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SCIENCE & TECHNOLOGY
May 7, 2001
Volume 79, Number 19
CENEAR 79 19 pp. 54-56
ISSN 0009-2347
QUININE REVISITED
Early efforts to synthesize quinine make a complex story, the historical record shows
A. MAUREEN ROUHI, C&EN WASHINGTON
Fifty-five years have passed since Gilbert Stork, now emeritus professor of chemistry at Columbia University, first considered constructing the alkaloid quinine in a fully controlled manner. He achieved that lifelong dream last month with the publication of the first completely stereoselective total synthesis of quinine [J. Am. Chem. Soc., 123, 3239 (2001)].
Yet Stork's first remark when asked about the work is, "Footnote 14 is the best part."
In footnote 14, Stork refers to the "quasiuniversal impression" that Harvard University chemists Robert B. Woodward and William von Eggers Doering achieved the synthesis of quinine with the construction in 1944 of an intermediate in a route to quinine.
Natural quinine comes from the bark of cinchona trees. For centuries, it was the only remedy for malaria. During World War II, ample supplies of quinine were critical to the U.S. war effort. At that time, plantations established by the Dutch on the island of Java were the major source of the bark. Japanese military action during the war abruptly cut off these supplies, causing alarm among the Allied powers and firing up research in synthetic antimalarials.
The claim that quinine had been synthesized catapulted Woodward, then only 27, onto the national scene. On May 4, 1944, the front page of the New York Times declared, "Synthetic quinine produced, ending century search." And on June 10, 1944, Science News Letter hailed Woodward and Doering for producing a drug vital to the war effort "without the aid of a tree." Other stories followed in national magazines.
The literature shows that those accolades were "in part based on wishful thinking," Stork says, because what was synthesized at Harvard in 1944 was an intermediate many steps away from quinine. It is only half of the molecule and lacks quinine's characteristic ring system. The final steps that Woodward and Doering assumed would take that intermediate to quinine likely would not have worked had they tried them.
Stork is widely regarded as one of the giants of synthetic chemistry. While acknowledging without question Woodward's extraordinary brilliance, Stork has nevertheless tried to correct the mistaken notion that Woodward and Doering synthesized quinine.
FOR EXAMPLE, in the Chemical Heritage Foundation's traveling exhibit called "Robert Burns Woodward and the Art of Organic Synthesis," Stork says he argued that the Woodward-Doering synthesis be accurately described as that of the intermediate cis-3-vinyl-4-piperidinepropionic acid, not of quinine. Last year, in a letter to C&EN (Sept. 25, 2000, page 8), he referred to the Woodward-Doering quinine synthesis--mentioned in the ACS publication the Pharmaceutical Century--as a "widely believed myth." Occasionally, he says, when asked to comment on biographies of Woodward, he has corrected attributions of quinine synthesis to the late Nobel Laureate. And in his latest paper, he provides a historical background that puts the different attempts to synthesize quinine in perspective.
Stork thinks the myth was encouraged by the media hype at the time. But despite his efforts to dispel the misconception, it persists to this day in encyclopedias, biographical compilations, and scholarly references. In Stork's opinion, the first total synthesis of quinine was achieved in 1970 by researchers at Hoffmann-La Roche in Nutley, N.J.
The historical perspective Stork provides in no way undermines the stature of Woodward. It "simply sets the record straight," comments Amos B. Smith III, a chemistry professor at the University of Pennsylvania. "The literature of synthetic organic chemistry is of historic importance, and it is important that it be correct. I believe that the community at large was not fully aware of the facts laid out in Gilbert Stork's paper."
According to Stork, the myth began with the title of a paper published in 1944 [J. Am. Chem. Soc., 66, 849]: "The Total Synthesis of Quinine." A full paper with the exact same title was published the following year [J. Am. Chem. Soc., 67, 860 (1945)]. In these two papers, Woodward and Doering describe primarily the synthesis of cis-3-vinyl-4-piperidinepropionic acid. "This was," Stork says, "an impressive achievement. But it wasn't quinine."
