Catalytic Aldol Reaction Research Articles

Primary amine-metal Lewis acid bifunctional catalysts: the application to asymmetric direct aldol reactions

The first example of metal Lewis acid-primary amine bifunctional cooperative catalyst derived from primary amino acids was developed, and it was found to catalyze aldol reactions of cyclic ketones highly efficiently with very good to excellent stereoselectivities.

Highly enantioselective synthesis of tertiary alcohols: C2-symmetric N,N′-dioxide-Sc(iii) complex promoted direct aldol reaction of α-ketoesters and diazoacetate esters

A C(2)-symmetric N,N'-dioxide-Sc(III) complex has been developed to promote the asymmetric catalytic aldol reaction of alpha-ketoesters and diazoacetate esters to afford tertiary alcohols in good yields with excellent enantioselectivities.

Homogeneous silicone modified primary amine-Brønsted acid salt catalyzed aldol reaction: unexpected synergistic effect of polysiloxane with remarkable improvement of efficiency and stereoselectivity

We have developed a new strategy to improve the stereoselectivity in enamine catalysis by the introduction of super-hydrophobic long-chain silicone/polysiloxane as support/functional group for a model aldol reaction. The homogeneous direct aldol reaction of cyclic ketones with different aromatic aldehydes catalyzed by polysiloxane-derived primary amines has been reported with high yields, good diastereoselectivity, and up to 99% ee.

Highly diastereo- and enantioselective catalytic synthesis of the bis-tetrahydrofuran alcohol of Brecanavir and Darunavir

An efficient highly diastereo- and enantioselective synthesis of the bis-tetrahydrofuran (bis-THF) alcohol of several HIV protease inhibitors, including Brecanavir and Darunavir, has been achieved utilizing an Evans Mukaiyama aldol reaction of (benzyloxy)acetaldehyde and a silyl ketene acetal. The lactone alcohol intermediate from the catalytic aldol reaction was reduced to a lactol. Palladium catalyzed hydrogenolysis removed the benzyl protection and promoted an in situ cyclization to form the epimer of the bis-THF alcohol in a 98:2 diastereomeric ratio and 97:3 enantiomeric ratio. The alcohol epimer was readily converted to the target in two steps by oxidation to a ketone followed by highly selective reduction to the bis-THF alcohol.

Catalytic Enantioselective Aldol‐type Reaction of β‐Ketosters with Acetals

Optically active β-oxycarbonyl compounds are useful intermediates in synthetic organic chemistry, and great efforts have been devoted to the development of catalytic asymmetric aldol reactions. Excellent methods have been developed with chiral Lewis acids and chiral secondary amines, in which ketones and their silyl derivatives react with aldehydes in a highly enantioselective manner. In contrast, readily enolizable 1,3-dicarbonyl compounds, such as β-keto esters and malonates have rarely been used as nucleophiles, probably because of insufficient nucleophilicity of the metal enolates of such compounds, although a plausible alternative explanation is that the products are unstable and readily undergo retro-aldol reaction (Scheme 1). Because of these general difficulties, there are only a few examples of the synthesis of optically active β-oxymalonates using π-allyl Pd chemistry, aldol reaction, and oxy-Michael reaction. As for catalytic aldol reactions of 1,3-dicarbonyl compounds, we recently reported a catalytic asymmetric hydroxymethylation of β-keto esters using paraformaldehyde as a C1 unit. However, reactions with less reactive aldehydes were difficult (vide infra), and we found no precedents in the literature. Previously, we showed that chiral Pd enolates were formed by the reaction of chiral Pd-bisphosphine complexes 1 with β-keto esters, being accompanied with the formation of a protic acid (Scheme 1). We envisaged that this proton might activate O,O-acetals to give an oxonium intermediate, so that aldol-type reactions with β-keto esters would proceed smoothly. Since the product is O-protected, we expected that the undesired retro-aldol reaction would be suppressed. The use of O,O-acetals as a synthetic equivalent of aldehydes has been extensively investigated in Lewis acid-mediated or catalyzed aldol-type reactions with silyl enolates. A general principle of these reactions is that chiral induction is hard to achieve, since the chiral Lewis acid interacts only weakly with the prochiral electrophile (Scheme 2). To our knowledge, no asymmetric version of such reactions has been reported. Here, we disclose the first example of a catalytic asymmetric aldol-type reaction of O,O-acetals using chiral Pd and Pt complexes, in which the chiral metal enolates of prochiral β-keto esters are the key intermediates.

