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Formulation and manufacture of lipid nanoparticles using the micropore AXF crossflow systems
Full text linkSince its discovery in 1961, the therapeutic utilisation of messenger RNA (mRNA) to combat viral infection and genetic predispositions became a strong focal point for the field of molecular biology. Unlike DNA, mRNA’s transient single strand structure alleviated concerns associated with long-circulation times and consequential offtarget toxicity whilst simultaneously harbouring a reduced risk of genetic recombination. Although promising, challenges facing effective mRNA delivery to the cell cytosol hindered its therapeutic potential. Both exogenous mRNA’s intrinsic immunostimulatory activity and susceptibility to host endonucleases inhibited mRNA’s translational activity and potency. The result led to the exploration of two avenues to mitigate these pitfalls: nucleoside modification of mRNA to protect against innate immune clearance mechanisms and optimisation of lipid nanoparticles (LNPs) to enable successful delivery and uptake to the cell cytosol. Expedited by the SARSCoV2 response, both played critical roles in the rapid development and success of Pfizer-BioNTech’s Comirnaty and Moderna’s Spikevax response. Despite the success of this LNP- based vaccine roll out, bottlenecks in the manufacture of LNPs highlighted the necessity for a scale-independent, uniform design, capable of formulating LNPs at benchtop to manufacturing throughputs. As such, varying microfluidic-based synthesis methods are being explored, one of which is the AXF crossflow technology developed by Micropore Technologies. This project aims to develop a thorough understanding of the effect of the process parameters and fluid mixing dynamics within the range of Micropore’s crossflow devices to support the fast and easy scale-up of LNP production processes and to enable local vaccine manufacture within developing countries. This will be achieved by evaluating the impact of operating speed, lipid concentration, choice of ionizable lipid on LNP critical quality attributes (CQAs) using Micropore AXF-Mini crossflow device. Succeeding this, LNP efficacy in vitro and methods scaling to an in vivo dosage concentration will be evaluated.Since its discovery in 1961, the therapeutic utilisation of messenger RNA (mRNA) to combat viral infection and genetic predispositions became a strong focal point for the field of molecular biology. Unlike DNA, mRNA’s transient single strand structure alleviated concerns associated with long-circulation times and consequential offtarget toxicity whilst simultaneously harbouring a reduced risk of genetic recombination. Although promising, challenges facing effective mRNA delivery to the cell cytosol hindered its therapeutic potential. Both exogenous mRNA’s intrinsic immunostimulatory activity and susceptibility to host endonucleases inhibited mRNA’s translational activity and potency. The result led to the exploration of two avenues to mitigate these pitfalls: nucleoside modification of mRNA to protect against innate immune clearance mechanisms and optimisation of lipid nanoparticles (LNPs) to enable successful delivery and uptake to the cell cytosol. Expedited by the SARSCoV2 response, both played critical roles in the rapid development and success of Pfizer-BioNTech’s Comirnaty and Moderna’s Spikevax response. Despite the success of this LNP- based vaccine roll out, bottlenecks in the manufacture of LNPs highlighted the necessity for a scale-independent, uniform design, capable of formulating LNPs at benchtop to manufacturing throughputs. As such, varying microfluidic-based synthesis methods are being explored, one of which is the AXF crossflow technology developed by Micropore Technologies. This project aims to develop a thorough understanding of the effect of the process parameters and fluid mixing dynamics within the range of Micropore’s crossflow devices to support the fast and easy scale-up of LNP production processes and to enable local vaccine manufacture within developing countries. This will be achieved by evaluating the impact of operating speed, lipid concentration, choice of ionizable lipid on LNP critical quality attributes (CQAs) using Micropore AXF-Mini crossflow device. Succeeding this, LNP efficacy in vitro and methods scaling to an in vivo dosage concentration will be evaluated
The effects of interfaces on heterogeneous nucleation of urea : experiments and simulations
No full textThe formation of crystals from solutions is a natural phenomenon, which is frequently
used in industrial separation and purification processes. Crystal nucleation commonly
occurs heterogeneously at interfaces, however, the processes are difficult to control
since the behaviour is not well understood. This work uses a combination of nucleation
experiments and atomistic molecular dynamics (MD) simulations to investigate the
mechanisms influencing heterogeneous nucleation in aqueous urea solutions.
