Asymmetric Formation of Quaternary Centers through Aza-Annulation of Chiral β-Enamino Amides with Acrylate Derivatives

The stereoselective formation of six-membered nitrogen heterocycles that contain an asymmetric quaternary carbon center was achieved through aza-annulation of β-enamino amide substrates with activated acrylate derivatives. Condensation of a racemic β-keto amide with an optically active primary amine, either ( R )-α-methylbenzylamine or α-amino esters, generated the corresponding optically active tetrasubstituted secondary enamine, in which the enamine tautomer was stabilized through conjugation with an amide carbonyl. Treatment of the intermediate enamine with acryloyl chloride, acrylic anhydride, or sodium acrylate/ethyl chloroformate resulted in aza-annulation to give the corresponding δ-lactam with high diastereoselectivity (>96% de). For the variety of different β-enamino amide substrate classes examined in this reaction, the optimum method for activation of the acrylate derivative was the use of EtO 2 CCl. When aza-annulation was performed with an α-acetamido-substituted acrylate derivative, the stereoselective formation of the quaternary carbon center was accompanied by poor selectivity for generation of the center α to the lactam carbonyl. Crystallographic analysis of one α-amido aza-annulation product was performed to identify the key structural features of these molecules.