Asymmetric Synthesis of 3-Amino-δ-lactams and Benzo[a]quinolizidines by Catalytic Cyclization Reactions Involving Azlactones

The first asymmetric three-component formal [4+2] cycloaddition reaction of azlactones, cinnamaldehydes, and primary amines were disclosed. Anisidine 3, 100mg 4A, and catalyst 5d was added chloroform under argon to a tube charged with aldehyde 2. The solution was stirred for 30 mm at room temperature and then for another 10 mm at 0°C. Subsequently, azlactone 1 in chloroform was added slowly at 0°C. The resulting reaction mixture was stirred at 0°C for three days. The reaction mixture was purified by flash column chromatography on silica gel to yield pure products. Use of a phosphoric acid derivative as the catalyst provided excellent enantioselectivities of up to 96% ee for a wide range of 3-amino-3,4-dihydropyridinones. This method is highly useful in the synthesis of cyclic nitrogenous structural motifs.