biostudies-literatureChan YCNational Institutes of Healtheli lilly and companyNIGMS NIH HHSNIH HHSEli Lilly and Company24573-24581https://www.ebi.ac.uk/biostudies/studies/S-EPMC8556314biostudies-literatureUnknown60(46)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.Angewandte Chemie (International ed. in English)Tunable and Cooperative Catalysis for Enantioselective Pictet-Spengler Reaction with Varied Nitrogen-Containing Heterocyclic Carboxaldehydes.PMC8556314R35 GM132092Frank SASak MHChan YCMiller SJfalseTunable and Cooperative Catalysis for Enantioselective Pictet-Spengler Reaction with Varied Nitrogen-Containing Heterocyclic Carboxaldehydes.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.2021-01-01T00:00:00Z2021 Nov2025-04-05T12:34:02.611Z2025-04-05T12:34:02.611ZS-EPMC85563143448741810.1002/anie.202109694