Diastereodivergent Pictet-Spengler Cyclization of Bicyclic N-Acyliminium Ions: Controlling a Quaternary Stereocenter

The diastereoselectivity of the Pictet-Spengler cyclization of bicyclic N-acyliminium ions that contain a 3-azabicyclo[n.3.0] alkane core and an electron-rich p-nucleophilic moiety, such as an indol-2-yl, indol-3-yl, 1-methylpyrrol-2-yl, or 3,5-dimethoxyphenyl group, was examined. The N-acyliminium ions were generated by protonation of the corresponding enamides or hemiaminals, which were derived from imides. Control of the quaternary stereocenter created at the newly formed ring junction was achieved in a diastereodivergent manner by fine-tuning the reaction conditions, which determined whether the reaction proceeded under kinetic or thermodynamic control. Mechanistic studies indicated that a retro-Pictet-Spengler reaction pathway is involved in the equilibration process.