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.

本研究以高收率合成了3种经亚甲基羧酸乙酯基团取代的新型双哌啶酮（bispidone）衍生物，将其作为潜在的铜-64（64Cu）络合配体，用于正电子发射断层成像（Positron Emission Tomography，PET）。通过氢核磁共振波谱法（1H NMR spectroscopy）与X射线晶体衍射法（X-ray crystallography），确定了该类化合物的溶液与固态结构。研究表明该双环骨架具有极强的刚性，其构象可依据N3与N7位的取代基差异，呈现椅-椅（chair–chair）或船-椅（boat–chair）两种构象。N3位的甲基取代基可稳定椅-椅构象；而乙酸乙酯或2-吡啶甲基取代基则能显著稳定船-椅构象。但当2-吡啶甲基取代基位于N7位时，反而会稳定椅-椅异构体。针对包括本次新合成的衍生物在内的6种N-取代双哌啶酮，本研究通过密度泛函理论（density functional theory）计算，对各异构体的相对能量与异构化过程进行了建模分析。取代基带来的微妙影响不仅与空间位阻对热力学稳定性的调控作用有关，还涉及弱氢键相互作用：包括吡啶甲基、乙酸乙酯等氢键受体，与吡啶环的sp²杂化碳氢键、双哌啶酮骨架不同位点的sp³杂化碳氢键等氢键供体之间的相互作用。