Stereospecific Csp3-Csp2 Cross-Coupling of Saturated Heterocyclic Boronates: A Transformative Disconnection for Drug Discovery

Lead Research Organisation: University of York
Department Name: Chemistry

Abstract

Cyclic oxygen- and nitrogen-containing compounds (ring compounds that contain a series of carbon atoms and an oxygen or nitrogen atom) are very common structural units in a wide range of commercial pharmaceuticals. One example is Paroxetine which was developed by GlaxoSmithKline for the treatment of depression. There is a growing interest for medicinal chemists in the pharmaceutical industry to work on chiral drug structures. Chiral molecules are compounds which exist in mirror image forms (just like our hands) - drugs need to be prepared with one handedness (known as single enantiomers) as each enantiomer can have different biological properties. One of the most widely used processes in the pharmaceutical industry to synthesise drug molecules is the Suzuki-Miyaura cross-coupling reaction, the importance of which was recognised with the award of the 2010 Nobel Prize. However, the Suzuki-Miyaura reaction has not been used to directly prepare chiral drug motifs - there is currently no method for the general Suzuki-Miyaura cross-coupling of chiral saturated heterocyclic boronates with aryl halides. This project will deliver such a process to enable transformative and non-traditional disconnections, fundamentally changing the way that three-dimensional saturated nitrogen- and oxygen-containing heterocycles are constructed. Reaction discovery and optimisation of suitable catalytic protocols will be driven by automated high throughput experimentation, rich data analysis and rigorous mechanistic studies. The ubiquity of chiral cyclic molecules containing in FDA-approved drugs ensures that the process will be an enabling and transformative technology for drug discovery in the pharmaceutical industry. Finally, there will be an opportunity to use our new methodology in the optimisation of fragment hits against proteins of interest for the treatment of covid-19.

Publications

10 25 50
 
Description We have developed new catalytic methods for the fsynthesis of molecules that are of relevance to the pharmaceutical industry. In particular, we have identified new routes to nitrogen and sulfur containing containing compounds which are common motifs in pharmaceutical drug molecules.
Exploitation Route The methods that have been developed could be used in the future to synthesise new pharmaceuticals - they would be used by researchers in medicinal chemistry within the pharmaceutical industry.
Sectors Pharmaceuticals and Medical Biotechnology

 
Description Stereospecific Csp3-Csp2 Cross-Coupling of Saturated Heterocyclic Boronates
Amount £120,885 (GBP)
Funding ID 2602928 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 08/2021 
End 09/2025
 
Description Stereospecific Suzuki-Miyaura Csp3-Csp2 Cross-Coupling of Saturated Heterocyclic Boronates: Programmable Exploration of 3-D Space
Amount £118,513 (GBP)
Funding ID 2602986 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 09/2021 
End 09/2025