Asymmetric Aldol Reaction In Water Research Articles

Artificial Enzymes Combining Proteins with Proline Polymers for Asymmetric Aldol Reactions in Water

Artificial enzymes, usually created by incorporating one or two abiological catalytic species into protein hosts, are becoming promising tools for biocatalysis. However, they are still far behind natural enzymes due to their limited active sites with low activity and selectivity. Here, we proposed a polymeric approach to generate artificial enzymes by combining proteins with organocatalytic polymers, in which multiple proline organocatalysts are grafted from protein scaffolds via atom-transfer radical polymerization. The resultant artificial polyenzymes, abbreviated as “ArPoly”, have similar physicochemical properties as natural enzymes and proved to be effective aldolase mimics for the aqueous asymmetric aldol reaction, in which an optimal ArPoly gave rise to 33% conversion and 94% enantioselectivity. Therefore, we proved the concept of water-soluble proline-based organocatalyst for aqueous asymmetric aldol reactions. This success not only expands the toolbox of asymmetric organocatalysis but also opens other avenues in the field of artificial enzymes where a plethora of proteins/enzymes can be combined with various well-designed organocatalytic polymers for synthetically useful reactions.

Synthesis of New Di- and Triamides as Potential Organocatalysts for Asymmetric Aldol Reaction in Water

New di- or triamide organocatalysts derived from (L)-proline were synthesized and successfully used in the direct asymmetric aldol reaction of aliphatic ketones and aromatic aldehydes in water at 0oC in the presence of benzoic acid as co-catalyst. (S)-methyl-2-((S)-3-hydroxy-2-((S)-3-pyrrolidine-2-carboxamido)propanamido)-3-phenylpropanoate (7c) as organocatalyst showed best results under these reaction conditions, and good diastereoselectivities (up to 99%), enantioselectivities (up to 98%) and yields (up to 91%) were observed.

L-proline functionalized pH-responsive copolymers as supported organocatalysts for asymmetric aldol reaction in water

pH-Responsive copolymers with reversible transformation ability have been investigated as new effective carriers for L-proline to catalyze asymmetric aldol reaction in water. A series of block copolymers of mPEG-b-P(DEAx-co-L-ProlAy) (mPEG-PDL) bearing L-proline catalytic sites and pH-responsive poly (diethylaminoethyl methacrylate) (PDEA) segments were synthesized by the reversible addition-fragmentation chain transfer (RAFT) polymerization in the presence of methyl polyethylene glycol (mPEG) trithiocarbonate macro-RAFT agent. The pH-induced self-assembly behaviors of three copolymer catalysts with different contents of PDEA were investigated via the combination of UV–visible spectrometer (UV–vis), dynamic light scattering (DLS) and transmission electron microscopy (TEM). Catalytic activity and stereoselectivity of these copolymer catalysts were evaluated by direct asymmetric aldol reaction of p-nitrobenzaldehyde and cyclohexanone in water. The results indicated that catalytic activity and stereoselectivity effected by the pH value of aqueous solution and the structures of copolymer catalyst assemblies. mPEG-PDL-2 give the aldol product with high conv., yield, anti/syn, and ee (92%, 91%, 92/8, 96%), respectively at pH 7.0. Furthermore, these pH-responsive copolymers supported L-proline are easily recycled by a reversible phase transition.

Catalytic Gels for a Prebiotically Relevant Asymmetric Aldol Reaction in Water: From Organocatalyst Design to Hydrogel Discovery and Back Again.

This paper reports an investigation into organocatalytic hydrogels as prebiotically relevant systems. Gels are interesting prebiotic reaction media, combining heterogeneous and homogeneous characteristics with a structurally organized active “solid-like” catalyst separated from the surrounding environment, yet in intimate contact with the solution phase and readily accessible via “liquid-like” diffusion. A simple self-assembling glutamine amide derivative 1 was initially found to catalyze a model aldol reaction between cyclohexanone and 4-nitrobenzaldehyde, but it did not maintain its gel structure during reaction. In this study, it was observed that compound 1 could react directly with the benzaldehyde to form a hydrogel in situ based on Schiff base 2 as a low-molecular-weight gelator (LMWG). This new dynamic gel is a rare example of a two-component self-assembled LMWG hydrogel and was fully characterized. It was demonstrated that glutamine amide 1 could select an optimal aldehyde component and preferentially assemble from mixtures. In the hunt for an organocatalyst, reductive conditions were applied to the Schiff base to yield secondary amine 3, which is also a highly effective hydrogelator at very low loadings with a high degree of nanoscale order. Most importantly, the hydrogel based on 3 catalyzed the prebiotically relevant aldol dimerization of glycolaldehyde to give threose and erythrose. In buffered conditions, this reaction gave excellent conversions, good diastereoselectivity, and some enantioselectivity. Catalysis using the hydrogel of 3 was much better than that using non-assembled 3—demonstrating a clear benefit of self-assembly. The results suggest that hydrogels offer a potential strategy by which prebiotic reactions can be promoted using simple, prebiotically plausible LMWGs that can selectively self-organize from complex mixtures. Such processes may have been of prebiotic importance.

