Efficient heterogeneous asymmetric catalysis of the Mukaiyama aldol reaction by silica- and ionic liquid-supported Lewis acid copper(II) complexes of bis(oxazolines)

Lewis acid complexes based on copper(II) and an imidazolium-tagged bis(oxazoline) have been used to catalyse the asymmetric Mukaiyama aldol reaction between methyl pyruvate and 1-methoxy-1-tri-methylsilyloxypropene under homogeneous and heterogeneous conditions. Although the ees obtained in ionic liquid were similar to those found in dichloromethane, there was a significant rate enhancement in the ionic liquid with reactions typically reaching completion within 2 min compared with only 55% conversion after 60 min in dichloromethane. However, this rate enhancement was offset by lower chemoselectivity in ionic liquids due to the formation of 3-hydroxy-1,3-diphenylbutan-1-one as a by-product. Supporting the catalyst on silica or an imidazolium-modified silica using the ionic liquid or in an ionic liquid-diethyl ether system completely suppressed the formation of this by-product without reducing the enantioselectivity. Although the heterogeneous systems were characterised by a drop in catalytic activity the system could be recycled up to five times without any loss in conversion or ee.

Synthesis of a 7-Membered Biaryl Guanidine Catalyst and its Use in the Vinylogous Aldol Reaction

The present thesis outlines the preparation of a 7-membered guanidine. Initial efforts to obtain this guanidine via 2-chloro-1,3-dimethylimidazolinium chloride induced ring forming chemistry failed to provide the target in a reproducible fashion. Changing strategies, we were able to obtain the desired guanidine through CuCl mediated amination of a 7-membered thiourea intermediate to arrive at the target. In addition, the catalytic activity of this compound was evaluated in a vinylogous aldol reaction of dibromofuranone and four aromatic aldehydes to generate chiral γ-butenolides with modest to good enantiomeric excess. It was found that electron-poor aldehydes resulted in higher, 81% ee, whereas electron rich aldehydes led to low, 41% ee, levels of enantiomeric excess.

DFT Studies of the Organocatalytic Aldol Reaction and a Frustrated Lewis Pair

The computational study, and in particular the density functional theory (DFT) study of the organocatalytic α-chlorination-aldol reaction and the chiral backbone Frustrated Lewis Pair (FLP) system served as a valuable tool for experimental purposes. This thesis describes methods to consider different transition states of the proline- catalyzed α-chlorination aldol reaction to determine the reasonable transition state in the reaction between the enamine and α-chloro aldehydes. Moreover, the novel intramolecular Frustrated Lewis pair based on a chiral backbone for the asymmetric hydrogenation of imines and enamines was designed and the ability of hydrogen splitting by this new FLP system was examined by computational modeling and calculating the hydrogen activation energy barrier.

Aldol reaction of butane-2,3-diacetal protected methyl glycerate

The addition of aldehydes to butane-2,3-diacetal has been investigated. The reaction was shown to be both regioselective and diastereoselective by 1H NMR spectroscopy. The configuration of the newly formed stereocenter was determined by Mosher’s ester analysis.

Asymmetric phase-transfer catalytic sulfanylation of some 2-methylsulfinyl cyclanones. Modeling of the stereochemical course of the aldol reaction of (SS,2S)-2-methylsulfinyl-2-methylsulfanylcyclohexanone

Increased diastereoisomeric excesses are obtained for the sulfanylation reactions of some 2-methylsulfinyl cyclanones under phase-transfer catalysis using the chiral catalyst QUIBEC instead of TEBA. The optically pure (SS,2S)-2-methylsulfinyl-2-methylsulfanylcyclohexanone thus prepared reacts with ethyl acetate lithium enolate affording, after hydrolysis, (R)-2-[(ethoxycarbonyl)methyl]-2-hydroxycyclohexanone in 60% ee. Density functional theory calculations (at the B3LYP/6-311++G(d,p) level) can successfully explain the origin of this result as the kinetically favored axial attack of the nucleophile to the carbonyl group of the most stable conformer of the cyclanone, in which the CH(3)SO and CH(3)S groups are at the equatorial and axial positions, respectively. (C) 2010 Elsevier Ltd. All rights reserved.

