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.     

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.     

Highly anti-selective catalytic aldol reactions of amides with aldehydes

Barium phenoxide-catalyzed, highly anti-selective direct-type aldol reactions of amides with aldehydes have been developed. In the presence of a slight excess amount of an amide, the desired reactions proceeded smoothly under mild conditions, and a wide range of aromatic, heterocyclic, alpha,beta-unsaturated aldehydes were applicable to afford the desired adducts in high yields with high anti-selectivities. A catalytic, enantioselective reaction of an amide with an aldehyde using a chiral ligand is also described.     

Telaprevir fragments as organocatalysts in asymmetric direct aldol reactions of aldehydes

We have demonstrated that the fragments of Telaprevir can act as organocatalysts for asymmetric aldol reactions between aromatic aldehydes and acetone under mild conditions. The reaction conditions have been optimized in terms of the catalyst nature, choice of temperature, solvent, additive, and the catalyst loading. Under proper conditions, fairly good yield and enantioselectivity have been achieved.     

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.     

Isoleucine-catalyzed direct asymmetric aldol addition of enolizable aldehydes

Isoleucine-catalyzed direct enantioselective aldol additions between enolizable aldehydes are reported. Intermediate acetal structures dictate the configurative outcome and were supported by a hydrogen bond. This direct isoleucine-catalyzed aldol addition represents a welcome complement to both proline- and histidine-catalyzed aldol additions of enolizable aldehydes.     

Small peptides catalyze highly enantioselective direct aldol reactions of aldehydes with hydroxyacetone: unprecedented regiocontrol in aqueous media

[reaction: see text] L-Proline-based small peptides have been developed as efficient catalysts for the asymmetric direct aldol reactions of hydroxyacetone with aldehydes. Chiral 1,4-diols 7, which are disfavored products in similar aldol reactions catalyzed by either aldolases or L-proline, were obtained in high yields and enantioselectivities of up to 96% ee with peptides 3 and 4 in aqueous media.     

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.     

Organocatalyzed highly enantioselective direct aldol reactions of aldehydes with hydroxyacetone and fluoroacetone in aqueous media: the use of water to control regioselectivity

An organocatalyst prepared from (2R,3R)-diethyl 2-amino-3-hydroxysuccinate and L-proline exhibited high regio- and enantioselectivities for the direct aldol reactions of hydroxyacetone and fluoroacetone with aldehydes in aqueous media. It was found that water could be used to control the regioselectivity. The presence of 20-30 mol% of the catalyst afforded the direct aldol reactions of a wide range of aldehydes with hydroxyacetone to give the otherwise disfavored products with excellent enantioselectivities, ranging from 91 to 99% ee, and high regioselectivities. Aldolizations of fluoroacetone with aldehydes mediated by 30 mol% of the organocatalyst in aqueous media preferentially occurred at the methyl group, yielding products with high enantioselectivities (up to 91% ee); however, these additions took place dominantly at the fluoromethyl group in THF. Optically active 3,5-disubstituted tetrahydrofurans and (2S,4R)-dihydroxy-4-biphenylbutyric acid were prepared by starting from the aldol reaction of hydroxyacetone. Theoretical studies on the role of water in controlling the regioselectivity revealed that the hydrogen bonds formed between the amide oxygen of proline amide, the hydroxy of hydroxyacetone, and water are responsible for the regioselectivity by microsolvation with explicit one water molecule as a hydrogen-bond donor and/or an acceptor.     

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.     

Practical and highly selective oxazolidinethione-based asymmetric acetate aldol reactions with aliphatic aldehydes

[reaction: see text] The utility of a valine-derived oxazolidinethione for auxiliary-based asymmetric acetate aldol reactions is reported. Titanium(IV) chloride, along with (-)-sparteine and N-methylpyrrolidinone, is employed for enolization. Subsequent aldol reaction with aliphatic aldehydes occurs with high diastereoselectivity (from 92:8 to 99:1 dr).     

