Rapid Synthesis of Phenazine-1-Carboxylic Acid Derived Small Molecules from Diverse Anilines: Privileged Structures for Discovery
The development of rapid approaches for the synthesis of privileged scaffold inspired chemical libraries is a driving force in drug discovery. Phenazines demonstrate a diverse array of biological activities (e.g. anticancer, antibacterial, antifungal, etc.) thus we consider the phenazine heterocycle to be a privileged scaffold of importance to drug discovery. Here, we have developed a synthetic approach that allows for the rapid preparation of four diverse derivatives of phenazine-1-carboxylic acid (PCA) in 3 to 4 linear synthetic steps from a single, commercially available aniline. This step-economy focused approach takes advantage of the Jourdan-Ullmann/sodium borohydride ring-closure pathway to synthesize a diverse set of PCA small molecules, followed by the rapid diversification using Curtius rearrangements and a series of amidation reactions to generate a library of 35 diverse phenazines.
Robert W Huigens III