Chiral spiroborate esters catalyzed highly enantioselective direct aldol reaction

Asymmetric catalysis of chiral spiroborate esters with an O₃BN framework toward the direct aldol reaction of acetone and aromatic aldehydes was examined, and a new, efficient chiral catalyst was discovered. In the presence of the novel catalyst, acetone was allowed to react with aromatic aldehydes at 0 °C for 50 h to afford chiral β-hydroxyketone in up to >99% ee and 92% yield. The catalyst, which is readily synthesized, is highly stable to hydrolysis, thermolysis, oxidation, and racemization, can be conveniently recovered.     

New chiral bis(diphenylphospholane) ligands: design, synthesis, and application to catalytic enantioselective aldol reaction to ketones

New chiral bidentate diphenylphospholanes were designed targeting a catalytic enantioselective aldol reaction to ketones. Ligands 5l and 5m having cis-2-butenyl and cyclopropyl groups at the linker part, respectively, were identified as effective chiral ligands for a CuF-catalyzed enantioselective aldol reaction to ketones. Catalysts prepared from CuF·3PPh₃·2EtOH and these ligands produced ketone aldol products with up to 66% ee, which is promising particularly for this extremely difficult and important catalytic enantioselective carbon-carbon bond forming reaction. The enantioselectivity was strongly dependent on the linker structure. Construction of a deep chiral pocket around the copper metal with stable bidentate chelation is the key to meaningful enantioinduction.     

Catalytic enantioselective intermolecular reductive aldol reaction to ketones

We describe the first example of a catalytic enantioselective intermolecular reductive aldol reaction. Three types of reactions were studied: (1) reactions between acetophenone and methyl acrylate; (2) reactions between symmetric ketones and β-substituted α,β-unsaturated esters; and (3) reactions between acetophenone derivatives and an allenic ester. Although only moderate enantioselectivity was obtained in the first reaction type, high to excellent enantioselectivity was realized in the enantio-induction at the α-position in the second reaction type and at the δ-position in the third reaction type. Specifically, the third reaction type afforded the corresponding tertiary alcohols with up to 99% ee. Pre-activation of the nucleophile by silyl enolate formation is not necessary in these one-pot catalytic enantioselective reductive aldol reactions.     

One-pot synthesis of α-diazo-β-hydroxyesters under phase-transfer catalysis and application to the catalytic asymmetric aldol reaction

The one-pot (three steps) synthesis of α-diazo-β-hydroxyesters from tosyl chloride under phase-transfer catalysis is described. The catalytic asymmetric aldol reaction between a diazoester and aldehydes was also investigated and gave moderate to good enantioselectivity.     

A direct intramolecular asymmetric catalytic aldol cyclodehydration of meso-3,4-disubstituted-1,6-dialdehydes

The intramolecular asymmetric catalytic aldol cyclodehydration of 1,6-dialdehydes to the corresponding cyclopentene carbaldehydes was accomplished for the first time on the cases of meso-3,4-disubstituted hexanedials. It was found that the presence of a hydroxyl group in the catalyst's molecule seems to be crucial to reach stereocontrol. The chiral centre, bearing the carboxylate functionality, in hydroxy amino acids controls the stereochemistry of the final product. In the case of amino alcohols, where carboxylate functionality does not exist, the configuration of the carbon, connected with the hydroxyl group, seems to be the key one. Additionally, it was observed that chiral phosphines and phosphites are effective catalysts for this cyclodehydration but without inducing stereocontrol.     

Prolinamides derived from aminophenols as organocatalysts for asymmetric direct aldol reactions

N-(2-Hydroxyphenyl)-prolinamides were synthesized with the aim to introduce an additional hydrogen bonding site to the prolinamide structure. These compounds were evaluated as organocatalysts for asymmetric aldol reactions between aromatic aldehydes and cyclohexanone. Very good yields, diastereoselectivities, and enantioselectivities were achieved in both organic solvents and water. The importance of the additional hydrogen bonding site was confirmed by comparative experiments with prolinamide derivatives without the hydroxyl group.     

模拟醛缩酶催化不对称直接Aldol反应新进展

对天然醛缩酶的作用机理进行了一般性阐述，在此基础上详细回顾了近几年对 两类醛缩酶的模拟催化不对称直接Aldol反应，并对其发展前景作了展望。     

Chiral Phebox-rhodium complexes as catalysts for asymmetric direct aldol reaction

Chiral bis(oxazolinyl)phenyl-rhodium complexes act as catalysts in the combination of AgOTf for direct aldol reaction of ketones and aromatic aldehydes to give the corresponding β-hydroxyketones in high anti-selectivity and a good to high enantioselectivity up to 91% ee.     

Development of an N-sulfinyl prolinamide for the asymmetric aldol reaction

A new class of organocatalysts is reported that incorporates an N-sulfinyl amide in place of the carboxylic acid of proline to serve as a hydrogen bond donor, chiral directing group, and solubilizing element. The successful application of this type of catalyst to the asymmetric aldol reaction of acetone and aryl aldehydes, for which proline performs poorly, is also described.     

