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

ABSTRACT

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 ß-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 ß-carboline in excellent yield, good enantioselectivity, and excellent regioselectivity. Extensive optimization of this transformation is described. Racemization kinetics experiments were also conducted on the individual atropisomers and their absolute configurations were determined by circular dichroism.