Methodology for the conversion of tetramates to pyroglutamates, and a study of their biological activity

Thesis

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.

Authors: Bagum, H

• DOI: 10.5287/ora-oz2m8yy90
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English