Resin-bound synthesis and template-based chemical libraries

• Main Author: Goddard, C. R.
• Published: University of Cambridge 2000
• Subjects: 547
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599454

The work described in this dissertation relates to the development of resin-bound techniques in organic synthesis and the application of these and other methods to the formation of chemical libraries around a central core. Chapter 2 focuses on techniques in resin-supported synthesis and on-bead analysis. A number of the methods developed and used in the course of this work are considered and compared with equivalent solution techniques. In particular, the effects of resins, solvents, loading levels and reaction strategy are considered and techniques in resin manipulation and analysis investigated. Improved procedures for the collection of on-bead <I>infra</I>-red and <SUP>13</SUP>C NMR spectra are demonstrated and gel-phase <SUP>19</SUP>F NMR spectroscopy used to consider site-isolation effects. The third chapter relates to the development of a strategy for combinatorial synthesis around a central core. A small aromatic template is selected and reaction and protection strategies developed to allow resin attachment and modification of this with only one deprotection step. A small example library is synthesised on polystyrene resin, using parallel synthesis methods. Difficulties in cleaving a newly developed linker and the presence of side-products require that the strategy be revised. Alternative methods and solutions to these problems are developed. Further strategies for the synthesis of compound libraries are considered in Chapter 4. A modification of the template approach is sought which would allow formation of cyclic libraries anchored to a central core at two points. A strategy is developed for the resin-bound synthesis of cyclic peptide libraries around an aromatic template and suitable protection methods found. The cyclisation of several library members is studied by molecular modelling to assess the relative likelihood of ring-closure. Some example library members are chosen and synthesised on-resin. Solid-supported synthesis is carried out both manually and by using a prototype parallel organic synthesiser. This requires the development of automated reaction protocols including modifications to the machine hardware and software. An example of a cyclised system is finally demonstrated.