Cooler asymmetric synthesis from Radleys
An Oxford University research group puts Radleys Discovery Technologies new cooled carousel reaction station to the test when synthesising β—amino acids
An Oxford University research group puts Radleys Discovery Technologies new cooled carousel reaction station to the test when synthesising β—amino acids
Professor Stephen Davies' research group at Oxford University's Dyson Perrins Organic chemistry laboratory specialises in the development of new methods of asymmetric synthesis and their application in the high speed parallel synthesis of enantiopure compounds.
The group, which includes undergraduate, graduate and postdoctoral workers, has established methodology to facilitate the asymmetric synthesis of a diverse range of enantiopure β-amino acids.
This work has resulted in a number of successful collaborative projects with pharmaceutical companies, where the group has developed chemistry to expedite quality compound libraries for lead optimisation — via solid phase or solution phase parallel synthesis.
This ability to provide high purity compounds with a well-defined structure, and continual feedback between medicinal chemists and the group, enables arrays to be continually fine-tuned and the drug discovery process optimised.
Examples of recent projects of commercial potential in which Professor Davies' group has been involved include the total synthesis of a range of Sperabillins; antibiotic natural products and the synthesis of the b-amino acid side chain used in the development of the cancer drug Taxol, a complex natural product deriving from the yew tree.
The ultimate commercial success, however, has been the establishment of Oxford Asymmetry (1992) and Oxford Diversity (1995), both founded by Professor Davies and later combined as divisions of Oxford Asymmetry International.
Floated in 1998 and recently merged with Evotec at a value of £316m (US$442m), the venture now known as Evotech OAI is the leading combinatorial chemistry/high throughput screening company in Europe.
Much of the chemistry carried out by the Group is performed at low temperatures, and traditionally the cooling was effected using a flask immersed in a cooling Dewar.
However, this technique was limited to a small number of reactions and was not amenable to parallelisation.
robust cooling reservoir
More recently, a cooled carousel reaction station has been installed in the laboratory. Manufactured by Radleys Discovery Technologies, the cooled carousel is based on the popular carousel personal reaction station, and allows efficient parallel synthesis of up to 12 samples simultaneously at temperatures as low as -78°C. Fitting on a standard stirrer, it incorporates a robust HDPE 'cooling reservoir' compatible with a wide range of manual freezing mixtures, including dry ice/acetone.
Typically the cooled carousel is used to synthesise β-amino acids in four steps:
The use of the cooled carousel enables intermediates and final products [up to six enantiopure β-amino acids] to be synthesised in a single run.
Dr Andy Mulvaney, a postdoctoral fellow with five years' experience in the group, has been instrumental in the use of both the carousel and cooled carousel reaction station, and is highly enthusiastic about the practical advantages and productivity gains they offer.
'The cooled carousel reaction station, like its forerunner the carousel, has been quickly assimilated into the daily chemistry operations within our laboratory for both parallel synthesis and for rapid reaction development and optimisation.
'The great thing about the cooled carousel is that it allows us to carry out more low temperature reactions, a lot more efficiently using standard methodology. Like the carousel, it is a simple, low-tech apparatus that is eminently affordable, resulting in a huge boost for parallel synthesis and combinatorial chemistry.'
He adds, 'The carousel reaction stations need less operator training, with the result that all of our undergraduate and graduate students are able to have formal training in carrying out parallel synthesis.
'The carousel and cooled carousel use the same reaction tubes and caps, allowing easy integration,' Dr Mulvaney explains.
'We sometimes use both systems in parallel synthesis, undertaking the first steps in the cooled carousel and the subsequent steps in the standard carousel.'