Synthesis of linoleic acid with chiral isotopic labelling at a flanking and a medial allylic methylene: the (8R,9Z,12Z)-[8-2H] and (11R,9Z,12Z)-[11-2H]-stereoisomers, and (Z)-[2,2-2H2]non-3-enal

Abstract

[1-²H]Oct-2-ynal is converted by fermenting bakers' yeast into (1S)-[1-²H]oct-2-yn-1-ol with an enantiomeric purity of >96% as measured by Mosher's MTPA method. The alcohol, as its tosyl ester, was then converted by copper-catalysed coupling with the di-Grignard of dec-9-ynoic acid and catalytic semi-hydrogenation, into (11R)-[11-²H]linoleic acid having less than 2%E-material and >95 atom %D. Provision for (11S)-[11-²H]linoleic acid was made by configurational inversion of (1R)-[1-²H]oct-2-yn-1-ol using Mitsunobu chemistry.

(8R)-[8-²H] Linoleic acid is made by a similar approach, the labelled chiral centre being formed on (8S)-8-hydroxy-[8-²H]octanoic acid (>96% ee). Reaction of the corresponding tosate with lithium acetylide–ethylenediamine complex gave, with configurational inversion, (8R)-[8-²H]dec-9-ynoic acid, built into (8R)-[8-²H]linoleic acid. A degradative circuit is applied to estimate the extent of configurational inversion in the displacement. Mitsunobu inversion of the (8S)-8-hydroxy compound provides access to (8S)-[8-²H] linoleic acid.

(Z)-Non-3-enal, a labile aldehyde from the enzymic degradation of linoleic acid, is made in [2,2-²H₂]-labelled form by a synthesis which uses, as a key step, the reaction between triheptynylborane and deuteriodiazoacetic ester.