Synthesis of Diarylpyrrole Pseudo-Natural Products: Cyanide-Mediated Nitrile-to-Nitrile Cyclocondensation and C–H Acidity-Guided Regioselectivity

Abstract

"Pseudo-natural products (pseudo-NPs)", the chemically re-engineered molecular skeletons generated by deconstruction of NPs into fragments and their newly recombination, have gained immense attention in recent time owing to their ability to occupy a significant portion of the medicinally-relevant NP-based molecular space, possess novel bioactivities, and address chemical and biological challenges. In this study, the fragments of Combretastatin, Steganacin, Podophyllotoxin, Colchicine other natural product and drug molecules, and their newly assembly by a cis-lock fusion-edge combination led to generation of diarylpyrrole pseudo-natural product functionalized skeleton, “Combretapyrrole”. These Combretapyrroles with excellent substrate scope were synthesized in good yields by a new method of cyanide-mediated nitrile-to-nitrile cycloaddition reaction of vic-dinitrile with TMG-mediated desilylative cleavage of TMSCN and in-situ generation of cyanide. The differential acidity of benzylic C-Hs of the vic-dinitrile intermediate was found to influence regioselectivity in the mechanistic pathway and provided different products. Cheminformatic analysis showed that the Combretapyrroles occupy a unique drug-relevant chemical space that is rarely covered by NPs. Combretapyrroles also were found to possess drug-like physicochemical properties.