Enantioselective direct aldol reaction: the blossoming of modern organocatalysis

The use of simple (S)-proline as catalyst for the intermolecular direct aldol reaction at the beginning of this century became a true milestone in the growth of organocatalysis as a useful synthetic strategy. Since then, a plethora of new organocatalytic systems have been developed allowing to reach extraordinary levels of efficiencies, widening the scope of substrates used. Several modifications have been introduced to overcome some of the initial drawbacks, such as long reaction times, high catalyst loading, excess of reagents, etc., improving the expectations for their use in large scale synthesis. All these achievements would not be possible without a partial understanding of the involved mechanism. The acquired knowledge in this area has allowed the application of this strategy to be used in the synthesis of natural products. Within this review, a comprehensive look of all these aspects will be discussed.     

Ionic liquid mediated recyclable sulphonimide based organocatalysis for aldol reaction

Sulphonimide based organocatalyst was used to catalyze the aldol reaction in ionic liquid media. On the basis of yield and selectivity the ionic liquid mediated system was found superior in comparison with organic solvents. The added advantages of this ionic liquid mediated organocatalysis are easy recovery of product and the recyclability of the organocatalyst.      

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.     

Switching the reactivity of dihydrothiopyran-4-one with aldehydes by aqueous organocatalysis: Baylis-Hillman, aldol, or aldol condensation reactions

An aqueous medium containing catalytic amounts of a tertiary amine was employed to direct the chemoselectivity of the reaction of aldehydes with 1a. With DBU, 2 was formed at room temperature as a rare exemplary of Baylis-Hillman reactions in heterocyclic enones. DABCO alternated the pathway toward an aldol reaction to form syn/anti mixtures of 3 with the syn isomers being the major products. With Et(3)N, aldol condensation dominated.     

Zn-proline catalyzed direct aldol reaction in aqueous media

Zn complexes of proline, lysine and arginine are efficient catalysts for the aldol addition of p-nitrobenzaldehyde and acetone in aqueous medium, giving quantitative yields and enantiomeric excesses up to 56% with 5 mol% of the catalysts at room temperature.     

Carbohydrate-based organocatalysts in direct asymmetric aqueous aldol reaction

Aldol reaction involving chiral amines as organocatalysts through enamine formation, like class-I aldolases, is one of the thriving areas of general interest and widely applicable asymmetric reactions. There are many natural and synthetic chiral templates known to work as efficient organocatalysts, but using carbohydrate templates for chiral induction in asymmetric aldol reactions is a relatively new area developed in the recent years. This review focuses on carbohydrates alone or their conjugates with previously known chiral moieties as organocatalysts for asymmetric aldol reactions.     

Highly enantioselective organocatalytic direct aldol reaction in an aqueous medium

We have demonstrated that small organic molecules 1 and 2 catalyzed the direct aldol reaction of both acyclic and cyclic ketones with different aldehydes in an excess of water/brine. Excellent enantioselectivities up to >99% and diastereoselectivities up to 99% with very good yields were obtained by using much lower catalyst loadings (0.5 mol %).     

Study of the lanthanide-catalyzed, aqueous, asymmetric Mukaiyama aldol reaction

The development of efficient methods for the asymmetric Mukaiyama aldol reaction in aqueous solution has received great attention. We have developed a new series of chiral lanthanide-containing complexes that produce Mukaiyama aldol products with outstanding enantioselectivities. In this paper, we describe an optimized ligand synthesis, trends in stereoselectivity that result from changing lanthanide ions, and an exploration of substrate scope that includes aromatic and aliphatic aldehydes and silyl enol ethers derived from aromatic and aliphatic ketones.     

Kinetic isotope and thermodynamic analysis of the nornicotine-catalyzed aqueous aldol reaction

A series of kinetic isotope effects and thermodynamic studies were performed to test key predictions of a computationally derived model for a nornicotine-catalyzed aqueous aldol reaction. The relative energies of the two computationally-derived transition states were challenged using the proton inventory, which demonstrated that a single water molecule from the solvent is involved in, or before, the rate-limiting step. These results suggest the importance of proton transfer in the aqueous aldol reaction and may assist the development of other aqueous organocatalytic processes.     

Direct asymmetric aldol reaction in aqueous media using polymer-supported peptide

PEG-PS resin-supported tripeptide/zinc chloride catalyst system has been developed for use in the direct asymmetric aldol reaction of acetone with aldehydes in aqueous media. The peptide catalyst could be separated from the reaction mixture by filtration, and was reusable at least five times without significant change in its activity and selectivity.     

Proline catalyzed aldol reactions in aqueous micelles: an environmentally friendly reaction system

The proline catalyzed aldol reactions of nitrobenzaldehydes with various ketones in aqueous anionic micelles were investigated. Both the selectivities and reaction yields were observed to be higher than those of the corresponding reactions in organic solvents. A reaction mechanism is proposed that is somewhat different from that in organic solvents.     