Optically active microspheres from helical substituted polyacetylene with pendent ferrocenyl amino-acid derivative. Preparation and recycling use for direct asymmetric aldol reaction in water

The contribution reports a novel type of chiral microspheres in which ferrocenyl amino-acid derived catalytic moieties were integrated with optically active helical substituted polyacetylene. The microspheres were prepared by suspension copolymerization of achirally and chirally substituted acetylenic monomers in a quantitative yield. SEM images showed the microspheres' regular spherical morphology. Circular dichroism and UV−vis absorption spectra demonstrated that the copolymer chains constituting the microspheres adopted predominantly one-handed helices, endowing the microspheres with optical activity. The microspheres were further used to catalyze aldol reaction between cyclohexanone and p-nitrobenzaldehyde in water media in the presence of Brøsted acid, providing the product with remarkable yield (up to 91%) and enantiomeric excess (up to 93%). Synergistic effects occurred in the helical polymer chains and the pendant catalytic moieties. The catalytic microspheres can be finely recycled and reused three times without significant loss of catalytic ability and enantio-selectivity.

Chitosan Aerogel Catalyzed Asymmetric Aldol Reaction in Water: Highly Enantioselective Construction of 3-Substituted-3-hydroxy-2-oxindoles

A chitosan aerogel catalyzed asymmetric aldol reaction of ketones with isatins in the presence of water is described. This protocol was found to be environmentally benign, because it proceeds smoothly in water and the corresponding aldol products were obtained in excellent yields with good enantioselectivities.

New and effective proline-based catalysts for asymmetric aldol reaction in water

ABSTRACTNew proline diamide organocatalysts with Pro-Phe peptide bonds were synthesized and their catalytic activities in asymmetric direct aldol reactions of aliphatic ketones with aromatic aldehydes were investigated. Catalyst 6a showed good enantioselectivity at 0 °C in the presence of p-nitrobenzoic acid as cocatalyst in water.

A monolithic 5-(pyrrolidin-2-yl)tetrazole flow microreactor for the asymmetric aldol reaction in water–ethanol solvent

An organocatalytic polystyrene monolithic column produces chiral β-hydroxyketones under benign, continuous-flow conditions with high long-term stability.

L-proline derivatives based on a calix[4]arene scaffold as chiral organocatalysts for the direct asymmetric aldol reaction in water

A new series of water-compatible proline catalysts (4–6) derived from calixarene bearing a hydrophobic nature have been synthesised. It was found that the compound 4 was a highly efficient organocatalyst for aldol reactions occurred in the water. Under optimised reaction conditions, high yields (up to 82%), good enantioselectivities (ee up to 81%) and high diastereoselectivities (dr up to 91:9) were obtained.

Calixarene-proline functionalized iron oxide magnetite nanoparticles (Calix-Pro-MN): An efficient recyclable organocatalyst for asymmetric aldol reaction in water

Calix[4]arene-based chiral organocatalyst derived from L-proline supported onto well-defined (15±3nm) magnetic Fe3O4 nanoparticles was used as a highly active, recoverable, and reusable catalyst for the asymmetric aldol reaction in water without need for organic solvents. The chiral organocatalyst showed high catalytic activity (up to 94%), enantioselectivity (up to 93%) and diastereoselectivity (up to 97:3) for the reaction between cyclohexanone and aromatic aldehydes. The catalyst could easily separated using an external magnetic field and reused for several times without any significant loss of activity.

Chitosan-supported cinchonine as an efficient organocatalyst for direct asymmetric aldol reaction in water

Chitosan-supported succinic anhydride-cinchonine (CTS-SA-CN) was synthesized via a two-step route with succinic anhydride as the linker. The catalyst was used to promote the direct asymmetric aldol reaction between cyclohexanone and a variety of aromatic aldehydes in aqueous medium. Aldol adducts were obtained in excellent yields (up to 99%) and good enantioselectivities (up to 96% ee). The CTS-SA-CN catalyst was successfully recycled simply by filtration after use, and was reused 5 times without any significant loss of activity.

Temperature-responsive hairy particle-supported proline for direct asymmetric aldol reaction in water

In this paper, three kinds of hairy particles with different brush structures were prepared and evaluated as chiral catalysts in the direct asymmetric aldol reaction.

Efficient synthesis of zirconium poly(styrene-phenylvinylphosphonate)phosphate-supported proline as a recyclable catalyst for direct asymmetric aldol reactions in water

A completely non-chromatographic and highly large-scale adaptable synthesis of zirconium poly(styrene-phenylvinylphosphonate)phosphate-supported l-proline (ZrPS-PVPA-Pr) has been developed in only three steps overall.

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).

ChemInform Abstract: Synthesis of Hybrid Ferrocene‐Proline Amides as Active Catalysts for Asymmetric Aldol Reactions in Water.

