Aldol Reactions with Ketone Acceptors

Scheme 2.7 Aldol reactions with ketone acceptors [33-36].

Scheme 14 Equilibria in aldol reactions with ketone and aldehyde acceptors...

O Scheme 25) [150]. The latter acts as an acceptor only because of its good electrophilic and non-nucleophilic character. The a-thioacetal functionality in this enantioselective crosscoupling allows access to highly oxidized, stereo-defined synthons of broad versatility. Moreover, the observed reactivity profile makes them pre-eminent substrates for highly selective cross-aldol reactions with ketone donors. 

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 2008, Zhao and coworkers used p,y-unsaturated keto esters 40 as acceptors in 30-catalysed asymmetrie aldol reactions with cyclic ketones in water to afford the corresponding quatemaiy aldols 41 bearing two adjacent stereocentres in high yields and with excellent enantiomeric excesses and diastereomerie ratios (Scheme 10.9). At the same time, acetone appeared applicable as a donor component in silyloiq roline 32-catalysed aldolisation of a,p-unsaturated trifluoromethylketones 42 in dichloromethane that enantioselectively produced valuable trifluoromethylated chiral aldols 43 bearing a quaternaiy stereocentre with enantioselectivities of 74-91%. ... 

CHART 3.9. Aliphatic aldehydes as acceptors in the aldol reaction with heterocyclic ketones. 

The role of stoichiometric amount of zinc compounds in the aldol reaction was studied 30 years ago (107). The first study of asymmetric zinc-catalyzed aldol reaction was carried out by Mukaiyama and co-workers the chiral zinc catalyst was prepared from diethylzinc and chiral sulfonamides and was effective in the reaction of ketene silyl ethers with aldehydes (108). Among the subsequent studies on zinc-catalyzed aldol reactions, Trost s group gave important contribution to zinc/prophenol ligand complexes (109,110). The chiral dinuclear zinc catalyst promotes the direct aldol reaction of ketones, including a-hydroxyketones, and aldehydes with excellent enantioselectivity (Scheme 17). It is proposed that one zinc metal coordinated different substrates to form zinc enolate, and another zinc metal center provided the bridge between the interaction of donor and acceptor. 

Since most often the selective formation of just one stereoisomer is desired, it is of great importance to develop highly selective methods. For example the second step, the aldol reaction, can be carried out in the presence of a chiral auxiliary—e.g. a chiral base—to yield a product with high enantiomeric excess. This has been demonstrated for example for the reaction of 2-methylcyclopenta-1,3-dione with methyl vinyl ketone in the presence of a chiral amine or a-amino acid. By using either enantiomer of the amino acid proline—i.e. (S)-(-)-proline or (/ )-(+)-proline—as chiral auxiliary, either enantiomer of the annulation product 7a-methyl-5,6,7,7a-tetrahydroindan-l,5-dione could be obtained with high enantiomeric excess. a-Substituted ketones, e.g. 2-methylcyclohexanone 9, usually add with the higher substituted a-carbon to the Michael acceptor ... 

The mixed Claisen condensation of two different esters is similar to the mixed aldol condensation of two different aldehydes or ketones (Section 23.5). Mixed Claisen reactions are successful only when one of the two ester components has no a hydrogens and thus can t form an enolate ion. For example, ethyl benzoate and ethyl formate can t form enolate ions and thus can t serve as donors. They can, however, act as the electrophilic acceptor components in reactions with other ester anions to give mixed /3-keto ester products. 

The Robinson annulation is a two-step process that combines a Michael reaction with an intramolecular aldol reaction. It takes place between a nucleophilic donor, such as a /3-keto ester, an enamine, or a /3-diketone, and an a,/3-unsaturated ketone acceptor, such as 3-buten-2-one. The product is a substituted 2-cyclohexenone. 

Crossed aldol condensations, where both aldehydes (or other suitable carbonyl compounds) have a-H atoms, are not normally of any preparative value as a mixture of four different products can result. Crossed aldol reactions can be of synthetic utility, where one aldehyde has no a-H, however, and can thus act only as a carbanion acceptor. An example is the Claisen-Schmidt condensation of aromatic aldehydes (98) with simple aliphatic aldehydes or (usually methyl) ketones in the presence of 10% aqueous KOH (dehydration always takes place subsequent to the initial carbanion addition under these conditions) ... 

