Reactions cross-benzoin

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. 

Several reports have described cross-benzoin reactions involving formaldehyde as the acceptor to obtain achiral hydroxymethyl ketones [22]. Although the chem-oselectivity was shown to be kinetically-controUed in some cases, the factors behind this selectivity remain unclear. 

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]. 

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]. 

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Attempted intermolecular cross-benzoin reactions typically generate a thermodynamically controlled mixture of products [50], although several groups including Enders [51], Suzuki [52] and You [53] have utilised catalysts 116-118 for the intramolecular crossed benzoin of keto-aldehydes (Scheme 12.22). 

Scheme 12.22 Asymmetric intramolecular cross-benzoin reactions...

The benzoin reaction typically consists of the homocoupling of two aldehydes, which results in the formation of inherently dimeric compounds, therefore limiting the synthetic utility. The aoss-benzoin reaction has the potential to produce four products, two homocoupled adducts and two cross-benzoin products. Several strategies have been employed to develop a selective cross-benzoin reaction, including the use of donor-acceptor aldehydes, acyl silanes, acyl imines, as well as intramolecular reactions. 

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. 

Table 2 Asymmetric enzymatic cross-benzoin reaction...

In an effort to circumvent a homodimerization event acyl silanes have been used to promote a cross-benzoin reaction. Initial reports by Johnson and co-workers employed potassium cyanide to catalyze the regiospecific cross silyl benzoin reaction to afford a single regioisomer in good yield (Eq. 2) [45 7]. 

Table 3 Acyl Silane cross-benzoin reaction catalyzed by lithiophosphites...

Suzuki and co-workers reported the intramolecular cross-benzoin reaction utilizing thiazolium pre-catalyst 35 to obtain products such as 37 and 38 (Eq. 3) [49],... 

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. 

Scheme 43 An example of the (a) benzoin reaction and (b) cross-benzoin reaction conducted using immobilized His6-tag BAL.

DMSO), a reaction temperature of 37 °C, and a residence time of 90 min, achieved by recirculating the reaction mixture through the PASSflow reactor at a flow rate of 1.0 ml min-1, the authors were able to attain 99.5% conversion of 116 to (R)-benzoin 159, determined by off-line GC analysis. Increasing the reactant concentration from 5.5 x 10 2 to 0.2 M, resulted in a reduction in benzoin 159 production of 5.9%, with longer reaction times required to attain high conversions with further increases in reactant concentration (typically 9h for 1.0 M 116). The authors subsequently demonstrated the cross-benzoin reaction between acetaldehyde... 

Scheme 9.6 Asymmetric intramolecular crossed benzoin reaction, according to Enders et al.

In contrast to the previously described intermolecular condensation reaction, intramolecular crossed benzoin reactions have been developed much less for a long time (Cookson and Lane 1976). 

Scheme 28. Intramolecular crossed benzoin reaction by Suzuki et al.

Enders D, Niemeier O, Raabe G (2006d) Asymmetric synthesis of chromanones via N-heterocyclic carbene catalyzed intramolecular crossed-benzoin reactions. Synlett 2006 2431... 

Enders D, Kallfass U (2002) An efficient nucleophilic carbene catalyst for the asymmetric benzoin condensation. Angew Chem Int Ed 41 1743-1745 Enders D, Niemeier O (2004) Thiazol-2-ylidene catalysis in intramolecular crossed aldehyde-ketone benzoin reactions. Synlett 2004 2111-2114 Enders D, Niemeier O, Balensiefer T (2006) Asymmetric intramolecular crossed-benzoin reactions by N-heterocyclic carbene catalysis. Angew Chem Int Ed 45 1463-1467... 

The asymmetric intramolecular crossed benzoin reaction catalysed by a chiral triazolium salt has been used to synthesise 3-hydroxychroman-4-ones 34 in good to high yields and ee. The absolute configuration at the quaternary stereocentre C-3 has been shown to be S by X-ray analysis of the camphanyl ester <06SL2431>. Both enantiomers of 2-(2-phenylethyl)chroman-4-one, flindersiachromanone, have been obtained from racemic l-phenylhex-5-en-3-ol after resolution via lipase-catalysed acetylation <06H(68)483>. 

Benzoin, Cross-benzoin and Aza-cross-benzoin Reaction... 

Recently, there has heen some work dealing with the cross-henzoin condensation to afford nonsymmetrical products chemoselectively. In this case, the Breslow intermediate has to he formed predominantly with only one of the aldehydes and react selectively with the other one. Kuhl and Glorius have succeeded in this area developing a selective hydro gmiethylation of aldehydes.With a different approach, it is also possible to use hindered ortho-substituted aldehydes to inhibit the retro-benzoin reaction and the attack of the As an extension, the cross-benzoin reaction has been... 

The earliest research on NHC-catalyzed reactions was mainly focused on the benzoin reaction. In 1943, Ugai and co-workers reported that thiazolium salts eould catalyze the self-condensation of benzaldehyde to produce benzoin. In 1966, Sheehan and Hunneman reported the first asymmetrie variant of the benzoin eondensation employing a ehiral thiazolium salt as precatalyst (up to 83% yield, 95% ee). Since asymmetric cross-benzoin reactions... 

Scheme 7.4 Asymmetric intramolecular cross-benzoin reaction of symmetrical diketones reported by Ema.

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). 

Scheme 7.6 Asymmetric cross-benzoin reactions of heteroaromatic aldehydes with trifluoromethyl aryl ketones reported by Enders.

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). 

Compared with the aldehyde-ketone cross-benzoin reaction, intermolecular aldehyde-aldehyde coupling reactions are much more challenging, as the addition of the second aldehyde means the number of possible products is quadrupled. 

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

Scheme 7.9 NHC-catalyzed dynamic kinetic asymmetric cross-benzoin reaction of P-stereogenic a-keto esters reported by Johnson.

Scheme 7.10 NHC-catal3 ed asymmetric cross-benzoin reaction of propanal and ortAo-trifluoromethyl benzaldehyde reported by Connon and Zeitler.

Scheme 7.12 Highly chemoselective cross-benzoin reaction of aliphatic and aromatic aldehydes catalyzed by NHCs with fused six-memhered rings reported by Gravel.

The first example of an aldehyde-imine cross-benzoin reaction catalyzed by thiazolylidene carbenes was reported by Murry, Frantz, and co-workers, using arylsulfonylamides as imine precursors. Later, Miller and co-workers disclosed an asymmetric variant of this work by implementing their peptide-derived thiazolium salt as a precatalyst to deliver aryl aldehyde... 

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