Published online 4 February 2008 | Nature | doi:10.1038/news.2008.554


A tonic for quinine chemistry

1940s re-enactment helps to verify old chemical claim.

Quinine, of gin and tonic fame, is still easiest to get from a plant rather than the lab.Simple stock shots

In 1918, German chemists Paul Rabe and Karl Kindler published a method for the final steps in making the potent antimalarial drug quinine. Little did Rabe know that 90 years later his lab books would be reopened and his procedure recreated, to help end a 60-year dispute about the synthesis of what was once the most potent antimalarial drug available.

Quinine is extracted from the bark of the cinchona tree, and despite over a century of trying, no synthetic recipe has been found that is cheaper and easier than the natural extraction.

The first production of the compound came in 1944, during an intense effort to make a synthetic version of the antimalarial during the Second World War, when the trade of natural products was blocked.

Robert Woodward and William Doering from Harvard University published a 17-step procedure that went as far as the compound d-quinotoxine1. Making quinine from here is just three steps, according to Rabe’s earlier work2. So Woodward and Doering claimed the total synthesis trophy by implication — as Rabe’s earlier work picked up where Woodward stopped, the entire reaction scheme was now known. Sticking together bits of known work in this way is quite common, and makes what is called a ‘relay’ or ‘formal’ total synthesis

But even though the total synthesis had been cracked, it was still easier to extract the stuff from the cinchona tree. So no one used the full recipe, instead focusing on refining and improving the synthesis, hoping to learn something more about the properties of the drug on the way, or to find a new drug candidate.

Pass the baton

Meanwhile, Woodward's and Doering's claim was disputed by some chemists, including Gilbert Stork from Columbia University in New York, who in 2001 published his own total synthesis of quinine — the first to produce a single specific shape of the molecule, rather than the mixtures of mirror-imaged shapes reported previously3. Stork emphasized that the 1944 work never actually produced quinine, and noted that there was no evidence that those final steps, as written by Rabe, would have worked for the team had they tried them.

Fast forward to 2007, when Robert Williams, at Colorado State University is still chasing a better way to make quinine. Williams realized that no one had ever reported trying to repeat Rabe’s reaction from d-quinotoxine to quinine, which if it worked would confirm that Woodward had been right to stop his synthesis where he did. So Williams asked his postdoctoral researcher Aaron Smith to have a go. “We just wanted to see if they were right or wrong,” says Williams.

Williams didn’t want to just recreate the reaction: he wanted to recreate the lab of the 1940s, with the conditions that Woodward and Doering would have been subject to. “I told [Smith] to pretend he was in 1944,” says Williams, "That’s when Doering would have had to do it." Thankfully, Rabe had published a follow-up paper to his 1918 version in 1939, with more details about the synthesis, so they didn't have to go right back to the start.

But it did mean no modern analytical techniques, no easy purification of intermediates and no way to purify the final product without a mastery of the dying art of crystallization. Purifying the products at the end of each step makes the following reactions easier, with smaller risks of side reactions spoiling things. Smith didn’t have this luxury and had to push ahead with a crude mixture. “It was challenging,” says Williams.

Finish line

Following the 1939 instructions, Williams and Smith came to the right product — quinine. The recreation is published in Angewandte Chemie4.

Although this time-consuming synthesis isn't very useful today, it is historically important, says Ian Paterson, a chemist at the University of Cambridge.


Paterson suspects that his students would have been horrified if he had asked them to do a reaction using only 1940s techniques and equipment. Successful chemical syntheses in the 1940s and before would have been “capricious” Paterson says.

Williams is still trying to perfect a route to quinine, even though its use to routinely treat malaria has largely been taken over by other drugs. His pursuit is mainly academic, but along the way Williams hopes to find analogues of the drug that could lead to potential new anti-malarial drugs — and a way to make them in the lab. 

  • References

    1. Woodward, R. B. & Doering, W. E. J. Am. Chem. Soc. 66, 849 (1944).
    2. Rabe, P. & Kindler, K. Ber. Dtsch. Chem. Ges. 51, 466-467 (1918). | Article | ChemPort |
    3. Stork, G. et al. J. Am. Chem. Soc. 123, 3239-3242 (2001). | Article | PubMed | ISI | ChemPort |
    4. Smith, A. C. & Williams, R. M. Angew. Chem. Int. Ed. doi:10.1002/anie.200705421 (2008).
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