Penny le Couteur & Jay Burreson (55 page)

Word that the bark of the
quina
tree could cure malaria quickly spread to Europe. In 1633 Father Antonio de la Calaucha recorded the amazing properties of the bark of the “fever tree,” and other members of the Jesuit order in Peru began using
quina
bark to both cure and prevent malaria. In the 1640s Father Bartolomé Tafur took some of the bark to Rome, and word of its miraculous properties spread through the clergy. The papal conclave of 1655 was the first without a death from malaria among the attending cardinals. The Jesuits were soon importing large amounts of the bark and selling it throughout Europe. Despite its excellent reputation in other countries, “Jesuit's powder”—as it became known—was not at all popular in Protestant England. Oliver Cromwell, refusing to be treated by a papists' remedy, succumbed to malaria in 1658.

Another remedy for malaria gained prominence in 1670, when Robert Talbor, a London apothecary and physician, warned the public to beware of the dangers associated with Jesuit's powder and started promoting his own secret formulation. Talbor's cure was taken to the royal courts of both England and France; his own king, Charles II, and the son of Louis XIV, the French king, both survived severe bouts of malaria thanks to Talbor's amazing medication. It was not until after Talbor's death that the miraculous ingredient in his formulation was revealed; it was the same cinchona bark as in Jesuit's powder. Talbor's deceit, while no doubt making him wealthy—presumably his main motive—did save the lives of Protestants who refused to be associated with a Catholic cure. That quinine cured the disease known as ague is taken as evidence that this fever, which had plagued much of Europe for centuries, was indeed malaria.

Through the next three centuries malaria—as well as indigestion, fever, hair loss, cancer, and many other conditions—was commonly treated with bark from the cinchona tree. It was not generally known what plant the bark came from until 1735, when a French botanist, Joseph de Jussieu, while exploring the higher elevations of the South American rain forests, discovered that the source of the bitter bark was various species of a broad-leafed tree that grew as high as sixty-five feet. It was a member of the
Rubiaceae,
the same family as the coffee tree. There was always great demand for the bark, and its harvesting became a major industry. Although it was possible to gather some of the bark without killing the tree, greater profits could be made if the tree was felled and all the bark stripped. By the end of the eighteenth century an estimated 25,000
quina
trees were being cut down each year.

With the cost of cinchona bark high and the source tree possibly becoming endangered, isolating, identifying, and manufacturing the antimalarial molecule became an important objective. Quinine is thought to have been first isolated, although probably in an impure form, as far back as 1792. Full investigation of what compounds were present in the bark started around 1810, and it was not until 1820 that researchers Joseph Pelletier and Joseph Caventou managed to extract and purify quinine. The Paris Institute of Science awarded these French chemists a sum of ten thousand francs for their valuable work.

Cinchona tree from whose bark quinine is obtained.
(Photo courtesy of L. Keith Wade)

Among the almost thirty alkaloids found in cinchona bark, quinine was quickly identified as the active ingredient. Its structure was not fully determined until well into the twentieth century, so early attempts to synthesize the compound had little chance of success. One of these was the effort of the young English chemist William Perkin (whom we met in Chapter 9) to combine two molecules of allyltoluidine with three oxygen atoms to form quinine and water.

Working in 1856 on the basis that the formula of allyltoluidine (C
₁₀
H
₁₃
N) was almost half that of quinine (C
₂₀
H
₂₄
N
₂
O
₂
), his experiment was doomed to fail. We now know that the structure of allyltoluidine and the more complicated structure of quinine are as follows:

While Perkin failed to make quinine, his work was extremely fruitful for making mauve—and money—for the dye industry and for the development of the science of organic chemistry.

As the Industrial Revolution brought prosperity to Britain and other parts of Europe during the nineteenth century, capital became available to tackle the problem of unhealthy, marshy farmland. Extensive drainage schemes turned bogs and fens into more productive farms, meaning that less stagnant water was available for breeding mosquitoes, and the incidence of malaria decreased in regions where it had been most prevalent. But the demand for quinine did not decrease. On the contrary, as European colonization increased in Africa and Asia, there was more demand for protection against malaria. The British habit of taking quinine as a prophylactic precaution against malaria developed into the evening “gin and tonic”—the gin being considered necessary to make the bitter-tasting quinine in the tonic water palatable. The British Empire depended on supplies of quinine, as many of its most valuable colonies—in India, Malaya, Africa, and the Caribbean—were in regions of the world where malaria was endemic. The Dutch, French, Spanish, Portuguese, Germans, and Belgians also colonized malarial areas. Worldwide demand for quinine was enormous.

