Direct aldol reaction enantioselective

Marhwald reported that ligand exchange of Ti(rac-BINOLate)(Of-Bu)2 with optically active a-hydroxy acids presents an unexpected and novel approach to enantio-selective direct aldol reactions of aldehydes and ketones (Scheme 12.19). The aldol products have been isolated with a high degree of syn diastereoselectivity. High enantioselectivities have been observed when using simple optically pure a-hydroxy acids. 

Trost s group reported direct catalytic enantioselective aldol reaction of unmodified ketones using dinuclear Zn complex 21 [Eq. (13.10)]. This reaction is noteworthy because products from linear aliphatic aldehydes were also obtained in reasonable chemical yields and enantioselectivity, in addition to secondary and tertiary alkyl-substituted aldehydes. Primary alkyl-substituted aldehydes are normally problematic substrates for direct aldol reaction because self-aldol condensation of the aldehydes complicates the reaction. Bifunctional Zn catalysis 22 was proposed, in which one Zn atom acts as a Lewis acid to activate an aldehyde and the other Zn-alkoxide acts as a Bronsted base to generate a Zn-enolate. The... 

Trost et al. [11] reported another impressive example of bimetallic catalysts in which a Zn-Zn homobimetallic complex (17, Scheme 7) serves as an effective catalyst for direct aldol reactions [11-13]. The proposed structure of the catalyst was verified by mass spectrometry and the best ratio of Et2Zn and the ligand. The chemical yield was moderate in the reaction of methyl ketones (1) (Scheme 7, top) [11,12], but a highly atom-economic system was achieved when a-hydroxylated ketones (10) were used as a substrate (Scheme 7, bottom) [13]. Excellent diastereo- and enantioselectivity were obtained under mild conditions. In contrast to the case of Shibasaki s heteropolymetallic catalyst, syn-1,2-diols (syn-11) were obtained as the major diastereomers. 

Aminocatalysis is a biomimetic strategy used by enzymes such as class I aldolases. Application of aminocatalysis in an asymmetric aldol reaction was reported in the early 1970s. Proline (19) efficiently promoted an intramolecular direct aldol reaction to afford Wieland-Miescher ketone in 93% ee [17,18]. More than 25 years later, in 2000, List, Barbas, and co-workers reported that proline (19) is also effective for intermolecular direct aldol reactions of acetone (le) and various aldehydes 3. Notably, the reaction proceeded smoothly in anhydrous DMSO at an ambient temperature to afford aldol adducts in good yield and in modest to excellent enantioselectivity (up to >99% ee, Scheme 9) [19-22]. The chemical yields and selectivity of proline catalysis are comparable to the best metallic catalysts, although high catalyst loading (30 mol %) is required. Proline (19)... 

Important extensions of proline catalysis in direct aldol reactions were also reported. Pioneering work by List and co-workers demonstrated that hydroxy-acetone (24) effectively serves as a donor substrate to afford anfi-l,2-diol 25 with excellent enantioselectivity (Scheme 11) [24]. The method represents the first catalytic asymmetric synthesis of anf/-l,2-diols and complements the asymmetric dihydroxylation developed by Sharpless and other researchers (described in Chap. 20). Barbas utilized proline to catalyze asymmetric self-aldoli-zation of acetaldehyde [25]. Jorgensen reported the cross aldol reaction of aldehydes and activated ketones like diethyl ketomalonate, in which the aldehyde... 

The phase-transfer-catalyzed enantioselective direct aldol reactions of glycine donor with aldehyde acceptors provide an ideal method for the simultaneous construction of the primary structure and stereochemical integrity of P-hydroxy-a-amino acids, which are extremely important chiral units. In the first report from the Miller s group, N-benzyldnchorudinium chloride (4a) was employed as a catalyst for the reaction of 1 with heptanal, and the corresponding aldol product 21 was obtained in 74% yield, though the diastereo- and enantioselectivities were unfortunately not satisfactory (Scheme 2.18) [40]. 

Maruoka and coworkers recently developed an efficient, highly diastereo- and enantioselective direct aldol reaction of glycine Schiff base 2 with a wide range of aliphatic aldehydes under mild phase-transfer conditions employing N-spiro chiral quaternary ammonium salt li as a key catalyst, as shown in Table 5.12 [41a]. 

Mechanism and transition states The basic principles of the proline-catalyzed direct aldol reaction are summarized in Section 6.2.1.1 [93, 94a], The preferred diastereo- and enantioselectivity were explained in terms of the potential transition states for the aldol reaction using hydroxyacetone shown in Scheme 6.38 [93], Thus, re-facial attack of the aldehyde at the si face of hydroxyacetone leads to the... 

Guillena G, Najera C et al (2007) Enantioselective direct aldol reaction the blossoming of modem organocatalysis. Tetrahedron Asymmetry 18 2249-2293... 

Hartree-Fock and density functional theory (DFT) calculations have been used to probe the enantioselectivity of the direct aldol reaction of acetone and 2,2-dimethyl-propanal, catalysed by (S)-proline, in DMSO solution.107... 

Hydroxyaldehydes, with an intervening quaternary centre, have been synthesized enantioselectively by direct aldol reactions of oqa-dialkylaldehydes with aromatic aldehydes, using a chiral bifunctional pyrrolidine sulfonamide organocatalyst.118... 

