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

Abstract

AbstractA synthesis of ethyl (E)‐4‐[2‐(3,4‐dihydro‐4,4‐dimethyl‐2H‐1‐benzopyran‐6‐yl)‐1‐propenyl]benzoate‐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 −78°C 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.