SCIENCE/TECHNOLOGY
Total Synthesis of Anticancer Agent Taxol Achieved by Two Different Routes • Long-standing efforts by several groups to make promising drug from simple starting materials finally bear fruit Stu Borman, C&EN Washington A fter years of ardent efforts by synjjL thetic organic chemists to synJ L J L thesize the anticancer drug taxol from simple starting materials, two groups have accomplished the feat within six weeks of each other. Taxol, originally isolated from the Pacific yew tree in the early 1960s, was recently approved by the Food & Drug Administration for use against ovarian cancer and has also shown activity against breast, lung, and other cancers. The drug
Space-filling model of taxol, with prominent side chain at left. was for a time a rare commodity, available only by extraction from yew bark. Bristol-Myers Squibb, which markets taxol, now intends to produce it by partial synthesis from 10-deacetylbaccatin HI, a precursor obtained from yew needles and
Journals and the press: a tricky relationship The close timing of the papers on the synthesis of taxol caused a perturbation of the generally accepted practice that the press does not report on scientific papers until after they are published. This stems, in part, from the understandable desire of journal editors to not have the scientific details of papers they have accepted reported elsewhere prior to actual publication. The flap was triggered by a news release from the Florida State University media relations office on the synthesis by Robert A. Holton and coworkers. The release, titled "FSU Researchers Win Race for Total Taxol Synthesis/' was dated Feb. 8, the day after the Journal of the American Chemical Society accepted the Holton Communications for publication. Subsequently, media reports on the Holton synthesis appeared. At that time, the publication date of the Holton paper had not been set (it was later set for Feb. 23), but the paper by K. C
32
FEBRUARY 21,1994 C&EN
Nicolaou and coworkers at Scripps Research Institute and the University of California, San Diego, was already scheduled to appear in the Feb. 17 issue of Nature. Alerted to Nicolaou's publication date and the FSU press release, JACS editor Allen J. Bard moved quickly to have Holton's Communications published in the Feb. 23 issue. C&EN had a short, nontechnical story on the synthesis in its Feb. 14 issue. But the circumstances still left C&EN in the position of being able to report in this Feb. 21 issue the scientific details of the Nicolaou synthesis, because it has already been published in Nature, but not of the Holton synthesis, which will not be published in JACS for another two days. Under these unusual circumstances, Bard made a unique exception to JACS policy, making it possible for C&EN to report on the Holton synthesis in this issue.
twigs. The company believes this semisynthetic process, developed at Florida State University, will eliminate the taxol shortage. Neither of the two new syntheses will be of practical use for commercial production of taxol. However, they "may enable researchers to devise more effective, less toxic drugs of the taxol class and could thus have a significant effect on cancer treatment,,, says Samuel Broder, director of the National Cancer Institute, the main federal funding source for research on taxol. One of the earliest groups involved in taxol synthesis was that of chemistry professor Robert A. Holton and coworkers at Florida State University (FSU), Tallahassee, who first published on taxol in 1984. They say they completed a total synthesis of the drug Dec. 9 and submitted Communications on the work to the Journal of the American Chemical Society on Dec. 21. The papers were accepted for publication on Feb. 7 and will appear in the Feb. 23 JACS [116, 1597 and 1599 (1994)]. A patent application has been filed. Another total synthesis of taxol was achieved Jan. 15 by chemistry professor K. C. Nicolaou and coworkers at Scripps Research Institute, La Jolla, Calif., and the University of California, San Diego. They submitted a paper to Nature that was accepted Jan. 31 and published in the Feb. 17 issue [367, 630 (1994)]. Patent protection is being sought. Nicolaou says the synthesis took only about two years from conception to completion. Hence, Holton claims to have completed the synthesis first and to have submitted a paper first. But Nicolaou counters that the date of acceptance of a manuscript after proper peer review is the most important date. Holton and Nicolaou used completely different strategies for constructing taxol, the core structure of which consists of four rings designated as A, B, C, and D. Holton used a linear approach, in which the molecule is built up piece by piece, whereas Nicolaou used a convergent
strategy, in which two halves of the molecule are made separately and then brought together. Holton's linear synthesis starts with camphor, an inexpensive commodity chemical. This is built up through many reactions into a structure containing taxol's six-membered ring A and eightmembered ring B. Oxygen groups are added at the bottom, and the six-membered ring C is closed. A four-membered oxetane ring (ring D) is then added to ring C, using a method developed independently a few years ago by two groups—Pierre Potier and coworkers at Centre National de la Recherche Scientifique (Gif-sur-Yvette, France), and Samuel J. Danishefsky and coworkers at Yale University (Danishefsky is now at M e morial Sloan-Kettering Cancer Center and Columbia University). After the oxetane is added, Holton and coworkers complete the synthesis by adding taxol's side chain to ring A—using a technique developed and patented by Holton and now used by
Bristol-Myers Squibb for commercial semisynthesis of taxol. The most difficult part of the synthesis, says Holton, was ring B, "an eightmembered ring at the center of taxol that is quite unusual and whose chemistry is poorly understood. The reason our synthesis was successful is that we spent years studying it, trying to learn about its conformations and reactivity/, 'The Holton synthesis is beautifully done," says Iwao Ojima, chemistry professor at the State University of New York, Stony Brook, who has developed taxol analogs. 'The stated 4 to 5% yield from a diol intermediate derived from camphor is excellent if you count the many steps involved."
