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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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« Resistance Isn't Quite Futile | Main | Vial Thirty-Three: One Up, One Down »

June 5, 2006

Hexacyclinol? Or Not?

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Posted by Derek

There's an interesting scandal brewing in synthetic organic chemistry - well, actually, more than one, but I haven't covered the Sames matter at all. This is a new one. Back in February, Angewandte Chemie, one of the most prestigious outlets for organic synthesis we have, published online a paper by James J. La Clair on the total synthesis of a nasty molecule called hexacyclinol, originally isolated from a Siberian fungus.

The paper is remarkable in several ways, and not just because I'd never heard of La Clair. The synthesis is over 30 steps long, which is unfortunately not as uncommon as it should be. (I'm afraid that my bias against total synthesis is showing). But La Clair is the only author, which is highly unusual for such a large effort. And it must have been a large one, since the paper makes reference to starting on a molar scale and finished with over three grams of the penultimate intermediate. Experienced organic chemists will wonder if two or three decimal points have been misplaced there, but that's what it says.

Here's a paragraph for my fellow synthetic geeks - everyone else can skip ahead. When you read it closely, this synthesis has some pretty odd steps in it. One oxidation (aldehyde to acid in the presence of a dithiane) is accomplished through the slow addition of silver oxide in paraffin wax, of all things. If that's a reagent combination that's ever appeared in the literature, I've missed it. Silver oxide, sure - but not delivered by a cheese grater. There's a Mitsunobu inversion, via thiophenol, which occurs on a brutally hindered tertiary alcohol, which is certainly not something I'd expect to happen, or count on midway through a thirty-odd step route. A bit later, La Clair has a mesylation that's accomplished by adding methanesulfonyl chloride/triethylamine once an hour for five hours, which is sort of believable, as the kind of thing that you're driven to by frantic experimentation, but still a bit odd-sounding.

As mentioned, La Clair is the sole author, with an address given at the Xenobe Research Institute. The usual reaction to that statement is "The what?", as I've found empirically by wandering down my hallway at work. (Or, as Stiles puts it, "not to be confused with the Scientology outpost in low orbit around Mars") Xenobe's site is a bit odd, giving off the distinctive feel of a one-man operation. I particularly like what happens when you click the "Support" button and are informed that the Institute is not accepting donations at this time. Before Xenobe, La Clair was at Bionic Bros. GmbH, in Berlin, which sounds unavoidably like a firm from a William Gibson novel. This is where much of the synthesis was done, according to a footnote in which he acknowledges, glancingly, "the assistance of five technicians". (In his defense, that's very much the German style of chemistry, for better or worse).

Now we get to the brow-furrowing part. In the preprint section of the ACS journal Organic Letters, Scott Rychnovsky of Cal-Irvine unveils a computational technique for predicting the carbon-13 NMR spectra of complex structures. His test case is. . .hexacyclinol, La Clair's baby. But according to Rychnovsky, the published structure for the natural product has to be wrong. His method seems to work quite well on similar polycyclic terpenoid nightmare structures, but feeding the accepted hexacyclinol structure into it yields a terrible correlation.

So what's the correct structure? Rychnovsky points out that a related species of fungus has been shown to produce another natural product, panepophenanthrin. If that reacted with some methanol and a bit of acid, which might easily happen during the isolation procedure, it would produce a compound with the same molecular weight as hexacyclinol. . .and that structure, run through the NMR predictor, gives a fit that's right in line with the other known cases he used. Rychnovsky's quite sure that his proposed structure is the real structure of hexacyclinol.

But if it is, how on earth did La Clair get the data he has? His paper includes a proton NMR of the natural product and one of his synthetic material for comparison. They're identical. But if Rychnovsky's right, La Clair synthesized the wrong structure entirely. The spectra shouldn't match at all - that's one of the remaining reasons for total synthesis, to make the compound and see if the spectral data really fit. Now, Rychnovsky's argument hinges on the carbon spectrum, but that should be easy to obtain, given the monstrously huge scale that La Clair seems to have been working on. And given the discrepency between the two proposed structures, I can't see how the proton NMRs can possibly line up by chance.

The strangest part of La Clair's paper is its final footnote, added in proof. Here's how it starts; make of this what you will: "The 1H NMR spectra for this Communication were determined by contract services. The spectra provided in the Supporting Information were collected by N. Voss (Berlin, Germany). The operator added the peak for CDCl3 to the spectrum of synthetic hexacyclinol (1), however, this was done incorrectly at 7.5 ppm and against the request of the author." That doesn't make a whole lot of sense. The NMR operator "added the peak" for solvent to a spectrum? Why? And he put the peak in at 7.5 ppm (the wrong place, for non-chemists)? With what, Photoshop? No, this is very strange indeed.

