Taxol – The Drama behind Total Synthesis

There is a genre known as total synthesis. It deals with the construction of mainly natural molecules having complicated structures starting from smaller molecules. Its original purpose was the full elucidation of the structure and the artificial supply of the rare compounds available only in small quantities from nature, but today its role seems to have become more of the opportunity for chemists to show the usefulness of and to refine newly developed chemical reactions. The first successful total synthesis of a popular molecule is a huge honor, and in places like the United States this kind of accomplishment directly affects the funding for future research, so everyone competes desperately for it. The molecule introduced in this section, taxol, is famous for the most competitive race in history for its first total synthesis (Figure 1).


Fig 1 taxol

Contest among Stars
Taxol was first discovered in 1966 in the bark of a type of yew tree as the result of the project by the U.S. National Institute of Health for the discovery of anticancer agents, and its structure was determined in 1971. The promising pharmaceutical potential of taxol for breast cancer was immediately recognized, but the amount that could be obtained from yew tree was not sufficient to provide a supply for all patients, prompting the necessity for chemical synthesis. In addition, the molecule had a remarkably unique structure, which was enough to motivate synthetic organic chemists to take the challenge.
More than thirty synthetic research groups worldwide, including the group I worked in as a college student, joined the race for taxol, the molecule with all the features to attract the interest of synthetic chemists. Among the famous researchers joined the race were Professor Samuel Danishefsky, who was one of the superstars in the field of organic chemistry, Professor Gilbert Stork, who had been the leading figure of the field since the 1940’s, Professor Leo Paquette, who was renowned for the total synthesis of dodecahedrane, Professor Paul Wender, who had completed the syntheses of numerous natural products, and Professor Teruaki Mukaiyama, who was a representative chemist from Japan. Furthermore, joined in the synthesis of the taxol’s side chain were the 2001 Nobel Laureate Professor Barry Sharpless and his former student Professor Eric Jacobsen, a young elite chemist at Harvard University, making it an all star game of organic chemistry. Finally, entering the 1990’s, Professor K. C. Nicolaou, another giant in the field of natural product synthesis, joined the contest as it was reaching its climax.
Despite the efforts by these prominent chemists all over the world, however, taxol resisted their challenges to remain as an unbeatable target for some time. The problem was simple. A chemical reaction proceeding with the yield of eighty percent is usually considered reasonably good, but if it is repeated in a twenty-step sequence, what will be left afterward is only one percent of the original starting material. The synthesis of taxol required at least forty steps with the possibility of branching out along the way, so a tremendous amount of experiments had to be done. My research group succeeded in the synthesis of the core skeleton early, but from there unexpected problems arose one after another, and the project reached a deadlock many times. I did not work on the project myself, but just watching it from the side was enough to understand how hard and dramatic total synthesis was, and to appreciate the intelligence, courage, and physical strength needed for it.

Final Showdown
In the later stage of the competition, an unexpected player showed up between the big names. It was Professor Robert Holton of Florida State University. Holton had begun working on the synthesis of taxane family compounds in the early 1980’s, and in 1988 he had already completed the total synthesis of taxusin, an analog of taxol that was also obtained from yew tree (Figure 2). Still, his synthetic route for taxusin had been considered difficult to be applied to taxol, and many thought that his research had reached a dead-end at taxusin. However, the Holton group never gave up, and they finally made a breakthrough to covert taxusin into taxol, putting themselves ahead of everyone else in the race.


Fig 2 taxusin

Approaching the finish line, the two front-runners were Holton and Nicolaou.
The duel made a good contrast, with Holton being an anonymous chemist who had started his research alone and made progress quietly but steadily, and Nicolaou being the authority in the field who pushed forward with an army of postdocs from all over the world.

