One of the most daunting challenges for synthetic chemists has finally been conquered. The effort to make palau'amine in the lab sparked heated competition for more than a decade between leading researchers, even though it may have little potential as a drug.

The yield of the 25-step synthesis, which was led by Phil Baran at the Scripps Research Institute in La Jolla, California, was just 0.015%: fewer than 2 in every 10,000 molecules of starting material made it through to the final product.

"Palau'amine is the pinnacle of technical difficulty," says organic chemist Patrick Harran of the University of California, Los Angeles, who has been trying to make the compound since 2002. "Phil and his students have set a standard against which all future work in the area will be judged."

But the synthesis, published last week in Angewandte Chemie1, is more than a technical achievement. The procedure demonstrates the effectiveness of a set of guiding principles for efficient organic synthesis that was articulated by Baran's group several years ago and is now gaining adherents for its focus on brevity and simplicity.

Palau’amine: fiendishly hard to make in the lab.

Palau'amine was isolated from the sponge Stylotella agminata, which is found in the waters around the Republic of Palau in the western Pacific Ocean. First reported in 1993 (ref. 2), it is part of a family of compounds known as pyrrole-imidazole alkaloids, which may help to deter fish from snacking on the sponge or prevent microbes from taking up residence. The molecule has antitumour, antibacterial and antifungal activity at levels that are "OK, but not fantastic", says Matthias Köck, a marine natural-products chemist at the Alfred Wegener Institute for Polar and Marine Research in Bremerhaven, Germany.

Thus, the main attraction in synthesizing the molecule is not its potential as a wonder drug, but the sheer challenge of making something so complex. The structure of palau'amine is crowded with spurs and joints in unusual places, and littered with nitrogen atoms that lie in wait to disrupt the chemical reactions used to stitch the compound together. At the molecule's heart lies a unique configuration of rings — two circles made up of carbon atoms and a nitrogen atom that are fused in a contorted configuration.

For more than a decade, chemists assumed that the rings were twisted into a bowl-like shape. But in 2004, Baran hypothesized that all the members of palau'amine's molecular family could be constructed with the same general strategy — implying that the accepted structure of palau'amine was wrong.

In 2007, his prediction was vindicated by three teams that independently worked out its true structure. Köck, who led the most detailed study, recalls that at first "almost no one believed us. Nearly everyone we spoke to thought we were misguided." But synthetic chemists soon switched their focus to the revised target. "Many groups had been chasing the wrong structure for years," says Köck.

Baran's synthesis adheres to a set of synthesis guidelines3 that aims to exploit the target molecule's inherent reactivity and stay as close as possible to the way it is made in nature, explains team member Ian Seiple. This includes using cascade reactions that can form many new chemical bonds in a single step, and avoiding the use of protecting groups to shield fragile parts of a molecule during synthesis because they increase the cost and complexity of the process.

Although none of the guidelines is new, applying them all within the same synthesis has become a hallmark of Baran's work. His goal is to prove that new drugs do not have to be built from the relatively limited pool of molecular motifs used by pharmaceutical companies.

The efforts to synthesize palau'amine have forced chemists to develop new reactions and techniques for assembling complicated molecules. Part of Baran's synthesis relies on a silver-based reagent, for example, that his lab invented to gently oxidize the half-built palau'amine molecule without disrupting its nitrogen atoms. That reagent is already being used by a pharmaceutical company to make a range of drug candidates, says Baran.

In the near future, he hopes to make grams of the compound instead of the few milligrams he has so far achieved, and to tweak his synthesis so that just one of the two possible mirror-image forms of the compound is produced. His team already has a working route that cuts ten steps from the beginning of the process. "For us, the story has just begun," Baran says.