Synthesis of (9 Z,12 Z,15 E)- and (9 E,12 Z,15 Z)-octadecatrienoic acids and their [1- 14C]-radiolabelled analogs

Abstract

In order to study the effect of the double bonds geometry of linolenic acid (18:3 n-3) on its biological activities, (9 Z,12 Z,15 E)- and (9 E,12 Z,15 Z)-octadecatrienoic acids, found in many refined vegetable oils, were made by total synthesis. Synthesis of 18:3 Δ9 c, 12 c, 15 t involves a Wittig reaction between 3-(2-tetrahydropyranyloxy)-propylphosphonium salt and ( E)-3-hexenal which gave (3 Z,6 E)-1-(2-tetrahydropyranyloxy)-nonadiene in 66% yield. The transformation of the ether function to a phosphonium salt, followed by a Wittig reaction with 8-( t-butyldimethylsilyloxy)-octanal afforded a C17 trienic ether. A one-carbon homologation of its corresponding bromide with potassium cyanide followed by hydrolysis in basic medium furnished 18:3 Δ9 c, 12 c, 15 t in high isomeric purity and high radiochemical purity for its [1- 14C]-labelled analog. In the synthesis of 18:3 Δ9 t, 12 c, 15 c, a Wittig reaction between ( E)-6-(2-tetrahydropyranyloxy)-hex-3-enylphosphonium salt, obtained in three steps from 6-(2-tetrahydropyranyloxy)-hex-3-yn-1-ol and ( Z)-3-hexenal afforded a C12 ( E, Z, Z)-trienic ether. After a six-carbon homologation of this ether, in three steps, the resulting nitrile was hydrolyzed to (9 E,12 Z,15 Z)-octadecatrienoic acid (99% purity) (99% radiochemical purity of its [1- 14C]-labelled analog).