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Title: Reaction and purification strategies in skeletal diversity construction
Author: Galloway, W. R. J. D.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2008
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The first project discussed in this report involves a diversity-oriented synthesis (DOS) approach starting from a structurally simple diazoacetate substrate. Overall, a library of 223 compounds based around 30 different core molecular skeletons was synthesized. The library was shown to span a comparatively large region of chemical space and phenotypic screening experiments identified a number of structurally novel compounds that displayed antibacterial activity against a pathogenic strain of MRSA. The second project discussed in this report involves studies towards the development of a novel solubility-control group for attached reagents, based on a triphenylene core, which would allow the facile removal of supported reagents and by-products from reaction mixtures. A triphenylene-supported triphenyphosphine derivative was synthesized, which preliminary studies suggested was functionally equivalent to triphenylphosphine in a Mitsunobu reaction. The generation of molecules based around a diverse range of molecular skeletons is key to maximising the functional (biological) diversity of a small molecule collection. Within this context medium rings constitute an interesting target skeleton; medium ring systems are present within numerous bioactive molecules yet there are few widely-applicable methods for their construction and thus they are often under-represented in small molecule libraries. Towards this end, the third project discussed in this report involves studies towards the synthesis of structurally novel benzo-fused medium lactone ring systems and the 12-membered benzo-fused lactone ring system present in the biologically active natural product lasiodiplodin. Methodology based around organocuprate oxidation was compared with more ‘traditional’ Sonogashira and Castro-Stephens approaches. In general, the synthesis of the desired ring systems could not be achieved, with none of these three approaches demonstrating broad synthetic utility.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available