Highly stereoselective access to an (E)-vinyl bromide from an aryl ketone leads to short syntheses of (Z)-tamoxifen and important substituted derivatives

Abstract

The enol triflate derived from a 1-(4-alkoxyphenyl)-2-phenyl-1-butanone is unstable, fragmenting to a vinyl cation that can be trapped by bromide ion. The E isomer of the vinyl bromide which is formed in preference (20:1) gave, upon palladium-catalyzed coupling with phenylzinc chloride, an immediate precursor of (Z)-tamoxifen. Similarly, coupling with other aryl metal reagents led to the first stereoselective synthesis of the potent antiestrogen metabolite (Z)-4-hydroxytamoxifen and to (E)-4-bromotamoxifen. The alkoxy substituent assisted fragmentation of the enol triflate, but as a 1-phenyl group was sufficient to allow stereoselective vinyl bromide formation, the methodology could have generality in the stereoselective synthesis of tetrasubstituted olefins that are styrene derivatives