Iron plays a fundamental role in the regulation of chemical processes within biological systems and the control of intracellular iron concentration has important consequences in the aetiology of a variety of disease states (e.g. neurodegenerative disorders). In this thesis, which is concerned with the identification of new macrocyclic receptors, the synthesis of (N,N',N''-((3S,7S,11S)-2,6,10-trioxo-1,5,9-trioxacyclododecane-3,7,11-triyl)tris(2,3-dihydroxybenzenesulfonamide), a mimic to the natural siderophore enterochelin, is reported. Two synthetic routes to the preparation of this macrocycle are presented where a sulfonamide residue is attached to a functionalised lactone core. The title compound was prepared either via the cyclotrimerzation of methyl N-((2,3-dimethoxyphenyl)sulfonyl)-L-serinate (âpre-functionalizationâ method) or by the elaboration of a preformed macrocyclic scaffold, (3S,7S,11S)-2,6,10-trioxo-1,5,9-trioxacyclododecane-3,7,11-triaminium chloride, with 2,3-dimethoxybenzenesulfonyl chloride (âpost-functionalizationâ method). Late-stage demethylation of the macrocyle formed in these reactions - N,Nâ,Nââ-((3S,7S,11S)-2,6,10-trioxo-1,5,9-trioxacyclododecane-3,7,11-triyl)tris(2,3-dimethoxybenzenesulfonamide) using BBr3 afforded the desired enterochelin analogue. These studies indicated that the âpost-functionalisationâ protocol afforded higher yields of the desired macrocycle in a process which was not marred by the concomitant formation of sulphonamide by-products. During the synthesis of 2,3-diacetoxy-5,6-dimethylsulfonyl chloride, a key intermediate for the assembly of functionalised sulphonamide siderophores, an ortho-quinone intermediate was found to undergo an intermolecular Diels-Alder reaction from which both the keto- ((1S*,4S*,4aR*,8aS*)-2,3,8,8a-tetramethyl-1,4,4a,8a-tetrahydro-1,4-ethanonaphthalene-5,6,9,10-tetraone) and enol- ((1S*,4R*,8aS*)-5-hydroxy-2,3,8,8a-tetramethyl-1,8a-dihydro-1,4-ethanonaphthalene-6,9,10(4H)-trione) tautomeric forms could be isolated and fully characterised by X-ray crystallography thereby constituting a rare example of desmotropy.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:748024 |
| Date | January 2017 |
| Creators | Bukhari, Abeer |
| Contributors | Quayle, Peter |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/towards-the-synthesis-of-new-macrocyclic-receptors(0bf6fd45-d433-4057-a77a-3dd4e93259ac).html |
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