Asymmetric Synthesis of an Atropisomeric β-Carboline via Regioselective Intermolecular Rh(I)-Catalyzed [2 + 2 + 2] Cyclotrimerization.

The rational design of atropisomeric small molecules is becoming increasingly common in chemical synthesis as a result of the unique advantages this property provides in drug discovery, asymmetric catalysis, and chiroptical activity. In this study, we designed a synthesis of a configurationally stable β-carboline in six steps. Our synthesis made use of an innovative Grignard addition/elimination reaction that formed an yne-ynamide precursor that then reacted with ethyl cyanoformate in a rhodium(I)-catalyzed [2+2+2] cyclotrimerization reaction to give the atropisomeric β-carboline in excellent yield, good enantioselectivity, and excellent regioselectivity.

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.