Abstract

In the century since Staudinger first reported the [2 + 2] cycloaddition reaction between a ketene and an imine to produce a β-lactam, many variants, including highly stereoselective versions, have appeared that demonstrate a reliable and versatile transformation which has become the major synthetic entry to β-lactams and products derived therefrom. Important advances have been made towards understanding the reaction mechanism, which in most cases is a stepwise process, as well as defining the variables which influence stereoselectivity. Successful diastereocontrol of the reaction can be achieved by using chiral auxiliaries attached at the ketene or the imine component, with diastereomeric ratios often above 95:5. Although most stereoselective methods afford β-lactams with the 3,4-cis relative configuration, procedures to generate both monocyclic and bicyclic β-lactams possessing the 3,4-trans configuration are also available. Whereas most current Staudinger protocols employ preformed imines, ketenes tend to be unstable and therefore are usually prepared in situ through dehydrohalogenation of acid chlorides by treatment with an excess of a tertiary amine base, or by in situ activation of carboxylic acids. Alternatively, stereoselective Staudinger reactions involving ketene generation by photolysis of Fisher chromium–carbene complexes or the Wolff rearrangement of α-diazo carbonyl compounds are also viable. By this methodology stereoisomerically enriched β-lactams can be prepared with a range of substitution patterns at the N1, C2, and C3 positions. The majority of the Staudinger reaction variants involve the synthesis of 3-amino- and 3-oxy-β-lactams, with fewer examples of 3-halo-, 3-thio-, or 3-carbon-substituted analogues. This chapter also describes applications of the Staudinger reaction to the synthesis of some important β-lactam and non-β-lactam products.