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Wurthmann, Alexander

Chemistry

2006

PhD

Two main projects were targeted for this dissertation; the synthesis of proline templated amino-acids and studies towards the synthesis of a cyclocystine alkene isostere. The ability to control and understand protein-protein interactions is predicated on the understanding of structural conformation. Both chapters of the dissertation have attempted to attain synthetic targets which have a biological significance. The synthesis of proline-templated amino-acids offers functional group analogy to the endogenous inhibitor, a diversifiable substrate for library synthesis and the control of the secondary structure. Four PTAAs were successfully synthesized with orthogonal protection to allow for diversification. The synthesis of the cyclocystine isostere was designed to test the sensitivity of the thioredoxin redox couple to backbone geometry. The strategy targeted the cis alkene isostere as an analogous system to the amide bond between adjacent cysteines. Unfortunately, the keystone ring-closing metathesis was unsuccessful and an alternate model strategy was developed to circumvent this impasse. The model study incorporated cross-metathesis as an entry into the fragment coupling of the amino and carboxy termini. This would allow for further understanding of the TR redox couple by first investigating the trans alkene cyclocystine isostere as the enzyme substrate.