Synthesis of biologically active compounds

• Main Author: Burnell, Erica Sinead
• Other Authors: Thomas, Jim
• Published: University of Manchester 2013
• Subjects: 547
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607116

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[10.3.1.03,5]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.