Carboxylic acid derivatives aldol-like reactions

The aldol-like reaction of an aromatic aldehyde 1 with a carboxylic anhydride 2 is referred to as the Perkin reaction. As with the related Knoevenagel reaction, an o ,/3-unsaturated carboxylic acid is obtained as product the /3-aryl derivatives 3 are also known as cinnamic acids. 

Preparation of a somewhat more complex leukotriene antagonist begins by aldol condensation of the methyl carbanion from quinoline (29-1) with meta-phthalalde-hyde (29-2) to give the stilbene-like derivative (29-3) dimer formation is presumably inhibited by the use of excess aldehyde. Reaction of that product with A,A-dimethyl-3-mercaptopropionamide in the presence of hexa-methylsilazane affords the silyl ether (29-4) of the hemimercaptal. Treatment of that intermediate with ethyl 3-mercaptopropionate leads to the replacement of the silyl ether by sulfur and the formation of the corresponding thioacetal (29-5). Saponification of the ester group leads to the carboxylic acid and thus to verlukast (29-6) [33]. 

Cordova et al. demonstrated in 2005 that the aldol condensation between 4-nitrobenzaldehyde (5 R=p-N02) and cyclic ketones or butanone in the presence of acyclic primary amino acids led to the antz-isomer 6 (Scheme 12.3). One year later, this author described the structure-activity relationship between acyclic amino acids and the aldol derivatives, the synthetic scope of catalysis by acyclic amino acids in aqueous media and water, and studies concerning the reaction mechanism. Excellent enan-tioselectivities (ee up to >99%) were achieved in several cases. As an example of the anh -induction, the (E)-enamine arising from cyclohexanone and the acyclic amino acid could display a proton transfer from the carboxylic acid function to the alkoxide, giving a six-membered chair-like conformation. The favoured approach of the aldehyde would then lead to an anfi-isomer. 

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