Aldol addition reactions 3-hydroxyaldehyde

You have seen that alcohols are dehydrated when they are heated with acid (Section 12.5). The )8-hydroxyaldehyde and j8-hydroxyketone products of aldol addition reactions are easier to dehydrate than many other alcohols because the double bond formed as the result of dehydration is conjugated with a carbonyl group. Conjugation increases the stability of the product (Section 8.3) and, therefore, makes it easier to form. If the product of an aldol addition is dehydrated, the overall reaction is called an aldol condensation. A condensation reaction is a reaction that combines two molecules while removing a small molecule (usually water or an alcohol). 

Here we recount the latest research on chemoenzymatic multistep and cascade strategies for the synthesis of iminocyclitols, carbohydrates, and deoxysugars from N-protected ami noaldehydes, hydroxyaldehydes, and simple alkylaldehydes, respectively. The key step in all of them is the stereoselective aldol addition reaction of dihydroxyacetone phosphate (DHAP) and its unphosphorylated analogs to the acceptor aldehydes using DH AP-dependent and dihydroxyacetone- (DH A)-utilizing aldolases, respectively, as biocatalysts. 

NaOH, H2O Aldol addition reaction Aqueous sodiiun hydroxide will cause an aldol addition reaction between two equivalents of an aldehyde or ketone to give a p hydroxyaldehyde (or a p-hydroxyketone). 

Now let s draw the forward scheme. We begin the synthesis with a directed aldol addition because the reaction involves two different partners (acetaldehyde and formaldehyde), which would otherwise give two possible addition products. That is, the enolate of acetaldehyde would be able to attack either acetaldehyde or formaldehyde, if both were present. It is true that formaldehyde is a better electrophile than acetaldehyde, so the desired product would be expected to predominate. Nevertheless, the minor product can be avoided altogether by using a directed aldol addition reaction. LDA is used as the base to deprotonate acetaldehyde irreversibly, with enolate formation proceeding to completion. This enolate can then be treated with formaldehyde, followed by water work-up, to give the aldol addition product (a P-hydroxyaldehyde). Reduction with LAH, followed by water work-up, gives a diol, which can be then be converted into the desired acetal upon treatment with formaldehyde in acid-catalyzed conditions (with removal of water). 

Now let s draw the forward scheme. Upon treatment with sodium hydroxide, acetaldehyde will undergo an aldol addition reaction, giving a P-hydroxyaldehyde. Reduction with LAH, followed by water work-up, gives a diol, which can be then be converted into the desired acetal upon treatment with formaldehyde in acid-catalyzed conditions (with removal of water). 

This dicarbonyl compound is 1,3-difimctionalized and can be made from a 5-hydroxyaldehyde, which can be made from propanal via an aldol addition reaction ... 

An aldol addition is a reaction between two molecules of an aldehyde or two molecules of a ketone. When the reactant is an aldehyde, the addition product is a jS-hydroxyaldehyde, which is why the reaction is called an aldol addition ( aid for aldehyde, ol for alcohol). When the reactant is a ketone, the addition product is a jS-hydroxyketone. Because the addition reaction is reversible, good yields of the addition product are obtained only if it is removed from the solution as it is formed. 

In an aldol addition, the enolate of an aldehyde or a ketone reacts with the carbonyl carbon of a second molecule of aldehyde or ketone, forming a j8-hydroxyaldehyde or a jS-hydroxyketone. The new C—C bond forms between the a-carbon of one molecule and the carbon that formerly was the carbonyl carbon of the other molecule. The product of an aldol addition can be dehydrated to give an aldol condensation product. In a Claisen condensation, the enolate of an ester reacts with a second molecule of ester, eliminating an OR group to form a j8-keto ester. A Dieckmann condensation is an intramolecular Claisen condensation. A Robinson annulation is a ring-forming reaction in which a Michael reaction and an intramolecular aldol addition occur sequentially. 

In order to construct the basic skeleton of tetrahydrolipstatin, an aldol addition is virtually predestined. The structure of tetrahydrolipstatin may be regarded formally as an a-branched carboxylic acid with oxygen functions at positions 3 and 5. These ought to be established easily by an anti-selective aldol reaction from a )S-hydroxyaldehyde and an enolate component at the oxidation level of a carboxylic acid. The hydroxy-function on the stereogenic centre at position 5 can be used moreover as a stereodifferentiating structural fragment. 

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... 

The aldol reaction is one of the most important ways to construct carbon-carbon bonds in organic synthesis. Nature itself seems to prefer this reaction in its biosynthetic processes, for example, in the prebiotic formation of saccharides [1]. Strictly speaking, the aldol reaction is the self-coupling of an aldehyde, having at least one active hydrogen in the a-position, to give a p-hydroxyaldehyde called an aldol (aldol addition), which sometimes dehydrates (aldol condensation). 

In this proper sense, aldol condensation includes reactions producing j3-hydroxyaldehydes or j3-hydroxyketones by self-condensation or mixed condensation of aldehydes and ketones these reactions are, in fact, additions of a C—H bond activated by the carbonyl to the C=0 bond of the other molecule, viz. 

The catalyhc efficiency of L-proline in ionic liquid was enhanced by the addition of DMF as cosolvent, which may be largely due to tlie increased mass transfer in the presence of DMF [79c]. Thus, the use of only 5 mol% L-proline was sufficient to accomplish the cross-aldol reactions of aliphatic aldehydes, affording a-alkyl-P-hydroxyaldehydes with extremely high enanhoselectivihes (>99% ee) in moderate to high diastereoselectivities (diastereomeric raho 3 1 >19 1). However, under the same reaction conditions, much lower ee-values and yields were observed in a one-pot synthesis of pyranose derivahves by sequential cross-aldol reachons. The L-proline immobilized in the ionic liquid layer could be recovered and reused without any deterioration in catalytic efficiency, with the diastereoselectivity,... 

Enantioselective additions of lithium enolates to aldehydes forming aldols ( 3-hydroxyaldehydes) are synthetically well established and have been reviewed elsewhere [20]. A catalytic variant, the Mukaiyma aldol reaction, i.e., the addition of silyl enol ethers to aldehydes, is usually mediated by chiral Lewis acids [21,22]. 

An aldol reaction is the addition of an enolate anion from one aldehyde or ketone to the carbonyl carbon of another aldehyde or ketone to form a /3-hydroxyaldehyde or J3- hyd roxyketon e. 

Aldol Reaction (Section 19.2) The aldol reaction involves nucleophilic addition of the enolate anion of one aldehyde or ketone to the carbonyl group of another aldehyde or ketone. The product of an aldol reaction is a j8-hydroxyaldehyde or a /3-hydroxyketone. An aldol reaction can be base catalyzed or acid catalyzed. If base is regenerated at the end of the reaction, it is base catalyzed, and if acid is regenerated, it is acid catalyzed. In both reactions, one or two new chiral centers are often created, leading to racemic products unless a starting aldehyde, ketone, or catalyst is chiral and present as a single enantiomer. 

Addition of a small amount of dilute aqueous sodium hydroxide to acetaldehyde at low temperature initiates the conversion of the aldehyde into a dimer, 3-hydroxybutanal, with the conunon name aldol (from aWehyde alcohoZ)- Upon heating, this hydroxyaldehyde dehydrates to give the final product, the a,j8-unsaturated aldehyde fra 5-2-butenal. This reaction is an example of the aldol condensation. The aldol condensation is general for aldehydes and, as we shall see, sometimes succeeds with ketones as well. We first describe its mechanism before turning to its uses in synthesis. 

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