Directed aldol reaction ketones

In general the reaction of an aldehyde with a ketone is synthetically useful. Even if both reactants can form an enol, the a-carbon of the ketone usually adds to the carbonyl group of the aldehyde. The opposite case—the addition of the a-carbon of an aldehyde to the carbonyl group of a ketone—can be achieved by the directed aldol reaction The general procedure is to convert one reactant into a preformed enol derivative or a related species, prior to the intended aldol reaction. For instance, an aldehyde may be converted into an aldimine 7, which can be deprotonated by lithium diisopropylamide (EDA) and then add to the carbonyl group of a ketone ... 

By using the directed aldol reaction, unsymmetrical ketones can be made to react regioselectively. After conversion into an appropriate enol derivative (e.g. trimethylsilyl enol ether 8) the ketone reacts at the desired a-carbon. 

This is known as the directed aldol reaction. Similar reactions have been performed with oc-lithiated dimethylhydrazones of aldehydes or ketones and with a-lithiated... 

The values of x = 0.5 and = 1 for the kinetic orders in acetone [1] and aldehyde [2] are not trae kinetic orders for this reaction. Rather, these values represent the power-law compromise for a catalytic reaction with a more complex catalytic rate law that corresponds to the proposed steady-state catalytic cycle shown in Scheme 50.3. In the generally accepted mechanism for the intermolecular direct aldol reaction, proline reacts with the ketone substrate to form an enamine, which then attacks the aldehyde substrate." A reaction exhibiting saturation kinetics in [1] and rate-limiting addition of [2] can show apparent power law kinetics with both x and y exhibiting orders between zero and one. 

Organic-Base Catalyzed. Asymmetric direct aldol reactions have received considerable attention recently (Eq. 8.98).251 Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with chiral cyclic secondary amines as catalysts.252 L-proline and 5,5-dimethylthiazolidinium-4-carboxylate (DMTC) were found to be the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding... 

As shown in Scheme 8-49, this multifunctional catalyst can be applied in direct aldol reactions between an aldehyde R CHO and a ketone R2COCH3."... 

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... 

Lithium salts of ketone derivatives such as imines, oximes and hydrazones have also been used for directed aldol reactions (Scheme 103).374 375 A recent example involves triple coordination of lithium in a very rigid transition state, to lead to regiospecificity in the product (Scheme 104).376... 

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). 

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... 

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). 

Direct" aldol reaction with non-modified ketone... 

Direct aldol reaction using unmodified ketones... 

Several organic molecules have been found to catalyze this process efficiently. As described in Section 6.2.1.1, the syntheses can be performed as indirect or direct aldol reactions. Thus, as nucleophiles, ketones were applied directly or enolates can be used as starting materials. 

In principle, L-proline acts as an enzyme mimic of the metal-free aldolase of type I. Similar to this enzyme L-proline catalyzes the direct aldol reaction according to an enamine mechanism. Thus, for the first time a mimic of the aldolase of type I was found. The close relation of the reaction mechanisms of the aldolase of type 1 [5b] and L-proline [4] is shown in a graphical comparison of both reaction cycles in Scheme 3. In both cases the formation of the enamines Ila and lib, respectively, represents the initial step. These reactions are carried out starting from the corresponding ketone and the amino functionality of the enzyme or L-proline. The conversion of the enamine intermediates Ha and lib, respectively, with an aldehyde, and the subsequent release of the catalytic system (aldolase of type I or L-proline) furnishes the aldol product. 

Epothilone A (2) is a natural product that exhibits taxoterelike anticancer activity. A new synthesis of the ketoacid 6, a common C1-C6 fragment used in the total synthesis of epothilone A, was accomplished by directed aldol reaction of acetone with the aldehyde 34 (Scheme 2.3c). The aldol reaction of acetone with the aldehyde 3 in the presence of D-proline proceeded smoothly to furnish the expected aldol product (4) in 75% yield and with greater than 99% ee. Intramolecular aldol reaction of the hydroxy ketone 4 in the presence of pyrrolidine gave the cyclohexenone 5 in good yield. Protection of the alcohol as a TBS ether followed by oxidation of the alkene then produced the desired ketoacid (6). 

The mechanism is similar to that of the barium-catalyzed direct aldol reaction (Scheme 16). The reaction commences with deprotonation of the ketone (2) by the Br0nsted base unit of the catalyst under generation of the enolate 81. After addition of the aldehyde 1 the Lewis acid-base adduct 82 is formed. Then the reaction of the aldehyde and the enolate occurs (82 83). After... 

Sample Problem 24.1 illustrates the steps of a directed aldol reaction between a ketone and an aldehyde, both of which have a hydrogens. 

The directed aldol reaction is an important means of selective carbon-carbon bond formation. This reaction is efficiently achieved by the transformation of one carbonyl group to a silylated enol derivative, which subsequently couples with another carbonyl compound with the aid of a Lewis acid, typically TiCl4, as formulated in Eq. (2). This type of directed aldol reaction is called the Mukaiyama aldol reaction, a standard and practical synthetic protocol with broad application which has, accordingly, been reviewed extensively [38-42] in addition to the reviews cited in the introductory section. The fundamental reactions between enol silyl ethers and an aldehyde or a ketone... 

Although both aldehydes and ketones also participate in the directed aldol reaction, the former are generally more reactive, as is exemplified in Eq. (6) [45]. Thus, the aldol reaction of an enol silyl ether with an aldehyde could be performed in the presence of a ketone. Equation (6) also demonstrates that the base (LDA)-mediated aldol reaction and the Mukaiyama-type reaction took place at the different position in a complementary manner to give the isomeric aldols. 

Acetals are a versatile alternative to aldehydes and ketones which have wide applicability in the titanium-mediated aldol reaction [51], Equation (10) shows the difference between an acetal and the parent aldehyde in the diastereoselective aldol reaction [52]. In this example the latter results in better diastereoselectivity than the former. The reactivity of an aldehyde and its acetal have been compared (Eq. 11) [53]. More examples of the directed aldol reaction starting from enol derivatives of aldehydes and ketones are summarized in Table 1. 

In the proline-catalyzed aldol reactions, enolizable achiral aldehydes and ketones are transformed into the corresponding enamines, which can then react with less enolizable carbonyl compounds, even in one-pot protocols. These reactions, unlike most catalytic aldol reactions, do not require preformed enolates, and constitute direct aldol reactions. 

Catalyst of the direct aldol reactions between ketones and aromatic aldehydes in water [254]... 

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