Beyond Macrocycles: Bond Disconnections Enabled by Olefin Metathesis


Umicore Precious Metals Chemistry


Olefin metathesis is a powerful tool that enables unique bond disconnection strategies via carbon-carbon bonds. It has been employed in commercial scale synthesis across multiple industries and in multiple reaction types including ring-closing, cross, and ring-opening metathesis. Among these, macrocyclization by ring-closing metathesis stands out as a hallmark of the technology. However, ring-closing metathesis can also serve as a highly efficient entry to smaller rings. In this article, we highlight retrosynthetic strategies toward 5- and 6-membered nitrogen heterocycles, including in the context of a commercial drug manufacturing process.

In the fifty years from its discovery to the 2005 Nobel Prize awarded to Yves Chauvin, Richard Schrock, and Robert Grubbs, olefin metathesis evolved from a curious oddity to a reliable tool for chemical synthesis and polymerization. These advances were made possible by tireless investigation of mechanism, (1) the development of well-defined catalysts, (2) and the exploration of those catalysts with a multitude of potential substrates (3).


Since 2005, this work has blossomed into new commercial applications in materials science,(4) biorenewable chemistry, (5) and pharmaceuticals (6).
Now, another generation of commercial-scale applications are currently in development, from pheromones for crop protection (7) to tough materials for 3D-printing (8) to structural paints for automotive coating (9).


Ruthenium-based catalysts in particular have found wide use in organic synthesis owing to their stability and functional group tolerance (Fig. 1) (10). First generation catalysts such as Grubbs Catalyst® M102 (Ru-1) paved the way for further development, while the two major families of second generation catalysts, Grubbs-type (Ru-2) an ...