Foto TjostilTjøstil Vlaar, PhD student in the Synthetic & Bio-organic Chemistry research group studied the use of isocyanides – a class of organic compounds – as building blocks in palladium catalysis for the sustainable production of drug-like molecules. His work underlines the potential of isocyanides in this type of chemistry and stimulates further developments in this field. He received his PhD degree cum laude on 15 May.

The utilization of the element palladium as a catalyst in chemical reactions has become indispensable in contemporary organic chemistry. In 2010, the Nobel prize for Chemistry was awarded to Heck, Negishi and Suzuki for their work in the development of palladium-catalyzed cross-coupling reactions.

Both academia and industry often use carbon monoxide as a building block in palladium catalysis for the production of fine chemicals and pharmaceuticals. Isocyanides can be seen as the nitrogen equivalents of carbon monoxide, but they have only scarcely been studied in palladium catalysis. Isocyanides have a variable group that allows for structural variation in products, which makes this class of compounds particularly useful for the synthesis of nitrogen-containing fine chemicals.

Structures of carbon monoxide and isocyanides

Structures of carbon monoxide and isocyanides

Structures of carbon monoxide and isocyanides

Drug-like molecules in single-reaction step In his PhD research, Tjøstil Vlaar explored the potential of isocyanide insertion in palladium-catalyzed reactions to obtain drug-like molecules. He synthesized a wide range of 4-aminophthalazin-1(2H)-ones: a rather unexplored molecular scaffold that has shown activity against cancer cells. To this end, Vlaar developed a one-pot multicomponent reaction that assembles this molecule in a single-reaction step. This approach is much more time-efficient compared to existing methods and enables structure-activity relationship studies.

Next to these synthetic studies, Vlaar thoroughly investigated the oxidative coupling of isocyanides and bisnucleophiles (molecules with two nucleophilic groups ions groups) in the presence of palladium catalysts. This oxidative coupling is broadly applicable to various bisnucleophiles and thus enables the synthesis of a wide range of biologically active molecular scaffolds. The reaction conditions are highly sustainable, as water is the only by-product. Vlaar applied oxidative coupling of isocyanides and bisnucleophiles to synthesize important drug-like compounds, like a known precursor of the antihistamine drug Astemizole.


Synthesis of the Astemizole precursor with palladium-catalyzed isocyanide insertion

Vlaar’s research demonstrates the synthetic utility of isocyanides in palladium catalysis, which is vital to the rapid development of this field. Nowadays, many other research groups around the world are developing similar reactions. This will further expand the synthetic toolbox and could make the production of pharmaceuticals more time-efficient, cheaper and environmentally benign.

Cum laude PhD degree

Tjøstil Vlaar conducted his PhD research under the supervision of Prof. dr. ir. Romano Orru and Dr. Eelco Ruijter in the Synthetic & Bio-organic Chemistry research group. He defended his thesis Isocyanides’ Latest Trick: Palladium-Catalyzed Imidoylative Cross-Coupling Reactions on 15 May at 13:45h in the Aula of the VU University and received his PhD degree cum laude.

Romano Orru explains: “Tjøstil took the initiative to move away from the ideas in the original research proposal and explored the full potential of isocyanide insertion chemistry, hence establishing a worldwide leading position for our group in this field. After our first publications, other groups all over the world jumped on the topic and the number of publications rose exponentially.

“Tjøstil build an impressive publication list of 10 papers in high impact journals like Angewandte Chemie in just 3 years. His work is already well-cited with over 80 citations in 2013. He also received the 2013 best PhD lecture prize at the 13th Netherlands’ Catalysis and Chemistry Conference in Noordwijkerhout. In short, Tjøstil is a young scientist of exceptional quality and therefore I found he highly deserved a cum laude PhD graduation. I am happy and proud that the promotion committee and additional external referees unanimously decided to grant this judicium to Tjøstil.”