Catalytic asymmetric borylative aldol reaction of 5,6-dihydro-2H-pyran-2-one and ketones

A copper(I)-catalyzed asymmetric borylative aldol reaction of 5,6-dihydro-2H-pyran-2-one and simple ketones (including aromatic ketones and an aliphatic ketone) was disclosed, which afforded a series of chiral diols after an oxidative work-up in moderate yields with moderate to high diastereoselectivity and excellent enantioselectivity. The lactone moiety was easily opened with methanol to generate a chiral triol in moderate yield.     

New N-terminal prolyl-dipeptide derivatives as organocatalysts for direct asymmetric aldol reaction

A series of new N-terminal prolyl-dipeptide derivatives have been synthesized and evaluated as organocatalysts for the direct asymmetric aldol reaction of acetone with electron-deficient aromatic aldehydes. At room temperature, the presence of 10 mol % of catalysts 2 and 5 efficiently catalyzes the direct asymmetric aldol reaction to give the aldol adducts with modest to excellent enantiomeric excesses (ee) values, which are up to 96%.     

Rationally designed organocatalyst for direct asymmetric aldol reaction in the presence of water

A rationally designed organocatalyst for direct asymmetric aldol reaction in the presence of water has been developed. High yield (up to 99%), diastereoselectivity (up to 99:1) and enantioselectivity (up to 97%) were obtained under optimal conditions.     

Direct asymmetric aldol reaction co-catalyzed by l-proline and isothiouronium salts

An efficient, simple, and highly selective protocol for the direct asymmetric aldol reaction between cyclohexanone and aromatic aldehydes using l-proline as a chiral catalyst is reported. Catalytic amounts of achiral isothiouronium iodide salt 1d have been used for the first time as a co-catalyst for this reaction, which proved to be an excellent catalyst, producing good to excellent yields (up to 93%) with good stereoselectivities (up to 93:7 dr and 99% ee). These aldols are formed under solvent-free catalytic system, inside a standard laboratory refrigerator, and without stirring.     

Unnatural tripeptide as highly enantioselective organocatalyst for asymmetric aldol reaction of isatins

The development of unnatural tripeptides as highly enantioselective organocatalysts for the asymmetric aldol reaction of isatins was achieved. H-Pro-Gly-d-Ala-OH with the d-alanine residue as the C-terminal amino acid residue expressed the best enantioselectivity. The H-Pro-Gly-d-Ala-OH-catalyzed reaction of isatins gave various aldol adducts with up to 93% yield and up to 97% ee. Investigation of the transition state via DFT calculation revealed that high optical purity was realized by the d-alanine controlled steric environment.     

Evaluation of mono- and dipeptides as organocatalysts for enantioselective aldol reaction

Catalytic activities of (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (THIQA)-based mono- and dipeptides and their l-proline analogs in asymmetric aldol reaction were investigated. THIQA-based dipeptides showed better enantioselectivity than proline analogs, whereas proline-based dipeptides gave higher yield in the aldol reaction of cyclohexanone with several aldehydes in dichloromethane at −10 °C in the presence of benzoic acid.     

Carbohydrate-based organocatalysts in direct asymmetric aqueous aldol reaction

Aldol reaction involving chiral amines as organocatalysts through enamine formation, like class-I aldolases, is one of the thriving areas of general interest and widely applicable asymmetric reactions. There are many natural and synthetic chiral templates known to work as efficient organocatalysts, but using carbohydrate templates for chiral induction in asymmetric aldol reactions is a relatively new area developed in the recent years. This review focuses on carbohydrates alone or their conjugates with previously known chiral moieties as organocatalysts for asymmetric aldol reactions.     

Highly efficient prolinamide-based organocatalysts for the direct asymmetric aldol reaction in brine

Four prolinamide-based organocatalysts were readily synthesized and applied to the direct asymmetric aldol reactions of ketones and aromatic aldehydes in brine. When 2,4-dinitrophenol (DNP) was used as an acidic additive, 1 mol % low loading of 2b afforded aldol products with excellent diastereoselectivity of up to 98/2 dr and high enantioselectivity of up to 97% ee.     

New simple and recyclable O-acylation serine derivatives as highly enantioselective catalysts for the large-scale asymmetric direct aldol reactions in the presence of water

New classes of O-acylation serine derived organocatalysts have been synthesized one-step by rational combination of serine with acyl chlorides at room temperature in trifluoroacetic acid. No protecting groups or chromatographic techniques are involved in any of the procedures, and certain combined serine-surfactant organocatalysts mediate the direct aldol reactions of ketones with a series of aromatic aldehydes to provide the aldol products in high yields (up to 99%) and enantioselectivities (up to 99% ee). The catalyst 1b can be easily recovered and reused, and without significant decrease of enantioselectivity was observed for five cycles. This novel catalyst can be efficiently used in large-scale reactions with the enantioselectivities being maintained at the same level, which offers a great possibility for application in industry.     

Concise enantioselective synthesis of duloxetine via direct catalytic asymmetric aldol reaction of thioamide

Direct catalytic asymmetric aldol reaction of thioamide offers a new entry to the concise enantioselective synthesis of duloxetine. The direct aldol protocol was scalable (>20 g) to afford the aldol product in 92% ee after LiAlH(4) reduction, and 84% of the chiral ligand was recovered after recrystallization. The following four steps of transformation delivered duloxetine.