Synthesis of Biologically Active Compounds

  • Erica Burnell

Student thesis: Phd


The research for this thesis was carried out at the University of Manchester by Erica Burnell for the degree of Doctor of Philosophy for the titled work "Synthesis of Biologically Active Compounds" submitted in 2013.Part 1 describes the synthesis of (2S,3S,4R,5R)-5-(6-(((7-bromo-2-(dimethylamino)-4-((3-methylisoxazol-5-yl)methoxy)benzo[d]oxazol-5-yl)methyl)amino)-9H-purin-9-yl)-3,4-dihydroxy-N-methyltetrahydrofuran-2-carboxamide, a selective A3 adenosine receptor agonist, and one of a number of adenosine analogues designed by Muscagen Ltd. with the purpose of treating cardiac ischaemia. The target compound was derived from a condensation of the known modified adenosine, (3aS,4S,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-N,2,2-trimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide with 5-(aminomethyl)-7-bromo-N,N-dimethyl-4-((3-methylisoxazol-5-yl)methoxy) benzo[d]oxazol-2-amine. The benzoxazole amine fragment was synthesised from commercially available nitroresorcinol. Part 2 details the synthesis of two potential M1 muscarinic receptor agonists -(3aS*,7R*,7aR*)-3,7-dibenzyl-3a-cyclobutylhexahydro-2H-pyrano[3,4-d]oxazol -2-one and (3aSR,7RS,7aRS)-3,5,7-tribenzyl-3a-cyclobutylhexahydrooxazolo[4,5 -c]pyridin-2(3H)-one, part of a series of compounds designed by Muscagen Ltd. for the treatment of Alzheimer's disease. Both targets were synthesised from the known carbamate intermediate, (S)-benzyl (1-((tert-butyldimethylsilyl) oxy)-2-cyclobutylbut-3-en-2-yl)carbamate, which was available from commercially available cyclobutyl carboxylic acid. Part 3, the final part, describes efforts made towards the total synthesis of the natural product, phomactin A, a desirable target for its biological activity as a platelet activating factor antagonist, in addition to its structural complexity. Building on previous research carried out in the group, advanced intermediate (2S*,3R*,5R*,12S*,13R*,15R*,E)-16-(hydroxymethyl)-5,9,12,13-tetramethyl-4-oxatricyclo[,5]hexadeca-1(16),8-diene-2,15-diol was synthesised from a macrocyclic intermediate tert-butyldiphenyl (((1S*,2S*,4E,8E,10R*,12S*,14R*) -1,4,8,14-tetramethyl-15-methylene-2-(phenylsulfonyl)-10-((2-(trimethylsilyl) ethoxy)methoxy)bicyclo[9.3.1]pentadeca-4,8-dien-12-yl)oxy)silane.
Date of Award1 Aug 2014
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorEric Thomas (Supervisor)

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