(S)-Pyrrolidine sulfonamide catalyzed asymmetric direct aldol reactions of aryl methyl ketones with aryl aldehydes

A (S)-pyrrolidine sulfonamide catalyzed asymmetric direct aldol reaction of aryl methyl ketones with aromatic aldehydes has been developed with moderate to good enantioselectivities. The study considerably broadens the substrate scope of chiral amines promoted aldol processes.     

Proline-catalyzed asymmetric aldol reactions of tetrahydro-4H-thiopyran-4-one with aldehydes

Proline-catalyzed enantioselective direct intermolecular aldol reactions of tetrahydro-4H-thiopyran-4-one with various aldehydes give anti adducts with high diastereo- and enantioselectivities in moderate to excellent yields. With the aromatic aldehydes best results were obtained in wet DMF whereas dry DMSO generally was superior with the aliphatic aldehydes. Desulfurization of the adducts with Raney Ni provides products equivalent to aldols from 3-pentanone with potential applications in polypropionate synthesis.     

Dipeptide-catalyzed direct asymmetric aldol reactions in the presence of water

The l-proline-based dipeptide has been discovered and developed as an efficient catalyst for the direct asymmetric aldol reactions of unmodified ketones with various aldehydes including aromatic, aliphatic, heteroaromatic, and unsaturated aldehydes in the presence of water at 0 °C. The resulted methodology and optimal conditions led to the corresponding aldol products with high yields (up to 94%) and good enantioselectivities (up to 97% ee).     

Non-linear effects in acyclic amino acid-catalyzed direct asymmetric aldol reactions

Non-linear effects were observed in acyclic amino acid-catalyzed direct asymmetric intermolecular aldol reactions. The non-linear effects are due to the equilibrium solid-liquid phase behavior of amino acids. The results suggest that the phase behavior of amino acids linked to asymmetric catalysis may have implications to the evolution of homochirality.     

Organocatalytic asymmetric syn-selective direct aldol reactions in water

A practical and convenient organocatalytic strategy is developed to provide a direct route to syn-selective aldol products in the presence of water. The siloxy serine organocatalyst mediates the direct aldol reaction of TBSO-protected hydroxyacetone with a variety of aldehydes to provide the aldol products in good yields and enantioselectivities up to 92%.     

A highly efficient organocatalyst for direct aldol reactions of ketones with aldehydes [corrected

L-proline amides derived from various chiral beta-amino alcohols that bear substituents with various electron natures at their stereogenic centers are prepared and evaluated for catalyzing the direct Aldol reaction of 4-nitrobenzaldehyde with acetone. Catalysts with strong electron-withdrawing groups are found to exhibit higher catalytic activity and enantioselectivity than their analogues with electron-donating groups. The presence of 2 mol % catalyst 4g significantly catalyzes the direct Aldol reactions of a wide range of aldehydes with acetone and butanone, to give the beta-hydroxy ketones with very high enantioselectivities ranging from 96% to >99% ee. High diastereoselectivity of 95/5 was observed for the anti Aldol product from the reaction of cyclohexanone, and excellent enantioselectivity of 93% ee was provided for anti Aldol product from the reaction of cyclopentanone.     

Organocatalytic asymmetric direct aldol reactions of trifluoroacetaldehyde ethyl hemiacetal with aromatic methyl ketones

The organocatalytic asymmetric direct aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with aromatic methyl ketones in the presence of a catalytic amount of (S)-5-(pyrrolidin-2-yl)-1H-tetrazole in dichloroethane at 40 °C proceeds smoothly to produce (R)-4,4,4-trifluoro-1-aryl-3-hydroxy-1-butanones in high yields with up to 90% ee.     

Water-compatible organocatalysts for direct asymmetric syn-aldol reactions of dihydroxyacetone and aldehydes

A novel organocatalyst was developed that effectively catalyzed the reactions of unprotected or protected dihydroxyacetone with a variety of aldehydes to provide syn-aldol products with good yields and ee values up to >99%. Significantly, this amide catalyst was effective with a variety of nonaromatic aldehyde acceptors that had proven difficult in the presence of other catalysts. Reactions of protected dihydroxyacetone proceeded in aqueous media without addition of organic solvents.