Methodology for the conversion of tetramates to pyroglutamates, and a study of their biological activity
<p>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 pyroglutam...
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| Other Authors: | |
| Format: | Thesis |
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2018
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| _version_ | 1817932341392179200 |
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| author | Bagum, H |
| author2 | Moloney, M |
| author_facet | Moloney, M Bagum, H |
| author_sort | Bagum, H |
| collection | OXFORD |
| description | <p>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.</p> <p>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.</p> <p>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.</p> <p>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.</p> <p>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.</p> <p>The synthesised compounds were tested for antibacterial activity against multidrug resistant pathogens and disappointingly, all of them showed very little or no activity.</p> |
| first_indexed | 2024-03-06T18:02:32Z |
| format | Thesis |
| id | oxford-uuid:004ebc8e-51d4-4bd0-94d7-812dab0ba25b |
| institution | University of Oxford |
| last_indexed | 2024-12-09T03:36:22Z |
| publishDate | 2018 |
| record_format | dspace |
| spelling | oxford-uuid:004ebc8e-51d4-4bd0-94d7-812dab0ba25b2024-12-02T09:53:11ZMethodology for the conversion of tetramates to pyroglutamates, and a study of their biological activityThesishttp://purl.org/coar/resource_type/c_db06uuid:004ebc8e-51d4-4bd0-94d7-812dab0ba25bORA Deposit2018Bagum, HMoloney, M<p>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.</p> <p>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.</p> <p>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.</p> <p>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.</p> <p>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.</p> <p>The synthesised compounds were tested for antibacterial activity against multidrug resistant pathogens and disappointingly, all of them showed very little or no activity.</p> |
| spellingShingle | Bagum, H Methodology for the conversion of tetramates to pyroglutamates, and a study of their biological activity |
| title | Methodology for the conversion of tetramates to pyroglutamates, and a study of their biological activity |
| title_full | Methodology for the conversion of tetramates to pyroglutamates, and a study of their biological activity |
| title_fullStr | Methodology for the conversion of tetramates to pyroglutamates, and a study of their biological activity |
| title_full_unstemmed | Methodology for the conversion of tetramates to pyroglutamates, and a study of their biological activity |
| title_short | Methodology for the conversion of tetramates to pyroglutamates, and a study of their biological activity |
| title_sort | methodology for the conversion of tetramates to pyroglutamates and a study of their biological activity |
| work_keys_str_mv | AT bagumh methodologyfortheconversionoftetramatestopyroglutamatesandastudyoftheirbiologicalactivity |