title: Stereoselective synthesis of oxazolidinonyl-fused piperidines of interest as selective muscarinic (M1) receptor agonists: a novel M1 allosteric modulator.
abstract: Syntheses of (1RS,2SR,6SR)-2-alkoxymethyl-, 2-hetaryl-, and 2-(hetarylmethyl)-7-arylmethyl-4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-ones, of interest as potential muscarinic M1 receptor agonists, are described. A key step in the synthesis of (1RS,2SR,6SR)-7-benzyl-6-cyclobutyl-2-methoxymethyl-4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-one, was the addition of isopropenylmagnesium bromide to 2-benzyloxycarbonylamino-3-tert-butyldimethylsilyloxy-2-cyclobutylpropanal. This gave the 4-tert-butyldimethylsilyloxymethyl-4-cyclobutyl-5-isopropenyloxazolidinone with the 5-isopropenyl and 4-tert-butyldimethylsilyloxymethyl groups cis-disposed about the five-membered ring by chelation controlled addition and in situ cyclisation. This reaction was useful for a range of organometallic reagents. The hydroboration-oxidation of (4SR,5RS)-3-benzyl-4-(tert-butyldimethylsilyloxymethyl)-4-cyclobutyl-5-(1-methoxyprop-2-en-2-yl)-1,3-oxazolidin-2-one gave (4SR,5RS)-3-benzyl-4-(tert-butyldimethylsilyloxymethyl)-4-cyclobutyl-5-[(SR)-1-hydroxy-3-methoxyprop-2-yl]-1,3-oxazolidin-2-one stereoselectively. 4,7-Diaza-9-oxabicyclo[4.3.0]nonan-8-ones with substituents at C2 that could facilitate C2 deprotonation were unstable with respect to oxazolidinone ring-opening and this restricted both the synthetic approach and choice of 2-heteroaryl substituent. The bicyclic system with a 2-furyl substituent at C2 was therefore identified as an important target. The addition of 1-lithio-1-(2-furyl)ethene to 2-benzyloxycarbonylamino-3-tert-butyldimethylsilyloxy-2-cyclobutylpropanal gave (4SR,5RS)-4-tert-butyldimethylsilyloxymethyl-4-cyclobutyl-5-[1-(2-furyl)ethenyl]-1,3-oxazolidinone after chelation controlled addition and in situ cyclisation. Following oxazolidinone N-benzylation, hydroboration at 35 °C, since hydroboration at 0 °C was unexpectedly selective for the undesired isomer, followed by oxidation gave a mixture of side-chain epimeric alcohols that were separated after SEM-protection and selective desilylation. Conversion of the neopentylic alcohols into the corresponding primary amines by reductive amination, was followed by N-nosylation, removal of the SEM-groups and cyclisation using a Mitsunobu reaction. Denosylation then gave the 2-furyloxazolidinonyl-fused piperidines, the (1RS,2SR,6SR)-epimer showing an allosteric agonistic effect on M1 receptors. Further studies resulted in the synthesis of other 2-substituted 4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-ones and an analogous tetrahydropyran.
authors.affiliation: Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3NB, UK.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Broadley
authors.affiliation: The School of Chemistry, The University of Manchester, Manchester, M13 9PL, UK. e.j.thomas@manchester.ac.uk.
authors.forename: Maxime G P
authors.initials: MG
authors.lastname: Buffat
authors.affiliation: The School of Chemistry, The University of Manchester, Manchester, M13 9PL, UK. e.j.thomas@manchester.ac.uk.
authors.forename: Erica
authors.initials: E
authors.lastname: Burnell
authors.affiliation: Muscagen Limited, 10, North Road, Cardiff, CF10 3DY, UK.
authors.forename: Robin H
authors.initials: RH
authors.lastname: Davies
authors.affiliation: The School of Chemistry, The University of Manchester, Manchester, M13 9PL, UK. e.j.thomas@manchester.ac.uk.
authors.forename: Xavier
authors.initials: X
authors.lastname: Moreau
authors.affiliation: The School of Chemistry, The University of Manchester, Manchester, M13 9PL, UK. e.j.thomas@manchester.ac.uk.
authors.forename: Stephen
authors.initials: S
authors.lastname: Snee
authors.affiliation: The School of Chemistry, The University of Manchester, Manchester, M13 9PL, UK. e.j.thomas@manchester.ac.uk.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Thomas
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D015394:Molecular Structure; D023303:Oxazolidinones / Q000737:chemistry*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D023303:Oxazolidinones; D010880:Piperidines; D043643:Receptor, Muscarinic M1