Synthesis of the heteroarotinoid ethyl (E)-4-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-YL)-1-propenyl] benzoate-9,10,11,20-14C4

A synthesis of ethyl (E)-4-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl)-1-propenyl]benzo ate-9,10,11,20-14C4 (1) is described via a multistep procedure similar to that used to obtained the unlabelled compound 2. The latter has shown good activity in several assays compared to the standard trans-retinoic acid (3). Treatment of methyl 3-phenoxypropionate (4) with methylmagnesium iodide (obtained from H314C-I) yielded the labelled tertiary alcohol 5. Cyclization of the alcohol 5 occurred in the presence of AlCl3 in nitromethane to give 4,4-dimethylchroman (6). Acetylation of 6 with H3C14C(O)Cl produced ketone 7 labelled at three carbons. Reduction of the carbonyl group in 7 was effected with LiAlH4 and gave alcohol 8. Phosphorylation with triphenylphosphine hydrobromide in methanol led to the corresponding phosphonium salt 9. Addition of n-butyllithium to 9 in ether at -780C generated the expected Wittig reagent in situ, and to this was added labelled ethyl 4-formylbenzoate [C2H5O214C-C6H4-CHO] (10). Workup, followed by chromatography of the oily product, afforded a solid. Recrystallization (abs. ethanol) gave 1 which was identical to 2 in terms of spectral data and melting point. The specific activity was determined to be 0.15 μCi/mg. (author)