Chiral drug-like building blocks by nickel-catalyzed enantioselective cross-coupling of olefins

NUS chemists have developed an efficient method to access enantioenriched drug-like compounds via multicomponent olefin cross-coupling using chiral nickel-based catalysts.

Chiral molecules containing enantioenriched tri- and tetrasubstituted stereogenic centers are found among many natural products and drugs. The spatial arrangement of atoms around such centers often dictates the overall shape of a molecule and affects its biological function or toxicity. Thus, the ability to produce enantiomerically pure compounds through asymmetric catalysis is of vital importance in pharmaceutical and agrochemical research. However, related strategies using non-precious metal-derived catalyst systems to promote enantioselective synthesis using cheap and abundant olefin feedstocks are often of limited scope. This limits their widespread adoption.

A research team led by Assistant Professor Koh Ming Joo, from the National University of Singapore’s Department of Chemistry, has devised a new strategy that utilizes widely available nickel catalysts containing hindered N-heterocyclic carbene (NHC) ligands to fuse olefins with a organotriflate and a metal alkoxide as a hydride donor. Replacing the metal alkoxide with an organometallic reagent allows the installation of two different carbogenic groups.

These multicomponent reactions provide an improved route to chiral molecules bearing enantiocarbon-enriched or heteroatom-substituted tertiary or quaternary stereocenters. This is a collaboration with Professor Shi-Liang Shi, from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences. The findings were published in Nature Catalysis.

Professor Koh said, “Through selective carbon functionalizations, we can even access opposite enantiomers of a chiral molecule using a single chiral antipode catalyst. This is difficult to achieve using alternative systems, demonstrating a unique advantage of our catalytic regime. We can now to use this new protocol as a general platform to produce valuable chiral molecules with high steric purity.”

“We believe that this methodology will greatly enrich the toolbox of asymmetric catalysis to facilitate countless applications in the stereoselective synthesis of natural products and drug discovery,” added Professor Koh.

The research group is developing new chiral NHC-nickel catalysts to promote olefin cross-coupling transformations that can potentially address other unsolved challenges in organic synthesis.