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  • Development of Novel Organocatalytic Boration Methods and the Employment of Cycloheptatriene as A Versatile Synthetic Building Block
    (2024) Ton, Nhan
    Thesis
    This thesis consists of two main parts. The first part focuses on exploring the application of organocatalysts, small non-metallic organic molecules, to facilitate novel borylation reactions. The second part discusses the development and applications of compounds containing the cycloheptatriene (CHT) moiety, an interesting and valuable building block, in organic synthesis. The two parts of this thesis might seem unrelated at the first glance, however they are connected through the common chemistry of tropylium ion, which is one of the organocatalysts for the first part and the building block for the second part. Chapter 1 provides a brief overview and establishes contexts for the research topics presented in the two subsequent parts of this thesis. This chapter discusses the use of tropylium ions and organic superbases as catalysts in organic reactions, as well as the versality of tropylium ions and cycloheptatriene motifs as synthetic building blocks. It further introduces common approaches for catalytic hydroboration and diboration of unsaturated compounds. Chapter 2 discusses a novel protocol for hydroboration reaction of alkynes, alkenes and epoxides, using tropylium salts as organocatalysts. Organoboron compounds are versatile precursors for cross coupling chemistry. Synthesis of these precursors have traditionally been mediated by transition metal or main group catalysts, which poses several issues with toxicity and product purification, as well as mechanistic understanding. Apart from the synthetic value of this metal-free efficient protocol, tropylium salts proved to be useful probes to explore mechanistic details of hydroboration reactions. This work offers interesting insights into the controversial topic of hidden or true catalysis for hydroboration reactions. Chapters 3 delves into the utilization of the highly efficient phosphazene organocatalyst P1−tBu, renowned for its exceptional strength as an organic Brønsted base, to promote 1,1-diboration reactions of electron-deficient terminal alkynes. A combination of thorough experimental and computational studies suggests interesting mechanistic insights for these phosphazene-catalyzed diboration reactions. Chapter 4 investigates a novel approach that harnesses the tropone oxime tosylate as a privileged synthetic building block. It can react with alcohols, phenols, thiols or terminal alkynes to yield a diverse family of Z,Z,Z-triene products through a rarely reported Nucleophile-intercepted Beckmann fragmentation (NuBFr) reaction. Chapter 5 investigates the ring-contraction rearrangement of cycloheptatrienes to transform them into benzyl groups. Substrate scope studies demonstrate the broad applicability of this method to furans and thiophenes. Simultaneously, the rearrangement of aryl or alkyl cycloheptatrienes into benzyl halides using tellurium(IV) halides as Lewis acid as well as halide source was also explored in this chapter. Chapter 6 offers concluding remarks to the thesis.
  • Biomarker Analysis: Machine Learning and Analytical Approaches to Enhance Diagnostic Accuracy
    (2023) Zhang, Diana
    Thesis
    Early disease diagnosis can significantly improve patient survival rates as appropriate treatment strategies can be timely administered. A promising approach for disease diagnosis is to analyse chemical biomarkers present in bodily fluids as these molecules can provide insights into human metabolic and physiological processes. Changes in the identity and concentrations of such chemicals can help distinguish healthy from disease states. However, some current methods used to collect, analyse, and identify these chemicals have been challenged by limitations in sampling protocols, the resolving power of instruments, and the ability to interpret advanced data analysis methods. This thesis comprises of five concurrent efforts to enhance diagnostic accuracy by investigating various machine learning and analytical approaches. Firstly, an interpretable machine learning framework for binary disease classification is presented. Using this framework on blood plasma and skin sebum data, the diagnostic performance for Parkinson’s disease and key disease biomarkers are reported. Secondly, a protocol and recommendations for robust skin sebum analysis is described. Following a semi-longitudinal study, the various factors that can impact the collection and detection of volatile organic compounds present in skin sebum is discussed. Thirdly, the clinical utility of high-field asymmetric waveform ion mobility spectrometry (FAIMS) for disease diagnosis is reported. Based on a systematic review and meta-analysis, the diagnostic accuracy and clinical implications of using FAIMS is discussed. Fourthly, the performance of high-resolution FAIMS resulting in enhanced ion separations is reported. Using high-resolution FAIMS, the fundamentals that govern the separation of protonation protein isomers is described. Finally, the use of high-resolution FAIMS to analyse volatile organic compounds present in exhaled breath is demonstrated. Using atmospheric pressure chemical ionisation coupled with high-resolution FAIMS, untargeted breath analysis on individual breath profiles is reported. Overall, by improving analytical and machine learning methods, these findings should increase diagnostic accuracy and enable greater confidence in biomarker analysis.