Cross aldol-type

A direct enantioselective cross-aldol-type reaction of acetonitrile with an aldehyde (RCHO) has been reported, giving /3-cyano alcohol product, R-CH (OH)-CH2-CN, (7e) in up to 77% ee.148 CH3CN, acting as an acetate surrogate, is chemoselectively activated and deprotonated using a soft metal alkoxide (CuO-Bu1) in a strong donor solvent (HMPA), with a bulky chiral diphosphine as auxiliary. 

Ruthenium hydride-catalyzed carbon-carbon double bond migration is applicable to isomerization of allylic acetals and ketals 31 to vinylic ones 32, which undergo selective cross-aldol type reaction by treatment with Bp3-Et20 to yield 33 (Eq. 12.12) [18]. 

Cross aldol-type reactions are catalyzed by Rh4(CO),2 The trimethylsi-lyl enolether 87 reacts with hexanal to give 88... 

Stannous triflate is an efficient catalyst for aldol-type condensations [ 23, 124, 125 Under conditions of kinetic control, it provides excellent diastereo-selectivity in various cross-aldol reactions (equation 61)... 

The reaction of an a-halo carbonyl compound with zinc, tin, or indium together with an aldehyde in water gave a direct cross-aldol reaction product (Eq. 8.90).226,227 A direct Reformatsky-type reaction occurred when an aromatic aldehyde reacted with an a-bromo ester in water mediated by zinc in low yields. Recently, it was found that such a reaction mediated by indium was successful and was promoted by son-ication (Eq. 8.91).228 The combination of BiCl3-Al,229 CdCl2-Sm,230 and Zn-Et3B-Eb0231 is also an effective mediator. Bismuth metal, upon activation by zinc fluoride, effected the crossed aldol reaction between a-bromo carbonyl compounds and aldehydes in aqueous media. The reaction was found to be regiospecific and syn-diastereoselective (Eq. 8.92).232... 

Intermolecular cross aldolization of metallo-aldehyde enolates typically suffers from polyaldolization, product dehydration and competitive Tishchenko-type processes [32]. While such cross-aldolizations have been achieved through amine catalysis and the use of aldehyde-derived enol silanes [33], the use of aldehyde enolates in this capacity is otherwise undeveloped. Under hydrogenation conditions, acrolein and crotonaldehyde serve as metallo-aldehyde enolate precursors, participating in selective cross-aldolization with a-ketoaldehydes [24c]. The resulting/ -hydroxy-y-ketoaldehydes are highly unstable, but may be trapped in situ through the addition of methanolic hydrazine to afford 3,5-disubstituted pyridazines (Table 22.4). 

Analysis of the Mukaiyama-type aldol coupling (Eq. 2) and the well-known hydrosilyla-tion of a,/l-unsaturated carbonyl compounds 11 in the presence of a rhodium catalyst, indicate that both can be explained by the intervention of the rhodium enolate 13. This line of reasoning provided the impetus to develop a new crossed aldol coupling using a hydrosilane, an a,yS-unsaturated ketone 11, and an aldehyde to form 15 (Scheme 6.4). 

Another important example is the cross-aldol condensation of citral and acetone, which yields pseudoionone (Scheme 14), an intermediate in the commercial production of vitamin A. Numerous commercial routes to the preparation of pseu-doionones are based on the aldol condensation using conventional homogeneous catalysts, such as aqueous alkali metal hydroxide solutions, alcoholates in alcohol or benzene solvents (126-129). The yields of the cross-condensation product vary between 50% and 80%, depending on the type of catalyst and conditions such as catalyst concentration, ratio of reagents, and temperature. 

On the basis of a catalytic system previously developed by the same group, Nicholls and collaborators [51] reported the preparation of an imprinted polymer for enantioselective formation of a C-C bond with properties of a metallo-enzyme aldolase type II. Polymers were imprinted using the two enantiomers of a 1,3-diketone, the (l.S, 35,45)-(75), and the corresponding (l/ ,3/ ,4/ )-(75), together with two 4-vinyl-pyridine held in place by a Co(II). The cross-aldol condensation... 

In 2008 Resmini et al. [76] presented their work on the synthesis of novel molecularly imprinted nanogels with Aldolase type I activity in the cross-aldol reaction between 4-nitrobenzaldehyde and acetone. A polymerisable proline derivative was used as the functional monomer to mimic the enamine-based mechanism of aldolase type I enzymes. A 1,3-diketone template, used to create the cavity, was... 

Cerium enolate complexes of type Cl2Ce(OCR=CHR) achieve higher yields in stoichiometric cross-aldol reactions of sterically crowded substrates than the corresponding lithium enolates (Scheme 26). The larger cerium is assumed to be more effective in the inital aldol chelate formation. Formation of oc-bromo-/ -hydroxyketones is also catalyzed [249]. 

