Catalytic asymmetric aldol reactions in aqueous media

Nature has perfected the stereospecific aldol reaction by using aldolase enzymes. While virtually all the biochemical aldol reactions use unmodified donor and acceptor carbonyls and take place under catalytic control in an aqueous environment, the chemical domain of the aldol addition has mostly relied on prior transformation of carbonyl substrates, and the whole process traditionally is carried out in anhydrous solvents. The area of aqua-asymmetric aldol reactions has received much attention recently in light of the perception both of its green chemistry advantages and its analogy to eon-perfected enzyme catalysis. Both chiral metal complexes and small chiral organic molecules have been recently reported to catalyze aldol reactions with relatively high chemical and stereochemical efficiency. This tutorial review describes recent developments in this area.     

Prolinamides derived from aminophenols as organocatalysts for asymmetric direct aldol reactions

N-(2-Hydroxyphenyl)-prolinamides were synthesized with the aim to introduce an additional hydrogen bonding site to the prolinamide structure. These compounds were evaluated as organocatalysts for asymmetric aldol reactions between aromatic aldehydes and cyclohexanone. Very good yields, diastereoselectivities, and enantioselectivities were achieved in both organic solvents and water. The importance of the additional hydrogen bonding site was confirmed by comparative experiments with prolinamide derivatives without the hydroxyl group.     

Enantiopure azetidine-2-carboxamides as organocatalysts for direct asymmetric aldol reactions in aqueous and organic media

A family of enantiopure azetidine-2-caboxamides was asymmetrically synthesized, and was examined as organocatalyst in direct aldol reactions. A well chosen chiral azetidine-2-caboxamide was found to smoothly catalyze the direct aldol reaction of various benzaldehydes with acetone in brine, and β-hydroxy ketones were produced with enantiomeric excess up to 96%. The reaction of benzaldehydes with cyclic ketones also led to the formation of anti-products in diastereomeric ratio up to 99:1 and enantiomeric excess up to 99%.     

Copolymer-supported heterogeneous organocatalyst for asymmetric aldol addition in aqueous medium

In the current study, a convenient and simple way is presented to synthesize a novel type of supported heterogeneous organocatalyst in 21-81% yield by the copolymerization of 9-amino-9-deoxy-epi-cinchonine organocatalyst with acrylonitrile using AIBN as radical initiator. The chemical compositions (x/y) and weight-average molecular weights of copolymers 1a-d were determined by (1)H NMR and GPC analysis respectively. Their porous and layered structure, and surface morphology were characterized by nitrogen adsorption-desorption, XRD and TEM. In the asymmetric aldol addition of p-nitrobenzaldehyde to cyclohexanone and 1-hydroxy-2-propanone in water, all the supported organocatalysts 1a-d afforded excellent isolated yields (90.2-94.7%) and stereoselectivities (96.8-97.8%ee anti, anti/syn = 91/9). The highest catalytic property (96% yield, anti/syn = 90/10 and 99%ee anti) in water as the sole solvent was achieved under the optimized conditions. Compared with cyclohexanone, cyclopentanone and acetone showed the less desired enantioselectivities in the same aldol reactions. At the end of the aldol reaction, the copolymer-supported organocatalyst 1a was readily recovered in 95-98% yield from reaction mixture by simple filtration using an organic membrane. Even in the fifth run, there was no significant loss in catalytic activity and stereocontrol (94.3% yield, 97.2%ee anti, anti/syn = 90/10). After continuous reuse five times, there was some drop in catalytic activity and stereoselectivity.     

A recyclable non-immobilized siloxy serine organocatalyst for the asymmetric direct aldol reaction

A recyclable siloxy-l-serine organocatalyst has been developed to catalyze asymmetric direct aldol reactions in [bmim][BF₄], furnishing the β-hydroxy carbonyl scaffold in high enantio- and diastereoselectivities using a selection of aromatic aldehydes and cycloalkanes. The siloxy serine organocatalyst in the ionic liquid can be reused for up to four successive cycles with comparable enantioselectivities.     

Acyclic amino acid-catalyzed direct asymmetric aldol reactions: alanine, the simplest stereoselective organocatalyst

The linear amino acid-catalyzed direct asymmetric intermolecular aldol reaction is presented; simple amino acids such as alanine, valine, isoleucine, aspartate, alanine tetrazole and serine catalyzed the direct catalytic asymmetric intermolecular aldol reactions between unmodified ketones and aldehydes with excellent stereocontrol and furnished the corresponding aldol products in up to 98% yield and with up to > 99% ee.     

Upper rim-functionalized calix[4]arene-based l-proline as organocatalyst for direct asymmetric aldol reactions in water and organic media

The synthesis of upper rim-functionalized calix[4]arene-based l-proline was described, and its catalytic efficiency as organocatalyst for the enantioselective aldol reaction in water was investigated. The results showed that the nature of the hydrophobic cavity of calixarene is critical for catalytic activity in water. The products of the reaction between various ketones and aldehydes with anti-configuration were obtained in high yields (up to 94%) with high diastereo- (up to 95:5 dr) and enantioselectivities (up to 80% ee).     

Organocatalytic direct asymmetric aldol reactions in water

We have developed direct asymmetric cross-aldol reactions that can be performed in water without addition of organic solvents. A bifunctional catalyst with a long hydrophobic alkyl chain efficiently catalyzed the reactions and afforded the desired aldol products in excellent yield with high enantiomeric excess, even when only an equal molar ratio of the donor and acceptor was used. These results reveal an effective design strategy for the development of aqueous organocatalytic systems.     

