Synthesis of 1,4-Diazabicyclo[3.3.1]nonan-6-ones

Abstract

1,4-Diazabicyclo[3.3.1]nonanes (aza-morphans) represent conformationally constrained piperazine derivatives. Herein, we report a six-step synthesis of the benzyl and allyl substituted bicyclic ketones 3a and 3b, which represent interesting building blocks for the synthesis of conformationally restricted receptor ligands. The key steps of the synthesis are the regioselective addition of ethyl acrylate to the piperazine 8, the sodium hexamethyldisilazide-induced Dieckmann cyclization of the diesters 10, and the decarboxylation of the enol esters 11 with dilute HCl. The complete sequence is only successful when a benzyl (10a) or allyl moiety (10b) is attached to N-1, since the tosyl derivative 10f failed to give a Dieckmann cyclization product, and the decarboxylation failed with the acyl derivatives 11c and 11d.

Stereoselective synthesis and structure–affinity relationships of bicyclic κ receptoragonists

“…The synthesis of the first series of k agonists started with the bicyclic ketone 4, which has been prepared in four reaction steps from ethyl piperazine-2-carboxylate. 18 Reductive amination of ketone 4 with pyrrolidine and NaBH(OAc) 3 19 provided diastereoselectively the endo-configured pyrrolidine 5a in 59% yield. The corresponding dimethylamine 5c was prepared in the same manner (38% yield).…”

“…Unfortunately, the direct synthesis of the sulfonamide 14 failed since the Dieckmann condensation of the tosyl-protected piperazine derivative did not give the corresponding bicyclic product. 18 Therefore, an exchange of the N-protecting group was performed. First, ketone 4 was protected as dimethyl acetal 12.…”

Conformationally Constrained κ Receptor Agonists: Stereoselective Synthesis and Pharmacological Evaluation of 6,8-Diazabicyclo[3.2.2]nonane Derivatives†

“…In the first series of ligands, the methyl moiety of 2 was connected with the N-atom in position 4 of the piperazine system, which resulted in the bicyclic κ agonists 3 . The diastereomeric compounds exo - 3 ( K i > 1000 nM) and endo - 3 ( K i = 73 nM) showed negligible and low κ receptor affinity, respectively, indicating that a dihedral angle ( N (pyrrolidine)−C−C− N (phenylacetamide)) of 180° ( exo - 3 ) is not tolerated and a dihedral angle of 58° ( endo - 3 ) is better accepted by the κ receptor protein. , …”

“…The diastereomeric compounds exo-3 (K i > 1000 nM) and endo-3 (K i = 73 nM) showed negligible and low κ receptor affinity, respectively, indicating that a dihedral angle (N(pyrrolidine)-C-C-N(phenylacetamide)) of 180°(exo-3) is not tolerated and a dihedral angle of 58°(endo-3) is better accepted by the κ receptor protein. 22,23 In a new series of conformationally constrained κ agonists, the methyl moiety of 2 was connected with the C-atom in position 5 of the piperazine ring. This connection leads to 6,8-diazabicyclo[3.2.2]nonanes of type 4, which allows further modifications by introduction of various residues R at the N-atom in position 6.…”