Asymmetric Aldol Reaction Research Articles

Complementary double-stranded helical oligomers bearing achiral bifunctional groups that catalyze asymmetric aldol reaction.

Two novel chiral dimer and trimer strands composed of m-terphenyl groups linked through p-diethynylbenzene units with the chiral amidine group and achiral piperazine group introduced at the terminus or center of the strands, respectively, and its complementary achiral carboxylic acid dimer and trimer were synthesized. The complementary chiral/achiral strands form an excess-handed double-helical structure as supported by intense split-type Cotton effects in the absorption regions of the conjugated backbones biased by the chiral amidinium-carboxylate salt bridges. The double-helical trimer was found to catalyze the direct aldol reaction of cyclohexanone with 4-nitrobenzaldehyde and produce the products with a moderate enantioselectivity despite the fact that the catalytically active bifunctional piperazine/carboxylic acid pair introduced in the middle is achiral, indicating the key role of the one-handed double-helical framework for supramolecular bifunctional organocatalysis.

Construction of Chiral 2,3-Allenols through Copper(I)-Catalyzed Asymmetric Direct Alkynylogous Aldol Reaction

Construction of Chiral 2,3-Allenols through Copper(I)-Catalyzed Asymmetric Direct Alkynylogous Aldol Reaction

Alternative Chiral Preparations of a Swaminathan Ketone via Asymmetric Aldol Reactions Mediated by Chiral Amines Bearing a Pyrrolidine

Alternative Chiral Preparations of a Swaminathan Ketone via Asymmetric Aldol Reactions Mediated by Chiral Amines Bearing a Pyrrolidine

Z-Enolate Geometry in the Thioamide Aldol Reaction Illuminated by the 7-Azaindoline Auxiliary.

Z or E enolate geometry is the primary determinant of diastereoselectivity in the aldol reaction. Although amide and thioamide enolates are anticipated to have predominantly the E geometry because of the intrinsic steric demand, spectroscopic confirmation of the geometry in solution has remained elusive, particularly in the realm of highly stereoselective catalytic asymmetric aldol reactions. Herein we demonstrate that the 7-azaindoline auxiliary enables direct observation of the exclusive formation of the Z-enolate of the thioamide en route to a highly syn-selective aldol reaction.

Construction of Chiral 2,3-Allenols through a Copper(I)-Catalyzed Asymmetric Direct Alkynylogous Aldol Reaction.

Chiral 2,3-allenols were constructed through copper(I)-catalyzed asymmetric direct alkynylogous aldol reaction. With aromatic and heteroaromatic aldehydes, the alkynylogous aldol reaction with (R)-DTBM-SEGPHOS as the ligand proceeded smoothly to furnish the products in excellent regioselectivity with good to high diastereoselectivity and excellent enantioselectivity. In the cases of aliphatic aldehydes, esters of but-2-yn-1-ol as the substrates and (R,R)-Ph-BPE as the ligand were found to be crucial to get good to high regio- and diastereoselectivity. The produced chiral 2,3-allenols are easily transformed into synthetically useful 2-furanones through cyclization. Finally, the developed method was successfully applied in the rapid synthesis of two chiral intermediates toward the synthesis of two pharmaceutically active compounds that have been proposed for the treatment of neurological disorders.

Asymmetric Direct Aldol Reaction in Confined Space: Molecular Conformations of Organocatalyst Affect Chiral Induction

AbstractWe have demonstrated that chiral induction in the aldol product is possible by generating an enzyme‐like cavity in molecular framework of the amphiphlic catalyst. The esters of trans‐4‐hydroxy‐L‐proline and long chain fatty acids have been synthesized by O‐acylation. Synthesized molecules were used as organocatalysts for asymmetric direct aldol reaction between 4‐nitrobenzaldehyde and cyclohexanone. The molecular framework of the catalyst not only induces the amphiphilicity but also acquires specific conformation leads to formation of catalytic cavity facilitating stereo‐induction in the aldol product. Systematic addition of olefinic bonds in the long hydrocarbon chain makes this cavity more robust stabilizing transition state of the aldol product. By proper tuning of the water content and % loading of the catalyst in aldol reaction, o/w or w/o type emulsion is formed due to aggregation of catalyst molecules. Performance based evaluation of catalytic activity suggests that aldol reaction proceeds with ∼ 99% yield, 84% dr and 97.94% ee in presence of 10% catalyst (having three π bonds), in an o/w emulsion (85 equiv. of water) within 12 h. The stereoselectivity of the catalyst is almost maintained up to 2.5% loading. The high stereoselectivity of the aldol reaction is maintained even on increasing the amount of water to 300 equiv. A plausible reason has been proposed for retaining the high stereoselectivity and corroborated by computational analysis.

