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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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January 11, 2010

Sure About That?

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Posted by Derek

There was a natural products paper (abstract) that I missed last fall which has finally come out in Bioorganic and Medicinal Chemistry Letters. Let's have a show of hands: how many chemists out there think that this structure is the correct one?
piperkadsin.png
Right. Going back through SciFinder, I don't find any anti-Bredt cyclobutene structures of this sort in the modern era - only speculations about whether or not they could even exist. I hope, for their sake, that the authors have assigned this one correctly, and it certainly would be neat and interesting if they have. But doubts afflict me.

Note - the most recent entry on the (inactive?) med-chem blog "One in Ten Thousand" was a raised eyebrow about this exact paper. Fear not, there's no curse - I'll continue posting. . .

Comments (48) + TrackBacks (0) | Category: Analytical Chemistry | Chemical News


COMMENTS

1. FormerMolecModeler on January 11, 2010 12:54 PM writes...

That thing is desperate to rearrange and aromatize.

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2. C. Bailey on January 11, 2010 2:04 PM writes...

yeah...no, that can't be a real structure

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3. RB Woodweird on January 11, 2010 2:26 PM writes...

Good news everyone! Peter Schultz' group is going to get right on the synthesis of this!

Wow, just looking at that structure - the ring strain is making my head hurt.

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4. d on January 11, 2010 2:35 PM writes...

Again, how did this get through the referees? It's hard to believe that it would have escaped the attention of any chemist

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5. anon the II on January 11, 2010 2:37 PM writes...

I think it's time we rethink this peer review thing. Somebody is asleep at the wheel.

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6. milkshake on January 11, 2010 3:04 PM writes...

the problem with over-confident NMR people who do structural assignments is that their cavalier attitude can lead to loss of several man-years for grad students and postdocs trying to re-synthesize the mis-assigned beast, not mentioning the ridiculous quantities of funding money wasted, Its not a joke, the burned out people ho could have had excellent career given a less shitty research project to work on.

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7. J-bone on January 11, 2010 3:10 PM writes...

That thing is desperate to rearrange and aromatize.

I was thinking the same thing.

No offense intended, but El Sevier journals collectively have much looser standards for peer review than other journals, it doesn't surprise me that this got approved. I mean, you can publish in Tet Lett with absolutely no supporting information. That's practically begging people to make stuff up and submit it to pad their resume (which sadly, I think a lot of people do).

Again, this fuels my denouncement of the current peer review process as nothing more than backscratching between colleagues. I shouldn't be able to have this tirade this often, it's getting ridiculous.

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8. CMCguy on January 11, 2010 3:13 PM writes...

With considerable effort I can make the ring system with my old Darling Model (although does say "flexible modecular model kit") set so that proves this compound can exist right? (I better take it apart before the shrapnel takes out an eye)

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9. Kindle on January 11, 2010 3:13 PM writes...

More losses on the Job front. Let's all head off to Grad School yeah!!! Pfizer and Merck plan to lay off hundreds more.

www.nj.com/news/index.ssf/2010/01/pfizer_merck_plan_hundreds_of.html

I think it should be clear that if the top 50 Grad schools produce 1000 PhDs per year, the 2007-2010 layoff massacres have created a glut of what by now?, maybe 10,000 unemployed PhDs.

A ten year supply!

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10. Sili on January 11, 2010 3:14 PM writes...

So you think they have NMR of this? I was just wondering how the Belgium it's even possible to make that assignment with the spectrum in hand? (And I'm a crystallographer!) Of course it's been a long time since I last had any data to work with - perhaps that's my strength: I'd know to check the books to make sure.

Thinking about IR should be able to give a yea-or-nay immediately, but noöne uses that anymore.

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11. RB Woodweird on January 11, 2010 3:19 PM writes...

@Sili - one of the links in Derek's post leads to complete NMR data.

@Kindle - I didn't go to one of the top 50 graduate schools, you insensitive clod!

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12. Sili on January 11, 2010 3:58 PM writes...

Thanks, but I'm just a poser. No subscriptions. Sorry.

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13. CMCguy on January 11, 2010 4:25 PM writes...

Retraction of Proof: I had forgotten the second double bond in the cyclohexane ring and with that installed could not force the bridge connection.

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14. Hap on January 11, 2010 4:59 PM writes...

I can connect up the bridging four-membered ring with my flexible models, but only if the ends of the olefin are orthogonal and then only if I have bent the other bridging cyclopropane bond (to the point of breaking). I don't think this passes the "drop the model on the floor" test as a measure of stability.

