Proline catalysts asymmetric aldol reaction

This is especially important in those cases where the catalyst has to be used in quite substantial amounts, as in the above-discussed (5)-proline-catalyzed asymmetric aldol reactions, where the catalyst is usually used at 30 mol.%. ... 

Aminocatalysis is a biomimetic strategy used by enzymes such as class I aldolases. Application of aminocatalysis in an asymmetric aldol reaction was reported in the early 1970s. Proline (19) efficiently promoted an intramolecular direct aldol reaction to afford Wieland-Miescher ketone in 93% ee [17,18]. More than 25 years later, in 2000, List, Barbas, and co-workers reported that proline (19) is also effective for intermolecular direct aldol reactions of acetone (le) and various aldehydes 3. Notably, the reaction proceeded smoothly in anhydrous DMSO at an ambient temperature to afford aldol adducts in good yield and in modest to excellent enantioselectivity (up to >99% ee, Scheme 9) [19-22]. The chemical yields and selectivity of proline catalysis are comparable to the best metallic catalysts, although high catalyst loading (30 mol %) is required. Proline (19)... 

Surprisingly, the catalytic potential of proline (1) in asymmetric aldol reactions was not explored further until recently. List et al. reported pioneering studies in 2000 on intermolecular aldol reactions [14, 15]. For example, acetone can be added to a variety of aldehydes, affording the corresponding aldols in excellent yields and enantiomeric purity. The example of iso-butyraldehyde as acceptor is shown in Scheme 1.4. In this example, the product aldol 13 was obtained in 97% isolated yield and with 96% ee [14, 15]. The remarkable chemo- and enantioselectivity observed by List et al. triggered massive further research activity in proline-catalyzed aldol, Mannich, Michael, and related reactions. In the same year, MacMillan et al. reported that the phenylalanine-derived secondary amine 5 catalyzes the Diels-Alder reaction of a,/>-un saturated aldehydes with enantioselectivity up to 94% (Scheme 1.4) [16]. This initial report by MacMillan et al. was followed by numerous further applications of the catalyst 5 and related secondary amines. 

It is worth noting that, in a similar manner to enzymatic conversions with type I or II aldolases, a direct asymmetric aldol reaction was achieved when L-proline was used as catalyst. Accordingly, the use of enol derivatives of the ketone component is not necessary, i.e. ketones (acting as donors) can be used directly without previous modification [72]. So far, most asymmetric catalytic aldol reactions with... 

The capability of L-proline - as a simple amino acid from the chiral pool - to act like an enzyme has been shown by List, Lemer und Barbas III [4] for one of the most important organic asymmetric transformations, namely the catalytic aldol reaction [5]. In addition, all the above-mentioned requirements have been fulfilled. In the described experiments the conversion of acetone with an aldehyde resulted in the formation of the desired aldol products in satisfying to very good yields and with enantioselectivities of up to 96% ee (Scheme 1) [4], It is noteworthy that, in a similar manner to enzymatic conversions with aldolases of type I or II, a direct asymmetric aldol reaction was achieved when using L-proline as a catalyst. Accordingly the use of enol derivatives of the ketone component is not necessary, that is, ketones (acting as donors) can be used directly without previous modification [6]. So far, most of the asymmetric catalytic aldol reactions with synthetic catalysts require the utilization of enol derivatives [5]. The first direct catalytic asymmetric aldol reaction in the presence of a chiral heterobimetallic catalyst has recently been reported by the Shibasaki group [7]. 

An approach has recently been made in which asymmetric aldol reactions are performed without the need for preformed metal enolates.1 In 2000, List and co-workers reported that the cyclic amino acid L-proline is an effective catalyst for the asymmetric aldol reaction of acetone with a variety of aromatic and aliphatic aldehydes2 (Scheme 2.3a). When L-proline was mixed with acetone... 

The enantioselective conjugate addition of tetrahydropyran-4-ones and their thio analogues to nitrostyrene is achieved using proline-based catalysts <06JA9624>, as is the asymmetric aldol reaction of these substrates with benzaldehydes (Scheme 27) <06JOC8198>. 

Simple L-alanine, L-valine, L-norvaline, L-isolecucine, L-serine and other linear amino acids [ 121 ] or chiral amino acids with a binaphthyl backbone [ 122] and peptides have also been used as asymmetric catalysts [123,124,125,126]. Solid-supported proline-terminated peptides have been used for heterogeneous catalysis of the asymmetric aldol reaction [ 127]. Apart from proline and derivatives, other cyclic compounds such as 5,5-dimethyl thiazolidinium-4-car-boxylate (DMTC) [128], 2-fert-butyl-4-benzyl imidazolidinones [129], (l/ ,25)-2-aminocy-clopentanecarboxylic acid [130], (5 -5-(pyrrolidin-2-yl)tetrazole, (5)-l,3-thiazolidine-4-car-boxylic acid, (5)-5,5-dimethyl-l,3-thiazolidine-4-carboxylic acid, and (5)-hydroxyproline are effective catalysts in asymmetric aldol reactions [126,131,132,133,134,135]. 

Onium ion-tagged proline catalysts 7 and 8 in [bmini][Tf2N] proved to be an excellent catalytic system for the direct asymmetric aldol reaction. The catalytic protocol developed makes use of use of a 6-fold lower amount of catalyst with respect to the proceeding reports based on the use of proline 12 and affords greater chemical yields and higher enantioselectivity. In particular, 8 in [bmim][Tf2N] gave better results compared both to the use of proline in the same IL and of 7 in DMSO. ... 

