A new type of amino amide organocatalyzed enantioselective crossed aldol reaction of ketones with aromatic aldehydes

A new type of amino amide organocatalysts was designed and synthesized from commercially available amino acids in easy steps. Their catalytic activities were examined in enantioselective crossed aldol reaction of various acyclic and cyclic ketones with aromatic aldehydes to afford the corresponding chiral anti-aldol adducts with good to excellent chemical yields, diastereoselectivities and enantioselectivities (up to 99%, up to syn:anti?=?1:99, up to 97% ee).     

The application of a structurally simple,recyclable, and large-scale l-prolinamide catalyst for asymmetric aldol reactions

A highly efficient, bifunctional prolinamide catalyst, which consists of chiral proline and trans-cyclohexanediamine moieties, was prepared and evaluated in the direct asymmetric aldol reactions of various ketones and aldehydes. The catalyst displayed impressive catalytic activity toward heterocyclic ketones containing oxygen, sulfur, or nitrogen, which have not been sufficiently explored. The substrate scope also covered cyclic and acyclic ketones. With heterocyclic ketones or cyclohexanone, the aldol reactions gave products in high yields and with respectable enantioselectivities (87–99% ee) and diastereoselectivities (up to >99:1 anti/syn). The catalyst could be recycled and reused up to seven times resulting in good yields and with good selectivities. This catalyst is also efficient in large-scale reactions with the enantioselectivities remaining at the same level as in the experimental scale reactions.     

Expanding the scope of the asymmetric anti-aldol addition of chiral N-amino cyclic carbamate hydrazones

An asymmetric anti-aldol addition process of ketone-derived donors that is not limited by the structure of the ketone is described. This is achieved by merging the enantioselective α,α-bisalkylation of N-amino cyclic carbamate (ACC) hydrazones with the asymmetric anti-aldol addition of ACC hydrazones. The products of this process are obtained with essentially perfect stereoselectivity. Using this procedure it is possible to gain access to ketone-based anti-aldol addition products that are inaccessible in a controlled sense via direct aldol methods.     

Asymmetric aldol reactions between cyclic ketones and benzaldehyde catalyzed by chiral Zn2+ complexes of aminoacyl 1,4,7,10-tetraazacyclododecane: effects of solvent and additives on the stereoselectivities of the aldol products

The direct aldol reaction between cyclic ketones and 4-nitrobenzaldehyde catalyzed by chiral Zn²⁺ complexes of aminoacyl 1,4,7,10-tetraazacyclododecane is reported. The anti-aldol products were mainly formed in cyclohexanone/N-methylpyrrolidone(NMP)/MeOH with good diastereo- and enantioselectivity, while syn-aldol adducts were obtained as major products with good enantioselectivity in cyclohexanone/H₂O and cyclohexanone/NMP/H₂O. The fact that the UV/vis spectra of 2,6-diphenyl-4-(2,4,6-triphenyl-1-pyridinio)phenolate (Reichardt’s dye) were nearly identical in these solvent systems suggests that the switch in the relative configuration of the aldol products is induced by a large excess of H₂O rather than the polarity of the solvent system. Furthermore, the addition of a small amount of TFA improved the enantioselectivity of the syn-aldol adducts produced in cyclohexanone/H₂O with up to 92% ee (anti/syn ratio = 30:70).     

Highly stereoselective direct aldol reactions catalyzed by (S)-NOBIN-l-prolinamide

(S)-NOBIN-l-prolinamide was employed as organocatalyst in the direct aldol reactions of different ketones and aromatic aldehydes using dioxane as solvent and in the presence of water as additive. Acetone led to the aldol products in up to 93% ee, while cyclic ketones furnished the anti-aldols in moderate to high yield, excellent diastereoselectivity (up to >99/<1 anti/syn ratio) and high ee (up to 95%).     

Direct asymmetric aldol reactions in brine using novel sulfonamide catalyst

Direct asymmetric aldol reactions of aldehydes with ketones in the presence of a catalytic amount of sulfonamide 4 and trifluoroacetic acid afforded the corresponding anti-aldol products in moderate to excellent yields with 85-93% ee.     

Highly enantioselective synthesis of syn- and anti-propionate aldols without diastereoselection in the chiral oxazaborolidinone-promoted aldol reaction with a silyl ketene acetal derived from ethyl 2-(methylthio)propionate

A mixture of syn- and anti-aldol products containing an α-methylthio group were obtained in good yields with high enantioselectivities in the chiral oxazaborolidinone-promoted aldol reactions of a novel silyl ketene acetal, derived from ethyl 2-(methylthio)propionate, with aldehydes. Subsequent desulfurization resulted in an effective preparation of essentially enantiopure syn- and anti-propionate aldols which were separable.     