The C13 ought to be characteristic, right? - the anti-Bredt olefin C's ought to be radical-like and probably electron-deficient> Don't know where the C-C stretch in IR would be for the olefin, though (or even the C-Hs).

Did they just draw it wrong, or is there a lot more data here than I know to support this structure?

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15. Sam on January 11, 2010 6:37 PM writes...

Looks like this is crying out for the synthesis and characterization skills of the Bionic Brothers!

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16. Special Guest Lecturer Charles Shaw on January 11, 2010 8:16 PM writes...

Oh, they already made grams of the stuff. NMR matches the literature values perfectly.

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17. MedInformaticsMD on January 11, 2010 8:54 PM writes...

Derek wrote: "Right. Going back through SciFinder, I don't find any anti-Bredt cyclobutene structures of this sort in the modern era."

I am curious, how would you have searched for this information without SciFinder?

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18. Jose on January 12, 2010 3:02 AM writes...

How in the world can anyone serious enough about chemistry to be attempting to do nat prod isolation and modern spectroscopy not look at that structure and laugh like a baboon on meth?

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19. Big Bob on January 12, 2010 3:44 AM writes...

Being slightly twisted I gave this molecule to my students last year with instructions to design a viable synthetic route. The best one would win £100...it's still in my desk unclaimed! 'Nough said!

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20. partial agonist on January 12, 2010 9:41 AM writes...

Move the methoxy over one carbon to the position where it looks like a para quinone waiting to be born, and move the bridging carbon bond to where the methoxy was, giving you a cyclopropane.

Then you have soemthing that doesn't look particularly happy but has at least it has all of the right functional groups, without the potential energy of a keg of TNT like their crazy structure does.

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21. partial agonist on January 12, 2010 9:47 AM writes...

well, not quite... now that I think about it. That structure I mentioned would still have a double bond exo to a cyclopropyl and constrained to a nearly flat ring.

Who knows what all they made up.

Some detective work with the NMR data, if it is real, should give something plausible if anyone cares to take the time.

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22. Hap on January 12, 2010 10:02 AM writes...

The cyclopropane structure would at least be plausible, although it ought to go off like a shot in acid or base or concentrated solution. The NMR ought to be sort of characteristic, also.

I haven't read the paper, but do they have lots of data to back this structure up, or was everyone in the chain of command just asleep?

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23. no more BMCL reviews on January 12, 2010 10:20 AM writes...

The problem with peer review at BMCL is not just with the reviewers but with the editors. Twice I've recommended rejecting terrible manuscripts, with their deficiencies thoroughly explained, only to see them accepted "without changes."

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24. P on January 12, 2010 10:37 AM writes...

They have data. I haven't gotten through it at length, but - leaving aside Bredt's Rule - the NMR does seem to fit the structure. I, too, had thought of the cyclopropane proposed above and it would be more stable (what wouldn't?) but still doesn't "look" satisfactory. I suspect there may have been some sort of cyclization between the acyclic olefin and the quinonoid ring with some funky shielding effects throwing off the NMR signals of some atoms.

The structure on this page is missing an OH - there is a benzylic alcohol that the authors claim to have used to make a Mosher ester and, thus, assigned absolute configurations. They give NMR data for those compounds as well.

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25. Jason on January 12, 2010 11:48 AM writes...

I had just finished up a post about another troubled Elsevier journal, Chaos, Solitons and Fractals, when I stopped by to see Derek's latest. I was interested to read J-bone's comment that Elsevier journals generally have loose peer review, which I didn't know.

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26. Matt on January 12, 2010 1:17 PM writes...

@P, where the hell is printed NMR spectrum?

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27. P on January 12, 2010 1:36 PM writes...

Ah, you wanted a printed spectrum? Nope. Just tables of data.

There is also an inconsistency with the IR reported in the manuscript and the one in the SI. Neither really gets at an alkene such as in their structure.
The OH proton also seems to be missing from the NMR.

I would always assume error rather than fraud. Perhaps that is naive.

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28. Hap on January 12, 2010 1:57 PM writes...

The alpha-methyl group on the side chain is a hydroxy group. It's easy to lose the OH NMR signal, I assume, by exchange. It looks like it still ought to fragment easily in acid, but I can't really find a good place to leave a (+) charge when you protonate the alcohol, lose water to get the cation, and fragment the bridging ring. The alkene C-H IR stetch could be lost in the aromatic C-H stretches?

This just looks awfully improbable.

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29. Sili on January 12, 2010 2:43 PM writes...

Tables of data? Welcome to the 21st century! Web 2.0!

