Asymmetric Aldol Reaction Research Articles

Immobilisation of L-proline onto mixed-linker zirconium MOFs for heterogeneous catalysis of the aldol reaction

Novel heterogeneous catalysts based on zirconium sulfonated metal-organic framework (MOF)-supported L-proline has been developed for the asymmetric aldol reaction. In this study, a chiral zirconium-based sulfonated MOF-proline was assembled through the solvothermal reaction of ZrCl4 with a combination of benzene-1,4-dicarboxylic acid (H2bdc) and sodium 4-carboxy-2-sulfobenzoate (H2bdc-SO3Na) in the presence of L-proline. The MOF showed excellent crystallinity, high porosity and thermal stability, making it an attractive catalyst for the aldol reaction since the bifunctionality can be enhanced to act both as Brønsted acid and Lewis base active sites. The reaction between acetone and two different aldehydes was investigated and the catalyst showed good activity and enantioselectivity, especially in the reaction with 4-nitrobenzaldehyde (83 % enantiomeric excess and 85 % conversion). The reusability of the catalyst was evaluated by organic solvent nanofiltration membranes. After three successive aldol reactions, the enantiomeric excess and conversion reaction of the catalyst showed only slight decreases, confirming good recyclability. Moreover, scale-up of the organic solvent nanofiltration membrane operation is relatively simple, promoting ease of operation on an industrial scale.

Development of fructose-1,6-bisphosphate aldolase enzyme peptide mimics as biocatalysts in direct asymmetric aldol reactions.

This study describes the design and synthesis of mimetic peptides modelled on the catalytic active site of the fructose-1,6-bisphosphate aldolase (FBPA) enzyme. The synthesized peptides consisting of the turn motifs and catalytic site amino acids of FBPA enzyme were evaluated for catalytic activity in direct asymmetric aldol reactions of ketones and aldehydes. The influence of substrate scope, catalyst loading and solvents including water, on the reaction were also investigated. Nuclear magnetic resonance (NMR) and circular dichroism (CD) were used to determine the secondary structure of the peptides to provide an understanding of the structure–activity relationship. The peptides showed catalytic activity and the aldol products were obtained in low yields (up to 44%), but excellent enantioselectivity (up to 93%) and moderate diastereoselectivity (65 : 35).

A Fluorous Proline Catalyst Immobilized on Teflon® for Highly Stereoselective Asymmetric Aldol Reactions

A Fluorous Proline Catalyst Immobilized on Teflon® for Highly Stereoselective Asymmetric Aldol Reactions

New small γ-turn type N-primary amino terminal tripeptide organocatalyst for solvent-free asymmetric aldol reaction of various ketones with aldehydes.

New small γ-turn type N-primary amino terminal tripeptides were synthesized and their functionality as an organocatalyst was examined in the asymmetric aldol reaction of various ketones with different aromatic aldehydes under solvent-free neat conditions to afford the desired chiral anti-aldol products in good to excellent chemical yields, diastereoselectivities and enantioselectivities (up to 99%, up to syn : anti/13 : 87 dr, up to 99% ee).

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.

Tripeptide-Catalyzed Direct Asymmetric Aldol Reaction of Activated Ketones

Tripeptide-Catalyzed Direct Asymmetric Aldol Reaction of Activated Ketones

Carbene‐Catalyzed Enantioselective Aldol Reaction: Post‐Aldol Stereochemistry Control and Formation of Quaternary Stereogenic Centers

AbstractThe dominated approaches for asymmetric aldol reactions have primarily focused on the aldol carbon–carbon bond‐forming events. Here we postulate and develop a new catalytic strategy that seeks to modulate the reaction thermodynamics and control the product enantioselectivities via post‐aldol processes. Specifically, an NHC catalyst is used to activate a masked enolate substrate (vinyl carbonate) to promote the aldol reaction in a non‐enantioselective manner. This reversible aldol event is subsequently followed by an enantioselective acylative kinetic resolution that is mediated by the same (chiral) NHC catalyst without introducing any additional substance. This post‐aldol process takes care of the enantioselectivity issues and drives the otherwise reversible aldol reaction toward a complete conversion. The acylated aldol products bearing quaternary/tetrasubstituted carbon stereogenic centers are formed in good yields and high optical purities.

Carbene-Catalyzed Enantioselective Aldol Reaction: Post-Aldol Stereochemistry Control and Formation of Quaternary Stereogenic Centers.

The dominated approaches for asymmetric aldol reactions have primarily focused on the aldol carbon-carbon bond-forming events. Here we postulate and develop a new catalytic strategy that seeks to modulate the reaction thermodynamics and control the product enantioselectivities via post-aldol processes. Specifically, an NHC catalyst is used to activate a masked enolate substrate (vinyl carbonate) to promote the aldol reaction in a non-enantioselective manner. This reversible aldol event is subsequently followed by an enantioselective acylative kinetic resolution that is mediated by the same (chiral) NHC catalyst without introducing any additional substance. This post-aldol process takes care of the enantioselectivity issues and drives the otherwise reversible aldol reaction toward a complete conversion. The acylated aldol products bearing quaternary/tetrasubstituted carbon stereogenic centers are formed in good yields and high optical purities.

