Crossed aldol addition

Butyraldehyde undergoes stereoselective crossed aldol addition with diethyl ketone [96-22-0] ia the presence of a staimous triflate catalyst (14) to give a predominantiy erythro product (3). Other stereoselective crossed aldol reactions of //-butyraldehyde have been reported (15). 

Only one of the aldol condensations of Table 13.7 (top, center) concerns the reaction of a carbonyl compound with itself. In all other reactions of Table 13.7, the ,/i-unsaturated carbonyl compounds are formed by two different carbonyl compounds. Such aldol condensations are referred to as crossed aldol condensations (cf. the discussion of crossed aldol additions in Section 13.3.1). 

Ketones generally react only as nucleophiles in crossed aldol additions because the addition of an enolate to their C=0 double bond is thermodynamically disadvantageous (Figure 13.44). 

Benzaldehyde, cinnamic aldehyde, and their derivatives do not contain any a-H atoms therefore, they can participate in crossed aldol additions only as electrophiles. 

The aldol addition reaction is one of the most versatile carbon-carbon bond forming processes available to synthetic chemists. The addition reaction involves readily accessed starting materials and can provide )9-hydroxy carbonyl adducts possessing up to two new stereocenters. The previous decade witnessed many substantive advances in the crossed aldol addition reaction as a result of the development of a variety of well-defined enolization protocols and the evolution of highly sophisticated understanding of the reaction mechanism. Moreover, the design of highly effective chiral auxiliary-based systems has allowed for impressive levels of stereocontrol in a number of asymmetric aldol processes. 

The use of lanthanide metal enolates in the aldol reaction has, to date, only been developed to a synthetically useful level in the case of cerium (Scheme S and Table 7). Stereoselectivities are no better than those of lithium enolates, but the cerium enolates of ketones woik well in crossed aldol additions to ketones (Table 7, entries 1-7) and sterically hindered aldehydes (Table 7, entries 9 and 10). Such crossed aldol reactions do not often work well with lithium enolates as enolate equilibration, retroaldolization and steric retardation of addition occur. Imamoto et al. have shown that cerium enolates (44), formed from anhydrous CeCb (1.2 equiv.) and the preformed lithium enolates of ketones in THF at -78 C, undergo such aldol reactions to give the corresponding p-hydroxy ketones (46), usually in high yield. The cerium suppresses the retroaldol reaction by efficient chelation of the aldolate (45). A similar effect is known for zinc halide mediated aldol reactions (Volume 2, (Chapter 1.8). The stereoselectivity of the... 

The preceding reaction is called a mixed aldol addition or a crossed aldol addition. The four products have similar physical properties, making them difficult to separate. Consequently, a mixed aldol addition that forms four products is not a synthetically useful reaction. 

Claisen condensation (p. 810) condensation reaction (p. 807) crossed aldol addition (p. 809)... 

Show how each of the four products shown at the beginning of this section is formed in the crossed aldol addition between... 

Scheme 5.129 Domino hydroformylation-cross aldol addition of acyclic olefins with aldehydes.

Scheme 5.131 Domino hydroformylation-cross aldol addition with a chiral rhodium catalyst and a chiral aldol condensation catalyst.

Recall that LDA causes irreversible enolate formation. If acetaldehyde is added dropwise to a solution of LDA, the result is a solution of enolate ions. Propionaldehyde can then be added dropwise to the mixture, resulting in a crossed aldol addition that produces one major product. This type of process is called a directed aldol addition, and its success is hmited by the rate at which enolate ions can equilibrate. In other words, it is possible for an enolate ion to function as a base (rather than a nucleophile) and deprotonate a molecule of propionaldehyde. If this process occurs too rapidly, then a mixture of products will result. 

Amino)cinnamoyl compounds 79 can be regarded as primary products they may arise from an aldol condensation catalyzed by base, add, or (most frequently) by Lewis acids [173]. Alternatively, quinoline formation may result from primary cross aldol addition, subsequent cydocondensation to an imine(4-hydroxy-3,4-dihydroquinoHne), and aromatization by H2O elimination [174]). 

If two different carbonyl compounds are used in an aldol addition— known as a crossed aldol addition—four products can be formed because reaction with hydroxide ion can form two different enolate ions (A and B ) and each enolate ion can react with either of the two carbonyl compounds (A or B). A reaction that forms four products clearly is not a synthetically useful reaction. 

Primarily one product can be obtained from a crossed aldol addition if one of the aldehydes does not have any a-hydrogens and, therefore, carmot form an enolate ion. That cuts the possible products from four to two. Then, if the aldehyde with a-hydrogens is added slowly to a solution of the aldehyde without a-hydrogens and hydroxide ion, the chance that the aldehyde with a-hydrogens, after forming an enolate ion, will then react with another molecule of its parent carbonyl compound will be minimized, so the possible products are cut to essentially one. 

A crossed Claisen condensation is a condensation reaction between two different esters. Like a crossed aldol addition, a crossed Claisen condensation is a useful reaction only if it is carried out under conditions that foster the formation of primarily one product. Otherwise, the reaction will form a mixture of products that are difficult to separate. 

In addition to crossed aldol additions and crossed Claisen condensations, a ketone can undergo a crossed condensation with an ester. If both the ketone and the ester have a-hydrogens, then LDA is used to form the needed enolate ion and the other carbonyl compound is added slowly to the enolate ion to minimize the chance of its forming an enolate ion and reacting with another molecule of its parent ester. 

The cross-aldol addition of a ketone to an aldehyde (Claisen-Schmidt reaction) is profitably carried out by using the silyl enol ether of the ketone in an organic solvent in the presence of TiCh (Mukaiyama reaction) [2], but this protocol is not suitable for acid-sensitive substrates. High pressure may be employed in place of the catalyst, but longer reaction times are required [4]. 

Hydroxymethylation is achieved by crossed aldol addition reaction (Section 18-6) of the malonic ester enolate with formaldehyde. 

The best performance vi as obtained when glycolaldehyde vi as added slowly by means of a syringe pump, then the rate of cross-aldol addition vi as greatly enhanced. 

As with to FSA and GO, the most significant feature of DERA is the ability to catalyze self- and cross-aldol additions of acetaldehyde. Therefore, the first aldol addition furnishes another aldehyde that can be used as acceptor by DERA, or in combination with other aldolases, for cascade aldol reactions (Scheme 10.31) [25-27,195]. 

Szekrenyi, A., Soler, A., Garrabou, X., Guerard-Helaine, C., Parella, T, Joglar, J., Lemaire, M., Bujons, J., and Clapes, R, Engineering the donor selectivity of D-fructose-6-phosphate aldolase for biocatalytic asymmetric cross-aldol additions of glycolaldehyde. Chem. Eur. J. 2014, 20 (39), 12572-12583. 

Stereoselectivities of aldol additions catalysed by histidine have been shown to contrast with those for proline. ° Quanmm mechanical calculations suggest that the imidazolium and CO2H functionalities of histidine stabilize the cyclic aldolization transition state through hydrogen bonding and that stereoselectivity is a consequence of minimization of gauche interactions around the forming C-C bond. Extensive computations have been used to support rules that enable prediction of the outcome for asymmetric cross-aldol additions between enolizable aldehydes catalysed by histidine. ... 

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