Stetter reactions catalysis

First attempts of an asymmetric Stetter reaction were made 1989 in our research group with the investigation of chiral thiazolium salts such as 136 as precatalysts. The reaction of n-bu Lanai (133) with chalcone (134) in a two-phase system gave the 1,4-diketone 135 with an enanan-tiomeric excess of 39%, but a low yield of only 4% (Scheme 37) (Tiebes 1990 Enders 1993 Enders et al. 1993b). The catalytic activity of thiazolium as well as triazolium salts in the Stetter reaction persisted at a rather low level. Triazolium salts have been shown to possess a catalytic activity in the non-enantioselective Stetter reaction (Stetter and Kuhlmann 1991), but in some cases stable adducts with Michael acceptors have been observed (Enders et al. 1996a), which might be a possible reason for their failure in catalysis. 

Abstract. Within the context of Lewis base catalysis /V-heterocyclic carbenes represent an extremely versatile class of organocatalyst that allows for a great variety of different transformations. Starting from the early investigations on benzoin, and later Stetter reactions, the mechanistic diversity of /V-hctcrocyclic carbenes, depending on their properties, has led to the development of several unprecedented catalytic reactions. This article will provide an overview of the versatile reactivity of A-heterocyclic carbenes. 

With respect to the application of asymmetric carbene catalysis as a tool for enantioselective synthesis, the last decade s major success is based on substantial improvements in catalyst development. Early reports dealt with implementing chirality in thiazolium scaffolds (Sheehan and Hunneman 1966 Sheehan and Hara 1974 Dvorak and Rawal 1998), but their catalytic performance suffered from either low yields or low ee-values. In this regard, the investigation of triazole heterocycles as an alternative core structure (Enders et al. 1995) has played a crucial role to provide heterazolium precatalysts improving both asymmetric benzoin and Stetter reactions. An intramolecular Stetter reaction yielding chromanones upon cyclization of salicylaldehyde-derived substrates is commonly used as a benchmark reaction to compare catalyst efficiency (Scheme 1 Ciganek 1995 Enders et al. 1996 Kerr et al. 2002 Kerr and Rovis 2004). 

Zeitler K (2006) Stereoselective synthesis of (E)-afi—unsaturated esters via carbene-catalyzed redox esterification. Qrg Lett 8 637-640 Zeitler K, Mager I (2007) An efficient and versatile approach for the immobilization of carbene precursors via copper-catalyzed [3+2]-cycloaddition and their catalytic apphcation. Adv Synth Cat 349 1851-1857 Zhao GL, Cordova A (2007) A one-pot combination of amine and heterocyclic carbene catalysis direct asymmetric synthesis of fi-hydroxy and fS-malonale esters from a,fS-unsaturated aldehydes. Tetrahedron Lett 48 5976-5980 Zhou ZZ, Ji FQ, Cao M, Yang GF (2006) An efficient intramolecular Stetter reaction in room temperature ionic liquids promoted by microwave irradiation. Adv Synth Cat 348 1826-1830... 

When addressing the synthesis of a 7,4-di-heterosubstitued portion of a target structure, one should consider a braod range of synthetic methods. While a stoichiometric umpolung is not the first choice, one should remember the advantage of in situ umpolung tactics. In the context of 7,4-difunctionalized skeletons, the most attractive variant is provided by the Stetter reaction [62] (Scheme 2.41), which emulates nature s thiamine catalysis (cf. p. 17). 

In 2011, the enantioseleetive intramolecular Stetter reaction of unactivated olefins was reported by the Glorius group. Under the catalysis of NHC H3 derived from r-phenylalaninol, chromanone derivatives 31 containing a newly formed quaternary stereocentre were obtained in good yield with up to 99% enantiomeric excess. Both electron-donating substituents and electron-withdrawing substituents worked well (Scheme 20.15). 

NHC-catalyzed reactions are unique in organic synthesis, and very useful for the construction of carbon-carbon bonds. Great success has been made for the NHC-catalyzed benzoin condensation, Stetter reactions, and a -d Umpolung reactions in the past decades. NHC catalysis has also hnd application in many other reactions, such as umpolung of Michael acceptors, Morita-Baylis-Hilman reaction, Michael additions, redox reaction, and reactions of ketenes. With the rapid development of NHC catalysis, more reactions will surely be found, and the wide applications in organic synthesis could be expected. 

Enals (92) react with modified chalcones (e.g. 93) in an enantioselective Stetter reaction, giving highly functionalized products (94) in ees up to 97%, using chiral NHC catalysis. A Michael-type addition of NHC-bound enal acyl anion to the chalcone is proposed. ... 

Scheme 22. First test reactions for an asymmetric Stetter reaction via thiazolium salt catalysis [ ]...

Yu, F. Zhang, R. Xie, C. Yu, S. (2010). Polyether-substituted thiazolium ionic liquid catalysts - a thermoregulated phase-separable catalysis system for the Stetter reaction. Green Chem. Vol. 12, No. 7, pp. 1196-1200, ISSN. 1463-9262... 

Carbene Catalysis Beyond the Benzoin and Stetter Reactions... 

Another approach to 1,4-dicarbonyl products is also quite versatile and powerful. It involves the conjugate addition of a carbonyl anion equivalent derived from an aldehyde to an a,p-unsaturated carbonyl compound, using either cyanide or thiazolium ion catalysis (Stetter reaction). In the scheme shown (Scheme 14), it is also possible to have R3 = H, by using vinyl ketones or their Mannich base equivalents (225). 

Carbenes belong to the most investigated reactive species in the field of organic chemistry. Besides their role as excellent ligands in metal-based catalytic reactions, organic carbene catalysis has emerged as an exceptionally fruitful research area. In 2002, Rovis reported a highly enantioselective intramolecular Stetter reaction of unsaturated esters 50 derived from salicylaldehyde by the catalysis of chiral aminoindanol-derived triazolium salt 49 (Scheme 36.14) [20a]. 

As well as the traditional benzoin and Stetter reactions, some new synthetic transformations were disclosed via carbene catalysis. In 2007, the Scheldt group developed an intramolecular Michael-type reaction with unsaturated substrates 56 through catalysis with chiral triazolium salt 55. The intermediates 57 were generated via a domino Michael addition/lactonization sequence, and bicyclic products 58 were afforded in satisfactory yields and with excellent enantioselectivity after... 

One of the pioneering applications of iV-heterocyclic car-bene (NHC) organocatalysts in the view of synthesizing natural products is the application by Orellana and Rovis of a Stetter reaction to construct the spirocyclic core of the antibiotic FD-838 (Scheme 11.46). Applying the triazole NHC precursor and activating the catalyst with 20 mol% of potassium 1,1,1,3,3,3-hexamethyldisilazide [potassium bis (trimethylsilyl)amide] (KHMDS), compound 197 underwent the Stetter reaction in a perfect 99% ee. This simplified skeleton of the bioactive molecule was one of the first examples applying the great power of NHC catalysis toward natural product synthesis. 

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