Development and application of synthetic methodologies based on organosulfur and organophosphorus chemistry

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Flynn, Aaran J.
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University College Cork
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This thesis describes the development and application of synthetic methodologies based on various aspects of organosulfur and organophosphorus chemistry with a focus on understanding the underlying features and synthetic application. The first chapter systematically compiles and reviews, for the first time, the synthetic and mechanistic aspects of sulfonyl migrations over the last twenty years. Notably, the fact that these reactions are frequently described as ‘unusual’, ‘unprecedented’, ‘unexpected’, ‘serendipitous’ and ‘novel’ by authors, highlights that these potentially synthetically powerful transformations remain only partially understood. This introductory chapter explores the synthetic utility of sulfonyl migrations, while significant attention is afforded to the efforts made to elucidate their underlying mechanisms. This literature review was inspired by the observation of an ‘unprecedented’ carbon–carbon 1,2-sulfonyl migration in our work, which is discussed in detail in Chapter 2. The second chapter describes the use of α-thio-β-chloroacrylamides, a series of highly functionalised sulfur containing compounds pioneered in our group, as versatile dipolarophiles in [3+2] dipolar cycloaddition reactions. The [3+2] dipolar cycloaddition of highly reactive α-diazoalkanes with a range of dipolarophiles is well explored in the synthesis of pyrazolines and pyrazoles, however, analogous cycloadditions of electron deficient terminal diazo compounds such as α-diazoacetates, α-diazosulfones and α-diazoacetamides remains significantly less studied despite the synthetic and biological importance of ester, sulfone and amide moieties. The reactivity of these α-thio-β-chloroacrylamides at each of the sulfide, sulfoxide and sulfone oxidation levels with electron deficient α-diazoacetates, and related derivatives, is explored in the formation of densely functionalised pyrazole derivatives that would otherwise be difficult to obtain via traditional methods. Observation of an unprecedented 1,2-carbon to carbon sulfonyl migration is of particular interest. Significant attention is afforded to the elucidation of the tautomeric composition of the 3,4,5-substituted pyrazole products, while the synthetic versatility of these products is demonstrated via a series of derivatisations. Chapter three details the design and preparation of a series of acyclic α-carboxy nucleoside phosphonate derivatives envisaged to possess anti-viral and/or anti-cancer properties. This chapter details the use of Mitsunobu coupling and transition metal catalysed O–H insertion methodology as key synthetic steps in the formation of these biological targets. This work was conducted in collaboration with Prof. Dr. Christa Müller and Prof. Jan Balzarini. The fourth chapter explores in detail synthetic challenges in the copper-catalysed asymmetric sulfur oxidation of aryl benzyl sulfides. Significant attention is afforded to the concept of self-disproportionation of enantiomers (SDE), an underappreciated phenomenon despite being known in the literature, but also to the observation of localised partitioning of enantiomers in the solid state even in the absence of SDE, which can lead to erroneous determination of enantiopurity. Each of chapters 2–4 is concluded with the associated experimental details, including spectroscopic and analytical data, for compounds synthesised during this work.
Cycloadditions , Tutomers , Pyrazoles , Nucleosides , Sulfur oxidation , Self disproportionation , Localised partitioning
Flynn, A. J. 2020. Development and application of synthetic methodologies based on organosulfur and organophosphorus chemistry. PhD Thesis, University College Cork.