Organocatalytic Aldol Reaction Research Articles

ChemInform Abstract: Synthesis of a Potential Intermediate for TMC‐95A via an Organocatalyzed Aldol Reaction.

AbstractThis describes the synthesis of pseudopeptide organocatalysts and their application in the asymmetric aldol reaction to yield compounds (III).

Fluorogenic aldehydes bearing arylethynyl groups: turn-on aldol reaction sensors for evaluation of organocatalysis in DMSO

Fluorogenic aromatic aldehydes bearing arylethynyl groups were developed. They were used for monitoring the reaction progress of organocatalytic aldol reactions in DMSO through an increase in the fluorescence intensity based on the formation of the florescent aldol product. The ratios of the fluorescence intensities of the aldols to the aldehydes were more than 300. These results suggest that the fluorescence assay system using the aldehyde is useful for the rapid identification of superior aldol catalysts and reaction conditions.

Aqueous organocatalyzed aldol reaction of glyoxylic acid for the enantioselective synthesis of α-hydroxy-γ-keto acids

N-Tosyl-(Sa)-binam-L-prolinamide is an efficient catalyst for the aqueous aldol reaction, between glyoxylic acid, as monohydrate or aqueous solution, and ketones. This reaction led to the formation of chiral α-hydroxy-γ-keto carboxylic acids in high levels of diastereo- and enantioselectivities achieving mainly anti aldol products.

Organocatalytic Asymmetric Aldol Reactions in Aqueous or Neat Conditions: Review of Data Published in 2009-2013

Organocatalytic Asymmetric Aldol Reactions in Aqueous or Neat Conditions: Review of Data Published in 2009-2013

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-OtBu) to act efficiently in aqueous or organic medium.

ChemInform Abstract: Asymmetric Organocatalytic Aldol Reaction in Water: Mechanistic Insights and Development of a Semi‐Continuously Operating Process.

AbstractA detailed study on the influence of the catalyst loading on conversion and enantioselectivity of the aldol reaction between acetone and an aromatic aldehyde is presented.

Synthesis of a Potential Intermediate for TMC-95A via an Organocatalyzed Aldol Reaction

N-Prolinylanthranilamide-based pseudopeptide organocatalyst 14 was shown to promote enantioselective direct aldol reaction of 7-iodoisatin and 2,2-dimethyl-1,3-dioxan-5-one with 90% conversion (75% isolated yield), 90% enantioselectivity, and 23:1 diastereoselectivity. To demonstrate the synthetic utility of this chemistry, the racemic aldol reaction product was converted in five steps to a potential intermediate for construction of the natural product TMC-95A.

Organocatalyzed Aldol Reaction between Pyridine‐2‐carbaldehydes and α‐Ketoacids: A Straightforward Route towards Indolizidines and Isotetronic Acids

Enantioselective aldol reactions between substituted pyridine carbaldehydes and α-ketoacids were shown to provide isotetronic acids or their corresponding pyridinium salts, depending on the nature of the substituents on the pyridine ring. The pyridinium salts were generated through nucleophilic attack of the pyridine nitrogen atom onto the reactive keto functional group. Moderate-to-good yields of both compounds were typically obtained and high levels of enantioselectivity were observed by using benzimidazole pyrrolidine I as a catalyst. Hydrogenation of the resulting pyridinium salts led to new indolizidines with high ee values and diastereocontrol. X-ray diffraction studies allowed the determination of the relative configuration of the products. Finally, DFT calculations were performed to rationalize the divergent pathway as a function of the pyridine substituents.

Towards catalyst compartimentation in combined chemo- and biocatalytic processes: Immobilization of alcohol dehydrogenases for the diastereoselective reduction of a β-hydroxy ketone obtained from an organocatalytic aldol reaction

The alcohol dehydrogenases (ADHs) from Lactobacillus kefir and Rhodococcus sp., which earlier turned out to be suitable for a chemoenzymatic one-pot synthesis with organocatalysts, were immobilized with their cofactors on a commercially available superabsorber based on a literature known protocol. The use of the immobilized ADH from L. kefir in the reduction of acetophenone as a model substrate led to high conversion (>95%) in the first reaction cycle, followed by a slight decrease of conversion in the second reaction cycle. A comparable result was obtained when no cofactor was added although a water rich reaction media was used. The immobilized ADHs also turned out to be suitable catalysts for the diastereoselective reduction of an organocatalytically prepared enantiomerically enriched aldol adduct, leading to high conversion, diastereomeric ratio and enantioselectivity for the resulting 1,3-diols. However, at a lower catalyst and cofactor amount being still sufficient for biotransformations with “free” enzymes the immobilized ADH only showed high conversion and >99% ee for the first reaction cycle whereas a strong decrease of conversion was observed already in the second reaction cycle, thus indicating a significant leaching effect of catalyst and/or cofactor.

Asymmetric Organocatalytic Aldol Reaction in Water: Mechanistic Insights and Development of a Semi-Continuously Operating Process

A detailed study on the impact of the catalyst loading on conversion and enantioselectivity of the direct aldol reaction of an aldehyde and acetone in aqueous solvent with nonimmobilized and immobilized proline amide-based organocatalysts is described. Based on a polymer-supported catalyst, batch and semi-continuously operating processes, comprising recycling studies in the latter case, were investigated.

Organocatalytic aldol reaction of indole-3-carbaldehydes with ketones: synthesis of chiral 3-substituted indoles

An efficient aldol reaction of indole-3-carbaldehydes with ketones is described. O-TBS-protected l -threonine promoted the aldol addition of ketones to indole-3-carbaldehydes affording 3-indolylmethanols with good to excellent yields and diastereoselectivities, and excellent enantioselectivities.

