Direct Asymmetric Aldol Reaction Research Articles

Cavity Catalysis of an Enantioselective Reaction under Vibrational Strong Coupling.

Strong light-matter interaction is emerging as an exciting tool for controlling chemical reactions. Here, we demonstrate an L-proline-catalyzed direct asymmetric Aldol reaction under vibrational strong coupling. Both the reactants (4-nitrobenzaldehyde and acetone) carbonyl bands are coupled to an infrared photon and react in the presence of L-proline. The reaction mixture is eluted from the cavity, and the conversion yields and enantiomeric excess are quantified using NMR and chiral HPLC. The conversion yields increase by up to 90 % in ON-resonance conditions. Interestingly, a large increase in the conversion yield does not affect the enantiomeric excess. Further control experiments were carried out by varying the temperature, and we propose that the rate-limiting step may not be the deciding factor in enantioselectivity. Whereas the formation of the enamine intermediate is modified by cavity coupling experiments. For this class of enantioselective reactions, strong coupling does not change the enantiomeric excess, possibly due to the large energy difference in chiral transition states. Strong coupling can boost the formation of enamine intermediate, thereby favouring the product yield. This gives more hope to test polaritonic chemistry based on enantioselective reactions in which the branching ratios can be controlled.

Polyacrylic Acid Supported L-proline as an Effective Heterogeneous Catalyst for the Direct Asymmetric Aldol Reaction.

L-proline is an efficient chiral small-molecule organocatalyst for the direct asymmetric aldol reaction between unmodified acetone and a variety of aldehydes. However, it is difficult to separate from the reaction medium for reuse. In this work, polyacrylic acid (PAA) supported The acylation reaction between L-hydroxyproline and PAA prepared l-proline (P(AA-co-PA)) catalysts with various catalyst loadings. Fourier characterized them transforms infrared spectroscopy, nuclear magnetic resonance spectrum, gel permeation chromatography and thermogravimetry analysis. These macromolecular catalysts were used to catalyze acetone and benzaldehydes' direct asymmetric aldol reaction. The influence of the catalyst structure on the catalytic performance was studied, and the reaction conditions were optimized. The results showed that P(AA-co-PA) with 50 mol% catalyst loading had excellent catalytic performance, much higher than that of L-proline and L-hydroxyproline. Its recovery was achieved by simple filtration. After being reused 7 times, its catalytic performance was still higher than that of L-proline.

Synthesis of D-Fructose-Based Bifunctional Primary Amine-Thiourea Organocatalysts and Their Applications in Asymmetric Reactions

The preparation of a new class of six bifunctional thiourea organocatalysts having a D-fructose scaffold and a primary amino group was demonstrated. In the present study, the novel organocatalysts exhibited excellent enantio- and moderate diastereoselectivities in the asymmetric Michael addition of aliphatic ketones and 1,3-diketone to substituted nitroolefins at room temperature. In addition, the direct asymmetric aldol reaction between cyclic aliphatic ketone and aromatic aldehydes was also studied in the presence of the saccharide-thiourea organocatalysts giving excellent yield with moderate enantioselectivity.

Synthesis and Evaluation of N-Diaminophosphoryl Aminothioureas as Bifunctional Catalysts for Vinylogous Aldol Reactions of Isatins and 2(3H)-Furanones.

The organocatalytic asymmetric direct vinylogous aldol reaction of N-methylisatins 1 and γ-butenolides 2 to provide 3-hydroxy-2-oxindole derivatives 3 was investigated. A series of N-diaminophosphoryl aminothiourea catalysts 4 was synthesized, and their utility for the stereoselective formation of 3 was examined.

Effect of Calix[4]arene as a Hydrophobic Substituent on Proline Catalysis of Direct Asymmetric Aldol Reactions in the Presence of Water

Effect of Calix[4]arene as a Hydrophobic Substituent on Proline Catalysis of Direct Asymmetric Aldol Reactions in the Presence of Water

Design of Bifunctional Amino Tf-Amide Organocatalysts and Application in Various Asymmetric Transformations.

