Stetter synthesis

In order to achieve good enantioselectivity in the Stetter synthesis of chroman-4-ones, it appears that a carbonyl function is necessary in the unsaturated side-chain of the salicylaldehyde-derived starting materials (Scheme 26) <03SL1934>. 

The Paal synthesis of thiophenes from 1,4-diketones, 4-ketoaldehydes and 1,4-dialdehydes has found great use in the synthesis of medicinally active compounds, polymers, liquid crystals and other important materials. Furthermore, the discovery of the catalyzed nucleophilic 1,4-conjugate addition of aldehydes, known as the Stetter reaction (Eq. 5.4.1), has enabled widespread use of the Paal thiophene synthesis, by providing 1,4-diketones from readily available starting materials. ... 

An interesting application of the Paal thiophene synthesis was documented for the synthesis of a polystyrene-oligothiophene-polystyrene copolymer. In the Stetter reaction of aldehyde 13 and P-dimethylaminoketone 14, in situ generation of the a,p-unsaturated ketone preceded nucleophilic 1,4-conjugate addition by the acyl anion... 

Two other examples of microwave-assisted Paal-Knorr reactions were reported in 2004, describing the synthesis of a larger set of pyrroles with different substituents around the ring. The methods differ mainly in the syntheses employed to produce the 1,4 dicarbonyl compounds required for the cyclization. A variation of the Stetter reaction between an acyl silane and dif-... 

Pioneering work on the desulphonylation of jS-ketosulphones was carried out by Corey and Chaykovsky - . This reaction was part of a sequence which could be used in the synthesis of ketones, as shown in equation (53). The main thrust of this work was in the use of sulphoxides, but Corey did stress the merits of both sulphones and sulphonamides for different applications of this type of reaction. The method soon found application by Stetter and Hesse for the synthesis of 3-methyl-2,4-dioxa-adamantane , and by House and Larson in an ingenious synthesis of intermediates directed towards the gibberellin skeleton, and also for more standard applications . Other applications of the method have also been madealthough it does suffer from certain limitations in that further alkylation of an a-alkyl- -ketosulphone is a very sluggish, inefficient process. Kurth and O Brien have proposed an alternative, one-pot sequence of reactions (equation 54), carried out at — 78 to — 50°, with yields better than 50%. The major difference between the two routes is that the one-pot process uses the desulphonylation step to generate the enolate anion, whereas in the Corey-House procedure, the desulphonylation with aluminium amalgam is a separate, non-productive step. 

Two types of synthesis of this skeleton are reported depending on the positions of the sulfur introduced either at the bridge or at the bridgehead the former has been studied by Stetter s research group189-191 and the latter by Klages and Schmidt192 starting from bicyclo[3.3.1]nonane derivatives and cyclohexane derivatives, respectively. 

The simplest and most accessible ring system is 2-aza-6-oxaadamantane (189), which was constructed by Stetter and Mehren in 1967.234 However, the oldest is the synthesis of l-aza-2,4,10-trioxaadamantane (190) in 1962235 followed by those of l,3-diaza-6-oxaadamantane (191)236 and l-aza-4,6-dioxaadamantane (192) in 1965,237 all by Stetter and his collaborators. l-Aza-4,6,10-trioxaadamantane once was called trimorpholine.238... 

The thiazolium-catalyzed addition of an aldehyde-derived acyl anion with a Michael acceptor (Stetter reaction) is a well-known synthetic tool leading to the synthesis of highly funtionalized products. Recent developments in this area include the direct nucleophilic addition of acyl anions to nitroalkenes using silyl-protected thiazolium carbinols <06JA4932>. In the presence of a fluoride anion, carbinol 186 is not cleaved to an aldehyde... 

An efficient high yielding synthesis of 3-substituted 2,3-dihydroquinolin-4-ones 90 was developed by using a one-pot sequential multi-catalytic process <06TL4365>. The scheme below shows the one-pot sequential multi-catalytic Stetter reaction of aldehyde 91 and a, (3-unsaturated esters 92, resulting in the formation of the desired dihydroquinolines 90. 

A different approach toward highly substituted pyrroles involving a one-pot sila-Stetter/Paal-Knorr strategy was realized by Bharadwaj and Scheidt (Scheme 6.182) [343]. In this multicomponent synthesis, catalyzed by a thiazolium salt, an acyl anion conjugate addition reaction of an acylsilane (sila-Stetter) was coupled in situ with the conventional Paal-Knorr approach. Employing microwave conditions at 160 °C for 15 min, the acylsilane was combined with the cx/l-unsaturated ketone in... 

Scheme 6.182 Sila-Stetter/Paal-Knorr pyrrole synthesis.

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. 

In an extension of traditional Stetter methodology, Miiller and co-workers have used the Stetter reaction in a one-pot multicomponent reaction for the synthesis of furans and pyrroles (Scheme 19) [85,86], The ot,P-unsaturated ketone XXVI is formed in situ and undergoes a Stetter reaction followed by a Paal-Knorr condensation. 

The first natural product synthesis that utilized the Stetter reaction was reported by Stetter and Kuhhnann in 1975 as an approach to aT-jasmone and dihydrojas-mone (Scheme 21) [93]. Thiazolium pre-catalyst 74 was effective in catalyti-cally generating the acyl anion equivalent with aldehydes 144 and 145, then adding to 3-buten-2-one 146 in good yield. Cyclization followed by dehydration gives cii-jasmone and dihydrojasmone in 62 and 69% yield, respectively, over two steps. Similarly, Galopin coupled 3-buten-2-one and isovaleraldehyde in the synthesis of ( )-rran5-sabinene hydrate [94]. 

Scheme 21 Stetter and Kuhlmann s synthesis of c/i-jasmone and dihydrojasmone...

The Stetter reaction has also been shown to be an important tool in the synthesis of CI-981, also known as LIPITOR [96]. Roth and co-workers demonstrate the ability of commercially available starting materials 153 and 154 to couple in the presence of 20 mol% thiazolium pre-catalyst 121 (Scheme 23) [97, 98]. Amide 155 was obtained in 80% yield and allowed for the convergent synthesis of CI-981 in nine steps. 

In the late 1990s, Tins and co-workers described a formal total synthesis of roseophihn [99, 100], The Stetter reaction was well suited for the coupling of partners 157 and 158 in the presence of 3-benzyl-5-(hydroxyethyl)-4-methyl thiazolium chloride (Scheme 24). 

In the process of developing the Stetter reaction in ionic liquids, Gree and coworkers applied their methodology to the synthesis of haloperidol (Scheme 25) [101], A variety of aromatic aldehydes react with methyl acrylate 160 when butyl-methylimidazolium tetrafluoroborate [bmim][BF ] is used as solvent. In the synthesis of haloperidol, electron-deficient aldehyde 153 was subjected to standard reaction conditions with 160 to provide 161 in good yield. 

Nicolaou and co-workers recently published a formal synthesis of ( )-platen-simycin utilizing Stetter methodology [102], Aldehyde 162 was treated with achiral A-pentafluorophenyl pre-catalyst 164 and readily underwent cyclization to yield 163 as a single diastereomer (Scheme 26). After an additional seven steps late stage intermediate 165 was formed to complete the formal synthesis. 

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