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Title: The synthesis of bioactive compounds by using phase-tagged germanium chemistry
Author: Tseng, Chih-Chung
ISNI:       0000 0004 2682 8615
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2009
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The research described in this thesis covers two fields of investigation: 1) Biaryl and styrene Synthesis by Cross-Coupling of Fluorous-tagged Photo-activated Arylgermanes and Towards the Preparation of Boscalid and Analogues Biaryls are generally prepared by cross-coupling between aryl metals. However, even the most robust of these aryl metal species cannot be carried through complex synthetic sequences due to their reactivity particularly towards electrophiles. In this thesis, the development of trialkylgermanes as ‘safety-catch’ coupling precursors for biaryl and styrene synthesis was achieved. The safety-catch germanes are fluorous-tagged to facilitate parallel synthesis using fluorous SPE techniques and are activated towards Pd(0)-catalysed cross-coupling with aryl bromides by oxidative photolysis using a UV lamp. The stability profile of the fluorous-tagged arylgermanes was examined. They are stable under strong basic, nucleophilic and reductive conditions but labile in acidic and oxidative environments. This stability profile provides unique opportunities for synthetic route design in target orientated syntheses by allowing the germane group to be installed early in the sequence but only activated for cross-coupling when required. This method has been applied to the synthesis of the plant anti-fungal agent boscalid® and its alkynyl derivatives. 2) Novel Protocol for Solid Phase Synthesis of Radio-iodinated Ligands for Imaging of Cannabinoid Receptors in the Brain Rimonabant® is a CB1 receptor antagonist indicated for the treatment of obesity, metabolic syndrome, addiction and smoking cessation. Radio-labelled analogues are potential PET (Positron Emission Tomography) and SPECT (Single Photon Emission Computed Tomography) imaging agents for visualising the distribution of cannabinoid receptors in the brain for medical research. Conventional methods for the preparation of radio-iodinated cannabinoid receptor ligands employ organostannane precursors which undergo electrophilic ipso-iododestannylation with concomitant formation of toxic organostannane by-products. Rigorous removed of organostannane residues is necessary prior to injection the ligand for in vivo experiments. In this thesis, a novel, non-toxic, solid-supported and facile approach for the parallel synthesis of iodinated cannabinoid receptor ligands based on the skeleton of rimonabant has been demonstrated.
Supervisor: Spivey, Alan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral