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 reengineered molecular skeletons generated by the deconstruction of NPs into fragments and their subsequent recombination, have gained immense attention in recent times owing to their ability to occupy a significant portion of the medicinally relevant NP-based molecular space, their possession of novel bioactivities, and their ability to address chemical and biological challenges. In this study, the reassembly of fragments of combretastatin, steganacin, podophyllotoxin, colchicine, and other natural products and drug molecules by a cis-lock fusion-edge recombination led to the generation of diarylpyrrole pseudo-NP-functionalized skeletons, named combretapyrroles. These combretapyrroles were synthesized with excellent substrate scope in good yields by a new cyanide-mediated nitrile-to-nitrile cycloaddition reaction of a vic-dinitrile combined with 1,1,3,3-tetramethylguanidine-mediated desilylative cleavage of TMSCN and in situ generation of cyanide. The differential acidity of the benzylic C–H moieties of the vic-dinitrile intermediate was found to influence regioselectivity in the mechanistic pathway and to provide different products. A 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.

Key words

pseudo-natural product - nitriles - cyclocondensation - cyclization - regioselectivity - diarylpyrroles

• References and Notes

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