Substitution-Assisted Stereochemical Control of Bispidone-Based Ligands

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• 作者：Tarik Legdali ; Amandine Roux ; Carlos Platas-Iglesias ; Franck Camerel ; Aline M. Nonat ; Lo茂c J. Charbonni猫re
• 刊名：The Journal of Organic Chemistry
• 出版年：2012
• 出版时间：December 21, 2012
• 年：2012
• 卷：77
• 期：24
• 页码：11167-11176
• 全文大小：532K
• 年卷期：v.77,no.24(December 21, 2012)
• ISSN：1520-6904

文摘

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鈥揷hair or a boat鈥揷hair conformation depending on the substituents in the N3 and N7 positions. A methyl substituent at N3 stabilizes the chair鈥揷hair conformation, whereas ethylacetate or 2-pyridylmethyl groups induce a considerable stabilization of the boat鈥揷hair conformation. However, when introduced in the position N7, a 2-pyridylmethyl substituent stabilizes the chair鈥揷hair 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.