Mimicking aldolases through organocatalysis: syn-selective aldol reactions with protected dihydroxyacetone

A practical organocatalytic strategy designed to mimic the l-rhamnulose 1-phosphate and D-fructose 1,6-diphosphate aldolases has been developed and shown to be effective in the preparation of carbohydrates and polyol derivatives. Threonine-based catalysts facilitated the aldol reaction of protected dihydroxyacetone or protected hydroxacetone with a variety of aldehydes to provide syn-aldol products with good yields and ee's up to 98%.     

Organocatalytic asymmetric Neber reaction for the synthesis of 2H-azirine carboxylic esters

The first enantioselective Neber reaction of β-ketoxime sulfonates catalyzed by a bifunctional thiourea has been developed. The reaction proceeds stereoselectively with 5 mol % of the catalyst to give the 2H-azirine carboxylic esters in good yields with up to 93% ee. In addition, the resulting azirines can be successfully employed in the stereoselective synthesis of di- and trisubstituted aziridines.     

Dramatic ligand effect in catalytic asymmetric reductive aldol reaction of allenic esters to ketones

A general catalytic asymmetric reductive aldol reaction of allenic esters to ketones is described. Two distinct constitutional isomers were selectively produced depending on the reaction conditions. A combination of CuOAc/(R)-DTBM-SEGPHOS/PCy3 as the catalyst predominantly produced gamma-cis-products in high yield with excellent enantioselectivity (up to 99% ee). The reaction was applicable to both aromatic and aliphatic ketones, including unsaturated ketones. On the other hand, CuF-Taniaphos complexes produced alpha-aldol products with high diastereo- and enantioselectivity (up to 84% ee). The new Taniaphos derivative L3, containing di(3,5-xylyl)phosphine and morpholine units, produced optimum results in the alpha-selective reaction. The products are versatile chiral building blocks in organic synthesis. Furthermore, the basic reaction pattern (i.e., conjugate addition-aldol reaction) was extended to a catalytic enantioselective alkylative aldol reaction to ketones using dialkylzinc reagents as the initiator.     

Stereoselective chloroacetate aldol reactions: syntheses of acetate aldol equivalents and darzens glycidic esters

Aldol reaction of the Ti-enolate derived from cis-1-tosylamido-2-indanyl chloroacetate with representative aldehydes proceeded in excellent yield and high diastereoselectivities. Removal of chlorine provided alternative access to highly diastereoselective acetate aldol equivalents or the corresponding glycidic ester condensation products. [reaction: see text]     

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.     

Total synthesis of (+)-geldanamycin and (-)-o-quinogeldanamycin with use of asymmetric anti- and syn-glycolate aldol reactions

Geldanamycin (GA), an antitumor Hsp90 inhibitor, was made for the first time by using an oxidative demethylation reaction as the final step. A biaryldioxanone auxiliary set the anti C11-12 hydroxy-methoxy functionality and a methylglycolate auxiliary based on norephedrine was used for the syn C6-7 methoxy-urethane. p-Quinone-forming oxidants, CAN and AgO, produced an unusual aza-quinone product. Nitric acid gave GA from a trimethoxy precursor in 55% yield as a 1:10 mixture with nonnatural o-quino-GA. [structure: see text]     

l-Proline catalysed asymmetric aldol reactions in PEG-400 as recyclable medium and transfer aldol reactions

l-Proline-catalysed direct asymmetric aldol reaction of acetone with various aldehydes in PEG-400 is described. Recycling of the catalyst and solvent (PEG) was possible up to ten runs without loss of catalyst activity. l-Proline was also found to be an efficient catalyst for the asymmetric transfer aldol reaction between various aldehydes and diacetone alcohol for the first time. Good yields and enantioselectivities were observed with both methods.     

