Stereoselectivity and generality of the palladium-catalysed cyclopropanation of α,β-unsaturated carboxylic acids derivatized with Oppolzer's sultam

Abstract

A series of α,β-unsaturated carboxylic acids derivatized with camphorsultam 1 as a chiral auxiliary has been stereoselectively cyclopropanated. The selectivity of the reaction produces cyclopropanated products with the 1R, 2R absolute configuration as indicated by the optical rotations as well as by an X-ray structure determination. The temperature dependence of the reaction was studied with three substrates. The highest stereoselectivity was obtained at temperatures above 25 °C. Branching at the α- or β-carbons disfavours complete conversion, and electron-withdrawing substituents at these positions seem to prevent the reaction. The auxiliary was removed by using titanium(IV) isopropoxide in benzyl alcohol followed by alkaline hydrolysis of the intermediate ester. The potent 5-HT_1A receptor agonist (1R,2S)-2-(2-hydroxyphenyl)-N,N-dipropylcyclopropylamine 13 was synthesized by this method.