Asymmetric Aldol Condensation Research Articles

Y(OTf)3-Salazin-Catalyzed Asymmetric Aldol Condensation.

The chiral aziridine-containing vicinal iminophenol tridentate ligands (named salazins) are a class of readily prepared chiral ligands from enantiopure aziridines and salicylaldehydes. Their scandium and yttrium triflate complexes show excellent reactivity and enantioselectivities in the catalytic asymmetric aldol condensation of electron-deficient aromatic aldehydes and ketones, including acetone and cycloalkanones. The stereoselectivity is rationalized to the strong π-stacking interaction between aromatic aldehydes and the vicinal iminophenol group in the chiral ligands.

Green chemistry approach for stereoselective aldol condensation catalyzed by amino acids under microflow conditions

Over the recent years, the pharmaceutical field has been under significant pressure to adapt to the principles of green chemistry. The industry is facing the challenge of environmental protection and securing people's health while sustaining its fundamental goals of efficiency and selectivity optimization. In this work, the reaction processes optimization has been acheived through the microfluidic approach to the widely used aldol condensation reaction. In accordance with the green chemistry principles, we have found that the best conditions include aqueous ethanol solvent and easily available amino acids used as catalysts. Asymmetric aldol condensation of para-nitrobenzaldehyde with cyclohexanone catalyzed by L-tert-Leu under microfluidic conditions provided the product with high yield and diastereoselectivity (anti/syn = 28:1) and 98% enantiomeric excess. The microfluidic reactor process, compared to the classical batch method (in a flask), provides comparable product yield, while the reaction time was reduced by an order of magnitude. It should be noted that this approach allows to carry out the reactions at low (below zero) temperatures with greater enantioselectivity.

Pyrrolidine-oxadiazolone conjugate as new organocatalyst for asymmetric aldol condensation

A proline-based, chiral bi-functional organocatalyst containing both pyrrolidine and oxadiazolone heterocycle, has been successfully applied for stereoselective aldol reactions. The replacement of polar -COOH group of proline with bioisostere oxadiazolone ring provides excellent solubility of this catalyst in various organic solvents compared to low soluble proline. As a result, the organocatalyst effectively catalyzed the asymmetric condensation reaction between differently substituted aromatic aldehydes and various symmetrical and unsymmetrical ketones to produce the corresponding aldol products with excellent stereoselectivities (dr: 97:3, ee >99.9%) at room temperature in open-air.

Chiral Ionic Liquids Based on l-Cysteine Derivatives for Asymmetric Aldol Reaction

Structure, and consequently properties, of ionic liquids can be easily tailored by changing cation/anion combinations and/or attaching functional groups. By grafting enantiopure moieties to the framework of ionic liquid it is possible to prepare bioinspired chiral molecules that can serve as a reaction medium, additive or even asymmetric catalyst. In this context, new chiral ionic liquids (CILs), based on biomolecules, such as aminoacids (l-Cysteine derivatives), have been synthesised and tested in asymmetric aldol condensation of aldehydes and ketones. The best results were obtained for CILs composed of S-methyl-l-cysteine cation and bis(trifluoromethane)sulfonimide anion, in the reaction of 2- or 4-nitrobenzaldehyde with acetone or cyclohexanone, giving the aldol product in moderate yields 70–76% and high ee values (up to 96%).

Enantioselective Synthesis Muqubilin and Negombatoperoxides B and C/D.

Muqubilin, negombatoperoxide B, and negombatoperoxide C/D were synthesized through enantioselective routes, with the quaternary center derived from a peroxy chiral building block of known absolute configuration. The C-2/C-3 stereogenic centers were introduced by asymmetric aldol condensation, and the 1,2-dioxane ring was constructed via an intramolecular alkylation of a hydroperoxide with a mesylate. The synthetic samples showed physical and spectroscopic data consistent with those reported in the literature and thus verified the configurations of the natural products. A potentially more expeditious enantioselective entry to the 1,2-dioxane-aldol moiety (C-1 to C-6) of such cyclic peroxides was also briefly explored, where the C-2/C-3 stereogenic centers were installed through a [2+2] cycloaddition and the 1,2-dioxane ring was closed via an intramolecular alkylation coupled with an alkyl-oxygen cleavage of a β-lactone.

Synthesis and Configuration of a p‐Aminoacetophenonic Acid Isolated from Endophyte of the Mangrove Plant Kandel candel

Two diastereomers of the title compound were synthesized through an enantioselective route, with the stereogenic center at the C‐2 derived from a commercially available reagent and the one at the C‐4 installed via Evans asymmetric aldol condensation. By comparison of 1H and 13C NMR spectra as well as optical rotation, the configuration of the natural product was as assigned as (‐2R,4R). Some interesting issues such as suppression of the undesired yet dominating formation of cyclic ethers associated with deprotection of a TBS protected terminal hydroxyl group and the previously unknown differences in 1H NMR and IR between the end product separated by normal phase chromatography and that by reverse phase chromatography are also presented.

