Synthesis of a P-Glycoprotein Inhibitor and Its High-Energy (<i>Z</i>)-Isomer by Carbenoid Eliminative Cross-Coupling

Abstract

To gauge the feasibility of carbenoid eliminative cross-coupling for the synthesis of polyfunctional alkenes, a P-glycoprotein inhibitor containing an (<i>E</i>)-configured 4-chromanylidene-type trisubstituted olefin was prepared as well as its previously undescribed (<i>Z</i>)-isomer. Stereospecific alkene synthesis required generation of functionalized enantioenriched α-metalated carbamates [R¹R²CM(O₂CN<i>i</i>-Pr₂), M = Li or Bneo], and problems associated with incorrect lithiation regioselectivity and unexpected organolithium configurational lability were encountered. Solutions to these difficulties are described together with a method for ee determination of α-carbamoyloxyboronates.