Ring distortion involves the rapid alteration of the core ring systems within a natural product, and results in complex small molecules containing unique scaffolds. This tactic utilizes chemoselective reactions that enable ring cleavage, ring expansion, ring rearrangement, or ring fusion. In an effort to synthesize a unique compound library for drug discovery, we worked with the commercially available (~$36/gram) complex indole alkaloid vincamine; a monoterpenoid indole alkaloid bearing a pentacyclic ring system containing three stereogenic centers and an α-hydroxyester fused to the indole nitrogen. Applying our ring distortion approach to vincamine, we were able to rapidly synthesize a library of &gt;65 elaborate and diverse molecules via an innovative series of chemoselective ring cleavage, ring fusion, and ring rearrangement. Of particular interest, we discovered a cascade reaction which employs the construction of a new ring fused scaffold via indole oxidation, and the Brønsted-acid catalyzed annulation of vincamine-derived amides. During these investigations, we found a novel small molecule stemming from our ring fusion chemistry to be biological active against a target relevant to opioid addiction. This new vincamine-derived compound demonstrated <i>in vivo</i> efficacy in both acute and reinstatement mouse models of morphine reward and abuse; however, vincamine showed no such activity. These findings have the potential to address the opioid crisis in the United States by providing novel compounds for therapeutic development. Therefore, this work demonstates the potential that ring distortion has in re-engineering the biological activity of select natural products for new applications of critical importance to human health.

Ring distortion of vincamine produces complex and diverse molecules for drug discovery

2019 Spring National Meeting

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