for copies of the spectra, and maybe for permission to post them? Paul could have another live blogging event (a la the NaH oxidation event) to examine the structure. Wouldn’t be quite as fun as running the NaH reactions, but it could be quite educational to hear from the NMR gurus out there.

    • bad wolf says:

      i’m sure they’ll jump at the chance to have their data roasted in an open forum.

      • Stir_bar says:

        I’m not sure if roasting is what people intend to do here. A scientist should be confident with their findings, especially if they published it. To not give out spectra would seem very suspicious, although I wouldn’t expect a quick reply granted all the “press” that has developed.

  • [...] Bioorganic and Medicinal Chemistry Letters chamou a atenção da comunidade química (por exemplo, aqui e aqui) por apresentar a estrutura de uma nova neolignana, piperkadsina C (1), com uma dupla [...]

  • antiaromatic says:

    A bit more regarding the modeling stuff. As it turns out, molecular mechanics force fields (any of the so-called “MM” methods) are parameterized based on some particular data sets. So they work best for molecules most similar to the molecules used to parameterize the force field. This is problematic in this case because undoubtedly, systems with antibredt olefins and non-aromatic cylcohexadienone tautomers were not included in such parameterizations. Whenever you encounter some truly unique architectural molecular feature, it is best to use ab initio calculations. For a molecule of this size, they aren’t terribly difficult to do, even with a half decent basis set. Only through those types of calculations will you be able to really get a feel for what these guys look like.

    • Tit Lett. says:

      I would argue, if a molecule as published existed it would not survive the extraction process, and most definitely would not survive chromatography. The problem is that we are discussing whether such a molecule could exist, not whether IT WOULD SURVIVE CHROMATOGRAPHY.

  • k-y says:

    This little stucture will [4 + 2] faster than you can steal candy from a baby.

    See: http://pubs.acs.org/doi/abs/10.1021/ol061737h

  • antiaromatic says:

    To me the alternate structure still has a big issue in terms of the nOe correlations. It’s hard to see how the alpha proton of the quinone methide would show an nOe to the methyl at the end of the quinone methide. Only way that could happen is if they misassigned that proton to be the beta proton on the other side of the ring. This misassignment would require the long range HMBC from the alpha proton to the allyl side chain to be relatively prominent.

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