Advances in Immobilized Organocatalysts for the Heterogeneous Asymmetric Direct Aldol Reactions

The aim of this article is to collect the results published from the beginning (2000) on asymmetric direct aldol reactions taking place in the presence of immobilized chiral organocatalysts. The seven groups of organocatalysts discussed are: asymmetric direct aldol reactions catalyzed by: (1) covalently bonded immobilized hydroxyproline organocatalysts; (2) covalently bonded immobilized prolinamide organocatalysts; (3) covalently bonded immobilized peptide organocatalysts; (4) other covalently bonded immobilized chiral organocatalysts; (5) chiral organocatalysts bonded by ionic groups; (6) chiral organocatalysts with adsorptive bonding; and (7) other types of immobilized chiral organocatalysts. The main objective of this article based on results obtained by using about 360 immobilized organocatalysts, to bring to the focus of catalyst systems in which the aldol reactions yield beta-hydroxyketones of maximal optical purity, while keeping catalyst concentrations and reaction times as low and as short as possible. Trends recognized in data obtained in this field of investigation may mark out further tasks for the purpose of practical application.     

Highly Efficient Threonine‐Derived Organocatalysts for Direct Asymmetric Aldol Reactions in Water

The introduction of siloxy groups at the hydroxy function of natural threonine resulted in efficient hydrophobic organocatalysts, which could efficiently catalyze the direct aldol reactions of both cyclic and acyclic ketones with aromatic aldehydes in water with excellent enantiomeric excess.     

New Simple Hydrophobic Proline Derivatives as Highly Active and Stereoselective Catalysts for the Direct Asymmetric Aldol Reaction in Aqueous Medium

New 4‐substituted acyloxyproline derivatives with different hydrophobic properties of the acyl group were easily synthesized and used as catalysts in the direct asymmetric aldol reaction between cyclic ketones (cyclohexanone and cyclopentanone) and several substituted benzaldehydes. Reactions were carried out using water, this being the best reaction medium examined. Screening of these catalysts showed that compounds bearing the most hydrophobic acyl chains [4‐phenylbutanoate and 4‐(pyren‐1‐yl)butanoate] provided better results. The latter catalysts were successfully used in only 2 mol% at room temperature without additives to give aldol products in excellent stereoselectivities. These results demonstrate that derivatization of the proline moiety with the proper simple hydrophobic substituent in the 4‐position can furnish highly active and stereoselective catalysts without the need of additional chiral backbones in the molecule. Finally, an explanation of the observed stereoselectivities in the presence of water is provided.     

L‐Prolinethioamides – Efficient Organocatalysts for the Direct Asymmetric Aldol Reaction

A series of novel L ‐proline derived thioamides has been synthesised. They have been evaluated as organocatalysts in the direct asymmetric aldol reaction for the first time. Thioamides exhibit catalytic ability higher than proline itself and the model aldol reaction of 4‐cyanobenzaldehyde with acetone proceeds well in the presence of 5 mol % of catalyst (ee up to 100%). Other aromatic aldehydes gave aldol products with high ees and moderate yields. Small changes in the catalyst's structure [e.g., N‐Bn versus N‐CH(CH₃)Ph] as well as the addition of an acid have a profound effect on their activity. The unexpected formation of the catalyst‐derived cyclic adducts was observed and their reactivity was established giving valuable insight into the course of the reaction.     

Mukaiyama Aldol Reactions in Aqueous Media

Mukaiyama aldol reactions in aqueous media have been surveyed. While the original Mukaiyama aldol reactions entailed stoichiometric use of Lewis acids in organic solvents under strictly anhydrous conditions, Mukaiyama aldol reactions in aqueous media are not only suitable for green sustainable chemistry but are found to produce singular phenomena. These findings led to the discovery of a series of water‐compatible Lewis acids such as lanthanide triflates in 1991. Our understanding on these beneficial effects in the presence of water will be deepened through the brilliant examples collected in this review.

     

Effect of Long Chain Fatty Acids on Organocatalytic Aqueous Direct Aldol Reactions

In an organocatalyzed, aqueous direct aldol reaction, the addition of a long chain fatty acid (1 mol%) such as stearic acid or erucic acid improved the aldol product yield and the enantioselectivity with low catalyst loading (1 mol%). The small particle size of the emulsion (less than 1 μm) was a key to the enhanced reactivity as shown by dynamic light scattering (DLS) analyses.     

Direct Catalytic Asymmetric Aldol Reactions Assisted by Zinc Complex in the Presence of Water

A combination of zinc triflate and chiral C₂‐symmetrical prolinamide ligand leads to high enantioselectivities in direct aldol reactions essentially assisted by water. The presence of 5 mol % of the catalyst affords an asymmetric intermolecular aldol reaction between unmodified ketones and aldehydes to give anti‐products with excellent enantioselectivities ranging from 86–98 % ee. The same bis(prolinamide) ligand is found to catalyze the direct aldol reactions in the presence of water (or in water) with excellent stereocontrol and furnish the corresponding aldols in up to 99 % ee. For the demonstrated catalytic systems organic solvent‐free conditions are applied.     

