Enantioselective synthesis of beta-hydroxy acid derivatives via a one-pot aldol reaction-dynamic kinetic resolution

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.

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.

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.

The reaction between two different carbonyl compounds comprising α hydrogen in the presence of a strong base like lithium diisopropylamide (LDA) to form a crossed aldol product is known as a directed aldol reaction. The directed aldol reaction is depicted in Figure 1.

Acetoacetic ester synthesis is a method to obtain ketones from alkyl halides and β-keto esters. The reaction occurs in the presence of an alkoxide base that abstracts the acidic proton of the β-keto esters. The step results in an enolate ion which is doubly stabilized. The enolate then reacts with an alkyl halide via the SN2 process to produce an alkylated ester intermediate with a new C–C bond. The hydrolysis of the intermediate, followed by acidification, results in an alkylated β-keto acid.

This lesson deals with the crossed aldol reaction using weak bases. The self-condensation of an aldehyde having α hydrogen is prevented by adding it slowly to a mixture of formaldehyde and weak bases like hydroxide and alkoxide. Upon slow addition of the aldehyde, the base deprotonates the α carbon of the aldehyde to form the corresponding enolate. The enolate subsequently attacks the formaldehyde to form a single crossed product. Figure 1 depicts the aforementioned reaction.