Anti-selective direct asymmetric Mannich reaction catalyzed by protease

The anti-selective direct asymmetric Mannich reaction of (hetero) aromatic aldehydes, 4-anisidine and O-protected hydroxyacetones for the synthesis of stereodefined anti-β-amino-α-hydroxycarbonyl compounds was developed. Protease type XIV from Streptomyces griseus (SGP) was used as a biocatalyst in 1,4-dioxane/phosphate buffer under mild reaction conditions. The excellent diastereoselectivities of up to >99:1 (anti/syn) and good enantioselectivities of up to 90% ee were achieved. This method provides a more sustainable complement to chemically catalyzed anti-selective direct asymmetric Mannich reactions.     

A catalytic asymmetric vinylogous Mukaiyama aldol reaction

A vinylogous Mukaiyama aldol reaction, conducted using 10 mol % of a BITIP catalyst and B(OMe)3 as an additive, effects an enantioselective four-carbon chain extension to give versatile E-alpha,beta-unsaturated thiol esters.     

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.     

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.     

The small peptide-catalyzed direct asymmetric aldol reaction in water

Simple modular di- and tripeptides with a primary amine at the N-terminus catalyze the aqueous asymmetric aldol reaction between unmodified ketones and aldehydes to furnish the corresponding beta-hydroxy ketones with up to 86% ee in water and 99% ee in aqueous media.     

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。     

l-Proline amide-catalyzed direct asymmetric aldol reaction of aldehydes with chloroacetone

l-Proline amides were evaluated for catalyzing the direct aldol reaction of 4-nitrobenzaldehyde with chloroacetone. The presence of 30 mol% (S)-pyrrolidine-2-carboxylic acid (2,4,6-trimethyl-phenyl)-amide catalyzed the direct aldol reactions of a range of aldehydes with chloroacetone to give anti-α-chloro-β-hydroxyketones with high regio-, diastereo- and enantioselectivity.     

Additive-controlled regioselective direct asymmetric aldol reaction of hydroxyacetone and aldehyde

A structurally simple dipeptide derivative 1b prepared from l-proline and l-valine has been developed for the direct asymmetric aldol reaction of hydroxyacetone and various aldehydes with moderate to high yields and high enantioselectivities. More importantly, this regioselective reaction could be easily regulated by changing the additives in the presence of the same organocatalyst 1b, to afford the normal 1,2-diol adducts and the disfavoured 1,4-diol products, respectively, in a highly regioselective fashion. A possible reaction mechanism has also been proposed.     

A simplified catalytic system for direct catalytic asymmetric aldol reaction of thioamides; application to an enantioselective synthesis of atorvastatin

A new catalytic system was developed for the direct catalytic asymmetric aldol reaction of thioamides. The new lithium-free Cu catalyst (second-generation catalyst) exhibited enhanced catalytic efficiency over the previously developed catalyst comprising [Cu(CH₃CN)₄]PF₆/Ph-BPE/LiOAr (first-generation catalyst), which required a tedious catalyst preparation process. In the reaction with the second-generation catalyst, the intermediate Cu-aldolate functioned as a Brønsted base to generate thioamide enolate, efficiently driving the catalytic cycle. The present aldol methodology culminated in a concise asymmetric synthesis of atorvastatin (Lipitor^®: atorvastatin calcium), a widely prescribed HMG-CoA reductase inhibitor for lowering low-density lipoprotein cholesterol.     

Ionic liquid-supported proline as catalyst in direct asymmetric aldol reaction

Ionic-liquid-supported proline derivative was synthesized starting from L-proline and was used to catalyze direct asymmetric aldol reaction of acetone with aldehydes. The yield and optical purity of the condensation products, the corresponding β-hydroxy carbonyl compounds were comparable with those obtained under homogeneous conditions. Moreover, the catalyst can be reused for at least four times. Published in Russian in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 12, pp. 1834–1837. The text was submitted by the authors in English.     

Primary amine catalyzed direct asymmetric aldol reaction assisted by water

l-Valine was found to be an active catalyst in the asymmetric direct aldol reaction. The aldol reaction of a variety of aromatic aldehydes with acetone was catalyzed by 20 mol % of l-valine at 35 °C with the aldol products obtained in moderate to good yields (48–83%) and enantiomeric excesses (42–72%). The reaction was more efficient catalytically with best results observed in the presence of 1 mol equiv of water, with respect to the aldehyde, in either DMSO or DMF as solvent. The effect of water concentration on the reaction rate and enantioselectivity was also investigated. Thus, with increasing water concentration in DMSO there was decreasing enantioselectivity. However, the reaction in the presence of l-phenylalanine showed a lower level of reactivity and enantioselectivity to afford the aldol in 25% with 31% ee. In marked contrast, reaction with l-phenylglycine resulted in the negligible formation of the aldol (<5%). Our results, suggest a new strategy in the design of new bioorganic catalysts for direct asymmetric aldol reactions.     

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.     

Biocatalytic direct asymmetric aldol reaction using proteinase from Aspergillus melleus

The direct asymmetric aldol reaction of aromatic aldehydes with cyclic or acyclic ketones was catalyzed by proteinase from Aspergillus melleus (AMP) in acetonitrile in the presence of water. A wide range of substrates could be transformed into the corresponding aldol products in yields up to 89%, enantioselectivities up to 91% ee and diastereoselectivities up to >99:1 (anti/syn). This work provided an example of enzyme catalytic promiscuity that widens the applicability of this biocatalyst in organic synthesis without the need for additional cofactors or special equipment.     

Proline-catalyzed direct asymmetric aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with ketones

l-Proline-catalyzed direct asymmetric aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with unmodified ketones smoothly occurred at ambient temperature to produce β-hydroxy-β-trifluoromethylated ketones with good to excellent diastereo (up to 96% de) and enantioselectivities (up to 91% ee).     

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%.     

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.     

Direct catalytic asymmetric aldol reactions of aldehydes

The development of a direct catalytic enantioselective aldol reaction of aldehydes with activated carbonyl compounds catalyzed by chiral amines is presented and the potential demonstrated by the synthesis of optically active beta-hydroxycarboxylic acid derivatives.     

A recyclable non-immobilized siloxy serine organocatalyst for the asymmetric direct aldol reaction

A recyclable siloxy-l-serine organocatalyst has been developed to catalyze asymmetric direct aldol reactions in [bmim][BF₄], furnishing the β-hydroxy carbonyl scaffold in high enantio- and diastereoselectivities using a selection of aromatic aldehydes and cycloalkanes. The siloxy serine organocatalyst in the ionic liquid can be reused for up to four successive cycles with comparable enantioselectivities.     

A direct catalytic asymmetric mannich-type reaction to syn-amino alcohols

The Mannich reaction is one of the most widely utilized chemical transformations for the construction of nitrogen-containing compounds. With the increasing occurrence of nitrogen in drugs and natural products, highly asymmetric variants of the Mannich reaction are desirable. In this communication, we report the application of our dinuclear zinc catalyst to a highly asymmetric Mannich-type reaction to generate syn 1,2-amino alcohols.