Ketones asymmetric aldol reaction

Aldol reactions of a-substituted iron-acetyl enolates such as 1 generate a stcrcogenic center at the a-carbon, which engenders the possibility of two diastereomeric aldol adducts 2 and 3 on reaction with symmetrical ketones, and the possibility of four diastereomeric aldol adducts 4, 5, 6, and 7 on reaction with aldehydes or unsymmetrical ketones. The following sections describe the asymmetric aldol reactions of chiral enolate species such as 1. 

Starting from ketone(i )-/(S )-49, the asymmetric aldol reaction with aldehyde in the presence of 45a or 45b affords all four isomers of //-hydroxyl ketone 47, 48, 50, and 51 with high yields and stereoselectivities (Scheme 3-17). 

Direct asymmetric aldol reactions, that is between aldehydes and unmodified ketones has been accomplished using a lanthanum trilithium tri(binaphth-oxide) complex1 281. 

Y. M. A Yamada, N. Yoshikawa, H. Sasai, M. Shibasaki, Direct Catalytic Asymmetric Aldol Reactions of Aldehydes and Unmodified Ketones, Angew. Chem. Int. Ed EngL 1997, 36,1871-1873. 

For the first example of direct catal3ftic asymmetric aldol reaction of ethyl ketones, see Mahrwald, R. Ziemer, B. Tetrahedron Lett. 2002, 43, 4459-4461. 

Scheme 17 Asymmetric aldol reactions with ketone donors...

Next to phosphoramides, Denmark reported an axially chiral A -oxide to catalyze the asymmetric aldol reaction of trichlorosilyl enol ethers with ketones [99]. Hashimoto reported an aldol reaction with 3 mol% of another axially chiral A -oxide [100] which gave good yields and enantioselectivities. 

By the use of chiral oxazolidines derived from a chiral norephedrine and methyl ketones, an asymmetric aldol reaction proceeds in a highly enantioselective manner. In the case of ethyl or a-methoxy ketones, the corresponding anti aldol products were obtained with high diastereo- and enantioselectivities. A chiral titanium reagent, generated from... 

The development of enantioselective aldol reactions has been widely studied in conjunction with the synthesis of natural products. Highly enantioselective aldol reactions have been achieved by employing chiral enolates of ethyl ketones and propionic acid derivatives.(1) On the other hand, achieving high asymmetric induction in the asymmetric aldol reaction of methyl ketones is still a problem.(2)... 

Based on this assumption, the asymmetric aldol reaction of chiral 1,3-oxazolidines 1 of methyl ketones was examined. It was found that the corresponding aldol products were obtained in good optical purity when divalent tin chloride was used as an additive metal salt. 

Table 1. Asymmetric Aldol Reaction of Methyl Ketones...

Fluoral hydrate and hemiacetals are industrial products. They are stable liquids that are easy to handle, and they react as fluoral itself in many reactions. Thus, in the presence of Lewis acids, they react in Friedel-Crafts reactions. They also react very well with organometallics (indium and zinc derivatives) and with silyl enol ethers.Proline-catalyzed direct asymmetric aldol reaction of fluoral ethyl hemiac-etal with ketones produced jS-hydroxy-jS-trifluoromethylated ketones with good to excellent diastereo- (up to 96% de) and enantioselectivities. With imine reagents, the reaction proceeds without Lewis acid activation. The use of chiral imines affords the corresponding 8-hydroxy ketones with a 60-80% de (Figure 2.49). ° ... 

Dialkylboron trifluoromethanesulfonates (triflates) are particularly useful reagents for the preparation of boron enolates from carbonyl compounds, including ketones, thioesters and acyloxazolidinones.4 Recently, the combination of dicylohexylboron trifluoromethanesulfonate and triethylamine was found to effect the enolization of carboxylic esters.5 The boron-mediated asymmetric aldol reaction of carboxylic esters is particularly useful for the construction of anti (3-hydroxy-a-methyl carbonyl units.6 The present procedure is a slight modification of that reported by Brown, et al.2... 

Studies of catalytic asymmetric Mukaiyama aldol reactions were initiated in the early 1990s. Until recently, however, there have been few reports of direct catalytic asymmetric aldol reactions [1]. Several groups have reported metallic and non-metallic catalysts for direct aldol reactions. In general, a metallic catalysis involves a synergistic function of the Bronsted basic and the Lewis acidic moieties in the catalyst (Scheme 2). The Bronsted basic moiety abstracts an a-pro-ton of the ketone to generate an enolate (6), and the Lewis acidic moiety activates the aldehyde (3). 

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)... 

