Seeking Chemocatalytic and Biocatalytic Solutions

Advances in palladium-catalyzed hydrogenation, visible-light photocatalysis, and chemocatalyisis for heterocycles are some recent developments.
Jun 05, 2012

Patricia Van Arnum
Catalysis plays a crucial role in the synthesis of pharmaceutical intermediates and APIs. Catalysts can enable more efficient chemical transformations, improve reaction conditions, better product yields, and produce greater enantioselectivity. Some key recent developments involve palladium-catalyzed hydrogenation, visible-light photocatalysis, chemocatalytic approaches for making heterocyclic compounds, and advances in biocatalysis.

Palladium-catalyzed hydrogenation

Palladium-catalyzed hydrogenation reactions are important in industrial chemistry and fine-chemicals manufacture, but precious metal catalysts, such as palladium, are costly. Researchers at Tufts University's School of Arts and Sciences and School of Engineering in Medford, Massachusetts, recently reported on the arrangement of individual atoms in a metal alloy and their ability to catalyze hydrogenation reactions.

Hydrogenation requires the presence of a catalyst, usually a metal or an alloy of both precious and common metals, which allows the hydrogen atoms to bind with other molecules. It is difficult to produce alloys that are selective hydrogenation catalysts and are able to attach the hydrogen atoms to specific sites of another molecule. Tufts chemists and chemical engineers reported that when single atoms of palladium were added to copper, which is much cheaper and readily available, the resulting "single atom alloy" became active and selective for hydrogenation reactions, according to a Mar. 9, 2012, Tufts University press release.

The Tufts scientists scattered single atoms of palladium less than half a nanometer wide onto a copper support. For this research, the Tufts team heated small amounts of palladium to almost 1000 °C. At that temperature, individual atoms embedded themselves on the copper surface. A scanning tunneling microscope enabled the team to see how these single atoms dispersed in the copper and how molecular hydrogen could then dissociate at individual, isolated palladium sites and spill over onto the copper surface layer, according to the Tufts release.

Specifically, the researchers used desorption measurements in combination with high-resolution scanning tunneling microscopy to show that the individual, isolated palladium atoms in a copper surface substantially lowered the energy barrier to both hydrogen uptake on and subsequent desorption from the copper metal surface. The hydrogen dissociation at the palladium atom sites and weak binding to copper allowed for very selective hydrogenation of styrene and acetylene as compared with pure copper or palladium metal alone (1).

Visible-light photocatalysis

A team of University of Arkansas (US) researchers reported on using visible-light photocatalysis with a ruthenium catalyst to produce a building block in pharmaceutical synthesis. Specifically, the researchers reported on a visible-light-mediated intermolecular [3+2] cycloaddition of mono- and bicyclic cyclopropylamines with olefins catalyzed by [Ru(bpz)3](PF6)2•2 H2O to produce aminocyclopentane derivatives in good yields. Saturated 5,5- and 6,5-fused heterocycles were obtained in synthetically useful yields and diastereoselectivity (2).

Enantioselective N-heterocycles

Heterocyclic compounds are important in pharmaceutical applications, and researchers at the California Institute of Technology (Caltech) recently reported on an advance in the synthesis of such compounds. They reported on their work in the enantioselective construction of quaternary N-heterocycles by palladium-catalyzed decarboxylative allylic alkylation of lactams (3).

"We think it's going to be a highly enabling reaction, not only for preparing complex natural products, but also for making pharmaceutical substances that include components that were previously very challenging to make," said Brian Stoltz, professor of chemistry at Caltech, in a Jan. 13, 2012, university press release. "This has suddenly made them quite easy to make, and it should allow medicinal chemists to access levels of complexity they couldn't previously access.

Specifically, the researchers reported on the highly enantioselective palladium-catalyzed decarboxylative allylic alkylation of lactams to form 3,3-disubstituted pyrrolidinones, piperidinones, caprolactams, and structurally related lactams. The researchers assert that the synthesis provides a new approach for the asymmetric synthesis of such structures, an important development given the prevalence of quaternary N-heterocycles in biologically active alkaloids and pharmaceutical agents. The researchers reported that the catalysis provided enantiopure quaternary lactams that intercept synthetic intermediates previously used in the synthesis of the Aspidosperma alkaloids, quebrachamine and rhazinilam, but that were previously produced by chiral auxiliary approaches or as racemic mixtures (3).