Camphor containing organocatalysts in asymmetric aldol reaction on water

A new class of bifunctional organocatalysts were synthesized and proved to be effective in catalyzing aldol reaction on water with high to excellent diastereo- and enantioselectivities.     

A new (S)-prolinamide modified by an ionic liquid moiety—a high performance recoverable catalyst for asymmetric aldol reactions in aqueous media

New prolinamide derivatives modified with ionic liquid moieties were synthesized and studied as organocatalysts in asymmetric aldol reactions in water. Aldol reactions between cycloalkanones or methylketones and aromatic aldehydes proceeded under studied conditions with high conversions (yields), diastereo- and enantioselectivities in the presence of a hydrophobic catalyst bearing a PF₆ anion (1-5 mol %). The procedure is scalable and the catalyst retained its diastereo- and enantioselectivity over at least four reaction cycles and its activity over at least three reaction cycles.     

Direct asymmetric aldol reactions inspired by two types of natural aldolases: water-compatible organocatalysts and Zn(II) complexes

In this article the utility of water-compatible amino-acid-based catalysts was explored in the development of diastereo- and enantioselective direct aldol reactions of a broad range of substrates. Chiral C(2)-symmetrical proline- and valine-based amides and their Zn(II) complexes were designed for use as efficient and flexible chiral catalysts for enantioselective aldol reactions in water, on water, and in the presence of water. The presence of 5 mol % of the prolinamide-based catalyst affords asymmetric intermolecular aldol reactions between unmodified ketones and various aldehydes to give anti products with excellent enantioselectivities. We also demonstrate aldol reactions of more demanding substrates with high affinity to water (i.e., acetone and formaldehyde). Newly designed serine-based organocatalyst promoted aldol reaction of hydroxyacetone leading to syn-diols. For presented catalytic systems organic solvent-free conditions are also acceptable, making the elaborated methodology interesting from a green chemistry perspectives.     

Highly diastereo- and enantioselective direct aldol reactions promoted by water-compatible organocatalysts bearing a pyrrolidinyl-camphor structural scaffold

Efficient synthetic routes have been developed for the synthesis of a series of pyrrolidinyl-camphor containing organocatalysts (1-10). Structural modifications were made by varying the stereo- and electronic properties of the camphor scaffold and the aromatic substituents. These readily tunable and amphiphilic organocatalysts were evaluated for the direct asymmetric aldol reaction of various aromatic aldehydes and cyclohexanone either in organic solvents or in the presence of water. The aldol reaction proceeded smoothly with excellent chemical yields (up to 99%), enantioselectivities (up to 99% ee), and anti-diastereoselectivities (up to 99:1) with a catalytical amount of the bifunctional organocatalysts (20 mol %) under optimal reaction conditions. Mechanistic transition models are proposed and the stereochemical bias of the asymmetric aldol reaction is presented.     

A highly efficient solvent-free asymmetric direct aldol reaction organocatalyzed by recoverable (S)-binam-L-prolinamides. ESI-MS evidence of the enamine-iminium formation

Recoverable (S(a))-binam-L-prolinamide in combination with benzoic acid is used as catalysts in the direct aldol reaction between cycloalkyl, alkyl, and alpha-functionalized ketones and aldehydes under solvent-free reaction conditions. Three different methods are assayed: simple conventional magnetic stirring, magnetic stirring after previous dissolution in THF and evaporation, and ball mill technique. These procedures allow one to reduce not only the amount of required ketone to 2 equiv but also the reaction time to give the aldol products with regio-, diastereo-, and enantioselectivities comparable to those in organic or aqueous solvents. Generally anti-isomers are mainly obtained with enantioselectivities up to 97%. The reaction can be carried out under these conditions also using aldehydes as nucleophiles, yielding after in situ reduction of the aldol products the corresponding chiral 1,3-diols with moderate to high enantioselectivities mainly as anti-isomers. The aldol reaction has been studied by the use of positive ESI-MS technique, providing the evidence of the formation of the corresponding enamine-iminium intermediates.     