Quiescent, cooling crystallisation experiments were performed and two high-throughput
methods were compared to determine the optimal experimental conditions and setup.
Concentrations of 1800-2280 g kg−1 and temperatures from -5-25 °C were tested, corresponding to moderate and high supersaturations. 15-20 °C provided the best induction
time measurements with low nucleation probabilities at 25 °C. Heterogeneous nucleation experiments were performed for aqueous urea solutions in contact with air, glass,
diamond and polytetrafluoroethylene (PTFE) surfaces. 1 ml solution samples were
contained in glass vials with a solution-air interface, which was taken as the control
system. The presence of a PTFE surface was found to significantly increase the nucleation probability, up to ×8, in comparison to the control samples, indicating that
heterogeneous nucleation occurred at the PTFE surface. The presence of a diamond
surface also showed a slight increase of nucleation probability, up to ×4.
MD simulations were used to study urea solutions in contact with PTFE, diamond,
α-quartz, and vacuum interfaces. Firstly, a force field validation protocol was developed, since the performance of MD simulations is highly dependent on the underlying models. Four GAFF and five OPLS force fields were compared, and a urea-specific
charge-optimised GAFF force field and the original all-atom OPLS force field were
found to be the best for simulating bulk crystals and aqueous solutions of urea. MD
simulations of urea solutions at the solid interfaces found that strong solute-surface
dispersion interactions enhanced the solute concentration near the interface. The interfacial urea concentration was enhanced by 32-59% and 13-29% for the PTFE and
diamond surfaces respectively. The enhanced interfacial concentration contributes to
the explanation for the observed heterogeneous nucleation rates and provides a new
basis for guiding materials selection to improve crystallisation processes and to reduce
fouling.The formation of crystals from solutions is a natural phenomenon, which is frequently
used in industrial separation and purification processes. Crystal nucleation commonly
occurs heterogeneously at interfaces, however, the processes are difficult to control
since the behaviour is not well understood. This work uses a combination of nucleation
experiments and atomistic molecular dynamics (MD) simulations to investigate the
mechanisms influencing heterogeneous nucleation in aqueous urea solutions.
Quiescent, cooling crystallisation experiments were performed and two high-throughput
methods were compared to determine the optimal experimental conditions and setup.
Concentrations of 1800-2280 g kg−1 and temperatures from -5-25 °C were tested, corresponding to moderate and high supersaturations. 15-20 °C provided the best induction
time measurements with low nucleation probabilities at 25 °C. Heterogeneous nucleation experiments were performed for aqueous urea solutions in contact with air, glass,
diamond and polytetrafluoroethylene (PTFE) surfaces. 1 ml solution samples were
contained in glass vials with a solution-air interface, which was taken as the control
system. The presence of a PTFE surface was found to significantly increase the nucleation probability, up to ×8, in comparison to the control samples, indicating that
heterogeneous nucleation occurred at the PTFE surface. The presence of a diamond
surface also showed a slight increase of nucleation probability, up to ×4.