GUH!!

P, what you're describing is Hanlon's Razor: Never attribute malice where incompetence may suffice.

What does IR say about the ketone? (I'm pleased that there actually is IR.) (Nudge nudge wink wink someone post the data here for us to pore over.)

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30. anon the II on January 12, 2010 2:59 PM writes...

Since I don't have a job or anything else to do, I might as well post here too. I looked at the paper and saw that the FAB MS gave a [M]+ ion. It shouldn't have. It should have given an [M + 1]+ ion. Which suggest that this molecule should have a nitrogen. Or maybe the base peak is not an M but an M - OCH3 from a bond heterolysis. That would be like a solvolysis product to you phys org types. Anyhow, the MS don't wash to my mind.

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31. partial agonist on January 12, 2010 3:00 PM writes...

IR: νmax 1740, 1636 cm−1
UV: λmax 235, 280 nm

I would paste in the NMR data too but I'm guessing that putting too much here tramples on BCML's copywright.

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32. partial agonist on January 12, 2010 3:19 PM writes...

OK, here's the analytical data, and Derek can delete it if it's not cool for me to just paste it:

In the positive mode FABMS of 1, a quasimolecular ion peak at 340 [M]+ was observed, and the molecular formula of 1 was determined to be C20H20O5 by HR-FABMS: observed, 340.1315 (calculated for C20H20O5, 340.1311).

The 1H NMR spectrum of 1 (Table 1) indicated the presence of a set of three aromatic protons at δ 6.75 (1H, dd, J = 1.5, 7.5 Hz, H-6), 6.76 (1H, d, J = 7.5 Hz, H-5), and 6.92 (1H, d, J = 1.5 Hz, H-2), an olefinic proton at δ 7.00 (1H, s, H-2′), one methoxy group at δ 3.82 (3H, s), one methylenedioxy group at δ 5.94 (2H, s), one methine and one oxymethine protons at δ 3.36 (1H, s, H-5′), 3.64 (1H, s, H-7), and a methyl group at δ 0.96 (1H, s, H-9). The other methylene at δ 2.91 (2H, dd, J = 1.5, 5.5 Hz, H-7′) and olefinic protons at δ 5.06 (1H, dd, J = 1.5, 5.5 Hz, H-9′a), 5.08 (1H, dd, J = 1.5, 12.0 Hz, H-9′b), and 5.82 (1H, m, H-8′) were assigned to the allyl group. These data were similar to those of neolignans isolated from this plant.[2] and [18]

As expected, the 13C NMR spectra showed 20 signals, including one carbonyl carbon signal at δ 197.2 (C-6′), six carbons for an aromatic ring, six carbons for olefinic carbon, one quaternary carbon at δ 50.4 (C-8), two methine carbons at δ 58.6 (C-5′), 65.3 (C-7), one methylene carbon at δ 33.0 (C-7′), one methyl carbon at δ 16.8 (C-9), one methoxy carbon at δ 59.2 (OCH3-4′), and one methylenedioxy carbon at δ 101.1 (O–CH2–O). These spectroscopic data suggested that the structure of 1 may be a neolignan skeleton.

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33. partial agonist on January 12, 2010 3:24 PM writes...

The paper also shows some NOESY and COSY data depicted in figures

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34. Sili on January 12, 2010 4:41 PM writes...

Thanks. I find it hard to believe that this should not be covered by fair use. It's here to be torn apart after all. (And it's not like there's anything really nifty like, say, raw data, here yet.)

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35. Malik on January 12, 2010 5:25 PM writes...

There are a few 4 bond HMBC correlations around the area of interest. One would need to see the original data to get a better idea of the correlation intensities. I agree with the others that the cyclopropyl is more likely.

Also, the NOESY data is incorrectly interpreted due to free rotation about C-7.

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36. Hap on January 12, 2010 6:15 PM writes...

The bridging olefin should have unusual 13C shifts, which they don't seem to mention - probably one should be pretty far downfield (protonated ketone territory), while the other should be pretty far upfield (at least for an olefin C). (I am assuming that the bridging olefin won't act much like an olefin, but will probably be highly polarized to mitigate strain). This doesn't seem to be consistent with what's reported - are my assumptions wrong?

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37. P on January 12, 2010 7:14 PM writes...

Hap, no, I don't think you're wrong. All the enol ethers I've seen have behaved that way in the 13C. This one should even moreso. Looking at it again - I'm spending too much time on this - the fact that the authors don't even mention strain is damning. I'd take this a lot better if they reported it while noting the highly strained structure and possibility of error. As it is, they describe it as if it's just another ho-hum molecule.

