Exploring forbidden reactions to discover new ways of chemical synthesis
The complex chemical compounds, like many of the drugs currently used, are obtained through sequences of synthesis that in the case of some complex anti-tumor drugs may involve up to forty stages. Multicomponent reactions, instead, allow synthesising complex molecules in very few steps since the different chemical bonds are formed almost simultaneously in a single operation. For medicinal chemistry, these direct reactions are of great interest, although only a few have been described. Now, researchers from the Faculty of Pharmacy of the UB have discovered new multicomponent reactions providing cyclic amidines, compounds with interesting pharmacological applications. The results of this study have recently been published in the high-impact journal in chemistry Angewandte Chemie International Edition.
The complex chemical compounds, like many of the drugs currently used, are obtained through sequences of synthesis that in the case of some complex anti-tumor drugs may involve up to forty stages. Multicomponent reactions, instead, allow synthesising complex molecules in very few steps since the different chemical bonds are formed almost simultaneously in a single operation. For medicinal chemistry, these direct reactions are of great interest, although only a few have been described. Now, researchers from the Faculty of Pharmacy of the UB have discovered new multicomponent reactions providing cyclic amidines, compounds with interesting pharmacological applications. The results of this study have recently been published in the high-impact journal in chemistry Angewandte Chemie International Edition.
As part of their research, the scientific team tested a reaction that is considered to be formally forbidden, since the theoretical product that would be obtained does not comply with the stability rules that apply to organic products, and if the product was formed, their bonds would break immediately. According to the researcher who has led the study, Rodolfo Lavilla, they decided to test one of these forbidden reactions - in particular, the Povarov reaction - because the strain limit a compound can have was not well-defined, and therefore it was worth testing it. The result of the reaction was that, indeed, the forbidden compound was not formed but, instead, there was a new reaction which involves the acetonitrile used as a solvent. “The experiment could have finished here, but we decided to study whether it was a general, and therefore interesting, reaction”, states Lavilla.
The researchers observed that the reaction was consistent and that if the reactive agents were modified, a collection of chemical compounds sharing the same scaffold could be obtained. In order to explain the factors that regulate the reactivity of these new mulitcomponent reactions, Lavillaʼs team collaborated with experts in computational chemistry from F. Javier Luqueʼs team, also from the Faculty of Pharmacy of the UB. “Calculations showed that some products obtained from the reaction were not those that could be intuitively expected, and that there exists a very fine orbital control of the reaction that regulates how the molecules take their final shape going through high-energy stages”, claims Lavilla.