SYNTHESIS AND ABSOLUTE CONFIGURATION OF ISOMERS OF HOMOISOCITRIC ACID (1-HYDROXY-1,2,4-BUTANETRICARBOXYLIC ACID) AND STEREOCHEMISTRY OF LYSINE BIOSYNTHESIS

The four isomers of homoisocitric acid, an intermediate in the α-aminoadipic acid pathway of lysine biosynthesis, have been synthesized and their absolute configurations determined. Diels-Alder condensations of 1- acetoxy-1,3-butadiene and methyl acrylate yields, after gas chromatographic separation and saponification, the two racemic forms of 2-hydroxy-3-cyclohexenecarboxylic acid. Each racemate was resolved. The four optically active isomers were then reduced to the saturated 2-hydroxy-3-cyclohexanecarboxylic acids, the absolute configurations of which are known. The four isomers of homoisocitric acid were obtained by ozonization of the four methyl-2-acetoxy-3-cyclohexenecarboxylates. Bioassay of the products, using homoaconitase, established that (+)-trans-2-hydroxy-3-cyclohexenecarboxylic acid yields natural homoisocitric acid. Thus, the absolute configuration of the natural compound can be designated as threo-Ds-homoisocitrate (l-(R)-hydroxy-2-(X)-l,2,4-butanetricarboxylic acid) and the enzymatic conversion of homocitrate into homoisocitrate is shown to be stereochemically analogous to the enzymatic conversion of citrate into isocitrate. © 1969, American Chemical Society. All rights reserved.