Institute of Advanced Materials, Physicochemical Processes, Nanotechnology & Microsystems, National Center for Scientific Research "Demokritos", Terma Patriarchou Gregoriou & Neapoleos, Aghia Paraskevi Attikis, 15310 Greece. Tel. +30210 6503796.
Beilstein J Org Chem. 2014 Apr 3;10:774-83. doi: 10.3762/bjoc.10.73. eCollection 2014.
β-Cyclodextrin (β-CD) dimers have been prepared using the bioorthogonal Staudinger ligation for the first time. In addition to a known linker, methyl 2-(diphenylphosphanyl)terephthalate, a doubly active linker was specifically developed that enabled connection of two β-CD units in a single step and in aqueous/organic media, under mild conditions and with good yields. A three-carbon spacer between the β-CD torus and the azido group was required for facile dimer formation. The products, as studied by NMR spectroscopy, were found to adopt closed conformations by intramolecular self-inclusion. On the other hand, association via intermolecular binding was also observed in aqueous solution, confirmed by DOSY NMR experiments. Despite self-inclusion, the β-CD cavities were capable of guest encapsulation, as shown by titration experiments: the binding constant with 1-adamantylamine was similar to that of natural β-CD. Theoretical calculations for isolated molecules (PM3 level of theory) and in the presence of solvent [water, PM3(COSMO)] as well as DFT calculations suggested that the compounds prefer to adopt conformations which bring the phenyl groups either inside the β-CD cavity (inclusion) or over its narrow side (vicinal). Thus, Staudinger ligation could be the method of choice for linking CDs exhibiting (i) ease of preparation in aqueous media, in short steps, under mild conditions and in good yields, (ii) satisfactory aqueous solubility and independent binding capacity of the cavities.
β-环糊精（β-CD）二聚体首次通过生物正交的 Staudinger 连接反应制备。除了已知的连接子甲基 2-（二苯基膦基）对苯二甲酸酯外，还专门开发了一种双活性连接子，可在温和条件下以良好的收率一步在水/有机介质中连接两个β-CD 单元。β-CD 环和叠氮基之间需要三个碳原子间隔物才能方便地形成二聚体。通过 NMR 光谱研究发现，产物通过分子内自包含形成封闭构象。另一方面，通过 DOSY NMR 实验证实，在水溶液中也观察到通过分子间结合的缔合。尽管存在自包含，但β-CD 空腔能够容纳客体，如滴定实验所示：与 1-金刚烷胺的结合常数与天然β-CD 相似。孤立分子的理论计算（PM3 理论水平）以及在溶剂[水，PM3（COSMO）]中的计算和 DFT 计算表明，这些化合物倾向于采用使苯基基团进入β-CD 空腔（包含）或其窄侧（相邻）的构象。因此，Staudinger 连接反应可能是连接具有以下特征的 CD 的首选方法：（i）在水介质中以短步骤、温和条件和良好的收率轻松制备；（ii）具有令人满意的水溶性和空腔的独立结合能力。
