Radical Reactions with Chiral Acylammonium Salts: Synthesis of Functionalized δ-Lactams through Giese-Initiated Organocascades

Enantioselective Giese reactions employing chiral alpha,beta-unsaturated acylammonium salts and subsequent diastereoselective trapping followed by lactamization deliver optically active delta-lactams. Alkyl iodides bearing tosylamides undergo radical initiation using triethylborane at low temperatures to provide carbon-centered radicals to initiate the described organocascade. Subsequent diastereoselective inter- or intramolecular trapping of the incipient alpha-radical leads to highly functionalized, enantioenriched mono- and bicyclic delta-lactams (up to 99:1 er, > 19:1 dr) bearing up to three stereogenic centers. Interestingly, benzotetramisole imparts diastereoselectivity that contradicts steric considerations alone. Results from DFT calculations rationalized the observed enantio- and diastereoselectivities, revealed an electrostatic interaction between the sulfone oxygens and the ammonium cation in the initial alpha-radical intermediate, and aided in application of this methodology to bicyclic delta-lactams through intramolecular trapping of the alpha-radical intermediate.