Tunable and Cooperative Catalysis for Enantioselective Pictet‐Spengler Reaction with Varied Nitrogen‐Containing Heterocyclic Carboxaldehydes

• Published in: Angewandte Chemie International Edition Vol. 60; no. 46; pp. 24573 - 24581
• Main Authors: Chan, Yuk‐Cheung, Sak, Marcus H., Frank, Scott A., Miller, Scott J.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 08.11.2021; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Aldehydes - chemistry; Benzaldehydes - chemistry; Carbolines - chemical synthesis; Carbolines - chemistry; Carboxylic acids; Carboxylic Acids - chemistry; Catalysis; Catalysts; Chemistry; Chemistry, Multidisciplinary; cooperative catalysis; Enantiomers; Estrogen receptors; Estrogens; heterocycles; Heterocyclic Compounds - chemistry; hydrogen bond donors; Hydrogen Bonding; Nitrogen - chemistry; peptides; Physical Sciences; Pictet–Spengler; Science & Technology; Stereoisomerism; Stereoselectivity; ASYMMETRIC CATALYSIS; DESIGN; hydrogen bond donors; cooperative catalysis; ORGANOCATALYSIS; peptides; FLUORINATION; INDOLES; ENANTIODIVERGENT; FUNCTIONALIZATION; heterocycles; Pictet-Spengler; AROMATICITY INDEX; STABILIZED BRONSTED ACIDS; DEAROMATIZATION
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202109694

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. We utilize diverse N‐heterocyclic carboxaldehyde and regioisomers in Pictet‐Spengler reaction. Compatibility was enabled by fine tuning the achiral carboxylic acid co‐catalyst in the presence of chiral peptidic squaramide. Synthetic utility was demonstrated by stereoselective synthesis of pyridine‐containing analogues of medicinally related molecules, including U.S. FDA approved drug Tadalafil.