Synthesis of selective A3 and M1 receptor agonists

• Main Author: Snee, Stephen
• Other Authors: Thomas, Jim
• Published: University of Manchester 2011
• Subjects: 547
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.686707

Detailed within this thesis is the synthesis of three A1 agonists which were designed by Muscagen using computational studies. The agonists are derived from condensation of the modified adenosine: (4S,6R)-6-(6-chloro-9H-purin-9-yl)-N,2,2-trimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide with novel heterocyclic primary amines. The amines 5-(aminomethyl)-N,N-diethyl-7-methyloxazolo[4,5-b]pyridin-2-amine, 5-(1-aminoethyl)-N,N,7-trimethyloxazolo[4,5-b]pyridin-2-amine and 5-(1-aminoethyl)-N,N-diethyl-7-methyloxazolo[4,5-b]pyridin-2-amine were prepared from 2-amino-6-((tert-butyldiphenylsilyloxy)methyl)-4-methylpyridin-3-ol which was available from 2,4-lutidine. The dimethylaminooxazole functionality was introduced by treating a 1,2-hydroxyaminopyridine with phosgene iminium chloride whereas the diethylamino-oxazoles were prepared by displacement of chloride from a 2-chloro-oxazole with diethylamine. Using chemistry developed by Ellman it was possible to introduce a methyl appendage into the scaffold. Also detailed within this thesis is the synthesis of the novel M1 agonist; (+/-) (3aS,7R,7aR)-3-benzyl-7-(furan-2-yl)hexahydrooxazolo[4,5-c]pyridin-2(3H)-one. Cyclobutanecarboxylic acid was elaborated to tert-butyl(4-cyanato-2-cyclobutylbut-2-enyloxy)dimethylsilane which underwent a [3,3]-sigmatropic rearrangement to afford tert-butyl(2-cyclobutyl-2-isocyanatobut-3-enyloxy)dimethyl silane which was treated with sodium benzalkoxide. This yielded the Cbz protected amine with the required quaternary centre installed. Ozonolysis of the olefin moiety gave an aldehyde to which (1-(furan-2-yl)vinyl)lithium was introduced with excellent diastereoselectivity. The resulting alkoxide underwent in situ cyclisation to form the oxazolidinone with concurrent loss of benzyl alcohol. Hydroboration was used to install the stereochemistry of the furan bearing carbon and the resulting alcohol was subjected to an intramolecular Fukuyama-Mitsunobu reaction to furnish the piperidine ring.