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Quinine is one of the most important molecules in history (see the C&EN feature as one of The Top Pharmaceuticals That Changed The World.  Nowadays the closest most of us come to this wonder-drug is the bitter taste in those fantastic gin & tonics at the local bar.  Modern tonic water doesn’t contain enough quinine to be clinically effective, so it is only added for that great alkaloid taste.



Quinine was originally used by the Incas to treat malaria, and was later used throughout the world by conquerors from the Europe (a couple of other blogs have been discussing the merits of folk remedies versus pharma developed drugs: @The Chem Blog,  @Chemical Musings).  Anyway, this compound has saved countless lives, although now other remedies (e.g., chloroquine) have replaced quinine as a usual malaria treatment for cheapness and synthetic accessibility.  Resistance to chloroquine may put quinine back into the spotlight, however.

Beyond its importance as a medicinal compound when isolated from natural sources (the bark of the cinchona tree), this has been a fascinating molecule for synthetic chemistry.  Most of the history of this story can be found in chapter 15 of Classics in Total Synthesis II, possibly the best chapter in either of the Classics books.  I’ll summarize some of this history here.

Let’s begin with Hofmann, who decided it might be possible to synthesize quinine from components of coal tar, and he talked his student, Perkin, into trying this.  The idea was to take two equivalents of N-allyltoluidine (C₁₀H₁₃N) and three atoms of oxygen and, since you have the right number of all the atoms you would need for quinine (C₂₀H₂₄N₂O₂), they might spontaneously assemble and make the natural product (with water as a byproduct).



Those of us who are familiar with total synthesis will recognize that this is a low-yielding reaction.  Perkin ended up with a bunch of tar.  When cleaning his glassware with alcohol, he found that a purple compound was extracted from the tar, and this could effectively dye cloth a royal purple color.  The dye, mauveine (actually a mixture of two compounds), led to Perkin becoming a very rich man.

Around the same time, Pasteur found that treating natural quinine with H₂SO₄ led to a different compound, now known as quinotoxine.  In 1918, Rabe reported the conversion of quinotoxine back into quinine.  Then some 25 years later, the great R. B. Woodward and his post-doc Doering synthesized quinotoxin, thereby completing a formal synthesis of quinine (details on the route here). 



Now it gets interesting.  This synthesis was a landmark for Woodward, and would certainly ensure that he get a tenured faculty position at Harvard.  However, there arose some questions about the validity of the formal synthesis, because the work of Rabe had not been repeated in Woodward’s lab.  There is a fantastic review in Angew. Chem. by Seeman which investigates this debate at length.  I highly recommend reading this article.  It’s 30 some pages, but worth every letter (DOI link also featured in C&EN here).  Seeman ultimately concludes that Rabe did in fact convert quinotoxin to quinine in 1918, but these results may be difficult to reproduce since the experimental details are not very extensive.

This is a very interesting example of prominent figures questioning the validity of results reported in chemistry journals.  This of course has been a hotbed of activity recently in light of Sames/Sezen-gate and hexacyclinol-gate.  The difference is that now RBW is not around to explain his actions and decisions.  Seeman did interview Doering (now an emeritus prof. at Harvard) and did get some insights.  It is hard to say with certainty with a 60 year gap in the record.

We should all learn from this story.  Chemistry is done by human beings, and that can be a good thing or a bad thing.  Was Woodward knowingly skipping over steps he knew would be difficult to reproduce, if they were reproducible at all?  Was this a situation where the most important factor was publishing in order to get tenure?  We can’t know what was going through his head.  Another point that Seeman makes, which is perhaps the most powerful in the whole debate, is that it is astonishing how quickly opinion turned against the Woodward report.  As we get more and more skeptical of published results, we also run into the danger of becoming too quick to judge something false.  The suggestion that results may be fabricated are certainly not a conviction, and the community must keep that in mind.  Suspicious results are one thing, proving them wrong is quite another.

Since the Woodward route was published, several others have appeared, notably one by Stork, who was one of the principle figures in questioning the validity of the Woodward/Rabe route.  Each of these syntheses is a great achievement.  Over the years quinine has touched the fields of medicine, synthetic dyes, politics, and ethics.  See, chemistry and history aren’t all that different after all!

By the way, the Stork paper has the greatest abstract of all time.


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[kylefinchsigmate]

That was an exceptionally well written piece.  Bravo.

[Bronwen Dekker]

I also really enjoyed this post, and found the Stork abstract very pleasing as well. 

Occassionally, I suffer from a twitching eyelid (blepharospasm - what an odd word) and in desparation once did a google search for something that would make it go away. This is the kind of thing that was spat out:

http://www.evansmcmahon.com.au/docs/autumn2006.htm#41 (scroll down to eye twtiches)

Anyway, I drank about a litre of tonic water (no gin mind you). The eyelid was still twitching at the end of this, but my vision had gone blurry....

[wintermute]

I guess nobody doubt that Rabe succeeded in transformation of quinotoxine to quinine. Unfortunately, experimental data seem to be lost. Thus, I have personal problem with Woodward's claim.
Seemans's paper is excellent piece of writing (and reading) but I simply did not find a single piece of evidence that Woodward's work could have been called formal synthesis.

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It's a pretty serious accusation to say that work reported by someone else was fabricated.  Rabe was a prominent, internationally respected chemist.  Woodward was an assistant professor.  Do you really think he was in a position to doubt Rabe's work?  The quotes from Doering state quite plainly that there was never any suspicion at the time about the validity of Rabe's work.  If that is the case, the how can you question Woodward's belief that he had completed a formal synthesis?

Unfortunately, experimental details have not always been required for publication, so results are quite often difficult to reproduce.  Even today there are journals that do not require explicit experimental details!

[wintermute]

I am sorry but I don't see any word on fabrication of data or questioning anyone's belief in my post. I do not accuse either Rabe or Woodward of any scientific missconduct. I just ask myself question whether the work that can't be reproduced should be considered as formal synthesis. Perhaps my post was not clear becouse of weak english. Sorry.

[movies]

Sorry, I think I misread your comment.  I understand your point now, and it is a valid one.

The problem of reproducibility is a vast one.  Different people have different expertise with different reactions.  Standard operating procedure for one person might be significantly different from that of another.  I think that the point of a formal synthesis is that you have proven that you can make a molecule which someone else has proven can be converted to a natural product.  It's more about the established precedent than it is about actually carrying out someone elses work.

There isn't much point in reinventing the wheel if someone has already established a method.

[Ψ×Ψ]

Personally, I'm a little suspicious of any pre-NMR work.  I don't mean it as an accusation, though.  Reactions can be tricksy hobbitses.  Sometimes you just don't know what it is until it's all over with and characterized.  And sometimes, even when you know what the product HAS TO BE, you're still wrong.  Better yet, show me a crystal structure.  In most cases, I'll believe that.

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The crystal structure was wrong for diazonamide!

[Ψ×Ψ]

Thus "in most cases."  Some are trickier than others!*

*Psi-star-psi isn't entirely sure what she's talking about, but crystallography is her favourite class this semester.

[Mitch]

Oh-no. Once they turn 21 they start talking about themselves in the third person. Mitch is glad it isn't just him.

[Albert]

Great post!

So, you couldn't wait, eh? 

[movies]

Heh, no.  I had been thinking of suggesting it to you for a while, actually.

I just talked about the synthesis, you could still tell me about how it actually works.  That is way beyond my expertise.