Organocatalytic syn‐Aldol Reactions of Hydroxy Ketones with (S)‐Isoserinal: Asymmetric Synthesis of 6‐Deoxy‐1,5‐iminohexitols and Related Compounds

AbstractAn improved and convenient preparation of protected (S)‐isoserinal on a large scale is reported. This key intermediate was reacted through organocatalyzed aldol reaction or Wittig based chain extension and functionalization to give enantiopure 1,5,6‐trideoxy‐1,5‐imino‐hexitols such as 10a (L‐manno) and 10b (D‐gluco). These two compounds are of interest as glycosidase inhibitors. The elaborated organocatalytic process includes diastereoselective syn aldol reaction of (S)‐isoserinal hydrate and hydroxyacetone or 1‐hydroxy‐2‐octanone and is promoted by various amino acid‐based catalysts. Diastereoselectivities of up to 8:1 were achieved, thus establishing a new, efficient synthetic route to these important carbohydrate mimics.

Asymmetric Synthesis of Gonioheptolide A Analogues via an Organocatalytic Aldol Reaction as the Key Step

An efficient asymmetric synthesis of the potential antitumor agent (–)-gonioheptolide A derivatives is described. By employing an (S)-proline-catalyzed aldol reaction, the RAMP hydrazone α-alkylation methodology, and a diastereoselective reduction with zinc borohydride five stereocenters are established in the target compound. 4-epi-Methoxy-gonioheptolide A was obtained in ten steps in 15% overall yield and excellent diastereo- and enantiomeric excesses (de ≥95%, ee ≥99%).

ChemInform Abstract: Organocatalytic Asymmetric Vinylogous Aldol Reactions

AbstractReview: about 50 refs.

A Liquid–Liquid Biphasic Homogeneous Organocatalytic Aldol Protocol Based on the Use of a Silica Gel Bound Multilayered Ionic Liquid Phase

AbstractAn innovative two stage liquid–liquid biphasic homogeneous protocol for the asymmetric organocatalytic aldol reaction is proposed, based on the use of the cis‐ion‐tagged proline 8 dissolved in the liquid film of a multilayered ionic liquid covalently bonded to silica gel 4. The resulting catalytically active material 9 is first soaked with cyclohexanone in the presence of water, resulting in a semi‐transparent gel, then the aldehyde is added and the mixture stirred at RT. In the first stage, 4 acts as a catalyst reservoir that delivers 8 to the cyclohexanone phase allowing the reaction to take place homogeneously. In the second stage, cyclohexanone is removed under vacuum and the resulting slurry is extracted with anhydrous diethylether. Now 4 acts as a catalyst sponge, redissolving 8. Product extraction is extremely selective; no trace of catalyst is detected in the product‐containing phase, and 9 can be easily reused several times with high cumulative productivity values (up to 523).

ChemInform Abstract: Enantioselective Organocatalytic Aldol Reaction of Unactivated Ketones with Isatins.

AbstractThe process affords 3‐alkyl‐3‐hydroxyindolin‐2‐ones including (R)‐convolutamydine A (IIIc).

ChemInform Abstract: Developing Novel Organocatalyzed Aldol Reactions for the Enantioselective Synthesis of Biologically Active Molecules

AbstractReview: ca. 100 refs.

ChemInform Abstract: Organocatalytic Asymmetric Aldol Reaction of Ketones with β,γ‐Unsaturated α‐Keto Esters: An Efficient Access to Chiral Tertiary Alcohol Skeletons.

This update describes a highly efficient organocatalytic aldol reaction of ketones and β,γ-unsaturated α-keto esters for constructing the chiral tertiary alcohol motif. With the application of 9-amino(9-deoxy)epi-Cinchona alkaloid and an acidic additive as catalysts, both acyclic and cyclic ketones react with β,γ-unsaturated α-keto esters smoothly to afford aldol adducts in good to excellent yields and asymmetric induction. This protocol offers a new pathway for the construction of adjacent chiral carbon centers and the synthesis of chiral β-hydroxy carbonyl compounds.

Toward a computational tool predicting the stereochemical outcome of asymmetric reactions: Development of the molecular mechanics‐based program ACE and application to asymmetric epoxidation reactions

The development and application of ACE, a program that predicts the stereochemical outcome of asymmetric reactions is presented. As major implementations, ACE includes a genetic algorithm to carry out an efficient global conformational search combined with a conjugate gradient minimization routine for local optimization and a corner flap algorithm to search ring conformations. Further improvements have been made that enable ACE to generate Boltzmann populations of conformations, to investigate highly asynchronous reactions, to compute fluctuating partial atomic charges and solvation energy and to automatically construct reactants and products from libraries of catalysts and substrates. Validation on previously investigated reactions (asymmetric Diels Alder cycloadditions and organocatalyzed aldol reactions) followed by application to a number of alkene epoxidation reactions and a comparative study of DFT-derived and ACE-derived predictions demonstrate the accuracy and usefulness of ACE in the context of asymmetric catalyst design.

Prolinethioamides versus Prolinamides in Organocatalyzed Aldol Reactions—A Comparative Study

Various organocatalysts have been developed for the aldol reaction but particular attention has been paid to prolinamide derivatives. They are easy to prepare and their catalytic activity can be readily tuned through structural modification. In this review, the comparison of catalytic activities between prolinethioamides and their respective amides in direct asymmetric aldol reactions is presented.