Another researcher who has worked on taxol, chemistry professor Gilbert Stork of Columbia University, agrees, calling Holton's yield "astonishing" and "simply fantastic." Stork says, "The Holton construction is based on a very sophisticated use of conformational control of the eight-membered ring to produce the stereochemistry and regiochemistry that he needs." He says this is a brilliant application of concepts and computational models developed by Columbia University chemistry professor W. Clark Still for controlling stereochemistry in medium-sized rings. In Nicolaou's convergent synthesis, rings A and C are made separately and brought together at the bottom. The
Florida State University taxol team includes (front row, from left) postdoctoral fellows Carmen Somoza, Hyeong-Baik Kim, Hossain Nadizadeh, and Chunlin Tao, graduate student Phong Vu, and chemistry professor Robert Holton; (middle row, from left) postdoctoral fellow Pingsheng Zhang, graduate student Chien-Tai Ren, postdoctoral fellow P. Douglas Boatman, graduate student Feng Liang, and postdoctoral fellow Suhan Tang; and (back row, from left) graduate student Chase C. Smith and postdoctoral fellows Ronald J. Biediger and Yukio Suzuki.
Holton approach is linear CH,
OPro ,0
C(CH3)2
Many reactions
Fragmentation reaction
,OPro OH
R
Close ring C
—r-—• of rings
Camphor
H3CCOO OPro
OPro
Add oxygens to bottom
to give ring B
OPro
OPro
OPro
OPro
OPro
H3CCOO OPro
Add oxetane ring and
HO
Add side chain
ketone
OPro^
Pro = protecting group R = alkyl precursor to ring C
OOCCH3 Taxol
FEBRUARY 21, 1994 C&EN
33
SCIENCE/TECHNOLOGY
Nicolaou synthesis is convergent OPro OPro p m _ n' r i u
w
NNHS02R
HO
OPro
Rings A
" N ^ ^s I
- i|
and c are
combined
OPro
/=r
&»iX H3CCOO
OH
9
Preprogramming
McMurry
(preparing for closure of ring B)
reaction to form ring B
J/
OPro
Manipulate functional groups
Open carbonate ring and
and add oxetane ring
add side chain OOCCH3
HN
y^ O"
6H
—rr H / V °
^H0
0
OOCCH3
O Taxol
Pro = protecting group R = aryl group
Taxol group at Scripps and UCSD includes (standing, from left) visiting scientist Elias A. Couladouros, postdoctoral fellows Jin-Jun Liu, K. Paulvannan, and Then Yang graduate student Erik J. Sorensen, postdoctoral fellow Philippe G. Nantermet, and visiting scientist Hiroaki Ueno; and (seated, from left) postdoctoral fellow Johanne Renaud, graduate student R. Kip Guy, professor K. C. Nicolaou, and graduate student Chris F. Claiborne. All are at Scripps, except Sorensen, who is at UCSD. Nicolaou has a joint appointment at Scripps and UCSD.
product is then "preorganized" (prepared for closure of ring B), and coupled at the top using a technique called McMurry coupling, developed by chemistry professor John E. McMurry of Cornell University. Use of the McMurry reaction to form ring B between rings A and C was first demonstrated in a simplified taxane system by chemistry professor Andrew S. Kende of the University of Rochester. Nicolaou says the key to the synthesis is assembling the appropriate groups on the periphery of ring B. "Many people have made the eight-membered ring," says Nicolaou, "but it was never functionalized enough to allow penetration to the final target. On the other hand, a lot of functionality makes it difficult to close the eight-membered ring/' He addresses this problem by introducing as 34
FEBRUARY 21,1994 C&EN
much functionality as possible from the beginning, closing the ring, and then adding missing groups. After ring B is formed, Nicolaou and coworkers use a resolution procedure to isolate an enantiomerically pure material. They add the oxetane ring (by the Potier-Danishefsky procedure), open a carbonate ring at the bottom of the structure (using a technique developed and published by Nicolaou's group), and attach the side chain (using a semisynthesis technique developed by Ojima) to form taxol. A reviewer of Nicolaou's paper says, "The route is remarkably efficient given the complexity of the molecule, and is extremely elegant." Stork calls Nicolaou7 s strategy for construction of ring C "brilliant" and his functionalization of ring A "unusually efficient."
"The achievement is an academic one at the moment," says Nicolaou, "but it could eventually pave the way to a more practical synthesis. We feel the main advance lies in our ability to construct designed taxols that have better biological activity than the natural one." Chemistry professor Paul A. Wender of Stanford University calls the two syntheses "an impressive step forward—a great testimonial to the field and to the efforts of the two groups." However, he points out that there is still much work to be done to reduce the number of steps required in the syntheses. Stork says, "In any synthesis of this complexity, there is no way you can avoid finding new, surprising, and interesting chemistry, and in both papers this is true. It's not just a matter of who got there first The amount of focused effort over a long period of time that is required to do something like this is just unbelievable, making it as much an achievement of the human spirit as a scientific one." •
