Design, Synthesis, and Physicochemical Studies of Configurationally Stable β-Carboline Atropisomers.

Axially chiral atropisomers have energetic barriers to rotation, Δ, that prevent racemization of the respective enantiomers. We used computational modeling to develop a suite of 10 bio-inspired 1-aryl-β-carbolines with varying Δ, from which a strong structure-activity relationship was observed for 2-substituted-1-naphthyl substituents. We then synthesized two of these atropisomers, and , by a four-step racemic synthesis and resolved the enantiomers via chiral chromatography. Racemization studies revealed experimental Δ values of 39.5 and 33.0 kcal/mol for and , respectively, which were consistent with our computational results. These atropisomers exhibited long half-lives, which allowed for their physicochemical characterization and stereochemical assignment via UV-vis spectroscopy, fluorescence spectroscopy, electronic circular dichroism, and vibrational circular dichroism.