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Title: Methodology for the conversion of tetramates to pyroglutamates, and a study of their biological activity
Author: Bagum, Halima
ISNI:       0000 0004 7652 8231
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Highly functionalised pyroglutamates, molecules of interest for their biological uses and applications, are readily accessible from a bicyclic tetramic acid as a substrate for functionalisation at C3 and C4 of tetramic acid ring. These molecules have structural features common to pyroglutamate and pyrrolinone-containing natural products and this thesis particularly focuses on the development of novel routes to 3-substituted and 3,4-disubstituted pyroglutamic acid derivatives. Chapter 1 represents an overview of antibacterial drug discovery and the need for the development of new antibiotics. It describes the importance of the pyroglutamate building block in natural product-inspired drug discovery. Preparation and application of 3-substituted pyroglutamate, pyrrolidinone, and pyroglutaminol derivatives have been extensively reviewed. Representative examples of lactam-derived natural products and their biological properties are also outlined. Chapter 2 describes the synthetic strategy for the conversion of tetramates to pyrrolinones that allows stereospecific C3 arylation via Suzuki coupling. Conformationally constrained 3-aryl pyrrolidinone and pyroglutaminol derivatives are efficiently achievable from these newly developed 3-arylpyrrolinones under hydrogenation and N,O-acetal deprotection conditions, respectively. These synthetic routes permit the preparation of a large library of pyroglutamate derivatives. Alternatively, attempted Reformatsky conjugate addition conditions were unsuccessful for the C3 functionalisation of enones. Chapter 3 effectively utilises the methodology developed in Chapter 2, for the synthesis of 3,4-disubstituted pyrrolinone and pyroglutamate derivatives. The use of an ethyl ester bicyclic tetramate or Weinreb amide did not work for the mesylation step as these tricarbonyls act as only a weak nucleophile and hence, further C4 functionalisation was thwarted. Chapter 4 demonstrates a novel approach for the synthesis of bicyclic tetramic acids in a low-cost strategy using 2-methylpropanal as condensing reagent. The obtained tetramic acids are useful for a number of chemical transformations described in Chapter 2 and Chapter 3. The synthesised compounds were tested for antibacterial activity against multidrug resistant pathogens and disappointingly, all of them showed very little or no activity.
Supervisor: Moloney, Mark G. Sponsor: Commonwealth Scholarship Commission in the UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available