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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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May 25, 2011

Getting Rid of Pesky Chirality

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Posted by Derek

A reader sends along this example of a "stereodestructive" synthesis. I have nothing in particular against N-alkylpyrroles, but do we need another route to them so badly that we have to tear up not-so-cheap hydroxyproline to get there, burning up two chiral centers in the process?

Readers are invited to submit other examples from the "wad it up and throw it away" school of chiral synthesis in the comments. . .

Comments (31) + TrackBacks (0) | Category: Chemical News


COMMENTS

1. student on May 25, 2011 11:36 AM writes...

If it's any consolation, it's in tet lett so it probably doesn't actually work anyways.

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2. CR on May 25, 2011 11:55 AM writes...

What a load of crap! How in the world this even made it past the editor is beyond me. Everyone associated with Tetrahedron Lett. (Elsevier, Editors, Reviewers) should be ashamed of this publication. Totally unbelievable.

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3. Od Timer on May 25, 2011 11:59 AM writes...

I don't know if it justifies this work, but I seem to remember hydroxyproline being the most abundant amino acid in mammals.

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4. New Prof on May 25, 2011 12:01 PM writes...

I have been screening postdoc candidates to start in my new lab this coming summer and have received a lot of applications (over 100 in 10 days). 90% have come from India where each candidate has >10 papers and has worked in industry. This makes sense if you are publishing papers like this to hit the quota. And yes Mr. Kumar was one of the 100 apps. Small world.

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5. student on May 25, 2011 12:12 PM writes...

It's ironic that this reaction requires a reduction when this paper requires a complete oxidation

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6. processchemist on May 25, 2011 12:18 PM writes...

Whenever I see a costly starting material used to access pretty common targets, I remember of an hilarious paper where a group was disclosing a "new and economic route" to Talampanel starting from Safrole (and safrole was outlawed because of his use in MDMA production one o two years before...)

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7. leftscienceawhileago on May 25, 2011 12:35 PM writes...

NewProf,
Not really cool to reveal Mr. Kumar's job application.

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8. Hap on May 25, 2011 1:03 PM writes...

It was over $1/g in Aldrich - I assume there are cheaper suppliers but that doesn't seem like all that cheap a starting material.

Is the yield or handling for the reaction of amines and succinaldehyde that suboptimal?

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9. GreedyCynicalSelfInterested on May 25, 2011 1:37 PM writes...

It's not synthesis, it's just vandalism!

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10. Useless Molecule on May 25, 2011 2:11 PM writes...

This demonstrate perfectly the overall intellectual level of academia. This paper is probably the father of all useless papers. And nowadays, sadly, most papers coming out of Ivy school chemistry departments are as irrelevant as this one.

This field is dying.

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11. HelicalZz on May 25, 2011 2:21 PM writes...

Wasn't this originally reported in the 'Journal of What I Learned while Trying to Rotovap off DMSO'?

Zz

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12. AlchemistOrganique on May 25, 2011 3:20 PM writes...

Although I know that N-alkylation of pyrroles can be tricky, this exemplifies a "Newspeak approach" to chemistry. Chirality is double plus ungood. Unchirality is double plus good.

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13. Brutus on May 25, 2011 3:22 PM writes...

These are the only papers that fascinate me:
"Design and synthesis of [some flat molecules], potent [in vitro activity]."
Why publish anything else?

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14. Jose on May 25, 2011 7:00 PM writes...

I once (at the request of my boss) had to mix the enantiomers of a very expensive custom amino acid, so it could be used in a combi chem library.

"You want me to mix this bottle with this one, so it will then be racemic- is that correct? You're really sure??"

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15. milkshake on May 25, 2011 7:00 PM writes...

one nice example of ruining chirality is synthesis of substituted pyrrole-2-carboxaldehyde from glucosamine and a 1,3-diketo compound. The polyol -pyrrol intermediate is then eaten with 4 equivs of periodate and volia- pyrrole aldehyde. The glucosamine works there as a aminoacetaldehyde surrogate.

Another exampoles of sugar vandalism is preparation of 5-hydroxymethyl furfural and levulinic acid

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16. a-non on May 25, 2011 11:16 PM writes...

I'm surprised that everyone is bagging this paper. Yes, this proceedure may not be incredibly useful now, but who knows about the future. I think that the field would be far better of if when a researcher noticed an "unexpected" reaction s/he published it. Not that I would ever have planned to, but I now know not to heat chiral hydroxyprolines in DMSO if I don't want to lose stereochemistry. I know that it's not nobel prize winning stuff, but it does add to the knowledge base of the field. I mean it's not like this is NaH oxidation, at least this will work.

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17. A chemist on May 26, 2011 12:16 AM writes...

Let's not forget the Grob fragmentation. A useful reaction, indeed, that erases two stereocenters. Very useful for making medium sized rings.

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18. chemist on May 26, 2011 1:56 AM writes...

interesting to look here
Decarboxylative formation of N-alkyl pyrroles from 4-hydroxyproline
Indubhusan Deb, Daniel J. Coiro and Daniel Seidel
Chem. Commun., 2011, 47, 6473-6475
DOI: 10.1039/C1CC11560J, Communication

http://pubs.rsc.org/en/content/articlepdf/2011/cc/c1cc11560j

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19. sepisp on May 26, 2011 2:08 AM writes...

Serious people, what the hell are you talking about? If you search hydroxyproline on alibaba, you'll find that it cost 1.70 $/kg in bulk. That's not really expensive, about the same as dichlorobenzene, methyl methacrylate or paraxylene. The products shown in this paper are very similar to the flat compounds often outsourced to Chindian manufacturers. The chirality isn't magic - it was never meant to be preserved, since the cheap hydroxyproline becomes a flat pyrrole. You people really live in an ivory tower.

