Within this last decade, there has been a renewed interest in leveraging stable atropisomerism to synthesize more potent and selective N-heterocyclic pharmaceuticals. One unaddressed challenge is the narrowed scope of synthetic methodologies to directly access these important atropisomeric scaffolds on desired “gram-scale” quantities. Herein we report an atroposelective nucleophilic aromatic substitution towards a diverse range of these aforementioned compounds in optimal enantioselectivities and yields. With leaving groups such as a fluoride or chloride, we perform kinetic resolutions and dynamic kinetic resolutions using nucleophilic thiophenols. Twice oxidation to the sulfone can lead to a subsequent nucleophilic substitution to virtually any functionality that medicinal chemistry would be interested in (e.g. various amines, methoxy-groups). Examples of N-heterocycles we have directly functionalized with this chemistry include 3-aryl pyrrolopyrimidines (PPYs, a well-studied kinase inhibiting scaffold) and 3-aryl quinolines (which are found in many FDA-approved drugs and bioactive compounds). We have since synthesized several atropisomeric PPY inhibitors for our recent chemical biology efforts using this strategy, as well as currently investigating 3-aryl quinoline scaffolds in various bioactive compounds.

Syntheses of pharmaceutically relevant N-heterocycles atropisomers via nucleophilic aromatic substitution

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

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.