The Catalytic Enantioselective Stetter Reaction

Flanigan, D. M.; Ozboya, K. E.; Muñoz, A.; Rovis, T.; Tanpure, S. D.; Blakemore, P. R.
1191  –  1330


The catalytic enantioselective Stetter reaction is the coupling of an aldehyde with an electron-deficient alkene via the conjugate addition of an acyl anion equivalent (Breslow intermediate) generated from the aldehyde and a chiral N-heterocyclic carbene (NHC) catalyst. The process affords 1,4-dicarbonyl compounds and related systems, such as β-nitroketones, in an efficient and atom-economical fashion and with generally good-to-excellent enantioselectivities when fused polycyclic chiral triazolylidenes are employed as the NHC catalysts. The scope of the transformation is particularly broad for intramolecular reactions, but in the case of the intermolecular variant, only certain types of aldehyde donors and electrophilic alkenes can be successfully coupled together.

This chapter describes theoretical and operational aspects of the catalytic enantioselective Stetter reaction such that the reader will be able to obtain optimal results in their own research. A detailed mechanistic overview is included to account for the factors that influence stereoselectivity and yield, and results from experimental and computational mechanistic studies are summarized. In addition, catalyst synthesis, reaction variants, applications in target-directed synthesis, and comparison to other methods for generating 1,4-dicarbonyl compounds are also presented. Tabular surveys are organized according to the modality of reactivity, either intra- or intermolecular, and the type of aldehyde donor. The literature is covered from the first disclosure of a catalytic enantioselective Stetter reaction in 1996 through to the end of 2019.