The Ugi-Smiles Reaction on Steroids: Discovery of Bioactive N,N-Disubstituted 3- Aminoestrones

The Ugi-Smiles multicomponent reaction is a powerful tool for obtaining N-arylamines from acidic phenols and has been widely used for gaining access to structurally diverse scaffolds. In this work we demonstrate that this isocyanide-based coupling can be used for the straightforward and efficient synthesis of N,N-disubstituted 3-aminoestrones, steroidal derivatives that usually show interesting biological activities. In this sense, we analyzed the scope and limitations of the reaction when applied to aromatic nitrosteroids and found that the outcome is highly influenced by the steric effects imposed by the steroidal skeleton. After optimization of the reaction conditions a set of thirteen N-substituted 3-aminoestromes were obtained, some of them with interesting antiproliferative and antiviral activities.