Michael-Stetter reaction

The mechanism of this reaction was hrst described by Breslow as early as 1958 [4], Subsequently, the natural enzyme thiamine, found in yeast, was replaced by related nucleophiles like thiazole [5,6], triazole [7] and imidazole [8], Reactions that follow this mechanism include the very important Stetter reaction (the benzoin condensation of aliphatic aldehydes), the Michael-Stetter reaction (a variant of the Stetter reaction where the aldehyde reacts with an a,P-unsaturated ketone) [1], transesteriflcations [9] or the acylation of alcohols [9,10], All four reactions are carbene catalysed nucleophilic acylation processes. 

Note The Michael-Stetter reaction is a benzoin condensation between an aliphatic aldehyde and an a, jd-unsaturated ketone. 

It is only a small step from the asymmetric benzoin condensation to the asymmetric Stetter reaction, the aliphatic variant of the benzoin condensation. The literatnre refers to the Stetter reaction when at least one of the two reactants is an aliphatic aldehyde. Normally, the reaction is performed as a cross-coupling reaction with two different reactants, one of which is not an aldehyde, bnt an a, 3-unsaturated ketone. Strictly speaking, most thiazole catalysed reactions referred to as Stetter reactions are in fact Michael-Stetter reactions [21,22] (see Fignre 6.4). The reaction received the name because Stetter used a Michael reagent, an acceptor with an activated double bond, as the second component of a cross-coupled Stetter reaction [11]. 

In an asymmetric Michael-Stetter reaction, the activated double bond is prochi-ral leading to a prodnct with a new asymmetric centre. Enders first attempt to react butanal with a chalcone resnlted in only 4% yield, but an ee of 39% [25] (see Figure 6.5). The steric concept was certainly valid, but the electronic properties clearly in want of improvement. 

Despite significant efforts to improve the yield and chiral resolution of the thiazolium catalysed asymmetric Michael-Stetter reaction, catalytic activity remained at the same dissatisfying low level [11]. A possible reason could be the irreversible reaction of the catalyst... 

Figure 6.4 Some thiazolium salts used In the MIchael-Stetter reaction [11,23,24],...

Figure 6.5 An asymmetric Michael-Stetter reaction using a chiral thiazolium salt as organo-catalyst [11],...

An interesting new development came with the realisation of Miller that a range of enan-tioselective reactions for which peptides based on the imiodazole sidechain of histidine were used as organocatalysts could possibly serve as a model for the asymmetric intramolecular Michael-Stetter reaction as well [32]. To this end. Miller synthesised thiazole based peptide-modified organocatalysts that can be described as having a thio-histidine as the crucial anuno acid (see Hgure 6.7). The respective amino acid was reported as thiazolylalanine (Taz). 

Figure 6.6 An asymmetric intramolecular Michael-Stetter reaction using triazolium based organocatalysts.

A detailed study has been published of the preparation of 1,4-diketones by the Michael-Stetter reaction, in which particular attention was paid to the effect of substituent variation on this rather unpredictable reaction. In general it was found that while the Michael component could tolerate both electron donating and... 

Other references related to the Michael-Stetter reaction are cited in the literature. ... 

Dicaibonyl derivatives from aldehydes and a,p-unsaturated ketones and esters. The thiazolium catalyst serves as a safe surrogate for "CN. Also known as the Michael-Stetter reaction. Cf. Benzoin condensation. 

NHC-catalyzed organocascades allowing the creation of both a C-C and a C-X bonds are rare. The group of Rovis has recently proposed a domino Michael/Stetter reaction for the preparation of optically active benzofuranones from salicylaldehydes and dimethyl acetylenedicarboxylate (DMAD) under dual catalytic conditions (Scheme 16.45) [94]. The reaction sequence involves a Lewis base-promoted oxa-Michael addition to produce a prochiral intermediate that then undergoes an NHC-catalyzed enantiodiscriminative Stetter reaction. Remarkably, the Lewis base not only triggers the initial oxa-Michael addition, but also serves as a Brpnsted base for deprotonation of the NHC precatalyst. The reaction scope could be extended to unsymmetrical alkynes and allenes with moderate to good stereoselectivities. 

SCHEME 16.45. Domino oxa-Michael/Stetter reaction for the enantioselective access to henzofiiranones. 

Scheme 2.16 Domino oxa-Michael-Stetter reaction catalysed by a combination of a chiral iV-heterocyclic carbene and a tertiaiy amine.

Scheme 43.7 Multi-catalytic asymmetric Michael/Stetter reaction.

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