Science
Researchers succeed in making aklavinone Three independent groups synthesize nonsugar portion of promising anticancer agent aclacinomycin A, look toward useful structural analogs Jeffrey L. Fox C&EN, Washington Three research groups at the University of Rochester, Harvard, and Hoffmann-La Roche, with a fourth trailing closely behind, have synthesized aklavinone, the nonsugar portion of the recently discovered, promising anticancer drug aclacinomycin A. These organic syntheses, each interesting in its own right, also set the way for making and eventually testing many structural analogs of this drug, some of which might become clinically useful and commercially profitable. Aclacinomycin A belongs to the anthracycline family of anticancer
drugs, which includes daunomycin and adriamycin. Though widely used for treating certain kinds of cancer, such as acute leukemia, these anthracyclines are far from ideal. Their most serious drawback is their toxic side effects, particularly their tendency to damage the heart. In potency, aclacinomycin A is similar to adriamycin but is 10 to 15 times less toxic. Hence, shortly after its isolation in 1975 by Japanese researchers at Sanraku-Ocean Co., aclacinomycin A was being called a "second generation" anthracycline. "These are pretty 'hot' compounds in the anticancer field," says organic chemist Andrew S. Kende of the Rochester group. "They might completely replace the adriamycins." Inasmuch as the adriamycin business amounts to roughly $50 million per year, according to Kende, that prospect imparts to the aklavinone synthesis a commercial as well as an intellectual significance. The three groups have published their syntheses of aklavinone back to back in the most recent issue of the Journal of the American Chemical
Society [103, 4247; 4248; and 4251 (1981)]. Kende's coworker on this project was graduate student James P. Rizzi. Another university-based research group, under the direction of Yoshito Kishi of Harvard's chemistry department, also has succeeded in devising a synthesis. Both of these research groups received support from the National Cancer Institute. The third synthesis was worked out by organic chemists at a pharmaceutical company. Pat N. Confalone, who has since moved to Du Pont's experimental station in Wilmington, Del., and his former coworker Giacomo Pizzolato developed their synthesis of aklavinone while at Hoffmann-La Roche in Nutley, N.J. Confalone says their synthesis actually was completed "two to three years ago, but publication was delayed because of patenting." A fourth route to synthesis, which still has not been published, has been developed by Tsung-tee Li and Yu Lin Wu at Syntex Research Center in Palo Alto, Calif. Confalone, Kende, and Kishi all were aware of one another's progress
Three separate routes to successful synthesis of aklavinone: key steps outlined Kishi and colleagues' synthesis
Kende and Rizzi synthesis
Confalone and Pizzolato synthesis
July 20, 1981 C&EN
31
Science Erythromycin, another difficult synthesis, now complete Synthesis of the antibiotic erythromycin recently was completed, a posthumous chapter in the phenomenal career of Harvard chemist Robert B. Woodward. His death in the summer of 1979 may have forestalled, but did not prevent, his colleagues from making this macrolide antibiotic [J. Am. Chem. Soc, 103, 3210; 3213; and 3215 (1981)]. Total stereospecif ic synthesis of the molecule took the efforts of about 50 chemists working during nearly a 10year period. Though this group was smaller in number than the one that Woodward led to synthesizing vitamin B12, it had to suffer the shock of losing the chief strategist. Harvard organic chemist Yoshito Kishi subsequently assumed the role of organizer. "Fortunately, we had an extremely cooperative group of postdoctoral fellows," Kishi says. "When Woodward died, the synthesis Erythromycin CH3 O OH HC V£! H CK HO
77CH3
CHj...
o A-ro-r^u
XH,
OH XH3 ChL
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toward a working synthesis of aklavinone, yet their strategies for getting there developed independently. "It's more natural to come up with different ways of synthesis than to come up with the same," Kishi says. "One's working from almost an infinite number of starting materials." The three groups shared some information. For example, Confalone's progress was tracked by Kishi because he consults for Hoffmann-La Roche. But quips Confalone: "Kishi knew the details, but he needed none of our observations." Kende also sees the three routes to aklavinone as being distinct. "The strategies are totally different except at the very end," he notes. There, his and Confalone's steps overlap on the way to the finish line, but only after each one of them covered very different ground. All three syntheses rely on building the molecule by a "convergent" strategy, meaning that parts of it are assembled separately and then fused relatively late along the way. "Kishi's synthesis is probably the 32 C&EN July 20, 1981
was just about complete," Kishi continues. "The basic plan was already well thought out." Erythromycin contains a 14-membered lactone ring with 10 asymmetric centers in it. The molecule also contains two unusual sugar molecules, L-cladinose and D-desosamine. Thus, erythromycin was built in stages: first, a straight-chain seco-acid derivative was made. Next, that derivative was converted into the macrolide. Finally, the sugars were added. "Glycosidation [adding sugars] is a very old reaction," Kishi says, "but one of the hardest to achieve." It was the major step remaining when Woodward died. "We tried many old methods before we found a successful one," Kishi adds. "It was not quite new but there's a lot of small but important know-how to glycosidation. Anytime you talk of sugars in organic synthesis, it means headaches." According to Kishi, Woodward's now-realized strategy for making erythromycin is an important fundamental contribution to organic chemistry. Among other things, it opens the possibility of testing what's required for successful macrocyclic lactone formation. The Harvard group tested about 30 intermediates trying to get cyclization, Kishi says, but only a few would cooperate. Figuring out why could prove interesting, he says.
