Stereospecific Csp3-Csp2 Cross-Coupling of Saturated Heterocyclic Boronates

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.

There are three specific research objectives:

(i) to carry out the optimisation of Suzuki-Miyaura cross-coupling reactions of saturated oxygen- and nitrogen-containing heterocycles using high throughput experimentation, rich data analysis and ligand design

(ii) to explore the scope and limitations of Suzuki-Miyaura cross-coupling reactions of saturated oxygen- and nitrogen-containing heterocycles (variations will include different boronates and aryl halides), drawing on mechanistic findings, particularly steps critical to productive catalysis

(iii) to apply the newly developed methodology to analogue and library synthesis including covid-19-related fragment hits

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/W522296/1 01/10/2021 30/09/2026
2602928 Studentship EP/W522296/1 01/10/2021 30/09/2025 Stuart McHale