Simple and Facile <Emphasis Type="SmallCaps">l</Emphasis>-Prolinamides Derived from Achiral Cycloalkylamines as Organocatalysts for the Highly Efficient Large-Scale Asymmetric Direct Aldol Reactions

Abstract  

A series of N-cycloalkylprolinamides have been designed and synthesized from achiral cycloalkylamines in a facile manner. They promoted high stereoselectivity in the cross-aldol reaction. N-cyclopropylprolinamide performed best with a smallest carbocyclic ring, and the anti-aldol products could be obtained with up to 99:1 anti/syn and 99% ee. Carbocyclic ring was found to play a significant role in the formation of the aldol products. This simple catalyst can be efficiently used in large-scale reactions with the enantioselectivity being maintained at the same level, which offers great possibility for applications in industry.     

Chiral Calix[4]arenes-Bearing Prolinamide Functionality as Organocatalyst for Asymmetric Direct Aldol Reactions in Water

The chiral calix[4]arene derivative (6) bearing an L-prolinamido group has been designed and proved to be a water compatible efficient organocatalysts for a direct enantioselective aldol reaction. Compound 6 catalyzes the aldol reaction of cyclohexanone and a variety of aromatic aldehydes yielding anti-aldol products in high yield with enantioselectivities of up to 93% and diastereoselectivity of up to 95:5.     

Diastereo‐ and Enantioselective Direct Aldol Reactions in Aqueous Medium: A New Highly Efficient Proline‐Sugar Chimeric Catalyst

A new synthetic catalyst, capable of acting like an enzyme in the accomplishment of direct aldol reactions, is presented. Excellent results, in terms of chemical yields and diastereo‐/enantiomeric ratios, are reported for the catalyzed additions of cyclohexanone to variously substituted benzaldehydes.     

Solid Acids as Heterogeneous Support for Primary Amino Acid‐Derived Diamines in Direct Asymmetric Aldol Reactions

We have achieved the non‐covalent immobilization of chiral primary amino acid‐derived diamines on organic and inorganic sulfonated solid acids through acid‐base interaction. With the commercial sulfonated fluoropolymer nafion® NR50 as support an optimal balance was found between activity and stereoselectivity of the supported catalyst in direct asymmetric aldol reactions of linear ketones and aromatic aldehydes. Under optimized conditions aldol products were obtained in high yields and with excellent enantioselectivities for the syn‐product (up to 98% ee). Furthermore, catalysis with the supported diamine was demonstrated to occur truly heterogeneously and the loaded nafion® NR50 beads could be reused several times. Ultimately, the immobilized catalyst/nafion® NR50 system was successfully implemented in a fixed‐bed reactor set‐up under continuous flow conditions.     

Direct Asymmetric Aldol Reactions in Water Catalysed by a Highly Active C2‐Symmetrical Bisprolinamide Organocatalyst

A novel C₂‐symmetrical bisprolinamide organocatalyst was synthesised and used to facilitate asymmetric direct aldol reactions in a water emulsion. Reactions were performed at room temperature with very low catalyst loadings (1–2.5 mol%) without the required use of additives, co‐catalysts or extended reaction times (24 h). This catalyst system was then used with a variety of aldehyde substrates showing good reaction generality for benzaldehydes with cyclohexanone (dr range 77/23 to >99/1, anti/syn; ee range 33% to >99%) and moderate scope with cyclopentanone (dr range 45/55 to 76/24, anti/syn; ee range 14% to 68%). Ultra‐low catalysts loadings (0.1 and 0.05 mol%) were also investigated demonstrating catalyst turnover numbers in the order of 1000.     

Chymopapain‐Catalyzed Direct Asymmetric Aldol Reaction

Chymopapain, a cysteine proteinase isolated from the latex of the unripe fruits of Carica papaya, displays a promiscuous activity to catalyze the direct asymmetric aldol reactions of aromatic and heteroaromatic aldehydes with cyclic and acyclic ketones in acetonitrile in the presence of a phosphate buffer. The excellent enantioselectivities of up to 96% ee and high diastereoselectivities of up to >99:1 (anti/syn) were achieved. The novel catalytic promiscuity of chymopapain widens the applicability of this biocatalyst in organic synthesis.     

Proline‐Functionalized Magnetic Core‐Shell Nanoparticles as Efficient and Recyclable Organocatalysts for Aldol Reactions

Novel magnetically tagged organocatalysts have been developed based on core‐shell nanoparticles consisting of magnetite cores and polyacrylate shells containing 4‐hydroxyproline moieties. These catalysts allow the performance of direct asymmetric aldol reactions of aromatic aldehydes with ketones in the presence of benzoic acid providing high yields and ees. Straightforward magnetic separation and recycling of a catalyst for up to 9 runs is possible without a significant loss of efficiency.     

<Emphasis Type="SmallCaps">l</Emphasis>-Valine Dipeptide Organocatalysts with Two Amide Units for the Direct Asymmetric Aldol Reaction in Brine

Abstract  

A series of valine dipeptide organocatalysts containing a primary amine group and two amide units have been developed and evaluated in the direct asymmetric intermolecular aldol reaction of 4-nitrobenzaldehyde and cyclohexanone. When 2,4-dinitrophenol (DNP) was used as an acidic additive, the catalyzed reactions of various aldehydes and ketones gave the corresponding aldol products with moderate to high enantioselectivities (up to 95%) and diastereoselectivities (up to >99/1, anti/syn) in the presence of 3c in brine.