Stetter Reaction - Scope

Scope

The Stetter reaction produces classically difficult to access 1,4-dicarbonyl compounds and related derivatives. The traditional Stetter reaction is quite versatile, working on a wide variety of substrates. Aromatic aldehydes, heteroaromatic aldehydes, and benzoins can all be used as acyl anion precursors with thiazolium salt and cyanide catalysts. However, aliphatic aldehydes can only be utilized if a thiazolium salt is used as a catalyst, as they undergo aldol condensation side reaction when a cyanide catalyst is used. In addition, α,β-unsaturated esters, ketones, nitriles, nitros, and aldehydes are all appropriate Michael acceptors with either catalyst. However, the general scope of asymmetric Stetter reactions is more limited. Intramolecular asymmetric Stetter reactions enjoy a range of acceptable Michael acceptors and acyl anion precursors in essentially any combination. Intramolecular asymmetric Stetter reactions can utilize aromatic, heteroaromatic and aliphatic aldehydes with a tethered α,β-unsaturated ester, ketone, thioester, malonate, nitrile or Weinreb amide. It has been shown that α,β-unsaturated nitros and aldehydes are not suitable Michael acceptors and have markedly decreased enantiomeric excess in such reactions. Another limitation encountered with intramolecular asymmetric Stetter reactions is that only substrates that result in the formation of a six-membered ring show synthetically useful enantiomeric excess; substrates which form five and seven-membered rings either do not react or show low stereoinduction. On the other hand, intermolecular asymmetric reactions are quite confined to specifically matched combinations of acyl anion precursor and Michael acceptor, such as an aliphatic aldehyde with a nitroalkene. In addition, these substrates tend to be rather activated, as the intermolecular asymmetric Stetter reaction is still in the early stages of development.