Design and preparation of a novel prolinamide-based organocatalyst for the solvent-free asymmetric aldol reaction

The preparation of four novel organocatalysts as highly diastereo and enantioselective catalysts for the solvent-free asymmetric aldol reaction was described. These organocatalysts were synthesized in eight steps applying simple and commercially available starting materials. The best results were obtained for the proline-derived catalyst, providing access to the desired adducts in up to 95% yield, 1:19 syn/anti and 98% e.e. Moreover, even sterically bulky aldehydes and substituted cyclohexanones were well tolerated. DFT calculations and control experiments indicated that several hydrogen bonding interactions between the aldehyde and the enamine intermediate are responsible for the stereoselective chiral induction process and that the trifluoroacetate counter-anion is crucial for the attainment of higher stereoselectivities.

Construction of Chiral 2,3‐Allenols through a Copper(I)‐Catalyzed Asymmetric Direct Alkynylogous Aldol Reaction

AbstractChiral 2,3‐allenols were constructed through copper(I)‐catalyzed asymmetric direct alkynylogous aldol reaction. With aromatic and heteroaromatic aldehydes, the alkynylogous aldol reaction with (R)‐DTBM‐SEGPHOS as the ligand proceeded smoothly to furnish the products in excellent regioselectivity with good to high diastereoselectivity and excellent enantioselectivity. In the cases of aliphatic aldehydes, esters of but‐2‐yn‐1‐ol as the substrates and (R,R)‐Ph‐BPE as the ligand were found to be crucial to get good to high regio‐ and diastereoselectivity. The produced chiral 2,3‐allenols are easily transformed into synthetically useful 2‐furanones through cyclization. Finally, the developed method was successfully applied in the rapid synthesis of two chiral intermediates toward the synthesis of two pharmaceutically active compounds that have been proposed for the treatment of neurological disorders.

Screening of functional solvent system for automatic aldehyde and ketone separation in aldol reaction: A combined COSMO-RS and experimental approach

An integrated reaction-separation process based on only solvents is presented, and thus without the need for related technical equipment (reactor-separator). Both product purification and reactant recovery are achieved automatically for an asymmetric aldol reaction employing a biphasic solvent system as compartmentalizing soft matter. Firstly, COSMO-RS based simulation is introduced as a theoretical guidance in the solvent selection for the reactant 3-chlorobenzaldehyde and non-solvent selection for the R-aldol product, (R)-4-(3-chlorophenyl)-4-hydroxybutan-2-one. This encompasses solubility as core critical parameter, as well as chemo-physical properties and environmental profiling. Such criteria-cascaded screening could effectively reduce a 7665 solvents-database into 1 candidate solvent, which is dodecane, before experimental process assessment. Secondly, this screening’s top candidate was validated as the best reaction solvent by first a solubility test and then by a batch reaction, in which a conversion of 69% was achieved. As desired, the mono-phase reaction yielded spontaneously the product layer and the separate dodecane phase as the second layer, which indeed allowed facile separation of the product from the residual reactant. In a third step, a segmented flow process was developed giving a highest product yield of 63% and a total conversion 92% respectively after a 2 h residence time.

Synthesis and asymmetric catalytic performance of one-handed helical poly(phenylacetylene)s bearing proline dipeptide pendants

One-handed helical substituted polyacetylene has received extensive attention due to its potential in chiral stationary phases and molecular recognition. Here, three one-handed helical poly(phenylacetylene)s bearing proline or proline dipeptide as the pendants (PPA-Pro, PPA-Pro-Pro and PPA-Pro-Hyp) were synthesized. As the catalyst, the three helical polymers separately catalyzed the asymmetric aldol reaction of acetone with p-nitrobenzaldehyde in a various media. The results indicate that PPA-Pro-Pro and PPA-Pro-Hyp bearing dipeptide pendants showed the higher catalytic activity and enantioselectivity than the PPA-Pro bearing proline pendants and the corresponding monomer catalysts. This indicates the synergistic effect of the dipeptide pendants with the one-handed helical mainchain of the polymer catalyst. The polymer catalysts can be recycled and maintain the catalytic performance after four circles. When imidazole was added to the reaction system, the reaction yield could be efficiently improved without affecting the enantioselectivity.

