Nature 505, 199–203 (2014)

Making complex and highly functionalized molecules from simple, relatively unreactive substrates is a goal of many modern synthetic techniques. The development of protocols that activate C–H bonds for reaction have in recent years opened up new areas of substrate reactivity and led to new syntheses of useful compounds. Techniques to activate C–C bonds have seen much less development and are more limited in scope, often suffering from selectivity problems. Now, a group of researchers, led by Ilan Marek from the Israel Institute of Technology, have discovered a new reaction that combines both of these challenging approaches in a single transformation and allows chemoselective sequential functionalization of a reactive intermediate.

In the method a zirconium-based reagent is employed in the activation of unsaturated cyclopropanes. When the substrate is an ω-ene-cyclopropane, the metal first activates the allylic C–H bond, before then carrying out a reversible 'walk' along the adjacent carbon chain (pictured, top). Once the metal reaches the cyclopropane, it irreversibly and selectively inserts into a C–C bond of the ring. This doubly activated organozirconium intermediate can then be quenched by successive additions of electrophiles. The first equivalent of electrophile reacts at the activated allylic carbon, which occurs diastereoselectively in enantiopure substrates, and the second at the metallated carbon of the now-fragmented cyclopropane. The technique is not limited to ω-ene-cyclopropanes; the same reactive organozirconium intermediate can be generated from alkylidenecyclopropane substrates, which can be easily prepared in enantiopure form. Because of the doubly activated nature of the reactive intermediate and the chemoselectivity of its reaction with electrophiles, a diverse range of acyclic and highly substituted molecules can be prepared from simple hydrocarbon substrates.

Marek and co-workers also report another mode of reactivity for unsaturated cyclopropanes (pictured, bottom). With a methoxymethyl substituent on the cyclopropane ring, a fragmentation mechanism from the metallated intermediate occurs giving acyclic unconjugated dienes with high selectivity for the E isomer. Owing to its selectivity, potential diversity, and wide application to substrates, the reported reaction is likely to find wide use.