Mechanism of racemisation of 5-substituted hydantoins in aqueous solution

• Main Author: Narduolo, Stefania
• Published: Cardiff University 2011
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.585249

This thesis describes our studies of the racemisation of substituted hydantoins and is divided in six chapters. Chapter 1 presents the concepts of chirality and racemisation and its implications in drug development. The literature on the stereolability of 5-substituted hydantoins is summarised. Chapter 2 describes detailed kinetic and mechanistic studies of the racemisation of (5)-5-benzylhydantoin and (5)-3-iV-methyl-5-benzylhydantoin, aimed at establishing the mechanistic aspects of racemisation of these molecules. Kinetics of H/D exchange and racemisation, kinetic isotope effects, and solvent kinetic isotope effects all favour the SeI mechanism of racemisation as opposed to the Se2 process proposed by others. Chapter 3 discusses the effects of structural modifications on the stereolability of a series of model 5-substituted hydantoins with improved water solubility as compared to (iS)-5-benzylhydantoin and (5)-3-A-methyl-5-benzylhydantoin. Hydantoins containing a protonated amino or an ammonium group showed increased stereolability. This finding was attributed to intramolecular facilitation of racemisation by the positive charge. The primary and solvent kinetic isotope effects on the racemisation of two model 5-substituted hydantoins were determined and again supported an SeI mechanism of racemisation. Chapter 4 deals with solvent effects on racemisation and H/D exchange of a series of 5-benzylhydantoins. DMSO added to phosphate buffers showed a marked rate-increasing effect for all of the substrates under study. Co-added 2-propanol and dioxane showed a rate-decreasing effect on neutral hydantoins and a rate-increasing effect on a cationic hydantoin. Solvent effects on the basicity of anionic catalysts and phenomena of preferential solvation were proposed as important factors affecting the rate constants in mixed media. Chapter 5 reports the preliminary results of exploratory experiments aimed at assessing potentials and limitations of VCD and IR spectroscopy for kinetic and mechanistic studies of racemisation. Finally, Chapter 6 summarises our findings and presents recommendation for future work.