With no synthetic route to quinine in sight, a different solution was sought—and found: the cultivation of cinchona species from the Amazon in other countries. Profit from the sale of cinchona bark was so great that the governments of Bolivia, Ecuador, Peru, and Colombia, in order to maintain their monopoly over the quinine trade, prohibited the export of living cinchona plants or seeds. In 1853, the Dutchman Justus Hasskarl, director of a botanical garden on the island of Java in the Dutch East Indies, managed to smuggle a bag of seeds from
Cinchona calisaya
out of South America. They were successfully grown in Java, but unfortunately for Hasskarl and the Dutch, this species of the cinchona tree had a relatively low quinine content. The British had a similar experience with smuggled seeds from
Cinchona pubescens,
which they planted in India and Ceylon. The trees grew, but the bark had less than the 3 percent quinine content needed for cost-effective production.

In 1861, Charles Ledger, an Australian who had spent a number of years as a
quina
bark trader, managed to persuade a Bolivian Indian to sell him seeds of a species of cinchona tree that supposedly had a very high quinine content. The British government was not interested in buying Ledger's seeds; their experience with cultivation of cinchona had probably led them to decide that it was not economically viable. But the Dutch government purchased a pound of seeds of the species, which became known as
Cinchona ledgeriana,
for about twenty dollars. Although the British had made the smart choice nearly two hundred years previously in ceding the isoeugenol molecule of the nutmeg trade to the Dutch in exchange for the island of Manhattan, it was the Dutch who made the correct call this time. Their twenty-dollar purchase has been called the best investment in history, as the quinine levels in
Cinchona ledgeriana
bark were found to be as high as 13 percent.

The
C. ledgeriana
seeds were planted in Java and carefully cultivated. As the trees matured and their quinine-rich bark was harvested, the export of native bark from South America declined. It was a scenario repeated fifteen years later, when smuggled seeds from another South American tree,
Hevea brasiliensis,
signaled the demise of indigenous rubber production (see Chapter 8).

By 1930 over 95 percent of the world's quinine came from plantations on Java. These cinchona estates were hugely profitable for the Dutch. The quinine molecule, or perhaps more correctly the monopoly on the cultivation of the quinine molecule, almost tipped the scales of World War II. In 1940 Germany invaded the Netherlands and confiscated the complete European stock of quinine from the Amsterdam premises of the “kina bureau.” The 1942 Japanese conquest of Java further imperiled the supply of this essential antimalarial. American botanists, led by Raymond Fosberg of the Smithsonian Institution, were sent to the eastern side of the Andes to secure a supply of
quina
bark from trees still growing naturally in the area. Although they did manage to procure a number of tons of bark, they never found any specimens of the highly productive
Cinchona ledgeriana
with which the Dutch had had such astounding success. Quinine was essential to protect Allied troops in the tropics, so once again its synthesis—or that of a similar molecule with antimalarial properties—became extremely important.

Quinine is a derivative of the quinoline molecule. During the 1930s a few synthetic derivatives of quinoline had been created and had proven successful at treating acute malaria. Extensive research on antimalarial drugs during World War II resulted in a 4-aminoquinoline derivative, now known as
chloroquine,
originally made by German chemists before the war, as the best synthetic choice.

Chloroquine contains a chlorine atom—another example of a chlorocarbon molecule that has been extremely beneficial to humanity. For over forty years chloroquine was a safe and effective antimalarial drug, well tolerated by most people and with little of the toxicity of the other synthetic quinolines. Unfortunately, chloroquine-resistant strains of the malaria parasite have spread rapidly in the past few decades, reducing the effectiveness of chloroquine, and compounds such as fansidar and mefloquine, with their greater toxicity and sometimes alarming side effects, are now being used for malarial protection.

The quest to synthesize the actual quinine molecule was supposedly fulfilled in 1944, when Robert Woodward and William Doering of Harvard University converted a simple quinoline derivative into a molecule that previous chemists, in 1918, had allegedly been able to transform into quinine. The total synthesis of quinine was finally presumed complete. But this was not the case. The published report of the earlier work had been so sketchy that it was not possible to ascertain what had really been done and whether the claim of chemical transformation was valid.