title: Diastereoselective Synthesis of Cyclic Five-Membered trans,trans-Configured Nitrodiols by Double Henry Reaction of 1,4-Dialdehydes.
abstract: Conformationally constrained perhydroquinoxalines 4 show high κ receptor affinity, selectivity over related receptors and full agonistic activity. Since the κ affinity can be correlated with the dihedral angle of the ethylenediamine pharmacophore (4a: 55°/71°), the dihedral angles of the postulated cyclopentane derivative 5a (73°/84°) and indane derivative 6a (77°/81°) were calculated. The first step of the synthesis represents a double Henry reaction of 1,4-dialdehydes 8 and 10 with nitromethane, leading predominantly to the trans,trans-configured nitrodiols 9 and 11. X-ray crystal structure analyses of 9 and 11 led to dihedral angles O2 N−C−C−OH of 73.4 and 88.3°, respectively, which reflect the calculated dihedral angles of the hypothesized final products 5a and 6a.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Münster, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Fröhlich
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Münster, Germany.
authors.forename: Kirstin
authors.initials: K
authors.lastname: Lehmkuhl
authors.affiliation: Organisch-Chemisches Institut der Universität Münster, Münster, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Fröhlich
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Münster, Germany.|Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), Westfälische Wilhelms-Universität Münster, Münster, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000447:Aldehydes / Q000737:chemistry*; D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000494:pharmacology; D008697:Methane / Q000031:analogs & derivatives / Q000737:chemistry; D015394:Molecular Structure; D009595:Nitroparaffins / Q000737:chemistry; D010795:Phthalic Acids / Q000737:chemistry; D017473:Receptors, Opioid, kappa / Q000819:agonists; D013329:Structure-Activity Relationship
chemical_list: D000447:Aldehydes; D000701:Analgesics, Opioid; D006576:Heterocyclic Compounds, 4 or More Rings; D009595:Nitroparaffins; D010795:Phthalic Acids; D017473:Receptors, Opioid, kappa; C015515:succindialdehyde; D008697:Methane; C008640:nitromethane
keywords: Dihedral angle; Double Henry reaction; Nitrocyclopentanediol; Nitroindanediol; trans,trans-Configuration; κ Agonists