The intermediate cis-3-vinyl-4-piperidinepropionic acid is one in a route to quinine based on a connectivity analysis ascribed to the German chemist Paul Rabe. A year before the first Woodward-Doering paper, the Sarajevo-born chemist Vladimir Prelog, later a Nobel Laureate, showed that cis-3-vinyl-4-piperidinepropionic acid derived from quinine could be converted to so-called quinotoxine, another intermediate in Rabe's route. And much earlier, in 1918, Rabe had claimed to have converted quinotoxine to quinine.
These previously reported steps should take cis-3-vinyl-4-piperidinepropionic acid to products that include quinine. On that basis, Woodward and Doering claimed total synthesis of quinine. These days, what they achieved would be called a "formal total synthesis," assuming that the earlier works could be reproduced as published.
As a young graduate student at the University of Wisconsin, Madison, also working on constructing quinine, Stork was very impressed with the Harvard work, he tells C&EN. "I never questioned it. But over the years, it became likely that they never made any quinine by the Rabe route."
Doering, now an emeritus professor of chemistry at Harvard, confirms that no quinine was produced from the cis-3-vinyl-4-piperidinepropionic acid prepared in 1944. After he and Woodward successfully converted this compound to quinotoxine, they wrote in 1945: "In view of [Rabe's] established conversion of quinotoxine to quinine, with the synthesis of quinotoxine, the total synthesis of quinine is complete."
But according to Stork, Rabe's documentation of that key conversion was "extremely sketchy." He notes that Rabe's paper--describing how a 3,4-disubstituted piperidine is transformed to a quininelike structure--takes only one-and-a-quarter pages of a book about the size of a large paperback. He speculates that Rabe's vagueness may have been due to the difficult situation in Germany around the end of World War I.
Fourteen years later, Rabe acknowledged that he had not described the details properly, Stork says. Rabe then proceeded to give a recipe--but for a compound similar to, but not, quinotoxine. Among other things, that compound does not have the vinyl group that's present in quinotoxine. Whether the recipe would work for a substrate containing such a reactive group is not clear.
Stork knows of no written document showing that others have tried to repeat the quinotoxine/quinine conversion using Rabe's recipe. He himself did not attempt to. "It would have been a thankless task," he says. "If you don't succeed, it would mean you're incompetent. If you succeed, so what?" But when one claims total synthesis on the basis of previously established transformations, one should at least verify that the transformations proceed as one believes, he explains. "For whatever reason, Woodward and Doering never tried the Rabe steps," Stork says.
In the 1960s, a team of researchers at Hoffmann-La Roche were studying the synthesis of quinine and its stereoisomer quinidine, which is an antiarrhythmic drug. "When we have a new project, we recheck the syntheses reported in the literature to prove the validity of published procedures," says Milan Uskokovi´c, the leader of that team. Rabe's recipe, he says, was not suitable for their purposes until they changed it in major ways. Eventually, the team developed several quinine syntheses independent of the Rabe sequence. They began publishing results in 1970.
"As far as the record showed, there was no established recipe for quinine until 1970," Stork says. The Hoffmann-La Roche synthesis "was a major achievement, especially if you assumed that there was no synthesis before that. Not only did they synthesize quinine, but they also applied considerable stereocontrol."
IN THE 1940S, stereocontrol was not a dominant concern of synthetic chemists. The Woodward-Doering synthesis of cis-3-vinyl-4-piperidinepropionic acid, says Stork, "was very clever and very elegant. But they obtained its required cis precursor as well as the undesirable trans isomer." And the part of the construction that relies on the Rabe recipe "was not possible to do in a controlled manner."
Stork claims the first successful effort toward stereoselective quinine synthesis. In 1946, he published the stereoselective synthesis of cis-3-ethyl-4-piperidineacetic acid, a compound closely related to cis-3-vinyl-4-piperidinepropionic acid. Although this synthesis controls only two of quinine's four asymmetric centers and substitutes a relatively benign ethyl group for the more reactive vinyl group, Stork says in his latest paper that it "deserves some notice as one of the earliest successful examples of stereorational planning related to natural product synthesis."
The Hoffmann-La Roche team had different objectives. "Our goal was to produce both quinine and quinidine, because both were useful to us," Uskokovi´c says. Consequently, the Hoffmann-La Roche syntheses had partial stereoselectivity only, producing equal amounts of quinine and quinidine, but none of the undesired stereoisomers epiquinine and epiquinidine.
