CHEMICAL & ENGINEERING •
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Scientists revise str ucture of coveted anticancer marine rîatural product
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TOTAL SYÏ^THESIS SURPRISE 1 rock more than a dozen organ1 ic research labs worldwide, chemists inTexas have won a race to synthesize what was believed to be a natural product with po tent anticancer properties. In do ing so, they have discovered that the structure assigned to the nat ural product more than 10 years ago is wrong. And even though the revised structure is just now being pub lished, another lab is in hot pur suit of the true molecule. Known as diazonamide A, the compound was found in a rare marine invertebrate known as Diazona angulata, which lives in waters off the coast of the Philip pines. In 1991, chemistry pro fessors William H. Fenical at the University of California, San Diego, andJon C. Clardy at Cor nell University first reported a structure for diazonamide A. Because ofthe compound's po tential pharmaceutical uses and the scarcity of the sea creature, numerous organic labs—includ ing those of K. C. Nicolaou at Scripps Research Institute and Philip D. Magnus at the Univer sity of Texas, Austin—have been laboring to synthesize it. This is a difficult task, Fenical notes, "because the architecture is so radically different than in oth er kinds ofmolecules seen before." W i t h t h e help of several unique approaches, assistant pro fessor Patrick G. Harran and his colleagues in the biochemistry
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department at the University of Texas Southwestern Medical Center in Dallas have crossed the finish line, synthesizing the molecule identical to the structure proposed in 1991. But after comparing what they had synthesized with a sample of the natural product, Harran's group saw that the two compounds clearly were not the same: The stuff they'd made degraded readily, for example. A deeper look at the original crystallography and N M R data
has resulted in a revision of key features in an X-ray crystal structure. This could not be better from a teaching standpoint." Harran's group also reports that, fortuitously, the structure they synthesized turns out to be every bit as powerful biologically as the true natural product. "We got very lucky that what we have made is biologically the same, since one of the major goals is to use synthetic derivatives to probe diazonamide function," Harran says. Those pursuing a total synthesis of the true natural product will "have to change our syntheses somewhat to accommodate the new diazonamide structure," says Joseph P. Konopelski, professor and chairman of the University of California, Santa Cruz, chemistry department. But even that race could soon
This is "beautiful synthetic work coupled with a bit ofdetective work." —Joseph P. Konopelski, University of California, Santa Cruz
turned up several key misassignments. THINK AGAIN For example, at one Harran finds alternative structure for natural product position, a p r o t o Diazonamide A nated nitrogen had H3CS^.CH3 Η3Ον^^ΟΗ3 been mistaken for an oxygen. H3C CH H3 CH Y H Τ > » 1 _/" Y ; ΗΑ=Ν Harran and coworkers' synthesis \ PI U of the original structure plus their determination of the revised structure, Original assignment Revised structure detailed in two papers published this be over: According to postdoc week [Angew. Chem. htt. Ed., 4 0 , Mali V. Reddy and graduate stu4765 and 4770 (20(31)], have idmiration dent Scott A. Snyder, b o t h in drawn both shock and -< Nicolaou's lab, their group has from diazonamide res marchers, been working to synthesize the "It's a nice piece of c hemistry," real diazonamide A and hopes to Magnus says. "Some Deople are complete a total synthesis in the going to be upset, but it's better next few months. to know than not to k now." The fascination with diazonClardy calls the rep
