Diastereoselective Synthesis of Cyclic Five‐Membered trans,trans‐Configured Nitrodiols by Double Henry Reaction of 1,4‐Dialdehydes

Conformationally constrained perhydroquinoxalines 4 show high receptor affinity, selectivity over related receptors and full agonistic activity. Since the affinity can be correlated with the dihedral angle of the ethylenediamine pharmacophore (4a: 55 degrees/71 degrees), the dihedral angles of the postulated cyclopentane derivative 5a (73 degrees/84 degrees) and indane derivative 6a (77 degrees/81 degrees) 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 O2NCCOH of 73.4 and 88.3 degrees, respectively, which reflect the calculated dihedral angles of the hypothesized final products 5a and 6a.