Graphene-based recyclable and bifunctional heterogeneous chiral catalyst for direct asymmetric aldol reaction

Application of metal-free heterogeneous asymmetric catalysis is of great interest in the field of asymmetric synthesis. Herein, two novel graphene-supported proline-based bifunctional carbocatalysts were prepared by post-grafting l-proline onto graphene oxide sheets via organoamine-functionalized graphene oxide (GO-NH2) and reduced graphene oxide (rGO-NH2). Different methods such as Fourier-transform infrared spectroscopy (FT-IR), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) and transmission electron spectroscopy (TEM) were employed to examine the surface functionalization of GO. The catalytic properties of these materials were investigated in the direct asymmetric aldol reaction. l-proline grafted heterogeneous catalyst, GO-Pro, was found to be an efficient and powerful organocatalyst for the enantioselective aldol reaction under mild conditions in hexane and afforded the corresponding aldol adducts with satisfactory isolated yields (up to 88%) and enantiomeric excesses (up to 85%). Furthermore, graphene-based carbocatalyst could be recovered and recycled easily by a simple washing procedure and re-used for several times without substantial reduction in its catalytic activity.

Direct anti Glycolate Aldol Reaction of Protected Chiral N‐Hydroxyacetyl Thiazolidinethiones with Acetals Catalyzed by a Nickel(II) Complex

The direct and stereocontrolled addition of (S)‐4‐isopropyl‐N‐(2‐pivaloyloxyacetyl)‐1,3‐thiazolidine‐2‐thione to dialkyl acetals of aromatic and α,β‐unsaturated aldehydes catalyzed by 2.5–5 mol‐% of a nickel(II) complex permits the synthesis of diastereomerically pure and fully protected anti aldol adducts in good to high yields. The catalytic species is formed in situ from commercially available and easy to handle (Me3P)2NiCl2, which makes this reaction a direct, catalytic, and experimentally simple approach to the asymmetric anti glycolate aldol reaction.

Reusable shuttles for exchangeable functional cargos: Reversibly assembled, magnetically powered organocatalysts for asymmetric aldol reactions

A supramolecular approach has been followed to support adamantyl substituted proline organocatalysts onto the surface of magnetite nanoparticles decorated with a β-cyclodextrin motif. The resulting magnetic nanoparticles (ca. ∼10 nm diameter) were used as modular, magnetically recyclable catalysts in the asymmetric aldol reaction of aromatic aldehydes with cyclic ketones in water. The catalytic assemblies can be easily dismantled in organic media, and the recovered nanoparticles (magnetically powered chemical shuttles) re-complexed with another suitably substituted catalytic unit (replaceable functional cargo).

Synthesis of a new chiral organocatalyst derived from (S)-proline containing a 1,2,4-triazolyl moiety and its application in the asymmetric aldol reaction. Importance of one molecule of water generated in situ

A simple and efficient preparation of a novel chiral derivative of (S)-proline containing a 1,2,4-triazolyl moiety is described. The high-yielding synthetic protocol includes the use of microwave irradiation to afford new chiral pyrrolidine derivatives in high yield. Our triazolyl-containing heterocycle was evaluated as organocatalyst (10 mol% load, under neat reaction conditions) in the enantioselective aldol reaction between four different types of ketones and a variety of aryl aldehydes. Good results in terms of enantioselectivity and chemical yield were observed under solvent-free reaction conditions and in the absence of any additive. Evidence is provided for the involvement of the water molecule generated upon enamine formation in the transition state of the aldol reaction.

Recyclable Mesoporous Organosilica Nanoparticles Derived from Proline-Valinol Amides for Asymmetric Organocatalysis

Going a step further from bulk organosilicas to nanosized materials, we describe herein the preparation of mesoporous organosilica nanoparticles derived from mono- and bis-silylated proline-valinol amides, both by grafting on preformed mesoporous silica nanoparticles (MSN) and by a co-condensation method in neutral medium using Brij-56/CTAB as templates. This is the first report on the obtention of functionalized MSN by a co-condensation procedure with a structurally complex chiral precursor. The functionalized MSN have been characterized by elemental analysis, 29Si and 13C CP MAS NMR, transmission electron microscopy, scanning electron microscopy, N2-sorption measurements, dynamic light scattering, ζ-potential, and powder X-ray diffraction. We have evaluated the activity of these materials as recyclable catalysts in the asymmetric aldol reaction. The best organocatalysts are those derived from the monosilylated precursor, observing good diastereo- and enantiomeric ratios with a simple and environmentally friendly optimized protocol (water, 0 °C, absence of cocatalyst). The nanocatalyst was easily recovered by centrifugation and recycled up to five runs without loss of activity and selectivity. The use of organosilica nanoparticles reduces the problems of diffusion and low reaction rates encountered with bulk organosilicas.

