Applications of organometallic chemistry to isotopic synthesis.

This thesis is concerned with the application of organometallic chemistry to isotopic synthesis. The potential of three different areas for the synthesis of isotopically labelled compounds is either highlighted or extended. The use of directed ortho-metallation chemistry, and more specifically directed lithiation, for the introduction of functionality into substituted aromatic systems is reviewed in Chapter 1. Alternative directed ortho-metallation systems, such as cyclorhodiation and cycloiridiation procedures for the regiospecific introduction of hydrogen isotopes into substituted aromatics via homogeneous catalytic reactions are also reviewed. The use of palladium-catalysed cross-coupling chemistry for the formation of new carbon-carbon bonds following reaction between organostannanes and organic electrophiles is reviewed. In Chapter 2, the use of intramolecular radical transfer processes and their potential for the area of isotopic synthesis is considered. Examples of alcohols where this approach might offer advantages over conventional approaches (ie. via ketones) are considered. In Chapters 4 and 5, the synthesis of a 2-trialkylstannyl derivative of N,N-diethyl-benzamide, via a directed lithiation procedure, and the characterisation of this product are presented. The subsequent use of this model substrate to investigate the synthesis of 2-acyl and 2-alkyl derivatives, via palladium coupling chemistry, on a scale amenable to isotopic syntheses is presented and discussed. The application of a cyclorhodiation procedure for the tritium labelling of a series of molecules of pharmacological interest to Fisons is presented in Chapters 4 and 5. Results of the use of (2-bromophenyl)chlorodimethylsilane as an alcohol protecting group and as a means of accessing a-deuteriated alcohols via a 1,5-intramolecular radical transfer process are discussed. The application of this approach to the synthesis of [3a-2H]cholesterol is presented