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38. Hap on January 12, 2010 7:32 PM writes...

Unfortunately, more time than lots of other people in the chain of command.

How can you miss the bridging four-membered anti-Bredt ring? If you came up with that structure, would some calculated parameters be in order (to assuage reviewers, etc., that "yes, the structure is nuts, but we looked at this carefully, and it fits")? The anti-Bredt paper seems to indicate that the structure ought to have at least 70 kcal of strain energy, probably more, and you might have figured that that would come up to someone in looking at this. Pretending that the molecule wasn't unusual doesn't seem to have been the correct rhetorical tactic. On the other hand, apparently some of the reviewers and editors required no assuaging.

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39. G2 on January 13, 2010 5:36 AM writes...

Since this paper is published in the first issue of BMCL is is available for free in 2010 via http://www.sciencedirect.com
With all the spectroscopic data presented I would not attack the reviewers so heavily. Any chance to solve the structure via X-ray?

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40. Hap on January 13, 2010 9:48 AM writes...

We don't have any idea what the reviewers said or did, nor the editors, so it's hard to ding them. On the other hand, it is a structure with (likely) many kcal of strain energy and which possesses a substructure not seen before and which appears to be eye-poppingly unstable - so someone (the writers, reviewers, or editors) ought to have had the same reactions as the people here.

While the spectra implies that the authors weren't faking anything (it's possible to fake spectra, but it's better to say as little as possible when you lie), there ought to be characteristic signs of a structure with that kind of strain. If they aren't there, then someone should probably ask why. If you suggest an unusual structure, you would like to have an idea whether it is likely to fit the data you have (and whether other related structures do not), so as to explain why it fits better than other structures. Maybe someone asked for that explanation, but it was approved anyway - I don't know. The people here shouldn't be smarter than the authors, reviewers, or editors (they could be, but probably not, for the most part), and so one would have figured that these questions would have been asked already (and evidence of their answering been given).

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41. J-bone on January 13, 2010 11:52 AM writes...

I have an idea what the reviewers said. It probably went something like this:

-Scan author list
-See friend's name
-Flip through pages casually
-Send comments to editor highly recommending it be published with minor grammatical, spelling, or sentence structure revision or no corrections whatsoever. Given that this is an ElSevier publication, I'll lean towards the latter.

Given the increasingly public nature of academic misconduct with respect to publications I find it absolutely appropriate to fleece the reviewers and editors of journals.

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42. sigma147 on January 13, 2010 12:18 PM writes...

Then there's compound #7, with the fused cyclopropane and cyclobutane rings within the cycloheptene system - I don't think that looks altogether happy, either. That cyclopropane ring is awfully strained. Are there other ring systems like this one out there?

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43. sigma147 on January 13, 2010 12:26 PM writes...

Never mind. Looks like compound 7 (isofutoquinol A) has an x-ray structure to confirm the 3,4,6 ring system. Nevertheless, those authors note that the C-C bond in the cyclopropane is 1.606 Angstroms long...

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44. chemdawg on January 14, 2010 10:44 PM writes...

Has anyone ever determined the # of structures proven incorrect by synthesis vs. the # confirmed by synthesis? A decent sized number would be one good justification for total synthesis.

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45. Norepi on January 16, 2010 3:20 PM writes...

Man, where is Scott Rychnovsky when we need him?

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46. Nick K on January 17, 2010 3:21 PM writes...

Just a thought - would an ortho- or para quinonemethide fit the NMR data just as well or better than the (absurd) proposed structure?

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47. Hap on January 19, 2010 7:32 PM writes...

I don't think there are enough olefinic/aromatic protons, at least for the ortho- or para-quinones - there should be one more proton on the central ring, which would form a doublet for the ortho-quinone and a singlet for the para-quinone, but which would give one too many protons in the olefinic/aromatic section.

At least the quinone methides would be precedented, but it would surprise me to see them as anything other than methanol/ethanol adducts in isolated form (or dimers for the ortho-quinone). Of course, we aren't supposed to have guess what this thing's structure is...

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48. Eric Stoner on February 29, 2012 5:41 PM writes...

I'm unemployed right now, so I don't have access to the article, but can somebody please pull the spectroscopic data and post it? I"m sure there is enough experience here to figure it out (assuming the data is for one compound and not a mixture). MS and any other characterization too if they have it. Tally ho! (Hmm, I wonder if this is not a chemdraw error of sorts, got the wrong structure, cut, paste and it is immortalized.

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