Kinetically controlled Z-alkene synthesis using iron-catalysed allene dialkylation

Abstract

Stereodefined trisubstituted alkenes are key constituents of biologically active molecules and also serve as indispensable substrates for a wide range of stereospecific reactions affording sp3-hybridized skeletons. However, there is a persisting lack of methods that generate the thermodynamically less stable Z-isomers. Here we report an iron-catalysed multicomponent strategy that merges allenes, dialkylzinc compounds and haloalkanes to construct trisubstituted alkenes with excellent control of regioselectivity and Z-selectivity. Selective installation of diverse C(sp3) groups enables access to a broad library of functionalized unsaturated products. The synthetic utility of the method is highlighted through the synthesis of a glucosylceramide synthase inhibitor. Contrary to conventional mechanisms for metal-catalysed allene functionalization, our studies suggest a kinetically controlled pathway involving sequential radical-mediated alkylferration of the less hindered C=C bond and inner-sphere alkylation via reductive elimination. Mechanistic and computational investigations reveal the origins of the stereochemical outcome. Catalytic methods that generate Z-alkenes are rare due to the energetic favourability of the corresponding E-alkenes. Now, a bisphosphine–iron catalyst mediates the multicomponent dialkylation of allenes, using dialkylzinc reagents and alkyl halides, to selectively form functionalized trisubstituted Z-alkenes.