Asymmetric Synthesis of β-Lactams via the Ketene-Imine Cycloaddition

Abstract

The formal [2+2] cycloaddition of ketenes with imines is undoubtedly the most powerful entry to β-lactams (2-azetidinones). Several classes of usually in situ formed ketenes, namely amino-, oxy-, thio-, halo- and alkylketenes, are competent reaction partners which upon reaction with the corresponding N-protected C-aryl-, alkyl-, or acyl-imine give access to β-lactam products with a large variety of substitution patterns at the three available positions on the resulting heterocycle. Since most of the β-lactam products are chiral, their asymmetric synthesis have been, and continues to be, a sough after goal. Both substrate-controlled and catalyst-controlled methods that provide very high asymmetric induction during the ketene-imine cycloaddition have been developed. Among the first, the reactions involving chiral imines derived from a chiral aldehyde, or chiral ketenes, particularly aminoketenes, are the most effective in controlling the diastereoselectivity. A few examples involving more than one chiral reactant (double and triple induction) have also been described. Major contributions to the field are presented along with a brief introduction to mechanistic issues and the factors that control the reaction stereochemistry.