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Synthesis

Quinine

Purpose Antimalarial

by RON DAGANI
June 20, 2005 | A version of this story appeared in Volume 83, Issue 25

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Credit: Courtesy of Daniel Rabinovich, UNC
This 1970 first day cover commemorates the 150th anniversary of Pelletier and Caventou's isolation of quinine.
Credit: Courtesy of Daniel Rabinovich, UNC
This 1970 first day cover commemorates the 150th anniversary of Pelletier and Caventou's isolation of quinine.

The bark of the cinchona tree, containing the alkaloid quinine, was the first effective treatment for malaria, appearing in therapeutics in the 17th century. It remained the antimalarial drug of choice until the 1940s, when other drugs took over. Since then, many effective antimalarials have been introduced, although quinine is still used to treat the disease in certain critical situations.

Malaria has afflicted humans for thousands of years. Today, an estimated 300 million to 500 million new cases occur each year, with more than 90% in sub-Saharan Africa. The disease claims between 1.5 million and 2.7 million lives annually, the vast majority of them young children.

Malaria is caused by a microscopic parasite called Plasmodium that infects humans when they are bitten by an infected female Anopheles mosquito. Inside the human host, the parasite multiplies in the liver and in red blood cells, which periodically release more parasites, concomitantly causing fever. These organisms can infect any mosquito that feeds on the host's blood, thus helping to spread the disease.

The natives of South America who became ill from malaria could not have understood what was causing the fever. But it seems they knew it could be assuaged by using a preparation of the bark of the cinchona, an evergreen that grew on the eastern slopes of the Andes Mountains from Venezuela to Bolivia. The Jesuits learned of the "quina-quina" bark's antimalarial properties in Peru and are credited with introducing cinchona bark into medical use in Europe around 1640. By 1681, it was widely accepted as a malaria remedy.

The medicine "raised demand for the bark, which culminated in the installation of a Spanish-owned commercial monopoly and the beginning of the slow extinction of the natural cinchona forests because of overharvesting," write chemists Teodoro S. Kaufman and Edmundo A. Rveda of the National University of Rosario, in Argentina, in a lengthy review article on quinine's history (Angew. Chem. Int. Ed. 2005, 44, 854).

In the mid-1700s, chemists in Europe began taking renewed interest in herbal remedies, including cinchona bark. They became convinced that the powdered bark contained a chemical compound that was responsible for the curative properties. That compound remained elusive until 1820, when two French pharmacists, Pierre-Joseph Pelletier and Joseph-Bienaim Caventou, isolated an alkaloid that they called quinine. After medical experiments by others established that this compound was indeed the active antimalarial principle in quina bark, the purified compound began to be used instead of the powdered bark to treat malaria. Pelletier and Caventou set up a factory in Paris for the extraction of quinine.

By the 1800s, the French, British, and Dutch all had colonies in malaria-infested areas, and the demand for quinine rose. Several efforts were made to cultivate the cinchona tree outside of South America, with limited success. In 1850, the French Society of Pharmacy called on chemists to find a way to prepare synthetic quinine.

"Organic synthesis was embryonic at that time," Kaufman and Rveda write, and "there were no appropriate concepts for [chemical] structure." The correct empirical formula for quinine wasn't even established until 1854. For the next 50 years or so, chemists focused on the difficult task of elucidating the molecular structure of quinine rather than trying to make it.

By 1908, chemists had figured out how quinine's atoms are connected to each other, although some stereochemical issues would not be clarified until the 1940s.

A big step came in 1944 when, driven by the quinine shortage during World War II, Robert B. Woodward and William von E. Doering at Harvard University synthesized d-quinotoxine, a molecule that, it was believed, could be converted into quinine using a procedure developed by German chemist Paul Rabe. However, Woodward and Doering did not report any evidence that they had actually converted d-quinotoxine into quinine. Rabe's procedure turned out to be very poorly documented and thus hard to follow, so Woodward and Doering's claim of the first formal total synthesis of quinine remained just a claim.

Even if the Harvard team had made quinine, the synthesis was plagued by low yields, did not allow control of the stereochemistry, and could not have afforded commercial quantities, according to Kaufman and Rveda. Nevertheless, the synthesis was viewed as a scientific milestone.

In succeeding decades, many new synthetic drugs, including chloroquine, primaquine, proguanil, and artemisinins, were deployed against malaria. But organic chemists never lost sight of the intellectual challenge of reproducing nature's own quinine in the laboratory.

In 1970, Milan R. Uskokovic and coworkers at Hoffmann-La Roche in Nutley, N.J., disclosed the first total synthesis of quinine, although stereocontrol was still incomplete.

It wasn't until 2001 that a fully stereochemically controlled total synthesis of quinine was achieved by Columbia University's Gilbert Stork and colleagues.

In 2004--60 years after Woodward and Doering's accomplishment--two new highly stereocontrolled total syntheses of the natural product were unveiled. One was achieved by Harvard's Eric N. Jacobsen and coworkers. The other came from Yuichi Kobayashi's group at Tokyo Institute of Technology in Yokohama, Japan.

The impetus behind these and other synthetic efforts was perhaps best explained by Stork, who said: "The value of a quinine synthesis has essentially nothing to do with quinine. It is like the solution to a long-standing proof of an ancient theorem in mathematics: It advances the field.


Quinine


Name: (8α ,9R)-6'-Methoxycinchonan-9-ol


CAS Registry: 130-95-0


Other names: (-)-Quinine, (R)-(-)-Quinine, 6'-methoxycinchonidine, chinine


Did you know that about 40% of commercial quinine is used by the pharmaceutical and fine chemicals industries? About 60% is used in the food industry as the bitter principle of soft drinks.


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