Gold(III)-Mediated Aldol Condensations Provide Efficient Access to Nitrogen Heterocycles

Quinolines, dihydroquinolines, and aza-xanthones can be synthesized efficiently and under mild reaction conditions by means of a reaction sequence employing Au(III)-catalyzed aldol reactions as the key step.

ChemInform Abstract: A Catalytic Aldol Reaction and Condensation Through in situ Boron “Ate” Complex Enolate Generation in Water.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Asymmetric synthesis of bicyclic piperidines via L‐proline catalyzed aldol reaction of 3‐phthalimidopropanal

A highly enantioselective approach for preparing optically active bicyclic piperidines is described. The key step for introducing chiral centers was a L-proline catalyzed direct enantioselective aldol reaction of 3-phthalimidopropanal with aliphatic ketones. In the reactions with alicyclic ketones, a highly enantioselective formation of anti-2-(3-phthalimido-1-hydroxypropyl)cycloketones 1a-1b (>99% ee) was observed. The aldol products 1 could be subsequently converted into bicyclic piperidines 2 via a consecutive reductive deprotection, acylation, ring closure, and hydrolysis.

Utilising high throughput technologies for the determination of the reaction network of the l-proline catalysed aldol reaction

The objective of this work is to facilitate the determination of a reliable reaction network for the l-proline catalysed aldol reaction using high throughput technologies (HTT). The availability of reliable reaction network is fundamental to predictive kinetic modelling including scale up, replacing a batch process with a continuous one, optimisation, thermal safety, process simulation, etc. The extent to which HTT experiments may be used to provide the necessary quantitative understanding of both physical and chemical phenomena of the system studied is assessed through a four stage development programme. For this particular system it is shown that, in conjunction with appropriate experimental designs, meaningful data streams for mechanistic/kinetic studies can be generated. The experimental data allowed a reaction network for the l-proline catalysed aldol reaction to be proposed and verified through a kinetic modelling exercise.

A Catalytic Aldol Reaction and Condensation through In Situ Boron “Ate” Complex Enolate Generation in Water

Kooperativer Katalysator: Der N-Butyl-1-benzimidazol-2-phenylboronsäure-Hydroxid-Komplex katalysiert die Aldolkondensation und -addition von Hydroxyaceton oder Aceton mit anderen Aldehyden in Wasser. Die katalytische Aktivität beruht auf kooperativen Wechselwirkungen zwischen dem Boronatkomplex und der Imidazolfunktion. Mit Aceton führt die Aldolkondensation zu ungesättigten Methylketonen, im Fall von Hydroxyaceton überwiegt die Aldoladdition.

A Catalytic Aldol Reaction and Condensation through In Situ Boron “Ate” Complex Enolate Generation in Water

A Catalytic Aldol Reaction and Condensation through In Situ Boron “Ate” Complex Enolate Generation in Water

Catalytic asymmetric aldol reactions in aqueous media

Nature has perfected the stereospecific aldol reaction by using aldolase enzymes. While virtually all the biochemical aldol reactions use unmodified donor and acceptor carbonyls and take place under catalytic control in an aqueous environment, the chemical domain of the aldol addition has mostly relied on prior transformation of carbonyl substrates, and the whole process traditionally is carried out in anhydrous solvents. The area of aqua-asymmetric aldol reactions has received much attention recently in light of the perception both of its green chemistry advantages and its analogy to eon-perfected enzyme catalysis. Both chiral metal complexes and small chiral organic molecules have been recently reported to catalyze aldol reactions with relatively high chemical and stereochemical efficiency. This tutorial review describes recent developments in this area.

