High throughput technique could help quickly identify chiral catalysts for drug manufacture

A new high throughput approach to screening for chiral catalysts has been developed by US scientists. The researchers say their method represents a ’standard workhorse’ for discovery and optimisation of chiral catalysts, such as those widely used by the pharmaceutical and pesticide industries.

Synthesis of chemicals of one particular enantiomeric form or ’handedness’ has become an extremely important process in industry - many new drugs, for instance, are single enantiomers. But until now, there has been no rapid way of identifying catalysts to carry out these syntheses. Now Eric Anslyn and colleagues at the University of Texas, Austin, say they have developed a technique that can be adapted for any type of compound to do just that.

’I don’t believe that anyone has actually put a general protocol into the literature for doing optical enantiomeric excess high throughput screening,’ says Anslyn. ’The protocol that we lay out, now we apply it to hydrobenzoin, but it’s really broadly applicable to any chiral functional group.’

Anslyn says his team’s technique, based on a colorimetric assay in a 96-well plate, will make a significant improvement on current methods, which rely on high performance liquid chromatography (HPLC).

’I think people are now limited by using chiral HPLC and I’m trying to remove that limitation,’ says Anslyn. ’What I really want is the synthetic organic chemistry community to start to adopt these assays and to work with me to actually transition them into the real life.’

The approach is a three step process. In the first step, the colorimetric assay is optimised by screening for an indicator and ’host’ combination that provides the best possible enantioselectivity for the chemical of interest. The indicator competes with the chemical for binding to the host - when bound, a colour change is triggered, allowing simple optical determination of selectivity for the ’guest’.

In the next step, the optical data for a range of different concentrations of guest molecules are entered into a powerful computer program known as an artificial neural network to ’train’ it for the final analysis. The final step involves robotically loading unknown reaction products into a 96-well plate, where they are analysed by the pre-trained program to identify those with high enantioselectivity.


Source: © Eric Anslyn

The researchers say their three-step process will be a significant improvement on current methods for discovery and optimisation of chiral catalysts

’This is a nice methodology paper on indicator displacement assays. It’s very elegant work,’ says Jean-Louis Reymond, who studies high throughput screening enzyme assays at the University of Berne in Switzerland. ’It’s one step off in the sense that it hasn’t been implemented, but I’m ready to believe that it’s doable.’

Hayley Birch