Selectively Creating Useful Ring-Shaped Molecules

With the help of computer simulations, scientists have devised a method to create ring-shaped molecules from inexpensive feedstock chemicals for use in the pharmaceutical industry.

AsianScientist (Mar. 7, 2018) – A team of researchers at the Institute for Basic Science (IBS) in South Korea have developed a strategy for synthesizing highly sought after ring-shaped cyclic molecules known as gamma-lactams. Their findings have been published in Science.

The conversion of hydrocarbons into nitrogen-containing compounds is an important area of research, where the challenge lies in breaking strong carbon-hydrogen (C-H) bonds and converting them into carbon-nitrogen (C-N) bonds in a controlled fashion. For this reason, hydrocarbons are difficult to use as starting materials, despite the fact that they exist in large quantities in nature.

Over the last 35 years, chemists have found ways of converting simple hydrocarbons into nitrogen-containing rings, such as indoles or pyrrolidines, but gamma-lactams proved impossible to prepare using the same approaches.

In this study, a research group led by Professor Chang Sukbok at IBS hypothesized that those failures were due to alternative chemical pathways that steer the reaction away from the desired rings: the reaction intermediate (carbonylnitrene) quickly breaks down into undesirable products that interfere with the formation of gamma-lactams.

The researchers used computer simulations to analyze the reaction mechanisms and calculate the energy required for the reaction to take place. According to their simulations, the reaction could proceed via three pathways, leading to the formation of either the desired gamma-lactam, an unwanted product (isocyanate), or the degradation of the catalyst caused by the substrate reacting with the catalyst backbone.

Combining experimental observations and detailed computer-assisted analyses, the team designed an iridium-based catalyst that was highly selective for gamma-lactam formation. In this way, the two undesired pathways were systematically shut down, leaving the formation of the nitrogen-containing ring as the only possible outcome.

Beyond using cheap feedstock hydrocarbons as substrates, the team was also successful in converting amino acids, steroids and other bio-relevant molecules into gamma-lactams, which might find a variety of applications as plant insecticide, drugs against parasitic worms or anti-aging agents. This technique grants much easier access to gamma-lactams, enabling the development of potential drugs in a much shorter amount of time and at a lower cost.

“In our study, we moved away from the existing amination strategy and opened the door to an entirely new way of turning C-H into C-N bonds. Our discovery offers a new conceptual foundation for many exciting developments to follow,” said Chang.

The IBS researchers are now keen on developing less expensive catalyst systems and expanding the range of products, for example, by producing rings with four or six atoms (known as beta-lactams and delta-lactams, respectively).

The article can be found at: Hong et al. (2018) Selective Formation of γ-lactams via C–H Amidation Enabled by Tailored Iridium Catalysts.


Source: Institute for Basic Science; Photo: Shutterstock.
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