In this personal account, we describe our recent developments on the four types of amino Tf-amide catalysts in asymmetric transformations. Firstly, axially chiral biaryl-based secondary-amino Tf-amide catalyzed various stereoselective reactions via enamine intermediates. Secondly, pyrrolidine-based secondary-amino aliphatic Tf-amide catalyzed asymmetric direct Mannich reaction. Thirdly, chiral primary-amino aliphatic Tf-amide catalyzed asymmetric direct aldol reaction and conjugate addition. Finally, modified chiral amino aromatic Tf-amide catalyzed asymmetric transformations. These four different strategies are illustrated by using various organocatalyzed asymmetric transformations.

Development of Green Asymmetric Organocatalytic Synthesis

Organocatalysts, which are less toxic than metal catalysis, as well as inexpensive, environmentally benign, and stable against moisture and oxygen compared to metal-based catalysts, have received considerable attention for being efficient and clean catalysts. With respect to green chemistry, the development of organocatalysis is a significant research subject for a sustainable society. This article reviews studies on the development of novel organocatalysts and the reactions achieved from using them. Focusing on the push-pull ethylene moiety, in which two electron-withdrawing groups (EWGs) were introduced, we proposed that the vinylogous amide proton (N-H) will lead to the design of organocatalysts. We have developed the diaminomethylenemalononitrile (DMM) organocatalysts, which are push-pull ethylenes having two cyano groups as EWGs, and proved that they are effective for highly stereoselective hydrophosphonylation with aldehydes. The catalytic ability of the DMM organocatalyst was demonstrated in the development of the first asymmetric hydrophosphonylation of ketones using organocatalysts. The DMM organocatalyst can be applied to the selective 1,4-addition asymmetric hydrophosphonylation of enones. In addition, we designed and synthesized novel organocatalysts bearing squaramide-sulfonamide motif as multiple hydrogen bond donors. Squaramide-sulfonamide organocatalysts efficiently catalyzed the asymmetric direct vinylogous aldol reactions of furan-2(5H)-one with aldehydes. Successively, we achieved the synthesis of γ,γ-disubstituted-δ-hydroxy-γ-butenolide via asymmetric direct vinylogous aldol reaction of furanone derivatives using the squaramide-sulfonamide organocatalysts.

Isothiouronium salt based chiral proline amide as efficient bifunctional organocatalyst for direct asymmetric aldol reactions in aqueous medium

We developed the first chiral proline amide-isothiouronium based bifunctional organocatalyst, it was prepared by methylation of the corresponding thiourea. This asymmetric catalyst provides aldol products in high to quantitative yields while achieving excellent control performance of diastereoselectivities (anti/syn, up to 95:5 dr) and enantioselectivity (up to 99% ee) in the aldol reaction of various benzaldehydes with a cyclohexanone in water and formic acid.

Efficient Asymmetric Biomimetic Aldol Reaction of Glycinates and Trifluoromethyl Ketones by Carbonyl Catalysis

AbstractThe direct asymmetric aldol reaction of glycinates represents an intriguing and straightforward strategy to make biologically significant chiral β‐hydroxy‐α‐amino‐acid derivatives. But it is not easy to realize the transformation due to the disruption of the reactive NH2 group of glycinates. Inspired by the enzymatic aldol reaction of glycine, we successfully developed an asymmetric aldol reaction of glycinate 5 and trifluoromethyl ketones 4 with 0.1–0.0033 mol % of chiral N‐methyl pyridoxal 7 a as the catalyst, producing chiral β‐trifluoromethyl‐β‐hydroxy‐α‐amino‐acid esters 6 in 55–82 % yields (for the syn‐diastereomers) with up to >20:1 dr and 99 % ee under very mild conditions. The reaction proceeds via a catalytic cycle similar to the enzymatic aldol reaction of glycine. Pyridoxal catalyst 7 a activates both reactants at the same time and brings them together in a specific spatial orientation, accounting for the high efficiency as well as excellent diastereo‐ and enantioselectivities.

Efficient Asymmetric Biomimetic Aldol Reaction of Glycinates and Trifluoromethyl Ketones by Carbonyl Catalysis.

