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Quinine, Definately…   

6 February 2008 21,652 views 29 Comments

Woodward and Doering, JACS, 1944, 66, 849. DOI: 10.1021/ja01233a516; JACS, 1945, 67, 860. DOI: 10.1021/ja01221a051.Group Website

Williams and Smith, ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200705421. Article PDF Supporting Information Group Website

It’s fair to say (in some respects at least) that this isn’t the freshest total synthesis report ever, but it’s certainly one of the most interesting, as a chapter of synthetic chemistry that has caused serious controversy has now been closed. This whole affair revolves around Woodward’s formal total synthesis of quinine, first published way back in 1944. His work with Doering led to an advanced intermediate, d-quinotoxine, which had featured in a synthesis of quinine performed by Rabe and Kindler way way back in 1918. However, some concern was voiced as the original 1918 paper was somewhat scant on detail. Indeed, there wasn’t a proper experiment (even by 1918 standards) – only a reference to the use of similar chemistry in analogous work.

Though this might seem to stitch these works together, one Gilbert Stork was still rather disgruntled with this work. (A full and interesting discussion of the history, politics and science of this affair can be read in Jeffrey Seeman’s awesome Angewandte) Somewhat interestingly, Stork originally voiced his opinion in 1944 by way of an unanswered letter to Woodward asking

“…Would you also tell me whether Rabe’s conversion of quinotoxine into quinine has been repeated by you in your recent work”

With no answer recieved, I guess Storks concern grew, along with his interest in the molecule. His own work on Quinine was complete in 2001 with a publication titled “The First Stereoselective Total Synthesis of Quinine” detailing Storks impressive stereoselective synthesis of our molecule. However, in that paper he once again suggests that the Rabe synthesis is flawed, and that there is no evidence that the chemistry works. With the Rabe work in question, the Woodward synthesis did indeed seem to be in doubt.

Recently, though, vindication was achieved for both Woodward and Rabe, as Williams has recently completed the Rabe chemistry “deploying the experimental protocols originally described by Rabe and his co-workers”. So, we finally get to some chemistry!

The Rabe chemistry begins with d-quinotoxine, available from an acidic degradation of quinine itself (thus turning this work into a sort-of-relay-synthesis). The SM was oxidised to the N-bromide, and the bromine displaced with the enolate of the ketone using a little base. This resulting (initially) in exclusive formation of quinidinon, which was found to isomerise to an equilibrium mixture of the desired quininone and quinidinone. Then to the crux of the problem – the reduction of the ketone to deliver quinine. Rabe states that they used “powdered aluminium” to perform this, so Williams did what any sensible 21st century chemist would do and cracked out the Aldrich pot. However, no product was isolated. To cut a long (and interesting) story short, they found that what they needed was Edwardian Al-powder, made from ground-up Sopwith Camels. With some aged Al-powder – quinine! Okay, the yield was rubbish, and the product was a mixture of diastereoisomers, but they did it. (I think the recrystalisations were somewhat traumatic, though :) – the group need to grow more facial hair if they want to improve their technique).

With the Woodward chemistry validated, I thought we’d look back at that 1944 chemistry and marvel at the skills involved. Please knock your synthetic brain into 1940′s mode though – no NMR, flash chromatography or TLC. Hard-core.

Woodward took a few steps about making our SM, starting with an elimination to give an exo-cyclic methylene, which was reduced. Then, time for a bit more hydrogen, taking that pyridine down entirely. The amine was protected, and then the remaining aryl group reduced again! Now we’ve reduced-away all the aromaticity, the alcohol was oxidised to form the corresponding cyclohexanone as a mixture of cis/trans-decalins.

Then, a bit of Woodward genius: a nitrite ester ring clevage (when was the last time you did that?). The mechanism is in Classics in Total Synthesis II. The oxime was then reduced and eliminated, and after a bit of protecting group juggling, the key Dieckmann condensation used to append the quinoline moiety, completing the formal synthesis. For sure!

A bit of ‘spect goes out to Jeffrey Seeman for the paper I mentioned above, and an amazing lecture he gave on this subject last year in Oxford. Also, I want to reaffirm my admiration for Gilbert Stork – good scientists are critical of the literature.

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29 Comments

  • Hap says:

    Stork is a really good chemist, but I don’t know that this does him honor. At least today, it isn’t standard practice to reproduce the literature synthesis in order to be able to claim a formal total synthesis (though, in that case, Woodward and Doering shouldn’t have sold their synthesis as a total synthesis, but the term “formal synthesis” may not have been in use yet) – you trust that the authors of the previous work have reported their work accurately. The Seeman article in ACIEE does a good job of dismantling the questionability of Rabe’s claims and without that, there isn’t really a good basis for Stork to claim that the formal synthesis of quinine wasn’t a synthesis of quinine at all.