L‐Prolinamide Catalyzed Aqueous Direct Aldol Reaction: An Environment‐Friendly Method for the Synthesis of β‐Hydroxylketones.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

L‐Prolinamide Catalyzed Aqueous Direct Aldol Reaction: an Environment‐friendly Method for the Synthesis of β‐Hydroxylketones

AbstractAn environment‐friendly L‐prolinamide catalyzed aldol reaction has been developed. The reaction exhibited broad substrate generality,and high yields with good diastereoselectivity were obtained for cyclic ketones. The simplicity of product isolation, usage of water as environmentally benign reaction medium, and the usage of cheap, readily available and recyclable catalyst make this process promising to be developed for large‐scale preparation of β‐hydroxyl ketones.

Pyrrolidine as an efficient organocatalyst for direct aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with ketones

Pyrrolidine-catalyzed aldol reaction of trifluoroacetaldehyde ethyl hemiacetal ( 1) with ketones or aldehydes was described. In the presence of 20 mol % of pyrrolidine, the reaction proceeded smoothly at room temperature to afford the aldol products in good to excellent yields (up to 95%). Pyrrolidine showed a much higher catalytic activity than piperidine in the reaction with less reactive ketones. GC analysis clearly indicated that the catalyst and the enamine intermediates were kept at extremely low concentration during the reaction. Based on these observations, we suggested that formation of the enamine would be a rate-determining step for the catalytic aldol reaction. In addition, the asymmetric aldol reaction of 1 with cyclohexanone catalyzed by l-proline derivatives was also discussed.

Stereoelectronic Effects Dictate Mechanistic Dichotomy between Cu(II)-Catalyzed and Enzyme-Catalyzed Reactions of Malonic Acid Half Thioesters

Previously we developed a Cu(II)-catalyzed, enantioselective aldol reaction between malonic acid half thioesters (MAHTs) and aldehydes based on the biosynthesis of polyketides and fatty acids in which MAHTs are decarboxylated enzymatically to afford ester enolates that condense with thioesters. We report evidence based on steric effects, kinetics, kinetic isotope effects, and crossover experiments in support of a different mechanism for the Cu(II)-catalyzed aldol reaction involving enolization of MAHTs by deprotonation, addition to the aldehyde, decarboxylation, and protonation of the β-hydroxy enolate. We also provide an explanation, based on stereoelectronic effects, for the mechanistic dichotomy between Cu(II)-catalyzed and enzyme-catalyzed reactions of MAHTs.

Organocatalytic asymmetric aldol reaction in the presence of water

Water was found to be a suitable solvent for the l-prolinethioamide catalysed aldol reaction of various cyclic ketones with aromatic aldehydes. Treatment of 4-nitrobenzaldehyde with as little as 1.2 equiv. of cyclohexanone in the presence of the protonated catalyst 1-TFA, afforded aldol products in high yields (up to 97%) with high diastereo- and enantioselectivity (up to >5 : 95 dr and 98% ee). The use of a high excess of ketone was avoided by conducting the aldol addition in the presence of water. Furthermore, different 'salting-out' and 'salting-in' salts were investigated and it was proven that the rate of acceleration and the stereochemical outcome of the reaction are affected by hydrophobic aggregation. Scope and limitation studies revealed that electron deficient aldehydes afforded aldol products with high stereoselectivity in the presence of 1-Cl(2)CHCO(2)H. It was shown that various cyclic ketones, under the conditions found, gave aldol products with fair yields, even if they are used in substoichiometric amounts (1.2 to 2.0 equiv.).

Highly anti‐Selective Catalytic Aldol Reactions of Amides with Aldehydes.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

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, α,β-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.

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.