Thiazolium precatalyst, Stetter reaction

Almost 20 years after the initial report of the Stetter reaction, Ciganek reported an intramolecular variant of the Stetter reaction in 1995 with thiazolium precatalyst 74 providing chromanone 73 in 86% yield (Scheme 10) [64]. This intramolecular substrate 72 has become the benchmark for testing the efficiency of new catalysts. Enders and co-workers illnstrated the first asymmetric variant of the intramolecnlar Stetter reaction in 1996 utilizing chiral triazolinylidene pre-catalyst 14 [65]. Despite moderate selectivity, the implementation of a chiral triazolinylidene carbene in the Stetter reaction laid the fonndation for future work. 

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. 

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). 

In 1995, Ciganek [39] reported the thiazolium salt 31 catalyzed intramolecular Stetter reaction of aldehyde, affording corresponding 4-chromanones in up to 86% yield. In 1996, Enders et al. [40] developed the enantioselective version, using chiral triazolium salt 2 as the precatalyst. Various 4-chromanones were obtained in good yields with moderate enantiomeric excesses (Scheme 7.21). 

Enders and co-workers were the first to report enantioselectivity in an intermolecular Stetter reaction promoted by a chiral iV-heterocyclic carbene " The chiral thiazolium precatalyst 27 effects a Stetter reaction between butanal (26) and chalcone (22) to give diketone 28 with low efficiency but measurable enantiomeric excess. 

Trost and co-workers are credited with the first intramolecular Stetter reaction in their total synthesis of hirsutic acid C. An excess of thiazolium precatalyst 34 is employed to promote the intramolecular cyclization of bicycle 33, which provides the key C2-C3 bond of the natural product in the tricyclic intermediate 35. 

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