Here the hapten (Scheme 2) is a 13-diketone, which incorporates structural features of both reactants - ketone donor and aldehyde acceptor (see below, Scheme 3) - in the aldol reaction of interest. In favorable cases the hapten reacts with the primary amino-group of a lysine residue in the complementary-determining region of an antibody to form a Schiffbase 5, which readily tautomerises to the more stable vinylogous amide 6. 

Furthermore, the N-alkylation of 2-aminobenzyl alcohol 114 with ketones 115 in the presence of [IrCl(cod)]2 and KOH gave quinoline derivatives 116 (Equation 10.28) [52]. The reaction may be initiated by the formation of ketimine from 114 and 115, and the ketimine thus formed is oxidized by Ir catalyst and the 114 which serves as a hydrogen acceptor giving the corresponding aldehyde, which is eventually converted into quinoline 116 through intramolecular aldol-type condensation. 

Typical starting materials, catalysts, and products of the enamine-catalyzed aldol reaction are summarized in Scheme 17. In proline-catalyzed aldol reactions, enantioselectivities are good to excellent with selected cyclic ketones, such as cyclohexanone and 4-thianone, but generally lower with acetone. Hindered aldehyde acceptors, such as isobutyraldehyde and pivalaldehyde, afford high enantioselectivities even with acetone. In general, the reactions are anti selective, but there are aheady a number of examples of syn selective enamine aldol processes [200, 201] (Schemes 17 and 18, see below). However, syn selective aldol reactions are still rare, especially with cychc ketones. 

In enamine-catalyzed aldol reaction, the donor aldehyde or ketone first forms an enamine and then reacts with another aldehyde to form the aldol product. If imines instead of aldehydes are used as acceptors, the end result is the formation of a... 

The first asymmetric enamine-catalyzed Mannich reactions were described by List in 2000 [208]. Paralleling the development of the enamine-catalyzed aldol reactions, the first asymmetric Mannich reactions were catalyzed by proline, and a range of cyclic and acyclic aliphatic ketones were used as donors (Schemes 24 and 25). In contrast to the aldol reaction, however, most Mannich reactions are syn selective. This is presumably due to the larger size of the imine acceptor, forcing the imine and the enamine to approach each other in a different manner than is possible with aldehyde acceptors (Scheme 23). 

The strategy of the sequence is a Michael addition to an a,/3-unsaturated ketone followed by an intramolecular aldol reaction. Treatment of a ketone enolate with a Michael acceptor gives a diketone intermediate which is poised to produce a six-membered ring if an enolate is produced and it intramolecularly adds to the carbonyl group. 

Boron-mediated ketone-ketone aldol reactions have been described, using boron enolates formed with dicyclohexylboron chloride and triethylamine.124 Following addition of the acceptor ketone to form a boron aldolate, oxidation with peroxide yields the aldol product. 

Scheme 2.1 The enamine catalytic cycle. An enamine derived from an amine- or amino acid-catalyst can react with a variety of electrophiles. The aldehyde and ketone reactants that form enamines and act as nucleophiles are often described as donors . Aldehyde and imine reactants that serve as electrophiles are described as acceptors for aldol and Mannich reactions, respectively. Ketones also serve as acceptors for aldol reactions.

In addition to broad-scope substrate specificity, 38C2 exhibits high enantioselectivity for the aldol reaction. Although this high degree of enantioselectivity has been observed for antibody-catalyzed ester hydrolysis reactions, it is certainly not a feature common to all such catalysts (Janda et al., 1989 Lo et al., 1997 Pollack et al., 1989 Tanaka et al., 1996 Wade and Scanlan, 1996). Furthermore, the rules for the enantioselectivity for 38C2-catalyzed aldol reactions are both simple and general (Hoffmann et al., 1998). For most ketone donors, attack occurs on the si side of the acceptor. However, when a ketone with an a-hydroxy substituent (such as hydroxyacetone) acts as donor, attack occurs on the reside (Scheme 5). 

In recent years the synthetic potential and mechanistic aspects of asymmetric catalysis with chiral Lewis base have been investigated. Aldol addition reactions between trichlorosilyl enolates with aldehydes have been also intensively studied. Now, full investigations of the trichlorosilyl enolates derived from achiral and chiral methyl ketones, in both uncatalysed and catalysed reactions with chiral and achiral aldehyde acceptors have been reported. The aldol addition is dramatically accelerated by the addition of chiral phosphoramides, particularly (137) and proceed with good to high enantioselectivity with achiral enolates and aldehydes (Scheme 34). ... 

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