Combining prolinamides with 2-pyrrolidinone: Novel organocatalysts for the asymmetric aldol reaction

Peptides and especially prolinamides have been identified as excellent organocatalysts for the aldol reaction. The combination of prolinamides with derivatives bearing the 2-pyrrolidinone scaffold, deriving from pyroglutamic acid, led to the identification of novel organocatalysts for the intermolecular asymmetric aldol reaction. The new hybrids were tested both in organic and aqueous media. Among the compounds tested, 22 afforded the best results in petroleum ether, while 25 afforded the products in brine in high yields and selectivities. Then, various ketones and aldehydes were utilized and the products of the aldol reaction were obtained in high yields (up to 100%) with excellent diastereo- (up to 97:3 dr) and enantioselectivities (up to 99% ee).     

Highly efficient primary amine organocatalysts for the direct asymmetric aldol reaction in brine

Organocatalytic systems made up of six primary amine organocatalysts, derived from natural primary amino acids, in combination with 2,4-dinitrophenol (DNP) have proven to be efficient in the presence of brine without further addition of organic solvents. The system formed by 1f and DNP was the most efficient one; it can catalyze the direct aldol reaction with a broad range of ketones and aromatic aldehydes, giving the corresponding aldol products in high yields with up to nearly perfect diastereo- and enantioselectivities (up to 99/1 syn/anti, >99% ee).     

Amino acid catalyzed direct asymmetric aldol reactions: a bioorganic approach to catalytic asymmetric carbon-carbon bond-forming reactions.

Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with commercially available chiral cyclic secondary amines as catalysts. Structure-based catalyst screening identified L-proline and 5,5-dimethyl thiazolidinium-4-carboxylate (DMTC) as the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding aldol products with high regio-, diastereo-, and enantioselectivities. Reactions employing hydroxyacetone as an aldol donor provide anti-1,2-diols as the major product with ee values up to >99%. The reactions are assumed to proceed via a metal-free Zimmerman-Traxler-type transition state and involve an enamine intermediate. The observed stereochemistry of the products is in accordance with the proposed transition state. Further supporting evidence is provided by the lack of nonlinear effects. The reactions tolerate a small amount of water (<4 vol %), do not require inert reaction conditions and preformed enolate equivalents, and can be conveniently performed at room temperature in various solvents. In addition, reaction conditions that facilitate catalyst recovery as well as immobilization are described. Finally, mechanistically related addition reactions such as ketone additions to imines (Mannich-type reactions) and to nitro-olefins and alpha,beta-unsaturated diesters (Michael-type reactions) have also been developed.     

Small organic molecule catalyzed enantioselective direct aldol reaction in water

Protonated pyrrolidine based small organic molecules have been designed and evaluated for the asymmetric direct aldol reaction in water. The designed organocatalysts are multifunctional in nature and exploit the combined effect of hydrogen bonding and hydrophobic interactions for enantioselective catalysis in water. As a result a unique direct asymmetric aldol reaction in water catalyzed by a small organic molecule having an amide linkage has been developed. The developed catalyst affords chiral β-hydroxyketones in good yields (93%) and enantioselectivities (upto 62%) in water.     

tert-Butyl esters of tripeptides based on Pro-Phe as organocatalysts for the asymmetric aldol reaction in aqueous or organic medium

The enantioselective aldol reaction between ketones and aldehydes constitutes one the most common reaction models for the evaluation of novel organocatalysts. The last few years, it has been shown that the organocatalytic aldol reaction can be performed in water. A family of tripeptides consisting of proline, phenylalanine, and tert-butyl esters of amino acids was successfully employed in this asymmetric transformation. The products of the reaction between various ketones and aldehydes were obtained in high yields (up to 99%) with excellent diastereo- (up to 97:3 dr) and enantioselectivities (up to 99% ee). The C-terminal amino acid determines the ability of the tripeptide (Pro-Phe-AA-O^tBu) to act efficiently in aqueous or organic medium.     

