Enantioselectivity cross-benzoin reaction

Miiller and co-workers have developed an enantioselective enzymatic crossbenzoin reaction (Table 2) [43, 44], This is the first example of an enantioselective cross-benzoin reaction and takes advantage of the donor-acceptor concept. This transformation is catalyzed by thiamin diphosphate (ThDP) 23 in the presence of benzaldehyde lyase (BAL) or benzoylformate decarboxylase (BFD). Under these enzymatic reaction conditions the donor aldehyde 24 is the one that forms the acyl anion equivalent and subsequently attacks the acceptor aldehyde 25 to provide a variety of a-hydroxyketones 26 in good yield and excellent enantiomeric excesses without contamination of the other cross-benzoin products 27. The authors chose 2-chlorobenzaldehyde 25 as the acceptor because of its inability to form a homodimer under enzymatic reaction conditions. 

In concurrent and independent work, Suzuki and Enders found that tethered keto-aldehydes undergo highly enantioselective cross-benzoin reactions using tria-zolium based catalysts [50, 51], The scope includes various aromatic aldehydes with alkyl and aryl ketones (Table 4). Additionally, aliphatic substrate 39a is cyclized in excellent enantioselectivity, albeit in 44% yield. 

Table 5 Enders et al. enantioselective cross-benzoin reaction...

Scheme 7.8 NHC-catal3 ed enantioselective cross-benzoin reaction of aliphatic aldehydes with a-keto esters reported by Gravel.

Chiral triazolium salt 20c was found to be an efficient precatalyst for the enantioselective cross-benzoin reactions of aromatic aldehydes with trifluoromethyl ketones, yielding a-hydroxy ketone in good yields and good enantioselectivities (Scheme 7.14) [32],... 

The enzymes benzaldehyde lyase (BAL) and benzoylformate decarboxylase (BFD) have also been shown to catalyze enantioselective cross-benzoin reactions. Aryl-aryl as well as aryl-alkyl products are produced in high yield and enantiomeric purity. In the case of aryl-aryl products, the success of the reaction depends on the empirical identification of suitable donor/acceptor pairs. Aldehydes containing or/Ao-substituents were found to be ideal acceptors in BAL and BFD-catalyzed cross-benzoin reactions. The preparation of (/ )-l-(4-bromophenyl)-2-(2-chlorophenyl)-2-hydroxyethanone (25) from 4-bromobenzaldehyde (23) and 2-chlorobenzaldehyde (24) highlights the high conversion and selectivity possible in this transformation. As with rac-benzoin, rac-l-(4-bromo-phenyl)-2-(2-chlorophenyl)-2-hydroxyethanone is easily resolved by BAL to give the (5)-enantiomer with high enantiomeric purity. 

Scheme 18.3 Enantioselective cross-benzoin reaction, according to Connon, Zeitler, and...

Scheme 7.5 Enantioselective intramolecular iV-tethered cross-benzoin reaction reported by You.

In 2010, the Enders group reported asymmetric cross-benzoin reactions of aldehydes with ketones by using a novel chiral triazolium NHC catalyst precursor with a sterically demanding silyl protecting group. Under the optimized conditions, several heteroaromatic aldehydes reacted smoothly with aromatic trifluoroketones (2.0 equiv.) providing cross-benzoin products in up to 96% yield and 85% ee, and the enantioselectivity was improved to 99% ee by further crystallization. Through direct observation of the reaction by NMR and racemization experiments, the authors showed that the product is formed under kinetic control (Scheme 7.6). 

In the same year, through the development of a new electron-deficient, valine-derived triazolium catalyst precursor. Gravel and co-workers realized a highly enantioselective intermolecular cross-benzoin reaction of aldehydes with a-keto esters. Excellent enantioselectivity was observed between aliphatic aldehydes (1.5 equiv.) and various aryl ct-keto esters (up to 98% yield, 94% ee) (Scheme 7.8). 

In 2005, Enders et al. reported the first enantioselective intramolecular crossed-benzoin reaction catalysed by novel chiral bicyclic D1 or tetracyclic El triazolium carbenes. A number of benzoin products 4 with a quaternary carbon stereocentre were obtained in high yields with good to high enan-tioselectivities (Scheme 20.4). ... 

Suzuki and Takikawa [99] developed an enantioselective carbene-catalyzed cross-benzoin reaction for the synthesis of (+)-sappanone B (266) (Scheme 17.46). Compared with the catalysts introduced by Rovis and co-workers [100], Suzuki and co-workers optimized and identified triazolium salt 264 by introducing electron-withdrawing substituents (two CF3 group) to improve the reactivity and enantiose-lectivity. The key cross-benzoin reaction commenced with benzaldehyde derivative 263 in the presence of triazolium salt 264 and the base Et3N to afford 265 (92%, 95% ee), which was subsequently converted into (+)-sappanone B (266). 