The direct asymmetric aldol reaction of glycinates represents an intriguing and straightforward strategy to make biologically significant chiral β-hydroxy-α-amino-acid derivatives. But it is not easy to realize the transformation due to the disruption of the reactive NH2 group of glycinates. Inspired by the enzymatic aldol reaction of glycine, we successfully developed an asymmetric aldol reaction of glycinate 5 and trifluoromethyl ketones 4 with 0.1-0.0033 mol % of chiral N-methyl pyridoxal 7 a as the catalyst, producing chiral β-trifluoromethyl-β-hydroxy-α-amino-acid esters 6 in 55-82 % yields (for the syn-diastereomers) with up to >20:1 dr and 99 % ee under very mild conditions. The reaction proceeds via a catalytic cycle similar to the enzymatic aldol reaction of glycine. Pyridoxal catalyst 7 a activates both reactants at the same time and brings them together in a specific spatial orientation, accounting for the high efficiency as well as excellent diastereo- and enantioselectivities.

Chiral Imidazolium Prolinate Salts as Efficient Synzymatic Organocatalysts for the Asymmetric Aldol Reaction.

Chiral imidazolium l-prolinate salts, providing a complex network of supramolecular interaction in a chiral environment, have been studied as synzymatic catalytic systems. They are demonstrated to be green and efficient chiral organocatalysts for direct asymmetric aldol reactions at room temperature. The corresponding aldol products were obtained with moderate to good enantioselectivities. The influence of the presence of chirality in both the imidazolium cation and the prolinate anion on the transfer of chirality from the organocatalyst to the aldol product has been studied. Moreover, interesting match/mismatch situations have been observed regarding configuration of chirality of the two components through the analysis of results for organocatalysts derived from both enantiomers of prolinate (R/S) and the trans/cis isomers for the chiral fragment of the cation. This is associated with differences in the corresponding reaction rates but also to the different tendencies for the formation of aggregates, as evidenced by nonlinear effects studies (NLE). Excellent activities, selectivities, and enantioselectivities could be achieved by an appropriate selection of the structural elements at the cation and anion.

Catalytic Sc(OTf)3 mediated direct asymmetric aldol reaction of (−)‐menthyl isothiocyanatoacetate with aldehydes by using (−)‐menthol as chiral auxiliary

AbstractThis method involves the direct asymmetric aldol reaction of (−)‐menthyl isothiocyanatoacetate 5 with a variety of substituted aromatic aldehydes, which offers a convenient method for the synthesis of intermediate containing biologically relevant α‐amino β‐hydroxyl groups in oxazolidine ring. In this methodology, the products show remarkable diastereoselectivity using Sc(OTf)3 as a catalyst and easily accessible (−)‐menthol as a chiral auxiliary. This approach includes some important aspects such as mild reaction conditions, high yields, and excellent diastereoselectivity with a number of substituted aromatic aldehydes. The optimization and effect of different catalysts were studied at different reaction conditions and it is found that Sc(OTf)3 shows excellent diastereoselectivity at −45°C.

Proline-Histidine Dipeptide: A Suitable Template for Generating Ion-Tagged Organocatalysts for the Asymmetric Aldol Reaction

AbstractProline-histidine dipeptide laid the foundation for the construction of three new ion-tagged organocatalysts, utilising the imidazole moiety of histidine for generating the quaternary species. A brief comparative investigation of the catalysts in the enamine-mediated direct asymmetric aldol reaction brought out their contrasting features, particularly under aqueous conditions. The best among them was also utilised in preparing some derivatives and effecting a desymmetrisation.

Direct Asymmetric Aldol Reaction in Continuous Flow Using Gel‐Bound Organocatalysts

AbstractContinuous flow catalysis using a microfluidic reactor with gel‐bound proline organocatalysts is an attractive approach in organic synthesis due to interesting advantages such as the permanent production of catalyst‐free products and the easy product isolation by evaporation. Further advantages are the online detection of reactions and an adjustment of reaction parameters while the reaction is already running. Herein the formation of differently substituted aldol products within minutes at mild conditions in good to almost quantitative yields is described. The effects of different solvent mixtures and temperatures on the conversion and selectivity are analyzed in detail by NMR as well as the relationship between the height of the polymer structures and the conversion behavior of the asymmetric aldol reaction of 4‐nitrobenzaldehyde and cyclohexanone. The applicability of this system is demonstrated for a wide range of differently substituted nitrobenzaldehydes. It is shown that the described reactor setup delivers high conversion and good selectivity over up to 144 hours and that a highly reusable system was established.

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).

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

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.

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