SCIENCE
Chemists Closing In on Synthesis of Scarce Anticancer Agent Taxol Florida group achieves total synthesis of taxusin, a natural product that contains the entire ring skeleton of naturally occurring taxol
Los Angeles Chemists at Florida State Universi ty have passed an important mile stone in the race to synthesize taxol, a scarce natural product with po tent anticancer activity. With their synthesis of taxusin—the first total synthesis of a naturally occurring
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October 10, 1988 C&EN
Graduate students Kim (left) and Williams (center) and chemistry professor Holton were among members ofFSU team that synthesized taxusin compound that contains the entire ring skeleton of taxol—chemistry professor Robert A. Holton and his coworkers are well on their way to the goal. Taxol, first isolated in 1971 from the bark of the Pacific yew tree, Taxus breviofolia, is being tested by the National Cancer Institute (NCI) in clinical trials against a variety of types of cancer. "We've seen the most encouraging results in ovari an cancer," says Matthew Suffness, a chemist at NCI's natural products branch. "However, there haven't been a lot of studies because of the lack of supply of the drug." NCI's small supply of taxol comes from forests in California, Oregon, and Washington. Because each kilo gram of dry bark yields only 50 to 100 mg of taxol, NCI contractors fell about 12,000 trees to obtain 2.5 kg of the drug. "The natural supply is a real concern," Suffness says. "The trees are slow growing. We're harvesting a lot faster than the trees are growing." Accordingly, NCI is supporting
several research studies toward a synthesis of taxol: Holton alone has NCI funds totaling almost $1 mil lion. He described his group's route to taxusin at an Organic Chemistry Division symposium on synthesis. It is also reported in a recent com munication in the Journal of the Amer ican Chemical Society [110,6558 (1988)]. Taxusin, which is not quite so complex as taxol, is the second step in Holton's plan to attack the taxane family of compounds in three stages. "Our initial target was to make the tricyclic taxane ring system, which we reported in 1984," he says. Taxol itself, of course, is the ultimate objective. "These are not easy compounds," Holton says, noting that numerous other research groups also are trying to make taxol. "The skeleton is an unusual ring system, including an eight-membered ring with a bridge head olefin. The rings are hard enough, yet you also have to put on a lot of substituents with the cor rect stereochemistry." Holton worked on the taxusin
synthesis with graduate students Hyeong B. Kim and Andrew D. Wil liams; postdoctoral associates R. R. Juo, Shinya Harusawa, and Sadamu Yogai; and then undergraduate Rich ard E. Lowenthal, who has just be gun graduate work in chemistry at Florida State. "This is a very, very unpredict able business," Holton says. "We're learning how little we know as chemists about the reactivity and conformations in eight-membered rings. We've taken a very conserva tive approach and built the mole cule in relatively small pieces." The central reaction of the chem ists' taxusin synthesis—about 30 steps all together—is the fragmen tation of a bicyclic epoxy alcohol. Their route begins with (-)-βpatchouline oxide, sold in bulk un der the name patchino by Interna-
Ring fragmentation is key ! to taxusin synthesis
Patchino
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(-)-Taxusin
tional Flavor & Fragrances Inc. Af ter rearranging the patchouline ring skeleton and several other steps, the researchers obtain an olefin inter mediate that is key to the fragmen tation scheme. They epoxidize the olefin, then fragment the resulting unstable ep oxide directly, without isolating it, to give a compound that contains two of the taxane skeleton's three rings, including the eight-membered ring. Further elaboration yields taxusin in 20 to 25% overall yield. Research Corp., acting for Florida State, has filed patent applications on several key intermediates. Holton would like to improve on his taxusin synthesis by developing a more convergent route—that is, one where larger pieces are put to gether in fewer steps. Also, his group's synthesis yields (—)-taxusin whereas the natural product is the (+)-enantiomer. He points out, how ever, that the naturally occurring enantiomer can also be made by their route by starting with the op posite enantiomer of patchino. The next goal for Holton's group is taxol. From taxusin to taxol is still a long road, however, with many functional groups to be incorporat ed stereospecifically. Rather than proceed directly from taxol, Holton plans to branch off somewhere in the synthetic scheme. The side chain attached to C-13 in taxol, which is crucial to the compound's anticancer activity, pre sents a real obstacle, Holton says. The hydroxyl group at C-13 is tucked under the concave face of the taxol molecule, making it ex tremely difficult to esterify selec tively. However, a group of re searchers in France led by Andrew E. Green at the University Joseph Fou rier of Grenoble has recently re ported a way to attach the N-benzoylphenylisoserine side chain [/. Am. Chem. Soc, 110,5917 (1988)]. "We hope ultimately we'll be able to develop a taxol synthesis that will be preferable to isolating it from yew trees," Holton says. "We also want to try to gain some under standing of how taxol works. We're just embarking on trying to find simpler molecules that will be as effective as anticancer agents." Pamela Zurer
