Stereoselective synthesis of (6 Z,10 E,12 Z)-octadeca-6,10,12-trienoic acid, (8 Z,12 E,14 Z)-eicosa-8,12,14-trienoic acid, and their [1- 14C]-radiolabeled analogs

Abstract

To study the metabolic fate of conjugated linoleic acid isomers, we synthesized, in seven steps, from 1-heptyne, (6 Z,10 E,12 Z)-octadeca-6,10,12-trienoic acid, (8 Z,12 E,14 Z)-eicosa-8,12,14-trienoic acid, and their [1- 14 C ]-analogs. In the case of (6 Z,10 E,12 Z)-octadecatrienoic acid, a series of palladium-catalyzed cross-coupling reactions between 1-heptyne and ( E)-1,2-dichloro-ethene, a coupling reaction with a Grignard reagent and cleavage of the dioxolane gave ( E)-dodec-4-en-6-ynal 3. Stereoselective Wittig reaction between aldehyde 3 and triphenyl-[5-(tetrahydro-pyran-2-yloxy)-pentyl]-phosphonium provided a dienyne. Stereocontrolled reduction of the triple bond and replacement of the tetrahydropyranyl group by a bromine gave (5 Z,9 E,11 Z)-1-bromo-heptadeca-5,9,11-triene 10. Formation of the alkenyl lithium derivative and carbonation with CO 2 furnished (6 Z,10 E,12 Z)-octadecatrienoic acid. (8 Z,12 E,14 Z)-eicosa-8,12,14-trienoic acid was obtained by the same route but using triphenyl-[5-(tetrahydro-pyran-2-yloxy)-heptyl]-phosphonium iodide for the Wittig reaction. [1- 14 C ]-analogs were obtained from the bromides by carbonation with 14 CO 2 . In all cases, chemical or radiochemical purities were found to be better than 95% after purification by flash chromatography on silica gel (>99% after additional purification by RP-HPLC). Metabolism studies in animals are in progress.