In 2005, Beilis and Kokotos synthesized a series of proline-based PPI chiral dendrimers possessing up to 126 proline end groups (Figure 4.38) [109]. These dendrimers were evaluated as the catalyst for asymmetric aldol reactions (Scheme 4.30). Using 6.5mol% of the second-generahon dendrimer catalyst, the products of the aldol reachons were obtained in moderate yields and enanhoselectivities (up... 

The direct asymmetric aldol reaction between unmodified aldehydes and ketones plays an important role in nature as a source of carbohydrates and it is used for the synthesis of chiral p-hydroxycarbonyl compounds. This reaction was performed by using (5)-proline/poly-(diallyldimethylammonium) hexafluorophosphate heterogeneous catalytic system 36. The catalyst was simply prepared by mixing a suspension of the commercially available polyelectrolyte 34 in methanol with a solution of (,S )-prolinc (35) in the same solvent (Scheme 3.11). 

Scheme 4.5 Asymmetric aldol reaction using onium-tagged proline as catalyst.

Routes by asymmetric organocatalysis are available to account for the occurrence of chiral molecules on earth. L-proline and L-serine yielded relatively high values of ee in aldol condensations (Cordova et al. 2005). An epimer of a distinct amino acid, for instance, proline or serine, can serve as a catalyst in aldol reactions (Cordova et al. 2005). The percentage of the catalyzing amino acid determines the ee of the reaction product. Thus, the preferred formation of D-ribose compared to that of L-ribose can be accounted for by the intrinsic property of the reaction system with an asymmetric molecule acting as biocatalyst. L-proline has exceptional properties due to its structure, Fig. 3.3. 

Novel organic molecules derived from L-proline and amines or amino alcohols, were found to catalyse the asymmetric direct aldol reaction with high efficiency. Notably those containing L-proline amide moiety and terminal hydroxyl group could catalyse direct asymmetric aldol reactions of aldehydes in neat acetone with excellent results[1]. Catalyst (1), prepared from L-proline and (IS, 2Y)-diphcnyl-2-aminoethanol, exhibits high enantioselectivities of up to 93% ee for aromatic aldehydes and up to >99% ee for aliphatic aldehydes. 

In our illustration of the graphical manipulations of data using reaction progress kinetic analysis, we will make use of the example of a model reaction, the intermolecnlar aldol reaction between acetone 1 and aldehyde 2 to form the aldol addition product 3, mediated by proline 4, as shown in Scheme 27.1. The demonstration by List, Lemer, and Barbas in 2000 that proline mediates intermolecular aldol reactions with a high degree of asymmetric induction heralded a revolution in the field of organocatalysis, encompassing the discovery of new catalysts and new catalytic transformations." ... 

The direct asymmetric aldol reaction has also received much recent attention. High ees have been obtained using lanthanide- or zinc-based bifunctional catalysts bearing both Lewis acidic and Lewis basic sites. The most significant recent advance in this area is the discovery that cheap, readily available organic catalysts such as L-proline are also effective. 

Type I aldolases activate the aldol donor by the formation of enamines with active site amino acids and an alternate approach to the direct catalytic asymmetric aldol reaction centres on mimicking this process using proline-based organocatalysts. In fact, one of the earliest examples of asymmetric catalysis uses (S)-profine (7.66) as a catalyst for the intramolecular aldol reaction (the Hajos-Eder-Saeur-Wiechert reaction).As an example the achiral triketone (7.67) cyclises to give the aldol product (7.68) with good enantioselectivity. 

A representative set of such structures (7.80-7.86) is shown, all of which result in the formation of aldol adducts with high ee. Replacement of the carboxylic acid moiety with a bioisosteric tetrazole results in a catalyst (7.80) that is both more reactive than L-proline (7.66) and more readily soluble in organic solvents such as THF.38a.b jji a similar vein, acyl sulfonamides such as (7.81) give good enantios-electivities in the aldol reaction with aromatic aldehydes in organic solvents such as dichloromethane and acetone. 3 The addition of stoichiometric amounts of water increases the activity of tetrazole (7.80) further and this allows the use of aldehydes such as chloral monohydrate (7.87) and formaldehyde, which have an affinity for water and are generally poor substrates for the catalytic asymmetric aldol reaction. 38 = Catalysts (7.82)38 (7.33) 3Sd ijpophilic substiments,... 

An alternate approach to the direct asymmetric Mannich reaction uses enan-tiomericaUy pure organocatalysts. L-Proline and derivatives, applied with much success to the catalytic asymmetric aldol reaction (see Section 7.1), also function as effective catalysts in the Mannich reaction. The mechanism of this process is similar to the L-proline-catalysed aldol reaction involving conversion of the donor into an enamine and proceeds via a closed six-membered transition state similar to that depicted in Figure 7.4. However, in contrast to the L-proline-catalysed aldol reaction, the sy -Mannich adduct is the major diastereomer formed and the si rather than the re-face of the acceptor undergoes attack, as depicted in Figure 7.5. 

Ellman and coworkers have shown that chiral sulfinate 14 can catalyse asymmetric aldol reactions of acetone, whereas proline itself gave poor results. However, more active and selective catalysts are prolinamides with general structure 16 containing two or more stereocentres in the molecule, and based on ot-alkylbenzylamines ISa," chiral (3-amino alcohols (16b-d, 16e-f, axially chiral amino hydroxyl-2,2 -binaphtyl amide 16i, ... 

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