The Acid-Catalyzed Aldol Reaction

The mechanism begins with the acid-catalyzed formation of the enol. 

Then the enol adds to the protonated carbonyl group of another molecule of acetone. 

Finally, proton transfers and dehydration lead to the product. 

Acid catalysis can promote fnrther reactions after the aldol condensation. An example is given in Review Problem 19.8. Generally, it is more common in synthesis for an aldol reaction to be condncted nnder basic rather than acidic conditions. 

One industrial process for the synthesis of 1-butanol begins with ethanal. Show how this synthesis might be carried out. 

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The aldol reaction is catalyzed by acid as well as by base. What is the reactive nucleophile in the acid-catalyzed aldol reaction Propose a mechanism. 

The carbon-carbon bond-forming step of the acid-catalyzed aldol reaction has an enol (allylic source) attacking a protonated carbonyl (which is just a lone-pair-stabilized carbocation). With those hints, give a mechanism for the acid-catalyzed aldol reaction. 

The mechanism of the acid-catalyzed aldol reaction involves an initial acid-catalyzed keto-enol tautomerization to provide the enol form protonation of a second molecule on the carbonyl oxygen creates an electrophilic oxonium ion that is then attacked by the nucleophilic enol, followed by loss of a proton to give the j8-hydroxy aldehyde or ketone product. 

In the aldol reaction the a carbon of one aldehyde or ketone molecule adds to the carbonyl carbon of another. Although acid catalyzed aldol reactions are known, the most common form of the reaction uses a base. The base most often used is OH, though stronger bases such as alkoxides (RO ) are sometimes employed. Hydroxide ion is not a strong enough base to convert substantially all of an aldehyde or ketone molecule to the corresponding enolate ion, that is, the equilibrium lies... 

The detailed mechanism of this enantioselective transformation remains under investigation.178 It is known that the acidic carboxylic group is crucial, and the cyclization is believed to occur via the enamine derived from the catalyst and the exocyclic ketone. A computational study suggested that the proton transfer occurs through a TS very similar to that described for the proline-catalyzed aldol reaction (see page 132).179... 

The aldol reactions introduced thus far have been performed under basic conditions where enolate species are involved as the reactive intermediate. In contrast to the commonly accepted carbon-anion chemistry, Mukaiyama developed another practical method in which enol species can be used as the key intermediates. He is the first chemist to successfully demonstrate that acid-catalyzed aldol reactions using Lewis acid (such as TiCU) and silyl enol ether as a stable enol equivalent can work as well.17 Furthermore, he developed the boron tri-fluoromethane sulfonate (triflate)-mediated aldol reactions via the formation of formyl enol ethers. 

While the Lewis acid-catalyzed aldol reactions in aqueous solvents described above are catalyzed smoothly by several metal salts, a certain amount of an organic solvent such as THF had still to be combined with water to promote the reactions efficiently. This requirement is probably because most substrates are not soluble in water. To avoid the use of the organic solvents, we have developed a new reaction system in which metal triflates catalyze aldol reactions in water with the aid of a small amount of a surfactant, such as sodium dodecyl sulfate (SDS). 

This reaction can be viewed as an acid-catalyzed aldol reaction between an ester and an aldehyde, where the carbonyl O of the ester is replaced with a (CO Cr group. 

Since 2000, remarkable advances in the ntility of the enamine-catalyzed aldol reaction have been made [83]. A massive effort has been devoted to the development of more effective variants of prohne [13, 26, 64, 68, 84-174]. In addition, alternative amino acids and peptides bearing primary amino groups [175-184] as... 

Entries 4 and 5 in Scheme 2.1 depict acid-catalyzed aldol reactions. In entry 4, condensation is accompanied by dehydration. In entry 5, a /i-chloroketone is formed by addition of hydrogen chloride to the enone. 

Several methods for the anti-selective, asymmetric aldol reaction recorded in the literature include (i) the use of boron, titanium, or tin(ll) enolate carrying chiral ligands, (ii) Lewis acid-catalyzed aldol reactions of a metal enolate of chiral carbonyl compounds, and (iii) the use of the metal enolate derived from a chiral carbonyl compound. Although many of these methods provide anti-aldols with high enantioselectivities, these methods are not as convenient or widely applicable as the method reported here, because of problems associated with the availability of reagents, the generality of reactions, or the required reaction conditions. 

