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Palau'amine Reconsidered

Structural revisions rankle chemists

by Bethany Halford
March 5, 2007 | A version of this story appeared in Volume 85, Issue 10

THE COMPLEX natural product palau'amine purportedly has beneficial biological effects, but these days it's giving some chemists a big headache. Following structural studies of the molecule's chemical cousins, three research groups report that the structures of palau'amine and all the marine natural products in its family probably need to be revised.

Any structural revision of palau'amine is sure to vex the pack of top organic synthesis groups that have been racing to complete the first total synthesis of the molecule. "Depending upon the synthetic approach being pursued, this structural revision, if correct, could represent a significant setback for groups engaged in its total synthesis," comments Larry E. Overman of the University of California, Irvine.

In their efforts to suss out the structure of some palau'amine congeners, teams led by natural products chemists Matthias Köck of Germany's Alfred Wegener Institute, Ronald J. Quinn of Australia's Griffith University, and Shigeki Matsunaga of the University of Tokyo independently found the same stereochemical discrepancies between palau'amine and their newly isolated structures (Angew. Chem. Int. Ed., DOI: 10.1002/anie.200604076; J. Org. Chem., DOI: 10.1021/jo062007; Tetrahedron Lett. 2007, 48, 2127).

These researchers suggest that the configuration originally assigned to the molecule's chlorinated carbon is incorrect and that the junction of two five-membered rings at the molecule's core is in a trans configuration, not cis. It's unusual to find trans-fused five-membered rings in organic compounds, particularly natural products, Köck notes. When his group first suggested the revised structure, he says, "no one believed us."

To date, no one has reported X-ray analysis of palau'amine or any of its relatives. Chemists don't know the molecule's absolute stereochemistry and can only report its relative configuration. Furthermore, palau'amine aficionados say initial reports of the molecule's promising biological activity haven't panned out.

On the bright side, the revised structure jibes with the current thinking on its biosynthetic pathway, according to Phil S. Baran of Scripps Research Institute. Baran also notes that revising palau'amine's structure doesn't detract from "what chemists can learn fundamentally from making these molecules."

Köck also sees a silver lining: "Usually, the synthetic groups tell the natural products chemists that they're wrong," he says. "It's good that this time we could correct ourselves."



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