MD simulations were used to study urea solutions in contact with PTFE, diamond,
α-quartz, and vacuum interfaces. Firstly, a force field validation protocol was developed, since the performance of MD simulations is highly dependent on the underlying models. Four GAFF and five OPLS force fields were compared, and a urea-specific
charge-optimised GAFF force field and the original all-atom OPLS force field were
found to be the best for simulating bulk crystals and aqueous solutions of urea. MD
simulations of urea solutions at the solid interfaces found that strong solute-surface
dispersion interactions enhanced the solute concentration near the interface. The interfacial urea concentration was enhanced by 32-59% and 13-29% for the PTFE and
diamond surfaces respectively. The enhanced interfacial concentration contributes to
the explanation for the observed heterogeneous nucleation rates and provides a new
basis for guiding materials selection to improve crystallisation processes and to reduce
fouling
Improving computational efficiency of wind energy resource assessment through novel statistical wake and access models
No full textWith the rapid growth of the wind energy sector and, consequently, site development, accurate and efficient resource assessment is becoming increasingly relevant. In-depth assessment requires a multitude of complex
considerations, including the study of highly stochastic environmental conditions such as wind field and wave patterns. Understanding these conditions is essential to many Key Performance Indicators such as Energy Yield, O&M cost, accessibility and Levelized Cost of Energy (LCOE). To achieve this, computationally complex techniques such as Monte Carlo simulations are typically employed, however these methods are rarely feasible for comparing long timespans or large areas. This thesis focuses on improving the computational efficiency of resource assessment for wind energy by producing novel methods in two key areas of environmental forecasting: access prediction and wake modelling. The improved efficiency enables quicker resource
assessment and comparison of large areas to optimise site selection. The first section proposes a highly accurate and efficient Markov Chain model, based on a weather and accessibility state space, to estimate several key accessibility traits, including the probability of instant access and estimated delay time of repairs due to weather. This model has competitive accuracy with existing
probabilistic methods but with improved computational cost, allowing for assessing a three-year North Sea dataset in an order of minutes. This model may be used instead of more intensive Monte-Carlo simulations whilst still producing high accuracy and associated confidence. The second section derives and solves a Fourier approximation of a Gaussian wake based on the Bastankhah Porte-Agel model [1], to be implemented in Strathfarm, a holistic wind farm simulation software aiming to produce medium-fidelity results in real-time. The current implementation requires computationally intensive look-up tables based on polynomial approximations. The proposed method derives an efficiently calculable polynomial in terms of farm conditions only, removing the need for extremely large look-up table storage and access. This new method significantly improves efficiency whilst maintaining the accuracy of the current
methodology within 10%. [References in thesis text]With the rapid growth of the wind energy sector and, consequently, site development, accurate and efficient resource assessment is becoming increasingly relevant. In-depth assessment requires a multitude of complex
considerations, including the study of highly stochastic environmental conditions such as wind field and wave patterns. Understanding these conditions is essential to many Key Performance Indicators such as Energy Yield, O&M cost, accessibility and Levelized Cost of Energy (LCOE). To achieve this, computationally complex techniques such as Monte Carlo simulations are typically employed, however these methods are rarely feasible for comparing long timespans or large areas. This thesis focuses on improving the computational efficiency of resource assessment for wind energy by producing novel methods in two key areas of environmental forecasting: access prediction and wake modelling. The improved efficiency enables quicker resource
assessment and comparison of large areas to optimise site selection. The first section proposes a highly accurate and efficient Markov Chain model, based on a weather and accessibility state space, to estimate several key accessibility traits, including the probability of instant access and estimated delay time of repairs due to weather. This model has competitive accuracy with existing
probabilistic methods but with improved computational cost, allowing for assessing a three-year North Sea dataset in an order of minutes. This model may be used instead of more intensive Monte-Carlo simulations whilst still producing high accuracy and associated confidence. The second section derives and solves a Fourier approximation of a Gaussian wake based on the Bastankhah Porte-Agel model [1], to be implemented in Strathfarm, a holistic wind farm simulation software aiming to produce medium-fidelity results in real-time. The current implementation requires computationally intensive look-up tables based on polynomial approximations. The proposed method derives an efficiently calculable polynomial in terms of farm conditions only, removing the need for extremely large look-up table storage and access. This new method significantly improves efficiency whilst maintaining the accuracy of the current
methodology within 10%. [References in thesis text
Enhancing offshore wind farm transmission efficiency : HVDC converters and DC collection systems
No full textExploring Diabetes online communities : a netnographic study of self-management behaviours of people with Type 1 Diabetes
No full textInformation seeking behaviour of UK retail banking customers towards online purchase adoption: an integrated UTAUT2 model
Full text linkDigitization has continued to transform the way we live and work. It is steadily changing the UK retail banking sector, where the rapid adoption of digital business models has led to the closure of traditional bank branches, a trend expected to persist. A smooth transition to a digital service model requires a deeper understanding of consumer behaviour.