Hence, if the proline-catalyzed aldol reaction between acetone and 4-nitrobenzal-dehyde in DM SO is carried out using 5 mol% proline, decarboxylation occurs and [3 + 2] cycloaddition between the resulting ylide and benzaldehyde gives a 1,3-oxazolidinone as the maj or side product [98]. Therefore, it is important that if catalyst loadings are to be reduced, either the carboxylic acid should be unable to decarbox-ylate (e.g. Appendix 7.B, Entries 12 [97, 98], 35 [99]) or else must be replaced by an isostere [101, 102] (e.g. Appendix 7.B, Entries 7 [103, 104], 8-10 [105], 11 [106], 28 [107]). Alternatively, the relative rate of the aldol reaction can be increased in order to minimize the concentration of iminium ion in solution and remove it from equilibrium before decarboxylation can take place. 

The usefulness of the gold-catalyzed aldol reaction was demonstrated by application of the method to the asymmetric synthesis of the important membrane components D-erythro and ffereo-sphingosines, and their stereoisomers (Scheme 8B1.2) [13], and MeBmt, an unusual amino acid in the immunosuppressive undecapeptide cyclosporine (Scheme 8B1.3) [14]. 

Intermediate 3 can either be isolated or used in situ for further elaboration. Fluoride-5 and Lewis-acid catalyzed aldol reactions cleanly give aldol adducts,5 and the reaction with phenylsulfenyl chloride gives a-phenylthio ketones in high yield.5... 

Chiral acylthiazolidinethiones such as 26 can readily be prepared from commercially available amino acids in three steps12 (Scheme 2.2k). They have been employed as a synthetically useful auxiliary in diastereoselective aldol reactions.13 The magnesium-catalyzed aldol reaction of the thiazolidinethione 26.S with cin-namaldehyde afforded 27 as a major diastereomer in 87% yield. Interestingly, compound 27 is the opposite anti-aldol diastereomer to that seen with the oxa-zolidinone 23S. 

From a mechanistic point of view, the first step is an acid catalyzed aldol reaction to IX/18. Acetalization of the remaining ketone, IX/19, and cleavage of the one-atom-bridge led to IX/20. This reaction was applied to the synthesis of bulnesol, IX/22, using the diketone, IX/21, as a starting material [7]. 

Diastereoselecttve aldol reactions. The diastereoselectivity in the Lewis acid-catalyzed aldol reaction of chiral oi-hydroxy aldehydes is independent of the geometry of the enol silyl ether. Also, the reaction does not involve prior Si-Ti or Si-Sn exchange. 

The preference for the amine-catalyzed aldol reaction to go through a TS having the features of 53a or 55a is now called the Houk-List model. This type of TS has three major characteristics (1) proton transfer from the carboxylic acid to the incipient alcohol concomitant with the formation of the C-C bond (TS D of Scheme 6.8) (2) the enamine is in the anti orientation and (3) the aldehyde substituent is anti to the enamine carbon. 

An interesting twist in the amino-acid-catalyzed aldol reaction is the use of histidine as catalyst. The key element of the Houk-List model is the proton transfer that accompanies the C-C bond formation. Histidine in aqueous solution can supply two sites for the proton transfer the carboxylic acid group (analogous to proline) or the imidazole. Experimental studies of the histidine-catalyzed aldol reaction demonstrates appreciable selectivity as shown in Reactions 6.22 and 6.23. ... 

Kiyooka et al. reported that the 3i-catalyzed aldol reaction of a silyl ketene acetal involving a dithiolane moiety with y3-siloxy aldehyde resulted in the production of syn and anti 1,3-diols with complete stereoselectivity depending on the stereochemistry of the catalyst used [45b]. This methodology was applied to the enantioselective synthesis of the optically pure lactone involving a syn-l,3-diol unit, known to be a mevinic acid lactone derivative of the HMG-CoA reductase inhibitors mevinolin and compac-tin (Sch. 2). 

The gold-catalyzed aldol reaction of a-keto esters gives the corresponding oxazolines with up to 90% ee, which are converted into optically actice ) -alkyl-) -hydroxyaspartic acid derivatives (Scheme 2-55) [77]. 

The gold-catalyzed aldol reaction has been successfully applied to the asymmetric synthesis of (l-aminoalkyl)phosphonic acids, phosphonic analogs of a-amino acids (Scheme 2-57) [80, 81]. The reaction of (isocyanomethyl)phosphonates 65 with... 

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