Researchers develop a cost-effective and versatile approach for drug synthesis

Different factors influence the cost-effectiveness of drug synthesis, the amount of waste generated being one of those.

Drug Discovery

Drug Discovery. Image Credit: metamorworks/Shutterstock.com

A group of scientists recently identified a catalyst that accomplishes exceptionally high-precision addition of hydrogen to carbon-carbon bonds, enhancing targeted synthesis by avoiding convoluted multi-level processes, and decreasing wasteful by-products.

The findings of the study have been published in the Angewandte Chemie journal. The scientists declare the reaction as especially useful in the making of complex natural substances like pheromones.

The environment consists of different natural products, many of which have also become indispensable drugs for humans. For instance, plant-based natural substances like pheromones and polyketides have substantial potential as antibiotics and antitumor drugs.

However, most of these pharmaceutically active substances are effective only in one of their two possible configurations, similar to mirror images of each other, and sometimes toxic in the other form.

To assure that the right substance is created, synthetic chemists generally have no other choice but to be wasteful—either by employing convoluted processes or by carrying out numerous different steps.

For instance, they may synthesize both forms of a compound, and later eliminate the unwanted one; or they may employ a specific, but potentially expensive, catalyst to only produce the form of interest.

Pher G. Andersson and his associates from Stockholm University, Sweden, identified that a catalyst made of heavy metal iridium and organic phosphorus-nitrogen units is exceedingly better at hydrogenating symmetrical organic compounds.

Apart from being extremely cost-effective with no by-products created, the resultant reaction is also particularly vital for drug synthesis as the configuration—that is, the handedness of the product—is determined at the time of hydrogenation.

Simple, symmetrical unsaturated bonds are best suited as precursors for the synthesis of polyketides and pheromone-derived natural products. The group’s iridium catalyst now allows hydrogenating one of the symmetrical carbon-carbon bonds in a targeted way.

This method represents the first example of iridium-catalyzed hydrogenative desymmetrization of dienes,” stated the researchers.

The scientists proved the usefulness of their new method by using dozens of precursor substances that they converted to the desired products. In all instances, virtually no by-products were produced.

The target configuration at the oxygen group near an unsaturated bond was crucial in the success of this method. Many polyketides or pheromones contain the so-called allyl carbinols with this oxygen-carbon arrangement, while others consist of nitrogen groups and are referred to as allyl carbamines.

Irrespective of the usage of iridium catalyst on nitrogen or oxygen, it provided the correct end configuration. Another commonly found structural motif in natural substances is lactones. When confronted with this structure, the iridium catalyst functioned effectively and the scientists were able to find a straightforward synthesis route by hydrogenative desymmetrization.

The researchers also employed the novel approach to perform formal total synthesis of two natural substances—initially, Zaragoza acid, a polyketide obtained from fungi, and secondly, invictolide, an ant pheromone.

The researchers are certain that with the high level of selectivity and the virtually total preference for one configuration along with providing the product with the correct handedness, the approach is a cost-effective and versatile alternative for producing numerous pharmaceutical products.

Source:
Journal reference:

Wu, H., et al. (2021) Site- and Enantioselective Iridium-Catalyzed Desymmetric Mono-Hydrogenation of 1,4-Dienes. Angewandte Chemie. doi.org/10.1002/anie.202107267.

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