Convenient approach to chiral 4-monosubstituted 1,3-oxazolidine-2-thiones

ABSTRACTChiral 4-monosubstituted 1,3-oxazolidine-2-thiones are regarded as one of the modified version of Evans auxiliaries in asymmetric aldol condensation, which can generate two adjacent chiral carbon centers in one time They have advantages over Evans auxiliaries in some aspects, however, their application is highly limited by their preparation approaches as toxic or flammable chemicals are involved. Here, a mild and applicable procedure for preparing the chiral oxazolidine-2-thione auxiliaries has been developed in this article. Potassium ethylxanthate and the corresponding chiral amino alcohols as the starting material in absolute ethanol are mixed and the mixture are heated under reflux for 1 h in open air to provide 1,3-oxazolidine-2-thiones chiral auxiliaries in moderate to excellent yields.

Magnetic Nanoparticles‐Supported Chiral Catalyst with an Imidazolium Ionic Moiety: An Efficient and Recyclable Catalyst for Asymmetric Michael and Aldol Reactions

AbstractA magnetic nanoparticles‐supported chiral aminocyclohexane in combination with sulfamide, which was modified by an imidazolium ionic moiety, was prepared and characterized by Fourier transform infrared spectroscopy (FT‐IR), X‐ray diffraction (XRD), transmission electron microscopy (TEM), vibrating sample magnetometry (VSM), thermal gravimetric (TG) analysis and elementary analysis. The catalyst was successfully applied not only in the enantioselective Michael addition but also in the asymmetric aldol condensation to afford good to excellent yields (70–94%) and satisfactory stereoselectivity (ee: 92–100%, dr: 91:9–99:1).The role of the ionic moiety was verified by comparison of the catalyst with an ionic moiety‐free counterpart. The heterogeneous catalyst was easily separated and recovered using external magnetic force and can be used for up to five times without obvious loss in its catalytic activity.magnified image

ChemInform Abstract: Zinc(II) Mediated Asymmetric Aldol Condensation Catalyzed by Chiral Aziridine Ligands.

ChemInform Abstract: Zinc(II) Mediated Asymmetric Aldol Condensation Catalyzed by Chiral Aziridine Ligands.

Zinc(II) mediated asymmetric aldol condensation catalyzed by chiral aziridine ligands

Exploration of chiral aziridine ethers and aziridine alcohols as ligands for the Zn(II) catalyzed enantioselective direct aldol condensations reaction is described. The reaction of acetone with NO2-substituted aromatic aldehydes in the presence of water gave the desired adducts in moderate chemical yields (40–70%) and good to excellent enantiomeric excesses (80–98% ee).

Highly efficient chiral polydentate sulfinyl ligands/catalysts containing prolinol moiety

New polydentate chiral ligands, containing the hydroxyl group, stereogenic sulfinyl group and enantiomeric prolinol moieties were synthesized and proved very efficient catalysts in the asymmetric diethylzinc addition to benzaldehyde, the asymmetric aldol condensation and the asymmetric Mannich reaction. Replacement of the central hydroxyl group with the second prolinol moiety of the same absolute configuration gave new ligands in which the sulfinyl group was not a stereogenic centre anymore, but which proved almost equally efficient as catalysts for the reactions investigated. The absolute configuration of the proline moiety exerted a decisive impact on the stereochemical outcome of these reactions, deciding about the absolute configuration of the products formed.

Optically Pure Aziridinyl Ligands as Useful Catalysts in the Stereocontrolled Synthesis

The synthesis of optically pure compounds remains a challenge in modern organic chemistry due to the great importance of single stereoisomers in the pharmaceutical, food, flavor, and fragrance industries. The crucial factor influencing the chemical yield and stereoselectivity of asymmetric reactions is the use of the appropriate chiral catalyst. Recently there has been a growing interest in the synthesis and modification of various chiral amine-functionalized compounds - especially aminoalcohols - to check their catalytic activity in various asymmetric reactions. On the basis of very few literature reports, it can be seen that aziridine-containing ligands exhibit a very high efficiency in reactions with organozinc reagents. In the existing review articles, this group of compounds has been described only randomly. The aim of the present paper is to review systematically the advances in the applications of chiral aziridine-containing derivatives as highly efficient catalysts in asymmetric synthesis, including also the results from our research group. In this review article, diverse aziridine-containing ligands such as aziridine alcohols, bis-aziridines, aziridine carbazides, and aziridine pyridines are described. The main attention is focused on the catalytic activity of the aforementioned ligands in the asymmetric reactions such as the addition of diethyl- and phenylethynylzinc to carbonyl compounds (aldehydes, enones), asymmetric allylic alkylation, direct asymmetric aldol condensation, nitroaldol (Henry) reaction, cyclopropanation and others. Keywords: Asymmetric synthesis, aziridine alcohols, bis-aziridines, chiral catalysts/ligands, metal-catalyzed asymmetric transformations, stereochemistry.

ChemInform Abstract: The Application of a Structurally Simple, Recyclable, and Large‐Scale L‐Prolinamide Catalyst for Asymmetric Aldol Reactions.