Computational Insight Into the Enantioselectivity of Homoboroproline Catalyzed Asymmetric Aldol Reaction

AbstractChiral amino boronic acids and their derivatives have a wide range of applications including enzyme inhibitors, anti‐cancer agents and molecular sensors. They also draw attention as effective catalysts. Recently, a new proline based amino boronic acid derivative, homoboroproline, was synthesized and demonstrated to be an efficient catalyst in an asymmetric aldol reaction. The reaction mechanism has been elucidated in the present study for the first time. Considering different orientations of the enamine intermediate and the aldehyde, potential alternative mechanisms were modeled with density functional theory (DFT) calculations via PCM/M06‐2X/6‐31G(d,p) method in acetone. The potential energy surface of each mechanism was explored to establish the rate‐determining and enantioselectivity‐determining steps. The calculated enantiomeric excess values (>99%) were found to be in agreement with the experimental values (93%, 95%). The detailed investigation of the transition state structures of the selectivity‐determining step has revealed that attractive interactions between boron and aldehyde oxygen are responsible for the selectivity confirmed by natural bond orbital (NBO) analysis. The results provide insight into the origin of enantioselectivity in asymmetric aldol reaction catalyzed by homoboroproline.

Synthesis and Stereochemical Revision of the Aromatic Polyketide NFAT-133.

NFAT-133, isolated from Streptomyces sp., is an immunosuppressive, antidiabetic, and antitrypanosomal aromatic polyketide with three contiguous stereocenters. The first enantioselective total synthesis of the proposed structure of NFAT-133 [(10R,11R,12S)-1] and its C10 epimer [(10S,11R,12S)-1] was achieved from a known aromatic ester (5) by a 10-step sequence that featured chiral auxiliary-directed asymmetric alkylation and the Evans asymmetric aldol reaction as the chirality-inducing steps. The 1H and 13C NMR data as well as the specific rotation value of natural NFAT-133 were not identical to those of the proposed structure, but were in good agreement with those of its C10 epimer. This led us to conclude that the absolute configuration of NFAT-133 should be revised to 10S, 11R, and 12S.

Synthesis of 1,2-Diamine Bifunctional Catalysts for the Direct Aldol Reaction Through Probing the Remote Amide Hydrogen

Background: While proline can catalyze the asymmetric direct aldol reactions, its catalytic activity and catalyst turnover are both low. To improve the catalytic efficiency, many prolinebased organocatalysts have been developed. In this regard, prolinamide-based bifunctional catalysts have been demonstrated by us and others to be highly efficient catalysts for the direct aldol reactions. Results: Using the β-acetamido- and β-tosylamidoprolinamide catalysts, the highly enantio- and diastereoselective direct aldol reactions between enolizable ketones and aldehydes were achieved (up to >99% ee, 98:2 dr). A low catalyst loading of only 2-5 mol % of the β-tosylamidoprolinamide catalyst was needed to obtain the desired aldol products in good to high yields and high stereoselectivities. Methods: By carefully adjusting the hydrogen bonding ability of the remote β-amide hydrogen of the 1,2-diamine-based prolinamide bifunctional catalysts, the catalytic activity and the asymmetric induction of these catalysts were significantly improved for the direct aldol reaction between aldehydes and enolizable ketones. Conclusion: Some highly efficient 1,2-diamine-based bifunctional prolinamide catalysts have been developed through probing the remote β-amide hydrogen for its hydrogen bonding capability. These catalysts are easy to synthesize and high enantioselectivities may be achieved at very low catalyst loadings.

Asymmetric Direct Aldol Reaction Catalyzed by (1R, 2R)-(+)-1, 2- Diammonium Cyclohexane-L-tartrate in Water

Background: A cheap and commercially available organocatalyst, (1R, 2R)-(+)-1, 2- diammonium cyclohexane-L-tartrate 1 was applied in direct aldol reaction in water. The organocatalyst 1 afforded aldol products from cyclohexanone and substituted aromatic aldehydes with high yield (up to 90%) and good stereoselectivity (up to 99% ee and up to 11.5:1 dr) in large volume of water (10 ml). Methods: The same aldol reaction when carried out in the presence of more expensive organocatalyst e.g. (1R, 2R)-(+)-1,2-diaminocyclohexane and 1,6-hexanediaoic acid as acid additive furnished the aldol products with only 20% yield, 2:1 anti/syn ratio and 92% ee. Results and Conclusion: In summary, we have applied a reasonably cheap and commercially available organocatalyst 1 for highly enantioselective direct aldol reaction in water at room temperature.

Tripeptide-Catalyzed Asymmetric Aldol Reaction Between α-ketoesters and Acetone Under Acidic Cocatalyst-Free Conditions

Here, we report the tripeptide-catalyzed asymmetric aldol reaction between α-ketoesters and acetone under acidic cocatalysts-free conditions. H-Pro-Tle-Gly-OH 3g-catalyzed reactions between α-ketoesters and acetone resulted in up to 95% yield and 88% ee. Analysis of the transition state using density functional theory (DFT) calculations revealed that the tert-butyl group in 3g played an important role in enantioselectivity.