Professors Sukbok Chang and Yoonsu Park from the Department of Chemistry have successfully developed a unique catalyst that can synthesize γ-chiral lactams, an essential component of several pharmaceutical agents. While they achieved a similar feat in their report published in March 2018, they now present a more refined catalyst that synthesizes the compound with little formation of unnecessary byproducts.
Chiral compounds are pairs of molecules, often called enantiomers, that are mirror images of each other. This structural difference consequently affects their individual properties: a relatively safe drug could become a dangerous one when converted into its enantiomeric structure. Synthesizing γ-chiral lactams without forming their other enantiomeric pair decreases the risk for potentially harmful side effects. However, previously established reaction processes normally require pre-manipulating the reactants, or precursors, by adding multiple functional groups to achieve optimal conditions, which compromises its cost-effectiveness.
A certain mechanism called carbon-hydrogen amidation could eliminate the need for complicated pre-manipulation. It also makes use of nature-abundant, commercially available hydrocarbon reactants, and is therefore a more economical approach to employ. But the intermediate products in this mechanism may decompose midway through the process, thus reducing the final reaction yield. Furthermore, the researchers reported that some precursors of the mechanism are underdeveloped. The catalyst created in this study overcomes these hurdles, hence being an efficient breakthrough solution to this problem.
The catalysts, which are iridium-based, produced high yields of the desired enantiomer with an enantioselectivity of at least 99%. Chiral lactams in various shapes and types like chiral pharmacophore fragments and paroxetine were also synthesized successfully. Analyses using computational chemistry simulations show that the hydrogen bonding formed between the chiral catalysts and initial ligands caused this enhancement, and structural modifications in the catalyst conversely lowered the enantioselectivity value.
Lactams, an important ingredient in clinical drugs, offer antibiotic and anti-inflammatory benefits to the body. Professor Chang hopes that his team’s research “will lead to developing new drugs that demonstrate fewer side-effects and higher efficacy”. His team also expects its findings to be useful in the fields of synthetic and medicinal chemistry.