Humans have looked to the natural world for medical provisions for millennia. The ancient Egyptians and Greeks knew of the painkilling properties of the opium poppy, and for centuries inflammation, pain and fever were treated with willow-bark extract, the active ingredient of which, salicin, was later used in the synthesis of aspirin. But not all natural therapeutics are as abundant as the willow tree and opium poppy, and without efficient mass production, they would be of little use to modern medicine.

Enter the chemists. They can develop synthetic recipes to recreate complex natural structures. The ideal approach is one that is efficient in terms of time, labour and resources. Barry Trost, an organic chemist at Stanford University in Palo Alto, California, now reports a very efficient method for the complete synthesis of a structurally complex compound called bryostatin 16.

Roughly 20 bryostatins are known to exist, and are found in Bugula neritina, a tiny, colony-forming marine creature. The compounds have been shown to have promising antitumour properties and cognition-boosting effects; however, further development is hindered by their complexity. Compared with earlier methods used to make other bryostatins, Trost and his graduate student, Guangbin Dong, cut the total number of steps required to make bryostatin 16 almost in half.

Trost chose bryostatin 16 because it has the potential to be a pivotal intermediate from which most other bryostatins can be constructed. The common bryostatin framework is a 26-member ring, with three 6-member rings embedded within it. “Bryostatin 16 has all the core structural elements, and a few other elements can be easily introduced in the end game,” he says. “You could also use it to make many unnatural bryostatins,” he adds.

Initially, Trost tried to synthesize bryostatins using a reaction called 'ring-closing metathesis'. This approach can be used to synthesize rings with up to 30 members. Metathesis is so broadly applicable to generating complicated molecules that it earned its discoverers the 2005 Nobel Prize in Chemistry. However, every organic reaction has its limitations, Trost says. “For this particular target, it totally failed.”

Trost and Dong turned to a method called a palladium-catalysed alkyne–alkyne coupling reaction. Trost had been studying the reaction in his lab for years, but he had never tried it with such a complicated structure. The technique generated the main bryostatin ring perfectly.

The new method is both resource-efficient — known as 'atom economy' — and time-efficient. For instance, Trost and Dong built the molecule's three pyran rings (rings comprising 5 carbons and 1 oxygen) using simple addition reactions, which avoid the generation of by-products, and so the extra steps that would be needed to remove these. Previous efforts to synthesize bryostatin analogues from scratch have 40-plus steps in the main, or linear, sequence and more than 70 steps in total. Trost's method has a linear sequence of 26 steps and a total of just 39 steps (see page 485).

The work is a major leap forward in synthetic-chemistry efficiency, says Trost. He sees fundamental chemistry research as crucial to improving the quality and diversity of drug candidates pursued by pharmaceutical companies. In drug-discovery efforts, complicated structures such as those of the bryostatins are often simplified to make them easier to make and to amend. But, Trost observes, “you don't want to compromise the structure in terms of its biological function if you don't have to”.