Stereoselective aldol additions of achiral ethyl ketone-derived trichlorosilyl enolates

Methods for the preparation of geometrically defined enoxy(trichlorosilanes) derived from ethyl ketone enolates have been developed. The addition of enoxy(trichlorosilanes) (trichlorosilyl enolates) to aldehydes proceeds with good yields in the presence of catalytic amounts of chiral phosphoramides. The reaction of Z-trichlorosilyl enolates to aryl aldehydes affords aldol products with good to excellent diastereo- and enantioselectivities. Phosphoramide-catalyzed aldol additions lacked substrate generality providing modest selectivities with unsaturated and aliphatic aldehydes. In all cases, the phosphoramide-catalyzed aldol addition of E-trichlorosilyl enolates to aldehydes provided good yields with moderate to good stereoselectivities.     

Novel sulfonylpolystyrene-supported prolinamides as catalysts for enantioselective aldol reaction in water

Five novel prolinamides derived from 1,n-diamines supported on commercially available sulfonylpolystyrene have been synthesized and successfully applied in diastereo- and enantioselective aldol reaction in water or, in one case, neat conditions. Excellent dr and er were obtained by reaction of different cyclohexanone derivatives with aromatic and heteroaromatic aldehydes in the presence of the catalysts and AcOH as co-catalyst. The supported organocatalysts work in low loading (5 mol %) exhibiting similar performances than homogeneous prolinamides, and can be reused, after activation, without loss of activity.     

Recoverable silica-gel supported binam-prolinamides as organocatalysts for the enantioselective solvent-free intra- and intermolecular aldol reaction

Silica-gel supported binam-derived prolinamides are efficient organocatalysts for the direct intramolecular and intermolecular aldol reaction under solvent-free conditions using conventional magnetic stirring. These organocatalysts in combination with benzoic acid showed similar results to those obtained under similar homogeneous reaction conditions using an organocatalyst of related structure. For the intermolecular process, the aldol products were obtained at room temperature and using only 2 equiv of the ketone with high yields, regio-, diastereo- and enantioselectivities. Under these reaction conditions, also the cross aldol reaction between aldehydes is possible. The recovered catalyst can be reused up to nine times providing similar results. More interestingly, these heterogeneous organocatalysts can be used in the intramolecular aldol reaction allowing the synthesis of the Wieland–Miescher and ketone analogues with up to 92% ee, with its reused being possible up to five times without detrimental on the obtained results.     

Highly diastereo- and enantioselective direct aldol reaction under solvent-free conditions

An efficient, solvent-free protocol for the asymmetric aldol reaction between aldehydes and ketones using prolinamides 1–4 as organocatalysts is reported. Catalysts 2–4, in the presence of TFA (the ratio of catalyst and TFA = 1/1.5), proved to be excellent catalysts, giving the aldol products between aromatic aldehydes and ketones with nearly perfect diastereo- and enantioselectivities (up to >99:1 dr and >99% ee). This catalytic system can also be applied in the cross-aldol reaction of isatin with ketones and the Michael reaction between cyclohexane and nitroalkenes. A mechanism is proposed to account for the formation of the major enantiomer in this reaction.     

Highly anti-selective asymmetric aldol reactions using chiral zirconium catalysts. Improvement of activities, structure of the novel zirconium complexes, and effect of a small amount of water for the preparation of the catalysts