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20. processchemist on May 26, 2011 3:22 AM writes...

@19

Wow! Sourcing on alibaba! Great idea! Why I never thought about it before?

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21. chiral on May 26, 2011 4:43 AM writes...

I once attended a lecture by Phil Kocienski wherein he showed a synthesis involving destruction of 3 chiral centers. He told it was like converting whisky into beer!

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22. G2 on May 26, 2011 6:40 AM writes...

@18
when you look how long it took to be accepted in Tet. Lett. you may think that the Chem. Commun. scientist potentially were the reviewer.

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23. sepisp on May 26, 2011 7:39 AM writes...

#20: alibaba comes to play since it's the easiest way to get in the ballpark with bulk prices. Since I'm posting a blog comment, not proposing investment, I think alibaba is good enough. The point still stands. Cheap natural products often have useless chirality, and no one would expect otherwise.

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24. processchemist on May 26, 2011 8:45 AM writes...

@23
alibaba is the easiest way to get bulk prices from unknown suppliers of dubious quality products asking for advanced payments. Since I'm not interested in advertsing any website, there are better places to look for asian suppliers and, guess what, prices can be really cheap, but not unbeliavable.

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25. RTW on May 26, 2011 12:58 PM writes...

Well - I have to agree with a-non on this one. We can't completely know the reasoning for the work behind the publication. As someone that has done a LOT of highly substituted pyrrole synthesis. I should point out one of the top selling drugs of all time is an n alkyl pryrrole (Lipitor). Could it be this was only the beginnings of an investigation into an alternate synthesis? Perhaps the ultimate goal is to use more complex hydroxyproline like materials? Could the group be ultimately looking for alternative means into a Lipitor like pharmacophore? Hard to know.

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26. anchor on May 26, 2011 1:59 PM writes...

I reckon that the authors were planning to do some sort of reductive amination, but then realized that after initial addition of aldehyde to pyrrolidine the resultant aminol was transformed to the incipient iminium salt setting of decarboxylation ( a la beta keto acid ) and then loss of water in a down hill process to give them the product they did not anticipate. My point was that the sequence of reaction that I aforementioned preempts reductive amination. What they do not realize is that the same product (if that was their goal) could have been obtained by simple condensation of amine with succinaldehyde dimethylacetal in acetic acid, a well known reaction. This chance observation by them did not warrant additional examples followed by publication. Mind is terrible thing to waste, they say!

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27. CH-med on May 26, 2011 2:06 PM writes...

If I had a dollar for every stereodestructive synthesis I've come across in the literature, I would need to apply for grants.

Bushing TL is unfair. Yes, there is plenty of useless stuff in there, but there's as much in fancier journals including JACS - Does anybody remember the NaH-oxidation (JACS-comm 2009 or 2010)?

We recently did a survey of truly useful step-saving methods in my group, and most of them turned out to hail from TL, followed by SC! Does Suzuki Ar/Ar coupling ring a bell?

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28. CH-med on May 26, 2011 2:21 PM writes...

No.18 proves my point. But hang on a minute, this CC article comes from New Jersey, not India, so it can't be crap, can it? And CC's Impact Factor is twice that of TL...

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29. CR on May 26, 2011 3:06 PM writes...

CH-med and sepisp:

It doesn't matter what the journal is, this is still a crappy publication and the editors/reviewers should be ashamed (just as the editors/reviewers for CC should be). Although after publishing this drivel, TL has dropped yet again to a new low.

It doesn't matter what their "future" intent is (looking for Lipitor-like molecules as CH-med suggests). They are not publishing that work - what they are publishing is an alkylation of pyrrole. If they showed substrates that did not work when starting with pyrrole, that might be a useful reaction; but as written it is not.

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30. CR on May 26, 2011 3:09 PM writes...

CH-med and sepisp:

It doesn't matter what the journal is, this is still a crappy publication and the editors/reviewers should be ashamed (just as the editors/reviewers for CC should be). Although after publishing this drivel, TL has dropped yet again to a new low.

It doesn't matter what their "future" intent is (looking for Lipitor-like molecules as CH-med suggests). They are not publishing that work - what they are publishing is an alkylation of pyrrole. If they showed substrates that did not work when starting with pyrrole, that might be a useful reaction; but as written it is not.

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31. TsOH on May 31, 2011 11:34 PM writes...

(Full discloure: I know one of the groups mentioned)

Surprising to see such a fuss about a Tet Lett from India when a Chem Comm from NJ describing a simultaneous discovery of this process was not criticized. Bias much?

Also, most people here seem to miss the point of these papers and the related works by Tunge (JACS 2009, 16626), Sun & Pan (JOC, 2011, 1167 & Chem-Eur J, 2010, 13352), and the authors mentioned above in the comments (Org Lett 2011, 812 & TL 2011, 777). Sure, you can usually N-alkylate a Na-pyrrole salt if you have the corresponding alkyl halide available. The methods based on decarboxylation and azomethine ylide isomerization are complementary for the cases where the desired alkyl fragment is much more readily available as the aldehyde than as the alkyl halide. Especially germane would be the alkyl substrates mentioned in the papers, such as citronellal, and the furan/thiophene cases where the 2-halomethyl compounds are lachrymators, vesicants, and prone to polymerization. The above reasoning also applies to the reliable R-NH2 + 2,5-diMeO-THF method: it works well IF the corresponding amine is available.

I generally hold the intellect of the commenters of this blog in higher regard than most of the internet, but some of the above comments really worry me. Either the pay-to-read literature has become really inaccessible in the past few years, or people automatically assume that something published in Tet Lett by Indian chemists can't be useful.

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