Development of a catalytic enantioselective intramolecular Stetter reaction: catalyst development and synthetic applications

Abstract

A triazolinylidene carbene-catalyzed enantioselective intramolecular Stetter reaction has been developed. The process involves direct conversion of an aldehyde into a chiral acyl anion equivalent and its addition into a pendant electron-deficient olefin. The development of chiral bicyclic nucleophilic carbene catalysts has allowed for increased efficiency and selectivity in this reaction, as well as an overall broadening of its synthetic utility. The highly stereoselective formation of five- and six-membered rings has been realized in this reaction manifold. Extensive catalyst development has identified a number of catalysts which often provide complementary reactivity and selectivity. Aliphatic and aromatic aldehydes both participate in the addition to a variety of Michael acceptors. Synthetically important enantioenriched 1,4-dicarbonyl compounds can be generated in a single operation from achiral materials. The Stetter reaction has been developed to construct challenging quaternary stereocenters with good efficiency and very high selectivity. The scope of this transformation is quite broad, and holds significant promise for further reaction development. Synthetic applications have been investigated in the arena of natural product synthesis. Progress has been made utilizing the Stetter reaction for a key bond construction in an effort to enantioselectively synthesize a complex alkaloid. The key Stetter reaction in this system affords the desired product in good yield and excellent enantioselectivity.