Stereoselective synthesis of (6Z,10E,12Z)-octadeca-6,10,12-trienoic acid, (8Z,12E,14Z)-eicosa-8,12,14-trienoic acid, and their [1-14C]-radiolabeled analogs.
To study the metabolic fate of conjugated linoleic acid isomers, we synthesized, in seven steps, from 1-heptyne, (6Z,10E,12Z)-octadeca-6,10,12-trienoic acid, (8Z,12E,14Z)-eicosa-8,12,14-trienoic acid, and their [1-(14)C]-analogs. In the case of (6Z,10E,12Z)-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 (5Z,9E,11Z)-1-bromo-heptadeca-5,9,11-triene 10. Formation of the alkenyl lithium derivative and carbonation with CO(2) furnished (6Z,10E,12Z)-octadecatrienoic acid. (8Z,12E,14Z)-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)CO2. 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.
Loreau
O
O
CEA/Saclay, Service de Marquage Moleculaire et de Chimie Bioorganique, Bât. 547, F-91 191 Cedex Gif sur Yvette, France. olivier.loreau@cea.fr
Chardigny
J M
JM
Sébédio
J L
JL
Noël
J P
JP
D002250:Carbon Radioisotopes; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D004537:Eicosanoic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D044243:Linoleic Acids, Conjugated / Q000138:chemical synthesis* / Q000737:chemistry*; D015394:Molecular Structure; D013237:Stereoisomerism
C481862:(6Z,10E,12Z)-octadeca-6,10,12-trienoic acid; C481861:(8Z,12E,14Z)-eicosa-8,12,14-trienoic acid; D002250:Carbon Radioisotopes; D004537:Eicosanoic Acids; D044243:Linoleic Acids, Conjugated