Unusual dinitrogen complex synthesized Los Angeles The synthesis and crystal structure of the first dinitrogen complex of an f-element were described in a symposium sponsored by the Inor ganic Chemistry Division. Tamara A. Ulibarri, a graduate student at the University of Cali fornia, Irvine, reported on the reaction of the unsolvated, bent metallocene, bis(pentamethylcyclopentadienyl)samarium, with molecular nitrogen:
2[C5(CH3)5]Sm + N 2
[C5(CH3)5]Sm
Sm[C5(CH3);
Not only is the complex the first definitively identified f-element dinitrogen complex, Ulibarri says, but it also exhibits a previously un observed metal-dinitrogen bonding
Ulibarri: bonding arrangement October 10. 1988 C&EN 23
arrangement—a planar, side-on bonding between two metals and the nitrogen molecule. Ulibarri carried out the research under the direction of Irvine chemistry professor William J. Evans and in collaboration with Irvine crystallographer Joseph W. Ziller. The Irvine chemists recently published details of the research [/. Am. Chem. Soc, 110,6877 (1988)]. The dinitrogen complex is structurally unusual in that the nitrogennitrogen distance in the complex is almost the same as in free N2· On the other hand, the Sm-N bond distances are in the range usually found for Sm(III)-NR2 bonds, and the distance between the samariums and the pentamethylcyclopentadienyl rings are in the range typi-
cal for eight-coordinate Sm(III) complexes. Usually reduction and complexation by a metal lengthens the nitrogen-nitrogen distance, converting an N-N triple bond to a doublebonded N22" species, Ulibarri says. In the case of the samarium-dinitrogen complex, the data suggest that the samariums undergo oxidation, but dinitrogen appears not to have undergone reduction. Research aimed at clarifying the bonding situation in the complex is under way in Evans' laboratory. The first metal-dinitrogen complex, Ru(NH3)sN2 2+ , was discovered in 1965 by Albert D. Allen of the University of Toronto and coworkers. Rudy Baum
Novel means to study reactions in solid phase
Los Angeles A novel technique for studying solid-state reactivity derived from matrix-isolation research was described in a presentation to a symposium sponsored by the Physical Chemistry Division. Free-radical reactions of chlorine with small hydrocarbons and the
Wight: chain reaction processes 24
October 10, 1988 C&EN
chain polymerization of formaldehyde have been probed in lowtemperature amorphous films formed by spray deposition of gaseous reagents onto a cryogenic window, according to Charles A. Wight, assistant professor of chemistry at the University of Utah, Salt Lake City. Understanding of solid-state reactivity currently is undergoing a period of remarkable growth, Wight says. Although many fruitful experiments have focused on reactions in crystalline solids, such studies are limited by a number of factors. Studying reactions in amorphous materials allows researchers greater flexibility in combining two or more reagents in a variety of concentrations. Wight also notes that "most solids in real life are amorphous." Nevertheless, studies in such materials also confront problems such as ill-defined structure, which makes mechanistic analyses difficult, and the propensity of many amorphous materials to scatter light, which impedes spectroscopic examination of the reagents and reaction products. To overcome these difficulties, Wight and graduate students Arthur J. Sedlacek and Edward S. Mansueto study reactions of free radicals in amorphous films formed by spray deposition of gaseous reagents such as chlorine and a hydrocarbon onto a cryogenic window. Chlorine radi-
cals are generated by laser photolysis. Product yields are obtained from infrared absorption spectra of the films before and after photolysis. "What distinguishes our work from research done previously is our emphasis on chain reaction processes," Wight says. The researchers focus on systems in which each absorbed photon of ultraviolet radiation leads to several steps in a chain reaction process. Features in the reactions that differ from the well-studied reactions in the gas phase and in solution provide clues to the influence of the solid-state environment on the reaction mechanism, Wight says. For instance, Wight described studies of the photochlorination of cyclopropane and propane in such amorphous thin films. In the gas phase, the reaction proceeds by hydrogen abstraction to form hydrogen chloride and chlorocyclopropane. In solution, both hydrogen abstraction and addition of chlorine to form 1,3-dichloropropane occurs. In the solid state, only the addition product is observed. The high quantum yields obtained for different mixtures of solid-state chlorine and cyclopropane indicate that this reaction proceeds via a true chain reaction mechanism. By contrast, the reaction of chlorine and propane deposited in such a film is characterized by low quantum yield, suggesting that for these reactants radical recombination processes dominate the reaction mechanism. The results have led Wight to propose a reaction mechanism for chlorine and cyclopropane in which ring opening leads to separation of the radical pair formed by photolysis. Wight believes the technique will be useful in studying a variety of solid-state chain reactions. He described research on the reaction of chlorine and formaldehyde. Formation of hydrogen chloride in this case initiates an ionic polymerization of formaldehyde, leading eventually to formation of polyoxymethylene upon warming of the film. The Utah chemists also are investigating the possibility of initiating acid-catalyzed chain reactions via excited-state proton transfer in a cryogenic film, Wight says. Rudy Baum