This study investigates consumer behaviour by integrating the Unified Theory of Acceptance and Use of Technology 2 (UTAUT2) with the Everyday Life Information Seeking (ELIS) model as its theoretical framework. A deductive approach was employed, using an online survey distributed nationwide via convenience sampling. A total of 438 responses were received, of which 377 were valid.
Findings from five research questions and 18 hypotheses, tested through PLS-SEM and PLS-MGA, highlight challenges in understanding online information available on bank websites, a lack of well-trained advisors, fear, poor user interfaces and complex purchasing processes as key barriers; and the need for information on security, charges, and requirements for tutorials and glossary of terms.
Many respondents noted that visiting bank branches is the most preferred information source, suggesting consumers lack the knowledge needed to make online purchasing decisions, and quick access and reliability of information are key determinants of channel choice. Younger consumers are more influenced by perceived information, while older consumers rely more heavily on perceived trust.
By integrating UTAUT2 with ELIS, this research advances interdisciplinary collaboration. The proposed integrated model incorporates trust into UTAUT2, a prerequisite for online transactions, and further explores digital information-seeking behaviour through ELIS. Addressing information and trust concerns can enhance technology adoption in financial markets.
The qualitative themes identified could inform interview questions for future mixed-method research. Additionally, larger datasets could support multi-group analysis with three classifications, providing deeper insights than a two-group approach.Digitization has continued to transform the way we live and work. It is steadily changing the UK retail banking sector, where the rapid adoption of digital business models has led to the closure of traditional bank branches, a trend expected to persist. A smooth transition to a digital service model requires a deeper understanding of consumer behaviour.
This study investigates consumer behaviour by integrating the Unified Theory of Acceptance and Use of Technology 2 (UTAUT2) with the Everyday Life Information Seeking (ELIS) model as its theoretical framework. A deductive approach was employed, using an online survey distributed nationwide via convenience sampling. A total of 438 responses were received, of which 377 were valid.
Findings from five research questions and 18 hypotheses, tested through PLS-SEM and PLS-MGA, highlight challenges in understanding online information available on bank websites, a lack of well-trained advisors, fear, poor user interfaces and complex purchasing processes as key barriers; and the need for information on security, charges, and requirements for tutorials and glossary of terms.
Many respondents noted that visiting bank branches is the most preferred information source, suggesting consumers lack the knowledge needed to make online purchasing decisions, and quick access and reliability of information are key determinants of channel choice. Younger consumers are more influenced by perceived information, while older consumers rely more heavily on perceived trust.
By integrating UTAUT2 with ELIS, this research advances interdisciplinary collaboration. The proposed integrated model incorporates trust into UTAUT2, a prerequisite for online transactions, and further explores digital information-seeking behaviour through ELIS. Addressing information and trust concerns can enhance technology adoption in financial markets.
The qualitative themes identified could inform interview questions for future mixed-method research. Additionally, larger datasets could support multi-group analysis with three classifications, providing deeper insights than a two-group approach
Institutional investors, networking, and sustainable environmental performance
Full text linkThis Ph.D. thesis, comprising two empirical chapters, assesses the effect of institutional
investors on a portfolio company’s decisions about sustainability. I focus on sustainability
outcomes that capture the actual performance of companies. In the first empirical study, I
employ a setup of MSCI-ACWI index addition that increases institutional ownership through
benchmarking and diversification for companies across forty-six countries worldwide. In the
second empirical study, I employ a setup of the distance between institutional investors, which
is an immutable factor to determine the strength of investor connections.
To examine whether Institutional Ownership (IO) mitigates ESG-Misbehavior (ESGMVR), I examine two hypotheses based on two questions. Do cross-sectional and temporal
variations in IO provide insight into future ESG-MVR variations for their portfolio firms?