best and most imaginative," Kende says in a show of modesty. "It involves a novel use of furan chemistry to attach a 'chunk' of carbon atoms to the growing molecule." Kishi also is modest in discussing his synthesis, despite the praise of others. "At the beginning, our synthesis was not too efficient," he says. "I don't know why we kept to our own route over the years. But for unidentified reasons, even to myself, we kept to it." That perseverance has paid off with a synthesis that "gives a fairly acceptable overall yield," Kishi says. "More important, the synthesis is flexible enough to modify it. We've made more than 10 analogs already by this method." The availability of such analogs (and, also, the availability of ways for adding sugars to them to give biologically active molecules) opens the way for testing structure-activity relationships. "It's not so easy to modify the chromophore," Kishi says of the nonsugar portion of the natural antibiotic. "Now we can do this." One drawback to Kishi's synthesis
is that it is not stereospecific. "This is a problem from the technical point of view," he says. "But we can use the undesired product and recycle it. We need a chromatographic separation at some point." By contrast, Kende's and Confalone's syntheses are stereospecific. "We had luck in the late steps," Kende says. For instance, a hydrogenation reaction essentially gives only the desired isomer. Also, the opening of an epoxy ring toward the end of the synthesis again results in the correct isomer, in a reaction that's used both by Confalone and by Kende. "Natural product syntheses tend to be real sagas, real battles," Confalone says, recalling some of the trickier parts of his successful campaign. Originally, he based his strategy for making aklavinone by comparing it to adriamycin. The absence of a carbon-11 hydroxyl group and the presence of a carbon-10 carbomethoxy group, creating another asymmetric center in aklavinone, "were the main differences to focus on," he says. Such differences, however, eliminate certain headaches inherent to adriamycin synthesis, and aklavinone's carbomethoxy group offers a means of controlling certain stereochemistry in the molecule during final steps, Confalone says. The trade-off is that aklavinone's missing hydroxyl group "invalidates" most or all adriamycin-styled approaches. Thus, Confalone and his colleague traveled down several blind alleys before they found "precise conditions to avoid undesirable reactions." For example, the system tends to undergo a Friedel-Crafts reaction at one point where an adriamycinlike intermediate could not have reacted in such a way. Later on, another key intermediate tends to undergo an undesirable rearrangement reaction, giving the wrong stereochemistry. Fortunately, some of the frustrations that abound in the early stages of the scheme dissolve into success toward the end. "We're gratified," he admits. Despite all the complications, "We do get the payoff we expected." Kende tells a similar tale: "The toughest part of the synthesis was actually something trivial. We couldn't get methyl groups off hydroxyl groups on the ring. Finally, my student found a method that didn't destroy the molecule." A determined spirit, familiarity with the wealth of special reactions and conditions that can solve particular problems, and a certain clever-
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Technology ness contribute to the self-confidence of organic chemists who increasingly declare that most any natural molecule can be made. "The joy is in taking some compound you can buy, and elaborating it into something else made only by nature prior to that," Confalone says. "It goes right back to the first synthesis of urea," by current standards a ridiculously simple molecule whose synthesis certified that "natural" products indeed could be made by chemists in laboratories. To be sure, these syntheses of aklavinone add something to the overall repertoire of organic chemists. But all three of these organic chemists see the principal benefit coming from this work to be new antibiotics. "You can expect to see some development of analogs useful to medicinal chemists from this synthesis rather than benefits to organic chemists," Kishi says. Kende and Confalone agree. "We can use these syntheses to custom build any anthracycline molecule you might need," Kende says. And Confalone adds: "All these syntheses are amenable to analog synthesis. All could lead to compounds that are not available naturally." •
Rockwell develops PCB incineration method A new incineration process for the destruction of toxic polychlorinated biphenyls has been tested successfully by the Energy Systems Group of Rbckwell International. Program manager John Blakeslee says that the new Rockwell process can destroy PCB's at about half the temperature required by other incineration processes. This, in turn, promotes longer equipment life, permits the use of less-expensive materials of construction with greater safety, and provides the option of portability for the incinerator. The process, originally developed at Rockwell's Rocky Flats, Colo., nuclear weapons plant, first was intended to destroy low-level transuranic contaminated combustible waste, and later was adapted to the destruction of PCB's. In the demonstration, a sample of PCB transformer coolant (52% by weight PCB and 48% trichlorobenzene) was destroyed with an efficiency of more than 99.9999%. This is well within the limits prescribed by the Environ-
ENVIRON
Worker checks fluid-bed incinerator
mental Protection Agency, which monitored the test. The combustion products were carbon dioxide, water, and sodium chloride. The process features a fluid-bed combustor followed by a catalytic afterburner. Temperatures in both
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C&EN July 20, 1981
