RESUMO
The straightforward and efficient synthesis of complex aza- and carbobicyclic compounds, which are of importance for medicinal chemistry, is a challenge for modern chemical methodology. An unprecedented metal-free six-step domino reaction of aldehydes with malononitrile was presented in our previous study to provide, in a single operation, these bicyclic nitrogen-containing molecules. Presented here is a deeper investigation of this atom-economical domino process by extending the scope of aldehydes, performing post-modifications of domino products, applying bifunctional organocatalysts and comprehensive NMR studies of selected domino products. The thermodynamic aspects of the overall reaction are also demonstrated using DFT methods in conjunction with a semi-empirical treatment of van der Waals interactions. Furthermore, biological studies of seven highly functionalized and artemisinin-containing domino products against human cytomegalovirus (HCMV) and Plasmodium falciparumâ 3D7 are presented. Remarkably, inâ vitro tests against HCMV revealed five domino products to be highly active compounds (EC50 0.071-1.8â µm), outperforming the clinical reference drug ganciclovir (EC50 2.6â µm). Against P.â falciparumâ 3D7, three of the investigated artemisinin-derived domino products (EC50 0.72-1.8â nm) were more potent than the clinical drug chloroquine (EC50 9.1â nm).
RESUMO
Aza- and carbobicyclic compounds possess favorable pharmaceutical properties, but they are difficult to access. Herein, we demonstrate an unprecedented organocatalytic two component six-step chemodivergent domino reaction, which provides a straightforward, sustainable and atom economical route to difficult-to-access complex bicyclic architectures: azabicycles and carbobicycles, whose ratios can be controlled by the applied electrophiles and catalysts. Detailed NMR and X-ray studies on the structures and relative stereochemistry of selected compounds are presented. Mechanistic investigations of the chemoselective branching step have been carried out with DFT methods in conjunction with semiempirical van der Waals interactions. This new domino reaction opens up a new vista of generating, in a single operation, new bioactive compounds with strong antiviral properties (EC50 up to 0.071 µM for human cytomegalovirus (HCMV)) outperforming clinically used ganciclovir (EC50 2.6 µM).
Assuntos
Antivirais/química , Compostos Aza/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Citomegalovirus/química , Antivirais/farmacologia , Compostos Aza/farmacologia , Catálise , Ciclização , Citomegalovirus/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , EstereoisomerismoRESUMO
The title reaction provides a direct entry to a range of biologically relevant annulated pyrroles via a domino process involving a regioselective one-carbon homologation of cyclic ketones as the key step.