Second, does the impact of IO on ESG-MVR vary depending on the investor type? With a
battery of robustness tests, I show that IO mitigates ESG-MVR. This empirical chapter
illustrates that institutional investors (II) help promote positive sustainability practices and
manage future cases of ESG-MVR.
In my second study, I investigate the impact of well-connected II on the portfolio
company’s carbon emissions. I examine three hypotheses based on the question: do wellconnected II influence carbon emissions? How does well-connected II prioritize mitigating
carbon emissions while promoting cohesion among their counterparts? I run a battery of
robustness tests and show that well-connected II reduces carbon emissions. This empirical
chapter illustrates that well-connected II promote sustainability practices through active
monitoring and activism.
In my thesis, I emphasize that investors demonstrate responsibility in their investment
decisions and prioritize the sustainable performance of their portfolio companies, which
significantly influences their decision-making process.This Ph.D. thesis, comprising two empirical chapters, assesses the effect of institutional
investors on a portfolio company’s decisions about sustainability. I focus on sustainability
outcomes that capture the actual performance of companies. In the first empirical study, I
employ a setup of MSCI-ACWI index addition that increases institutional ownership through
benchmarking and diversification for companies across forty-six countries worldwide. In the
second empirical study, I employ a setup of the distance between institutional investors, which
is an immutable factor to determine the strength of investor connections.
To examine whether Institutional Ownership (IO) mitigates ESG-Misbehavior (ESGMVR), I examine two hypotheses based on two questions. Do cross-sectional and temporal
variations in IO provide insight into future ESG-MVR variations for their portfolio firms?
Second, does the impact of IO on ESG-MVR vary depending on the investor type? With a
battery of robustness tests, I show that IO mitigates ESG-MVR. This empirical chapter
illustrates that institutional investors (II) help promote positive sustainability practices and
manage future cases of ESG-MVR.
In my second study, I investigate the impact of well-connected II on the portfolio
company’s carbon emissions. I examine three hypotheses based on the question: do wellconnected II influence carbon emissions? How does well-connected II prioritize mitigating
carbon emissions while promoting cohesion among their counterparts? I run a battery of
robustness tests and show that well-connected II reduces carbon emissions. This empirical
chapter illustrates that well-connected II promote sustainability practices through active
monitoring and activism.
In my thesis, I emphasize that investors demonstrate responsibility in their investment
decisions and prioritize the sustainable performance of their portfolio companies, which
significantly influences their decision-making process
"It's your bread and butter" : an exploration of teacher perceptions of nurture principles in the whole class setting
Full text linkThe Six Principles of Nurture (Holmes & Boyd, 1999) have been used in schools for over two decades to support children and young people’s wellbeing. They are expected to form whole class and whole school wellbeing approaches in Scotland (Scottish Government, 2017).
The aim of this study was to explore teacher perceptions of the principles and their relevance to everyday practice in the mainstream classroom. Included in the study was an appraisal of the term nurturing pedagogy, as first developed in early years education in Ireland (Hayes, 2008), and the extent to which Scottish teachers were aware of the concept as it aligned with current nurturing practice.
This research used a case study design with four embedded units of analysis: 3 primary schools and 1 secondary school in a ‘cluster’ of schools in one Scottish local authority. Visually-mediated focus groups and semi-structured interviews were carried out to investigate the views of 27 participants. Three overarching themes were identified. Professional stance revealed that participants perceived nurture practice as a natural approach for teachers, which included concepts of care and empathy as tantamount to nurturing approaches in the classroom. Professional behaviours for equitable practice detailed participants' understanding of nurture principles as similar to the everyday actions of teachers to provide equitable education in their classrooms. This included adult understanding of children and young people’s family backgrounds and experiences. Finally, the challenges of using nurture principles in the mainstream classroom were explored in tensions and dilemmas in nurture practice. Findings included concerns over resources, time, staff development, and perceived imbalance between nurture principles and behaviour management strategies.
