Iridium-catalyzed hydrogen addition, yielding natural substances from plants and insects

The cost-effectiveness of drug synthesis depends on a number of factors, including the amount of waste produced. A team of researchers has just discovered a catalyst that can add hydrogen to carbon-carbon bonds with exceptional precision, improving targeted synthesis by avoiding convoluted multi-step processes and reducing byproduct waste. In the journal Angewandte Chemie, the authors announce that this reaction is particularly useful for the production of complex natural substances such as pheromones.

The natural world contains a wide range of natural products, many of which have also become indispensable medicines for humans. For example, natural substances of plant origin such as polyketides and pheromones have great potential as antitumor and antibiotic drugs. However, many of these pharmaceutically active substances are only effective in one of their two possible configurations, which are mirror images of each other, and may even be harmful in the other form.

To ensure that the right substance is produced, synthetic chemists usually have no choice but to be wasteful: either by using convoluted processes or by performing a number of different steps. For example, they may synthesize both forms of a compound and then have to eliminate the unwanted one, or use a specific, but potentially expensive, catalyst to produce only the form they are interested in.

Pher G. Andersson and his team at Stockholm University in Sweden have just discovered that a catalyst composed of a heavy metal, iridium, and organic phosphorus and nitrogen units is exceptionally efficient at hydrogenating symmetrical organic compounds. The resulting reaction is not only very economical, with no by-product formation, but also particularly important for drug synthesis, because the configuration - that is, the hand of the product - is decided at the time of hydrogenation.

Simple, symmetrical unsaturated bonds are suitable as precursors for the synthesis of polyketides and natural products derived from pheromones. The team's iridium catalyst now allows one of the symmetric carbon-carbon bonds to be hydrogenated in a targeted manner. "This method represents the first example of iridium-catalyzed hydrogenating de-symmetrization of dienes," say the authors. They demonstrated the utility of their new method using dozens of precursor substances that they converted into the desired products. In all cases, virtually no byproducts were formed.

The target configuration at the oxygen group near an unsaturated bond was critical to the success of this approach. Many pheromones or polyketides contain allylic carbinols with this oxygen-carbon arrangement, while others contain nitrogenous groups and are referred to as allylic carbamines. Whether the iridium catalyst was used on nitrogen or oxygen, it gave the correct final configuration. Another common structural motif in natural substances is lactones. Even when confronted with this structure, the iridium catalyst worked well and the researchers were able to find a simple synthesis route via hydrogen deymetrization.

The authors also used the new method to achieve formal total synthesis of two natural substances: first, zaragozic acid, a polyketide obtained from fungi, and second, invictolide, an ant pheromone. The authors are convinced that due to the high level of selectivity and the almost total preference for one configuration, giving the product with the right hand, the method is an economical and versatile alternative for the synthesis of many pharmaceuticals.