Organocatalytic direct asymmetric aldol reactions in water

We have developed direct asymmetric cross-aldol reactions that can be performed in water without addition of organic solvents. A bifunctional catalyst with a long hydrophobic alkyl chain efficiently catalyzed the reactions and afforded the desired aldol products in excellent yield with high enantiomeric excess, even when only an equal molar ratio of the donor and acceptor was used. These results reveal an effective design strategy for the development of aqueous organocatalytic systems.     

Catalytic asymmetric aldol reactions in aqueous media

Nature has perfected the stereospecific aldol reaction by using aldolase enzymes. While virtually all the biochemical aldol reactions use unmodified donor and acceptor carbonyls and take place under catalytic control in an aqueous environment, the chemical domain of the aldol addition has mostly relied on prior transformation of carbonyl substrates, and the whole process traditionally is carried out in anhydrous solvents. The area of aqua-asymmetric aldol reactions has received much attention recently in light of the perception both of its green chemistry advantages and its analogy to eon-perfected enzyme catalysis. Both chiral metal complexes and small chiral organic molecules have been recently reported to catalyze aldol reactions with relatively high chemical and stereochemical efficiency. This tutorial review describes recent developments in this area.     

Direct catalytic asymmetric aldol reactions of pyruvates: scope and mechanism

The direct aldol reaction of 2-ketoesters catalyzed by chiral bisoxazoline copper(II) complexes has been investigated. First the direct homo-aldol reaction of ethyl pyruvate is reported which proceeds to give diethyl 2-hydroxy-2-methyl-4-oxoglutarate. This was isolated as the more stable optically active isotetronic acid in good yield and enantiomeric excess in the absence of bases such as amines. Detailed investigations of the use of different chiral Lewis acids as the catalyst, amines, ratios of chiral bisoxazoline copper(II) salts:amine, and solvents gave up to 96% ee of the isotetronic acid. Then the reaction was extended to a cross-aldol reaction of various 2-ketoesters with activated carbonyl compounds to give the cross-aldol adduct with excellent enantiomeric excess. Furthermore, the synthesis of the isotetronic acids was investigated from these cross-aldol adducts giving important information about the formation of the stereogenic centers during the aldol reaction. Based on the absolute configuration of the homo-aldol adduct the mechanism for the aldol reaction is discussed.     

Recent applications of organocatalysts in asymmetric aldol reactions

The asymmetric aldol reaction is one of the most powerful synthetic tools for carbon–carbon bond-forming reactions. This method provides a beneficial route to access chiral β-hydroxy carbonyl compounds, which are versatile synthetic motifs found in biologically active natural products and pharmaceutically attractive intermediates. The aim of this review is to provide an overview of the many contributions and recent advances in the field of organocatalytic asymmetric aldol 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.     

Proline-catalyzed asymmetric aldol reactions between ketones and alpha-unsubstituted aldehydes

[reaction: see text] With this communication we extend the methodology of proline-catalyzed direct asymmetric aldol reactions to include alpha-unsubstituted aldehydes as acceptors. This important aldehyde class gives the corresponding aldols in 22-77% yield and up to 95% ee when the reactions are performed in pure acetone or in ketone/chloroform mixtures. On the basis of these results we have developed a concise new synthesis of (S)-ipsenol.     

Regioselectivity-reversed asymmetric aldol reaction of 1,3-dicarbonyl compounds

Reverse regioselectivity: The first catalytic asymmetric C-1 functionalization of 1,3-dicarbonyl compounds by an aldol reaction is described, which regioselectively affords 6-hydroxyhexane-2,4-dione derivatives as the only product with high optical purity of up to 93?%?ee. Furthermore, this method provides a facile access to enantioenriched oxygen-containing spirooxindoles and spirobutyrolactones from simple commercial available starting materials.     