The study conclusions contribute a Framework for Nurturing Pedagogy to improve teacher understanding and use of nurture principles in their classrooms. The framework adds to the academic field and enhances the relevance of The Six Principles of Nurture (Holmes & Boyd, 1999) in classrooms today through a deeper exploration of additional concepts such as care, empathy, consistency, flexibility, equity, and understanding behaviour. Implications for educational policy are identified alongside the next steps for research in nurture practice.The Six Principles of Nurture (Holmes & Boyd, 1999) have been used in schools for over two decades to support children and young people’s wellbeing. They are expected to form whole class and whole school wellbeing approaches in Scotland (Scottish Government, 2017).
The aim of this study was to explore teacher perceptions of the principles and their relevance to everyday practice in the mainstream classroom. Included in the study was an appraisal of the term nurturing pedagogy, as first developed in early years education in Ireland (Hayes, 2008), and the extent to which Scottish teachers were aware of the concept as it aligned with current nurturing practice.
This research used a case study design with four embedded units of analysis: 3 primary schools and 1 secondary school in a ‘cluster’ of schools in one Scottish local authority. Visually-mediated focus groups and semi-structured interviews were carried out to investigate the views of 27 participants. Three overarching themes were identified. Professional stance revealed that participants perceived nurture practice as a natural approach for teachers, which included concepts of care and empathy as tantamount to nurturing approaches in the classroom. Professional behaviours for equitable practice detailed participants' understanding of nurture principles as similar to the everyday actions of teachers to provide equitable education in their classrooms. This included adult understanding of children and young people’s family backgrounds and experiences. Finally, the challenges of using nurture principles in the mainstream classroom were explored in tensions and dilemmas in nurture practice. Findings included concerns over resources, time, staff development, and perceived imbalance between nurture principles and behaviour management strategies.
The study conclusions contribute a Framework for Nurturing Pedagogy to improve teacher understanding and use of nurture principles in their classrooms. The framework adds to the academic field and enhances the relevance of The Six Principles of Nurture (Holmes & Boyd, 1999) in classrooms today through a deeper exploration of additional concepts such as care, empathy, consistency, flexibility, equity, and understanding behaviour. Implications for educational policy are identified alongside the next steps for research in nurture practice
Nineteenth-century working men’s reading rooms
Full text linkThis thesis explores the establishment, operation, and cultural significance of
nineteenth-century working men’s reading rooms in Britain, focusing on the North of
England and Scotland. These reading rooms, which proliferated throughout towns and
villages during the Victorian era, served as pivotal spaces for intellectual engagement,
self-education and social interaction among the working class. By examining a variety
of sources, including newspapers, periodicals, and archival records, this study
reconstructs the physical and social environments of these reading rooms. The
research highlights how these spaces, often initiated by local elites or industrial
employers, were managed and utilised by their patrons. The thesis delves into the
committees that governed these rooms, illustrating the power dynamics and the often
paternalistic control exerted by the middle and upper classes.
Key chapters analyse the funding mechanisms, literature provided, and the
diverse recreational and educational activities available in these rooms. Case studies
of specific reading rooms reveal the varied influences of local industries,
demographics, and community interests. Additionally, the thesis examines the role of
women, who, though less frequently members, contributed significantly to the support
and operation of these reading rooms. This work contributes to the broader
understanding of working-class culture, the history of reading, and the development of
public leisure and educational institutions in the nineteenth century. It underscores the
importance of these reading rooms in fostering a culture of reading and self-improvement among working men, while also highlighting the complexities and
challenges faced by these institutions in balancing control and accessibility.This thesis explores the establishment, operation, and cultural significance of
nineteenth-century working men’s reading rooms in Britain, focusing on the North of
England and Scotland. These reading rooms, which proliferated throughout towns and
villages during the Victorian era, served as pivotal spaces for intellectual engagement,
self-education and social interaction among the working class. By examining a variety
of sources, including newspapers, periodicals, and archival records, this study
reconstructs the physical and social environments of these reading rooms. The
research highlights how these spaces, often initiated by local elites or industrial
employers, were managed and utilised by their patrons. The thesis delves into the
committees that governed these rooms, illustrating the power dynamics and the often
paternalistic control exerted by the middle and upper classes.
