American Chemical Society
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Substitution-Assisted Stereochemical Control of Bispidone-Based Ligands

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posted on 2012-12-21, 00:00 authored by Tarik Legdali, Amandine Roux, Carlos Platas-Iglesias, Franck Camerel, Aline M. Nonat, Loïc J. Charbonnière
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.