A 17-year-long intense competition to synthesize a fascinatingly weird and complex compound has finally ended.

The first 25-step process for building the compound, Palau'amine, out of molecular components was published in Angewandte Chemie last week.

You might think that the substance causing all the fuss is slated to be a medical miracle, and indeed it does have some fascinating antifungal, antibiotic and anticancer properties (.pdf). But the real reason dozens of chemistry Ph.D. students put their blood, sweat and tears into synthesizing it was simpler: glory.

Because the compound, called Palau'amine, is so strange and so difficult to make, it became a sort of Excalibur, with several labs around the world vying to be the first to build it. Many people had tried to synthesize the chemical, and many had failed until Phil Baran's Scripps Research Institute team finally got it right.

"[Synthetic chemistry] is a voyage into finding out how little we know," Baran said.

After this particular adventure, we now know a little more about how to join atoms together in exotic molecular structures. It might not change your life today, but the techniques developed to build it could one day be used create other medicinal compounds.

Palau'amine got its the name from its home island in the South Pacific. It was isolated from a marine sponge like the one in the photo above 17 years ago. The sponge produces the strange substance to kill anything trying to eat it.

"It's known by the indigenous people of Palau as the toxic sponge," Baran said. "They know, don't mess with that sponge. And part of the reason is that it makes crazy things like this."

While the chemical synthesis of molecules may not be voted "Sexiest Field" in a scientific popularity contest, chemists like Baran and his competitors create the many drugs of modern medicine, among other things. The process of synthesizing molecules remains largely trial-and-error. Different substances are mixed at different temperatures and pressures in hopes of finding just the right transformations to create a desired configuration of atoms.

Some chemical structures are easy to create, while others possess attributes that make them particularly hard to build. Palau'amine represents the extreme end of the difficulty scale. Larry Overman, an organic chemist at the University of California, Irvine, told Chemical and Engineering News that "its nasty physical properties had undermined total synthesis endeavors in leading laboratories worldwide."

So, Baran's lab had to come up with some new ways of doing chemistry. First, they had to deal with its nine nitrogen atoms. Nitrogen atoms are extremely difficult to deal with at a molecular level. Baran said there's an old joke that "every one nitrogen atom adds seven years" to the Ph.D.-student time necessary to learn to synthesize it. Most approaches to nitrogen components focus on covering them up with what Baran called "wet blanket" molecules that keep them messing up reactions.

"What we tried to do was take off the blanket and deal with the naked groups," he said. And it worked.

Second, the actual structure of the compound is difficult to hold together. Two of its ring structures in particular cause problems.

"It's a highly strained compound," Baran said. "If you make a plastic model of the compound, it wants to pop open."

The structure is so odd, in fact, that after years of study, the hypothesized structure of the compound had to be cast aside in 2007.

Despite the long history of synthesis failures, Baran's lab kept at it. While the rest of the chemistry world had been working with a flawed model structure, his team's work with other compounds produced by similar sponges led them to the right structure long before other scientists realized the errors in their ways.

Baran doesn't expect to see Palau'amine commercialized, so don't expect to see it curing disease anytime soon. Some of the tools his lab came up with to synthesize the compound, like a silver-based oxidizer, are already making their way into the chemistry world.

"The overriding goal is invention," Baran concluded. "The general theme of our lab is to at least match, if not outdo, nature."

Image: Carlos F. Barbas

Citation: "Total Synthesis of Palauamine" by Ian Seiple, Shun Su, Ian S. Young, Chad A. Lewis, Junichiro Yamaguchi, and Phil S. Baran

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