    The yield of Williams and Smith sucks, but if yu’re working on the scale of their progenitors, 5% is at least a reasonable amount of product (as long as you can recrystallize and don’t have to column).

  • Spiro says:

    This is a must-read for total synthesis geeks. But, frankly, do the NIH have to support that kind of science, and did science progress with this attempt to repeat a 1910′s work?
    I hope our grandchildren will never read a 2090 Angewandte paper entitled “LaClair Rest in Peace: Confirmation oh Hexacyclinol…”

  • PMP says:

    This paper is indeed remarkable for a several reasons:

    1) The authors were actually able to reproduce both the Rabe-Kindler reduction protocol *and* the isolation / crystallization of quinine from the mixture. The art of obtaining pure, crystalline products from very difficult mixtures is, unfortunately, a skill where the chemists of today do not always excel. As stated in the paper: “We must despair that the mastery of crystallization techniques in the early part of the 20th century certainly surpasses that routinely practiced today.”

    2) In my past life, I used to work with pyrotechnic mixtures, including various glitter and flitter type formulas. The multitude of sparks, glittering flashes, silvery showers etc. are almost exclusively made with different grades of aluminium. There are spherical powders, stamped flakes, greasy-smelling flakes that leave small silvery specks everywhere, dark pyro grades, and the coarse “Griess” -type powders… each of these behave quite differently, and oftentimes it is very hard to find a good substitute if your favorite brand is no longer supplied. As such, it is almost certain that in 2007 in the USA, one will not find the same brand of aluminium that Rabe and Kindler used in 1918.

    Even today, I like to kick off a difficult Grignard with pyro-grade magnesium, fresh from the supplier. What a difference to the old bottle of “Späne nach Grignard zur Synthese”.

  • willyoubemine says:

    Kudos Totally Synthetic for a historic post. Love this, keep em coming.

  • Big C says:

    Tot. Syn. delivers again. Informative and comprehensive, as always.

  • bad wolf says:

    Fascinating topic! “Critical of the literature” is certainly appropriate but the Angewandte paper was reminiscent of watching “Amadeus”, with Stork as Salieri stewing for fifty years over his own missed chances…

  • ZZZZZ says:

    ZZZZZ

    …fantastic topic. I think Stork brought up a great point, namely that people had NOT been able to reproduce the Rabe work in the past. The fact that it is now (poorly) reproducible does not necessarily diminish the important issue that he raised. Frankly, I’m surprised that it took so long for someone to clear this up in the lab. Unfortunately, Woodward and Doering would have avoided a lot of the controversy over the years had they just repeated the Rabe procedure themselves. Oh, a small point by the way: it’s a Claisen condensation (not a Dieckmann). OK, back to sleep for me…

    ZZZZZ

  • TWYI says:

    Can anyone send me the link to Woodward’s supporting info to his one page JACS communication?

  • rosko says:

    How in the world did chemists at that time determine the structure of a molecule as complex as quinine? That’s almost as amazing as the synthesis.

    Also, from the article:

    “The Polaroid Corporation was interested in quinine, because they used quinine in manufacturing light-polarizing material. And so they set Bob Woodward to work, trying to create synthetic quinine”

    Wasn’t there some more readily available asymmetric molecule known at the time (I’m assuming chirality is the property of interest here–correct me if I’m wrong).

  • Tot. Syn. says:

    ZZZZZ:

    I thought it was a Claisen condensation too… but it’s clearly stated in the source material that it is a Diekmann condensation. The Diekmann is effectively an intramolecular Claisen, but this isn’t even intramolecular, so definately a Claisen, right?

  • PENN CHEM says:

    When you get a chance you should check out the total synthesis of okilactomycin (came out ~3 months ago in JACS). It’s a real nice piece of work and a full paper should be out shortly, the two post-docs that worked on it were outstanding, keep an eye out.

  • Former OSU Chem says:

    Penn Chem,
    I second that suggestion of the okilactomycin paper. I used to work with one of the authors when he was a grad student at OSU.

  • Tot. Syn. says:

    Good call, will do asap.

  • canuck chemist says:

    rosko:

    maybe it had to do with the fact that quinine fluoresces…just a shot in the dark.