AbstractA bifunctional catalyst having a trans‐cyclohexane and a proline amide moiety is developed and successfully applied to the asymmetric aldol condensation of cyclic ketones with aldehydes.

Unprecedented 8,9'-neolignans: enantioselective synthesis of possible stereoisomers for structural determination.

(+)-Wutaienin (3) and its C-7 methyl ether (4), isolated from Zanthoxylum wutaiense, were found to be unprecedented 8,9'-neolignans containing an (S)-2-(1,1-dimethyl-1-hydroxymethyl)-7-methoxydihydrobenzofuran skeleton. Wutaienin (3) was present in the plant as an inseparable 1:1 mixture of the (7,8)-syn-diastereoisomers. The diastereoisomeric mixture was characterized by comparison with four possible diastereoisomers, which were enantioselectively synthesized from (S)-5-bromo-(1,1-dimethyl-1-hydroxymethyl)-7-methoxydihydrobenzofuran using Evans' oxazolidinone-assisted asymmetric aldol condensation to install the chiral centers at the C-7 and C-8 positions.

Direct asymmetric aldol reactions in aqueous media catalyzed by a β-cyclodextrin–proline conjugate with a urea linker

Covalently attaching proline to β-CD through a urea linkage resulted in the synthesis of a water-soluble chiral organocatalyst 1 in high yield. Catalytic asymmetric aldol condensations between aldehydes and acetone were carried out under water-containing conditions by using 5mol% of 1 as catalyst, and moderate to high yields and enantioselectivities (up to 99% ee) were achieved for a broad range of aldehydes. Substrate selectivity was also tested. Recycling experiments were performed to confirm good recyclability and reusability of the catalyst.

Studies toward asymmetric synthesis of leiodelide A

An enantioselective route for oxazoline 4, a key fragment toward the asymmetric synthesis of leiodelide A, is described. We synthesized northern subunit 6 through a Julia–Lythgoe olefination and subsequent Sharpless asymmetric dihydroxylation. Moreover, a highly diastereoselective method using well-established Evans’ asymmetric aldol condensation was developed for preparation of southern fragment 5. The additional feature of this synthetic route is the formation of oxazoline 4 through DAST-promoted cyclization of the amidation product from subunits 5 and 6.

ChemInform Abstract: Sugar Amide‐Pyrrolidine Catalyst for the Asymmetric Michael Addition of Ketones to Nitroolefins.

AbstractNovel furano sugar‐amide derivatives are developed and used as catalyst for the asymmetric aldol condensation of cyclic ketones and acetone with nitrostyrenes.

Syntheses of 1′,2′-cyclopentyl nucleosides as potential antiviral agents

To discover novel nucleosides as potential antiviral agents, 1′,2′-cyclopentyl nucleosides were designed as hybrids of sofosbuvir and GS-6620. An asymmetric aldol condensation reaction was used as the key transformation to prepare the versatile 1′,2′-cyclopentyl ribose 6, which is useful to explore diverse bases at 1′ and its utility was demonstrated via the syntheses of nucleosides 9 and 11. The 2′-β-methyl-1′,2′-cyclopentyl ribonucleoside scaffold was exemplified via a C-nucleoside which was prepared using a RCM reaction as the key step leading to novel nucleoside 35.

Enhanced heterogeneous asymmetric catalysis via the acid–base cooperation between achiral silanols of mesoporous supports and immobilized chiral amines

The heterogeneous acid–base cooperation between achiral silanols of mesoporous silica and immobilized chiral amines in asymmetric catalysis has been investigated in this work using direct asymmetric aldol condensation as model reaction. To accomplish the acid–base cooperative asymmetric catalysis as expected, not only the quantity and the acidity of surface hydroxyls have been controlled by the silyation of silica surface and the incorporation of framework aluminum, but also the structure of chiral pyrrolidine amines has been tuned. With appropriate acidity and sufficient quantity of surface silanols, impressive activity acceleration has been achieved for each pyrrolidine amine. For immobilized (2S)-N-(quinine-9-yl)pyrrolidine-2-carboxamid, in which the chiral pyrrolidine amine is modified with neighboring carboxamine moiety, the enantioselectivity has been well preserved, even though the achiral acidic sites compromise the asymmetric induction. The mechanism for the acid–base cooperative asymmetric catalysis between achiral silanols and immobilized chiral amines has been discussed.

ChemInform Abstract: Titanium Mediated Olefination of Aldehydes with α‐Haloacetates: An Exceptionally Stereoselective and General Approach to (Z)‐α‐Haloacrylates.

An exceptionally stereoselective and general synthesis of (Z)-α-haloacrylates, ready to undergo various synthetic transformations, has been demonstrated from α-haloacetates and aldehydes in a one-pot manner via the titanium-enolate based asymmetric aldol condensation. Besides being an expedient synthetic procedure, the ready availability of diverse α-haloacetates, exceptional stereoselectivity, and high yields make the process a versatile transformation in organic synthesis. The potential of this method in up-scaling operations has been illustrated.