Catalytic asymmetric aldol reactions of silyl enol ethers with aldehydes (Mukaiyama aldol reactions) have been performed using novel chiral zirconium catalysts. The reactions proceeded in high yields under mild conditions, and anti-adducts were obtained in high diastereo- and enantioselectivities. The catalysts were first prepared from zirconium(IV) tert-butoxide (Zr(O(t)Bu)(4)), (R)-3,3'-diiodo-1,1'-binaphthalene-2,2'-diol ((R)-3,3'-I(2)BINOL), a primary alcohol, and a small amount of water. It was revealed that the primary alcohol played an important role in completing the catalytic cycle and that a small amount of water was essential for obtaining high selectivities. Moreover, activities of the chiral zirconium catalysts were enhanced by using new ligands, (R)-3,3'-I(2)-6,6'-X(2)BINOL (X = Br, I, C(2)F(5)), and it has been shown that even aldol reactions of less reactive substrates proceeded smoothly using the novel zirconium catalysts. Finally, NMR studies of these catalysts were performed, which suggested that the catalyst would form a dimeric structure and that the water affected the catalyst formation.     

Aminophosphonates as organocatalysts in the direct asymmetric aldol reaction: towards syn selectivity in the presence of Lewis bases

Chiral alpha-aminophosphonates have been synthesized and their performance was evaluated as organocatalysts in the direct asymmetric aldol reaction. High enantioselectivities (up to 99% ee) were achieved for a range of substituted cyclohexanones and benzaldehydes. Several organic bases, such as DBU, DBN, and TMG, were used together with the alpha-aminophosphonates in the aldol reactions and were found to favor syn-selectivity.     

Review of the aldol reaction

Aldol condensation is an important synthetic method widely used in organic synthesis. Development of catalytic methods that avoids the production of stoichiometric by-products while maintaining high levels of control available from stoichiometric processes provides an atom-economical alternative for these important transformations. Indeed, numerous catalysts for the aldol reaction have been reported in recent years, including enzymes, catalytic antibodies, organometals, organocatalysts, and small molecules. The direct aldol reaction is the most important reaction employed by synthetic chemists and is common in nature. Recently, various Lewis acids have been examined as catalysts for aldol reactions, but aldol condensation in a micellar medium has not been studied in detail so far. Because of stronger environmental concerns, organic reactions in green media, especially in water, have attracted more attention. It is believed that micelles act as nano reactors to enhance the reaction rates and give very good to excellent yields of end products.     

Trichlorosilyl triflate for enantioselective direct-type aldol reaction with chiral phosphine oxide

Trichlorosilyl triflate, in the presence of a chiral Lewis base catalyst, provides an effective method for the enantioselective direct-type aldol reaction of aldehydes and ketones. A chiral Lewis base induces both the production and activation of trichlorosilyl enol ether, yielding an aldol product in good yield and with high diastereo- and enantioselectivities.     

Proline dipeptides containing fluorine moieties as oganocatalysts for the asymmetric aldol reaction

A series of dipeptide analogues consisting of proline, phenylalanine and aniline- or phenol-fluorine derivatives were synthesized. Their catalytic ability was evaluated in the intermolecular asymmetric aldol reaction, both in organic and aqueous media. Aniline-fluorine derivatives proved to be superior and the best results were obtained, when 2-CF₃ aniline was employed. A diverse substrate scope consisting of both aromatic and aliphatic aldehydes, as well as different ketones was demonstrated, where aromatic aldehydes afforded products in high yields (up to 100%) with excellent diastereo- (up to 95:5) and enantioselectivities (up to 97%), whereas the aliphatic aldehydes afforded also excellent selectivities, but relatively low yield. A simple addition of fluorine to a dipeptide analogue affords organocatalysts with new interesting properties that can catalyze the aldol reaction more efficiently.     

Synthesis of chiral organocatalysts derived from aziridines: application in asymmetric aldol reaction

We report the synthesis of a new series of highly efficient chiral organocatalysts derived via the regio- and stereoselective ring opening of chiral aziridines with azide anions. The catalysts have proved to be very efficient for a direct asymmetric aldol reaction, both with cyclic as well as acyclic ketones in brine with 2 mol % of catalyst loading, and afforded the products in excellent yields (up to 99%) and enantioselectivities (up to >99%). The chiral aldol adduct obtained has further been converted to a chiral azetidine ring via a convenient pathway.