One of these guys is wrong. And reading Rychnovsky's paper, it's clear that he's not in much doubt about who it is: "Recently, a provocative synthesis of hexacyclinol was reported (footnote to La Clair's paper), and interest in the paper triggered my reexamination of the original structural assignment." By the standards of organic chemistry, that's a gloved slap in the face in the public square. Someone at Angewandte Chemie should probably be feeling the sting, too.

Thanks to Dylan Stiles for calling this business to my attention - his post's comments, which are much more potentially libelous than things tend to get around here, are well worth a read for those interested. Update: La Clair has made an appearance in Dylan's comments, rather to everyone's surprise, I'd say. Still no word on a C-13 spectrum, though.

Comments (21) + TrackBacks (0) | Category: Chemical News | The Scientific Literature


COMMENTS

1. RET on June 5, 2006 8:26 PM writes...

Derek, I am glad you brought up the material supply issues. As someone who has developed a 35+ step sequence to a complex natural product I can tell you that making 3.6 grams of anything through a 37 step linear sequence would be extremely difficult. Add a several steps without precedence and you have a paper that should never have been accepted without a detailed experimental section.

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2. secret milkshake on June 5, 2006 9:22 PM writes...

I never did anything similar in lenght but my friend spent his entire thesis on synthesizing Phtalascidine, a simplified version of Etinoscidine. Starting from a scaled-up (and fairly advanced) chiral material made by his predecessors he was able to produce miligram quantities of phtalascidine and its analogs. EJ then asked him to scale up, which he did, delivering 0.85g of phtalascidine at the end. He had to extend his grad school for extra 1 year to complete this scale-up.

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3. RET on June 5, 2006 10:35 PM writes...

A convergent synthesis like the Corey route would be a different story. Even if you are doing the same number of total steps at some point the molecular weight increases substantially. The La Clair synthesis is completely linear. Unless the reaction proceeds quantitatively, every step lowers the amount of material you have.

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4. Chrispy on June 5, 2006 10:59 PM writes...


If you want to see the structures in question,check out:
http://totallysynthetic.com/blog/?p=110

I am amazed that we can make molecules like this.

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5. Jeff Bonwick on June 5, 2006 11:26 PM writes...

Derek -- what ever became of vial #33?

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6. secret milkshake on June 6, 2006 1:07 AM writes...

I agree. The harder one looks, the more phony this hexacyclinol synth appears.

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7. Morten on June 6, 2006 1:10 AM writes...

And as always the Onion is fastest: http://www.theonion.com/content/node/49180

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8. JSinger on June 6, 2006 8:53 AM writes...

(Or, as Stiles puts it, "not to be confused with the Scientology outpost in low orbit around Mars")

I also liked "My mental image of the Bionic Brothers is 5 guys in matching Adidas track suits with a ghetto blaster, breakdancing on a big piece of cardboard." If only because that's the exact mental image *I* had upon reading that name.

Stiles is a terrific writer...

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9. Cryptic Ned on June 6, 2006 9:40 AM writes...

As a molecular biologist, I would have a distinctly negative reaction to any paper with only one author that then said "J.J.L.C. acknowledges the assistance of five technicians." without even bothering to mention who they are. German biologists certainly don't do that - most German papers I've seen have about 1.5 times the number of authors as an American paper.

But whatever.

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10. Derek Lowe on June 6, 2006 10:03 AM writes...

Ned, the German chemical tradition is that lab assistants are definitely on a different plane than the PhDs, even more so than here in the US. But German friends of mine have said that even by those standards, La Clair's nameless acknoledgement is extreme.

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11. JSinger on June 6, 2006 10:06 AM writes...

(Or, as Stiles puts it, "not to be confused with the Scientology outpost in low orbit around Mars")

I also liked "My mental image of the Bionic Brothers is 5 guys in matching Adidas track suits with a ghetto blaster, breakdancing on a big piece of cardboard." If only because that's the exact mental image *I* had upon reading that name.

Stiles is a terrific writer...

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12. Giagan on June 6, 2006 10:21 AM writes...

