Enantioselectivity benzoin condensation

Fig. 9.2 Chiral thiazolium salts for enantioselective benzoin condensation.

Isoflavonoids isolated from the subfamily Leguminosae have been reviewed <07NPR417>. Isoflavanones have been obtained with 100% atom efficiency by the Au-catalysed reaction between salicylaldehydes and arylalkynes (Scheme 37) <07AG(E)1117, 07TL8343>. The cyclisation of enolisable keto aldehydes to 3-substituted 3-hydroxychromanones by an enantioselective benzoin condensation is effected by chiral triazolium salts designed to minimise competing aldol reactions <07OL2713>. 

XueLiang H, Song Y (2010) Enantioselective benzoin condensation catalyzed by bifunctional N-heterocychc carbenes. Chinese Sci Bull 55 1753-1757... 

Scheme 6.2 The first enantioselective benzoin condensations catalyzed by chiral iV-heterocyclic carbenes.

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. 

Benzamido-cinnamic acid, 20, 38, 353 Benzofuran polymerization, 181 Benzoin condensation, 326 Benzomorphans, 37 Benzycinchoninium bromide, 334 Benzycinchoninium chloride, 334, 338 Bifiinctional catalysts, 328 Bifiinctional ketones, enantioselectivity, 66 BINAP allylation, 194 allylic alcohols, 46 axial chirality, 18 complex catalysts, 47 cyclic substrates, 115, 117 double hydrogenation, 72 Heck reaction, 191 hydrogen incorporation, 51 hydrogen shift, 100 hydrogenation, 18, 28, 57, 309 hydrosilylation, 126 inclusion complexes, oxides, 97 ligands, 19, 105 molecular structure, 50, 115 mono- and bis-complexes, 106 NMR spectra, 105 olefin isomerization, 96... 

The thiazolium and, particularly, triazolium catalysts discussed above have been developed to the extent that they perform remarkably well in the asymmetric benzoin condensation of aromatic aldehydes. Triazolium catalysts are also very effective in the (non-stereoselective) condensation of aliphatic aldehydes [250]. It seems, however, that no catalyst is yet available that enables condensation of aliphatic aldehydes with synthetically useful enantioselectivity. The best ee yet obtained are in the range 20-25%, e.g. in the dimerization of the straight-chain C2-C7 aldehydes [251]. 

Unfortunately, the chiral bicyclic triazolium salt that had been found to be an excellent catalyst for the enantioselective intermolecular benzoin condensation proved to be ineffective in the intramolecular reaction. In searching for alternative catalysts, we synthesized the novel triazolium salts 19 and 20, starting from easily accessible enantiopure polycyclic y-lactams (Schemes 9.4 and 9.5) that finally delivered good results in the enantioselective intramolecular cross-benzoin condensation [35]. 

The precatalyst 20 led to excellent results in the enantioselective intramolecular crossed benzoin condensation of the aldehyde ketones 24, as shown in Scheme 9.6. The quaternary stereocenter of the acyloins 25 was created with good to very good yields and excellent ee-values. (For experimental details see Chapter 14.20.1). The precatalyst 19 proved to be even more active, and the yields were consistently excellent, albeit accompanied by lower ee-values (63-84%). 

The substrates of the enantioselective intramolecular crossed benzoin condensation were varied to widen the scope of the reaction. Promising results were... 

Further contributions to the research on the asymmetric benzoin condensation were made by Leeper et al. using novel chiral, bicyclic thia-zolium salts, which led to enantiomeric excesses up to 21% and yields up to 50% (Knight and Leeper 1997). Another thiazolium catalyst containing a norbonane backbone gave benzoin in quantitative yields with an enantiomeric excess of 26% (Gerhards and Leeper 1997). In 1998, Leeper et al. reported novel chiral, bicyclic triazolium salts that produced aromatic acyloins with varying enantioselectivities (20%—83% ee) (Knight and Leeper 1998). 

Applying (S)-102 in the asymmetric benzoin condensation hS i-ben-zoin (6, R = Ph) was produced in very good enantioselectivity (90% ee, 83% yield) (Enders and Kallfass 2002). The condensation of numerous other aromatic aldehydes 6 yielded the corresponding a-hydroxy ketones 85 with excellent enantiomeric excesses up to 99%. As previously observed, electron-rich aldehydes gave higher asymmetric inductions than the electron-deficient ones. Lower reaction temperatures (0°C instead of room temperature) or lower amounts of catalyst caused decreased yields but slightly enhanced enantiomeric excesses (Scheme 27). 

Unfortunately the bicyclic triazolium salt that had successfully been used in our research group for the enantioselective intermolecular benzoin condensation (Enders and Kallfass 2002) did not show any catalytic activity in the intramolecular reaction. We thus searched for alternative, easily accessible enantiopure polycyclic y-lactams as precursors for the synthesis of novel triazolium salts (Enders et al. 2006c for a related study see Takikawa et al. 2006). The rigid polycyclic structure of the catalysts should allow high asymmetric inductions. A first tar-... 