Key chapters analyse the funding mechanisms, literature provided, and the
diverse recreational and educational activities available in these rooms. Case studies
of specific reading rooms reveal the varied influences of local industries,
demographics, and community interests. Additionally, the thesis examines the role of
women, who, though less frequently members, contributed significantly to the support
and operation of these reading rooms. This work contributes to the broader
understanding of working-class culture, the history of reading, and the development of
public leisure and educational institutions in the nineteenth century. It underscores the
importance of these reading rooms in fostering a culture of reading and self-improvement among working men, while also highlighting the complexities and
challenges faced by these institutions in balancing control and accessibility
Iridium-catalysed hydrogen isotope exchange of pharmaceutically-relevant sulfoximines and selective fragment coupling of two unactivated alcohols
No full textChapter 1
Deuterium- and tritium-labelled pharmaceutical candidates have become invaluable for in
vivo and in vitro studies conducted in both a preclinical and clinical context. The preparation
of these deuterium, or tritium, containing molecular architectures has been largely enabled
by transition metal-catalysed hydrogen isotope exchange.
Within this field, work in our laboratory has led to the design of a suite of iridium(I) Nheterocyclic carbene complexes tailored towards the late-stage functionalisation of C(sp2
)–H
sites located within aromatic and heteroaromatic systems ortho to a Lewis basic directing
group.
Within this chapter, we describe the expansion of our ortho-directed labelling strategy to the
sulfoximine functional group. Extending from this, a method for the straightforward
prediction of the outcome of the arene functionalisation process was developed. Moreover,
we have uncovered a novel C–H activation pathway at challenging to label S-methyl C(sp3
)–H
centres. The generality of our catalytic systems is demonstrated through the successful
delivery of isotopic substituents into high-complexity substrates.
Chapter 2
Metal-catalysed allylic substitution has emerged as a leading technology for the construction
of carbon–carbon and carbon–heteroatoms bonds at C(sp3
)-centres of allylic electrophiles.
However, within this arena highly substituted allylic frameworks are seldom used.
In recognition of this, this section of this thesis describes development of a method to directly
couple unactivated highly substituted allylic electrophiles and alcohols, to form ether
products. Through use of a catalyst design plan an optimal pre-catalyst was identified for an
iridium-catalysed etherification protocol that operates under hydrogen activation. Following this, mechanistic understanding of this transformation was used to develop
another etherification system which utilises an acid additive, in place of the hydrogen
atmosphere. To accelerate the discovery and development of the acid additive system, a highthroughput screening approach was utilised to enable the rapid identification of promising
acid additives.
Preface
Research within modern medicinal chemistry has been devoted to the generation and
diversification of novel frameworks in the pursuit of previously elusive molecular solutions
for high value targets. Among these motifs, sulfoximines have risen to prominence within the
pharmaceutical industry. We therefore envisioned that our range of iridium(I) carbene precatalysts could be programmed to permit access to an unprecedented collection of
isotopically-enriched pharmaceutically relevant free and N-functionalised sulfoximine
architectures, through a synergistic experimentally and computationally guided approach.
Through this approach existing pre-catalysts that our group have previously developed were
computationally screened to identify an appropriate hydrogen isotope exchange catalyst for
our targeted transformation. From this, an ortho-directed labelling strategy mediated via the
sulfoximine functional group and a complementary system capable of labelling C(sp3
)–H
centres located at S-methyl position were established. Following completion of the first project focus was placed on showcasing the versatile nature
of our iridium(I) pre-catalyst range through expansion of their use to other areas of transitionmetal catalysis. Accordingly, we targeted the direct functionalisation of highly substituted
unactivated allylic alcohols to provide access to a range of products substituted at C(sp3
)-
centres, given the statistical correlation between the degree of carbon saturation and the
presence of stereogenic centres featured in medicinal candidates with clinical success.
