Prephenic acid

Prephenic acid occurs naturally as an intermediate in the biosynthesis of phenylalanine and tyrosine via the shikimic acid pathway. It is formed from chorismic acid by chorismate mutase:

The biosynthesis involves a [3,3]-sigmatropic Claisen rearrangement of chorismic acid.

Prephenic acid can be dehydrated by prephenate dehydratase to phenylpyruvic acid, which is a precursor of phenylalanine.

prephenic acid     CO₂ + H₂O   CO₂ + H₂O   phenylpyruvic acid

Alternatively, it can be decarboxylated and oxidised by prephenate dehydrogenase to give 4-hydroxyphenylpyruvic acid, which is a precursor of tyrosine:

prephenic acid + NADP⁺       CO₂ + H⁺   CO₂ + H⁺   4-hydroxyphenylpyruvic acid + NADPH  

Prephenic acid is unstable; as a 1,4-cyclohexadiene, it is easily aromatized, for example, under the influence of acids or bases. This instability makes both isolation and synthesis difficult. Prephenic acid was first isolated from mutants of Escherichia coli that were unable to convert prephenic acid to phenylpyruvic acid. During this process, the barium salt was obtained.

Prephenic acid is an example of achiral (optically inactive) molecule which has two pseudoasymmetric atoms (i.e. stereogenic but not chirotopic centers), the C1 and the C4 cyclohexadiene ring atoms. It has been shown that of the two possible diastereoisomers, the natural prephenic acid is one that has both substituents at higher priority (according to CIP rules) on the two pseudoasymmetric carbons, i.e. the carboxyl and the hydroxyl groups, in the cis configuration, or (1s,4s) according to the new IUPAC stereochemistry rules (2013).

The other stereoisomer, i.e. trans or, better, (1r,4r), is called epiprephenic.