Asymmetric Cross-Benzoin Condensation

Remarkably, the 2,2 -disubstituted benzoin or the mixed benzoin substituted in the 2 position was not generated in any of these reactions, revealing that the ortho-substituted benzaldehydes 40a-40c react selectively as acceptors, as expected. 

Subsequently, the concept was extended to selective donor molecules. With 2-chlorobenzaldehyde as the selective acceptor a vast variety of unsymmetrical benzoins was accessible, among which 41d-41f were obtained selectively, proving that4-(trifluoromethyl)benzaldehyde, 4-bromobenzaldehyde, and 3-cyanobenzal-dehyde were selective donor substrates for BFD H281A under these reaction conditions [67, 69]. 

The selective donor-acceptor concept can be transferred to other ThDP-dependent enzymes. For example, enantiopure mixed benzoins were obtained when 2-chlorobenzaldehyde reacted with a variety of selective donor aldehydes in the presence of BAL [67]. By performing various cross-benzoin condensation reactions with this enzyme, not only new selective donors but also additional aldehydes reacting selectively as acceptors, such as 2-iodobenzaldehyde or 2,6-difluorobenzaldehyde, could be identified. Again all the mixed benzoins generated exhibited an R-configuration and were obtained with high to excellent enantiomeric excesses [69]. 

The selectivity is caused not only by the electronic properties of the substrates which are dependent on the nature of their substituents, as is the case in the chemical cross-benzoin condensation. Rather, steric demands of the aldehyde substituents and interactions of these with the active site of the biocatalyst, which (obviously) is different for each enzyme used, are also of significance. 

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P. Dtinkelmann, D. Kolter-Jung, A. Nitsche, A. S. Demir, P. Siegert, B. Lingen, M. Baumann, M. Pohl, M. Muller, Development of a donor-acceptor concept for enzymatic cross-coupling reactions of aldehydes, the first asymmetric cross-benzoin condensation. f Am. Chem. Soc. 2002, 124, 12084-12085. 

Duenkelmann, P., Kolter-Jung, D., Nitsche, A., Demir, A. S., Siegert, P., Lingen, B., Baumann, M., Pohl, M., Mueller, M. Development of a Donor-Acceptor Concept for Enzymatic Cross-Coupling Reactions of Aldehydes The First Asymmetric Cross-Benzoin Condensation. J. 

Starting from the findings of the racemic cross-benzoin condensation [66], and assuming that aldehydes not accepted as donor substrates might still be suitable acceptor substrates, and vice versa, a mixed enzyme-substrate screening was performed in order to identify a biocatalytic system for the asymmetric cross-carboligation of aromatic aldehydes. For this purpose the reactions of 2-chloro-(40a), 2-methoxy- (40b) and 2-methylbenzaldehyde (40c), respectively, were studied with different enzymes in combination with benzaldehyde (Scheme 2.2.7.23) [67]. The three ortho-substituted benzaldehyde derivatives 40a-40c were... 

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... 

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. 

A review of the asymmetric Stetter and asymmetric benzoin reactions focuses mainly on two classes of highly successful catalysts NHCs and metallophosphites. A new NHC, pyrido[l,2-a]-2-ethyl[l,2,4]triazol-3-ylidene (99), is a powerful catalyst of benzoin condensation in the presence of potassium f-butoxide. A DFT study of the mechanism suggests that the f-butanol solvent is explicitly involved. o-Phthalaldehyde chalcones (100) undergo intramolecular aldehyde-ketone crossed-benzoin condensation to naphthalenone tertiary alcohols (101) in yields up to 94%, in 20 min, using NHC catalysis. ... 

The cross-benzoin reaction between two different aldehydes typically produces a statistical mixture of products, although in some cases a single thermodynamic product predominates. A number of approaches have been developed to circumvent the limitations of the cross-benzoin reaction. In one approach, a thiamine diphosphate-dependent enzyme is used to promote a selective cross-benzoin reaction, often with high levels of asymmetric induction. In other approaches, one aldehyde coupling partner is replaced with a selective acyl donor. Cyanohydrin derivatives have proven to be ideal preformed acyl donors, and their use constitutes a stepwise benzoin condensation that is stoichiometric in cyanide. The discovery that acylsilanes can serve as cyanohydrin precursors has led to the development of a highly selective cyanide-catalyzed cross-benzoin condensation. By employing a chiral metallophosphite catalyst instead of potassium cyanide, good to excellent levels of asymmetric induction are possible. 

Later, the same group expanded this chemistry further by developing a cascade Michael addition/cross-benzoin condensation sequence of enolizable aldehydes 43 and activated enones 44 [27]. The reaction proceeded by means of enamine activation of aliphatic aldehydes to induce an asymmetric Michael addition to activated enones followed by an intramolecular cross-benzoin condensation (Scheme 9.30). Compared with their previous work, complex cyclopentanones with complementary substitution patterns were observed. Screening of the reaction parameters revealed that the chiral triazolium catalyst was necessary to ensure a satisfactory stereochemical outcome. Further mechanistic insights indicated that the high diasteroselectivity observed attributed to the secondary amine-induced epimerizing of the a-position of intermediate aldehyde 89. 

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... 

It is only a small step from the asymmetric benzoin condensation to the asymmetric Stetter reaction, the aliphatic variant of the benzoin condensation. The literatnre refers to the Stetter reaction when at least one of the two reactants is an aliphatic aldehyde. Normally, the reaction is performed as a cross-coupling reaction with two different reactants, one of which is not an aldehyde, bnt an a, 3-unsaturated ketone. Strictly speaking, most thiazole catalysed reactions referred to as Stetter reactions are in fact Michael-Stetter reactions [21,22] (see Fignre 6.4). The reaction received the name because Stetter used a Michael reagent, an acceptor with an activated double bond, as the second component of a cross-coupled Stetter reaction [11]. 

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