Brønsted Acid Catalyzed Pictet-Spengler Cyclization of Keto Acids

Significance

Dixon and co-workers report the chiral phosphoric acid 1 catalyzed reaction between tryptamines and δ- and γ-keto acids furnishing polycyclic tetrahydro-β-carbolines in good yields and high enantioselectivities. The reaction is assumed to proceed via initial condensation of amine and ketone. Under Brønsted acid catalysis the generated imine reacts further with the acid or ester function to give two diastereoisomeric N-acyl iminium ion pairs, equilibrating with the two possible enamide intermediates. The authors ­propose that only one of the diastereomeric N-acyliminium ion pairs is attacked by the nucleophilic indole to give the desired products in a dynamic kinetic asymmetric cyclization.