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TOTAL SYNTHESIS SURPRISE
Scientists revise structure of coveted anticancer marine natural product
In a development sure to rock more than a dozen organic research labs worldwide, chemists in Texas have won a race to synthesize what was believed to be a natural product with potent anticancer properties. In doing so, they have discovered that the structure assigned to the natural product more than 10 years ago is wrong.
And even though the revised structure is just now being published, another lab is in hot pursuit 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 Philippines. In 1991, chemistry professors William H. Fenical at the University of California, San Diego, and Jon C. Clardy at Cornell University first reported a structure for diazonamide A.
Because of the compound's potential pharmaceutical uses and the scarcity of the sea creature, numerous organic labs--including those of K. C. Nicolaou at Scripps Research Institute and Philip D. Magnus at the University 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 other kinds of molecules seen before."
With the help of several unique approaches, assistant professor Patrick G. Harran and his colleagues in the biochemistry 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 NMR data turned up several key misassignments. For example, at one position, a protonated nitrogen had been mistaken for an oxygen.
Harran and coworkers' synthesis of the original structure plus their de-termination of the revised structure, detailed in two papers published this week [Angew. Chem. Int. Ed., 40, 4765 and 4770 (2001)], have drawn both shock and admiration from diazonamide researchers.
"It's a nice piece of chemistry," Magnus says. "Some people are going to be upset, but it's better to know than not to know."
Clardy calls the report "an impressive bit of analysis." And chemistry professor Edwin Vedejs at the University of Michigan, Ann Arbor, says: "Synthetic chemists are going to love this. Harran's effort 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 be over: According to postdoc Mali V. Reddy and graduate student Scott A. Snyder, both in Nicolaou's lab, their group has been working to synthesize the real diazonamide A and hopes to complete a total synthesis in the next few months.
The fascination with diazonamide won't stop at total synthesis, however. "The work on this structural type is really just beginning," Konopelski says.
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Copyright © 2001 American Chemical Society