Natural Stetter reaction

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]. 

Despite the unrivaled easy access to 1,4-dicarbonyl compounds, only a few examples of the application of Stetter reactions in the synthesis of natural products have been reported to date [55]. Tius et al. have employed a diastereoselective in-termolecular Stetter reaction and a ring-closing metathesis reaction as the key steps in their elegant synthesis of roseophilin (58 Scheme 9.16) [56]. The 1,4-... 

What starting material would be required for formation of the natural product ds-jasmone by an intramolecular aldol reaction (Chapter 27). How would you make this compound using a 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. 

Besides the Michael addition of heteroatomic nucleophiles initiating cyclocondensations, acceptor substituted unsaturated systems can also be reacted with carbon nucleophiles stemming from aldehydes in the sense of an umpolung, generally referred to as the Stetter reaction [244-246]. This process is organocatalytic and furnishes in turn 1,4-dicarbonyl compounds, intermediates that are well suited for Paal-Knorr cyclocondensations giving rise to furans or pyrroles. Among numerous heterocycles furans and pyrroles have always been the most prominent ones since they constitute important classes of natural products [247-249], of synthetic... 

Thiazolidinethiones constitute a class of versatile chiral auxiliaries for asymmetric synthesis. Their easy preparation from readily available /3-amino alcohols and the high levels of asymmetric induction they provide make them excellent chiral auxiliaries for the preparation of chiral intermediates in the synthesis of natural products. These chiral auxiliaries have been utilized in a wide variety of synthetic transformations such as asymmetric aldol-type acyloin condensation, stereoselective alkylation of different electrophiles (Stetter reaction), and stereoselective differentiation of enantiotopic groups in molecules bearing prochiral centers <2002COR303>. 

The absolute stereochemistry of natural roseophilin was determined by means of asymmetric total synthesis by M.A. Tius and co-workers. The trisubstituted pyrrole moiety of the natural product was installed using the Paai-Knorr pyrrole synthesis starting from a macrocyclic 1,4-diketone. This diketone was prepared by reacting an exocyclic a, 3-unsaturated ketone with excess 6-heptenal in the presence of 3-benzyl-5-(hydroxyethyl)-4-methylthiazolium chloride as the catalyst. The major product was the trans diastereomer and the macrocyclization was achieved via aikene metathesis. It is worth noting that when the aldehyde was tethered to the cyclopentenone, all attempts to close the macrocycle in an intramolecular Stetter reaction failed. 

The Stetter reaction is an extremely useful Umpolung procedure for the synthesis of 1,4-dicarbonyl compounds [41,42,43]. Since its discovery in 1973, it has found widespread application in the preparation of key organic intermediates and in natural product synthesis. However, despite the importance and useful-... 

Development of Stetter reaction, particularly, in the synthesis of natural compounds 06CJ0906. 

A series of chiral triazolium salts have been reacted with a base to form the corresponding chiral carbenes, which was shown to catalyze the Stetter reaction efficiently and to provide 1,4-dicarbonyl products in high yields and enantioselectivities (eq 33). A survey of common bases identified KHMDS as providing an optimal balance between the yield and selectivity in this reaction. The reaction is sensitive to the nature of the Michael acceptor while electron deficient -alkenes provided the desired product in good yields and enantioselectivities, no reaction was observed in the case of Z-alkenes. ... 

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 a series of publications beginning in 1973, Hermann Stetter and coworkers reported that activated olefins could intercept the putative acylanion intermediate of the benzoin reaction. Typical catalysts for the benzoin reaction, sodium cyanide and thiazolylidine carbenes, were found to perform well in this new reaction. Stetter also established that the success of the reaction is due to the reversible nature of the benzoin condensation relative to the irreversible formation of 1,4-dicarbonyl products. As a consequence, benzoins or aldehydes can be used interchangeably as reactants. The reaction has proven to be a highly efficient method for the synthesis of 1,4-dicarbonyl compounds and 4-oxonitriles. A resurgence of interest in acyl anion chemistry has resulted in many new discoveries, including alternative acyl donors, as well as catalysts capable of highly enantioselective intra- and intermolecular Stetter reactions. ... 

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. 

Figure 18.4 Natural products synthesized using a Stetter reaction.

Application of Stetter Reactions to Natural Product Synthesis... 

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. 

As an obvious extension of the benzoin reaction, the cross-coupling of aldehydes or of aldehydes and ketones was first achieved with the thiamine-dependent enzyme benzoylformate decarboxylase. This linked a variety of mostly aromatic aldehydes to acetaldehyde to form the corresponding a-hydroxy ketones, both chemo- and stereoselectively [31]. Synthetic thiazolium salts, developed by Stetter and co-workers and similar to thiamine itself [32], have been successfully used by Suzuki et al. for a diastereoselective intramolecular crossed aldehyde-ketone benzoin reaction during the course of an elegant natural product synthesis [33], Stereocontrol was exerted by pre-existing stereocenters in the specific substrates, the catalysts being achiral. 

Figure 7.25 N-Heterocyclic carbenes catalyze reactions between ary aldehydes and enals. Depending on the nature of the catalysts, " "" 1,4-diones (Stetter products), y-lactones or even a 2+1 adduct (a hemiacetal) can be formed...

Magnus and co-workers extended on work by Stetter and Lauterbachr to produce an intermediate common to the natural products linderalactone, isolinderalactone and neolinderalactone. Compounds of this class have been shown to exhibit a host of biological properties including analgesic, anti-inflammatory, antiemetic, antibacterial and antiviral. The Feist-Benary reaction of ethyl 2-chloroacetoacetate and 5-(methoxymethyl)-5-methylcyclohexane-l,3-dione in the presence of potassium hydroxide gave the desired tetrasubstituted furan in 57% yield. 

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