Asymmetric synthesis 1,2,3-triazoles utilising the copper-catalysed azide-alkyne cycloaddition

The copper-catalysed azide-alkyne cycloaddition (CuAAC) is a highly efficient reaction and is the cornerstone of “click” chemistry. However, unlike many common metal-mediated transformations asymmetric CuAAC variants are relatively sparse. This thesis details asymmetric “click” reactions with Chapter 1 introducing the CuAAC and the asymmetric variants already present in the literature. Chapter 2 outlines research demonstrating the first example of kinetic resolution of an alkyne via a CuAAC reaction. Selectivity factors of up to 22.1 ± 0.5 were obtained and triazoles and alkynes were obtained in ≤ 80% enantiomeric excess (ee). This chapter also contains a study on the simultaneous kinetic resolution of azides and alkynes; azides were obtained in >30% $e$$e$, alkynes in >40% $e$$e$ and a triazolic diastereomeric product was obtained in up to 90% $e$$e$. In Chapter 3 the Bull-James three-component boronic acid assembly is successfully employed for the kinetic resolution of primary amine alkynes with selectivity factors of up to 4.1 obtained. The principle behind the assembly is also elaborated upon in this chapter leading to its use in both dynamic combinatorial chemistry and as a pedagogical tool. Chapter 4 details work on atropisomerism in triazolic systems. A series of novel triazoles, iodotriazoles and triazolium salts were successfully synthesised and their atropisomeric stability probed. Chapter 5 presents feasibility studies towards the asymmetric synthesis of 5,5’-bis(triazoles) and ruthenium olefin metathesis catalysts in the formation of 1,5-triazoles

General method for the synthesis of pseudodisaccharides. Diels-Alder approach to the synthesis of pseudodisaccharides

This thesis describes a new method for the synthesis of pseudodisaccharides containing a carbasugar analogue attached to a "true" sugar. The methodology is based on a Diels-Alder cycloaddition of vinyl sugars and appropriately substituted pyran-2-ones, followed by chemical manipulation of the resulting cycloadducts. The thesis also describes the synthesis of inhibitors of Golgi ¿-mannosidase II and glucokinase. The first chapter is a comprehensive survey of the reported synthetic routes to pseudodisaccharides from the literature. The results and discussions are presented in chapter 2. This chapter starts by discussion of the preparation of vinyl sugars and pyran-2-ones and the regio- and stereoselectivity of their cycloadditions. This is followed by reporting the chemical manipulations of these cycloadducts and the synthesis of a pseudodisaccharide. Cycloadducts are shown to lose carbon dioxide at elevated temperatures to afford dihydrobenzenes. The loss of the bridging carbon dioxide from the cycloadducts is experimentally and computationally investigated. The resulting dihydrobenzenes are shown to also be useful as precursors in the synthesis of pseudodisaccharides. The chemical manipulation of these dihydrobenzenes is used towards the synthesis of a pseudodisaccharide. The third and fourth chapters focus on the synthesis of new inhibitors of Golgi ¿-mannosidase II and glucokinase respectively. A range of 6-aminoglucose and mannose derivatives were prepared and tested for the inhibition of Jack bean ¿-mannosidase, but were found to lack any inhibition. Similarly, a range of 6-triazologlucose derivatives were prepared but were found to lack any cytotoxicity. The fifth chapter contains the details of the preparation, experimental procedures and spectroscopic characterisation of the synthesised chemical compounds. Rate calculations are reported in Appendix I and the X-ray crystallographic data are presented in the Appendix II