Premium
Diastereoselective Synthesis of Cyclic Five‐Membered trans , trans ‐Configured Nitrodiols by Double Henry Reaction of 1,4‐Dialdehydes
Author(s) -
Fröhlich Janine,
Lehmkuhl Kirstin,
Fröhlich Roland,
Wünsch Bernhard
Publication year - 2015
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201500114
Subject(s) - dihedral angle , chemistry , nitromethane , indane , stereochemistry , selectivity , derivative (finance) , ethylenediamine , nitroaldol reaction , crystal structure , pyrrolidine , crystallography , organic chemistry , enantioselective synthesis , molecule , hydrogen bond , financial economics , economics , catalysis
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 O 2 NCCOH of 73.4 and 88.3°, respectively, which reflect the calculated dihedral angles of the hypothesized final products 5a and 6a .