Affordable iron catalysts offer sustainable route to valuable Z-alkenes

Chemists at the National University of Singapore (NUS) have developed an iron-catalyzed method that overcomes a significant challenge in the sustainable synthesis of trisubstituted Z-alkenes by inserting two alkyl chemical groups into a class of compounds called arenes. has been developed. The results of this study were published in the journal Nature Synthesis.

Trisubstituted alkenes are major building blocks of biologically active molecules and serve as important substrates for a wide range of stereospecific reactions to form sp3 hybridization scaffolds. However, catalytic methods that selectively produce the Z isomer of these alkenes are rare. This is because the Z isomer is more energetically unstable than the corresponding E isomer. To overcome this thermodynamic bias, a kinetically controlled catalytic process is required.

The research team, led by Associate Professor Koh Ming Joo from the NUS Department of Chemistry, takes advantage of the affordable and readily available bisphosphine iron catalyst to fuse arenes with other simple chemical building blocks, particularly sp3 hybrid organohalides. We have developed a new method to do this. Organozinc reagent.

This multicomponent strategy allows us to add various aliphatic groups to arenes while controlling both site and Z selectivity. Additionally, the use of catalysts derived from iron, a nontoxic, abundant, and inexpensive transition metal, increases the economic and environmental attractiveness of this green protocol.

The research team also applied a newly developed method to simplify the preparation of glucosylceramide synthase inhibitors containing trisubstituted Z-alkenes. Here, the Z-configuration is essential for its biological activity.

The research was conducted in collaboration with Dr. Xinglong Zhang of the Chinese University of Hong Kong and the Institute of High Performance Computing of the Agency for Science, Technology and Research (A∗STAR).

Professor Koh said: “By providing an easy way to access trisubstituted Z-alkenes, our method not only fills an important gap in the literature, but also improves the use of these valuable but hard-to-find materials in routine experimental studies. “This will enable meaningful research into difficult hydrocarbon compounds.” For applications such as drug discovery. ”

“Our study also suggests a unique mechanism involving radical-mediated alkyl ironation in the outer sphere followed by carbon-carbon bond formation in the inner sphere, which may be a key mechanism for the kinetics of arenes and other π-systems. “This provides important insights for designing controlled reactions,” added Professor Koh.

Based on these insights, the research team is designing other multicomponent transformations that upgrade abundant raw materials into value-added chemical products for a variety of industrial applications.