Professor Robert Phipps (l) with Dr Antti Lahdenperä and PhD student Daniel Davies in the lab, courtesy Chemistry Photography
Scientists here have developed a new catalyst that could make it easier to synthesise the complex molecules used in areas from perfume to pharmaceuticals.
In research published today in Science, researchers in the Phipps group describe the development and application of a new chiral catalyst which can perform an important radical process known as hydrogen atom transfer in an enantioselective manner.
Radical vs. ionic
Chemical reactions can, broadly speaking, be classified into two distinct types: those in which the electrons move singly and those in which they move in pairs, referred to respectively as ‘radical reactions’ and ‘ionic reactions.’
Historically, two-electron chemistry has dominated mainstream synthetic methods, but in recent times there has been a surge of research into radical reactions. This has been driven by a relatively new technology called photoredox catalysis, which uses visible light irradiation with a special catalyst.
The researchers used this technology to develop a new catalyst, which can provide a step forward in addressing a significant challenge in radical chemistry related to hydrogen atom transfer (HAT). HAT is a chemical transformation in which two elementary particles, a proton and an electron, move between two different molecules in a single step, forming a newly synthesised molecule. In some cases, this can also introduce a new stereocentre.
Typically in HAT it is difficult to exert stereoselective control when new stereocentres are formed. But influence over which whether a ‘left-handed’ or ‘right-handed’ molecule is formed, known as enantioselectivity, is important because it gives scientists more control over the characteristics of the new molecule, such as the way they interact with biological systems. The new catalyst developed by the Phipps group will allow researchers to use HAT with control over selectivity, for a number of important molecule types.
New catalyst
To obtain their catalyst the researchers made a relatively minor modification to a well-known compound from the Cinchona alkaloid family of natural products, which is readily and cheaply extracted from tree bark. The Cinchona alkaloids are chiral molecules, which means that they are naturally ‘right-handed’ or ‘left-handed’. They have been used for many years as the basis for chiral catalysts in a wide range of reaction types and the Phipps group have now found another way of making the most of this ‘gift’ from nature to organic chemists.
The scientists used an excited photocatalyst to oxidise a nitrogen atom in the catalyst structure, which then allows it to abstract a hydrogen atom from the targeted environments. Because the molecules used as substrates possess symmetry, this hydrogen atom abstraction allows the symmetry to be broken and this produces new stereocentres. Using their novel catalyst they found that the new stereocentres could be formed with very high levels of selectivity.
The structure of the catalyst means it can transfer its chiral information to the new molecule and then be used again, so only a small amount of it is needed to produce ten times as much product. The catalyst can be used to produce molecules that are many times more complex than the starting materials and may have applications in areas such as pharmaceutical research and even fragrances (the ‘handedness’ of a molecule can drastically impact its smell).
Dr Robert Phipps, who led the research, said: “This research is important because hydrogen atom transfer is a really fundamentally important type of radical process which is prevalent in biology and chemistry. We have developed the first catalyst that is able to abstract a hydrogen atom from a substrate with a very high control of enantioselectivity and allow the radical to remain to be used in further transformations.”
First author Dr Antti Lahdenperä, who is a postdoctoral researcher in the Phipps group, said: “We have been very pleasantly surprised by the effectiveness of the catalyst system, and it will be interesting to see how widely used it will eventually be.”
Research
A. S. K. Lahdenperä, J. Dhankhar, D. J. Davies, N.Y.S. Lam, P. D. Bacoş, K. de la Vega-Hernández and R. J. Phipps, A Chiral Hydrogen Atom Abstraction Catalyst for the Enantioselective Epimerization of Meso Diols, Science (2024).