L-proline/cholesterol and diosgenin based thiourea cooperative system for the direct asymmetric aldol reaction in the presence of water.

A series of cholesterol and based hydrophobic urea and thiourea compounds were synthesized and successfully used as a cocatalyst for L-proline catalyzed aldol reactions in the presence of water. The anticonfigured products were obtained with good yields (up to 94%), high diastereoselectivities (up to 95:5), and high enantiomeric excesses (up to 93% ee ). The successful results for catalytic efficiency of L-proline in the presence of water reveal the importance of the hydrophobic nature of cholesterol and diosgenin parts of thiourea on the reactivity and selectivity in the presence of water.

Synthesis of Chiral MOF-74 Frameworks by Post-Synthetic Modification by Using an Amino Acid.

The synthesis of chiral metal–organic frameworks (MOFs) is highly relevant for asymmetric heterogenous catalysis, yet very challenging. Chiral MOFs with MOF‐74 topology were synthesised by using post‐synthetic modification with proline. Vibrational circular dichroism studies demonstrate that proline is the source of chirality. The solvents used in the synthesis play a key role in tuning the loading of proline and its interaction with the MOF‐74 framework. In N,N′‐dimethylformamide, proline coordinates monodentate to the Zn2+ ions within the MOF‐74 framework, whereas it is only weakly bound to the framework when using methanol as solvent. Introducing chirality within the MOF‐74 framework also leads to the formation of defects, with both the organic linker and metal ions missing from the framework. The formation of defects combined with the coordination of DMF and proline within the framework leads to a pore blocking effect. This is confirmed by adsorption studies and testing of the chiral MOFs in the asymmetric aldol reaction between acetone and para‐nitrobenzaldehyde.

New Mesoporous Silica-Supported Organocatalysts Based on (2S)-(1,2,4-Triazol-3-yl)-Proline: Efficient, Reusable, and Heterogeneous Catalysts for the Asymmetric Aldol Reaction.

Novel organocatalytic systems based on the recently developed (S)-proline derivative (2S)-[5-(benzylthio)-4-phenyl-(1,2,4-triazol)-3-yl]-pyrrolidine supported on mesoporous silica were prepared and their efficiency was assessed in the asymmetric aldol reaction. These materials were fully characterized by FT-IR, MS, XRD, and SEM microscopy, gathering relevant information regarding composition, morphology, and organocatalyst distribution in the doped silica. Careful optimization of the reaction conditions required for their application as catalysts in asymmetric aldol reactions between ketones and aldehydes afforded the anticipated aldol products with excellent yields and moderate diastereo- and enantioselectivities. The recommended experimental protocol is simple, fast, and efficient providing the enantioenriched aldol product, usually without the need of a special work-up or purification protocol. This approach constitutes a remarkable improvement in the field of heterogeneous (S)-proline-based organocatalysis; in particular, the solid-phase silica-bonded catalytic systems described herein allow for a substantial reduction in solvent usage. Furthermore, the supported system described here can be recovered, reactivated, and reused several times with limited loss in catalytic efficiency relative to freshly synthesized organocatalysts.

Synthesis of Extended Bipyridine‐proline Chiral Catalysts and Resulting Effects on the Asymmetric Aldol Reactions of Bulkier Aldehyde Derivatives with Cyclohexanone

AbstractAxially‐unfixed 2,2′‐bipyridine‐based chiral catalysts were synthesized using enantiopure amino acids as chiral sources, which were successfully used in asymmetric aldol reactions of p‐nitrobenzaldehyde with cyclohexanone, while the bulkier aldehyde derivatives (2‐naphthaldehyde, 9‐anthracenecarboxaldehyde, and 1‐pyrenecarboxaldehyde) were selected to further elucidate the catalytic properties. Particularly, the influences of the bipyridine‐proline chiral structures and the polarities of used solvents (petroleum ether, toluene, CH2Cl2, ethanol, DMF, DMSO, and water) on the catalytic performance were investigated. The results indicated that the structure of bipyridine catalysts, the molecular volume of aldehydes, and the polarity of solvents have significant effects on the catalytic activities, in which, the smaller steric effects were conducive to the improvement of the yields and stereoselectivities for asymmetric aldol reaction, along with the increased polarity of used solvents and the decreased molecular volume of aldehydes. Meanwhile, the chemical identity of all compounds was confirmed by 1H‐NMR, 13C‐NMR, HRMS, and HPLC analysis.

Recyclable Helical Poly(phenyl isocyanide)-Supported l-Proline Catalyst for Direct Asymmetric Aldol Reaction in Brine

A novel helical poly(phenyl isocyanide) bearing Boc protected l-proline pendants (poly-1m) was designed and synthesized. Removed the protecting Boc groups on the l-proline pendants led to the formation of helical polymer poly-2m, which showed high optical activity owing to the preferred right-handed helix of polyisocyanide main chain. Optically active helical poly-2m showed excellent catalytic ability on asymmetric aldol reaction. Helical polymer catalysts exhibited enhanced stereoselectivity in aldol reaction compared to small molecule l-proline. Under the optimized aldol reaction condition, the enantiomeric excess (ee) and diastereomeric ratio (dr) values of the aldol reaction product were respectively up to 90% and > 20/1. Moreover, the helical polyisocyanide catalyst Poly-2m can be easily recovered and reused in the aldol reaction for at least five cycles with maintained its activity and stereoselectivity. Enantioselective aldol reaction catalyzed by poly-2m.

