A triple-aldol cascade reaction for the rapid assembly of polyketides

The Knoevenagel condensation is an aldol-type reaction involving the condensation of aldehydes or ketones with active methylene compounds such as β-diesters to produce substituted olefins.

Intramolecular aldol reaction occurs in dicarbonyl compounds such as dialdehydes, diketones, and keto-aldehydes. The dicarbonyl compounds possess more than one nucleophilic ⍺ carbon for the base to deprotonate and form the enolates. For example, in symmetrical diketones, there are four ⍺ carbons. Hence, four types of enolates are possible when treated with a base. However, since the molecule is symmetrical, the enolates formed on either side of one carbonyl group are equivalent to those formed...

The aldol reaction of a ketone under acidic conditions successfully forms an unsaturated carbonyl as the final product instead of an aldol. The acid-catalyzed aldol reaction is depicted in Figure 1.

As depicted in Figure 1, base-catalyzed aldol addition involves adding two carbonyl compounds in aqueous sodium hydroxide to form a β-hydroxy carbonyl compound.

Aldol condensation is an important route in synthetic organic chemistry used to generate a new carbon–carbon bond under basic or acidic conditions. The aldol condensation reaction presented in Figure 1 constitutes an aldol addition reaction followed by the dehydration process.

The reverse of the aldol addition reaction is called the retro-aldol reaction. Here, the carbon–carbon bond in the aldol product is cleaved under acidic or basic conditions to form two molecules of carbonyl compounds. The mechanism of the reaction consists of three steps.
In the first step, as depicted in Figure 1, the base deprotonates the β-hydroxy ketone at the hydroxyl group to form an alkoxide ion.