A ribozyme for the aldol reaction

Directed in vitro evolution can create RNA catalysts for a variety of organic reactions, supporting the "RNA world" hypothesis, which proposes that metabolic transformations in early life were catalyzed by RNA molecules rather than proteins. Among the most fundamental carbon-carbon bond-forming reactions in nature is the aldol reaction, mainly catalyzed by aldolases that utilize either an enamine mechanism (class I) or a Zn(2+) cofactor (class II). We report on isolation of a Zn(2+)-dependent ribozyme that catalyzes an aldol reaction at its own modified 5' end with a 4300-fold rate enhancement over the uncatalyzed background reaction. The ribozyme can also act as an intermolecular catalyst that transfers a biotinylated benzaldehyde derivative to the aldol donor substrate, coupled to an external hexameric RNA oligonucleotide, supporting the existence of RNA-originated biosynthetic pathways for metabolic sugar precursors and other biomolecules.     

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.     

A correlation between Hammett acidity of catalysts and their activity in temperature-programmed reaction of cumene dealkylation

On the basis of TPR spectra of cumene adsorbed on oxide catalysts, the relationship between Hammett acidity and reciprocal benzene formation temperature (H₀ = 32.50 – 18.37 10³/T_m) has been found. Using this relationship, it is possible to estimate a value of H₀ for oxide materials in an interval of –5.6 < H₀ < –16. The correlation between acidic strength of B-sites and rate constants of heterogeneous catalytic reactions is discussed.This revised version was published online in December 2005 with corrections to the Cover Date.     

A modular approach to catalyst hydrophobicity for an asymmetric aldol reaction in a biphasic aqueous environment

Catalyst 5, an ion pair consisting of a hydrophilic cation and a lipophilic anion, fulfils the solubility requirements needed to couple efficiency (enantioselectivities and anti-diastereoselectivities up to > or = 99%) and catalyst recyclability in asymmetric aldol reactions under aqueous biphasic conditions.     

Novel enantiocontrol system with aminoacyl derivatives of glucoside as enamine-based organocatalysts for aldol reaction in aqueous media

Introduction of carbohydrate auxiliary into enanine-based catalyst provided a novel enantiocontrol for aqueous aldol reaction. Methyl 2-(l-prolyl)amido-2-deoxy-α-d-glucopyranosides led to the enantiocontrol as parent amino acids did in the reaction of acetone with 4-nitrobenzaldehyde, and provided R-aldol in an improved efficiency compared with that of l-proline in aqueous media. The enantioreversal control of that with parent amino acid was observed in the reaction with methyl 2-(l-tert-leucyloxy)-α-d-glucopyranoside, which provided S-aldol predominantly in moderate efficiency. The novel enantiocontrol system was proposed to occur as a result of the generation of the transition state through the reaction of enamine with hydroxyl group on glucoside auxiliary.     

Quadruple domino organocatalysis: an asymmetric aza-michael/michael/michael/aldol reaction sequence leading to tetracyclic indole structures with six stereocenters

Quadruple domino/Wittig-one pot: An organocatalytic, asymmetric, three-component quadruple cascade, which leads to tetracyclic double-annulated indole derivatives, is described. The domino products were further derivatized by aldehyde olefination under one-pot conditions to obtain complex isoindolo[2,?1-a]indole derivatives bearing six stereogenic centers in a highly stereoselective fashion.     

High acceleration of the direct aldol reaction cocatalyzed by BINAM-prolinamides and benzoic acid in aqueous media

The enantioselective direct aldol reaction, organocatalyzed by recoverable BINAM-prolinamide derivatives can be highly accelerated by a catalytic amount of a carboxylic acid without a detrimental of the obtained enantioselectivities. From the study of suitable acids and reaction conditions, benzoic acid in aqueous DMF or in water was shown to give the best results with high yields and enantioselectivities. Thus, the reaction between p-nitrobenzaldehyde and acetone catalyzed by (S_a)-BINAM-l-Pro and benzoic acid can be carried out at −20 °C in only 8.5 h to give the expected product with 86% ee. In the case of butan-2-one, the iso- and the anti-isomers are obtained in a 1:1 isomer ratio up to 99% ee. Cyclohexanone gives the anti-aldol in up to 99% dr and 97% ee in only 2 h. The opposite diastereoselectivity is obtained in the case of cyclopentanone with lower ee up to 65% for the syn and 85% for the anti-isomer.     

Substrate-controlled stereoselectivity in the Yamamoto aldol reaction

The Yamamoto aldol reaction is a vinylogous aldol reaction that relies on bulky aluminium-based Lewis acids. These activate both the aldehyde as well as become part of the enolate moiety. The report discloses the first detailed study on the substrate-controlled Yamamoto aldol reaction in which 2,3-syn and 2,3-anti disubstituted aldehydes serve as the stereodirecting elements. The "size" of the substituent in the β-position strongly determines the facial selectivity of enolate addition to the aldehyde. Large substituents favour formation of 1,3-syn diols while slim alkynyl groups preferentially lead to 1,3-anti products.