Enantioselective, Bro̷nsted Acid-Catalyzed Anti-selective Hydroamination of Alkenes

• Published in: Journal of the American Chemical Society 2024-06, Vol.146 (25), p.17180-17188
• Main Authors: Guria, Sudip, Volkov, Alexander N., Khudaverdyan, Raffi, Van Lommel, Ruben, Pan, Rittwika, Daniliuc, Constantin G., De Proft, Frank, Hennecke, Ulrich
• Format: Article
• Language: English
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.4c03306

Chiral pyrrolidines are common structural motives in natural products as well as active pharmaceutical ingredients, explaining the need for methods for their enantioselective synthesis. While several, often metal-catalyzed, methods for their preparation do exist, the enantioselective synthesis of pyrrolidines containing quaternary stereocenters remains challenging. Herein, we report a Bro̷nsted acid-catalyzed intramolecular hydroamination that provides such pyrrolidines from simple starting materials in high yield and enantioselectivity. Key to an efficient reaction was the use of an electron-deficient protective group on nitrogen, the common nosyl-protecting group, to avoid deactivation of the Bro̷nsted acid by deprotonation. The reaction proceeds as a stereospecific anti-addition indicating a concerted reaction. Furthermore, kinetic studies show Michaelis–Menten behavior, suggesting the formation of a precomplex similar to those observed in enzymatic catalysis.