Stereochemical behaviour of κ-agonistic 2,4-dipyridin-2-yl-3,7-diazabicyclo[3.3.1]nonanones—influence of the substituent in position N3

Abstract

2,4-Diaryl substituted 3,7-diazabicyclo[3.3.1]nonan-9-one-1,5-dicarboxylates are attracting interest as opioid-like analgesics. Since the stereochemistry is of great importance for a high affinity to the κ-receptor, the influence of substituents on the skeleton has to be considered. As a part of a greater project the influence of substituents in position N3 of the 3,7-diazabicyclo[3.3.1]nonanone on the conformation and configuration of the ring system was studied here. Whereas the variations of the substitution pattern of the arene rings revealed the cis substituted isomers in a chair–chair conformation mostly to be the thermodynamically stable form, alkyl substituents at N3 of increasing size induce the trans configuration of the phenyl rings often combined with a boat–chair conformation. The configuration was confirmed by X-ray analysis. Semiempirical calculations were performed to elucidate the thermodynamic stability of the isomers. However, some substituents having unsaturated bonds, such as propargyl (prop-2-enyl) and phenylethyl residues, seem to stabilise the cis configuration of the arene rings in a chair–chair conformation.