Asymmetric synthesis of novel immunosuppressive agents

This thesis presents the synthesis of several structural analogues of the immunosuppressant THI. In the first Chapter a review is made of the human immune system and its response to solid organ transplants. Current immunosuppressive drug therapies are examined with regard to organ transplantation as well as autoimmune diseases such as diabetes. The biological significance of THI is tabulated, as well as the detailed aims and synthetic strategies of this project. A number of preliminary model studies are presented in Chapter 2 towards the synthesis of 2-acetyl-4-substituted imidazole compounds. A number of different synthetic routes are reported including C4 metallation and Heck reactions to introduce the C4-substituent onto imidazole. In addition, a synthetic route to a new 4,4'-biimidazole heterocyclic system is presented. In Chapter 3 the Stille coupling reaction and the Sharpless asymmetric dihydroxylation reaction were developed to suit the synthesis of several mono- and trihydroxy-THI analogues. The enantiomeric purity and the stereochemical outcome of the Sharpless asymmetric dihydroxylation reactions is presented, which was based upon ^H NMR analysis of Mosher MTPA esters. The synthesis of all eight stereoisomers of THI is presented in Chapter Stille coupling and Sharpless asymmetric dihydroxylation reactions using chiral substrates were investigated and the limitations of these reactions examined. The eight stereoisomers of THI were isolated as their tetraacetates and the stereochemical assignments confirmed via chemical correlation. A direct synthetic route for the conversion of aldehydes into (E)-trimethylvinylstannanes is also described. A brief summary of all THI analogues synthesised is presented in Chapter as well as current and future work in this area.