Nitrogen-containing structural motifs are prevalent in pharmaceutical scaffolds. According to a statistical analysis of nitrogen heterocycles in U.S. FDA-approved drugs, 59% of small-molecule drugs contain a nitrogen heterocycle. Among other nitrogen heterocycles, piperazines are the third most common nitrogen six-membered ring system found in pharmaceuticals. Traditional methods to synthesize piperazines often involve transition metal-mediated cyclization. However, these syntheses lack structural diversity, specifically carbon substitution diversity on the piperazine ring. This new method explores [3+3] ring expansion of bicyclic aziridines to access functionalized piperazines <i>via </i>aziridinium ylides. Asymmetric silver-catalyzed alkene aziridination is followed by an attack of the aziridine lone pair on the rhodium-stabilized imino carbene to produce the key aziridinium ylide intermediate. Subsequent concerted, asynchronous pseudo-[1,4]-sigmatropic rearrangement of the ylide delivers the piperazine scaffolds in high diastereoselectivity. DFT calculations support the current proposed mechanism in which this reaction proceeds through an aziridnium ylide. This work highlights a ring expansion of aziridines as a key strategy to access larger nitrogen-containing molecules.

Intermolecular [3+3] ring expansion of bicyclic aziridines to access functionalized piperazines via aziridinium ylides

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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