The development of a catalytic asymmetric bromination reaction of alkenes

This thesis describes our investigations into the development of a general method for the catalytic, asymmetric bromination of alkenes. The bromination catalysts employed in the research are ortho-substituted iodobenzenes, which are hypothesised to deliver Br+ to the alkene substrate via a hypervalent I(III)-Br bond. Initially, endeavours to achieve a large scale preparation of our asymmetric bromination catalyst, 2,6-di-[(4R,5R)-4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl]iodobenzene, or R-IBAM, are detailed. In order to facilitate this, a large quantity of enantiopure 1,2-diphenylethylene diamine was required to form the chiral amidine moieties of our R-IBAM catalyst. Thus, the development of two novel methods for the synthesis and resolution of 1,2-diphenylethylene diamine are described and the subsequent application of each route to a large scale preparation of the enantiopure diamine. The subsequent novel and optimised preparation of our catalyst to produce 25 g of R-IBAM is detailed. The following studies into the catalytic asymmetric bromination of alkenes include the screening of the various reaction conditions, stoichiometric addition of N-bromosuccinimide to the catalysts and the synthesis and screening of a range of R-IBAM derivatives and analogues. An improved understanding of the catalytic cycle and the possible mechanisms of loss of enantioexcess in our brominated product is detailed. The final section of the thesis describes research into the exchange of Br+ between enantiopure bromonium ions and alkenes. The generation of an enantiopure bromonium ion in the absence of alkene was achieved via the rearrangement of enantiopure bromohydrin, (2S)-1-bromo-1-phenylpropan-2-ol. The intermediate bromonium ion was trapped by chloride to produce the enantiopure bromochlorinated product. This, to the best of our knowledge, represents the first example of the generation and trapping of an enantiopure bromonium ion. Our subsequent investigations into Br+ transfer from the bromonium ion to added alkene are described.Imperial Users onl

One-pot near-ambient temperature syntheses of aryl(difluoroenol) derivatives from trifluoroethanol

Difluoroalkenylzinc reagents prepared from 1-(2’-methoxy-ethoxymethoxy)-2,2,2-trifluoroethane and 1-(N,N-diethylcarbamoyloxy)-2,2,2-trifluoroethane at ice bath temperatures, underwent Negishi coupling with a range of aryl halides in a convenient one pot procedure. While significant differences between the enol acetal and carbamate reagents were revealed, the Negishi protocol compared very favourably with alternative coupling procedures in terms of overall yields from trifluoroethanol

INCREASING ENGAGEMENT IN ONLINE LEARNING

Motivated by the need to improve students’ engagement and learning outcomes, in 2018/2019 we implemented two engagement interventions to 1650 students in twelve online courses across Science, Education, Engineering and Accounting at a regional university. Both “click” data and video analytics were used to measure engagement. The first initiative applied findings from behavioural research to ‘nudge’ students toward early engagement with key learning resources and to create ‘teaching presence’ (Garrison, 2007). The second initiative was to help move ‘knowledge’ to ‘know-how’ by nudging videos to offer a sense of real-life expertise, application, motivation and advanced connection. We aimed to improve student learning outcomes and their online engagement by providing explicit guidance about which course resources were critical for students’ success. We were interested in interrogating the data in both learning management systems (Moodle®) and Video analytics (Vimeo®) to answer questions about learner engagement and to explore evidence of impact. The nudges successfully engaged students in the key online resources showing an 18% average increase in access and confirmed via student feedback. The project developed a Nudge Guidelines document that has been presented institutionally and nationally to enable academics to utilise the strategies in their courses

Protocol for a systematic review: Interventions for anxiety in school-aged children with autism spectrum disorder (ASD): a mixed methods systematic review