壳聚糖负载辛可宁催化剂的制备及其在水中催化不对称Aldol反应

以丁二酸酐为连接臂,经两步反应制备了壳聚糖负载辛可宁有机催化剂(CTS-SA-CN),并研究了CTS-SA-CN在水体系中对酮与多种芳香醛的直接不对称aldol反应的催化性能。结果表明,在CTS-SA-CN催化下,酮与多种芳香醛发生直接不对称aldol反应,可得到99%的产率和96%的ee值。另外, CTS-SA-CN可通过简单过滤实现回收,重复使用5次活性并没有明显下降。     

Rationally designed organocatalyst for direct asymmetric aldol reaction in the presence of water

A rationally designed organocatalyst for direct asymmetric aldol reaction in the presence of water has been developed. High yield (up to 99%), diastereoselectivity (up to 99:1) and enantioselectivity (up to 97%) were obtained under optimal conditions.     

壳聚糖负载辛可宁催化剂的制备及其在水中催化不对称Aldol反应

以丁二酸酐为连接臂,经两步反应制备了壳聚糖负载辛可宁有机催化剂(CTS-SA-CN),并研究了CTS-SA-CN在水体系中对酮与多种芳香醛的直接不对称aldol反应的催化性能。结果表明,在CTS-SA-CN催化下,酮与多种芳香醛发生直接不对称aldol反应,可得到99%的产率和96%的ee值。另外, CTS-SA-CN可通过简单过滤实现回收,重复使用5次活性并没有明显下降。     

手性胺催化不对称水相aldol反应研究进展

Aldol反应作为最重要的碳碳键形成反应之一,在有机合成中有着重要作用,本文综述了手性伯胺,仲胺催化剂催化的水相aldol反应的最新研究进展。     

A highly efficient organocatalyst for direct aldol reactions of ketones with aldehydes [corrected

L-proline amides derived from various chiral beta-amino alcohols that bear substituents with various electron natures at their stereogenic centers are prepared and evaluated for catalyzing the direct Aldol reaction of 4-nitrobenzaldehyde with acetone. Catalysts with strong electron-withdrawing groups are found to exhibit higher catalytic activity and enantioselectivity than their analogues with electron-donating groups. The presence of 2 mol % catalyst 4g significantly catalyzes the direct Aldol reactions of a wide range of aldehydes with acetone and butanone, to give the beta-hydroxy ketones with very high enantioselectivities ranging from 96% to >99% ee. High diastereoselectivity of 95/5 was observed for the anti Aldol product from the reaction of cyclohexanone, and excellent enantioselectivity of 93% ee was provided for anti Aldol product from the reaction of cyclopentanone.     

Direct asymmetric aldol reactions catalyzed by a siloxy serine organocatalyst in water

A siloxy-l-serine organocatalyst has been developed to catalyze direct asymmetric aldol reactions in the presence of water, furnishing the β-hydroxy carbonyl scaffold in high enantio- and diastereoselectivities. The direct aldol reaction between a selection of aromatic aldehydes and cyclohexanone resulted in good yields and high enantioselectivities.     

Carbohydrate-based organocatalysts in direct asymmetric aqueous aldol reaction

Aldol reaction involving chiral amines as organocatalysts through enamine formation, like class-I aldolases, is one of the thriving areas of general interest and widely applicable asymmetric reactions. There are many natural and synthetic chiral templates known to work as efficient organocatalysts, but using carbohydrate templates for chiral induction in asymmetric aldol reactions is a relatively new area developed in the recent years. This review focuses on carbohydrates alone or their conjugates with previously known chiral moieties as organocatalysts for asymmetric aldol reactions.     

New organocatalysts derived from tartaric and glyceric acids for direct aldol reactions

The synthesis of several new pyrrolidine based asymmetric organocatalysts derived from tartaric, glyceric acids and a pyrrolidine moiety is described with a study of their application in the development of an enantioselective aldol protocol. The influence of different proton donor groups, such as a primary hydroxyl or a carboxylic acid group, or their absence, on the efficiency of the organocatalyst was studied. The configuration of the tartrate derived catalysts and the presence of the rigid butane-2,3-diacetal were found to have a strong influence on the stereoselective outcome of the aldol reaction.     

Proline–threonine dipeptide as an organocatalyst for the direct asymmetric aldol reaction

A new proline–threonine (H-Pro-Thr-OH) dipeptide has been demonstrated as an efficient organocatalyst for a direct asymmetric aldol reaction. It was found that this new peptide-based catalyst efficiently catalyzed the reaction between an aldehyde and acetone to provide β-hydroxy ketones in good yields with good enantioselectivities.     

Zn-proline catalyzed direct aldol reaction in aqueous media

Zn complexes of proline, lysine and arginine are efficient catalysts for the aldol addition of p-nitrobenzaldehyde and acetone in aqueous medium, giving quantitative yields and enantiomeric excesses up to 56% with 5 mol% of the catalysts at room temperature.     

Direct organocatalytic aldol reactions in buffered aqueous media

Organocatalytic cross-aldol reactions catalyzed by cyclic secondary amines in aqueous media provide a direct route to a variety of aldols including carbohydrate derivatives and may warrant consideration as a prebiotic route to sugars.     

Silica-immobilized piperazine: A sustainable organocatalyst for aldol and Knoevenagel reactions

Silica-supported piperazine was found to be an efficient catalyst for aldol reactions of aromatic aldehydes and ketones with straightforward product isolation and catalyst reuse. Furthermore, the catalyst is active in Knoevenagel-type reactions to afford coumarin derivatives, using 2-methyltetrahydrofuran (2-MeTHF) as a novel bio-based solvent.