Direct asymmetric aldol reactions in brine with recyclable fluorous β-aminosulfonamide organocatalysts

Fluorous organocatalyst 3 promotes direct asymmetric aldol reactions of ketones with aldehydes in brine, leading to the synthesis of the corresponding anti-aldol products in high yields with up to 96% ee. Fluorous organocatalyst 3 is easily recovered by solid-phase extraction using fluorous silica gel and can be reused up to five times without purification.     

Chiral enolates for highly stereoselective aldol reactions—Scope and limitations

Enantioselective approaches to the formation of α,β-disubstituted ketones through aldol reactions are compared. A one-pot ACA/aldol domino process is lower yielding than alternative procedures involving enantiomerically pure β-substituted silyl enol ethers. The use of chiral acetals derived from hydrobenzoin provides access to syn and anti diols in moderate to good yields and high diastereoselectivities. A novel synthesis of functionalized β,γ-unsaturated acetals is also described.     

Inherently chiral calix[4]arene-based bifunctional organocatalysts for enantioselective aldol reactions

Two optical pure m-dimethylamino substituted inherently chiral calix[4]arene derivatives 8a and 8b bearing an l-prolinamido group have been synthesized by two routes, and structurally studied by the usual spectroscopic methods and X-ray crystallographic analysis. It was found that both of 8a and 8b could be utilized as bifunctional organocatalysts to efficiently promote the aldol reactions between aromatic aldehydes and ketones in the presence of acetic acid. Especially, with 8a as the catalyst, the reaction between 4-nitrobenzaldehyde and cyclopentanone at −20 °C gave the anti-aldol product up to 94% ee, while the anti-aldol product in up to 94:6 dr and 79% ee was obtained when 4-cyanobenzaldehyde was used as the aldol donor. Moreover, it was also demonstrated that the inherently chiral calixarene skeleton with (cS)-conformation in 8a was identified as the matched configuration of the stereogenic elements, and the inherently chiral moiety might play an important role in helping to stereocontrol the reaction.     

Enantioselective Nickel-Catalyzed anti-Arylmetallative Cyclizations onto Acyclic Ketones

Domino reactions involving nickel-catalyzed additions of (hetero)arylboronic acids to alkynes, followed by cyclization of the alkenylnickel intermediates onto tethered acyclic ketones to give chiral tertiary-alcohol-containing products in high enantioselectivities, are described. The reversible E/Z isomerization of the alkenylnickel intermediates enables overall anti-arylmetallative cyclization to occur. The ring system of the products are substructures of certain diarylindolizidine alkaloids.     

Highly Enantioselective Aldol Reactions between Acetaldehyde and Activated Acyclic Ketones Catalyzed by Chiral Primary Amines

Highly enantioselective cross‐aldol reactions between acetaldehyde and activated acyclic ketones are reported for the first time. Various acyclic ketones, such as saturated and unsaturated keto esters, reacted with acetaldehyde in the presence of a chiral primary amine and a Brønsted acid to afford optically enriched tertiary alcohols in good yields and with excellent enantioselectivities. Trifluoromethyl ketones were tolerable under the reaction conditions, thereby affording the trifluoromethyl carbinol in good‐to‐excellent yields and enantioselectivities. Structural modification of the chiral amines from the same chiral source switched the stereoselectivity of the products. The utility of aldol chemistry was demonstrated in the brief synthesis of functionally enriched δ‐lactones. Theoretical calculations on the transition‐state structure indicated that the protonated tertiary amine could effectively activate the carbonyl group of a keto ester to promote the addition process through hydrogen‐bonding interaction and, simultaneously, provide an appropriate attacking pattern for the approach of the keto ester to the enamine, which is formed from acetaldehyde and the chiral catalyst, on a particular face, resulting in high enantioselectivity.     

Switching diastereoselectivity of direct Mannich-type reaction of cyclic ketones by polymeric laponite nanoclay catalyst

A new polymeric laponite nanoclay heterogeneous catalytic system based on HPMC (hydroxypropyl methyl cellulose) was developed for direct Mannich-type reaction of ketones with substituted benzaldehydes and anilines to afford corresponding β-amino ketones in good to high yields. Interestingly, cyclic ketones exhibited different chemoselectivity. Cyclopentanone underwent aldol condensation to give crossed-aldol product, while cyclohexanone and cyclopentanone afforded corresponding Mannich adducts. In the case of cyclohexanone, stereoselectivity was changed depending on the nature of the substitution on benzaldehydes, in which, moderate electron-donating and electron-withdrawing groups afforded the anti isomer as major products, but strongly electron-donating substituted benzaldehydes led to syn isomer as the major Mannich adducts. Mannich reaction with cycloheptanone led to Mannich adducts with excellent syn selectivity.     

