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Title: Analogues of bredinin : synthesis of 5-hydroxyimidazoles from acyclic precursors
Author: Middleton, Danielle Fiona
ISNI:       0000 0001 3397 6438
Awarding Body: University of Hull
Current Institution: University of Hull
Date of Award: 2008
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Compared to 1-substituted-5-aminoimidazoles relatively few 1-substituted-5-hydroxyimidazoles have been reported; however, an interesting 1-substituted-5-hydroxyimidazole is the immunosuppressive agent bredinin, which shows antiviral, antimalarial, antitumour and antiarthritic activities. Bredinin is obtained naturally by extraction from a fermentation process, and current synthetic strategies for the synthesis are ambiguous and don’t easily allow for the synthesis of analogues. Surprisingly, relatively few analogues of bredinin are known hence a convenient route to such types of compounds would be useful in providing a library of compounds for structural activity studies to be made.The aim of the present study was to develop a synthetic strategy which employed inexpensive and readily available acyclic precursors to synthesise a library of analogues of bredinin. An advantage of using acyclic precursors to synthesise imidazoles is that the introduction of substituents, in particular, those in the 1-position is unambiguous. Therefore, our approach has been to explore an efficient and general route to 1-substitued-5-hydroxyimidazoles employing inexpensive and readily available startingmaterials.Our initial target was to synthesise ethyl 1-substituted-5-hydroxyimidazole-4-carboxylates since such ester intermediates have the potential to be converted to a wide variety of related 4-substituted imidazoles. A variety of ethyl 1-substituted-5-hydroxyimidazole-4-carboxylates were synthesised. Those synthesised using lipophilic amines at position 1 of the imidazole ring (structures 39-43), were obtained in high yields and easily purified. However, those synthesised using polar amines at position 1 (structures 43-45), were more difficult to isolate and purify due to their increased hydrophilic nature.In addition, the adopted strategy offers the opportunity to introduce a variety of substituents in the 2-position of the imidazole ring (structures 48-49), however this increase in chain length at position 2 had a direct effect on the yield of the imidazole obtained. The longer the chain length, the lower the yields, due to the steric hindrance experienced in the cyclisation step of the synthetic sequence.In summary a novel convergent synthetic strategy was devised and both ethyl 1,2-substituted-5-hydroxyimidazole-4-carboxylates, with both aryl and alkyl groups atposition 1, and benzyl 1-benzyl-5-hydroxyimidazole-4-carboxylate were successfully synthesised. Both lipophilicity and steric bulk were found to play a crucial role in the successful cyclisation and subsequent isolation and purification of the imidazoles, and a compromise between the two must be achieved to give the optimal reaction conditions.In an attempt to gain a greater understanding of these ethyl 1-substituted-5-hydroxyimidazole-4-carboxylates systems, their reactivity under different reactions conditions was assessed. Ethyl 1-benzyl-5-hydroxyimidazole-4-carboxylate was used as the model system and was found to be stable to all targeted manipulation at position 2 and 4 of the imidazole ring. Additionally, all attempts to protect the 5-hydroxyl function, to allow the subsequent manipulation of the ethyl ester, were also unsuccessful. The unexpected benzylation of the nitrogen at position 3 of the imidazole ring, to form the quaternary ammonium salt, confirms that this is the most nucleophilic atom within the imidazole ring system.A novel linear synthetic strategy using acyclic precursors was developed which enabled the addition of substituents in positions 1, 2, 4 and 5 of the imidazole ring unambiguously. A particular advantage of this route is that it would be possible to synthesise 4-substituted-5-hydroxyimidazoles.An interesting difference between the two synthetic routes is that nucleosides of the 5-hydroxyimidazoles were successfully synthesised using the linear synthetic strategy, however they could not be synthesised using the convergent strategy. This indicates the important role nucleophilicity could play in the intramolecular cyclisation step of the convergent synthetic strategy.The most important implications of the present study are the development of two separate, unambiguous synthetic routes to the 5-hydroxyimidazoles, employinginexpensive acyclic precursors. The routes could provide access to a variety of substituted 5-hydroxyimidazoles in order to build a library of these compounds.
Supervisor: Boa, Andrew ; Mackenzie, Grahame Sponsor: EPSRC (Sponsor) ; The University of Hull (Sponsor) ; Department of Chemistry, The University of Hull (Sponsor)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Physical Science