The bifunctional nature and the presence of a stereocenter make a-hydroxyketones (acyloins) amenable to further synthetic transformations. There are two classical chemical syntheses for these a-hydroxyketones the acyloin condensation and the benzoin condensation. In the acyloin condensation a new carbon-carbon bond is formed by a reduction, for instance with sodium. In the benzoin condensation the new carbon-carbon bond is formed with the help of an umpolung, induced by the formation of a cyanohydrin. A number of enzymes catalyze this type of reaction, and as might be expected, the reaction conditions are considerably milder [2-4, 26, 27]. In addition the enzymes such as benzaldehyde lyase (BAL) catalyze the formation of a new carbon-carbon bond enantioselectively. Transketolases (TK)... 

The addition of HCN to aldehydes or ketones produces cyanohydrins. This is an equilibrium reaction, and for aldehydes and aliphatic ketones the equilibrium lies to the right therefore the reaction is quite feasible, except with sterically hindered ketones such as diisopropyl ketone. However, ketones ArCOR give poor yields, and the reaction cannot be carried out with ArCOAr since the equilibrium lies too far to the left. With aromatic aldehydes the benzoin condensation (16-55) competes. With ot, 3-unsaturated aldehydes and ketones, 1,4-addition competes (15-38). The reaction has been carried out enantioselectively optically active cyanohydrins were prepared with the aid of optically active catalysts.Hydrogen cyanide adds to aldehydes in the presence of a lyase to give the cyanohydrin with good enantioselectivity. " Cyanohydrins have been formed using a lyase m an ionic liquid. 

Variants of the Michael addition include the allylation of cyclopropenone acetals and the intramolecular Stetter reaction. So far, only moderate enantioselectivity for the latter reaction has been achieved. (Note that the same chiral catalyst is useful for benzoin condensation. )... 

Scheme 1.5 The enantioselective AT-heterocyclic carbene catalyzed benzoin condensation reported by Enders.

In this context, the first attempts to employ chiral iV-heterocyclic carbenes as organocatalysts in an enantioselective reaction were carried out in the context of the benzoin condensation, which combines two molecules of an aldehyde (usually an aromatic one). The first pioneering examples were developed by Sheehan and coworkers, which were followed by several authors, highlighting the report by Enders in 2002, in which, for the first time, a highly enantioselective A -heterocyclic carbene-catalyzed benzoin condensation was reported (Scheme 6.2). As can be seen in this scheme, the general principle applied to the design of these catalysts relied on a thiazolium central unit as the precursor of... 

Melchione s team reported the asymmetric catalysis of Diels-Alder reactions of IQDs (Scheme 11, equation 1) [69, 70], In addition to other nitro-substituted arylethenes, methyleneindolinones were employed as dienophiles. A limited selection of the compounds synthesized is shown in Scheme 11 (30-32). The third compound (32) is the result of a final cross-benzoin condensation. Chen and colleagues effected an asymmetric Diels-Alder reaction of IQDs (33) generated under mild acidic conditions from 2-methyl-3-indolemethanols and a,p-unsaturated aldehydes (equation 2) [71], Three representative indoles that were prepared in this fashion are 34 to 36. The IQD 33 is presumed to be in equilibrium with the 3-vinylindolenium species. A wide range of substituted trani-cinnamalde-hydes was successfully employed. Although other acids (HOAc, TFA, PhCO H, silica gel) effected the reaction, Montmorillonite KIO clay was superior in terms of yield, enantioselectivity, and diastereoselectivity. 

Benzoin reaction that involved the construction of carbon-carbon bond played unique roles in organic synthesis. The first benzoin reaction dated back to 1832 when Wohler and Liebig [ 13] reported cyanide-catalyzed coupling of benzaldehyde for the synthesis of benzoin. In 1943, Ugai et al. [4] reported that thiazolimn salts can catalyze the self-condensation of benzaldehyde to produce benzoin. In 1966, Sheehan and Hunneman [14] reported an asymmetric benzoin condensation afforded benzoin in 22% ee under the catalyst of the chiral thiazolimn salt la. Later on, a series of chiral thiazoium salts have been tested for the reaction with varied enantioselectivities achieved (Scheme 7.1) [15]. 

The pioneering work of Sheehan showed as early as 1966 that the use of the chiral thiazolium precatalyst (+)-7 imparted low but measurable enantioselectivity in the conversion of benzaldehyde to benzoin. Since this report, many groups have developed chiral carbene catalysts that effect asymmetric benzoin condensation reactions. The best catalyst identified to date with respect to enantioselectivity is the triazolium pre-catalyst 8 reported... 

Milller and co-workers recently developed an enantioselective benzoin dimerization using purified enzymes from Pseudomonas. The thiamine diphosphate (ThDP) dependent enzymes benzaldehyde lyase (BAL) and benzoylformate decarboxylase (BED) were found to catalyze the reversible benzoin condensation of aromatic aldehydes. The reaction is driven in the forward direction by the poor solubility of the benzoin products in aqueous media. A wide variety of aromatic aldehydes are accepted by BAL, and products of the (/ )-configuration are produced in excellent yield and enantiomeric purity. The (S)-enantiomer of benzoin is also available in high enantiomeric purity from a BAL-catalyzed kinetic resolution of rac-benzoin. In the presence of excess acetaldehyde, BAL selectively converts (i )-benzoin into (/ )-2-hydroxy-l-phenylpropanone, while the (iS)-benzoin enantiomer is not a substrate for the enzyme. At 49% conversion, (5)-benzoin is resolved to > 99% ee. BED can produce (i )-benzoin from benzaldehyde in comparable yield and enantiomeric purity with respect to BAL, but the substrate scope appears more limited. ... 

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. ... 

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