More specifically, the establishment of a system that can directly couple allylic electrophiles
and alcohols, to form ether products was pursued. To achieve this, we used a catalyst design
plan to tune our pre-catalyst range to promote this allylic substitution type transformation,
where we moved away from the electron rich variants of our pre-catalysts that are used in
the hydrogen isotope exchange of various molecules. Collectively, the second chapter of this
report outlines the broadening of the utility of our laboratories iridium(I) pre-catalyst range
through the development of an iridium-catalysed fragment coupling protocol.Chapter 1
Deuterium- and tritium-labelled pharmaceutical candidates have become invaluable for in
vivo and in vitro studies conducted in both a preclinical and clinical context. The preparation
of these deuterium, or tritium, containing molecular architectures has been largely enabled
by transition metal-catalysed hydrogen isotope exchange.
Within this field, work in our laboratory has led to the design of a suite of iridium(I) Nheterocyclic carbene complexes tailored towards the late-stage functionalisation of C(sp2
)–H
sites located within aromatic and heteroaromatic systems ortho to a Lewis basic directing
group.
Within this chapter, we describe the expansion of our ortho-directed labelling strategy to the
sulfoximine functional group. Extending from this, a method for the straightforward
prediction of the outcome of the arene functionalisation process was developed. Moreover,
we have uncovered a novel C–H activation pathway at challenging to label S-methyl C(sp3
)–H
centres. The generality of our catalytic systems is demonstrated through the successful
delivery of isotopic substituents into high-complexity substrates.
Chapter 2
Metal-catalysed allylic substitution has emerged as a leading technology for the construction
of carbon–carbon and carbon–heteroatoms bonds at C(sp3
)-centres of allylic electrophiles.
However, within this arena highly substituted allylic frameworks are seldom used.
In recognition of this, this section of this thesis describes development of a method to directly
couple unactivated highly substituted allylic electrophiles and alcohols, to form ether
products. Through use of a catalyst design plan an optimal pre-catalyst was identified for an
iridium-catalysed etherification protocol that operates under hydrogen activation. Following this, mechanistic understanding of this transformation was used to develop
another etherification system which utilises an acid additive, in place of the hydrogen
atmosphere. To accelerate the discovery and development of the acid additive system, a highthroughput screening approach was utilised to enable the rapid identification of promising
acid additives.
Preface
Research within modern medicinal chemistry has been devoted to the generation and
diversification of novel frameworks in the pursuit of previously elusive molecular solutions
for high value targets. Among these motifs, sulfoximines have risen to prominence within the
pharmaceutical industry. We therefore envisioned that our range of iridium(I) carbene precatalysts could be programmed to permit access to an unprecedented collection of
isotopically-enriched pharmaceutically relevant free and N-functionalised sulfoximine
architectures, through a synergistic experimentally and computationally guided approach.
Through this approach existing pre-catalysts that our group have previously developed were
computationally screened to identify an appropriate hydrogen isotope exchange catalyst for
our targeted transformation. From this, an ortho-directed labelling strategy mediated via the
sulfoximine functional group and a complementary system capable of labelling C(sp3
)–H
centres located at S-methyl position were established. Following completion of the first project focus was placed on showcasing the versatile nature
of our iridium(I) pre-catalyst range through expansion of their use to other areas of transitionmetal catalysis. Accordingly, we targeted the direct functionalisation of highly substituted
unactivated allylic alcohols to provide access to a range of products substituted at C(sp3
)-
centres, given the statistical correlation between the degree of carbon saturation and the
presence of stereogenic centres featured in medicinal candidates with clinical success.
More specifically, the establishment of a system that can directly couple allylic electrophiles
and alcohols, to form ether products was pursued. To achieve this, we used a catalyst design
plan to tune our pre-catalyst range to promote this allylic substitution type transformation,
where we moved away from the electron rich variants of our pre-catalysts that are used in
the hydrogen isotope exchange of various molecules. Collectively, the second chapter of this
report outlines the broadening of the utility of our laboratories iridium(I) pre-catalyst range
through the development of an iridium-catalysed fragment coupling protocol
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