This review aims to synthesise evidence about interventions to reduce anxiety symptoms in school-aged children with autism spectrum disorder (ASD). While clinical studies will not be excluded per se, this review seeks to move beyond interventions that are relevant only for clinical practice and care in clinical settings and prioritise studies that draw out implications for school-aged children that will help their functioning in real-world settings such as school and the home. To achieve this aim, the review will employ a mixed-methods systematic review which can accommodate the anticipated diverse types of available studies. These studies are likely to use quantitative methods such as quasi-experimental, mixed-methods randomised control trial approaches as well as qualitative methods such as action-research and case-study designs. This publication outlines the methodology which will be used in the systematic review and covers the criteria for inclusion and exclusion of studies in the review, the search strategy to be used for identification of relevant studies, the bibliographic databases and other sources used for searching, the data collection process including the selection process and data synthesis and analysis, and the timeframe for this project

Drug Use in Street Sex worKers (DUSSK) study – results of a mixed methods feasibility study of a complex intervention to reduce illicit drug use in drug dependent female sex workers

OBJECTIVES: The majority of female street-based sex workers (SSWs) are dependent on illicit drugs and sell sex to fund their drug use. They typically face multiple traumatic experiences, starting at a young age, which continue through sex work involvement. Their trauma-related symptoms tend to increase when drug use is reduced, hindering sustained reduction. Providing specialist trauma care to address post-traumatic stress disorder (PTSD) alongside drug treatment may therefore improve treatment outcomes. Aims to (1) evaluate recruitment and retention of participants; (2) examine intervention experiences and acceptability; and (3) explore intervention costs using a mixed methods feasibility study. SETTING: Female SSW charity premises in a large UK inner city. PARTICIPANTS: Females aged 18 years or older, who have sold sex on the street and used heroin and/or crack cocaine at least once a week in the last calendar month. INTERVENTION: Female SSW-only drug treatment groups in a female SSW-only setting delivered by female staff. Targeted PTSD screening then treatment of positive diagnoses with eye movement desensitisation and reprocessing (EMDR) therapy by female staff from a specialist National Health Service trauma service. RESULTS: (1) Of 125 contacts, 11 met inclusion criteria and provided informed consent, 4 reached the intervention final stage, (2) service providers said working in collaboration with other services was valuable, the intervention was worthwhile and had a positive influence on participants. Participants viewed recruitment as acceptable and experienced the intervention positively. The unsettled nature of participant's lives was a key attendance barrier. (3) The total cost of the intervention was £11 710, with staff costs dominating. CONCLUSIONS: Recruitment and retention rates reflected study inclusion criteria targeting women with the most complex needs. Two participants received EMDR demonstrating that the three agencies working together was feasible. Staff heavy costs highlight the importance of supporting participant attendance to minimise per participant costs in a future trial

Speciation control during Suzuki-Miyaura cross-coupling of haloaryl and haloalkenyl MIDA boronic esters

Boronic acid solution speciation can be controlled during the Suzuki-Miyaura cross-coupling of haloaryl MIDA boronic esters to enable the formal homologation of boronic acid derivatives. The reaction is contingent upon control of the basic biphase and is thermodynamically driven: temperature control provides highly chemoselective access to either BMIDA adducts at room temperature or BPin products at elevated temperature. Control experiments and solubility analyses have provided some insight into the mechanistic operation of the formal homologation process

Does Course Specific Nudging Enhance Student Engagement, Experience and Success?: A Data-Driven Longitudinal Tale

Low levels of online student engagement impact negatively on student success and adversely affect attrition. Course learning analytics data (CLAD), combined with nudging initiatives, have emerged as strategies for engaging online students. This article presents a mixed method case study involving a staged intervention strategy focussing on the employment of timely, strategic communication interventions conducted across 19 courses and six disciplines. The research methodology utilised CLAD, online surveys, student interviews and student evaluations of teaching. The findings substantiate benefits for both academics and students. Academics benefitted from the provision of a relatively simple, accessible and proactive intervention for increasing students’ capacities to be more in control and engaged in their learning. Students benefitted as the intervention accentuated critical resources to assist them to better address assessment requirements, align their expectations more realistically with those of the course, and more readily demonstrate their learning obligations and responsibilities

Multiplex immunofluorescence to measure dynamic changes in tumor-infiltrating lymphocytes and PD-L1 in early-stage breast cancer.

