A stereoselective synthetic route to (R)-zearalanone.

Abstract

A stereoselective synthetic route to (R)-zearalanone was studied to determine the effect of absolute configuration on uterotropic activity. Starting with the naturally occurring (S)-zearalenone the phenolic groups were converted into their respective benzyl ethers followed by ketalization of the carbon-6 carbonyl function using ethylene glycol to give 3 in high yield. The 14-membered lactone could then be opened without racemization of the carbon-10 position by treatment of 3 with sodium hydroxide in dimethyl sulfoxide to yield 4 which was converted to its methyl ester 5 with diazomethane. The reaction of hydroxy ester 5 with p-toluenesulfonyl chloride in pyridine yielded toluenesulfonic ester 6. The reaction of 6 with tetraethylammonium acetate in refluxing methyl ethyl ketone gave 7. The methyl ester in 7 was hydrolyzed to give 8 which was hydrolyzed in aqueous tetrahydrofuran to yield 9. Hydroxy acid 9 was cyclized with trifluoroacetic anhydride in benzene to yield 10 which was reduced and hydrogeneolyzed to give (R)-zearalanone. The mouse uterotropic assay revealed that (R)-zearalanone had no activity but a mixture of (R) and (S) gave approximately the same response as (S) suggesting that (R) has a synergistic effect on the uterotropic activity of (S).