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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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In the Pipeline

« Peptide Craziness | Main | Back To Life »

July 23, 2006

Hexacyclinol Rides Again

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Posted by Derek

The hexacyclinol controversy has taken a very interesting new twist, which I learned about on Friday from Dylan Stiles. To recap: the molecule is a complex natural product, which was the subject of a total synthesis paper earlier this year by James La Clair. The paper had several unusual features, such as single authorship with acknowledgements to several unnamed co-workers, an odd source (the "Xenobe Research Institute" and "Bionic Bros. GmbH" and (not least) several key chemical steps that appear to make little sense, backed up by fishy NMR data.

Then Prof. Scott Rychnovsky of UC-Irvine popped up with a proposal that the structure of hexacyclinol had been wrongly assigned in the first place. He assigned a completely different structure, with rather solid-looking reasoning behind it, which raised the question of just what La Clair had synthesized. How can you get the right spectral data by making the wrong structure, when the structures are so different as to make that impossible?

Turns out that Rychnovsky had another ace to turn over. The web site for Angewandte Chemie, where the original La Clair paper ran, has now put up advance notice of a paper on the synthesis of the revised structure of hexacyclinol, which appears to indeed match the published spectral data. This grenade is from Paul John Porco at BU, some of his students, and. . .Scott Rychnovsky, who apparently wasn't going out on as much of a limb as I thought.

La Clair has seen the writing on the wall, and apparently realizes that he has indeed been weighed in the balance and found wanting. During the day on Friday, the Xenobe Research Institute web page was updated. It now features Rychnovsky's revised structure (Update: or does it? See the comments!), with this text:

Desoxoudol (previously named desoxohexacyclinol)...

Efforts are underway to identify pathways that regulate the growth and development of four parasites responsible for Malaria, Plasmodium vivax, P. malariae, P. falciparum and P. ovale. Our first study conducted on desoxohexacyclinol, currently renamed as desoxoudol, is a terpene isolated from cultures of a German Borstiger Knäueling mushroom (Lentinus strigosus = Panus rudis Fr.). Earlier 2006, Dr. La Clair published the synthesis of desoxoudol demonstrated its conversion to udol and 5-epi-udol. Due to the unconventional nature of this effort, efforts are now underway to repeat this isolation and synthesis. Samples of these intermediates will be verified through analysis by a panel of external laboratories.

Unconventional. . .well, yeah, in a way. It's unconventional to synthesize a complex molecule and get the NMR structure of something completely different, that's for sure. But it's very conventional indeed to go back and attempt to spray-paint the record to make it appear as if something strange and embarassing hadn't happened. Oh, that part happens all the time. And that's exactly what I think is going on here.

For more comments on all this, see the Stiles link and The Chemblog. This is turning into the biggest stink-bomb in organic synthesis in many years.

Comments (12) + TrackBacks (0) | Category: Chemical News


COMMENTS

1. MTK on July 23, 2006 10:55 PM writes...

After reading through all the comments on this and the tenderbutton blog, I was struck that not one person asked for the names of the five technicians who worked on this project.

If this is fraudelent, I doubt that he could produce five people who could all get their stories straight.

Permalink to Comment

2. McPostdoc on July 23, 2006 11:39 PM writes...

I'm sure La Clair's talk at the upcoming ACS meeting will be quite entertaining. I won't be there, but I bet there will be a plethora of chemists willing to report the details.

Oh, and it's John Porco, not Paul.

Permalink to Comment

3. Canuck Chemist on July 24, 2006 1:28 AM writes...

This Xenobe Research Institute looks very fishy indeed. If you go to the website (xenobe.org), you will find that they have no addresses, no contact information, and no descriptions of anyone involved in the organization. It describes itself as a non-profit organization, involved in over 80 studies. Has anyone met anyone other than Dr. LaClair who is a part of this organization? Where are the donors to pay for all these studies? This kind of "mystery" seems more like something one would see from someone trying to sell miracle cures to gullible people. I'm guessing that something of this level of fishiness in the small and well-educated world of organic synthesis and chemical biology must take an extremely high level of self-delusion. It'll be interesting (but likely not pretty) to see how this plays out.