Enantioselective aldol reactions with aqueous 2,2-dimethoxyacetaldehyde organocatalyzed by binam-prolinamides under solvent-free conditions

Aqueous 2,2-dimethoxyacetaldehyde (60% wt solution) is used as an acceptor in aldol reactions, with cyclic and acyclic ketones and aldehydes as donors, organocatalyzed by 10 mol % of N-tosyl-(S_a)-binam-l-prolinamide [(S_a)-binam-sulfo-l-Pro] at rt under solvent-free conditions. The corresponding monoprotected 2-hydroxy-1,4-dicarbonyl compounds are obtained in good yields and with high levels of diastereo- and enantioselectivity mainly as anti-aldols. In the case of 4-substituted cyclohexanones a desymmetrization process takes place to mainly afford the anti,anti-aldols. 2,2-Dimethyl-1,3-dioxan-5-one allows the synthesis of a useful intermediate for the preparation of carbohydrates in higher yield, de and ee than with l-Pro as the organocatalyst.     

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.     

Chiral base-catalyzed aldol reaction of trimethoxysilyl enol ethers: effect of water as an additive on stereoselectivities

An aldol reaction of trimethoxysilyl enol ether catalyzed by lithium binaphtholate is described. The aldol reaction of trimethoxysilyl enol ether derived from cyclohexanone under anhydrous conditions predominantly afforded the anti-aldol adduct with moderate enantioselectivity, whereas the reaction under aqueous conditions predominantly resulted in the syn-adduct and the enantioselectivity of the syn-adduct was considerably improved. The best enantioselectivity was obtained in the reaction of trimethoxysilyl enol ether derived from 1-indanone with cyclohexanecarboxaldehyde (97% ee (syn)). This is the first example of an aldol reaction of trimethoxysilyl enol ether catalyzed by a chiral base.     

Enantioselective aldol reactions of trichlorosilyl enol ethers catalyzed by chiral N,N-dioxides and monodentate N-oxides

Chiral N,N^′-dioxides and monodentate N-oxides were employed as catalysts in catalytic, enantioselective aldol reactions of trichlorosilyl enol ethers. The reactions of acyclic enol ethers using N,N^′-dioxides resulted in the anti-adducts from (E)-enol ethers and the syn-adducts from (Z)-enol ethers. The reactions of cyclic (E)-enol ethers using N,N^′-dioxides gave the anti-adducts, whereas monodentate N-oxides predominantly gave the syn-adducts.     

The first example of a catalytic asymmetric aldol-Tishchenko reaction of aldehydes and aliphatic ketones

A number of combinations of Lewis acids and chiral ligands has been screened for the enantioselective direct tandem aldol condensation--Evans-Tishchenko reduction of aldehydes and ketones. Chiral ytterbium complexes were found to catalyze the condensation of aromatic aldehydes with 3-pentanone (and other ketones) giving rise to the anti-1,3-diol monoesters in good yield, and with high diastereocontrol and moderate levels of enantioselectivity. Three adjacent stereogenic centers are created in one reaction sequence in acyclic systems.     

Construction of quaternary carbon centers by a base-catalyzed enantioselective aldol reaction and related reactions of trimethoxysilyl enol ethers

The aldol reactions of trimethoxysilyl enol ethers catalyzed by lithium binaphtholate were found to be powerful tools for the construction of quaternary asymmetric carbon centers. The stereoselectivities were greatly affected by the presence of water. Trimethoxysilyl enol ether derived from a cyclic ketone, such as cyclohexanone, was used as a substrate to obtain the anti-adduct preferentially under anhydrous conditions; by contrast, the syn-adduct was preferentially obtained under aqueous conditions with high stereoselectivity. The aldol-Tishchenko reaction of a trimethoxysilyl enol ether derived from acyclic ketones proceeded to give monoacyl 1,3-diol derivatives in high enantioselectivities.     

On the Mechanism of the Asymmetric Aldol Addition of Chiral N-Amino Cyclic Carbamate Hydrazones: Evidence of Non-Curtin–Hammett Behavior

he mechanistic details of the aldol addition of N-amino cyclic carbamate (ACC) hydrazones is provided herein from both an experimental and computational perspective. When the transformation is carried out at room temperature the anti-aldol product is formed exclusively. Under these conditions the anti- and syn-aldolate intermediates are in equilibrium and the transformation is under thermodynamic control. The anti-aldolate that leads to the anti-aldol product was calculated to be 3.7 kcal mol⁻¹ lower in energy at room temperature than that leading to the syn-aldol product, which sufficiently accounts for the exclusive formation of the anti-aldol product. When the reaction is conducted at −78 °C it is under kinetic control and favors formation of the syn-aldol addition product. In this case, it was found that a solvent separated aza-enolate anion and aldehyde form a σ-intermediate in which the lithium cation is coordinated to the aldehyde. The σ-intermediate collapses with a very small activation barrier to form the β-alkoxy hydrazone intermediate. The chiral nonracemic lithium aza-enolate discriminates between the two diastereotopic faces of the pro-chiral aldehyde, and there is no rapid direct pathway that interconverts the two diastereomeric intermediates. Consequently, the reaction does not follow the Curtin–Hammett principle and the stereochemical outcome at low temperature instead depends on the relative energies of the two σ-intermediates.