BACKGROUND: The H&E stromal tumor-infiltrating lymphocyte (sTIL) score and programmed death ligand 1 (PD-L1) SP142 immunohistochemistry assay are prognostic and predictive in early-stage breast cancer, but are operator-dependent and may have insufficient precision to characterize dynamic changes in sTILs/PD-L1 in the context of clinical research. We illustrate how multiplex immunofluorescence (mIF) combined with statistical modeling can be used to precisely estimate dynamic changes in sTIL score, PD-L1 expression, and other immune variables from a single paraffin-embedded slide, thus enabling comprehensive characterization of activity of novel immunotherapy agents. METHODS: Serial tissue was obtained from a recent clinical trial evaluating loco-regional cytokine delivery as a strategy to promote immune cell infiltration and activation in breast tumors. Pre-treatment biopsies and post-treatment tumor resections were analyzed by mIF (PerkinElmer Vectra) using an antibody panel that characterized tumor cells (cytokeratin-positive), immune cells (CD3, CD8, CD163, FoxP3), and PD-L1 expression. mIF estimates of sTIL score and PD-L1 expression were compared to the H&E/SP142 clinical assays. Hierarchical linear modeling was utilized to compare pre- and post-treatment immune cell expression, account for correlation of time-dependent measurement, variation across high-powered magnification views within each subject, and variation between subjects. Simulation methods (Monte Carlo, bootstrapping) were used to evaluate the impact of model and tissue sample size on statistical power. RESULTS: mIF estimates of sTIL and PD-L1 expression were strongly correlated with their respective clinical assays (p \u3c .001). Hierarchical linear modeling resulted in more precise estimates of treatment-related increases in sTIL, PD-L1, and other metrics such as CD8+ tumor nest infiltration. Statistical precision was dependent on adequate tissue sampling, with at least 15 high-powered fields recommended per specimen. Compared to conventional t-testing of means, hierarchical linear modeling was associated with substantial reductions in enrollment size required (n = 25➔n = 13) to detect the observed increases in sTIL/PD-L1. CONCLUSION: mIF is useful for quantifying treatment-related dynamic changes in sTILs/PD-L1 and is concordant with clinical assays, but with greater precision. Hierarchical linear modeling can mitigate the effects of intratumoral heterogeneity on immune cell count estimations, allowing for more efficient detection of treatment-related pharmocodynamic effects in the context of clinical trials. TRIAL REGISTRATION: NCT02950259

Design, Synthesis, and Evaluation of Lung-Retentive Prodrugs for Extending the Lung Tissue Retention of Inhaled Drugs

A major limitation of pulmonary delivery is that drugs can exhibit suboptimal pharmacokinetic profiles resulting from rapid elimination from the pulmonary tissue. This can lead to systemic side effects and a short duration of action. A series of dibasic dipeptides attached to the poorly lung-retentive muscarinic M3 receptor antagonist piperidin-4-yl 2-hydroxy-2,2-diphenylacetate (1) through a pH-sensitive-linking group have been evaluated. Extensive optimization resulted in 1-(((R)-2-((S)-2,6-diaminohexanamido)-3,3-dimethylbutanoyl)oxy)ethyl 4-(2-hydroxy-2,2-diphenylacetoxy)piperidine-1-carboxylate (23), which combined very good in vitro stability and very high rat lung binding. Compound 23 progressed to pharmacokinetic studies in rats, where, at 24 h post dosing in the rat lung, the total lung concentration of 23 was 31.2 μM. In addition, high levels of liberated drug 1 were still detected locally, demonstrating the benefit of this novel prodrug approach for increasing the apparent pharmacokinetic half-life of drugs in the lungs following pulmonary dosing