Synthesis of Condensed Tetrahydroisoquinoline Class of Alkaloids by Employing TfOH-Mediated Imide Carbonyl Activation

Isoquinoline‐based polycyclic lactams such as isoindoloisoquinolinones, pyrroloisoquinolinones, and benzo[a]quinolizinones were successfully assembled from the corresponding imides by using a TfOH‐mediated (TfOH = trifluoromethanesulfonic acid) imide carbonyl activation and cyclization strategy. By employing this simple method, the isoquinoline alkaloids crispine A, trolline/oleracein E, and erythrinarbine were successfully synthesized in racemic form. The reaction of unsymmetrical N‐phenethylphthalimides with TfOH displayed excellent regioselectivity, which was rationalized by DFT calculations. The isoquinoline‐based polycyclic lactams and simple isoquinoline alkaloids were successfully assembled from the corresponding imides by using a TfOH‐mediated (TfOH = trifluoromethanesulfonic acid) imide carbonyl activation and cyclization strategy. The regioselective cyclization of unsymmetrical phenethylimides with TfOH was studied by experimental and computational methods.