Derek,

Douglass Taber published a JOC note in 2003 entitled "Grubbs' Catalyst in Paraffin: An Air-Stable Preparation for Alkene Metathesis".

http://dx.doi.org/10.1021/jo030005p

I remember thinking at the time that this was clever. The catalyst is added to molten paraffin wax (mp = 48-50 C) and the mixture is stirred to homogeneity. After cooling, the solid is broken into useful-sized pieces and stored in a bottle. A sample stored for 22 months with no special precautions showed no loss of activity. The metathesis reactions are purified by silica gel flash chromatography to separate the paraffin from the reaction product.

Taber also gives a reference for the practice of coating air-sensitive catalysts with paraffin and remarks that it's a common industrial practice, particularly in the patent literature. (Personally, until La Clair's work, this was the only time I'd ever seen the technique used.)

My reaction to the La Clair business is that it's highly sketchy. (Why would anyone be adding to or in any way doctoring NMR spectra?) But with 3.6 g of the material in hand he should be able to vindicate himself easily enough. How about an X-ray structure of a crystalline derivative?

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13. weirdo on June 6, 2006 11:50 AM writes...

Derek,
There are a lot of things weird about this paper, but the conversion of 11 to 13 might actually work. Ag2O/paraffin is obviously based on Fetizon's reagent, and that is not really an oxidation of an aldehyde to an acid, but the oxidation of a hemiacetal to a lactone. That's why he needs step "L" to hyrolyze the lactone. Now, Mitsunobu conditions with an intramolecular closure . . . not 100% wacko.

I see how a reviewer might let that sequence through.

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14. weirdo on June 6, 2006 11:53 AM writes...

Ooops, I see you're talking the later Mitsunobu (19b to 20). Never mind!

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15. Hap on June 6, 2006 12:27 PM writes...

The Mitsunobu on a tertiary alcohol (with inversion seems like a step that is hard to believe - with inversion, anchimeric assistance is unlikely, and if it could happen with inversion, how does the nucleophile get to the carbon center? Also, doing a 37-step linear sequence without an on-site NMR for much of the work seems nontrivial, particularly since reaction sequences such as this would seem to require lots of optimization. The source of the synthesis (the firm which assisted Dr. La Clair) is sort of sketchy - not where you would expect (downtown Berlin, I think) and with previous experience in gaming (video, not gambling).

If everything is real, Angewandte could have helped a lot by requiring fuller experimental procedures and data for intermediates, as well as asking for some explanation of the unusual steps - silver oxide in paraffin, tertiary Mitsunobu, and the key [2+2+2] (which La Clair says is based on biosynthetic considerations in his comment, but which seems to have little literature precedent - one post on D.'s blog claims that the references don't appear to point to relevant systems). It seems like these would have been good questions for a reviewer to ask, and if they were answered reasonably, it would have obviated all of the commentary from questions to slander/insults.

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16. elephant on June 12, 2006 2:18 AM writes...

I do admire anyone who produces 3 grams of stuff after a 35 step synthesis - even if it's an exaggeration, it's certainly takes balls to claim it, true or not!

Myself I've recently done a 25-step synthesis - it was an oligomer, many repetitive reactions that I have had the chance to optimize - still it starts on 10 gram scale and ends with 50 mg or so. So I can imagine what it would take to make 3 grams. I do sometimes wonder if my advisor would spring for a kilolab....

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17. eugene on June 12, 2006 6:58 PM writes...

Maybe it was a 3 "milli"gram synthesis and there was a typo of some sort? You know, they put down "3 mgrams of product were obtained", but the 'm' got lost in the translation from German to English.

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18. F on June 27, 2006 4:44 PM writes...

weirdo,

You're right that it's likely that he's oxidizing the lactol (hemiacetal) to the lactone, but it's even more bizarre that he makes a big deal out of hydrolyzing the lactol to the aldehyde in the previous step (step j).

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19. a chemist on June 30, 2006 5:31 PM writes...

What if Mitsunobu is not an actual Sn2, but rather a formation of a phosphonium oxide followed by Sn1 (e.g. through a carbocation)? Whatever is the reason, but he gets net inversion...? You can do it with lactols (through formation of of an oxonium).

PS. DIBAL-H reduction of a nitrile in the presence of a methyl ketal is strange. You go from -78 to rt. In my practice, no ketal would servive that...

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20. wowowo on July 23, 2006 12:57 PM writes...

if you calculate his coupling constant of NMR, you will find more interesting....

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21. lubiao on July 25, 2006 11:56 PM writes...

I didn't believe the paper without detailed experimental operation.

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