AbstractSome new ferrocene‐proline amides are prepared.

ChemInform Abstract: L‐Proline Supported on Ionic Liquid‐Modified Magnetic Nanoparticles as a Highly Efficient and Reusable Organocatalyst for Direct Asymmetric Aldol Reaction in Water.

Grafting L-proline on imidazolium-based ionic liquid (IL)-functionalized magnetic nanoparticles afforded a magnetically recoverable L-proline catalyst. Characterization technologies suggested the presence of an L-proline backbone, an IL linker, and a magnetic ferrite core in the catalyst. The resulting L-proline catalyst was efficient for direct asymmetric aldol reaction in water without the need for organic solvents and co-catalysts. Such efficiency is attributed to the fact that the IL moiety facilitated the accessibility of hydrophobic reactants to active sites in water and stabilized the formed enamine intermediate during the reaction. High activity (yield = 92%), diastereoselectivity (dr; 88/12) and enantioselectivity (ee; 85%) were obtained using 10 mol% of a catalyst for the reaction between cyclohexanone and 2-nitrobenzaldehyde within 12 h, where the pristine L-proline and IL-free counterpart were almost inactive. The catalyst was easily separated using a permanent magnet externally and can be reused several times without significant loss of activity.

Synthesis of Hybrid Ferrocene‐Proline Amides as Active Catalysts for Asymmetric Aldol Reactions in Water

AbstractFerrocenyl substituents were employed as lipophilic moieties and introduced into a prolinamide scaffold to afford new catalysts that were suitable for use in “on water” conditions. Five proline amides that contain a ferrocene unit were synthesized from easily accessible ferrocenylamines and evaluated as catalysts in the asymmetric direct aldol condensation of cyclohexanone with aldehydes in an aqueous medium. Optimal substrate conversion and stereoselectivity were achieved in brine and in the presence of benzoic acid as an additive. All the examined catalysts displayed good activity with a catalyst loading of 5 mol‐%, and the best results in terms of enantioselectivity were obtained by using a ferrocenyl‐prolineamide with an additional (S) chiral center. In the presence of this catalyst, a variety of aromatic aldehydes underwent a reaction in a reasonable amount time with just 2 equiv. of the cyclic ketone to give the expected aldol products in high yields (65–98 %) and with high stereoselectivities (up to 94 % ee, dr up to 93:7).

Thermoresponsive Polymer-Supported l-Proline Micelle Catalysts for the Direct Asymmetric Aldol Reaction in Water.

l-Proline moieties bound to a thermoresponsive polymer nanoreactor efficiently directed the asymmetric aldol reaction in water with excellent yields and enantioselectivity (ee). The reactions were efficient at higher temperatures in direct contrast to the low yields and ee values found when the reaction was carried out in a DMF/water mixture due to the location of the l-proline moieties within the hydrophobic pocket inside the core of the nanoreactors. This ideal environment formed for catalysis allows control over the water content as well as enhancing interactions between the carboxylic acid of l-proline and the aldehyde substrate. The nanoreactors were disassembled to fully water-soluble polymers by lowering the temperature to below the lower critical solution temperature (LCST) of the polymer, resulting in precipitation of the product in near pure form. The product was isolated by centrifugation and the polymer/water solution reused in additional catalytic cycles by heating the polymer above its LCST and thus reforming the nanoreactors. Although a small decrease in yield after five cycles was observed, the selectivity (anti/syn ratio and ee) remained high.

Organocatalysis of asymmetric aldol reaction in water: comparison of catalytic properties of (S)-valine and (S)-proline amides

(S)-Valine amides containing (S)- or (R)-α-phenylethyl substituents at N1 atom efficiently catalyze asymmetric aldol reactions between cyclic (heterocyclic) ketones and aromatic aldehydes in water, predominantly giving rise to the aldol anti-diastereomers in high yields (up to 98%) and enantiomeric excess (up to 94%).

L-Proline supported on ionic liquid-modified magnetic nanoparticles as a highly efficient and reusable organocatalyst for direct asymmetric aldol reaction in water

Grafting L-proline on imidazolium-based ionic liquid (IL)-functionalized magnetic nanoparticles afforded a magnetically recoverable L-proline catalyst. Characterization technologies suggested the presence of an L-proline backbone, an IL linker, and a magnetic ferrite core in the catalyst. The resulting L-proline catalyst was efficient for direct asymmetric aldol reaction in water without the need for organic solvents and co-catalysts. Such efficiency is attributed to the fact that the IL moiety facilitated the accessibility of hydrophobic reactants to active sites in water and stabilized the formed enamine intermediate during the reaction. High activity (yield = 92%), diastereoselectivity (dr; 88/12) and enantioselectivity (ee; 85%) were obtained using 10 mol% of a catalyst for the reaction between cyclohexanone and 2-nitrobenzaldehyde within 12 h, where the pristine L-proline and IL-free counterpart were almost inactive. The catalyst was easily separated using a permanent magnet externally and can be reused several times without significant loss of activity.