Towards the synthesis of new macrocyclic receptors

  • Abeer Bukhari

Student thesis: Phd

Abstract

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 (“pre-functionalization” 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 (“post-functionalization” method). Late-stage demethylation of the macrocyle formed in these reactions - N,N’,N’’-((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 “post-functionalisation” 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.
Date of Award1 Aug 2017
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorPeter Quayle (Supervisor)

Keywords

  • Siderophore
  • desmotropy
  • Enterochelin
  • Iron

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