Streamlined Access to Novel Activators and Degraders of the Aryl Hydrocarbon Receptor through a Rewired Multicomponent Reaction

A rewired Yonemitsu multicomponent reaction was designed to readily synthesize a family of 6-substituted indolocarbazoles. In this approach, indole 2-carboxaldehyde and nucleophilic species directly yield the final adducts through a domino reaction. The scope of the new process was analyzed, and the range of the indole aldehydes and nucleophiles was established. Comparative studies with analogous compounds reveal important details on the reaction mechanism. Experimental and computational studies address the conformational behavior of representative adducts, determining their potential chirality. These novel structures are potent activating ligands of the human aryl hydrocarbon receptor, importantly being non-toxic. Furthermore, the scaffold may be included in a 2-step synthesis of (homo)-PROTACs that efficiently and specifically degrade the receptor. Our approach allows the control of this important target in biomedicine through a designed new chemistry.