  • antiaromatic says:

    Maybe it’s just me, but the heart of the issue that Stork brought up still isn’t resolved by William’s repetition of the Rabe route. The issue at hand is whether or not Woodward actually knew that he had quinine. I know it sounds subtle, but it’s an important point.

  • TWYI says:

    Has this turned into a portal where you can push your own work?

    Incredibly diasappointing and it saddens me.

  • milkshake says:

    when the work is not crap then there is no reason for sadness. Paul has the last say. Let see how he handles those quid-pro-quo offers

  • ... says:

    I recommend Movassaghi’s latest alkaloid synthesis in ACIEE. Tonnes of complexity in very few steps.

  • ZZZZZ says:

    ZZZZZ

    …Hey Tot. Syn., yeah I saw that they called it a Dieckmann too, but as far as I know that is not accurate by today’s standards. As you said, Dieckmann is an intramolecular Claisen, so it’s not a big point to be sure. Maybe the named-reactions have changed slightly since then…

    ZZZZZ

  • chemist says:

    Stork raised the point of reproducibility yet in 40′s. The point is that there is a big difference between making merequinine and quinine. Woodward made merequinine, which is a great achievement at those times, but he, probably, wouldn’t succeed at making quinine. With a 5% yield for the reduction step, one would need large amounts of merequinine (10-100g) to complete the synthesis.

  • Tot. Syn. says:

    That’s not entirely true. As shown in the paper above, Quinine can be transformed into d-quinotoxine in one reasonable step. Woodward could then use this material to “bulk-up” the quanity of d-quinotoxine produced in his synthesis, and complete the low-yielding Rabe chemistry. This is known as a “relay” approach to total synthesis, and is still used occassionally. Look at Steve Ley’s synthesis of Azadirachtin for a more modern example.

  • ZZZZZ says:

    ZZZZZ

    …true, a relay synthesis could have been used. I think you meant azadirachtin by the way Tot. Syn….

    ZZZZZ

  • Tot. Syn. says:

    Comment corrected!

  • Hap says:

    I think Seeman made the points that 1) Rabe’s procedure might have been hard to reproduce and neither Woodward or Doering wanted to try and fail to complete the conversion to quinine (Woodward was still a young professor at the time) and 2) no one else was eager to reproduce Rabe’s steps, either – everyone else assumed that they could be reproduced and moved on. Just as now, it’s hard to prove that chemistry actually doesn’t work (as opposed to the researcher being not competent enough), so even if Woodward couldn’t convert d-quinotoxine to quinine, it would not effectively prove it couldn’t be done. Later work of Woodward’s indicated that perhaps he should have reproduced Rabe’s work at the time (though it doesn’t appear that he did later).

    I still don’t concur that Woodward needed to repeat Rabe’s work – though he did not make clear enough that his was a formal synthesis, we don’t have the expectation that people who complete formal synthesis should have repeated the steps of the referenced syntheses. Repeating some of the closing steps of today’s syntheses would likely be more difficult because of the small scale of such syntheses – as was discussed in a post on In The Pipeline, the yields of most total syntheses (and maybe anything else about them) are likely irreproducible. Perhaps formal synthesis going away wouldn’t be so bad, but it probably wouldn’t be good, either.

  • chemist says:

    Relay synthesis would be a possibility. However, there is a big difference between a relay synthesis and a total synthesis. Quinine made Woodward famous. He was all over the newspapers and radio. At that moment there was a demand in quinine, and Woodward created a myth that he can make it synthetically in large amounts. Let’s assume that Woodward would have no problems with the relay synthesis or even could repeat the steps of Rabe with a low yield. The point raised by Stork (and Corey with Woodward-Hoffman rules) is different:

    There was a star called R. B. Woodward. He is “the father of the modern organic chemistry”. He was a superhuman, god, Legend, etc. However, Stork and Corey correct these impressions a little bit. They don’t deny most of the Woodward’s achievements. They just say that besides Woodward’s brilliance there is a lot of advertisement. The old guys like Stork, Corey, Roberts and Doering realize it, but the new generation doesn’t have an idea and tends to think about Woodward like he is a Goddess.

    BTW. There is a few interesting quotes about Woodward given by Doering. One of them about Woodward’s abilities to do a lab work.

  • TWYI says:

    I can’t access the papers at home, what solvent was the second hydrog done in? (If any at all).

    3000psi and 150 degrees C. Wouldn’t fancy leaving that one overnight

  • Dude says:

    Chemist,

    You bring up some good points. Woodward also died relatively young, which has not hurt his fame. Where would one find those Doering quotes?

  • chemist says:

    Dude,

    The quotes are in the Seeman’s ACIEE review (closer to the end)