The Kinugasa Reaction

Chmielewski, M.; Kutaszewicz, R.; Ulikowski, A.; Michalak, M.; Wołosewicz, K.; Stecko, S.; Furman, B.
223 – 506


Among the methods of synthesizing the β-lactam ring, the copper(I)-mediated reaction between a nitrone and a terminal alkyne in the presence of an organic base is a remarkably simple and direct strategy. This transformation, known as the Kinugasa reaction, is a cascade process that involves a 1,3-dipolar cycloaddition of a copper acetylide onto the nitrone, followed by a rearrangement step. Initially reported in 1972, this reaction stereoselectively allows access to cis-substituted β-lactam products. Achiral, diastereoselective, and catalytic enantioselective versions of the Kinugasa reaction have been described, both in inter- and intramolecular contexts. To date, only aldimine-derived nitrones have been demonstrated in the reaction.

This chapter presents a comprehensive overview of the Kinugasa reaction. Mechanistic proposals and the factors involved in the stereochemistry of the reaction are followed by a discussion of the scope of the reaction and its limitations. Specifically, the combinations of aldonitrones and terminal alkynes that can be used in the achiral and diastereoselective Kinugasa reaction are presented. Enantioselective and intramolecular variants of the reaction are discussed in detail, as are successful synthetic applications, with an emphasis on the preparation of β-lactam antibiotics. The Kinugasa reaction is compared with more classical and well-established methods of β-lactam synthesis, and finally, typical experimental conditions and examples of procedures for selected variants of the Kinugasa reaction are provided. The Tabular Survey covers Kinugasa reactions performed through the end of 2021.