The goal of controlling all four of quinine's stereocenters in a total synthesis still was unachieved. However, Stork found a way to fulfill his lifelong dream through one of the Hoffmann-La Roche steps--oxidation of a mixture of deoxyquinine and deoxyquinidine to quinine and quinidine, respectively.
"That step was very efficient," Uskokovi´c says. So if a totally stereoselective route to deoxyquinine alone could be developed, totally stereoselective synthesis of quinine would be achieved. Deoxyquinine thus became Stork's synthetic goal.
With collaborators Deqian Niu, A. Fujimoto, Emil R. Koft (deceased), James M. Balkovec, James R. Tata, and Gregory R. Dake, working singly and on and off on the problem, Stork achieved that goal. Conversion of deoxyquinine according to the Hoffmann-La Roche procedure gave quinine in 78% yield. The synthetic quinine's spectra, melting point, and optical rotation match those of an authentic natural sample.
The work of all who have attempted to prepare quinine must be judged according to their times, Uskokovi´c says. "Our synthesis satisfied the need we were addressing. Stork's synthesis is outstanding, with every step controlled. It is a modern, novel synthesis."*
PATHFINDER
Fresh Look Yields Stereoselective Solution To Old Puzzle
The quinuclidine ring, composed of three fused piperidine rings, characterizes the group of alkaloids that includes quinine. A common theme of earlier quinine syntheses is construction of this ring by linking C-8 to N-1 of a 3,4-disubstituted piperidine.
"That disconnection leads to difficult problems" if the goal is totally stereocontrolled construction, says Gilbert Stork, emeritus professor of chemistry at Columbia University. He began working on his planned synthesis of quinine 55 years ago, while he was a graduate student at the University of Wisconsin, Madison. Working on and off on the problem over the years, he finally solved the puzzle last month [J. Am. Chem. Soc., 123, 3239 (2001)].
The solution came down to discarding the time-honored disconnection and taking a fresh look at the problem. In Stork's synthesis, the quinuclidine ring is constructed by linking C-6 to N-1.
"Stork's dissection of the problem is novel," says Wisconsin chemistry professor Steven D. Burke. Liberated from the old disconnection, Stork was "able to employ an element of conformational control that could not be used by previous groups."
"At first sight, this solution looks worse," Stork says. The precursor would have to be a trisubstituted piperidine. Instead of only two stereocenters in the disubstituted piperidine required by the old disconnection, three centers now have to be controlled.
But three stereocenters aren't so bad if the conformational relations are dissected. In the new precursor, the stereocenters at positions 3 and 4 must be trans to each other, rather than cis as in the old disconnection. And the third center must be cis to that at position 4. A piperidine in which these substituents are all equatorial would give the required cis/trans orientations.
The compound Stork chose for that construction is a trisubstituted tetrahydropyridine in which the third substituent is attached to the carbon of a C=N bond. The ring can flip from one chair conformation to the other. The flipping changes equatorial substituents to axial substituents, reversing the cis/trans orientations. But the cost of that change is high enough that only one chair conformation seems to be involved, Stork explains.
This locking in of one chair conformation also ensures the stereospecific reduction of the C=N bond. If that reaction results in axial addition of hydrogen, then the third substituent in the reduced product would be equatorial, as required.
It turns out that, in hydride reduction of C=N bonds in six-membered rings, hydride would be expected to come in axially because it adds to a vacant orbital that is about perpendicular to the plane of the ring. "We didn't invent that," Stork says. "We expected it mostly from theoretical considerations introduced by others."
In fact, Stork says he didn't invent anything new for this synthesis. "Total synthesis is such a tremendous amount of work that no one in his right mind tries things that are really very new, although you may be forced to," he says. "In many cases, you are happy to find a way--as elegant and novel as possible, to be sure--that finally gets you there."
Strategy is the hallmark of Stork's synthesis, comments Stanford University chemistry professor Paul A. Wender. Likening total synthesis to a ballet, he says: "An inexperienced observer of a great performance might leave with a view that there are no new steps. But one schooled in the field will see the exquisite choreography, the remarkable timing, the efficiency of execution, and the economy of movement--and leave inspired. I have seen the individual steps in Stork's synthesis in other contexts, but never in this arrangement and never working so well."