Permalink to Comment

4. Still Scared of Dinosaurs on July 24, 2006 5:24 AM writes...

Right near the top of the list of reasons I never, in earnest, advocate cheating is the conviction that I'm gonna get caught. This is in the analysis of clinical trials data, where something like a fortuitous (sp?) programming error could easily be excused, especially when cheating takes the form of finding the bug and not reporting it.
It just stuns me that someone could try to cheat, and I'm assuming this is the case here based on my very nonexpert reading of the above, when reporting molecular synthesis, cloning humans, missing link skulls, divinely regulated evolution, WMDs, honest elections in Ohio, the Prime Minister of Germany secretly wants you, and stuff like that.
On second thought, maybe there is reason to believe you can get away with anything in this world.

Permalink to Comment

5. JM on July 24, 2006 5:34 AM writes...

Derek - the structure posted on the Xenobe website is not Rychnovsky's new structure. It is actually the original structure from the J Antibiotics isolation paper - in his arrogance LaClair has just renamed it! So, all he has conceded is that hexacyclinol is the name that should be used for Rychnovsky's structure - LaClair still believes that Desoxoudol is isolated from the natural source and that the proposed structure is correct.

Permalink to Comment

6. JSinger on July 24, 2006 8:50 AM writes...

My favorite, in the ChemBlog comments:

Oh my, Scott D. Rychnovsky’s student is in the same session as La Clair. This will be the best ACS conference ever.

Permalink to Comment

7. MTK on July 24, 2006 11:26 AM writes...

I'm actually a little dismayed at some of the comments regarding the ACS meeting. It's almost like people going to a car race just to see the wrecks. Some of the poters want to see a steel cage death match, not a real scientific debate. I can understand the appeal of a good debate and the fireworks that can result, but this looks like it's going to have all the suspense of the Christians vs. lions.

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8. Elia Diodati on July 24, 2006 4:37 PM writes...

If anyone's interested, I did a reasonably high-level ab initio calculation on the two reported structures. At the LMP2/cc-pVDZ level of theory with optimized geometries, La Clair's structure has a higher ground state energy than Rychnovsky's structure by 61.87 kcal/mol. It's not a screaming red flag, but it's worth noting.

Permalink to Comment

9. Petros on July 25, 2006 4:14 AM writes...

Fascinating saga. Sounds like the ACS session might be entertaining, if JJC shows up.

Interestingly Googling around finds such wonders as

"James J. La Clair, Founder, BIONIC Bros GmbH,"

"The BIONIC BROS GmbH, a Berlin Germany based bioelectronics company, announce the release of a new Artificial Life gaming engine. Initially developed for the biotechnolgy and information technology sectors, the engine behind this game offers a dynamic realm of new challenges for its players. The game is in itself a piece of scientific research. A sneak preview of the this system can be viewed now through www.bionicbros.de. It can be played simultaneously using cards, dice or a PC."

And JJC still found time for all that synthesis as well.

Permalink to Comment

10. Steven Jens on July 26, 2006 8:42 PM writes...

MTK, surely there is room at the ACS conference for both serious scientific debates and really cool car crashes, don't you think?

Permalink to Comment

11. Hap on July 28, 2006 12:20 PM writes...

There is now a C+E News story on this fiasco in which the writers talked to Dr. La Clair (and in which he is quoted), and at Chemical Forums there is an account by another scientist as the Natural Products Gordon Research Conference in which Dr. La Clair gives an explanation of the situation (although the author was inebriated, the account is confirmed by another attendee who wrote on Dylan Stiles' blog (the original posting site) - don't know either of them though).

This just keeps getting more bizarre.

Permalink to Comment

12. MTK on July 28, 2006 1:52 PM writes...

Jens,

I guess a fiery wreck or two is OK.

I'll admit I'm wavering on this one bit. On one hand, I'm not in favor of public executions, but on the other hand, the guy has it coming to him.

Permalink to Comment

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