Metathesis method makes E-alkenyl halides

When it comes to making 1,2-disubstituted olefins with metathesis chemistry, most synthetic chemists have taken sides. That is to say, they’ve tended to produce Z-olefins, in which the substituents are oriented to the same side of the double bond. Chemists led by Boston College’s Amir H. Hoveyda have now switched sides by developing a cross-metathesis route to E-alkenyl chlorides and fluorides. Selective synthesis of the E-isomers, in which the substituents are oriented to opposite sides of the double bond, had previously proven challenging via metathesis (Science 2016, DOI: 10.1126/science.aaf4622). The new transformation, which uses a molybdenum catalyst to swap the C=C bonds between an olefin and a simple E-dihaloalkene, uses kinetic control to guide formation of the thermodynamically less-stable E-isomer. Hoveyda’s team used the reaction to prepare derivatives of medicinally important compounds, such as the motion-sickness drug cinnarizine (shown). Alois Fürstner, a metathesis expert at the Max Planck Institute for Coal Research, who was not involved in the research, comments that the work marks a breakthrough even though the scope of the method is currently limited to specific alkenyl halides as the products. “The results show that there is light at the end of the tunnel, which in turn will inspire future catalyst design,” Fürstner says.