AsianScientist (Mar. 5, 2019) – A team of scientists in South Korea has developed a method to selectively generate chiral compounds—molecules that are mirror images of each other, just like a person’s right and left hand. Their findings are published in the journal Nature Catalysis.
More than half of the drugs currently in use are chiral. Since the body interacts with each molecule differently, a chiral drug may produce the desired effects from one molecule, but its mirror image form may cause unwanted side effects. Scientists have sought methods to make pure compounds without forming unnecessary mirrored versions, but selective synthesis has remained one of the most difficult challenges in drug discovery.
In the present study, researchers led by Professor Chang Sukbok at the Institute for Basic Science (IBS), South Korea, reported a group of new chiral iridium catalysts for the selective synthesis of chiral lactams. Though lactams are key building blocks in many pharmaceutical agents, for example, the antibiotic penicillin, there have been few efficient ways to single out only one molecule from a pair of the symmetric mirror images.
Because the atoms in chiral drugs are connected in the same way but differ in how they are oriented in space, the researchers identified specific iridium catalysts that induced a ‘righty’ rotation and those that caused a ‘lefty’ rotation. Combining experimental observations and detailed computer simulations, they found that transient formation of hydrogen bonding between a substrate and the catalyst allowed the biased synthesis of one chiral product over the other, with 99 percent selectivity.
The researchers further demonstrated that hydrogen bonding stabilizes intermediates and transition states during the course of synthesis reactions, eventually leading to the production of chiral lactams with high selectivity.
“It was key to understand the reaction mechanism in order to facilitate further catalyst development. This mechanism-based approach and reaction design model allowed us to find this novel transformation,” said Dr. Park Yoonsu of IBS.
Notably, the study suggests a sustainable protocol to produce highly sought-after chiral lactams. By using inexpensive and readily available feedstock hydrocarbons, the researchers produced a group of chiral lactams in different shapes.
As their chirality and diverse structures enable lactams to function as an active compound in the body for antibiotic, anti-inflammatory, or anti-tumoral functions, this study may facilitate the development of potential drugs in a more efficient and cheaper way.
“This is a major step forward in the area of asymmetric catalysis. As lactams find several applications in medicinal, synthetic and material chemistry, our study may offer foundations in developing safer and more effective clinical drugs,” said Chang.
The article can be found at: Park & Chang (2019) Asymmetric Formation of γ-lactams via C–h Amidation Enabled by Chiral Hydrogen-bond-donor Catalysts.
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Source: Institute for Basic Science; Photo: Shutterstock.
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