Aldol reactions water/additives, importance

Lewis acid catalysts activate the aldehyde by coordination to the carbonyl oxygen. Shibasaki et al. [13] were able to demon,strate that the activation of the enol ether is possible too. The reaction of the aldehyde 37 with the silyl enol ether 38 in the presence of the catalyst 39 proceeds with good, but still not excellent enantioselectivity to yield the aldol adduct 40. Only 5 mol % of the chiral palladium(II) complex 39 was used (Scheme 6a). Activation of the Pd(lI)-BINAP complex 39 by AgOTf is necessary. Therefore, addition of a small amount of water is important. 

The importance of aqueous reactions is now generally recognized, and development of carbon-carbon bond-forming reactions that can be performed in aqueous media is now one of the most challenging topics in organic synthesis [59]. It has been found that Sc(OTf)3 was effective in aldol reactions of silyl enolates with aldehydes in aqueous media (water-THF Eq. 16) [4]. Reaction between aromatic and aliphatic aldehydes such as benzaldehyde and 3-phenylpropionaldehyde and silyl enolates have been performed successfully in aqueous solvents. In addition, direct treatment of aqueous solutions of water-soluble formaldehyde and chloroacetaldehyde with silyl enolates affords the corresponding aldol adducts in good yields. Water-sensitive silyl enolates could be used in aqueous solutions with Sc(OTf)3 as catalyst. 

Serine is an important precursor for other amino acids. Thus, a retro-aldol reaction gives glycine, while elimination of water and addition of hydrogen sulfide produces cysteine. 

Tollens addition between HCOH and CH3CHO and the intermolecular aldol addition of CH3CHO have been used as reaction models to study, by quantum-mechanical methods, the importance of water in aldol-like reactions carried out in aqueous media [22]. Water accelerates the addition process because it coordinates the reactants, making the geometry of the initial complex more suitable for the reaction, and stabilizes the transition state of the reaction. Water therefore acts as a catalyst. 

Aldol reactions with cydoaUcanone donors predominantly afford anti-aldols and water and/or another IL additive (up to 10 equiv.) may exert beneficial effect on reaction diastereoselectivity [29]. The IL nature plays an important role here the yield and enantiomeric excess of aldols 1 (R = = H) increased (up to 99%) when... 

Condensations are some of the most important enolate reactions of carbonyl compounds. Condensations combine two or more molecules, often with the loss of a small molecule such as water or an alcohol. Under basic conditions, the aldol condensation involves the nucleophilic addition of an enolate ion to another carbonyl group. The product, a /3-hydroxy ketone or aldehyde, is called an aldol because it contains both an aldehyde group and the hydroxy group of an alcoho/. The aldol product may dehydrate to an a,/3-unsaturated carbonyl compound. 

Besides the very low stereosdectivities, a major problem encountered with this substrate is the low chemical yield (due to subsequent reaction between the resulting zinc enolate and the starting material) and the hi volatility of the product. Using TADDOL-phosphoramidite 27 in a tandem lj4-addition-aldol condensation to cydopentenone we were only able to obtain an ee of 37%, but the enantiosele-ctLvity was raised to 62% in the presence of wet powdered molecular sieves (4 A) [52]. This beneficial effect of water and molecular sieves in some catalytic 1,4-additions has been observed in other cases recently [52, 59]. Important to note is that the yidds in the tandem version are dramatically increased, presumably due to in situ trapping of the reactive enolate (vide infra). Pfaltz et al. reported a 72% ee in the addition of Et Zn to 44 when using BINOL-oxazoline phosphite ligand 22 [47]. 

This is a reversal of the aldol (or ketol) condensation it assumes preparative importance in the fission of citral which, as an, / -unsaturated aldehyde, is cleaved by boiling potassium carbonate solution into methylheptenone and acetaldehyde,77 a reaction in which addition of water to give a tertiary alcohol must be assumed ... 

The first experiments of an organocatalysed aldol condensation between acetone and 4-nitrobenzaldehyde with aliphatic amino acids in anhydrous conditions (DMSO acetone 4 l) led to the desired adduct in very low yields (<10%). In 2005, Amedjkouh and Cordova independently showed the importance of additional water in the reaction medium to improve the yields. The concept was based on the hypothesis that a molecule of water would participate in a proton relay in the aldolase system, and would allow for a faster hydrolysis of the intermediates. A hydrophobic amino acid might be efficient in aqueous media by strong association with hydrophobic reactants. Furthermore, water would restore the catalyst from its deactivation by condensation with the aldehyde. 

The mechanism of the amino acid-catalyzed Mannich reactions is depicted in Scheme 4.14. Accordingly, the ketone or aldehyde donor reacts with the amino acid to give an enamine. Next, the preformed or in situ- generated imine reacts with the enamine to give after hydrolysis the enantiomerically enriched Mannich product, and the catalytic cycle can be repeated. It is important to bear in mind that N-Chz-, N- Boc-, or A-benzoyl-protected imines are water-sensitive. Thus, they can hydrolyze and thereby decrease the yield of the transformation. Moreover, in the case of cross-Mannich-type addition with aldehydes as nucleophiles the catalytic self-aldolization pathway can compete with the desired pathway and lead to nonlinear effects [63]. 

Because an aldol addition is reversible, when the product of an aldol addition (the jS-hydroxyaldehyde or 8-hydroxyketone) is heated with hydroxide ion and water, the aldehyde or ketone that formed the aldol addition product can be regenerated. In Section 18.21 we will see that a retro-aldol addition is an important reaction... 

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