Ion-tagged prolinamide organocatalysts for the direct aldol reaction on-water

A concise synthesis of two imidazolium ion-tagged prolinamide organocatalysts 3 and 4, varying in anionic component (CF3COO- and PF6 -, respectively) is presented. The latter could be classified as an ionic liquid with a melting point of 66.3 °C, and glass transition temperature of 14.5 °C. The efficiency of each catalyst was compared via a direct aldol reaction revealing a large contrast in catalytic performance, with the catalyst bearing the PF6 - anion being superior. The optimal conditions were determined to be an on-water reaction system, and substrate scoping gave a range of desired aldol products in high conversion (up to >99 %), dr (up to 98:2), and er (up to 96:4). The application of these catalysts to beta-nitrostyrene conjugate addition is also presented. Graphical Abstract: [Figure not available: see fulltext.]

Enantioselective direct aldol reaction of α-keto esters catalyzed by (Sa)-binam-D-prolinamide under quasi solvent-free conditions

(Sa)-Binam-D-prolinamide (20 mol%), instead of (Sa)-binam-L-prolinamide, in combination with chloroacetic acid (100 mol%) is an efficient organocatalyst for the direct aldol reaction between α-keto esters as electrophiles and alkyl and α-functionalised ketones, under quasi solvent-free conditions, providing access to highly functionalised chiral quaternary γ-keto α-hydroxyesters with up to 92% ee.

Asymmetric aldol reaction with BINAM-sulfonyl polymeric organocatalyst

The BINAM-sulfonyl polymeric organocatalysts was prepared by the AIBN-promoted copolymerization of BINAM-derived sulfonamide, styrene and divinylbenzebe. The polymer catalyzed the asymmetric aldol reaction of aliphatic ketones with aromatic aldehydes to give the aldol products in up to 83% yield and with up to 95% ee. The catalysts could be recovered upt to 6 times with only a slight decrease on its activity.

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 (Sa)-binam-l-prolinamide in combination with benzoic acid is used as catalysts in the direct aldol reaction between cycloalkyl, alkyl, and α-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.

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.

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.

Glyoxylic Acid versus Ethyl Glyoxylate for the Aqueous Enantio­selective Synthesis of α-Hydroxy-γ-Keto Acids and Esters by the N-Tosyl-(S a)-binam-l-prolinamide-Organocatalyzed Aldol Reaction

N-Tosyl-(S a)-binam-l-prolinamide is an efficient catalyst for the aqueous aldol reaction between ketones and glyoxylic acid, as the monohydrate or as an aqueous solution, or a 50% toluene solution of ethyl glyoxylate. These reactions led to the formation of chiral α-hydroxy-γ-keto carboxylic acids and esters in high levels of diastereo- and enantioselectivities (up to 97% ee), providing mainly anti aldol products. Only cyclopentanone and cyclohexane-1,4-dione afforded an almost 1:1 mixture of the syn/anti-diastereoisomers; however, the reaction between 4-phenylcyclohexanone and ethyl glyoxylate gave the corresponding syn,syn-product as the major diastereoisomer.

Aqueous Enantioselective Aldol Reaction of Methyl- and Phenylglyoxal Organocatalyzed by N-Tosyl-(S a)-binam-l-prolinamide

The direct aldol reaction between methylglyoxal (40% aqueous solution) or phenylglyoxal monohydrate and ketones or aldehydes is catalyzed by N-tosyl-(S a)-binam-l-prolinamide to afford the corresponding chiral γ-oxo-β-hydroxy carbonyl compounds, mainly as anti isomers with enantioselectivities up to 97%.

Bio-renewable enantioselective aldol reaction in natural deep eutectic solvents

Among the deep eutectic solvents (DES), natural deep eutectic solvents (NADES) formed by D-glucose and racemic malic acid are suitable media to perform the enantioselective L-proline catalyzed intermolecular aldol reaction, creating simultaneously and selectively a C–C bond and a new stereocenter. The scope of the reaction was found to be broad, with products being obtained with good levels of diastereo- and enantioselectivities. Furthermore, when the reaction was performed at a large scale, the catalyst together with the reaction media can be recovered by simple water extraction and reused at least three times affording similar results. Therefore, the use of NADES as reaction media to carry out a VOC-free selective process has been demonstrated for the first time. The process is clean, cheap, simple and scalable and meets most of the criteria to be considered as a sustainable and bio-renewable process, with the reaction media and catalyst arising directly from Nature.