ASYMMETRIC FORMATION OF QUATERNARY CENTERS THROUGH AZA-ANNULATION OF CHIRAL BETA-ENAMINO ESTERS WITH ACRYLATE DERIVATIVES

The aza-annulation of beta-enamino ester substrates with acrylate derivatives was used for the stereoselective formation of quaternary carbon centers. Tetrasubstituted secondary enamines, in which the enamine tautomer was stabilized through conjugation with an ester carbonyl, were generated from the optically active primary amine (R)-alpha-phenethylamine and the alpha-amino esters of L-valine and (R)-phenylglycine. Treatment of the enamine with either acryloyl chloride or sodium acrylate/ethyl chloroformate resulted in aza-annulation to give the corresponding delta-lactam with high diastereoselectivity (>84% de). The effects of reaction temperature, solvent, and acrylate reagent on the stereoselectivity of this reaction were examined. Aza-annulation with crotonyl chloride resulted in concomitant formation of two vicinal stereogenic centers with >97% stereoselectivity. Quaternary carbon centers were formed stereoselectively during aza-annulation with alpha-substituted acrylate derivatives, but poor selectivity was observed for generation of the stereogenic center alpha to the lactam carbonyl.