SolutionsIbuprofen
Exercise 1
In the Boots route, the step from 4-isobutylacetophenone to the homologous aldehyde uses the Darzens condensation. Write its stages and say what kind of retrosynthetic operation it represents.
The enolate of ethyl chloroacetate adds to the ketone and the alkoxide displaces the chloride, giving an α,β-epoxy ester (glycidate). Hydrolysis of the ester and decarboxylation of the glycidic acid give the enol, which tautomerizes to the aldehyde ArCH(CH3)CHO. It is a homologation: one carbon (which will be C1 of the acid) is added to the ketone.
Exercise 2
Ibuprofen is sold as the racemate. What method from this course would allow (S)-ibuprofen to be obtained? Propose one resolution method and one asymmetric method.
Resolution: diastereomeric salts with a chiral amine, such as (S)-1-phenylethylamine or lysine, fractional crystallization and release of the acid; or enzymatic resolution of the ester with a lipase. Asymmetric: hydrogenation of 2-(4-isobutylphenyl)acrylic acid with a ruthenium–BINAP catalyst (Noyori), which gives (S)-ibuprofen in very high enantiomeric excess.