Substitution-Assisted Stereochemical Control of Bispidone-Based Ligands

Three new bispidone derivatives substituted by methylenecarboxylic
ethyl ester groups have been synthesized in high yields as potential
ligands for 64Cu complexation and PET imaging. Their solution
and solid-state structures have been determined by 1H NMR
spectroscopy and X-ray crystallography. These studies reveal a strong
rigidity of the bicycle, which adopts either a chair–chair
or a boat–chair conformation depending on the substituents
in the N3 and N7 positions. A methyl substituent at N3 stabilizes
the chair–chair conformation, whereas ethylacetate or 2-pyridylmethyl
groups induce a considerable stabilization of the boat–chair
conformation. However, when introduced in the position N7, a 2-pyridylmethyl
substituent stabilizes the chair–chair isomer. The relative
energies of the isomers and the isomerization process have been modeled
by density functional theory calculations on a series of six N-substituted
bispidones, including those newly synthesized. The subtle influence
of the substituents has been related not only to the effect of steric
hindrance on the thermodynamic stability but also to the presence
of weak H-bonding interactions involving hydrogen-bonding acceptors,
such as pyridylmethyl or ethylacetate substituents, and donors, such
as C­(sp2)-H of the pyridyl rings or C­(sp3)-H at various positions
of the bispidone skeleton.