Surprise Move at the End
Then, the moment finally came for the conclusion of the fiercest competition. In the year of 1993, the Holton group succeeded in the first-ever synthesis of taxol ahead of the Nicolaou group. Holton immediately sent his report to Journal of American Chemical Society (JACS), but one problem came up. Nicolaou, who finished his total synthesis shortly after Holton, published his result on the journal Nature. Nature had a shorter turnaround time for the review and the publication processes than JACS, so that resulted in a twisted situation where Holton’s paper was received first by JACS, but Nicolaou’s paper was published first on Nature. It is extremely rare that a total synthesis paper gets to be on Nature, and this surprise move by the Nicolaou side in the last second complicated the outcome of the race until the very end.
The controversial case, which involved even popular magazines like Newsweek, eventually settled as the Holton’s victory by “replay decision.” Professor Nicolaou was a global authority in the field of total synthesis recognized by anyone, but the honor of the first synthesis of taxol, he had to see it given to Professor Holton. Each step of the total synthesis by the Holton group was refined to perfection, with the average chemical yield for the entire synthetic steps reaching ninety three percent. This was also why their synthesis was such a historical achievement, and their impressive result certainly deserved the victory.

After the Race
In 1993, the same year Holton completed the total synthesis, taxol was released into the market as the treatment for breast cancer, and ever since it has been in clinical use universally. However, the taxol used currently as the drug for cancer treatment is not supplied by total synthesis. All of the syntheses reported so far require more or less forty steps of reactions, often including some highly specialized reactions, so it has been practically impossible to prepare taxol on kilogram scale by total synthesis. Fortunately, though, it was found that a compound called baccatin III (Figure 3), a molecule with taxol’s structure without the side chain part) could be obtained in a large quantity from the leaf of yew tree. Taxol can therefore be obtained by attaching the side chain to it. The whole supply of taxol used clinically today comes via this “semisynthesis.”


baccatin III

Then, was the worldwide race for the total synthesis completely useless? The answer is definitely no. The new synthetic methods developed to challenge taxol will be valuable for the future synthesis of useful compounds. The knowledge on the properties of the compound gained only through building it from scratch is also utilized in the ongoing research for the development of even better drugs than taxol.
After the end of the taxol race, the reports of the total synthesis of natural products have been continuing to make frequent appearances on scientific journals. However, in recent years there have been critical voices against the practice of total synthesis itself (An example: Robert F. Service, “Race for Molecular Summits”, Science vol.285 (AAAS, 1999), p.184-187. ). How much scientific significance does total synthesis research have, if it is done simply by the repetition of known chemical reactions and if its goal is to make compounds of questionable value by spending so much time and money? Are there still discoveries left that will contribute for the advancement of human society? On one hand, it is an undeniable fact that total synthesis produces and improves synthetic methods, and it is extremely effective as the opportunity for students to develop knowledge and techniques. But on the other hand, these critical questions do have their point, which means that synthetic chemists will have to have their answers.
Recently, more and more researchers go beyond total synthesis, producing results by applying the compounds they synthesized to the area of biology. One could say that this is one of the answers from chemists to the criticisms on total synthesis. The new genre “chemical biology” has now become one of the hottest fields in natural science.
The synthetic methods available today are so advanced, that there may not be target molecules left that are as difficult and attractive as taxol, and perhaps there will not be another race for total synthesis that are as thrilling. In any case, it seems that total synthesis, a genre that symbolized an era in the history of chemical science, has come to a turning point.

A few years after the end of competition for the first place, the laboratory I worked in finally completed their synthesis, and the report was published on JACS. Reading this article, I saw their entire synthetic processes condensed in just two pages and a figure, and the mountains of the trials and errors they made and countless failed experiments were not mentioned. Thinking that this was the summary of the time that many of my friends devoted their youth to for almost ten years simply made me sigh. I presume that behind a small scientific progress that we don’t always notice, there are the unsung efforts and hard work by probably dozens of scientists.

Notes
Taxol is the name licenced by a pharmaceutical company, while the name paclitaxel is the more appropriate chemical name. The more widely recognized name taxol is used in this text.

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