Stetter Reaction - Asymmetric Stetter Reaction

Asymmetric Stetter Reaction

The first asymmetric variant of the Stetter reaction was reported in 1996 by Enders et al, employing a chiral triazolium catalyst 1. Subsequently, several other catalysts were reported for asymmetric Stetter reactions, including 2, 3, and 4.

The success of the Rovis group's catalyst 2 led them to further explore this family of catalysts and expand their use for asymmetric Stetter reactions. In 2004, they reported the enantioselective formation of quaternary centers from aromatic aldehydes in an intramolecular Stetter reaction with a slightly modified catalyst. Further work extended the scope of this reaction to include aliphatic aldehydes as well. Subsequently, it was shown that the olefin geometry of the Michael acceptor dictates diastereoselectivity in these reactions, whereby the catalyst dictates the enantioselectivity of the initial carbon bond formation and allylic strain minimization dictates the diastereoselective intramolecular protonation.

The inherent difficulties of controlling enantioselectivity in intermolecular reactions made the development of an intermolecular asymmetric Stetter reaction a challenge. While limited enantiomeric excess had been reported by Enders in the early 1990s for the reaction of n-butanal with chalcone, conditions for a synthetically useful asymmetric intermolecular Stetter reaction were not reported until 2008 when both the groups of Enders and Rovis published such reactions. The Enders group utilized a triazolium-based catalyst to effect the coupling of aromatic aldehydes with chalcone derivatives with moderate yields. The concurrent publication from the Rovis group also employed a triazolium-based catalyst and reported the Stetter reaction between glyoxamides and alkylidenemalonates in good to excellent yields.

Rovis and coworkers subsequently went on to explore the asymmetric intermolecular Stetter reaction of heterocyclic aldehydes and nitroalkenes. During optimization of this reaction, it was found that a catalyst with a fluorinated backbone greatly enhanced enantioselectivity in the reaction. It was proposed that the fluorinated backbone helps to lock the conformation of the catalyst in a way the increases enantioselectivity. Further computational studies on this system verified that the stereoelectronic attraction between the developing partial negative charge on the nitroalkene in the transition state and the partial positive charge of the C-F dipole is responsible for the increase in enantiomeric excess observed with the use of the catalyst with backbone fluorination. While this is a marked advance in the area of intermolecular asymmetric Stetter reactions, the substrate scope is limited and the catalyst is optimized for the specific substrates being utilized.

Another contribution to the development of asymmetric intermolecular Stetter reactions came from Glorius and coworkers in 2011. They demonstrated the synthesis of α-amino acids enantioselectively by utilizing N-acylamido acrylate as the conjugate acceptor. Significantly, the reaction can be run on a 5 mmol scale without loss of yield or enantioselectivity.