Syntheses and Applications of Singh’s Catalyst

Singh’s catalyst has emerged as one of the most promising and valuable catalysts in the field of asymmetric synthesis. Since its discovery, it has proven to be one of the best organocatalysts for asymmetric direct aldol reactions, and is equally efficient in aqueous and organic media. In this Short Review, we summarize reactions utilizing Singh’s catalyst under various conditions.1 Introduction2 Synthesis of Singh’s Catalyst3 Applications in Asymmetric Synthesis4 Conclusion

Organocatalytic asymmetric aldol reaction using protonated chiral 1,2-diamines

Organic-catalyzed stereoselective reactions have gained attention because they avoid the problems associated with metal catalysts, but existing catalysts based on proline have limitations. Therefore, (R,R)-(+)-1,2-diphenylethylenediamine (DPEN) was selectively mono-N-alkylated through reductive alkylation and used as an organic catalyst for the aldol reaction. Using a variety of aldehydes in the catalytic aldol reaction, the N-alkylated DPEN catalyst proceeded from primary amine to enamine and iminium intermediates and achieved both a high yield (80%) and enantioselectivity (90%). It was found that the steric hindrance of the N-alkyl substituent of the chiral diamine and the hydrogen bond between the ammonium moiety and the oxygen of the aromatic aldehyde determine the enantioselectivity. Various aromatic aldehydes were tested, and electron-withdrawing substituents led to good yields, whereas electron-donating substituents led to poor yields via the deactivation of the carbonyl group of the aldehyde. Further, ortho substituents resulted in higher stereoselectivities than para substituents because the stereoscopic effect was enhanced.

Asymmetric Aldol Reaction of Pyruvate Promoted by Chiral Tertiary Amines

AbstractThe direct asymmetric aldol reaction of α‐ketoesters catalyzed by chiral tertiary amines is reported. The described methodology is characterized by mild reaction conditions and distinct product selectivity determined by the starting materials. In the developed transformation pyruvates undergo highly selective self‐condensation reaction, whereas cross‐aldol reaction take place predominantly for their carbon chain homologues in presence of aldehyde acceptors. Notably, addition of bulky phenol moiety into pyruvate inhibit the spontaneous lactonization of products and enhance the enantioselectivity.

Enantioselective Total Synthesis of Chondrosterins I and J by Catalytic Asymmetric Intramolecular Aldol Reaction Using Chiral Diamine Catalyst

The first enantioselective total synthesis of chondrosterins I and J was accomplished. The synthetic method focuses on an intramolecular aldol reaction through catalytic asymmetric desymmetrization using chiral diamine catalyst. An intensive investigation of this reaction improved the enantiomeric excess up to 92 % ee. In addition, stereoselective reduction of the ketone moiety efficiently converted chondrosterin I to chondrosterin J.

A Simple and Efficient Protocol for Proline-Catalysed Asymmetric Aldol Reaction

The proline-catalysed asymmetric aldol reaction is usually carried out in highly dipolar aprotic solvents (dimethylsulfoxide, dimethylformamide, acetonitrile) where proline presents an acceptable solubility. Protic solvents are generally characterized by poor stereocontrol (e.g., methanol) or poor reactivity (e.g., water). Here, we report that water/methanol mixtures are exceptionally simple and effective reaction media for the intermolecular organocatalytic aldol reaction using the simple proline as the catalyst.

Enantiodivergent Aldol Condensation in the Presence of Aziridine/Acid/Water Systems

A series of novel chiral imines was synthesized from corresponding aldehydes and 1-(2-aminoalkyl)aziridines with good chemical yields. Such imines were tested as catalysts in the direct asymmetric aldol reaction between aromatic aldehydes and acetone/cyclohexanone in the presence of catalytic amounts of water and an acidic additive. The corresponding aldol products were formed in excellent yields and with very high enantioselectivities (98% and 99% ee, respectively).

Peptide-Catalyzed Highly Asymmetric Cross-Aldol Reaction of Aldehydes to Biomimetically Synthesize 1,4-Dicarbonyls.

β-Turn tetrapeptides were demonstrated to catalyze asymmetric aldol reaction of α-branched aldehydes and α-carbonyl aldehydes, i.e. glyoxylates and α-ketoaldehydes, to biomimetically synthesize acyclic all-carbon quaternary center-bearing 1,4-dicarbonyls in high yield and excellent enantioselectivity under mild conditions. The spatially restricted environment of the tetrapeptide warrants high enantioselectivity and yield with broad substrates. Using this protocol, (R)-pantolactone, the key intermediate of vitamin B5, was readily accessed in a practical, efficient, and environmentally benign process from inexpensive starting materials.