Aldol and Mannich-Type Reactions 27 Table 2.6 (S)-Proline-catalyzed cross-aldol reactions of aldehyde donors.3)... 

Under acidic conditions enamines such as compound A in Figure 12.18 and aldehydes undergo condensation to form the conjugated iminium ions D. These will be deprotonated by the concomitantly formed hydroxide ions, In this way dienamines of type F are formed, which will then be hydrolyzed upon acidic workup to give a carbonyl group. The generation of the a,/i-unsaturated ketones E is thus completed. You will learn about type E compounds in Section 13.4.1 in connection with the so-called crossed aldol condensation products. It should be noted that it is not possible to form the same unsaturated ketone by reacting cyclopentanone or its equilibrium fraction of enol with an aliphatic aldehyde. Instead, a cyclodehydration of... 

Much the same type of arguments applies here as applied in the crossed aldol reaction (Chapter 27). We must be quite sure that we know which compound is going to act as the enol partner and which as the acylation partner. 

As we learned in Section 23.3, the a hydrogens between two carbonyl groups are especially acidic, and so they are more readily removed than other a H atoms. As a result, the p-dicarbonyl compound always becomes the enolate component of the aldol reaction. Figure 24.2 shows the steps for the crossed aldol reaction between diethyl malonate and benzaidehyde. In this type of crossed aldol reaction, the initial P-hydroxy carbonyl compound always loses water to form the highly conjugated product. 

Cross-coupling between allylic alcohol and aldehyde is efficiently catalyzed by RuCl2(PPh3)3 in water to form an aldol-type product 48 [22], This reaction has limitations in the substituents of the aldehydes, and the use of aliphatic aldehydes provides complicated mixtures. Cross-coupling of imines with allylic alcohols under similar conditions generates Mannich-type reaction products 50 as major products, together with aldol-type products 48 [22], The selectivity of the reaction was improved by using methanol as the solvent, whereupon no aldol-type product was observed (Eqs. 12.19 and 12.20). 

The Claisen-Schmidt Reaction. When aromatic aldehydes are treated with aliphatic ketones in the presence of base, three reactions might be expected a Cannizzaro reaction of the aromatic aldehyde an aldol-type reaction of the ketone or a crossed aldol reaction between the ketone and the aromatic aldehyde. In either of the last two possibilities dehydration might also occur. Undoubtedly all these reactions will take place in strong base, but by employing about 10 per cent aqueous sodium hydroxide, good yields are often obtained of j3-unsaturated carbonyl conipounds derived from a crossed aldol reaction between the aldehyde and the ketone. This reaction, generally called a Claisen-Schmidt reaction, can be illustrated by the synthesis of benzalacetophenone.16... 

Proline is a stable, nontoxic, cyclic, secondary pyrrolidine-based amino acid with an increased pK value. Thus, proline is a chiral bidentate compound that can form catalytically active metal complexes (Melchiorre et al. 2008). Bidentate means that proline has not only one tooth but also a second one to bite and react. The greatest difference to other amino acids is a Lewis-base type catalysis that facilitates iminium and enamine-based reactions. It is especially noteworthy that cross-aldol condensations of unprotected glycoladehyde and racemic glyceralde-hyde in the presence of catalytic amounts of the Zn-(proline)2 gave a mixture of pentoses and hexoses (Kofoed et al. 2004). Again, proline seems to play the decisive role. The conditions are prebiotic the reaction proceeded in water for seven days at room temperature. It is remarkable that the pentose products contained ribose (34%), lyxose (32%), arabinose (21%), and xylose (12%) and that all are stable under the conditions. Thus, the diastereomeric and enantiomeric selection observed support the idea that amino acids have been the source of chirality for prebiotic sugar synthesis. 

The stereoselectivity of the aldol additions shown in Schemes 5.25 and 5.26 are obviously the result of a complex series of factors, among which are the Felkin-Anh preference dictated by the a-substituent on the aldehyde, the proximal stereocenters on the enolate, etc. Additionally, the more remote stereocenters, such as at the p-position of the aldehyde, may influence the selectivity of these types of reactions. Evans has begun an investigation into some of the more subtle effects on crossed aldol selectivity, such as protecting groups at a remote site on the enolate [131], and of P-substituents on the aldehyde component [132], and also of matched and mismatched stereocenters at the a and P positions of an aldehyde (double asymmetric induction) [133]. Further, the effect of chiral enolates adding to a,P-disubstituted aldehydes has been evaluated [134]. The latter turns out to be a case of triple asymmetric induction, with three possible outcomes fully matched, partially matched, and one fully mismatched trio. 

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