In 2002, Muller and coworkers disclosed cross-benzoin reactions between o-unsubstituted and o-Cl or o-F benzaldehyde derivatives catalyzed by thiamin diphosphate-dependent enzymes [23]. In these highly chemo- and enantioselective reactions, the less sterically hindered o-unsubstituted benzaldehyde selectively forms the Breslow intermediate, which then attacks the more electrophilic o-halo benzaldehyde. Similar chemoselectivity was later shown by Glorius and coworkers using achiral N-aryl or N-alkyl thiazohum salts [24]. 

In 2011, Connon, Zeitler, and coworkers reported detailed studies on intermolecular cross-benzoin reactions using triazoUum and thiazoUum salts [26]. These systematic studies clearly showed the intricate interplay of various factors influencing the outcome of cross-benzoin reactions. In line with the results of Miller and coworkers, the use of o-substituted benzaldehydes resulted in selective formation of benzylic alcohol products using either triazolium or thiazolium salts. When using o-unsubstituted benzaldehydes, the same chemoselectivity could be achieved with an a-branched aliphatic aldehyde and an N-QFs triazolium catalyst. Crossover experiments showed the reaction to be under kinetic control in many cases. When using chiral catalyst 31, good chemo- and enantioselectivity was achieved in the reaction between o-trifluoromethylbenzaldehyde (30) and propanal (29) (Scheme 18.3). 

The enantioselective intramolecular cross-coupUng of aldehydes and ketones to access cyclic a-hydroxy ketones has also been demonstrated. Issues of chemoselectivity are largely avoided in these cases, and the benzoin reaction can be achieved in a highly efficient and enantioselective manner (up to 93% yield and 99% ee) [28]. The usefulness of the intramolecular cross-benzoin reaction was elegantly illustrated in two separate cydizations for the synthesis of seragakinone A, an antifungal and antibacterial natural product [29]. 

Enders and coworkers reported moderate to good enantioselectivity for the coupling of heteroaromatic aldehydes and highly electrophiUc trifluoromethyl ketones in the presence of chiral triazohum salt 41 (Scheme 18.5) [30]. It was shown that a reversible homo-benzoin reaction takes place initiaUy, foUowed by an irreversible cross-benzoin reaction involving the ketone (40). 

Connon, Zeitler, and coworkers showed a-ketoesters to be competent reaction partners when using N-C Fs triazolium salt 17 [31]. Even aliphatic a-ketoesters could serve as substrates while avoiding possible competing aldol pathways. The enantioselective version of the reaction proved challenging, and cross-benzoin product 44 could be obtained in only moderate yield and enantioselectivity (Scheme 18.6). Intermolecular formal cross-benzoin reactions using pyruvate as an aldehyde equivalent were also shown to be possible, using a thiamine-dependent enzyme, with broad substrate scope [32]. 

Shortly after publishing the racemic cross silyl benzoin reaction, Johnson and co-workers reported an enantioselective variant ntilizing metallophosphite catalysis [48]. The lithiophosphite adds to the acyl silane and proceeds throngh the remain-... 

The catalytic enantioselective crossed aldehyde-ketone benzoin cyclization has been reported.145 The reactions have been performed in the presence of Rovis aminoindanol- derived chiral triazolium salts (37) as catalysts with excellent enantioselectivities (up to 99% ee) (Scheme 19). 

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

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. 

In 2012, a highly enantioselective cross-aza-benzoin reaction of aliphatic aldehydes and imines was developed by Rovis et A variety of aliphatic aldehydes that contained a diverse range of functionality proved suitable for the reaction, resulting in formation of the desired products 23 in high yield and excellent enantioselectivily, but a-branched aldehydes did not participate in the reaction (Scheme 20.12). 

Recently, Chi and coworkers disclosed the enantioselective cross-aza benzoin reaction of enals with isatin-derived ketimines, affording the 3-aminooxindoles 29 bearing a quaternary stereogenic centre with high enantioselectivities. The electron-deficient and sterically noncongested car-bene catalyst H2 was shown to favour the pathway of enal acyl anion leading to an aza-benzoin reaction (Scheme 20.14). 

In 2005, the asymmetric cross-coupling reactions of aldehydes 33 with arylsul-fonylamides 34 were reported by Miller and co-workers [37]. In the presence of 15 mol% of peptide-derived NHC 32, the corresponding aza-benzoin adduct 35 was obtained in good yields with good enantioselectivities (Scheme 7.19). 

Michael-cross-benzoin cyclisation reaction afforded the corresponding chiral polyfunctionalised cyclopentanones bearing three contiguous stereocentres in good yields, moderate to excellent diastereoselectivities of up to 98% de, and good to high enantioselectivities of up to 96% ee, as shown in Scheme 2.31. 

The chemo- and enantioselective cross-couphng of two different aldehydes via a benzoin reaction remains a significant challenge. Four different benzoin products can be formed (two homo- and two cross-benzoin products), each as two possible enantiomers. The challenge is compounded by the commonly observed reversibility of the reaction. 

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