Mechanism of the double aldol reaction: the first spectroscopic characterization of a carbon-bound boron enolate derived from carboxylic esters

The novel doubly borylated enolate is identified as an intermediate of the double aldol reaction of acetate esters. As a precursor to the formation of the doubly borylated enolate, carbon-bound boron enolates of carboxylic esters are spectroscopically characterized for the first time. When 2,6-diisopropylphenyl acetate (10d) is treated with c-Hex(2)BOTf (1.3 equiv) and triethylamine (1.5 equiv) in CDCl(3), the corresponding mono-enolate is formed as a mixture of oxygen- (11d) and carbon-bound (12d) forms in 71% and 20% yields, respectively. The structures of these enolates have been unambiguously determined by NMR spectroscopy. Investigation of the enolization of a series of substituted aryl acetates shows that the steric factor of the acetate affects the degree of the mono-enolate (as a mixture of oxygen- and carbon-bound enolates) and the doubly borylated enolate formation. Studies also revealed that oxygen- and carbon-bound boron enolates exist as equilibrium mixtures and that a proton transfer process occurs between oxygen- and carbon-bound enolates. The doubly borylated enolate formation is general for a variety of carbonyl compounds. Besides acetate esters, carbonyl containing compounds, such as acetic acid, dimethylacetamide, methoxyacetone, and 3-acetyl-2-oxazolidinone, also produce the doubly borylated enolates when treated with c-Hex(2)BOTf (2.5 equiv) and triethylamine (3.0 equiv). A plausible pathway of the double aldol reaction involving a carbon-bound boron enolate as a key intermediate is proposed.     

Anti-selective direct catalytic asymmetric aldol reaction of thiolactams

An anti-selective direct catalytic asymmetric aldol reaction of thiolactam is described. A soft Lewis acid/hard Br?nsted base cooperative catalyst comprised of mesitylcopper/(R,R)-Ph-BPE exhibited high catalytic performance to produce an anti-aldol product with high stereoselectivity. The highly chemoselective nature of the present catalysis allows for the use of enolizable aldehydes as aldol acceptors. The diverse transformations of the thiolactam moiety highlight the synthetic utility of the present anti-aldol protocol.     

Polymer-supported proline-decorated dendrons: dendritic effect in asymmetric aldol reaction

The yield and enantioselectivity of an asymmetric aldol reaction, catalyzed by a proline derivative immobilized on polystyrene via dipolar cycloaddition, are remarkably improved by the dendronization of the support.     

Current applications of organocatalysts in asymmetric aldol reactions: An update

The aldol reaction is one of the most important carbon–carbon bond formations in synthetic organic chemistry. An enantioselective aldol reaction should provide an enantioenriched product. The organocatalytic asymmetric aldol reaction via an in situ generated enamine intermediate is one of the most powerful synthetic tools to achieve enantiomerically pure products. This approach is often used to obtain chiral β-hydroxycarbonyl compounds with excellent enantioselectivity. In this report, we update our previous review regarding the applications of organocatalysts in asymmetric aldol reactions leading to chiral β-hydroxycarbonyl compounds as versatile synthetic motifs frequently found in pharmaceutically desired intermediates and biologically active naturally occurring compounds.     

Current progress in the asymmetric aldol addition reaction

Control of stereochemistry during aldol addition reactions has attracted considerable interest over the years as the aldol reaction is one of the most fundamental tools for the construction of new carbon-carbon bonds. Several strategies have been implemented whereby eventually any single possible stereoisomeric aldol product can be accessed by choosing the appropriate procedure. With earlier methods, stoichiometric quantities of chiral reagents were required for efficient asymmetric induction, with the auxiliary most often attached covalently to the substrate carbonyl. Lewis acid catalyzed addition reactions of silyl enolates to aldehydes (Mukaiyama reaction) later opened the way for catalytic asymmetric induction. In the last few years, both chiral metal complexes and small chiral organic molecules have been found to catalyse the direct aldol addition of unmodified ketones to aldehydes with relatively high chemical and stereochemical efficiency. These techniques along with the more recent developments in the area are discussed in this tutorial review.