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Catalytic Enantioselective Hydrogen Atom Transfer

School of Chemistry

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Dr Craig Johnston , Prof Andreas Gansäuer No more applications being accepted Funded PhD Project (Students Worldwide)
St Andrews United Kingdom Inorganic Chemistry Organic Chemistry Synthetic Chemistry

About the Project

Catalysis is an enabling branch of science that provides access to novel products and materials. Therefore, it is ideally suited to deliver sustainable solutions for the demands of modern society. The catalyst, which is a small quantity of a substance that is not consumed during a reaction and can be recycled, enhances the rate of product formation and imparts high levels of selectivity. The latter is fundamentally important for certain applications, for example, dictating the absolute spatial arrangement of atoms in a drug–known as enantioselective control. This is key for potency and reducing side effects, as the shape of the drug must be complementary to the three-dimensional structure of its biological target.

Tertiary carbon stereocentres are tremendously common in biologically active natural products and synthetic drugs. These occur when a carbon atom is connected to four different substituents and one of these is a hydrogen atom. However, the methods currently available to introduce the hydrogen in a spatially specific or enantioselective manner are dominated by ionic transformations. These reactions involve the movement of pairs of electrons during bond formation. For hydrogen this would involve the enantioselective transfer of a proton (no electrons) or a hydride (two electrons). In stark contrast, methods for the enantioselective transfer of a hydrogen atom (one electron) are rare. This can be rationalised by the well-known difficulty of controlling short-lived radical species, which have an unpaired electron and whose reactions involve the transfer of single electrons during bond formation. This imbalance has severely restricted access to valuable areas of chemical space as radical reactivity is orthogonal to its ionic counterpart.

To address these challenges, this project seeks to merge the features of radical chemistry with those of transition metal and phase-transfer catalysis. In particular, the project will take a novel approach to the synthesis of titanium-based hydrogen atom donors that will be used to transfer hydrogen enantioselectively to a radical intermediate to form a new tertiary carbon stereocentre. This strategy will enable us to perform reactions in biphasic systems under phase-transfer catalysis. These systems utilise small quantities of a lipophilic ion to extract an oppositely charged reagent from an aqueous or solid phase into an organic solvent. In this manner, the advantages of all these fields can be combined. For example, the high functional group tolerance of radical reactions, and the exquisite ability of metal complexes to control the enantioselectivity of reactions. Moreover, cheap inorganic salts, such as formate, can be used as hydrogen sources under phase-transfer conditions rather than toxic and expensive hydrogen atom donors, such as stannanes. This would render the proposed system more attractive especially for large-scale industrial applications.

Overall, the project approach will utilise titanium, an earth-abundant and non-toxic metal, alongside ligands and a phase-transfer catalyst, all of which will be benign organic compounds composed of non-metallic elements. Therefore, the project will provide a sustainable solution to a challenging radical reaction involving enantioselective hydrogen atom transfer that gives access to highly desirable drug-like molecules bearing tertiary carbon stereocentres not currently possible through ionic reactivity.

The scholarship will support a co-tutelle doctoral degree programme between the School of Chemistry at St Andrews and the University of Bonn in Germany. The student will be supervised by Dr Craig Johnston (University of St Andrews) and Professor Andreas Gansäuer (University of Bonn).

Informal enquiries regarding this scholarship may be addressed to Dr Craig Johnston – email [Email Address Removed]

The student must start their degree in September 2021. The student will be expected to spend approximately half of the award term at the University of St Andrews and half at the University of Bonn.

Funding Notes

Duration of funding is up to 3.5 years. The award covers full tuition fees for the period of time spent at the University of St Andrews. For this period, the student will also receive a stipend payable at the standard UK Research council rate (the 2021-22 annual rate is £15,560). For the period spent at the University of Bonn no tuition fees will be due and the student will receive maintenance award.
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