Several reports deal with aqueous media. Acid-base catalysis by pure water has been explored, using DFT, for the model aldol reaction of acetone and acetaldehyde.125 A Hammett correlation of nornicotine analogues (28) - a series of meta- and para-substituted 2-arylpyrrolidines - as catalysts of an aqueous aldol reaction shows p = 1.14.126 Also, direct aldol reactions have been carried out in water enantioselectively, using protonated chiral prolinamide organocatalysts.127... 

Trost et al. have discovered a novel design of dinuclear zinc catalyst that can catalyze diastereoselective and enantioselective direct aldol reactions [17]. The dinuclear zinc catalysts 5a-7a are generated in situ by exposing the appropriate ligands 5-7, respectively, to 2equiv. diethylzinc in THF (Scheme 3). 

The phase-transfer-catalyzed enantioselective direct aldol reactions of a glycine donor with aldehyde acceptors provide an ideal method for the simultaneous con-... 

Luo, Z.-B., Dai, L.-X. Novel small organic molecules for a highly enantioselective direct Aldol reaction. Chemtracts 2003, 16, 843-847. 

As discussed above, all of the cinchona-based quaternary ammonium salts used as catalysts gave only poor to moderate diastereoselectivities and enantioselectivities for direct aldol reactions. Quite recently, a highly enantioselective, catalytic, direct aldol reaction was realized by adopting the enamine catalysis approach [12], in which 9-amino-epi-cinchona alkaloids are employed as aminocatalysts [13, 14]. 

By using of a modified proline, L-prolinamide 47 (which is known to be a more reactive catalyst than L-proline in cross-aldol reactions [80]), the enantioselectivity of the direct aldol reactions in ionic liquid [bmim][BF4] was remarkably increased as compared with the reaction carried out in acetone (69% ee) (Scheme 7.26) [81]. However, the reusability of the recovered 47 when immobilized in the ionic liquid layer was somewhat inferior to that of the L-proline catalyst this effect could be ascribed to the increased solubility of the organocatalyst 47 in the extracting organic solvents (not provided in the literature), leading to an increased leaching of the catalyst. 

Scheme 11.20 Highly diastereoselective and enantioselective direct aldol reactions.

Novel organic molecules derived from L-proline and amines or amino alcohols, were found to catalyse the asymmetric direct aldol reaction with high efficiency. Notably those containing L-proline amide moiety and terminal hydroxyl group could catalyse direct asymmetric aldol reactions of aldehydes in neat acetone with excellent results[1]. Catalyst (1), prepared from L-proline and (IS, 2Y)-diphcnyl-2-aminoethanol, exhibits high enantioselectivities of up to 93% ee for aromatic aldehydes and up to >99% ee for aliphatic aldehydes. 

Pesciaioli E, Righi P, Mazzanti A, GianeUi C, MancineUi M, BartoUi G, et al. Cinchona alkaloid-catalyzed enantioselective direct aldol reaction of N-boc-oxindoles with polymeric ethyl glyoxylate. Adv Synth Catal 2011 353(16) 2953-9. 

Owing to the increased acidity of an NH group of thioamide relative to the parent amide, proline-thioamide 25a behaves as an excellent catalyst. It has been demonstrated that the reaction occurs in a biphasic medium. Najera" and Li independently synthesised thioamides 25b and 25c,d for enantioselective direct aldol reactions. These ligands were found to be better alternatives to L-prolinamides and provided excellent levels of enantio-seiectivity as compared to their parent ligands. 

Barbas and researchers identified that the diamine la TFA salt can catalyse the asymmetric intermolecular direct aldol reactions of a,a-dialkylaldehydes with aromatic aldehydes (Scheme 9.2). The bifunctional catalytic system exhibited excellent reactivity to give products with moderate diastereo- and enantioselectivities. Notably, L-proline is an ineffective catalyst for this class of aldol reactions. The re-face attack of an enamine intermediate on an aryl aldehyde was proposed, causing the observed stereochemistry. 

In 2006 Gu and coworkers proposed the use of 4,4 -disubstituted-prolines as highly enantioselective catalysts for the direct aldol reaction. The 1-methylnaphthyl 4,4 -disubstituted catalyst 30 was applied successfully for the reaction of acetone with some selected aromatic and aliphatic aldehydes (Scheme 11.26). ... 

Based on the observations obtained for i-proline-based dipeptides Gong and coworkers were the first to report an efficient catalytic protocol for the asymmetric direct aldol reaction of aldehydes with hydroxyacetone yielding a series of 1,4-diols as major product (1,2-diols just as minor product) in aqueous media providing good yields and excellent enantioselectivities. " ... 

In 2013, the Rahman group studied the application of various polar tripeptides for the direct aldol reaction of substituted aromatic aldehydes and aliphatic ketones in an aqueous medium. In the course of their investigations histidine-containing peptide 35 showed the best results for the aldol reactions due to stabilising hydrogen bonding of the side chains of the peptide catalyst (Scheme 13.22b). This catalytic system could be further extended to aldoketoreductase-based mimetic octapeptides for the preparation of chiral p-hydro)yketones in excellent yield and diastereoselectivity and good enantioselectivity. ... 

Guillena, G. Najera, C. Ramon, D. J. Tetrahedron Asymmetry 2007,18, 2249—2293. (Review on enantioselective direct aldol reaction using organocatalysis.)... 

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