Molecular Editing of Pyrroles via a Skeletal Recasting Strategy

Heterocyclic scaffoldsare commonly found in numerous biologicallyactive molecules, therapeutic agents, and agrochemicals. To probechemical space around heterocycles, many powerful molecular editingstrategies have been devised. Versatile C-H functionalizationstrategies allow for peripheral modifications of heterocyclic motifs,often being specific and taking place at multiple sites. The pastfew years have seen the quick emergence of exciting single-atomskeletal editing strategies, through one-atom deletion oraddition, enabling ring contraction/expansion and structural diversification,as well as scaffold hopping. The construction of heterocycles viadeconstruction of simple heterocycles is unknown. Herein, we disclosea new molecular editing method which we name the skeletal recastingstrategy. Specifically, by tapping on the 1,3-dipolar property ofazoalkenes, we recast simple pyrroles to fully substituted pyrroles,through a simple phosphoric acid-promoted one-pot reaction consistingof dearomative deconstruction and rearomative reconstruction steps.The reaction allows for easy access to synthetically challenging tetra-substitutedpyrroles which are otherwise difficult to synthesize. Furthermore,we construct N-N axial chirality on our pyrrole products, aswell as accomplish a facile synthesis of the anticancer drug, Sutent.The potential application of this method to other heterocycles hasalso been demonstrated. We presenta skeletal recasting strategyfor synthesis of fully substituted pyrroles from simple pyrroles viasequential dearomative deconstruction and rearomative reconstructionsteps.

Automated summary

A new molecular editing method called skeletal recasting strategy is developed to synthesize fully substituted pyrroles from simple pyrroles through dearomative deconstruction and rearomative reconstruction steps, leading to the synthesis of challenging tetra-substituted pyrroles and anticancer drug Sutent.