Dihydrostilbenes of Cannabis. Synthesis of canniprene

Abstract

Canniprene (10) is synthesised via reaction of a phenolate-anion ylide with a benzyl-protected aldehyde. Benzoylation, followed by hydrogenation and hydrogenolysis of the resulting stilbene, leads to a half-benzoylated bibenzyl which is converted into its O-dimethylprop-2-ynyl derivative. Semi-hydrogenation, Claisen rearrangement, and debenzoylation gives canniprene. In a second synthesis the prenylated (3-methylbut-2-enylated) and benzyl-protected ring-B section is made first and converted by Wittig reaction into a dibenzyl-protected stilbene. The stilbene is reduced and the benzyl groups removed in one step, without affecting the prenyl group, by sodium in butanol: magnesium in methanol is capable of stilbene reduction without debenzylation. This practical synthesis proceeds in 19% overall yield from the dimethylprop-2-ynyl ether of isovanillin (14) and is applicable to isotope-labelling. The use of p-bromophenacyl (PBP) ether and methoxyethoxymethyl (MEM) ether protection as the basis for canniprene synthesis is also considered.

Other bibenzyls relevant to the natural products of Cannabis are made and the methylated chroman (37) derived from canniprene is also synthesised.