Stetter catalytic, enantioselective

In a related process, Johnson and co-workers have developed an asymmetric metallophosphite-catalyzed intermolecular Stetter-hke reaction employing acyl silanes [81, 82], Acyl silanes are effective aldehyde surrogates which are capable of forming an acyl anion equivalent after a [l,2]-Brook rearrangement. The authors have taken advantage of this concept to induce the catalytic enantioselective synthesis of 1,4-dicarbonyls 118 in 89-97% ee and good chemical yields for a,p-unsaturated amides (Table 11). Enantioselectivities may be enhanced by recrystallization. 

It is worth noting, however, that the rise of enantioselective benzoin and Stetter reactions were one of the forerunners of the new generation of NHC-catalyzed processes that have been reported since 2004. These studies, particularly the work of Knight and keeper on chiral triazolium salts for benzoin and Stetter reactions, formed the basis for the design and synthesis of the now widely used chiral NHCs (Scheme 14.2). These designs were elegantly extended by Enders and by Rovis for the development of catalytic enantioselective benzoin condensations, intramolecular Stetter reactions, and the wide variety of enantioselective NHC-catalyzed transformations detailed below. 

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. 

Kerr MS, Rovis T (2004) Enantioselective synthesis of quaternary stereocenters via a catalytic asymmetric Stetter reaction. J Am Chem Soc 126 8876-8877... 

Moore JL, Kerr MS, Rovis T (2006) Enantioselective formation of quaternary stereocenters using the catalytic intramolecular Stetter reaction. Tetrahedron 62 11477-11482... 

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). 

Kerr, M. S., Read de Alaniz, J., Rovis, T. A Highly Enantioselective Catalytic Intramolecular Stetter Reaction. J. Am. Chem. Soc. 2002, 124, 10298-10299. 

Other different chiral carbene catalysts have been developed by other authors and tested specifically in intramolecular Stetter reactions (Scheme 6.10). This is the case of menthol-derived thiazolium salt 121 ° and tripeptide 122 incorporating a thiazolylalanine amino acid as constituents, which were used as pre-catalysts in the same reaction shown in Schemes 6.3 and 6.4 leading to chromanones. However, these two new catalytic systems, although active and able to promote rather efficiently the reaction, only furnished moderate levels of enantioselection. In a different approach, a C2-symmetric imidazoli-dinium salt 123 has been employed to generate the corresponding catalytically active carbene species and employed in the cyclization of 7-oxo-2-pentenoates leading to chiral cyclopentenones. In this case, this intramolecular Stetter reaction proceeded with moderate to good yields and enantioselectivities up to 80% ee. 

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]. 

Chiral A-heterocyclic carbenes (NHC), weU known as potent nucleophihc organocatalysts in numerous transformations such as benzoin condensation and Stetter reaction [22], have also recently been reported to catalyze asymmetric esterification of ketenes [23]. By surveying different alcohols and optimizing the reaction conditions, it was found that the addition of benzhydrol to a range of ketenes was efficiently catalyzed by a catalytic amount of NHC 54 , the later being formed in situ from the precatalyst 54 (12 mol%) and cesium carbonate (10 mol%). Some selected results presented in Scheme 3.24 show that enantioenriched esters 53 could be obtained in up to 95% ee, although both the enantioselectivity and the yield appeared to be highly substrate dependent. 

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