Carbonyl Addition Diethylzinc has been added to benzaldehyde at room temperature in the presence of an ephedra-derived chiral quat (8) to give optically active secondary alcohols, a case in which the chiral catalyst affords a much higher enantioselectivity in the solid state than in solution (47 to 48, Scheme 10.6) [30]. Asymmetric trifluoromethylation of aldehydes and ketones (49 to 50, Scheme 10.6 [31]) is accomplished with trifluoromethyl-trimethylsilane, catalyzed by a quaternary ammonium fluoride (3d). Catalyst 3d was first used by the Shioiri group for catalytic asymmetric aldol reactions from silyl enol ethers 51 or 54 (Scheme 10.6) [32]. Various other 1,2-carbonyl additions [33] and aldol reactions [34] have been reported. 

C. DIRECT CATALYTIC ASYMMETRIC ALDOL REACTION OF AN ACETYLENE KETONE... 

A similar asymmetric aldol reaction was used for a synthesis of 11-deoxydaunomy-cinone (11) and related compounds. The key step was the reaction of the acetal 9 from L-( + )-2,3-butanediol with the ketone 10 in the presence of BF3 at —78°. Two aldols were formed in the ratio 13 1 in 80-85% combined yield. The major aldol 11 was used for synthesis of 12. 

The required aldehyde precursor 186 was obtained by a Sn(II)-catalyzed asymmetric aldol reaction [90]. It was then mixed in one pot with o-methoxy aniline 187 and enol ether 188 to afford the key /7-amino ketone 189 in a 2 1 diastereomeric ratio through a Mannich-type three-component reaction. This reaction was performed in an aqueous medium and the use of a surfactant such as dodecyl sulfate (DS) was essential. The diastereomeric mixture 189 was treated with HF and the... 

The asymmetric aldol reaction is one of the most important topics in modern catalytic synthesis [54]. The products, namely />-hydroxy carbonyl compounds, have a broad range of applications and play a key role in the production of pharmaceuticals [55], Since the discovery of the catalytic asymmetric aldol reaction with enolsi-lanes by Mukaiyama et al. [56], steady improvements of the metal-catalyzed asymmetric aldol reaction have been made by many groups [57]. For this type of aldol reaction a series of chiral metal catalysts which act as Lewis acids activating the aldol acceptor have been shown to be quite efficient. It was recently shown by the Shibasaki group that the asymmetric metal-catalyzed aldol reaction can be also performed with unmodified ketones [57a], During the last few years, several new concepts have been developed which are based on use of organocatalysts [58], Enolates and unmodified ketones can be used as aldol donors. 

In the text below organocatalytic asymmetric aldol reactions are classified into indirect aldol reactions and direct aldol reactions . Indirect aldol reactions are syntheses which require a modified ketone as a starting material (Scheme 6.9, pathway 1). For example, enolates which are prepared in a previous step starting from the ketone are often used. Syntheses which allow the direct use of a ketone, in a non-activated form, as a nucleophile are defined as direct aldol reaction (Scheme 6.9, pathway 2). 

It is worth noting that, in a similar manner to enzymatic conversions with type I or II aldolases, a direct asymmetric aldol reaction was achieved when L-proline was used as catalyst. Accordingly, the use of enol derivatives of the ketone component is not necessary, i.e. ketones (acting as donors) can be used directly without previous modification [72]. So far, most asymmetric catalytic aldol reactions with... 

Asymmetric aldol reactions.4 The borane complex 3 can also serve as the Lewis acid catalyst for the aldol reaction of enol silyl ethers with aldehydes (Mukaiyama reactions).5 Asymmetric induction is modest (80-85% ee) in reactions of enol ethers of methyl ketones, but can be as high as 96% ee in reactions of enol ethers of ethyl ketones. Moreover, the reaction is syn-selective, regardless of the geometry of the enol. However, the asymmetric induction is solvent-dependent, being higher in nitroethane than in dichloromethane. 

The capability of L-proline - as a simple amino acid from the chiral pool - to act like an enzyme has been shown by List, Lemer und Barbas III [4] for one of the most important organic asymmetric transformations, namely the catalytic aldol reaction [5]. In addition, all the above-mentioned requirements have been fulfilled. In the described experiments the conversion of acetone with an aldehyde resulted in the formation of the desired aldol products in satisfying to very good yields and with enantioselectivities of up to 96% ee (Scheme 1) [4], It is noteworthy that, in a similar manner to enzymatic conversions with aldolases of type I or II, a direct asymmetric aldol reaction was achieved when using L-proline as a catalyst. Accordingly the use of enol derivatives of the ketone component is not necessary, that is, ketones (acting as donors) can be used directly without previous modification [6]. So far, most of the asymmetric catalytic aldol reactions with synthetic catalysts require the utilization of enol derivatives [5]. The first direct catalytic asymmetric aldol reaction in the presence of a chiral heterobimetallic catalyst has recently been reported by the Shibasaki group [7]. 

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