Tunable and Cooperative Catalysis for Enantioselective Pictet‐Spengler Reaction with Varied Nitrogen‐Containing Heterocyclic Carboxaldehydes
Yuk‐Cheung Chan, Marcus H. Sak, Scott A. Frank, Scott J. Miller
Abstract
Herein we report an organocatalytic enantioselective functionalization of heterocyclic carboxaldehydes via the Pictet-Spengler reaction. Through careful pairing of novel squaramide and Brønsted acid catalysts, our method tolerates a breadth of heterocycles, enabling preparation of a series of heterocycle conjugated β-(tetrahydro)carbolines in good yield and enantioselectivity. Careful selection of carboxylic acid co-catalyst is essential for toleration of a variety of regioisomeric heterocycles. Utility is demonstrated via the three-step stereoselective preparation of pyridine-containing analogues of potent selective estrogen receptor downregulator and U.S. FDA approved drug Tadalafil.